Management of Heart Failure: Medical

Management of Heart Failure

Management of Heart Failure Volume 1: Medical

Edited by

Ragavendra R. Baliga, MD, MBA, FRCP, FACC Chief, Section of Cardiovascular Medicine, University Hospital East, Professor of Internal Medicine, The Ohio State University, Columbus, OH, USA

Bertram Pitt, MD Professor of Internal Medicine, Cardiovascular Division, University of Michigan Health System, Ann Arbor, MI, USA and

Michael M. Givertz, MD, FACC Medical Director, Heart Transplant and Circulatory Assist Program, Brigham and Women's Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, MA, USA

Ragavendra R. Baliga, MD, MBA, FRCP, FACC Chief, Section of Cardiovascular Medicine University Hospital East Professor of Internal Medicine The Ohio State University Columbus, OH, USA

Michael M. Givertz, MD, FACC Medical Director, Heart Transplant and Circulatory Assist Program Brigham and Women's Hospital and Associate Professor of Medicine Harvard Medical School Boston, MA, USA

Bertram Pitt, MD Professor of Internal Medicine Cardiovascular Division University of Michigan Health System Ann Arbor, MI, USA

ISBN: 978-1-84800-101-5 e-ISBN: 978-1-84800-102-2 DOI: 10.1007/978-1-84800-102-2 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2008920050 © Springer-Verlag London Limited 2008 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper 9 8 7 6 5 4 3 2 1 Springer Science + Business Media springer.com

Preface

It is believed that 20% of the global population suffers from diseases that predispose it to heart failure. The prevalence and hospitalization rates for heart failure continue to increase, in part, because improved therapy has increased life expectancy. Heart failure, now, is the most common hospital discharge diagnosis, and the Medicare budget spends more money for diagnosis and treatment of heart failure than for any other diagnosis. The total and indirect cost of heart failure approaches $30 billion annually in the USA alone. Although a great deal of progress has been made in the development of both pharmacological and non-pharmacological therapies for this common but potentially fatal disorder, the number of available therapies has increased. But this increase has rendered clinical decision making far more complicated and the timing and sequence of initiating strategies for treatment and the appropriateness of prescribing them in combination more complex. Despite these advances in treatment, the number of heart failure deaths continues to increase. Keeping this in mind we have assembled a group of experts in the field to put together a state of the art treatise on the management of heart failure.

The advantage of this publication is that it is a multiauthor book which brings in perspectives from all around the globe. The other major strength of this publication is that the chapters are relevant to day-to-day clinical practice. In conjunction with volume 2, Surgical Management of Heart Failure, this book provides a comprehensive overview of the management of heart failure. This book is intended for health care providers involved in the prevention and management of heart failure: nurses, physician assistants, house officers, general practitioners, internists, and cardiovascular specialists. We hope that this book will therefore not only contribute to reducing the increasing burden of heart failure worldwide but also serve as a stimulus for new research in the field of heart failure.

Ragavendra R. Baliga The Ohio State University Bertram Pitt University of Michigan Health System Michael Givertz Harvard Medical School & Brigham and Women’s Hospital

v

Contents

1.

Epidemiology of Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Robert Neil Doughty and Harvey D. White

1

2.

Mechanisms of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Douglas S. Lee and Ramachandran S. Vasan

13

3.

Diagnostic Testing and the Assessment of Heart Failure . . . . . . . . Savitri E. Fedson and Allen S. Anderson

47

4.

Nonpharmacologic Management of Heart Failure . . . . . . . . . . . . . Jeffrey A. Spaeder and Edward K. Kasper

57

5.

Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Grigorios Giamouzis, Syed A. Agha, and Javed Butler

77

6.

Neurohormonal Blockade in Heart Failure . . . . . . . . . . . . . . . . . . . Ragavendra R. Baliga

95

7.

Early Medical Management of Acute Heart Failure Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Nils P. Johnson, Alec J. Moorman, Peter S. Pang, Sean P. Collins, Micah J. Eimer, and Mihai Gheorghiade

8.

Management of Arrhythmias in Heart Failure . . . . . . . . . . . . . . . . 159 Evan C. Adelstein and Leonard I. Ganz

9.

Device Therapy in Heart Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 J. Julia Shin, Andrew L. Smith, and Angel R. Leon

10.

Management of Comorbidities in Heart Failure . . . . . . . . . . . . . . . 227 Chim C. Lang and Donna M. Mancini

11.

Evaluation for Ventricular Assist Devices and Cardiac Transplantation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 Katherine Lietz and Leslie W. Miller Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 vii

Contributors

Evan C. Adelstein, MD Cardiovascular Institute University of Pittsburgh Medical Center Pittsburgh, PA, USA Syed A. Agha, MD Emory University Hospital Atlanta, Georgia Allen S. Anderson, MD Heart Failure Program – Cardiac Transplant University of Chicago Hospitals Chicago, IL, USA Ragavendra R. Baliga, MD, MBA, FRCP (Edin), FACC Department of Cardiovascular Medicine The Ohio State University Columbus, OH, USA Javed Butler, MD, MPH Emory University Hospital Atlanta, Georgia Sean P. Collins, MD, MSc Department of Emergency Medicine University of Cincinnati Cincinnati, OH, USA

Savitri E. Fedson, MD Section of Cardiology, Heart Failure & Transplantation University of Chicago Medical Center Chicago, IL, USA Leonard I. Ganz, MD Department of Cardiac Electrophysiology The Western Pennsylvania Hospital Pittsburgh, PA, USA Mihai Gheorghiade, MD Division of Cardiology Department of Medicine Northwestern University Feinberg School of Medicine Chicago, IL, USA Grigorios Giamouzis Emory University Hospital Atlanta, Georgia Michael M. Givertz, MD Cardiovascular Division Brigham and Women’s Hospital Harvard Medical School Boston, MA, USA

Robert Neil Doughty, MD, FRACP, FRCP, FCSANZ Department of Medicine The University of Auckland Auckland, New Zealand

Nils P. Johnson, MD Division of Cardiology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Micah J. Eimer, MD Division of Cardiology Northwestern University Feinberg School of Medicine Chicago, IL, USA

Edward K. Kasper, MD, FACC Division of Cardiology Johns Hopkins Bayview Medical Center Baltimore, MD, USA

ix

x

Ghazanfar Khadim, MD Medical College of Wisconsin Milwaukee, WI, USA Chim C. Lang, MD, FRCP, FACC Department of Cardiology University of Dundee Nine Wells Hospital and Medical School Dundee, Scotland, UK Douglas S. Lee, MD, PhD, FRCPC Department of Medicine (Cardiology) Institute for Clinical Evaluative Sciences and University Health Network University of Toronto Toronto, ON, Canada Angel R. Leon, MD Cardiology Division Emory University School of Medicine Atlanta, GA, USA Katherine Lietz, MD, PhD Cardiovascular Division University of Minnesota Minneapolis, MN, USA Donna M. Mancini, MD Department of Medicine Columbia University Presbyterian Hospital New York, NY, USA Leslie W. Miller, MD Cardiovascular Division University of Minnesota Minneapolis, MN, USA Alec J. Moorman, MD Northwestern University Feinberg School of Medicine Chicago, IL, USA

Contributors

Peter S. Pang, MD Department of Emergency Medicine Northwestern University Feinberg School of Medicine Chicago, IL, USA Bertram Pitt, MD Division of Cardiology University of Michigan Health System Ann Arbor, MI, USA Ramachandran S. Vasan, MD, DM, FACC National Heart, Lung and Blood Institute Framingham Heart Study Framingham, MA, USA and Cardiology Section and the Department of Preventive Medicine and Epidemiology Boston University School of Medicine Boston, MA, USA J. Julia Shin, MD Center for Advanced Cardiac Therapy Cardiac Transplant and Assist Device Program Montefiore Medical Center Albert Einstein College of Medicine, Bronx, NY Andrew L. Smith, MD Department of Cardiology Emory University School of Medicine Atlanta, GA, USA Jeffrey A. Spaeder, MD Division of Cardiology Johns Hopkins University Baltimore, MD, USA Harvey D. White, DSc, FRACP, FACC, FESC, FAHA, FCSANZ, FRSNZ Green Lane Cardiovascular Services Auckland City Hospital Auckland, New Zealand

1 Epidemiology of Heart Failure Robert Neil Doughty and Harvey D. White

1.1. Introduction Heart failure is a complex clinical syndrome occurring as the end result of many different forms of heart disease. There are many different definitions and classifications of heart failure (Table 1.1) but a simple, practical definition of the syndrome of heart failure is that it is characterized by typical symptoms such as shortness of breath, exercise limitation and fatigue and clinical signs of peripheral and/or pulmonary congestion, associated with abnormalities of cardiac structure and function1. The syndrome of heart failure results in significant impairment of quality of life, more so than with many other chronic diseases2, and is associated with high morbidity and mortality. Heart failure frequently occurs in the setting of preserved left ventricular (LV) ejection fraction3,4 and thus a practical clinical definition of the syndrome1, rather than reliance on a single factor such as impaired LV ejection fraction, allows identification of the broad group of patients affected by this condition The recent ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure have taken a new approach to the classification of heart failure (Figure 1.1)5. This classification has taken a perspective of the evolution and progression of heart failure as part of the spectrum of cardiovascular disease from patients at high risk of developing heart failure but who do not at that stage have any structural heart disease (Stage A, e.g. patients with hypertension and/or coronary artery disease), through to those patients with structural heart disease and end-stage heart failure (Stage D). In this

classification, patients with the clinical syndrome of symptomatic heart failure will fall within Stages C and D (Figure 1.1). This classification is of value for several reasons: 1. Firstly, it clearly places heart failure as a clinical syndrome occurring in patients with structural heart disease 2. Secondly, it recognizes the importance of risk factors and structural heart disease in an asymptomatic patient and that therapy directed towards these abnormalities may help to prevent or delay the onset of the syndrome of heart failure 3. Thirdly, it allows recommendations for treatments of patients at the different stages of their disease process. When heart failure is classified in this way, the epidemiology of heart failure requires consideration of the epidemiology of each of the four stages A–D. The purpose of this chapter is to review the epidemiology of the syndrome of symptomatic chronic heart failure, and thus only Stages C and D will be considered in detail. However, it is important to recognize that the epidemiology of conditions such as hypertension and coronary artery disease will impact on the syndrome of heart failure.

1.2. Incidence Data on the incidence of heart failure have mainly been derived from large epidemiological cohort studies such as the Framingham study6. The Framingham Heart Study6 was initiated in 1946

1

Note: Definitive diagnosis if two major or one major and two minor criteria were present concurrently

Major or minor criteria Weight loss ≥4.5 kg in 5 days in response to treatment Note: Not more than 4 points allowed from each of the three categories Not required Required

Rales (basilar, 1; > basilar, 2) (1 or 2) Wheezing (3) S3 gallop (3) Chest radiograph Alveolar pulmonary oedema (4) Interstitial pulmonary oedema (3) Bilateral pleural effusions (3) Cardiothoracic ratio ≥ 0.5 (3) Upper zone flow redistribution (2)

Acute pulmonary oedema S3 gallop Increased venous pressure 16 cm water Circulation time ≥ 25 s Hepatojugular reflux

Minor criteria Ankle oedema Night cough Dyspnoea on exertion Hepatomegaly Pleural effusion Vital capacity ↓1/3 from maximum Tachycardia (rate of ≥120/min)

ESC criteria (1,64)

History Symptoms of heart failure, typically breathlessness or Rest dyspnoea (4) fatigue, either at rest or on exercise, or ankle swelling Orthopnoea (4) and objective evidence of cardiac dysfunction at rest Paroxysmal nocturnal dyspnoea (3) Dyspnoea on walking on level (2) Dyspnoea on climbing (1) A clinical response to treatment directed at heart failure Physical examination alone is supportive but not sufficient for the diagnosis Heart rate (91–110/min, 1; >110/ min, 2) (1 or 2) Elevated jugular venous pressure (JVP) (> 6 cm H2O, 1; > 6 cm H2O plus hepatomegaly or oedema, 2) (1 or 2)

Boston HF score (63) (points in parentheses)

Major criteria Paroxysmal nocturnal dyspnoea or orthopnoea Neck vein distention Rales Cardiomegaly

Framingham Heart Study (7)

Objective evidence of cardiac Not required dysfunction required

Criteria

Definition

Table 1.1. Criteria for diagnosis of heart failure from several studies.

1. Epidemiology of Heart Failure Stage A At high risk for heart failure but without structural heart disease or symptoms of HF

e.g., Patients with: - hypertension - coronary artery disease - diabetes mellitus or patients - using cardiotoxins - with FHx CM

THERAPY - Treat hypertension - Encourage smoking cessation - Treat lipid disorders - Encourage regular exercise - Discourage alcohol intake, illicit drug use - ACE inhibition in appropriate patients (see text)

3 Stage B Structural heart disease but without symptoms of HF

Structural heart disease

e.g., Patients with: - previous MI - LV systolic dysfunction - asymptomatic valvular disease

Development of symptoms of HF

THERAPY - All measures under stage A - ACE inhibitors in appropriate patients (see text) - Beta-blockers in appropriate patients (see text)

Stage C Structural heart disease with prior or current symptoms of HF

Stage D Refractory HF requiring specialized interventions

e.g., Patients with: - known structural heart disease - shortness of breath and fatigue. reduced exercise tolerance

e.g., Patients who have marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

THERAPY - All measures under stage A - Drugs for routine use: Diuretics ACE inhibitors Beta-blockers Digitalis - Dietary salt restriction

Refractory symptoms of HF at rest

THERAPY - All measures under stages A. B. and C - Mechanical assist decises - Heart transplantation - Continuous (not intermittent) IV inotropic infusions for palliation - Hospice care

Figure 1.1. Stages in the evolution of heart failure and recommended therapy by stage. Reproduced with permission from reference (5). Copyright 2001, with permission from Elsevier

for the purpose of defining risk factors for and the natural history of cardiovascular disorders. An early report from the 5,209 people in the original Framingham cohort based a diagnosis of heart failure on selected clinical criteria (Table 1.1)7. Based on these criteria, 3.5% of men and 2.1% of women (total of 142 people) developed heart failure over 16 years of follow-up. The development of heart failure was strongly associated with advancing age. In 1971, children of the original study participants and the spouses of these children were entered into the Framingham Offspring Study8 and data regarding heart failure, using the same definition, from these two cohorts were reported in 19939. Among these 9,405 participants followed from 1948 to 1988, congestive heart failure developed in 652 (6.9%). Age-adjusted incidence rates among persons aged over 45 years were 7.2 cases/1000 men and 4.7 cases/1000 women. Incidence rates increased markedly with increasing age. The Eastern Finland Study (1986–1988) reported that the age-adjusted annual incidence of heart failure in a rural community was 4.1/1000 in men and 1.6/1000 in women10. In this study, heart failure was defined by Framingham and Boston criteria (Table 1.1). The difference between men and women in

this population was accounted for by an excess of ischemic heart disease in men. The Rotterdam Study was a prospective, population-based cohort study involving 7,983 people over the age of 55 years recruited between 1989 and 1993 and followed until 2000. In this study, heart failure was defined according to the European Society of Cardiology criteria1. The overall incidence rate of heart failure in this study was 14.4/1000 person-years and was higher in men (17.6/1000 man-years) than in women (12.5/1000 woman-years). The incidence rates were strongly age-related, increasing from 1.4/1000 person-years in those aged 55–59 years to 47.4/1000 person-years in those aged 90 years or over. In a cross-sectional study in primary care in Scotland (1999–2000), the incidence of heart failure was 2/1000 people, increasing to 90/1000 among patient over the age of 85−years11. The incidence of heart failure obviously varies somewhat between these studies, differences that may in part be explained by differences in the definition of heart failure that was used, the methodology, geographical location or time period of the study. While the studies cannot be directly compared, they consistently demonstrate that heart failure is a common problem, and one that increases markedly with advancing age.

4

R.N. Doughty and H.D. White

Few studies have reported the changes in incidence of heart failure over time12,13. The study by Senni et al. reported that the incidence of heart failure was unchanged from 1981 to 199112. Such studies are difficult due to the need for long-term follow-up of cohorts over several decades, with standardized methodology, including standardized definition of heart failure, over time. A recent analysis of data from the Framingham study has suggested that since the 1950s and 1960s the incidence rate of heart failure has remained unchanged in men but has decreased by about one third in women13. However, it appears that this decline in incidence in women occurred in the 1970s and that over the last 20 years incidence rates in women have remained unchanged13. It thus appears that incidence rates have remained unchanged over recent decades, although it should be acknowledged that long-term data are relatively limited.

1.3. Prevalence In the USA, there has been a doubling of the prevalence of heart failure over the last 20 years. It is currently estimated that ~71.3 million people (24% of the population) are affected by cardiovascular disease and that 5 million people have heart failure14, representing about 1.6% of the total population. This compares to the estimated prevalence of heart failure in 1983 of ~2.3 million persons15.

The Rotterdam Study (1989–2000) reported prevalence rates of between 6.5% and 7.0% in a population over the age of 55 years16. Prevalence was higher in this study in men (8%) than in women (6%). Prevalence increases with advancing age; for example, from the Rotterdam Study prevalence was 0.9% in those aged 55–64 years compared with 9.7% in those aged 75–84 years16. A similar age gradient in the prevalence of heart failure was observed in the study of men born in 1913 (a population study of men living in Gothenburg): prevalence was 2% at age 50 and 13% at age 6717. Data from the Framingham study showed an approximate ‘doubling by decade’, with prevalence of heart failure in the age group 50–59 years being 1% compared with about 10% in those aged 80–89 years18. The prevalence of heart failure is also increasing as the population ages and the proportion of the population over the age of 65 increases19. The US Census estimates that there will be 40 million Americans aged 65 and older by 2010. In New Zealand, a population of ~4 million people, it is projected that the proportion of the population over the age of 65 years will increase from 12% in 2001 to 14% in 2011 and 18% in 2021 (Figure 1.2)20. Assuming a prevalence of heart failure of ~10% in those aged 65 and over, it can be expected that the number of people affected by heart failure will increase by ~50% over the next few decades. This increase in prevalence will increase the burden of heart failure on health care resources over coming decades.

9 0+ 8 5- 89

Male

Female

Male

Female

Male

Female

8 0- 84 7 5- 79 7 0- 74

1986

2021

2001

6 5- 69 6 0- 64 5 5- 59 5 0- 54 4 5- 49 4 0- 44 3 5- 39 3 0- 34 2 5- 29 2 0- 24 15 -19 10 -14 5- 9 0- 4

7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7

Percent

Percent

Figure 1.2. Aging of the population in New Zealand (See Color Plates)

Percent

1. Epidemiology of Heart Failure

5

1.4. Lifetime Risk of Heart Failure Long-term population-based cohort studies allow the estimation of lifetime risk of developing heart failure. The Framingham study reported that the lifetime risk of developing heart failure was 20% at age 4021. In this study, the remaining lifetime risk did not change because of rapidly increasing incidence rates of heart failure with increasing age. The Rotterdam Study reported lifetime risk of developing heart failure of 33% for men and 29% for women at age 5516. Lifetime risk decreased with advancing age in both men and women to ~23% who reached age 85 years. Differences observed between these two studies may be accounted for by methodological differences between the studies (e.g. definition of heart failure and age ranges studied) and that the studies were conducted during different eras (Framingham study 1971–1996 and Rotterdam Study 1989–2000). Despite these differences, these two studies demonstrate high lifetime risk of developing heart failure of between one in four and one in three people over the age of 40–55.

1.5. Hospitalizations for Heart Failure Heart failure is characterized by high rates of hospital admission in most Western countries22-32. In the USA, it is estimated that there are about 900,000 hospital admissions with a primary diagnosis of heart failure each year and about 2.6 million admissions for heart failure as a primary or secondary diagnosis(33). Heart failure is the most common diagnosis in patients over the age of 64 years hospitalized in the USA33. Readmissions for worsening heart failure are common following first admissions for heart failure, reported at about 30% in Scotland at 12 months23 and about the same proportion in the USA within 6 months30. Hospital admissions for heart failure have increased over the 1980s and 1990s in many developed countries22-25,27-30,32. This pattern has been mirrored in New Zealand with steady increases in age-standardized hospitalizations for heart failure over the last 15 years (Figure 1.3). The reasons for this are probably multi-factorial and may be associated with an increased number of elderly individuals in the population, and improved survival following

350

Admissions/100,000 population

300

250

200

150 Men

100

Women

50

0 1988

1989

1990

1991

1992

1993

1994

1995

1996

Year

Figure 1.3. Age-standardized hospital admissions for congestive heart failure in New Zealand

1997

6

acute myocardial infarction. Recent indications are that the increase in admissions observed in the 1980s and 1990s is now stabilizing, although hospitalization data need to be followed closely over the next few years to determine whether these trends will continue, or whether further increases will occur. Several studies have reported that most of the increase in hospital admissions observed over recent years has been in the elderly22,27. Elderly patients also have longer hospital stay23 and higher rates of hospital readmission34,35 than do younger patients. Data on length of hospital stay quoted in studies of hospitalized patients with heart failure is highly dependent on the method of data collection and the health care system in which the study was performed. For example, mean length of stay in Scotland in 1990 was 20 days23 compared with 5 days in Oregon, USA, in 199131. Despite methodological differences between studies, it has been clearly demonstrated that length of hospital stay for heart failure has progressively decreased during the 1980s and 1990s23,26,31, with average length of stay now ~1 week. The length of stay is strongly agerelated; for example, in Scotland in patients aged 25–44 mean length of stay was ~7 days compared with 26 days in patients over the age of 75 years23. There is a risk that the length of stay could become too short with patients being discharged before being stabilized and, if post-discharge care is inadequate, earlier readmission occurring. The optimal length of hospital stay is uncertain and will depend at least in part on the local health care environment (both hospital and community). The total and indirect/direct cost of heart failure in the USA has been estimated to be approximately $29.6 billion in 200636. The cost of heart failure is high due largely to the large number of hospitalizations36,37. Hospital admissions associated with heart failure constitute 1–2% of total annual health spending in most developed nations26,38,39.

1.6. Heart Failure Prognosis Heart failure is associated with poor survival7,9,16. Early data from the Framingham Heart Study (1950s and 1960s)7 suggested that mortality rates were high, with less than 50% of men being alive 5 years after the diagnosis of heart failure. A further

R.N. Doughty and H.D. White

report from the Framingham study followed 9,405 subjects for a median of 14.8 years during the 1970s and 1980s, during which time 652 (6.9%) people developed heart failure9. These patients with heart failure were followed for a mean of 3.9 years after the onset of heart failure during which time 551 died (84.5%). Median survival was 1.7 years for men and 3.2 years for women. Increasing age was associated with increasing mortality, with a 27% increase in mortality per decade of advancing age in men and a 61% increase per decade in women. The extent of the severity of mortality associated with heart failure has often been underestimated. The poor survival rates associated with high profile conditions such as cancer often receive considerable attention but the comparative mortality of heart failure has not until recently been determined. A recent report from Scotland has compared mortality among 16,224 men and 14,842 women presenting with heart failure, acute myocardial infarction or cancer (lung, large bowel, prostate, bladder or breast)40. With the exception of lung cancer, heart failure was associated with the worst 5-year survival rates (~25%). This population-based study has clearly demonstrated that heart failure is a ‘malignant’ disease process, with outcome worse than many different forms of cancer. This information reinforces the need for aggressive, preventive and therapeutic strategies across the stages of heart failure (Figure 1.1). No temporal changes in mortality rates were observed in earlier reports from the Framingham cohort9. The follow-up in the Framingham study was almost exclusively before the widespread use of evidence-based therapies such as neurohormonal antagonists and device-based therapy proven to decrease mortality5 and does not therefore address the effect of widespread implementation of interventions on survival in heart failure patients. The series of major mortality trials have demonstrated progressive declines in overall mortality in patients with heart failure enrolled in these trials as multiple therapies have been added in sequence (Figure 1.4). However, these data do not determine the temporal trends in mortality in patients with heart failure. Several recent reports, from population-based datasets rather than randomized trial cohorts, have now demonstrated that mortality from heart failure is declining (Table 1.2)13,41-44. The Framingham

1. Epidemiology of Heart Failure

Annual % Mortality

20

7 Placebo Treatment

15

device-based therapy for patients with heart failure remains an important component of strategies to continue to improve the outcome for patients with this malignant condition.

10

1.7. Etiology of Heart Failure

5 0

SOLVD-Rx Diuretics + + Digoxin + + ACE inhibitors – + Beta-blockers – – ARBs – –

CIBIS II + + + + + + + – – –

CHARM + + + + + + + + + –

Figure 1.4. Changing mortality in the large trials of neurohormonal antagonists. Studies referenced are the large-scale randomized trials, including SOLVD treatment trial 46, CIBIS II47, and the CHARM Programme49. Annualized mortality rates for the placebo and treatment arms in these trials are quoted. ARBs = angiotensin receptor blockers

study has reported significant declines in mortality associated with heart failure over the last 40 years, reductions equivalent to ~12% per decade13. However, mortality remains high with 1-year mortality rates from the Framingham study of 28% for men and 24% for women in the 1990s. Hospitalbased cohorts have also recently demonstrated improved survival associated with heart failure following hospitalization for heart failure41-44. Despite these improvements in outcome, current mortality associated with heart failure remains high, with estimated mortality 1 year following hospitalization for heart failure of between 26%44 and 38%43. The benefits of angiotensin-converting enzyme (ACE) inhibitors45,46, beta-blockers47,48 and angiotensin receptor antagonists49 in patients with heart failure have been demonstrated in large, placebo-controlled trials. Widespread implementation of these and other evidence-based therapies should contribute to the improved survival that has been observed for patients with heart failure. Encouragingly, a recent report from Canada has demonstrated that improvement in mortality in patients over the age of 65 years with heart failure during the 1990s in Alberta, Canada, was associated with the use of neurohormonal antagonists. Widespread use of appropriate medical- and

Coronary artery disease now appears to be the most common cause of heart failure50,51, occurring in approximately two thirds of patients with impaired LV systolic function. Many patients with coronary artery disease have preceding hypertension, as hypertension is one of the common risk factors for the development of coronary artery disease. In the Framingham cohort, most of the populationattributable risk for heart failure was accounted for by hypertension, with myocardial infarction having a higher risk ratio but lower overall prevalence and hence lower population-attributable risk52. However, determining the underlying cause of heart failure is often difficult; many patients with established heart failure are not subject to extensive investigations and hence the exact underlying etiology is never determined. Whatever the exact proportions, coronary artery disease and hypertension remain major causes of heart failure and are likely to remain so over coming decades with the aging of the population. Heart failure occurring in the setting of acute myocardial infarction has long been recognized as being associated with poor outcome53. Recent data from large registries have provided data on the impact of existing or new heart failure in the setting of acute coronary syndromes, and established that heart failure remains a major contributor to outcome54-56. The Second National Registry of Myocardial Infarction (NRMI-2) reported data from 190,518 patients admitted to US hospitals with acute ST elevation myocardial infarction, 19% of whom had heart failure on admission54. Heart failure was associated with markedly higher in-hospital mortality (21.4%) compared with that in those without heart failure (7.2%). The VALIANT Registry included 5,573 consecutive patients with acute myocardial infarction at 84 hospitals in nine countries between 1999 and 200155. Forty-two per cent of these patients had heart failure and/or LV systolic dysfunction during hospitalization; in-hospital mortality rate among these patients was 13% compared

8

R.N. Doughty and H.D. White Table 1.2. Temporal changes in mortality associated with heart failure. Beginning of cohort Men

Women

End of cohort Men

Women

Percent change Men

Women

−8.3% −6.6%

−44.4% −14.3%

Community-based studies Levy, Framingham13 Years 30-day mortality 1-year mortality

1950–1969 12% 18% 30% 28%

1990–1999 11% 10% 28% 24%

1986 19.9% 46.7%

1995 18.6% 42.4%

−6.5% −9.2%

Baker, MediCare USAa 42 Years 30-day mortality 1-year mortality

1991–1992 9.3% 36.6%

1997 7.9% 31.3%

−15.3% −14.6%

Blackledge, Englanda 43 Years 30-day mortality 1-year mortality

1993/1994 28% 55%

2000/2001 18% 38%

−35.7% −30.9%

Hospital-based studies MacIntyre, Scotlanda 41 Years 30-day mortality 1-year mortality

Schaufelberger, Sweden44 Years 30-day mortality 1-year mortality a

1988 15% 40%

2000 16% 43%

10% 26%

12% 30%

−33.3% −35%

−25% −30.2%

Data not available for men and women separately.

with 2.3% in those patients without heart failure and normal LV systolic function. The GRACE Registry has recently reported data on the impact of heart failure among 16,166 patients with acute coronary syndromes admitted to 94 hospitals in 14 countries56. Heart failure on admission was associated with poor survival rates compared with that in patients without heart failure both in hospital (12% vs. 2.9%) and at 6 months post-discharge (8.5% vs. 2.8%). Heart failure was also associated with increased mortality rates even in those patients with normal cardiac biomarkers. The presence of heart failure at admission in each of these registries was associated with longer hospital stay, and lower rates of procedures and use of therapies proven to reduce mortality54–56. These large registries provide data on the impact of heart failure in the contemporary setting of acute coronary syndromes and reinforce the importance

of heart failure and LV systolic dysfunction in this group of patients54–56. Worryingly these patients appear to be under-treated compared to those without heart failure, despite being a group at higher absolute risk who will have potentially greater gains from the proven therapies. Early identification of such patients is important to allow appropriate evidence-based therapies to be utilized to improve patient outcomes.

1.8. Future Burden of Heart Failure As discussed, heart failure is a major burden in the population and to the health care systems of most developed countries. The combined effects of aging of the population and improved survival for

1. Epidemiology of Heart Failure

patients with cardiovascular disease (including for those with heart failure) are projected to increase this burden. By 2020, it has been projected that first hospitalizations for heart failure will increase 34% in men and 12% in women in Scotland57. The epidemic of diabetes and metabolic syndrome will continue to fuel an increase in the incidence of cardiovascular disease including heart failure. Diabetes is a significant independent risk factor for the development of heart failure58 and occurs in ~20–30% of patients with heart failure59,60. The incidence of diabetes is projected to increase over the next few years, with estimates that 5.4% of the adult population worldwide will have diabetes by 202561. Obesity is another important risk factor for heart failure which is increasing with the increase in sedentary lifestyle62. Thus, all indications are that heart failure will remain a major public health problem for years to come. Attention to the patients at risk of developing heart failure (Stage A, Figure 1.1) will be an important part of the strategy to prevent or delay the onset of heart failure. Meanwhile, aggressive management of patients with established heart failure is essential to decrease the morbidity and mortality associated with this condition.

1.9. Summary and Key Points • Approximately one in three or one in four people in the general population will develop heart failure during their lifetime. • The incidence of heart failure in the population is ~1–2/1000 population per year, but increases steeply with advancing age. • The overall prevalence of heart failure in the general population is ~1% but increases markedly with increasing age to ~10% in the over 80-year-olds. • Incidence rates have remained stable over the last 30 years but prevalence is expected to rise as the population ages. • Hospitalization rates for heart failure have risen over the last 20 years • Costs associated with heart failure account for ~1–2% of the total health budget in most Western countries. • While the prognosis for patients with heart failure appears to be improving, heart failure remains a malignant disease with 1-year mortality rates of 26–38% following first admission for heart failure.

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• Therapeutic strategies to prevent heart failure include management of the common conditions which cause heart failure, including coronary artery disease, hypertension and diabetes.

References 1. The Taskforce on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J. 1995;16:741-751. 2. Dargie HJ, McMurray JJV. Diagnosis and management of heart failure. BMJ. 1994;308:321-328. 3. Dougherty AH, Naccarelli GV, Gray EL. Congestive heart failure with normal systolic function. Am J Cardiol. 1984;54:778-782. 4. Ramachandran SV, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: An epidemiologic perspective. J Am Coll Cardiol. 1995;26:1565-1574. 5. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (committee to revise the 1995 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol. 2001;38:2101-2113. 6. Dawber TR, Meadors GF, Moore FE. Epidemiological approaches to heart disease: The Framingham study. Am J Public Health. 1951;41:279-286. 7. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of heart failure: The Framingham study. N Engl J Med. 1971;285:1141-1146. 8. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families: The Framingham Offspring Study. Am J Epidemiol. 1979;110:281-290. 9. Ho KKL, Anderson KM, Kannel WB. Survival after the onset of congestive heart failure in the Framingham Heart Study subjects. Circulation. 1993;88:107-115. 10. Remes J, Reuanen A, Aromaa A, Pyorala K. Incidence of heart failure in eastern Finland: A population-based surveillance study. Eur Heart J. 1992;13:588-593. 11. Murphy NF, Simpson CR, McAlister FA, et al. National survey of the prevalence, incidence, primary care burden and treatment of heart failure in Scotland. Heart. 2004;90:1129-1136. 12. Senni M, Tribouilloy CM, Redeheffer RJ, et al. Congestive heart failure in the community. Trends in incidence and survival in a 10-year period. Arch Intern Med. 1999;159:29-34. 13. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347:1397-1402.

10 14. American Heart Association. Heart Disease and Stroke Statistics—2006 Update. Dallas, TX: American Heart Association; 2006. 15. Smith WM. Epidemiology of congestive heart failure. Am J Cardiol. 1985;55:3A-8A. 16. Bleumink GS, Knetsch AM, Sturkenboom MCJM, et al. Quantifying the heart failure epidemic: Prevalence, incidence rate, lifetime risk and prognosis of heart failure: The Rotterdam Study. Eur Heart J. 2004;25:1614-1619. 17. Eriksson H, Svardsudd K, Caidahl K, et al. Early heart failure in the population. The study of men born in 1913. Acta Medica Scandinavica. 1988;223:197-209. 18. Ho KKL, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart failure: The Framingham Heart Study. J Am Coll Cardiol. 1993;22:6A-13A. 19. Butler RN. Population aging and health. BMJ. 1997;315:1082-1084. 20. Statistics New Zealand. National Population Projections. Wellington, NZ; 2002. 21. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: The Framingham Heart Study. Circulation. 2002;106:3068-3072. 22. Ghali JK, Cooper R, Ford E. Trends in hospitalisation rates for heart failure in the United States, 1973– 1986. Arch Intern Med. 1990;150:769-773. 23. McMurray J, McDonagh T, Morrison CE, Dargie HJ. Trends in hospitalisation for heart failure in Scotland, 1980–1990. Eur Heart J. 1993;14:1158-1162. 24. Gillum RF. Epidemiology of heart failure in the United States. Am Heart J. 1993;126:1042-1047. 25. Reitsma JB, Mosterd A, de Craen AJM, et al. Increase in hospital admission rates for heart failure in the Netherlands, 1980–1993. Heart. 1996;76:388-392. 26. Doughty R, Yee T, Sharpe N, MacMahon S. Hospital admissions and deaths due to congestive heart failure in New Zealand, 1988–1991. NZ Med J. 1995;108:473-475. 27. Rodriguez-Artalejo F, Guallar-castillon P, Banegas Banegas JR, del Rey Calero J. Trends in hospitalisation and mortality for heart failure in Spain, 1980–1993. Eur Heart J. 1997;18:1771-1779. 28. Croft JB, Giles WH, Pollard RA, Casper ML, Anda RF, Livengood JR. National trends in the initial hospitalisation for heart failure. J Am Geriatr Soc. 1997;45:270-275. 29. Roughead LE, Gilbert AL. Australian trends in hospitalisation and mortality associated with chronic heart failure. Med J Aust. 1998;168:256. 30. Haldeman GA, Croft JB, Giles WH, Rashidee A. Hospitalisation of patients with heart failure: National Hospital Discharge Survey, 1985–1995. Am Heart J. 1999;137:352-360.

R.N. Doughty and H.D. White 31. Ni H, Nauman DJ, Hershberger RE. Analysis of trends in hospitalisations for heart failure. J Card Fail. 1999;5:79-84. 32. Mosterd A, Hoes AW. Epidemiology of heart failure: What does the future hold? In: McMurray JJV, Cleland JG (eds.), Heart Failure in Clinical Practice. 2nd edn. London: Martin Dunitz; 2000:3-17. 33. Rich MW. Epidemiology, pathophysiology, and etiology of congestive heart failure in older adults. J Am Geriatr Soc. 1997;45:968-974. 34. Vinson JM, Rich MW, Sperry JC, Shah AS, McNamara PM. Early readmission of elderly patients with congestive heart failure. J Am Geriatr Soc. 1990;38:1290-1295. 35. Krumholz HM, Parent EM, Tu N, et al. Readmission after hospitalization for congestive heart failure among Medicare beneficiaries. Arch Int Med. 1997;157:99-104. 36. American Heart Association. Heart Disease and Stroke Statistics—2006 Update. Dallas, TX: American Heart Association; 2006. 37. McMurray M, Petrie MC, Murdoch DR, Davie AP. Clinical epidemiology of heart failure: Public and private health burden. Eur Heart J. 1998;19(suppl P): P9-P16. 38. McMurray J, Hart W, Rhodes G. An evaluation of the cost of heart failure to the National Health Service in the UK. Br J Med Econ. 1993;6:99-110. 39. Tavazzi L. Epidemiological burden of heart failure. Heart. 1998;Suppl 2:S6-S9. 40. Stewart S, MacIntyre K, Hole DJ, Capewell S, McMurray JJV. More ‘malignant’than cancer? Fiveyear survival following a first admission for heart failure. Eur J Heart Fail. 2001;3:315-322. 41. MacIntyre K, Capewell S, Stewart S, Chalmers JWT. Evidence of improving prognosis in heart failure: Trends in case fatality in 66547 patients hospitalised between 1986 and 1995. Circulation. 2000;102:1126-1131. 42. Baker DW, Einstadter D, Thomas C, Cebul RD. Mortality trends for 23,505 Medicare patients hospitalized with heart failure in Northeast Ohio, 1991 to 1997. Am Heart J. 2003;146:258-264. 43. Blackledge HM, Tomlinson J, Squire IB. Prognosis for patients newly admitted to hospital with heart failure: Survival trends in 12 220 index admissions in Leicestershire 1993-2001. Heart. 2003;89:615-620. 44. Schaufelberger M, Swedberg K, Koster M, Rosen M, Rosengren A. Decreasing one-year mortality and hospitalization rates for heart failure in Sweden: Data from the Swedish Hospital Discharge Registry 1988 to 2000. Eur Heart J. 2004;25:300-307. 45. The CONSENSUS trial study group. Effects of enalapril on mortality in severe heart failure: The results of the Cooperative North Scandinavian Enalapril

1. Epidemiology of Heart Failure Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429-1435. 46. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302. 47. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet. 1999;353:9-13. 48. MERIT-HF Study Group. Effect of metoprolol CR/ XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001-2007. 49. Pfeffer M, Swedberg K, Granger CB, et al., for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall Programme. Lancet. 2003;362:759-766. 50. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: A manifestation of coronary artery disease. Circulation. 1998;97:282-289. 51. Bourassa MG, Gurne O, Bangdiwala SI. Natural history and patterns of current clinical practice in heart failure. J Am Coll Cardiol. 1993;22(suppl A):14A-19A. 52. Levy D, Larson D, Vasan RS, Kannel WB, Ho KKL. The progression from hypertension to congestive heart failure. J Am Med Assoc. 1996;275:1557-1562. 53. Killip T, Kimball J. Treatment of myocardial infarction in a coronary care unit: A two year experience with 250 patients. Am J Cardiol. 1967;20:457-464. 54. Wu AH, Parsons L, Every NR, Bates ER. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction: A report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol. 2002;40:1389-1394.

11 55. Velazquez EJ, Francis GS, Armstrong PW, et al. An international perspective on heart failure and left ventricular systolic dysfunction complicating myocardial infarction: The VALIANT registry. Eur Heart J. 2004;25:1911-1919. 56. Steg PG, Dabbous OH, Feldman LJ, et al. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: Observations from the Global Registry of Acute Coronary Events (GRACE). Circulation. 2004;109:494-499. 57. Stewart S, MacIntyre K, Capewell S, McMurray JJV. Heart failure and the aging population: An increasing burden in the 21st century? Heart. 2003;89:49-53. 58. Aronow WS, Ahn C. Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest. 1999;115:867-868. 59. Shindler DM, Kostis JB, Yusuf S, et al. Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) Trials and Registry. Am J Cardiol. 1996; 77:1017-1020. 60. Solang L, Malmberg K, Ryden L. Diabetes mellitus and congestive heart failure. Eur Heart J. 1999;20:789-795. 61. King H, Aubert RE, Herman WH. Gobal burden of diabetes, 1995–2025. Diabetes Care. 1998;21:14141431. 62. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347: 305-313. 63. Carlson KJ, Lee DC, Goroll AH, Leahy M, Johnson RA. An analysis of physicians’ reasons for prescribing long-term digitalis therapy in outpatients. J Chron Dis. 1985;38:733-739. 64. Remme WJ, Swedberg K. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure. Task force for the diagnosis and treatment of chronic heart failure. Eur J Heart Fail. 2002;4:11-22.

2 Mechanisms of Disease Douglas S. Lee and Ramachandran S. Vasan

2.1. Introduction Heart failure is a condition that is associated with high rates of disability, morbidity, and mortality. The adverse clinical outcomes and progressive nature of the syndrome has led to the systematic investigation of multiple mechanisms that may contribute to disease initiation and progression. The initial view of heart failure as primarily a hemodynamic disorder was supplemented by several important mechanistic insights. The advances in our understanding of the pathophysiological basis of heart failure have led to paradigm shifts in the management of the condition. In this chapter, we review the diverse mechanisms that underlie heart failure progression. Potentially important mechanistic pathways that play a fundamental role in heart failure include neurohormones, inflammation, oxidative stress, growth factors, and abnormalities of calcium homeostasis (Figure 2.1). Three key concepts are worth noting in this context. First, although culprit pathways have been categorized to guide research efforts, such a division is empirical because these mechanisms are by no means mutually exclusive. Indeed, complex interrelations between the pathways act in a combinatorial manner to contribute to heart failure progression1. Second, the relative clinical importance of these mechanisms in the setting of heart failure patient care will be determined partly by the amenability of disease pathways to modification by pharmacologic or other therapeutic means. Indeed, the increased recognition of multiple disease mechanisms has led to important therapeutic advances including angiotensin-converting

enzyme (ACE) inhibitors, angiotensin receptor blockers, vasodilators, β-adrenergic receptor antagonists, and aldosterone antagonists. Third, much of the initial work on heart failure mechanisms focused on systolic heart failure. More recently, mechanistic insights into diastolic heart failure are emerging as well.

2.2. Part 1. Neurohormonal Mechanisms 2.2.1. Background Heart failure was initially considered to be primarily a disorder of cardiac pump function. However, early studies showed that in spite of therapies that improve pump function, progression of heart failure and adverse outcomes occurred. The neurohormonal hypothesis of heart failure was proposed as a key participatory mechanism and strategies to modulate neurohormonal pathways to improve heart failure survival evolved2. Early studies primarily investigated the sympathetic and the renin–angiotensin systems, catalyzed in part by reports of adverse outcomes associated with elevated neurohormonal markers in heart failure patients. Subsequent analyses of randomized trials, including Valsartan Heart Failure Trial II (Val-HeFT II) and Studies of Left Ventricular Dysfunction (SOLVD), demonstrated that levels of neurohormones in heart failure patients critically influence prognosis, and that neurohormonal antagonism results in major improvements in survival3-5.

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D.S. Lee and R.S. Vasan

Figure 2.1. Mechanistic pathways that play a fundamental role in ventricular remodeling and the development of heart failure

2.2.2. Catecholamines in Heart Failure Early studies implicated catecholamines in the pathogenesis of heart failure with the demonstration of decreased β-adrenergic receptor density in the failing human myocardium6. Once overt heart failure becomes established, norepinephrine plasma levels are increased and the degree of elevation correlates with symptom status. Among ambulatory heart failure patients, plasma norepinephrine concentrations were higher in patients with New York Heart Association (NYHA) class III compared with NYHA class II symptoms7. Norepinephrine may contribute to progression of the condition via several potential mechanisms. These include direct myocardial toxicity, promotion of apoptosis, renal sodium and water retention, peripheral vasoconstriction, and activation of the renin–angiotensin system. The synergistic interaction between the renin–angiotensin system and sympathetic activation has been suggested by studies that have found lowered levels of norepinephrine in patients treated with ACE inhibitors7. Norepinephrine levels decrease also in response to therapy with diuretics and β-blockers 8-11. Additionally, norepinephrine has hypertrophic effects on cardiac muscle

mediated by α1-adrenergic receptors located on cardiac myocytes12.

2.2.3. Renin–Angiotensin–Aldosterone System in Heart Failure 2.2.3.1. Renin–Angiotensin System in Overt Heart Failure In heart failure, activation of the systemic, tissue, and cardiac renin–angiotensin system occurs13. Plasma and cardiac tissue levels of renin are increased in heart failure, and marked increases in these levels lead to further worsening of renal sodium retention and cardiac decompensation14. Activation of the renin–angiotensin system is associated with several pathophysiological events that may affect heart failure adversely. These include modulation of myocardial collagen synthesis15, increased norepinephrine release16, increased cardiac sympathetic nerve activity17,18, and association with hemostatic abnormalities that predispose to thromboembolic events19,20. The renin–angiotensin system, specifically activation of the angiotensin subtype 1 receptor (AT1), has also been implicated in immunological activation typically associated with heart failure21.

2. Mechanisms of Disease

2.2.3.2. Aldosterone in Overt Heart Failure The end-products of the renin–angiotensin system have been of particular interest since the advent of ACE inhibitors as heart failure therapy. However, a closer examination suggests that despite ACE inhibitor therapy, complete neurohormonal blockade does not occur. Over time, reactivation of vascular angiotensin I (ATI) to angiotensin II (ATII) conversion occurs despite administration of ACE inhibitors22. Similarly, despite vascular inhibition of the converting enzyme, as suggested by ATII to ATI ratio ≤ 0.05, plasma aldosterone levels are increased in heart failure despite long-term therapy with maximal doses of ACE inhibitors23. It has been reported that aldosterone escape may occur in up to 40% of patients treated with long-term ACE inhibitor therapy24,25. Heart failure is a progressive disease, and the incomplete blockade of ATII or aldosterone escape may predict the progression of adverse ventricular remodeling and worse outcomes. However, direct studies correlating “neurohormonal escape” to ventricular remodeling or clinical outcomes are lacking. Aldosterone decreases nitric oxide (NO) bioactivity in vascular smooth muscle cells and upregulates the conversion of ATI to ATII26,27. Aldosterone is also inversely related to arterial compliance in heart failure28. This association is particularly important since arterial compliance is partly influenced by the effects of NO and vascular angiotensin29,30. The peripheral vascular actions of aldosterone occur independent of systemic blood pressure and NYHA functional class27. The effects of aldosterone on ventricular remodeling are detailed subsequently.

2.2.3.3. Influence of Genetic Variation in RAAS Genetic polymorphisms of the ACE gene may also affect the neurohormonal milieu in heart failure. A 287-base pair insertion/deletion (I/D) polymorphism at intron 16 of the ACE gene has been found to correlate with serum ACE levels31. Individuals homozygous for the deletion allele (DD) have been reported to have higher levels of serum and tissue ACE activity compared with (ID) heterozygotes and nondeletion (II) homozygotes31,32. The presence of the DD genotype has been associated with dilated cardiomyopathy and greater heart failure

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progression33. Heart failure patients with the deletion allele exhibit more rapid disease progression and shorter transplant-free survival times34. Genetic variation can also impact therapeutic responses to ACE inhibitors. Cicoira et al.35 reported that heart failure patients with “aldosterone escape” have a higher prevalence of the DD genotype than patients without aldosterone escape. All patients with the II genotype had adequate suppression of aldosterone with ACE inhibitor therapy.

2.2.4. Natriuretic Peptide Axis in Heart Failure 2.2.4.1. Physiologic Effects Atrial and B-type (ANP and BNP) natriuretic peptides are released by the myocardium in heart failure36,37. BNP, a 32-amino acid peptide, binds to the natriuretic peptide receptor A, which exerts its biological actions via a cyclic GMP-mediated second messenger pathway38. BNP has also been reported to have greater natriuretic activity and to undergo lesser degree of degradation by neutral endopeptidase compared with ANP39. Secretion of BNP from cardiac ventricles is affected by myocardial stretch, injury, or ischemia40. BNP has a wide array of biological activities including natriuresis, vasodilation, lusitropy, and inhibitory action on neurohormonal systems41,42. ANP and BNP have an inhibitory effect on renin release and decrease the production of ATII and aldosterone43-47.

2.2.4.2. Natriuretic Peptides in Overt Heart Failure Plasma BNP levels are elevated in patients with heart failure, on the basis of left or right ventricular dysfunction48,49. Plasma ANP and BNP levels correlate with atrial and ventricular filling pressures and severity of symptoms50-53. BNP levels are also associated with reduced functional capacity and impaired oxygen uptake (Vo2) at peak exercise54. Although natriuretic peptides induce vasodilation, the vasodilatory effects in heart failure may be blunted47,55. This attenuation of the effects of natriuretic peptides in heart failure may be due to altered receptor density or changes in local clearance mechanisms, or a result of uncoupling of the cyclic GMP-mediated signal transduction pathway56-58.

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Natriuretic peptides inhibit cardiac sympathetic activity59-62. Importantly, BNP also reduces renal sympathetic activity in heart failure, which may have important pathophysiologic implications. Specifically, activation of renal sympathetic activity stimulates the renin–angiotensin–aldosterone pathway and promotes sodium and water retention63,64. The effects of BNP on sympathetic activity may be partially explained by the effect on cardiac filling pressure rather than a direct humoral effect59,65. The effects of natriuretic peptides on sympathetic nervous activity are clinically important because activation of cardiac adrenergic drive precedes generalized sympathetic activation in heart failure66. Dysfunction of cardiac sympathetic nervous activity is also associated with poor survival in patients with established heart failure67-69.

2.2.5. Endothelin in Heart Failure 2.2.5.1. Physiologic Effects Endothelin-1 (ET-1) is among the most potent endogenous vasoconstrictors70. Its production is stimulated by catecholamines, ATII, and arginine vasopressin71. The pulmonary circulation is the primary source of expression of this neurohormone, and ET-1 levels have been found to correlate with pulmonary vascular resistance72-74. ET-1 also acts as a local autocrine/paracrine factor via the ETA and ETB receptors, which are expressed on cardiomyocytes75,76. ET-1 regulates the cellular effects of ATII on cardiac myocyte growth and influences matrix turnover.

2.2.5.2. Endothelin in Overt Heart Failure Heart failure is associated with an increase in plasma levels of ET-1 that contribute to pathophysiologic perturbations77-79. ET-1 promotes ventricular remodeling and causes coronary, pulmonary, and peripheral vasoconstriction80-83. It also stimulates endogenous production of ANP, a phenomenon antagonized by ETA receptor blockade84-86. Activation of ET-1 occurs early during the transition from subclinical to overt heart failure in experimental studies. Increased expression of myocardial and plasma ET-1 system may also precede activation of the myocardial and plasma renin-angiotensin system87. The physiologic significance of such activation is not entirely clear because antagonism of ETA receptors in the

D.S. Lee and R.S. Vasan

early phase of heart failure results in further activation of the renin–angiotensin system and increased sodium retention87.

2.2.6. Neurohormonal Activation in Asymptomatic Left Ventricular Dysfunction or Preclinical Heart Failure In asymptomatic left ventricular (LV) dysfunction, activation of norepinephrine and ANP antedates activation of the renin–angiotensin system88. Early activation of neurohormones is predictive of mortality in patients with asymptomatic LV dysfunction. Neurohormonal analysis of the SOLVD study found that plasma norepinephrine was a strong predictor of multiple adverse cardiovascular outcomes including mortality89,90. The progression from the early changes in LV geometry to progressive LV dilation and dysfunction is associated with concomitant increases in tissue angiotensinogen mRNA and ACE activity91. After LV dilatation and dysfunction occurs, plasma norepinephrine levels begin to increase further 92.

2.2.7. Neurohormonal Activation in Preclinical Heart Failure: Example of Natriuretic Peptides The prognostic importance of natriuretic peptides extends to individuals who do not have overt heart failure. Wang et al.93 examined plasma levels of BNP and N-terminal pro-ANP in community-based participants of the Framingham Heart Study without heart failure or other cardiovascular disease at baseline. BNP level was predictive of new-onset heart failure, with a tripling of risk for individuals with plasma BNP levels greater than the 80th percentile. N-terminal pro-ANP was also highly predictive of heart failure. Both natriuretic peptides were also associated with death and the onset of atrial fibrillation.

2.2.8. Renal Effects of Neurohormonal Activation in Heart Failure Neurohormonal activation in heart failure is in part a physiological response to maintain perfusion of vital organs, including the kidneys, and to expand arterial blood volume94-97. The importance of the

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cardiorenal system is reflected by studies reporting the prognostic importance of renal function in established heart failure98,99.

2.2.8.1. Early Heart Failure Even before clinical/biochemical manifestations of renal dysfunction occur, subclinical abnormalities are evident in heart failure with LV systolic dysfunction. Patients with mild heart failure have a reduced natriuretic response to salt loading, therefore increasing the tendency for sodium retention 100,101. Subtle impairment of renal function is evident even among patients with asymptomatic LV dysfunction, manifesting initially as an abnormal renal vasodilatory response to amino acid infusion. These early renal abnormalities are reversed by both enalapril and losartan, and, therefore, implicate an ATIImediated mechanism. Both hemodynamic and neurohormonal mechanisms contribute to renal impairment in heart failure. Studies of natriuretic peptides have associated heart failure with early renal dysfunction. Hillege et al.102 observed that in systolic heart failure, N-terminal ANP levels correlated with reduced glomerular filtration rate (r = −0.53, P < .001), whereas LV ejection fraction (LVEF) did not.

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2.2.9. Neurohormonal Activation in Diastolic Heart Failure Few studies have evaluated the neurohormonal associations with diastolic heart failure. Kitzman et al.103 examined the neurohormonal profile of patients with systolic (LVEF ≤ 0.35) and diastolic (LVEF ≥ 0.50) heart failure. Plasma norepinephrine levels were elevated to a similar extent in diastolic and systolic heart failure patients compared with controls. Plasma natriuretic peptide levels were increased in patients with diastolic heart failure compared with healthy controls, although the degree of elevation was less compared with that in patients with systolic heart failure103. In acute-decompensated heart failure, natriuretic peptide levels are elevated in patients with preserved systolic function although to a lesser degree than in patients with reduced systolic function104.

2.2.10. Neurohormonal Activation and Heart Failure Prognosis and Therapy A number of studies implicate neurohormones as potentially important factors leading to heart failure progression and, ultimately, death. In Val-HeFT, elevated circulating levels of BNP and norepinephrine (Figure 2.2) conferred an increased risk of

Figure 2.2. Plasma β-type natriuretic peptide (BNP, left panel) and norepinephrine (NE, right panel) were measured before randomization and during follow-up in 4,300 patients in the Valsartan Heart Failure Trial. The baseline values for BNP and NE in quartiles is shown. Kaplan–Meier curves show a significant quartile-dependent increase in mortality. From Anand et al.105. © 2003 American Heart Association, Inc. All rights reserved. Reprinted with permission (See Color Plates)

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death over time 105. Additionally, temporal changes in neurohormone levels were significantly associated with mortality. Heart failure patients who experienced the greatest increase in plasma BNP or norepinephrine levels had the highest mortality105. In acute heart failure, neurohormonal markers (notably plasma natriuretic peptides and endothelin) rapidly decrease with diuretic and vasodilator therapy. Other markers such as plasma norepinephrine take longer to normalize106. Elevated plasma ET-1 levels in heart failure have been associated with an adverse prognosis, with increased rates of worsening heart failure, heart failure hospitalizations, and death107,108. Activation of the cardiac endothelin system has also been demonstrated in the hearts of patients with endstage disease109. These changes include increased tissue levels of ET-1 and alterations in the balance of ETA versus ETB receptors109. Further elucidation of the role of ET-1 in heart failure progression is required since clinical trials of endothelin antagonists have not demonstrated clinical benefits in heart failure patients110,111. The extent of neurohormonal activation may also indicate responsiveness to specific therapeutic agents. Thus, elevated circulating levels of renin, norepinephrine, and natriuretic peptides are associated with greater likelihood of benefit from ACE inhibitor therapy12,113. The mortality benefit associated with ACE inhibitor therapy also correlates positively with plasma levels of catecholamines, ATII, aldosterone, and ANP114. Elevated levels of natriuretic peptides at heart failure onset predict greater benefit from β-blocker therapy115. Conversely, heart failure patients with persistently high BNP levels despite optimized therapy with ACE inhibitors and β-blockers experienced a very high mortality due largely to pump failure or sudden death116.

2.3. Part 2. Inflammatory Mechanisms 2.3.1. Background In addition to the fundamental role of neurohormonal activation in the pathogenesis of heart failure, there is increasing recognition of the role of systemic inflammation in this disorder. Early

D.S. Lee and R.S. Vasan

descriptions of the role of immunological activation were provided by Paul Wood, who reported on the relationship between the erythrocyte sedimentation rate and the clinical outcome of heart failure patients117. More recent investigations have systematically evaluated inflammatory biomarkers. Interpretation of plasma levels of inflammatory markers in heart failure is challenged by their correlations, reciprocal relations among select mediators, dynamic changes during the evolution of heart failure, the impact of disease severity, and the effects of therapy.

2.3.2. Individual Inflammatory Markers in Heart Failure 2.3.2.1. Tumor Necrosis Factor 2.3.2.1.1. Physiologic Effects: One of the earliest inflammatory markers implicated in heart failure was tumor necrosis factor α (TNF-α); Levine and colleagues first reported elevated plasma levels among heart failure patients in 1990118. The biological actions of TNF-α are mediated by its receptors, TNFR1 and TNFR2119. TNF-α expression is increased in failing hearts of patients with dilated cardiomyopathy, and levels of its soluble receptors are increased in plasma in heart failure120. Myocardial TNF receptor protein levels are reduced in patients with heart failure compared with normal hearts120,121. In experimental studies, overexpression of TNF in cardiomyocytes results in myocarditis and dilated cardiomyopathy122,123. TNF-α production in the failing heart may be induced by increased ventricular wall stress124,125. TNF-α has a negative inotropic effect on cardiomyocytes, in part mediated by altered sarcoplasmic calcium homeostasis126. Also, TNF-α induces endothelial dysfunction by increasing production of oxygen free radicals and by downregulating endothelial constitutive NO synthase (eNOS) expression. The mechanisms by which TNF-α inhibits eNOS include interference with phosphorylation pathways, degradation of eNOS mRNA, and activation of endothelial cell apoptosis127-131. Serum from patients with severe heart failure downregulates eNOS and increases apoptosis, a phenomenon only partially attenuated by anti-TNF-α antibody132.

2. Mechanisms of Disease

2.3.2.1.2. Correlates of Increased Plasma TNF-α in Heart Failure: Plasma TNF-α levels correlate with severity of heart failure symptoms, and with peak oxygen consumption upon exercise133. In addition to the severity of heart failure symptoms, levels of plasma TNF-α and its soluble receptors have been reported to be associated with other aspects of the heart failure syndrome. An early report suggested that heart failure patients with elevated circulating levels of TNF-α were more likely to be cachectic, hyponatremic, anemic, and azotemic118. Plasma TNF-α is associated with cachexia and has been inversely related to body mass index in heart failure. Anker et al.134 reported that elevated TNF-α levels were paralleled by increases in the cortisol/DHEA ratio, indicating higher catabolic activity. Sex-related differences in plasma TNF-α have been reported in heart failure also. Whereas TNF-α levels increased linearly with age in men with NYHA class III-IV heart failure, concentrations are low in women with heart failure until approximately age 50, when the levels of this inflammatory marker increase sharply135. In advanced heart failure, ventricular unloading with mechanical circulatory support is associated with a decrease in intracardiac TNF-α level136. Further, patients who exhibited a greater reduction in cardiac TNF-α were more likely to recover cardiac function136.

2.3.2.2. Interleukin-6 2.3.2.2.1. Physiologic Effects: Interleukin-6 is a 185-amino acid polypeptide, which has both pro-inflammatory and anti-inflammatory effects. It is produced by immune cells, endothelial cells, vascular smooth muscle cells, and cardiac myocytes137,138. The IL-6 receptor consists of two membrane-bound glycoproteins, a ligand-binding component termed IL-6R and a signal transducing component termed gp130. The IL-6/sIL-6R complex is a potent agonist of the membrane-bound receptor gp130. The gp130 pathway is an essential stress-activated myocyte survival mechanism, and activation of the gp130 signaling pathway leads to cardiac hypertrophy. The Janus kinases-signal transducers and activators of transcription (JAK-STAT) signaling pathway has been shown to mediate the hypertrophic and the

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potential cytoprotective effects of gp130 activation in cardiomyocytes139-144. IL-6 is a proinflammatory cytokine. It increases hepatic synthesis of C-reactive protein (CRP). With transactivation by soluble IL-6R, it increases expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin by endothelial cells45. IL-6 has been shown to decrease LV function via a direct negative inotropic effect mediated via myocardial NO synthase46. IL-6 may have a beneficial effect in the early stages of inflammation, but the constitutive activation of IL-6 may accelerate myocardial damage. The complexities of the biological effects of IL-6 are also reflected in murine myocardial models. In untreated animals, TNF-α, IL-1β, and IL-6 levels were markedly elevated in the noninfarcted myocardium with a twofold higher expression of IL-6 compared with TNF-α and IL-1β. In rats treated with metoprolol, myocardial expression of TNF-α and IL-1β was reduced, but IL-6 expression remained high147. In metoprolol-treated rats, these latter findings occurred despite attenuation of myocardial remodeling manifested as decreased LV dilatation and preservation of systolic function147. 2.3.2.2.2. IL-6 in Heart Failure: Elevated plasma levels of IL-6 have been demonstrated in humans with asymptomatic and symptomatic LV systolic dysfunction. Circulating IL-6 levels are related to the severity of ventricular dysfunction and correlate positively with the degree of neurohormonal activation148. Heart failure patients with higher IL-6 levels also have higher plasma renin activity and ANP levels149. However, increased plasma IL-6 levels in heart failure are most likely of nonmyocardial origin150. Increased levels of IL-6 have been found to correlate with heart failure progression. Higher IL-6 levels were associated with worse functional class, lowered ejection fraction, greater LV dilation, and an adverse prognosis149,151-154.

2.3.2.3. Monocyte Chemoattractant Protein-1 2.3.2.3.1. Physiologic Effects: Monocyte chemoattractant protein-1 (MCP-1) is a proinflammatory chemokine that is produced

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in response to injury or exposure to other cytokines55,156, including TNF-α157, and ATII157-159. MCP-1 expression occurs in endothelial cells, infiltrating cells, and possibly cardiac myocytes 160,161 . MCP-1 binds predominantly to the chemokine receptor CCR-2162. MCP-1 contributes to heart failure by its potent chemoattractant properties for monocytes and macrophages. Indeed, plasma levels of MCP-1 correlate with levels of neopterin, a marker of monocyte/macrophage activation163. In addition to promoting myocardial infiltration by inflammatory cells, MCP-1 may influence myocardial remodeling via other mechanisms. MCP-1 induces the expression of ICAM-1164, other cytokines including IL-6 and IL-8165, matrix metalloproteinases (MMPs)166, and transforming growth factor-β167. The interaction of MCP-1 with other cytokines is complex. Cytokines that upregulate MCP-1 may lead to downregulation of the MCP-1 receptor and thus modulate the recruitment of monocytes and other potential actions of MCP-1. MCP-1 also induces oxidative stress by enhancing reactive oxygen species (ROS) generation in monocytes168. Heart failure patients with greater elevation of MCP-1 have the highest levels of ROS163. Experimental studies demonstrate that overexpression of MCP-1 in transgenic mice results in myocarditis and heart failure169. MCP-1 has been demonstrated to be upregulated in both pressure and volume overload models of heart failure 160,161. 2.3.2.3.2. MCP-1 in Heart Failure: Heart failure patients have increased circulating levels of MCP-1, with the highest levels being observed in patients with NYHA class IV symptoms163. In one study, plasma MCP-1 level was inversely related to LVEF163. Plasma chemokine levels were increased regardless of the etiology of heart failure, although higher levels have been observed in ischemic cardiomyopathy163.

2.3.2.4. Other Markers of Systemic Inflammation Other markers of inflammation have been studied with evidence for a mechanistic role in heart failure. A potential role for soluble intercellular adhesin molecule-1 (sICAM-1) in LV remodeling is sug-

D.S. Lee and R.S. Vasan

gested by evidence that cardiomyocytes increase expression of ICAM-1 in response to stimulation with MCP-1164. Serum levels of soluble VCAM-1, Pselectin, and E-selectin are also increased in heart failure, raising the possibility of a pathogenetic role for these markers170. Cardiotrophin-1 (CT-1) is a marker of systemic inflammation with potential importance in LV remodeling171-173. CT-1 is a member of the IL-6 family of cytokines and a ligand for gp130, activating mitogen-activated protein kinase and the JAK-STAT signaling pathways. CT-1 induces cardiomyocyte hypertrophy and prolongs myocyte survival. The hypertrophic response induced by CT-1 resembles that of a volume overload pattern, with an increase in cardiac cell size typified by increased cell length but no change in cellular width176. This pattern of myocyte hypertrophy contrasts with that of ET-1 and ATII, which induce a proportionally uniform increase in size, suggesting that the effects of CT-1 are likely independent of these neurohormones177. Excessive activation of the CT-1 pathway is counterbalanced by downregulation of gp130, via internalization and degradation, and induction of suppressors of cytokine signaling proteins178. The heart is the major source of circulating CT-1179. Levels are increased in heart failure180,181 and correlate with symptoms and LV mass177. Plasma soluble IL-2 receptor (sIL-2R) levels, a marker of enhanced T-cell activation182, have also been reported to be elevated in heart failure and reflect clinical severity183. A member of the IL-1 receptor family, known as ST2, is induced by mechanical stress in cardiomyocytes and may be elevated in heart failure184. Serum ST2 can be detected in human serum after an acute myocardial infarction, and levels in the blood correlate inversely with ejection fraction184. CRP, a widely studied inflammatory marker for coronary artery disease, has also been shown to be elevated in heart failure. Patients with higher serum concentrations of CRP had a greater risk of death, hospitalization for heart failure, or cardiac transplantation, and the prognostic associations remained even after accounting for LVEF185. Both CRP and TNF-α levels are increased in patients with progressively worsening NYHA functional class, and both are predictive of an adverse outcome in multivariable analysis185.

2. Mechanisms of Disease

2.3.2.5. Inflammatory Markers Antedating Heart Failure There is mounting evidence of the potential importance of systemic inflammation as an antecedent of heart failure. Vasan et al.186 reported that elevated systemic levels of inflammatory markers were associated with the future development of clinical heart failure in individuals who were free of the condition. In this study, elevation in biomarkers, including serum IL-6, monocyte production of TNF-α, and CRP, were associated with the risk of developing clinical heart failure. Participants with a serum CRP concentration ≥ 5 mg/dL experienced a near tripling of heart failure risk.

2.3.2.6. Impact of Treatment on Inflammation in Heart Failure Despite the wealth of experimental data implicating TNF-α in heart failure, clinical trials with TNF-α antagonists have been disappointing. Early studies of the TNF-α antagonist, etanercept, demonstrated improvement in cardiac function and clinical status in patients with moderate to severe heart failure187. However, larger studies failed to identify any clear benefits of TNF-α antagonism188,189. Future analyses of cytokine levels in heart failure need to consider the natural variability of cytokines and cytokine receptor levels in heart failure patients as well as the relationship (or lack thereof) between plasma and tissue levels. Since intraindividual variation in inflammatory markers may be considerable, sample size should be carefully considered to discern fluctuations in markers that are potentially unrelated to treatment interventions190. Elevated plasma levels of TNF-α, IL-6, MCP-1, and sIL-2R, but not IL-10, were observed in heart failure patients with LV systolic dysfunction enrolled in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)191. Treatment with metoprolol, however, did not lower the levels of any inflammatory markers (with the exception of sIL-2R) when compared with placebo191. However in another trial, AT1 receptor antagonism lowered levels of several markers (TNF-α, IL-6, sICAM, VCAM, and BNP) over a 3-month period21. These studies suggest that in heart failure, the interrelations of the β-adrenergic system, neurohormones, and inflam-

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matory cytokine/chemokine activation are complex and may be further complicated by the presence of enhanced sympathetic tone and β-adrenoceptor downregulation192.

2.3.2.7. Inflammatory Cytokines and Prognosis Several studies have found an association between inflammatory cytokines and prognosis. An analysis of the Vesnarinone Evaluation of Survival Trial (VEST) (n = 1,200) examined the prognostic impact of increased levels of circulating TNF-α, IL-6, and the soluble TNF receptors, sTNFR1 and sTNFR2135. This study was one of the largest examining the prognostic impact of inflammatory markers and found that patients with the highest levels of these cytokines had the worst prognosis after a mean duration of follow-up of 55 weeks135. Although these markers were correlated modestly with age, they remained significant predictors of mortality after adjustment for age, sex, NYHA class, ejection fraction, and serum sodium concentration135.

2.4. Part 3. Oxidative Stress In heart failure, the nitroso–redox balance that regulates NO and superoxide formation shifts from that of physiologic nitrosylation of downstream effector molecules to a pathological state of protein oxidation and oxidative stress193. Consequently, heart failure is associated with increased systemic oxidative stress194-196. Evidence of oxidant stress has also been found in the pericardial fluid of patients with heart failure197. ROS reflect leakage of electrons from the mitochondrial electron transport chain. Such leakage of electrons or “oxygen wastage” results in decreased myocardial efficiency from uncoupling of mitochondria and oxidative phosphorylation198. Increased oxidative stress has been observed in experimental heart failure199-201 and is associated with contractile dysfunction, a phenomenon inhibited by the xanthine oxidase inhibitor, allopurinol202. Redox-sensitive alterations in and nitrosylation of proteins involved in excitation–contraction coupling (such as sarcolemmal ion channels/exchangers, calcium release channels of the sarcoplasmic reticulum,

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and creatine kinase) contribute to contractile dysfunction203-207. Oxidative stress-induced myocyte hypertrophy, altered gene expression, and myocyte apoptosis are critical components of LV remodeling in experimental studies208. Of specific interest is the effect of ROS on apoptosis via influences on redoxsensitive protein kinases, such as mitogen-activated protein kinases209. In heart failure, the proapoptotic kinases, c-Jun NH2-terminal protein kinase and p38 kinase, are increased, whereas the antiapoptotic kinase, extracellular signal-regulated kinase, is decreased210-212. ROS promote collagen degradation by activation of myocardial MMPs 213,214 and inactivation of the cardiac tissue inhibitors of metalloproteinases (TIMPs)215. In addition to these myocardial effects, ROS activate central neurohumoral mechanisms via the hypothalamic (paraventricular and supraoptic) nuclei, resulting in sympathoexcitation216. ROS also damage cardiac sympathetic nerves217. Additionally, increased oxidative stress is associated with endothelial dysfunction and peripheral vasoconstriction218. Neurohormones and inflammatory pathways interact with mechanisms of oxidative stress. Angiotensin, endothelin, TNF-α, and α-adrenergic receptor stimulation can cause myocyte hypertrophy via pathways involving ROS219-221. Myocyte apoptosis, induced by cytokines and adrenergic stimulation, may also be mediated by ROS. Proinflammatory cytokines also stimulate peroxynitrite generation in the heart, contributing to myocyte contractile dysfunction222. Norepinephrine can increase apoptosis by stimulation of β1-adrenoceptors and is attenuated by antagonism of superoxide dismutase223. Furthermore, treatment with β-blockers in heart failure decreases levels of circulating lipid peroxides and improves ventricular function and survival224. The oxidative stress that is increased in animal models of postmyocardial infarction heart failure is also attenuated by administration of ACE inhibitors and AT1 receptor blockers225. Furthermore, these agents maintain the endogenous antioxidant reserve provided by myocardial glutathione225,226. Oxidative stress pathways have also been implicated in the transition from cardiac hypertrophy to failure227-229. In experimental LV hypertrophy, myocardial NADPH oxidase is initially upregulated209. The burden of myocardial ROS tracked the transition from compensated LV hypertrophy to decom-

D.S. Lee and R.S. Vasan

pensated LV failure, characterized by increased LV mass and cavity size230. Administration of therapeutic agents including ACE inhibitors230, probucol 231, dimethylthiourea232, and vitamin E200 decreased this progression with concomitant reduction of myocardial ROS generation. ROS may play a greater role in specific types of heart failure such as cardiomyopathies secondary to doxorubicin or iron overload. Even after a single dose of doxorubicin, increased myocardial oxidative stress may result from NADPH oxidasedependent superoxide generation, a phenomenon associated with increased lipid peroxidation, MMP activation, and nitrosative stress233. Iron overload is also associated with increased oxidative stress and altered cellular calcium handling in cardiomyocytes234-236. Oxidative stress has also been implicated in postmyocardial infarction heart failure. Postmyocardial infarction patients (treated with aspirin) who develop heart failure have increased plasma 2,3-dihydroxybenzoic acid:salicylic acid ratios, an indicator of increased oxidative stress237. An increased 2,3-dihydroxybenzoic acid:salicylic acid ratio correlates with circulating levels of TNF-α and its soluble receptors237. Oxidative stress also decreases peripheral blood flow and increases systemic vascular resistance, thereby contributing to reduced exercise tolerance and muscle fatigue in heart failure238-241. Oxidative mechanisms may also play a role in mediating the lipotoxic effects of lipid overload. Lipocardiotoxicity may result from excessive lipid overload and impaired ability to direct lipids to adipocytes242,243. Lipid overload in nonadipocytes may exceed the oxidative capacity for fatty acids, channeling fatty acids to pathways of nonoxidative metabolism242. This results in an increase in ceramide synthesis, which may increase production of oxidative free radicals via upregulation of inducible NO synthase243. Ceramide may also impair mitochondrial function244 and may lead to apoptosis in cardiomyocytes245-247. In Zucker Diabetic Fatty (fa/fa) rats with loss-of-function mutations of the leptin receptor, ceramide levels increase in islet cells and in the myocardium with resultant impaired contractility leading to cardiomyopathy248,249. It has been suggested that leptin, a hormone produced by adipocytes, may play a vital role in protecting nonadipocyte tissues from steatosis243.

2. Mechanisms of Disease

Deficiency of leptin or resistance to its effects has been purported to result in steatosis of myocardium, pancreatic β-cells, and skeletal muscles, leading to fatty acid-induced apoptosis or lipoapoptosis. In congenital lipodystrophy, there is lack of adipose tissue and leptin, leading to insulin resistance, diabetes, and myocardial steatosis manifested as cardiomyopathy248-250. Theoretical linkages between leptin and lipocardiotoxicity in human diet-induced obesity (and potentially the metabolic syndrome) have been proposed243. However, leptin also acts on the hypothalamus to regulate food intake251-253, and therefore may act via multiple liporegulatory mechanisms with its attendant downstream effects. The role of the leptin pathway on obesity-related syndromes, such as the metabolic syndrome, has yet to be clearly elucidated.

2.5. Part 4. Growth Factors in Heart Failure 2.5.1. Insulin-Like Growth Factor-1 Insulin-like growth factor-1 (IGF-1) is a 70-amino acid peptide that is a product of the growth hormone (GH) pathway, the major stimulus for IGF-1 release. IGF-1 exerts autocrine and paracrine functions in the myocardium via the presence of specific hormonal receptors254. IGF-1 mediates the growth-promoting properties of GH on end-organs and has a number of effects that may potentially affect myocardial remodeling. IGF-1 activates myocyte hypertrophic responses255,256, produces cardiac hypertrophy in vivo257, prevents myocyte apoptosis 258,259, and attenuates myocyte elongation that occurs in dilated cardiomyopathy260. IGF-1 also improves cardiac pump function by enhancing uptake of calcium into the sarcoplasmic reticulum and increasing the availability of Ca2+ to the contractile apparatus 261,262. In humans, serum levels of IGF-1 were inversely correlated with the incidence of heart failure in individuals free of prior myocardial infarction or heart failure263. IGF-1 levels decrease with age and have been shown to attenuate the production of proteins that are associated with myocyte senescence and age-related myopathy264. Evidence for the role of IGF-1 in ventricular remodeling is further buttressed by the finding that serum IGF-1 levels correlate linearly with LV mass265. Depressed levels of IGF-1

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may also contribute to loss of skeletal muscle mass and the catabolic state observed in heart failure patients266,267. However, an intervention study of experimental administration of recombinant human GH, the primary stimulus for IGF-1 release, demonstrated an increase in LV mass but no change in NYHA functional status265. In addition, the use of these hormones may be further complicated by the potential for increased cancer risk, a potential consequence of enhanced cellular longevity in extracardiac tissues268-270.

2.5.2. Neuregulin Neuregulin (NRG) is a paracrine growth factor that can activate survival pathways in ventricular cells in vitro 271,272. The neuregulins are important for normal cardiac morphogenesis, are expressed on nonmyocytes, and induce a growth response in isolated cardiac myocytes272-275. Tissue-specific mutation of ErbB2 (involved in NRG signaling) in cardiomyocytes can cause dilated cardiomyopathy in adult mice276. In a large-scale clinical trial, treatment of breast cancer patients with trastuzumab, an antibody against ErbB2, led to improvement in survival but was associated with cardiomyopathy as an uncommon side effect277. Ventricular ErbB2 mutations are associated with a phenotype of early dilated cardiomyopathy, with prominent chamber dilation, wall thinning, and decreased ventricular contractility278. Therefore, ErbB2 signaling may be important in preventing dilated cardiomyopathy. These data suggest a potentially important role for NRG signaling in heart failure. The role of NRG signaling in ventricular remodeling has not been investigated in cancer-free humans.

2.6. Part 5. Ventricular Remodeling: Integration of Multiple Pathways and Cellular Mechanisms 2.6.1. An Overview Chronic hemodynamic overload results in increased LV wall stress and triggers myocardial remodeling through release of cytokines, signaling peptides, neurohumoral mediators and elevated oxidative stress. Adaptive and maladaptive changes in the

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myocardium ensue as a result. Hypertrophy of myocytes and interstitial fibrosis in the matrix compartment normalize ventricular wall stress initially but these occur at the price of diminished ventricular compliance. Activation of the fetal gene program results in expression of fetal contractile proteins (myosin heavy chains, MHC). The adult human heart has 90% β-MHC and 10% α-MHC. α-MHC has relatively more ATPase activity and an increased velocity of shortening, whereas β-MHC shortens more slowly and contributes to greater fuel economy. In the failing myocardium, there is decreased expression of α-MHC, possibly contributing to decreased velocity of shortening. An additional feature of myocytes from the failing heart is a hypertrophic response characterized by the addition of sarcomeres in series. Such addition results in myocyte elongation and likely contributes to ventricular dilatation. Dysregulation of calcium handling proteins contributes further to impairment of both contraction and relaxation. A reduction in the inotropic and chronotropic responses to exercise and sympathetic stimulation is a hallmark of heart failure. The decrease in response to heightened adrenergic activity is related in part to changes in β1-adrenergic receptor coupling. In the failing myocardium, β-adrenergic receptor kinase activity is increased and the level of β1-adrenergic receptor mRNA is reduced. This imbalance leads to increased phosphorylation of receptors paralleled by reduction in transcription of new β1-adrenergic receptors. Thus, notwithstanding the increased catecholamine levels, there is desensitization and degradation of β1-adrenergic receptors. Myocytes that are not able to adapt undergo programmed cell death (apoptosis). Investigators have demonstrated that apoptosis occurs in myocardial biopsies obtained from patients with heart failure by staining for fragmented DNA, a hallmark of the apoptotic process279,280. Although the slow loss of myocytes via apoptosis may contribute to a progressive decline in cardiac systolic function, the relative magnitude of the contribution of apoptosis to heart failure has been the subject of debate. LV remodeling is characterized morphologically by changes in the geometric shape and volume of the LV. Myocardial remodeling is a complex process that includes numerous changes at the cellular and molecular levels in cardiac myocytes

D.S. Lee and R.S. Vasan

and the interstitium. These changes result in alterations of myocardial structure and function and eventually LV geometry and pump function, and are associated with adverse prognosis. Hemodynamic and neurohormonal factors are some of the important variables that influence the development of LV remodeling 281,282. In addition to neurohormonal mechanisms, other factors including oxidative stress and inflammatory cytokines may contribute to and regulate the remodeling process. The net result of the diverse processes driving myocardial remodeling is further impairment in cardiac pump function and increased wall stress, thus contributing to a vicious cycle that further aggravates ventricular dysfunction.

2.6.2. Neurohormonal Effects on Remodeling The processes initiating the development of LV remodeling can occur by mechanisms that are dependent on or independent of the renin– angiotensin pathway283,284. However, progression of established LV hypertrophy, interstitial fibrotic changes, and the transition to heart failure are influenced substantially by ATII activity on the AT1 receptor285. ATII participates in ventricular remodeling, by accelerating myocyte hypertrophy and promoting collagen synthesis and interstitial fibrosis286, processes reversed by blockade of the AT1 receptor287-289. At the cellular level, activation of the AT1 receptor leads to enhanced RNA-to-DNA ratios, increased rates of protein synthesis, and greater activity of protein kinase C in myocytes290. The AT2 receptor may counterbalance the effects of AT1 by inhibiting cellular differentiation, growth, and apoptosis291-293. Thus, it has been suggested that activation of AT2 receptors may mediate in part some of the cardioprotective effects of AT1 receptor antagonism294,295. The renin–angiotensin pathway may also interact with ET-1 to exert its effects on myocardial remodeling. Both ET-1 and ATII are G-protein-coupled receptor agonists, which can result in myocyte hypertrophy and interstitial fibrosis296. Thus, the autocrine/paracrine effects of ET-1 may facilitate ATII-induced cardiac hypertrophy297. Emerging evidence suggests the potentially important role of aldosterone in LV remodeling298. Upregulation of the aldosterone synthase gene in

2. Mechanisms of Disease

the myocardium is a key event in heart failure299,300. Aldosterone exerts its bioactivity via a mineralocorticoid receptor that is expressed in human cardiomyocytes, endothelial cells, and cardiac fibroblasts, and induces collagen synthesis and fibroblast proliferation301-304. Increased plasma and myocardial aldosterone levels are associated with LV hypertrophy, increased LV end-diastolic volume index, and increased plasma BNP305-307. It is not surprising, therefore, that aldosterone antagonism had a beneficial effect on mortality in heart failure patients308, possibly by effects on cardiac collagen formation309.

2.6.3. Inflammation and Ventricular Remodeling Enhanced local myocardial production of inflammatory cytokines in response to hemodynamic overload influences the growth and death of cardiomyocytes, thereby contributing to the process of myocardial remodeling. Examples of such cytokines include MCP-1 and TNF-α. MCP-1 influences LV remodeling principally via recruitment of myocardial mononuclear cells and release of other cytokines, notably TNF-α, TGF-β, and IL-1β310. TNF-α may exert its role on myocardial remodeling in several ways. TNF-α increases myocyte apoptosis, promotes abnormal sarcoplasmic calcium homeostasis311-313, accelerates interstitial collagen degradation by MMPs314-317, and decreases activity of tissue inhibitors of metalloproteinases in the myocardium318. In addition, TNF-α promotes hypertrophy of adult cardiac myocytes319. In experimental studies, TNF-α blockade attenuates LV remodeling perhaps by antagonism of all aforementioned mechanisms. Another potentially important factor in the TNF-α signaling cascade may be the role of the TNF receptor subtypes. Although both TNFR1 and TNFR2 are activated by TNF-α, the cellular domains differ and the receptors may activate differing downstream signaling pathways320,321. Although most of the biological activities of TNF are mediated by TNFR1119,322, complex interactions may occur between the receptor subtypes. Disruption of the TNFR1 gene in mice with cardiac-specific overexpression of TNF-α prevented myocarditis, reduced cardiac remodeling, preserved contractile function, and improved survival323. However, disruption of

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the TNFR2 gene exacerbated ventricular remodeling, worsened heart failure, and reduced survival in mice323. Therefore, the counterbalancing effects of the TNFR1 and TNFR2 subtypes may be important in heart failure progression and in regulation of LV remodeling.

2.6.4. MMPs and Ventricular Remodeling Although myocytes are the major components of cardiac mass, they are outnumbered by nonmyocyte cellular constituents including fibroblasts, smooth muscle cells, and endothelial cells. The extracellular matrix includes collagen fibers, proteoglycans, glycoproteins such as fibronectin, several peptide growth factors, proteases, and antiproteases. The extracellular matrix of the ventricular myocardium plays a fundamental role in maintaining LV shape and geometry. Collagenous matrix proteins maintain the alignment of cardiac myocytes. The collagenous network of matrix proteins is degraded by MMPs, a family of zinc-dependent enzymes324. All primary cell types in the myocardium, including myocytes, express and synthesize MMPs325. Important subtypes include the gelatinases, MMP-2 and MMP-9, which have been reported to be elevated in animal models and humans with heart failure214,326. The substrates of the gelatinases include basement membrane molecules, collagen IV and laminin, which conjoin myocytes with the intercellular matrix324. TIMPs are the natural physiological regulators of MMPs327-330. The relative ratio of MMP to TIMP activity may be critical in the remodeling processes that determine the molecular architecture of the myocardial interstitium331-333. The relative MMP and TIMP balance determines the rate of matrix degradation and turnover. Elevated MMP activity favors myocyte slippage, reduced myocyte-tomyocyte mechanical coupling, and resultant ventricular dilation. Greater TIMP activity results in a net antagonism of MMP activity and increased fibrosis, with consequent increased myocardial stiffness and impaired nutrient supply because of greater capillary-to-myocyte distance. A number of studies have found that MMP activity is increased in end-stage heart failure214,326,334 paralleled by a decrease in TIMP activity335,336. MMP-induced disruption of myocardial collagen

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cross-linkage is associated with LV dilation in heart failure337. Increased matrix metalloproteinase activity has been found to be temporally associated with progressive LV dilation and wall thinning in experimental studies331,338-340. Inhibition of MMPs attenuates the remodeling process and improves ventricular contractile performance by reducing myocyte growth and improving collagen matrix integrity341. Inhibition of MMPs (other than MMP-1) improves fibrillar collagen structure, architecture, and thickening. Enhanced structural integrity of the interstitial matrix stabilizes intermyocyte collagen and results in greater fidelity of transduction of myocyte shortening to global LV contraction and ejection fraction342,343. There is differential involvement of MMPs in the remodeling processes that lead to end-stage heart failure. For example, it has been reported that myocardial MMP-1 is reduced in patients with cardiomyopathy, whereas MMP-2, MMP-3, and MMP-9 are increased. These MMP alterations are paralleled by TIMP downregulation, a phenomenon that is reversed by left ventricular assist device (LVAD) support in advanced heart failure334,344. Myocardial levels of all TIMP subtypes (TIMP-1 to TIMP-4) have been implicated to have a potential role in the adverse remodeling process and pathogenesis of ischemic and dilated cardiomyopathy333,345,346. Among these, changes in myocardial TIMP-1 have been identified as a potentially important regulator of remodeling in animal models and in human hearts334,344,346-349. Additional evidence implicating MMPs and TIMPs is provided by the observation that plasma levels of MMP-9 may be elevated in patients with established heart failure350,351. Polymorphisms in the genes for MMP-3 and MMP-9 influence prognosis in patients with LV systolic dysfunction352. Additionally, alterations in MMPs and TIMP may antedate heart failure. Detectable plasma levels of MMP-9 were found to correlate with increased echocardiographic LV end-diastolic dimension, and LV mass353. Plasma TIMP-1 levels were inversely associated with systolic function and echocardiographic indices of LV hypertrophy354. The finding of an increase in the MMP-9/TIMP-1 and MMP9/TIMP-2 ratios in heart failure351 and correlation of the MMP/TIMP ratio with LV dimensions and cardiac index355 support the notion that the MMP to TIMP ratio may be an important correlate of underlying LV structure and function.

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2.7. Part 6. Systolic and Diastolic Dysfunction Whereas prior research focused on mechanisms of systolic heart failure, the molecular underpinnings of diastolic heart failure have become an area of greater focus. Diastolic heart failure is characterized by abnormal active relaxation and increased passive stiffness of the myocardium356. In contrast, systolic heart failure is attributed to abnormal LV chamber or muscle properties leading to impaired pump function and concomitant pulmonary congestion. Although a clinical distinction is often made between systolic and diastolic heart failure, the recognition of early contractile abnormalities even among those with diastolic heart failure may suggest that the two entities may coexist to a greater degree than is commonly appreciated357.

2.7.1. Altered Calcium Homeostasis in Systolic and Diastolic Heart Failure Decreased contractile performance of the myocyte and the left ventricle characterize the transition to systolic heart failure. In severe heart failure, there is decreased myocyte response to inotropic stimulation, in particular to β-adrenergic stimuli. This process is partly due to dysfunctional Ca2+ homeostasis and/or altered myofilament sensitivity to Ca2+. Physiologic ventricular contraction and excitation–contraction coupling are dependent on the initial activation of transmembrane Ca2+ channels that are activated by membrane depolarization358,359. These channels are regulated by transmitters, hormones, and cellular messengers that modify the influx of Ca2+ into the sarcoplasm360. Fundamentally, the cycle of release of Ca2+ into the cytosol and subsequent reuptake into the sarcoplasmic reticulum must be maintained to allow for preserved excitation–contraction–relaxation coupling. Thus, abnormalities in calcium transients contribute to depressed myofilament activation361, resulting in both systolic and diastolic dysfunction. In isolated failing myocytes, the basal concentration of intracellular calcium is elevated, and there is an attenuation of the peak rise in calcium with depolarization362-364. Abnormalities of Ca2+ handling in heart failure may result from (i) abnormal sarcoplasmic reticulum calcium ATPase activity (SERCA2)365,366, (ii) alterations

2. Mechanisms of Disease

in phospholamban, (iii) impaired ability of L-type Ca2+ channels to activate release of Ca2+ stores from the sarcoplasmic reticulum367, (iv) defects of the ryanodine receptor368, and (v) myocardial cytoskeletal abnormalities369. Phospholamban regulates the activity of SERCA2 in the cardiac myocyte, thereby controlling cytosolic calcium concentrations. Whereas expression of both phospholamban and SERCA2 is reduced in the failing myocardium, the decline in SERCA2 is greater. Thus, the ratio of phospholamban to SERCA2 is increased in the failing myocardium, resulting in a downward shift of ventricular end-systolic pressure–volume relations, thereby indicating worsening systolic function. It has been suggested that depressed activity of the sarcoplasmic reticulum and reduction in Ca2+ transients may be an adaptive response to reduce contractile dysfunction and energy expenditure361. However, this maladaptive response is of importance in the pathophysiology of heart failure. The availability of intracellular Ca2+ correlates with the magnitude and duration of contractility in myocytes, and abnormal Ca2+ uptake by sarcoplasmic reticulum has been recognized as a potential cellular mechanism of systolic heart failure370,371. Several studies have found decreased Ca2+ transport in experimental and human heart failure363,372-375. Mutational disruption of one copy of the cardiac SERCA gene results in altered Ca2+ homeostasis, increased cardiac hypertrophy and dilatation, and development of both systolic and diastolic dysfunction376. Defects of SERCA2 or its modulators, protein kinases and protein phophatases, can also lead to myocyte contractile dysfunction377,378. Disturbed Ca2+ balance may also result in impaired facilitation, a phenomenon where the increased Ca2+ entry that results from higher frequency of activation of Ca2+ channels is disrupted 379 . Potential cellular mechanisms of impaired facilitation in human heart failure may be attributed to low intracellular cAMP causing reduced opening of Ca2+ channels and altered reuptake of Ca2+ by the sarcoplasmic reticulum379. The degree of Ca2+ loading by the sarcoplasmic reticulum has been previously shown to be a determinant of the force–frequency relationship380,381. In animal models, impairment of the force–frequency relationship has been found to be an early feature of the incipient transition to heart failure382,383.

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Relaxation of the ventricle is also dependent on Ca2+ traffic that is influenced by the activity of SERCA2, which, in turn (as noted earlier), is regulated by phospholamban384,385. When dephosphorylated, phospholamban reduces the activity of SERCA2, resulting in impaired relaxation. In contrast, phosphorylation of phospholamban by cAMP-dependent processes and Ca2+/calmodulindependent protein kinases enhances the activity of cardiac SERCA386. Mutation of the phospholamban gene at a critical hinge region caused structural alteration of the protein, resulting in inhibition of cardiac SERCA sequestration of cytosolic Ca2+382. Interestingly, this defect of Ca2+ homeostasis manifested as an impairment of relaxation which progressed temporally to eventual cardiac enlargement and heart failure382. The critical role of cardiac isoforms of SERCA2 in modification of diastolic function was supported by gene transfer studies which demonstrated dose-dependent correction of relaxation abnormalities from myocytes of hearts with pure diastolic dysfunction387.

2.7.2. Other Mechanisms Implicated in Diastolic Heart Failure In addition to abnormalities of Ca2+ homeostasis, the renin–angiotensin system and adverse remodeling contribute to the development of both systolic and diastolic heart failure, thereby providing evidence of shared substrates and mechanisms. However, distinctions between pathways leading to systolic versus diastolic heart failure may exist. An example of such a distinction within the renin–angiotensin system is the relative role of AT1- versus AT2-mediated effects that may lead to pathophysiologically predominant systolic or diastolic heart failure388-390. Diastolic heart failure is associated with LV hypertrophy, upregulation of ANP and BNP genes, and interstitial collagen accumulation. As noted previously, ATII stimulates myocardial ANP gene expression, ET-1 production, and collagen accumulation via activation of the AT1 receptor. Antagonism of angiotensin pathways with ACE inhibitors and angiotensin receptor blockers was found to reduce these effects and reduce heart failure secondary to diastolic dysfunction288. AT1 receptor blockade prevented the development of diastolic heart failure and reduced LV fibrosis in salt-sensitive

28

hypertensive rats, even after the development of LV hypertrophy and early diastolic dysfunction391,392. Mechanisms by which AT1 receptor blockade may ameliorate diastolic function include decrease in myocardial stiffness, attenuation of the prolongation of Tau (the time constant of LV relaxation), increase in SERCA protein levels, and a reduction in the dephosphorylation of phospholamban389,392. Hypertension and concomitant LV hypertrophy are common precursors of diastolic heart failure. The contributions of putative pathways vary with the stage in the progression to diastolic heart failure. Thus, distinctions have been proposed between events leading to LV hypertrophy and those that occur in the stage of decompensated heart failure. For example, in the stage of compensatory LV hypertrophy, gene expression of ACE and the AT1 receptor was increased but expressions of prepro-ET-1 and endothelin converting enzyme-1 were not388. With the development of diastolic heart failure, gene expression of the endothelin pathway and upregulation of ET receptors occurred and ACE was further increased without downregulation of AT1388. Cardiac hypertrophy and pathological cardiac remodeling are also affected by guanosine 3′,5′cyclic monophosphate and phosphodiesterase-5A (PDE5A) pathways393,394. Inhibition of guanosine 3′,5′-cyclic monophosphate catabolism with the PDE5A inhibitor, sildenafil, prevented further myocyte and cardiac hypertrophy and reversed preexisting hypertrophy395. Inhibition of PDE5A may suppress signaling pathways [such as the calcineurin/nuclear factor of activated T-cells, phosphoinositide-3 kinase/Akt, and extracellular signal-regulated kinase 1/2], possibly representing a novel pharmacologic approach to reverse LV hypertrophy and subsequent remodeling395. The endothelin pathway may also contribute to the pathogenesis of diastolic heart failure. Myocardial ET-1 was upregulated in hearts with established LV hypertrophy that transitioned to progressive LV dysfunction and was inhibited by bosentan396. The progression to LV dysfunction and heart failure was inhibited to a greater degree by combinatorial blockade of both ET-1 and AT1 receptors, and combined blockade resulted in an improved hemodynamic and neurohormonal profile397. Also, pharmacologic ETA receptor antagonism has been demonstrated to reduce myocardial stiffness in hypertensive animal models398.

D.S. Lee and R.S. Vasan

As noted previously, ventricular remodeling is a fundamental feature of both systolic and diastolic heart failure. The transition to heart failure from a state of compensated hypertrophy occurs by remodeling processes including fibrosis, myocyte degeneration, compensatory hypertrophy, autophagic cell death, oncosis, and altered myocardial cell phenotype from increased myocyte length and reduction in cross-sectional area342,399. Abnormal deposition and accumulation of collagen may be partly responsible for stiffness of the left ventricle. Myocardial stiffness that is characteristic of diastolic heart failure is partly mediated by excessive collagen synthesis, and possibly an unfavorable ratio of collagen subtypes (increased ratio of collagen type I to III), shifting the matrix phenotype in the direction of increased myocardial stiffness389,400. Matrix metalloproteinase activity and gene expression have been found to precede temporally the change to progressive LV dilatation in the hypertensive rat model401. Systolic and diastolic heart failure are both associated with reduced TIMP gene expression and increased MMP-2 and MMP-9 activity402. However, the degree of MMP-9 activation was higher with more diffuse myocardial involvement in systolic heart failure402.

2.8. Summary Multiple pathways contribute to the development of heart failure, and ventricular remodeling. The structural and functional abnormalities that constitute the clinical syndrome of heart failure are the result of molecular/cellular alterations that arise from the activation of neurohormonal, inflammatory, oxidative stress, and growth factor pathways. Although we distinguish clinically between systolic and diastolic heart failure, these mechanistic pathways contribute to both types of heart failure. There are many gaps in our knowledge of heart failure mechanisms. Pathways leading to diastolic heart failure and its associated adverse outcomes, and the interrelations between mechanisms of diastolic and systolic heart failure, have not been elucidated completely. The temporal sequence of events and the relative contributions of these mechanisms to the evolution of clinical heart failure from preclinical stages have also not been delineated. Further progress in our

2. Mechanisms of Disease

understanding of these fundamental mechanisms underlying heart failure will likely identify novel therapeutic targets. Such advances will help to prevent the development of heart failure and reduce the mortality and morbidity associated with this disorder.

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dilated cardiomyopathy: Potential role of MMP-9 in myosin-heavy chain degradation. Eur J Heart Fail. 1999;1(4):337-352. Ohtsuka T, Hamada M, Saeki H, et al. Serum levels of matrix metalloproteinases and tumor necrosis factor-alpha in patients with idiopathic dilated cardiomyopathy and effect of carvedilol on these levels. Am J Cardiol. 2003;91(8):1024-1027, A8. Wilson EM, Gunasinghe HR, Coker ML, et al. Plasma matrix metalloproteinase and inhibitor profiles in patients with heart failure. J Card Fail. 2002;8(6):390-398. Mizon-Gerard F, de Groote P, Lamblin N, et al. Prognostic impact of matrix metalloproteinase gene polymorphisms in patients with heart failure according to the aetiology of left ventricular systolic dysfunction. Eur Heart J. 2004;25(8):688-693. Sundstrom J, Evans JC, Benjamin EJ, et al. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: The Framingham Heart Study. Circulation. 2004;109(23):2850-2856. Sundstrom J, Evans JC, Benjamin EJ, et al. Relations of plasma total TIMP-1 levels to cardiovascular risk factors and echocardiographic measures: The Framingham Heart Study. Eur Heart J. 2004;25(17):1509-1516. Schwartzkopff B, Fassbach M, Pelzer B, Brehm M, Strauer BE. Elevated serum markers of collagen degradation in patients with mild to moderate dilated cardiomyopathy. Eur J Heart Fail. 2002;4(4):439-444. Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure—Abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004;350(19):1953-1959. Yu CM, Lin H, Yang H, Kong SL, Zhang Q, Lee SW. Progression of systolic abnormalities in patients with “isolated” diastolic heart failure and diastolic dysfunction. Circulation.2002;105(10):1195-1201. Fabiato A. Simulated calcium current can both cause calcium loading in and trigger calcium release from the sarcoplasmic reticulum of a skinned canine cardiac Purkinje cell. J Gen Physiol. 1985;85(2):291-320. Bers DM, Perez-Reyes E. Ca channels in cardiac myocytes: Structure and function in Ca influx and intracellular Ca release. Cardiovasc Res. 1999;42(2):339-360. McDonald TF, Pelzer S, Trautwein W, Pelzer DJ. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev.1994;74(2):365-507. Perez NG, Hashimoto K, McCune S, Altschuld RA, Marban E. Origin of contractile dysfunction in

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D.S. Lee and R.S. Vasan heart failure: Calcium cycling versus myofilaments. Circulation. 1999;99(8):1077-1083. Beuckelmann DJ, Nabauer M, Erdmann E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation. 1992;85(3):1046-1055. Hasenfuss G, Reinecke H, Studer R, et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)-ATPase in failing and nonfailing human myocardium. Circ Res. 1994;75(3):434-442. Schwinger RH, Munch G, Bolck B, Karczewski P, Krause EG, Erdmann E. Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation. J Mol Cell Cardiol. 1999;31(3):479-491. Schmidt U, Hajjar RJ, Helm PA, Kim CS, Doye AA, Gwathmey JK. Contribution of abnormal sarcoplasmic reticulum ATPase activity to systolic and diastolic dysfunction in human heart failure. J Mol Cell Cardiol. 1998;30(10):1929-1937. Flesch M, Schwinger RH, Schnabel P, et al. Sarcoplasmic reticulum Ca2 + ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy. J Mol Med. 1996;74(6):321-332. Gomez AM, Valdivia HH, Cheng H, et al. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science. 1997;276(5313):800-806. Marx SO, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts. Cell. 2000;101(4):365-376. Li D, Tapscoft T, Gonzalez O, et al. Desmin mutation responsible for idiopathic dilated cardiomyopathy. Circulation. 1999;100(5):461- 464. Kinugawa S, Tsutsui H, Satoh S, et al. Role of Ca2+ availability to myofilaments and their sensitivity to Ca2+ in myocyte contractile dysfunction in heart failure. Cardiovasc Res. 1999;44(2):398-406. Igarashi-Saito K, Tsutsui H, Yamamoto S, et al. Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure. Am J Physiol. 1998;275(1 pt 2):H31-H40. Arai M, Matsui H, Periasamy M. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res. 1994;74(4):555-564. Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure. A possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res. 1993;72(2):463-469.

374. Feldman AM, Weinberg EO, Ray PE, Lorell BH. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ Res. 1993;73(1):184-192. 375. Qi M, Shannon TR, Euler DE, Bers DM, Samarel AM. Downregulation of sarcoplasmic reticulum Ca(2+)ATPase during progression of left ventricular hypertrophy. Am J Physiol. 1997;272(5 pt 2):H2416-H2424. 376. Schultz JJ, Glascock BJ, Witt SA, et al. Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity. Am J Physiol Heart Circ Physiol. 2004;286(3):H1146-H1153. 377. Gupta RC, Shimoyama H, Tanimura M, Nair R, Lesch M, Sabbah HN. SR Ca(2+)-ATPase activity and expression in ventricular myocardium of dogs with heart failure. Am J Physiol. 1997; 273(1 pt 2): H12-H18. 378. Gupta RC, Mishra S, Rastogi S, Imai M, Habib O, Sabbah HN. Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts. Am J Physiol Heart Circ Physiol. 2003;285(6):H2373-H2381. 379. Barrere-Lemaire S, Piot C, Leclercq F, Nargeot J, Richard S. Facilitation of L-type calcium currents by diastolic depolarization in cardiac cells: Impairment in heart failure. Cardiovasc Res. 2000;47(2):336-349. 380. Kadambi VJ, Ball N, Kranias EG, Walsh RA, Hoit BD. Modulation of force-frequency relation by phospholamban in genetically engineered mice. Am J Physiol. 1999;276(6 pt 2):H2245-H2250. 381. Pieske B, Maier LS, Bers DM, Hasenfuss G. Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium. Circ Res. 1999;85(1):38-46. 382. Schmidt AG, Zhai J, Carr AN, et al. Structural and functional implications of the phospholamban hinge domain: Impaired SR Ca2+ uptake as a primary cause of heart failure. Cardiovasc Res. 2002;56(2):248-259. 383. Inagaki M, Yokota M, Izawa H, et al. Impaired force-frequency relations in patients with hypertensive left ventricular hypertrophy. A possible physiological marker of the transition from physiological to pathological hypertrophy. Circulation. 1999;99(14):1822-1830. 384. Luo W, Grupp IL, Harrer J, et al. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ Res. 1994;75(3):401-409. 385. Kadambi VJ, Ponniah S, Harrer JM, et al. Cardiacspecific overexpression of phospholamban alters

2. Mechanisms of Disease

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calcium kinetics and resultant cardiomyocyte mechanics in transgenic mice. J Clin Invest. 1996;97(2):533-539. Wegener AD, Simmerman HK, Lindemann JP, Jones LR. Phospholamban phosphorylation in intact ventricles. Phosphorylation of serine 16 and threonine 17 in response to beta-adrenergic stimulation. J Biol Chem. 1989;264(19):11468-11474. Hirsch JC, Borton AR, Albayya FP, Russell MW, Ohye RG, Metzger JM. Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction. Am J Physiol Heart Circ Physiol. 2004;286(6):H2314-H2321. Yamamoto K, Masuyama T, Sakata Y, et al. Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: Absence of AT1 receptor downregulation and “overdrive” of the endothelin system. Cardiovasc Res. 2000;46(3):421-432. Sakata Y, Yamamoto K, Mano T, et al. Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix. J Hypertens. 2003;21(9):1737-1745. Ichihara S, Senbonmatsu T, Price E, Jr, Ichiki T, Gaffney FA, Inagami T. Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation. 2001;104(3):346-351. Yamamoto K, Masuyama T, Sakata Y, et al. Roles of renin-angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts. Cardiovasc Res. 2000;47(2):274-283. Sakata Y, Yamamoto K, Mano T, et al. Temocapril prevents transition to diastolic heart failure in rats even if initiated after appearance of LV hypertrophy and diastolic dysfunction. Cardiovasc Res. 2003;57(3):757-765. Knowles JW, Esposito G, Mao L, et al. Pressureindependent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest. 2001;107(8):975-984.

45 394. Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res. 2003;93(4):280-291. 395. Takimoto E, Champion HC, Li M, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11(2):214-222. 396. Iwanaga Y, Kihara Y, Hasegawa K, et al. Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation. 1998;98(19):2065-2073. 397. New RB, Sampson AC, King MK, et al. Effects of combined angiotensin II and endothelin receptor blockade with developing heart failure: Effects on left ventricular performance. Circulation. 2000;102(12):1447-1453. 398. Yamamoto K, Masuyama T, Sakata Y, Nishikawa N, Mano T, Hori M. Prevention of diastolic heart failure by endothelin type A receptor antagonist through inhibition of ventricular structural remodeling in hypertensive heart. J Hypertens. 2002;20(4):753-761. 399. Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: Structural deterioration and compensatory mechanisms. Circulation. 2003;107(7):984-991. 400. Fielitz J, Hein S, Mitrovic V, et al. Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol. 2001;37(5):1443-1449. 401. Sakata Y, Yamamoto K, Mano T, et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: Its inhibition as a primary effect of Angiotensinconverting enzyme inhibitor. Circulation. 2004;109(17):2143-2149. 402. Nishikawa N, Yamamoto K, Sakata Y, et al. Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation. Cardiovasc Res. 2003;57(3):766-774.

3 Diagnostic Testing and the Assessment of Heart Failure Savitri E. Fedson and Allen S. Anderson

3.1. Introduction Physicians employ many tools in the diagnosis and assessment of heart failure. As in the case of other areas in medicine, increasing reliance is placed on advanced imaging technologies and diagnostic tests, and less upon the traditional history and physical examination used by previous generations of physicians. In this chapter, we will review the range of diagnostic testing available to evaluate the cardiovascular system from the history and physical examination through the most advanced modalities. We will present each testing method in terms of its diagnostic utility in heart failure. It is important to remember that these techniques have the properties of diagnostic tests and therefore are associated with such variables as sensitivity and specificity as well as positive and negative predictive values. For some techniques, these statistical parameters will vary with the examiner or interpreter while others are less affected.

3.2. History Despite the shift toward high technology assessment, important information will be gained by interviewing the patient. Taking a history provides the examiner an opportunity to gauge the duration and severity of symptoms, to understand the patient’s perception of these symptoms (which may often be misleading), to assess mental status, and to develop points for future education about the disease of heart failure (1). Patients who develop heart failure gradually are often unaware of the etiology

of their symptoms and can be dismissive of their physical limitations. Common misdiagnoses include respiratory tract infections, such as bronchitis and pneumonia; asthma; gastrointestinal disorders; obesity; or aging2. It is common to see young adults presenting with heart failure who were originally misdiagnosed for months with pulmonary disorders, asthma being the most common. Because of the impact of concomitant disease upon heart failure, careful questioning to investigate the medical history and provide a list of medical problems, which may complicate or be complicated by heart failure, is necessary. A complete review of systems may also identify confounding factors in the heart failure patient. Screening questions for sleepdisordered breathing, or for neurological symptoms, may increase the chances of diagnosing sleep apnea or identify a need for chronic anticoagulation. A history of syncope is always concerning since it raises the possibility of cardiac dysrhythmias and sudden cardiac death. Certain historical questions have special utility in evaluating patients with prior heart failure as well as those with acute exacerbations of chronic heart failure. Two high-yield historical questions pertain to the presence of orthopnea and/or paroxysmal nocturnal dyspnea. The presence of these symptoms is strongly correlated with an elevated pulmonary capillary wedge pressure (PCWP) and may help the examiner differentiate the cause of the dyspnea and raise the suspicion for heart failure. Furthermore, abdominal discomfort and especially right upper quadrant fullness or tenderness may help guide the examiner toward the diagnosis of heart failure and away from an intraabdominal process such as

47

48

cholecystitis. These symptoms of “right-sided” heart failure are very common in younger patients and may represent hepatic and other abdominal organ congestion due to chronic central venous hypertension. Early satiety and anorexia are commonly associated with these abdominal complaints, and may be present when more obvious findings such as peripheral edema are absent. An elevated central venous pressure (CVP) is consistent with advanced biventricular failure as well as cor pulmonale, and right ventricular failure often follows left ventricular failure of many etiologies. A careful family history is in order, particularly when nonischemic cardiomyopathy is the diagnosis. It is now recognized that in addition to the genetic mutations associated with hypertrophic cardiomyopathy, at least 30% of patients with dilated cardiomyopathy also have a genetic etiology. Other familial cardiomyopathies include arrhythmogenic right ventricular dysplasia, muscular dystrophies, and left ventricular noncompaction3. Thus, identifying a potential index case may prompt screening of other relatives, including offspring, and facilitate earlier diagnosis of cardiomyopathy. Family history questions should not be limited to heart failure but should include any history of early sudden death and include young family members who died an unexpected or unexplained death, or those who have had an unusual history of “heart attacks.” Testing for a limited number of genetic abnormalities associated with hypertrophic and dilated cardiomyopathy is clinically available, but more are anticipated3. Review of the patient’s social history provides an opportunity for the physician to understand the effects of chronic heart failure on not only the patient but also the family, other caregivers, and personal relations4. It is also important to identify barriers to care, which will complicate patient management. Drug or alcohol addiction, an inability to pay for standard medical therapies, or misperceptions about the necessity of chronic medical therapy will limit the physician’s ability to intervene successfully.

3.3. Physical Examination A thorough physical examination continues to be warranted in the practice of medicine, although its diagnostic utility has limitations. It is well recognized that newer generations of physicians

S.E. Fedson and A.S. Anderson

display less skill and aptitude at physical diagnosis, especially the cardiovascular examination. Even specialists in cardiology fail to recognize and identify common abnormal cardiac findings5. It is also becoming apparent that additional diagnostic modalities such as echocardiography (to be further discussed later) can aid in the correct interpretation of these findings. It is important to recognize which physical findings have particular diagnostic utility in patients with heart failure and those which may be misleading. Two of the more classic physical findings associated with heart failure are the presence of rales and peripheral edema. While the specificity of rales and peripheral edema is excellent (95–100%), the sensitivity of these findings is only 15 and 25%, respectively6,7. Many patients who present with acute decompensation of chronic heart failure have clear lungs by auscultation. The presence of rales suggests the presence of interstitial fluid and pulmonary edema correlating with a PCWP > 18 mmHg7. However, many patients, even with markedly elevated PCWP, do not develop pulmonary edema in the setting of significant volume overload. Peripheral edema is frequently absent and volume overload may be manifested by the abdominal symptoms described above. Estimation of the jugular venous pressure may be used to determine volume status; however, even in experienced examiners’ hands, it may have limited diagnostic utility. It may be difficult to assess the level of jugular venous distention because of anatomical constraints such as obesity or the presence of catheters or other medical devices that may obscure the waveform. Among patients in whom jugular venous pressure waveforms can be analyzed, the sensitivity and specificity are high (80 and 98%, respectively), but in up to 15% of patients it cannot be adequately measured7. The presence of cool extremities, acral cyanosis, and a narrowed pulse pressure suggests a low cardiac output (CO) state seen in advanced chronic heart failure. This assessment of CO, in combination with a physical assessment of PCWP, can be used to classify patients into hemodynamic subsets (Figure 3.1) for the purpose of selecting initial therapy for the acutely decompensated patient. The cardiac examination, especially auscultation, is one of the most difficult components of the physical examination to learn. The increasing incidence of obesity among Americans has further complicated

3. Diagnostic Testing and the Assessment of Heart Failure

49

Figure 3.1. A rapid bedside evaluation to assess the presence or absence of congestion and low perfusion can be used to categorize heart failure patients into one of four profiles: A, warm and dry; B, warm and wet; L, cold and dry; and C, cold and wet. These simple profiles carry prognostic information and can be used to guide initial treatment of acute decompensated heart failure. Adapted from Nohria et al. (8), with permission

the reliability of physical diagnosis in general, and the cardiac examination in particular. Palpation of the heart by assessing the size, placement, and intensity of the point of maximal impulse (PMI); assessing right ventricular function; and feeling for the presence of a palpable third heart sound may provide useful information regarding ventricular function. A palpable pulmonic component of the second heart sound (P2) correlates with significant pulmonary arterial hypertension (PAH). Auscultation of the heart remains one of the most persistent classical techniques today, but the skill of examiners is decreasing. Despite these limitations, cardiac auscultation remains useful. Drazner et al.9 have shown that the presence of an audible, left-sided S3 gallop has prognostic significance in patients with heart failure. Differentiating right-sided S3 and S4 gallops can identify significant right heart failure seen in pulmonary hypertension, and primary right ventricular failure. An accentuated P2 may first alert the examiner to the presence of significant PAH. Auscultation for valvular disease may provide early clues as to the etiology of acute decompensation of heart failure such as primary valvular regurgitation or stenosis. These findings should always be confirmed with echocardiography; in fact, echocardiography has been shown to identify cardiac lesions missed during physical examinations5. Measurement of vital signs provides subtle information beyond the absolute values of heart rate, blood

pressure, and respirations particularly in patients who present urgently or emergently with heart failure. Classic findings of advanced left ventricular failure include a narrow pulse pressure, pulsus alternans (an alternating weak and strong pulse), and resting tachycardia. The presence of an irregular rhythm is often associated with atrial fibrillation but may also include other dysrhythmias such as atrial flutter, atrial tachycardia with variable atrioventricular (AV) block, or frequent premature atrial or ventricular contractions.

3.4. Chest Roentgenography Chest radiography has been the mainstay of routine assessment for patients presenting to the hospital with dyspnea. Its greatest utility today is in excluding gross pathology such as lobar pneumonia, masses, large pleural effusions, acute pulmonary edema, interstitial diseases, and pneumothoraces, rather than in identifying the patient with an acute heart failure exacerbation. Assessment of cardiac size by chest radiography may be limited because of body habitus or radiographic technique. The size of the cardiac silhouette does not necessarily reflect the size of the heart itself (e.g., in the case of pericardial effusion), and the cardiac silhouette gives little indication of the state of ventricular function. It is also well recognized that the presence of noncardiogenic pulmonary edema makes utilization of the chest

50

radiography for assessing the etiology of such fluid limited. As is the case with chest auscultation, many patients with chronic heart failure who present with acute decompensation have no or minimal interstitial edema on chest x-ray10.

3.5. Electrocardiography Electrocardiography is another mainstay of cardiovascular assessment and continues to provide useful information for the urgent assessment of patients with cardiovascular disease. Despite limitations, its utility in diagnosing acute myocardial infarction and rhythm disturbances is well known. There are certain electrocardiographic findings which are particularly useful to consider when assessing patients with heart failure patients11. Left ventricular hypertrophy, when present, suggests the common etiology of hypertensive heart disease. Low voltage, especially in conjunction with increased left ventricular wall thickness, should raise suspicion for an infiltrative cardiomyopathy such as cardiac amyloidosis12. Left bundle branch block has been shown in numerous studies to be associated with an increased risk of mortality in patients with heart failure and reduced systolic function. In addition, the presence of a left bundle branch block in patients with symptomatic heart failure can identify a subgroup of patients who may respond to biventricular pacing13,14.

3.6. Laboratory Testing Routine laboratory testing provides useful information in assessing the severity of heart failure as well as prognosis. Hyponatremia is consistently identified as a marker for poor prognosis in patients with chronic heart failure. Hypokalemia and hypomagnesemia may be associated with a greater risk of arrhythmias15. Fonarow and others have shown that elevation of the blood urea nitrogen (BUN) and creatinine along with the systemic blood pressure can provide a useful algorithm for predicting mortality in patients hospitalized with acute decompensated heart failure16. The presence of renal insufficiency in ambulatory heart failure patients also confers a worse prognosis. Mild elevation of hepatic enzymes may be associated with

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hepatic congestion while more severely elevated levels are more ominous and may identify early shock liver. Mild elevations of bilirubin and alkaline phosphatase can be seen in patients with heart failure and may wax and wane with the state of volume overload. An elevated BUN to creatinine ratio is sometimes viewed as a sign of volume depletion. However, in patients with heart failure, “prerenal” azotemia may be multifactorial and is equally likely to be a sign of poor effective arterial blood flow to the kidney as is seen in the low CO state as it is of volume depletion from overdiuresis. There is increasing evidence that anemia of chronic disease may increase the risk of hospitalization for worsening heart failure. Even mild anemia (hemoglobin 10–11 mg/dl) may be a risk factor for adverse outcomes, and clinical trials are currently underway to test the safety and efficacy of correcting anemia with erythropoietic agents17. Recently developed assays for B-type natriuretic peptide (BNP), which is secreted by the cardiac ventricles in response to ventricular stretch, may be useful for diagnosis and management of heart failure. Recommendations regarding the use of BNP testing are now integrated into many of the heart failure guidelines. In the Breathing Not Proper Trial, Maisel et al.18 demonstrated the utility of a bedside, point of care assay for BNP. Among patients presenting to the emergency department with dyspnea, the negative predictive value of a BNP level less than 80 pcg/ml was over 95%. Conversely, patients who displayed elevated BNP levels were more likely to have heart failure as an etiology for their dyspnea, although the positive predictive value of an elevated BNP level was lower due to other conditions (e.g., pulmonary embolism) which cause elevation of serum BNP levels. Given the limitations of history and physical examination noted above, the addition of BNP testing to the diagnostic algorithm can improve diagnostic accuracy in the acute setting. A low BNP level virtually excludes heart failure as the cause of dyspnea in patients presenting with this symptom. BNP levels may also be useful in the longitudinal assessment of patients with chronic heart failure. However, while BNP levels correlate with functional capacity and predict mortality, there remains substantial overlap between groups of patients with heart failure. Currently available assays offer point of service testing with results available within

3. Diagnostic Testing and the Assessment of Heart Failure

20 min of a routine venipuncture. BNP levels in the acute assessment of heart failure are limited by the observation that they may increase slowly with decompensation such that patients can present with acute pulmonary edema and a normal BNP level. Mild to moderate elevations in BNP are seen in conditions other than heart failure such as left ventricular hypertrophy, hypertrophic cardiomyopathy, acute pulmonary embolism, or right heart failure with pulmonary arterial hypertension19. In the outpatient clinic, changes in the BNP level over time in individual patients may correlate with relative states of compensated or decompensated heart failure. Lesser elevations may be seen in patients with morbid obesity as the result of impaired ability to release natriuretic peptide and/or increased clearance20.

3.7. Echocardiography Perhaps the single most useful diagnostic test available today for the assessment of cardiac structure and function is echocardiography. Contemporary echocardiography provides an excellent noninvasive means of evaluating valve morphology and function, chamber sizes, wall motion and thicknesses, and ventricular performance. Intracardiac and pulmonary artery pressures can also be estimated. Numerous indices exist for quantifying both systolic and diastolic function. Ejection fraction, the most widely used assessment of ventricular function, should be only a part of the assessment of ventricular performance. Overreliance upon this single parameter as an assessment of heart failure is common. Ejection fraction is associated with prognosis, and clinical studies generally use a cutoff of an ejection fraction of 40% or less to be associated with an increased risk of death from worsening heart failure or sudden cardiac death. However, ejection fraction may be suboptimal to assess patients with ventricular dysfunction on an ongoing basis as it is dependent upon the loading conditions of the heart that may fluctuate substantially. Furthermore, the precise measurement of ejection fraction requires geometric assumptions unless automated border detection software is utilized. Poor acoustic windows will hamper the ability to see the cardiac structures and identify endocardium for the purpose of measuring chamber size.

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A variety of echo contrast agents can enhance the visualization of the ventricle and endocardial border to assess function and screen for left ventricle (LV) thrombus. While ejection fraction is not likely to be abandoned as an index of ventricular function, it is important to recognize other useful measurements when assessing heart failure, especially in patients with a normal ejection fraction. As many as one-half of patients admitted to the hospital with heart failure have preserved systolic function. Diastolic dysfunction is one cause of heart failure with preserved systolic function (HF-PSF), with valvular heart disease and hypertrophic cardiomyopathy examples of other etiologies. Echocardiography can provide a noninvasive assessment of the diastolic properties of the LV and estimate both left ventricular end diastolic and left atrial pressure. Doppler measurements of mitral valve inflow in conjunction with tissue Doppler imaging (TDI) can be used to assess active and passive components of ventricular diastole, thus identifying the subset of patients with HF-PSF who do in fact have diastolic dysfunction as their primary disease process. The presence of pulmonary hypertension can be assessed not only by Doppler measurement of tricuspid regurgitant velocity but also by the presence of right-sided chamber enlargement, right ventricular hypertrophy, or pulmonary artery enlargement. All patients with the diagnosis of heart failure should undergo a complete echocardiographic examination including two-dimensional (2-D) imaging and Doppler evaluation. The Doppler study should include an assessment of valvular disease as well as parameters of ventricular performance and estimate LV filling pressures21.

3.8. Radionuclide Imaging Radionuclide imaging methods are utilized in the diagnosis and management of heart failure in three ways: to determine the presence of coronary artery disease (CAD), evaluate ventricular function, and assess myocardial viability (Table 3.1). Myocardial perfusion imaging (MPI) combined with either exercise or pharmacologic stress testing is a mainstay of the noninvasive assessment for patients with CAD. While this modality has some utility in patients with chronic heart failure,

+ + + + + + ++

CT angiography Electron beam CT

++ +

++

+ + +

+

+

++

+

+

+

+++

++

+

+++

+

++

++

+ +

+

+

++ + (Calcification) +

+

+++

+ ++ ++ +

+

++

+

++ +++ ++

+

Ventricular LV Valvular Intracardiac Ventricular Coronary artery Myocardial function relaxation morphology filling pressures volumes/mass anatomy/disease viability

Right/left heart Angiography Ventriculography

RNA/MUGA SPECT Perfusion

2-D M-mode, Doppler, contrast Tissue Doppler 3-D

Imaging mode

Implanted hardware (PPM, AICD), breath hold, imaging duration, patient isolation

Gated heart rate, radiation, renal insufficiency

Limited availability Renal insufficiency, body habitus, x-radiation, invasive

Arrhythmias, body habitus

Poor acoustic windows, body habitus

Limitations/ contraindications

LV, left ventricle; ECHO, echocardiography; RNA, radionuclide angiography; MUGA, multichannel uptake gated acquisition; SPECT, single photon emission computed tomography; PET, positron emission tomography; CT, computed tomography; CMRI, cardiac magnetic resonance imaging; AICD, automatic implantable cardioverter defibrillator; PPM, permanent pacemaker

CMRI

CT

PET Cardiac catheterization

Radionuclide scanning1

ECHO

Imaging technique

Table 3.1. A comparison of the diagnostic imaging modalities used in heart failure assessment.

52 S.E. Fedson and A.S. Anderson

3. Diagnostic Testing and the Assessment of Heart Failure

regional abnormalities in myocardial perfusion may be seen in patients with nonischemic cardiomyopathy. These abnormalities may reflect abnormal perfusion due to small vessel dysfunction and represent ischemia in the face of “normal” epicardial coronary arteries. Therefore, the specificity of MPI in patients with heart failure is only 40–50%, whereas the negative predictive value of a normal MPI study in heart failure is quite good—in some reports as high as 100%22. Ventricular function can be measured either by tagging the red blood cell pool with an isotope and performing multichannel uptake gated acquisition (MUGA) scanning or by injecting a radioisotope intravenously and monitoring its first pass through the heart in real time with a gamma counter (first pass and equilibrium radionuclide angiography or RNA). RNA is also an effective method to evaluate diastolic function23, LV wall motion, and right ventricular function. MPI with gated single proton emission computed tomography (SPECT) can provide an ejection fraction measurement with routine stress testing. These tests are often perceived as being “the most accurate” means of assessing an ejection fraction, perhaps because they provide an absolute number as opposed to a range or a qualitative assessment of systolic function. However, the presence of significant rhythm irregularities due to atrial fibrillation or frequent extra systoles can limit the accuracy of these measurements22. When radioisotopic tests are compared with echocardiography and even with left ventricular angiography, there is close agreement between the various measurement techniques under ideal conditions for each modality. The acceptance of the data acquired from any of these methods should be with an adequate understanding of the limitations of each technique. Radioisotope scans lack the resolution to provide fine structural detail of the heart. Being highly reproducible, radioisotope methods are also useful for serial measurements of ventricular function, such as monitoring for anthracycline-induced cardiotoxicity during cancer chemotherapy. Assessment of myocardial viability is often performed in patients with ischemic cardiomyopathy and suitable revascularization targets. Hypoperfused myocardial segments are chronically ischemic, displaying potentially reversible contractile dysfunction if proper blood flow is

53

restored. Thallium and technetium imaging or positron emission tomography (PET) scanning with fluorodeoxyglucose uptake coupled with nitrogen-13 ammonia perfusion imaging are common techniques to assess myocardial viability. Thallium and technetium methods have better sensitivity than PET, while PET scanning is more specific22. Newer techniques for assessment of viability include cardiac magnetic resonance imaging (MRI) and PET completed tomography (see below).

3.9. Cardiac Catheterization and Angiography Cardiac catheterization and angiography can also provide important information regarding the structure and function of the heart. It is the task of the evaluating physician to decide the proper balance of invasive and noninvasive techniques to obtain the information necessary to manage the individual heart failure patient. Despite being invasive, the risk of complications from diagnostic cardiac catheterization is quite low (<2%, including interventional procedures). Diagnostic angiography remains the best means for assessing coronary anatomy, and catheterization remains the gold standard for measuring hemodynamics. For many patients, the diagnostic technique provides an immediate assessment of the need for and success of interventional therapies. Determining the presence of CAD is essential in the assessment of patients with heart failure, as coronary disease is associated with worse outcomes. The presence of ischemic territories amenable to revascularization may lead to improved cardiac function and reduced symptoms. The American College of Cardiology/American Heart Association Guidelines identify a Class IIa indication for angiography in the absence of symptoms of angina or ischemia and a Class I indication if coronary disease or angina is present21. An important component of cardiac catheterization in the heart failure patient is the assessment of hemodynamics. While a great deal of information about the hemodynamic status of the patient may be obtained noninvasively with the various techniques already described, the direct measurement of intracardiac pressures, pulmonary artery pressures, systemic and peripheral vascular resistances, and CO often provides additional useful information regarding clinical

54

status, or as a guide to diagnosis or therapy. A variety of retrospective studies have described the “tailoring” of hemodynamics with intravenous and/or oral therapies (such as vasodilators and diuretics) to achieve more optimal hemodynamic parameters—a lower PCWP and/or systemic vascular resistance. Stevenson et al.24,25 demonstrated the use of hemodynamically tailored therapy in patients referred to a tertiary care center for cardiac transplant evaluation. They demonstrated that many patients referred for cardiac transplant do not, in fact, need transplant but rather more optimal medical therapy. The utility of right heart catheterization to achieve optimal hemodynamics is described in these studies24,25. Whether this treatment strategy could alter the outcome of unselected patients admitted to the hospital with heart failure was recently assessed in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE)26. While the results did not demonstrate a mortality benefit or shorter hospitalization, they showed that the invasive approach was safe and resulted in improved symptoms. The assessment of hemodynamics in patients referred for transplant evaluation is necessary because of the potential risk that pulmonary hypertension may compromise the function of the cardiac allograft. Significant pulmonary hypertension is a risk factor for right heart failure following transplantation, and it has been demonstrated that the ability to reverse pulmonary artery pressures with a variety of vasodilators may decrease this risk27. The invasive hemodynamic assessment of patients with right heart failure and precapillary pulmonary arterial hypertension is also well described and is a cornerstone of diagnostic and therapeutic intervention for these patients. Several groups have demonstrated the ability to identify patients who might respond more optimally to medical therapy based on their response to infusion of agents such as intravenous adenosine or epoprostenol, or to inhaled nitric oxide28,29. Response to these drugs may identify a group of patients more likely to respond to oral calcium channel blockers or confirm the need to initiate IV prostaglandin therapy sooner. During the initial assessment of PAH, the direct measurement of Left Ventricular End-Diastolic Pressure (LVEDP) by left heart catheterization is preferred over PCWP when characterizing diastolic function as a potential etiology. The use of pulmonary artery catheterization varies among heart failure programs. Generally accepted practice is to assess patients noninvasively and

S.E. Fedson and A.S. Anderson

initiate therapy based on these findings and resort to more invasive assessment of hemodynamics only when the patient seems to be responding poorly. The ACC/AHA guidelines suggest that catheterization be performed in conjunction with coronary angiography depending upon the clinical suspicion for ischemia. There is a Class I indication for the assessment of volume status, which is usually by physical examination.

3.10. New Imagining Modalities 3.10.1. Computed Tomography Computed tomography (CT) scanning comprises a number of imaging modalities, including SPECT, which are typically categorized under nuclear imaging. Standard CT has two main imaging methods: electron beam CT (EBCT) and multirow detector spiral CT (MDCT). EBCT is the established “gold standard” for assessing coronary artery calcification, when used with electrocardiographic triggering. It has a high temporal and spatial resolution that makes it suitable for noninvasive imaging of the coronary arteries. Accepted sensitivities for detection of CAD are 73–95%, with specificity of 86–95%30. In the setting of heart failure, EBCT and other CT modalities permit the measurement of resting wall motion, myocardial mass, and both left and right ventricular ejection fraction. When compared with other imaging modalities, such as MRI, however, CT measurements tend to overestimate ventricular volumes because of resolution difficulties. The multislice CT is a technologic advancement from EBCT that has less motion artifact because of shorted image acquisition times. However, the imaging time does limit the ability to analyze wall motion. While the technology has improved in this regard, there are still significant limitations in the ability of CT to evaluate time-dependent parameters of LV filling31.

3.10.2. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) is finally evolving into an imaging modality useful to cardiologists. Its utility remains limited in patients who have implanted hardware such as prosthetic valves, cardiac pacemakers, and/or implantable cardioverter defibrillators (ICDs)—a rapidly expanding segment of the heart failure population. MRI is generally accepted to be the best method for assessing the

3. Diagnostic Testing and the Assessment of Heart Failure

right ventricle and diagnosing arrhythmogenic right ventricular dysplasia/cardiomyopathy. It is also considered by some to be the standard for quantification of left ventricular function and mass because there are no geometric assumptions made about the ventricular morphology as in echocardiographic measurements32. In addition, 3-D velocity measurements can be obtained to estimate hemodynamics, valvular regurgitant volumes, and shunts. In the setting of cardiomyopathies, MRI can characterize tissue, such as in the setting of hemachromatosis or sarcoidosis33, and for patients with ischemic heart failure, enhancement with gadolinium can be used to determine myocardial viability.

3.10.3. Impedance Cardiography Thoracic bioimpedance (TBI) is a noninvasive means of assessing hemodynamics and has been most widely applied to patients with heart failure. This technique utilizes the thoracic impedance to a small current to estimate changes in thoracic blood volume. Stroke volume and CO measurements are then derived. Since impedance is affected by total thoracic fluid content, baseline changes in impedance have been suggested to reflect volume status in patients with heart failure. Generally, there is reasonable correlation between CO measurements obtained by thermodilution and bioimpedance34. Utilizing bioimpedance to estimate PCWP is less accurate. This technique of noninvasive hemodynamic assessment is also being utilized in conjunction with the newest generation of ICDs. Preliminary data suggest that tracking daily changes in thoracic fluid content by bioimpedance can identify patients at risk for heart failure hospitalizations. Such technology could have a significant impact on identifying such patients prior to the development of overt symptoms and allow for earlier intervention. These data, which are collected on a daily basis and stored in the device, are available to the practitioner by interrogating the device, either in the office or remotely. The accumulation of day-today information permits more detailed trending and thus overcomes the problem of assessing hemodynamics only during an office visit. Other implantable devices are equipped with software designed to facilitate home monitoring of vital signs, daily weights, and perhaps even medication complications.

55

3.11. Summary The diagnosis of heart failure can be quite challenging, particularly in the acute setting. Assessment of chronic heart failure can be equally difficult. Physical examination skills are declining while physicians seek to apply imaging technologies and other diagnostic tools in an attempt to improve the speed and accuracy of diagnoses; however, these methodologies have limitations as well. A thorough history and a competent physical examination, followed by an electrocardiogram (ECG), basic laboratory studies, and an echocardiogram, remain a sound approach to the initial evaluation of heart failure. These evaluations should be followed by an assessment for CAD and for unusual etiologies of heart failure when the diagnosis remains obscure. The optimal use of noninvasive tools for the management of heart failure remains to be determined, but improved strategies are needed.

References 1. Davis RC, Hobbs FD, Lip GY. ABC of heart failure. History and epidemiology. Br Med J. 2000;320(7226):39-42. 2. Fedson S, Tsuang SW, Lewis EF, et al. At risk for missed diagnosis of heart failure symptoms. J Card Fail. 2004;10(4):S94. 3. Bowles KR, Bowles NE. Genetics of inherited cardiomyopathies. Expert Rev Cardiovasc Ther. 2004;2(5):683-697. 4. Philbin EF, Dec GW, Jenkins PL, DiSalvo TG. Socioeconomic status as an independent risk factor for hospital readmission for heart failure. Am J Cardiol. 2001;87(12):1367-1371. 5. Spencer K, Anderson A, Bhargava A, et al. Physician performed point of care echocardiography using a laptop platform compared to physical examination in the cardiovascular patient. J Am Coll Cardiol. 2001;37(8):2013-2018. 6. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA. 1989;261(6): 884-888. 7. Butman SM, Ewy GA, Standen JR, Kern KB, Hahn E. Bedside cardiovascular examination in patients with severe chronic heart failure: Importance of rest or inducible jugular venous distension. J Am Coll Cardiol. 1993;22(4):968-974. 8. Nohria A, Lewis EF, Stevenson LW. Medical management of advanced heart failure. JAMA. 2002; 287:628-640.

56 9. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. [see comment]. N Engl J Med. 2001;345(8):574-581. 10. Thomas JT, Kelly RF, Thomas SJ, et al. Utility of history, physical examination, electrocardiogram, and chest radiograph for differentiating normal from decreased systolic function in patients with heart failure. [see comment]. Am J Med. 2002;112(6):437-445. 11. Davie AP, Francis CM, Love MP, et al. Value of the electrocardiogram in identifying heart failure due to left ventricular systolic dysfunction. Br Med J. 1996;312(7025):222. 12. Rahman JE, et al. Noninvasive diagnosis of biopsyproven cardiac amyloidosis. J Am Coll Cardiol. 2004;43(3):410-415. 13. Bristow M, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-2150. 14. Cleland J, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-1549. 15. Leier C, Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: Hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J. 1994;128(3):564-574. 16. Fonarow G, et al. Risk stratification for in-hospital mortality in acutely decompensated heart failure. JAMA. 2005;293(5):572-580. 17. Anand I, et al. Anemia and its relationship to clinical outcome in heart failure. Circulation. 2004;110(2):149-154. 18. Maisel AS, McCord J, Nowak RM, et al. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the breathing not properly multinational study. J Am Coll Cardiol. 2003;41(11):2010-2017. 19. Sagnella GA. Measurement and importance of plasma brain natriuretic peptide and related peptides. Ann Clin Biochem. 2001;38(pt 2):83-93. 20. Wang TJ, Larson MG, Levy D, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004;109(5):594-600. 21. Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 guidelines for the evaluation and management of heart failure). J Am Coll Cardiol. 2001;38(7):2101-2113.

S.E. Fedson and A.S. Anderson 22. Klocke FJ, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2003;American College of Cardiology Web Site. 23. Bonow RO. Radionuclide angiographic evaluation of left ventricular diastolic function. Circulation. 1991;84(Suppl 3):I208-I215. 24. Stevenson LW, Dracup KA, Tillisch JH. Efficacy of medical therapy tailored for severe congestive heart failure in patients transferred for urgent cardiac transplantation. Am J Cardiol. 1989;63(7):461-464. 25. Stevenson LW. Tailored therapy before transplantation for treatment of advanced heart failure: Effective use of vasodilators and diuretics. J Heart Lung Transplant. 1991;10(3):468-476. 26. Stevenson LW, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: The ESCAPE trial. JAMA. 2005;294(13):1625-1633. 27. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: Testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol. 1992;19(1):48-54. 28. Morgan JM, McCormack DG, Griffiths MJ, Morgan CJ, Barnes PJ, Evans TW. Adenosine as a vasodilator in primary pulmonary hypertension. Circulation. 1991;84(3):1145-1149. 29. Ricciardi MJ, Knight BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension: A safe and effective agent for predicting response to nifedipine. J Am Coll Cardiol. 1998;32(4):1068-1073. 30. Budoff MJ, Achenbach S, Duerinckx A. Clinical utility of computed tomography and magnetic resonance techniques for noninvasive coronary angiography. J Am Coll Cardiol. 2003;42(11):1867-1878. 31. Mahnken AH, Koos R, Katoh M, et al. Sixteen-slice spiral CT versus MR imaging for the assessment of left ventricular function in acute myocardial infarction. Eur Radiol. 2005;15(4):714-720. 32. Bellenger NG, Burgess MI, Ray SG, et al. Compari son of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance: Are they interchangeable? Eur Heart J. 2000;21(16): 1387-1396. 33. Constantine G, Shan K, Flamm SD, Sivananthan MU. Role of MRI in clinical cardiology. Lancet. 2004;363(9427):2162-2171. 34. Rosenberg P, Yancy CW. Noninvasive assessment of hemodynamics: An emphasis pon bioimpedance cardiography. Curr Opin Cardiol. 2000;15:151-155.

4 Nonpharmacologic Management of Heart Failure Jeffrey A. Spaeder and Edward K. Kasper

Although a variety of prescription treatments have had a dramatic impact upon improving the outcome of people with heart failure, there are a number of nonpharmacologic and non–device-oriented treatments which have been shown to improve clinical outcomes. Disease Management programs, exercise training and appropriate modification of diet, have the potential to decrease the number of hospitalizations and mortality in patients with congestive heart failure (CHF). These interventions have few adverse side effects and have benefits which rival the benefits derived from angiotensin-converting enzyme-inhibitor (ACE-I) therapy. However, lacking commercial backers these therapies have not been aggressively “marketed,” but are nevertheless valuable adjuncts to existing therapy.

4.1. Patient Awareness Unlike acute disease where patients interact with health care providers during a significant proportion of the illness, in chronic diseases like heart failure, patients spend a relatively small proportion of “illness time” in contact with health care providers. Therefore, the burden of health care for patients with heart failure shifts from the health care system to the patient and his or her family. Additionally, since heart failure admissions are often heralded by a change in symptoms, patients can influence further decomposition by accurately detecting these changes and instituting appropriate interventions. This was demonstrated in a study of 83 consecutive patients with documented heart failure who were admitted to an urban hospital and were interviewed

about symptoms that preceded hospitalization. Dyspnea with walking occurred in 89% of patients an average of 8.4 days prior to admission, while edema developed in 77% of patients an average of 12.4 days prior to admission1. In another study involving a chart review of 181 admissions for heart failure during 1 year, increasing dyspnea was documented in 92% of the admissions an average of 3 days prior to hospitalization2. Therefore, patient awareness of symptoms is important in identifying early clinical deteriorations. Unfortunately, a significant proportion of patients are not capable of actively participating in their care. This is highlighted by the fact that 22% of inpatients at an urban hospital admitted for heart failure and at least one prior admission of heart failure were unaware that they had been diagnosed with heart failure1. Similar findings were present in a study of patients in a rural community who were being enrolled into a specialized heart failure clinic or home care agency where 25% of them were unaware of the diagnosis of heart failure3. Lack of awareness of heart failure limits patient participation in their care; however, beyond ignorance of diagnosis, patients exhibit poor understanding of the factors involved in effectively managing their illness. In a study of heart failure patients ready for hospital discharge, only 52% were aware of restricting sodium intake, and only 26% knew the importance of weighing themselves on a regular basis4. Although another study found that 60% of new attendees at a specialized heart failure clinic recognized the importance of regularly weighing themselves, 38% thought that they should drink “lots of fluid”5. In another study of

57

58

139 patients following discharge from a hospital for heart failure or enrollment into a heart failure clinic, 27% of patients did not ascribe much importance to dyspnea at rest, and 50% did not think that a sudden weight gain of 3 lb was important6. However, patients can be trained to be more aware of their symptoms. Wright et al. showed that patient education involving 6-weekly visits to an outpatient heart failure clinic and two group educational sessions augmented with additional clinic visits and telephone follow-up during a 1year period significantly improved the frequency of obtaining self-weight as well as having an action plan in the event of an increase in weight compared with usual care7. Since patient-controlled factors have such a significant impact upon the treatment of heart failure, and given the generalized lack of knowledge about properly treating the illness, it is not surprising that between 42% and 64% of hospitalizations for heart failure are due to nonadherence with the prescribed medical regimen (including diet or medications)1,8,9. This failure by patients to appropriately participate in their care is in large part because most health care delivery systems are optimized to care for patients with acute illnesses requiring episodic care. These systems were not designed to provide the longitudinal, multidisciplinary care with appropriate follow-up, which is essential to properly treat patients with heart failure. For this reason, the concept of Disease Management developed in the 1980s. Initially this concept grew out of the practice of Care Management, which involved outpatient supervision of patients for discrete time intervals by nurses following discharge from a hospital. Although these programs provided patients with greater outpatient care during the early discharge phase during which patients were most at risk for readmission, they were nevertheless episodic in nature.

4.2. Disease Management In the 1980s, it was becoming apparent that a multidisciplinary, longitudinal approach was needed to manage patients with heart failure, and the concept was popularized under the name “Disease Management” by Boston Consulting Group. The concept of Disease Management was to convert the

J.A. Spaeder and E.K. Kasper

care of a patient with a chronic illness from a series of discrete events where each interaction is viewed as the relevant unit of analysis to an integrated approach where the patient’s disease is viewed as the unit of analysis10. In this new approach, communication between various components of the health care delivery system (hospitals, outpatient physicians, pharmacists, etc.) was stressed to optimize guideline-based care for patients. Early Disease Management studies in heart failure incorporated1 intensive patient education,2 individualized discharge planning,3 interdisciplinary communication and optimization of appropriate medications, and4 ongoing evaluation by specially trained nurses11,12. These early studies showed reduced hospitalization in the patients receiving Disease Management following discharge from a hospital admission for heart failure. Rich et al. showed that at 90 days, in patients older than 70 years who were discharged from a hospitalization for CHF, there was a 56% reduction in the number of admissions for heart failure in the Disease Management group compared with the control group (p = 0.04), and a 19% increase in the percentage of patients who did not require any hospitalization during the study period; however, the result was not statistically significant (64.1% in the Disease Management group and 53.6% in the control group p = 0.09)12. Following these initial studies, additional research has been performed, some of which is summarized in Table 4.1. Review of these studies indicates that most of them report improved outcomes; however, the interventions and primary end points are heterogeneous. In an effort to quantify the impact of these various interventions, McAlister et al. performed a systematic review of the published multidisciplinary randomized Disease Management studies in heart failure25. The authors of this study divided the interventions into four general types:1 Multidisciplinary heart failure clinic,2 Multidisciplinary team providing follow-up in a nonclinic setting,3 Telephone (or telemedicine) follow-up with referral to primary care physician if clinical deterioration, and4 Enhanced patient self-care. An example from the analysis of each of these interventions is instructive. 1. Multidisciplinary heart failure clinic—Kasper et al. performed a randomized control study in patients who had been hospitalized with the primary diagnosis of New York Heart Association

N

142

282

97

40

88

200

Author

Naylor et al.11

Rich et al.12

Stewart et al.13

Jerant et al.14

Krumholz et al.15

Kasper et al.16

Intervention

Study duration

6 months

1 year

6 months

18 months

Usual care vs. inpatient edu90 days cation about CHF, diet, optimization of discharge medications, nurse home visits, and telephone contact

Usual care vs. discharge plan2 weeks ning with 2 telephone calls in 2 weeks after discharge

Usual care vs. single postdischarge home visit by a nurse and pharmacist to identify early deterioration and optimize medication treatment Hospitalized patients All participants received two with CHF nurse home visits in 60 days and usual care, bimonthly telephone calls, or monthly video-assisted outpatient monitoring Admission diagnosis Usual care vs. inpatient educaof CHF or evidence tion, home or clinic visit of CHF on admiswithin 2 weeks of discharge, sion radiograph weekly telephone calls for 1 month, then biweekly × 8 weeks, then monthly for 9 months. Patients told to contact physician if clinical deterioration detected Hospitalized patients Monthly clinic visits with a with class III-IV CHF specialized nurse, and CHF telephone calls from a call center: within 72 h of discharge, weekly × 1 month, twice in the second month, and then monthly

Hospitalized patients with CHF

Elderly hospitalized patients with heart failure

Hospitalized patients with congestive heart failure (CHF)

Enrollment population

Table 4.1. Summary of various Disease Management studies. Outcome

Financial outcome

Readmission or death

Readmission or death

43 CHF admissions and 7 deaths in the intervention group compared with 59 CHF admissions and 13 deaths in the control group (p = −0.09)

(continued)

Health care expenses not statistically different between control and intervention

56% of patients in intervention group Hospital costs $6,985 had at least one admission comless per patient pared with 82% in the control (p in intervention = 0.01). Intervention group had a (including programs 39% decrease in total admission expenses) (p = 0.06)

CHF-related medical 84–86% lower mean expenses comexpenses pared with usual care (p = NS), Both interventions equally successful

16% readmission in control vs. 4% in 63% reduction in all intervention (p = 0.02) health care costs in intervention group (includes cost of the program) Survival without 91 of 142 patients in the intervenHospital costs $1,058 readmission tion survived without readmission less per patient in compared with 75 of 140 control the intervention, patients (p = 0.09) which included program costs ($3,236 vs. $2,178, p = 0.03) Frequency of unplanned Intervention group had 64 readmisreadmissions sions vs. 125 in the control group (p = 0.02)

Primary end point Readmission

288

239

338

1,069 Outpatients with docu- Usual care vs. telephonic 18 months mented reduced EF monitoring with care manand symptoms of aged by commercial Disease CHF Management company 462 Review of hospital Predischarge education and then 1 year charts for symptoms regular outpatient telephone and signs of heart calls by nurses who also failure regulated heart failure medications vs. usual care

Goldberget al.20

Naylor et al.21

Atienza et al.22

Galbreath et al.23

1 year

6 months

3 months

Hospitalized patients Usual care vs. predischarge edu- Median with decompensated cation, and clinic visits within follow-up CHF 2 weeks following discharge, 509 days and then every 3 months

Ejection fraction, EF; emergency department, ED.

DeBusk et al.24

216

90 days

Benatar et al.19

Study duration 12 months

287

Intervention

Usual care vs. visit to specialized CHF clinic within 2 weeks following discharge followed by 6-weekly visits alternating between primary physician/CHF clinic and group education sessions 2–6 weeks and 6 months Hospitalized patients Usual care vs. discharge planwith primary or ning, education, telephone secondary diagnosis contact in weeks 1, 2, 3, 4, 6, of CHF 8, 10, and 12 Hospitalized patients Home nurse visits: three visits with diagnosis of in first week, two visits in CHF weeks second and third, and one visit in weeks forth and fifth) vs. home telephonic transmission of vital signs Hospitalized patients Heart failure clinic vs. heart with class III–IV failure clinic plus home telCHF ephonic monitoring of signs and symptoms Hospitalized CHF Three months of nurse-directed, patients > 65 years clinic-based outpatient moniold toring with 8 visits

Enrollment population

Hospitalized patients with primary diagnosis of CHF

Laramee et al.18

N

197

Doughty et al.17

Author

Table 4.1. (continued) Primary end point

Outcome Combined end point was not statistically different; however, there was a 26% reduction in readmission rates (95% CI 0.52–0.96)

46% fewer admissions in telemedicine group vs. home visit group (p < 0.001)

Financial outcome

Rehospitalization rates No difference in rehospitalization rates; however, the telephonic monitoring group had a 56% reduction in mortality (p < 0.003) Time to rehospitaliza- Time to readmission longer in the tion or death intervention group (p = 0.026) and total number of admissions lower in intervention group(104 vs. 162 p = 0.047) Event-free survival 47% event rate reduction in the inter- €2063 per patient vention group (95% CI 29–65; reduction in hospip < 0.001) tal costs (Disease Management costs included) All-cause mortality Intervention group had lower mortal- No reduction in health ity (p = 0.037) and lived ~76 days care costs (cost of longer than the control group. Disease Management not included) Time to rehospitaliza- No statistical difference between tion; and combined groups end point of rehospitalization, ED visit or death

CHF readmissions

All-cause readmission Readmission rate of 37% in both rate groups (p = NS)

Readmission or death

4. Nonpharmacologic Management of Heart Failure

class III-IV due to systolic dysfunction and having a high risk for readmission16. In addition to the patient’s primary care physician, patients randomized to the intervention had a team of three additional health care providers participating in clinical management: a CHF cardiologist, a telephone nurse coordinator, and a CHF clinic nurse. The CHF cardiologist saw patients at baseline and then every 6 months. This physician designed the patient’s treatment plan that was put into operation by a CHF clinic nurse. This nurse saw patients in clinic on at least a monthly basis, and titrated appropriate medications using predefined algorithms. Finally a telephone nurse coordinator contacted patients within 72 h of discharge, then weekly in the first month, twice in the second month, and then monthly unless a problem occurred which required more frequent follow-up. Clinical problems not rectified during a phone call were referred to the CHF clinic nurse for a potential face-to-face visit. 2. Multidisciplinary team providing specialized follow-up in nonclinic setting—Naylor et al. evaluated all hospitalized patients over the age of 65 who were admitted with the diagnosis of heart failure21. An advanced practice nurse visited the patient at home within 24 h of discharge, then weekly in the first month, and then biweekly during the second and third months after discharge. The advanced practice nurses assisted in discharge planning, then evaluated patients for evidence of clinical deterioration, and worked through the patient’s primary care physician to make appropriate changes in therapy. 3. Telephone follow-up and attendance with primary care physician if clinical deterioration—Riegel et al. enrolled patients who were hospitalized with the primary cause being heart failure26. Patients were called by registered nurses within 5 days following discharge, and then on a decreasing intensity basis as recommended by a decision-support software which also guided the nurses about clinical priorities and frequency of telephone contact. Patients received an average of 17 calls over 6 months of study enrollment. Additionally automated reports generated by the decision-support system were sent to physicians on a monthly basis. Any changes in therapy were deferred to the physician. 4. Enhanced patient self-care—Jaarsma et al. enrolled patients aged 50 years or older who had

61

been admitted to a cardiology service with the diagnosis of heart failure27. These patients were given intensive, systematic education CHF prior to discharge by a nurse. This was supplemented by a home visit 1 week after discharge where this education was reinforced. Following this visit, patients were instructed to contact their cardiologist in the event of difficulties. The analysis performed by McAlister in Table 4.2 shows that there is an overall positive effect of the combined Disease Management programs upon all-cause mortality, all-cause hospitalization, and heart failure hospitalization rates. However, it appears that clinic-based multidisciplinary CHF programs have more of a mortality benefit than (in decreasing order of effectiveness) non–clinic-based multidisciplinary, telephone-only outpatient monitoring, and enhanced self-care Disease Management programs. Unfortunately, such clinic-based programs are resource intensive and have been implemented mainly in academic medical settings with established heart failure programs that have access to specially trained personnel and a large potential patient base. Telephone follow-up programs are more easily deployed and have greater efficiencies than multidisciplinary clinic and non–clinic-based Disease Management programs. It is for this reason that a variety of commercial entities have attempted to pursue this form of Disease Management strategy. However, McAlister’s analysis and three studies in 2003–2004 question the efficacy of these telephone-only programs. In an 18-month study by Galbreath et al., 1,069 patients with both systolic and diastolic heart failure were identified from health care databases23. Patients were randomized to either usual care or decreasing frequency telephone calls (initially weekly and then monthly) from a commercial Disease Management vendor with data from each call forwarded to the patient’s primary care physician (PCP) along with recommendations generated by a proprietary management protocol. Patients in the Disease Management intervention had a lower mortality rate (p = 0.037), which translated into a modest prolongation of life span by 76 days. Although the benefits of Disease Management were more apparent in patients with systolic heart failure and NYHA class III or IV CHF, there was no evidence of reduced cost. In this study, 30% of

62

J.A. Spaeder and E.K. Kasper

Table 4.2. Effect of various Disease Management interventions26. Type of intervention Multidisciplinary heart failure clinic Multidisciplinary team providing follow-up in nonclinic setting Telephone follow-up with referral to primary care physician for deterioration Enhanced patient self-care Total

All-cause mortality

All-cause hospitalization Heart failure hospitalization rates

0.66 (0.42, 1.05)

0.76 (0.58, 1.01)

0.76 (0.58, 0.99)

0.81 (0.65, 1.01)

0.81 (0.72, 0.91)

0.72 (0.59, 0.87)

0.91 (0.67, 1.29)

0.98 (0.80, 1.20)

0.75 (0.57, 0.99)

1.14 (0.67, 1.94) 0.83 (0.70, 0.99)

0.73 (0.57, 0.93) 0.84 (0.75, 0.93)

0.66 (0.52, 0.83) 0.73 (0.66, 0.82)

the patients had diastolic heart failure, and only 22% and 3% of the patients had NYHA class III or IV heart failure, with 60% of the patients receiving ACE-I at study enrollment. DeBusk et al. performed a similar study in 462 patients who were identified upon review of charts of patients who were hospitalized with shortness of breath and had physical examination signs or radiological findings consistent with heart failure24. Patients were randomized to usual care or a Disease Management program. The program involved a 1-h in-hospital videotape, printed educational material, and then weekly nurse telephone calls for 6 weeks, biweekly for 8 weeks, monthly for 3 months, and then bimonthly for 6 months. After 1 year of evaluation, there was no difference in all-cause hospitalization between the two groups [proportional hazard, 0.98 (95% CI 0.76–1.27)], and there was no difference in time to first rehospitalization for heart failure. Etiology of heart failure was unknown in this patient population, and only 59% had a study to document left ventricular (LV) systolic function, which was nearly evenly divided between an ejection fraction (EF) less than or greater than 0.40, with 50% of patients having NYHA class II-IV heart failure. By the end of the study, 88–90% of patients were on an ACE-I. In the WHARF Study20, patients with NYHA class III (75%) or IV (25%) heart failure and EF < 35% were recruited from outpatient cardiology heart failure programs and were randomized to continued heart failure care or existing heart failure care augmented with a telemedicine device which transmitted the patient’s weight and responses to questions about symptoms to a centralized facility which was

monitored by a cardiac nurse employed by the vendor of the telemedicine device. Patients were requested to utilize the home monitoring system twice a day. Increases in weight or change in symptoms prompted the nurse to contact the patient’s cardiologist who specialized in heart failure treatment. After 6 months, there was no difference in hospitalization rates, which was the study’s primary end point; however, there was a 56% reduction in mortality (p < 0.003) with the telemonitoring. At enrollment, 73–74% of patients were receiving an ACI-I. It is not clear why these three telephone-followup studies did not show the same effect as the prior clinic-based studies. Certainly the physical interaction between a patient and a health care provider may be critical for building trust and in performing a thorough patient evaluation, which may be lacking in telephone-only interactions. However, as seen in Table 4.3, it is striking that the recent telephone-only studies have a much lower event rate than the older clinic-based interventions. Some commentators have suggested that this lower event rate is due to increased usage of ACE-I; however, several clinic-based studies had very high ACE-I treatment and still showed a positive outcome with intervention. Therefore, it is likely that recruitment of patients with lower risk of rehospitalization may account for the lower event rate, which, in turn, may have made the effects of Disease Management less significant. Alternatively, the lack of integration between health care providers who monitor the patients and those who make medication changes may have been the cause for less intensive outpatient management. In both the study by Galbreath and the WHARF Study, the patient’s primary

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Table 4.3. Severity of congestive heart failure in various Disease Management studies. % Class III–IV (or average class)

Study 12

Rich et al. Stewart et al.13 Kasper et al.16 Doughty et al.17 Krumholz et al.15 Goldberg et al.20 Galbreath et al.23 DeBusk et al.24

NR 25% 59% 100% NR 100% 24% 50%

Readmission rate during study in control group 0.67, 90 days 2.6, 18 months 1.11, 6 months 1.84, 12 months 1.82, 12 months 0.2, 6 months NR 1.02, 12 months

% on ACE-I or ARB

% EF < 45%

Average EF

59 40 95 89 60 74 73 NR

NR NR 87 NR NR 70 100* 28a

42 39 NR 32 38 NR NR NR

a EF < 40%. Ejection fraction, EF; angiotensin-converting enzyme-inhibitor, ACE-I; angiotensin receptor blocker, ARB

physician was notified of changes in the patient’s health, but any change in therapy was left with the physician. Resistance by physicians to taking “orders” from a call center or concern about adjusting medications remotely may have kept physicians from acting upon treatments suggested by health care providers who were monitoring the patients as part of the Disease Management program. The importance of correctly identifying high-risk patients for enrollment into a Disease Management program is underscored by economic considerations. As shown in Table 4.1, most studies that evaluate cost show that Disease Management interventions reduce medical expenditures when clinical outcomes are improved, even when accounting for the cost of the program. However, the positive results are observed most frequently in highrisk populations, whereas studies performed in a lower risk population, which have lower baseline costs, are less likely to have an impact upon health care costs. This was reinforced by a study by Riegel et al.28 in which total health care costs were 288% higher in patients with NYHA class I CHF who received multidisciplinary Disease Management program compared with patients who received usual care. The authors speculated that the improved access to care in this relatively asymptomatic patient population may have resulted in the increased medical expenditures. However, in the same study, patients with class II CHF had a trend toward lower costs with Disease Management intervention compared with usual care. This again illustrates the importance of identifying and enrolling patients into Disease Management programs who are at high risk for future medical expenses.

Since hospital readmission is the largest cost driver in CHF, identification of patients who are at high risk for readmission is important. Clinical criteria in hospitalized patients, such as prior admission within the past year, prior diagnosis of heart failure, diabetes, and creatinine level > 2.5 mg/dl, have been shown to be associated with increased readmission29. Identification of high-risk patients can also be performed using administrative data and diagnosis-based case-mix measures such as Adjusted Clinical Groups or Diagnostic Cost Groups30,31. Use of either appropriate clinical predictors or analysis of administrative data will likely identify patients who are at high risk for readmission, who would likely therefore benefit from enrollment into a Disease Management program. It has long been assumed that by reducing CHF hospitalizations, Disease Management programs primarily improve outcomes by reducing heart failure admissions, which are the largest drivers of cost. In fact multiple studies in high-risk patient populations do show a reduction in CHF-related admissions; however, there is evidence that heart failure itself is far from the only cause for readmission. As seen in Table 4.4, even in patients who are at high risk for readmission, only 40–60% of subsequent hospitalizations are due to heart failure, with only approximately a third of admissions in low-risk patients due to heart failure. Ischemic heart disease, arrhythmias, renal or metabolic disorders, infectious diseases, and peripheral vascular disease are common comorbidities in CHF and have been shown to contribute to rehospitalizations24. This is not surprising since heart failure is a common end pathway for a variety of other

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J.A. Spaeder and E.K. Kasper Table 4.4. Cause for readmission in various Disease Management studies. Study

% of readmissions due to CHF in control

% of readmissions due to CHF in intervention

58 42 61 53 77 37 30 51

45 30 48 45 45 32 n/a 41

Rich et al.12 Doughty et al.17 Atienza et al.22 Krumholz et al.15 Kasper et al.16 DeBusk et al.24 Babayan et al.32 Average congestive heart failure, CHF.

diseases, and the development of heart failure does not cease the ongoing progression of these illnesses. Therefore, programs that concentrate solely on management of heart failure to the exclusion of other disease processes ignore comorbidities which will significantly influence etiologies of future hospitalizations. Therefore, effective Disease Management programs not only need to prospectively identify patients at high risk for future hospitalizations but must also address the patient’s comorbidities in addition to heart failure. Education and longitudinal feedback are essential components as well as close outpatient monitoring. This has been achieved in multidisciplinary heart failure programs where the health care providers monitoring the patients can rapidly effect medication changes. However, it is difficult to replicate these programs outside of academic medical centers. Therefore, the future of Disease Management in heart failure will rely on extracting the beneficial components of existing Disease Management programs and making them more accessible. The use of the internet as well as automated telemedicine systems33 will likely play a role in this development. Additionally, with an increasing number of patients receiving implantable devices, it is conceivable that data from these devices may enable real-time physiologic data collection, medication manipulation, and identification of clinical deteriorations. However, in spite of the potential new methods of obtaining data from patients, it is unlikely that future Disease Management programs that take advantage of these new forms of outpatient monitoring will succeed unless they are integrated seamlessly into the usual delivery of care to patients by their physicians. For

this reason, Disease Management programs that separate patient monitoring and education from medical management are unlikely to be successful. However, convincing physicians to be active participants in delivery of medical care in such a new method is likely to be resisted for several reasons. First, it involves a new paradigm of medical care which is based on proactively preventing clinical deteriorations rather than reacting to medical problems. Second, physicians may feel that they are being asked to provide care that is uncompensated. Third, the logistics of conveying outpatient data to physicians will require a robust information technology infrastructure. These potential obstacles may be overcome with incentives which reward physician participation in these programs and developing robust information technology interfaces which reduce the paperwork and improve the efficiency of interacting with these systems.

4.3. Exercise Despite the lack of evidence, it was a common supposition into the 1980s that patients with heart failure should be restricted from strenuous physical activity or exercise rehabilitation programs34,35. This was based on the prevailing assumption that “Heart failure denotes an inability to maintain an output adequate for the needs of the body. Those needs can be minimized by eliminating physical activity.”36. As a result, bed rest was commonly advocated for most heart failure patients and strict confinement to bed with the exception of a bedside commode was prescribed for those with advanced heart failure36. However, beginning in the late

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1970s and continuing into the 1980s, small uncontrolled clinical studies suggested that exercise was not harmful and might actually have physiologic benefits. Finally, Coats’ randomized cross-over study in 1990 showed increased exercise duration and peak oxygen consumption following exercise, which culminated in the statement that “The commonly held belief that rest is the mainstay of treatment of heart failure should no longer be accepted.”34. If fatigue and dyspnea on exertion are due entirely to inadequate cardiac output, then the historical admonition against exercise would be appropriate. However, it has been well established that there is little correlation between exercise capacity and left ventricular function37,38. Furthermore, although central hemodynamic parameters can be rapidly improved with appropriate medications, exercise tolerance is only modestly improved acutely, whereas long-term use of these medications results in significantly improved exercise capacity39-41. These findings suggest that systolic function and acute changes in cardiac output are mediated by other factors that determine a person’s exercise capacity. Because total muscle mass in noncachectic CHF patients predicts peak oxygen consumption, the peripheral skeletal muscles likely contribute to the development of fatigue in heart failure42–44. Biopsies of skeletal muscle in patients who have heart failure show increased intracellular lipid accumulation and decreased percentage of aerobic slow-twitch type I fibers and an increase in the percentage of fast-twitch, anerobic type IIb fibers45-47. On a molecular level, the percentage of skeletal muscle myosin heavy chain (MHC) isoenzyme MHC I is decreased in patients with CHF48, whereas increases in the percentage of MHC IIa (fast oxidative) and MHC 2b (fast glycolytic) are associated with the severity of heart failure49. Because daily physical activity is reduced in patients with CHF50, it is tempting to ascribe these changes in muscle structure to disuse or deconditioning. However, the myopathy observed in disuse atrophy is distinctly different from that seen in CHF51. The skeletal muscles in patients with CHF have impaired metabolism that is not explained by the blood flow to the muscles52,53. When compared with aerobically-matched sedentary men, males with CHF have lower oxidative enzyme 3-hydroxyl

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coenzyme A dehydrogenase activity, whereas such differences were not seen in sedentary women and females with CHF54. Additionally, skeletal muscles in CHF have mitochondrial volume density that is significantly lower than that of normal muscles47. This reduced oxidative capacity of skeletal muscle observed in CHF combined with the shift in MHC isoenzyme to a less efficient utilization of energy stores, resulting in earlier depletion of muscle phosphocreatine and increased formation of lactic acid compared with normal subjects55-59. Therefore, independent of blood flow to skeletal muscles, in CHF these muscles utilize oxygen less efficiently and are more prone to develop lactic acid. Although the mechanism by which CHF induces these changes in the skeletal muscles is unknown, possible etiologies include chronically reduced “nutritive” blood flow60, decreased oxygen supply of the microcirculation due to decreased capillary density per muscle fiber61, or an inability of the muscular vasculature to vasodilate during exercise62. Increased levels of endothelin63, other mediators of increased sympathetic tone64, or decreased endothelium-dependent vasodilation65 may be responsible for this impaired skeletal blood flow. Additionally, increased levels of cytokines, tumor necrosis factor α (TNF-α) and IL-6, which are increased in CHF, have been postulated to promote loss of skeletal muscle mass and cachexia66. Although increased acidosis at the level of the skeletal muscles may explain the symptom of muscle fatigue, whether this increased acidosis supplies sufficient respiratory drive to cause the symptom of breathlessness is debatable. However, both symptoms occur at nearly the same level of ventilator response to CO2 production, leading some authors to equate them as “two sides of the same coin”67, and there is evidence to indicate that ergoreceptors, intramuscular afferent nerves which are sensitive to metabolic products of skeletal muscle work, may directly contribute to increased ventilatory response68. Although exercise increases the demand for blood supply to skeletal muscles that could potentially “overtax” the supply of cardiac output in a failing heart, exercise also has many potential benefits which can reverse the maladaptive skeletal muscle and peripheral vascular changes described above. Forty minutes of exercising at

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70% of predicted maximum heart rate in patients with class II-III heart failure resulted in a 41% increase in the surface density of cytochrome c oxidase positive mitochondria, and an increase in the percentage of type I muscle fibers69. It has been shown that 20 min of daily exercise using a bicycle ergometer in patients with class II-III CHF results in significantly reduced local skeletal expression of the inflammatory markers TNF-α, IL-6, and inducible nitric oxide synthase70. Bicycle ergometery training in patients with class II-III CHF also improved endothelial dysfunction, although the effects appear to be limited to the exercised extremity71. Thirty to forty-five minutes of exercising at Vo2 peak in patients with class II-III CHF for 16 weeks has also been shown to reduce resting levels of angiotensin, aldosterone, vasopressin, and atrial natriuretic peptide by 26–32%72, and 6 min of combined bicycle, strength training, and stretching three times a week in patients with class II-III CHF dramatically reduces muscle sympathetic nerve activity, which is a measure of sympathetic activation73. Home bicycle ergometer training has also been shown to correct the impaired oxidative capacity of skeletal muscle described in CHF74. Although these effects might be due to improved myocardial function, isolated exercise of calf muscles for 24 min five to seven times a week resulted in improved oxidative capacity of the calf muscles by P-31 MRI spectroscopy without increased calf blood flow75. Furthermore, in patients with dilated cardiomyopathy, combined aerobic and strength training improves muscle glucose uptake by 55% (p < 0.05), which is independent of changes in muscle perfusion, and suggests that the training improves insulin sensitivity of the skeletal muscles76. This suggests that exercise has effects directly upon skeletal muscles that reverse some of the maladaptive processes observed in CHF. Not only does exercise improve the efficiency of skeletal muscles in heart failure, but it also appears to improve the efficiency of the left ventricle. In a study of 16 patients with mild (mean NYHA class 1.2–1.6) idiopathic dilated cardiomyopathy, participants were divided into a control group and an exercise group based on proximity to the training center. The nine training patients used an incremental cycle ergometer with an initial intensity of 50% peak oxygen consumption increasing to a goal of 70% peak oxygen consumption performed three times

J.A. Spaeder and E.K. Kasper

a week for a duration of 45 min with resistance training added 4 weeks after enrollment, which was augmented by home exercising two times a week77. After 5 months, the exercise group demonstrated statistically significant increased ejection fraction, decreased end-systolic diameter, reduced biventricular oxidative metabolism, and improved forward work efficiency compared to the nontrained group. This finding was reinforced in a study of patients under the age of 70 who had stable heart failure due to systolic dysfunction (mean EF 27%) and underwent bicycle ergometer exercise 20 min a day to a target heart rate corresponding to 70% peak oxygen consumption78. After 6 months of exercise, EF in the trained group had a small but significant improvement in stroke volume at rest and exercise due to a decrease in end-diastolic volume and significant reduction in peripheral resistance compared with the control group. Aerobic exercise has also been shown to improve left ventricular filling in patients with dilated cardiomyopathy and abnormal LV relaxation79. A number of studies have been performed to investigate the clinical effects of exercise training in CHF. Although several of these studies have enrolled over 100 patients, most are relatively small, with an average of only 30 subjects80. Many, but not all, of these studies report some form of physiologic improvement; however, one study with a negative result bears special mention. Jugdutt et al. studied 13 patients who underwent 12 weeks of exercise training, which started 15 weeks following an anterior transmural myocardial infarction81. Following exercise training, EF decreased from 43% to 30%, with the effects most pronounced in severely impaired LV function. However, subsequent studies have shown that patients with large myocardial infarctions derive greater benefit from exercise than patients who have small- or medium-sized infarcts82. Although the small size of the exercise studies in CHF makes the improvement reported by them less convincing, systemic analysis of their results has been performed by several investigators. Smart and Marwick reviewed 81 studies which enrolled a total of 2,387 patients80. In studies in which peak oxygen consumption was measured, aerobic training resulted in a 17% increase in Vo2 peak, whereas only 9% increase in patients who underwent strength training alone was seen. Importantly in Smart and Marwick’s analysis, there were no

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reported deaths directly related to exercise during the more than 60,000 patient-hours of exercise, and a nonsignificant reduction in the combined end point of deaths or adverse events in patients who exercise (56 combined events vs. 75 combined events OR 0.98; 95% CI 0.61–1.32 p = 0.60). A meta-analysis by the ExTraMATCH Collaborative Group of exercise studies in CHF in which data sets were obtained from the investigators resulted in a study population of 801 patients83. In this analysis with a mean follow-up of 705 days, exercise training significantly reduced mortality (hazard ratio 0.65; 95% CI 0.46–0.92). The combined end point of death or hospitalization was also reduced by exercise training (hazard ratio 0.72; 95% CI 0.56–0.93). Given the results from the ExTraMATCH Group as well as Smart and Marwick, it appears that exercise therapy in CHF not only has biochemical benefits but also demonstrable clinical and mortality benefits. However, several caveats must be mentioned. First, the mean age of the patients in the studies evaluated in the ExTraMATCH analysis was 60.5 years, which is younger than the typical patient with CHF. Gottlieb et al. studied a 6-month graded exercise program in 33 elderly patients, and found that in the 17 randomized to exercise, 6 patients (35%) were unable to tolerate the exercise program, and in those who did, there was a modest improvement in peak oxygen consumption (2.4 = /−2.8 m:/kg/min p < 0.05) and improved 6-min walk (194 ft p < 0.05); however, there was no difference in quality of life as measured by the Minnesota Living with Heart Failure Questionnaire84. Owen et al. studied the effects of exercise in a cross-over study with 31 patients with an average age of 81 years. Only 11 of the 19 patients who underwent exercise training were able to complete the 12-week intervention in which patients exercised on a weekly basis on six exercise machines that alternated between stamina and strength training85. In those able to complete the intervention, 6-min walk increased 20% (p < 0.012); however, there was no statistically significant effect upon quality of life metrics. Therefore, although there is evidence that exercise training may have benefit in the elderly, long-term compliance may be more difficult and its effects less pronounced than in younger patients. In addition to the unresolved magnitude of benefit in elderly patients, it is difficult to separate

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what effect frequent interaction with health care providers who are present at exercise training centers might have upon the improved health compared with the effects of the exercise itself. Additionally, whether such benefits will extend to patients with class IV CHF is unknown. Finally, the optimal intensity, duration, and frequency of exercise is still also unknown; however, these questions should be answered by a study performed by the National Heart, Lung, and Blood Institute named “Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing” (HF-ACTION), which is a multicenter trial that will randomize 3,000 patients with EF < 35% and NYHA class II-IV CHF. However, pending the results of HF-ACTION, clinicians currently face the question about starting exercise therapy in patients with CHF. On the basis of the biochemical, physiologic, and clinical evidence, the Committee on Exercise, Rehabilitation, and Prevention of the American Heart Association Council on Clinical Cardiology concluded that exercise training in patients with heart failure appears to be safe and have an overall benefit in improving exercise capacity, exercise duration, and quality of life86. Although the optimal form, intensity, and duration of exercise for patients with CHF has not been determined, most positive studies had the following components: 1. Treadmill, stationary bicycle, or other aerobic exercise to achieve 70–80% of peak oxygen consumption, although for deconditioned patients, initial intensity of 60–65% may be required. Telemetry monitoring is prudent during initiation of exercise program (first 6–12 sessions87 ), but after establishing clinical stability, the exercise can be transitioned to the home. 2. Warm up of at least 10 min with stretching to reduce the risk of musculoskeletal injury followed by 20–30 min of exercise followed by a cooldown period. 3. Exercise frequency: three to five times a week. Despite the benefits of exercise and encouraging exercise effort from patients, exercise should be halted in patients87 1. whose systolic blood pressure persistently drops below baseline despite an increase in workload; 2. with increasing angina;

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3. with central nervous system symptoms (ataxia, dizziness, syncope); 4. with serious arrhythmias; 5. with signs of poor perfusion; and 6. who request to stop. Additionally, respiratory distress, significant fatigue or supraventricular tachycardias, or excessive ST or QRS changes would be relative indications to halt exercise. Although it is unknown when the maximal effects of exercise therapy in CHF is achieved, it appears that the beneficial effects are cumulative, and do not peak before 16 weeks. For example, in a study of 134 patients, peak Vo2 was greater after 16 weeks of supervised training than after 6 weeks88. Additionally, it appears that exercise training needs to be continued to maintain its benefit, and that 6 months after terminating exercise training, there is no sustained benefit89. Most exercise training in CHF has been achieved with aerobic exercise. Because of the concern about increasing systemic vascular resistance, strength or resistive training has been discouraged. However, in patients with stable CHF, EF remains stable during resistance exercise90. More invasive hemodynamic assessments in patients with EF < 30% and a mean peak oxygen consumption of 16.6 ml/kg/min who had stable CHF during resistive leg press at 80% of maximum voluntary contraction reveal that systemic vascular resistance actually decreases while cardiac stroke work index increases during resistance training. Studies of resistance training in patients with CHF have also shown that strength and type I skeletal muscle fiber area increases as does 6-min walk and peak oxygen consumption91,92. The resistance exercises in these studies usually include seated leg press, knee flexion, chest press, tricep extension, and bicep flexion with alternation between upper and lower body exercise. Although the optimal resistance exercise regimen has not been identified, the current American Heart Association statement regarding resistance exercise in patients with cardiovascular disease recommends that resistance training be performed two to three times per week with a goal of 10–15 repetitions per exercise with weight increasing 5% once 15 repetitions are achieved87. Finally, many patients with CHF are unable to tolerate aerobic or strength training exercise

J.A. Spaeder and E.K. Kasper

programs. For this reason, there has been interest in electrical stimulation of skeletal muscles in patients unable to tolerate more traditional exercise programs. Long-term titanic contraction of thigh muscles in patients with refractory CHF has been shown to be safe and improve muscle strength; however, such therapy may be unpleasant93. For this reason, chronic low-frequency electrical stimulation has been investigated. In one study, lowfrequency electrical stimulation was shown to improve peak oxygen consumption, increase type I isoenzyme isoform expression, and increase citrate synthase activity94. Whether such direct stimulation of the skeletal muscles will play an important role in the future of CHF treatment has yet to be determined. However, it appears that more traditional aerobic and strength training can be significant therapies in the treatment of CHF.

4.4. Diet A patient’s diet is one of the components of heart failure management that is entirely under the patient’s control. Restriction of sodium intake has long been advocated, and there is evidence that increasing protein intake may be of benefit; however, supplements such as creatine, coenzyme Q10, and vitamin E provide no benefit.

4.4.1. Sodium Underfilling of the arterial vascular system due to reduced cardiac output results in decreased sodium and water excretion95. Activation of the reninangiotensin system in heart failure and impaired release of atrial natriuretic peptide in response to sodium diet are thought to result in enhanced proximal renal tubular absorption of sodium even in a euvolumic state96. It is this avidity of sodium reabsorption that is thought to lead to edema and pulmonary edema when patients consume large amounts of sodium. Between 22% and 57% of admissions for heart failure are ascribed to excessive sodium intake8,97,98. As a result, moderate sodium restriction is recommended in heart failure with a 2 g sodium restriction in patients with severe heart failure99,100. Despite the fact that sodium restriction in heart failure is intuitive, there has never been a study

4. Nonpharmacologic Management of Heart Failure

examining the impact of a low-sodium diet on clinical outcomes in patients with heart failure. In fact, there is data to suggest that in patients with mild-moderate, stable heart failure, a 15-day lowsodium diet results in decreased weight and lower blood pressure, and there is an increase in the activity of the renin-angiotensin aldosterone system, which is postulated to be a counter-regulatory process induced by volume depletion101. However, notwithstanding caveats regarding the potential acute effects upon the neurohormonal activity in heart failure patients, chronically elevated sodium intake likely requires increasingly higher doses of diuretics, which may lead to hypertrophy and hyperplasia in the epithelial cells of the distal renal convoluted tubule, which blunts the effects of diuretics and potentially leads to diuretic resistance102. Therefore, sodium restriction may allow for lower doses of diuretics, which, in turn, may decrease the risk of developing diuretic resistance. Sodium restriction may also promote the effects of some ACE-I103.

4.4.2. Protein and Caloric Intake Wasting and weight loss are common in nonobese patients with heart failure. Elevated circulating levels of tumor necrosis factor, increased resting metabolic rate, and inadequate caloric intake are potential causative factors104–107. This negative nitrogen balance has prompted several authors to suggest that caloric intake guidelines be increased in nonobese patients with heart failure105,107, with Aquilani et al. suggesting the following daily nutritional recommendations to prevent muscle wasting: 1. Wasted patients: 31.8 kcal/kg + 1.37 g protein/kg 2. Normally nourished patients: 28.1 kcal/kg + 1.12 g protein/kg 3. Obese patients: 24.3 kcal/kg

4.4.3. Supplements In addition to prescription medications, many patients with heart failure ingest nonprescription medications. In a study published in 1999 from an ambulatory heart failure clinic in Alberta, Canada, 82% of CHF patients and 79% of control patients reported using nonprescription medications at least once a week108. Patients only report half of these

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nonprescription medications on written questionnaires but more readily admit to such use during structured interviews109. This mirrors our anecdotal experience and for this reason we explicitly query CHF patients about all nonprescription medications and supplements during clinic visits.

4.4.3.1. Creatine Creatine is a naturally occurring compound found in meat and fish and is also synthesized in the liver. At rest, creatine phosphokinase converts creatine to phosphocreatine through phosphorylation of ATP to ADP. However, when ATP stores are depleted, phosphocreatine acts as a buffer to maintain ATP concentrations by rephosphorylation of ADP. In patients with stable heart failure, supplementation with 20 g of creatine a day improved leg muscle endurance 10–20%110, whereas another study found that daily supplementation with 20 g improved exercise endurance only at near maximal workloads, but not at less strenuous levels of exertion111. These studies evaluated short-term supplementation and the effects of longer-term treatment are unknown. Additionally several researchers have raised the possibility that in the acidity of the stomach, creatine might develop N-nitrososarcosine which has been shown to be a carcinogen in animal models112.

4.4.3.2. L-Arginine Patients with heart failure have endothelial dysfunction. l-arginine is an amino acid that can be converted to nitric oxide by nitric oxide synthase. Nitric oxide, in turn, is a major component of endothelium-derived relaxing factor, which is important in flow-dependent vasodilatation. Intravenous infusion of l-arginine significantly reduces systemic vascular resistance and improves stroke volume113. Oral supplementation with 5.6– 12.6 g/day of l-arginine for 6 weeks resulted in significantly improved forearm blood flow during exercise and an increase of 32 m during 6-min walk compared with placebo114. Long-term efficacy and safety are yet unknown.

4.4.3.3. L-Carnitine Carnitine is an essential cofactor in the intermediary metabolism of fatty acids. Because oxidized fatty

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J.A. Spaeder and E.K. Kasper Table 4.5. Comparison of exercise and disease management with ACE-I therapy. Intervention ACE-I127 Disease Management25 Exercise83

Mortality 0.74 (95% CI 0.66–0.83) 0.83 (95% CI 0.70–0.99) 0.65 (95% CI 0.46–0.92)

Heart failure hospitalization 0.74 (95% CI 0.63–0.85) 0.73 (95% CI 0.66–0.82)

Angiotensin-converting enzyme-inhibitor, ACE-I.

acids are the primary substrate for cardiac muscle, carnitine deficiency can impair cardiac function. Because myocardial carnitine levels are reduced in a variety of cardiomyopathies115, carnitine supplementation has been advocated as a potential therapy. In unblinded studies, carnitine supplementation (500 mg TID for 2 weeks) resulted in increased exercise capacity and peak oxygen consumption116. In a randomized study involving 70 patients who received either 2 g/day of carnitine or placebo, supplementation resulted in a statistically significant reduction in mortality at mean of 34 months of treatment117. However, this small study has not been replicated. Carnitine has also been shown to prevent skeletal muscle apoptosis in rats118. Long-term safety of carnitine has not yet been evaluated.

following development of a cardiomyopathy has been shown to result in a significant improvement of LV systolic function124 and fewer cardiac deaths than continued consumption of alcohol125. However, recent studies indicate that the improvement of LV systolic function is similar between compete abstinence and moderate alcohol consumption of up to 60 g/day126. This should not be viewed as encouragement to continue abuse of alcohol, but does suggest that well-controlled alcohol intake may not be detrimental to LV systolic function in patients who developed cardiomyopathy due to alcohol abuse. Whether alcohol intake of up to 60 g in patients with cardiomyopathy due to other causes is also safe is yet unknown.

4.5. Summary 4.4.3.4. Antioxidants The use of vitamin E is common in patients with CHF and 31% of patients report utilizing vitamin E at least once a week108. However, controlled clinical trials utilizing 500 I.U. of vitamin E for 12 weeks did not improve biochemical markers of oxidative stress or neurohumoral prognostic markers119. Additionally, meta-analysis of high dose (> 400 I.U./day) of vitamin E has been shown to increase all-cause mortality120. Therefore, in the absence of a compelling indication, high-dose vitamin E supplementation should not be advocated for patients with CHF. The antioxidant coenzyme Q10 is also commonly used by patients with heart failure, but results from randomized trials do not indicate that it has any significant physiologic effect121,122. Therefore, there is no convincing reason for CHF patients to be taking supplemental coenzyme Q10.

4.4.3.5. Alcohol Chronic alcohol abuse is a known cause of cardiomyopathy123. Complete abstinence from alcohol

Despite the advances in pharmacologic and devicebased treatment of heart failure, there are a variety of other measures that can benefit people who have heart failure. Limiting sodium intake may reduce the development of diuretic resistance, and certainly avoiding high sodium loads will avoid preventable episodes of fluid overload. Regular exercise is an effective method of improving exercise capacity and may also reduce hospitalization and mortality in patients with heart failure although the effects in the elderly and patients with class IV heart failure are less well studied. Additionally, an integrated Disease Management program targeted at appropriate high-risk patients which incorporates aggressive outpatient monitoring, patient education, and coordination with medical decisionmakers can also reduce mortality, hospitalization, and medical expenses. In fact the effects of exercise and Disease Management are comparable with the effects of ACE-I treatment (Table 4.5). Finally, there may be a future role of readily available over-the-counter supplements such as creatine, l-arginine, and carnitine; however,

4. Nonpharmacologic Management of Heart Failure

long-term studies are currently lacking and safety has not been evaluated.

References 1. Schiff GD, Fung S, Speroff T, McNutt RA. Decompensated heart failure: Symptoms, patterns of onset, and contributing factors. Am J Med. 2003;114(8):625-630. 2. Friedman MM. Older adults’ symptoms and their duration before hospitalization for heart failure. Heart Lung. 1997;26(3):169-176. 3. Clark JC, Lan VM. Heart failure patient learning needs after hospital discharge. Appl Nurs Res. 2004;17(3):150-157. 4. Artinian NT, Magnan M, Christian W, Lange MP. What do patients know about their heart failure? Appl Nurs Res. 2002;15(4):200-208. 5. Ni H, Nauman D, Burgess D, Wise K, Crispell K, Hershberger RE. Factors influencing knowledge of and adherence to self-care among patients with heart failure. Arch Intern Med. 1999;159(14):1613-1619. 6. Carlson B, Riegel B, Moser DK. Self-care abilities of patients with heart failure. Heart Lung. 2001;30(5):351-359. 7. Wright SP, Walsh H, Ingley KM, et al. Uptake of selfmanagement strategies in a heart failure management programme. Eur J Heart Fail. 2003;5(3):371-380. 8. Ghali JK, Kadakia S, Cooper R, Ferlinz J. Precipitating factors leading to decompensation of heart failure. Traits among urban blacks. Arch Intern Med. 1988;148(9):2013-2016. 9. Michalsen A, Konig G, Thimme W. Preventable causative factors leading to hospital admission with decompensated heart failure. Heart. 1998;80(5):437-441. 10. Gray J, Lawyer P. The promise of disease management. In: Stern CW, Stalk G (eds.), Perspectives on Strategy; from Boston Consulting Group. New York, NY: Johns Wiley & Sons, Inc.; 1998;296-304. 11. Naylor M, Brooten D, Jones R, Lavizzo-Mourey R, Mezey M, Pauly M. Comprehensive discharge planning for the hospitalized elderly. A randomized clinical trial. Ann Intern Med. 1994;120(12):999-1006. 12. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med. 1995;333(18):1190-1195. 13. Stewart S, Vandenbroek AJ, Pearson S, Horowitz JD. Prolonged beneficial effects of a home-based intervention on unplanned readmissions and mortality among patients with congestive heart failure. Arch Intern Med. 1999;159(3):257-261.

71 14. Jerant AF, Azari R, Nesbitt TS. Reducing the cost of frequent hospital admissions for congestive heart failure: A randomized trial of a home telecare intervention. Med Care. 2001;39(11):1234-1245. 15. Krumholz HM, Amatruda J, Smith GL, et al. Randomized trial of an education and support intervention to prevent readmission of patients with heart failure. J Am Coll Cardiol. 2002;39(1):83-89. 16. Kasper EK, Gerstenblith G, Hefter G, et al. A randomized trial of the efficacy of multidisciplinary care in heart failure outpatients at high risk of hospital readmission. J Am Coll Cardiol. 2002;39(3):471-480. 17. Doughty RN, Wright SP, Pearl A, et al. Randomized, controlled trial of integrated heart failure management: The Auckland Heart Failure Management Study. Eur Heart J. 2002;23(2):139-146. 18. Laramee AS, Levinsky SK, Sargent J, Ross R, Callas P. Case management in a heterogeneous congestive heart failure population: A randomized controlled trial. Arch Intern Med. 2003;163(7):809-817. 19. Benatar D, Bondmass M, Ghitelman J, Avitall B. Outcomes of chronic heart failure. Arch Intern Med. 2003;163(3):347-352. 20. Goldberg LR, Piette JD, Walsh MN, et al. WHARF Investigators. Randomized trial of a daily electronic home monitoring system in patients with advanced heart failure:The Weight Monitoring in Heart Failure (WHARF) trial. Am Heart J. 2003;146(4):705-712. 21. Naylor MD, Brooten DA, Campbell RL, Maislin G, McCauley KM, Schwartz JS. Transitional care of older adults hospitalized with heart failure: A randomized, controlled trial. J Am Geriatr Soc. 2004;52(5):675-684. 22. Atienza F, Anguita M, Martinez-Alzamora N, et al. PRICE Study Group. Multicenter randomized trial of a comprehensive hospital discharge and outpatient heart failure management program. Eur J Heart Fail. 2004;6(5):643-652. 23. Galbreath AD, Krasuski RA, Smith B, et al. Long-term healthcare and cost outcomes of disease management in a large, randomized, community-based population with heart failure. Circulation. 2004;110(23):35183526. Epub 2004 Dec 7. 24. DeBusk RF, Miller NH, Parker KM, et al. Care management for low-risk patients with heart failure: A randomized, controlled trial. Ann Intern Med. 2004;141(8):606-613. 25. McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: A systematic review of randomized trials. J Am Coll Cardiol. 2004;44(4):810-819. 26. Riegel B, Carlson B, Kopp Z, LePetri B, Glaser D, Unger A. Effect of a standardized nurse casemanagement telephone intervention on resource

72 use in patients with chronic heart failure. Arch Intern Med. 2002;162(6):705-712. 27. Jaarsma T, Halfens R, Huijer Abu-Saad H, et al. Effects of education and support on self-care and resource utilization in patients with heart failure. Eur Heart J. 1999;20(9):673-682. 28. Riegel B, Carlson B, Glaser D, Hoagland P. Which patients with heart failure respond best to multidisciplinary disease management? J Card Fail. 2000;6(4):290-299. 29. Krumholz HM, Chen YT, Wang Y, Vaccarino V, Radford MJ, Horwitz RI. Predictors of readmission among elderly survivors of admission with heart failure. Am Heart J. 2000;139(1 pt 1):72-77. 30. Starfield B, Weiner J, Mumford L, Steinwachs D. Ambulatory care groups: A categorization of diagnoses for research and management. Health Serv Res. 1991;26(1):53-74. 31. Ellis RP, Pope GC, Iezzoni L, et al. Diagnosis-based risk adjustment for Medicare capitation payments. Health Care Financ Rev. 1996;17(3):101-128. 32. Babayan ZV, McNamara RL, Nagajothi N, et al. Predictors of cause-specific hospital readmission in patients with heart failure. Clin Cardiol. 2003;26(9):411-418. 33. Spaeder JA, Najjar SS, Gerstenblith G, et al. Rapid titration of Carvedilol in patients with CHF: A randomized trial of automated telemedicine versus frequent outpatient clinic visits. Circulation. 2004. 34. Coats AJ, Adamopoulos S, Meyer TE, Conway J, Sleight P. Effects of physical training in chronic heart failure. Lancet. 1990;335(8681):63-66. 35. McHenry MM. Medical screening of patients with coronary artery disease. Criteria for entrance into exercise conditioning programs. Am J Cardiol. 1974;33(6):752-756. 36. Friedberg CK. Diseases of the Heart. Philadelphia: W.B. Saunders Company; 1966; 342. 37. Carell ES, Murali S, Schulman DS, Estrada-Quintero T, Uretsky BF. Maximal exercise tolerance in chronic congestive heart failure. Relationship to resting left ventricular function. Chest. 1994;106(6):1746-1752. 38. Gulec S, Ertas F, Tutar E, et al. Exercise performance in patients with dilated cardiomyopathy: Relationship to resting left ventricular function. Int J Cardiol. 1998;65(3):247-253. 39. Massie BM, Kramer B, Haughom F. Acute and long-term effects of vasodilator therapy on resting and exercise hemodynamics and exercise tolerance. Circulation. 1981;64(6):1218-1226. 40. Drexler H, Banhardt U, Meinertz T, Wollschlager H, Lehmann M, Just H. Contrasting peripheral shortterm and long-term effects of converting enzyme inhibition in patients with congestive heart failure. A

J.A. Spaeder and E.K. Kasper double-blind, placebo-controlled trial. Circulation. 1989;79(3):491-502. 41. Metra M, Nardi M, Giubbini R, Dei Cas L. Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1994;24(7):1678-1687. 42. Cicoira M, Zanolla L, Franceschini L, et al. Skeletal muscle mass independently predicts peak oxygen consumption and ventilatory response during exercise in noncachectic patients with chronic heart failure. J Am Coll Cardiol. 2001;37(8):2080-2085. 43. Volterrani M, Clark AL, Ludman PF, et al.Predictors of exercise capacity in chronic heart failure. Eur Heart J. 1994;15(6):801-809. 44. Anker SD, Swan JW, Volterrani M, et al.The influence of muscle mass, strength, fatigability and blood flow on exercise capacity in cachectic and noncachectic patients with chronic heart failure. Eur Heart J 1997;18(2):259-269. 45. Lipkin DP, Jones DA, Round JM, Poole-Wilson PA. Abnormalities of skeletal muscle in patients with chronic heart failure. Int J Cardiol. 1988;18(2):187-195. 46. Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation. 1990;81(2):518-527. 47. Drexler H, Riede U, Munzel T, Konig H, Funke E, Just H. Alterations of skeletal muscle in chronic heart failure. Circulation. 1992;85(5):1751-1759. 48. Sullivan MJ, Duscha BD, Klitgaard H, Kraus WE, Cobb FR, Saltin B. Altered expression of myosin heavy chain in human skeletal muscle in chronic heart failure. Med Sci Sports Exerc. 1997;29(7):860-866. 49. Vescovo G, Serafini F, Dalla Libera L, et al. Skeletal muscle myosin heavy chains in heart failure: Correlation between magnitude of the isozyme shift, exercise capacity, and gas exchange measurements. Am Heart J. 1998;135(1):130-137. 50. Oka RK, Stotts NA, Dae MW, Haskell WL, Gortner SR. Daily physical activity levels in congestive heart failure. Am J Cardiol. 1993;71(11):921-925. 51. Vescovo G, Serafini F, Facchin L, et al. Specific changes in skeletal muscle myosin heavy chain composition in cardiac failure: Differences compared with disuse atrophy as assessed on microbiopsies by high resolution electrophoresis. Heart. 1996;76(4):337-343. 52. Shoemaker JK, Naylor HL, Hogeman CS, Sinoway LI. Blood flow dynamics in heart failure. Circulation. 1999;99(23):3002-3008. 53. Wiener DH, Fink LI, Maris J, Jones RA, Chance B, Wilson JR. Abnormal skeletal muscle bioenergetics during exercise in patients with heart failure: Role

4. Nonpharmacologic Management of Heart Failure of reduced muscle blood flow. Circulation. 1986; 73(6):1127-1136. 54. Duscha BD, Annex BH, Green HJ, Pippen AM, Kraus WE. Deconditioning fails to explain peripheral skeletal muscle alterations in men with chronic heart failure. J Am Coll Cardiol. 2002;39(7):1170-1174. 55. Okita K, Yonezawa K, Nishijima H, et al. Skeletal muscle metabolism limits exercise capacity in patients with chronic heart failure. Circulation. 1998;98(18):1886-1891. 56. Massie BM, Conway M, Rajagopalan B, et al. Skeletal muscle metabolism during exercise under ischemic conditions in congestive heart failure. Evidence for abnormalities unrelated to blood flow. Circulation. 1988;78(2):320-326. 57. Mancini DM, Ferraro N, Tuchler M, Chance B, Wilson JR. Detection of abnormal calf muscle metabolism in patients with heart failure using phosphorus-31 nuclear magnetic resonance. Am J Cardiol. 1988;62(17):1234-1240. 58. Sullivan MJ, Green HJ, Cobb FR. Altered skeletal muscle metabolic response to exercise in chronic heart failure. Relation to skeletal muscle aerobic enzyme activity. Circulation. 1991;84(4):1597-1607. 59. Andrews R, Walsh JT, Evans A, Curtis S, Cowley AJ. Abnormalities of skeletal muscle metabolism in patients with chronic heart failure: Evidence that they are present at rest. Heart. 1997;77(2):159-163. 60. Wilson JR, Martin JL, Schwartz D, Ferraro N. Exercise intolerance in patients with chronic heart failure: Role of impaired nutritive flow to skeletal muscle. Circulation. 1984;69(6):1079-1087. 61. Bekedam MA, van Beek-Harmsen BJ, Boonstra A, et al. Maximum rate of oxygen consumption related to succinate dehydrogenase activity in skeletal muscle fibres of chronic heart failure patients and controls. Clin Physiol Funct Imaging. 2003;23(6):337-343. 62. LeJemtel TH, Maskin CS, Lucido D, Chadwick BJ. Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure. Circulation. 1986;74(2):245-251. 63. McMurray JJ, Ray SG, Abdullah I, Dargie HJ, Morton JJ. Plasma endothelin in chronic heart failure. Circulation. 1992;85(4):1374-1379. 64. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990;82(5):1724-1729. 65. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991;84(4):1589-1596.

73 66. Anker SD, Ponikowski PP, Clark AL, et al. Cytokines and neurohormones relating to body composition alterations in the wasting syndrome of chronic heart failure. Eur Heart J. 1999;20(9):683-693. 67. Clark AL, Sparrow JL, Coats AJ. Muscle fatigue and dyspnoea in chronic heart failure: Two sides of the same coin? Eur Heart J. 1995;16(1):49-52. 68. Ponikowski PP, Chua TP, Francis DP, Capucci A, Coats AJ, Piepoli MF. Muscle ergoreceptor overactivity reflects deterioration in clinical status and cardiorespiratory reflex control in chronic heart failure. Circulation 2001;104(19):2324-2330. 69. Hambrecht R, Fiehn E, Yu J, et al. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol 1997;29(5):1067-1073. 70. Gielen S, Adams V, Mobius-Winkler S, et al. Antiinflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol. 2003;42(5):861-868. 71. Kobayashi N, Tsuruya Y, Iwasawa T, et al. Exercise training in patients with chronic heart failure improves endothelial function predominantly in the trained extremities. Circ J 2003;67(6):505-510. 72. Braith RW, Welsch MA, Feigenbaum MS, Kluess HA, Pepine CJ. Neuroendocrine activation in heart failure is modified by endurance exercise training. J Am Coll Cardiol. 1999;34(4):1170-1175. 73. Roveda F, Middlekauff HR, Rondon MU, et al. The effects of exercise training on sympathetic neural activation in advanced heart failure: A randomized controlled trial. J Am Coll Cardiol. 2003;42(5):854-860. 74. Adamopoulos S, Coats AJ, Brunotte F, et al. Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol. 1993;21(5):1101-1106. 75. Ohtsubo M, Yonezawa K, Nishijima H, et al. Metabolic abnormality of calf skeletal muscle is improved by localised muscle training without changes in blood flow in chronic heart failure. Heart 1997;78(5):437-443. 76. Kemppainen J, Stolen K, Kalliokoski KK, et al. Exercise training improves insulin stimulated skeletal muscle glucose uptake independent of changes in perfusion in patients with dilated cardiomyopathy. J Card Fail. 2003;9(4):286-295. 77. Stolen KQ, Kemppainen J, Ukkonen H, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2003;41(3):460467. 78. Hambrecht R, Gielen S, Linke A, et al. Effects of exercise training on left ventricular function and peripheral

74 resistance in patients with chronic heart failure: A randomized trial. JAMA. 2000;283(23):3095-3101. 79. Belardinelli R, Georgiou D, Cianci G, Berman N, Ginzton L, Purcaro A. Exercise training improves left ventricular diastolic filling in patients with dilated cardiomyopathy. Clinical and prognostic implications. Circulation. 1995;91(11):2775-2784. 80. Smart N, Marwick TH. Exercise training for patients with heart failure: A systematic review of factors that improve mortality and morbidity. Am J Med. 2004;116(10):693-706. 81. Jugdutt BI, Michorowski BL, Kappagoda CT. Exercise training after anterior Q wave myocardial infarction: Importance of regional left ventricular function and topography. J Am Coll Cardiol. 1988;12(2):362-372. 82. Sakuragi S, Takagi S, Suzuki S, et al. Patients with large myocardial infarction gain a greater improvement in exercise capacity after exercise training than those with small to medium infarction. Clin Cardiol. 2003;26(6):280-286. 83. Piepoli MF, Davos C, Francis DP, Coats AJ; ExTraMATCH Collaborative. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ. 2004;328(7433):189. Epub 2004 Jan 16. 84. Gottlieb SS, Fisher ML, Freudenberger R, et al. Effects of exercise training on peak performance and quality of life in congestive heart failure patients. J Card Fail. 1999;5(3):188-194. 85. Owen A, Croucher L. Effect of an exercise programme for elderly patients with heart failure. Eur J Heart Fail. 2000;2(1):65-70. 86. Pina IL, Apstein CS, Balady GJ, et al. American Heart Association Committee on exercise, rehabilitation, and prevention. Exercise and heart failure: A statement from the American Heart Association Committee on exercise, rehabilitation, and prevention. Circulation. 2003;107(8):1210-1225. 87. Fletcher GF, Balady G, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise standards. A statement for healthcare professionals from the American Heart Association. Writing Group. Circulation. 1995;91(2):580-615. 88. European Heart Failure Training Group. Experience from controlled trials of physical training in chronic heart failure. Protocol and patient factors in effectiveness in the improvement in exercise tolerance. European Heart Failure Training Group. Eur Heart J. 1998;19(3):466-475. 89. Willenheimer R, Rydberg E, Cline C, et al. Effects on quality of life, symptoms and daily activity 6 months after termination of an exercise training programme in heart failure patients. Int J Cardiol. 2001;77(1):25-31.

J.A. Spaeder and E.K. Kasper 90. Karlsdottir AE, Foster C, Porcari JP, Palmer-McLean K, White-Kube R, Backes RC. Hemodynamic responses during aerobic and resistance exercise. J Cardiopulm Rehabil. 2002;22(3):170-177. 91. Pu CT, Johnson MT, Forman DE, et al. Randomized trial of progressive resistance training to counteract the myopathy of chronic heart failure. J Appl Physiol. 2001;90(6):2341-2350. 92. Selig SE, Carey MF, Menzies DG, et al. Moderateintensity resistance exercise training in patients with chronic heart failure improves strength, endurance, heart rate variability, and forearm blood flow. J Card Fail. 2004;10(1):21-30. 93. Quittan M, Wiesinger GF, Sturm B, et al. Improvement of thigh muscles by neuromuscular electrical stimulation in patients with refractory heart failure: A single-blind, randomized, controlled trial. Am J Phys Med Rehabil. 2001;80(3):206-214. 94. Nuhr MJ, Pette D, Berger R, et al. Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Eur Heart J. 2004;25(2):136-143. 95. Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med. 1999;341(8):577-585. 96. Volpe M, Magri P, Rao MA, et al. Intrarenal determinants of sodium retention in mild heart failure: Effects of angiotensin-converting enzyme inhibition. Hypertension. 1997;30(2 pt 1):168-176. 97. Bennett SJ, Saywell RM Jr, Zollinger TW, et al. Cost of hospitalizations for heart failure: Sodium retention versus other decompensating factors. Heart Lung. 1999;28(2):102-109. 98. Michalsen A, Konig G, Thimme W. Preventable causative factors leading to hospital admission with decompensated heart failure. Heart. 1998;80(5): 437-441. 99. Krauss RM, Eckel RH, Howard B, et al. Revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. J Nutr. 2001;131(1):132-146. 100. Hunt SA, Baker DW, Chin MH, et al. American College of Cardiology/American Heart Association. ACC/ AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38(7):2101-2113. 101. Alvelos M, Ferreira A, Bettencourt P, et al. The effect of dietary sodium restriction on neurohumoral activity and renal dopaminergic response in patients with heart failure. Eur J Heart Fail. 2004;6(5):593-599.

4. Nonpharmacologic Management of Heart Failure 102. De Bruyne LK. Mechanisms and management of diuretic resistance in congestive heart failure. Postgrad Med J. 2003;79(931):268-271. 103. Westendorp B, Schoemaker RG, Buikema H, de Zeeuw D, van Veldhuisen DJ, van Gilst WH. Dietary sodium restriction specifically potentiates left ventricular ACE inhibition by zofenopril, and is associated with attenuated hypertrophic response in rats with myocardial infarction. J Renin Angiotensin Aldosterone Syst. 2004;5(1):27-32. 104. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;323(4):236-241. 105. Poehlman ET, Scheffers J, Gottlieb SS, Fisher ML, Vaitekevicius P. Increased resting metabolic rate in patients with congestive heart failure. Ann Intern Med. 1994;121(11):860-862. 106. Pasini E, Opasich C, Pastoris O, Aquilani R. Inadequate nutritional intake for daily life activity of clinically stable patients with chronic heart failure. Am J Cardiol. 2004;93(8A):41A-43A. 107. Aquilani R, Opasich C, Verri M, et al. Is nutritional intake adequate in chronic heart failure patients? J Am Coll Cardiol. 2003;42(7):1218-1223. 108. Ackman ML, Campbell JB, Buzak KA, Tsuyuki RT, Montague TJ, Teo KK. Use of nonprescription medications by patients with congestive heart failure. Ann Pharmacother. 1999;33(6):674-679. 109. Hensrud DD, Engle DD, Scheitel SM. Underreporting the use of dietary supplements and nonprescription medications among patients undergoing a periodic health examination. Mayo Clin Proc. 1999;74(5):443-447. 110. Gordon A, Hultman E, Kaijser L, et al. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc Res. 1995;30(3):413-418. 111. Andrews R, Greenhaff P, Curtis S, Perry A, Cowley AJ. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur Heart J. 1998;19(4):617-622. 112. Archer MC. Creatine: A safety concern. Toxicol Lett. 2004;152(3):275. 113. Koifman B, Wollman Y, Bogomolny N, et al. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol. 1995;26(5):1251-1256. 114. Rector TS, Bank AJ, Mullen KA, et al.H Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation. 1996;93(12):2135-2141. 115. Regitz V, Shug AL, Fleck E. Defective myocardial carnitine metabolism in congestive heart failure

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secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseases. Am J Cardiol 1990;65(11):755-760. Anand I, Chandrashekhan Y, De Giuli F, et al. Acute and chronic effects of propionyl-L-carnitine on the hemodynamics, exercise capacity, and hormones in patients with congestive heart failure. Cardiovasc Drugs Ther. 1998;12(3):291-299. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and Lcarnitine administration. Am Heart J. 2000;139(2 pt 3):S120-123. Vescovo G, Ravara B, Gobbo V, et al. L-Carnitine: A potential treatment for blocking apoptosis and preventing skeletal muscle myopathy in heart failure. Am J Physiol Cell Physiol. 2002;283(3):C802-810. Keith ME, Jeejeebhoy KN, Langer A, et al. A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure. Am J Clin Nutr. 2001;73(2):219-224. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46. Epub 2004 Nov 10. Watson PS, Scalia GM, Galbraith A, Burstow DJ, Bett N, Aroney CN. Lack of effect of coenzyme Q on left ventricular function in patients with congestive heart failure. J Am Coll Cardiol. 1999;33(6):1549-1552. Khatta M, Alexander BS, Krichten CM, et al. The effect of coenzyme Q10 in patients with congestive heart failure. Ann Intern Med 2000;132(8):636-640. Urbano-Marquez A, Estruch R, Navarro-Lopez F, Grau JM, Mont L, Rubin E. The effects of alcoholism on skeletal and cardiac muscle. N Engl J Med. 1989;320(7):409-415. Guillo P, Mansourati J, Maheu B, et al. Longterm prognosis in patients with alcoholic cardiomyopathy and severe heart failure after total abstinence. Am J Cardiol. 1997;79(9): 1276-1278. Fauchier L, Babuty D, Poret P, et al. Comparison of long-term outcome of alcoholic and idiopathic dilated cardiomyopathy. Eur Heart J. 2000;21(4):306-314. Nicolas JM, Fernandez-Sola J, Estruch R, et al. The effect of controlled drinking in alcoholic cardiomyopathy. Ann Intern Med. 2002;136(3):192-200. Flather MD, Yusuf S, Kober L, et al. Longterm ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: A systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355(9215):1575-1581.

5 Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure Grigorios Giamouzis, Syed A. Agha, and Javed Butler

This chapter will focus on the use of digoxin, diuretic, and vasodilator therapy in the management of patients with heart failure (HF) due to left ventricular systolic dysfunction.

5.1. Digoxin Historically, cardiac glycosides have been used in the treatment of HF for over two centuries. Of these, digoxin is the most commonly prescribed regimen due to its convenient pharmacokinetics, alternative routes of administration, and widespread availability of serum drug level measurements. Digoxin is effective in relieving HF symptoms associated with atrial fibrillation and a rapid ventricular rate. However, its efficacy in patients with HF and normal sinus rhythm, for years supported by anecdotal evidence, has been questioned. The American College of Cardiology and the American Heart Association’s (ACC/AHA) recent guidelines for the management of patients with HF recommend initiation of cardiac glycosides in patients with left ventricular dysfunction, who remain symptomatic despite optimal standard therapy1. These recommendations are also endorsed by the European Society of Cardiology and the Heart Failure Society of America 2,3.

5.1.1. Mechanism of Action Digoxin exerts inotropic effects by inhibiting the Na+-K+-ATPase pump in myocardial cells. This inhibition leads to an increase in intracellular sodium concentration, which is then exchanged for extracel-

lular calcium through the Na+/Ca2+ exchanger4. The net effect of these adjustments is increased intracellular calcium during systole, which increases the velocity and extent of sarcomere shortening and results in increased systolic function. Digoxin also exerts anti-adrenergic actions by inhibiting sympathetic outflow and augmenting parasympathetic tone5. It reduces neurohormonal activation by decreasing serum epinephrine concentration, plasma rennin activity and, in a lesser degree, aldosterone levels6. Importantly, these actions take place even at lower serum digoxin levels than those needed to achieve the inotropic effects7.

5.1.2. Pharmacokinetics In patients with normal renal function the half-life of digoxin is 36 to 48 hours8. The drug is excreted mostly unchanged through the kidneys, its excretion rate being proportional to the glomerular filtration rate (GFR). A steady state in the serum is reached when the rate of excretion equals daily intake. In normal renal function steady state is reached after four to five half-lives, which equals about seven days. There is usually no need for a loading dose unless treating certain supraventricular tachycardias. When a loading dose must be used, 0.9 to 1.8 mg given in divided doses over 24 hours will achieve a therapeutic serum level. Digoxin crosses the placenta however it is contraindicated neither in pregnancy nor during lactation. Oral bioavailability is 60% to 80%9. Meals usually delay its absorption but the absolute bioavailability remains unaffected. Individual patient variation as well as interaction 77

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with co-administered drugs does affect its bioavailability. In advanced HF, the use of vasodilators will increase renal digoxin clearance and adjustment of maintenance dose might be required10.

5.1.3. Physiologic Effects Although digoxin does increase ventricular contractility, it is not associated with a significant alteration in the cardiac output in normal subjects. This may be due to the increase in vascular resistance related to digoxin6. In patients with left ventricular systolic dysfunction in sinus rhythm, digoxin therapy has been associated with an improvement in ejection fraction and reduction in pulmonary capillary wedge pressure and, in turn, an increase in cardiac output. However, these effects are minimized if hemodynamics are normalized with diuretics and vasodilators, in which case no further improvement in hemodynamics is observed11. Digoxin therapy in patients with low cardiac output is associated with an improvement in baroreceptor function, decreased activation of the sympathetic nervous system, and increased vagal tone5. Digoxin therapy at therapeutic doses decreases the serum norepinephrine concentration and plasma renin activity12-14. Finally, digoxin’s parasympathomimetic action on myocardium slows conduction, prolonging the atrioventricular node refractory period6.

5.1.4. Clinical Efficacy Studies Several studies have assessed the efficacy of digoxin in the management of patients with stable HF and sinus rhythm15–17. Because of the small sample size of these studies, the indications for digoxin therapy and the optimal therapeutic plasma levels were not clearly established then. Subsequently, several trials compared digoxin to placebo or other medications and demonstrated benefits in terms of improved symptoms and quality of life but no improvement in survival was seen18–26. Subsequently, two trials examined the importance of digoxin in terms of the effect of its withdrawal in patients with HF27,28. In the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) trial, withdrawal of digoxin or its continuation was studied in a randomized, double-blind, placebo-controlled fashion in patients with chronic, stable, mild to moderate HF who were in normal sinus rhythm29. These

G. Giamouzis, S.A. Agha, and J. Butler

patients were on long-term digoxin and diuretics but not angiotensin-converting enzyme (ACE) inhibitor therapy. After a mean follow-up of 3 months, patients withdrawn from digoxin showed an increase in worsening failure, worsening in maximal exercise capacity, a lower ejection fraction, an increased body weight, and a higher mean heart rate. Deterioration occurred even in patients with mild disease30. In the Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE) trial, 178 patients with New York Heart Association (NYHA) class II–III HF symptoms and ejection fraction ≤ 35% in sinus rhythm while receiving digoxin, diuretics, and an ACE inhibitor were studied. The patients were randomized to either continue digoxin (85 patients) or be switched to placebo (93 patients) for 3 months. The incidence of worsening HF, necessitating withdrawal from the study, appeared significantly highes in the placebo group compared with the digoxin group (relative risk 5.9, 95% CI 2.1–17.2). Functional capacity deteriorated in patients receiving placebo as compared with those continuing digoxin. In addition, patients switched from digoxin to placebo had a significantly lower quality-of-life score, reduction in ejection fractions, and increase in heart rate and body weight. Predictors of clinical deterioration after digoxin withdrawal included cardiothoracic ratio greater than 0.57, absence of ACE inhibitor therapy, and lower left ventricular ejection fraction31.

5.1.4.1. The Digitalis Investigator Group Trial The aforementioned studies primarily assessed symptoms, exercise tolerance, and quality of life among patients with mild to moderate HF. The effect of digoxin on survival in patients with HF was assessed in the Digitalis Investigator Group (DIG) trial32. This study evaluated almost 6,800 patients with symptomatic HF on baseline therapy with ACE inhibitors and diuretics as clinically indicated. Patients with ejection fraction ≤ 45% were randomly assigned to digoxin or placebo. In a parallel trial of 988 patients with ejection fraction > 45%, 492 patients were randomly assigned to digoxin and 496 to placebo. After 37 months of average follow-up, there was no difference in survival between patients on digoxin or placebo; however, digoxin use was associated with a trend toward a lower mortality from worsening HF (11.6 vs. 13.2%

5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

for placebo, p = 0.06). This benefit was counterbalanced by an increase in non-HF cardiac deaths, including arrhythmic deaths (15 vs. 13%, p = 0.04). Digoxin use was also associated with a decrease in hospitalization for cardiovascular causes, primarily due to a decrease in hospitalization for HF (26.8 vs.34.7%, p < 0.001). Interestingly, the reduction in hospitalization rate was similar in patients with either reduced or preserved ejection fraction. With no survival benefit therefore, digoxin use is primarily reserved for patients with symptomatic HF.

5.1.5. Studies Raising Potential Concerns Few recent studies have raised concerns regarding the use of digoxin therapy in subgroups of patients with HF.

5.1.5.1. Gender Differences A post hoc analysis of the DIG trial assessed the importance of gender and the response to digoxin33. In women (22% of the cohort), digoxin use was associated with a significant absolute increase in total mortality (33.1 vs. 28.9% in the placebo group, adjusted hazard ratio 1.23). There was also an increase in the secondary outcomes of death from cardiovascular disease or worsening HF. The rate of death was similar between men assigned to digoxin and those to placebo. Women also had a less prominent reduction than men in hospitalization for HF with digoxin (hazard ratio 0.87 vs. 0.66 compared to placebo). Women had a small but significantly higher serum digoxin concentration (SDC) at 1 month (0.9 ng/ml vs. 0.8 ng/ml), but there was no difference at 1 year (0.6 ng/ml in both groups).

5.1.5.2. “Therapeutic” Serum Digoxin Concentration and Mortality Trials with digoxin that have demonstrated benefit with therapy generally had serum digoxin concentrations ranging from 0.7 to 1.75 ng/ml.19,20 The DIG trial maintained digoxin levels between 0.5 and 1.5 ng/dl in most patients and ∼70% received 0.25 mg/day of digoxin32. There was no relationship between the SDC and any clinical end point in the PROVED and RADIANCE trials34. Thus, the general recommendations were to not guide therapy based on SDC. However, in order to avoid toxicity, it was generally recommended to keep the serum levels to <1.8–2.0 ng/dl.

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Another post hoc analysis of the DIG trial recently demonstrated a significant correlation between SDC and survival35. In an analysis restricted to 3,782 men with an left ventricular ejection fraction ≤ 45%, patients assigned to receive digoxin were divided into three groups based on SDC at 1 month; 0.5–0.8 ng/ml (n = 572), 0.9–1.1 ng/ml (n = 322), and ≥1.2 ng/ml (n = 277). They were compared with patients randomly assigned to receive placebo (n = 2,611). All-cause mortality was significantly lower for those with a SDC of 0.5–0.8 ng/ml than for the placebo group (29.9 vs. 36.2%), while mortality was increased for those with a SDC above 1.2 ng/ml. These associations remained significant after adjustment for differences between the groups. A similar relationship between digoxin concentrations and survival in women was seen; however, there were only 330 women in the analysis and results were not statistically significant. A more recent post hoc analysis of the DIG trial demonstrated that digoxin at SDC 0.5–0.9 ng/ml reduces mortality and hospitalizations in all HF patients, including those with preserved systolic function36. At higher SDC, digoxin reduces HF hospitalization but has no effect on mortality or all-cause hospitalizations.

5.1.6. Clinical Use and Recommendations Indication: Digoxin is recommended for patients with left ventricular systolic dysfunction who continue to have NYHA functional class II–IV symptoms despite appropriate medical therapy and optimization of volume status. Serum digoxin concentration: Based on the data from the DIG trial correlating SDC and survival, it is ideal to maintain digoxin levels between 0.5 and 0.8 ng/ml till further data are available. Higher levels should be avoided since they are associated with an increased risk of toxicity, potential adverse cardiovascular outcomes, and without clear evidence of enhanced efficacy. Asymptomatic patients: There is no evidence that digoxin therapy in asymptomatic patients with left ventricular systolic dysfunction and normal sinus rhythm is of any benefit. Women: In women with HF, digoxin should be used cautiously and lower serum levels should be targeted till further data are available.

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Acute HF: Digoxin is not indicated as a first-line therapy for the stabilization of patients with acutely decompensated HF. However, digoxin may be initiated as part of a long-term treatment strategy. Impaired renal function: Renal excretion of digoxin is directly related to glomerular filtration rate. Thus although in normal volunteers with preserved renal function, digoxin has a half-life of 1.5–2.0 days, the half-life in anuric patients is prolonged to 3.5–5.0 days. Additionally, digoxin is not removed well by dialysis. Thus, dose reduction with worsening renal function or withholding digoxin therapy in acute renal failure should be considered. Electrolyte imbalance: With hypokalemia or hypomagnesemia, digoxin toxicity may occur despite lower serum digoxin concentrations. It is therefore recommended to maintain normal serum potassium and magnesium concentrations in patients on digoxin therapy. Hypercalcemia may also predispose the patient to digoxin toxicity and needs careful attention. Elderly: The older patients with HF in general may have a lower lean body mass and also reduced renal function. Thus, digoxin use should be carefully monitored to avoid side effects and toxicity. Right HF: Digoxin may improve cardiac output and also reduce plasma norepinephrine concentration in patients with isolated right ventricular

failure due to cor pulmonale. Unfortunately, there are no clinical data on the use of digoxin in these patients and individual decisions have to be made in any given circumstances. Acute myocardial infarction: Use of any inotropic agent in the setting of acute ischemia may be harmful secondary to potential increase in myocardial oxygen demand and ischemia. Several studies have assessed the role of digoxin in the setting of myocardial infarction and show that patients tend to fare worse on digoxin. Thus, digoxin therapy should be avoided in this setting in general. HF with preserved ejection fraction: In the ancillary study of DIG trial mentioned above, a total of 988 patients with HF and ejection fraction above 45% were studied. No survival benefit was observed, whereas the reduction in hospitalization rate was similar in patients with either reduced or preserved ejection fraction. Thereby, the recently published ACC/AHA guidelines for the treatments of patients with HF and normal ejection fraction give digoxin a class IIb recommendation, since its usefulness is not well established.1

5.1.7. Side Effects Side effects with digoxin therapy are listed in Table 5.1.

Table 5.1. Digoxin side effects. Cardiovascular First-degree, second-degree (Wenckebach), or third-degree heart block (including asystole) Heart blocks especially in patients with preexisting sinoatrial or atrioventricular conduction disorders Atrial tachycardia with block, atrioventricular dissociation Accelerated junctional (nodal) rhythm Unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy) Ventricular tachycardia and ventricular fibrillation Gastrointestinal Anorexia Nausea and vomiting Diarrhea and abdominal pain Intestinal ischemia and hemorrhagic necrosis of the intestines (uncommon) Central nervous system Visual disturbances (blurred or yellow vision) Headache Weakness Dizziness Mental disturbances (such as confusion, anxiety, depression, delirium, and hallucination) Other Gynecomastia, thrombocytopenia, maculopapular rash, and other skin reactions

5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

5.1.8. Digitalis Toxicity Digoxin poisoning can be life-threatening. In patients with HF, overt toxicity tends to emerge at serum concentrations greater than 2.0 ng/ml, but substantial variation to this rule is seen clinically. Neurological or gastrointestinal complaints may be the presenting symptoms. Disturbances in cardiac impulse formation and conduction are commonly seen with digitalis toxicity. Common electrocardiographic manifestations include ectopic beats of atrioventricular, junctional, or ventricular origin; first-degree atrioventricular block; an excessively slow ventricular rate response to atrial fibrillation; or an accelerated atrioventricular junctional pacemaker37. These changes may require only dose adjustment and monitoring. Sinus bradycardia, sinoatrial arrest or exit block, and second- or thirddegree atrioventricular conduction delay often respond to atropine, but temporary ventricular pacing may be necessary. Oral potassium administration is often useful for atrial, atrioventricular, junctional, or ventricular ectopic rhythms, even when serum potassium is in the normal range, unless high-grade atrioventricular block is also present. However, potassium must be monitored carefully to avoid hyperkalemia, especially in patients with renal failure.

5.1.8.1. Anti-Digoxin Immunotherapy Life-threatening severe digoxin toxicity can be reversed by anti-digoxin immunotherapy38. Purified Fab fragments from digoxin-specific antisera have known effectiveness and safety in treating digoxin toxicity including cases of massive ingestion with suicidal intent. It is indicated in the setting of ingestion of more than 10 mg of digoxin in adults or 4 mg in children, or plasma digoxin concentration above 10 ng/ml, and in the presence of life-threatening arrhythmia (ventricular tachycardia or fibrillation, progressive bradycardia, or high-degree atrioventricular nodal block). After infusion, the Fab fragments rapidly bind intravascular digoxin, followed by diffusion of the fragments into the interstitial space to bind free digoxin at that site. The affinity of the fragments for digoxin is greater than the affinity of digoxin for Na-K-ATPase. As a result, the free digoxin concentration in the interstitial space is

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markedly reduced, creating a favorable concentration gradient for the efflux of digoxin out of the cells. Bound digoxin cannot reassociate with Na-K-ATPase. A dramatic fall in the plasma potassium concentration can occur after fragment therapy, as reversal of Na-K-ATPase inhibition results in abrupt pumping of extracellular potassium into the cells. Thus, plasma potassium concentration should be carefully monitored.

5.2. Diuretics Diuretics are the mainstay of therapy for the removal of excess fluid in patients with HF. They are equally important for use in patients with decompensated HF as well as in those with stable chronic HF to maintain euvolemia. There are no randomized control trials assessing the use of diuretics in patients with HF and they are likely to be never conducted. Since volume regulation is the cornerstone of HF therapy, it will be unethical to withhold therapy and even if done, will likely lead to substantial crossover rate, rendering results difficult to assess, at best. Thus, most of the discussion on the use of diuretics in patients with HF is based on theoretical concerns and clinical experience. In this section, we will discuss primarily the use of diuretics for management of volume regulation. Thus, diuretics used primarily for blood pressure control (e.g., hydrochlorthiazide) or neurohormonal antagonism (e.g., spironolactone and eplerenone) will not be discussed here and are covered in separate sections.

5.2.1. Classification and Mechanism of Action Diuretics are generally divided into four major classes based on their site of action within the renal tubule: 1. Carbonic anhydrase inhibitors act in the proximal tubule 2. Loop diuretics act in the thick ascending limb of the loop of Henle 3. Thiazide-like diuretics act in the distal tubule and connecting segment 4. Potassium-sparing diuretics act in the cortical collecting tubule

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To understand the mechanism of action of diuretics, it is necessary to review the process by which sodium is reabsorbed. Sodium-transporting cells contain Na+-K+-ATPase pumps in their basolateral membrane39. These pumps return the reabsorbed sodium to the systemic circulation and also maintain cell sodium concentration at relatively low levels. The latter effect is important since it allows filtered sodium to passively enter the cells down a favorable concentration gradient. Since charged particles cannot freely cross the lipid bilayer of the cell membrane, this process requires a transmembrane carrier or a sodium channel. Each of the major segments in the nephron has a unique sodium entry mechanism, and the ability to inhibit this step explains the nephron segment at which a particular diuretic will exert its effect.

5.2.2. Loop Diuretics 5.2.2.1. Mechanism of Action

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intravenous administration, diuresis begins within 15 min and peaks at 30–60 min with a duration of action of 2 h. Sixty percent of furosemide is excreted unchanged in the urine. In renal insufficiency, especially when glomerular filtration rate is less than 30 ml/min, the elimination half-life is prolonged, although the diuretic response is impaired largely because of reduced drug delivery to the site of action within the tubule.43 In HF, the pharmacokinetics of oral furosemide is also altered and the absorption is delayed, which leads to a delay in the time at which peak concentration occurs.

5.2.2.3. Bumetanide Bumetanide is 40 times more potent than furosemide on miligram to milligram basis. In normal individuals, the bioavailability is 80% following oral administration, and the onset of action is within 30 min and peaks within 1 h. The duration of action is between 3 and 6 h and half-life between 1 and 3.5 h.

This class of drugs is the most potent of all diuretic agents. The four commonly used drugs in this class include furosemide, bumetanide, torsemide, and ethacrynic acid. Loop diuretics are more than 98% protein-bound and thus not freely filtered by the glomerulus; rather, they are secreted into the tubular lumen via an organic anion transporter. This secretion may be impaired and their action limited by the presence of organic acids, as occurs in renal failure, probenecid, salicylates, and nonsteroidal anti-inflammatory drugs40. Once in the lumen of the tubule, loop diuretics compete with chloride for binding to the Na+/K+/2Cl− cotransporter situated on the apical membrane of cells of medullary thick ascending limb, thereby inhibiting the reabsorption of both sodium and chloride. The urinary diuretic concentration best represents the fraction of drug delivered to the thick ascending limb and significantly correlates with the natriuretic response following diuretic administration41.

Torsemide differs from other agents in the class in that 80% of the drug is metabolized by the liver and 20% is excreted unchanged in the urine. As such, its half-life is minimally altered in renal failure. It is rapidly absorbed and has a bioavailabilty of 80%. In patients with chronic renal insufficiency or with cirrhosis, the natriuretic response following a dose of torsemide is unaffected by the route of administration.44 The onset of action is 1–2 h after either oral or intravenous administration. The half-life is 3.3 h but is prolonged to 8 h in those with cirrhosis.41,45 When selecting an oral agent in patients with HF, oral torsemide may have an advantage over furosemide since its absorption is unimpaired and less variable than furosemide41. In fact, the pharmacokinetics of torsemide in HF is almost comparable to that in healthy individuals.

5.2.2.2. Furosemide

5.2.2.5. Ethacrynic Acid

Furosemide is the most widely used loop diuretic and is the prototype of this class. In normal patients, the oral bioavailability of furosemide is about 50%. Following an oral dose, the onset of action is within 30–60 min, peaks at 1–2 h, and has a duration of action of 6 h with a half-life of 50 min 42. Following

Ethacrynic acid is less widely used because it may be more ototoxic in high doses, and its relative insolubility makes it very difficult to administer intravenously. The primary indication for its use is in patients who are allergic to sulfonamide derivatives such as furosemide, bumetanide, and thiazide diuretics.

5.2.2.4. Torsemide

5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

5.2.3. Thiazide Diuretics Thiazide diuretics primarily inhibit sodium transport in the distal tubule47–51. This segment normally reabsorb less of the filtered load than does the loop of Henle and as a result, the thiazide-type diuretics are generally less potent. When given in maximum dosages, they inhibit the reabsorption of about 5% of the filtered sodium. Furthermore, the net diuresis may be partially limited by increased reabsorption in the cortical collecting tubule52,53. These responses make the thiazides less useful in the treatment of edematous states.

5.2.4. Major Side Effects 5.2.4.1. Loop Diuretic Specific Hypersensitivity reaction: Furosemide, bumetanide, and torsemide can cause hypersensitivity reactions, usually manifested as a rash or rarely as acute interstitial nephritis, similar to those produced by other sulfonamide drugs. There is also a risk of an allergic reaction to loop diuretics in patients with known sulfonamide allergy. In a review of 969 patients who had an allergic reaction to a sulfonamide antibiotic and were subsequently treated with a nonantibiotic sulfonamide, including loop and thiazide diuretics and sulfonylureas, an allergic reaction occurred in 9.9% of patients within 30 days of administration54. This was significantly higher than the 1.6% incidence in controls who did not have a prior allergic reaction to a sulfonamide antibiotic. However, among the patients with a prior reaction to a sulfonamide antibiotic, the risk of an allergic reaction to penicillin was even greater than that to a nonantibiotic sulfonamide. Thus, the increased risk of an allergic reaction to a nonantibiotic sulfonamide appears to reflect a predisposition to allergic reactions rather than cross-reactivity with sulfonamide drugs. However, caution should be exercised in these patients and careful follow-up is suggested. Ethacrynic acid is the only loop diuretic that is not a sulfonamide derivative and can be used alternatively in these patients. Ototoxicity: The risk of ototoxicity is more pronounced at higher doses of furosemide (e.g., above 240 mg/h), especially with rapid intravenous infusions43. However, deafness, which may be permanent, has been reported in patients with acute renal

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failure receiving the equivalent of 80–160 mg/h (2–4 g/day) of furosemide55. Patients concurrently treated with an aminoglycoside may be at risk at even lower doses. Ethacrynic acid may be more ototoxic in high doses than is furosemide.

5.2.4.2. General Diuretic-Related Side Effects A variety of fluid and electrolyte abnormalities can result from diuresis per se. These include hypokalemia and metabolic alkalosis, signs of decreased tissue perfusion such as hypotension and worsening renal function associated with elevations in blood urea nitrogen and serum creatinine concentration, hyperuricemia, and hyponatremia. In patients with chronic HF, both hypokalemia caused by potassium-wasting diuretics and hyperkalemia caused by potassium supplements, especially when administered along with a potassium-sparing diuretic or a renin–angiotensin-aldosterone system modulator, may contribute to significant morbidity and mortality. The level of dietary salt intake may also contribute to the extent of renal potassium wasting with diuretics. High-salt diets increase delivery of sodium to the distal tubular potassium secretory sites, and very low-salt diets may stimulate aldosterone-induced potassium secretion. Any β-agonist or phosphodiesterase inhibitor lowers potassium levels by shifting potassium into skeletal muscle through a β2-adrenergic or cAMP pathway effect56,57. It is generally recommended that serum potassium be maintained between 3.5 and 5.0 mEq/l58. However, for patients with HF, it is preferable to maintain serum K+ between 4.0 and 5.0 mEq/l. One of the reasons for the higher serum K+ maintenance is that patients with HF are often being treated with agents where the proarrhythmic effects are exacerbated by hypokalemia, including digoxin, type III antiarrhythmics, β-agonists, or phosphodiesterase inhibitors. Because patients with chronic HF are at a high risk for malignant ventricular arrhythmias and sudden cardiac death, it is important to monitor potassium levels frequently and maintain them well up in the normal range. Oral supplementation may be necessary.

5.2.4.3. Other Metabolic and Electrolytic Disturbances Diuretics may be associated with multiple other metabolic and electrolytic disturbances, including

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hypomagnesemia, hyponatremia, metabolic alkalosis, hyperglycemia, hyperlipidemia, and hyperuricemia59. Hypomagnesemia can be caused by both loop and thiazide diuretics, but its detection, due to poor correlation of total serum magnesium levels with either ionized levels or total-body stores, is difficult and its impact is uncertain. Magnesium replacement therapy should be given for signs or symptoms that could be due to hypomagnesemia (arrhythmias, muscle cramps), and may be given to all subjects receiving large doses of diuretics or requiring large amounts of potassium replacement. Hyponatremia is usually a manifestation of advanced HF with very high degrees of activation of the vasopressin system or inadequate renin–angiotensin system inhibition. Hyponatremia can typically be treated by more stringent water restriction or an optimization of the renin–angiotensin system. Metabolic alkalosis with diuretics can generally be treated by increasing potassium supplementation, lowering diuretic doses, or with the use of acetazolamide. The glucose intolerance or hyperlipidemia produced by thiazide diuretics should be controlled according to standard guidelines. Hyperuricemia from thiazide diuretics is occasionally a problem and may precipitate gout, particularly in predisposed subjects or in the presence of renal dysfunction. If the use of a thiazide diuretic is absolutely necessary, allopurinol may be administered concomitantly.

5.2.4.4. Osteoporosis Calcium reabsorption in the loop of Henle is primarily driven by the gradient created by Na+ Cl− transport60,61. Inhibition of sodium and chloride reabsorption leads to a parallel increased calcium excretion, thereby increasing the risk of osteoporosis with long-term therapy. This also explains the use of loop diuretics in the management of patients with hypercalcemia.

5.2.5. Treatment of Resistant Edema A variety of factors can account for persistent fluid retention in patients with HF, including inadequate diuretic dose, excess sodium intake, delayed intestinal absorption of oral drugs, decreased diuretic excretion into the urine, and increased sodium reabsorption at non–diuretic-sensitive sites in the

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nephron47,62,63. In addition, non-steroidal antiinflammatory drugs should be discontinued, if possible, since diminished synthesis of vasodilator and natriuretic prostaglandins can impair diuretic responsiveness64,65. Diuretic dose: The approach to diuretic dose in refractory edema should consider each of the above factors. First, the single effective dose should be determined. Diuretics have a dose–response curve, with no natriuresis seen until a threshold rate of drug excretion is attained. Thus, a patient who does not respond to 40 mg of furosemide may not be exceeding this threshold. The dose should be increased to 80 mg rather than giving the same dose twice a day. Second, maintenance of a high-sodium intake can prevent net fluid loss even though an adequate diuresis is being achieved. Thus, a 24-h urine should be collected to assess sodium excretion; a value above 100 mEq/day in a patient whose daily weight is stable indicates an adequate diuretic response and the likelihood that non-compliance with sodium restriction is responsible for the apparent resistance to therapy. Third, some patients with severe HF may require initial intravenous therapy, since decreased intestinal perfusion, reduced intestinal motility, and perhaps mucosal edema may substantially slow down the rate of drug absorption and therefore the rate of drug delivery to the kidneys66. This is often reversible with intravenous diuretic use. In general, a patient who is resistant to furosemide is not likely to respond to a similar dose of another loop diuretic. It is important to appreciate, however, that there are differences in bioavailability among the oral preparations of these drugs. Only about 50% of oral furosemide is absorbed in edematous states, and some patients are well below this level. In this setting, apparent resistance to seemingly adequate doses of oral furosemide may be overcome by increasing the dose of furosemide or by switching to oral bumetanide or torsemide, agents which are much more completely absorbed. Decreased diuretic secretion: One reason for resistance to loop diuretics is reduced secretion of these agents in the tubular lumen. Decreased renal perfusion and competitive inhibition of tubular secretion in renal failure may contribute to diuretic unresponsiveness. The treatment of impaired efficiency of secretion is to raise the plasma level and therefore the rate of urinary excretion by increasing the diuretic dose to the maximum effective dose.

5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

The maximum effective dose represents the dose at which loop sodium chloride transport is presumably completely inhibited. High-dose intravenous therapy should be given slowly over 30–60 min to minimize the risk of ototoxicity67–69. Intravenous infusion: An alternative to bolus injections in diuretic-refractory patients is to use continuous intravenous drips. Constant infusion maintains an optimal rate of drug delivery to the renal tubules and, in turn, has more consistent inhibition of sodium reabsorption. Continuous infusion of a loop diuretic was compared to bolus injections in a Cochrane review of eight trials in 254 patients with HF70. The urine output was modestly higher (+271 mL/24 h) with continuous infusions and less ototoxicity was seen. However, the review concluded that overall data were insufficient to confidently recommend one approach as superior to another. Infusion with albumin: Some patients with low serum albumin levels may be resistant to diuretic therapy. Some data would suggest these patients may respond to furosemide if salt-poor albumin is added to the infusion. Furosemide–albumin complex is felt to act by enhancing diuretic delivery to the kidney, primarily by keeping the diuretic in the vascular space. In one study, this approach substantially increased sodium excretion71. However, another study in patients with nephrotic syndrome found that combination therapy resulted in only a modest increase in sodium excretion compared to furosemide alone72. This increase was roughly the same as the amount of sodium contained in the colloid solution, and therefore volume expansion may have actually resulted in the enhanced natriuresis. Posture: Some patients with HF may be unable to increase cardiac output adequately with assumption of the upright position, resulting in reduced renal perfusion and diuretic delivery to the kidneys. Assumption of the supine position can increase creatinine clearance by up to 40% and can result in significantly improved diuretic response73. Enhanced tubular sodium reabsorption: Some patients develop resistance to loop diuretics because of increased tubular sodium reabsorption in other segments of the nephron, which may be a result of angiotensin II, norepinephrine, or aldosterone excess among other possibilities74. This neurohumoral activation may occur both related to HF and as a consequence of diuretic-induced fluid

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loss. In these circumstances, diuretic effect may be improved with sodium restriction. Alternatively, the loop diuretic can be given two to four times a day rather than once. Another option is to inhibit sodium reabsorption at multiple sites within the nephron by concurrently administrating a thiazide diuretic to block distal reabsorption. Combination therapy requires careful monitoring as it may lead to excessive sodium and potassium losses75.

5.2.6. Are all Loop Diuretics Equal? Until recently, except for pharmacokinetic and allergy reasons, there was no particular reason to choose one loop diuretic over another as efficacy with all these agents was felt to be the same. However, some recent data suggest alternatively. For example, in one study the investigators showed a reduction in cardiac fibrosis among patients with HF treated with torsemide as compared with those treated with furosemide76. Another group of investigators showed decreased levels of aldosterone binding to cardiac receptors with torsemide therapy as compared with furosemide therapy77. Whether these findings would dictate a change in clinical practice still remains uncertain.

5.2.7. Diuretic Use and Prognosis Several studies have recently shown an association between high-dose loop diuretic use and increased mortality risk among patients with HF78. Although this relationship persists after controlling for other confounding variables, it is still clinically difficult to judge whether this is related to diuretic use per se or whether the higher diuretic dose use represents sicker patients. One potential problem with diuretic therapy is that it can worsen renal function and recent data suggest that worsening renal function is associated with poorer outcomes79. A recent study suggested that chronic diuretic use was associated with increased long-term mortality and hospitalizations in a wide spectrum of patients with both systolic and diastolic HF. The findings of this study challenge the wisdom of routine chronic use of diuretics in asymptomatic or minimally symptomatic patients with HF, who are not fluid overloaded and are on complete neurohormonal blockade80. This area is of intense investigation and newer agents are being assessed that improve diuresis without affecting renal function.

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5.2.8. New Agents 5.2.8.1. Arginine Vasopressin Receptor Antagonists Arginine vasopressin is secreted from the pituitary gland and its effects are mediated by three receptor types, V1A, V1B, and V2 receptors. V2 receptors are located in the distal renal tubules and collecting duct81. Arginine vasopressin via the V2 receptors leads to an increase in the intracellular cAMP levels, which then acts as a second messenger in the translocation of vesicles containing the water channel aquaporin-2 and in increasing the transcription of aquaporin-2. Arginine vasopressin regulated aquaporin-2 activity determines the water permeability of the collecting duct and is associated with decreased diuresis82. In HF, arginine vasopressin may be secreted in excess because of a low blood pressure or diminished arterial volume, and leads to hyponatremia. Thus, V2 receptor antagonism results in enhanced diuresis while retaining electrolyte balance. Tolvaptan is a novel oral, nonpeptide, selective vasopressin V2-receptor antagonist. In early (phase 2) trials in patients with HF, tolvaptan showed a decrease in body weight and edema, and improved hyponatremia, without exerting any significant adverse effect83,84. Recently, results from the EVEREST trials confirmed the positive impact of tolvaptan on some, but not all, signs and symptoms when used in addition to standard therapy in patients with HF, whereby the drug was well tolerated85. However, it did not have any significant effect on long-term mortality or HF-related morbidity86. Therefore, tolvaptan might be considered another useful tool, when used appropriately in the treatment of advanced HF.

5.2.8.2. Adenosine A1 Receptor Antagonists Elevated plasma adenosine levels, as seen in patients with HF, can contribute to renal dysfunction. Adenosine can regulate renal function by interacting with two different G-protein-coupled receptors, the A1 and A2 receptors87. The A1 receptor inhibits adenylate cyclase and activates potassium channels, whereas the A2 receptor activates adenylate cyclase. Adenosine lowers cortical blood flow resulting in anti-natriuretic responses88. Selective A1 adenosine receptor blockade decreases

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afferent arteriolar tone, increases urinary flow, and causes natruresis89. Furthermore, tubuloglomerular feedback, which occurs when an acute increase in sodium in the proximal tubule feeds back to decrease the glomerular filtration rate by way of the macula densa, can be affected by adenosine. A1 receptor antagonists have been shown to cause diuresis and natriuresis, while minimally affecting potassium excretion or glomerular filtration. These agents are currently under investigation, and have shown promising results in early studies. BG9928 produced significant increases in diuresis without a decline in renal function and was well tolerated90. In a similar study KW-3902 showed improved diuretic response to loop diuretics in acutely decompensated HF patients91. Thus, selective A1 adenosine receptor blockade seems a promising alternative therapeutic approach when conventional therapy fails to keep the patient asymptomatic.

5.3. Vasodilators This section will deal with drugs that are primarily used for their vasodilator properties orally in patients with HF. Agents that are used for other indications but also possess vasodilator properties, mainly inodilators (milrinone) or neurohormonal antagonists (ACE inhibitors), will not be reviewed. Similarly, drugs that are used intravenously, natriuretic peptides or levosimendan, will not be discussed.

5.3.1. Rational for Vasodilator Therapy The rationale for vasodilator therapy was based on hemodynamic observations in patients with HF. Phentolamine, an α-adrenergic antagonist, and nutroprusside were noted to augment hemodynamic response and improve clinical status of patients with HF92, 93. Impairment of cardiac contractility leads to a reduction in cardiac output. In response, several compensatory neurohormonal systems are activated, including the sympathetic nervous system, the rennin-angiotensin-aldosterone system, and arginine vasopressin94. Although in the short term, activation of these systems helps stabilize the hemodynamic abnormalities and maintain adequate cardiac output, uninhibited prolonged activation leads to further circulatory deterioration. Activation of

5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

the rennin-angiotensin-aldosterone system leads to excessive salt and water retention and vasoconstriction of the venous and arterial beds; alters cardiac preload and afterload, further worsening cardiac output and myocardial remodeling. Impaired systolic cardiac function causes a baroreceptor-mediated increase in sympathetic tone95. Although beneficial in the short term due to the positive inotropic and chronotropic effects, in the long run this leads to increased myocardial oxygen demand, down-regulation of the β1-adrenoreceptor, with consequent decreased effectiveness, increase in ventricular pre- and afterload, and myocyte apoptosis, the programmed cell death96, 97. Vasodilators theoretically are very attractive to reverse the aforementioned hemodynamic abnormalities by increasing venous capacitance, decreasing systemic vascular resistance, improving arterial distensibility, and, in turn, reducing wall stress and impedance to left ventricular ejection. This leads to augmentation of stroke volume and cardiac output and, in turn, improves circulation in the short term, potentially slowing the adverse remodeling process.

5.3.2. Mortality Trials with Vasodilators 5.3.2.1. The Veterans Administation Cooperative Vasodilator Heart Failure Trial (V-HeFT) The effect of vasodilators on actual outcomes was first assessed in the Veterans Administration Cooperative Vasodilator Heart Failure Trial (VHeFT)98. In this multicenter randomized doubleblind placebo-controlled trial, 642 men with mild to moderate symptoms on baseline therapy with diuretics and digoxin were treated with placebo, or prazosin (target dose 5 mg four times a day), or with a combination of hydralazine (target dose 75 mg four times a day) and isosorbide dinitrate (target dose 40 mg four times a day). The primary end point was all- cause mortality. After 2 years of randomization, the mortality in the hydralazine/ isosorbide combination arm was 25.6% versus 34.3% in the placebo group, a highly statistically significant difference (p = 0.028). The mortality in the prazosin group was similar to that in the placebo group. Similarly, the combination therapy arm showed significant increase in left ventricular

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ejection fraction, whereas there were no changes in the other two arms. Thus, a combination of hydralazine and isosorbide dinitrate in the presence of diuretics and digoxin seemed to have significant mortality benefit. However, it should be noted that almost 20% of the patients discontinued therapy because of side effects and only 55% of the patients were taking full doses of both drugs at 6 months. While these positive data were developing for the use of vasodilators, data were emerging on the significant hemodynamic improvements with ACE inhibitors, leading to mortality trials with ACE inhibitors versus placebo and vasodilators99. With the positive results of the V-HeFT I trial and another study with ACE inhibitor enalapril against placebo (the Cooperative North Scandanavian Enalapril Survival Study), V-HeFT II was sought to assess and compare the efficacy of hydralazine and isosorbide dinitrate versus enalapril100,101. Entry criteria for VHeFT II were similar to those for V-HeFT 1. A total of 804 men on diuretic and digoxin therapy were randomized to either similar hydrazine/isosorbide dinitrate regimen as in V-HeFT I or enalapril 10 mg twice a day. After 2 years of therapy, the mortality in the enalapril arm was 18% as compared to 25% in the hydrazine/isosorbide dinitrate arm. The survival curve for hydrazine/isosorbide dinitrate in V-HeFT I was found to be almost identical to that in V HeFT II, confirming the benefits of combination vasodilator therapy, but ACE inhibitor seemed to confer additional benefits. Interestingly, however, although the mortality benefit was clearly in favor of ACE inhibitors, the changes in other physiologic variables were more in favor of combination vasodilator therapy. Left ventricular ejection fraction increased with both regimens, but was more significant with hydralazine/isosorbide combination. Similarly, peak exercise oxygen consumption improved more with combination vasodilator therapy. Although in this study, principally ACE inhibitors were used as a vasodilator, the disconnect between mortality versus the physiologic outcomes questioned the vasodilator theory for improved outcomes and eventually led to improved understanding of the importance of neurohormonal antagonism in HF. Thus, ACE inhibitors became the preferred therapy for HF patients, leading to multiple clinical trials in different HF patient populations. Vasodilator therapy with hydralazine and isosorbide dinitrate

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was restricted to only those patients who were intolerant to ACE inhibitor therapy, until recently.

5.3.2.2. The African–American Heart Failure Trial As mentioned previously, ACE inhibitors were initially used as vasodilators until the physiologic importance of their neurohormonal antagonism was fully realized. Similarly, hydrazine and isosorbide dinitrate were used primarily as vasodilators until recently, when the role of oxidative stress and endothelial dysfunction in the progression of HF was better understood. Endothelial dysfunction is associated with alteration in nitric oxide bioavailability worsening oxidative stress, which, in turn, may contribute to adverse remodeling102–107. Since isosorbide dinitrate is a nitric oxide donor and hydralazine has antioxidant properties, it was subsequently postulated that the benefit from this combination in HF may be due to reasons beyond hemodynamic alterations alone. Moreover, there were significant differences identified in the renin–angiotensin system activation and availability of nitric oxide among whites and blacks 108–111 . Finally, retrospective analysis of earlier HF trials suggested that black patients tended to have a clinically significant response to the combination therapy with hydralazine and isosorbide dinitrate as compared to whites112,113. Based on all these data, a clinical trial was specifically designed to study the effects of combination therapy with hydralazine and isosorbide dinitrate in black patients on standard HF therapy. In this study, 1,050 black patients with NYHA class III or IV symptoms were randomly assigned to receive isosorbide dinitrate plus hydralazine or placebo in addition to standard HF therapy114. The main study end point was a composite score made up of weighted values for death from any cause, a first hospitalization for HF, and change in the quality of life. Interestingly, the study was terminated early secondary to a significantly higher mortality rate in the placebo group (overall mortality rate of 10.2%) as compared to the active treatment arm group (overall mortality rate of 6.2%). Similarly, the mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group, and so were the individual components of the combined end point. Thus, according to the ACC/

G. Giamouzis, S.A. Agha, and J. Butler

AHA guidelines, the isosorbide dinitrate/hydralazine combination is currently considered standard of care in addition to ACE inhibitors in black patients1. Whether the combination therapy adds anything to standard care in other racial groups is yet to be determined.

5.3.3. Calcium Channel Blockers Calcium channel blockers (CCBs) are potent vasodilators with anti-ischemic effects and have been beneficial in patients with hypertension and ischemic heart disease, co-morbidities seen in as high as 70% of HF population. These agents have been shown to acutely reduce systemic vascular resistance and increase cardiac output115–117. However, a large number of studies involving the majority of CCBs failed to establish a definite therapeutic role for this group of agents in patients with HF.

5.3.3.1. First-Generation Calcium-Channel Blockers Initial hemodynamic improvement has been reported after a single-dose administration of each of all first-generation CCBs, nifedipine,118 diltiazem,119 and verapamil120. However, long term administration of these agents has been shown to increase the incidence of episodes of symptomatic deterioration and portents worse outcomes, thus their use in patients with HF should be avoided121–125. The adverse outcomes of the first-generation calcium channel blockers, despite their initial hemodynamic advantage, have been attributed to several different mechanisms, including negative inotropic properties and neurohormonal activation123, 126, 127.

5.3.3.2. Second-Generation CalciumChannel Blockers Data are less negative with the second-generation, more vaso-selective and longer acting CCBs amlodipine and felodipine. Several mechanistic studies have assessed their role in modulating exercise tolerance, functional capacity, and quality of life in HF patients, whereas two large-scale studies have assessed potential mortality benefits128–130. The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial randomized 1,153 patients, who were on standard HF therapy with digoxin, diuretics, and ACE inhibitors, to receive

5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure

either placebo or amlodipine131. This study showed a 9% reduction in the risk of fatal and nonfatal event rate with amlodipine, along with a non-significant 16% reduction in morality (p = 0.07) after an average follow-up of 420 days. Interestingly, in a subgroup analysis of the PRAISE trial, there was an interaction with HF etiology that was observed. Patients with non-ischemic cardiomyopathy had a significant reduction in both fatal and non-fatal event rate and all-cause mortality, as opposed to patients with ischemic heart disease. The third Vasodilator-Heart Failure Trial (V-HeFT III) assessed the role of felodipine in patients with HF on standard baseline therapy with diuretics and enalapril132. A total of 451 male patients were randomized to either felodipine (5 mg) or placebo and followed for an average of 540 days. Total mortality rate was 14% with no difference in the felodipine and the placebo arms. Similarly, felodipine demonstrated beneficial effect on neither peak exercise capacity nor plasma norepinephrine levels.

5.3.3.3. New Calcium-Channel Blockers The largest CCB trial in patients with HF, the Mortality Assessment in Congestive Heart Failure (MACH-1) trial, was designed to evaluate the efficacy and safety of a novel CCB, mibefradil133. Mibefradil is the only CCB able to block both L- and T-type calcium channels and its efficacy and safety was demonstrated in small, preliminary clinical trials in hypertensive patients with known coronary artery disease. MACH-1 was a multicenter, double-blind, placebo-controlled trial that randomized 2,590 patients with systolic dysfunction to either mibefradil or placebo. Mibefradil showed a trend towards increased mortality and interacted significantly with other commonly used drugs, such as the statins and amiodarone. Specifically, patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of sudden death. As a result, mibefradil was withdrawn from the market.

5.3.3.4. The Role of Calcium-Channel Blockers in Heart Failure Based on these large HF mortality trials, the recent ACC/AHA guidelines state that CCBs should not be considered as first-line therapy for HF1. Rather, they should be considered for alternative indications, such as uncontrolled hypertension or angina

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pectoris. In general, patients who have both angina and HF should be given drugs that relieve angina (i.e. nitrates) along with increased dosages of drugs that are appropriate in the management of HF (i.e. beta-blockers). In conclusion, the systemic and coronary vasodilator actions of CCBs have not been translated into clinical benefits in controlled clinical trials in HF. Therefore, most CCBs should be avoided in patients with HF, even when used for the treatment of angina or hypertension. Of available agents, however, only amlodipine has been shown not to adversely affect survival, although experience with the drug exists largely in patients who are not taking beta-blockers131.

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5. Digoxin, Diuretics, and Vasodilators in Patients with Heart Failure 89. Munger KA, Jackson EK. Effects of selective A1 receptor blockade on glomerular hemodynamics: involvement of renin-angiotensin system. The American journal of physiology 1994;267(5 Pt 2): F783-90. 90. Greenberg B, Thomas I, Banish D, et al. Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study. Journal of the American College of Cardiology 2007; 50(7):600-6. 91. Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC. The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance. Journal of the American College of Cardiology 2007;50(16):1551-60. 92. Gould L, Zahir M, Ettinger S. Phentolamine and cardiovascular performance. British heart journal 1969;31(2):154-62. 93. Franciosa JA, Limas CJ, Guiha NH, Rodriguera E, Cohn JN. Improved left ventricular function during nitroprusside infusion in acute myocardial infarction. Lancet 1972;1(7752):650-4. 94. McNamara D. Neurohormonal and cytokine activation in heart failure. In: Heart Failure: A Comprehensive Guide Diagnosis and Treatment. 1st Edition ed: Marcel dekker 2005:117-36. 95. Leimbach WN, Jr., Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73(5):913-9. 96. Katz AM. The myocardium in congestive heart failure. The American journal of cardiology 1989;63(2):12A-6A. 97. Bristow MR, Ginsburg R, Umans V, et al. Beta 1- and beta 2-adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 1986;59(3):297-309. 98. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. The New England journal of medicine 1986;314(24):1547-52. 99. Packer M, Lee WH, Kessler PD, Gottlieb SS, Bernstein JL, Kukin ML. Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation 1987;75(5 Pt 2):IV80-92. 100. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide

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6 Neurohormonal Blockade in Heart Failure Ragavendra R. Baliga

6.1. Introduction Neurohormonal blockade reduces symptoms of heart failure (HF), reverses cardiac remodeling, and improves survival, and therefore it is the mainstay in the management of chronic HF and with “pay-for-performance” expectations for physicians (1), HF patients are expected to be considered for therapy with angiotensin-converting enzyme (ACE) inhibitiors, β-blockers, and aldosterone receptor blockers (2). In this chapter, we discuss randomized clinical trials and other reports that provide evidence for neurohormonal blockade, including ACE inhibition, β-blockade, and aldosterone receptor blockade, in American College of Cardiology/American Heart Association (ACC/ AHA) stage B–C HF Figure 6.1) (3).

6.2. Inhibition of Renin-Angiotensin System 6.2.1. Systolic Dysfunction 6.2.1.1. Angiotensin-Converting Enzyme Inhibition The efficacy of ACE inhibition in the prevention and management of chronic HF is well established. ACE inhibitors reduce HF incidence by 37% among patients with reduced left ventricular (LV) systolic function and by 23% among patients with coronary artery disease and normal systolic function (4). Several ACE inhibitors have been found to be efficacious in HF (Tables 6.1 and 6.2).

6.2.1.2. Hemodynamic Effects (5–7) One of the earliest studies showing that ACE inhibition improves cardiac index (CI), decreases pulmonary capillary wedge pressure (PCWP), reduces systemic vascular resistance (SVR), and reduces systemic blood pressure (SBP) used captopril (5). This study involved 10 patients with stable chronic HF poorly controlled by digitalis and diuretics. At single daily doses of 25–150 mg, the CI rose from 1.75 ± 0.18 to 2.27 ± 0.39 (mean ± SD) l/min/m2 (p < 0.001), and PWCP fell from 26.5 ± 7.5 to 17.3 ± 6.1 mm Hg (p < 0.01). SVR decreased from 2006 ± 300 to 1393 ± 238 dyne s/cm (p < 0.001), and mean SBP fell from 83.7 ± 7.0 to 70.3 ± 9.9 mm Hg (p < 0.001) (mean ± SD). Heart rate (HR) did not change. Hemodynamic alterations peaked at 90 min and persisted for 3–4 h. Changes in hemodynamic values did not correlate with control plasma renin activity (ranging from 1.1 to 7.3 ng/ml/h). Three patients on long-term treatment maintained clinical improvement. The same group of investigators evaluated the hemodynamic effects of captopril in 10 patients with severe chronic HF poorly controlled by digitalis and diuretics (6). After administration of a 25-mg dose, the CI increased from 1.82 ± 0.14 to 2.28 ± 0.30 l/min/m2 (p < 0.05) while PCWP decreased from 22.7 ± 2.0 to 14.7 ± 4.7 mm Hg (p < 0.05). Mean BP and SVR decreased from 85.7 ± 6.7 to 71.2 ± 12.0 mm Hg (p < 0.001) and from 1,909 ± 246 to 1,362 ± 347 dynes s/cm5 (p < 0.001), respectively. HR in this study similarly did not change significantly. There was an inverse relation between maximal augmentation in CI and maximal reduction in PCWP (r = −0.82, 95

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Figure 6.1. Stages of heart failure (HF) and treatment options for systolic HF. Patients with stage A HF are at high risk for HF but do not have structural heart disease or symptoms of HF. This group includes patients with hypertension, diabetes, coronary artery disease, previous exposure to cardiotoxic drugs, or a family history of cardiomyopathy. Patients with stage B HF have structural heart disease but have no symptoms of HF. This group includes patients with LV hypertrophy, previous MI, LV systolic dysfunction, or valvular heart disease, all of whom would be considered to have NYHA class I symptoms. Patients with stage C HF have known structural heart disease and current or previous symptoms of HF. Their symptoms may be classified as NYHA classes I, II, III, or IV. Patients with stage D HF have refractory symptoms of HF at rest despite maximal medical therapy, are hospitalized, and require specialized interventions or hospice care. All such patients would be considered to have NYHA class IV symptoms. ACE denotes angiotensinconverting enzyme, ARB angiotensin-receptor blocker, and VAD ventricular assist device (3). Copyright© 2003, Massachusetts Medical Society. All rights reserved.

Table 6.1. Doses of ACE inhibitors used in HF due to LV systolic dysfunction. ACE inhibitors Agent Captopril Enalapril Lisinopril Fosinopril Quinapril Ramipril Trandalopril Perindropril

Starting dose 12.5 mg three times daily 2.5 mg twice daily 2.5–5 mg once daily 5–10 mg once daily 10 mg twice daily 1.25–2.5 mg once daily 1 mg once daily 2 mg once daily

Dose 50 mg three times a day 10 mg twice a day 20–40 mg once a day 40 mg once daily 40 mg twice daily 10 mg once daily 4 mg once daily 8–16 mg once daily

p < 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic HF whose plasma renin activity

was also within normal range (1.1–7.3 ng/ml/h) as in patients with stable HF. Another group of investigators found similar hemodynamic effects with enalapril (7). They measured these effects acutely in 15 chronic HF patients and after 4 weeks of maintenance therapy in 7 patients (7). They reported that the initial hemodynamic effects were characterized by a significant increase in CI (from 2.1 ± 0.7 to 2.6 ± 0.7 l/min/m2) and a decrease in PCWP (from 30 ± 6 to 24 ± 7 mm Hg), right atrial pressure (from 14 ± 5 to 11 ± 4 mm Hg), mean SBP (from 96 ± 16 to 80 ± 17 mm Hg), and SVR (from 1,820 ± 480 to 1,200 ± 410 dynes s/cm−5) without any significant change in HR, pulmonary artery pressure, and pulmonary vascular resistance. They found that during maintenance therapy the dose of diuretics had to be increased because of systemic venous hypertension. The repeat hemodynamic assessment showed that after 4 weeks of therapy, CI (2.1 ± 0.7 vs. 3.0 ± 0.08 l/min/m2) and stroke volume index (24 ± 10 vs. 36 ± 7 ml/m2)

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Table 6.2. Total mortality or hospitalization for chronic heart failure by duration of follow-up and agent for randomized trials of ACE inhibitors (20). Permission to obtained from JAMA

Agent

No. of trials

Allocation, No. Events/ No. Randomized ACE inhibitors

Captopril Enalapril Lisinopril Quinapril Ramipril All other trials Total

4 7 4 5 6 4 30

27/292 157/1690 10/351 3/548 33/714 9/215 239/3810

Captopril Enalapril† Lisinopril Quinapril Ramipril All other trials Total

3 3 0 2 2 0 10

52/214 559/1282 … 2/218 2/210 … 615/1834

Controls

O-E

90 days or less of follow-up 42/288 −7.56 259/1691 −51.24 10/195 −3.02 3/327 −0.52 44/513 −11.22 14/164 −3.28 372/3178 −76.84 More than 90 days of follow-up 66/206 −8.26 592/1187 −38.65 … … 2/210 −0.04 3/83 −0.65 … … 663/1686 −47.60

Variation of O-E

OR (95% Cl)

14.89 78.90 4.32 1.37 17.16 4.93 121.58

0.60 (0.36–1.00) 0.52 (0.42–0.65) 0.50 (0.19–1.27) 0.68 (0.13–3.66) 0.52 (0.32–0.83) 0.51 (0.21–1.24) 0.53 (0.44–0.63)

21.26 151.76 … 0.99 1.19 … 175.20

0.68 (0.44–1.04) 0.78 (0.66–0.91) … 0.96 (0.14–6.87) 0.58 (0.10–3.48) … 0.76 (0.66–0.88)

O-E is summation of observed-expected over all trials and Var of O-E is sum of individual variance over all trials and OR, over-all point estimate.

remained elevated and PCWP was lower than in controls (30 ± 6 vs. 16 ± 6 mm Hg), indicating sustained improvement in LV performance. Plasma renin activity increased and plasma norepinephrine (PNE) levels decreased after enalapril therapy and these humoral changes persisted during maintenance therapy. All patients receiving chronic therapy had symptomatic improvement. These investigators also reported a fall in SBP with the initiation of therapy.

6.2.1.3. LV Remodeling Improvements in LV systolic function with ACE inhibition also involved the use of captopril (8). This 6-month study used sequential symptom monitoring, treadmill exercise testing, echocardiography, nuclear scintigraphy, and cardiac catheterization to evaluate nine patients with severe chronic LV failure (New York Heart Association, NYHA classes III–IV). They found that captopril lowered PCWP (from 23 to 14 mm Hg acutely, p < 0.001, and to 14 mm Hg, p < 0.01, with continuous 6-month therapy); concomitantly, captopril increased CI from 2.03 to 2.46 l/min/m2 initially (p < 0.02) and to 2.33 l/min/m2 (p < 0.02) at 6 months. Simultaneously, it raised left ventricular ejection fraction (LVEF) from 0.21 to 0.25 acutely (p < 0.01) and to 0.30 (p < 0.001) and to 60 mm

(p < 0.001) at 6 months. These effects were accompanied by decreases in LV end-diastolic (LVED) and end-systolic (LVES) dimensions. The beneficial actions of captopril therapy on LV pump function also increased the treadmill exercise duration (from 339 to 426 s initially, p < 0.05, and to 499 s, p < 0.05, at 6 months) while considerably improving chronic HF symptoms (p < 0.001).

6.2.1.4. Effect on Exercise Capacity A number of studies have shown significant improvements in symptoms and exercise tolerance in patients with chronic HF treated with ACE inhibitors (9–19). Sharpe and coworkers evaluated the effects of enalapril in 36 patients with NYHA functional classes II–III HF who were clinically stable on digoxin and diuretic therapy. After baseline determination of symptoms, exercise capacity, and results of echocardiography and right heart catheterization, patients were randomly assigned to treatment with 5 mg enalapril twice daily (n = 18) or placebo (n = 18) in a double-blind fashion. The two groups had similar clinical, echocardiographic, and hemodynamic characteristics before treatment. After 3 months of treatment, the enalapril group showed a significant improvement as judged by subjective patient impression, functional class, and exercise duration (9.3 ± 5.7 vs. 17.6 ± 5.6 min;

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p < 0.001). Diuretic dosage was reduced in six patients and increased in one patient, one patient had died, and another had been withdrawn from the study. In the placebo group, there was no significant change with respect to patient impression, functional class, or exercise duration; diuretic dosage was increased in seven patients and four patients had died. Echocardiographic LV dimensions were significantly reduced and LV shortening fraction significantly increased in the enalapril group but was unchanged in the placebo group. Similar results on symptoms and exercise tolerance were obtained by Franciosa et al. (11) when they compared the effects of enalapril to those of placebo, in addition to digoxin and diuretic drugs, in 17 patients with chronic HF who were followed up for 12 weeks. In a random doubleblind manner, nine patients received enalapril and eight got placebo. Cardiac dimensions and function improved slightly but insignificantly in both groups. Treadmill exercise duration increased from a mean value (± SD) of 9.1 ± 3.2 to 12.0 ± 3.5 min during enalapril administration (p < 0.025) and remained unchanged during placebo administration (10.1 ± 3.7 vs. 11.1 ± 5.2 min). Maximal oxygen consumption (peak VO2) also increased during enalapril therapy (15.8 ± 3.4 to 18.4 ± 4.4 ml/min/kg, p < 0.05) and remained unchanged during placebo treatment (16.0 ± 6.4 vs. 17.0 ± 4.6 ml/min/kg). Clinical functional class (Yale scale) improved 3.1 ± 1.9 points (p < 0.01) during enalapril therapy but not during placebo treatment (0.8 ± 3.5 points, no significant difference). No significant side effects were observed. Jennings et al. (12) also studied the effects of enalparil in 12 ambulatory patients with severe cardiac failure who were also receiving digoxin and diuretic agents. The study was conducted in a double-blind, parallel, placebo-controlled, and randomized manner. The clinical characteristics and pretreatment exercise performance were similar in the two groups of patients. All vasodilator drugs had been withdrawn 2 weeks before the start of the trial. At 12 weeks, the patients receiving enalapril showed a significant improvement in the functional class of the disease, exercise time (p < 0.01), and maximum workload achieved, and experienced relief fromsymptoms. Lewis (13) conducted a multicenter, randomized, double-blind assessment of 130 HF patients (NYHA functional classes II–IV) to assess

R.R. Baliga

the therapeutic efficacy of lisinopril. All study subjects received concurrent therapy with digoxin and diuretics. Assessments performed periodically over 12 weeks revealed that the active treatment was associated with significant improvements in treadmill exercise time, cardiothoracic ratio, LVEF, functional status, and clinical signs and symptoms of HF. The captopril multicenter, double-blind, placebo-controlled study compared the effects of captopril therapy with those of digoxin treatment during maintenance diuretic therapy in patients with mild-to-moderate HF. The study investigators found that when compared with placebo, captopril therapy resulted in significantly improved exercise time (mean increase, 82 s vs. 35 s) and improved NYHA class (41% vs. 22%), but digoxin therapy did not.

6.2.1.5. Effect on Survival Currently, use of either ACE inhibitors or angiotensinreceptor blockers (ARBs) is considered essential for the management of HF because of the survival benefit with therapy and is now considered a “core-measure” medication for HF patients by CMS (Centers for Medicare & Medicaid Services). ACE inhibitors have been evaluated in over 7000 patients with HF (20) and the largest amount of data regarding reduction in mortality is with enalapril (Table 6.2). Although captopril, ramipril, lisinopril, and quinapril have not shown statistically significant reduction in mortality, the point estimates are consistent with the overall effect of ramipril (see Table 6.2).

6.2.2. HF due to Systolic Dysfunction The CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) was one of the first studies to demonstrate survival benefits with the use of ACE inhibitors. In this study (21), enalapril reduced mortality by 40% (p = 0.002) in patients with NYHA class IV HF—the crude mortality rate at the end of 6 months (primary end point) was 26% in the enalapril group and 44% in the placebo group. At the end of 1 year, the reduction in mortality was 31%. By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group—a reduction of 27% (p = 0.003). Other important findings were a signifi-

6 Neurohormonal Blockade in Heart Failure

cant improvement in NYHA class in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for HF. V-HeFT II (Vasodilator-Heart Failure TrialsII) (22) was one of the first studies (see Chap. 5) to report the incremental benefits of ACE inhibition compared to other vasodilators. These investigators, led by Jay Cohn, compared the effects of enalapril (20 mg) with those of hydralazine (300 mg) plus isosorbide dinitrate (160 mg) in 804 HF male patients receiving digoxin and diuretics. This was a randomized double-blind study. The investigators found that death after 2 years of therapy was significantly lower in the enalapril arm (18%) than in the hydralazineisosorbide dinitrate arm (25%) (p = 0.016; reduction in mortality, 28%), and overall mortality tended to be lower (p = 0.08). They reported that the lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (NYHA class I or II). These authors concluded that the similar 2-year mortality in the hydralazine-isosorbide dinitrate arms in the previous Vasodilator-HF Trial (26%) and in the present trial (25%), as compared with that in the placebo arm in the previous trial (34%), and the further survival benefit with enalapril in the present trial (18%) suggested the benefits of ACE inhibition in chronic HF. In the SOLVD–Treatment (Studies of Left Ventricular Dysfunction–Treatment) study (23), ACE inhibition resulted in a 16% risk reduction for mortality in patients with NYHA classes II–III systolic HF. In the SOLVD study, patients receiving conventional treatment for HF(LVEF < 35%) were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5–20 mg/day in a double-bind trial. In this study, about 90% of the patients were in NYHA functional classes II and III and the follow-up averaged 41.4 months. These investigators, led by Salim Yusuf, found that the mortality rate in the enalapril group was 35.2% (n = 452 deaths) and that in in the control group was 39.7% (n = 510 deaths) (reduction in risk, 16%; 95% CI, 5–26%; p = 0.0036). Although reductions in mortality were observed in several categories of cardiac mortality, the largest reduction occurred among the deaths attributed to progressive HF (209 in the enalapril group vs. 251

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in the placebo group; reduction in risk, 22%; 95% CI, 6–35%). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening HF (736 in the placebo group and 613 in the enalapril group; risk reduction, 26%; 95% CI, 18–34%; p < 0.0001).

6.2.2.1. Asymptomatic Systolic Dysfunction The SOLVD–Prevention study (24) reported that in asymptomatic patients with HF (NYHA class I patients) enalapril therapy was associated with a 20% reduction in the incidence of HF and the rate of related hospitalizations, as compared with the rates in the group given placebo (24). In this study, asymptomatic HF patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5–20 mg/day in a doubleblind trial. The follow-up averaged 37.4 months. The investigators found that there were 313 deaths in the enalapril group as compared with 334 deaths in the placebo group (reduction in risk, 8% by the log-rank test; 95% CI, −8%, an increase of 8%, to 21%; p = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (265 deaths in the enalapril group vs. 298 deaths in the placebo group; risk reduction, 12%; 95% CI, −3% to 26%; p = 0.12). When the investigators combined patients in whom HF developed and those who died, the total number of deaths and cases of HF were lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29%; 95% CI, 21–36%; p < 0.001). In addition, fewer patients given enalapril died or were hospitalized for HF (434 in the enalapril group vs. 518 in the placebo group; risk reduction, 20%; 95% CI, 9–30%; p < 0.001). There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril. The SOLVD investigators also studied the effects of enalapril on the development of myocardial infarction (MI) and unstable angina in HF patients (25). The study cohort composed of 6797 patients with LVEF ≤ 0.35 enrolled into the two SOLVD trials. They randomly assigned patients to enalapril at doses of 2.5–20 mg/day (n = 3396) or placebo (n = 3401) in the two concurrent double-blind trials with the same protocol. The treatment trial had 2569 patients and those without HF entered the prevention trial (n = 4228). The average follow-up was

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40 months. They found that in each trial there were significant reductions in the number of patients developing MI (treatment trial: 127 enalapril vs. 158 placebo, p < 0.02; prevention trial: 161 vs. 204, p < 0.01) or unstable angina (187 vs. 240, p < 0.001; 312 vs. 355, p < 0.05). Combined, there were 288 patients with MI in the enalapril group compared with 362 in the placebo group (risk reduction 23%, 95% CI, 11–34%; p < 0.001). Four hundred ninety-nine patients in the enalapril group developed unstable angina compared with 595 in the placebo group (risk reduction 20%, 95% CI, 9–29%, p < 0.001). There was also a reduction in cardiac deaths (615 enalapril, 711 placebo; p < 0.003), so that the reduction in the combined end point of deaths, MI, and unstable angina was highly significant (20% risk reduction, 95% CI, 14–26%; p < 0.0001). They concluded that treatment significantly reduced MI, unstable angina, and cardiac mortality in patients with low LVEFs.

6.2.2.2. Systolic Dysfunction Following Acute MI The SAVE (Survival And Ventricular Enlargement), AIRE (Acute Infarction Ramipril Efficacy), and TRACE (Trandolapril Cardiac Evaluation) studies) are important studies that demonstrate the benefits of ACE inhibition in those who developed LV systolic dysfunction as a consequence of an acute MI (26, 27). The SAVE investigators, led by Marc Pfeffer (26), found that in patients with asymptomatic LV dysfunction after MI, long-term ACE inhibition was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events. These benefits were observed in patients who received thrombolytic therapy, aspirin, or β-blockers, as well as in those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of MI. The SAVE investigators randomly assigned 2231 MI patients with an LVEF of ≤ 40% but without overt HF or symptoms of myocardial ischemia to captopril within 3–16 days after MI, to receive double-blind treatment with either placebo (1116 patients) or captopril (1115 patients). The patients were followed up for an average of 42 months. The investigators found that all-cause mortality was significantly reduced in the captopril group (228 deaths, or 20%) as com-

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pared with that in the placebo group (275 deaths, or 25%); the reduction in risk was 19% (95% CI, 3–32%; p = 0.019). They also found that the incidence of both fatal and nonfatal major cardiovascular events was reduced in the captopril group. The reduction in risk was 21% (95% CI, 5–35%; p = 0.014) for death from cardiovascular causes, 37% (95% CI, 20–50%; p < 0.001) for the development of severe HF, 22% (95% CI, 4–37%; p = 0.019) for chronic HF requiring hospitalization, and 25% (95% CI, 5–40%; p = 0.015) for recurrent MI. The AIRE study enrolled 2006 patients who had shown clinical evidence of HF at any time after an acute MI. Patients were randomly allocated to double-blind treatment with either ramipril (1014 patients) or placebo (992 patients) or on day 3 to day 10 after acute MI (day 1). In this study, patients with severe HF resistant to conventional therapy, in whom the attending physician considered the use of an ACE inhibitor to be mandatory, were excluded. Follow-up period was for a minimum of 6 months with an average of 15 months. These investigators, led by Stephen Ball, found that on intention-to-treat analysis mortality from all causes was significantly lower for patients randomized to receive ramipril (170 deaths; 17%) than for those randomized to receive placebo (222 deaths; 23%). The observed risk reduction was 27% (95% Cl, 11–40%; p = 0.002). Analysis of prespecified secondary outcomes revealed a risk reduction of 19% for the first validated outcome (i.e., first event in an individual patient)—namely, death, severe/resistent HF, MI, or stroke (95% Cl, 5–31%; p = 0.008). These investigators concluded that oral administration of rampiril to patients with clinical evidence of either transient or ongoing HF, initiated between the second and ninth day after MI, resulted in a substantial reduction in premature death from all causes. This benefit was apparent as early as 30 days and was consistent across a range of subgroups. In a subsequent report, these group of investigators, led by A.S. Hall, demonstrated that the effects of ramipril are long lasting (28). The TRACE study (29) investigators, led by Kober, also found the benefits of ACE inhibition in patients with post-MI dysfunction; the mortality benefit was found while enrolling 25% of consecutive patients screened. They screened 6676 consecutive patients with 7001 MIs. A total of 2606 patients had an LVEF ≤ 35%. On days 3–7 after

6 Neurohormonal Blockade in Heart Failure

infarction, 1749 patients were randomly assigned to receive either oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24–50 months. They found that during the study period, 34.7% (n = 304) in the trandolapril group died, as compared with 42.3% (n = 369) in the placebo group (p = 0.001). The relative risk (RR) of death in the trandolapril group, as compared with the placebo group, was 0.78 (95% CI, 0.67–0.91). Trandolapril also reduced the risk of death from cardiovascular causes (RR, 0.75; 95% CI, 0.63–0.89; p = 0.001) and sudden death (RR, 0.76; 95% CI, 0.59–0.98; p = 0.03). Progression to severe HF was less frequent in the trandolapril group (RR, 0.71; 95% CI, 0.56–0.89; p = 0.003). In contrast, the risk of recurrent MI (fatal or nonfatal) was not significantly reduced (RR, 0.86; 95% CI, 0.66–1.13; p = 0.29). These investigators conclude that long-term treatment with trandolapril in patients with reduced LV function soon after MI significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe HF. Although therapy with ACE inhibitors reduced mortality and morbidity in HF, most HF patients were not receiving these agents or were being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The Assessment of Lisinopril and Survival (ATLAS) study (30, 31), led by Barry Massie and Milton Packer, therefore, examined the safety and tolerability of high- compared with low-dose lisinopril in HF. The ATLAS study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized by receiving medium-dose lisinopril (12.5 or 15.0 mg once daily) for 2–4 weeks and then randomized to high- (35.0 or 32.5 mg once daily) or low-dose (5.0 or 2.5 mg once daily) groups. Patients with NYHA classes II–IV chronic HF and LVEF ≤ 0.30 (n = 3164) were randomized and followed up for a median of 46 months. These investigators examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction. When compared with the low-dose group, patients in the high-dose group had a nonsignificant lower risk of mortality

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(8%, p = 0.128) but a significant lower risk of death or hospitalization for any reason (12%, p = 0.002) and 24% fewer hospitalizations for HF (p = 0.002). Dizziness and renal insufficiency was more frequently observed in the high-dose group, but the two groups were similar in the number of patients requiring discontinuation of the study medication (31). The investigators found that of the 405 HF patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in > 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (BP < 120 mm Hg; creatinine ≥ 1.5 mg/dL, ≥132.6 µmol/l; age, ≥ 70 years; and patients with diabetes) generally tolerated the high-dose strategy. These investigators concluded that ACE inhibitor therapy in most HF patients can be successfully titrated to and maintained at high doses, and that more frequent use of these agents was desirable. Currently, use of either ACE-inhibitors or ARBs is considered essential for management of HF and is now considered a “core-measure” medication for HF patients by CMS.

6.2.2.3. ACE Inhibition, Race, and LV Dysfunction (32, 33) Population-based studies have found that black patients with chronic HF have a higher mortality rate than do whites with the same condition. This finding has been attributed to differences in the severity, causes, and management of HF, the prevalence of coexisting conditions, and socioeconomic factors. Retrospective analysis of the SOLVD study by Exner et al. suggested that there may be racial differences in the outcome of asymptomatic and symptomatic LV systolic dysfunction—blacks with mild-to-moderate LV systolic dysfunction appear to be at higher risk for progression of HF and death from any cause than do similarly treated whites (32, 33). In the SOLVD study, the mean

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(± SD) follow-up was 34.2 ± 14 months in the prevention trial and 32.3 ± 14.8 months in the treatment trial among the black and white participants. These investigators found that overall mortality rates in the prevention trial were 8.1 per 100 person-years for blacks and 5.1 per 100 person-years for whites. In the treatment arm, the rates were 16.7 per 100 person-years and 13.4 per 100 person-years, respectively. After adjusting for age, coexisting conditions, severity and causes of HF, and use of medications, these investigators found that blacks had a higher risk of death from all causes in both the SOLVD prevention trial (RR, 1.36; 95% CI, 1.06–1.74; p = 0.02) and the SOLVD treatment trial (RR, 1.25; 95% CI, 1.04–1.50; p = 0.02). In both trials, blacks were also at higher risk for death due to pump failure and for the combined end point of death from any cause or hospitalization for HF—the two predefined indicators of the progression of LV systolic dysfunction. To address whether racial differences in the response to drug treatment contribute to differences in outcome, the SOLVD investigators pooled and analyzed data from the prevention and treatment trials. They used a matched-cohort design in which up to four white patients were matched with each black patient according to trial, treatment assignment, sex, LV LVEF, and age. A total of 1196 white patients (580 from the prevention trial and 616 from the treatment trial) were matched with 800 black patients (404 from the prevention trial and 396 from the treatment trial). They found that despite the black patients and the matched white patients having similar demographic and clinical profile, black patients had higher rates of mortality from any cause (12.2 vs. 9.7 per 100 person-years) and of hospitalization for HF (13.2 vs. 7.7 per 100 personyears). Even though the doses of ACE inhibitor in the two groups were similar, enalapril therapy, as compared with placebo, was associated with a 44% reduction (95% CI, 27–57%) in the risk of hospitalization for HF among the white patients (p < 0.001) but with no significant reduction among black patients (p = 0.74). At 1 year, enalapril therapy was associated with significant reductions from baseline in systolic BP (by a mean, ± SD, of 5.0 ± 17.1 mm Hg) and diastolic BP (3.6 ± 10.6 mm Hg) among the white patients, but not among the black patients. They observed no significant change in the risk of mortality in association with enalapril therapy in

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either group. These findings suggest that ACEinhibitor therapy is associated with a significant reduction in the risk of hospitalization for systolic HF among white patients, but not among similar black patients. Adverse effects with ACE inhibitors can be classified into two broad categories: (a) related suppression of angiotensin: hypotension and worsening azotemia and (b) related to kinin production: cough and angioedema.

6.2.2.4. Cough with ACE Inhibitors About 5–10% will discontinue therapy usually because of a dry, hacking cough. Often before discontinuing therapy, it is important to ensure that the cough is not due to increased LV end-diastolic pressure (LVEDP) due to congestion of HF. ARBs should be initiated in those who cannot tolerate ACE inhibitors because of cough.

6.2.2.5. Renal Function and ACE Inhibition Renal dysfunction, due to mild or moderate HF, usually improves with initiation of ACE-inhibitor therapy. Worsening renal function with initiation of ACE-inhibitor therapy suggests significant renal artery stenosis and may require discontinuation of therapy. When serum creatinine is >2 mg/dL or blood urea nitrogen (BUN) exceeds 50 mg/dL, adjustment of ACE-inhibitor therapy is best done by a HF specialist or in collaboration with a nephrologist. The SAVE investigators, reported that in patients (34) with acute MI and LV systolic dysfunction, worsening kidney function (defined as an increase of >0.3 mg/dL within the first 2 weeks in creatinine) is fairly common (12.0%) and when this occurs it is associated with a significant increase in risk for cardiovascular outcomes and mortality. This risk that is associated with worsening kidney function was most significant in patients who received placebo and seems to be attenuated in patients who receive captopril. These findings suggest that careful monitoring of renal function during the first few weeks after acute MI may aid in long-term risk stratification for cardiovascular events and suggest against discontinuation of ACE-inhibitor therapy after small, stable increases in serum creatinine. In diabetic nephropathy, ACE inhibitors are safe and tolerated in advanced renal function, indicating that ACE inhibitors should be

6 Neurohormonal Blockade in Heart Failure

considered even in patients with advanced renal disease (35).

6.2.2.6. Pregnancy and ACE Inhibitors The use of ACE inhibitors during the first (36), second, and third trimesters of pregnancy is contraindicated because of their association with an increased risk of fetal malformations. Infants with first-trimester exposure to ACE inhibitors also have increased risk of major congenital malformations (RR, 2.71; 95% CI, 1.72–4.27) as compared with infants who had no exposure to antihypertensive medications. In contrast, fetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk (RR, 0.66; 95% CI, 0.25–1.75). Infants exposed to ACE inhibitors were at increased risk for malformations of the cardiovascular system (RR, 3.72; 95% CI, 1.89–7.30) and the central nervous system (RR, 4.39; 95% CI, 1.37–14.02). Exposure to ACE inhibitors during pregnancy is unsafe and should be avoided. Pregnancy is an absolute contraindication to initiation or continuation of ACE-inhibitor therapy.

6.2.2.7. Breastfeeding and ACE Inhibitors Captopril is the only ACE inhibitor that has been designated safe in breastfeeding mothers. The other ACE inhibitors currently remain contraindicated while breastfeeding because of lack of data. Captopril, however, is not routinely used because it contains a sulfhydryl group which is associated with rashes, neutropenia, and nephrotic syndrome. All these side effects are dose dependent and neutropenia tends to occur in those with underlying collagen vascular disease.

6.2.2.8. Diuretics and ACE Inhibitors Diuretic dosage may decrease with initiation of ACE-inhibitor therapy. It is best to avoid increasing the doses of both diuretics and ACE inhibitors simultaneously to avoid the risk of hypotension. ACE inhibitors’ doses are best increased when the patient is “wet” (as opposed to β-blockers where it is better to increase the dose or initiate therapy when the patient is relatively “dry”); increasing the ACE-inhibitor dose when the patient is “dry” often results in azotemia.

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6.2.2.9. Angiotensin Receptor Blockers as Alternatives to Angiotensin-Converting Enzyme Inhibition Although ACE inhibitors have emerged as the first-line therapy for HF because of LV systolic dysfunction, ARBs are considered a reasonable alternative to suppress the renin-angiotensin system as evidenced by the findings of the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial (Table 6.3).

6.2.2.10. Hemodynamic Effects ARBs have similar hemodynamic benefits as ACE inhibitors (37, 38). Angiotensin II receptor blockade with losartan causes both vasodilator and neurohormonal effects in HF patients. The vasodilator response is not incremental with doses of more than 25 mg in one study, suggesting that neurohormonal activation might limit the efficacy of high doses of losartan (37). In this study, led by Stephen Gottlieb, after baseline hemodynamic measurements using balloon-tipped pulmonary artery and radial arterial catheters, HF patients were randomized to receive a single dose of placebo or 5, 10, 25, 75, or 150 mg losartan in a double-blind, sequential fashion. Hemodynamic and neurohormonal parameters were then measured over a period of 24 h. These investigators found that losartan caused vasodilation in a dose-dependent manner. Using the area-under-the-curve method, they found that the reduction in Mean arterial pressure (MAP) and SVR grew larger up to a dose of 25 mg, but the higher 75- and 150-mg doses did not produce incremental vasodilation. In response to losartan, there were compensatory increases in both angiotensin II concentrations and in plasma renin activity, which were greatest at the highest doses. Aldosterone concentrations were significantly lowered with losartan. Another study showed that losartan administered to patients with symptomatic HF resulted in Table 6.3. Dose of angiotensin-receptor blockers for heart failuredue to left ventricular systolic dysfunction. Angiotensin receptor blockers

Starting dose

Maximum dose

Losartan Candesartan Valsartan

25 mg daily 4 mg daily 40 mg twice daily

50 mg daily 32 mg daily 160 mg twice daily

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beneficial hemodynamic effects in the short term, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. The study reported that these effects were seen with both 25 and 50 mg, with the greatest effect seen with 50 mg (38). These investigators conducted a multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic HF and systolic LV dysfunction (LVEF < 40%). They performed invasive 24-h hemodynamic assessment after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were determined in addition. They enrolled 144 patients, of which 134 (baseline PCWP ≥ 13 mm Hg) were studied as per protocol. During short-term administration, SVR (largest reduction of 197 dyne s−1/cm−5 at 4 h against placebo) and BP fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no discernible effects were seen with 2.5 and 10 mg. After 12 weeks of treatment, similar effects were seen on SVR and BP (maximal fall in SVR against placebo, 318 dyne s−1/cm−5 at 5 h with 50 mg). In addition, PCWP fell with 2.5, 25, and 50 mg (largest reduction of 6.3 mm Hg at 6 h with 50 mg against placebo), CI rose with 25 and 50 mg, and HR was lower with all active treatment groups. There was no excessive cough in the active treatment group.

6.2.2.11. Effect on Exercise Capacity Losartan has also been shown to have beneficial effects on exercise capacity in a multicenter, double-blind, parallel, enalapril-controlled study of 166 stable HF patients in NYHA classes III–IV and LVEF ≤ 35%(39). After a 3-week stabilization period with optimal therapy, including digitalis, diuretic drugs, and ACE inhibitors, HF patients were randomly assigned to 8 weeks of therapy with losartan, 25 mg/day (n = 52); losartan, 50 mg/ day (n = 56); or enalapril, 20 mg/day (n = 58). Patients were monitored with frequent clinical and laboratory evaluation and exercise testing. The investigators found no significant differences between groups in terms of changes in exercise capacity (6-min walk test) and clinical status (dyspnea–fatigue index). The results suggest that losartan and enalapril are of comparable efficacy

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and tolerability in the short-term treatment of moderate or severe HF.

6.1.2.12. Clinical Impact The ELITE (Evaluation of Losartan In The Elderly) study (40) compared losartan with captopril in older (age ≥ 65 years of age) HF patients to determine whether specific angiotensin II receptor blockade with losartan offers safety and efficacy advantages in the treatment of HF over ACE inhibition. These investigators, led by Bertram Pitt, randomly assigned 722 ACE-inhibitor naive patients (aged ≥ 65 years) with NYHA classes II–IV HF and LVEFs of ≤ 40% to double-blind captopril (n = 370) titrated to 50 mg three times daily or losartan (n = 352) titrated to 50 mg once daily, for 48 weeks. The primary end point of this study was the tolerability measure of a persisting increase in serum creatinine of 26.5 µmol/l or more (≥ 0.3 mg/dL) on therapy; the secondary end point was the composite of death and/or hospital admission for HF; and other efficacy measures were total mortality, admission for HF, NYHA class, and admission for MI or unstable angina. The investigators found that the frequency of persisting increases in serum creatinine was the same in both groups (10.5%). Fewer losartan patients discontinued therapy for adverse experiences (12.2% vs. 20.8% for captopril, p = 0.002). No losartan-treated patients discontinued because of cough compared with 14 in the captopril group. Death and/or hospital admission for HF was recorded in 9.4% of the losartan and 13.2% of the captopril patients (RR 32%, 95% CI, −4% to + 55%, p = 0.075). This risk reduction was primarily due to a decrease in all-cause mortality (4.8% vs. 8.7%; RR 46%, 95% CI, 5–69%, p = 0.035). Admissions with HF were the same in both groups (5.7%), as was improvement in NYHA functional class from baseline. Admission to hospital for any reason was less frequent with losartan than with captopril treatment (22.2% vs. 29.7%). In this small study of elderly HF patients, treatment with losartan was associated with an unexpected lower mortality than that found with captopril. Although there was no difference in renal dysfunction, losartan was generally better tolerated than captopril and fewer patients discontinued losartan therapy. These study investigators, therefore, recommended a larger study.

6 Neurohormonal Blockade in Heart Failure

6.2.2.13. Effect on Survival The ELITE-2 (41) Losartan HF Survival Study was, therefore, conducted to confirm whether losartan is superior to captopril in improving survival and is better tolerated. This study was a double-blind, randomized, controlled trial of 3,152 patients aged ≥60 years with NYHA classes II–IV HF and LVEF ≤ 40%. Patients, stratified for β-blocker use, were randomly assigned losartan (n = 1,578) titrated to 50 mg once daily or captopril (n = 1,574) titrated to 50 mg three times daily. The primary and secondary end points were all-cause mortality, and sudden death or resuscitated arrest. The safety and tolerability was assessed and analysis was by intention to treat. The median follow-up period was 555 days. These investigators found that were no significant differences in all-cause mortality (11.7% vs. 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0% vs. 7.3%) between the two treatment groups (hazard ratios, HRs 1.13, 95.7% CI, 0.95–1.35, p = 0.16 and 1.25, 95% CI, 0.98–1.60, p = 0.08). Fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7% vs. 14.7%, p < 0.001), including cough (0.3% vs. 2.7%), suggesting that losartan is better tolerated. ELITE-2 although designed to show superiority of losartan failed even to show equivalence with captopril. These results suggest that the size of the trial is important in providing definitive guidance; ELITE-1 was too small whereas ELITE-2 is still inconclusive as the “non-inferiority” of ARBs. CHARM-Alternative (42), led by Christopher Granger, investigated whether candesartan, an ARB, could improve outcome in patients not taking an ACE inhibitor. This study enrolled 2028 patients with symptomatic HF and LVEF ≤ 40% who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for chronic HF. Analysis was by intention to treat. They found that the most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 33% (n = 334) of 1013 patients in the candesartan group and 40% (n = 406) of 1015

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patients in the placebo group had cardiovascular death or hospital admission for chronic HF (unadjusted HR 0.77, 95% CI, 0.67–0.89, p = 0.0004; covariate adjusted 0.70, 95% CI, 0.60–0.81, p < 0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for chronic HF. Study-drug discontinuation rates were similar in the candesartan (30%) and placebo (29%) groups. CHARM–Alternative found only one case of angioedema associated with candesartan in the 39 patients who were intolerant of ACE inhibitors because of angioedema. They concluded that candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF and intolerance to ACE inhibitors.

6.2.2.14. Angiotensin-Receptor Blockers in Addition to Angiotensin-Convering Enzyme Inhibitors CHARM-Added (43), led by John McMurray, investigated whether adding ARBs to ACE inhibitors improved clinical outcome in HF. CHARMAdded showed benefit in HF patients already on a β-blocker and an ACE inhibitor. These findings contradicted Val–HeFT, which raised concern about the potential safety of this combination. The CHARM result, therefore, was reassuring. The CHARM investigators enrolled 2548 patients with NYHA functional classes II–IV chronic HF and LVEF ≤ 40%, and who were being treated with ACE inhibitors. HF patients were randomly assigned to candesartan (n = 1276, target dose 32 mg once daily) or placebo (n = 1272). Fifty-five percent of patients were also treated with β-blockers and 17% with spironolactone, at baseline. The composite of cardiovascular death or hospital admission for chronic HF was the primary outcome. An intention-to-treat analysis was done. The median follow-up period was 41 months. These investigators found that 38% (n = 483) patients in the candesartan group and 42% (n = 538) in the placebo group experienced the primary outcome (unadjusted HR 0.85, 95% CI, 0.75–0.96, p = 0.011; covariate adjusted p = 0.010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for chronic HF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline

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β-blocker treatment. They concluded that addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with chronic HF and reduced LVEF. This study also showed the benefit in HF patients on recommended doses of an ACE inhibitor; therefore this benefit cannot be explained by the fact that these patients were not using a high enough dose of ACE inhibitor.

6.2.3. Angiotensin Receptor Blockers as Alternatives to Angiotensin-Converting Enzyme Inhibition in Acute MI Angiotensin receptor blockade with valsartan is as effective as ACE inhibition with captopril in patients who are at high risk for cardiovascular events after acute MI (44). However, combining valsartan with captopril increased the rate of adverse events without improving survival. In a double-blind trial, Marc Pfeffer et al. compared the effect of valsartan, captopril, and the combination of the two on mortality in patients with MI complicated by LV systolic dysfunction, HF, or both (44). These investigators randomly assigned patients, 0.5–10 days after acute MI, to additional therapy with valsartan (4909 patients), valsartan plus captopril (n = 4885 patients), or captopril (n = 4909 patients). The primary end point was death from any cause. The median follow-up period was 24.7 months. Nine hundred seventy-nine patients in the valsartan group died, as compared to 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (HR in the valsartan group as compared with that in the captopril group, 1.00; 97.5%, CI, 0.90–1.11%; p = 0.98; HR in the valsartan-and-captopril group as compared with that in the captopril group, 0.98; 97.5% CI, 0.89–1.09%; p = 0.73). The upper limit of the one-sided 97.5% CI for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (p = 0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (p < 0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group.

R.R. Baliga

The VALIANT (Valsartan in Acute Myocardial Infarction Trial) investigators (45), led by Harvey White, randomized 14,703 patients with HF and/or LVEF < 40% to receive captopril, valsartan, or both. Their goal was to determine the impact of angiotensin receptor blockade in the elderly. Mortality and a composite end point, including cardiovascular mortality, readmission for HF, reinfarction, stroke, and resuscitated cardiac arrest, were compared for the age groups of <65 (n = 6988), 65–74 (n = 4555), 75–84 (n = 2777), and ≥85 (n = 383) years. They found that with increasing age, 3-year mortality almost quadrupled (13.4%, 26.3%, 36.0%, and 52.1%, respectively), composite end point events more than doubled (25.2%, 41.0%, 52.3%, and 66.8%, respectively), and hospital admissions for HF almost tripled (12.0%, 23.1%, 31.3%, and 35.4%, respectively). Outcomes did not differ between the three study treatments in any age group. Adverse events associated with captopril and valsartan were more common in the elderly and in patients receiving combination therapy. With increasing age, use of aspirin, β-blockers, and statins declined, and use of digoxin, calciumchannel blockers, and non-potassium-sparing diuretics increased. On 3-year multivariable analysis, each 10-year age increase was associated with an HR of 1.49 (95% CI, 1.426–1.557; p < 0.0001) for mortality and an odds ratio of 1.38 (95% CI, 1.31–1.46; p < 0.0001) for readmission with HF. They concluded that outcomes remained poor in elderly patients with HF and/or impaired LV systolic function after acute MI, although most received β-blockers and all received an ACE inhibitor and/ or an ARB. Better therapies and increased use of aspirin, β-blockers, and statins are needed in this important and increasing patient group. OPTIMAAL (Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan) (46) is another multicenter, randomized trial, led by Dickstein, that tested the hypothesis that the angiotensin II receptor blocker losartan would be superior or noninferior to the ACE inhibitor captopril in decreasing all-cause mortality in high-risk patients after acute MI. The study cohort was composed of 5477 European patients ≥ 50 years of age (mean age 67.4 years, SD 9.8), with confirmed acute MI and HF during the acute phase or a new Q-wave anterior infarction or reinfarction. Patients were randomized and titrated to a target dose of

6 Neurohormonal Blockade in Heart Failure

losartan (50 mg once daily) or captopril (50 mg three times daily) as tolerated. The primary end point was all-cause mortality and the analysis was by intention to treat. The investigators found that 946 deaths during a mean follow-up of 2.7 (0.9) years: 499 (18%) in the losartan group and 447 (16%) in the captopril group (RR 1.13, 95% CI, 0.99–1.28, p = 0.07). The results for the secondary and tertiary end points were as follows: sudden cardiac death or resuscitated cardiac arrest 239 (9%) versus 203 (7%), 1.19 (0.98–1.43), p = 0.07, and fatal or nonfatal reinfarction 384 (14%) versus 379 (14%), 1.03 (0.89–1.18), p = 0.72. The all-cause hospital admission rates were 1806 (66%) versus 1774 (65%), 1.03 (0.97–1.10), p = 0.37. They found that losartan was significantly better tolerated than captopril, with fewer patients discontinuing study medication (458, 17% vs. 624, 23%, 0.70, 0.62–0.79, p < 0.0001). However, since there was a nonsignificant difference in total mortality in favor of captopril, these investigators showed that ACE inhibitors should remain first-choice treatment in patients after complicated acute MI. Losartan, therefore, cannot be generally recommended in this population. Losartan, therefore, like other ARBs, is best used in ACE-inhibitor intolerant patients.

6.2.4. Diastolic Dysfunction 6.2.4.1. ACE Inhibition PEP–CHF (Perindopril in Elderly People with Chronic Heart Failure) (47) is a randomized double-blind trial, led by John Cleland, that compared placebo with perindopril, 4 mg/day in 850 HF patients aged ≥ 70 years treated with diuretics and an echocardiograhic evidence of LV diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease. The primary end point was a composite of all-cause mortality and unplanned HF-related hospitalization with a minimum follow-up of 1 year. Their mean age was 76 ± 5 years and 55% were women. Median follow-up was 2.1 (interquartile range, IQR, 1.5–2.8) years. The study investigators reported that enrollment and event rates were lower than anticipated, reducing the power of the study to show a difference in the primary end point to 35%. Many patients withdrew from perindopril (28%) and placebo (26%) after 1 year and started taking open-label ACE inhibitors. Overall, 107 patients assigned to placebo and 100

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assigned to perindopril reached the primary end point (HR 0.919, 95% CI, 0.700–1.208; p = 0.545). By 1 year, reductions in the primary outcome (HR 0.692, 95% CI, 0.474–1.010; p = 0.055) and hospitalization for HF (HR 0.628, 95% CI, 0.408– 0.966; p = 0.033) were observed and functional class (p < 0.030) and 6-min corridor walk distance (p = 0.011) had improved in those assigned to perindopril. Given the insufficient power of this study for the primary end point of this study, uncertainty remains about the effects of perindopril on long-term morbidity and mortality in this clinical setting; however, improved symptoms and exercise tolerance and fewer HF hospitalizations in the first year were observed on perindopril, during which time most patients were on assigned therapy, suggesting that it may be advantageous in this patient population.

6.2.4.2. Angiotensin Receptor Blockade CHARM-Preserved (48) investigators, led by Salim Yusuf, studied the effect of addition of an ARB to current treatments. Between March1999 and July 2000, they randomly assigned 3023 patients candesartan (n = 1514, target dose 32 mg once daily) or matching placebo (n = 1509). Patients had NYHA functional classes II–IV chronic HF and LVEF ≥ 40%. The primary outcome was cardiovascular death or admission to hospital for chronic HF. Analysis was done by intention to treat. Median follow-up duration was 36.6 months. Twenty-two percent (n = 333) patients in the candesartan group and 24% (n = 366) in the placebo group experienced the primary outcome (unadjusted HR 0.89, 95% CI, 0.77–1.03, p = 0.118; covariate adjusted 0.86, 95% CI, 0.74–1.0, p = 0.051). Cardiovascular mortality did not differ between groups (170 vs. 170), but fewer patients in the candesartan group than in the placebo group were admitted to hospital for chronic HF once (230 vs. 279, p = 0.017) or multiple times. Composite outcomes that included nonfatal MI and nonfatal stroke showed similar results to the primary composite (388 vs. 429; unadjusted 0.88, 95% CI, 0.77–1.01, p = 0.078; covariate adjusted 0.86, 95% CI, 0.75–0.99, p = 0.037). They concluded that candesartan has a moderate impact in preventing admissions for chronic HF among patients who have HF and LVEF ≥ 40%.

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VALIDD (Valsartan in Diastolic Dysfunction) study, led by Scott Solomon (49), found that lowering BP improves diastolic function in hypertensives irrespective of the type of antihypertensive medication used. They randomly assigned hypertensive patients with evidence of diastolic dysfunction to receive either the ARB valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant BP-reducing medications that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic BP and under 80 mm Hg diastolic BP. The primary end point was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue Doppler imaging. Analyses were done by intention to treat. One hundred eighty-six patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. Forty-three patients were lost to follow-up or discontinued the assigned intervention. The investigators found that over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in BP in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in BP reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p < 0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p < 0.0001) by week 38. They found no significant difference in the change in diastolic relaxation velocity between the groups (p = 0.29). This trial suggested that LV diastolic dysfunction accompanying hypertension improves with effective antihypertensive therapy. Another trial investigating the impact of ARB on LV diastolic dysfunction is I–PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function)— which is evaluating irbesartan (50). I-PRESERVE, led by Peter Carson, is currently enrolling 4100 patients with HF due to LV diastolic dysfunction to determine whether 300 mg irbesartan is superior to placebo in reducing mortality and prespecified categories of cardiovascular hospitalizations.

6.2.4.3. Pooled Data on Angiotensin Receptor Blockade on Systolic and Diastolic Dysfunction CHARM-Overall (51) investigators’, led by Marc Pfeffers, goal was to determine whether the use of an ARB could reduce mortality and morbidity. In parallel, randomized, double-blind, controlled,

R.R. Baliga

clinical trials they compared candesartan with placebo in three distinct populations. They evaluated patients with LVEF ≤ 40% who were not receiving ACE inhibitors because of previous intolerance or who were currently receiving ACE inhibitors, and patients with LVEF ≥ 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n = 3803, titrated to 32 mg once daily) or matching placebo (n = 3796), and followed up for at least 2 years. The primary outcome of the overall program was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for chronic HF. Analysis was by intention to treat. Median follow-up duration was 37.7 months. Twenty-three percent (n = 886) patients in the candesartan group and 25% (n = 945) in the placebo group died (unadjusted HR 0.91, 95% CI, 0.83–1.00, p = 0.055; covariate adjusted 0.90, 95% CI, 0.82–0.99, p = 0.032), with fewer cardiovascular deaths (691, 18% vs. 769, 20%, unadjusted 0.88, 95% CI, 0.79–0.97, p = 0.012; covariate adjusted 0.87, 95% CI, 0.78–0.96, p = 0.006) and hospital admissions for chronic HF (757, 20% vs 918, 24%, p < 0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia. These investigators concluded that candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for HF. LVEF or treatment at baseline did not alter these effects. ARBs, like ACE inhibitors, are also associated with hypotension, worsening azotemia, and elevated serum potassium levels. Although angioedema is less common with ARBs, there are reports of patients who have developed it with ARBs. Given that ARBs have a similar side-effect profile as ACE inhibitors, combining both could potentially increase the risk of hyperkalemia and renal dysfunction and therefore combining both with aldosterone receptor blockade is best avoided. Despite the success with ACE inhibitors, data from the SOLVD study reported a 2-year mortality of 10% with NYHA class I asymptomatic patients (Box 6.1) and as high as 50% in class IV patients, which prompted investigators at that time to explore further avenues for the treatment of HF. Aldosterone blockade and β-blockade emerged as a result of these investigations.

6 Neurohormonal Blockade in Heart Failure

Box 6.1 NYHA class and mortality (from SOLVD study) NYHA class

2 -year mortality (%) on ACE inhibitors

I II III IV

10 20 30–40 40–50

Practical recommendations for usage of ACE inhibitors/ARBs: Currently, all patients with LV systolic dysfunction should be prescribed ACE inhibitors unless there are specific contraindications. ARBs should be prescribed in ACE inhibitors-intolerant patients when there are no specific contraindications to ARBs. It is recommended that treatment should be started at low doses and dosage increased gradually (Table 6.1). Patient’s renal function and serum potassium should be monitored. In controlled clinical trials, target doses of ACE inhibitors/ARBs were achieved. In the clinical setting, patients are on multiple neurohormonal-blocking agents that reduce blood pressure, including diuretics, beta-blockers, and aldosterone receptor block-

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ers, compelling the practicing clinician to titrate the dose as tolerated. The results of the ATLAS trial suggest that every effort must be made to achieve target doses of either ACE inhibitors or ARBs

6.3. Aldosterone Antagonists ACE-I therapy does not reliably suppress aldosterone production, and “aldosterone escape” occurs in up to 40% of patients with congestive HF (Figure 6.2) (52). Aldosterone blockade therefore allows better inhibition of the renin-angiotensin-aldosterone system. Beneficial effects of aldosterone receptor blockers include (a) prevention and reduction of cardiac fibrosis, (b) prevention of sudden death, and (c) improvement of hemodynamics.

6.3.1. Systolic Dysfunction 6.3.1.1. Hemodynamic Effects Both spironolactone and eplerenone are known to reduce BP (53, 54) and consequently slow the progression of cardiac remodeling. They also improve vascular endothelial function (55), promote natriuresis (56), and moderate diuresis.

Aldosterone “Escape” Despite Angiotensin II Blockade 60 40

Candesartan 4 mg Candesartan 8 mg Candesartan 16 mg Candesartan 4 mg + enalapril 20 mg Candesartan 8 mg + enalapril 20 mg Enalapril 20 mg

change in Aldosterone 20 from Baseline 0 (pg/mL) −20 −40

17 weeks

43 weeks

RESOLVD Investigators. American College of Cardiology. 1998.

Figure 6.2. Aldosterone escape despite angiotensin II blockade. Figure produced from data from (87).

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6.3.1.2. LV Remodeling Spironolactone has beneficial effects on parameters of LV reverse remodeling in chronic HF. One study looked at the impact of spironolactone added to an angiotensin II receptor blocker (candesartan, 8 mg) compared to ARB alone on LV function, mass, and volumes in patients with chronic HF (57). The study cohort composed of 51 HF patients who were randomized to ARB + spironolactone versus ARB + placebo. All subjects underwent cardiac magnetic resonance (MR) imaging for determination of LV end-diastolic and end-systolic volumes (LVEDVs, LVESVs) and echocardiography for assessment of Doppler tissue contractile parameters and cyclic variation of integrated backscatter (CVIB) at randomization and at 26 and 52 weeks. In this study, data were available for 48 patients. These investigators found that subjects randomized to ARB + spironolactone had larger LVEDVs and LVESVs than did those randomized to ARB alone (154.68 ± 14.21 vs. 138.03 ± 10.29 and 120.3 ± 14.7 vs. 101.96 ± 9.4 ml, p = 0.34 and 0.29, respectively) at baseline. LVEF was 26 ± 2% and 28 ± 2% in the two groups and at 26 weeks rose to 31 ± 3% and 30 ± 2% (p < 0.01 vs. baseline for ARB + spironolactone). This was accompanied by a statistically significant decrease to 130.01 ± 15.13 in LVEDV in the ARB + spironolactone group versus a nonsignificant change to 136.84 ± 9.43 in the ARB group. Statistically significant increases in systolic strain were seen in the ARB + spironolactone group, but not in the ARB-alone group. CVIB increased from 10.58 ± 0.69 to 13.3 ± 1.0 dB in the ARB ± spironolactone group (p < 0.05) compared to no significant change in the ARB group. The decrease in LV volumes and improvement function persisted at 52 weeks in the combined group versus continued no change in the ARB-alone group. The study investigators concluded that although this study had a small sample size (< 25 patients in each group), the addition of spironolactone to candesartan in a relatively low dose results in significant favorable remodeling of the LV in patients with chronic HF that is not seen with low-dose candesartan alone. The data regarding CVIB suggest that addition of spironolactone altered the morphologic characteristics of myocardial tissue, which has been a proposed mechanism of the beneficial effect of aldosterone receptor blockers.

R.R. Baliga

The presumed benefit of addition of spironolactone is to counteract the angiotensin escape phenomenon, which occurs with chronic ARB and allows a more complete blockade of this important pathway in HF (see Figure 6.2).

6.3.1.3. Effect on Survival The RALES (Randomized Aldactone Evaluation Study) was the first landmark study which demonstrated survival benefits with aldosterone receptor blockade (58). This study, led by Bertram Pitt, enrolled 1663 patients who had NYHA classes III– IV HF (LVEF ≤ 35%) who were being treated with an ACE inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was mortality from all causes. The study investigators were required to halt the trial early after a mean follow-up period of 24 months, because an interim analysis found that spironolactone was efficacious (reduced the risk of both morbidity and death). There were 386 deaths in the placebo group (46%) and 284 in the spironolactone group (35%; RR of death, 0.70; 95% CI, 0.60–0.82; p < 0.001). This 30% reduction in the risk of mortality among patients in the spironolactone group was attributed to a lower risk of death from progressive HF and sudden death from cardiac causes (Figure 6.3). The frequency of hospitalization for worsening HF was 35% lower in the spironolactone group than in the placebo group (RR of hospitalization, 0.65; 95% CI, 0.54–0.77; p < 0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of HF, as assessed on the basis of the NYHA functional class (p < 0.001). Ten percent of men who were treated with spironolactone had breast pain or gynecomastia, as compared with 1% of men in the placebo group (p < 0.001). They found that the incidence of serious hyperkalemia was minimal in both groups of patients. The effect of spironolactone on clinical outcomes in patients with mild HF is unclear. One retrospective analysis (59) in patients with mild HF (NYHA classes I–II) treated with a thiazide diuretic found that the use of spironolactone is associated with reduced risk of major cardiac event (MCE) or HF rehospitalization. This study analyzed 482 consecutive patients with LVEF ≤ 40% and NYHA I–II symp-

6 Neurohormonal Blockade in Heart Failure

111

1.00 0.95 0.90

Probability of Survival

0.85 0.80 0.75 0.70

Spironolactone

0.65 0.60 0.55

Placebo

0.50 0.45 0.00 0

3

6

9

12

15

21

24

27

565 483 608 526

379 419

280 316

18

30

33

36

Months No. AT Risk 841 775 723 Placebo Spironolactone 822 766 739

678 628 698 669

592 639

179 92 193 122

36 43

Figure 6.3. Kaplan–Meier analysis of the probability of survival among patients in the placebo group and patients in the spironolactone group. The risk of death was 30% lower among patients in the spironolactone group than among patients in the placebo group (p < 0.001) (58). Copyright© 1999, Massachusetts Medical Society. All rights reserved.

toms. MCE was defined as death, LV assist device implantation, or United Network of Organ Sharing 1 cardiac transplantation. Proportional hazards analysis was used to determine predictors of MCE and to derive an adjusted hazard for spironolactone therapy. Spironolactone was prescribed to 58% (n = 279) HF patients and mean follow-up duration was 1029 days. The study authors found that after controlling for predictors of clinical events, spironolactone treatment was associated with a trend for lower risk of MCE or HF rehospitalization (HR, 0.68; 95% CI, 0.43–1.07; p = 0.095). On analyzing interactions, these investigators found that treatment with the combination of spironolactone and thiazide diuretics was associated with lower risk of clinical events | (HR, 0.32; 95% CI, 0.12–0.89; p = .029). Although a randomized, controlled trial is necessary to accurately define the clinical effects of spironolactone

in patients with mild HF, it probably will never be cohort because a large study cohort would be needed to demonstrate mortality benefits.

6.3.1.4. Post-MI LV Systolic Dysfunction Eplerenone is the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs). These new agents have a lower affinity for androgen and progesterone receptors, and should, therefore, minimize these side effects, allowing better compliance. The EPHESUS (Eplerenone Heart Failure Efficacy and Survival Study) trial (60), led by Bertram Pitt, showed that addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute MI complicated by LV dysfunction and HF. This trial was a double-blind,

112

placebo-controlled study evaluating the effect of eplerenone, a selective aldosterone blocker, on morbidity and mortality among patients with acute MI complicated by LV dysfunction and HF. In this study, HF patients were randomly assigned to eplerenone (25 mg/day initially, titrated to a maximum of 50 mg/day; n = 3313) or placebo (n = 3319) in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for HF, acute MI, stroke, or ventricular arrhythmia. The mean follow-up period was 16 months. There were 478 deaths in the eplerenone group and 554 deaths in the placebo group (RR, 0.85; 95% CI, 0.75–0.96; p = 0.008). Of these deaths, 407 in the eplerenone group and 483 in the placebo group were attributed to cardiovascular causes (RR, 0.83; 95% CI, 0.72–0.94; p = 0.005). The rate of the other primary end point, death from cardiovascular causes or hospitalization for cardiovascular events, was reduced by eplerenone (RR, 0.87; 95% CI, 0.79–0.95; p = 0.002), as was the secondary end point of death from any cause or any hospitalization (RR, 0.92; 95% CI, 0.86–0.98; p = 0.02). There was also a reduction in the rate of sudden death from cardiac causes (RR, 0.79; 95% CI, 0.64–0.97; p = 0.03) (Figure 6.4). The rate of serious hyperkalemia was 5.5% in the eplerenone group and 3.9% in the placebo group (p = 0.002), whereas the rate of hypokalemia was 8.4% in the eplerenone group and 13.1% in the placebo group (p < 0.001). The EPHESUS investigators in another publication reported that eplerenone 25 mg/day significantly reduced all-cause mortality 30 days after randomization (when initiated at a mean of 7.3 days after acute MI) in addition to conventional therapy in patients with an LVEF ≤ 40% and signs of HF (61). They reported that 30 days after randomization, eplerenone reduced the risk of all-cause mortality by 31% (3.2% vs. 4.6% in eplerenone and placebo-treated patients, respectively; p = 0.004) and reduced the risk of CV mortality/CV hospitalization by 13% (8.6% vs. 9.9% in eplerenone and placebo-treated patients, respectively; p = 0.074). Eplerenone also reduced the risk of CV mortality by 32% (p = 0.003) and the risk of sudden cardiac death by 37% (p = 0.051). On the basis of their findings of early survival benefit, they recommended that eplerenone should be administered in the hospital after acute MI.

R.R. Baliga

6.3.1.5. Hyperkalemia in Aldosterone Receptor Blockade The use of aldosterone receptor blockers has been associated with significant hyperkalemia in one study where the patients were not closely monitored for azotemia and hyperkalemia (62). In one populationbased time series analysis to examine trends in the rate of spironolactone prescriptions and the rate of hospitalization for hyperkalemia in ambulatory patients before and after the publication of RALES study, the investigators linked prescription-claims data and hospital-admission records for more than 1.3 million adults aged ≥ 66 years They found that among HF patients treated with ACE inhibitors who had recently been hospitalized for HF, the spironolactone-prescription rate was 34/1000 patients in 1994, and it increased immediately after the publication of RALES to 149/1000 patients by late 2001 (p < 0.001). Hospitalization rates for hyperkalemia increased from 2.4/1000 patients in 1994 to 11.0/1000 patients in 2001 (p < 0.001), and the associated mortality rate increased from 0.3/1000 to 2.0/1000 patients (p < 0.001). As compared with the expected numbers of events, there were 560 (95% CI, 285–754) additional hyperkalemia-related hospitalizations and 73 (95% CI, 27–120) additional hospital deaths among older patients with HF who were also on ACE inhibitors. Publication of RALES was not associated with significant decreases in the rates of readmission for HF or death from all causes. The authors of this study concluded that the publication of RALES resulted in abrupt increases in the rate of prescriptions for spironolactone and in hyperkalemia-associated morbidity and mortality. The excess mortality due to hyperkalemia in these patients could have been averted by diligent monitoring of serum potassium. Other reports have also raised attention to the increased incidence of hyperkalemia with spironolactone therapy (63). Careful follow-up of serum potassium and renal function is advisable in all patients and during intercurrent illness. It is recommended that serum electrolytes, creatinine, and BUN be monitored at the start of therapy with aldosterone receptor blockers, a week after initiating therapy, and monthly thereafter if these values are normal. If potassium levels are elevated options are to discontinue therapy altogether, half the dose of the aldosterone receptor blockers, or adopt an alternative day regimen.

6 Neurohormonal Blockade in Heart Failure

113

A Cumulative Incidence (%)

40

P=0.008 RR=0.85 (95% Cl, 0.75−0.96)

35 30

Placebo

25 20

Eplerenone

15 10 5 0 0

No. at Risk Placebo Eplerenone

3

6

9

12 15 18 21 24 Months since Randomization

3313 3064 2983 2830 2418 1801 1213 709 3319 3125 3044 2896 2463 1857 1260 728

27

323 99 336 110

30

33

36

2 0

0 0

0 0

B Cumulative Incidence (%)

40

Placebo

P=0.002 RR=0.87 (95% Cl, 0.75−0.95)

35 30

Eplerenone

25 20 15 10 5 0 0

No. at Risk Placebo Eplerenone

C

3

6

9

12 15 18 21 24 Months since Randomization

27

30

33

36

3313 2754 2580 2388 2013 1494 995 558 247 3319 2816 2680 2504 2096 1564 1061 594 273

77 91

2 0

0 0

0 0

10 P=0.003 RR=0.79 (95% Cl, 0.64−0.97)

Cumulative Incidence (%)

9

Placebo

8 7 Eplerenone

6 5 4 3 2 1 0 0

No. at Risk Placebo Eplerenone

3

6

9

12 15 18 21 24 Months since Randomization

27

3313 3064 2983 2830 2418 1801 1213 709 323 99 3319 3125 3044 2896 2463 1857 1260 728 336 110

30

33

36

2 0

0 0

0 0

Figure 6.4. Kaplan–Meier estimates of the rate of death from any cause (Panel A), the rate of death from cardiovascular causes or hospitalization for cardiovascular events (Panel B), and the rate of sudden death from cardiac causes (Panel C) (60). Copyright© 2003, Massachusetts Medical Society. All rights reserved.

114

R.R. Baliga

6.3.1.6. Diastolic Dysfunction It is hypothesized that aldosterone receptor blockade will be beneficial in LV diastolic dysfunction. In order to test this hypothesis, an National Institutes at Health (NIH) funded study, Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist (TOPCAT), is currently ongoing. TOPCAT is a randomized, double-blinded, placebo-controlled trial of aldosterone antagonist therapy (15 -mg dose of spironolactone or placebo; titrated up to 45 mg/day) in 4,500 adult patients with HF and preserved systolic function (64). Patients will be treated, and followed up for ∼2 years. Primary end points are aborted cardiac arrest and composite of hospitalization for the management of HF (i.e., hospitalization for nonfatal MI or nonfatal stroke). Secondary end points are all-cause mortality, composite of cardiovascular Table 6.4. Doses of aldosterone receptor antagonists in heart failure due to systolic dysfunction. Aldosterone receptor antagonists

Starting dose

Maximum dose

Spironolactone

12.5–25 mg daily

Eplerenone

25 mg once daily

25 mg once or twice daily 50 mg once daily

mortality or cardiovascular-related hospitalization, hospitalization for the management of HF incidence rate, sudden death, or aborted cardiac arrest. Practical recommendations: Aldosterone receptor blockers should be considered in all patients with NYHA classes III–IV HF due to LV systolic dysfunction (Table 6.4). Their usage should be avoided in those patients with serum creatinine > 2.5 mg/dL, estimated creatinine clearance < 50 ml/ min or serum potassium > 5 mg Eq/l (Box 6.2). Initiation of these medications should include monitoring serum potassium and renal function at onset, a week after initiating therapy, and monthly thereafter. Consider dose reduction when serum potassium levels cross 5.5 mg Eq/l or renal function worsens.

6.4. β-Blockers Although the discovery of ACE inhibitors was a quantum leap in the management of HF, data from the SOLVD study (Box 6.1) showed that mortality remained dismal in this condition. And, therefore, in the relentless quest for effective pharmacologic agents, investigators revisited the role of β-blockers in HF. Beta-blockers have been evaluated in over 15,000 patients with HF in randomized clinical

Box 6.2 Guidelines for minimizing the risk of hyperkalemia in patients treated with aldosterone antagonists (84). Reprinted from J Am Coll Cardiol, 46 (6), Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to update the 2001 Guidelines for the Evaluation and Management of Heart Failure), 28 pages, (2005), with permission from Elsevier. 1. Impaired renal function is a risk factor for hyperkalemia during treatment with aldosterone antagonists. The risk of hyperkalemia increases progressively when serum creatinine exceeds 1.6 mg/dL.* In elderly patients or others with low-muscle mass in whom serum creatinine does not accurately reflect glomerular filtration rate, determination that glomerular filtration rate or creatinine clearance exceeds 30 ml/min is recommended. 2. Aldosterone antagonists should not be administrated to patients with baseline serum potassium in excess of 5.0 mg Eq/l. 3. An initial dose of spironolactone 12.5 mg or eplerenone 25 mg is recommended, after which the dose may be increased to spironolactone 25 mg or eplerenone 50 if appropriate. 4. The risk of hyperkalemia is increased with concomitant use of higher doses of ACEIs (captopril greater than or equal to 75 mg daily; enalapril or lisinopril greater than or equal to 10 mg daily). 5. Nonsteroidal antiinflammatory drugs and cyclo-oxygenase-2 inhibitors should be avoided. 6. Potassium supplements should be discontinued or reduced. 7. Close monitoring of serum potassium is required; potassium levels and renal function should be checked in 3 days and at 1 week after initiation of therapy and at least monthly for the first 3 months. 8. Diarrhea or other causes of dehydration should be addressed emergently. ACEI indicates angiotensin-converting enzyme inhibitor. * Although the entry criteria for the trials of aldosterone antagonists included creatinine greater than 2.5 mg/dL, the majority of patients had creatinine much lower; in 1 trial (98), 95% of patients had creatinine less than or equal to 1.7 mg/dL.

6 Neurohormonal Blockade in Heart Failure NYHA ll CHF 12%

Other 24%

115 NYHA lll

CHF 26%

NYHA lV

Other 15% Other 11%

Sudden death 64%

Sudden death 59%

n=103

n=232 Number of deaths

Sudden death 33%

CHF 56%

n=27

Figure 6.5. Severity of heart failure and mode of death with permission from Lancet (71). Reprinted from The Lancet, 353, (9169), Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF), 2001-2007, Copyright (1999), with permission from Elsevier

6.4.1. LV Remodeling Long-term therapy with metoprolol results in a reversal of cardiac maladaptive remodeling, including reduction in LV volumes, regression of LV mass, and improved ventricular geometry by 18 months (66). In this study, 26 male HF patients with dilated cardiomyopathy underwent serial echocardiography on days 0 and 1 and months 1 and 3 of either metoprolol (n = 16) or standard treatment (n = 10). At 3 months, all patients on standard therapy were crossed over to metoprolol, and late echocardiograms were obtained after 18 ± 5 (mean ± SD) months of metoprolol therapy. These investigators found that patients treated with metoprolol had an initial decline (day 1 vs. day 0) in ventricular function (increase in end-systolic volume and decrease in LVEF). Ventricular function

Anglotensin l 1000

100

100

fmol/mol

1000

10 1

10 1 0.1

0.1 A B C D

Anglotensi anglotens 10 mol/mol

Anglotensin ll

fmol/mol

studies and several large randomized multicenter trials, including Cardiac Insufficiency Bisoprolol Study (CIBIS), Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT–HF), Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study group, COMET (Carvedilol Or Metoprolol European Trial), and US carvedilol trials, have established the survival benefit of β-blockers in HF when added to ACE-inhibitor therapy. The survival benefits of β-blockers have been attributed to reduction in cases of sudden death by reducing the burden of lifethreatening cardiac arrhythmias in NYHA classes I–II and by reversing LV modeling (Figure 6.5). It has been suggested that β-blockers mediate some of their effects by suppressing the renin-angiotensinaldosterone system (65) (Figures 6.6 and 6.7).

1 0.1 0.01

A B C D

A B C

Group

Figure 6.6. Blood concentrations of angiotensin II and angiotensin I, and angiotensin II/angiotensin I ratio. Group A = patients with HF, receiving ACE inhibitors; group B = patients with HF, receiving ACE inhibitors and, ß-blockers; group C = controls; group D = controls, receiving ß-blockers (86).

improved between months 1 and 3 (p = 0.013, metoprolol vs. standard therapy). LV mass regressed at 18 months (333 ± 85 to 275 ± 53 g, p = 0.011) but not at 3 months. LV shape became less spherical and assumed a more normal elliptical shape by 18 months (major/minor axis ratio 1.5 ± 0.2 to 1.7 ± 0.2, p = 0.0001). They concluded that HF patients treated with metoprolol do not demonstrate an improvement in systolic performance until after 1 month of therapy and may have a mild reduction in function initially. However, long-term treatment with metoprolol results in a reversal of maladaptive cardiac remodeling with reduction in LV volumes, regression of LV mass, and improved LV geometry by 18 months. The REVERT (REversal of VEntricular remodeling with Toprol-XL) study is another trial that showed that β-blocker therapy can ameliorate LV remodeling in HF patients with LV systolic dysfunction (67);

116

R.R. Baliga 14

Without b - blockers

12

P<.0002

With b - blockers

Mean Units

10 8 6 P < .02

4 2 0

P = .002

Plasma Renin Activity (ng / mL / h)

Angiotensin II (pg / mL)

Aldosterone (mg / day)

Figure 6.7. Following 1-month washout of antihypertensive agents, 16 patients with hypertension were randomized to a daily dose of β-blocker. After 1 week, the β-blocker was discontinued and a placebo was administered for 1 week with a repeat for alternate β-blocker. Four β-blockers were studied in total and included long-acting propranolol, penbutolol, tertatolol, and bisoprolol (65).

the patients were asymptomatic in this cohort. The authors of this study, led by Wilson Colucci, investigated whether β-blocker therapy ameliorates LV remodeling in asymptomatic patients with LV systolic dysfunction. In this study, 149 HF patients with LVEF < 40%, mild LV dilation, and no symptoms of HF (NYHA class I) were randomly assigned to receive extended-release metoprolol succinate (Toprol-XL, AstraZeneca) 200 mg or 50 mg or placebo for 12 months. Echocardiographic assessments of LV end-systolic volume, enddiastolic volume, mass, and LVEF were performed at baseline and at 6 and 12 months. The patients randomized to the three treatment groups (200 mg, n = 48; 50 mg, n = 48; and placebo, n = 53) were similar with regard to all baseline characteristics including age (mean, 66 year), gender (74% male), plasma B-type naturetic peptide (BNP) (79 pg/ml), LVEDV index (110 ml/m2), and LVEF (27%). At the end of 12 months, there was a 14 ± 3 ml/m2 decrease (least square mean ± SE) in end-systolic volume index and a 6 ± 1% increase in LVEF (p < 0.05 vs. baseline and placebo for both) in the 200-mg group,. The decrease in end-diastolic volume index (14 ± 3) was different from that seen at baseline (p < 0.05) but not with placebo. In the 50-mg group, end-systolic and end-diastolic volume indexes decreased relative to baseline but were not different from what was seen with placebo,

whereas ejection fraction increased by 4 ± 1% (p < 0.05 vs. baseline and placebo). The CARMEN (Carvedilol and ACE-Inhibitor Remodeling Mild HF Evaluation) (68) trial showed that early combination of ACE inhibitors and carvedilol reverses LV remodeling in patients with mild-to-moderate HF and LV systolic dysfunction. This study, led by Willem Remme, investigated, the need for combined treatment for remodeling and order of introduction by comparing the ACE inhibitor enalapril against carvedilol and their combination. In a parallel-group, three-arm study of 18 months duration, 572 mild HF patients were randomly assigned by the study investigators to carvedilol (n = 191), enalapril (n = 190), or their combination (n = 191). In the latter, they up-titrated carvedilol before enalapril. LV remodeling was determined by echocardiography (biplane, modified Simpson) at baseline and after 6, 12, and 18 months of maintenance therapy. Primary comparisons considered the change in LV endsystolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril. They found that in the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favor of combination therapy compared to enalapril. They found that the second primary comparison tended to favor carvedilol to enalapril (p = NS). In the

within-treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.

6.4.2. Effect on Survival The US carvedilol trials, led by Milton Packer, found that carvedilol reduces mortality as well as the risk of hospitalization for cardiovascular causes in patients with HF who are receiving treatment with digoxin, diuretics, and an ACE inhibitor (69). This study enrolled 1094 chronic HF patients in a double-blind, placebo-controlled, stratified manner, in which these patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols, patients with mild, moderate, or severe HF with LVEF ≤ 0.35 were randomly assigned to receive carvedilol (n = 696) or placebo (n = 398). In this study, all patients were on background therapy with digoxin, diuretics, and an ACE inhibitor that remained constant. End points were mortality or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild HF). These investigators found that overall mortality rate was 7.8% in the placebo group and 3.2% in the carvedilol group; the reduction in risk attributable to carvedilol was 65% (95% CI, 39–80%; p < 0.001) (Figure 6.8). These findings led to early termination by the Data and Safety Monitoring Board before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27% reduction in the risk of hospitalization for cardiovascular causes (19.6% vs. 14.1%, p = 0.036), as well as a 38% reduction in the combined risk of hospitalization or death (24.6% vs. 15.8%, p < 0.001). They also found that worsening HF as an adverse reaction during treatment was less frequent in the carvedilol group than in the placebo group. This study was not powered for mortality although it showed significant reductions in mortality. The CIBIS-II study (70) investigated the efficacy of bisoprolol, a β-selective adrenoceptor blocker, in decreasing all-cause mortality in chronic HF. This trial was a multicenter double-blind randomized placebo-controlled trial that enrolled 2647 stable

117

Probability of Survival

6 Neurohormonal Blockade in Heart Failure 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55

Carvedilo Placebo

0

50

100 150 200 250 300 350 40

Days of Therapy No. AT Risk 398 353 329 305 163 71 55 Placebo Carvedilol 696 637 581 546 314 131 106

43 83

Figure 6.8. Kaplan–Meier analysis of survival among patients with chronic heart failure (HF) in the placebo and carvedilol groups. Patients in the carvedilol group had a 65% lower risk of death than did patients in the placebo group (p < 0.001) (69). Copyright© 1996, Massachusetts Medical Society. All rights reserved.

symptomatic NYHA classes III or IV HF patients, with LVEF ≤ 35%, receiving standard therapy with diuretics and ACE inhibitors. The HF patients were randomly assigned bisoprolol 1725 mg (n = 1327) or placebo (n = 1320) daily, the drug dosage being progressively increased to a maximum of 10 mg/day. The mean follow-up period was 173 years. Analysis was by intention to treat. CIBIS-II was stopped early by the Data Safety Monitoring Board, after the second interim analysis, because bisoprolol showed a significant mortality benefit (Figures 6.9 and 6.10). These investigators found that all-cause mortality was significantly lower with bisoprolol than with placebo (156, 1178%, vs. 228, 1773%, deaths with a HR of 0766, 95% CI, 0754–0781, p < 070001). There were significantly fewer sudden deaths among patients on bisoprolol than among those on placebo (48, 376%, vs. 83, 673%, deaths), with a HR of 0756, 0739–0780, p = 070011). The study investigators emphasized that these results should not, however, be extrapolated to patients with severe class IV symptoms and recent instability. This study was conducted in Europe and had very few black patients. The MERITHF study (71) assessed whether metoprolol succinate controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with

118

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Survival

Bisoprolol 0.8 Placebo

p<0.0001

0.6 0 0

200 400 600 Time after inclusion (days)

800

Figure 6.9. There were significantly fewer cardiovascular deaths among patients on bisoprolol than among those on placebo (p = 0.0049). Significantly fewer patients on bisoprolol were admitted to hospital for all causes than patients on placebo (p = 0.0006) as well as for the combined end point of cardiovascular death and admission to hospital for cardiovascular events (p = 0.0004). The number of permanent treatment withdrawals was similar in the two groups (76). Copyright© 2001, Massachusetts Medical Society. All rights reserved.

Bisoprolol (n/total)

Placebo (n/total)

Ischaemia

75/662

121/654

Primary DCM

13/160

15/157

Undefined

68/505

92/509

NYHA lll

116/1106 173/1096

NYHA lV

Figure 6.10. Relative risk (RR) of treatment effect on mortality by etiology and functional class at baseline. Horizontal bars represent 95% CIs (76).

40/221

55/224

Total Relative risk 0.4

decreased LVEF (≤ 40%) and symptoms of HF. Three thousand nine hundred ninety-nine HF patients in NYHA functional classes II–IV and with LVEF ≤ 40%, stabilized with optimum standard therapy, were enrolled in a double-blind randomized controlled study. These investigators preceded randomization by a 2-week single-blind placebo run-in period. One thousand nine hundred ninety patients were assigned to metoprolol CR/XL 12.5 mg (NYHA III–IV) or 25 mg once daily (NYHA II) and 2001 were assigned to placebo. The target dose was 200 mg once daily and doses were up-titrated over an 8-week period. The primary end point of this study was all-cause mortality. Analysis was by intention to treat. This

0.6

0.8

1.0

1.2

1.4

1.6

1.8

study was also stopped early because of the beneficial effects of β-blocker on mortality. Mean follow-up period was 1 year. All-cause mortality was lower in the metoprolol CR/XL group (145, 7.2%, per patient-year of follow-up) than in the placebo group (217 deaths, 11.0%, RR, 0.66, 95% CI, 0.53–0.81; p = 0.00009 or adjusted for interim analyses p = 0.0062). The investigators found that were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs. 132, 0.59, 0.45–0.78; p = 0.0002) and deaths from worsening HF (30 vs. 58, 0.51, 0.33–0.79%]; p = 0.0023). Again this study did not include black patients. An important takeaway from the study was that most of the mortality in NYHA classes

6 Neurohormonal Blockade in Heart Failure

119

II–III was due to sudden death (presumably due to cardiac arrhythmias), and in class IV patients it was predominantly due to CHF (or pump failure) (Figure 6.5). It has been suggested that the mortality benefit due to β-blockers is due to reduction in the rate of sudden death by decreasing the burden of ventricular arrhythmias and due to improving HF by improving pump function. The COPERNICUS led by H. Krum showed that β-blockade was beneficial in severe NYHA classes III–IV HF patients who were clinically euvolemic. They conducted a randomized, double-blind, placebocontrolled trial in 2289 patients with symptoms of HF at rest or with minimal exertion who were clinically euvolemic and had an LVEF < 25%. They randomly assigned patients to receive carvedilol, with start dosage of 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily (n = 1156), or placebo (n = 1133), in addition to their usual medications for HF. Death, hospitalization, or permanent withdrawal from the study drug, as well as adverse events during the first 8 weeks of treatment, were the main outcome measures. They found that the carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 vs. 25; HR, 0.75; 95% CI, 0.41–1.35); who died or were hospitalized (134 vs. 153; HR, 0.85; 95% CI, 0.67–1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs. 188; HR, 0.83; 95% CI, 0.68–1.03). These effects were similar in direction and magnitude to those observed during the entire study and were particularly apparent in the 624 HF patients with recent or recurrent decompensation or a very depressed LVEF. They found that differences in favor of carvedilol became apparent as early as 14–21 days following initiation of treatment. Worsening HF was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs. 5.1%).

trate (target dose 50 mg twice daily). The study cohort was composed of NYHA II–IV chronic HF patients, with previous admission for a cardiovascular reason, an LVEF ≤ 0.35, and who have been treated optimally with diuretics and ACE inhibitors unless not tolerated. The primary end points were all-cause mortality and the composite end point of all-cause mortality or allcause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). Mean LVEF was 0.26 ± 0.07 and the mean age 62 ± 11 years. They found that all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (HR, 0.83, 95% CI, 0.74–0.93; p = 0.0017) (Figure 6.11). The reduction in all-cause mortality was consistent across predefined subgroups. The composite end point of mortality or all-cause admission occurred in 74% (n = 1116 of 1511) on carvedilol and in 76% (1160 of 1518) on metoprolol (0.94, 95% CI, 0.86– 1.02; p = 0.122). This study suggested that carvedilol was superior to short-acting metoprolol tartrate in improving survival in HF patients.

6.4.3. Is Metoprolol Tartrate Superior to Carvedilol?

Number at risk Carvedilol 1511 Metoprolol 1518

The COMET (72), led by Phillip Poole-Wilson, compared the effects of carvedilol and metoprolol tartrate on survival in HF trials. This is a multicenter, doubleblind, and randomized trial that assigned 1511 patients with chronic HF to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol tar-

Figure 6.11. All-cause mortality (72). Reprinted from The Lancet 362 (9377), Poole-Wilson PA, et al, Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): Randomised controlled trial, 7 pages, (2003), with permission from Elsevier.

6.4.4. β-Blockers for Post-MI LV Systolic Dysfunction The CAPRICORN (Carvedilol Post-Infarct Survival Control in Left-Ventricular Dysfunction) study (73), led by Henry Dargie, investigated the impact of carvedilol on morbidity and mortality in patients with LV dysfunction after acute MI. This

Mortality (%)

40

Metoprolol Carvedilol

30 20 10 0 0

1 1366 1359

2 3 Time (years) 1259 1234

1155 1105

4

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1002 933

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study was a randomized, placebo-controlled trial of 1959 patients with an acute MI and an LVEF ≤ 40%. Nine hundred seventy-five patients were randomly assigned to 6.25 mg carvedilol and 984 to placebo. The dose was progressively increased to a maximum of 25 mg twice daily over a 4–6week period. These patients were followed up until the requisite number of primary end points had happened. The primary end point was all-cause mortality or hospital admission for cardiovascular problems. Analysis was by intention to treat. The study investigators found that although there was no difference between the carvedilol and placebo groups in the number of patients with the primary end point (340, 35% vs. 367, 37%, HR 0.92, 95% CI 0.80–1.07), all-cause mortality alone was lower in the carvedilol group than in the placebo group (116, 12% vs. 151, 15%, HR 0.77, 95% CI, 0.60–0.98; p = 0.03). Cardiovascular mortality, nonfatal MIs, and all-cause mortality or nonfatal MI were also lower on carvedilol than on placebo. The study investigators concluded that carvedilol reduced the frequency of all-cause and cardiovascular mortality, and recurrent, nonfatal MIs in patients treated long term after an acute MI complicated by LV systolic dysfunction. These beneficial effects are in addition to those of ACE inhibitors. Carvedilol has beneficial effects on morbidity and mortality not only in patients with mild-tomoderate HF but also in patients with severe HF (74). The study cohort was composed of 2289 HF patients who were symptomatic at rest or on minimal exertion, who were clinically euvolemic, and who had an LVEF ≤ 25%. These investigators, led by Milton Packer, in a double-blind fashion, randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for HF was continued. They excluded patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs. They found that there were 130 deaths in the carvedilol group and 190 deaths in the placebo group. This difference reflected a 35% decrease in the risk of death with carvedilol (95% CI, 19–48%; p = 0.00013, unadjusted; p = 0.0014, adjusted for interim analyses). A total of 425 patients died or were hospitalized in the carvedilol group, as

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compared with 507 in the placebo group. This difference reflected a 24% decrease in the combined risk of death or hospitalization with carvedilol (95% CI, 13–33%; p < 0.001). They found that the favorable effects on both end points were seen consistently in all the subgroups examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (p = 0.02).

6.4.5. Elderly The SENIORS study (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors With Heart Failure), led by Marcus Flather, found that nebivolol, a β-blocker with vasodilating properties, is an effective and well-tolerated treatment for HF in the elderly (≥70 years), regardless of LVEF (75). These investigators, led by Marcus Flather, randomly assigned 2128 patients aged ≥ 70 years with a history of HF (hospital admission for HF within the previous year or known LVEF ≤ 35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily) and 1061 to placebo. The primary end point was a composite of all-cause mortality or cardiovascular hospital admission (time to first event). Analysis was by intention to treat. The mean duration of follow-up was 21 months. Mean age was 76 years (SD 4.7), 37% were female, mean LVEF was 36% (with 35% having LVEF > 35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. They found that the primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo (HR, 0.86, 95% CI, 0.74–0.99; p = 0.039). There was no significant influence of age, gender, or LVEF on the effect of nebivolol on the primary outcome. Allcause mortality was 15.8% with nebivolol (n = 169) and 18.1% (n = 192) with placebo (HR, 0.88, 95% CI, 0.71–1.08; p = 0.21).

6.4.6. β-Blockers and Race The BEST (Beta-Blocker Evaluation of Survival Trial) study investigators, led by Eric Eichhorn, found that β-blockade with bucindolol did not provide significant survival benefit (76). Substudy

6 Neurohormonal Blockade in Heart Failure

121

analyses suggested that bucindolol provided benefit to Caucasians but not to blacks. In this study, a total of 2708 patients with HF designated as NYHA functional classes III (in 92% of the patients) or IV (in 8%) and a LVEF ≤ 35% were randomly assigned to double-blind treatment with either bucindolol (n = 1354) or placebo (n = 1354) and followed for the primary end point of death from any cause. The trial was stopped early by the Data and Safety Monitoring Board after the seventh interim analysis. At the time of stopping the trial, there was no significant difference in mortality between the two groups (unadjusted p = 0.16). Average follow-up period was 2 years. These investigators found that there were a total of 449 deaths in the placebo group (33%) and 411 deaths in the bucindolol group (30%; adjusted p = 0.13). The risk of the secondary end point of death from cardiovascular causes was lower in the bucindolol group (HR, 0.86; 95% CI, 0.74–0.99), as was the risk of heart transplantation or death (HR, 0.87; 95% CI, 0.77–0.99). It has been suggested that the lack of efficacy of bucindolol in this study was due to a lack of efficacy in black patients. The U.S. Carvedilol Heart Failure Trials Program investigators, led by Clyde Yancy, found that the benefit of carvedilol was of similar magnitude in both black and nonblack HF patients (77). These investigators randomly assigned 217 black and

877 nonblack patients, in NYHA classes II–IV and with a LVEF ≤ 0.35, to receive either placebo or carvedilol (at doses of 6.25–50 mg twice daily) and followed them up for up to 15 months. They retrospectively compared the effects of carvedilol on LVEF, clinical status, and major clinical events between black and nonblack patients. They found that as compared with placebo, carvedilol lowered the risk of mortality from any cause or hospitalization for any reason by 48% in black patients and by 30% in nonblack patients (Figure 6.12). Carvedilol reduced the risk of worsening HF (HF leading to death, hospitalization, or a sustained increase in medication) by 54% in black patients and by 51% in nonblack patients. The ratios of the RRs associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95% CI, 0.42–1.34) and 0.94 (95% CI, 0.43–2.05), respectively. They also found that carvedilol improved NYHA functional class, LVEF, and the patients’ and physicians’ global assessments in both the black patients and the nonblack patients. Carvedilol was superior to placebo, for all these measures of outcome and clinical status, within each racial cohort (p < 0.05 in all analyses), and there was no significant interaction between race and treatment (p > 0.05 in all analyses).

US Carvedilol Program: Effect of Race on Outcomes All-cause mortality + all-cause hospitalization

Blacks (n = 217) Nonblacks (n = 877)

All-cause mortality + cardiovascular hospitalization All-cause mortality + HF hospitalization All-cause mortality* 0.2

0.6

1.0

1.4

Favors carvedilol Favors placebo *Not a primary end point. Yancy CW et al. N Engl J Med. 2001;344:1358 –1365. Hazard Ratio Mean duration 6.5 months.

Figure 6.12. US Carvedilol Program: Effect of race on outcomes (77).

122

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MODEL 3

1.0 0.99 (0.73–1.35) 1.26 (1.03–1.52)†

1.0 0.96 (0.71–1.31) 1.25 (1.03–1.52)†

1.0 0.98 (0.72–1.34) 1.28 (1.04 –1.57)†

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* Model 1 adjusted for age, sex, race, and use of other antihypertensive medications. Model 2 adjusted for the variables included in model 1, as well as body-mass index, waist-to-hip ratio, level of education, smoking status, alcohol use, and physical-activity level. Model 3 adjusted for the variables included in model 2, as well as systolic blood pressure, diastolic blood pressure, fasting serum insulin concentration, and the presence or absence of hypercholesterolemia, cardiovascular disease, pulmonary disease, renal insufficiency, and a family history of diabetes. ACE denotes angiotensin-converting enzyme.

†P<0.05 for the comparison with subjects taking no antihypertensive medication.

Figure 6.13. Risk of diabetes mellitus among 3804 subjects with hypertension, according to category of antihypertensive medication (78).

10

Proportion of events (%)

Atenolol-based regimen Amlopidine-based regimen 8

6

4 2

HR-0.70 (95% Cl 0.63-0.78), p<0.0001

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3 Time (years)

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Amlopidine-based regimen (567 events)

9639

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9165

8966

8726

7618

Atenolol-based regimen (799 events)

9618

9295

9014

8735

8455

7319

Number at risk

6

Figure 6.14. Kaplan–Meier curves of cumulative incidence of new-onset diabetes mellitus (79).

β-blockers and insulin sensitivity: There is emerging evidence that β-blockers impair insulin sensitivity. The ARIC (Atherosclerosis Risk in Communities) study investigators found that long-term β-blocker therapy increases the risk of diabetes mellitus (78). In this study, subjects who were taking ACE inhibitors and calcium-channel blockers were not at greater risk for type 2 diabetes mellitus than those not taking any medication whereas individuals with hypertension on b-block-

ers had a 28% higher risk of developing subsequent type 2 diabetes (RR, 1.28; 95% CI, 1.04–1.57) (Figure 6.13). The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) also suggested increased incidence of new-onset diabetes in hypertensives treated with atenolol compared to amlodipine (79) (Figure 6.14). It has been suggested that carvedilol improves insulin sensitivity compared to metoprolol tartarate (80) (Figure 6.15).

6 Neurohormonal Blockade in Heart Failure

123 ALL CAUSE MORTALITY 25

7.3

20

P = .65

% MORTALITY

Mean [SE] HbA 1C (%)

7.4

7.2

7.1

Baseline

Month 5

Carvedilol (n = 454)

1A Above the median PNE Below the median PNE

15 p=0.002

10

5

Figure 6.15. Mean (SE) HbA 1c (%) for metoprolol tartrate: baseline = 7.20 (.02); month 5 = 7.34 (.03). One thousand one hundred eleven patients (90%) were evaluable for efficacy, having both a valid baseline and at least one on-therapy HbA 1c assessment (80).

0

Figure 6.16. Adjusted all-cause mortality in participants with prerandomization plasma norepinephrine (PNE) above (n = 255) and below (n = 254) the medial value of 393 pg/ ml (81). Benedict CR, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation 1996; 94(4):690–697.

Initiation of beta blockade in heart failure patients (cont’d) metoprolol CR/XL* target dose: 200 mg qd

carvedilol+ target dose range: 6.25–25 mg bid

200 mg qd 100 mg qd 50 mg qd 25 mg qd

25 mg bid 12.5 mg bid 6.25 mg bid

12.5 mg qd 0

2 4 6 8 10 0 2 4 6 8 10 weeks weeks * target dose recommendations from MERIT- HF † target dose recommendation from US carvedilol trial and MOCHA

Figure 6.17. Initiation of beta-blockade in heart failure.

Practical recommendations: β-blockers are recommended for all hemodynamically stable patients with HF due to systolic dysfunction. β-blockers are prescribed in asymptomatic HF because elevated sympathetic activity is associated with increased mortality in HF (81) and emerging evidence of its survival benefit in this cohort of patients (Figure 6.16). It is not necessary to be on maximum-dose ACE-inhibitor therapy to

initiate (67) β-blockers, as most patients enrolled in clinical trials were not on high-dose ACE inhibitors. Dosing should include “start low and go slow” with dosing increments (Figure 6.17 and Table 6.4). It is desirable to achieve target doses if tolerated by the patient. Side effects of β-blockers include bradycardia, hypotension, impotence, fluid retention, and fatigue (Figure 6.18). Relative contraindications to β-blockers

124

R.R. Baliga

16%

Six-month mortallty (%)

14%

n=13

* p<.05 vs. placebo ** p<.001 vs. placebo # p<.07 vs. placebo

15.5%

12% 10% 8%

# n=6 6.7%

* n=5

6%

6.0%

4% ** n=1 1.1%

2% 0% Placebo

6.25 mg bid

12.5 mg bid

25 mg bid

Carvedilol

Figure 6.18. The crude mortality rate as a percentage of randomized subjects in the four treatment groups. The placebo-treated group had 13 deaths, for a 15.5% crude mortality over 6 or more months of the study. As can be observed in the figure, there was a dose-related, statistically significant reduction in mortality in the carvediloltreated groups, with respective mortality rates of 6.0% (log-rank analysis: relative risk, RR, 0.356 with 95% CI of 0.127–0.998, p < .05), 6.7% (RR, 0.416 and 95% CI, 0.158–1.097, p = .07), and 1.1% (RR, 0.067 and 95% CI, 0.009 to 0.512, p < .001) for the carvedilol doses of 6.25 mg BID, 12.5 mg BID, and 25 mg BID, respectively. As shown in the figure, the reduction in mortality by carvedilol was highly statistically significant (p < .001) by the linear trend test (88). Bristow MR, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996; 94(11):2807–2816. Table 6.5. Dose of β-blockers in heart failure due to systolic dysfunction. β-blockers

Starting dose

Maximum dose

Bisoprolol Carvedilol Carvedilol controlled (carvedilol CR) Metoprolol succinate extended) release (metoprolol CR/XL

1.25 mg once daily 3.125 mg twice daily 10 mg once daily 12.5–25 mg once daily

10 mg once daily 25 mg twice daily 80 mg once daily 200 mg once daily

include decompensated HF (it is best to start β-blockers when the patient is “dry”), bronchial asthma, bradycardia, patients on β-agonists (such as dobutamine), and hypotension.

therapy because of ethical issues to give a final answer on this ongoing controversy.

6.5. Conclusions 6.4.7. ACE Inhibitors or β-Blockers First It has been argued that beta-blockers as monotherapy may be adequate for management of systolic HF. Others have argued that β-blockers needed to be started first (82, 83). With the current data, it is recommended that all patients be on ACE-inhibitor therapy and β-blockers (84). It is unlikely trials will be conducted in HF without ACE-inhibitor

The development of neurohormonal blockers in non-ischemic and post-MI LV dysfunction is one of the success stories of cardiovascular pharmacology and their benefits have been demonstrated in several trials (see Table 6.5). Despite this success, the utilization of ACE inhibitors/ARBs, β-blockers, and aldosterone receptor blockers remains woefully suboptimal, compelling CMS to mandate that all HF patients should be considered for ACE

6 Neurohormonal Blockade in Heart Failure

125

Table 6.6. Trials demonstrating benefits of neurohormonal blockade in heart failure.

ACE inhibitors Post-MI

AIRE/SAVE (ramipril/captpril)

Mild-to-Moderate HF

SOLVD Treatment (enalapril)

Severe HF

CONSENSUS (enalapril)

Angiotensin receptor blockers

β-blockers

VALIANT OPTIMAAL CAPRICORN (carvedilol) CHARM US Carvedilol/MERIT (carvedilol/ metoprolol XL) CHARM COPERNICUS (carvedilol)

inhibitors/ARBs—a “core-measure” of for HF. Finally, despite optimal neurohormonal blockade, HF remains associated with a marked reduction in well-being and survival (85), making the quest for better therapies for HF urgent.

Acknowledgement This chapter contains text verbatim from publications cited.

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R.R. Baliga inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995; 333(25):1670–1676. 30. Massie, B. M.; Armstrong, P. W.; Cleland, J. G. et al. Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: Results from the ATLAS trial. The Assessment of Treatment with Lisinopril and Survival. Arch Intern Med 2001; 161(2):165–171. 31. Packer, M.; Poole-Wilson, P. A.; Armstrong, P. W. et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100(23):2312–2318. 32. Exner, D. V.; Dries, D. L.; Domanski, M. J.; Cohn, J. N Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001; 344(18):1351–1357. 33. Dries, D. L.; Exner, D. V.; Gersh, B. J.; Cooper, H. A.; Carson, P. E.; Domanski, M. J. Racial differences in the outcome of left ventricular dysfunction. N Engl J Med 1999; 340(8):609–616. 34. Jose, P.; Skali, H.; Anavekar, N. et al. Increase in creatinine and cardiovascular risk in patients with systolic dysfunction after myocardial infarction. J Am Soc Nephrol 2006; 17(10):2886–2891. 35. Hebert LA. Optimizing ACE-inhibitor therapy for chronic kidney disease. N Engl J Med 2006; 354(2):189–191. 36. Cooper, W. O.; Hernandez-Diaz, S.; Arbogast, P. G. et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354(23):2443–2451. 37. Gottlieb, S. S.; Dickstein, K.; Fleck, E. et al. Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation 1993; 88(4 Pt 1):1602–1609. 38. Crozier, I.; Ikram, H.; Awan, N. et al. Losartan in heart failure. Hemodynamic effects and tolerability. Losartan Hemodynamic Study Group. Circulation 1995; 91(3):691–697. 39. Dickstein, K.; Chang, P.; Willenheimer, R. et al. Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol 1995; 26(2):438–445. 40. Pitt, B.; Segal, R.; Martinez, F. A. et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997; 349(9054):747–752. 41. Pitt, B.; Poole-Wilson, P. A.; Segal, R. et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: Randomised

6 Neurohormonal Blockade in Heart Failure trial–the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355(9215):1582–1587. 42. Granger, C. B.; McMurray, J. J.; Yusuf, S. et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARMAlternative trial. Lancet 2003; 362(9386):772–776. 43. McMurray, J. J.; Ostergren, J.; Swedberg, K. et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: The CHARMAdded trial. Lancet 2003; 362(9386):767–771. 44. Pfeffer, M. A.; McMurray, J. J.; Velazquez, E. J. et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349(20):1893–1906. 45. White, H. D.; Aylward, P. E.; Huang, Z. et al. Mortality and morbidity remain high despite captopril and/or Valsartan therapy in elderly patients with left ventricular systolic dysfunction, heart failure, or both after acute myocardial infarction: Results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Circulation 2005; 112(22):3391–3399. 46. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360(9335):752–760. 47. Cleland, J. G.; Tendera, M.; Adamus, J.; Freemantle, N.; Polonski, L.; Taylor, J. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27(19):2338–2345. 48. Yusuf, S.; Pfeffer, M. A.; Swedberg, K. et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: The CHARMPreserved Trial. Lancet 2003; 362(9386):777–781. 49. Solomon, S. D.; Janardhanan, R.; Verma, A et al. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: A randomised trial. Lancet 2007; 369(9579):2079–2087. 50. Carson, P.; Massie, B. M.; McKelvie, R. et al. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: Rationale and design. J Card Fail 2005; 11(8):576–585. 51. Pfeffer, M. A.; Swedberg, K.; Granger, C. B et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARMOverall programme. Lancet 2003; 362(9386):759–766. 52. Struthers AD. The clinical implications of aldosterone escape in congestive heart failure. Eur J Heart Fail 2004; 6(5):539–545. 53. Schersten, B.; Thulin, T.; Kuylenstierna, J. et al. Clinical and biochemical effects of spironolactone adminis-

127 tered once daily in primary hypertension. Multicenter Sweden study. Hypertension 1980; 2(5):672–679. 54. Williams, G. H.; Burgess, E.; Kolloch, R. E. et al. Efficacy of eplerenone versus enalapril as monotherapy in systemic hypertension. Am J Cardiol 2004; 93(8):990–996. 55. Bauersachs, J.; Heck, M.; Fraccarollo, D et al. Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction: Role of vascular superoxide anion formation and endothelial nitric oxide synthase expression. J Am Coll Cardiol 2002; 39(2):351–358. 56. Bauersachs, J.; Fraccarollo, D.; Ertl, G.; Gretz, N.; Wehling, M.; Christ, M. Striking increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE inhibition: Mechanistic evidence to support RALES. Circulation 2000; 102(19):2325–2328. 57. Chan, A. K.; Sanderson, J. E.; Wang, T. et al. Aldosterone receptor antagonism induces reverse remodeling when added to angiotensin receptor blockade in chronic heart failure.J Am Coll Cardiol 2007; 50(7):591–596. 58. Pitt, B.; Zannad, F.; Remme, W. J. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341(10):709–717. 59. Baliga, R. R.; Ranganna, P.; Pitt, B.; Koelling, T. M. Spironolactone treatment and clinical outcomes in patients with systolic dysfunction and mild heart failure symptoms: A retrospective analysis. J Card Fail 2006; 12(4):250–256. 60. Pitt, B.; Remme, W.; Zannad, F. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348(14):1309–1321. 61. Pitt, B.; White, H.; Nicolau, J. et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol 2005; 46(3):425–431. 62. Juurlink, D. N.; Mamdani, M. M.; Lee, D. S. et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351(6):543–551. 63. Georges B, Beguin C, Jadoul M. Spironolactone and congestive heart-failure. Lancet 2000; 355(9212):1369–1370. 64. Clinical Trials Gov. TOPCAT trial. [cited; Available from: http://www.clinicaltrials.gov/ct2/show/NCT0009 4302. 65. Blumenfeld, J. D.; Sealey, J. E.; Mann, S. J. et al. Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensinaldosterone system in normotensive and hypertensive subjects. Am J Hypertens 1999; 12(5):451–459.

128 66. Hall, S. A.; Cigarroa, C. G.; Marcoux, L.; Risser, R. C.; Grayburn, P. A.; Eichhorn, E. J. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol 1995; 25(5):1154–1161. 67. Colucci, W. S.; Kolias, T. J.; Adams, K. F. et al. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: The Reversal of Ventricular remodeling with Toprol-XL (REVERT) trial. Circulation 2007; 116(1):49–56. 68. Remme, W. J.; Riegger, G.; Hildebrandt, P. et al. The benefits of early combination treatment of carvedilol and an ACE-inhibitor in mild heart failure and left ventricular systolic dysfunction. The carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN). Cardiovasc Drugs Ther 2004; 18(1):57–66. 69. Packer, M.; Bristow, M. R.; Cohn, J. N. et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334(21):1349–1355. 70. CIBIS Investigators, The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial. Lancet 1999; 353(9146):9–13. 71. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353(9169):2001–2007. 72. Poole-Wilson, P. A.; Swedberg, K.; Cleland, J. G. et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): Randomised controlled trial. Lancet 2003; 362(9377):7–13. 73. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: The CAPRICORN randomised trial. Lancet 2001; 357(9266):1385–1390. 74. Packer, M.; Coats, A. J.; Fowler, M. B. et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344(22):1651–1658. 75. Flather, M. D.; Shibata, M. C.; Coats, A. J et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005; 26(3):215–225. 76. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344(22):1659–1667. 77. Yancy, C. W.; Fowler, M. B.; Colucci, W. S. et al. Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure. N Engl J Med 2001; 344(18):1358–1365.

R.R. Baliga 78. Gress, T. W.; Nieto, F. J.; Shahar, E.; Wofford, M. R.; Brancati, F. L. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med 2000; 342(13):905–912. 79. Dahlof, B.; Sever, P. S.; Poulter, N. R. et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomised controlled trial. Lancet 2005; 366(9489):895–906. 80. Bakris, G. L.; Fonseca, V.; Katholi, R. E et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: A randomized controlled trial. Jama 2004; 292(18):2227–2236. 81. Benedict, C. R.; Shelton, B.; Johnstone, D. E. et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation 1996; 94(4):690–697. 82. Fang JC. Angiotensin-converting enzyme inhibitors or beta-blockers in heart failure: Does it matter who goes first? Circulation 2005; 112(16):2380–2382. 83. Remme WJ. Beta blockers or angiotensin-convertingenzyme inhibitor/angiotensin receptor blocker: What should be first? Cardiol Clin 2007; 25(4):581–594; vii. 84. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005; 46(6):e1–82. 85. Cleland, J. G.; Charlesworth, A.; Lubsen, J. et al. A comparison of the effects of carvedilol and metoprolol on well-being, morbidity, and mortality (the “patient journey”) in patients with heart failure: A report from the Carvedilol Or Metoprolol European Trial (COMET). J Am Coll Cardiol 2006; 47(8):1603–1611. 86. Campbell, D. J.; Aggarwal, A.; Esler, M.; Kaye, D. beta-blockers, angiotensin II, and ACE inhibitors in patients with heart failure. Lancet 2001; 358(9293): 1609–1610. 87. McKelvie, R. S.; Yusuf, S.; Pericak, D. et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation 1999; 100(10):1056–1064. 88. Bristow, M. R.; Gilbert, E. M.; Abraham, W. T. et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation 1996; 94(11):2807–2816.

7 Early Medical Management of Acute Heart Failure Syndromes Nils P. Johnson, Alec J. Moorman, Peter S. Pang, Sean P. Collins, Micah J. Eimer, and Mihai Gheorghiade

7.1. Introduction This chapter outlines the practical, initial 24 h of management in patients with acute heart failure syndromes (AHFS). In the United States, emergency department (ED) physicians and internists provide the majority of management.

7.1.1. Patient Profile Table 7.1 provides baseline patient characteristics from major US and European registries totaling over 200,000 AHFS admissions. 1–3 The median age is 75 years, 50% are women, 75% are Caucasian, 20% are African-American, 75% have a prior history of chronic heart failure (HF), 50% have a reduced ejection fraction (EF < 40%) but 50% have preserved EF, 70% have hypertension, 55% have coronary artery disease (CAD), 30% have a history of myocardial infarction (MI), 30% have atrial fibrillation, 45% have diabetes, 20% have a creatinine over 2.0 mg/dl, and 10% have a pacemaker or implanted defibrillator.

7.1.2. Clinical Course Most patients respond to traditional therapy.4–7 Despite symptom relief, postdischarge event rates remain high. Although admission for HF itself identifies a group of patients with a relatively low inhospital mortality (roughly 5%1-3), the postdischarge event rate is significant (60–90-day readmission rate

of 30% with a mortality which varies from 5% to 15% depending on admission blood pressure).

7.1.3. Cost In 2004, the estimated direct and indirect costs of HF in the United States totaled $25.8 billion,8 of which an estimated 75% was consumed by in-patient care9. An average hospital stay lasted 4 days, with 20% of patients treated in an intensive care unit1. Each admission for HF costs from $6,000 to $12,000.10 Of note, hospital discharges for HF rose from 377,000 in 1979 to 995,000 in 2001 and are predicted to continue to increase given the aging of the population.8,11

7.2. Evidence-Based Practice Compared to acute MI, a disease with a similar number of annual hospitalizations, there are fewer high-quality epidemiologic studies or randomized controlled trials in AHFS. Table 7.2 compares the present state of knowledge in AHFS and MI. Despite its high prevalence, significant rates of associated morbidity and mortality, and enormous cost, the entity of AHFS remains inadequately defined and understudied.12 Published guidelines, the first from 2005, are only now emerging.13-16 Current therapy for AHFS is mainly empiric. Regrettably, most placebo-controlled pharmacologic trials conducted to date for AHFS have shown limited success with regard to both efficacy and safety.17

129

130

N.P. Johnson et al. Table 7.1. Patient demographics from AHFS registries.

Age Women Caucasian African-American Prior HF Reduced LVEF CAD Hypertension Diabetes Atrial fibrillation Renal insufficiency

ADHERE (159,168)1

EHFS II (3,580)2

OPTIMIZE-HF (48,682)3

72 years 52 (%) 74 21 76 51 (EF < 40%) 58 74 – 31 30

70 years 39 (%) – – 63 66 (EF < 45%) 54 63 33 39 17

73 years 52 (%) – 18 12 51 (EF < 40%) 46 23 – 31 –

Abbreviations: ADHERE Acute Decompensated Failure National Registry, EHFS II EuroHeart Failure Survey II, AHFS acute heart failure syndromes, CAD coronary artery disease, HF heart failure, LVEF left ventricular ejection fraction, OPTIMIZE-HF Organized Program to Initiate Lifesaring Treatment in Hospitalized Patients with Heart Failure.

Table 7.2. Significance of AHFS. AHFS Hospitalizations (2001 in U.S.)8 In-hospital mortality Postdischarge mortality Readmission rate Guidelines for risk stratification Guidelines for therapy Large-randomized trials

995,000 5%2,3 10% at 60 days3,27 30% at 60–90 days3 Emerging Emerging Few

Acute myocardial infarction 795,000 10–15%123,124 ~ 3–9% at 30 days Low Established Established Many

Based on updated version of Table 1 in Felker et al.12 Abbreviations: AHFS acute heart failure syndromes.

7.3. General Management Principles 7.3.1. Clinical Presentation A number of pathophysiologic mechanisms, including cardiac dysfunction, renal dysfunction, and activation of neurohormones, can slowly or rapidly result in clinical signs and symptoms of elevated ventricular filling pressures and/or reduced cardiac output (CO). Three clinical syndromes based on blood pressure make up the spectrum of AHFS: (1) symptoms with hypertension [systolic blood pressure (SBP) > 140 mmHg], (2) symptoms with SBP = 100–160 mmHg, and

(3) symptoms with relative hypotension (SBP < 100 mmHg).13,18 Within each of these blood pressure ranges, patients can concurrently have acute coronary syndromes (ACS, ~10%), precipitating arrhythmia (5%), or clinical pulmonary edema (3–5%). While presentations of end-stage or treatment-refractory HF and cardiogenic shock are infrequent (< 5%), they almost always occur in the group with SBP < 100 mmHg. Table 7.3 provides a framework for the initial evaluation and management of patients based on the blood pressure and clinical manifestations. This is an arbitrary classification and many patients may simultaneously have, or rapidly develop, features of multiple clinical syndromes.19

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Table 7.3. Blood pressure directed initial management of the clinical syndrome in AHFS. Syndrome

SBP>160 mmHg

SBP 100-160 mmHg

SBP<100 mmHg

Worsening chronic HF

1. Vasodilators 2. Diuretics

1. Diuretics 2. Vasodilators

1. Inotropes (dobutamine, milrinone, levosimendan) or pressors (phenylephrine, epinephrine, vasopressin) 2. Diuretics

Acute coronary syndrome

1. PCI for STEMI 2. Antiplatelet and antithrombin therapy 3. Nitrates 4. Diuretics

1. PCI for STEMI 2. Antiplatelet and antithrombin therapy 3. Nitrates 4. Diuretics

1. 2. 3. 4. 5. 6.

Pulmonary edema

1. 2. 3. 4.

1. PPV 2. MSO4/Nitrates 3. Diuretics

1. Inotropes 2. Diuretics 3. IABP

End-stage HF

Rare

Rare

1. 2. 3. 4.

Inotropes Ultrafiltration LVAD IABP

Cardiogenic shock

N/A

N/A

1. 2. 3. 3. 4.

Catherizartion Norepinephrine Surgery if temponade or VSD Inotropes IABP or LVAD

Atrial Arrhythmia (atrial fibrillation or flutter)

1. Control rate 2. Consider cardioversion

1. Control rate 2. Consider cardioversion

1. Cardioversion 2. Consider cardioversion

MSO4/Nitrates Vasodilators Diuretics PPV if low pH or high pCO2

PCI for STEMI Antiplatelet and antithrombin therapy Nitrates Diuretics Consider IABP Cautious inotropes if no IABP available

All patients should have a recent echocardiographic evaluation. Abbreviations: AHFS acute heart failure syndromes, PAC pulmonary artery catheter, PPV positive pressure ventilation, MSO4 morphine sulfate, IABP intra-aortic balloon pump, HF heart failure, BP blood pressure, LVAD left ventricular assist device. pH = acid/base status. VSD = ventricular septal defect. pCO2 = arterial partial pressure of carbon dioxide. PCI = percutaneous coronary intervention. STEMI=ST segment elevation myocardial infarction.

7.4. Myocardium at Risk An emerging concept in the management of AHFS is the importance of avoiding injury to myocardium.12 Areas of viable but noncontracting myocardium are often present and may be demonstrated by magnetic resonance imaging, echocardiography, or nuclear imaging. These areas occur in both ischemic and nonischemic cardiomyopathies. Myocardial hibernation is a process in which myocardial contraction is downregulated in response to a chronic reduction in myocardial blood supply. In both cases, the level of tissue perfusion is sufficient to maintain cellular viability but insufficient for normal contractile function. In nonischemic cardiomyopathy a heterogeneous group of etiologies produces viable but noncontracting myocardium. Several mechanisms in AHFS may exacerbate myocardial injury: increased left-ventricular filling pressure (LVFP) producing subendocardial ischemia,

hypotension as a result of therapy with vasoactive agents resulting in decreased coronary perfusion, myocardial ischemia and endothelial dysfunction in patients with CAD, increased contractility of hibernating myocardium as a result of therapy with inotropic agents without a concomitant increase in coronary blood flow, and further and excessive activation of neurohormones.20 Treatment choices should influence the myocyte demand–supply balance in a positive fashion, for example, avoiding reductions in perfusion and minimizing increases in LVFP.

7.5. Evaluation 7.5.1. Location of Management During the first 24 h of management, the ED followed by an inpatient setting with or without telemetry is the most common location for treatment. Certain types of therapy demand telemetry, respiratory therapists,

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or invasive hemodynamic monitoring, which may be available only in specific units. Figure 7.1 suggests criteria for triaging patients. The location of initial management may affect time to therapeutic intervention and perhaps patient outcome as well. The time between arrival and initiation of diuretic or vasoactive therapy is lower in the ED compared to that in an inpatient ward, and emerging, although etrospective, data suggest that faster doorto-therapy times in the ED reduce length of stay.21 The emergency department observation unit (EDOU) exists as a designated area where simultaneous risk assessment and treatment can occur for up to 23 h before a decision is made on transfer to an inpatient unit or discharge home. It has the advantage of faster door-to-therapy times mentioned above, without the need and cost for a full inpatient admission. Establishing an EDOU can decrease cost, readmission rates, and length of stay.22,23 Although EDOU management of HF is not as widespread as ED chest pain units, management protocols for AHFS patients exist.24-26

7.6. Initial Assessment The initial assessment of every patient should begin with the basic “airway, breathing, circulation”

N.P. Johnson et al.

evaluation. This immediately identifies patients in cardiogenic shock or respiratory failure who must be treated emergently. Options for patients who present in extremis include noninvasive or invasive mechanical ventilation, blood pressure reduction with intravenous (IV) vasodilators for hypertensive emergency, and inotropic support for cardiogenic shock. After hemodynamic and respiratory stability has been achieved, a more detailed assessment of the patient with suspected HF should establish the diagnosis and evaluate CO and congestion.3 An emerging concept to guide immediate therapy is blood pressure,19 as detailed below. Patients with low blood pressure comprise a small percentage of the total (~5%).3

7.6.1. History, Physical, and Basic Tests The diagnosis of HF should be aggressively pursued. About 80% of patients present with a known diagnosis of HF.1,27 See Chap. 3 on “Diagnostic and Management Tools” for an in-depth discussion on the diagnosis of HF. Approximately 75% or more of patients present with congestion, while only 5% or less have evidence of systemic hypoperfusion. These two clinical syndromes can combine in four pro-

Figure 7.1. Risk stratification and disposition algorithm for patients hospitalized with heart failure

7. Early Medical Management of Acute Heart Failure Syndromes

files: congestion without hypoperfusion (“wet and warm”), congestion with hypoperfusion (“wet and cold”), no congestion or hypoperfusion (“dry and warm”), and no congestion with hypoperfusion (“dry and cold”).28,29 Note that this two-by-two classification scheme was developed for and validated in end-stage or treatment-refractory HF30 and thus may be less applicable in the acute setting.

7.6.1.1. History A detailed history should include a search for precipitants as outlined in Table 7.4. Previous records, including home daily weights, discharge summaries, and laboratory results, provide valuable information about baseline status as well as the time course of decompensation. Current symptoms such as dyspnea, either at rest or with exertion, orthopnea, and paroxysmal nocturnal dyspnea should be elicited to serve as a reference point during treatment. While these signs and symptoms can be helpful when present, their intermediate likelihood ratios and low sensitivities suggest that they are not ideal screening tools.31,32.

Table 7.4. Precipitants of AHFS. Idiopathic or disease progression Patient-related factors • Noncompliance with diet/fluids • Noncompliance with medication • Alcohol or cocaine use Medication effects • Nonsterodial anti-inflammatory drugs (NSAIDs) • Calcium-channel antagonists (except amlodipine) • Class 1A and 1C antiarrhythmics • Thiozolidinedione • Pregabalin Cardiovascular disease • Acute coronary syndromes • New or uncontrolled arrhythmia • Uncontrolled hypertension High output states • Hyperthyroidism • Anemia • Febrile illness Pulmonary disease • Pneumonia • COPD/asthma exacerbation Abbreviations: AHFS acute heart failure syndromes, COPD chronic obstructive pulmonary disease.

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7.6.1.2. Physical Examination The most important vital signs are the blood pressure, heart rate, and respiratory rate. The pulse oximetry saturation, temperature, and standing weight should also be recorded, although the standing weight is practical only for inpatients. A physical examination must specifically look for jugular venous distention (JVD), pulmonary rales, and peripheral edema. Secondary physical examination findings which appear less frequently or more difficult to evaluate are changes in mental status, a third-heart sound, and hepatojugular reflux.

7.6.1.3. Initial Diagnostic Testing Tests that should be considered in most patients are serum electrolytes (including magnesium), blood urea nitrogen (BUN) and creatinine, complete blood count including differential, troponin, B-type naturetic peptide (BNP), electrocardiogram (ECG), and chest x-ray (CXR). Additional studies which can be considered based on the history and physical examination include an arterial blood gas, liver function and coagulation tests to assess hepatic congestion, and thyroid function tests. Echocardiography (usually after initial management), which should always be performed with Doppler, provides invaluable information on overall left and right ventricular function and the presence of focal wall motion abnormalities, pericardial fluid, valvular lesions, and estimated pulmonary artery (PA) pressure. A low threshold should exist for performing echocardiography, especially in patients who have decompensated greatly from their previously known clinical status.

7.6.2. Assessment of Cardiac Output Patients with AHFS rarely present with hypotension or cardiogenic shock. Nonetheless, a low SBP, high heart rate, narrow pulse pressure, decreased mental status, and cool or dusky extremities are suggestive of a critically low CO. Bioimpedance provide as estimate of CO by using low-level alternating current to study of the variation in impedance (either whole-body or thoracic) over time, from which it is possible to compute the stroke volume.33 It has been shown to correlate well with thermodilution techniques in a wide range of clinical situations,33,34 including AHFS,35 although some data exist for underestimation at high CO36.

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Emerging data suggest that the early use of impedance cardiography can impact management.37 A slightly more invasive option is the Lidco device, which requires arterial and venous access and calculates CO by a lithium dilution technique.38 There is currently no data on the accuracy of this device in patients with AHFS. Measuring CO via a PA catheter remains the gold standard. However, the low output state is generally defined not by CO but by clinical assessment (low SBP, cold extremities, decreased or no urine output).

7.6.3. Assessment of Congestion Assessing congestion noninvasively poses a significant clinical challenge,31 especially after initial treatment in the ED has resolved the most flagrant signs and symptoms. Patients who complain of dyspnea, either at rest or with exertion, orthopnea, and paroxysmal nocturnal dyspnea likely have elevated leftsided filling pressures, although these symptoms can occur in noncardiac conditions.32 However, while patients with more rapid volume overload present with rales on physical examination and congestion on CXR, those with chronic volume overload may have less or absent rales and few CXR findings in spite of very high filling pressures. Therefore, limits exist to the physical examination and CXR in worsening chronic HF. Of the techniques described below, the most important are noting JVD, an elevated BNP level, and residual congestion on CXR.

7.6.3.1. Physical Examination Physical examination techniques such as assessment of JVD, a ventricular third-heart sound, pulmonary rales, hepatojugular reflux, and peripheral edema provide gross evidence of congestion, and their resolution with treatment indicates a decreased plasma volume. Nonetheless, these physical findings lack either sensitivity or specificity or both. In chronic volume overload, rales may be absent entirely and JVD may prove a more useful finding. Note that in patients with a high PA pressure, the JVD may be difficult to observe at 45 degrees and these patients should be examined while sitting upright.

7.6.3.2. Chest X-Ray The CXR provides a noninvasive method to assess and track volume status. CXR findings that suggest

N.P. Johnson et al.

congestion include pulmonary vascular congestion, alveolar infiltrates, enlarged cardiac silhouette, lymphatic hypertrophy (Kerley lines), and cardiomegaly. Quantitative markers such as the vascular pedicle correlate with changes in volume status.39 In chronic volume overload, increased lymphatic uptake may limit CXR findings [no radiographic congestion despite a high pulmonary capillary wedge pressure (PCWP)], in contrast to acute volume overload (radiographic congestion which reflects a high PCWP). While pulmonary edema is virtually diagnostic for ADHF when present, chest radiography may lack congestion in up to 20% of patients.1,2,40,41

7.6.3.3. B-Type Natriuretic Peptide A cutoff value of 100 pg/ml for a single BNP level is 90% sensitive and 73% specific for the diagnosis of HF.42 The value should be interpreted in the context of the patient’s age, gender, body weight, and renal function. Ideally, every patient would have a recorded BNP level that reflects a “dry weight” as the basis of comparison. Elevations in BNP may not correspond to fluid overload in the setting of renal failure and sepsis. The BNP level correlates better with the wedge pressure early during presentation, but this diminishes after initial treatment. Its use is particularly valuable in patients with preserved systolic function.

7.6.3.4. Dynamic Assessment These maneuvers are most helpful after initial management to determine the extent of residual congestion. Both BNP level and CXR congestion suffer from a therapeutic lag between a decrease in wedge pressure and its resultant manifestation on these tests. While these maneuvers play a more limited role in the ED, they can be useful on selected inpatients. For patients without HF, a decrease in preload produces a decrease in CO and SBP. However, for patients with HF, a decrease in preload may not change the CO or SBP and may even increase it (Figure 7.2). Three hemodynamic maneuvers exist which exploit this relationship: orthostatic changes, sublingual nitroglycerin, and the Valsalva maneuver. All decrease venous return and hence decrease preload. If any maneuver produces no change or increase in CO or SBP, then this can be taken as evidence of a high PCWP.

7. Early Medical Management of Acute Heart Failure Syndromes

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Relationship between CO/SBP and PCWP

4

CO or BP

Moderate HF *Severe HF PCWP (mm Hg)

Figure 7.2. Relationship between CO (cardiac output)/SBP (systolic blood pressure) and pulmonary capillary wedge pressure (PCWP). * denotes decreased CO/BP (blood pressure) due to worsening mitral regurgitation, increase in afterload, and subendocardial ischemia due to high leftventricular filling pressure (LVFP)

To assess for orthostatic changes, first measure SBP and heart rate (HR) after 5 min of supine rest. Repeat these measurements immediately after standing. Again, repeat these measurements after 1–3 min of continued standing. A seated measurement may be substituted if the patient is unable to stand. A decrease of at least 5–10 mmHg after standing or sublingual nitroglycerine implies euvolemia. Sublingual nitroglycerin should be administered as follows. First, the patient should be placed in a seated or supine position. Next, measure the SBP and HR. Then, place 400 mcg of nitroglycerin under the tongue and wait for 3–5 min. Repeat the measurements of SBP and HR, and, optionally, again 15 min later. For the Valsalva maneuver,32,43,44 first measure the SBP while the patient is breathing quietly with normal tidal volumes. Then, inflate a blood pressure cuff to 15 mmHg above resting SBP. Ask the patient to finish a normal inspiratory effort and then strain as if he were having a bowel movement. After 10 s of constant straining, instruct the patient to relax his abdomen and resume normal respirations. During this procedure, and for 30 s afterwards, lock the cuff pressure 15 mmHg above the previously determined baseline SBP while Korotkoff sounds are sought by auscultation over the brachial artery. The normal arterial blood pressure response to the Valsalva maneuver (Figure 7.3)43 is an initial rise associated with the onset of straining (phase 1), followed by a sharp fall to below baseline levels as the straining is maintained (phase 2). Release of strain (phase 3) is followed in normal subjects by a distinct

Arterial pressure (mm Hg)

Normal

200 150 100 50 0

A

150

B

1 2

3

1 2 3

100 50 0 200 150 100 50 0

C

1

Start

2

3

Stop

Figure 7.3. Arterial Pressure Tracings with the Valsalva Maneuver. (A) Sinusoidal arterial pressure response (Normal). (B) Absent overshoot arterial pressure response (mild HF). (C) Square wave arterial pressure response (severe HF). Start = start of Valsalva, Stop = end of Valsalva. 1 = onset of Valsalva, 2 = normal decrease in pressure during strain phase, 3 = overshoot and end of strain phase. From Zema et al.43 Reproduced with permission from the BMJ Publishing Group

overshoot of the arterial pressure (phase 4), creating a typical sinusoidal response. Only phases 2 and 4 register clinically, as phases 1 and 3 are too short to be noticed. The examiner should listen for Korotkoff sounds during continued straining of the patients (phase 2) and after relaxation (phase 4). Three types of responses to the Valsalva maneuver exist: (a) sinusoidal (normal), (b) absent overshoot, and (c) square wave. This maneuver requires significant experience, may be difficult to perform in the acute setting, and may need to wait until after initial stabilization. An automated device has been developed that measures the blood pressure response during the Valsalva maneuver. Preliminary data suggest that it is a promising device,45 but further prospective study is warranted before adopting this in the ED.

7.6.3.5. Pulmonary Artery Catheter The majority of patients can be managed initially using noninvasive techniques. Placement of a PA catheter should be considered later during treatment only for situations where

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• the diagnosis of HF is unclear despite noninvasive testing, • patients do not respond to treatment, • hypotension arises, especially when volume status is unclear, • renal failure worsens or is unexplained. A trial randomized patients hospitalized with severe HF without hypotension or renal insufficiency to receive management by either PA catheter and clinical assessment or clinical assessment alone.46 Results showed no added benefit from PA catheter use,47 but also did not find an increase in adverse events, as had been suggested by earlier studies.48 A PA catheter should only be placed if its assessment49 will change management, and careful attention should be paid to minimizing the risk of line-related infection.

N.P. Johnson et al.

7.7.1.3. Cardiac Troponin Myocardial ischemia and injury play a critical role in AHFS, although it is often unclear whether the ischemia is primary or secondary to the HF. Elevated cardiac troponin levels predict worse outcomes in AHFS patients,63 including both primary ischemia64 and those in whom an acute ischemic event is not suspected (secondary ischemia).65 Combining cardiac troponins with BNP levels may improve overall predictive power.55,65,66

7.7.1.4. Renal Function Worsening renal function (increased BUN but not creatinine) or renal failure during AHFS is associated with higher morbidity and mortality as well as increased length of stay.67-73 At least 20% of patients in large AHFS registries have significantly elevated creatinine levels,1,74,27,73 a high baseline risk exists.

7.7. Risk Stratification 7.7.1.5. Hyponatremia

7.7.1. Prognostic Variables 7.7.1.1. Blood Pressure The majority of patients admitted with AHFS have normal or elevated blood pressure, and only 3% of patients have a SBP below 90 mmHg.1 Low SBP is associated with advanced cardiac failure and predicts higher rates of readmission and mortality.50-52 SBP upon admission predicts both in-hospital and 60–90-day postdischarge mortality.3 A monotonic, inverse relationship exists between SBP and AHFS mortality, with patients whose SBP < 120 mmHg having a 7% in-hospital mortality rate compared to 2% for those with SBP > 160 mmHg.

7.7.1.2. B-Type Naturetic Peptide BNP, and the related inactive metabolite N-terminal pro-BNP, provide a serum marker of ventricular stretch.53 They correlate modestly with PCWP, although their release from the ventricle takes time and lags the acute elevation of left-sided pressures.54 High admission and discharge levels of BNP, as well as BNP trajectories during hospitalization, predict both readmission and mortality independent of other accepted clinical and laboratory parameters.55-61 Its measurement has been shown in a randomized trial to help guide management, reduce ED stay and rehospitalization, and overall health care costs.62

Twenty percent of patients admitted for AHFS have a serum sodium concentration < 136 mEq/l.75 Hyponatremia is related to the nonosmotic release of vasopressin, which is mediated by activation of the sympathetic nervous system and the renin– angiotensin–aldosterone system (RAAS).76 Low serum sodium is a marker of neurohormonal activation and disease severity, and several studies have demonstrated that hyponatremia is associated with a poor prognosis50,77-80 and its resolution during admission is associated with better outcomes.81 Hyponatremia can be corrected with vasopressin antagonists,5 but this does not alter long-term outcome.6

7.7.1.6. Left-Ventricular Filling Pressure Nearly all patients with AHFS have symptoms and signs of elevated LVFP. Persistent elevation in LVFP is associated with an increased risk of progressive HF death, sudden death, and overall mortality in patients hospitalized with AHFS.82 Conversely, freedom from congestion predicts good survival.83 LVFP is usually inferred noninvasively using the techniques described above.

7.7.1.7. Etiology of HF Etiology affects not only management decisions but also prognosis. In two large prospective trials,

7. Early Medical Management of Acute Heart Failure Syndromes

an ischemic HF etiology was shown to predict higher rates of mortality and readmission.84,85 While ischemic etiology plays less of an acute role, optimal management of underlying CAD throughout admission is imperative when treating patients with AHFS.

7.7.1.8. Arrhythmias Arrhythmias, whether preexisting or new-onset, can not only precipitate HF but also correlate with worse outcomes. Roughly 5% of AHFS patients have new arrhythmias, of which half are either atrial fibrillation or flutter. The presence of a new arrhythmia is associated with higher in-hospital mortality, as well as higher readmission or death at 60 days, compared to patients without a new arrhythmia.86

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While a simple triad of BUN at least 43 mg/dl, SBP less than 115 mmHg, and serum creatinine at least 2.75 mg/dl predicts a 25% in-hospital mortality rate, it is found in only 2% of patients. Conversely, the combination of BUN less than 43 mg/dl and SBP at least 115 mmHg predicts a 2% in-hospital mortality rate but is found in 66% of patients (Table 7.5).92 Although several quantitative schemes have been published, their application to a validation cohort95 suggests a heterogeneity likely reflective of the derivation populations. Currently, no single quantitative scheme for risk stratification has emerged, unlike the Framingham score for atherosclerosis or the Thrombolysis In Myocardial Infarction (TIMI) score for ACS.

7.8. Clinical Presentations 7.7.1.9. Anemia Anemia may precipitate or be associated with HF, and adversely affects outcome. A low hemoglobin has been identified as an independent predictor of readmission and mortality.71,87-90 Low hemoglobin could simply be a marker of hemodilution in the disease process or might contribute actively by promoting left ventricular hypertrophy in addition to a high output state.91

7.7.2. Quantitative Schemes Quantitative systems for assessing in-hospital,92,93 30-day78 or 1-year mortality,78,94 and 60-day mortality and/or readmission77 for hospitalized HF are emerging. Predictive variables include low SBP, high BUN, elevated creatinine, hyponatremia, advanced age, and comorbid conditions.

7.8.1. Worsening Chronic HF Most patients with AHFS present with signs and symptoms of congestion and a known history of HF (chronic HF). Roughly 90% have dyspnea (at rest, with exertion, or both), 70% have rales and peripheral edema, and 80% have CXR findings consistent with congestion.1 Clinical pulmonary congestion (rales or radiographic congestion) may be less marked in patients with long-standing HF in spite of a very high LVFP. The pathophysiology of congestion is multifactorial and currently incompletely understood. Renal dysfunction and further neurohormonal activation contribute significantly to the congestive state. Achieving euvolemia and neurohormonal blockade are the primary modalities of treatment. The goal is to achieve the lowest possible LVFP that

Table 7.5. Risk stratification scheme for AHFS. Risk group Low Intermediate 3 Intermediate 2 Intermediate 1 High

BUN (mg/dl)

Systolic blood pressure (mmHg)

< 43 < 43 ≥ 43 ≥ 43 ≥ 43

≥ 115 < 115 ≥ 115 < 115 < 115

Based on Figures 1–3 of Fanarow et al.92 Abbreviations: AHFS acute heart failure syndromes.

Serum creatinine (mg/dl) N/A N/A N/A < 2.75 ≥ 2.75

Frequency

In-hospital mortality

65.3% 12.8% 15.8% 4.4% 1.7%

1.8% 4.5% 8.0% 14.1% 25.0%

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N.P. Johnson et al.

allows for adequate end-organ perfusion without activation of neurohormones. Volume status should be frequently assessed and used to titrate and guide therapy in an “assess–treat–reassess” cycle.

7.8.1.1. Pharmacologic Therapy First-line agents may include loop diuretics and/or vasoactive agents depending on the blood pressure at clinical presentation (Tables 7.6 and 7.8). Combination therapy should be the rule and not the exception. 7.8.1.1.1. Loop Diuretics Loop diuretics remain a cornerstone of management despite a lack of prospective, randomized trials examining their safety or efficacy.

IV furosemide causes venodilation within 15 min and induces diuresis ~30 min after administration, with peak effect between 1 and 2 h. Reasonable initial dosing converts the patient’s outpatient oral regimen to the same dose but IV. If the patient has not previously been on furosemide, a common starting dose is 20 mg times the serum creatinine in milligrams per deciliter. If there is no response within 1 h to the initial dose, and congestion is still felt to be present, then the dose can be doubled and repeated. A more potent loop diuretic, such as bumetanide, may be considered for patients who are resistant to large doses of furosemide. Twice daily dosing helps prevent rebound sodium retention. The administration of furosemide or other loop diuretics by continuous infusion, rather than bolus therapy, may be associated with a better response with less prerenal

Table 7.6. Vasodilators and diuretic therapy.

↓ PCWP

↑ Cardiac Performance

Ideal agent

++

++

Furosemide Morphine Nesiritide Nitroglycerin Hydralazine Nitroprusside

+ ++ ++ ++ 0 ++

0 0 ? 0 0 0

Agent

HR

↓ In-hospital and postdischarge ↑ ↑ ↑ O2 Myocardial mortality Arrhythmia Diuresis demand RAAS injury in AHFS

BP

0 or ↓ (depends on SBP) 0 ↑/↓ ↓ ↓ 0 ↓ ↓ (reflex) ↓↓ ↓ (reflex) ↓↓ ↓ (reflex) ↓↓↓ 0

0

++

0

↓

↓

+

+ + 0 0 + 0

+++ 0 + 0 0 0

0 0 0 0 (↓) + 0 (↓)

↑ ? ↓ ? ↑ ?

? ? ? ? ? ?

? 0 0 0 0 0

Adapted from Fanarow.96 Abbreviations: AHFS acute heart failure syndromes, SBP systolic blood pressure, PCWP pulmonary capillary wedge pressure, RAAS renin–angiotensin–aldosterone system, BP blood pressure.

Table 7.7. Inotrope therapy.

Agent Ideal agent Levosimendan Milrinone Digoxin Dobutamine

↑ BP Arrhythmia

↑ Renal ↑O2 perfusion demand RAAS

↓ In-hospital and postdisMyocardial charge mortality injury in AHFS

↓ PCWP

↑ Inotropy

HR

++ +

+++ +++

0 0

0 0

0 0

++ 0

0 0

↓ ?

↓ No data

+ +/0 (?)

+ + +

++ ++ +++

↑ ↓ ↑

↓ 0 ↑/↓

++ ++ ++

+ + +

? 0 ++

↑/? ↓ ?

↑ ↑ ↑

0 0 0

Adapted from Fanarow.96 Abbreviations: PCWP pulmonary capillary wedge pressure, RAAS renin–angiotensin–aldosterone system, BP blood pressure.

20–40 mg IV

Initial dose

5–15 µg/kg/min

15 µg/kg/min

Yes

Yes

Yes

q 3h q 5 min

1–2 µg/kg/min

200–300 mg/day 10 µg/kg/min

q 3h

No

50–75 mg qid Lowest effective

0.03 µg/kg/min

200 µg/min

Widely variable

Variable

6h

Low BP, tachycardia

Low BP, tachycardia Low BP, cyanide toxicity

Respiratory depression Low BP, methoglobinemia Low BP, ARF

ARF, hypokalemia

ARF, hypokalemia

Adverse effects

BP

BP ICU, metabolite levels

BP, RF

Respiratory rate, BP, O2 sat BP

UOP, routine BP, electrolytes, RF

Monitoring

Hypotension, arrhyth- Telemetry, RF mia 1–2 days Arrhythmia Electrolytes, RF, dig level 2 min Ischemia, arrhythmia Telemetry

2–4 h

80 h

3–7 h 2 min

q 5– 2–4 h 30 min q 3–5 min 3 min

NA

Titration Half-life

12–24 µg/kg bolus; 0.1–0.2 µg/kg/min 0.4–0.6 µg/kg/min 0.05–0.1 µg/kg/ min 50 µg/kg bolus; 0.2– 0.375–0.75 µg/kg/ 0.75 µg/kg/min 0.3 µg/kg/min min 8–12 µg/kg 125–250 µg qd 250 µg qd

2 µg/kg bolus; 0.01 µg/kg/min 5–10 mg IV q4h 0.1–0.2 µg/kg/min

NA

20 mg po qd

480–600 mg/day

Max dose

NA

As required to achieve euvolemia

Target dose

Abbreviations: CAD coronary artery disease, SBP systolic blood pressure, RAAS renin–angiotensin–aldosterone system, BP blood pressure.

Dobutamine

Digoxin

Milrinone

INOTROPES Levosimendan

Hydralazine Nitroprusside

Nesiritide

10–20 mg bolus; 5–20 mg qd VASODILATORS Morphine 2–5 mg IV q 5–30 min Nitroglycerin 5 µg/min

Metolazone

Furosemide

DIURETICS

Agent

Table 7.8. Administration information for commonly used drugs.

Do not use in ACS or AF

↓K+ potentiates toxicity

Redose in renal failure

Pending regulatory approval

20% nonresponders, do not use with sildenafil Do not use if SBP < 90, Adjunct to loop diuretic. Activates RAAS Tachyphylaxis, do not use in ACS or severe CAD

Increases ICU admissions

Combine metolazone with loop diuretic for diuretic refractory patients

Comments

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azotemia and neurohormonal activation.97 Patients who are being aggressively diuresed should have electrolytes measured and repleted twice daily. Diuretic-induced electrolyte disturbances, especially hypokalemia, lower the threshold for arrhythmia. Excessive diuresis may result in renal hypoperfusion and decreased tubular function producing a significant elevation of BUN even in patients who continue to be fluid overloaded. In spite of initial benefit, diuretics, especially in high doses over 300mg daily can have long-term deleterious effect manifested by increased overall mortality and rehospitalization.98 Therefore, other vasoactive agents should be considered to avoid very high doses of diuretics. 7.8.1.1.2. Nesiritide Nesiritide is an IV formulation of recombinant human BNP. The endogenous form of the hormone is released by mechanical stretch of ventricular tissue and serves as a counter-regulatory response to increased LVFP. It relaxes vascular smooth muscle and produces natriuresis, but does not increase inotropy or myocardial oxygen demand. Nesiritide offers the theoretical benefit of blunting some of the adverse neurohormonal effects of diuretics. It appears superior to dobutamine and placebo in achieving hemodynamic goals,99,4 and is less proarrhythmic than dobutamine.100 It achieved statistically significant improvement in dyspnea at 3 hours but not at 24 hours when compared to placebo in a randomized trial.4 However, the small doses of nitroglycerin used in the trial question whether more aggressive titration would produce similar results. Nesiritide proves most useful for hypertensive patients but should be avoided in those who are hypotensive. A 2 µg/kg bolus of nesiritide is followed by a 0.01 µg/kg/min infusion. If there is concern about hypotension, then the infusion may be started without a bolus and/or at a rate of 0.005 mg/kg/ min. The half-life of nesiritide is ~60 min and the infusion rate should be titrated every 3 h with a maximum rate of 0.03 µg/kg/min. Sixty percent of the maximal effect will be observed within 15 min and 95% within 1 h. Its efficacy in AHFS has been demonstrated only when added to standard therapy including loop diuretics.101,4 Nesiritide is contraindicated if the SBP is less than 90 mmHg.4 Reportedly, the rate of symptomatic hypotension is similar to those for other vasodilators,4 but prolonged hypotension may persist even

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after drug discontinuation. Frequent blood pressure monitoring is necessary, although neither invasive measurements nor intensive care unit monitoring is specifically required. Caution should be used in patients with concomitant myocardial ischemia, and recent data have questioned its safety and efficacy in AHFS, specifically with regards to worsened renal function and increased mortality.102-105 7.8.1.1.3. Overcoming Loop Diuretic Resistance For patients exhibiting loop diuretic resistance, a distally active agent such as an oral thiazide, metolazone, or an aldosterone antagonist such as spironolactone may be added. Aldosterone blocking agents may be particularly beneficial in right-sided HF, given the fact that spironolactone is metabolized by the liver and excessive levels may occur. Metolazone is commonly given 30 min prior to loop diuretics, although data on the exact timing of concomitant administration are lacking. There is an unpredictable lag time in achieving synergy that may range from hours to days.106 It is reasonable to start with a low dose (1.25–2.5 mg) and titrate up as needed, with careful maintaining of renal function and serum potassium levels. 7.8.1.1.4. Tolvaptan Tolvaptan is an oral vasopressin V2-receptor antagonist.107 Arginine vasopressin secretion from the posterior pituitary is primarily regulated by serum osmolality. Elevated levels of arginine vasopressin are believed to be part of the “neurohormonal activation” seen in AHFS. Its effect on the V2-receptor at physiologic doses increases aquaporin expression in the renal collecting tubules. This promotes electrolyte-free water retention. Therefore, tolvaptan’s V2antagonism produces aquaresis and may be helpful in correcting hyponatremia. A dose of tolvaptan 30 mg daily was tested in patients with left ventricular ejection fraction < 40% hospitalized for AHFS. It was started within 48 h of admission in addition to standard therapy, including diuretics. Tolvaptan modestly improved signs and symptoms of congestion compared to placebo throughout hospitalization, with no increase in heart rate, renal dysfunction or hypotension.5 However, tolvaptan had no effect on all-cause mortality or cardiovascular mortality or HF readmission within 60 days of starting the medication, inspite of a sustained

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decrease in weight.6 Thus, while well tolerated and offering a short-term benefit, tolvaptan’s immediate benefits do not persist. As these trials excluded patients with preserved left-ventricular (LV) systolic function, the effect in this population, while theoretically beneficial, has not been well studied. 7.8.1.1.5. Therapeutic Implications If there is no evidence of hypoperfusion with adequate response to diuretic therapy, there is generally no need for inotropes with the exception of digoxin. Digoxin may be used in patients with AHFS and an EF less than 35%, particularly when atrial fibrillation is present. Angiotensin-converting enzyme-inhibitor (ACE-I) therapy should be initiated and increased to the target doses as the blood pressure and creatinine permit. If there is inadequate response to diuretics, especially in the setting of azotemia, then serious consideration should be given to the placement of a PA catheter. When the CO is low, vasoactive agents should be titrated to maximize renal blood flow and diuresis. In the patient with both hypoperfusion and volume overload, or in patients not responding to diuretics, ultrafiltration108 can be considered. Ultrafiltration allows for fluid removal without requiring an increase in renal blood flow. Although its use is limited by blood pressure, it can typically be tolerated at lower pressures than hemodialysis. While these methods offer theoretical advantages, data on their practical and routine use in this setting are emerging.109,110 Diastolic HF is suggested by signs and symptoms of HF with a preserved EF and absence of significant valvular abnormalities. Elevated levels of BNP have also been reported in patients with diastolic HF. There are few clinical trials of therapies for diastolic HF. Acute presentations often exhibit elevated blood pressure. As a result, vasodilators are a cornerstone of therapy. Primary management after stabilization involves diuresis followed by maneuvers that prolong diastolic filling time. This includes calcium channel blockers, β-blockers, and management of tachyarrhythmias, especially atrial fibrillation. Exacerbating factors such as ischemia and hypertension should also be aggressively managed. 7.8.1.1.6. Cardiorenal Syndrome The relationship between HF and renal failure has long been recognized, although complete characterization of the pathophysiology remains under

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investigation. Worsening cardiac failure and arterial underfilling result in neurohormonal activation, leading to sodium and water retention and worsening cardiac failure.111,112 If left uninterrupted, this vicious cycle worsens hemodynamics and establishes a difficult-to-treat syndrome of progressive cardiorenal dysfunction. Unfortunately, many agents used in the management of AHFS have the potential to cause or worsen renal failure and may negatively impact survival. Diuretics, although helpful in the short-term, activate neurohormones113 and may worsen renal failure and outcomes, especially at doses over 300 mg daily.114 The continuous infusion of a loop diuretic, as opposed to bolus dosing, has been shown to decrease neurohormonal activation and can be considered.97 This meta-analysis suggests that there is a 200–300 cc/24 h greater urine output using a continuous infusion compared to bolus administration, and continuous infusions have a better overall safety profile. Blockade of the RAAS with ACE-I may also promote renal failure in the volume-depleted HF patient by inhibiting adaptive vasoconstriction in the glomerular efferent arteriole. However, in contrast to diuretic therapy, there is no evidence that an ACE-I negatively alters outcomes. Accurate assessment of fluid status is crucial when faced with worsening renal function in a patient with HF. A common error is the assumption that a hypotensive patient with azotemia and a high BUNto-creatinine ratio is hypovolemic. A key finding is the presence of JVD that indicates that the patient is not volume depleted. In the absence of JVD, a PA catheter may be necessary to determine fluid status accurately. Other techniques for assessing volume status, such as radiolabelled albumin or semi-automated Valsalva response recorders, are either limited in availability or under clinical investigation.

7.8.2. High Blood Pressure A superimposition of increased afterload on impaired cardiac reserve (often diastolic HF) results in elevated LV filling pressures, which are, in turn, transmitted to the pulmonary vasculature and result in pulmonary congestion.115 This takes place over hours to days, resulting in fluid redistribution, not total body volume overload. The exact level of blood pressure that causes these changes is unknown and depends, in part, on ventricular

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compliance, valvular competence, and chronicity. However, a somewhat arbitrary level of 160– 180 mmHg systolic is reasonable. These patients are more likely to be older, women, and AfricanAmerican with preserved LV systolic function and high creatinine.116,117 Blood pressure control with vasodilators is the primary treatment modality. The goal is to realign afterload with CO in a rapid and safe manner. Blood pressure should be frequently assessed and used to titrate and guide therapy in an “assess– treat–reassess” cycle. Nitroglycerin is the first-line agent in patients who present with HF and elevated blood pressure.18,118 Those patients with continued elevated blood pressure despite aggressive titration of nitroglycerin are considered candidates for nitroprusside and nesiritide. IV nicardipine may be used, but it has not been tested in patients with hypertension complicated by HF. None of these medications has any negative inotropic effects and therefore should be safe in patients with malignant hypertension and systolic LV dysfunction. A study of nitroprusside use during acute MI and severe HF demonstrated increased mortality.119 While similar data are not available for the other vasodilators, they pose the same theoretical risk. Diuresis can serve as a temporizing measure to relieve congestion, although these patients are not total body fluid overloaded. Combination therapy should be the rule and not the exception. In the long term, blood pressure must to be brought back to normal values. Chronic blood pressure medications should be titrated to target doses.120 For patients with acute respiratory failure, noninvasive ventilation (NIV) with continuous positive airway pressure (CPAP) may obviate the need for intubation and mechanical ventilation (see section on Pulmonary Edema below).

7.8.3. Acute Coronary Syndromes Consideration and recognition of myocardial ischemia is an essential step in the evaluation of patients presenting with HF. Patients who present with an ACS accompanied by HF have a considerable mortality and may require emergent therapy.121-123 Initial ischemic evaluation includes, at minimum, a thorough history and physical, ECG, and cardiac markers of necrosis. The basic goal for treatment is to improve coronary flow while awaiting revascularization.

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Patients with ST elevation MI and HF clearly benefit from emergent revascularization via thrombolytic therapy or percutaneous coronary intervention.124 Patients with non-ST elevation MI and HF constitute a high-risk population who also benefit from an early invasive strategy with the timing depending on the severity of the HF and the clinical stability of the patient.125 Medical management includes the standard therapies for ACS124,125 (antiplatelet therapy and anticoagulation) with the exception that β-blockers are contraindicated in overt HF with a severely reduced EF. β-blockers are not contraindicated, and are probably helpful, in patients with ACS and diastolic HF, particularly when they present with hypertension and atrial fibrillation with a rapid ventricular response. One area of considerable confusion concerns the release of troponin during a HF exacerbation, which may not reflect coronary thrombosis. Cardiac enzyme elevation in the absence of true ACS possibly represents subendocardial necrosis due to elevated transmural pressure, hypotension, tachycardia, and/or elevated catecholamines. Patients with a true ACS are more likely to have ischemic ECG abnormalities, higher levels of cardiac enzymes, and chest discomfort. However, it remains difficult to distinguish between the two scenarios, especially early in the presentation.

7.8.4. Pulmonary Edema Pulmonary edema is the extravasation of fluid from pulmonary capillaries into the interstitial or alveolar space. This results in abnormalities of oxygen exchange and increased work of breathing. A distinction should be made between severe radiographic pulmonary edema, which is common and occurs in up to 80% of CXR in AHFS1, and the clinical syndrome of pulmonary edema (rapid and severe respiratory distress), which occurs in only about 5% of admissions. In the authors’ experience, while untreated clinical pulmonary edema can be rapidly fatal, these patients have a paradoxically good prognosis once the blood pressure normalizes and congestion resolves. Clinical pulmonary edema is seen with rapid changes in filling pressures, for example, malignant hypertension, acute MI, or acute valvular insufficiency. Three key variables help guide immediate treatment in pulmonary edema. A normal or low

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blood pressure argues against the administration of vasodilators. An elevated arterial partial pressure of carbon dioxide or low pH suggested that agents like morphine which produce respiratory depression may be deleterious.

7.8.4.1. Pharmacologic Therapy (See Tables 7.6–7.8) 7.8.4.1.1. Morphine Morphine is a peripheral vasodilator that reduces preload and, to a lesser extent, afterload. It decreases the sensation of dyspnea and slows the heart rate by inhibiting the sympathetic nervous system. IV morphine may be given in 2–5 mg boluses every 5–30 min. Respiratory rate, blood pressure, heart rate, and rhythm should be monitored closely. Its primary adverse effect is central respiratory depression, and its use has been associated with increased rates of intensive care unit admission and mechanical ventilation.126 Severe hypotension may occur when morphine is given to a patient who is intravascularly depleted or preload dependent. Thus, it should be used in AHFS with caution, given the potential for myocardial supply–demand imbalance. In addition to the risk of bradyarrhythmia secondary to sympathetic nervous system inhibition, tachyarrhythmias may occur secondary to enhanced automaticity. The effects of morphine can be rapidly reversed with naloxone. 7.8.4.1.2. Nitrates Nitrates reduce congestion primarily through direct venodilation. Arteriodilation, including dilation of the coronary arteries, occurs with gradually increasing doses, thereby reducing afterload and improving myocardial blood flow. However, ~20% of HF patients are resistant to any dose of nitroglycerin.127,128 Sublingual nitroglycerin provides an immediate 400 µg bolus, which can be repeated every 5 min. IV nitroglycerin should be started at a dose of 20–50 µg/min and titrated up every 5 min to the highest tolerated dose. The maximum dose is 200 µg/min before the patient is labeled nitrate resistant. Onset of action is immediate, and the serum half-life is ~3 min. Nitrate tolerance occurs early and limits the effectiveness of continuous infusion. It has been the authors’ experience that sublingual nitroglycerin is effective even when given to patients who have developed tolerance to

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the IV form. Isosorbide dinitrate is an effective oral nitrate preparation shown to reduce mechanical ventilation needs.129 Mild hypotension from nitrate administration may cause reflex tachycardia and worsening ischemia in patients not on β-blockers. Patients should be specifically questioned regarding the recent use of type-5 phosphodiesterase inhibitors, such as sildenafil, as the interaction with nitrates can be fatal. A potential reduction in the anticoagulative properties of IV heparin remains controversial.130,131 Nitrates may also cause headaches that can be disabling. Extreme caution with nitrates is warranted in patients with heavily preload-dependent hemodynamics as well as critical aortic stenosis.

7.8.4.2. Oxygen Therapy Oxygen therapy by nasal cannula or face mask is the least invasive choice. The fraction of inspired oxygen (Fio2) in room air is roughly 21%. The following modalities can be used to increase the FiO2: • Nasal cannula provides an additional 3–4% FiO2 for each liter per minute (L/min) of oxygen, up to ~44% at 6 L/min. • A simple face mask offers no valves or oxygen reservoir and provides FiO2 in the range 40–60% from 6 to 8 L/min. • Partial rebreather masks utilize an oxygen reservoir to offer FiO2 from 60 to 80% at 6–10 L/min. • Nonrebreather masks provide both valves and an oxygen reservoir, allowing FiO2 from 80 to 95% at 10–15 L/min. 7.8.4.2.1. Noninvasive Ventilation Depending on the severity of the pulmonary edema as well as the presence of other comorbidities, some patients may require ventilatory assistance. In conjunction with clinical judgment, parameters which suggest the need for urgent intervention include use of accessory muscles, tachypnea (respiratory rate above 20–25 breaths/ min), pulse oximetry saturation below 90%, pH below 7.35, arterial partial pressure of oxygen below 60 mmHg, and arterial partial pressure of carbon dioxide above 40 mmHg. NIV takes the form of either CPAP or noninvasive positive pressure ventilation (NPPV).132 Increased intrathoracic pressure decreases venous return to the heart, providing an additional benefit for patients without evidence of

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hypoperfusion. However, NIV increases patient discomfort and the risk of aspiration. NIV cannot be used in patients with hemodynamic instability, altered mental status, apnea, abnormal facial anatomy, an inability to protect their airway, or at high risk for aspiration (e.g., continued vomiting). Table 7.6 lists indications and contraindications for NIV. CPAP provides a constant, positive level of airway pressure at all times during the respiratory cycle. The initial pressure setting of 5 cm H2O can be incremented by 2 cm H2O as needed for effect and tolerated by the patient.132 NPPV provides a baseline positive airway pressure but gives added pressure during inspiration, resulting in a bilevel pattern. Initial settings of 2–4 cm H2O baseline pressure and 8–10 cm H2O inspiratory pressure can be incremented by 2–4 cm H2O to a maximum of 20 cm H2O baseline and 24 cm H2O inspiratory.132 In addition, both CPAP and NPPV allow for titrateable FiO2. Table 7.6 lists the initial settings and titration increments for NIV. The use of CPAP in cardiogenic pulmonary edema (Table 7.9) decreases the absolute need for endotracheal intubation by 26%,133 while the same has not yet been shown for NPPV.134 The concern of increased rates of acute MI in patients receiving NPPV135,136 has not been found in all studies,137–138 but for the moment CPAP should be considered the first-line therapy. Two recent meta-analysis suggest that NIV significantly reduced in-hospital mortality and the need for intubation.140,141 7.8.4.2.2. Endotracheal Intubation Endotracheal intubation offers definitive management of the airway, with subsequent greater control over oxygenation and ventilation, but at the expense of patient discomfort and risk of complications. Its use should be reserved for patients with acute respiratory failure and/or those who have failed to respond adequately to other methods. 7.8.4.2.3. Therapeutic Implications Subsequent management of pulmonary edema should reflect the underlying mechanism. The most common causes of pulmonary edema are ischemia (causing transient systolic or diastolic dysfunction), acute valvular dysfunction, labile hypertension, arrhythmia, and systemic illnesses such as sepsis

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or anemia superimposed on significant cardiovascular disease. Urgent transthoracic echocardiography is critical to determine the cause of acutely elevated LVFP if this is not readily apparent from the clinical picture. The management of ischemia, hypertension, and arrhythmia is discussed in their respective sections. The pathophysiology of acute valvular dysfunction consists almost exclusively of regurgitant lesions as acute valvular stenosis is exceedingly uncommon. Many etiologies of acute regurgitation exist including endocarditis, papillary muscle rupture, torn chordae, and aortic dissection. The management of all of these, however, is ultimately

Table 7.9. Treatment of pulmonary edema and dyspnea. Vasodilators • Nitrates ° Sublingual nitroglycerin, 400 µg, can be repeated every 5 min ° IV nitroglycerin start at 5 µg/min titrated every 5 min to the highest tolerated dose • Morphine ° IV morphine in 2–5 mg boluses every 5–30 min Oxygen therapy • Nasal cannula ° 21–44% from room air to 6 L/min • Simple face mask ° 40–60% from 6 to 8 L/min • Partial rebreather mask ° 60–80% at 6–10 L/min • Nonrebreather mask ° 80–95% at 10–15 L/min Noninvasive ventilation • Indications ° RR ≥ 30 breaths/min ° Spo2 ≤ 90% on oxygen therapy alone ° At risk for endotracheal intubation • Contraindications ° Apnea ° Hemodynamic instability ° Inability to protect airway ° High risk for aspiration (e.g., vomiting) ° Altered mental status • Continuous positive airway pressure ° Start with 5 cm H2O ° Increment by 2 cm H2O as needed and tolerated • Noninvasive positive pressure ventilation ° Start with 8–10 cm H2O inspiratory pressure, 2–4 cm H2O baseline pressure ° Increment by 2–4 cm H2O as needed and tolerated ° Maximum 24 cm H2O inspiratory pressure, 20 cm H2O baseline pressure Based in part on Tables 2 and 3 of Panacek and Kirk.131

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surgical, and covered in-depth in the surgical volume of this series. Hemodynamic stabilization using medical therapy may improve operative outcomes. An intra-aortic balloon pump (IABP) may be helpful or even life-saving in acute mitral regurgitation but is contraindicated in aortic regurgitation. If transthoracic echo does not reveal any abnormalities, evaluation for renal artery stenosis after initial management and stabilization is warranted. In one small series, nearly 25% of patients with renal artery stenosis had episodes of pulmonary edema requiring hospitalization142.

7.8.5. End-Stage HF Chronic HF is a syndrome of progressive deterioration, and many patients will eventually fail conventional measures. End-stage or treatmentrefractory HF can be defined as symptoms limiting daily life despite maximal medical therapy.143 Less than 5% of admissions are for end-stage HF. Current management guidelines for end-stage or treatment-refractory HF are based largely on consensus rather than on data from randomized trials.144 Prompt diagnosis with identification, and if possible reversal, of precipitating causes is crucial.144 The most common reason for treatment failure in advanced HF is the development of the “cardiorenal” syndrome, in which diuresis results in progressive renal dysfunction.30 Ultimately many patients become refractory to diuretic therapy. Continuous renal replacement therapy, notably Table 7.10. Classification of heart failure. Acute new-onset HF (about 10%) • Acute coronary syndromes • Acute valvular dysfunction • Pericardial disease • New-onset arrhythmia (especially atrial fibrillation) • Myocarditis • Malignant hypertension Worsening chronic HF (about 85%) • First presentation (20%) • Known existing HF (65%) End-stage or refractory HF (< 5%) • Symptoms limiting daily life despite therapy with ACE-I, diuretics, beta-blockers, and digoxin142 Abbreviations: ACE-I angiotensin-converting enzyme-inhibitor, HF heart failure.

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ultrafiltration, may be necessary to optimize hemodynamics for end-stage patients with renal failure, volume overload, and inability to tolerate or respond to IV diuretics.145 Inotropic infusions and left or biventricular assist devices may be utilized in patients as a bridge to transplant.146,147 Cardiac transplant remains the only therapy that offers durable benefits. However, because of the limited number of donors (less than 2,500 annually8) and the many exclusion criteria, transplant is not an option for most patients. Research into the long-term use of left ventricular assist device (LVAD) for end-stage HF, so-called “destination” therapy, offers promise (see Chap. 11).148,149 Palliative care should become the focus of management for patients who are not candidates for, or do not desire, transplant or LVAD (see Chap. 12).

7.8.6. Cardiogenic Shock Less than 5% of patients present with an SBP less than 90 mmHg or cardiogenic shock.1,27 In the presence of adequate filling pressures, a low SBP, high heart rate, narrow pulse pressure, decreased mental status, and cool or dusky extremities are suggestive of a critically low CO. The initial management of cardiogenic shock seeks to restore perfusion to vital organs including the brain, kidneys, and myocardium. This is best achieved with norepinephrine and IABP (absent contraindications) as they provide an acceptable balance between raising blood pressure and increasing myocardial oxygen demand. For ED settings or institutions where emergent IABP may require time, use of a “medical” balloon pump—inotropes plus vasopressors—can serve as a temporizing measure. Once the patient has been stabilized, a transthoracic echocardiogram should be performed to exclude causes other than “pump failure” as the etiology of hypoperfusion. In the case of tamponade or mechanical complications of ischemia, for example, a ventricular septal defect, prompt percutaneous or surgical intervention is indicated. If the echocardiogram reveals only a low EF then available pharmacologic maneuvers to increase CO include dobutamine, milrinone, levosimendan (in Europe), and digoxin. Mechanical treatment of cardiogenic shock includes IABP and LVAD.

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IABPs are less invasive than LVAD and can be placed in the cardiac catheterization laboratory or at the bedside.150 An IABP has the advantage of increased coronary flow, decreased afterload, and increased renal perfusion without increasing myocardial oxygen demand, particularly in patients with CAD. Major complications of IABP use are limb ischemia and bleeding, although these complications rates are less than 1% in an international registry.150 LVAD implantation has been primarily reserved for patients awaiting transplantation. Percutaneous ventricular assist devices and devices that augment aortic flow are currently under investigation as a bridge in critically ill patients to make definitive surgical treatment or recovery.146,147

7.8.7. Arrhythmias Any arrhythmia can precipitate HF in a susceptible individual. Patients at risk may have elevated filling pressures from numerous underlying etiologies, including aortic stenosis, hypertrophic cardiomyopathy, mitral stenosis, and systolic or diastolic dysfunction. The most common arrhythmia to cause HF is atrial fibrillation. The primary objective for patients with symptomatic HF and atrial fibrillation is restoration of sinus rhythm. If the patient is unstable (hypotensive or with impending respiratory failure), then synchronized cardioversion is indicated. If the patient is stable, then chemical cardioversion may be considered, although great care must be taken to evaluate the risk of embolization as well as selection of an antiarrhythmic drug in patients with ischemia, structural heart disease, and renal dysfunction. For HF precipitated by atrial fibrillation, a strategy of rhythm control may be preferable to rate control as comparative studies have excluded patients with prominent symptoms. Current long-term options to maintain sinus rhythm include antiarrhythmic medications, radiofrequency catheter ablation, and iterations of the Cox-Maze procedure. If the suspected arrhythmia is not observed upon presentation, 24–48 h of telemetry may be useful. If telemetry does not reveal an arrhythmia and the clinical suspicion remains high, then the patient should undergo Holter or event monitoring. Among those at risk for ventricular arrhythmias, especially patients with decreased

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LV function or nonrevascularized ischemia, provocative testing in the electrophysiology lab or prophylactic cardioverter-defibrillator implantation may be appropriate.

7.8.8. Inotropic Therapy Presently, inotropic therapy should be reserved for patients who do not respond to other therapies and continue to have a high LVFP and a low output state. Randomized data suggest an increased morbidity and/or mortality when used in normotensive patients with a normal CO.151

7.8.8.1. Dobutamine Dobutamine stimulates β1 and β2 adrenergic receptors in a 3:1 ratio with the primary effect of increasing heart rate and contractility, thereby raising CO. Dobutamine is also a modest vasodilator. The effect on blood pressure is difficult to predict and depends on the relative effects of dobutamine on decreasing SVR and increasing CO. Dobutamine decreases blood pressure in subjects with normal CO, but will increase blood pressure in low-output cardiac failure. In cases of dobutamine-induced hypotension, lowdose dopamine can be added to stabilize the blood pressure. An increase in blood pressure marks a sign of appropriate dobutamine therapy. However its use in ischemic cardiomyopathy patients demands caution given the potential for myocardial injury. Dobutamine should be started at a dose of 1–2 µg/ kg/min and slowly increased to the lowest effective dose, usually in the range of 3–10 µg/kg/min. The onset of action is within 1–2 min, with a half-life of ∼2 min. In chronic therapy, tolerance develops secondary to receptor downregulation. As a result, therapy must be tapered off rather than stopped abruptly so as to avoid decompensation. The use of a β-blocker may limit dobutamine’s inotropic effect. Dobutamine promotes tachyarrhythmia and is contraindicated in patients with supraventricular arrhythmias, especially atrial fibrillation, and ventricular tachycardia. It has been shown to increase mortality in patients with advanced HF,152 likely due to increasing myocardial oxygen demand with resultant ischemia and injury to hibernating myocardium.153,154 Chronic dobutamine infusions have also been associated with hypersensitivity myocarditis and hemodynamic deterioration.

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7.8.8.2. Milrinone Milrinone is a phosphodiesterase type 3 inhibitor that increases contractility by increasing cAMP in cardiac muscle. It also causes peripheral vasodilation. It is not thought to increase myocardial oxygen demand and so should not promote ischemia and injury in at-risk myocardium. Milrinone is typically started at a rate of 0.2– 0.3 µg/kg/min after a loading dose of 50 µg/kg, although the loading dose may be omitted if there is concern for hypotension. The usual effective dose is in the range of 0.375–0.75 µg/kg/min. Onset is within 5–15 min with a half-life of ~2.5 h. Milrinone is cleared by the kidney, and the dose must be adjusted when creatinine clearance is less than 50 ml/min. Monitoring should include continuous telemetry, frequent blood pressure checks, and serum renal function tests. Patients with a theoretical benefit of milrinone over dobutamine include those with significant arrhythmias, secondary pulmonary hypertension or myocardial ischemia, or those on β-blockers. A large, randomized, placebo-controlled trial studied the safety and efficacy of milrinone in AHFS.155 There was a statistically significant increase in the rate of supraventricular and ventricular arrhythmias and sustained hypotension with milrinone and a trend toward higher mortality.85 Milrinone resulted in increased postdischarge mortality in patients with CAD. Milrinone did not decrease the length of the index hospitalization or decrease the total number of hospitalization days within 60 days of discharge.

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Although it increases CO, the drug can decrease blood pressure and produce reflex tachycardia through its vasodilator effects. Blood pressure should be monitored during administration, and some guidelines suggest that the SBP must be above 85 mmHg before beginning infusion.14 One major advantage of levosimendan is that it does not increase myocardial oxygen demand and so does not threaten hibernating myocardium. Levosimendan has been shown to be less proarrhythmic than dobutamine.156 Two randomized studies, one of patients with low-output HF and the other in patients with LV dysfunction due to acute MI, have demonstrated a mortality benefit of levosimendan compared to dobutamine.157,158 However, preliminary results from two large controlled trials in AHFS gave conflicting results. In preliminary results from the Randomised multicentre evoluation of intravenous levosimendan efficacy versus placebo in the short term treatment of decompensated heart failure (REVIVE-II) study, levosimendan was reported to have a superior effect in the composite primary end point compared to placebo.7 But it appeared to be associated with increased early mortality, hypotension, and arrhythmias (ventricular tachycardia and atrial fibrillation) compared to placebo. In Survival of Patients with acute heart failure in need of intravenous inotropic support trail (SURVIVE) despite a trend to early benefit with levosimendan, there was no difference in effect on long-term outcome versus dobutamine.159 Levosimendan has been approved for use in many European countries, but not in the United States.

7.8.8.3. Levosimendan Levosimendan sensitizes myofibrils to calcium, thereby increasing CO without increasing intracellular calcium levels. It also causes vasodilation via ATP-dependent potassium channels. The overall hemodynamic benefits are increased stroke volume, reduced systemic and pulmonary resistance, and lowered filling pressures. A loading dose of 12–24 µg/kg is followed by an infusion rate of 0.05–0.1 µg/kg/min with a target rate of 0.1–0.2 µg/kg/min. The maximum rate used is 0.4–0.6 µg/kg/min. Levosimendan has a half-life of 80 h, and therefore its hemodynamic effects persist long after its infusion has stopped. This sustained effect is due in large part to an active metabolite (OR-1896).

7.8.8.4. Digoxin Digoxin inhibits the sodium–potassium ATPase pump, promoting sodium–calcium exchange. It results in an increased CO and a decreased heart rate, LVFP and right atrial pressure, as well as an acute attenuation of neurohormonal abnormalities.160,161 A loading dose for digoxin of 0.25 mg IV given twice 6 h apart followed by a maintenance dose of 0.125–0.25 mg daily is typical. When given intravenously, the onset of action is within 5–30 min, with peak action occurring at 1–4 h. The half-life is 1.5–2 days in patients with normal renal function and 3 days in anuric patients. The maintenance dose, but not the loading dose, needs to be adjusted in renal insufficiency.

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Digoxin has many advantages. It decreases conduction through the AV node and is useful in AHFS with atrial fibrillation. Its inotropic action increases CO and improves many of the symptoms related to HF. It has also been shown to attenuate the neurohormonal activation known to be deleterious in HF.160 Digoxin remains unique among AHFS therapies in that it does not produce hypotension, tachycardia, or renal failure. However it has not been studied explicitly in AHFS. Its adverse effects relate to its narrow therapeutic window and dose-dependent toxicity. The serum digoxin concentration should be the lowest effective level and certainly less than 1 ng/ml. The most serious manifestations of toxicity are arrhythmias, including atrioventricular block, ventricular tachycardia, and ventricular fibrillation. Digoxin should be used with caution in ACS because myocardial ischemia enhances these arrhythmogenic effects.162 Toxic drug levels are also associated with gastrointestinal and central nervous system disorders. Hypokalemia and/or ischemia potentiates digoxin toxicity and electrolytes must be closely monitored in addition to serum drug levels. Renal failure necessitates special dosing, and digoxin is not effectively cleared by hemodialysis. Digoxin should not be used in patients with sinoatrial or second- or third-degree atrioventricular block unless a functional pacemaker is present. It should also not be used in Wolff-ParkinsonWhite syndrome, hypertrophic or restrictive cardiomyopathy, or amyloid heart disease.163

7.9. Postmanagement Classification An episode of AHFS can be definitively classified only after its acute management. Table 7.10 divides AHFS into acute first-time HF, worsening chronic HF, and end-stage or refractory HF. Such a classification scheme is independent of the clinical presentations, which guide treatment. Classification can help with long-term management.

7.9.1. Acute Heart Failure Acute or de novo HF arises from a sudden injury, structural failure, or secondary to overwhelming hemodynamic effects. It constitutes ~10% of

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AHFS.1,27,164 Etiologies include ACS, acute valvular dysfunction (due, e.g., to endocarditis, aortic dissection, or papillary muscle rupture), pericardial disease, new arrhythmia (especially atrial fibrillation), myocarditis, and malignant hypertension.

7.9.2. Worsening Chronic Heart Failure Between 60% and 70% of patients have known HF but have not yet reached end-stage or treatment-refractory status.1,27,164 For this vast majority of patients, the time course of HF is one of gradual decline punctuated by episodes of acute decompensation. Many causes of these acute decompensations exist (see Table 7.4), and a given episode may be multifactorial. Approximately 20% of patients have chronic HF which manifests itself for the first time.1,27 These patients often have risk factors for HF such as hypertension or ischemic heart disease.

7.9.3. End-Stage or Refractory Heart Failure End-stage or refractory HF can be defined as symptoms limiting daily life despite maximal medical therapy with ACE-I, angiotensin receptor blockers, diuretics, β-blockers, and digoxin.143 Roughly 5% or less of presentations are for end-stage HF.1,27,164

7.10. Discharge 7.10.1. Initiation and Titration of Chronic HF Therapy Patient education, lifestyle modification, thorough assessment for underlying reversible or treatable causes (e.g., CAD or valvular disease), initiation of life-saving therapies (both pharmacologic and device implantation), and pharmacologic optimization should take place either during the HF admission or soon afterwards to decrease readmission and mortality. The use of a dedicated pharmacist to coordinate these efforts is highly effective.165 Predischarge initiation of the β-blocker carvedilol increases the number of patients receiving β-blockade at 60 days without an increase in side effects or length of stay166 and decreases 60–90day mortality and rehospitalization.167 As β-blockers are underutilized in HF despite a proven mortality benefit,119,166 they should and can be safely initiated or titrated during an HF admission.

7. Early Medical Management of Acute Heart Failure Syndromes

Comprehensive discharge planning and multidisciplinary postdischarge care use a combination of nurse-led patient education, dietary services, home visits, telephone contact, increased clinic follow-up, and pharmacist-led medication review to decrease readmission and mortality. Recent meta-analyses and prospective, randomized trials support the efficacy of disease management programs to positively affect these end points.168-171

7.10.2. Discharge End Points Several goals must be reached before patient discharge. Patients must be hemodynamically stable, off all IV medications, and tolerating an oral regimen. Any identified exacerbating factors must be sufficiently corrected. The patient’s volume status should be optimized, meaning the lowest LVFP that allows for adequate end-organ perfusion. Therapies which improve survival in chronic HF, such as β-blockers, ACE-I, angiotensin receptor blockers

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(ARB), aldosterone antagonists, hydralazine/nitrate combination, and cardiac resynchronization therapy (CRT), should be started or titrated if indicated. Adherence to emerging guidelines for AHFS can shorten length of stay.172 Patient and family members must receive education regarding lifestyle, dietary, and medication compliance. Guidelines for patient selfassessment, such as daily weights, as well as short and long-term follow-up should be in place. Before discharge, patients who do not have endstage HF should be able to climb at least one flight of stairs or walk for more than 450 m. The patient’s exercise capacity and tolerance can be evaluated with a 6-min walk test, which also provides prognostic information.173 Of current American College of Cardiology/American Heart Association (ACC/AHA) performance measures for AHFS patients, only ACE-I and β-blocker use is associated with 60–90-day mortality and rehospitalization.174

Table 7.11. Summary box. • The management of AHFS in the first 24 h of presentation should be guided by clinical presentation and blood pressure. Three clinical syndromes based on blood pressure make up the spectrum of AHFS: 1. Symptoms with SBP > 160 mmHg 2. Symptoms with SBP = 100–160 mmHg 3. Symptoms with SBP < 100 mmHg • Within each of these blood pressure ranges patients can concurrently have acute coronary syndromes (~10%), precipitating arrhythmia (5%), or clinical pulmonary edema (3–5%). • Presentations of end-stage or treatment-refractory HF and cardiogenic shock are infrequent (< 5%), they almost always occur in the group with SBP < 100 mmHg. • The major treatment goal in the majority of cases is to reduce congestion and blood pressure while avoiding myocardial ischemia. • Most patients can be assessed and managed using noninvasive techniques. • The use of a PA catheter should be reserved for situations where 1. 2. 3. 4.

the diagnosis is unclear despite noninvasive testing, patients do not respond to treatment, patients have hypotension, especially when volume status is unclear renal failure worsens or is unexplained.

• Dual therapy of diuretics with vasodilators should be the rule in the majority of cases. • Inotropic therapy should be limited to patients who do not respond to other therapies and continue to have a high LVFP and a low output state. • Rare patients will require cardioversion or mechanical support. • After acute management, classification into three categories can take place: acute first-time HF, worsening chronic HF, and endstage or refractory HF. • Chronic HF therapy should be initiated and/or titrated. Patient education along with a long-term plan for follow-up should also implemented prior to discharge Abbreviations: AHFS acute heart failure syndromes, SBP systolic blood pressure, LVFP left-ventricular filling pressure, PA pulmonary artery, HF heart failure.

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7.11. Conclusions The AHFS encompass six clinical presentations: (1) worsening HF with normal or increased blood pressure (~70–80% of all cases), (2) ACS (10%), (3) clinical pulmonary edema (3–5%), (4) end-stage or treatment-refractory HF (2–3%), (5) cardiogenic shock (<1%), and (6) HF resulting from an arrhythmia (<1%). The management of AHFS in the first 24 h of presentation should be guided by clinical presentation and blood pressure (Table 7.11). The major goal in the majority of cases is to treat congestion and reduce blood pressure while avoiding myocardial ischemia and/or renal damage. Most patients can be assessed and managed using noninvasive techniques. The use of a PA catheter should be reserved for situations where the diagnosis is unclear despite noninvasive testing, patients who do not respond to treatment, those with hypotension, especially when volume status is unclear, and those with worsening or unexplained renal failure. Dual therapy of diuretics with vasodilators should be the rule in the majority of cases. Inotropic therapy should be limited to patients who do not respond to other therapies and continue to have a high LVFP and a low output state. Rare patients will require cardioversion or mechanical support. After acute management, classification into three categories can take place: acute first-time HF, worsening chronic HF, and end-stage or refractory HF. Chronic HF therapy should be initiated and/or titrated. Patient education along with a long-term plan for follow-up should also implemented prior to discharge.

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N.P. Johnson et al. with advanced heart failure. J Am Coll Cardiol. 2002;39(11):1780-1786. [PMID: 12039491] 90. Kosiborod M, Smith GL, Radford MJ, Foody JM, Krumholz HM. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114(2):112-119. [PMID: 12586230] 91. Silverberg DS, Wexler D, Iaina A. The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron? J Nephrol. 2004;17(6):749-761. [PMID: 15593047] 92. Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ; ADHERE Scientific Advisory Committee, Study Group, and Investigators. Risk stratification for in-hospital mortality in acutely decompensated heart failure: Classification and regression tree analysis. JAMA. 2005;293(5):572580. [PMID: 15687312] 93. Rohde LE, Goldraich L, Polanczyk CA, et al. A simple clinically based predictive rule for heart failure in-hospital mortality. J Card Fail. 2006;12(8):587593. [PMID: 17045176] 94. Siirila-Waris K, Lassus J, Melin J, Peuhkurinen K, Nieminen MS, Harjola VP; FINN-AKVA Study Group. Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure. Eur Heart J. 2006;27(24):3011-3017. [PMID: 17127708] 95. Auble TE, Hsieh M, McCausland JB, Yealy DM. Comparison of four clinical prediction rules for estimating risk in heart failure. Ann Emerg Med. 2007;50(2):127-135, 135.e1-2. [PMID: 17449141] 96. Fonarow GC. Pharmacologic therapies for acutely decompensated heart failure. Rev Cardiovasc Med. 2002;3(suppl 4):S18-27. [PMID: 12439427] 97. Salvador DR, Rey NR, Ramos GC, Punzalan FE. Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev. 2005;(3):CD003178. [PMID: 16034890] 98. Ahmed A, Husain A, Love TE, et al. Heart failure, chronic diuretic use, and increase in mortality and hospitalization: An observational study using propensity score methods. Eur Heart J. 2006;27(12):1431-1439. [PMID: 16709595] 99. Silver MA, Horton DP, Ghali JK, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol. 2002;39(5):798-803. [PMID: 11869844] 100. Burger AJ, Elkayam U, Neibaur MT, et al. Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy. Am J Cardiol. 2001;88(1):35-39. [PMID: 11423055]

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8 Management of Arrhythmias in Heart Failure Evan C. Adelstein and Leonard I. Ganz

Heart failure (HF) in patients with reduced left ventricular systolic function creates an arrhythmogenic substrate that presents myriad challenges to the clinician. Fatal arrhythmias comprise a significant percentage of HF mortality. As HF severity progresses, both total and sudden death mortality increase, although sudden death comprises a smaller proportion of overall HF deaths as the proportion of pump failure deaths increases (Figure 8.1).1,2 Sudden cardiac death (SCD) is implicated in 50–80% of New York Heart Association (NYHA) class II mortality, whereas sudden cardiac death comprises 30–50% of NYHA class III mortality. In NYHA class IV patients, up to 30% of deaths are sudden. As medical therapies for HF continue to improve, resulting in fewer complications arising from pump failure itself, arrhythmic morbidity and mortality prevention will become an even more significant part of HF management. Current medications and implantable devices have reduced arrhythmic mortality substantially. Undoubtedly, these therapies will improve, effecting further mortality reductions. However, patients with HF will continue to experience nonfatal arrhythmias, particularly atrial fibrillation, and the treatment of recalcitrant supraventricular arrhythmias poses an additional difficult challenge. This chapter discusses the arrhythmias commonly seen in the HF population, focusing on the treatment of these arrhythmias. Recommendations will be grounded upon evidence-based medicine, and generalized treatment suggestions are listed at the end of this chapter. However, antiarrhythmic therapy in any particular HF patient should ultimately

be individualized; each patient presents a unique set of challenges dictated by the particular arrhythmia, symptoms, comorbidities, genetics, and personal treatment preferences.

8.1. Arrhythmias in Heart Failure: The Scope of the Problem Patients with heart failure (HF) have a propensity to develop both ventricular and supraventricular arrhythmias. HF increases the risk of ventricular tachyarrhythmias, specifically sudden cardiac death (SCD), with the incidence and lethality rising as left ventricular (LV) function declines. Supraventricular tachycardias (SVTs) also are common in patients with HF; atrial fibrillation (AF) and atrial flutter (AFL) are the primary culprits (Table 8.1). While both AF and AFL do occur in the non-HF population, they present a particular challenge in the patient with reduced LV function, as these rhythms tend to be more frequent, more hemodynamically compromising, and more refractory to medical treatment. Additionally, many antiarrhythmic agents are contraindicated in patients with LV dysfunction because of proarrhythmic propensities. Nonpharmacologic therapies, including the use of radiofrequency ablation (RFA) and implantable devices, have thus been explored in HF patients with supraventricular tachyarrhythmias. Patients with HF do develop paroxysmal SVTs that are otherwise observed in the healthy population. They may present with atrioventricular nodal reentrant tachycardia (AVNRT), atrioventricular tachycardia (AVRT) mediated by bypass tracts,

159

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E.C. Adelstein and L.I. Ganz NYHA II Other 24%

CHF 12%

Sudden death 64%

NYHA III Other 15%

CHF 26%

Sudden death 59%

n = 103

n = 232

NYHA IV CHF 56% Other 11% Sudden death 33%

n = 27

(n=number of deaths)

Figure 8.1. Causes of mortality as a percentage of total mortality in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), stratified by New York Heart Association (NYHA) class. Adapted from MERIT-HF Study Group.2 Copyright 1999, with permission from Elsevier

or atrial tachycardias (AT). Such arrhythmias are generally treated in a similar fashion as in patients without LV dysfunction. As a rule, the threshold for performing curative RFA in HF patients should be lower for those arrhythmias that are easily amenable to such therapy (i.e., AVNRT, AVRT). These SVTs will not be discussed further. Arrhythmias in the HF population are not confined to tachyarrhythmias. While the everincreasing percentage of HF patients implanted with devices capable of pacing precludes quantification of bradycardic risk at the current time, earlier registries illustrated that bradyarrhythmias with electromechanical dissociation (EMD) were the mechanism of SCD in a significant number of selected HF patients.4

8.2. Ventricular Tachyarrhythmias 8.2.1. Sudden Cardiac Death The prevention of sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), or the entity termed SCD, has evolved from nonspecific pharmacotherapy, to patient-specific pharmacotherapy, to device therapy—the current primary treatment modality. However, as implantable cardioverter-defibrillators (ICDs) become more ubiquitous in the HF population, it must be emphasized that these devices are highly effective in preventing SCD but do not inhibit the initiation of the arrhythmias that underlie SCD; preventing

these arrhythmias, if recurrent, has reemphasized the role of pharmacotherapy, albeit in an adjunctive manner. The etiology of HF has some role in determining antiarrhythmic therapy. Patients with ischemic cardiomyopathy (ICM) were the initial focus of clinical trials. However, more recent trials have either specifically targeted patients with nonischemic cardiomyopathies (NICM) or enrolled a mixed population of patients with ICM and NICM, collectively referred to as dilated cardiomyopathy (DCM). These trials have, in general, minimized treatment differences between the two populations, and the overall trend has been one of more homogeneous therapy, regardless of etiology. While the treatment and prevention of SCD demand specifically targeted therapy, background medical therapy must not be ignored. Medical treatment of HF with β-adrenergic receptor blockers (βblockers), angiotensin-converting enzyme-inhibitors (ACE-I), angiotensin-receptor blockers (ARBs), aldosterone antagonists, digitalis preparations, and diuretics must be optimized for each patient.

8.2.2. Optimal Pharmacologic Therapy: Standard Heart Failure Medications Several classes of nonantiarrhythmic pharmacologic agents significantly reduce the risk of SCD. Although often seen in conjunction with a decrease in overall mortality, such concordance is not obligate. Reductions in arrhythmogenic mortality, while

8. Management of Arrhythmias in Heart Failure

161

Table 8.1. Relative percentage of patients with atrial fibrillation in various clinical trials, grouped according to the predominant New York Heart Association class examined. Predominant NYHA class type

Prevalence of AF, %

I

4

II–III

10–26

III–IV

20–29

IV

50

Study (year) SOLVD-prevention (1992) SOLVD-treatment (1991) CHF-STAT (1995) MERIT-HF (1999) DIAMOND (1999) Middlekauff (1991) Stevenson (1996) GESICA (1994) CONSENSUS (1987)

NYHA New York Heart Association, AF atrial fibrillation, SOLVD Studies of Left Ventricular Dysfunction, CHF-STAT Survial Trial of Antiarrhythmic Therapy in Congestive Heart Failure, MERIT-HF Metoprolol CR/XL Randomized Intervention Trail in Congestive Heart Failure, DIAMOND Danison Investigation of Arrhythmia and Mortality an Dofetilde, GESICA Grupo de Estudio de la Sobrevida en la Insuficienca Cardiaca en Argentina (V), CONSENSUS Co-operative North Scandinavian Enalapril Survival Study. Source: Adapted from Hynes et al.3

of particular interest to the electrophysiologist, may not be accompanied by improved overall mortality, which, of course, is the ultimate goal in all patients.

8.2.2.1. b-Adrenergic Antagonists β-adrenergic receptor blockers are a mainstay of therapy in New York Heart Association (NYHA) classes II–IV HF. Multiple studies have convincingly demonstrated improved overall survival in HF patients, driven not in small part by a decrease in SCD. The purported mechanisms by which β-blockers reduce SCD are myriad. By inhibiting renin release, β-blockers reduce the adverse effects of angiotensin on fluid homeostasis, myocardial fibrosis, and vascular tone. β-blockers mitigate the adverse effects of catecholamines upon myocardial oxygen demand, coronary blood flow, and arrhythmogenesis, as well as prevent induction of myocyte apoptosis.5 Reduction in the tendency for hypokalemia is another important effect. Evidence for SCD prevention stems from multiple studies. The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), which examined the effects of controlled-release metoprolol in patients with NYHA classes II–IV HF and a left ventricular ejection fraction (LVEF) less than 40%, demonstrated a 41% reduction in SCD in the active treatment cohort (Figure 8.2).2 Of note, the etiology of

HF was ischemic in only 65% of the MERIT-HF population, and the benefit with respect to SCD was most robust in NYHA class II patients. The reduction in SCD with β-blockers was again demonstrated in the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), which found a 41% reduction in SCD, associated with a total mortality benefit of 34%, in patients treated with bisoprolol.6 The severity of HF in CIBIS-II was more advanced than in MERIT-HF; enrollment criteria were NYHA classes III–IV and an LVEF less than 35%. CIBIS-II enrolled nearly equal numbers of ICM and NICM patients. Selective blockade of the β1-adrenergic receptor is not the only means by which β-blockers prevent SCD. Carvedilol effected a 56% reduction in SCD (1.7% vs. 3.8%) in NYHA classes II–IV patients with an LVEF less than 35% in the US Carvedilol Heart Failure Trials Program.7 Carvedilol is a nonselective β-blocker with α1-blocking properties. Carvedilol exerts perhaps an even more powerful effect on reducing SCD than β1-selective agents; in addition to demonstrating a 17% overall mortality reduction when compared to metoprolol tartrate in the Carvedilol Or Metoprolol European Trial (COMET), carvedilol decreased SCD by 3% (14% vs. 17%).8 Although it is difficult to draw broader conclusions comparing carvedilol and sustained-release metoprolol based upon this study, an intriguing mechanism may underlie the benefits of

162

E.C. Adelstein and L.I. Ganz

Cumulative mortality (%)

12

Sudden death

9

p = 0.0002 6

3

0 0

3

6

9

12

15

18

21

Follow-up (months)

Figure 8.2. Kaplan–Meier plot for sudden cardiac death (SCD) in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERITHF). SCD mortality in patients randomized to metoprolol XL is depicted by the dashed line. The solid line illustrates SCD mortality for patients randomized to placebo. Adapted from MERIT-HF Study Group.2 Copyright 1999, with permission from Elsevier

carvedilol. β2-blockade may prevent proarrhythmic hypokalemia by inhibiting the Na+, K+-ATPase that usually extrudes Na+ from the cell at the expense of extracellular K+.9 In summary, β-blockade reduces SCD mortality in symptomatic HF patients by 40–50%, based upon several large-scale clinical trials. This sizable relative risk reduction is matched by an equally impressive 4.4% absolute reduction in mortality.10

8.2.2.2. Renin Angiotensin System Inhibitors Angiotensin-converting enzyme-inhibitors have also convincingly demonstrated a salutary effect on SCD in HF trials. Initial studies were not powered to demonstrate such a benefit, but several recent trials have shown a reduction of between 30 and 50% in SCD.11 Absolute reduction in SCD has been estimated at 6.1%.10 Putative antiarrhythmic effects of ACE-I are numerous; they possess sympatholytic properties, increase bradykinin levels, reduce vascular tone, and counterbalance diureticinduced hypokalemia. Reduced sympathetic tone

and improved endothelial function may prevent proarrhythmic ischemia. Additional effects at the cardiac myocyte level include inhibition of infarct expansion, profibrotic aldosterone production, and hypertrophy.12 Furthermore, captopril may prevent reentrant arrhythmias by prolonging ventricular refractoriness compared to the combination of hydralazine and isosorbide dinitrate.13 This is consistent with experimental data demonstrating K+ current inhibition and augmentation of the L-type calcium current. These effects serve to prolong the cardiac action potential and potentially prevent reentry.14 The Vasodilator Heart Failure Trial II (V-HeFT II) demonstrated that enalapril was superior to a combination of hydralazine and isosorbide dinitrate in preventing SCD, with a relative risk reduction of 39%.15 Additional benefit has been shown in studies involving postinfarct patients with evidence of LV dysfunction, specifically the Acute Infarction Ramipril Efficacy (AIRE) and Trandolapril Cardiac Evaluation (TRACE) studies. AIRE, which randomized patients to ramipril or placebo, demonstrated a 27% reduction in SCD over a 15-month period.16 TRACE randomized early postinfarct patients with an LVEF of less than 35% to trandolapril or placebo for 24–50 months. A significant 24% reduction in SCD was seen in this study, with absolute event rates of 12 and 15.2% in the trandolapril and placebo arms, respectively (Figure 8.3).17 A recent analysis of the Heart Outcomes Protection Evaluation (HOPE) study demonstrated that ACE-I may prevent SCD in patients at risk for HF (i.e., stage A heart failure).18 HOPE examined the effect of ramipril upon a large group of patients with known atherosclerosis, manifest clinically as coronary artery disease (CAD), peripheral arterial disease, or prior stroke, or with known diabetes and an additional risk factor for clinically overt atherosclerosis. Post hoc analysis revealed a significant 21% reduction in SCD and resuscitated SCD. Angiotensin-receptor blockers may also reduce SCD in the HF population. By acting directly upon the angiotensin-1 (AT1) receptor, ARBs exert effects similar to those of ACE-I, although ARBs more completely block the renin–angiotensin– aldosterone system (RAAS) by acting more distally in the cascade. The high density of angiotensin1 receptors inhabiting the cardiac conduction

8. Management of Arrhythmias in Heart Failure

163

50 Sudden Death 40

30

Placebo

20

Trandolapril

10

Relative risk. 0.76 p = 0.03

0 0

1

2

3

4

Figure 8.3. Kaplan–Meier plot for sudden cardiac death (SCD) in Trandolapril Cardiac Evaluation (TRACE), comparing patients randomized to receive the angiotensin-converting enzyme-inhibitor trandolapril versus placebo. Adapted from Kober et al.17 Copyright 1995 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008

system implicates angiotensin in arrhythmogenesis. Angiotensin II increases conduction velocity and shortens the myocyte refractory period, as well as stimulates LV hypertrophy.19 Blocking these effects could potentially reduce the propensity for reentrant tachyarrhythmias. Specific clinical trials involving ARBs have sought to determine if these agents are superior to or additive to ACE-I in treating HF. Data are mixed as to whether there is incremental benefit in improving either overall or arrhythmic mortality by adding an ARB to a medical regimen that already contains an ACE-I. Valsartan Heart Failure Trial (Val-HeFT) did not find a survival advantage in patients randomized to valsartan who were already receiving optimal HF pharmacotherapy, and it raised the possibility of an adverse effect when valsartan was added to regimens already containing both an ACE-I and a β-blocker.20 The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trials examined the utility of candesartan in discrete populations of patients with HF. When added to a regimen including an ACE-I, candesartan reduced CV mortality

by 16%,21 and when used in lieu of an ACE-I, a similar reduction was observed.22 In the overall population with LV dysfunction, defined as an LVEF no more than 40%, overall mortality was significantly improved (12%), from 31 to 28%. However, this study was not powered to elicit a specific effect upon SCD. The Valsartan In Acute Myocardial Infarction Trial (VALIANT) studied the efficacy of captopril, valsartan, or both in patients with HF and/or LV dysfunction in the immediate postinfarct period.23 Neither drug was deemed superior, and the combination was no more efficacious than either drug individually, although the combination of valsartan and captopril did increase side effects. As in CHARM, this trial did not specifically address the issue of SCD.

8.2.2.3. Aldosterone Antagonists Aldosterone antagonists also reduce both total and sudden cardiac mortality in patients with LV dysfunction. Possible mechanisms include prevention of hypokalemia, regression of myocardial fibrosis, and attenuation of adverse ventricular remodeling. The Randomized Aldactone Evaluation Study (RALES), which examined the addition of spironolactone to standard HF pharmacotherapy (which, at that time, included an ACE-I, digoxin, and loop diuretic) in NYHA classes III–IV patients with an LVEF no greater than 35%, found a 29% reduction in SCD, mirroring the 30% reduction in overall mortality over a mean follow-up of 24 months.24 Two caveats deserve mention. First, β-blockade use was only 10%. This shortcoming has been addressed, albeit in a somewhat different patient population, in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).25 Second, the increased risk of hyperkalemia seen in patients taking concomitant ACE-I cannot be ignored. Despite spironolactone’s safety in the controlled setting of RALES, a subsequent outcome analysis in Canada called attention to a nearly sevenfold increase in hyperkalemic mortality.26 Both RALES and EPHESUS excluded patients with a serum creatinine concentration greater than 2.5 mg/dL and potassium (K+) concentration over 5 mEq/dL. EPHESUS tested the efficiency of the selective aldosterone antagonist, eplerenone, in patients with

164

E.C. Adelstein and L.I. Ganz 10 P = 0.03 RR = 0.79 (95% Cl,0.64−0.97)

Cumulative Incidence (%)

9

Placebo

8 7 Eplerenone

6 5 4 3 2 1 0 0

No. at Risk Placebo Eplerenone

3

6

9

12

15

18

21

24

27

30

33

36

99 110

2 0

0 0

0 0

Months since Randomization 3313 3064 2983 2830 2418 1801 1213 3319 3125 3044 2896 2463 1857 1260

709 728

323 336

Figure 8.4. Kaplan–Meier plot for sudden cardiac death (SCD) in EPHESUS, comparing patients randomized to the selective aldosterone antagonist eplerenone versus placebo. Adapted from Pitt et al.25 Copyright 2003 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008

LV dysfunction in the immediate postinfarct period with concomitant HF or diabetes. Over a mean follow-up of 16 months, there was a significant 21% reduction in SCD (Figure 8.4). The reduction in SCD comprised a significant proportion of the improvement observed in total mortality; in fact, death from worsening HF, although reduced by eplerenone, did not achieve statistical significance. Clinical use of aldosterone antagonists requires close surveillance of serum K+ concentrations, particularly with initiation and dose adjustments. Particular caution should be taken when using these agents in patients with even mild renal insufficiency, and they should be avoided generally in individuals with even modest renal insufficiency. Careful attention should also be given to discontinuation of potassium supplements and avoidance of foods high in potassium.

8.2.2.4. Hydralazine and Nitrates In the African-American Heart Failure Trial (A-HeFT), the combination of hydralazine and isosorbide dinitrate, proven inferior to ACE-I in V-HeFT II for the overall HF population, was shown to improve overall mortality when added to background medical therapy, including an ACE-I or ARB, in patients who identify themselves as black and have moderate-to-severe LV dysfunc-

tion.27 Specific effects upon arrhythmic end points have not been presented.

8.2.2.5. Statins Statins, or inhibitors of the HMG-CoA reductase enzyme, help prevent the development of HF in patients with known CAD, yet the impact of these drugs, usually reserved for patients with ischemic heart disease, on patients with extant HF has yet to be determined.28 Because low cholesterol levels are a poor prognostic indicator in HF, there has been some reluctance to use these medications in the HF population in the event that extremely low serum lipid levels increase mortality directly, instead of being a marker of more advanced disease. However, the pleiotropic effects of statins provide theoretical benefit in HF, even in the absence of CAD; statins promote vasodilation via improved nitric oxide synthesis and inhibit the production of deleterious cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6.29 Statins may also cause reverse ventricular remodeling. A prospective analysis of 551 patients referred to a single university center for HF, 55% of whom had a nonischemic etiology and 45% of whom were using statins, demonstrated greater survival in those individuals taking statins.30 Survival was improved at 2 years by over 50%, with a similar

8. Management of Arrhythmias in Heart Failure

165

trend seen in both ICM and NICM. This relationship held true after controlling for multiple known prognostic factors. Randomized trials are clearly warranted.

8.2.3. Antiarrhythmic Pharmacotherapy The discussion of antiarrhythmic medications requires a basic working knowledge of the cardiomyocyte action potential, mechanisms of arrhythmia, and the specific actions of antiarrhythmic agents.

8.2.3.1. Cellular Electrophysiology Resting myocytes have a negative transmembrane potential, maintained by the Na+, K+-ATPase and selective permeability only to K+. Depolarization occurs once the transmembrane potential reaches threshold, spontaneously in pacemaker cells and subsequently via cell-to-cell interactions. Depolarization is rapid via inward flux of sodium (Na+) ions (INa) during stage 0 of the action potential (Figure 8.5). This is immediately followed by partial repolarization via the transient outward K+ current during stage 1 (Ito). Stage 2 is characterized

Atrial & Ventricular Cells lNa lCa-L lCa-T [ lNS ] lNa / Ca

lK1 lK lIc lK-G lC1 lpump [ lK(ATP)]

Sino-Atrial Node Cells 0 or small lCa-L lCa-T lNa /Ca

0 1 2

? ? ?

ll lNa-B lK lK-G lpump

Figure 8.5. Representation of the cardiac action potential in ventricular myocytes and pacemaker cells. Above and below the action potential diagrams are schematic representations of the relative activity and timing of membrane ion channels throughout the phases of the action potential. Inward currents are illustrated above the action potential, and outward currents are depicted below the action potential. Adapted from Priori et al.31 Copyright 1999 American Heart Association, Inc. All rights reserved. Reprinted with permission (See Color Plates)

by a plateau in transmembrane potential, as an inward calcium (Ca2+) current (ICa) and an outward K+ current (Ikr) compete. Repolarization is effected when Ikr overwhelms depolarizing currents (stage 3). Stage 4 is the resting state, which is characterized by a slow inward current (If) in cells with pacemaker capability. The transmembrane potential in these pacemaker cells increases until reaching threshold, triggering the next action potential.

8.2.3.2. Mechanisms of Arrhythmogenesis Tachyarrhythmias are caused by one of three mechanisms: (1) increased automaticity, (2) reentry, or (3) triggered activity. Reentrant rhythms are the most common tachyarrhythmias overall, particularly in HF patients. These circuits are perpetuated by the interplay of conduction velocity, cellular refractoriness, and anatomy. Regardless of the initiating mechanism, organized ventricular tachyarrhythmias, such as VT with relatively long cycle lengths, may degenerate into more chaotic, faster rhythms. Whereas organized, slower tachyarrhythmias may be hemodynamically tolerated, VF and polymorphic VT are not compatible with effective cardiac output. Hemodynamic collapse ensues, as VF eventually gives way to asystole (Figure 8.6). This accounts for the precipitous fall in survival with time to defibrillation in cardiac arrest.33 There are some significant differences between ICM and NICM with respect to the pathophysiology of arrhythmias. Patients with an ICM tend to have one or more large scars, the residua of prior myocardial infarctions (MIs). Such scars support reentrant circuits for ventricular tachyarrhythmias, particularly VTs that are readily inducible with programmed stimulation in the electrophysiology (EP) laboratory. Initial trials in SCD prevention therefore utilized the EP study as a screen for SCD risk. The Multicenter Unstable

Typical sequence of electrical events:

Sinus rhythm

Ventricular tachycardis

Ventricular fibrillation

Asystolo

Figure 8.6. Typical electrical sequence in the progression of sudden cardiac death (SCD). Adapted from Huikuri et al.32 Copyright 2001 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008

166

Tachycardia Trial (MUSTT) registry, however, has called into question both the sensitivity and the specificity of inducible tachyarrhythmias in predicting SCD, even in ICM patients.34 As the severity of ICM progresses, the predictive value of the EP study diminishes.35 Data from the second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) has also cast doubt upon the role of EP testing as a method of risk stratification in these patients. NICMs are less amenable to induction of VT via programmed stimulation in the EP laboratory. Paradoxically, while the negative predictive value for ventricular programmed stimulation is poor,36 the risk of SCD remains high.37 Both NICM and ICM are also marked by myocyte hypertrophy and fibrosis, which are associated with diminished repolarization currents, prolonged action potential duration, and diminished cell-to-cell electrical coupling. This creates a milieu ripe for VT and VF.38 Electrolyte abnormalities, often iatrogenic from diuretics or potassium supplements, and elevated sympathetic tone may facilitate lethal arrhythmia induction in this conducive substrate. Induction of polymorphic VT and VF, while easily accomplished via aggressive programmed stimulation, is not specific for risk of SCD, yet these tachyarrhythmias are frequently the cause of SCD when occurring spontaneously.

8.2.3.3. Antiarrhythmic Drugs The Vaughn-Williams schema classifies antiarrhythmic drugs according to their primary effect upon the cardiac action potential (Table 8.2).39 Briefly, class I drugs slow depolarization primarily via blockade of the rapid inward Na+ current, thereby slowing conduction velocity. The QRS duration may be prolonged as a consequence. Furthermore, these drugs are use dependent, in that their pharmacodynamic efficacy increases as heart rate accelerates. Theoretically, this should provide more benefit in terminating tachyarrhythmias than in preventing their initiation. Class Ia agents, namely, quinidine, procainamide, and disopyramide, are moderately potent inhibitors of Na+ channels, possess negative inotropic properties, prolong the QT interval modestly, and act in both atrial and ventricular myocytes. Class Ib agents, namely, lidocaine, tocainide, mexilitine, and phenytoin, are weak Na+-channel blockers. With the exception of

E.C. Adelstein and L.I. Ganz

lidocaine, these drugs are rarely used clinically. They are most helpful in acute ischemic VT. Class Ic agents, consisting of flecainide, propafenone, and moricizine, are the most potent inhibitors of Na+-channels. Class II agents are β-blockers, and inhibitors of the L-type calcium channel, including the nondihydropyridine agents diltiazem and verapamil, comprise class IV drugs. These drugs are not classic antiarrhythmic agents, in that they do not specifically target the cardiac action potential, but they are quite useful for treating certain tachyarrhythmias. Class III drugs primarily prolong the action potential, and as such prolong the duration of depolarization. This manifests clinically in the ventricle as prolongation of the QT interval. These drugs have slightly different mechanisms of action, but most inhibit repolarizing K+-channels. As a rule, these drugs are reverse use dependent; their effects become more manifest at slower heart rates, making them more efficient prophylactic agents than acute therapeutic agents. With the exception of amiodarone and azimilide, these drugs, including sotalol, dofetilide, and ibutilide, are renally excreted. Amiodarone warrants mention independently from the other class III drugs because it possesses pleiotropic actions, including antagonism of Na+-, Ca2+-, and K+-channels. In fact, its calcium channel- and β-blocking effects led to its original development as an anti-ischemic medication.

8.2.3.4. Clinical Trials of Antiarrhythmic Drugs The use of antiarrhythmic agents to prevent and treat ventricular arrhythmias has changed drastically since the 1980s. The general trend observed in clinical trials has been one of repeated failure and limited success; for the most part, results have demonstrated that class I drugs should be avoided in HF, and although class III agents do not generally adversely affect mortality, trials have yielded mixed results (Table 8.3). Consequently, with the exception of β-blockers, antiarrhythmic drugs are no longer used prophylactically for improving survival in HF patients. Rather, these agents are used either to treat supraventricular arrhythmias or as adjunctive therapy to suppress VT and VF in patients with ICDs. Historically, the attempt to prevent lethal arrhythmias in high-risk patients began with the car-

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167

Table 8.2. The Vaughn-Williams classification of antiarrhythmic drugs. Class

Cellular mechanism

Effect upon action potential

Specific agents

Clinical use

Side effects

I

Na+-channel blockade

Ia

Moderate Na+channel blockade

Slow depolarization

Quinidine Procainamide

Some K+-channel blockade

Prolong AP

Disopyramide

Weak Na+channel blockade

Weakly slow depolarization

Lidocaine Mexiletine Phenytoin (tocainide)

VT

Ic

Strong Na+channel blockade

Markedly slow depolarization

Flecainide Propafenone Moricizine

AF VT

Proarrhythmia Metallic taste

II

β-Adrenergic receptor blockade

Slow pacemaker cell depolarization

Metoprolol Atenolol Carvedilol

AF VT

Bradycardia Fatigue Worsen HF

III

K+-channel blockade

Prolong action potential

Amiodarone Sotalol Dofetilide Ibutilide (azimilide) (bretylium)

AF VT

Proarrhythmia See text for drugspecific effects

IV

Ca2+-channel blockade (non-DHP)

Slow pacemaker cell depolarization

Diltiazem Verapamil

AF Idiopathic VTs

Worsen HF Edema Bradycardia Constipation Headache

Ib

Use dependence UD

AF VT

Proarrhythmia Diarrhea Lupus syndrome Exacerbate BPH Blood dyscrasias Tremor Seizures Nausea

Reverse UD

Drugs mentioned in parentheses are not available for clinical use in the USA. NAPA N-acetyl procainamide, AP action potential, DHP dihydropyridine, UD use dependent, BPH benign prostatic hyperplasia. Source: Adapted from Roden.39

diac arrhythmia suppression trials, which impacted immensely upon cardiology and advanced the cause of evidence-based medicine. The first Cardiac Arrhythmia Suppression Trial (CAST I) was initiated because of the increased mortality seen in postinfarct patients with ventricular premature depolarizations (VPDs).47 Prevailing wisdom dictated that suppressing VPDs with class I drugs would improve mortality; in fact, some objected to the trial because it would deny potentially lifesaving treatment to the patients randomized to placebo. As summarized in Table 8.3, flecainide, encainide, and moricizine actually increased mortality in this population.40 CAST I and II demonstrated that while antiarrhythmic drugs may suppress VPDs by altering myocardial conduction and refractoriness, these same effects can promote proarrhythmia. These trials

also illustrated that it is clinical effect, specifically overall mortality, that ultimately defines benefit; the legitimacy of surrogate end points such as VPD suppression must be proven in clinical trials before assuming a beneficial effect in patients. A meta-analysis of 51 randomized trials evaluating class I antiarrhythmic agents in the postinfarct population, 16 of which were specific to Ic agents, demonstrated that the odds ratio of death was 1.14 (p = 0.03).48 While all patients had CAD, these trials were not confined to patients with reduced LV function. Given their greater risk of SCD and proarrhythmia, a more compromised cohort, such as patients with CAD and postinfarct LV dysfunction, may fare even more poorly with class I antiarrhythmics. With the demise of prophylactic class I antiarrhythmics in the postinfarct and HF populations,

Enrollment criteria

Moricizine vs. placebo

d-Sotalol vs. placebo

Amiodarone vs. placebo

SWORD,41 1996

GESICA,42 1994

516 patients (40% ICM)

No sustained VT

Systolic dysfunction by CXR, EF, or LVEDD (mean LVEF 20%) 13 months

NYHA classes II–IV (48% NYHA class III)

148 days

3,121 patients

LVEF < 40% LVEF < 40% (mean 31%)

Recent MI (6–42 days) or HF with remote MI (93% NYHA classes II–III)

1,325 patients

10 months

1,727 patients

Trial size/mean follow-up

Post-MI (<90 days)

No LVEF cutoff

Flecainide, encainide vs. placebo Post-MI (6 days–2 year) >5 VPDs/h

a

Agent(s) studied

CAST II,4 1992

CAST I, 1989

40

Trial, date published

Importance of clinical vs. surrogate end points

Recognition of proarrhythmia

Clinical implications

Empiric d-sotalol increases mortality in ICM

Caveats

Reduced both SCD (27%) and HF death (23%) [NS]

Poor overall survival (OMT has improved markedly since 1994)

Arrhythmic death increased 77% (p = 0.008) Mortality reduced 28%: Amiodarone may Significant 33.5% vs. 41.4% improve mortality in Chagas popu(p = 0.024) mixed CMP populalation limits tion generalized applicability

Increased mortality 65%: 5% vs. 3.1% (p = 0.006)

Terminated prematurely

Terminated prematurely Excess mortality during Same as CAST I the initial 14 days (RR 5.6)

Active treatment increased mortality (RR 2.5): 7.7% vs. 3.0%.

Results

Table 8.3. Summary of clinical trials conducted to examine the effect of antiarrhythmic agents upon mortality in patients with left ventricular dysfunction.

168 E.C. Adelstein and L.I. Ganz

Amiodarone vs. placebo

Amiodarone vs. placebo

Amiodarone vs. placebo

CHF-STAT,43 1995

EMIAT,44 1997

CAMIAT,45 1997

No LVEF or NYHA criteria reported

Complex ventricular ectopy (≥10 VPD/h or NSVT) 1.8 years

1,202 patients

1.7 years

Recent MI No NYHA criteria (47% NYHA class I)

Recent MI (6–45 days)

1,486 patients

(71% ICM) 45 months

674 patients

LVEF < 40% (mean 30%)

LVEF < 40% 10 VPD/h (symptomatic)

NYHA classes II–IV

Possible synergy between amiodarone and β-blockers

Amiodarone may decrease SCD in patients with recent MI and ICM

High discontinuation rates suggest excessive vigilance for ADEs

High discontinuation rates (36.4% amiodarone, 25.5% placebo)

Total mortality reduced 18% (NS)

(continued)

High d/c rates (40% amiodarone, 21% placebo) 38% reduction in actual/ Amiodarone may No inclusion aborted SCD (NS) decrease SCD and criteria relmortality in recent MI evant to HF survivors with ventricular ectopy

SCD reduced 35%: 4% vs. 2.6% (p = 0.05)

No effect on SCD Trend for improved mortality in NICM (p = 0.07) Identical overall mortality

No significant mortality Amiodarone may difference (30% at 2 improve mortality in years) NICM

8. Management of Arrhythmias in Heart Failure 169

Azimilidea vs. placebo

ALIVE,5 2004

No NYHA criteria (48% NYHA class I)

Recent MI (5–21 days) LVEF 15–35% (mean 29%)

ClCr > 20 cc/min

QTc < 460 ms (<500 ms if BBB)

Recent HF hospitalization (>90% NYHA classes II–III)

LVEF < 35%

Enrollment criteria

1 year

3,717 patients

18 months

(67% ICM)

1,518 patients

Trial size/mean follow-up

75% of drug-induced TdP occurs in first 3 days Dofetilide converted and maintained SR in patients with baseline AF TdP reduced with dosing change (4.8% vs. 2.9%) Mortality same (12%) Azimilide is safe in ICM AF reduced 50%: 0.5% Azimilide may reduce vs. 1.2% (p < 0.04) PAF in ICM patients

< 1% torsade de pointes and neutropenia

Caveats

High overall mortality Dosing protocol altered in midst of study

Dofetilide is safe in HF Only 10% on β-blockers

Clinical implications

HF hospitalization Dofetilide may decrease reduced 25%: 30% vs. HF admissions by pre38% (p < 0.001) venting AF

Mortality same (41%)

Results

When not specifically mentioned, all comparisons in results column refer to active treatment compared to placebo. TdP torsade de pointes, ADEs adverse drug effects, SR sinus rhythm, LVEDD left ventricular end-diastolic diameter. Trial acronyms: CAST Cardiac Arrhythmia Suppression Trial, GESICA Grupo de Estudio de la Sobrevida en la Insuficienca Cardiaca en Argentina, CHF-STAT Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure, EMIAT European Myocardial Infarction Amiodarone Trial, CAMIAT Canadian Amiodarone Myocardial Infarction Arrhythmia Trial, DIAMOND-HF Danish Investigations of Arrhythmia and Mortality on Dofetilide in Heart Failure, ALIVE Azimilide Postinfarct Survival Evaluation. a Encainide and azimilide are not approved for clinical use in the USA.

Dofetilide vs. placebo

Agent(s) studied

DIAMOND-HF, 1999

46

Trial, date published

Table 8.3. (continued)

170 E.C. Adelstein and L.I. Ganz

8. Management of Arrhythmias in Heart Failure

A meta-analysis of 13 randomized, controlled trials of prophylactic amiodarone in patients with either HF or recent MI, in which 89% of patients had a history of any MI and the mean LVEF was 31%, demonstrated a 15% total mortality reduction, which was of borderline statistical significance.50 This benefit resulted entirely from a 29% reduction in SCD. Additionally, symptomatic HF best predicted SCD. Despite a high rate of amiodarone withdrawal (41%), a significant proportion of purported adverse effects were likely not related to amiodarone, given the 27% rate at which placebo was stopped (Figure 8.7). The risk of bradyarrhythmias was 1–7%, and the incidence of pulmonary toxicity was 1% annually. As discussed later, the Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) would ultimately disprove the benefit of amiodarone in SCD prevention. The multitude of adverse effects seen with chronic amiodarone use has spurred examination of alternative class III agents, including dofetilide and azimilide. Dofetilide prolongs the action potential in both atrial and ventricular myocytes via blockade of Ikr. Its safety in the HF population was verified in the Danish Investigations of Arrhythmia and Mortality on Dofetilide in Heart Failure (DIAMOND-HF) Study.46 Over a median follow-up of 18 months, overall mortality was identical (41%) with dofetilide and placebo in predominantly NYHA 50 Amiodarone Cumulative rate (%)

interest shifted toward class III agents. The beneficial effects of sotalol were first demonstrated in a study by Julian et al.,49 which showed a nonsignificant 19% mortality reduction in postinfarct patients treated with the racemic mixture of d- and l-sotalol. The Survival With Oral D-sotalol (SWORD) study sought to discern whether this survival benefit stemmed from the dextrostereoisomer’s selective inhibition of rapid potassium ion channels (Ikr), as opposed to the β-blockade provided by l-sotalol.41 D-sotalol increased mortality in SWORD. SCD was increased to a greater extent in patients with moderate LV dysfunction, whereas the detrimental effect upon mortality in severe HF was more evenly distributed between worsening HF and SCD. This differential effect illustrated the proarrhythmic potential of d-sotalol. Amiodarone gained interest as a potential prophylactic agent in primary prevention of SCD in NICM with the publication of two studies: GESICA and CHF-STAT. The Grupo de Estudio de la Sobrevida en la Insuficienca Cardiaca en Argentina (GESICA) demonstrated a salutary effect on mortality and hospitalization in a mixed HF population.42 However, a significant minority of patients had Chagas disease, potentially limiting the generalizability of this study. The Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure (CHF-STAT) demonstrated a neutral survival effect with amiodarone in NYHA functional classes II–IV patients (71% ischemic), with moderate-to-severe LV dysfunction and at least 10 asymptomatic VPDs per hour.43 However, there was a trend toward a mortality benefit in nonischemic patients. In survivors of MI, two major studies sought to expand the beneficial effects of amiodarone: CAMIAT and EMIAT. Although inclusion criteria were vague, amiodarone did exert a nonsignificant effect in reducing arrhythmic death and resuscitated VF in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT).45 The European Myocardial Infarction Amiodarone Trial (EMIAT), which did have discrete inclusion criteria for LV dysfunction, demonstrated a decrease in arrhythmic mortality, although overall survival was unchanged.44 Furthermore, discontinuation rates were high, even in the placebo group, raising the possibility of excessive vigilance for amiodarone intolerance. EMIAT also suggested a possible synergistic effect between amiodarone and β-blockers.

171

40 30 Placebo

20 10 0 0

3

6 12 18 Time since randomisation (months)

24

Figure 8.7. Kaplan–Meier curves illustrating the rates at which amiodarone and placebo were discontinued in the meta-analysis of 13 randomized trials of prophylactic amiodarone. Adapted from Connolly et al.40 Copyright 1997, with permission from Elsevier

172

E.C. Adelstein and L.I. Ganz

classes II–III patients (Figure 8.8). There was no difference in arrhythmic or nonarrhythmic mortality in the cohort, about two-thirds of whom had ischemic heart disease. The observed mortality rate was quite high, perhaps a reflection of the underuse of concomitant β-blockers (10%). Interestingly, despite the absence of a mortality effect, hospitalization for worsening HF was reduced 21% (30% vs. 38%), a benefit observed in patients both with and without AF. One explanation proffered for this finding is a reduction in new episodes of AF. As with any drug that prolongs the action potential, proarrhythmia, particularly torsade de pointes, is of particular concern with dofetilide. DIAMOND did alter its protocol in the midst of the study, creating a renally based dosing nomogram that reduced the incidence of torsade de pointes from 4.8 to 2.9%. Approximately three-quarters of cases occurred during the first 3 days of treatment, during which time hospitalization was mandatory, and risk was increased by NYHA class (odds ratio 3.9 if NYHA classes III–IV at baseline, as compared to NYHA classes I–II) and female gender (odds ratio 3.2). The most recently studied class III drug is azimilide, which has yet to be approved in the USA for clinical use. Azimilide was evaluated prospectively in the Azimilide Postinfarct Survival Evaluation (ALIVE), targeting a cohort of patients with LV dysfunction post MI.51 There was no difference in overall or arrhythmic mortality at

1 year (12% overall mortality). Azimilide did reduce the incidence of AF by 50%, although the absolute percentages were small (1.2% vs. 0.5%). Furthermore, azimilide was quite safe; although there was slightly more torsade de pointes and severe neutropenia in the patients treated with azimilide, adverse effects were rare. In summary, there is little role for prophylactic antiarrhythmic medications for the primary prevention of SCD in patients with HF. Clinical trials have convincingly demonstrated that class I agents pose excess mortality risk. Current class III drugs appear to be safe, but their impact upon mortality is neutral. Their main role is in the secondary treatment of VT and VF. The success of implantable cardioverter-defibrillators (ICDs) has usurped the role of antiarrhythmic drugs in primary SCD prophylaxis.

8.2.4. Implantable Cardioverter-Defibrillators The ICD was developed to prevent recurrent SCD in individuals who survived SCD, and it has evolved into the most effective means of prophylaxis against SCD for high-risk patients. Unequivocal efficacy has been established by a series of randomized clinical trials (Table 8.4) that have progressively expanded the role of these devices in patients with impaired LV function. Table 8.5 summarizes current indications for ICD implantation.

No Atrial Fibrillation

1.0

Probability of Survival

Probability of Survival

Atrial Fibrillation Dofetilide

0.8 Placebo

0.6 0.4 0.2 0.0

1.0 0.8

Dofetilide

0.6

Placebo

0.4 0.2 0.0

0

12

24 Month

36

0

12

24

36

Month

Figure 8.8. Kaplan–Meier survival curves in Danish Investigations of Arrhythmia and Mortality on Dofetilide in Heart Failure (DIAMOND-HF) according to a history of known atrial fibrillation prior to enrollment. Adapted from Torp-Pedersen et al.46 Copyright 1999 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008

CASH,37 2000

Secondary Prevention Trials AVID,52 1997

Trial, date published

Drug/device tested Enrollment criteria

No prespecified NYHA class (25% NYHA class I)

No prespecified EF (mean EF 46%)

Excluded reversible causes

Antiarrhythmic [empiric LVEF ≤ 40% (mean 32%) amiodarone (90%) or sotalol (EPS- or Holter-guided dose)] vs. ICD Hemodynamically compromising ventricular arrhythmia (VF; VT with syncope, HF, HoTN) ICD vs. antiarrhythmic Resuscitated from primary VT/VF (metoprolol, amiodar(>72 h from acute MI) one, or propafenone)

Table 8.4. Summary of ICD trials.

57 months

349 patients

18.2 months

1,016 patients

Trial size/mean follow-up ICD improves survival in patients with SCD or its surrogate and LV dysfunction

Clinical implications

No mortality difference between amiodarone, metoprolol (total or SCD)

ICD reduced mortality 23%: 36.4% vs. 44.4% (p = 0.08)

Amiodarone does not alter mortality in survivors of SCD

Propafenone increases mortality in survivors of SCD

Propafenone ICD seems to increased mortal- improve survival ity 61% vs. ICD in survivors of after 11 months SCD

Mortality reduced 29%: 16% vs. 24% (p < 0.02)

Results

(continued)

Mortality lower than expected (study was underpowered)

Relatively high mean LVEF may have diluted benefit

Registry population had poor survival

Caveats

8. Management of Arrhythmias in Heart Failure 173

MUSTT,55 1999

MADIT I,54 1996

Primary Prevention Trials

CIDS, 2000

53

Trial, date published

Table 8.4. (continued)

27 months

Prior MI (>3 weeks)

EP-guided therapy (AADs, with ICD if VT not suppressed or hemodynamiccally stable) vs. none

CAD 39 months NSVT (> 4 days after MI or revascularization)

No prespecified NYHA class (65% II–III) LVEF ≤ 40% (mean 29%)

704 patients

196 patients

3 years

659 patients

Trial size/mean follow-up

LVEF ≤ 35% (mean 26%)

No prespecified NYHA class (50% “no HF”)

No prespecified EF (mean 34%)

>72 h from acute MI

VF, SCD, VT with syncope, or syncope with inducible MMVT

Enrollment criteria

NSVT (~50% on antiarrhythInducible VT, not suppressed mics, with amiodarone by procainamide most frequent)

ICD vs. standard medical therapy

ICD vs. amiodarone

Drug/device tested Caveats

No PCI within 2 months

ICDs improve Amiodarone d/c’ survival in ICM ed in 46%. patients with NSVT, LVEF < 35%, and inducible VT No CABG within 3 months

Only 50% had spontaneous VF (i.e., true SCD)

ICD improves Significantly more survival in survivors ICD patients taking of SCD or its surβ-blocker rogate, primarily by reducing SCD

Clinical implications

Mortality reduced EP-guided AAD Protocol changed 27% in EP-guided therapy does not mid-study (fewer patients (entirely decrease mortality AADs needed accounted for by in ICM patients before empiric ICD ICDs) with NSVT implanted)

ICD reduced mortality 54%: 16% vs. 39% (p = 0.009)

ICD reduced SCD 33%: 3.0% vs. 4.5% (p = 0.094)

ICD reduced mortality 20%: 8.3% vs. 10.2% (p = 0.14)

Results

174 E.C. Adelstein and L.I. Ganz

ICD vs. OPT

ICD (epicardial) vs. OPT in patients undergoing CABG

ICD vs. OPT

MADIT II,52 2002

CABG-PATCH,2 1997

DEFINITE,56 2004

1,232 patients

LVEF ≤ 35% (mean 21%)

Indication for CABG Abnormal SAECG No prespecified NYHA class (73% NYHA classes II–III)

LVEF ≤ 35% (mean 27%)

458 patients

32 months

900 patients

Prior MI (>1 month) 20 months No prespecified NYHA class (evenly divided NYHA classes I–III)

LVEF < 30% (mean 23%)

Noninducible patients followed in registry

Inducible VT

Similar ICD discharge rate as MADIT I (57% at 2 year) Mortality reduced 33% (12% vs. 17%), p = 0.08

Trial terminated prematurely

(continued)

ICDs reduce SCD 10% of control arm mortality in NICM had ICD (for patients with syncope) ventricular ectopy

SAECG has a poor PPV for predicting SCD risk

Trial terminated prematurely No difference in ICDs do not OMT not truly | mortality: 4-year improve mortality optimal, but equal mortality 24% in patients with (OPT) vs. 27% ICM undergoing (ICD) CABG

Many ICDs were early generation, thoracotomy devices

ICD improved ICDs improve mortality: 48% mortality in this vs. AADs, 51% cohort vs. none Mortality reduced Empiric ICD No revascularization 31%: 14.2% vs. implantation within 3 months 19.8% (p = 0.016) reduces mortality in ICM

Registry challenges NPV of EPS

8. Management of Arrhythmias in Heart Failure 175

OPT vs. amiodarone vs. ICD

CRT-D vs. CRT-P vs. OPT

COMPANION (57), 2004

Drug/device tested

SCD-HeFT,37 2005

Trial, date published

Table 8.4. (continued)

2,521 patients

29 months

Trial size/mean follow-up

1,520 patients

12 months

NYHA classes III–IV

CMP (56% ICM) LVEF < 35% (mean 21%)

Any CMP NYHA classes II–III 45.5 months No ectopy specified (¼ had NSVT)

No prespecified NYHA class (78% II–III) LVEF ≤ 35%

Frequent ectopy (NSVT or > 10 VPD/h); only 9% had no NSVT

NICM (mean duration 2.8 year)

Enrollment criteria

More benefit seen in NYHA class III patients

ICDs set at VVI-40

Caveats

Similar results in ICM and NICM

CRT-P provided trend toward improved survival

ICDs, not amiodar- ICDs set at VVI-50 one, improve mortality in patients with symptomatic LV dysfunction

Strong trend toward overall mortality reduction

Clinical implications

Total mortality: 29% placebo, 28% amiodarone, 22% ICD CRT-P (15%) and CRT-P improves CRT-D (12%) HF morbidity in reduced mortality selected patients over OPT (19%)

ICD reduced mortality 23%

Amiodarone had no mortality effect (HR 1.06 vs. placebo)

SCD reduced 79%: 1% vs. 6% (p = 0.006)

Results

176 E.C. Adelstein and L.I. Ganz

ICD vs. OPT

Impaired autonomic function No NYHA class IV

Recent MI (6–40 days) 30 months

674 patients

ICD reduced arrhythmic mortality 58% (p = 0.009)

CRT improved morbidity Trend for increased ICDs improve overall mortality arrhythmic mortalwith ICD ity but do not alter total mortality in patients with recent, large MI

Addition of ICD to CRT improves mortality

When not specifically mentioned, all comparisons in results column refer to ICD therapy compared to placebo or medical therapy. OPT optimal pharmacologic therapy, NPV negative predictive value, PPV positive predictive value, HoTN hypotension, SAECG signal-averaged electrocardiogram, CRT-P cardiac resynchronization therapy with pacing only, CRT-D cardiac resynchronization therapy with defibrillation, MMVT monomorphic ventricular tachycardia, HR hazard ratio. Trial acronyms: AVID Antiarrhythmics Versus Implantable Defibrillators, MADIT Multicenter Automatic Defibrillator Implantation Trial, MUSTT Multicenter Unsustained Tachycardia Trial, CASH Cardiac Arrest Survivor Hamburg, CIDS Canadian Implantable Defibrillator Study, CABG-PATCH Coronary Artery Bypass Graft Patch, DEFINITE Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation, SCD-HeFT Sudden Cardiac Death Heart Failure Trial, COMPANION Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure.

DINAMIT,58 2005

HF hospitalization within prior 12 months LVEF ≤ 35%

QRS > 120 ms (mean 160)

8. Management of Arrhythmias in Heart Failure 177

178

Briefly, ICDs are devices that constantly monitor cardiac rhythm and provide rapid automatic treatment of life-threatening arrhythmias. First invented in the 1970s by Mirowski and Mower,59 modern iterations of the ICD are compact devices that are typically implanted subcutaneously in the pectoral region, with one or more transvenous leads. ICDs detect and treat tachyarrhythmias utilizing overdrive pacing, cardioversion, and defibrillation. Additionally, ICDs provide bradycardia pacing. More recently developed biventricular defibrillators improve myocardial function by providing cardiac resynchronization therapy (CRT-D). Clinical trials studying the effects of ICDs upon mortality have been predicated upon several observations. First, survivors of SCD, especially those with significant LV dysfunction, remain at high risk for future arrhythmic events. Most clinical trials of secondary SCD prevention have excluded patients with ostensibly reversible or transient causes of the index arrhythmia, on the assumption that such secondary episodes of SCD do not herald future events. The validity of this conclusion has been questioned, however.60 Second, not only do frequent VPDs and NSVT predict increased mortality in HF patients,61 but such ectopy is quite prevalent; 34–79% will exhibit NSVT on ambula-

E.C. Adelstein and L.I. Ganz

tory ECG monitoring.56 Unfortunately, suppressing these ambient arrhythmias with medications does not improve survival, as illustrated dramatically by CAST. Subsequent efforts have thus shifted focus toward devices. Finally, the high mortality rate in patients with either significant LV dysfunction and/or severe symptomatic HF, combined with the increasingly recognized poor negative predictive value of the EP study in risk stratification of HF patients, has spurred trials without ventricular arrhythmias, either spontaneous or induced, as an inclusion criterion.

8.2.4.1. Secondary Prevention of SCD with Implantable Cardioverter-Defibrillators Initial ICD trials established the role of the ICD in secondary prevention of SCD. The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial demonstrated a nearly 30% reduction in total mortality when ICD therapy was compared to class III antiarrhythmic agents in survivors of sustained, hemodynamically compromising ventricular arrhythmias with concomitant LV dysfunction.52 Two additional studies, the Cardiac Arrest Survivor Hamburg (CASH) trial and Canadian Implantable Defibrillator Study (CIDS), both found

Table 8.5. Current indications for ICD implantation. • Survivor of VF in absence of acute MI, WPW, or reversible cause (CASH)a • Prior sustained VT in setting of structural heart disease (AVID)a • Syncope with inducible ventricular arrhythmia upon EP study (no further clarification)a • EF ≤ 30%, prior MI (MADIT II)a–c • EF ≤ 35%, NSVT, prior MI, positive EP study (MADIT I)a–c • EF ≤ 35%, ICM, NYHA classes II–III (SCD-HeFT)a–c • EF ≤ 35%, NICM (>9 months duration), NYHA classes II–III (SCD-HeFT)a,c • EF ≤ 35%, NICM (3–9 months duration), NYHA classes II–III, entered in clinical trial or registry (SCD-HeFT)a,c • Familial or arrhythmic syndrome posing high risk of SCD (e.g., LQTS, Brugada, ARVD, HCM)a • EF ≤ 40%, CAD, NSVT, positive EP study (MUSTT) • Awaiting cardiac transplant (high-risk patients)c Current Indications for CRT-D Implantation • EF ≤ 35%, QRS ≥ 120 ms, NYHA classes III–IV despite optimal medical therapy Trials indicated in parentheses demonstrated benefit for patients with each particular criterion and are discussed elsewhere. WPW Worff-Parkinson White, LQTS long QT syndrome, ARVD arrhythmogenic right ventricular dysplasia, HCM hypertrophic cardiomyopathy. Italicized indications are reimbursed on an individual case-by-case basis but are generally regarded as appropriate. a Denotes an indication that is reimbursed by Medicare, as of the coverage decision on January 27, 2005. b Must be at >40 days from acute MI or >3 months after revascularization (either coronary artery bypass grafting or percutaneous intervention). c Not currently considered a formal indication for ICD implantation. In fact, NYHA class IV patients with narrow QRS complex have never been studied in clinical trials, and CMS considers this group to not be indicated for ICD implantation. Consider CRT-D in patients with EF ≤ 35%, QRS ≥ 120 ms, NYHA class III despite optimal medical therapy.

8. Management of Arrhythmias in Heart Failure

nearly significant trends for improved mortality with ICDs in survivors of SCD, despite being relatively underpowered and the absence of an ejection fraction cutoff.37,53 AVID, CASH, and CIDS specifically excluded patients in whom SCD was deemed secondary to reversible or transient causes, including myocardial ischemia, electrolyte imbalances, proarrhythmia from antiarrhythmic agents, illicit drug use, hypoxemia, or sepsis. However, patients followed in the AVID registry had a worse prognosis compared with those patients not randomized in AVID. The 2-year survival was 71% for the cohort with secondary causes of SCD, whereas 79% of the nonrandomized primary SCD patients survived. The survival advantage was perhaps a result of differential ICD implantation rates, as nearly half the primary cohort received an ICD, compared to only 20% of the secondary group.60 An additional study demonstrated that in survivors of SCD with concomitant structural heart disease who went on to receive an ICD, no significant difference in survival or ICD therapies was noted when comparing those patients whose index event was associated with an abnormal serum potassium concentration.58 Although revascularization is often performed in lieu of ICD implantation in patients found to have ischemia in the setting of VT or VF, this may be inadequate. In a group of patients with ICDs who had an episode of VT or VF, there was no change in recurrent ICD therapies or overall mortality in those who had evidence of ischemia and underwent surgical revascularization.62 These were not randomized trials, but one may conclude that any survivor of SCD with structural heart disease, regardless of the cause, is at high risk of further events and should be considered for ICD implantation. Secondary ventricular arrhythmias may herald an increased risk of future events, in that the electrical milieu easily supports ventricular tachyarrhythmias. This ICD implantation is generally recommended when SCD is associated with electrolyte abnormalities or myocardial ischemia; patients who present with SCD early in the course of an MI usually do not receive ICDs, although data supporting this practice are limited and somewhat dated.

179

8.2.4.2. Primary Prevention of SCD in Patients with Nonsustained Ventricular Ectopy The poor prognosis associated with NSVT in patients who have experienced a prior MI is well known; 2-year mortality in this population is nearly 30%.63 This observation sparked two landmark studies in patients with ICM and NSVT that conclusively demonstrated the salutary effects of ICDs in the primary prevention of SCD: the Multicenter Automatic Defibrillator Implantation Trial (now MADITI)54 and the Multicenter Unsustained Tachycardia Trial (MUSTT).55 MADIT I evaluated patients with an LVEF no greater than 35%, prior MI, ambulatory NSVT unrelated to acute infarction, and inducible VT on EP testing that could not be suppressed with intravenous procainamide. Eligible patients were randomized to ICD implantation or standard medical therapy, which could include antiarrhythmic drugs at the treating physician’s discretion. ICDs reduced overall mortality 54% over a mean follow-up of 27 months. MUSTT, which randomized 704 patients with CAD, an LVEF no greater than 40%, and NSVT not related to acute infarction, was designed to test the merits of EP-guided antiarrhythmic therapy versus no specific treatment in patients with inducible NSVT. An ICD was implanted if no agent could suppress inducible VT or render the patient hemodynamically stable. MUSTT was complicated by a change in protocol that allowed ICD implantation with failure of fewer drugs. Nevertheless, the utility of ICDs and limitations of antiarrhythmic drugs were displayed. Mortality was reduced 27% with EP-guided therapy compared to the control group. However, benefit was derived solely from the use of ICDs; ICD implantation reduced total mortality 48% compared to antiarrhythmic therapy and 51% compared to no therapy. In NICM, the role of the ICD in primary prophylaxis against SCD remained unclear until more recently. The Amiodarone Versus Implantable Cardioverter-Defibrillator Trial (AMIOVERT) did not demonstrate a difference in overall mortality, SCD, or quality of life between nonischemic patients randomized to amiodarone or an ICD over 2 years.64 AMIOVERT enrolled only 103 patients

180

with NICM, asymptomatic NSVT, and LVEF no more than 35%. There was a trend toward improved arrhythmia-free survival with amiodarone, although this finding was biased by improved arrhythmic surveillance obligately provided by ICDs, a high crossover rate (15% in the amiodarone group received an ICD and 24% of ICD patients required amiodarone, largely for AF), and a nearly 50% withdrawal rate with amiodarone. All syncopal episodes in the ICD group stemmed from ventricular tachyarrhythmias. AMIOVERT highlighted amiodarone’s poor tolerability and the fact that syncope in NICM patients is very commonly caused by ventricular tachyarrhythmias. A somewhat more definitive answer to the optimal treatment of patients with NICM and ambient ventricular arrhythmias was provided by the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE).65 DEFINITE randomized 458 patients with NICM and an LVEF no more than 35% who were found to have NSVT or more than 10 VPDs/h on ambulatory monitoring to ICD implantation with optimal medical therapy (OMT) or standard medical therapy alone. Despite the fact that 10% of the control group eventually received an ICD for unexplained syncope, there was a nearly significant 33% improvement in overall survival (mortality 12% vs. 17%) at 29 months, with a significant 79% relative reduction in SCD (1% vs. 6%). Overall survival was significantly improved in NYHA class III patients. Of note, the patients enrolled in DEFINITE did not have new HF; the mean duration of HF symptoms was 2.8 years.

E.C. Adelstein and L.I. Ganz

testing.66 However, NYHA class IV patients were excluded. Overall mortality in these patients, almost 90% of whom had their MI over 6 months prior, was reduced 31% over a 20-month followup, from 19.8 to 14.2%, resulting in the trial’s premature termination. The Sudden Cardiac Death Heart Failure Trial (SCD-HeFT) corroborated the benefit of ICD implantation in NICM seen in DEFINITE and definitively refuted prior studies suggesting a benefit for prophylactic amiodarone in DCM. This large trial randomized patients with mild-to-moderate HF symptoms (NYHA classes II–III) and systolic dysfunction (LVEF ≤ 35%) regardless of etiology to one of three arms: conventional HF therapy (also known as optimal pharmacologic therapy, or OPT) plus placebo, OPT plus amiodarone, or OPT with an ICD.67 The study population was almost evenly split between ICM and DCM, and nearly one-quarter had documented NSVT. After a median follow-up of 45.5 months, overall mortality was unaltered by amiodarone (hazard ratio 1.06), whereas ICDs reduced mortality 23% (Figure 8.9). Subgroup analyses revealed that both ischemic and nonischemic patients benefited from an ICD, perhaps with a greater effect in the latter, and that NYHA class II patients appeared to benefit more than NYHA class III patients. SCD-HeFT has established symptomatic LV dysfunction as a new criterion for prophylactic ICD implantation. At the time of this writing,

8.2.4.3. Primary Prevention of Sudden Cardiac Death in Patients Without Documented NSVT The most recent clinical trials have defined a role for ICDs in primary prevention of SCD in patients deemed high risk because of severe LV dysfunction or HF symptoms, regardless of ambient or inducible ventricular arrhythmias. MADIT II focused on ICM, and SCD-HeFT examined a mixed DCM population. The Second Multicenter Automatic Defibrillator Implantation Trial (MADIT II) enrolled 1,232 patients with a prior MI and severe LV dysfunction (LVEF no greater than 30%), regardless of HF symptoms, ambient ventricular ectopy, or EP

Figure 8.9. Total mortality Kaplan–Meier plots for patients randomized to amiodarone, implantable cardioverter-defibrillator (ICD) implantation, or placebo in Sudden Cardiac Death Heart Failure Trial (SCD-HeFT). Adapted from Bardy et al.67 Copyright 2005 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008 (See Color Plates)

8. Management of Arrhythmias in Heart Failure

the Center for Medicare Services has approved reimbursement for ICD implantation in patients with an LVEF less than or equal to 35%, NYHA classes II–III HF, and either NICM of greater than 9 months duration or ICM (Table 8.5).

8.2.4.4. Timing of ICD Implantation Two trials suggest that there is an interval of time that should elapse prior to ICD implantation in the setting of acute MI or the diagnosis of NICM: CAT and DINAMIT. The Cardiomyopathy Trial (CAT) found no beneficial effect for ICDs in patients with a newly diagnosed NICM, defined as fewer than 9 months and an LVEF less than 30%, leading to the trial’s premature termination.68 Furthermore, an ICD conferred no advantage in patients with preexisting NSVT on ambulatory monitoring. Of note, however, was the fact that patients who received an ICD and subsequently required appropriate therapies had a significantly worse prognosis. CAT was also underpowered. Given these findings, NYHA classes II–III patients with an LVEF less than or equal to 35% and NICM of 3–9 months duration are covered by Medicare only for ICD implantation if enrolled in a clinical trial or registry. The Defibrillator In Acute Myocardial Infarction Trial (DINAMIT) sought to bridge the gap between acute MI or revascularization and ICD implantation specified in prior trials.69 By enrolling patients with severe LV dysfunction and evidence of impaired autonomic function in the immediate postinfarct period, DINAMIT examined a patient population excluded from MADIT II. These patients were quite ill; most had anterior Q-wave infarcts, and the mean LVEF was less than 30%. A majority had clinically relevant HF during the acute infarct, although NYHA class IV patients were excluded. Nevertheless, while arrhythmic mortality was significantly diminished by 58%, overall mortality was unchanged; a tendency toward greater mortality in the ICD patients occurred because of more nonarrhythmic deaths. The appropriate timing of prophylactic ICD implantation in patients with a recent MI remains elusive, as the results of DINAMIT are disparate from other ICD trials. Perhaps a significant proportion of patients in DINAMIT recovered enough LV

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function to nullify the beneficial effects of an ICD. However, the large size of the infarcts suggests that this was not the case. An alternative explanation is that patients who would have died suddenly succumbed to pump failure or EMD. Another possibility is that ICD implantation with defibrillation testing poses an increased risk in the immediate postinfarct period. At the present time, enthusiasm for ICD implantation in the immediate post-MI period has been tempered by DINAMIT. A related issue is the role of the ICD in the sickest patients. Device therapy studies, with the notable exception of The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, have excluded NYHA class IV patients. Some authorities have suggested that ICDs confer minimal or no benefit in this population, yet data are scant. Appropriate ICD discharges clearly indicate patients with a higher overall mortality risk,70 yet it is precisely these discharges that protect patients from SCD.71 However, while the role of ICDs in the severely compromised HF population remains uncertain, CRT-D should proceed in stable NYHA class IV patients who meet COMPANION criteria (see below). ICD implantation should also be strongly considered in high-risk patients awaiting orthotopic cardiac transplantation; in a nonrandomized series, ICDs improved survival to transplant among listed NYHA classes III–IV patients, with nearly one-third of those implanted receiving appropriate ICD therapy.72

8.2.5. The Role of Cardiac Resynchronization Therapy Recently, biventricular pacing, or cardiac resynchronization therapy (CRT), has become an integral component of therapy for advanced HF patients with evidence of dyssynchronous contraction of the left ventricle. CRT is utilized primary for symptomatic relief in NYHA classes III–IV patients. Studies have demonstrated the ability of CRT to improve LV function, decrease functional mitral regurgitation, and reduce LV size.73 These salutary changes are collectively referred to as reverse remodeling. Meta-analyses,74 as well as the recent Cardiac Resynchronization-Heart Failure (CARE-HF) trial,57 have suggested a significant reduction in total mortality with CRT pacemakers

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(CRT-P, i.e., no ICD), which may reflect the longterm benefits of reverse remodeling. The COMPANION trial examined the clinical effects of biventricular pacemakers (CRT-P) and biventricular defibrillators (CRT-D) upon morbidity and mortality in NYHA classes III–IV patients, regardless of underlying HF etiology, and a QRS duration at least 120 ms.75 The primary end point of mortality and all-cause hospitalization was reduced 20% by both CRT-P and CRT-D. While CRT-P reduced mortality by 24% at 1 year when compared to OMT, CRT-D lowered mortality 36% (p = 0.06 and p = 0.004, respectively). COMPANION thus demonstrated the salutary effect of CRT upon HF morbidity and mortality, in addition to extending the survival benefit of ICDs seen in earlier trials to a sicker population. The nearly significant reduction in mortality with CRTP, similar to that seen in the meta-analysis, suggested that CRT’s effects upon reverse remodeling do indeed improve longer-term clinical outcomes. The recently published Cardiac ResynchronizationHeart Failure trial has more definitively provided data supporting the survival benefit of CRT-P. The addition of CRT-P to OMT improved survival by 36% in NYHA classes III–IV patients with an LVEF less than or equal to 35%, LV dilatation, and either marked QRS prolongation (≥150 ms) or modest prolongation (120–149 ms) with echocardiographic evidence of dyssynchrony.57 A reduction in mortality from both pump failure (by 42%) and SCD (by 24%) contributed to this outcome. This is the first indication that CRT-P reduces SCD, independent of the ability to provide defibrillation. While CRT’s ability to coordinate electrical activation of the left ventricle may eliminate possible reentrant loops, it appears more likely that delaying or reversing the progression of HF is the means by which CRT prevents SCD. Since ICD discharges portend a worse prognosis, perhaps CRT holds the promise of true antiarrhythmic therapy without the risk of proarrhythmia posed by current antiarrhythmic drugs.

8.2.6. Management of ICD Discharges ICDs comprise the cornerstone of SCD prevention in the HF population, regardless of etiology. Conventional ICDs prevent SCD but do not inhibit the inciting ventricular tachyarrhythmia. The substrate for these tachyarrhythmias remains,

E.C. Adelstein and L.I. Ganz

and not infrequently, patients will present with ICD discharges. These ICD discharges (“shocks”) are painful and disruptive; some patients may become incapacitated by the specter of additional shocks, even to the point of presenting with phantom shocks. Multiple ICD discharges may induce serious psychological distress and even posttraumatic stress disorder.76 Patients should be forewarned prior to implantation that the device may actually shock them. Once implanted, patients should understand that a single, isolated ICD shock should generally be evaluated expediently but not necessarily emergently in the outpatient setting in the absence of symptoms indicative of a decline in health status. However, multiple discharges should be evaluated immediately for several reasons.77 First, the patient may be experiencing recurrent arrhythmias, or the arrhythmia may never have been successfully terminated. So-called “electrical storm,” if present, must be aggressively treated. Second, electrical noise may, in fact, be the trigger. Not only does this cause inappropriate detection of VT/VF, but if it is the result of an internal lead fault (e.g., an insulation break), therapy for true tachyarrhythmias may be compromised. Finally, multiple ICD discharges may result from an SVT, usually sinus tachycardia or AF; while programmed algorithms seek selective detection of ventricular tachyarrhythmias, these devices are not infallible.

8.2.6.1. General Approach Initial evaluation of the patient who has received ICD discharges should focus upon any possible precipitants for arrhythmias, including myocardial ischemia, metabolic and/or electrolyte abnormalities, drug toxicities, worsening HF, or noncardiac illness, in addition to concomitant interrogation of the implanted device. Device interrogation should proceed with several issues in mind: (1) Did the device actually deliver therapy? Phantom shocks are not uncommon. (2) Was the shock appropriate? Therapy may be delivered for SVT or noise. (3) If the therapy was appropriate, would antitachycardia pacing (ATP) have potentially terminated the rhythm, thus allowing pain-free therapy before a shock discharge? (4) Should adjunctive pharmacologic therapy or catheter ablation be considered? (5) If the rhythm was SVT,

8. Management of Arrhythmias in Heart Failure

is a change in programming or institution of drug therapy warranted, or might catheter ablation be considered? (6) If artifact caused spurious therapy, is reprogramming or system revision necessary? One must bear in mind that it may not be possible to distinguish definitively between VT and SVT, particularly with a single-chamber device.

8.2.6.2. Device-Related Therapy Once the underlying rhythm disturbance is identified, appropriate therapy should be instituted. The consulting electrophysiologist may be able to reprogram tachyarrhythmia detection and therapy to provide ATP for a particular rate range, thus preventing shock discharges. Discriminators between VT and SVT may also be added or adjusted. Precipitants should be addressed, although these “reversible” causes should not be overemphasized and should not preclude adequate therapy. Ultimately, pharmacotherapy may be necessary. Antitachycardia pacing has been demonstrated in the PainFREE trials to provide an effective and safe alternative to shock discharges, even at rates previously deemed too rapid for this modality. The efficacy of ATP in terminating VT with relatively slow rates (i.e., ≤ 200 bpm) is known to be nearly 90%.78 Use of ATP for faster VT has been limited by concerns over efficacy, the possibility of accelerating the arrhythmia and rendering it more difficult to terminate, and the increased risk of syncope with a possible delay in effective therapy or transformation into a more hemodynamically compromising rhythm. The PainFREE Rx II randomized trial corroborated the safety and efficacy of ATP demonstrated in a pilot study, while also confirming that the use of ATP as an initial therapy modality improves quality of life compared to initial full shock discharge.79,80 A significant proportion of detected ventricular tachyarrhythmias fell into the “fast VT” range, defined as a rate between 188 and 250 bpm. ATP successfully terminated 75% of such fast VTs with a very low rate of syncope or rate acceleration, comparable to that seen in patients with shock-only ICDs.

8.2.6.3. Adjunctive Pharmacotherapy Pharmacologic therapy for recurrent ventricular arrhythmias in patients with an ICD generally

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involves titration of β-blockers if tolerated, followed by the use of class III agents, in particular, amiodarone, sotalol, and dofetilide. Although the risk of SCD resulting from the proarrhythmic effects of class I drugs should be less of a concern than in the “unprotected” patient, class I drugs are generally avoided. Class III medications have proven safety in HF patients, and their reverse use dependence may make them more useful as prophylactic agents. Amiodarone is often the initial therapy in patients with ICD discharges for appropriate ventricular tachyarrhythmias. Because of its efficacy in controlling paroxysmal AF and AFL, amiodarone is also useful in preventing inappropriate shocks for these rhythms. There is extensive anecdotal experience attesting to the efficacy of amiodarone in preventing additional ICD discharges. The Cardiac Arrest in Seattle, Conventional Versus Amiodarone Drug Evaluation (CASCADE) trial, which randomized survivors of out-of-hospital VF without acute MI to empiric amiodarone or guided class I therapy, provides some evidence-based support for this practice.81 Patients enrolled in CASCADE had significant ambient ventricular ectopy, and the mean LVEF was 35% despite a diagnosis of HF in only half. Amiodarone reduced the incidence of the primary end point, a composite of cardiac mortality, resuscitated VF, or syncope with an ICD discharge from 41 to 29% at 6 years. Of the 45% of patients who had an ICD, amiodarone reduced the number of shocks significantly; at 2 years, shock-free survival was 77% in patients receiving amiodarone and 42% for those using class I agents. Sotalol has been prospectively confirmed to prevent ICD discharges in the d,l-Sotalol Implantable Cardioverter-Defibrillator Study,82 which randomized 302 NYHA classes I–II patients with ICDs to racemic sotalol or placebo. The enrolled patients had a mean EF of 38%, with one-third less than 30%. Nearly 70% had prior infarcts. Sotalol improved shock-free survival in all patients by 49% at 12 months, including those with severe LV dysfunction (Figure 8.10). Both appropriate and inappropriate discharges were minimized with sotalol, and only one patient in each group experienced torsade de pointes. A smaller study comparing sotalol and metoprolol in patients with an ICD demonstrated equal efficacy in preventing recurrent episodes of VT or VF.83 Increasing

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E.C. Adelstein and L.I. Ganz

Proportion of Patients

1.0 0.9 0.8

Sotalol

0.7 0.6 P < 0.001

0.5

Placebo

0.4 0.0 0

30 60 90 120 150 180 210 240 270 300 330 360 390 Days after Randomization

No. AT Risk Placebo 151 129 114 101 90 84 84 77 70 151 136 123 119 115 109 104 101 99 Sotalol

70 95

69 91

65 90

49 70

Figure 8.10. Kaplan–Meier plot for percentage of patients who were free of implantable cardioverterdefibrillator (ICD) discharges following randomization to sotalol or placebo. Adapted from Pacifico et al.82 Copyright 1999 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008

β-blockade may thus be considered prior to instituting antiarrhythmic therapy. The Optimal Pharmacological Therapy in Implantable Cardioverter-Defibrillator Patients (OPTIC) trial also suggests that amiodarone is extremely effective for reducing ICD shocks in patients with dual-chamber devices.84 Compared to β-blockers alone (metoprolol, bisoprolol, or carvedilol), the addition of amiodarone reduced total ICD discharges by 73% at 1 year. This was matched by a 70% decline in appropriate shocks or ATP, and a 78% reduction in inappropriate shocks. Patients randomized to sotalol monotherapy experienced a trend toward 39% fewer shocks than patients on β-blockers. However, the reductions in the individual end points of appropriate shocks alone or inappropriate shocks alone did not reach statistical significance. An unexpected finding was that sotalol was less well tolerated than amiodarone; rates of study drug discontinuation at 1 year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for β-blocker alone. Dofetilide’s electrophysiologic effects are more pronounced in the atria than the ventricles, and clinical trial data confirm that dofetilide is indeed more effective in suppressing AF than VT. Although dofetilide suppresses VT acutely dur-

ing EP testing in ∼40–45% of patients, long-term efficacy data are lacking.85 One trial randomizing 131 patients with an ICD, a majority of whom had significant LV dysfunction, to dofetilide or placebo found no significant difference in the incidence of monomorphic VT, although dofetilide did reduce the frequency of multiple episodes.86 Furthermore, an increased incidence of polymorphic VT offset any benefit. Another recently evaluated agent for preventing ICD discharges is azimilide. The Shock Inhibition Evaluation with Azimilide (SHIELD) trial randomized 633 patients to azimilide or placebo for 1 year.87 Patients treated with azimilide experienced 50% fewer shocks and ATP, both appropriate and inappropriate. Reduction in all-cause shocks was not significant, suggesting that azimilide was most effective in reducing arrhythmias requiring ATP, perhaps reflecting greater efficacy for VT than VF. Adverse effects included a low incidence of torsade de pointes (five azimilide vs. one placebo patient) and one reversible episode of neutropenia with azimilide. This drug is not currently approved for clinical use in the USA. In summary, class III antiarrhythmic drug therapy reduces the likelihood of ICD therapy. Although proarrhythmia is generally less of a concern in patients “protected” with an ICD, extracardiac toxicity, particularly with amiodarone, remains a risk. At present, there is no indication for the routine initiation of prophylactic antiarrhythmic drug therapy in patients undergoing ICD implantation.

8.2.7. Catheter Ablation Medically refractory ventricular arrhythmias are potentially curable with catheter-based radiofrequency ablation (RFA). Hemodynamically tolerated monomorphic VTs are more amenable to this approach than more disorganized rhythms (i.e., polymorphic VT and VF). Patients with an ischemic substrate present additional difficulties, as scar-ridden myocardium provides multiple reentrant circuits, and sustained VT needed for endocardial mapping may precipitate ischemia. The recent use of scar mapping during sinus rhythm has allowed catheter RFA of such hemodynamically

8. Management of Arrhythmias in Heart Failure

unstable arrhythmias, particularly in patients with CAD.88 The discussion of techniques for mapping and ablation of VT is beyond the scope of this chapter. Bundle branch reentrant ventricular tachycardia (BBRVT) is a macroreentrant rhythm seen primarily in patients with DCM and baseline left bundle branch block (LBBB). Unlike most VT in patients with NICM or ICM, BBRVT is easily curable with RFA. The diagnosis of BBRVT should be suspected when a patient with a dilated LV presents with monomorphic VT with a LBBB pattern and a LBBB-type intraventricular conduction delay while in sinus rhythm. Upon EP testing, infranodal conduction delay is the rule, accounting for the LBBB seen in sinus rhythm. When induced, VT demonstrates a His bundle electrogram before each QRS complex. This is not the case for most forms of VT, in which reentry does not involve specialized conduction tissue. Therapy involves ablation of the right bundle branch, although preexisting infrahisian conduction disease is often severe enough that subsequent implantation of a permanent pacing device is required. As these patients are at high risk for other life-threatening ventricular tachyarrhythmias, this device is generally an ICD.

8.2.8. Clinical Use of Antiarrhythmic Drugs for Ventricular Arrhythmias Amiodarone is the workhorse of antiarrhythmics used in HF patients with ventricular tachyarrhythmias, as it is clearly the safest agent from a proarrhythmia perspective. Intravenous amiodarone is effective for termination of hemodynamically stable VT, and it is also the drug of choice for unstable VT and VF after prompt defibrillation. The oral form is relegated to use in patients with an ICD in whom ventricular tachyarrhythmias become problematic and may be used with or without initial intravenous loading. Dosing amiodarone is largely empiric. It may be administered intravenously in the acute setting for ventricular arrhythmias, followed by oral dosing. Because of its lipophilic nature, only the intravenous formulation has the capability of rapid efficacy. Furthermore, the half-life of amiodarone is at least 1 month, delaying achievement of steady-state plasma levels and complete elimination when discontinued. Amiodarone is usually given

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as an intravenous bolus, followed by a continuous infusion, when used for acute suppression of ventricular (and atrial) arrhythmias. For pulseless VT or VF, a 300-mg bolus should be administered, in addition to prompt defibrillation. This bolus may be associated with hypotension, largely an effect of its diluent. If used for stable VT or frequent salvos of NSVT, an initial 150-mg bolus administered over 10 min, followed by continuous infusion at 1 mg/min, is sufficient. The infusion rate is usually reduced to 0.5 mg/min after 6–12 h. Additional boluses may be given for recurrent VT, and the infusion rate may be kept at the higher dose until more complete arrhythmia suppression. An infusion should be continued for at least 48 h in most circumstances, and in patients in whom oral therapy is not possible or is limited by malabsorption, it may be continued for several weeks. If necessary, intravenous amiodarone should be overlapped with oral loading. Oral administration of amiodarone involves completing initial loading followed by maintenance dosing. In general, an initial cumulative intravenous and oral amiodarone load for ventricular arrhythmias should total 6–10 g. Oral loading typically involves 400 mg three to four times daily for several days, followed by a decrease to 400 mg twice daily for 1–2 weeks, followed by maintenance dosing, which is usually 200–400 mg daily. Since amiodarone toxicity increases with cumulative exposure, the lowest effective dose should be sought during long-term follow-up. In patients who are clinically stable on a maintenance dose of 200 mg/day, even lower doses of amiodarone may be tried. Younger patients, the elderly, and those deemed at risk for significant bradycardia should be less aggressively loaded, typically using 400 mg twice daily or 200 mg thrice daily, administered over a longer duration. Chronic maintenance, however, remains 200–400 mg daily. HF patients with tenuous hemodynamics may require even less aggressive oral loading. In general, amiodarone should not be the first drug utilized in younger patients, given its cumulative multiorgan toxicities. However, it is often preferred for patients who are elderly, have advanced HF symptoms, or have significant renal impairment. Amiodarone’s potential toxicities are myriad, including effects on the central nervous system (tremor and optic neuritis), the eyes (scleral

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and corneal deposits), the skin (blue discoloration and photosensitivity), the liver (transaminitis), the lungs (pneumonitis and pulmonary fibrosis), the gastrointestinal tract (diarrhea), and the thyroid gland (hyper- or hypothyroidism). Surveillance for adverse effects in patients taking amiodarone is essential.89 Liver-associated enzymes and thyroid function tests should be monitored every 3 to 6 months after ensuring an absence of abnormalities at baseline and at 3 months. Hyperthyroidism is uncommon in the iodinereplete American diet; hypothyroidism, however, is relatively common, at 3–4%. Amiodarone may be continued in the setting of hypothyroidism with concurrent thyroid replacement therapy. However, iatrogenic hyperthyroidism generally necessitates discontinuation of amiodarone. Transaminitis requires a search for alternative etiologies, particularly in patients taking other possible culprit drugs (e.g., statins). Pulmonary function should be evaluated at baseline, including an assessment of the diffusing capacity of carbon monoxide (DLCO). Although the risk of pulmonary toxicity is low, especially with the smaller cumulative doses used in present practice, it does occur in ~1% of patients per year. Chest radiographs or high-resolution computed tomography (CT) should be performed yearly and in the setting of unexplained new dyspnea. Any new radiographic abnormalities should be followed by repeat PFTs. Some physicians follow PFTs with a measurement of DLCO every 6–12 months even in the absence of symptoms. Caution should be exercised when used in patients with preexisting lung disease, although there is no evidence that pulmonary toxicity is more common in these patients. Finally, periodic dermatologic and ophthalmologic evaluations should be performed. Adverse cardiac effects of amiodarone primarily manifest as bradycardia, particularly in elderly patients with underlying conduction system disease, concomitant AF, or ischemic heart disease.90 The overall incidence of symptomatic bradycardia is only 5%, and the risk of ventricular proarrhythmia is less than 1%, making amiodarone a relatively safe class III medication. Pacemaker (or ICD, if significant LV dysfunction exists) implantation may become necessary in patients in whom amiodarone is deemed indispensable; this risk is increased fourfold in women. In summary, although the adverse drug event rate is quite high

E.C. Adelstein and L.I. Ganz

in some studies, it is our experience that, if used judiciously in the lowest effective dose with meticulous follow-up, amiodarone may be safely administered in appropriate patients longitudinally. Amiodarone has several significant drug–drug interactions that require consideration, including an increase in the effective concentrations of quinidine, procainamide, warfarin, and digoxin. While procainamide and quinidine are used rarely in HF patients, digoxin and warfarin are used commonly. The INR must be followed carefully in patients on warfarin, often necessitating a 25% reduction in dose upon initiation of amiodarone. In addition to a direct impact upon warfarin metabolism in the liver, amiodarone-induced alterations in thyroid function may affect the therapeutic effect of warfarin. Increased serum levels of digoxin should also be anticipated, with compensatory dose adjustments made to reduce proarrhythmia risk. Sotalol, administered as the d- and l-racemic mixture, has no role in monotherapy for SCD prophylaxis without concomitant ICD implantation. However, sotalol is the antiarrhythmic drug of choice for younger patients with preserved renal function in whom ventricular arrhythmias occur after implantation of an ICD. Sotalol is generally initiated with at least 72 h of continuous monitoring and careful assessment of the QT interval. The necessity of this in patients with ICDs is uncertain. In general, the β-blocking action of sotalol is seen at lower doses than its class III effects, which are observed with a daily dose of 240 mg or more. With daily doses greater than 320 mg, the risk of proarrhythmia increases steeply. Toxicities stemming from its β-blocking effects include bradyarrhythmias and exacerbation of HF. The latter effect often limits its use to NYHA classes I–II patients. Clinical dosing of sotalol is guided by the heart rate, efficacy, and QT interval. Additionally, renal function affects dosing, as sotalol is excreted via the kidneys. The initial dose should be 80–120 mg twice a day in patients with normal renal function. Oncedaily dosing should be used in patients with a creatinine clearance of 30–60 mL/min. Sotalol should be avoided when the glomerular filtration rate is less than 30 mL/min. In patients with symptomatic LV failure, careful monitoring for exacerbation of symptoms related to negative inotropic effects is warranted. While dofetilide is safe for use in HF patients, its efficacy in prophylaxis against ventricular

8. Management of Arrhythmias in Heart Failure

arrhythmias is unproven. Its major utility is in patients with AF, although a therapeutic trial may be warranted in NYHA classes III–IV patients with ventricular tachyarrhythmias after ICD implantation in whom amiodarone is either ineffective or contraindicated. Dofetilide is renally dosed, and requires extreme caution in patients with compromised or labile renal function, with dosing titrated according to the observed QT interval. Furthermore, patients must be continuously monitored for polymorphic VT for 72 h upon initiation. There are few adverse effects other than proarrhythmia. One must be mindful that a number of drugs are unsafe for concomitant use, either because they actively slow the excretion of dofetilide, compete with its elimination, or themselves prolong the QT interval (Table 8.6). Additional considerations include drug–drug and drug–device interactions. When switching from one antiarrhythmic agent to another in the same class, particularly among class III agents, one should allow sufficient time for nearly complete washout, usually four to five half-lives. The risk of QT prolongation and precipitating torsade de pointes is the primary concern when overlapping these drugs. Also, the interaction between antiarrhythmic medications and implanted devices must not be overlooked, as these agents alter pacing thresholds, Table 8.6. Drugs contraindicated with concomitant dofetilide use. Drugs excreted via same mechanism (relative contraindication) Triamterene Metformin Amiloride

Drugs that slow renal transport (absolute system contraindication) Cimetidine Verapamil Ketoconazole Trimethoprim Prochlorperazine Megestrol

QT-prolonging drugsa Class III agents Class Ia agents Bepridil Phenothiazines Tricyclic antidepressants Erythromycin Cisapride Spar-, gati, moxifloxacin

Drugs that are excreted via the renal cation transport system may compete with dofetilide excretion and are therefore relatively contraindicated. Drugs that directly inhibit excretion of dofetilide are absolutely contraindicated. The concomitant use of drugs that also prolong the QT interval is not recommended. a This list of QT-prolonging drugs is not all-inclusive. A comprehensive, updated list may be found at the website www.torsades.org.

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sensing of intrinsic electrical activity, the rate and morphology of tachyarrhythmias, and defibrillation thresholds (DFTs). Medication–device interactions are most critical in patients with ICDs. In general, class I agents increase DFTs, whereas class III drugs increase the amount of energy needed to terminate VF. Amiodarone typically increases the DFT with chronic use. Although the clinical utility of monitoring serum levels of amiodarone and desmethylamiodarone is limited, their concentrations do correlate positively with the DFT.91 If an antiarrhythmic drug is initiated in a patient with an ICD, repeat DFT testing should be considered upon achieving steady state. This may be performed noninvasively through the device with intravenous sedation. Noninvasive programmed stimulation may also provide insights into changes in clinically relevant tachyarrhythmias after loading with antiarrhythmic drugs. The cycle length of VT may be prolonged, resulting in lack of device detection if rate parameters are not adjusted. Unstable, extremely rapid VT may be slowed into a pace-terminable VT. Underlying sinus- and/or atrioventricular (AV)node function may be depressed, preventing significant sinus tachycardia or rapidly conducted AF from achieving rates approaching those of VT. This may allow for more aggressive ATP programming.

8.3.

Atrial Fibrillation

Atrial fibrillation (AF) becomes more commonplace as LV function deteriorates and NYHA functional status declines (Table 8.1). Meanwhile, its hemodynamic significance and symptomatic effects become magnified. In a patient with normal LV function, the atrial contribution to total cardiac output may be as high as 20%, yet atrial “kick” contributes a greater percentage to cardiac output in systolic HF.92 Furthermore, the lack of an atrial systole necessitates a higher mean left atrial (LA) pressure to maintain adequate LV filling, predisposing patients to pulmonary edema. Although it has not conclusively been proven that maintaining sinus rhythm in patients with HF improves survival, AF is consistently associated with increased mortality.93 Whether AF is merely a marker of cardiovascular disease severity or actively contributes to greater mortality remains unresolved. Treatment of

188

E.C. Adelstein and L.I. Ganz Atrial Fib / Flutter First episode or rare recurrences Frequent recurrences or severe Sx Duration > 24 - 36 hours TEE*

Duration < 24 - 36 hours

Anticoagulation

Cardiovert

Refractory Symptoms

Antiarrhythmic Therapy

Cardiovert Anticoagulation Consider anticoagulation / long-term medical therapy

Rate Control and Anticoagulation

Ablation (if atrial flutter)

Refractory Symptoms AV Junctional Ablation & Pacemaker

Focal AF Ablation

* with appropriate anticoagulation

Figure 8.11. Atrial fibrillation treatment algorithm. Adapted from Ganz.94 Copyright 2005 Lippincott Williams & Wilkins. Reproduced with permission

AF must be individualized; a general treatment algorithm is proposed in Figure 8.11.

8.3.1. Secondary Treatment of Atrial Fibrillation Identification of AF in a patient with HF should prompt several treatment considerations, namely, (1) controlling the ventricular response, (2) minimization of thromboembolic risk, (3) restoration of sinus rhythm, and (4) maintenance of sinus rhythm. The first two treatment imperatives should be addressed immediately, whereas rhythm-control issues may often be deferred. Prevention of cardioembolic events, primarily ischemic stroke, will not be discussed further; multiple trials have demonstrated the benefits of chronic anticoagulation with warfarin in reducing cerebrovascular accidents, as both primary95-97 and secondary prevention.98 LV dysfunction is, itself, a risk factor for thromboembolic complications in the setting of concomitant AF.99 The annual stroke risk for patients younger than 75 years of age with HF (with or without additional risk factors) is ∼5–6% without chronic anticoagulation, yet this risk becomes less than 2% with warfarin. The salutary effect upon stroke risk is magnified

in the elderly HF population, in whom the annual stroke risk is at least 8% in those not on warfarin and 1.2% with anticoagulation. Given the high prevalence of additional embolic risk factors in the HF population, including LV dysfunction, diabetes mellitus, prior CVA, hypertension, and CAD, anticoagulation should be instituted in the absence of true contraindication(s).100 The clinician must not neglect the search for a possible reversible cause of AF in patients for whom this is a new diagnosis. This differential should include hyperthyroidism, ischemia, pericarditis, pulmonaryembolism, other concomitant pulmonary disease, or alcohol abuse. Identifying a precipitant other than worsening HF is unusual, but doing so may allow specific therapy and obviate the need for antiarrhythmic drugs.

8.3.1.1. Acute Rate Control Slowing the ventricular response should be the first priority in patients with hemodynamically stable AF. Agents that slow AV-nodal conduction include digitalis, β-blockers, and nondihydropyridine calcium channel blockers (CCBs). In the future, long-acting adenosine analogs may join this armamentarium.

8. Management of Arrhythmias in Heart Failure

189

Digoxin is generally the least effective AV-nodal blocking agent. Its inefficacy is compounded by an onset of action measured in hours, not minutes. It should therefore not be used as the sole rate-control agent in HF patients who present with rapid ventricular rate during AF. However, it may be a useful adjunct, especially in circumstances in which other agents may exacerbate hypotension or in which necessary inotrope administration accelerates AV-nodal conduction of underlying AF. Dosing digoxin is largely empiric. Acutely, loading 1 mg, divided over 24 h, is a reasonable approach. For example, 0.25 mg orally or intravenously, given immediately, then every 6 h for a total of 1 mg, constitutes a typical load. Subsequent dosing Table 8.7. A simple dosing algorithm for maintenance digoxin. Age

SCr < 65 < 1.5 > 1.5 HD

> 65

0.25 mg QD 0.125 mg QD

0.125 mg QD 0.125 mg QOD 0.125 mg after HD

SCr serum creatinine concentration, in mg/dL, HD hemodialysis, QD daily, QOD every other day.

is based upon age and renal function. Table 8.7 illustrates one simple nomogram for chronic digoxin dosing. Obtaining routine serum digoxin levels may help avoid potential toxicity, particularly if its clearance has been altered by other recently initiated medications or diminished renal function. Renal dysfunction and electrolyte disturbances are particularly common in HF patients treated with diuretics. Concomitant amiodarone therapy increases digoxin levels, requiring a reduced digoxin dose. Calcium channel blockers are generally poorly tolerated in patients with moderate-to-severe HF because they are more potent negative inotropes than β-blockers. Moreover, CCBs have never been shown to improve survival in HF patients, unlike β-blockers. However, if difficulty is encountered controlling acute ventricular response, intravenous diltiazem may be transiently employed for this purpose. A general initial bolus is 0.15 mg/ kg. Adjusting for blood pressure, heart rate, and patient size, this bolus ranges from 10 to 20 mg. With an adequate heart rate response, a continuous drip at 5–15 mg/h may then be used. If there is an inadequate response to the initial bolus, a second bolus of 0.25 mg/kg may be required.

Patients without a change of therapy (%)

100 80 60 40 Log rank = 77.02 p < 0.0001

20

Beta-blocker Calclum channel blocker Digoxin alone

0 0

1

BB: CCB: Digoxin:

777,0 (100) 631,0 (100) 315,0 (100)

2

3

4

5

Time (Years)

N.Events (%) 598,147 (81) 461,139 (77) 190,104 (66)

500,191 (75) 379,187 (69) 142,140 (53)

315,210 (71) 246,220 (62) 92,160 (45)

164,213 (70) 128,238 (58) 43,165 (42)

35,216 (68) 20,247 (48) 5,172 (29)

Figure 8.12. Kaplan–Meier plots depicting the efficacy of rate control for regimens containing β-blockers, calcium channel blockers (CCBs), or digoxin. Adapted from Olshansky et al.103 Copyright 2004, with permission from the American College of Cardiology Foundation

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Assuming adequate rate control without excessive hypotension, this is followed by a continuous infusion adjusted according to heart rate and blood pressure. Additional 5–10-mg boluses of diltiazem may be administered, followed by incremental increases in infusion rate, should rate response prove recalcitrant. If diltiazem is to be continued chronically, which, again, is usually contraindicated in patients with symptomatic LV dysfunction, conversion from an intravenous infusion to the immediate-release oral preparation should proceed expeditiously once rate is controlled. Transitioning to daily dosing with a sustained-release preparation should then occur when discharge is imminent. Verapamil should be avoided as a rule in HF patients. Its negative inotropic effects are too potent to support its use, especially given diltiazem’s equivalent efficacy but greater tolerability. β-blockers are usually sufficient to control ventricular rate in the acute setting. Since they also provide a long-term survival benefit, it is sensible to initiate a drug that should be continued chronically, instead of an agent that may need to be discontinued. In the emergency setting, intravenous metoprolol, administered in 2.5–5-mg doses spaced at least 5 min apart, is generally adequate. This is followed by either additional intravenous doses, generally every 4–6 h, or initiation of oral dosing at 25–50 mg every 8–12 h. An alternative agent is intravenous esmolol, which offers ext remely rapid offset owing to its metabolism by erythrocytes. Although easily titrated like diltiazem, esmolol is quite expensive, requires intensive hemodynamic monitoring, and constitutes a significant fluid load. No oral equivalent exists, either. Esmolol infusions should thus be confined to patients with tenuous blood pressure. In the nonemergent setting, it is frequently adequate to simply administer an oral β-blocker, often an additional dose of the agent already used by the patient as a part of his or her HF regimen. The longer onset of action using oral β-blockers is offset by less hypotension. Unfortunately, this simple, safe option is underutilized, resulting in many unnecessary hospital admissions. Once an adequate response is noted, the patient may be discharged home with a higher β-blocker dose compared with that upon presentation.

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8.3.1.2. Rationale for Maintaining Sinus Rhythm Historically, efforts to maintain sinus rhythm were deemed preferable to rate-control strategies. Several recent studies, most notably the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, have challenged this supposition.101 The inclusion criteria for these studies, however, largely excluded the HF population. In AFFIRM, for example, the LVEF was normal (defined as ≥ 50%) in 74% of the total population, and the mean EF was nearly 55%. Only ∼9% of the population studied in the Rate Control Versus Electrical Cardioversion for Patients with Persistent Atrial Fibrillation (RACE) study carried the diagnosis of cardiomyopathy.102 The population as a whole had a mean fractional shortening of 30 ± 10%, which is within normal limits, although 50% of subjects had a prior diagnosis of HF. Furthermore, NYHA class IV patients were excluded, and only 3% of the patients had class III HF. Thus, the larger randomized controlled studies evaluating the merits of rate- versus rhythm control have excluded the true HF population. Whereas these studies demonstrate that in a not necessarily symptomatic population with relatively preserved LV function, controlling ventricular rate and attempting to maintain sinus rhythm led to similar outcomes as long as anticoagulation is continued, this strategy has not been convincingly studied in the HF population. There are data suggesting that actually maintaining sinus rhythm is beneficial from a mortality standpoint, highlighting another limitation of AFFIRM. AFFIRM tested the strategies of rate or rhythm control, but the tools for maintaining sinus rhythm were (and continue to be) of limited efficacy. A recent on-treatment analysis of AFFIRM revealed that the presence of sinus rhythm was associated with reduced mortality (hazard ratio 0.53). Antiarrhythmic drug therapy was not found to increase mortality if sinus rhythm was present. Digoxin use, however, was associated with higher mortality, although this finding is likely confounded by higher rates of LV dysfunction in those patients treated with this medication.104 A retrospective study from Duke University demonstrated similar 2-year mortality rates in patients treated with rate control versus rhythm management in HF patients.105 The question is being prospectively

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Heart disease?

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Disopyramide, Procainamide, Quinidine

Figure 8.13. ACC/AHA/ESC Practice Guidelines for atrial fibrillation (AF). *For adrenergic AF, β-blockers or sotalol are the initial drugs of choice. †Consider nonpharmacological options for rhythm control if drug failure occurs. Adapted from Fuster et al.107 Copyright 2001, with permission from the American College of Cardiology Foundation

studied in the Atrial Fibrillation in Congestive Heart Failure (AF-CHF) study.106 Regardless of data emerging from clinical trials, in any particular patient, reason may dictate that all efforts must be made to maintain sinus rhythm. HF patients may be more symptomatic with AF, as mean LA pressure rises and cardiac output falls. While the question of whether a strategy of rhythm management versus rate control should be addressed in a randomized trial similar to AFFIRM in the general HF population, at present this decision must be made on a case-by-case basis. Another consideration is that already decompensated HF patients may experience worsening hemodynamics with AF. In such a setting, vigorously attempting to restore sinus rhythm may be one of the few available therapeutic options short of transplantation or circulatory support. Conducting a rigorous trial in such patients would be ethically difficult. From a practical standpoint, maintaining sinus rhythm may be particularly useful in individuals with ICDs who receive spurious therapies for rapidly conducted AF. Rhythm control in this circumstance may not

provide a mortality benefit, but may improve quality of life and prevent potential hospitalizations.

8.3.1.3. Chronic Control of Ventricular Response β-blockers enjoy demonstrable mortality benefits in HF, regardless of etiology. Furthermore, they possess excellent AV-nodal blocking properties, making them ideal agents for controlling the ventricular response in AF. Carvedilol may possess a general advantage in the HF population over short-acting metoprolol (8), but its effects on the AV node are less potent. Metoprolol either in the conventional (tartrate) preparation or in the long-acting form (succinate) may be a superior choice for this reason. Atenolol may also be used, although it has not been prospectively evaluated in HF patients. In general, daily doses of metoprolol required to effectively control the ventricular rate are 50–150 mg, either divided twice daily (as metoprolol tartrate) or dosed once daily (as metoprolol succinate). The clinician must be mindful of the

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possibility that the negative inotropic effects of these doses may aggravate the underlying cardiomyopathy. Acute decompensation may mandate slower dose titration than in a stable patient. Nonpharmacologic methods may be required in such circumstances. β-Blockers have demonstrable superiority over CCBs for control of ventricular rate, possibly because of direct antiarrhythmic effects. An analysis of AFFIRM revealed that β-blockade, with or without concomitant digoxin, achieved rate control in a greater percentage of patients than did CCBs with or without digoxin (70% vs. 54%).103 Furthermore, more patients were switched to regimens containing β-blockers than were switched from these drugs (Figure 8.12). Antiarrhythmic benefits of β-blockers in AF have been prospectively studied; a trial of patients converted to sinus rhythm from persistent AF demonstrated that extended-release metoprolol reduced AF recurrence by almost 30%.106 These findings must be tempered by the fact that only one-quarter of the study population had HF. However, the observed benefit was similar in patients with normal and abnormal fractional shortening. Digoxin is the oldest and least efficacious medication used to slow the ventricular response to AF. While effective at rest via increasing vagal tone, digoxin loses this effect with increased sympathetic activity, particularly exercise.109 Theoretically, digoxin does have several advantages that make its use reasonable in NYHA classes II–IV patients with concomitant AF, whether permanent or paroxysmal. These include its positive inotropic effects, improvement in HF symptoms, reduction in HF hospitalizations, and increased vagal tone.110 Digoxin is not without drawbacks. It possesses no antiarrhythmic effects, does not convert AF to sinus rhythm, and does not maintain sinus rhythm once achieved. In fact, digoxin may be proarrhythmic. Its effects on intracellular Ca2+ increase the frequency of delayed after-depolarizations that may trigger arrhythmias. Digoxin also shortens atrial refractoriness and is thus profibrillatory. This property is the opposite of class III drugs that are the most effective agents for preventing AF. By shortening atrial refractoriness, digoxin may actually facilitate the microreentrant circuits that perpetuate AF. Digoxin toxicity is aggravated by alterations in extracellular potassium concentra-

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tions, which may be labile in HF patients on highdose diuretics or with renal insufficiency. Finally, digoxin may achieve toxic levels in patients with unstable renal function.

8.3.1.4. Rhythm-Control Strategy Once the decision is made to pursue rhythm control, several considerations must be addressed. These include conversion to sinus rhythm, use of antiarrhythmic medications, and rate control for asymptomatic, recurrent paroxysms. Anticoagulation should not be stopped, as there are no adequate methods for ensuring complete rhythm control. Moreover, in AFFIRM, the majority of strokes occurred in patients in whom warfarin had been discontinued or in whom anticoagulation was subtherapeutic.101 Cardioversion may be performed electrically or chemically, as in non-HF patients. Unless the duration of AF is known to be brief, restoration of sinus rhythm should be deferred until LA appendage thrombus is excluded with transesophageal echocardiography (TEE) or therapeutic anticoagulation is documented for at least 3 weeks (Figure 8.11).111 While guidelines suggest that embolic risk is low in patients with AF of less than 48 h duration, many clinicians shorten this window to less than 24–36 h, particular in patients at high risk for cardioembolism.99 Given the high incidence of AF in HF patients, as well as the fact that AF is often asymptomatic, prudence dictates that conservative practice should prevail. However, if a patient is anticoagulated chronically, and the INR is therapeutic, AF may be cardioverted without delay or TEE. Following restoration of sinus rhythm, anticoagulation should generally be continued indefinitely for HF patients. One specific situation that deserves mention is the possibility of cardioversion performed at the time of ICD implantation or generator change. The clinician must not forget that defibrillation testing may also convert AF to sinus rhythm. Consequently, DFT testing should be preceded by TEE if therapeutic anticoagulation during the previous several weeks cannot be documented or if therapeutic anticoagulation is suspended for more than 24–36 h. In most instances, the first recognized paroxysm of AF may be cardioverted in the absence of antiarrhythmic agents, unless there is extremely high

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suspicion that AF will recur quickly. Recurrences should prompt consideration of antiarrhythmic therapy; in general, it may be tolerable to accept the need to cardiovert a patient once yearly rather than initiate antiarrhythmic therapy, given its potential toxicities. However, more frequent paroxysms of AF that are of sufficient duration to require cardioversion should warrant reconsideration of this strategy. Spurious ICD shocks for rapidly conducted AF may also warrant antiarrhythmic treatment. Antiarrhythmic drug therapy for AF is rarely perfect; almost all patients experience recurrences despite treatment, and many paroxysms are undetected. As such, AV-nodal blocking agents should be used in conjunction with most antiarrhythmic drugs, particularly class I agents that do not slow AV-nodal conduction, may potentiate conduction via vagolytic properties, and may organize AF into AFL. AFL, in the presence of potent Na+-channel blockers, may conduct in a one-to-one fashion to the ventricles, thus posing the risk of hemodynamic collapse. Quinidine was the mainstay of AF therapy for years. An analysis of the Stroke Prevention in Atrial Fibrillation (SPAF) trial revealed that quinidine and other class Ia agents, as well as class Ic agents, are associated with higher mortality when used in patients with HF for the treatment of AF. Cardiac mortality was almost fivefold increased, and arrhythmic mortality was elevated by a factor of 4. A similar effect was not observed in the population without HF.112 Practically, quinidine is poorly tolerated, largely because of diarrhea and requisite multiple daily doses. A more serious obstacle includes the potential for “quinidine syncope,” which after years was unmasked as torsade de pointes. Disopyramide is poorly tolerated in patients with HF because of its potent negative inotropic activity. Another drawback is its anticholinergic effect, which exacerbates urinary retention in benign prostatic hyperplasia and may accelerate AV-nodal conduction during breakthrough paroxysms of AF. As such, it has no role in systolic HF patients. Procainamide suffers from similar shortcomings as the other Ia agents. In addition, it has an active metabolite, N-acetyl procainamide (NAPA), with class III properties. NAPA is renally excreted, such that a decline in renal function may substantially

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increase NAPA levels and thus the risk of proarrhythmia. In general, procainamide has little use for preventing AF in the HF population, although it may have a limited role in patients with recalcitrant ventricular arrhythmias who have an ICD. In its favor, procainamide is the best-tolerated Ia agent and is also available in both intravenous and oral forms. If used, procainamide and NAPA levels should be regularly assessed. The summed procainamide and NAPA concentrations should be no greater than 20 mg/dL. Adverse effects specific to procainamide include serositis from drug-induced lupus, rash, fever, and gastrointestinal distress. Class Ic agents, while efficacious in paroxysmal AF and not encumbered by multiple extracardiac side effects, are contraindicated in HF patients, largely because their risk of proarrhythmia. In rare instances, these drugs, particularly flecainide, are used in HF patients protected with an ICD. However, such therapy requires extreme caution, as there are reports of SCD in patients using flecainide despite the presence of an ICD. Presumably, these individuals experience EMD. In summary, class Ic drugs are generally used in patients with a structurally normal heart and are contraindicated in the HF population. Class Ia drugs are used with less frequency overall than in the past and are also generally avoided in HF patients. Class Ib agents are inefficacious for atrial arrhythmias. Figure 8.13 illustrates current treatment guidelines for antiarrhythmic use in AF by consensus of the American College of Cardiology, American Heart Association, and European Society of Cardiology. Class III antiarrhythmics, including amiodarone, sotalol, and dofetilide, have supplanted all other agents for rhythm control in HF patients. Studies have demonstrated both safety and efficacy in this population. Furthermore, class III drugs generally cause fewer extracardiac side effects than class Ia agents. As a rule, age, comorbidities, and NYHA status dictate which drug is used to treat AF in HF patients. Also, the risk of torsade de pointes necessitates carefully avoiding other drugs that may potentiate QT prolongation. Because of their reverse use dependence, class III agents are typically more effective for maintaining sinus rhythm than for acute cardioversion. This is especially true for sotalol. Amiodarone is at best modestly successful for chemical cardioversion, and dofetilide is probably somewhat more

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effective. Ibutilide, which is administered only intravenously, is the most successful class III agent for cardioversion, and, in fact, is only used for this purpose. One must be mindful that the risk of torsade de pointes with all class III drugs is greater in patients with a history of HF. Amiodarone is by far the most widely used medication for AF suppression because of its efficacy, absence of significant negative inotropic effects, infrequent ventricular proarrhythmia, and ease of use. Similar precautions apply to its use in AF as when used in the prevention of ventricular arrhythmias, including multiple end-organ toxicities, bradycardia, and drug–drug interactions. Amiodarone may be safely initiated as an outpatient, especially in patients protected with an implanted pacing device. However, if there is a high suspicion of inducing bradycardia, amiodarone should be initiated in the inpatient setting. Patients at high risk include the elderly, particularly females, and those with the tachy-brady syndrome. Amiodarone toxicities are less frequent in patients using this agent for AF suppression, as the effective chronic cumulative dose is often less than that required for ventricular arrhythmias. The initial cumulative load of amiodarone for AF should be 5–7 g, followed by chronic suppressive doses of 200 daily. If a 200 mg daily oral dose proves efficacious, the dose may be reduced to 100 mg daily, which may be sufficient. Loading may be achieved intravenously, orally, or with a hybrid approach, as discussed in the section on ventricular arrhythmias. Intravenous loading provides modest rate control and may potentially effect chemical cardioversion. As such, therapeutic anticoagulation and exclusion of LA thrombus must be assured prior to its initiation. Amiodarone is not approved by the Food and Drug Administration for use in AF despite its proven efficacy. Sotalol may be particularly useful in younger, healthier patients, because its side effects are related to daily, not cumulative, dosage. Renal function must be intact and monitored carefully. As when used for ventricular tachyarrhythmias, patients must be able to tolerate its β-blocking effects, including possible exacerbation of HF, bradycardia, and obstructive lung disease. Offset pauses are possible in patients initiating sotalol while actively in AF. Proarrhythmia is also a

E.C. Adelstein and L.I. Ganz

potential concern. For these reasons, initiation is typically performed as an inpatient. Data from clinical trials demonstrates that amiodarone is the most effective drug for AF suppression. The Canadian Trial of Atrial Fibrillation (CTAF) directly compared sotalol, amiodarone, and propafenone.113 Although it did not focus upon HF patients (only 12% had an LVEF < 50% and NYHA classes III–IV patients were excluded), CTAF demonstrated the superiority and safety of intermediate-term amiodarone over sotalol and propafenone. After a mean followup of 16 months, 35% of patients treated with amiodarone had a recurrence of AF, whereas 63% of the sotalol/propafenone patients had a documented episode of AF (Figure 8.14). Outcomes with sotalol and propafenone were virtually identical. For comparison, the mean daily doses of amiodarone, sotalol, and propafenone were 186 ± 48, 224 ± 83, and 471 ± 121 mg, respectively. Similar percentages of patients experienced adverse events, including the need for intravenous HF therapy, mortality, bradycardia, and ventricular arrhythmias. More patients discontinued amiodarone because of noncardiac side effects (18% vs. 11%; p = 0.06). A randomized substudy of the rhythm-control arm of AFFIRM corroborated the findings of CTAF.114 For the entire follow-up period, 60% of patients treated with amiodarone remained in sinus rhythm, compared with 38% of sotalol patients. Amiodarone was also more efficacious in maintaining sinus rhythm than physician-chosen class I agents at 1 year (62% vs. 23%). Dofetilide is a newer treatment option for AF in HF patients. It is primarily an alternative to amiodarone, particularly when HF symptoms preclude sotalol’s use. It does possess certain advantages over sotalol and even amiodarone. DIAMONDHF demonstrated dofetilide to be mortality-neutral in this population,46 whereas such safety has only been inferred with sotalol. Moreover, the βblocking effects of sotalol have never been shown to improve survival in HF patients. β-blockers may be used concomitantly with, and titrated independently of, dofetilide; both amiodarone and sotalol may preclude this option. Dofetilide does have drawbacks, however. Its efficacy in patients with paroxysmal AF has never been documented.

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Patients without Recurrence (%)

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100 Amiodarone (n = 201)

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Figure 8.14. Kaplan–Meier plots for recurrence of atrial fibrillation in Canadian Trial of Atrial Fibrillation (CTAF) according to treatment group. Adapted from Roy et al.113 Copyright 2000 Massachusetts Medical Society. All rights reserved. Reprinted with permission

Also, dofetilide use creates the opportunity for multiple drug–drug interactions and carries a risk of torsade de pointes. Azimilide is currently in phase III clinical trials and is not approved for human use. Preliminary studies suggest that it is efficacious in AF prevention, and its safety in the ICM population was confirmed in the Azimilide Postinfarct Survival Evaluation (ALIVE).115

8.3.2. Primary Prevention of Atrial Fibrillation Interest in preventing AF in patients with HF has continued, despite the largely negative clinical trials involving antiarrhythmic drugs for ventricular and supraventricular arrhythmias. There are data suggesting that nonantiarrhythmic medications may prevent AF, despite a dearth of randomized trials. ACE-I, ARBs, and statins may

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prevent AF, perhaps via effects upon myocardial fibrosis or autonomic tone. Studies in experimental animals with induced LV failure are intriguing, but this possibility requires prospective study in humans. An observational study of patients on statins with stable CAD and no prior history of AF found a greater than 50% reduction in the incidence of future AF over 5 years.116 This effect, which appeared to be dose-related, held true after controlling for confounding variables. Whether such a possible benefit is independent of actual cholesterol-lowering and also occurs in patients without manifest CAD is unknown. Additional data suggest that the anti-inflammatory effects of statins may play a role in preventing AF. Primary prevention of AF using antiarrhythmics continues to attract interest, despite little demonstrable success to date. Dofetilide, whose safety in the HF population was confirmed in DIAMOND-HF, may provide chemoprophylaxis in patients with HF at risk for AF.46 Despite a lack of mortality benefit, hospitalization for worsening HF was reduced 21%, possibly by decreasing new episodes of AF. Azimilide, evaluated prospectively in postinfarction patients with LV dysfunction in ALIVE, reduced the incidence of AF by 50%.51 Again, despite no difference in overall mortality, azimilide’s role in preventing AF remains to be determined. The newest investigational antiarrhythmic examined in AF is dronedarone, a class III agent similar to amiodarone but lacking the iodine that accounts for much of the latter drug’s adverse effects. Two recent clinical trials have evaluated its efficacy in preventing paroxysmal AF: the American– Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS) and the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS).117,118 Both placebo-controlled trials followed just over 600 patients with a recent paroxysm of AF for 12 months. Patients with NYHA classes III–IV HF or prior amiodarone inefficacy were excluded. Dronedarone was associated with a modestly longer duration to first documented AF episode in both trials and an ~25% reduction in the number of patients with recurrent paroxysms, including those with structural heart disease, with no increased risk of torsade de pointes. Furthermore,

E.C. Adelstein and L.I. Ganz

like amiodarone, dronedarone slowed the ventricular rate significantly during AF paroxysms. This drug will require specific assessment in HF patients, particularly with respect to safety.

8.3.3. Initiating Antiarrhythmic Drugs Initiation of antiarrhythmic agents is often performed in the inpatient setting. This, of course, may be inconvenient to both the patient and the treating physician. In addition to disrupting daily routines, patients often question the need to spend several days confined to a hospital ward for the sole purpose of wearing a telemetry monitor. Nevertheless, it is prudent to initiate most antiarrhythmic drugs in the hospital when treating HF patients. The rationale for inpatient antiarrhythmic initiation rests upon several principles. First, this approach allows direct observation of a medication’s effect upon the index arrhythmia. This is clearly more important in those circumstances when the arrhythmia is potentially fatal (i.e., VT or VF) as opposed to bothersome (i.e., the majority of AF or AFL). Second, adverse drug effects, both cardiac and noncardiac, may be detected. Provocation of arrhythmias is the primary concern, including sinus bradycardia, AV-nodal block, ventricular ectopy, and rapid conduction of AFL. Sinus bradycardia, often in the form of offset pauses upon return of sinus rhythm, is of particular concern in patients who convert from AF and have underlying sinus node disease, especially in those only observed in AF in whom adequacy of sinus node function is unknown. Sinus bradycardia or transient asystole, as well as varying degrees of AV-nodal block, may be seen with amiodarone and sotalol, in particular. Malignant ventricular ectopy and torsade de pointes are the primary reasons for continuous monitoring when initiating drugs that prolong repolarization (i.e., class III and Ia agents). Finally, class Ic drugs, if not used concomitantly with AV-nodal blockers, may transform AF into AFL, which may then conduct in a one-to-one fashion to the ventricles and potentially trigger VF. Nonarrhythmic cardiac effects include negative inotropy, which is of concern particularly with sotalol and class Ia agents, as well as gastrointestinal and other end-organ effects. Proarrhythmia may be primary or secondary.119 Primary proarrhythmia indicates that a new agent

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alters the existing electrophysiologic milieu such that new arrhythmias are able to be initiated and sustained. Hospitalization during antiarrhythmic drug initiation allows monitoring for primary proarrhythmia with reasonable efficacy, although the long effective half-life of amiodarone makes observation until achieving steady state impractical. Distinct from primary proarrhythmia, secondary proarrhythmia may occur at any time during therapy. In this instance, the antiarrhythmic agent interacts unfavorably with transient alterations in the electrical substrate, resulting in proarrhythmia. ICDs provide substantial protection against SCD resulting from this scenario.

8.3.4. Nonpharmacologic Therapy Invasive approaches to AF management have similar goals as pharmacologic therapy, involving both rate-control and rhythm-management strategies. Destroying the AV node via radiofrequency ablation (RFA) is the invasive equivalent of rate control, whereas posterior LA RFA is a nonpharmacologic means of maintaining sinus rhythm.

8.3.4.1. Atrioventricular Node Radiofrequency Ablation Radiofrequency ablation of the AV node with concomitant implantation of a device capable of permanent pacing is an alternative to rate and rhythm control. Such an “ablate-and-pace” strategy may be necessary in patients in whom paroxysms of AF result in uncontrollable ventricular rates despite medications, in whom AV-nodal blockers cause excessive hemodynamic compromise because of their negative inotropic properties, or in whom bradycardic episodes occur despite lack of adequate rate control while in AF. Patients in permanent AF, especially those already implanted with an ICD or pacemaker, may prefer AV-nodal ablation to regularize their heart rate. This treatment option does improve symptoms, even in patients with HF in whom right ventricular (RV) pacing may be hemodynamically unfavorable.120 Unfortunately, despite such symptomatic improvement, the long-term effects of RV pacing may be detrimental. One study examining patients treated with the ablate-and-pace strategy found late hemodynamic deterioration, with ventricular dilatation

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and increased mitral regurgitation.121 From a technical standpoint, AV-node RFA rarely fails, with procedural success rates approaching 98%.122 These adverse effects may be prevented or attenuated by CRT. The Left Ventricular-Based Cardiac Stimulation Post AV-Nodal Ablation Evaluation (PAVE) study provides some guidance for deciding whether prophylactic CRT should be used in patients undergoing AV ablation.123 PAVE randomized patients to conventional RV pacing or biventricular pacing after AV-nodal ablation for intractable high ventricular rates in AF. A notable exclusion criterion was consideration of ICD implantation. Although underpowered to detect a mortality difference, PAVE did demonstrate that CRT improved exercise capacity and preserved LV function, while patients paced from the RV experienced a small decline in LV function at 6 months. Preliminary PAVE analyses suggest that RV pacing-induced LV dysfunction may be limited to patients with baseline LV dysfunction. This effect was independent of baseline QRS duration. Thus, when considering an ablate-and-pace strategy, thought should be given to implantation with a CRT-P or CRT-D device, based upon the baseline LVEF and presence of symptomatic HF.

8.3.4.2. Posterior Left Atrial Radiofrequency Ablation Radiofrequency ablation of the posterior LA, with electrical isolation of the pulmonary veins, is a therapeutic option gaining popularity in patients refractory to antiarrhythmic pharmacotherapy. This approach stems from the finding that in patients with structurally normal hearts, a significant proportion of AF is triggered by atrial premature depolarizations (APDs) originating at the junction of the pulmonary veins and LA myocardium.124 Additional triggers may arise from foci near the superior vena caval-right atrial junction or at other sites where the homogeneity of myocyte orientation is interrupted by adjoining structures. Radiofrequency ablation is not routinely performed in HF patients at the present time. Advanced HF patients may be too ill to tolerate the procedure, which may be prolonged and requires deep sedation or general anesthesia. HF patients may also have higher rates of recurrent AF, likely because their atria are pathologically distinct from

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patients with “lone” AF; the atria of HF patients demonstrate significant myocardial fibrosis and are anatomically distorted from the hemodynamic stress of high filling pressures, and oftentimes, significant mitral regurgitation. Repeat procedures may be more common, exposing patients to additional risk. Recent evidence suggests that AF RFA may not only abolish recurrent episodes of AF and thus improve quality of life among patients with highly symptomatic paroxysmal AF but also improve LV function. Reported by Haisseguerre’s group, improvement in cardiac function did not appear to be mediated by reversal of tachycardia-induced cardiomyopathy, as a similar augmentation of LV function occurred regardless of the adequacy of prior rate control.125 The study compared 58 consecutive patients with HF from any cause in whom at least two antiarrhythmics had been ineffective or intolerable with 58 consecutive patients without HF undergoing AF RFA. All HF patients had an LVEF less than 45% and at least NYHA class II symptoms, and almost all patients were classified as having persistent or permanent AF. Over a follow-up of 12 months, 78% of HF patients and 84% of control patients were still in sinus rhythm, although the proportion in sinus rhythm unaided by antiarrhythmic agents was lower in the HF group (69 and 71%, respectively). Almost half of all patients required a second RFA procedure. The intriguing findings of the Haisseguerre study relate to improvements in LV function and dimensions. In patients with HF, LVEF improved by 21 ± 13% (p < 0.001) from a baseline of 35 ± 7%, and LV end-systolic diameter was reduced by 8 ± 7 mm (p < 0.001). Almost three-quarters of the HF population experienced either marked improvement in LV function, defined as an increase of at least 20% in LVEF, or normalization of LVEF to over 55%. Recurrent AF despite antiarrhythmic therapy was the only variable found to negatively impact LV functional recovery. Prior to this landmark, albeit preliminary study, AF RFA was considered by many to be too high risk a procedure for the potential cure of an entity that is not life-threatening. However, the potential for improvement in LV function and clinical NYHA status, with low rates of morbidity and mortality in experienced hands (one patient in each group had pericardial tamponade requiring pericardiocentesis

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and one HF patient had a stroke), may bring AF RFA to the forefront of treatment in HF patients with AF. Before AF RFA becomes standard therapy in HF patients, similar outcomes in terms of efficacy, safety, and improvement in LV function will need to be replicated in larger, randomized, multicenter studies. Furthermore, whether improvements in LV function and dimensions are surrogate markers of improved survival remains unproved.

8.3.4.3. Surgical Treatments of Atrial Fibrillation Prior to percutaneous posterior LA RFA, surgical therapies pioneered the invasive treatment and prevention of AF.126 These procedures are predicated upon interrupting the critical mass of electrically contiguous atrial tissue required to perpetuate the reentrant waves that comprise AF. By electrically isolating segments of the left atrium, the Cox MAZE procedure, currently practiced as the Cox III MAZE, is effective in eliminating AF and preserving atrial function in about 90% of patients.127 The Mayo Clinic experience has demonstrated not only that this operation is feasible in HF patients but also that it improves LV function in the majority of cases.128 Overall surgical mortality is on the order of 2–3%. Newer surgical treatments are less invasive and are often performed in the setting of additional cardiothoracic surgery. Whereas the MAZE procedure physically interrupts atrial tissue with incisions that are subsequently sutured, a variety of hybrid procedures incorporating multiple energy sources have been developed to obviate the need for the “cutand-sew” technique. Lesions are created on the epicardium using radiofrequency energy, microwaves, lasers, and cryotherapy, all of which seek to destroy tissue that may perpetuate AF. Multiple procedures exist, differing by both energy source and in ablation pattern, with success rates between 50 and 85%.129–131 A promising new energy source is high-frequency focused ultrasound, which allows for the creation of transmural epicardial lesions that do not pose danger to interspersed nonmyocardial elements, such as coronary arteries.132

8.3.4.4. Atrial Flutter Ablation Atrial flutter (AFL) is more commonplace in HF patients than in the general population; in

8. Management of Arrhythmias in Heart Failure

contradistinction to AF, AFL is unusual in the absence of structural cardiac pathology. The acute treatment of AFL mirrors that of AF, in that rate control is paramount. However, rate control is very difficult to achieve and may require high doses of negative inotropes. Given the high success rates and low morbidity of ablating AFL, this is typically the preferred treatment modality. Success rates in the general population approach 90% for AFL RFA.133 However, there are no specific data regarding procedural success rates in the HF population.

8.3.4.5. Atrial Arrhythmia Management Devices Atrial arrhythmia management devices (AAMDs) were developed as a self-contained, implantable means of terminating SVTs, primarily atrial tachycardias and AF. AAMDs, such as the Metrix Atrioverter, consist of a pectoral pulse generator attached to transvenous leads, including right atrial and coronary sinus leads for cardioversion and sensing, and an RV lead for sensing and pacing. Subsequent devices have had the capacity for ventricular, as well as atrial, defibrillation in the event that atrial cardioversion precipitates VT or VF. The theoretical basis behind the development of AAMDs included several considerations. First, by allowing self-administered therapy, AAMDs would offer patients with paroxysmal AF the opportunity to avoid hospitalization and repeated physician visits. Second, by limiting the duration of AF episodes, thromboembolic risk could potentially be reduced. Finally, in reducing the overall burden of AF, AAMDs offered the possibility of preventing the electrical remodeling that is believed to beget additional AF burden which in turn may contribute to ventricular remodeling.134 Initial studies suggested that AAMDs were well tolerated and safe, in that they effectively cardioverted AF to sinus rhythm and detected atrial arrhythmias with adequate sensitivity and specificity.135 However, initial enthusiasm has been tempered by several factors, effectively leading to their demise. AAMD therapies are poorly tolerated despite the use of self-administered sedatives and low energy therapy delivered during hours of sleep. Repeated device therapies are increasingly poorly tolerated from a symptomatic standpoint. Immediate recurrence of atrial fibrillation (IRAF)

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also limits the clinical utility of AAMDs. Finally, asymptomatic AF negates the theoretical benefit of early cardioversion in patients who are anticoagulated.

8.4.

Bradyarrhythmias

Bradyarrhythmia management in the HF population mirrored that in the general population until recently. Two recent, related breakthroughs, namely, the discovery of the deleterious effects of RV pacing and the advent of biventricular pacing, or cardiac resynchronization therapy (CRT), have revolutionized the paradigm for pacing HF patients.

8.4.1. Lessons Learned from ICD Trials When multiple trials demonstrated the benefits of single-chamber ICDs for patients with ICM, implantation rates surged. Although most patients had no significant bradycardia, many dual-chamber devices were implanted, partly because of improved discrimination between VT and SVT. However, these devices also often paced the RV unnecessarily. Some experts advocated dual-chamber pacing as a means of ensuring AV synchrony, decreasing the incidence of AF, maximizing cardiac output, and allowing higher doses of β-blockers. The anticipated cumulative effect would be an improvement in mortality, morbidity, and quality of life. MADIT II, while broadening the clinical indications for ICDs drastically, had an unexpected observation: a greater percentage of patients who received an ICD suffered new or worsening HF. Almost 20% of ICD patients were hospitalized for HF, as opposed to only 15% of control patients. The improved overall survival offered by ICDs may have contributed to this finding, in that patients who lived longer essentially “had more time” to experience a HF exacerbation. A second possibility was that RV pacing caused hemodynamic deterioration in patients with LV dysfunction. The Mode Selection Trial in Sinus-Node Dysfunction (MOST) provided an additional clue to the possibly deleterious effects of RV pacing, even in patients without LV dysfunction.136 An analysis of those patients in both the VVI(R)

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with equivalent β-blockade, confirmed suspicions aroused by MADIT II and MOST.

(rate-responsive backup ventricular pacing) and the DDD(R) (rate-responsive AV-synchronous pacing) groups who had a QRS duration less than 120 ms prior to pacemaker implantation demonstrated that HF hospitalizations were two- to threefold greater in patients whose ventricles were paced a significant proportion of the time. Furthermore, the risk of developing AF rose 1% for each 1% increment of time spent RV pacing.137 Although only a small minority of the patients in MOST had an underlying cardiomyopathy (20% had prior HF and 12% had a cardiomyopathy), data were mounting against RV pacing. Definitive evidence of the deleterious effects of RV pacing in HF patients came in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial.138 DAVID randomized 506 patients with an EF less than 40% and an indication for ICD implantation but not chronic pacing to a dualchamber pacemaker programmed to either VVI-40 (backup ventricular pacing at 40 bpm) or DDD(R)70 (rate-responsive AV-synchronous pacing at 70 bpm). The composite end point of mortality and HF hospitalization was increased significantly in the DDD(R)-70 patients by 61%, with the curves diverging at only 6 months (Figure 8.15). Both individual end points occurred more frequently in the DDD(R)-70 group, albeit without reaching statistical significance. These data, obtained

8.4.2. Device Therapy MOST and DAVID have altered clinical practice significantly. At many institutions, efforts are now made to minimize RV pacing in patients receiving implantable devices, both ICDs and pacemakers. Single-chamber devices should be set to backup VVI-40 or VVI-50 pacing in patients with intact sinus node function and AV-node conduction. Dual-chamber devices should be programmed to maximize the A-V interval and promote intrinsic conduction. If this cannot be achieved in DDD(R) or DDI(R) modes, then backup VVI pacing may be preferable. Newer pacing algorithms further reduce RV pacing. RV pacing is detrimental hemodynamically because it forces ventricular depolarization to occur dyssynchronously; instead of myocardial depolarization occurring in a coordinated manner from base to apex in the septum, then back to the base in both ventricles simultaneously, an obligate LBBB occurs. As has been shown in patients with a cardiomyopathy and a wide, left bundle QRS morphology, ventricular dyssynchrony is physiologically maladaptive. Ventricular dyssynchrony reduces LV efficiency and output, and echocardiography has demonstrated that restoring synchrony

Dual-Chamber Rate-Responsive pacing (DDDR) Ventricular Backup Pacing (VVI)

Death of First Hospitalization for New of Worsened CHF Cumulative Probability

0.4

A No. at Risk DDDR VVI

First Hospitalization for New or Worsened CHF

Death From Any Cause

Relative Hazard (95% Cl.1.54 (0.97-2.46)

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Relative Hazard (95% Cl.1.61 (0.84-3.09)

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0

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Figure 8.15. Kaplan–Meier plots for combined end point of mortality and hospitalization for worsening heart failure (HF) (A), hospitalization for HF (B), and cumulative mortality in Dual Chamber and VVI Implantable Defibrillator (DAVID) (C), comparing backup VVI-40 and DDD(R)-70 pacing. Adapted from Wilcoff et al.131 Copyright 2002 American Medical Association. All rights reserved. Reprinted with permission

8. Management of Arrhythmias in Heart Failure

of the lateral wall and septum with CRT reverses this disadvantageous contraction pattern, with significant hemodynamic and symptomatic benefits in the majority of patients.139 Logic suggests that preventing dyssynchrony may yield similar benefits. The advent of CRT has added another wrinkle to the management of bradycardia, both spontaneous and iatrogenic. CRT reduces morbidity and mortality in patients with advanced HF, moderate-to-severe LV dysfunction, and ventricular dyssynchrony.140 This begs the question of whether patients with systolic dysfunction and an indication for an ICD who will be ventricularly paced a significant portion of the time, yet do not have symptoms of HF, should receive a prophylactic CRT device. Additionally, should patients with drug-refractory AF in whom AV-nodal ablation is being considered also receive CRT, as these patients will be obligately paced? If such patients present with HF symptoms, are these symptoms attributable to rapid ventricular response, a tachycardia-induced cardiomyopathy, or underlying LV dysfunction? Symptoms related to the first two conditions will be ameliorated by a standard pacemaker with AV-nodal ablation, whereas the last group of patients would benefit from CRT. PAVE suggests that prophylactic CRT may benefit patients, particularly in the setting of preexisting LV dysfunction, although its effects upon hard end points remain to be determined. The preponderance of data at this time suggests several general management guidelines. Conventional ICD (and pacemaker) programming should minimize RV pacing in all patients with little need for ventricular pacing. In HF patients who require frequent or obligate pacing, CRT may be the preferred modality, and an LV lead should be considered at ICD implantation (i.e., CRT-D). Patients with an underlying cardiomyopathy for whom an ablate-and-pace strategy is to be used for AF may also benefit from prophylactic CRT-P or CRT-D. At present, these clinical decisions should be tailored to the individual patient. Ongoing studies will clarify some of the aforementioned questions. MADIT-CRT and REVERSE will evaluate whether prophylactic CRT-D slows the progression of clinical HF in NYHA classes I–II patients with QRS prolongation undergoing prophylactic ICD implantation, and DAVID II will further elucidate the role of atrial-based pacing in patients with an ICD indication.

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8.5. Syncope in the Heart Failure Patient Syncope is defined as a transient loss of consciousness, marked by loss of postural tone and followed by spontaneous recovery.141 Syncope is common, regardless of LV function. Whereas syncope in patients with structurally normal hearts is vasovagal in nature in the majority of cases and does not confer a poor prognosis, it may portend life-threatening ventricular arrhythmias in patients with DCM.142 Alternatively, syncope may be a manifestation of bradyarrhythmias or, less commonly, supraventricular tachyarrhythmias. Unfortunately, determining the underlying cause of syncope is often a diagnostic challenge, as the history may not suggest a particular etiology, and diagnostic tests suffer from a poor positive or negative predictive value. The management of syncope in the HF population has been markedly simplified by recent data derived from SCD primary prevention trials. In general, any patient with an ejection fraction less than 35% and NYHA classes II–III symptoms should receive an ICD even in the absence of syncope. This is based upon findings from SCDHeFT, DEFINITE, and MADIT II. Prior to these landmark studies, the ominous nature of syncope in patients with DCM was appreciated. Syncope occurs in 12–23% of patients with advanced HF, and the SCD risk over the subsequent 2 years ranges from 15–45%.143 In patients with DCM, one small series found that patients with syncope and a negative EP study who went on to receive an ICD, when compared with a group of patients with no CAD and a documented cardiac arrest, had a greater number and earlier onset of appropriate ICD discharges.144 Furthermore, all syncopal recurrences were associated with recorded ventricular tachyarrhythmias. This is similar to the finding in AMIOVERT that all syncopal episodes in patients with an ICD were related to ventricular arrhythmias. Another series of patients with NICM and syncope found that 40% of those implanted with an ICD received appropriate therapy, and none had recurrent syncope over a mean follow-up of 22 months. Those who did not receive an ICD had an SCD mortality rate of 15%.135 Other causes of syncope in HF must be considered. Orthostasis is not uncommon in patients with

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HF, with high-dose diuretics and vasodilators comprising medical regimens. This combination predisposes patients to alterations in blood pressure, with subsequent transient cerebral hypoperfusion. The addition of nitrates in ICM exacerbates this milieu, as does autonomic dysfunction that may accompany diabetes mellitus and aging. Ventricular underfilling may also trigger neurocardiogenic reflexes that subsequently cause frank syncope. Syncope in the setting of exercise or exertion suggests the possibility of an ischemic trigger. At the minimum, stress testing should be performed, preferably with exercise; provocation of a tachyarrhythmia, while placing the patient at some risk, would in most circumstances require follow-up with coronary angiography, particularly if polymorphic, not monomorphic, VT is witnessed. A more difficult issue arises in patients who are revascularized in this setting yet have underlying LV dysfunction; clinical trials have not examined this population, yet registries such as AVID suggest a poor overall prognosis. Nonrandomized series suggest that polymorphic VT/VF in the setting of ischemia but not acute infarction is best treated with revascularization and an ICD.62 EP testing with programmed stimulation is a useful means of characterizing the arrhythmogenic substrate, both for bradyarrhythmias and for tachyarrhythmias. Bradyarrhythmias, however, if seen with surface ECG monitoring in patients with a history of syncope, often do not require such an invasive test and are more appropriately treated with a pacemaker, especially in the elderly, in whom bradyarrhythmias are far more common. When the decision is made to implant a pacemaker in a patient with impaired LV function, the issue of prophylactic ICD as well as CRT-D implantation should be addressed. Medications and intrinsic conduction system disease are the underlying causes of bradyarrhythmias in HF patients. Although negative chronotropic agents may be discontinued when bradycardia is discovered, often β-blockers and antiarrhythmic agents, particularly amiodarone and sotalol, are an important part of the HF medical regimen. Iatrogenic bradycardia is a class I indication for pacing when these medications are deemed medically necessary.145 Induction of tachyarrhythmias via programmed stimulation, while a useful adjunct in certain clinical

E.C. Adelstein and L.I. Ganz

scenarios, is no longer the gold standard in determining risk for future tachyarrhythmias in HF patients. A negative EP study in a HF patient with a history of syncope may simply reflect poor sensitivity and be considered a false-negative test, particularly in NICM. Furthermore, empiric ICD implantation in almost all symptomatic patients with an LVEF less than or equal to 35% and no ambient ventricular arrhythmias or history of syncope has been validated in recent large-scale clinical trials. It is precisely because of the observed shortcomings of the screening EP study in the HF population that these clinical trials were performed in the first place. Additional issues that must be addressed in HF patients with syncope are future risk of syncope and restriction of driving. Patients must be warned that ICD implantation may not prevent future syncopal episodes. The purpose of the ICD in this case is to prevent SCD, hopefully reducing future recurrences of syncope as well. Driving restrictions vary from state to state; practitioners should be aware of local laws and comply with regulations. Patients must be aware that it is not only their lives at stake; passengers, pedestrians, and other drivers may be injured in the event of a syncopal episode while behind the wheel.

8.6. Conclusion The treatment of arrhythmias in HF has evolved and continues to progress in the face of everincreasing clinical data. Significant lessons, particularly the perils of proarrhythmia and the efficacy of ICDs, have revolutionized treatment paradigms and saved many lives. The ascendancy of implantable devices over antiarrhythmic pharmacotherapy is a trend that will likely continue in the foreseeable future. Hopefully, new insights into ion channel function and genetic polymorphisms will herald a new era of antiarrhythmic therapy that is both more effective and safer than currently available pharmaceuticals.

General Guidelines for Antiarrhythmic Drugs •

All antiarrhythmic drugs possess potential proarrhythmic toxicity, although amiodarone has a low incidence of ventricular proarrhythmia in HF.

8. Management of Arrhythmias in Heart Failure •

• •

•

•

•

• •

•

Class I drugs should never be used without the protection afforded by an ICD. Class Ic agents have almost no role in HF patients, particularly those with an underlying ICM. If long-term therapy is likely in a young patient, generally avoid amiodarone as a first-line agent. If a patient has significant underlying lung disease, particularly restrictive disease, avoid amiodarone as an initial choice. In patients with renal insufficiency, avoid sotalol and dofetilide. Amiodarone should be the firstline medication. If the QT interval is prolonged in the absence of reversible electrolyte abnormalities or acute ischemia, amiodarone is the safest class III agent. In elderly patients with bradycardia, use amiodarone and sotalol with caution without concomitant ICD or pacemaker implantation. Class III agents are the least dangerous antiarrhythmics in HF patients. Of class III drugs, amiodarone is the safest and most efficacious in preventing ventricular tachyarrhythmias. Sotalol and dofetilide may also be used to prevent ventricular tachyarrhythmias and reduce ICD discharges, although the latter’s efficacy is less clear.

203 •

•

•

Atrial Fibrillation in Heart Failure Patients • •

•

Consideration of prophylactic ICD implantation should be made in patients with any of the following: (1) NYHA classes II–III HF with an LVEF ≤ 35% and either CAD or NICMP* (2) LVEF ≤ 30% with prior MI (3) Nonsustained VT and ICM with LVEF 35– 40% (if EP study is positive for inducible ventricular tachyarrhythmia) (4) LVEF ≤ 35% (ICM or NICM) and syncope (5) NYHA class IV HF awaiting transplantation, especially if leaving hospital on home inotropic therapy.

•

•

Prophylactic CRT-D should be considered in patients with LVEF ≤ 35%, NYHA classes III–IV HF, and QRS ≥ 120 ms. Consideration of ICD implantation for secondary prevention should be made in patients with prior SCD, including sustained VT, that was not in the setting of acute ST-elevation MI.

Controlling the ventricular rate is the most important immediate concern in new-onset AF. All HF patients with AF that is not clearly related to a reversible precipitant (excluding acute decompensated HF) should be chronically anticoagulated in the absence of an overwhelming contraindication. Left atrial appendage thrombus must be excluded via transesophageal echocardiography prior to cardioversion in the following circumstances: (1) duration of AF is not known to be ≤ 24–36 h (2) anticoagulation has been interrupted for ≥ 24–36 h prior to cardioversion (3) there is a prior history of thrombus with no documented dissolution (4) DFT testing will occur, and anticoagulation has been interrupted ≥ 24–36 h.

Prevention of Sudden Cardiac Death •

Antiarrhythmic therapy without an ICD does not afford protection from SCD in patients with an LVEF < 40%. Patients with a CMP and unexplained syncope are at high risk and generally should undergo ICD implantation. * CMS Guidelines stipulate duration of NICMP ≥ 9 months, or ≥ 3 months if enrolled in clinical trial or registry.

Maintaining sinus rhythm in HF patients may prevent long-term morbidity, unlike non-HF patients. •

• • • •

Digoxin is rarely effective as monotherapy for rate control, but may be helpful in conjunction with a β-blocker. Class III medications are the safest antiarrhythmics for AF. Amiodarone is definitively the most efficacious drug for preventing recurrent paroxysms of AF. The role of posterior left atrial RFA remains to be determined. If an ablate-and-pace strategy is used in patients with LV dysfunction, prophylactic CRT-D should be considered.

Device Programming in Heart Failure Patients •

RV pacing should be minimized in patients with LV dysfunction.

204 •

Antitachycardia pacing should be incorporated into tachyarrhythmia treatment algorithms in patients for whom ventricular arrhythmias have occurred.

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205 tomatic ventricular arrhythmia. N Engl J Med. 1995;333:77-82. 44. Julian DG, Camm AJ, Frangin G, et al. Randomised trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. European myocardial infarction amiodarone trial investigators. Lancet. 1997;49:667-674. 45. Cairns JA, Connolly SJ, Roberts R, Gent M. Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarizations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial investigators. Lancet. 1997;49:675-682. 46. Torp-Pedersen C, Møller M, Bloch-Thomsen E, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med. 1999;341:857-865. 47. Mukharju J, Rude RE, Poole WK, et al. Risk factors for sudden death after acute myocardial infarction: Two-year follow-up. Am J Cardiol. 1984;54:31-36. 48. Teo KK, Yusuf S, Furberg CD. Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: An overview of results from randomized trials. JAMA. 1993;270:1589-1595. 39. Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet. 1982;I:1142-1147. 50. Connolly S, Cairns J, Gent M, et al. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: Meta-analysis of individual data from 6500 patients in randomized trials. Lancet. 1997;350:1417-1424. 51. Camm AJ, Pratt CM, Schwartz PJ, et al. Mortality in patients after a recent myocardial infarction: A randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation. 2004;109:990-996. 52. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med. 1997;337:1576-1583. 53. Connolly SJ, Gent M, Roberts RS, et al. Canadian Implantable Defibrillator Study (CIDS): A randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101:1297-1302. 54. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary artery disease at high risk for ventricular arrhythmia. N Engl J Med. 1996;335: 1933-1940. 55. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in

206 patients with coronary artery disease. N Engl J Med. 1999;341:1882-1890. 56. Teerlink JR, Jalaluddin M, Anderson S, et al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. Circulation. 2000;101:40-46. 57. Cleland JGF, Daubert J-C, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549. 58. Michaud GF, Strickberger SA. Should an abnormal serum potassium level be considered a correctable cause of cardiac arrest? J Am Coll Cardiol. 2001;38:1224-1225. 59. Mirowski M, Mower MM, Gott VL, et al. Feasibility and effectiveness of low-energy catheter defibrillation in man. Circulation. 1973;47:79-85. 60. Wyse DG, Friedman PL, Brodsky MA, et al. Life threatening ventricular arrhythmias due to transient or correctable causes: High risk for death in followup. J Am Coll Cardiol. 2001;38:1718-1724. 61. Singh SN, Fisher SG, Carson PE, et al. Prevalence and significance of nonsustained ventricular tachycardia in patients with premature ventricular contractions and heart failure treated with vasodilator therapy. J Am Coll Cardiol. 1998;32:943-947. 62. Natale A, Sra J, Axtell K, et al. Ventricular fibrillation and polymorphic ventricular tachycardia with critical coronary artery stenosis: Does bypass surgery suffice? J Cardiovasc Electrophysiol. 1994;5:988-994. 63. Buxton AE, Marchlinski FE, Waxman HL, et al. Prognostic factors in nonsustained ventricular tachycardia. Am J Cardiol. 1984;69:250-258. 64. Strickenberger SA, Hummel JD, Bartlett TG, et al. Amiodarone Versus Implantable CardioverterDefibrillator: Randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia-AMIOVERT. J Am Coll Cardiol. 2003;41:1707-1712. 65. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350:2151-2158. 66. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883. 67. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-237. 68. Bänsch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: The Cardiomyopathy Trial (CAT). Circulation. 2002;105:1453-1458.

E.C. Adelstein and L.I. Ganz 69. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004;351:2481-2488. 70. Moss AJ, Greenberg H, Case R, et al. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;110:3760–3765. 71. Domanski MJ, Sakseena S, Epstein AE, et al. Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias. J Am Coll Cardiol. 1999;34:1090-1095. 72. Saba S, Atiga WL, Barrington W, et al. Selected patients listed for cardiac transplantation may benefit from defibrillator implantation regardless of an established indication. J Heart Lung Transplant. 2003;22:411-418. 73. St. John Sutton MG, Plappert T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation. 2003;107:1985-1990. 74. McAlister FA, Szekowitz JA, Wiebe NM, et al. Systematic review: Cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med. 2004;141:381-390. 75. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140-2150. 76. Schron EB, Exner DV, Yao Q, et al. Quality of life in the antiarrhythmics versus implantable defibrillators trial: Impact of therapy and influence of adverse symptoms and defibrillator shocks. Circulation. 2002;105:589-594. 77. Stevenson WG, Chaitman BR, Ellenbogen KA, et al. Clinical assessment and management of patients with implanted cardioverter-defibrillators presenting to nonelectrophysiologists. Circulation. 2004;110:38663869. 78. Sweeney MO. Antitachycardia pacing for ventricular tachycardia using implantable cardioverter defibrillators. Pacing Clin Electrophysiol. 2004;27:1292-1305. 79. Wathen MS, Sweeney MO, DeGroot PJ, et al. Shock reduction using antitachycardia pacing for spontaneous ventricular tachycardia in patients with coronary artery disease. Circulation. 2001;104:796-801. 80. Wathen MS, DeGroot PJ, Sweeney MO, et al. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators. Circulation. 2004;110:2591-2596.

8. Management of Arrhythmias in Heart Failure 81. Dolack GL. Clinical predictors of implantable cardioverter-defibrillator shocks (results of the CASCADE trial). Am J Cardiol. 1994;73:237-241. 82. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. N Engl J Med. 1999;340:1855-1862. 83. Kettering K, Mewis C, Dornberger V, et al. Efficacy of metoprolol and sotalol in the prevention of recurrences of sustained ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Pacing Clin Electrophysiol. 2002;25: 1571-1576. 84. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: The OPTIC study: A randomized trial. JAMA. 2006;295:165-171. 85. Echt DS, Lee JT, Murray KT, et al. A randomized, double-blind, placebo-controlled, dose-ranging study of dofetilide in patients with inducible sustained ventricular tachyarrhythmias. J Cardiovasc Electrophysiol. 1995;6:687-699. 86. Mazur A, Anderson ME, Bonney S, Roden DM. Pause-dependent polymorphic ventricular tachycardia during long-term treatment with dofetilide. J Am Coll Cardiol. 2001;37:1100-1105. 87. Dorian P, Borggrefe M, Al-Khalidi HR, et al. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter-defibrillator. Circulation. 2004;110:3646-3654. 88. Sra J, Bhatia A, Dhala A, et al. Electroanatomically guided catheter ablation of ventricular tachycardias causing multiple defibrillator shocks. Pacing Clin Electrophysiol. 2001;24:1645-1652. 89. Goldschlager N, Epstein AE, Naccarelli G, et al. Practical guidelines for clinicians who treat patients with amiodarone. Practice guidelines subcommittee, North American society of pacing and electrophysiology. Arch Intern Med. 2000;160:1741-1748. 90. Essebag V, Hadjus T, Platt RW, et al. Amiodarone and the risk of bradyarrhythmia requiring permanent pacemaker in elderly patients with atrial fibrillation and prior myocardial infarction. J Am Coll Cardiol. 2003;41:249-254. 91. Pelosi F Jr, Oral H, Sticherling C, et al. Effect of chronic amiodarone therapy on defibrillation energy requirements in humans. J Cardiovasc Electrophysiol. 2000;11:736-740. 92. Upshaw CB Jr. Hemodynamic changes after cardioversion of chronic atrial fibrillation. Arch Intern Med. 1997;157:1070-1076. 93. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in

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94.

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103.

104.

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208 105. Al-Khatib SM, Shaw LK, Lee KL, et al. Is rhythm control superior to rate control in patients with atrial fibrillation and congestive heart failure? Am J Cardiol. 2004;95:797-800. 106. The AF-CHF Trial Investigators. Rationale and design of a study assessing treatment strategies of atrial fibrillation in patients with heart failure: The Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial). Am Heart J. 2002;144:597-607. 107. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ ESC guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol. 2001;38:1266i-12661xx. 108. Kuhlkamp V, Scjirdewan A, Stangl K, et al. Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation. J Am Coll Cardiol. 2000;36:139-146. 109. Lang R, Klein HO, Weiss E, et al. Superiority of oral verapamil therapy to digoxin in treatment of chronic atrial fibrillation. Chest. 1983;83:491-499. 110. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533. 111. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med. 2001;344:1411-1420. 112. Flaker GC, McBride R,Canmal RA, Depenin JL, Hart RG, Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. JACC. 1992;20:527532. 113. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med. 2000;342:913-920. 114. The AFFIRM Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol. 2003;42:20-29. 115. Pratt CM, Singh SN, Al-Khalidi HR, et al. The efficacy of azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction: Results from the Azimilide Postinfarct Survival Evaluation (ALIVE) trial. J Am Coll Cardiol. 2004;43:1211-1216. 116. Young-Xu Y, Ravid S. Statin drugs protect against atrial fibrillation. Cardiol Rev. 2004;21:20-24. 117. ADONIS. American-Australian-African trial with dronedarone in atrial fibrillation or flutter for the maintenance of sinus rhythm. Presented at the

E.C. Adelstein and L.I. Ganz European Society of Cardiology Congress, August 2004. 118. EURIDIS. European trial in atrial fibrillation or flutter patients receiving dronedarone for the maintenance of sinus rhythm. Presented at the European Society of Cardiology Congress, August 2004. 119. Prystowsky EN. Inpatient versus outpatient initiation of antiarrhythmic drug therapy for patients with supraventricular tachycardia. Clin Cardiol. 1994;17(Suppl 2):II7-II10. 120. Brignole M, Menozzi C, Gianfranchi L, et al. Assessment of atrioventricular junction ablation and VVIR pacemaker versus pharmacological treatment in patients with heart failure and chronic atrial fibrillation: A randomized, controlled study. Circulation. 1998;98:953-960. 121. Vanderheyden M, Goethals M, Anguerra I, et al. Hemodynamic deterioration following radiofrequency ablation of the atrioventricular conduction system. Pacing Clin Electrophysiol. 1997;20:24222428. 122. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol. 2000;23:1020-1028. 123. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation (the PAVE study). J Cardiovasc Electrophysiol. 2005;16:1160-1165. 124. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998;339:659-666. 125. Hsu LF, Jais P, Sanders P, et al. Catheter ablation for atrial fibrillation in congestive heart failure. N Engl J Med. 2004;351:2373-2383. 126. Cox JL, Schuessler RB, D’Agostino HJ, et al. The surgical treatment of atrial fibrillation: III. Development of a definitive surgical procedure. J Thorac Cardiovasc Surg. 1991;1101:569-583. 127. Prasad SM, Maniar HS, Camillo CJ, et al. The Cox Maze III procedure for atrial fibrillation: Longterm efficacy in patients undergoing lone versus concomitant procedures. J Thorac Cardiovasc Surg. 2003;126:1822-1827. 128. Schaff HV, Dearani JA, Daly RC, et al. The CoxMaze procedure for atrial fibrillation: The Mayo clinic experience. Semin Thorac Cardiovasc Surg. 2000;12:30-37. 129. Sie HT, Beukema WP, Misier AR, et al. Radiofrequency modified maze in patients with atrial fibrillation undergoing concomitant cardiac surgery. J Thorac Cardiovasc Surg. 2001;122:249-256. 130. Knaut M, Spitzer SG, Karoli L, et al. Intraoperative microwave ablation for curative treatment of atrial

8. Management of Arrhythmias in Heart Failure fibrillation in open heart surgery. The MICRO-STAF and MICRO-PASS pilot trial. Thorac Cardiovasc Surg. 1999;47(Suppl II):379-384. 131. Raman JS, Ishikawa S, Power JM. Epicardial radiofrequency ablation of both atria in the treatment of atrial fibrillation: Experience in patients. Ann Thorac Surg. 2002;74:S1301-S1306. 132. Cox JL. Surgical treatment of atrial fibrillation: A review. Europace. 2004;5:(Suppl 1): S20-S29. 133. Scheinman MM, Huang S. The 1998 NASPE prospective catheter ablation registry. Pacing Clin Electrophysiol. 2000;23:1020-1028. 134. Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: A study in awake chronically instrumented goats. Circulation. 1995;92:1954-1968. 135. Wellens HJJ, Lau C-P, Luderitz B, et al. Atrioverter: An implantable device for the treatment of atrial fibrillation. Circulation. 1998;98:1651-1656. 136. Lamas GA, Lee KL, Sweeney MO, et al. Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med. 2002;346: 1854-1862. 137. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107:2932-2936.

209 138. Wilkoff BL, Cook JR, Epstein AE, et al. Dualchamber pacing or ventricular backup pacing in patients with an implantable defibrillator. JAMA. 2002;288:3115-3123. 139. Kazanki H, Jacques D, Sade LE, et al. Regional correlation by color-coded tissue Doppler to quantify improvements in mechanical left ventricular synchrony after biventricular pacing therapy. Am J Card. 2003;92:752-755. 140. Bristow MR, Saxon LA, Boehmer J, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140-2150. 141. Kapoor WN. Current evaluation and management of syncope. Circulation. 2002;106:1606-1609. 142. Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med. 2002;347:878-885. 143. Stevenson EG, Ellison KE, Sweeney MO, et al. Management of arrhythmias in heart failure. Cardiol Rev. 2002;10:8-14. 144. Knight BP, Goyal R, Pelosi F, et al. Outcome of patients with nonischemic dilated cardiomyopathy and unexplained syncope treated with an implantable defibrillator. J Am Coll Cardiol. 1999;33:1964-1970. 145. Gregoratos G, et al. ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices. Circulation. 2002;106: 2145-2161.

9 Device Therapy in Heart Failure J. Julia Shin, Andrew L. Smith, and Angel R. Leon

9.1. Introduction Heart failure is rapidly becoming a pervasive cause of cardiovascular disease in the USA. Despite significant advances in medical knowledge and treatment, heart failure remains a challenging problem, resulting in high morbidity and mortality. Comprehension of the pathophysiology and treatment of ventricular dysfunction has undergone an evolution over the past two decades. Initially composed of digitalis and diuretics, the pharmacologic armamentarium has expanded to include vasodilators, inhibitors of the renin–angiotensin–aldosterone system, as well as neurohormonal and sympathetic modulators. This polypharmaceutical approach underscores the complexity of heart failure pathophysiology. Despite these advances, there remain a substantial group of patients who do not tolerate, do not respond to, or worsen despite optimal medical therapy. Approximately half of patients with dilated cardiomyopathy succumb to sudden cardiac death, and refractory pump failure is the next most common cause of mortality in this population(1,2). In the early 1990s, the need for novel treatment modalities ushered in the era of device therapy for heart failure, namely, the use of implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT).

9.2. Implantable CardioverterDefibrillators The majority of patients with dilated cardiomyopathy exhibit ventricular tachyarrhythmias(3,4). The

development of ventricular arrhythmias in heart failure portends a worse prognosis and the use of antiarrhythmic drugs to prevent sudden death in this population has not been shown to be successful. The ICD rapidly detects and terminates sustained ventricular tachycardia or fibrillation. To protect patients at a high risk for malignant ventricular arrhythmias, trials were initiated investigating the role of ICD therapy in both ischemic and nonischemic cardiomyopathy.

9.2.1. Primary Prevention Trials in Ischemic Cardiomyopathy The first substantial trial investigating the role of ICDs in primary prevention of death in heart failure patients was the Multicenter Automatic Defibrillator Implantation Trial (MADIT) (Table 9.1)(5). This trial enrolled 196 patients with depressed left ventricular ejection fraction (LVEF) no more than 35%, prior myocardial infarctions, and documented nonsustained ventricular tachycardia with inducible ventricular arrhythmia by electrophysiologic study. Eligible patients needed to be at least 3 weeks from a myocardial infarction without indications for revascularization. These patients were randomly assigned to ICD implantation or conventional medical therapy, which could include antiarrhythmic medications at the discretion of the treating physician. At a mean follow-up time of 27 months, there were 54% fewer deaths in the ICD group (15% ICD vs. 39% medical-therapy group, P = 0.009). Of note, 60% of patients implanted with an ICD had a shock discharge within 2 years after enrollment. 211

104 1,232 103 458 674

2,521

CAT MADIT-II AMIOVIRT DEFINITE DINAMIT

SCD-HeFT

NICM + ICM

NICM ICM NICM NICM ICM

ICM ICM ICM

Population

35(24)

30(24) 30(23) 35(22) 36(21) 35(28)

35(27) 36(27) 40(30)

LVEF% (mean) Positive EPS Abnormal SAECG Positive EPS, EPSguided AAD New-onset NICM Positive EPS not required NSVT NSVT Recent MI, depressed HR variability/ elevated average HR 52% NICM, 48% ICM

Other patient characteristics

3.8

1.9 1.7 2.2 2.4 2.5

2.3 2.7 3.3

Mean followup (year)

II–III (100% II–III) I–III (60% II–III) I–III (87% II–III) I–III (75% II–III) I–III (87% II–III)

II–III (100% II–III)

↓

I–III (63% II–III) I–IV (71% II–III) I–III (63% II–III)

↓ « ↓ « ↓ « ↓ «

Enrolled NYHA class

Mortality

2005

2002 2002 2003 2004 2004

1996 1997 1999

Year published

(12)

(9) (8) (10) (11) (13)

(5) (6) (7)

Reference

AAD antiarrhythmic drugs, EPS electrophysiology study, HR heart rate, ICM ischemic cardiomyopathy, LVEF left ventricular ejection fraction, NICM nonischemic cardiomyopathy, NSVT nonsustained ventricular tachycardia, NYHA New York Heart Association, MI myocardial infarction, SAECG signal-average electrocardiogram. Trial name: AMIOVIRT Amiodarone Versus Implantable Defibrillator Randomized Trial, CABG Coronary Artery Bypass Graft, CAT Cardiomyopathy Arrhythmia Trial, DEFINITE Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation, DINAMIT Defibrillator in Acute Myocardial Infarction Trial, MADIT-I Multicenter Automatic Defibrillator Implantation Trial I, MADIT-II Multicenter Automatic Defibrillator Implantation Trial II, MUSTT Multicenter Unsustained Tachycardia Trial, SCD-HeFT Sudden Cardiac Death in Heart Failure Trial.

196 900 704

n

MADIT-I CABG-Patch MUSTT

Trial

Table 9.1. Implantable cardioverter-defibrillator primary prevention trials.

212 J.J. Shin et al.

9. Device Therapy in Heart Failure

In contrast to the MADIT results, the Coronary Artery Bypass Graft (CABG)-Patch trial did not find a survival advantage in the use of ICD devices(6). In CABG-Patch, the investigators randomly assigned 900 patients with ventricular dysfunction who were undergoing coronary bypass surgery to receive epicardial ICD patches versus control, with the hypothesis that prophylactic implantation of ICD would improve long-term survival in patients at high risk for sudden cardiac death. Eligible patients included those with LVEF of 35% or less, who were stratified as higher risk for malignant ventricular rhythms by positive signal-averaged electrocardiograms. At a mean follow-up of 32 months, there was no difference in cardiovascular mortality between the two groups. Similar to MADIT, 57% of patients who were implanted with an ICD device received a shock within 2 years of implantation. Beta-blockers were more frequently used in the control arm, and this has been postulated as a possible mechanism of the lack of benefit in the ICD group. In addition, the authors suggest that the benefit of coronary bypass surgery in decreasing the rate of sudden death may have also contributed to these findings. Indeed, overall mortality rates were lower in the CABGPatch trial compared to those in MADIT. The Multicenter Unsustained Tachycardia Trial (MUSTT) enrolled a patient population similar to that in the MADIT and CABG-Patch trials. In MUSTT, 704 individuals with ischemic cardiomyopathy, LVEF less than or equal to 40%, and inducible ventricular tachycardia in the electrophysiology laboratory were randomized to receive ICD therapy, antiarrhythmic drug therapy, or no therapy(7). Serial electrophysiologic testing was performed for guided antiarrhythmic drug therapy, and patients could be assigned to ICD implantation if drugs failed to control their ventricular arrhythmias. At 5-year follow-up, analysis of the data revealed a 31% mortality benefit in those who had received an ICD (55% in no-ICD arm vs. 24% in ICD-implanted arm, P < 0.001). Furthermore, the survival benefit associated with electrophysiology-guided therapy was derived entirely from ICD therapy, not antiarrhythmic medications. The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), unlike previous trials of ICD therapy in ischemic heart failure, did not attempt to risk stratify patients by invasive

213

electrophysiology study, signal-averaged electrocardiograms, or other features indicating a high risk for ventricular tachycardia(8). Instead, MADITII randomly assigned 1,232 patients with LVEF no more than 30% and a history of remote prior myocardial infarction to receive ICD implantation or conventional medical therapy. This trial was stopped before the goal recruitment of 1,500 patients because defibrillator therapy was found to cross the efficacy-stopping boundary. At a mean follow-up of 20 months, all-cause mortality risk was 31% lower in the ICD group (19.8% in the medical-therapy group vs. 14.2% in the ICD group) (Figure 9.1). The mortality benefit of ICD therapy was seen despite the degree of left ventricular (LV) dysfunction or QRS duration (another marker for ventricular arrhythmia risk). There was, however, an increased risk of hospitalizations for heart failure in the ICD group, which the authors hypothesized was possibly due to either intermittent right ventricular pacing with subsequent dyssynchrony or longer survival in the ICD-implanted patients.

9.2.2. Primary Prevention Trials in Nonischemic Cardiomyopathy As evidenced in the above trials, ICD therapy clearly confers a survival benefit in those with cardiomyopathy of ischemic etiology. This provided rationale to study defibrillators in the nonischemic cardiomyopathy population (Table 9.2). Initial trials were inconclusive. For example, the Cardiomyopathy Arrhythmia Trial (CAT)(9), which enrolled patients with newly diagnosed (within 9 months) nonischemic systolic dysfunction (LVEF < 30%) randomized to ICD versus control, and the Amiodarone Versus Implantable Defibrillator Randomized Trial (AMIOVIRT)10, which randomized similar patients with nonischemic cardiomyopathy (LVEF ≤ 35% and nonsustained ventricular tachycardia) to ICD implantation versus amiodarone therapy, did not find any statistical difference in mortality between the treatment groups. The CAT and the AMIOVIRT were limited by their small size, and the lack of a placebo control group in AMIOVIRT. The overall mortality rates in the control group of the CAT were lower than expected, which may explain the lack of benefit from ICD therapy. Larger trials were initiated in order to investigate the role of ICD

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Figure 9.1. Multicenter Automatic Defibrillator Implantation Trial II (MADIT II). Kaplan-Meier estimates of the probability of survival in the group assigned to receive an implantable defibrillator and the group assigned to receive conventional medical therapy. The difference in survival between the two groups was significant (nominal P = 0.007, by the log-rank test)

therapy in nonischemic heart failure and there have been several major randomized, controlled trials published to date. In the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, 458 patients with nonischemic cardiomyopathy, LVEF less than or equal to 35%, and documented frequent premature ventricular contractions or nonsustained ventricular tachycardia were followed for ~30 months after randomization to defibrillator or medical therapy(11). At the conclusion of the study, ICD therapy was shown to decrease the risk of sudden cardiac death compared to the medical therapy (8.1% in the ICD arm vs. 13.8% in the control arm, P = 0.06). The largest defibrillator trial to date, the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), randomized 2,521 patients with both ischemic and nonischemic left ventricular dysfunction (LVEF ≤ 35%) and New York Heart Association (NYHA) class II or III symptoms to ICD plus conventional medical therapy, amiodarone plus conventional therapy, or placebo and conventional therapy(12). The etiology of cardiomyopathy was ischemic in 52% and nonischemic in 48%. With a median follow-up of 45.5 months, ICD therapy resulted in a significant reduction in all-cause mortality

compared to placebo with a 23% reduction in the relative risk of death (HR 0.77, 97.5% CI 0.62– 0.96, P = 0.007) (Figure 9.2). In the ICD-treated arm, there was no difference in mortality between the ischemic and nonischemic subpopulations, and the majority of survival benefit was seen in NYHA class II, not class III, patients. The average annual rate of all ICD shocks was 7.5%, of which 68% were deemed appropriate (delivered for rapid ventricular tachycardia or ventricular fibrillation). Treatment with amiodarone yielded no survival benefit compared to placebo in either the ischemic or the nonischemic population. In fact, among patients with NYHA class III symptoms there was a relative 44% increase in risk of death in the amiodarone group compared to placebo. There was no excess death with amiodarone use in the NYHA class II subgroup. The previous ICD trials excluded patients with recent myocardial infarctions. In contrast, the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT) was designed to study the benefits of ICD therapy in patients shortly after an acute myocardial infarction(13). This study selected 676 patients with an LVEF of 35% or less, who were within 6–40 days of a myocardial infarction and

9. Device Therapy in Heart Failure

215 Hazard Ratio (97.5% CI) 1.06 (0.86 – 1.30) 0.77 (0.62 – 0.96)

Amiodarone vs. placebo ICD therapy vs. placebo 0.4

Placebo (244 deaths; 5-yr event rate, 0.361)

0.3 Mortality Rate

P Value 0.53 0.007

ICD therapy (182 deaths; 5-yr event rate, 0.289)

Amiodarone (240 deaths; 5-yr event rate, 0.340)

0.2

0.1

0.0 0

12

24

36

48

60

280 304 304

97 89 103

Months of Follow-up No. at Risk Amiodarone Placebo ICD therapy

845 847 829

772 797 778

715 724 733

484 505 501

Figure 9.2. Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Kaplan-Meier estimates of death from any cause. CI denotes confidence interval (See Color Plates)

demonstrated either depressed heart rate variability or an elevated average heart rate on 24-h Holter monitoring. The patients were randomly assigned to ICD therapy versus no-ICD therapy. Although ICD therapy correlated with a significant reduction in arrhythmic death (HR 0.42, 95% CI 0.22–0.83, P = 0.009), it was also associated with a significant increase in nonarrhythmic death (HR 1.75, 95% CI 1.11–2.76, P = 0.02), resulting in a lack of difference in all-cause mortality at a mean follow-up of 30 months. Supporting this finding, a subgroup analysis of MADIT-II also showed that those patients enrolled with the most recent infarctions did not benefit from ICD therapy(14). The use of defibrillator therapy in patients with recent acute myocardial infarctions requires further investigation before definitive recommendations can be made.

9.2.3. Secondary Prevention Trials Survivors of sustained malignant ventricular arrhythmias in the setting of dilated cardiomyopathy are at a high risk for subsequent death from cardiac arrest, with a 2-year incidence of 20–45%(15,16). These patients should undergo implantation of a cardiac defibrillator, as large-scale, randomized controlled trials have proven the superiority of ICD therapy over antiarrhythmic drug therapy in

the secondary prevention of sudden cardiac death (Table 9.2). For example, the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial revealed an absolute survival benefit of 11.3% in the ICD group over antiarrhythmic drug therapy group at 3 years (75.4% vs. 64.1%, P < 0.02)(17). AVID enrolled patients with an LVEF of less than 40% who had survived a ventricular fibrillatory arrest or severely symptomatic sustained ventricular tachycardia. The mortality benefit attained from ICD implantation was most prominent in those with the most severe reduction in ejection fraction, less than 35%. The Canadian Implantable Defibrillator Study (CIDS)(18) and Cardiac Arrest Study Hamburg (CASH)(19) also enrolled patients with left ventricular systolic dysfunction who were resuscitated from ventricular fibrillation or sustained symptomatic ventricular tachycardia. Those eligible for enrollment were randomized to ICD versus antiarrhythmic drug therapy. Both CIDS and CASH showed an improvement in mortality in the ICD arm, although neither reached statistical significance.

9.2.4. Adjunctive Therapy Repeated shocks from a cardioverter-defibrillator device can cause significant mental health concerns,

288

CASH

SCD

81% ICM 82% ICM

Population

Any(46)

40(32) 35(33)

LVEF% (mean)

SCD survivors, ICD vs. AAD

SCD survivors SCD survivors

Other patient characteristics

4.8

1.5 3

Mean followup (year)

↓?

↓ ↓?

Mortality

I–III (48% I–II, 7% III) I–IV (40% I–II, 11% III–IV) I–III (77% II–III)

Enrolled NYHA class

2000

1997 2000

Year published

(19)

(17) (18)

Reference

AAD antiarrhythmic drug therapy, ICM ischemic cardiomyopathy, LVEF left ventricular ejection fraction, NYHA New York Heart Association, SCD sudden cardiac death, ? nonsignificant. Trial name: AVID Antiarrhythmics Versus Implantable Defibrillator, CIDS Canadian Implantable Defibrillator Study, CASH Cardiac Arrest Study Hamburg.

1,016 659

n

AVID CIDS

Trial name

Table 9.2. Implantable cardioverter-defibrillator secondary prevention trials.

216 J.J. Shin et al.

453

581

369

1,520

813

MIRACLE

CONTAK CD

MIRACLE-ICD

COMPANION

CARE-HF

120(160)

120(160)

130(165)

120(160)

130(167)

150 (176 SR, 206 AF)

QRS (mean)

35(25)

35(22)

35(24)

35(21)

35(22)

35 (22 SR, 26 AF)

LVEF% (mean) NYHA III, LVEDD > 60 37% ICM and 63% NICM in SR group 27% ICM and 73% NICM in AF group NYHA III–IV, LVEDD > 55 Approved indication for ICD, NYHA II–IV Approved indication for ICD, NYHA III–IV NYHA III–IV, hospitalized within 12 month NYHA III–IV

Other patient characteristics

↑ ↑

N/A

«

↑ ↑ ↑

↑

«

↑

N/A

↑

↑

↑

↑

↑

↑

↑

MVo2

QOL

6MWD

↑

↑

↑

«

↑

↑

NYHA

↓

↓

«

↓?

↓

↓

Hospitalization

↓

↓ with ICD

«

↓?

N/A

N/A

Mortality

2005

2004

2003

2003

2002

2001

(34)

(33)

(32)

(31)

(30)

(29)

Year published Reference

AF atrial fibrillation, ICM ischemic cardiomyopathy, ICD implantable cardioverter-defibrillator, LVEDD left ventricular end-diastolic dimension, LVEF left ventricular ejection fraction, 6MWD 6-min walk distance, MVO2 peak oxygen consumption, NYHA New York Heart Association, NICM nonischemic cardiomyopathy, QOL quality of life, SR sinus rhythm. Trial name: CARE-HF, Cardiac Resynchronization Heart Failure, COMPANION Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure, MIRACLE Multicenter InSync Randomized Clinical Evaluation, MUSTIC Multisite Stimulation in Cardiomyopathies.

131

n

MUSTIC

Trial name

Table 9.3. Cardiac resynchronization therapy trials.

9. Device Therapy in Heart Failure 217

218

such as anxiety, fatigue, and psychological distress20. It becomes vitally important, then, to decrease the frequency of malignant ventricular rhythms in those patients who are receiving frequent shocks. Current devices can attempt to terminate ventricular tachycardia by antitachycardic pacing before delivering shock therapy. Various algorithms can also discriminate between supraventricular and ventricular tachyarrhythmias, thus decreasing the frequency of unnecessary defibrillator discharges. Antiarrhythmic drugs also play an important role in conjunction with ICD therapy. For example, some may decrease the frequency of both supraventricular and ventricular tachyarrhythmias. Others can decrease the defibrillation threshold, thus making the device more successful at terminating malignant rhythms. These drugs, however, must be used with caution, as many are proarrhythmic and can raise defibrillation thresholds. In addition to drug therapy, catheter ablation can play a role in abolishing or decreasing the frequency of refractory ventricular tachycardias. Further advances in radiofrequency ablation, including the use of newer mapping techniques, holds promise for the higher success of ventricular tachycardia ablation in dilated cardiomyopathy.

9.2.5. Current Recommendations The trial data to date has demonstrated that ICD therapy is superior to medical therapy in both primary and secondary prevention of sudden cardiac death in patients with ischemic and nonischemic etiologies of left ventricular dysfunction. It should be noted that almost all studies of cardioverterdefibrillator therapy in heart failure excluded NYHA class IV patients from enrollment, and device implantation in these patients cannot be recommended at the present time. In the ACC/ AHA/NASPE guidelines for the implantation of antiarrhythmia devices (Table 9.4), which were updated in 2002(21), ICD implantation is considered a class I indication in those patients with nonsustained ventricular tachycardia in the setting of coronary disease, prior myocardial infarction, left ventricular dysfunction, and inducible ventricular fibrillation or sustained ventricular tachycardia at electrophysiological study that is not suppressible by a class I antiarrhythmic drug. The level of evidence in this recommendation was raised to “A” from “B” in the 1998 guidelines. The 2002

J.J. Shin et al.

guidelines consider prophylactic ICD implantation in patients with LVEF of less than or equal to 30%, at least 1 month post myocardial infarction, and 3 month post coronary artery revascularization surgery a class IIa indication. The results of DINAMIT argue against ICD implantation in patients who are less than 1 month from an acute myocardial infarction. In addition, ICD therapy shortly after revascularization (less than 3 months) cannot be recommended, as the CABG-Patch trial failed to show a survival benefit in these patients. In those patients who are on the cardiac transplantation waiting list, a group highly susceptible to sudden death, ICD therapy is regarded as a class IIb indication by the 2002 guidelines in those with significant symptoms, such as syncope, attributable to sustained ventricular tachyarrhythmias. The 2005 ACC/AHA Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult(22) provides additional recommendations regarding the use of ICDs in the heart failure population (Table 9.4). These guidelines advocate a class IIa indication for prophylactic ICD implantation in patients with ischemic cardiomyopathy who are at least 40 days from a myocardial infarction, have an LVEF of 30% or less, are NYHA class I on optimal medical therapy, and have a “reasonable expectation of survival with a good functional status for more than 1 year.” For the prophylactic use of defibrillator therapy in patients without symptoms of heart failure who have nonischemic cardiomyopathy and an LVEF less than or equal to 30%, the 2005 guidelines give a class IIb recommendation. In patients with symptoms of heart failure, class I indications include (1) secondary prevention to prolong survival in patients who have a history of cardiac arrest, ventricular fibrillation, or hemodynamically destabilizing ventricular tachycardia; (2) primary prevention in patients with ischemic heart disease who are at least 40 days post myocardial infarction, have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms; and (3) primary prevention in patients with nonischemic cardiomyopathy who have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms. Placement of an ICD is “reasonable,” a class IIa indication, in patients with an LVEF of 30–35% of any origin with NYHA functional class II or

9. Device Therapy in Heart Failure

219

Table 9.4. Combined ACC/AHA guidelines on use of implantable cardioverter-defibrillator therapy in heart failure. 2002 Class I

Class IIa

Class IIb

Class III

2005

Nonsustained VT in patients with coronary disease, An ICD is recommended as secondary prevention to prolong prior myocardial infarction, LV dysfunction, and survival in patients with current or prior symptoms of HF inducible VF or sustained VT at electrophysiand reduced LVEF who have a history of cardiac arrest, ological study that is not suppressible by a class I ventricular fibrillation, or hemodynamically destabilizing antiarrhythmic drug. (Level of Evidence: A) ventricular tachycardia. (Level of Evidence: A) Implantable cardioverter-defibrillator therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with ischemic heart disease who are at least 40 days post MI, have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms while undergoing chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: A) Implantable cardioverter-defibrillator therapy is recommended for primary prevention to reduce total mortality by a reduction in sudden cardiac death in patients with nonischemic cardiomyopathy who have an LVEF less than or equal to 30%, with NYHA functional class II or III symptoms while undergoing chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: B) Patients with refractory end-stage HF and implantable defibrillators should receive information about the option to inactivate defibrillation. (Level of Evidence: C) Patients with LV ejection fraction of less than or Placement of an ICD is reasonable in patients with ischemic equal to 30%, at least 1 month post myocardial cardiomyopathy who are at least 40 days post MI, have infarction and 3 months post coronary artery an LVEF of 30% or less, are NYHA functional class I revascularization surgery. (Level of Evidence: B) on chronic optimal medical therapy, and have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: B) Placement of an ICD is reasonable in patients with LVEF of 30–35% of any origin with NYHA functional class II or III symptoms who are taking chronic optimal medical therapy and who have reasonable expectation of survival with good functional status of more than 1 year. (Level of Evidence: B) Severe symptoms (e.g., syncope) attributable to Placement of an ICD might be considered in patients without ventricular tachyarrhythmias in patients awaiting HF who have nonischemic cardiomyopathy and an LVEF cardiac transplantation. (Level of Evidence: C) less than or equal to 30% who are in NYHA functional class I with chronic optimal medical therapy and have a reasonable expectation of survival with good functional status for more than 1 year. (Level of Evidence: C) Syncope in patients with advanced structural heart disease in which thorough invasive and noninvasive investigation has failed to define a cause. (Level of Evidence: C) Aggressive procedures performed within the final days of life (including intubation and implantation of a cardioverterdefibrillator in patients with NYHA functional class IV symptoms who are not anticipated to experience clinical improvement from available treatments) are not appropriate. (Level of Evidence: C) (continued)

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Table 9.4 (continued) HF heart failure, ICD implantable cardioverter-defibrillator, LV left ventricular, LVEF left ventricular ejection fraction, MI myocardial infarction, NYHA New York Heart Association, VT ventricular tachycardia, VF Ventricular fibrillation. Classification of recommendations: Class I: Conditions for which there is evidence for and/or general agreement that a given procedure or treatment is beneficial, useful, and effective. Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful. Level of Evidence A: Data derived from multiple randomized clinical trials or meta-analyses. Level of Evidence B: Data derived from a single randomized trial or nonrandomized studies. Level of Evidence C: Only consensus opinion of experts, case studies, or standard of care.

III symptoms who are on optimal medical therapy with good 1-year life expectancy. The 2005 guidelines advise against implantation of an ICD in patients with NYHA functional class IV symptoms who are not anticipated to experience clinical improvement from available treatments (class III recommendation), and also suggest that physicians should offer patients with end-stage refractory heart failure the option of turning off the device (class I recommendation).

9.3. Cardiac Resynchronization Therapy Myocardial dyssynchrony occurs from regional delays in contraction of the dilated left ventricle, resulting in impaired contractile efficiency and worsening mitral regurgitation. Cardiac resynchronization therapy, or biventricular pacing, was developed to address the issue of mechanical dyssynchrony in dilated cardiomyopathy. In this procedure, in addition to conventional right atrial and right ventricular leads, a pacing lead is placed in a branch of the coronary sinus to stimulate the lateral wall of the left ventricle, thereby “synchronizing” inter- and intraventricular contractions. These devices can also be combined with ICD functionality. The mechanism of benefit from CRT includes improved contractile efficiency, decreased end-diastolic volume, reverse myocardial remodeling, and decreased arrhythmias. Indeed, early efficacy trials of CRT devices confirmed multiple potential benefits. For instance, biventricular pacing

improved ejection fraction, NYHA functional class, and exercise tolerance, while reducing mitral regurgitation(23-25). CRT also improves hemodynamic parameters such as pulmonary capillary wedge pressure and cardiac output(26,27). With cessation of biventricular pacing, ventricular volumes quickly regress to original dimensions(28), indicating that CRT plays an important role in reversing the adverse remodeling associated with heart failure. QRS prolongation represented the initial correlate to ventricular dyssynchrony, and the major trials in CRT (Table 9.3) enrolled patients on the basis of QRS duration. The Multisite Stimulation in Cardiomyopathies (MUSTIC) trial was the first landmark study demonstrating the benefit of biventricular pacing in heart failure(29). The MUSTIC investigators enrolled 131 patients with LVEF of 35% or less and QRS duration longer than 150 ms who demonstrated NYHA class III heart failure. This trial included those patients in atrial fibrillation. The etiology of cardiomyopathy for the majority of the MUSTIC cohort was nonischemic. This study was designed as a blind crossover at 3 months of biventricular pacing or inactive pacing. At the end of both phases, the MUSTIC trial found that patients increased their 6-min walk distance during the active biventricular pacing mode compared to the inactive mode (399 ± 101 vs. 326 ± 134 m, P < 0.001). There were also significant improvements in quality of life and peak oxygen consumption, as well as fewer hospitalizations for heart failure during the active pacing phase. In addition, CRT resulted in an improvement in LVEF with a decrease in severity

9. Device Therapy in Heart Failure

of mitral regurgitation. Benefits to CRT were seen in both sinus rhythm and atrial fibrillation groups. This trial was not designed to study mortality. Subsequent to the MUSTIC trial, the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial was completed(30). This trial enrolled a greater number of patients but utilized similar enrollment criteria: NYHA class III–IV symptoms with LVEF less than or equal to 35% and QRS duration 130 ms or greater. This trial excluded patients in atrial fibrillation. CRT devices were implanted in all enrollees, and they were randomized in a parallel manner to active versus inactive biventricular pacing. Similar to the MUSTIC trial, at the end of 6-month follow-up there were significant improvements in quality of life, 6-min walk distance, and NYHA class in the active biventricular-pacing group. Cardiac resynchronization was also associated with a shortening of QRS duration and concomitant increase in LVEF. As in the MUSTIC trial, there was a decrease in the magnitude of mitral regurgitation in the CRT group. There was also a decrease in the combined risk of death and worsening heart failure; the differences in favor of biventricular pacing were seen as early as 1 month after device implantation. The CONTAK CD(31) and MIRACLE-ICD (also referred to as InSync ICD)(32) trials were designed to assess the safety and effectiveness of resynchronization therapy when combined with an implantable defibrillator. In CONTAK CD, eligible patients included those with LVEF of 35% or less, QRS duration 120 ms or greater, NYHA functional class II–IV, with a conventional indication for ICD therapy. Four hundred and ninety patients were implanted with a CRT plus ICD device, and randomized to active versus inactive biventricular pacing. At end of follow-up, active pacing significantly improved peak oxygen consumption, 6-min walk distance, and ejection fraction. There was a nonsignificant reduction in heart failure progression and improved quality of life. The clinical improvements seen in CONTAK CD were limited to patients with NYHA III or IV symptoms. MIRACLE-ICD also studied the effects of combined CRT and ICD therapy in 369 patients with ejection fractions no more than 35% and QRS durations longer than 130 ms. In MIRACLE-ICD, NYHA functional class, peak oxygen consumption, and quality of life improved significantly in resynchronized patients.

221

There were inconsistent effects of CRT on 6-min walk distance, and no differences were detected in LVEF and rates of hospitalizations. CONTAK CD and MIRACLE-ICD were small studies with brief follow-up (6 months) and were not designed to evaluate mortality. To define further potential benefits of adding cardioverter-defibrillator capability to resynchronization therapy, the Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure (COMPANION) trial enrolled 1,520 patients with ejection fractions less than 35% and QRS durations greater than 120 ms in NYHA class III or IV heart failure(33). Approximately one half of the COMPANION population had cardiomyopathy of nonischemic origin. Patients were randomly assigned to CRT, CRT with ICD, or medical therapy. At the conclusion of the trial, CRT with ICD conferred a 43% relative risk reduction in all-cause mortality compared to the medical-therapy arm. Both CRT and CRT with ICD arms also exhibited a statistically significant improvement in functional class and reduction in hospitalizations for heart failure. CRT therapy with or without ICD reduced the risk of the primary end point of death or hospitalization from any cause by ~20%; there was no difference between the two groups. Regarding death or hospitalization for cardiovascular causes, CRT with ICD resulted in a 28% risk reduction compared to medical therapy, and CRT alone offered a risk reduction of 25%. CRT therapy provided an even better survival from death or hospitalizations from heart failure (relative risk reduction 34% CRT and 40% CRT + ICD). Based upon the results of this trial, the US Food and Drug Administration approved the use of CRT-ICD devices in patients meeting criteria for resynchronization therapy. The Cardiac Resynchronization Heart Failure (CARE-HF) trial was the first large study to demonstrate mortality benefits from resynchronization alone(34). This trial enrolled patients with ejection fractions of 35% or less and QRS durations of more than 120 ms. Patients with a QRS interval of 120– 149 ms were required to meet additional echocardiographic criteria for dyssynchrony in order to meet enrollment criteria. Inclusion criteria included NYHA class III or IV heart failure, and atrial fibrillation was excluded from this study. The CARE-HF patients were randomly assigned to CRT therapy

222

J.J. Shin et al.

versus medical therapy alone in parallel fashion. A total of 813 patients were enrolled and followed for a mean of 29.4 months. As compared with medical therapy, CRT significantly reduced QRS duration, end-systolic volume index, and the area of the mitral regurgitant jet. Furthermore, resynchronization increased LVEF and improved heart failure symptoms and quality of life. More importantly, resynchronized patients exhibited a decrease in mortality, largely due to reduction in deaths from worsening pump function. In the CRT group, 82 patients died, as compared with 120 patients who had been assigned to medical therapy alone (20% vs. 30%). The cause of death was attributed to worsening heart failure in 47% who died in the medical-therapy group and in 40% of the patients who died in the resynchronization group. The mortality rate in the medical-therapy arm was 12.6% at 1 year and 25.1% at 2 years, as compared with 9.7% at 1 year and 18.0% at 2 years in the CRT arm (Figure 9.3).

9.3.1. Unresolved Issues in CRT Intraventricular conduction delay occurs in only about 30% of heart failure patients(35) and the majority of patients in CRT trials exhibited left bundle branch blocks. It is unknown if the remainder of these patients, those with normal QRS durations or right bundle branch blocks, would

B

100

75 Cardiac resynchonization 50

25

Medical therapy P<0.001

0 0

500

1000

1500

100 Cardiac resynchonization 75

50

Medical therapy

25 P<0.002 0 0

Days No. at Risk 409 Cardiac resynchronization Medical therapy 404

Percentage of Patients Free of Death from Any Cause

Percentage of Patients Free of Death from Any Cause or Unplanned Hospitalization for a Major Cardiovascular Event

A

also derive symptomatic and/or mortality benefit from resynchronization therapy. It has been demonstrated, for example, that left ventricular dyssynchrony assessed by tissue-Doppler imaging is a strong predictor of clinical events in patients with heart failure and normal QRS duration(36). Current ongoing trials evaluating the effectiveness of CRT in patients with normal QRS durations and other features of ventricular dyssynchrony assessed by methods such as echocardiography or MRI should provide valuable information in the future. Furthermore, QRS duration may not be the best predictor of response to cardiac resynchronization, for as many as 30% of patients with a prolonged QRS do not respond to, or even worsen with, biventricular pacing(37,38). The reason for this unpredictable lack of response remains unclear. The optimal site for left ventricular stimulation by the coronary sinus lead is generally assumed to be the posterolateral or lateral wall. Some patients, however, with dyssynchrony demonstrated by echocardiography do not exhibit delayed mechanical contraction at these sites, and it is uncertain whether these patients would derive benefit from biventricular pacing. Those with infarcted scar tissue in the lateral left ventricle may also not respond to pacing at these sites. The efficacy of CRT in atrial fibrillation requires further definition. Atrial fibrillation occurs fre-

500

1000

1500

Days 323

273

166

68

7

292

232

118

48

3

No. at Risk Cardiac resyn409 chronization Medical therapy 404

376

351

213

89

8

365

321

192

71

5

Figure 9.3. Cardiac Resynchronization Heart Failure (CARE-HF). Kaplan-Meier estimates of the time to the primary end point (Panel A) and the principal secondary outcome (Panel B). The primary outcome was death from any cause or an unplanned hospitalization for a major cardiovascular event. The principal secondary outcome was death from any cause (See Color Plates)

9. Device Therapy in Heart Failure

quently in patients with cardiomyopathy, and the prevalence increases in parallel to the severity of heart failure, up to 50% in NYHA class IV patients(39). To date, there have been no large-scale randomized, controlled trials enrolling this population. However, some retrospective and smaller studies have shown benefits of CRT equivalent to those patients in sinus rhythm. The MUSTIC atrial fibrillation trial, for example, included 59 patients with permanent atrial fibrillation and a prolonged QRS duration with an indication for permanent pacing due to bradycardia (29). These patients were randomly assigned to right ventricular only or biventricular pacing in a crossover design. After 6 months, the CRT patients had an increase in 6-min walk distance and peak oxygen consumption compared to the right ventricular-pacing group; these improvements persisted at 1-year follow-up. Optimization of the CRT device may enhance response to this therapy. Current devices have the

223

capability to adjust the timing of both atrioventricular and ventriculo-ventricular stimulation. In sequential atrioventricular-paced hearts, significant extremes of the PR interval may cause functional mitral regurgitation and impair optimal diastolic filling. Optimizing the programmed atrioventricular delay in dual-chamber devices by Doppler echocardiography has been shown to increase cardiac output(40). In addition to atrioventricular timing, interventricular timing may also be important in obtaining maximal benefit from CRT. Some studies have found that varying the timing of sequential left ventricle and right ventricle pacing has an impact on contractile reserve and diastolic filling time(41,42). It is well established that chronic pacing from the right ventricular apex can worsen left ventricular dysfunction. For example, in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, patients were preexisting ventricular dysfunction

Table 9.5. Combined ACC/AHA guidelines on use of cardiac resynchronization therapy in heart failure. 2002 Class I

Class IIa

2005 Patients with LVEF less than or equal to 35%, sinus rhythm, and NYHA functional class III or ambulatory class IV symptoms despite recommended, optimal medical therapy and who have cardiac dyssynchrony, which is currently defined as a QRS duration greater than 0.12 s, should receive cardiac resynchronization therapy unless contraindicated. (Level of Evidence: A)

Biventricular pacing in medically refractory, symptomatic NYHA class III or IV patients with idiopathic dilated or ischemic cardiomyopathy, prolonged QRS interval (greater than or equal to 130 ms), LV end-diastolic diameter greater than or equal to 55 mm, and ejection fraction less than or equal to 35%. (Level of Evidence: A)

LVEF left ventricular ejection fraction, NYHA New York Heart Association, LV left ventricular. Classification of recommendations: Class I: Conditions for which there is evidence for and/or general agreement that a given procedure or treatment is beneficial, useful, and effective. Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful. Level of Evidence A: Data derived from multiple randomized clinical trials or meta-analyses. Level of Evidence B: Data derived from a single randomized trial or nonrandomized studies. Level of Evidence C: Only consensus opinion of experts, case studies, or standard of care.

224

had worse heart failure outcomes with dualchamber pacing compared to backup pacing only(43). The question arises then, whether all patients with left ventricular dysfunction who require permanent pacing for bradyarrhythmias should receive a biventricular device.

9.3.2. Current Recommendations The 2005 ACC/AHA Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult(22) recommends cardiac resynchronization in all patients with LVEF less than or equal to 35%, QRS duration greater than 120 ms, and NYHA functional class III–IV despite optimal medical therapy in sinus rhythm (class I indication) (Table 9.5). This is an update from the 2002 ACC/ AHA/NASPE guidelines for the implantation of antiarrhythmia devices, which gave a class IIa recommendation for biventricular pacing in medically refractory, NYHA class III or IV patients with idiopathic dilated or ischemic cardiomyopathy, prolonged QRS interval greater than or equal to 130 ms, LV end-diastolic diameter greater than or equal to 55 mm, and ejection fraction less than or equal to 35%(21). Most patients who are candidates for a biventricular-pacing device are also candidates for ICD therapy. Of note, NYHA functional class I and II patients are not included in the recommendations for CRT. Furthermore, according to the ACC/ AHA guidelines, QRS duration, not bundle branch morphology or other measures of dyssynchrony, remains the standard for evaluation.

9.4. Conclusion Heart failure is a disease associated with significant morbidity and mortality. Device therapy in the heart failure population has resulted in decreased death rates and an improvement in quality of life for selected patients. Both ICD and CRT devices have significantly decreased mortality from sudden cardiac death and the morbidity associated with advanced heart failure. These therapies have thus become an important adjunct to the medical management of patients with heart failure. This field remains an evolving one, and future trial data are likely to result in new or expanded indications for device therapy in this growing population.

J.J. Shin et al.

References 1. CONSENSUS Investigators. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316(23):1429-1435. 2. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325(5):293-302. 3. Hynes BJ, Luck JC, Wolbrette DL, Boehmer J, Naccarelli GV. Arrhythmias in Patients with Heart Failure. Curr Treat Options Cardiovasc Med. 2002;4(6):467-485. 4. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J Cardiol. 1986;57(3):3B-7B. 5. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335(26): 1933-1940. 6. CABG Patch Trial Investigators. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med. 1997;337(22): 1569-1575. 7. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999;341(25): 1882-1890. 8. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12): 877-883. 9. Bänsch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation. 2002;105(12):1453-1458. 10. Strickberger SA, Hummel JD, Bartlett TG, et al. Amiodarone versus implantable cardioverter-defibrillator:randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia--AMIOVIRT. J Am Coll Cardiol. 2003;41(10): 1707-1712.

9. Device Therapy in Heart Failure 11. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350(21): 2151-2158. 12. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3): 225-237. 13. Hohnloser SH, Kuck KH, Dorian P, et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004;351(24): 2481-2488. 14.Wilber DJ, Zareba W, Hall WJ, et al. Time dependence of mortality risk and defibrillator benefit after myocardial infarction. Circulation. 2004;109(9):1082-1084. 15. Myerburg RJ, Kessler KM, Estes D, et al. Long-term survival after prehospital cardiac arrest: analysis of outcome during an 8 year study. Circulation. 1984;70(4):538-546. 16. Eisenberg MS, Hallstrom A, Bergner L. Long-term survival after out-of-hospital cardiac arrest. NEJM. 1982;306(22):1340-1343. 17. AVID Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID). N Engl J Med. 1997;337(22): 1576-1583. 18. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS) : a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;101(11): 1297-1302. 19. Kuck KH, Cappato R, Siebels J, Rüppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest : the Cardiac Arrest Study Hamburg (CASH). Circulation. 2000;102(7):748-754. 20. Carroll DL, Hamilton GA. Quality of life in implanted cardioverter defibrillator recipients: the impact of a device shock. Heart Lung. 2005;34(3):169-178. 21. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation. 2002;106(16): 2145-2161. 22. Hunt SA, Abraham WT, Chin MH, et al. ACC/ AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult—

225 Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation. 2005;112(12): e154-e235. 23. Kerwin WF, Botvinick EH, O’Connell JW, et al. Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony. J Am Coll Cardiol. 2000;35(5):1221-1227. 24.Yu CM, Chau E, Sanderson JE, et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation. 2002;105(4):438-445. 25. Lau CP, Yu CM, Chau E, et al. Reversal of left ventricular remodeling by synchronous biventricular pacing in heart failure. Pacing Clin Electrophysiol. 2000;23(11pt2):1722-1725. 26. Blanc JJ, Etienne Y, Gilard M, et al. Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation. 1997;96(10):3273-3277. 27. Leclercq C, Cazeau S, Le Breton H, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol. 1998;32(7):1825–1831. 28. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation. 1999;99(12):1567–1573. 29. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the MUltisite STimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol. 2002;40(1): 111-118. 30. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346(24):1845-1853. 31. Higgins SL, Hummel JD, Niazi IK, et al. Cardiac resynchronization therapy for the treatment of heart failure in patients with intraventricular conduction delay and malignant ventricular tachyarrhythmias. J Am Coll Cardiol. 2003;42(8):1454-1459. 32. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. 2003;289(20):2685-2694. 33. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without

226 an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21): 2140-2150. 34. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15): 1539-1549. 35. Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improving survival for patients with atrial fibrillation and advanced heart failure. J Am Coll Cardiol. 1996;28(6):1458-1463. 36. Cho GY, Song JK, Park WJ, et al. Mechanical dyssynchrony assessed by tissue Doppler imaging is a powerful predictor of mortality in congestive heart failure with normal QRS duration. J Am Coll Cardiol. 2005;46(12):2237-2243. 37. Kass DA. Ventricular resynchronization: pathophysiology and identification of responders. Rev Cardiovasc. Med. 2003;4(Suppl 2):S3-S13. 38. Abraham WT. Cardiac resynchronization therapy: a review of clinical trials and criteria for identifying the appropriate patient. Rev Cardiovasc Med. 2003;4(Suppl 2):S30-S37.

J.J. Shin et al. 39. Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, pathophysiology, and rationale for therapy. Am J Cardiol. 2003;91 (6A):2D-8D. 40. Nishimura RA, Hayes DL, Holmes DR Jr, Tajik AJ. Mechanism of hemodynamic improvement by dualchamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol. 1995;25(2):281-288. 41. Sogaard P, Egeblad H, Pedersen AK, et al. Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging. Circulation. 2002;106(16): 2078-2084. 42. Porciani MC, Dondina C, Macioce R, et al. Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol, 2005. Am J Cardiol. 2005;95(9):1108-1110. 43. Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002;288(24):3115-3123.

10 Management of Comorbidities in Heart Failure Chim C. Lang and Donna M. Mancini

10.1. Introduction Heart failure (HF) represents one of the major public health problems faced by healthcare systems worldwide, and continues to grow largely because of the increasing age of the population. HF is the leading diagnosis at hospital discharge for patients 65 years or older, accounting for more than 600,000 Medicare hospital discharges in 19961. Among the more than 1 million patients hospitalized annually for HF in the USA, more than 80% are 65 years or older, and more than 50% are 75 years or older2. The cost of managing HF is increasing mainly as a consequence of frequent and prolonged hospitalization. In most patients, and particularly in elderly patients, HF is accompanied by a range of comorbidities that play an integral role in its progression and response to treatment. Comorbidity is defined as a chronic condition that coexists in an individual with another condition that is being described. A distinction is made between noncardiac comorbidities and cardiac conditions that are directly related to the presence of HF such as arrhythmias as well as conditions that predate and contribute to its etiology such as hypertension, diabetes mellitus, and hyperlipidemia. In this chapter, we will focus on noncardiac comorbidities discussing initially the overall problem of comorbidity in HF. The second section will examine specific comorbidities and how best to manage HF in these patients. The final section will consider the problem of polypharmacy when managing patients with comorbidities.

10.2. Problem of Comorbidities in HF Much of the previous data on the presence and effect of comorbidities on HF were derived from geographically limited studies of relatively small number of patients such as those done in Olmstead County, MN3, and Framingham, MA4, as data from multicenter HF trials are largely derived from younger patients with few or no comorbidities5. More recently, there have been a number of studies utilizing databases to examine the impact of comorbidity in larger groups of elderly patients with HF (6–9). Utilizing data from 27,477 Scottish morbidity records listing HF, Brown and Cleland6 reported that 11.8% of admissions were associated with chronic airways obstruction, 8.3% with chronic or acute renal failure, and 5.3% with cerebrovascular accident. In the USA, the National Heart Failure (NHF) project, an effort by the Centers for Medicare & Medicaid Services, found that comorbidity was common among 34,587 Medicare patients aged 65 years or older hospitalized with a principal diagnosis of HF between April 1998 and March 199910. About a third (32.9%) had chronic obstructive pulmonary disease (COPD), 18% had a history of stroke, and 9.2% had dementia. More recently, Braunstein and colleagues reported the findings of a cross-sectional analysis of 122,630 individuals aged 65 years or older with HF identified through a 5% random sampling of all US Medicare beneficiaries11. Nearly 40% of patients with HF had 5 or more noncardiac comorbidities

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Table 10.1. Twenty most common noncardiac chronic disease conditions for patients aged older than 65 years with heart failure (n = 122,630). Chronic disease defined by CCS code Essential hypertension Diabetes mellitus COPD and bronchiectasis Ocular disorders (retinopathy, macular disease, cataract, glaucoma) Hypercholesterolemia Peripheral and visceral atherosclerosis Osteoarthritis Chronic respiratory failure/insufficiency/arrest or other lower respiratory tract disease excluding COPD/bronchiectasis Thyroid disorders Hypertension with complications and secondary hypertension Alzheimer’s disease/dementia Depression/affective disorders Chronic renal failure Prostatic hyperplasia Intravertebral injury, spondylosis, or other chronic back disorders Asthma Osteoporosis Renal insufficiency (acute and unspecified renal failure) Anxiety, somatoform disorders, and personality disorder Cerebrovascular disease, late effects

% Prevalence (n) 55 (68.211) 31 (38.175) 26 (32.275) 24 (29.548) 21 (25.219) 16 (20.027) 16 (19.929) 14 (17.610) 14 (16.751) 11 (13.732) 9 (10.839) 8 (9.371) 7 (8.652) 7 (8.077) 7 (8.469) 5 (6.717) 5 (6.688) 4 (5.259) 3 (3.978) 3 (3.750)

COPD, chronic obstructive pulmonary disease. Source: With permission from Braunstein et al.11. Copyright 2003, with permission from Elsevier.

Prevealence Frequency

1.0

CHF ACSC Any ACSC Any Hospitalization

0.8

0.6

0.4

0.2

0.0 0

Overall 1 2 3 4 5 6 7 8 9 10+ Non-Cardiac Chronic Dlsease Comorbidities

Figure 10.1. Impact of noncardiac comorbidity burden on the annual probability of a Medicare beneficiary with heart failure (HF) experiencing a hospitalization due to any cause, a preventable hospitalization, or a preventable hospitalization due to HF. p < 0.0001 for linear trend for all outcomes. ACSC, ambulatory care sensitive conditions. With permission from Braunstein et al.11. Copyright 2003, with permission from Elsevier

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and this group accounted for 81% of the total inpatient hospital days experienced by patients with HF. The most common noncardiac conditions were COPD/bronchiectasis (26%) and osteoarthritis (16%) (Table 10.1). The risk of hospitalization and potentially preventable hospitalizations strongly increased with the number of chronic conditions (Figure 10.1). After controlling for demographic factors and other diagnoses, comorbidities that were associated consistently with higher risks for HF hospitalizations and mortality included COPD/ bronchiectasis, renal failure, diabetes, depression, and lower respiratory tract diseases. Several reasons may explain why older HF patients with greater comorbidity may experience more adverse events that lead to preventable hospitalizations (Table 10.2). These include underutilization of effective HF therapies in the presence of other conditions because of safety concerns [e.g., use of beta-blockers in asthma or angiotensinconverting enzyme (ACE) inhibitors in renal insufficiency], patient nonadherence to or inability to recall complex medication regimens, inadequate postdischarge care, failed social support, and failure to promptly seek medical attention during symptom recurrence. Psychological stress from chronically poor health may also predispose to worse outcomes. Finally, elderly patients with multiple comorbidities and polypharmacy are also susceptible to poor coordination of care and at increased risk for experiencing adverse drug reactions from drug–drug interactions. Table 10.2. Possible reasons that lead to hospitalization in elderly heart failure patients with multiple comorbidities. 1. Underutilization of effective HF therapies in the presence of other conditions because of safety concerns (e.g., use of beta-blockers in asthma or angiotensin-converting enzyme inhibitors in renal insufficiency) 2. Patient nonadherence 3. Patient inability to recall complex medication regimens 4. Inadequate postdischarge care 5. Failed social support 6. Failure to promptly seek medical attention during symptom recurrence 7. Psychological stress from chronically poor health 8. Poor coordination of care 9. Polypharmacy with increased risk of adverse drug reactions from drug–drug interactions HF, heart failure.

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The association between comorbidity and healthcare costs has also been examined in a Medicare healthcare expenditure study12. HF patients with expensive comorbidities included those with chronic obstructive pulmonary disease (COPD) (33% of patients, mean total expenditure $23,104 per patient), renal disease (8% of patients, mean total expenditure $33,014 per patient), rheumatologic disease (5% of patients, $20, 527 per patient), and dementia (15% of patients, $26, 263 per patient).

10.3. Management of Specific Noncardiac Comorbidity 10.3.1. Respiratory Disorders The interaction between HF and concomitant respiratory tract disease is important. Many patients with HF are misdiagnosed as having airflow obstruction on the basis of overlapping symptoms (and vice versa). In patients presenting to the emergency department with dyspnea, brain natruretic peptide (BNP) has been shown to be useful in improving the diagnostic accuracy of HF13. Recently, in a controlled study of NT-proBNP use in 305 patients presenting to their family practitioners with symptoms and/or signs of HF14, this test also proved useful, in particular when the result was normal. Further examination of these patients with a normal BNP showed that they did not have HF. When both HF and respiratory disorders coexist, it is important to quantify the relative contribution of cardiac and pulmonary components to the disability. Exercise testing with simultaneous gas exchange or blood gas measurements may be helpful in this regard, particularly when used in conjunction with right heart catheterization15. Optimum assessment and management of these patients requires careful consideration of the possibility that cardiac and respiratory tract disease may coexist in the individual patient. Some drugs used to treat HF can produce or exacerbate pulmonary symptoms. ACE inhibitors can cause a persistent nonproductive cough that can be confused with a respiratory infection, and conversely, ACE inhibitors may be inappropriately stopped in patients with pulmonary causes of cough. Indeed, ACE-related cough occurs in less than 10% of patients receiving these agents. Persistent cough, particularly nocturnal cough, in

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patients with HF more frequently reflects worsening volume overload rather than a pulmonary or ACE-related cough. However, persistent cough which does not clear despite increased diuretic therapy warrants further investigation. Therefore, physicians should seek a pulmonary cause in all patients with HF who complain of cough, whether or not they are taking an ACE inhibitor. The cough should be attributed to the ACE inhibitor only if respiratory disorders have been excluded and the cough disappears after cessation of ACE inhibitor therapy and recurs after reinstitution of treatment.

10.3.1.1. Obstructive Airways Disease Beta-blockers are thought to be contraindicated in patients with HF and airflow obstruction. In practice, because of the overwhelming benefits of these agents in systolic HF, many patients with fixed or limited airways reversibility are treated with betablockers and tolerate them surprisingly well16. Whether beta-1-selective agents offer advantages over nonselective agents, such as carvedilol, is not clear17. Cardioselective beta-blockers given to patients with mild–moderate reversible airway disease or COPD do not produce adverse respiratory effects in the short term. Given their demonstrated benefit in HF, these agents should not be withheld from such patients, but long-term safety (especially their impact during an acute exacerbation) still needs to be established.

10.3.1.2. Sleep-Disordered Breathing There has been increasing interest in the role of sleep-disordered breathing (SDB) in patients with HF. It is of significance that both HF and SDB constitute multisystem disorders involving respiratory, cardiovascular, and neurohumoral axes. Two major types of SDB observed in HF patients are obstructive sleep apnea (OSA) and central sleep apnea (CSA). These operate through different pathophysiological mechanisms, although they can coexist and interact18. While often neglected in clinical practice they have recently been gaining recognition on the basis of their clinical relevance19. OSA, likely a risk factor for cardiovascular disease20,21, may also contribute to both the development and the progression of HF. Moreover, OSA shares with HF many aspects of deranged neurohumoral and

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immunological function. CSA, on the other hand, may be a consequence of HF22,23, but when present may increase the arrhythmic risk24 and impair prognosis25,26. The prevalence of SDB in patients with HF is extremely high, ranging from 45 to 82%. This wide range in prevalence likely reflects differences in the study populations (ambulatory vs. hospitalized, time from the last instabilization and pharmacological regimen, inclusion or exclusion of obese subjects), and the different diagnostic criteria for sleep apnea, such as the apnea-hypopnea index (AHI) cutoff27-30. The prevalence of OSA is not dissimilar to that reported in the normal population31, although OSA tends to be more frequent in newly diagnosed patients with a recent episode of acute decompensation30, in selected patients with suspected sleep apnea32, and in patients with HF secondary to isolated diastolic dysfunction28. The prevalence of CSA, which ranges from 40 to 63%, is also high, suggesting a special link between this breathing disorder and HF. 10.3.1.2.1. Treatment of CSA Hemodynamic improvement following medical treatment is often associated with a significant improvement in the nocturnal breathing pattern22,33. In patients with persistent SDB, especially when CSA is associated with marked desaturations and refractory HF, a specific treatment of the breathing disorder should be considered. The evidence of prolonged benefit of early treatment of CSA by continuous positive airway pressure (CPAP), persisting even after withdrawal of therapy, raises the question of whether to start treatment in all patients at the time of initial diagnosis of CSA. Several therapeutic approaches have been shown to be potentially effective in reducing CSA in HF (Table 10.3).

Table 10.3. Therapeutic approaches for treating central sleep apnea. 1. Nocturnal nasal CPAP 2. Adaptive servo-ventilator 3. Nocturnal O2 supplementation 4. Theophylline 5. Overdrive pacing CPAP, continuous positive airway pressure.

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10.3.1.2.2. Nocturnal Nasal CPAP

10.3.1.2.4. Nocturnal Oxygen Supplements

Nocturnal nasal CPAP may result in a 50% reduction in central respiratory events, and attenuation of the associated arousals and oxygen desaturations34-36. Hemodynamic improvement, increased lung volumes, and slight increases in carbon dioxide above the apnea threshold are some of the possible mechanisms invoked to explain the effectiveness of CPAP in reducing CSA in HF. Trials of CPAP have also shown an improvement in ventricular function37, autonomic dysfunction in terms of baroreflex sensitivity38, and in the plasma and urinary levels of norepinephrine35. These effects, in particular those on ventricular function, persist after the treatment has been withdrawn, suggesting that either remodeling of the left ventricle or a resetting of neural circulatory control mechanisms has occurred. The benefits seem to translate into an improved prognosis. Encouraging, although preliminary, data indicated that CPAP may improve transplant-free survival in patients with CSA. Sin and colleagues33 reported that the mortality rate in treated patients (n = 12) was 25% versus 56% in untreated patients (n = 15) (p = 0.017). The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial randomized 258 patients [mean age 63, left ventricular ejection fraction (LVEF) 25%] to receive CPAP or no CPAP for up to 2 years. Although CPAP had an early beneficial effect on SDB and norepinephrine levels, there were no differences between the groups in transplant-free survival39. Unfortunately, only a fraction of patients with CSA seem to respond to treatment with CPAP (43%)40.

Although the rationale for using oxygen (O2) supplements in CSA is not clear, it has been hypothesized that O2 may stabilize the breathing by removing any enhancement of the hypercapnic chemoreflex and attenuating any independent influence of hypoxic chemoreflex activation on the hyperventilatory response42. Oxygen has been shown by several groups to be effective in reducing the number of central respiratory events and improving oxygen saturation43,44, and, in the long term, reducing the overnight urinary excretion of norepinephrine45. In a crossover study of HF patients in NYHA functional class IV46, singlenight treatments with O2 supplements and nasal CPAP were equally effective in decreasing the AHI arousal index and degree of desaturation. While a clear advantage of O2 is the greater acceptability by the patients, data on the effect of nocturnal O2 on long-term clinical and functional end points are not currently available. Interesting results have been shown with oral theophylline, which, in the short term, resulted in a 50% reduction in AHI and related arousals47. Among the potential mechanisms, an increased inotropic effect and a direct stimulation (and stabilization) of the central ventilatory drive have been invoked as playing a role in reducing the respiratory events. Data on long-term efficacy and safety are not available at present. Finally, overdrive pacing has been shown to elicit a 60% reduction in both central and obstructive apneas in a small group of highly selected patients with symptomatic sinus bradyarrhythmias and coexisting sleep apnea48. While interesting, these results should be considered preliminary. A generalization of the results to other categories of patients with sleep apnea is uncertain remains unproven.

10.3.1.2.3. Adaptive Servo-Ventilator A novel and promising approach designed for the treatment of CSA in HF is the adaptive servoventilator which provides a baseline degree of ventilatory support, where the subject’s ventilation is servo-controlled to maintain the ventilation at 90% of the long-term average41. In a crossover trial conducted in 14 patients with New York Heart Association (NYHA) class II–III HF, this approach provided an additional 83% reduction in central apneas when compared with nasal CPAP, and was better tolerated.

10.3.2. Renal Dysfunction in HF The close relation between cardiovascular and renal function in normal physiology is also apparent in disease; renal dysfunction may develop secondary to cardiac disease or vice versa. As a consequence of accelerated atherosclerotic coronary artery disease, concomitant hypertension, and fluid retention, patients with primary renal disease are at high risk of HF49. In the Third National Health

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and Nutrition Examination Study (NHANES III), which represents a cross-sectional sample of the US population aged 18-64, renal dysfunction was defined as a serum creatinine level greater than 1.7 mg/dl for women and greater than 2.0 mg/dl for men. In those with renal dysfunction, 27.6% had HF compared with only 1.8% of those without renal dysfunction50. Conversely, many patients with HF have evidence of kidney dysfunction in the absence of intrinsic renal disease. One-half or more of patients with HF have chronic kidney disease (CKD), defined as a serum creatinine level of 1.5 mg/dl or more or a creatinine clearance rate of less than 60 ml/min51. The observed low glomerular filtration rate in chronic HF is a consequence of diminished cardiac output, with decreased renal perfusion and intrarenal vasoconstriction accompanied by sodium and water retention51. Indeed, given the relation between renal function and cardiac output, renal dysfunction is not surprisingly an adverse prognostic marker52.

10.3.2.1. Heart Failure Therapy in Patients with Renal Dysfunction The effects of cardiovascular medications in HF patients with renal dysfunction have not been well studied53. Patients with renal hypoperfusion or intrinsic renal disease show an impaired response to diuretics and ACE inhibitors54,55 and are at increased risk of adverse effects during treatment with digoxin. Most HF trials have studied patients with relatively preserved renal function with only a few reporting subgroup analysis of patients with renal dysfunction. In the second Cardiac Insufficiency Bisoprolol Study (CIBIS II), patients with moderate to severe renal failure had a similar reduction in mortality and hospitalization with bisoprolol treatment compared to those with normal renal function56. Perhaps the most impressive effect of a beta-blocker in HF and end-stage renal disease (ESRD) was recently reported by Cice et al.57. A total of 114 dialysis patients with dilated cardiomyopathy were randomized to receive either carvedilol or placebo in addition to standard therapy. At 2 years, the carvedilol group had smaller cavity diameters in both systole and diastole and had higher ejection fractions. By 2 years, 52% of the patients in the carvedilol group had died

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compared with 73% in the placebo group. There were significantly fewer cardiovascular deaths and fewer hospital admissions among the patients receiving carvedilol. These data strongly support the use of beta-blockers in HF patients with CKD. In view of the extremely high cardiovascular morbidity and mortality in CKD and ESRD, there is clearly a need for routine use of such cardioprotective agents in patients with cardiovascular disease. Since the renal vasoconstriction that develops in the setting of reduced cardiac output depends on angiotensin II, treatment with an ACE inhibitor or angiotensin-receptor blocker commonly leads to an increase in the serum creatinine concentration. Generally, these rises in serum creatinine levels are small and reversible, and are infrequently the cause of drug discontinuation. Most patients with HF tolerate mild to moderate degrees of functional renal impairment without difficulty. However, if the serum creatinine level increases to more than 2.5 mg/dl, the presence of renal insufficiency can severely limit the efficacy and enhance the toxicity of established treatments. An arbitrary creatinine cutoff value to define renal insufficiency (serum creatinine level > 2.5 mg/dl) for spironolactone has been suggested in published guidelines19. However, this may not be appropriate in the elderly because of the competing age-related decline in creatinine as a result of decline in muscle mass and rise in creatinine as a result of decline in glomerular filtration rate. In a prescription-linked study, Juurlink and colleagues58 found that immediately after the publication of the Randomized Aldactone Evaluation Study (RALES), the prescription rate in Canada rose sharply and was associated with an increase in the rate of admission for hyperkalemia, from 2.4 per 1,000 patients in 1994 to 11.0 per 1,000 patients in 2001 (p < 0.001). In addition, hyperkalemia-associated mortality rose from 0.3 per 1,000 patients to 2.0 per 1,000 patients (p < 0.001). However, it should be noted that there were several differences between this “real patient” population and the cohort in the RALES trial. These older patients received a higher dose of spironolactone without close attention to serum creatinine or follow-up. In another study of 125 elderly patients with HF who were followed on spironolactone, 36% of the patients developed hyperkalemia (>5 mmol/l, with 10% having serum potassium levels greater than

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6 mmol/l59. An increase of more than 20% in serum creatinine level was seen in 55%, and an increase of more than 50% was found in approximately onequarter. These alterations in serum creatinine and potassium levels were not more frequent in patients treated with ACE inhibitors or beta-blockers or different doses of spironolactone. The authors recommended that1 particular caution is mandated in elderly patients with an left ventricular ejection fraction less than 20%,2 potassium supplementation should be discontinued,3 changes in body weight should raise concern, and4 dose-adjustment of concomitant diuretics should be considered. Care should be also be given to frequent monitoring of electrolytes and renal parameters. In patients with a serum creatinine level greater than 5 mg/dl, hemofiltration or dialysis may be needed to control fluid retention, minimize the risk of uremia, and allow the patient to respond to and tolerate the drugs routinely used for the management of HF19.

10.3.3. Anemia Anemia has recently been recognized as an important comorbid condition and potentially novel therapeutic target in patients with HF. Anemia is common in HF patients, with a prevalence ranging from 4 to 55%60. Reasons for this wide variation include differences in the HF population studied and in the study methods and definition of anemia used. Although the most commonly accepted definition of anemia is that of the World Health Organization (Hb level < 13 g/dl in men or < 12 g/dl in women), studies have varied considerably in the criteria used to classify patients as anemic. In general, the prevalence of anemia is greater in less-selected populations (such as claims data) and lower in highly selected populations such as patients enrolled in clinical trials. Anemia appears to be more common in patients with more severe disease, with a reported prevalence in patients with NYHA functional class IV HF as high as 79%. Patients hospitalized with HF have significantly higher rates of anemia than outpatient populations. Multiple potential mechanisms of interaction exist between anemia and the clinical syndrome of HF. Heart failure is a disease of the elderly, a population where the prevalence of anemia is high irrespective of cardiac status. Multiple

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comorbid conditions are common in HF patients, in particular renal insufficiency, which is closely associated with the development of anemia. Other potential contributing factors include hemodilution, proinflammatory cytokines, malnutrition due to right-sided HF, decreased perfusion to the bone marrow, and drug therapy (such as ACE inhibitors). With respect to hemodilution, expansion of plasma volume is a hallmark of the HF syndrome, and, therefore, some anemia may be dilutional rather than due to a true decrease in red blood cell mass. In a recent study of 37 HF patients, we found that true anemia (i.e., a decrease in red blood cell mass) was present in 54% and hemodilution was present in 46%. Notably, in this study both hemodilution and true anemia were associated with adverse outcomes, with the worst survival seen in patients with hemodilution61. In the general population, it is likely that several of these mechanisms are active simultaneously, and that anemia in HF is the result of a complex interaction between cardiac performance, neurohormonal and inflammatory activation, renal function, and bone marrow responsiveness. This interplay has been termed by some the “cardiorenal-anemia syndrome”62. A prospective ongoing study including both specialty and community sites [the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry] is evaluating the prevalence, etiologies, and mechanisms of anemia in a broad population of HF patients63. A growing body of literature from observational databases and clinical trials suggests that anemia is an independent risk factor for adverse outcomes in patients with HF64,65. The increasing recognition of this association has led to substantial interest in anemia as a potential therapeutic target in HF. Preliminary data involving small groups of patients suggest that treatment of anemia may result in significant symptomatic improvement in HF66-68. We evaluated the effect of 3 months of erythropoietin treatment on exercise capacity in a single-blind, placebo-controlled study of 26 patients with anemia and NYHA class III–IV HF68. Erythropoietin treatment resulted in significant improvements in peak oxygen consumption (Vo2 max) [from 11 ± 0.8 to 12.7 ± 2.8 ml/kg/min (p < 0.05) vs. no significant change in the control group, Figure 10.2]. A significant correlation was observed between elevations in Hb with erythropoietin treatment and

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(such as iron deficiency or occult blood loss) and subsequent treatment, if identified, is appropriate in all patients. Although pilot data on the treatment of anemic HF patients with erythropoietin analogs are promising, the studies published thus far have been significantly limited by very small sample size, lack of blinding, and the use of subjective end points. More carefully controlled clinical trials will be required before treatment of anemia can be considered a viable therapy in HF.

10.3.4. Cognitive Dysfunction and Depression 10.3.4.1. Cognitive Dysfunction

Figure 10.2. The effect of erythropoietin on peak oxygen consumption (Vo2) in the treated (lower panel) and control (upper panel) groups [with permission from Mancini et al.68]. Copyright 2003 American Heart Association. All rights reserved

increased Vo2. Notably, the improvement in exercise performance with erythropoietin was observed whether the anemia was found to be from decreased red blood cell mass or from hemodilution. Newer erythropoietin analogs have been developed (such as darbepoetin alfa) that have a longer half-life and require less frequent administration, potentially making them more attractive for HF therapy. However, it should be noted that aggressive treatment of anemia may also be associated with increased risk of hypertension or thrombosis. Multiple ongoing studies will provide definitive data on the balance of risks and benefits of anemia treatment in chronic HF. The STAMINA HeFT study is an ongoing double-blind, placebo-controlled trial of about 300 HF patients with anemia (defined as a Hb level <12 g/dl) who will be randomized to treatment (subcutaneous injections every 2 weeks for 1 year) with darbepoetin alfa (Aranesp) or placebo. Exercise treadmill tests will be performed at baseline and again at 13 and 27 weeks. Change in functional status will be the primary end point. At present there is insufficient data to make a general recommendation for aggressive treatment of anemia in patients with HF. A diagnostic evaluation for potentially reversible causes of anemia

Cognitive dysfunction frequently coexists with HF69. Reduced cardiac output from HF may further compromise cerebral blood flow in a patient with borderline cerebral perfusion. Additionally, chronic HF is largely driven by vascular disease and cerebrovascular disease is an important contributor to multi-infarct dementia. Measures of cognitive function have rarely been used in HF trials, unlike recent hypertension trials. Given the consistent reporting of impaired cognitive function in cross-sectional studies of patients with HF, this should be considered as an end point for future trials of HF pharmacotherapy.

10.3.4.2. Depression and HF The prevalence rates of depression in patients with HF range from 13 to 77%70-72. Depression is a graded, independent risk factor for several adverse outcomes, including decreased compliance with treatment recommendations73, and increases in healthcare costs74, hospital admissions75, and mortality rates76,77. If desired, physicians can readily assess depression by using any of a number of easily administered and scored self-report inventories such as the Geriatric Depression Scale, the Zung Self-Rating Depression Scale, the Beck Deptession Inventory II (BDI-II), and the Center for Epidemiologic Studies Depression Scale (CES-D). All tools are written at third- to fifth-grade reading levels and can be used to monitor the patient’s response to treatment. These instruments are useful in screening for depression and assessing the severity of depressive symptoms, but they are not substitutes

10. Management of Comorbidities in Heart Failure

for a diagnostic interview conducted by a mental health professional. All positive screening tests should precipitate full interviews incorporating standard diagnostic criteria to determine the presence of specific depressive disorders. Cognitive-behavior therapy is the preferred psychological treatment. Cognitive-behavior therapy emphasizes the reciprocal interactions among physiology, environmental events, thoughts, and behaviors, and how these may be altered to produce changes in mood and behavior. Pharmacologically, the selective serotonin reuptake inhibitors are recommended, whereas the tricyclic antidepressants are not recommended for depression in HF patients. Consideration should also be given to potential interactions between antidepressant medications and those commonly used in the treatment of HF. For example, the tricyclics, as well as fluoxetine, paroxetine, and sertraline, have been reported to interact with warfarin to elevate prothrombin time. The combination of a selective serotonin reuptake inhibitor with cognitive-behavior therapy is often the most effective treatment for depression.

10.3.5. Arthritis Many patients with chronic HF are older and have other noncardiovascular disorders of this age-group. Arthritis is one such disorder, and its treatment influences HF status. Both nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective inhibitors, widely prescribed to patients with arthritis, are associated with potentially significant cardiovascular adverse effects78,79. Sodium and water retention with these agents may adversely affect volume status80 partly because of activation of vasodilator prosatglandins such as E2 and I2. The role of the prostaglandin inhibitor aspirin in attenuating the beneficial effects of renin–angiotensin blockade in chronic HF is highly controversial81,82. There is new concern regarding the use of certain cyclooxygenase-2 inhibitors which may be prothrombotic and could have an unfavorable effect in chronic HF, particularly with an ischemic etiology83. Inhibition of tumor necrosis factor (TNF)-α, now an established therapy for rheumatoid arthritis and other autoimmune disorders84, has been studied in patients with HF. Blockade of this cytokine in chronic HF is based on its multifaceted contribution to progression of this disease. However,

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neither the TNF-receptor fusion protein etanercept nor the monoclonal antibody infliximab resulted in beneficial outcomes in this clinical setting and there was a trend toward worsening HF85.

10.3.6. Obesity Obesity is an increasingly prevalent condition that has been associated with increased cardiovascular risk, including increased risk of developing HF86. Based on the associations of obesity with cardiac structural and hemodynamic alterations, as well as case reports of reversal of cardiomyopathy with weight loss, obesity has been presumed to have a deleterious effect in patients with HF. However, several recent studies have shown that in patients with established HF, obesity is not associated with increased mortality, but rather with improved survival87-90. Weight gain from fat or muscle in HF patients on therapy may reflect diminished activation of the neurohumoral system, an enhanced protection against endotoxin/inflammatory cytokines, and/or an increased nutritional and metabolic reserve as a consequence of effective treatment. Further investigations into the relationship between obesity and the progression of HF are necessary. Ultimately, clinical trials are needed to provide definitive guidance to the management of obese and overweight HF patients.

10.4. Comorbidity and Polypharmacy In the HF patient with complex comorbidities, physicians typically face the challenge of managing several conditions requiring multiple medications. Unfortunately, little evidence is available to guide polypharmacotherapy in patients with HF and multiple comorbidities. Given the lack of data, how should one approach polypharmacy in HF? Collaborative disease management programs that include the careful review of medication lists have been shown to reduce hospital admission rates and costs of care91. Whenever possible, patients with HF with multiple competing comorbidities and polypharmacy should be enrolled in such programs. Regardless of the availability of disease management, clinicians need to have systems in place to

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review medication lists carefully at every outpatient visit, with the goal of eliminating medications that are not known to provide a clear benefit. When initiating new medications, particular attention needs to paid to the possibility of adverse drug interactions. In treating coexisting conditions many commonly used medications need to be avoided whenever possible in patients with HF, based on known pharmacological principles and recommendations from guidelines. For example, thiazolidinediones are not recommended in patients with diabetes with advanced symptomatic HF because they cause fluid retention and may exacerbate HF. In patients with renal dysfunction, drug dosages need to be adjusted appropriately for the estimated glomerular filtration rate, with the appreciation that serum creatinine may provide an overly optimistic estimate of renal function, particularly in elderly women.

10.5. Conclusions In conclusion, noncardiac comorbidity frequently complicates HF care particularly in elderly patients who are most likely encountered in clinical practice. Underrepresentation of patients with comorbidities in large HF clinical trials makes generalization of trial findings to these patients somewhat difficult. Clinical research must adapt to ensure its relevance, and trials need to include not just young patients with systolic dysfunction and little comorbidity. Ongoing studies enrolling the often ignored group of patients with preserved systolic function92 are an encouraging development but only represent the beginning of a necessary trend. Future trials must also focus on optimal strategies for the comprehensive management of the patient with HF rather than the isolated effects of single drugs. At this time, cardiologists and/or primary care physicians caring for HF patients with comorbidities should be more aware of those conditions that complicate care, and reduce quality of life and functional status. Improved communications with other specialists or providers is needed when quality of care seems suboptimal. The introduction of multidisciplinary disease management teams should be encouraged. Given the steady rise in HF incidence and prevalence in an aging population, optimizing outcomes for this high-risk population is a public health priority.

C.C. Lang and D.M. Mancini

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237 patients with congestive heart failure. Am J Respir Crit Care Med. 1996;153:272-276. 26. Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G, Colombo R, Donner CF, Gianuzzi P. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation. 1999;99:14351440. 27. Lofaso F, Verschueren P, Rande JHD, Harf A, Goldenberg F. Prevalence of sleep-disordered breathing in patients on a transplant waiting list. Chest. 1994;106:1689-1694. 28. Chan JJ, Sanderson J, Chan W, Lai C, Choy D, Ho A, Leung R. Prevalence of sleep-disordered breathing in diastolic heart failure. Chest. 1997;111:1488-1493. 29. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation. 1998;97:2154-2159. 30. Tremel F, Pepint JL, Veale D, Wuyam B, Siche JP, Mallion JM, Levy P. High prevalence and persistence of sleep apnea in patients referred for acute left ventricular failure and medically treated over 2 months. Eur Heart J. 1999;20:1201-1209. 31. Young T, Palta M, Dempsey J, Skarrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. New Engl J Med. 1993;328:1230-1235. 32. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med. 1999;160:1101-1106. 33. Walsh JT, Andrews R, Starling R, Cowley AJ, Johnston ID, Kinnear WJ. Effects of captopril and oxygen on sleep apnoea in patients with mild to moderate congestive heart failure. Br Heart J. 1995;73:237-241. 34. Krachman SL, Crocetti J, Berger TJ, Chatila W, Eisen HJ, D’Alonzo GE. Effects of nasal continuous positive airway pressure on oxygen body stores in patients with Cheyne-Stokes respiration and congestive heart failure. Chest. 2003;123:59-66. 35. Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med. 1995;152:473-479. 36. Naughton MT, Liu PP, Benard DC, Goldstein RS, Bradley TD. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med. 1995;151:92-97. 37. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in

238 patients with heart failure and obstructive sleep apnea. N Engl J Med. 2003;348:1233-1241. 38. Tkacova R, Dajani HR, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Continuous positive airway pressure improves nocturnal baroreflex sensitivity of patients with heart failure and obstructive sleep apnea. J Hypertens. 2000;18:1257-1262. 39. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353:2025-2033. 40. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation. 2000;101:392-397. 41. Teschler H, Döhring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation. A novel treatment for Cheyne–Stokes respiration in heart failure. Am J Respir Crit Care Med. 2001;164:614-619. 42. Francis DP, Willson K, Davies CL, Coats AJ, Piepoli M. Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications. Circulation. 2000;102:2214-2221. 43. Hanly PJ, Millar TW, Steljes DG, Baert R, Frais MA, Kryger MH. The effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med. 1989;111:777-782. 44. Franklin KA, Eriksson P, Sahlin C, Lundgren R. Reversal of central sleep apnea with oxygen. Chest. 1997;111:163-169. 45. Staniforth AD, Kinnear WJ, Starling R, Hetmanski DJ, Cowley AJ. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and CheyneStokes respiration. Eur Heart J. 1998;19:922-928. 46. Krachman SL, D’Alonzo GE, Berger TJ, Eisen JE. Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure. Chest. 1999;116:1550-1557. 47. Javaheri S, Parker TJ, Wexler L, Liming JD, Lindower P, Roselle GA. Effect of theophylline on sleep-disordered breathing in heart failure. New Engl J Med. 1996;335:562-567. 48. Garrigue S, Bordier P, Jais P, Shah DC, Hocini M, Raherison C, Tunon De Lara M, Haissaguerre M, Clementy J. Benefit of atrial pacing in sleep apnea syndrome. New Engl J Med. 2002;346:404-412. 49. Ruilope LM, van Veldhuisen DJ, Ritz E, Luscher TF. Renal function: The Cinderella of cardiovascular risk profile. J Am Coll Cardiol. 2001;38:1782-1787. 50. Obrador GT, Pereira BJG, Kausz AT. Chronic kidney disease in the United States. Semin Nephrol. 2002;22:441-448. 51. Hillege HL, Girbes AR, de Kam PJ, et al. Renal function, neurohormonal activation, and survival

C.C. Lang and D.M. Mancini in patients with chronic heart failure. Circulation. 2000;102:203-210. 52. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35:681-689. 53. Shlipak MG. Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med. 2003;138:917-924. 54. Risler T, Schwab A, Kramer B, Braun N, Erley C. Comparative pharmacokinetics and pharmacodynamics of loop diuretics in renal failure. Cardiology. 1994;84(Suppl 2):155-161. 55. Philbin EF, Santella RN, Rocco TA Jr. Angiotensinconverting enzyme inhibitor use in older patients with heart failure and renal dysfunction. J Am Geriatr Soc. 1999;47:302-308. 56. Erdmann E, Lechat P, Verkenne P, et al. Results from post-hoc analyses of the CIBIS II trial: Effect of bisoprolol on high-risk patient groups with chronic heart failure. Eur J Heart Fail. 2001;3:469-479. 57. Cice G, Ferrara L, D’Andrea A, et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy. J Am Coll Cardiol. 2003;41:448-454. 58. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351:543-545. 59. Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D. How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? J Card Fail. 2004;10:297-303. 60. Felker GM, Adams KF Jr, Gattis WA, O’Connor CM. Anemia as a risk factor and therapeutic target in heart failure. J Am Coll Cardiol. 2004;44:959-966. 61. Androne AS, Katz SD, Lund L, et al. Hemodilution is common in patients with advanced heart failure. Circulation. 2003;107:226-229. 62. Silverberg DS. Outcomes of anaemia management in renal insufficiency and cardiac disease. Nephrol Dial Transplant. 2003;18:7-12. 63. Adams KF, Patterson JH, Pina I, et al. STAMINAHFP (Study of Anemia in a Heart Failure Population) registry: Rationale, design, and patient characteristics. J Card Fail. 2003;9:73. 64. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. J Am Coll Cardiol. 2002;39:1780-1786.

10. Management of Comorbidities in Heart Failure 65. Felker GM, Gattis WA, Leimberger JD, et al. Usefulness of anemia as a predictor of death and rehospitalization in patients with decompensated heart failure. Am J Cardiol. 2003;92:625-628. 66.Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol. 2000;35:1737-1744. 67. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: A randomized controlled study. J Am Coll Cardiol. 2001;37:1775-1780. 68. Mancini DM, Katz SD, Lang CC, Lamanca J, Hudaihed A, Androne AS. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation. 2003;107:294-299. 69. Scall RR, Petrucci RJ, Brozena SC, Cavarocchi NC, Jessup M. Cognitive function in patients with symptomatic dilated cardiomyopathy before and after cardiac transplantation. J Am Coll Cardiol. 1989;14:1666-1672. 70. Murberg TA, et al. Functional status and depression among men and women with congestive heart failure. Int J Psychiatry Med. 1998;28:273-291. 71. Vaccarino V, et al. Depressive symptoms and risk of functional decline and death in patients with heart failure. J Am Coll Cardiol. 2001;38:199-205. 72. Thomas SA, et al. Depression in patients with heart failure: Physiologic effects, incidence, and relation to mortality. AACN Clin Issues. 2003;14(1):3-12. 73. Evangelista LS, et al. Relationship between psychosocial variables and compliance in patients with heart failure. Heart Lung. 2001;30(4):294-301. 74.Sullivan M, et al. Depression-related costs in heart failure care. Arch Intern Med. 2002;162(16):1860-1866. 75. Bennett SJ, et al. Psychosocial variables and hospitalization in persons with chronic heart failure. Prog Cardiovasc Nurs. 1997;12:4-11. 76. Murberg TA, et al. Depressed mood and subjective health symptoms as predictors of mortality in patients with congestive heart failure: A two-years follow-up study. Int J Psychiatry Med. 1999;29(3):311-326. 77. Guck TP, Elsasser GN, Kavan MG, Barone EJ. Depression and congestive heart failure. Congest Heart Fail. 2003;9:163-169. 78. Feenstra J, Grobbee DE, Mosterd A, Stricker BH. Adverse cardiovascular effects of NSAIDs in patients with congestive heart failure. Drug Saf. 1997;17: 166-180.

239 79. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: An underrecognized public health problem. Arch Intern Med. 2000;160:777-784. 80. Harris CJ, Brater DC. Renal effects of cyclooxygenase-2 selective inhibitors. Curr Opin Nephrol Hypertens. 2001;10:603-610. 81. Cleland JGF. Anticoagulant and antiplatelet therapy in heart failure. Curr Opin Cardiol. 1997;12:276-287. 82. Teo KK, Yusuf S, Pfeffer M, et al. Effects of longterm treatment with angiotensin-converting-enzyme inhibitors in the presence or absence of aspirin: A systematic review. Lancet. 2002;360:1037-1043. 83. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: The human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA. 1999;96:272-277. 84. Pisetsky DS, St Clair EW. Progress in the treatment of rheumatoid arthritis. JAMA. 2001;286:27872790. 85. Mann DL. Tageted anticytokine therapy and the failing heart. Am J Cardiol. 2005;95:9C-16C. 86. Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347:305313. 87. Horwich TB, Fonarow GC, Hamilton MA, et al. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol. 2001;38:789795. 88. Mosterd A, Cost B, Hoes AW, et al. The prognosis of heart failure in the general population: The Rotterdam study. Eur Heart J. 2001;22:1318-1327. 89. Davos CH, Doehner W, Rauchhaus M, et al. Body mass and survival in patients with chronic heart failure without cachexia: The importance of obesity. J Card Fail. 2003;9:29-35. 90. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: The obesity paradox. Am J Cardiol. 2003;91:891-894. 91. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney RM. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med. 1995;333:1190-1195. 92. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:23382345.

11 Evaluation for Ventricular Assist Devices and Cardiac Transplantation Katherine Lietz and Leslie W. Miller

11.1. Introduction Despite many advances in the medical therapy of heart failure, an increasing number of patients become refractory to medical therapy. In its most advanced stages, heart transplantation becomes the only means of improving quality of life and survival (Figure 11.1). However, transplantation is available only to a fraction of those who need it due to the chronic shortage of available donors, which totaled less than 2,300 in 2004 and has not changed over the last decade1 (Figure 11.2). In recent years, the constantly growing population of patients awaiting transplantation, the chronic limitation in donor organ supply, and the overwhelming need for definitive therapeutic solutions in advanced heart failure have led to the design of mechanical circulatory support devices as a potential alternative to cardiac transplantation. So far, however, the outcomes of permanent implantation of left ventricular assist devices (LVADs) have not equaled the long-lasting benefits of cardiac transplantation. In the recent Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, which compared optimal medical therapy to mechanical circulatory support, only 29% of patients survived 2 years after device implantation2,3 (Figure 11.3). Because of the severe shortage of donor organs and the number of patients awaiting transplantation, the selection of transplant candidates is crucial to distribute human hearts to those patients with the greatest need and who would derive the most benefit. Detailed guidelines regarding criteria for

patient selection for heart transplantation were proposed in 1995 by the Committee on Heart Failure and Cardiac Transplantation of the American Heart Association,4 but did not have broad adoption. The current most endorsed guidelines were developed as a result of a consensus conference with representatives of over 60 participating heart transplant programs and now represent the standard in the field.5 This chapter discusses the process of transplant candidate selection, including indications and contraindications to transplantation, listing policies of the United Network of Organ Sharing (UNOS), and medical and surgical management of patients awaiting transplantation.

11.2. Indications for Heart Transplantation Unlike end-stage renal or hepatic disease, there is no biochemical test that defines irreversible heart failure. A detailed list of symptoms and test results that should prompt a referral for cardiac transplantation is presented in Table 11.1.6 In general, the following conditions should warrant evaluation for heart transplantation: 1. cardiogenic shock requiring either continuous intravenous ionotropic support or mechanical circulatory support with an intra-aortic balloon pump (IABP) counterpulsation device or an LVAD, 2. persistent New York Heart Association (NYHA) functional class IV heart failure symptoms

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K. Lietz and L.W. Miller Adult Heart Transplantation

Figure 11.1. Actuarial survival after heart transplantation [United Network of Organ Sharing (UNOS): January 1982 to June 2002; n = 62,952]. (From 2004 annual report of the International Society for Heart and Lung Transplantation, accessed January 10, 2005, at http://www.ishlt.org/registries/slides.asp.)

ISHLT Registry 1/1982−6/2002

100

Half-life = 94 years Conditional Half-life = 12.0 years

Survival (%)

80 60 40

N = 62,952

20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Years

Figure 11.2. Chart comparing the number of heart transplantations (closed circle) to the number of patients placed on cardiac transplant waiting list (closed squares) at the end of the calendar years 1993–2002. Bars show the percentage of patients who remained on the waiting list longer than 2 years. (From 2003 annual report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients, accessed January 10, 2005, at http://www.optn.org/data/annualReport.asp.)

Waiting Time for Heart Transplantation ISHLT Registry 1/1982 − 6/2002 4500 4000 80

3500 3000

60

2500 2000

40

1500 1000

20

Number of patients

% Candidates waiting > 2 years

100

500 0

0

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Number of patients on the waiting list Number of heart transplantations % Candidates waiting > 2 years

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P=0.0077 60%

40% LVAD 20% OMM 0% 0

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

Months Left-Ventricular Assist Device (LVAD) - Destination Therapy Optimal Medical Management (OMM)

Figure 11.3. The actuarial survival of 129 patients with end-stage heart failure ineligible to transplantation who were enrolled in the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial between July 1998 and July 2001, including 61 patients who were treated with optimal medical management (OMM) and 68 patients randomized to left ventricular assist device (LVAD) implantation.2 The device therapy was superior to medical management regardless of treatment crossover; P = 0.008. As of July 2003, the 1-year survival rate was 52% for patients receiving LVADs versus 28% for medically managed patients, and the 2-year survival rate was 29% versus 13% for the two groups, respectively. (From Park et al.3) Copyright 2005, with permission from Elsevier

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Table 11.1. Indication criteria for cardiac transplantation. Indication for heart transplant Symptoms and conditions Accepted

Probable

Too well

HFSS high risk Sustained dependence on inotropic or mechanical circulatory support Peak Vo2 < 10 mL/kg/min after reaching anaerobic threshold NYHA class III or IV heart failure refractory to maximal medical therapy Severely limiting ischemia not amenable to interventional or surgical revascularization Recurrent, symptomatic ventricular arrhythmia refractory to therapy HFSS medium risk Peak Vo2 < 14 mL/kg/min and severe functional limitations Instability of fluid status and renal function despite good compliance, daily weights, salt and fluid restriction, and flexible diuretics Recurrent, unstable ischemia not amenable to revascularization HFSS low risk alone Peak Vo2 > 15–18 mL/kg/min without other indications Left ventricular EF < 20% alone History of NYHA class III or IV symptoms alone History of ventricular arrythmias alone ACE inhibitor, β-blockade, and spironolactone therapy not attempted No structured evaluation in a designated cardiac transplantation center

ACE angiotensin-converting enzyme, EF ejection fraction, HFSS Heart Failure Survival Score, ICD implantable cardioverterdefibrillator, NYHA New York Heart Association, Vo2 oxygen consumption. Source: Adapted from Deng et al.7

refractory to maximal medical therapy or disabling symptoms of heart failure with unacceptable quality of life, 3. intractable or severe anginal symptoms in patients with coronary artery disease not amenable to percutaneous or surgical revascularization, and 4. intractable life-threatening arrythmias unresponsive to medical therapy or implantation of a cardioverter-defibrillator (ICD).

11.3. Optimization of Medical Treatment Before patients are considered for heart transplantation, it is imperative to optimize their medical therapy, identify and treat reversible etiologies, and consider any alternative forms of conventional treatment for heart failure (e.g., biventricular pacing), ventricular arrhythmias, intractable angina, or coronary artery disease. Detailed guidelines on the management of patients with advanced heart failure can be found in recent published guidelines.4-6 Patients with significant functional limitation despite maximally tolerated medical therapy may warrant a formal evaluation to determine their eligibility for transplantation.

11.4. Selecting Patients for Heart Transplantation The major aim of the evaluation process is to assess disease severity and identify patients at highest risk of death who would most likely benefit from heart transplantation, and exclude those with coexistent medical conditions or contraindications, which may reduce the expected outcome of heart transplantation.

11.5. The Severity of Heart Disease Patients with symptoms of moderate heart failure, who are stable on oral heart failure medications, are not usually considered candidates for heart transplantation. The usual candidate exhibits decompensated heart failure with NYHA class IV symptoms or those with refractory heart failure who require IABP or mechanical circulatory support. Although there are several predictors of poor survival in patients with heart failure, the following four categories have proved helpful to predict the risk of mortality in patients with the most advanced

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disease: (1) etiology of heart disease, (2) hemodynamic measures of cardiac pump performance, (3) functional capacity (peak oxygen consumption, Vo2), and (4) laboratory and electrocardiographic (ECG) parameters. Although many individual parameters have been shown to have prognostic importance, no single parameter more highly correlates with mortality in patients with advanced heart failure than do peak oxygen consumption.8 This test is the most important screening test to confirm cardiogenic etiology to patient symptoms and demonstrate loss of cardiac reserve. Use of percentage predicted peak Vo2 allows individualization of results and is more predictive of outcomes in patients with extremes of body size or age.9

11.5.1. Etiology of Heart Disease Ischemic cardiomyopathy is the most common etiology of heart failure in patients referred for heart transplantation. It is present in 45% of adult heart transplant recipients and carries the poorest prognosis of all heart disease etiologies.1 The 2-year survival rate in patients with ischemic cardiomyopathy is estimated to be only 31%, in contrast to 50–60% for patients with other conditions.10 Ideally, all patients with demonstrated ischemia should be evaluated for revascularization. However, because of the lack of prospective trials comparing revascularization therapy to cardiac transplantation, there are no specific criteria to accurately predict which patient would benefit most from either therapy. Therefore, the decision to proceed with cardiac transplantation has been traditionally reserved for patients with predicted high mortality from revascularization procedure. Dilated nonischemic cardiomyopathy is the second most common condition seen in 46% of heart transplant candidates, and encompasses a wide variety of etiologies.1,11 Many of them have a potential for spontaneous remission, such as lymphocytic myocarditis, peripartum cardiomyopathy, and alcoholic cardiomyopathy.12,13 Although a search for etiology of diliated cardiomyopathy is attempted in every patient, the specific cause can be identified in less than 20% of cases, rendering idiopathic etiology the major cause of dilated cardiomyopathy. In patients with new-onset cardiomyopathy, who are referred for transplantation, myocardial function can improve with introduction

K. Lietz and L.W. Miller

and dose optimization of drugs in as many as 50% of patients, allowing them to avoid being listed for heart transplantation. Especially with acute onset, patients who are stable should not undergo formal evaluation for at least 3 months.

11.5.2. Hemodynamics The majority of patients referred for heart transplantation present with left ventricular ejection fraction less than 20% and severely impaired hemodynamic profiles. However, hemodynamics at rest may be misleading in patients with primarily exertional symptoms. Use of exercise hemodynamics may be very important in demonstrating limited cardiac reserve.14 In the most advanced stages of heart failure, most of the hemodynamic variables lose their predictive value. Some patients with extensive left ventricular dysfunction are remarkably symptom free. Therefore, in patients with low left ventricular ejection fraction (<20%), the following parameters have been suggested to more accurately predict the risk of mortality, including poor right ventricular ejection fraction, high pulmonary artery wedge pressure, and low stroke work index. 14 The predictive value of these variables can be further enhanced by optimal reduction in preload and afterload, as well as by performing the measurements during exercise.15

11.5.3. Functional Capacity Determination of ejection fraction is a static test and may not correlate with functional capacity. Patients in NYHA class IV have consistently been reported to have the worst prognosis of all heart failure patients, reported to exceed an annual mortality of 50%.2,14 The total exercise duration on a treadmill or stationary bicycle correlates well with patient mortality; however, it has very high inter- and intrapersonal variability. To eliminate this problem, exercise testing in patients with heart failure is currently used in conjunction with respiratory gas analysis. The measurement of oxygen uptake and the anaerobic threshold during exercise has proved to be an objective and reproducible measurement of patient cardiac reserve.8,9 Maximal oxygen consumption is an accurate measurement of patients cardiac output and an excellent predictor of clinical decompensation

11. Evaluation for Ventricular Assist Devices and Cardiac Transplantation

and mortality8,9,16 (Figure 11.4). It is the product of maximal cardiac output and maximal arterial– venous oxygen difference and is always maximal at completion of symptom-limited exercise, irrespective of the degree of functional impairment. It is generally accepted that patients with peak oxygen consumption (Vo2max) less than 14 mL/kg/min or less than 50% of that predicted for gender and body surface area should be considered for heart transplantation.6,9,14 Only those tests in which patients reach anaerobic threshold or respiratory exchange ratio greater than 1.1 are considered valid. In a study evaluating the predictive value of oxygen consumption in ambulatory patients awaiting heart transplantation, the 1-year survival rate for the group with Vo2max greater than 14 mL/kg/min was 94%, and in patients with Vo2max less than 14 mL/ kg/min was 70% for those accepted for heart transplantation and 47% for those not undergoing transplantation.15

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therapy. Patients with short duration of heart failure symptoms have been shown to have a greater likelihood of spontaneous improvement, but also very high mortality rates early after referral.18 If the condition of patients with recent-onset cardiomyopathy deteriorates, such patients should have a priority to be listed for heart transplantation.

11.6. Contraindications to Cardiac Transplantation Through the years of experience in heart transplantation, a series of absolute and relative exclusion criteria have been empirically derived, including various comorbidities (e.g., significant renal insufficiency or pulmonary hypertension), as well as laboratory and psychosocial factors, which can significantly increase perioperative risk or decrease long-term survival after heart transplantation (Table 11.2).

11.5.4. Heart Failure Survival Score The Heart Failure Survival Score (HFSS) is a composite risk score determined from peak Vo2, mean arterial blood pressure, heart rate, left ventricular ejection fraction, serum sodium, heart failure etiology, and width of QRS complex.17 The HFSS has been shown to predict survival in patients with advanced heart failure and guide the selection of patients for cardiac transplantation16 (Figure 11.5).

11.5.5. Duration of Illness Patients with recent-onset cardiomyopathy, especially if not due to coronary artery disease, require close clinical surveillance and aggressive medical

11.6.1. Upper Age Limit One of the most controversial aspects of patient selection is the upper age limit for cardiac transplantation. In 1970s, heart transplantation was reserved only for patients younger than 50–55 years. In the early 1980s, when the introduction of cyclosporine improved results of heart transplantation, these criteria were modified to include patients older than 55 years. The Medicare Health System prohibits discrimination based on age alone. A significant number of patients undergo renal and hepatic transplantation when they are older than65 years of age. The guidelines indicate that there is no absolute cutoff for heart transplantation by age, Adult Heart Transplantation By Recipient Age (Years) ISHLT Registry 1 / 1982 − 6 / 2002

100 80

Survival (%)

Figure 11.4. Event-free survival rate by peak Vo2 at reevaluation for cardiac transplantation. One hundred thirty-four (59%), 70 (31%), and 23 patients (10%) were in the low-, medium-, and high-risk peak Vo2 strata at reevaluation, respectively, with corresponding 1-year event-free survival rates of 78 ± 4, 72 ± 6, and 25 ± 10% and median event-free survival times of 1,077, 597, and 174 days, respectively. (Adapted from Lund et al.,16 with kind permission of DM Mancini.) (See Color Plates)

60 40 18-34 (N = 1,916) 50-64 (N = 12,182) 70+ (N= 183)

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0

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2

3

4

Years

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(n=227) Cum. Survival

0.8

82% Low risk (n=118)

0.6 0.4 0.2

62%

Overall : p<0.0001 Low vs Med: p<0.0002 Low vs Hi: p<0.0002 Med vs Hi: p=0.3

Med risk (n=80)

42%

Hi risk (n=29)

0.0 91

365

639

Time (days) Figure 11.5. Event-free survival rate by Heart Failure Survival Score (HFSS) at reevaluation for cardiac transplantation. Seven parameters of the HFSS were collected, the score was calculated, and patients were separated into the three HFSS and peak Vo2 risk strata according to the previously defined cutoffs. The following equation was used: HFSS = ([0.0216 × heart rate at rest] + [− 0.0255 × mean arterial blood pressure] + [−0.0464 × left ventricular ejection fraction] + [−0.0470 × serum sodium] + [−0.0546 × peak Vo2] + [0.6083 × presence (1) or absence (0) of intraventricular conduction defect (QRS interval ≥ 120 ms due to left or right bundle branch block, nonspecific intraventricular conduction delay, or ventricularly paced rhythm)] + [0.6931 × presence (1) or absence (0) of ischemic cardiomyopathy]). The seven products are summed and the absolute value is taken as the HFSS. The HFSS values associated with each risk stratum are ≥ 8.10 for low risk, 7.20–8.09 for medium (med) risk, and ≤ 7.19 for high (hi) risk. (Adapted from Lund et al.,16 with kind permission of DM Mancini.)

but older patients require more in-depth review for coexisting comorbidities associated with advancing age. Currently, the age of 65 years is considered the general upper age limit, although successful cardiac transplantations have been performed in patients up to 70 years old.3,4 A comparison of outcomes of heart transplantation in patients older than 65 years to younger patients showed not only a similar allograft survival but also lower rates of acute rejection episodes19,20 (Figure 11.6). However, older patients had higher rates of infections, more frequent hospitalizations, and higher functional limitation when compared to younger patients. Also, steroid-induced diabetes and osteoporosis were more likely to occur in older patients, which may warrant closer screening of these patients for comorbid conditions.

11.6.2.

Pulmonary Hypertension

Right heart failure is the second leading cause of death in the first month after heart transplantation.1,21,22 This is due to the relatively high incidence of pulmonary hypertension in recipients prior to transplantation. The implantation of a healthy donor

heart with a relatively thin walled right ventricle unaccustomed to elevated afterload (pulmonary artery pressure) and fixed elevated pulmonary resistance may lead to acute dilation of the donor right ventricle, with progressive right ventricular failure, renal dysfunction, and early posttransplant death. Since secondary pulmonary hypertension is a common complication of severe chronic heart failure, evaluation of the presence and reversibility of pulmonary vascular resistance has become a critical component of evaluation of heart transplant candidates.23 In most programs, a fixed pulmonary vascular resistance greater than 6 Wood units with maximal vasodilation to maintain systemic arterial pressures greater than 90 mmHg is considered a relative contraindication to orthotopic transplantation and these patients should be given strong consideration for ventricular assist device (VAD) implantation. Additional parameters used to assess pulmonary hypertension include pulmonary vascular resistance index (Wood units × body surface area) or transpulmonary pressure gradient (mean pulmonary artery pressure – mean pulmonary capillary wedge pressure). The reversibility of pulmonary hypertension

11. Evaluation for Ventricular Assist Devices and Cardiac Transplantation

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Table 11.2. Contraindications to cardiac transplantation. I. Absolute Contraindications 1. Systemic illness that will limit survival despite heart transplant including the following: a. active or recent solid organ or blood malignancy (e.g., leukemia) within 5 years (including low-grade neoplasms of prostate with persistently elevated prostate-specific antigen) b. HIV/AIDS (CDC (Centers for Disease Control) definition of CD4 count of < 200 cells/mm3) c. systemic lupus erythematosus, sarcoid or amyloidosis that has multisystem involvement and is still active d. irreversible renal or hepatic dysfunction in patients considered for only-heart transplantation e. significant obstructive pulmonary disease (FEV1 < 1 L/min) 2. Fixed pulmonary hypertension Pulmonary artery systolic pressure > 60 mmHg Mean transpulmonary gradient > 15 mmHg Pulmonary vascular resistance > 6 Wood units or 3 Wood units after treatment with vasodilators II. Relative Contraindications Age over 70 years (age alone is not a contraindication) Any active infection (with exception of device-related infection in VAD recipients) or systemic infection making immunosuppression risky (e.g., diverticulitis) Active peptic ulcer disease Severe diabetes mellitus with end-organ damage (neuropathy, nephropathy, or retinopathy) Severe peripheral arterial or cerebrovascular disease – Peripheral arterial disease not amenable to surgical or percutaneous revascularization – Asymptomatic carotid stenosis < 75% or symptomatic carotid stenosis of less severity – Ankle brachial index < 0.7 or substantial risk of limb loss with diminished perfusion – Uncorrected abdominal aortic aneurysm > 6 cm Morbid obesity (body mass index > 40) or cachexia (body mass index < 21) Creatinine > 2.5 mg/dL, or creatinine clearance < 40–50 mL/mina Bilirubin > 2.5 mg/dL, serum transaminases > 3× normal, INR > 1.5 off warfarin Severe pulmonary dysfunction with FEV1 < 40% normal Recent pulmonary embolism (within 3 months) Any condition that limits active exercise and rehabilitation (e.g., stroke) Irreversible neurologic or neuromuscular disorder Psychosocial impairment that would jeopardize the transplanted heart (see Table 11.3) AIDS acquired immunodeficiency syndrome, HIV human im3munodeficiency virus, FEV1 forced expiratory volume in 1 s, VAD ventricular assist device a May be suitable for cardiac transplantation if inotropic support and hemodynamic management produce a creatinine level < 2 mg/dL and creatinine clearance > 50 mL/min. Transplantation may also be advisable as combined heart–kidney transplant.

1.0

Cum. Survival

78%

(n=227)

0.8 VO2>14 (n=134)

0.6

72%

VO2 10-4 (n=70)

0.4 0.2 0.0

Overall: p<0.0001 VO2 >14 vs 10-14: p<0.04 VO2 >14 vs <10: p<0.0001 VO2 10-14 vs <10: p<0.0003

91

25%

365

VO2<10 (n=23)

639

Time (days) Figure 11.6. Actuarial survival after heart transplantation stratified by recipient age [United Network of Organ Sharing (UNOS): January 1982 to June 2002; n = 62,952]. (From 2004 annual report of the International Society for Heart and Lung Transplantation, accessed January 10, 2005, at http://www.ishlt.org/registries/slides.asp.)

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can best be achieved pharmacologically with the use of vasodilators, inotropes, inhaled nitric oxide, intravenous or inhaled prostacyclin, or a combination of these drugs.23 Some patients who do not respond acutely may respond to chronic continuous inotropes. New therapies that have recently emerged to aid in the treatment in refractory pulmonary hypertension include sildenafil,24 nesiritide,25 biventricular pacing,26 and left ventricular assist device (LVAD).27

K. Lietz and L.W. Miller

titers should receive postoperative prophylactic therapy with either gancyclovir or valgancyclovir, because reactivation of CMV in immunocompromised transplant recipients may increase alloreactivity and accelerate chronic graft rejection. Acquired immunodeficiency syndrome is an absolute contraindication to transplantation, although few centers have transplanted patients with HIV and a negative HIV viral load.30

11.6.3.3. Pulmonary Disease

11.6.3. Comorbid Conditions Any coexistent systemic illness that limits survival independent of heart disease should be considered a possible contraindication to heart transplantation. In general, the decision to accept an individual as a transplant candidate is based on the collective comorbidies, not a single problem. Examples of severe primary diseases which may limit survival after transplantation and jeopardize the outcome of heart transplantation include advanced or irreversible pulmonary, hepatic, or renal dysfunction, irreversible neurologic or neuromuscular disorders, and systemic diseases, such as sarcoidosis or systemic amyloidosis, which frequently may affect the allograft itself.

11.6.3.1. Malignancy The most obvious contraindication to transplantation is the diagnosis of recent malignancy (within 5 years from listing). A recent or active malignancy is an absolute contraindication to heart transplantation and all heart transplant candidates should be thoroughly screened for presence of occult malignancy prior to being placed on the waiting list. A remote history of treated malignancy without evidence of recurrence and tumors localized to the heart are not a contraindication and these patients have successfully received heart transplants.28

11.6.3.2. Infection The presence of an active infection is usually a temporary contraindication to heart transplantation until it is adequately treated. The only exception to this rule is infections of the VAD, which are usually “cured” with transplantation. Patients with infective endocarditis without metastatic infection may also be considered for transplantation.29 Patients with positive cytomegalovirus (CMV)

Since the relative contribution of pulmonary disease to heart failure–related dyspnea is often difficult to assess, pulmonary function tests are routinely performed in all transplant candidates. In general, patients who have a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 40–50% of predicted or severe obstructive disease (FEV1 < 50% of that predicted) despite optimal medical therapy are considered poor candidates for heart transplantation.31 Chronic obstructive pulmonary disease may predispose patients to pulmonary infections and difficult removal of ventilatory support after surgery. Pulmonary infarct is, on the other hand, only a temporary contraindication. It is recommended that transplantation be delayed at least 3 months after a pulmonary infarct to avoid the risk of recurrent emboli and pulmonary cavitation abscess, before or after immunosuppression is instituted.32

11.6.3.4. Renal Dysfunction Many patients with advanced heart failure have mild-to-moderate abnormalities of renal function. The serum creatinine concentration may often exceed 2 mg/dL and creatinine clearance less than 50 mL/min, both of which have been shown to adversely impact survival after transplantation.33 Patients with renal dysfunction secondary to impaired renal perfusion may improve with optimization of vasoactive therapy, and it is more likely that the renal function will improve after transplantation. Underlying intrinsic renal disease may represent significant comorbidity. If intrinsic renal disease is suspected, patients should undergo further workup with a 24-h urine collection for protein excretion and creatinine clearance, renal ultrasound for kidney size, and possibly evaluation for renal artery stenosis. Standard urinalysis will exclude most parenchymal diseases.

11. Evaluation for Ventricular Assist Devices and Cardiac Transplantation

11.6.3.5. Hepatic Dysfunction Transaminase levels more than twice their normal value with or without elevated bilirubin, and associated coagulation abnormalities may reflect right heart failure or passive congestion, but primary liver disease, in particular cirrhosis, needs to be excluded. The role of routine liver biopsy in patients undergoing transplant evaluation remains unknown.

11.6.3.6. Peptic Ulcer Recent peptic ulcer disease is a relative contraindication to transplantation due to the risk of bleeding in the posttransplant period from high-dose steroid treatment and the increased risk of infection from possible colonization of the ulcer crater with CMV or candida.

11.6.3.7. Diabetes Except for patients with juvenile-onset diabetes with end-organ damage, diabetes is currently not a contraindication to transplantation. Recent studies have shown that patients with well-controlled diabetes without end-organ damage such as nephropathy, neuropathy, or retinopathy have similar outcomes of transplantation as nondiabetics, in terms of survival. In addition diabetic patients experience similar rates of posttransplant complications, such as rejection, infection, renal disease, and transplant vasculopathy compared to nondiabetics.34 Nevertheless, it is important to remember that diabetic patients receiving corticosteroids may require multiple adjustments of their oral or insulin regimens. Many patients with diabetes can be managed long-term posttransplant with steroid-free immunosuppression regimens.

11.6.3.8. Hypertension Symptomatic hypertension requiring multidrug therapy generally suggests a primary target for medical therapy rather than cardiac transplantation. Hypertension may worsen following transplant with calcineurin inhibitor treatment and steroid therapy.

11.6.3.9. Vascular Disease Although peripheral arterial disease is not a contraindication to heart transplantation, the following conditions must be considered in patients with vascular disease: (1) the possibility of precipitating an acute thrombotic or embolic event during acute hemodynamic changes in the early postoperative period or the need for placement of an IABP if

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early graft function is poor, (2) the effect of chronic steroid therapy on disease progression, and (3) the feasibility of surgical revascularization if symptoms due to peripheral or cerebrovascular disease worsen after transplantation.4 In some instances, carotid endarterectomy has been performed before heart transplantation to minimize the risk of postoperative cerebrovascular events. Similarly, claudication that limits ambulation may warrant intervention prior to transplantation or early posttransplant to prevent limitation of rehabilitation and exercise.

11.6.3.10. Cachexia and Morbid Obesity Morbid obesity and cardiac cachexia represent relative contraindications to transplantation due to significant increased morbidity, complications and poor perioperative survival, and difficulty identifying an appropriately sized donor heart.35,36 Obesity carries risks of accelerated cardiac allograft vasculopathy, hypertension, and wound infection, which can be further accentuated by long-term corticosteroid therapy.

11.7. Psychosocial Evaluation All transplant candidates should undergo evaluation by a trained mental health professional and social workers before the decision is made to proceed with heart transplantation5 in order to ensure that they are able to receive adequate postoperative care and medications. Psychosocial criteria that may predict a poor postoperative outcome include previous noncompliance, chemical dependencies (alcohol and drugs), lack of adequate support system, personality disorder, underlying mental illness, organic brain disorders, or mental retardation. Current guidelines in psychosocial risk stratification, including indications and contraindications to transplantation, are shown in Table 11.3.5

11.8. Patient Enrollment on the Heart Transplant Waiting List Those patients with Vo2max less than 14 mL/kg/min or more than 55% predicted Vo2 and who meet all other criteria for transplantation5 are placed on the national heart transplant waiting list. The United Network of Organ Sharing (UNOS), which

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Table 11.3. Recommendations for psychosocial criteria for transplant listing. Axis I

Axis IIa

Low-risk patients High-risk patients

Successful predictors Absence of Substance abuse Active psychosis Suicidal behavior Personality disorder Characteristics of noncompliant patients: Unmarried/less family support Antisocial personality disorder Current substance abuse Less education Less income Longer time posttransplant No axis I or axis II diagnosis or axis I diagnosis only Both axis I and axis II diagnosis present

Presence of Demonstrated medical compliance Adequate neurocogntive function Adequate social support system Adequate financial support system

Source: Adapted from Miller et al.33 a Caution is needed with an axis II diagnosis. The legal definition of the term “individuals with handicaps” includes patients with a low IQ. By law, “handicapped” individuals cannot be discriminated against or excluded from programs that receive federal funds.

controls organ allocation independent of individual bias, has proposed the following classification of clinical status of heart transplant candidates in accordance to urgency to receive a heart transplant: status IA, IB, 2, and 7 (Table 11.4). Once heart transplant candidate status is approved, all patients are categorized by UNOS according to their body size, ABO blood group, and time on the waiting list to ensure appropriate priority and matching with the donor. At the time of UNOS listing all patients should undergo immunological evaluation, including HLA typing and panel reactive antibodies. The purpose of these tests is to exclude the presence of preformed donor-specific antibodies, which typically require a donor cross-match to be obtained prior to heart transplantation to avoid hyperacute rejection of the allograft. Some high-volume transplant centers have developed programs that offer nonoptimal transplant candidates (older candidates or younger with comorbidities) organs from marginal donors (with hepatitis C, noncritical coronary artery disease, moderate left ventricular hypertrophy) that would otherwise not be offered to other transplant candidates.37 This practice of maintaining an alternate or B list remains controversial. All patients who remain on the waiting list for more than 6 months should be reevaluated as to their continued need for transplantation, rather than receiving a higher priority based on accumulation

of time on the waiting list. Spontaneous improvement as well as deterioration of patient condition may occur, which may either remove the patient from the list or increase his or her priority status for a new heart. For listed ambulatory patients, visits every 4–8 weeks are usually scheduled to reassess prognosis, optimize therapy, and enhance patient education regarding heart transplantation.

11.9. Medical Treatment of Patients Awaiting Transplantation Some controversy surrounds the use of outpatient inotrope infusion for symptomatic relief in patients awaiting transplantation, because of the reports of increased risk of mortality, especially with higher doses.38-40 More recent studies have demonstrated better outcomes in inotrope-dependent patients with use of LVADs.41 With brief hospitalizations for hemodynamic monitoring to optimize use of diuretics and vasoactive therapy, patients often sustain improvement lasting for weeks or even months. Careful monitoring for infection related to indwelling catheters is required. The use of anticoagulants as prophylaxis against systemic or pulmonary thromboembolism is practiced routinely at some centers. Transplant candidates with preformed anti-HLA antibodies, as measured by routine panel reactive

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Table 11.4. Heart transplant candidate status. Status IA

1B

2 7

Criteria Inpatient on mechanical circulatory support (VAD ≤ 30 days; TAH; IABP; ECMO) or Outpatients on mechanical circulatory support >30 days with significant device-related complications or mechanical ventilation or Continuous infusion of one high-dose or multiple inotropes with continuous invasive hemodynamic monitoring or Life expectance less than 7 days without transplant VAD > 30 days or Continuous infusion of intravenous inotropes or Justified exceptional case Does not meet status 1A or 1B criteria Temporarily unsuitable to receive organ

VAD ventricular assist device, TAH total artificial heart, IABP intra-aortic balloon pump, ECMO extracorporeal membrane oxygenation.

11.10. Mechanical Circulatory Support in Patients Awaiting Transplantation Patients with profound circulatory failure refractory to conventional medical therapy, who are unlikely to survive without transplantation, may require a VAD to mechanically support their

100 90

% of Pateints not Transplanted

antibody (PRA) testing, may require additional therapy to reduce the titer of the circulating antibodies. The presence of anti-HLA antibodies increases the risk of hyperacute humoral rejection, which is almost always associated with poor allograft outcome. To minimize the risk of humoral rejection potential cardiac transplant recipients who test positive for anti-HLA antibodies undergo a prospective cross-match to exclude antibody reactivity against donor tissue. A positive cross-match precludes the potential recipients from receiving a donor heart and repeatedly positive tests prolong waiting time for cardiac transplantation. Therefore, all allosensitized transplant candidates undergo desensitization therapy (Figure 11.7). The protocols vary among transplant centers, but most desensitization protocols employ a combination of intravenous immunoglobulins and plasmapheresis. Adjunct treatment with B-cell- directed immunosuppression such as cyclophosphamide and antiCD20 monoclonal antibodies have also been used successfully.42,43

80

P(log - rank) = 0.001

70 60 50

Anti-HLA class I antibody (n=37)

40 No anti-HLA class I antibody (n=18)

30 20 10 0 0

4

8

12

16

20

Time to Transplantation (months)

Figure 11.7. Effect of IgG antibodies against human leukocyte antigen (HLA) class I antigen on waiting time to cardiac transplantation. In 37 sensitized LVAD recipients (open triangles), presence of IgG antibodies against HLA class I antigen increased waiting time to cardiac transplantation compared with 18 nonsensitized LVAD recipients (open squares) (P = 0.001). (Adapted from John et al.42) Copyright 1999 American Heart Association, Inc. All rights reserved. Reprinted with permission

circulation. Increasing number of patients on the transplant list deteriorate while waiting. In large volume centers, 20% or more of all heart transplant recipients are supported with left or biventricular assist devices.44

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There are three major, often overlapping, indications for the use of circulatory assist devices: (1) as a bridge to myocardial recovery in patients with cardiogenic shock due to potentially reversible cardiac insult, (2) as a bridge to heart transplantation for candidates with severe acute or acute on chronic heart failure who continue to deteriorate despite maximal medical treatment, and (3) as destination therapy for patients ineligible for transplantation. Several types of early assist devices include intra-aortic balloon counterpulsation and extracorporeal membrane oxygenation (ECMO), but more long-term support is available with univentricular and biventricular nonpulsatile and pulsatile ventricular assist devices (VADs), and the total artificial heart (Table 11.5). The two most popular long-term LVADs are the HeartMate XVE pump (Thoratec Corp., Pleasanton, CA) and Novacor (WorldHeart, Ottawa, Canada) (Figures 11.8 and 11.9). Newer generation axial flow pumps, including the DeBakey, Jarvik, and HeartMate II, are also under intense clinical investigation or early clinical use. The decision about which device to use is based on duration of predicted use, reversibility of the underlying cause of cardiogenic shock, need for univentricular versus biventricular support, the patient’s size, and institutional resources. The success

of mechanical assistance, however, on large part depends on quick and appropriate patient selection (Table 11.6).46,47

11.10.1. Hemodynamic Indications for Mechanical Support Mechanical support is generally indicated in patients who have profound circulatory failure refractory to conventional therapy. Although there are no fixed hemodynamic criteria for device implantation, the following criteria should prompt the consideration for circulatory assist: cardiac index less than 2 L/min/m2, stroke volume less than 25 cm3 or sinus tachycardia more than 130/min; systemic blood pressure less than 75–80 mmHg, mean arterial pressure less than 65 mmHg or need for vasopressor agents, pulmonary capillary wedge pressure greater than 20 mmHg and pulmonary venous saturation less than 40%, impaired renal function or poor peripheral perfusion despite treatment with adequate ventricular preload, intra-aortic balloon counterpulsation, and/or inotropic therapy. A downward trend in hemodynamics or increasing inotropic requirements to maintain hemodynamics and vital organ perfusion may be more important than the absolute numbers, and following strict hemodynamic criteria should not delay the decision to use VADs.

Table 11.5. Summary of external (a) and implantable (b) mechanical circulatory support devices. (a) External Mechanical Circulatory Support Devices Device name

Ventricle supported Flow Duration Power source Patient ambulation

ECMO

Abiomed

Biomedicus

Thoratec

Cardiopulmonary Centrifugal, nonpulsatile Short Electric No

Left, right Pulsatile Short Pneumatic No

Left, right Centrifugal, nonpulsatile Short Electric No

Left, right Pulsatile Intermediate to long Pneumatic Yes

(b) Implantable Mechanical Circulatory Support Devices Device name

Ventricle supported Flow Duration Power source Patient ambulation

Heartmate P

Heartmate VE, XVE, Jarvik 2000, DeBakey Cardiowest TAH, Abiomed Novacor Micromed TAH

Left Pusher plate, pulsatile Long term Pneumatic Yes

Left Pusher plate, pulsatile Long term Electric Yes

ECMO extracorporeal membrane oxygenation.

Left Axial, nonpulsatile Long term Electric Yes

Left and right Pulsatile Long term Pneumatic/Electric Yes

11. Evaluation for Ventricular Assist Devices and Cardiac Transplantation Figure 11.8. Components of the left ventricular assist device. The inflow cannula is inserted into the apex of the left ventricle, and the outflow cannula is anastomosed to the ascending aorta. Blood returns from the lungs to the left side of the heart and exits through the left ventricular apex and across an inflow valve into the prosthetic pumping chamber. Blood is then actively pumped through an outflow valve into the ascending aorta. The pumping chamber is placed within the abdominal wall or peritoneal cavity. A percutaneous drive line carries the electrical cable and air vent to the battery packs (only the pack on the right side is shown) and electronic controls, which are worn on a shoulder holster and belt, respectively. (Adapted from Rose et al.2) Copyright 2001 Massachusetts Medical Society. All rights reserved. Adapted with permission for publication in 2008 (See Color Plates)

253

Aorta

Vent adapter and vent filter

External battery pack

Outflowvalve housing

Inflowvalve housing

Drive line Prosthetic left ventricle System controller

Skin line

Figure 11.9. The axial flow pumps are much smaller than the two conventional pulsatile pumps, such as HeartMate (upper left) or Novacor (upper right). The DeBakey pump (bottom) is the first axial pump designed in 1988 which can produce high-flows using electromagnetically actuated impeller housed within a very small titanium pump (1.2 × 3.0 inches). (Adapted from Lietz and Miller.45) (See Color Plates)

Table 11.6. Patient selection criteria for ventricular assist device support as a bridge to cardiac transplantation. 1. Upper age consistent with successful cardiac transplantation, usually about age 70 2. Lower age limit determined by patient size large enough to accommodate a device: a. Thoratec VAD: usually >1.0 m2 b. HeartMate: usually >1.5m2 c. Novacor: usually >1.5m2 d. Cardiowest total artificial heart: usually >1.5 m2 3. Suitable candidate for cardiac transplantation by accepted guidelines 4. Refractory heart failure with imminent risk of death before donor heart availability, usually with evidence of deterioration on maximal appropriate inotropic and/or intra-aortic balloon support or inotrope dependent 5. General hemodynamic guidelines: a. cardiac index < 1.8 L/min/m2 b. systolic arterial blood pressure < 90 mmHg c. pulmonary capillary wedge pressure > 20 mmHg despite appropriate pharmacological management d. impaired organ perfusion/function (e.g., oliguria) e. absence of fixed pulmonary hypertension (pulmonary vascular resistance > 6 Wood units) 6. Adequate psychologic criteria and external psychosocial support for transplantation and potentially prolonged LVAD support 7. Informed consent of patient or family 8. Absence of irreversible renal or hepatic failure (LVAD support not expected to reverse existing renal or hepatic dysfunction) VAD ventricular assist devices, LVAD left ventricular assist devices. Source: Adapted from Kirklin et al.48

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11.10.2. Indications for Single- Versus Biventricular Support The majority of patients in cardiogenic shock or with advanced heart failure refractory to medical therapy who are evaluated for mechanical circulatory support can be managed with the support of only the left ventricle. The implantation of biventricular assist devices or total artificial heart is considered in 15–20% patients with evidence of chronic severe biventricular failure, including excessively high right-sided filling pressures (Right Atrial (RA) > 20 mmHg) and large right ventricular size (>200 mL in diastole), as well as intractable ventricular arrythmias.46-48 Although elevated right-sided pressure, which is seen in 20–30% of patients, is not an absolute contraindication to LVAD-only implantation, single-chamber support is often associated with high right-sided pressures, poor renal function, and poor postimplant survival.49,50 Some patients with high right-sided pressures considered for LVAD implantation may respond to strategies to improve RV (Right ventricular) function such as ultrafiltration, IABP, and mechanical ventilation with or without the use of nitric oxide. In other patients a temporary mechanical support for 24–48 h of the right ventricle may decrease the need for long-term RVAD (Right Ventricular Assist Device) use without excessive morbidity. The implantation of an LVAD has certain anatomical requirements, including adequate body size—usually body surface area grater than 1.5 m2 (Table 11.7). These requirements are not necessary in recipients of total artificial heart, which replaces the native heart, but the size of the total artificial

K. Lietz and L.W. Miller

heart restricts its use in many patients. The latter option is more likely to be used in patients with certain etiologies of heart disease that may be challenging for LVAD implantation, such as hypertropic cardiomyopathies, acute myocardial infarction with a large ventricular septal defect, endocarditis with heart failure, tachyarrythmiainduced heart failure, and heart failure in patients with congenital cardiac disease.51

11.10.3. Indications for Short-Term Mechanical Support In patients with medical emergencies, such as cardiogenic shock after thoracotomy or in the setting of acute myocardial infarction, acute myocarditis, or cardiac arrest as a complication of an interventional cardiac procedure, the situation may demand immediate device placement. Patients often require high doses of multiple vasopressor drugs to maintain blood pressure. In these circumstances, the practice of short-term support with a less invasive and expensive device is becoming more common (i.e., bridgeto-bridge strategy). In patients in very poor condition with oliguria and high right-sided pressures there is a trend to start therapy with less invasive methods (e.g., IABP) to improve subendocardial perfusion, but if this strategy fails more definitive VADs are warranted emergently. After 2–14 days, a more accurate assessment can be made, particularly in regard to neurological condition and end-organ function, to allow the decision to either terminate support or implement long-term VAD support.

Table 11.7. Medical and anatomical considerations prior to left ventricular assist device placement. Medical Considerations: 1. Uncontrolled sepsis 2. Bleeding diathesis 3. Hypercoagulable state may preclude use of VAD not requiring anticoagulation 4. Cachexia, malnutrition Anatomical Considerations: 1. Appropriate body habitus, usually body surface area (BSA) > 1.5 m2 2. Aortic valve incompetence needs to be corrected at time of VAD implantation as it may lead to progressive regurgitation of blood from the outflow cannula back into the left ventricle 3. Metallic prosthetic aortic or mitral valves are not a contraindication, but typically require use of warfarin or in case of aortic valves conversion to a bioprosthesis to obviate the need for anticoagulation 4. Patent foramen ovale or atrial septal defect should be surgically closed at time of LVAD implantation to prevent right to left shunting of blood and paradoxical emboli as the left side of the heart is decompressed VAD ventricular assist devices, LVAD left ventricular assist devices.

11. Evaluation for Ventricular Assist Devices and Cardiac Transplantation

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11.10.4. Indications for Long-Term Mechanical Support

11.10.6. Complications of Mechanical Support

It is generally agreed that patients considered for long-term circulatory support should fulfill the criteria for transplant recipient selection. Since end-organ dysfunction and irreversible pulmonary hypertension are the two major contraindication to transplantation, it is recommended that implantations be performed in patients with potentially reversible end-organ dysfunction and modest right ventricular dysfunction. In this regard, optimization of medical therapy with drugs and use of IABP may not only decrease right-sided pressures prior to LVAD implantation but also improve renal and hepatic function. Chronic ventricular unloading can reduce pulmonary vascular resistance in many LVAD recipients.27 LVAD use as destination therapy should be considered a relatively elective procedure in stable patients with end-stage heart failure.

Most of the complications seen in device recipients occur perioperatively, such as bleeding, infection, right ventricular failure, and multiorgan failure, and are the major causes of early mortality after LVAD implantation. Long-term mortality is mostly related to device dysfunction and infectious complications. Although sepsis and local infections rarely affect transplant outcomes, they are an important cause of morbidity and mortality in LVAD recipients. Most of the infections begin at the exit of the driveline; however, they may proceed deeper to involve the LVAD pocket or mediastinum, leading to devicerelated endocarditis or infection of the device itself. Bleeding and neurologic dysfunction (Transient Ischemic Attack (TIA) and stroke) are the other common complications.

11.10.5. Mortality and Risk of Death in Patients Supported Mechanically The major causes of death in long-term mechanical support are related to multiorgan failure, renal failure, right ventricular failure, bleeding, and infection.52 Outcomes appear to be better in patients who receive elective implantation, compared to patients who receive urgent or emergent implant.53 Several studies have shown the following preimplantation risk factors to increase the risk of death: right heart failure, previous sternotomy, acute myocardial infarction, significant underlying pulmonary dysfunction, nutritional deficiency and/or cachexia, abnormal coagulation profile, active infection, and significant renal or hepatic dysfunction.54,55 The Acute Physiology and Chronic Health Evaluation (APACHE) II score,7 an aggregate of scores assigned to critically ill patients, and the HFSS54 have been shown to have significant prognostic power in patients with advanced heart failure and are also predictive of poor outcome after LVAD implantation. The Seattle Heart Failure Model is a web-based scoring system that uses easily obtainable clinical data to provide an accurate estimate of survival.56

11.10.7. Listing Status and LVAD Implantation Under current guidelines, patients on LVAD or Bi-VAD support can be listed as status 1A for up to 30 days only; after this time the patients are listed as status 1B even if they remain in the hospital. A patient can be listed as status 1A, if device-related complications develop. • Before heart transplantation is considered, it is imperative to optimize medical therapy in stable patients with advanced heart failure and consider alternative forms of conventional treatment (i.e., biventricular pacing, coronary artery bypass grafting). • Peak oxygen consumption is the single best predictor of disease severity in patients with advanced heart failure. • Fixed pulmonary hypertension more than 6 Wood units and any coexistent systemic illness that limits survival independent of heart disease should be considered as a relative contraindication to heart transplantation (e.g., active infection or malignancy). • Patients considered for long-term circulatory support should fulfill the same criteria as transplant candidates.

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11. Evaluation for Ventricular Assist Devices and Cardiac Transplantation 24. Alaeddinin J, Uber PA, Park MH, et al. Sildenafil is effective and safe in reversing pulmonary hypertension in advanced heart failure. J Heart Lung Transplant. 2004;23:S199-S120. 25. Bhat G, Costea A. Reversibility of medically unresponsive pulmonary hypertension with nesiritide in a cardiac transplant recipients. ASAIO J. 2003;49:608-610. 26. Healy JS, Davies RA, Tang ASL. Improvement of apparently fixed pulmonary hypertension with cardiac resynchronization therapy. J Heart Lung Transplant. 2004;23:650-652. 27. Salzberg SP, Lachat ML, von Harbou K, Zund G, Turina MI. Normalization of high pulmonary vascular resistance with LVAD support in heart transplantation candidates. Eur J Cardiothorac Surg. 2005;27(2):222-225. 28. DiSalvo T, Naftel D, Kasper EK, et al. The differing hazard of lymphoma vs. other malignancies in the current era—A multiinstitutional study. J Heart Lung Transplant. 1998;17:70. 29. DiSesa VJ, Sloss LJ, Cohn LH. Heart transplantation for intractable prosthetic valve endocarditis. J Heart Lung Transplant. 1990;9:142-143. 30. Calabrese LH, Albrecht M, Young J, et al. Successful cardiac transplantation in an HIV-1 infected patient with advanced disease. N Engl J Med. 2003;348:2323-2328. 31. Light RW, George RB. Serial pulmonary function in patients with acute heart failure. Arch Intern Med. 1983;143:429-433. 32. Young JN, Yazbeck J, Esposito G, et al. The influence of acute preoperative pulmonary infarction on the results of heart transplantation. J Heart Transplant. 1986;5:20-22. 33. Miller LW. Listing Criteria for Heart Transplantation: Transplantation, 1998, 66(7):947–951. 34. Odim J, Wheat J, Laks H, et al. Peri-operative renal function and outcome after orthotopic heart transplantation. J Heart Lung Transplant. 2006;25:162-166. 35. Lang CC, Beniaminovitz A, Edwards N, et al. Morbidity and mortality in diabetic patients following cardiac transplantation. J Heart Lung Transplant. 2003;22:244-249. 36. Lietz K, John R, Burke EA, et al. Pretransplant cachexia and morbid obesity are predictors of increased mortality after heart transplantation. Transplantation. 2001;72(2):277-283. 37. Grady KL, White-Williams C, Naftel D, et al. Are preoperative obesity and cachexia risk factors for post heart transplant morbidity and mortality: A multi-institutional study of preoperative weight-height indices. Cardiac Transplant Research Database (CRTD) Group. J Heart Lung Transplant. 1999;18(8):750-763.

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38. Laks H, Marelli D, Fonarow GC, et al. UCLA Heart Transplant Group. Use of two recipient lists for adults requiring heart transplantation. J Thorac Cardiovasc Surg. 2003;125(1):49-59. 39. Felker GM, O’Connor CM. Inotropic therapy for heart failure: An evidence-based approach. Am Heart J. 2001;142(3):393-401. 40. Stevenson LW. Clinical use of inotropic therapy for heart failure: Looking backward or forward? Part II: Chronic inotropic therapy. Circulation. 2003;108(4):492-497. 41. Krell MJ, Kline EM, Bates ER, et al. Intermittent, ambulatory dobutamine infusions in patients with severe congestive heart failure. Am Heart J. 1986;112:787-791. 42. Aaronson KD, Eppinger MJ, Dyke DB, et al. Left ventricular assist device therapy improves utilization of donor hearts. J Am Coll Cardiol. 39(8):12471254. 43. John R, Lietz K, Burke E, et al. Intravenous immunoglobulin reduces anti-HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left-ventricular assist device recipients. Circulation. 1999;100:II229-II235. 44. Itescu S, Burke E, Lietz K, et al. Iravenous pulse administration of cyclophosphamide is an effective and safe treatment for sensitized cardiac allograft recipients. Circulation. 2002;105(10):1214-1219. 45. Deng MC, Edwards LB, Hertz MI, et al. Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation: Second annual report—2004. J Heart Lung Transplant. 2004;23(9):1027-1034. 46. Lietz K, Miller LW. Will left -ventricular assist device therapy replace heart transplantation in the foreseeable future? Curr Opin Cardiol. 2005;20(2): 132-137. 47. Miller LW. Patient selection for use of ventricular assist devices as a bridge to transplantation. Ann Thorac Surg. 2003;75:S66-S71. 48. Lietz K, Miller LW. Left ventricular assist devices: Evolving devices and indications for use in ischemic heart disease. Curr Opin Cardiol. 2004;19(6): 613-618. 49. Kirklin JK, McFriffin D, Young JB. Heart Transplantation. New York: Churchill Livingstone; 2002. 50. Farrar DJ, Hill JD. Univentricular and biventricular Thoratec VAD support as a bridge to transplantation. Ann Thorac Surg. 1993;55:276-282. 51. El Banayosy A, Arusoglu L, Kizner L, et al. Patients bridged to transplantation with the Thoratec VAD device: A single-center retrospective study on more than 100 patients. J Heart Lung Transplant. 2000;19:964-968.

258 52. Copeland JG, Smith RG, Arabia FA, et al. Cardio West Total Artificial Heart Investigators. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004;351(9):859-867. 53. Morgan JA, John R, Rao V, et al. Bridging to transplant with the HeartMate left ventricular assist device: The Columbia Presbyterian 12-years experience. J Thorac Cardiovasc Surg. 2004;127(5):1309-1316. 54. Deng MC, Weyand M, Hammel D, et al. Selection and management of ventricular assist device patients: The Muenster experience. J Heart Lung Transplant. 2000;19:S77-S82.

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Index

A AAMD. See Atrial arrhythmia management devices (AAMDs). Abiomed LVADs, 252f ACC/AHA. See American College of Cardiology/ American Heart Association (ACC/AHA). ACE. See Angiotensin-converting enzyme (ACE) inhibitors. Acidosis, 65 ACS. See Acute coronary syndrome (ACS). Action potential diagrams, 165f Acute coronary syndrome (ACS) management of, 130, 131t treatment options in, 142 Acute Decompensated Failure National Registry (ADHERE), 130t Acute heart failure syndrome (AHFS) assessment of, 131–137 clinical presentation of, 129, 137–141, 150 components of, 141–148 costs of, 129 drugs for, 143–149 evidence-based practice for, 129 management principles in, 130–131 management summary table for, 149t patient demographics in, 129, 130t precipitants of, 133t prognostic variables in, 136–137 Acute Infarction Ramipril Efficacy (AIRE), 100, 162 Acute rate control, 188–190, 189t Adaptive Servo-Ventilators, 231 Adenosine A1 receptor antagonists, 86 Advanced practice nurses, follow-up by, 61 AFFIRM. See Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. African-American Heart Failure Trial (A-HeFT), 88, 163–165

African-Americans beta-blockers for, 120–121 mortality rates in, 88, 101–102 Age/aging beta blockers effect on, 120 comorbidities in, 229 digoxin’s effect on, 80 heart failure prevalence and, 3, 5 length of stay and, 6 in New Zealand, 4–5 for transplantation, 245–246 AHFS. See Acute heart failure syndrome (AHFS). AIRE. See Acute Infarction Ramipril Efficacy (AIRE). Albumin, infusion of, 85 Alcohol abuse, 70 Aldactone, 163 Aldosterone, 15, 24–25, 28, 103 Aldosterone antagonists in diastolic dysfunction, 114 dosage of, 114t effects on survival, 110–111 hemodynamic effects of, 109–110 hyperkalemia with, 112, 114b LV remodeling with, 110 mechanism of, 163–164 mortality with, 113f post-MI, 111–112 “Aldosterone escape,” 109 Allergy to loop diuretics, 83 American College of Cardiology/American Heart Association (ACC/AHA) on cardiac glyocosides, 77 catheterization guidelines of, 53–54 on CCBs, 89 on CRT, 224 evaluation and management guidelines of, 1 guidelines for atrial fibrillation treatment, 191f on ICDs, 218

259

260 Amiodarone adverse effects and drug interactions with, 171, 185–186 benefits of, 166, 193–194 in clinical trials, 168–169, 171, 173–176, 180f, 195t dosage of, 185, 194 with ICDs, 183–184 Amiodarone Versus Implantable Defrbrillator Randomized Trial (AMIOVERT), 212t, 213 AMIOVERT. See Amiodarone Versus Implantable Defrbrillator Randomized Trial (AMIOVERT). Amlodipine, 88–89, 122f Anemia, 137, 228t, 233–234 Angina pectoris, 243 Angiography modality comparison of, 52t, 53–54 radionuclide (RNA) type of, 51–53 Angiotensin-converting enzyme (ACE) inhibitors with ARBs, 105–106 vs. ARBs in MI, 106–107 vs. beta-blockers, 124f cough with, 102, 105, 229–230 with diuretics, 103 dosage of, 96t, 109 exercise capacity with, 97–98 hemodynamic effects of, 95–97 LV remodeling with, 97 mortality benefit of, 18, 87, 98–99, 109b pregnancy and breastfeeding with, 103 race and, 101–102 rationale for, 95 renal function with, 102–103 side effects of, 108 studies on, 63t, 70t, 162–163 Angiotensin I and II, 115f, 163 Angiotensin receptor blockers (ARBs) vs. ACE inhibitors, 103, 106–107 with ACE inhibitors, 105–106 benefits of, 7 clinical impact of, 104 dosage of, 103t, 108 exercise capacity with, 104 hemodynamic effects of, 103–104 mechanism of, 162–163 mortality rates with, 105 pooled data on, 108–109 side effects of, 108 studies on, 63t, 103–107 Angiotensin subtype receptors (AT1 and AT2), 14–15 Anglo-Scandinavian Outcomes Trial (ASCOT), 122 ANP. See Atrial natriuretic peptide (ANP). Anti-HLA antibodies, 251

Index Antiarrhythmic drugs. See also specific drugs and drug categories. for AFib, 187–188 clinical trials on, 166–172 defibrillation thresholds with, 187 ECG changes with, 166 general guidelines for, 202–203 vs. ICDs, 173–177 indications for, 185–187 initiation of, 196–197 limitations of, 193 mortality comparison tables of, 168–170 rationale for, 190–191 in rhythm control strategy, 196–197 side effects of, 167t strategy for use, 192–195 for V tach, 160–172, 185–187 Antiarrhythmics Versus Implantable Defibrillator (AVID) Trial, 215 Anticoagulant therapy, 192 Antidepressant medications, 235 Antihypertensive medications, comparison of, 122f Antioxidant supplements, 70 Antitachycardia therapy (ATP), 183 Apoptosis of myocytes, 18–19, 23–24 Arginine vasopressin receptor antagonists, 86 ARIC. See Atherosclerosis Risk in Communities (ARIC) study. Arrhythmias atrial. See Atrial fibrillation (AFib). atrial vs. ventricular, 146 bradyarrhythmias, 196, 199–201 proarrhythmia, 196–197, 215–218 as prognostic variable, 137 as transplantation indication, 243 ventricular. See Ventricular tachyarrhythmias. Arrhythmogenesis, mechanism of, 165–166 Arterial pressure tracings, 135f Arthritis, 228t, 235 ASCOT. See Anglo-Scandinavian Outcomes Trial (ASCOT). Assessment of Lisinopril and Survival (ATLAS), 101 Atenolol for diabetic patients, 122f Atherosclerosis Risk in Communities (ARIC) study, 122 ATLAS. See Assessment of Lisinopril and Survival (ATLAS). Atrial arrhythmia management devices (AAMDs), 199 Atrial fibrillation (AFib) AAMDs for, 199 ablation therapy for, 197–198 ACC/AHA guidelines for, 191f acute rate control in, 188–190 clinical presentation of, 146

Index control of ventricular response in, 191–192 CRT for, 222–223 drugs for, 187–188, 196–197 management of, 130, 131t, 203 mortality with, 187 overview of, 187–188 primary prevention of, 195–196 radiofrequency ablation for, 197–198 relative percentages of, 161t rhythm control strategy in, 192–195 secondary treatment of, 188 surgical treatments for, 198–199 treatment algorithm for, 188f treatment rationale in, 190–191 ventricular response in, 191–192 Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 190–192, 194 Atrial flutter ablation, 198–199 Atrial natriuretic peptide (ANP), 15–18 Atrial premature depolarizations (APDs), 197 Auscultation, 48–49 AVID. See Antiarrhythmics Versus Implantable Defibrillator (AVID) Trial. Azimilide, 168, 170t 172, 184, 194–195 B B-type natriuretic peptide (BNP) activation of, 15–18 assays for, 50–51 interpretation of, 134 plasma values of, 17–18 as prognostic variable, 136 Beta-blockers (B-adrenergic antagonists) vs. ACE inhibitors, 124f for African-Americans, 120–121 benefits of, 7, 18 vs. CCBs, 192 dosage of, 123–124 in drug comparison table, 189t effects on elderly patients, 120 for hypertension, 116f LV remodeling with, 115–117 mortality with, 114–115, 119–120, 124f post-MI, 119–120 race and, 120–121 as rate control agent, 190 as SCD prevention, 161, 162f Bilirubin, 247f Bioavailability (digoxin), 77–78 Biomedicus LVADs, 252f Biopsy of skeketal muscle, 65–66 Bisoprolol dosage of, 124f mortality with, 117–118

261 Blood pressure (BP) as prognostic variable, 136 systemic (SBP), 95 BNP. See B-type natriuretic peptide (BNP). Boston heart failure score, 2t Bradyarrhythmias antiarrhythmic agents for, 196 CRT for, 199, 201 ICDs for, 199–201 syncope in, 202 Breastfeeding with ACE inhibitors, 103 Bumetanide, 82 C C-reactive protein (CRP), 20 CABG-Patch. See Coronary artery bypass graft (CABG)-Patch. Cachexia, 19, 249 Calcium altered homeostasis in, 26–27 digoxin’s effect on, 77 diuretics’ effect on, 84 Calcium channel blockers (CCBs) ACC/AHA guidelines for, 89 dosage of, 189–190 in drug comparison table, 189t first-generation type of, 88 second-generation type of, 88–89 Calorie intake, 69 Candesartan, 103–109 Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial with ACE inhibitors, 163 CHARM-Alternative and CHARM-Added trials, 105 CHARM-Overall, 108 CHARM-Preserved, 107 findings in, 7f, 103 CAPRICORN. See Carvedilol Post-Infarct Survival Control in Left-Ventricular Dysfunction (CAPRICORN) study. Captopril dosage of, 96t, 97t, 98 studies on, 95 Carbonic anhydrase inhibitors, 81 Cardiac Arrthythmia Supression Trials (CAST), 167, 168t Cardiac catheterization ACC/AHA guidelines for, 53–54 modality comparison in, 52t, 53 Cardiac glycosides, 77 Cardiac index (CI), ACE inhibitors and, 95 Cardiac Insufficiency Bisoprolol Study (CIBIS), 115, 161, 232

262 Cardiac output (CO) initial testing of, 133–134 interelationships of, 135f low level at presentation, 48 Cardiac resynchronization therapy (CRT) for atrial fibrillation, 222–223 for bradyarrhythmias, 199, 201 clinical trials on, 217t, 220–222 optimization of, 223 role in arrhythmias, 181–182 unresolved issues in, 222–224 Cardiac transplantation candidate selection in, 243–245, 251f contraindications to, 245–249 enrollment on waiting list, 249–250 indications for, 241–243 vs. LVADs, 241 mortality rates after, 243–244, 247f recipient age-specific, 245–246 UNOS listing policy, 249, 255 waiting period management of HF, 243, 250–255 waiting times for, 242f, 251f Cardiogenic shock management of, 131t systolic blood pressure in, 145–146 as transplantation indication, 241 Cardiomyopathies, familial, 48 Cardiomyopathy Arrhythmia Trial (CAT), 212t, 213 “Cardiorenal” syndrome, 145 Cardiotrophin-1 (CT-1), 20 Cardioversion, 192–194 Cardiowest TAH LVADs, 252f CARMEN. See Carvedilol and ACE Inhibitor Remodeling Mild HF Evaluation (CARMEN). Carvedilol dosage of, 124f effects on morbidity, 120 vs. metoprolol, 119, 161–162 mortality with, 117–119 race and, 121f studies on, 115–117 Carvedilol and ACE Inhibitor Remodeling Mild HF Evaluation (CARMEN), 116–117 Carvedilol Post-Infarct Survival Control in LeftVentricular Dysfunction (CAPRICORN) study, 119–120 Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study, 115 CAST I and II. See Cardiac Arrthythmia Supression Trials (CAST). CAT. See Cardiomyopathy Arrhythmia Trial (CAT). Catecholamines, heart failure-related, 14 Catheter ablation. See Radiofrequency ablation (RFA). Catheterization. See Cardiac catheterization.

Index Cellular electrophysiology, 165–166 Central sleep apnea (CSA), 230 CHARM Programme. See Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial. Chest radiograph (CXR, chest x-ray) as diagnostic tool, 2t, 49–50 markers on, 134 CI. See Cardiac index (CI). CIBIS II treatment trial, 7f, 117 Class Ia drugs, 193 CO. See Cardiac output (CO). Cognitive behavior therapy, 235 Cognitive impairment, as risk factor, 228t, 234, 250t Comorbidity. See also specific disorders and diseases. condition-specific management of, 228t, 229–235 defined, 227 overview of, 47, 227–229 polypharmacy in, 235–236 as transplant contraindication, 248 Computed tomography (CT) scan as diagnostic tool, 54 by electron beam (EBCT), 52t, 54 modality comparison of, 52t Congestion assessment of, 134 bedside evaluation of, 49f Congestive heart failure (CHF), team approaches to, 59–61 CONSENSUS. See Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Continuous positive airway pressure (CPAP), 143–144, 230–231 Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), 98 COPERNICUS. See Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. Coronary Artery Bypass Graft (CABG)-Patch, 212t, 213 Coronary artery disease (CAD), as heart failure cause, 7 Costs/cost effectiveness future increases in, 227 studies on, 59–60 Cough with ACE inhibitors, 102, 229–230 with ARBs, 105 CoxMAZE procedure, 198 CPAP. See Continuous positive airway pressure (CPAP). Creatine supplements, 69 CRT. See Cardiac resynchronization therapy (CRT). CSA. See Central sleep apnea (CSA). Ct. See Computed tomography (CT) scan. Cyclo-oxygenase-2 (COX-2) selective inhibitors, 235 Cytokines, proinflammatory, 19–21

Index D DD. See Deletion allele (DD). DeBakey LVADs, 252f DeBakey Micromed LVADs, 253f Defibrillation thresholds (DFTs), 187, 215–218 Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE), 212t, 214 DEFINITE. See Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE). Deletion allele (DD), 15 Depression, 228t, 234–235 Device therapy device selection criteria for, 252 evolution of, 211 Diabetes medications, as risk factor, 9 Diabetes mellitus (DM) antihypertensive medications for, 122f as transplant contraindication, 247f, 249 Diagnostic imaging. See also specific modalities. disease-specific modality comparison in, 52t Diastolic dysfunction ACE inhibitor therapy with, 107 aldosterone antagonists in, 114 ARB therapy with, 107 coexistence with systolic, 26 neurohormonal effects on, 17 vs. systolic, 27–28, 51 Diets/diet therapies high-salt diets, 83 sodium restriction, 68–69 DIG trial. See Digitalis Investigator Group (DIG) trial. Digitalis Investigator Group (DIG) trial, 78–79 Digitalis toxicity anti-digoxin immunotherapy, 81 in atrial fibrillation, 192 ECG manifestations of, 81 effects on electrolytes, 80 Digoxin anti-digoxin immunotherapy, 81 clinical use and recommendations for, 79–80, 141, 147 comparison tables of, 138t, 139t contraindications to, 148 diuretics with, 87 dosage of, 189, 192 effects on intracellular calcium, 77 ejection fraction with, 78, 80 gender and, 79 mechanism and pharmacokinetics of, 77–78 mortality rates with, 79, 190–191 physiologic effects and efficacy of, 78–79 as rate control agent, 189, 192 systemic-specific side effects of, 80t, 81 Diltiazem, 88, 190

263 Discharge planning criteria, 148–149, 215–218 Disease Management programs comparison tables of, 62t, 63t, 64t components of, 70t studies on, 57–64 Disopyramide, 193 Diuretics/diuresis with ACE inhibitors, 103 categories of, 81–84 classifications and mechanisms of, 81–82 clinical use and prognosis with, 85 comparison tables of, 138t, 139t decreased secretion of, 84–85 digoxin with, 87 dosage of, 84 drug interactions with, 233 effects on electrolytes, 84, 140 intravenous infusion of, 85 side effects of, 83–84 Dobutamine administration of, 146 comparison tables of, 138t, 139t Dofetilide in clinical trials, 168, 170t, 171–172, 184 dosage of, 186–187 drugs contraindicated with, 187t limitations of, 194–195 Donor organ shortage, 241 Doppler measurements, mitral, 51 Dronedarone, 196 Drugs. See also specific drugs and drug categories. ACE inhibitors. See Angiotensin-converting enzyme (ACE) inhibitors. adjunctive to ICDs, 183 antihypertensive medications. See specific drugs. ARBs. See Angiotensin receptor blockers (ARBs). beta-blockers. See Beta-blockers (B-adrenergic antagonists). Class Ia drugs, 193 initiation and titration of, 148–149 interactions with, 185–186, 233 vasodilators. See Vasodilators. Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, 200, 223–224 Dynamic assessment, 134–135 Dyspnea with exercise, 65 presenting, 57 Dyssynchrony, myocardial, 217t, 220–223 E Eastern Finland study, 3 ECBT. See Electron beam CT.

264 Echocardiogram/graphy (ECHO) with ACE inhibitors, 98 as diagnostic tool, 51 modality comparison of, 52t ECMO LVADs, 252f Edema presenting, 57 treatment of resistant edema, 84–85 EHFS II. See EuroHeart Failure Survey II (EHFS II). Ejection fraction (EF) as diagnostic tool, 51 with digoxin, 78, 80 as ICD indication, 178t in ICD trials, 212t Elderly patients. See Age/aging. Electrocardiograph/graphy (ECG/EKG) changes with antiarrhythmic drugs, 166 as diagnostic tool, 50 digoxin’s effect on, 81 QRS criteria for CRT, 217t, 220–223 wave sequence in SCD, 165f Electrolytes digoxin toxicity and, 80 diuretic effects on, 83–84, 140 Electron beam CT, 52t, 54 Electrophysiology, cellular, 165–166 ELITE. See Evaluation of Losartan in the Elderly (ELITE). Emergency department (ED) door-to-therapy times, 132 Enalapril administration of, 87 dosage of, 96t, 97t, 98 mortality trials with, 99–100 race and, 102 studies on, 162 End-stage heart failure defined, 148 LVADs for, 242f management of, 131t renal function in, 145 Endothelial constitutive nitric oxide (eNOS) expression, 18, 21–22 Endothelin-1 (ET-1) ETA and ETB receptors, 16, 28 physiologic effects of, 16, 18, 24 Endotracheal intubation, 144 Ephesus. See Eplerenone Heart Failure Efficacy and Survival Study (EPHESUS). Epidemiology, 1–9 Eplerenone Heart Failure Efficacy and Survival Study (EPHESUS), 111–112, 163–164 Eplerenone, post-MI, 111–112 Erythropoietin, 233–234 Esmolol, 190

Index ET. See Endothelin-1 (ET-1). Ethacrynic acid action of, 82 ototoxicity from, 83 Etiology, 7–8 EuroHeart Failure Survey II (EHFS II), 130t European Society of Cardiology (ESC) criteria, 2t Evaluation of Losartan in the Elderly (ELITE), 104 Evidence-based practice for HF, 129 Exercise capacity with ACE inhibitors, 97–98 with ARBs, 104 Exercise testing, 244–245 Exercise training programs comparisons of, 67 dyspnea with, 65 erythropoietin and, 233–234 halting of, 67–68 overview of, 64–66 resistance vs. aerobic, 68 studies on, 70t syncope with, 202 Extramatch collaborative group, 67 F Felodipine, 88–89 Flecainide, 193 Fosinopril, 96t, 97t Framingham Heart Study, 1, 3–9 Framingham Offspring Study, 3 Functional capacity, 244, 252–253 Furosemide action of, 82 comparison tables of, 138t, 139t dosage of, 84 ototoxicity from, 83 G Gender digoxin and, 79 heart failure and, 4 TNF levels and, 19 Genes/genetics ACE gene, 15 variations in RAAS, 15 Glomerular filtration rate (GFR), 232 Grace registry, 8 Growth factors, 23 Guanosine 3′, 5′-cyclic monophosphate, 28 H Haisseguerre study, 198 Heart Failure and a Controlled Trial Investigating Outcomes of Exercise Training (HF-action), 67

Index Heart failure (HF) acute, 80, 148 as acute syndrome. See Acute heart failure syndrome (AHFS). classification of, 145t, 148. See also New York Heart Association (NYHA). comorbidity in. See Comorbidity. congestive. See Congestive heart failure (CHF). definition, incidence, and prevalence of, 1, 3–5 device therapy for. See Device therapy; specific devices. diagnosis of. See Diagnostic imaging; Laboratory evaluations. diagnostic criteria for, 2t diastolic. See Diastolic dysfunction. disposition algorithm in, 132f duration of, 245 early stages of, 17 end-stage HF, 131t, 145, 148 epidemiology of, 1–9 etiology of, 7–8, 136–137 evolution of treatment for, 211 evolutionary stages of, 3f future burden of, 8–9 mortality rates in. See Mortality rates. nonpharmacologic management of, 57–71. See also specific modalities. pharmacological management of. See Drugs; specific drugs. prognosis in. See Prognosis. right-sided, 80 risk stratification for, 132f stages and classifications of, 96f. See also New York Heart Association (NYHA). syncope in, 201–202 systolic. See Systolic dysfunction. treatment for. See specific treatments; Treatment/ therapies. worsening chronic HF, 131t, 137–141, 148, 200f Heart Failure Survival Score (HFSS), 245, 246f Heart Outcomes Protection Evaluation (HOPE), 162 Heart rate, rhythm patterns of, 49 Heartmate LVADs, 252f, 253f Hemodilution, 233 Hemodynamics ACE inhibitors effects on, 95–97 aldosterone’s effects on, 109–110 assessment of, 53 transplantation and, 244, 252–253 Hepatic dysfunction, 249 History-taking, 47–48, 132–133 Homeostasis and calcium, 26–27 HOPE. See Heart Outcomes Protection Evaluation (HOPE).

265 Hospitalization rates ACE inhibitor-specific, 97t comorbidity-specific, 227 length of stay in, 6 mortality-specific, 70t in New Zealand, 5f prevalence of, 5–6 readmission rates, 63–64 studies on, 62t in worsening HF, 200f Hydralazine comparison tables of, 138t, 139t studies on, 162 Hydralazine-isosorbide combination mortality trials with, 99–100 studies on, 87–88 Hyperkalemia/hypokalemia, 83, 112, 114b, 232–233 Hyperlipidemia, diuretic-related, 84 Hypersensitivity reactions, 83 Hypertension beta-blockers for, 116f as heart failure cause, 7 as precursor, 27–28 as transplant contraindication, 249 treatment options in, 141–142 Hypertrophy, left ventricular (LVH), 27–28 Hyperuricemia, 84 Hypomagnesemia, 84 Hyponatremia, 84, 136 Hypoperfusion, 141, 232 I I and D (incision and drainage), 7 ICAM. See Intercellular adhesion molecule-1 (ICAM-1). ICDs. See Implantable cardioverter-defibrillators (ICDs). ICM. See Ischemic heart disease/cardiomyopathy (ICM). IGF. See Insulin-like growth factor (IGF-1). IL. See Interleukins. Impedance cardiography, 55 Implantable cardioverter-defibrillators (ICDs) vs. antiarrhythmics, 173–177 defibrillation thresholds for, 187, 215–218 discharges/shocks from, 182–183, 184f, 215–218 drugs adjunctive to, 183 implantation timing for, 181 indications for, 178t, 218–220 limitations of, 160 mortality with, 214f overview of, 178 for primary prevention, 179–181, 211–215 as SCD prevention, 172, 178–181 for secondary prevention, 178–179, 215, 216t trials on, 172–177, 199–200

266 Infection/s, 247f, 248 Inflammation/inflammatory response biomarkers of, 14f, 18–20 treatment for, 21 ventricular remodeling and, 25 Inotropic therapy comparison tables of, 138t, 139t morbidity with, 146 Insulin-like growth factor (IGF-1), 23 Intercellular adhesion molecule-1 (ICAM-1), 20 Interleukin-2 (IL-2), 20 Interleukin-6 (IL-6), 19, 21 Intravenous (IV) therapy of albumin, 85 for diuretics, 85 Ischemic heart disease/cardiomyopathy (ICM) ICD prevention trials in, 178t, 211–215 vs. nonischemic, 160, 160–165 transplantation with, 244 Isosorbide dinitrate rationale for, 143 studies on, 87–88, 162 J Jarvik 2000 LVADs, 252f Jugular venous pulse (JVP), 48 K Kidneys, neurohormonal effects on, 16–17 Kinases, 22 L L-carnitine supplements, 69–70 Laboratory evaluations. See also specific tests. initial diagnostic tests, 133 overview of, 50–51 Left ventricular assist devices (LVADs) complications of, 255 components of, 253f device selection criteria for, 252 with end-stage HF, 242f history of, 251–252 models/types of, 252f mortality awaiting transplant, 251f mortality with, 255 patient selection criteria for, 253f, 254f short- vs. long-term, 254–255 single vs. biventricular, 254 vs. transplantation, 241 Left ventricular dysfunction ACC/AHA glycoside guidelines for, 77 neurohormonal activation of, 16–18 Left-ventricular filling pressure (LVFP), as prognostic variable, 136

Index Left ventricular hypertrophy, 27–28 Left ventricular remodeling with ACE inhibitors, 97 aldosterone antagonists and, 110 MMP effects on, 28 neurohormonal effects on, 24–25 overview of, 23 TNF effects on, 21 Length of stay (in hospital), 6 Leptin, 22–23 Levosimendan administration of, 147 comparison tables of, 139t Lipid overload, 22–23 Lipocardiotoxicity, 22–23 Lisinopril, 96t, 97t, 98, 101 Loop diuretics action of, 81–82 administration of, 138–141 equal efficacy of, 85 resistance to, 140 side effects of, 83–84 types of, 82 Losartan, 103–109 LVH. See Hypertrophy, left ventricular (LVH). M M-mode doppler, modality comparison of, 52t MACH-I. See Mortality Assessment in Congestive Heart Failure (MACH-I) trial. MADIT. See Multicenter Automatic Defibrillator Implantation Trials (MADIT) I and II. Magnesium, diuretic effects on, 84 Magnetic resonance imaging (MRI), modality comparison of, 52t, 54–55 Major cardiac events (MCEs), 110–111 Malignancy, 247f, 248 Matrix metalloproteinases (MMPS), 25–26, 28 Mechanisms of disease growth factor-related, 14f, 23 inflammatory, 14f, 18–21, 25 neurohormonal, 13–18, 24–25 oxidative, 14f, 21–23 pathway concept in, 13, 14f in systole and diastole dysfunction, 14f, 26–28 ventricular remodeling and, 14f, 23–26 MERIT-HF. See Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Metabolic alkalosis, 83–84 Metabolic syndrome, 9 Metoprolol vs. carvedilol, 119, 161–162 dosage of, 124f, 190, 191–192

Index efficacy of, 123f studies on, 21, 115, 117–118 Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), 115, 117–118, 160f, 161, 162f MHC. See Myosin heavy chains (MHC). Mibefradil, 89 Milrinone administration of, 147 comparison tables of, 138t, 139t MMPS. See Matrix metalloproteinases (MMPs). Mode Selection Trial in Sinus Node Dysfunction (MOST), 199–200 Monocyte chemoattractant protein-1 (MCP-1), 19–20 Morbidity carvedilol effects on, 120 comorbidities. See Comorbidity. inotropes effects on, 146 Moricizine, 168 Morphine, 138t, 139t, 143 Mortality Assessment in Congestive Heart Failure (MACH-I) trial, 89 Mortality rates with ACE inhibitors, 87, 97–101 in African-Americans, 88, 101–102 with aldosterone antagonists, 113f annualized, 6–8 antiarrhythmic agents effects on, 168–170 with ARBs, 105 with beta-blockers, 114–115, 119–120, 124f with carvedilol, 117–119 with digoxin, 79, 190–191 in general, 6–8 with LVADs, 251, 255 neurohormone-related, 17–18 oxygen consumption-related, 245f after transplantation, 242f, 243–244, 247f treatment specific, 70t with vasodilators, 87–88, 99–100 in worsening chronic HF, 200f MPI. See Myocardial perfusion imaging (MPI). MRI. See Magnetic resonance imaging (MRI). Multicenter Automatic Defibrillator Implantation Trials (MADIT) I and II, 174t, 178t, 179–181, 201 Multicenter Unsustained Tachycardia Trial (MUSST), 212t, 213 Multichannel uptake gated acquisition (MUGA) scan, 52t, 53 MUSTT. See Multicenter Unsustained Tachycardia Trial (MUSTT). Myocardial hibernation, 131 Myocardial infarction (MI), acute (AMI) ACE inhibitors vs. ARBs in, 106–107 aldosterone antagonists after, 111–112

267 beta-blockers after, 119–120. See also Beta-blockers. digoxin’s effect on, 80 as heart failure cause, 7 ICDs after, 212t, 214–215. See also Implantable cardioverter-defibrillators (ICDs). systolic dysfunction after, 100–101, 111–112 Myocardial perfusion imaging (MPI), 51–53 Myocardium, avoiding injury to, 131 Myosin heavy chains (MHC), 24, 65 N Na-K-ATPase, 77, 81 Natriuretic peptides activation of, 16 physiologic effects of, 15–18 Nesiritide administration of, 138–140 comparison tables of, 138t, 139t Neuregulin (NRG), 23 Neurohormonal blockade. See also specific drugs. agent categories for, 95 benefits of, 7 table of trials on, 125t Neurohormones/neurohormonal response activation of, 16–18, 89 mortality-related, 17–18 renal effects of, 16–17 in SOLVD Trial, 13 New York Heart Association (NYHA) classifications of HF, 115f, 159, 161t, 219t on transplantation criteria, 241, 243 New Zealand, 4–5 NICM. See Nonischemic cardiomyopathy (NICM). Nifedipine, 88 Nitrates, 143 Nitric oxide (NO) aldosterone effects on, 15 endothelial constitutive NO synthase (eNOS) expression, 18, 21–22 Nitroglycerin administration of, 142 comparison tables of, 138t, 139t Nitroprusside, 86, 138t, 139t NO. See Nitric oxide (NO). Noninvasive positive pressure ventilation (NPPV), 143–144 Noninvasive ventilation (NIV), 143–144 Nonischemic cardiomyopathy (NICM) ICD prevention trials in, 178t, 179–180, 213–215 vs. ischemic, 160, 165–166 Nonsteroidal anti-inflammatory drugs (NSAIDS), 235 Nonsustained ventricular tachyarrhythmia (NSVT), 178t, 179–180 Norepinephrine (noradrenaline), 14, 17–18 Novacor LVADs, 252f, 253f

268 NPPV. See Noninvasive positive pressure ventilation (NPPV). NRG. See Neuregulin (NRG). NRMI-2. See Second National Registry of Myocardial Infarction (NRMI-2). NSVT. See Nonsustained ventricular tachyarrhythmia (NSVT). Nuclear medicine. See Radionuclide imaging. Nurses in advanced practice, 61 NYHA. See New York Heart Association (NYHA). O Obesity as risk factor, 9, 228t, 235 as transplant contraindication, 247f, 249 Obstructive airway disease beta blockers and, 230 as transplant contraindication, 247f, 248 Obstructive sleep apnea (OSA), 230 Optimal Therapy in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL), 106–107 Organized Program to Initiate Life-saving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF), 130t Orthostatic changes, 134–135 OSA. See Obstructive sleep apnea (OSA). Osteoporosis, diuretic-related, 84 Ototoxicity from loop diuretics, 83 Oxidative stress, 15, 18, 21–23 Oxygen (O2) therapy administration of, 143–145 nocturnal supplements of, 231 P Patient awareness, 57–58 PAVE. See Post AV-Nodal Ablation Evaluation (PAVE). PCWP. See Pulmonary capillary wedge pressure (PCWP). PEP-CHF. See Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF). Peptic ulcer disease, 249 Perfusion bedside evaluation of, 49f RNA/MUGA SPECT for, 52t, 53 Perindopril dosage of, 96t studies on, 107 Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF), 107 Peripheral edema, 48 Phentolamine, 86 Phosphodiesterase-5a (PDE-5a), 28 Phospholamban, 27

Index Physical examination, 48–49, 133–134 PNE. See Prerandomization plasma norepinephrine (PNE). Polypharmacy, 235–236 Positron emission tomography (PET) scan as diagnostic tool, 53 modality comparison of, 52t Post AV-Nodal Ablation Evaluation (PAVE), 197 Potassium contraindications to supplements of, 163–165, 233 diuretic effects on, 83 Potassium-sparing diuretics, 81 PRAISE trial. See Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial. Prazosin, 87–88 Pregnancy with ACE inhibitors, 103 Prerandomization plasma norepinephrine (PNE), 123f Procainamide, 193 Prognosis. See also under specific disorders. blood pressure-related, 136 BPN-related, 136 cytokine-related, 21 in general, 6–8 neurohormone-related, 17–18 with ventricular arrhythmias, 137, 211 Propafenone, 173, 194–195 Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, 88–89 Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), 78–79 Prostaglandin inhibitor aspirin, 235 Protein intake, 69 Psychosocial issues. See Cognitive impairment. Pulmonary artery catheterization, 135–136 Pulmonary capillary wedge pressure (PCWP) ACE inhibitors and, 95 interelationships of, 135f Pulmonary edema clinical presentation of, 142–143 management of, 130, 131t Pulmonary hypertension, 246–248 Q Quantitative schemes, as prognostic variable, 137 Quinapril, 96t, 97t Quinidine, 193 R Race ACE inhibitors and, 101–102 beta-blockers and, 120–121 carvedilol and, 121f RADIANCE. See Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE).

Index Radiofrequency ablation (RFA) for atrial fibrillation, 197–198 for atrial flutter, 198–199 indications for, 184–185 Radiography of chest, 2t, 49–50, 134 Radionuclide imaging, 51–53. See also Angiography. Rales, presenting, 48 Ramipril dosage of, 96t, 97t studies on, 100, 162 Randomized Aldactone Evaluation Study (RALES), 110–112, 163, 232–233 Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE), 78–79 Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH), 241, 242f Reactive oxygen species (ROS), 15, 20–23 Regurgitation, valvular, 144–145 Renal function with ACE inhibitors, 102–103 with diuretics, 81–85 drugs effects on, 77, 141 dysfunction overview and therapies, 228t, 231–233 in end-stage HF, 145 impairment and drug clearance, 80 neurohormonal effects on, 16–17 as prognostic variable, 136 as transplant contraindication, 247f, 248 Renin, 14 Renin-angiotensin-aldosterone system (RAAS) activation of, 14–15 ARBs effects on, 162–163 BNP effects on, 16 genetic variation in, 15 vasodilator effects on, 86–87 Resistance training, 68 Respiratory disorders, 228t, 229–230 Respiratory system, 21–23 Reversal of Ventricular Remodeling with Toprol-XL (REVERT), 115–116 Right ventricular (RV) pacing, 199–201 Risk factors, 9 Rotterdam study, 3–5 S SARAs. See Selective aldosterone receptor antagonists (SARAs). Sarcoplasmic reticulum Ca2+ATpase (SERCA2), 26–27 SAVE. See Survival and Ventricular Enlargement (SAVE) trial. SBD. See Sleep-disordered breathing (SBD). Scotland, 3, 6

269 Second National Registry of Myocardial Infarction (NRMI-2), 7 Selective aldosterone receptor antagonists (SARAs), 111–112 Selective serotonin reuptake inhibitors (SSRIs), 235 Self-care, patient, 61 SERCA2. See Sarcoplasmic reticulum Ca2+ATPase (SERCA2). Serum creatinine (Crt), 137t, 232, 247f Shocks/discharges from ICDs, 182–183, 184f, 215–218 Sildenafil, 28 Single-photon emission computed tomography (SPECT), RNA/MUGA type of, 52t, 53 Sinus node dysfunction, 199–200 Sleep-disordered breathing (SBD), 230 Sodium hi-salt diets, 83 restriction of, 68–69 tubular reabsorption of, 85 Sodium retention, 17 SOLVD trials. See Studies of Left Ventricular Dysfunction (SOLVD) trials. Sotalol in clinical trials, 168, 195t dosage of, 186, 194 with ICDs, 183–184 SPECT. See Single-photon emission computed tomography (SPECT). Spironolactone dosage of, 114 LV remodeling with, 110–113 studies on, 163, 232–233 Statins, mechanism of, 164–165 Studies of Left Ventricular Dysfunction (SOLVD) trials on neurohormones, 13 race in, 101–102 SOLVD-treatment study, 7f, 99 Sublingual nitroglycerin, 134–135 Sudden Cardiac Death in Heart Failure trial (SCDHeFT), 212t, 214, 215f Sudden cardiac death (SCD) cumulative mortality in, 162f drug-related prevention of, 160–172, 185–187, 196–197 ECG wave sequence in, 165f ICD prevention of, 172, 178–181 preventive devices against, 172–181, 199 preventive procedures against, 181–182, 184–185, 197–198 preventive strategy for, 203 Sulfonamide drugs, allergic reaction to, 83 Supplements, dietary, 69–70 Supraventricular tachycardias (SVTs), 159–160 Surgical techniques for atrial fibrillation, 198–199

270 Survival. See Mortality rates. Survival and Ventricular Enlargement (SAVE) trial, 100 SVR. See Systemic vascular resistance (SVR). SVTs. See Supraventricular tachycardias (SVTs). Syncope/presyncope in bradyarrhythmias, 202 in clinical trials, 201 with exercise, 202 Systemic vascular resistance (SVR), ACE inhibitors and, 95 Systolic blood pressure (SBP) in AHFS, 130 in cardiogenic shock, 145–146 interelationships of, 135f Systolic dysfunction ACE inhibitors for, 98–101 aldosterone antagonists in, 109–113 beta-blockers for, 119–120 coexistence with diastolic, 26 vs. diastolic, 27–28, 51 post-MI, 100–101, 111–112 T TBI. See Thoracic bioimpedance (TBI). Technetium imaging, 53 Telephone follow-up, 61 Thallium imaging, 53 Thiazide-like diuretics, action of, 81 Thoracic bioimpedance (TBI), 55 Thoratec implantable LVAD, 252f Thromboembolic events, 188, 192 Tissue inhibitor of metalloproteinases (TIMP), 26, 28 TNF. See Tumor necrosis factor (TNF). Tolvaptan, 86, 140–141 TOPCAT. See Treatment of Preserved Cardiac Function HF with Aldosterone Antagonist (TOPCAT). Torsemide, 82 TRACE. See Trandolapril Cardiac Evaluation (TRACE). Trandolapril dosage of, 96t studies on, 100–101, 162 Trandolapril Cardiac Evaluation (TRACE), 100–101, 162, 163f Transplantation, heart. See Cardiac transplantation. Treadmill stress testing with ACE inhibitors, 98 Treatment of Preserved Cardiac Function HF with Aldosterone Antagonist (TOPCAT), 114 Treatment/therapies. See also specific treatments and therapies. follow-up for, 61 mortality rates after, 242f neurohormone-related, 17–18 by stage, 3t

Index Troponin elevation of, 142 as prognostic variable, 136 Tumor necrosis factor (TNF) benefits of treatment, 21 inhibition of, 235 in LV remodeling, 25 physiologic effects of, 18–19 receptors TNFR1 and TNFR2, 18 U Ultrafiltration, 141 United Network for Organ Sharing (UNOS), 249–250, 255 V V-HeFT-I. See Veterans Administration Cooperative Vasodilator Heart Failure Trial (V-HeFT). V-HeFT-II. See Vasodilator Heart Failure Trials-II (V-HeFT-II). V-HeFT-III. See Vasodilator-Heart Failure Trial (V-HeFT-III). Val-HeFT. See Valsartan Heart Failure Trial II (Val-Heft-II). Valiant registry, 7–8 VALIDD. See Valsartan in Diastolic Dysfunction (VALIDD). Valsalva maneuver, 134–135 Valsartan, 13, 103–109, 163 Valsartan Heart Failure Trial II (Val-HeFT-II) on survival advantage, 163 for urinary system, 13 Valsartan in Acute Myocardial Infarction Trial (VALIANT) vs. ACE inhibitors, 106 with captopril, 163 Valsartan in Diastolic Dysfunction (VALIDD), 108 Valvular dysfunction, regurgitation-related, 144–145 Vascular disease, as transplant contraindication, 249 Vasodilator-Heart Failure Trial (V-HeFT-III), 89 Vasodilator Heart Failure Trials-II (V-HeFT-II), 99 Vasodilators administration of, 144t comparison tables of, 138t, 139t mortality trials with, 87–88, 99–100 rationale for, 86, 142 Vaughn-Williams schema, classification of antiarrhythmic drugs, 166, 167t Ventricular arrhythmias, clinical presentation of, 146 Ventricular premature depolarizations (VPDs), 167 Ventricular remodeling. See Left ventricular remodeling.

Index Ventricular tachyarrhythmias catheter ablation for, 184–185 CRT for, 181–182 devices for, 172–184 drugs for, 160–172, 185–187 mechanism of, 165–166 overview of, 159–160 prognosis with, 211 Ventriculography, modality comparison of, 52t Verapamil, 88, 190 Vesnarinone Evaluation of Survival Trial (VEST), 21

271 Veterans Administration Cooperative Vasodilator Heart Failure Trial (V-HeFT), 87 VPDs. See Ventricular premature depolarizations (VPDs). W Warfarin, 192 Wasting, 69 Weight/self-weighing loss of (wasting), 69 patient awareness of, 57–58