The Year in Interventional Cardiology 2002

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THE YEAR IN INTERVENTIONAL CARDIOLOGY 2002

THE YEAR IN INTERVENTIONAL CARDIOLOGY 2002 Edited by

HD WHITE, PJ DE FEIJTER, B MEIER, A COLOMBO, AP BANNING, R SCHRÄDER

CLINICAL PUBLISHING SERVICES OXFORD

Clinical Publishing Services Ltd Oxford Centre for Innovation Mill Street, Oxford OX2 OJX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 Web: www.clinicalpublishing.co.uk Distributed by: Plymbridge Distributors Ltd Estover Road Plymouth PL6 7PY, UK Tel: +44 1752 202300 Fax: +44 1752 202333 E mail: [email protected] © Clinical Publishing Services Ltd 2002 First published 2002 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing Services Ltd A catalogue record for this book is available from the British Library ISBN 0-203-01188-0 Master e-book ISBN

ISBN 0 9537339 7 1 (Print Edition) The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work Commissioning Editor: Jonathan Gregory Project Manager: Rosemary Osmond

Contents

Contributors

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Part I Pharmacological management of acute coronary syndromes Harvey D White 1.

Risk stratification in acute coronary syndromes L Kristin Newby

2.

Use of glycoprotein IIb/IIIa inhibitors before percutaneous coronary intervention Neal S Kleiman

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3.

Use of antithrombin therapy in patients undergoing percutaneous coronary intervention Derek P Chew

30

4.

Drug management post-percutaneous coronary intervention Mark W I Webster

39

4

Part II Percutaneous coronary intervention in acute coronary syndromes Pim J de Feijter 5.

Percutaneous coronary intervention in ST-segment elevation myocardial infarction Felix Zijlstra

47

6.

Early invasive versus early conservative strategy in non-ST elevation acute coronary syndromes Benno Rensing

57

7.

Percutaneous coronary intervention after thrombolytic therapy Frits Bär and George Moschos

69

Part III Stents Bernhard Meier 8.

Stent versus angioplasty: indication for stents in stable angina Roby Rakhit and Bernhard Meier

9.

Stent design and coatings Stephan Windecker

102

Carotid and renal artery stenting Nicola Corvaja and Carlo Di Mario

119

10.

91

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Part IV Restenosis Antonio Colombo 11.

Pathophysiology, pharmacology and patient factors in restenosis David P Faxon

140

12.

Management of in-stent restenosis Antonio Colombo and Konstantinos Toutouzas

150

13.

Vascular brachytherapy for restenosis Ron Waksman

170

Part V Cardiac imaging outside the cardiac catheter lab Adrian P Banning 14.

Nuclear cardiology and stress echocardiography Andrew D Kelion

191

15.

3D echocardiography Harald Becher and Dana Dawson

206

16.

Magnetic resonance imaging in coronary artery disease Stefan Neubauer

220

17.

Coronary artery imaging using electron beam CT and multislice CT John McGuire

235

Part VI Contrast agents in interventional cardiology 18.

Recent trial results Rainer Schräder

257

List of abbreviations

261

Index of papers reviewed

267

General index

277

Contributors

ADRIAN BANNING, MD, MRCP, FESC, John Radcliffe Hospital, Oxford, UK. FRITS BÄR, MD, Department of Cardiology, University Hospital Maastricht, Maastricht, The Netherlands. HARALD BECHER, MD, PhD, John Radcliffe Hospital, Cardiac Clinical Centre, Oxford, UK. DEREK CHEW, MB, BS, FRACP, Harvard School of Public Health, Boston, Massachusetts, USA. ANTONIO COLOMBO, MD, EMO Centro Cuore Columbus, Milan, Italy. NICOLA CORVAJA, MD, Centro Cuore Columbus, Milan, Italy. DANA DAWSON, University of Oxford, Cardiovascular Department, John Radcliffe Hospital, Oxford, UK. CARLO DI MARIO, MD, FACC, FESC, Centro Cuore Columbus, Milan, Italy. DAVID FAXON, MD, Cardiology, University of Chicago, Chicago, USA. PIM DE FEIJTER, Erasmus MC, Thoraxcenter, Rotterdam, The Netherlands. ANDREW KELION, DM, MRCP, Department of Cardiology, Harefield Hospital, Harefield, Middlesex, UK. NEAL KLEIMAN, MD, FACC, The Baylor College of Medicine and The Methodist Hospital, Houston, Texas, USA. JOHN McGUIRE, MBBS, FRANZCR, Queensland Diagnostic Imaging, Holy Spirit Northside Hospital, Chermside, Queensland, Australia. BERNHARD MEIER, MD, Swiss Cardiovascular Center, Bern, Switzerland. GEORGE MOSCHOS, MD, Department of Cardiology, University Hospital Maastricht, Maastricht, The Netherlands. STEFAN NEUBAUER, MD, Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. KRISTIN NEWBY, MD, Duke Clinical Research Institute, Durham, North Carolina, USA. ROBY RAKHIT, MD, MRCP, Swiss Cardiovascular Center, Bern, Switzerland. BENNO RENSING, MD, Department of Cardiology, St Antonius Hospital, Nieuwegein, The Netherlands. RAINER SCHRÄDER, FSCAI, Medizinische Klinik III-CCB, Frankfurt am Main, Germany. KONSTANTINOS TOUTOUZAS, MD, EMO Centro Cuore Columbus, Milan, Italy. RON WAKSMAN, MD Washington Hospital Center, Washington, DC, USA.

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MARK WEBSTER, MB, ChB, FRACP, FAHA, Green Lane Hospital, Auckland, New Zealand. HARVEY WHITE, DSc, FRACP, FACC, FESC, FAHA, Director of Coronary Care and Cardiovascular Research, Green Lane Hospital, Auckland, New Zealand. STEPHAN WINDECKER, MD, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland. FELIX ZIJLSTRA, MD, PhD, Department of Cardiology, Isala Klinieken, Hospital De Weezenlanden, Zwolle, The Netherlands.

Part I Pharmacological management of acute coronary syndromes

Pharmacological management of acute coronary syndromes

Introduction Worldwide there are increasing numbers of patients presenting with coronary artery disease. These patients require investigation and may require anti-ischaemic, antiplatelet and antithrombotic treatment, revascularization, and secondary preventative measures. When patients present with a non-ST elevation acute coronary syndrome, it is important that they are risk-stratified so that newer therapies can be appropriately targeted. Kristin Newby stresses the importance of the clinical history and examination as well as the baseline electrocardiogram, and reviews the now considerable information available about troponins, showing their value in risk stratification, their correlation with the pathophysiology of complex ulcerated plaques with distal platelet emboli causing myocyte necrosis, and their value in identifying the patients most likely to benefit from low molecular weight heparins, glycoprotein IIb/IIIa inhibitors or revascularization. IIb/IIIa inhibitors have been clearly shown to reduce the rate of periprocedural myocardial infarction (MI) in patients undergoing percutaneous coronary intervention (PCI) and, in a number of trials, pretreatment with IIb/IIIa inhibitors prior to PCI or coronary artery bypass grafting has resulted in a significant reduction in MI. Neal Kleiman reviews several studies concerning the use of IIb/IIIa inhibitors with PCI, including a meta-analysis of eight abciximab trials evaluating the effects of these agents on long-term mortality, the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, the Do Tirofiban and ReoPro Give similar Efficacy (TARGET) trial, the Treat Angina with aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) trial, and a registry study of abciximab readministration. In the ESPRIT trial, the small semi-synthetic molecule, eptifibatide, reduced the composite 30-day end-point of death/MI/ target vessel revascularization. In the TARGET trial, which directly compared two IIb/IIIa antagonists (abciximab and tirofiban), abciximab was shown to be superior to tirofiban in the dosing regimens used. In the registry study of abciximab readministration, profound thrombocytopenia occurred in 2.4% of patients (i.e. a rate approximately four times that seen with first-time administration) and was often a delayed reaction. In the TACTICS-TIMI 18 trial, ‘upstream’ administration of tirofiban combined with an invasive strategy significantly reduced the composite six-month end-point of death/MI/rehospitalization, although mortality alone was not significantly reduced. There is substantial clinical trial evidence supporting the use of antiplatelet therapy in patients undergoing PCI, but clinical trial information on the use of thrombin inhibitors is only just emerging. Derek Chew reviews the pooled analysis from large-scale clinical trials supporting previous clinical guidelines that have

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advocated higher levels of anticoagulation in patients undergoing PCI when heparin alone is used without an adjunctive IIb/IIIa inhibitor. He also reviews studies of low molecular weight heparins which have demonstrated the feasibility of using these agents during PCI without the need for monitoring, and a reanalysis of the data on bivalirudin indicating that this direct thrombin inhibitor may reduce ischaemic and bleeding outcomes more effectively than heparin alone. The evidence supporting the use of low molecular weight heparin and bivalirudin in patients undergoing PCI is still limited, but the studies reviewed herald the next step in the development of optimal antithrombin therapy for patients undergoing PCI. After PCI and stenting, clopidogrel has replaced ticlopidine because of its better safety profile. Mark Webster reviews these data and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCICURE) trial, which reported better outcomes when clopidogrel was used prior to PCI and for nine months afterwards. He also reviews the value of traditional myocardial protective therapies such as β-blockers in reducing the incidence of periprocedural MI.

1 Risk stratification in acute coronary syndromes

Introduction The acute coronary syndromes represent a spectrum of coronary artery disease presentations ranging from acute ST elevation myocardial infarction (MI) to unstable angina. Although they share a common pathophysiology of plaque rupture, platelet activation and thrombosis, they are characterized by varying degrees of thrombotic occlusion of the epicardial coronary arteries and distal embolization with small vessel occlusion. Not only does the risk of subsequent cardiac events vary across this spectrum of patients, but also the appropriateness of available treatment strategies and the magnitude of benefit derived from them vary within this group. A number of tools are available to the clinician to identify and risk stratify patients presenting with acute coronary syndromes. The critical first step is the initial history and physical examination. The importance of baseline demographic and clinical information obtained from this first assessment of the acute coronary syndrome patient has been demonstrated previously by several investigators |1,2|. In particular, the age, Killip class, heart rate, and markers of previous or extensive coronary artery disease are key prognostic indicators in most of these analyses. The baseline electrocardiogram (ECG) is the first objective risk stratification tool available to most acute coronary syndrome patients. Not only does it provide the basis for segregating patients into those who are eligible for reperfusion therapy (i.e. those with ST elevation or bundle branch block) and those who are ineligible, but it also provides important short- and long-term prognostic information. Patients who have both ST elevation and ST depression have the highest 30-day death/MI and 6-month mortality risks, followed by those with either one or the other; patients presenting with only T wave inversion have the lowest risk |3|. Importantly, the risk stratification information provided by the baseline ECG remains significant after adjustment for demographic and clinical baseline characteristics. An important question in the assessment of patients with non-ST elevation acute coronary syndromes has been whether the magnitude of ST depression, as opposed to simply its presence or absence, provides further prognostic information. The importance of both baseline and serial measures of markers of myocardial necrosis (particularly creatine kinase [CK]-MB and the troponins) in risk stratification of both ST elevation MI and non-ST elevation acute coronary syndrome patients has been firmly established |4–7|. Furthermore, the magnitude of marker elevation is roughly linearly correlated with the extent of subsequent risk of cardiac events |5–8|.

© Clinical Publishing Services Ltd

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Beyond prognostic significance, the benefit of glycoprotein IIb/IIIa inhibitors and low molecular weight heparins may be particularly prominent in the presence of troponin elevation |9–11|. However, despite the prognostic importance of the troponins and their utility in defining patients who may benefit most from specific therapies, it is recognized that detection of troponins in the serum reflects the presence of myocardial damage. The ultimate goals of marker testing should be to identify high-risk patients early and treat them before necrosis has occurred, and to identify which troponin-negative patients may also be at high risk of subsequent events. Ongoing development of tests for markers of ‘ischaemia’, and evaluation of novel markers such as B-type natriuretic peptide (BNP), C-reactive protein and other markers of inflammation, may ultimately yield tests to fill this current void. The following articles published over the past year were selected to highlight recent developments in each of these areas, and may point the way to prognostic evaluation of the acute coronary syndrome patient in the years to come. Prognostic value of ST segment depression in acute coronary syndromes: insights from PARAGON-A applied to GUSTO-IIb. P Kaul, Y Fu, W-C Chang, et al. J Am Coll Cardiol 2001; 38:64–71. BACKGROUND. The vast majority of acute coronary syndrome patients do not present with ST elevation on their ECG. Those with ST depression have previously been shown to be at higher risk of subsequent cardiac events than patients with T wave inversion, non-specific ECG changes, or normal ECGs. Although at somewhat lower immediate risk of cardiac events, patients with ST depression on their initial ECG have a similar 30-day risk to that of patients presenting with ST elevation |3|. However, little information has been available to define the relationship of the magnitude of ST depression to the extent of subsequent cardiac risk. Using systematic core laboratory interpretation of baseline ECGs from 7889 patients randomized into two large clinical trials (the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network [PARAGON]-A trial and the Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO]-IIb trial), Kaul et al. investigated the relationship between various degrees of ST depression and outcomes in non-ST elevation acute coronary syndrome patients. From this work, they developed a model to define the importance of quantitative ST-segment evaluation in the presence of other clinical predictors of risk. INTERPRETATION. As shown in Fig. 1.1, increased levels of ST depression on the initial ECG were associated with increasingly poor event-free survival in both acute coronary syndromes cohorts. The majority of the risk differential was manifest within the first 30 days after the event. In multivariate modelling, ST depression was the strongest

predictor of the occurrence of one-year mortality, accounting for 35% of the model’s predictive power. Patients with ≥ 2 mm of ST depression were nearly six times as likely to die within one year compared with patients without ST depression (odds ratio [OR] 5.7; 95% confidence interval [CI] 2.8–11.6). Fig. 1.2 shows the strength of ST depression as a predictor of one-year mortality relative to other clinical predictors of risk.

Comment As this study highlights, important information for risk stratification of patients with acute coronary syndromes is provided by information obtained not only from the initial history and physical examination, but also from the baseline ECG. Because these data may be available much earlier than results of cardiac marker testing, quantification of the magnitude of ST depression appears to be a simple and useful tool for

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Fig 1.1 Survival curves corresponding to the categories of no ST depression, 1 mm ST depression and ≥ 2 mm ST depression in the PARAGON-A study |12| (a) and the GUSTO-IIb study |13| (b). Log-rank tests were used to compare the survival curves. All curves were statistically significantly different at P<0.05. Source: Kaul et al. (2001).

refining prognosis in this group of patients and to assist in early triage and treatment using a strategy that is complementary to cardiac marker testing.

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Fig 1.2 Relative contribution of baseline risk factors in predicting one-year mortality (PARAGON-A data) |12|. CHF=congestive heart failure, COPD=chronic obstructive pulmonary disease, CVD=cerebrovascular disease, PTCA=coronary angioplasty, PVD=peripheral vascular disease. Source: Kaul et al. (2001).

Admission troponin T level predicts clinical outcomes, TIMI flow, and myocardial tissue perfusion after primary percutaneous intervention for acute ST-segment elevation myocardial infarction. E Giannitsis, M Muller-Bardorff, S Lehrke, et al. Circulation 2001; 104: 630–5. BACKGROUND. Although it is known that elevation of troponin T above the upper limit of normal at presentation with ST elevation MI signals a poorer prognosis than if there is no ST elevation |6|, the underlying pathophysiology for this finding had not previously been investigated. Giannitsis et al. sought to determine the relationships between troponin status and pathophysiological mechanisms for poorer outcome at the most extreme of the spectrum of acute coronary syndromes—patients with ST elevation acute MI. 140 consecutive patients with ST elevation MI presenting within 12 hours of symptom onset were stratified by troponin T status (positive or negative) at baseline. Of note, troponin T-positive patients presented later, were older, and were more likely to have diabetes. All patients had coronary angiography within 30 minutes of arrival. PCI restored Thrombolysis in Myocardial Infarction (TIMI)-3 flow |14| in 84.3% of cases. Among patients in whom TIMI-3 flow was established, tissue level perfusion was assessed using ratios and slopes of cardiac marker release and ST resolution. As in previous studies, troponin positivity at baseline was associated with greater mortality at both 30 days (OR 4.5; 95% CI 1.1–17.2, P=0.02) and in the long-term (mean 274 days; OR 5.6; 95% CI 1.5–20.9; P=0.02). No differences in non-fatal end-points were observed (Table 1.1). Failure to restore TIMI-3 flow was more frequent among troponin T-positive patients than troponin T-negative patients (25% versus 7. 9%; OR 3.89; 95% CI 1.42–10.6). Among the 118 patients in whom TIMI-3 flow was achieved, the ratios and slopes of myoglobin, CK-MB and troponin T were significantly lower than in troponin-negative patients. Similarly, >50% or 70% resolution of ST elevation was less frequent in troponin T-positive patients. INTERPRETATION. Troponin-positivity at baseline in patients with ST elevation MI identifies a population of patients with worse short- and long-term outcomes. The underlying pathophysiology associated

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with this relationship of troponin-positivity with outcome seems to be related to a decreased ability to establish TIMI-3 flow and, when TIMI-3 flow is established, a reduced likelihood of establishing adequate tissue-level perfusion.

Comment This paper highlights the fact that, as in the non-ST elevation acute coronary syndromes, an important component of troponin-positivity at baseline and poorer prognosis may be related to microvascular obstruction. An understanding of the pathophysiological mechanisms underlying the poorer prognosis of troponin-positive ST elevation acute MI patients should help to guide the development of Table 1.1 Patient outcomes cTnT-positive (n=64)

cTnT-negative (n=76)

30 Days Death 10 (15.6) 3 (3.9) Cardiac death 8 (12.5) 3 (3.9) Non-fatal reinfarction — 1 (1.3) Target vessel revascularization CABG 5 (7.7) 2 (2.6) PCI 1 (1.6) 4 (5.2) Combined end-point 13 (20.3) 9 (11.8) Long-term Death 12 (18.8) 3 (3.9) Cardiac death 9 (14) 3 (3.9) Non-fatal reinfarction 1 (1.6) 5 (6.5) Target vessel revascularization CABG 9 (14) 3 (3.9) PCI 3 (5) 10 (13.2) Combined end-point 22 (34) 18 (23.7) Values given as absolute counts with relative frequencies in parentheses. Modified from Giannitsis et al. (2001).

OR (95% CI)

P

4.5 (1.1–17.2) 3.5 (0.9–13.7) —

0.02 0.06 0.4

3.1 (0.6–16.7) 0.3 (0.03–2.6) 1.9 (0.7–4.8)

0.2 0.2 0.2

5.6 (1.5–20.9) 3.9 (1.03–15.4) 0.2 (0.03–1.9)

0.005 0.03 0.2

3.9 (1.03–15.4) 0.3 (0.09–1.2) 1.7 (0.8–3.5)

0.03 0.09 0.2

treatment strategies aimed at addressing the deficiencies. However, it must be emphasized that only randomized clinical trials designed to assess the impact of such treatment strategies on clinical outcomes will determine whether targeting a specific pathophysiological mechanism is beneficial in practice. Benefit of glycoprotein llb/llla inhibition in patients with acute coronary syndromes and troponin Tpositive status: the PARAGON-B troponin T substudy. L K Newby, E M Ohman, R H Christenson, et al. Circulation 2001; 103: 2891–6. BACKGROUND. Although previous retrospective assessments had suggested a relationship between troponin status and treatment benefit from IIb/IIIa inhibitors in patients with non-ST elevation acute coronary syndromes |9,10|, the PARAGON-B investigators sought to prospectively quantify this

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relationship. In this study, 1160 patients had troponin T measured at the time of randomization into the main PARAGON-B study. This was a randomized comparison of the effect of the IIb/IIIa

inhibitor, lamifiban, plus heparin with standard heparin therapy for treatment of non-ST elevation acute coronary syndromes. The relationship of troponin status (positive or negative) with clinical outcomes at 30-days and the interaction of troponin status with treatment assignment were assessed. In addition, a meta-analysis of this interaction was performed. As expected and consistent with numerous previous studies, troponin-positive status was associated with worse 30-day outcomes than troponin-negative status. Furthermore, in this prospective assessment, troponin T-positive patients who were treated with lamifiban had significant reductions in the 30-day end-points of death/MI/recurrent ischaemia and death/MI compared with patients who received lamifiban-placebo (Table 1.2). No treatment benefit was observed in patients who were troponin Tnegative. A meta-analysis combining these results with those of previously published evaluations of treatment effect by troponin status in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) study (testing the benefit of abciximab in patients with acute coronary syndromes in whom coronary lesions had been identified and PCI was performed) and the Platelet Receptor Inhibition in Ischaemic Syndrome Management (PRISM) study (evaluating tirofiban for management of patients with acute coronary syndromes) confirmed the consistency and significance of this interaction across all IIb/ IIIa inhibitors |9,10|. Fig. 1.3 demonstrates this relationship. INTERPRETATION. Among patients with acute coronary syndromes, troponin-positive status identifies a high-risk subgroup of patients who derive particular benefit from treatment with intravenous IIb/IIIa inhibitors. It is believed that this association of treatment benefit with troponin-positive status is related to the pathophysiological observations of more complex coronary lesions associated with a greater thrombus burden in troponin-positive patients |15–17|.

Comment This study and those that preceded it have collectively identified troponin status as an important consideration in the decision to use a IIb/IIIa inhibitor for treatment Table 1.2 Clinical outcomes at 30 days by baseline troponin T status and treatment assignment

Death/reinfarction/severe recurrent ischaemia Death/reinfarction Death Reinfarction Severe recurrent ischaemia

Troponin T-positive

Troponin T-negative

Lamifiban (n=227)

Placebo (n=237)

Lamifiban (n=344)

Placebo (n=349)

11.0% 11.0% 3.1% 9.3% 0.4%

19.4% 19.0% 5.1% 17.3% 0.4%

10.8% 9.6% 1.2% 9.3% 1.5%

11.2% 10.3% 2.0% 9.7% 0.9%

Source: Newby et al. (2001).

of non-ST elevation acute coronary syndrome patients. However, such a relationship may ultimately prove too simplistic on the individual patient level. As observed in PRISM and suggested by Antman, the relationship of enhanced treatment benefit with troponin-positive status may be ‘U-shaped’, with a less

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Fig. 1.3 Odds ratios with 95% confidence intervals for death/MI in troponin-negative and troponin-positive patients and for the interaction of troponin status with treatment effect in the PRISM |9|, CAPTURE |10| and PARAGON-B trials, and for these trials combined. The values to the left of 1.0 indicate a benefit of IIb/IIIa inhibition. Source: Newby et al. (2001).

marked benefit at very high or minimally elevated levels (Figs. 1.4 and 1.5) |9,18|. Only further prospective study will definitively resolve this issue. Relationship between interleukin-6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or non-invasive strategy. E Lindmark, E Diderholm, L Wallentin, A Siegbahn. JAMA 2001; 286: 2107–13. BACKGROUND. The role of inflammation in the genesis of atherosclerosis and acute coronary syndromes is increasingly recognized, and markers of inflammatory activity (including C-reactive protein and its inducer, interleukin-6 [IL-6]) have been associated with prognosis both in apparently healthy individuals and in patients with acute coronary syndromes |19–23|. Lindmark et al. performed a prospective substudy of the

Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC-II) study to evaluate the relationship between IL-6 elevation and prognosis in unstable coronary artery disease. Furthermore, they investigated whether, analogous to the situation with troponins and IIb/IIIa inhibitors, elevation of this marker would identify a group for which an early invasive treatment strategy or prolonged treatment with low molecular weight heparin would be particularly beneficial. The design of the FRISC-II study is shown in Fig. 1.6. After five days of standard open-label treatment with either unfractionated heparin or dalteparin, patients were randomized to receive either dalteparin or placebo subcutaneously twice daily for 90 days. Patients who had no contraindications to early coronary angiography were also randomized to early invasive care or a non-invasive strategy. Blood samples for IL-6, troponin T and C-reactive protein were obtained at baseline from all patients. Among medically-treated patients in the randomized invasive versus non-invasive comparison, those with elevated IL-6 levels (≥ 5 ng/ml) had a one-year mortality rate 3.5 times that of patients without elevated

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Fig. 1.4 Adjusted hazard ratios (95% CI) for treatment with tirofiban by troponin I quartiles and troponin T quintiles. The benefit of treatment was defined as a decrease in death/MI at 30-day follow-up. Hazard ratios lower than 1.0 show a benefit for treatment with tirofiban compared with heparin. Source: Heeschen et al. (1999) |9|. IL-6 levels (7.9% versus 2.3%, P<0.001). Furthermore, elevated IL-6 levels were predictive of mortality independent of troponin T and C-reactive protein. As demonstrated in Fig. 1.7, among patients randomized in the interventional versus non-invasive comparison there was a highly significant reduction in mortality at one year among patients who had elevated IL-6 levels and

received the invasive strategy compared with those who were randomized to the non-invasive strategy (OR 0.35; 95% CI 0.17–0.74; P=0.004). Among patients without elevated IL-6 levels, no such treatment

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Fig. 1.5 Proposal for therapeutic decision-making based on quantitative troponin results, showing the U-shaped relationship between absolute levels of troponin and the risk of death/MI following administration of intravenous IIb/ IIIa inhibitors. Patients with undetectable troponin levels or barely elevated troponin levels are at low risk and unlikely to benefit from an intravenous IIb/IIIa inhibitor. Those with intermediate troponin levels derive the greatest benefit, while those with progressively higher troponin levels have increasing amounts of completed myocardial damage and are less likely to benefit from intravenous IIb/IIIa inhibitors. The relationship shown in this figure is in part based on data from Lindahl et al. |17| and from Heeschen et al. |9|. Source: Antman (2001) |18| benefit of an early invasive versus conservative strategy was observed (OR 0.85; 95% CI 0.44–1.65). A similar pattern of enhanced benefit from prolonged dalteparin therapy was also observed among patients not eligible for randomization in the early invasive versus conservative strategy comparison (Fig. 1.8). INTERPRETATION. Markers of inflammation, in this case IL-6, identify acute coronary syndrome patients at high risk of mortality at 1 year. Furthermore, this study suggests that IL-6 levels at or within several days after presentation with an acute coronary syndrome may identify those patients who will preferentially benefit from a strategy of early coronary arteriography and revascularization.

Comment This study suggests that assessment of markers of inflammation may become an important part of our armamentarium for risk stratification of acute coronary syndrome patients and their selection for various treatment strategies. Further investigation of the pathophysiological mechanisms by which the enhanced treatment benefit occurs is warranted. Is it possible that PCI is anti-inflammatory, or did the response differ within the invasively treated group according to dalteparin versus placebo assignment? This paper does not address this question. Finally, in order to make the use of IL-6 or other inflammatory markers feasible for risk stratification on a large scale, development of relatively simple, rapid and inexpensive assays will be needed. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. J A de Lemos, D A Morrow, J H Bentley, et al. N Engl J Med 2001; 345: 1014–21. BACKGROUND. BNP is a neurohormone produced by the ventricular myocardium in response to pressure overload and ventricular dilatation. It has been shown to be elevated not only in patients with heart failure, but also after acute MI. When measured after MI it provides prognostic information that

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Fig. 1.6 Overview of the main FRISC-II study |29,30|. 366 patients were enrolled after the end of recruitment for the intervention trial. Source: Lindmark et al. (2001). is independent of left ventricular function and baseline characteristics |24–26|. Less is known about the prognostic importance of this neurohormonal marker in patients across the spectrum of acute coronary syndromes. De Lemos and colleagues studied the prognostic role of BNP across the spectrum of acute coronary syndromes using a subset of patients randomized in the OPUS (Orbofiban in Patients with Unstable coronary Syndromes)-TIMI-16 study of the oral IIb/IIIa inhibitor, orbofiban, versus placebo. From the 10288 patients randomized, 2525 had BNP measured in samples collected a mean of 40±20 hours after symptom onset.

For analysis of the relationship between BNP level and outcome, patients were divided into quartiles by BNP level. As shown in Table 1.3, there were a number of significant differences in baseline characteristics by BNP quartile. In particular, patients in the highest quartile were older, more frequently female, and more likely to have heart failure, peripheral and cerebro-vascular disease, diabetes, hypertension and a higher Killip class at presentation. Fig. 1.9 shows the unadjusted relationships between BNP quartiles and mortality at 10 months. In multivariate modelling (taking into account age; troponin I level; Killip class II, III, or IV at presentation; history of heart failure, renal insufficiency, or peripheral vascular disease; prior therapy with diuretics, angiotensin-converting-enzyme inhibitors, nitrates, or heparin; heart rate; blood pressure; and ST deviation) higher levels of BNP remained independently predictive of 10-month

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Fig. 1.7 12-month probability of death in the invasive and non-invasive cohorts, categorized by IL-6 plasma levels. The vital status was unavailable for one patient, who requested to be withdrawn from follow-up. In patients with low IL-6 levels, there were 16 events among the 826 patients at baseline in the invasive group and 19 events among the 383 patients in the non-invasive group at 12 months. In patients with high IL-6 levels, there were 9 events among the 324 patients in the invasive group and 25 events among the 318 patients in the non-invasive group at 12 months. Source: Lindmark et al. (2001). mortality (relative to quartile 1: quartile 4 OR 5.8; 95% CI 1.7–19.7; quartile 3 OR 4.0; 95% CI 1.2–13. 7; quartile 2 OR 3.8; 95% CI 1.1–13.3). Table 1.3 Baseline clinical characteristics according to the quartile of BPN level

N Age* Males Caucasian Medical history Hypertension congestive heart failure Coronary artery disease Peripheral vascular disease Cerebrovascular disease Diabetes mellitus

Quartile 1 (5.0– 43.7 pg/ml)

Quartile 2 (43.7– Quartile 3 (81.3– Quartile 4 (137. 81.2 pg/ml) 137.8 pg/ml) 9–1456.6 pg/ml)

P value for trend

631 57±10 years 474 (75%) 575 (91%)

632 59±11 years 465 (74%) 592 (94%)

632 61±12 years 472 (75%) 605 (96%)

630 66±11 years 405 (64%) 603 (96%)

<0.001 <0.001 <0.001

246 (39%) 26 (4%)

254 (40%) 28 (4%)

263 (42%) 26 (4%)

298 (47%) 56 (9%)

0.003 <0.001

329 (52%)

312 (49%)

294 (47%)

327 (52%)

0.7

33 (5%)

43 (7%)

48 (8%)

57 (9%)

0.008

24 (4%)

32 (5%)

39 (6%)

60 (10%)

<0.001

138 (22%)

133 (21%)

132 (21%)

152 (24%)

0.4

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Quartile 1 (5.0– 43.7 pg/ml)

Quartile 2 (43.7– Quartile 3 (81.3– Quartile 4 (137. 81.2 pg/ml) 137.8 pg/ml) 9–1456.6 pg/ml)

15

P value for trend

Hypercholesterol 199 (32%) 191 (30%) 173 (27%) 149 (24%) <0.001 aemia Smoking status <0.001 current smoker 233 (37%) 263 (42%) 236 (37%) 189 (30%) Never smoked 193 (31%) 161 (26%) 185 (29%) 254 (40%) Former smoker 204 (32%) 205 (33%) 209 (33%) 186 (30%) Index diagnosis <0.001 ST elevation MI 141 (22%) 189 (30%) 231 (37%) 264 (42%) Non-ST 87 (14%) 137 (22%) 159 (25%) 182 (29%) elevation MI Unstable angina 402 (64%) 306 (48%) 241 (38%) 184 (29%) Physical findings Systolic blood 130±20 mm Hg 129±19 mm Hg 129±22 mm Hg 129±21 mm Hg 0.3 pressure* Killip class II, III 31 (5%) 36 (6%) 56 (9%) 109 (18%) <0.001 or IV Results of diagnostic tests Creatine 146 (24%) 185 (31%) 229 (38%) 350 (58%) <0.001 clearance ≥ 90 ml/ min CK-MB >upper 212 (58%) 308 (72%) 349 (79%) 388 (86%) <0.001 limit of normal ST depression ≥ 0. 270 (43%) 297 (47%) 311 (49%) 356 (57%) <0.001 5 mm *Plus-minus values are means±standard deviations. For each variable, the percentages reflect the total number of patients for whom data were available. In some instances, this number was less than the total number of patients in the quartile. Source: de Lemos et al. (2001).

INTERPRETATION. This study identifies another novel class of markers (neurohormonal) that are able to risk stratify patients with acute coronary syndromes independently of the presenting ECG and troponin status. Furthermore, their prognostic importance appears to be independent of the presence or absence of heart failure or Killip class. Finally, the ability to differentiate risk seemed most prominent in what may be the most difficult groups to risk stratify, namely those with unstable angina and non-ST elevation MI (Fig. 1.10).

Comment As with the troponins and markers of inflammation, BNP as a representative of the class of neurohormonal markers appears to add risk stratification information that is complementary to the ECG and clinical risk stratification. Although this study is preliminary and retrospective in nature, its results warrant further prospective investigation of the role of neurohormonal markers in risk stratification of acute coronary

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Fig. 1.8 6-month probability of death/MI in the medical study, categorized by IL-6 plasma levels in relation to randomized treatment. Follow-up data were unavailable for 14 patients in the dalteparin group and 18 patients in the placebo group. In patients with low IL-6 levels, there were 105 events among the 786 patients at baseline in the dalteparin group and 94 events among the 760 patients in the placebo group at 6 months. In patients with high IL-6 levels, there were 32 events among the 272 patients in the dalteparin group and 43 events among the 301 patients in the placebo group at 6 months. Source: Lindmark et al. (2001).

syndrome patients, alone and in combination with other time-tested methods for risk stratification in this population. Conclusion As suggested by these representative papers, although the options for risk stratification of patients presenting with acute coronary syndromes continue to grow, the basic principles remain firm: history and physical examination on presentation accompanied by further objective testing. The baseline ECG pattern has remained an independent predictor of risk in the acute coronary syndromes despite the continued development of markers of myocardial necrosis, including the troponins. Preliminary evidence now suggests that quantification of ST depression may help to further risk stratify non-ST elevation acute coronary syndrome patients in a manner that is complementary to troponin testing (Kaul, unpublished data). Furthermore, its presence may help to define a group of patients that has enhanced benefit from early PCI |27|. The troponins remain the benchmark for biochemical risk stratification, but ultimately are limited because they can only be detected after myocardial necrosis has occurred. The development and clinical evaluation of markers of inflammation, neurohormonal markers such as BNP, and other markers of plaque activity such as pregnancy-associated plasma protein-A |28|, provide a glimpse of the future where earlier and more detailed risk stratification in the acute coronary syndromes will be possible. Together, the availability of such tests along with the traditional history, physical examination and 12-lead ECG will fill many of the existing gaps in risk stratification and management of these patients.

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Fig. 1.9 Kaplan-Meier curves showing the cumulative incidence of death at 10 months, according to the quartile of BNP level at enrolment. The range of BNP levels was as follows: 5.0–43.6 pg/ml (quartile 1), 43.7–81.2 pg/ml (quartile 2), 81.3–137.8 pg/ml (quartile 3), and 137.9–1456.6 pg/ml (quartile 4) (P<0.001 for the interquartile trend). Source: de Lemos et al. (2001).

References 1.

2.

3.

4.

5.

6.

Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41021 patients. Circulation 1995; 91:1659–68. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL, Akkerhuis KM, Harrington RA, Deckers JW, Armstrong PW, Lincoff AM, Califf RM, Topol EJ, Simoons ML. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation: results from an international trial of 9461 patients. Circulation 2000; 101:2557–67. Savonitto S, Ardissino D, Granger CB, Morando G, Prando MD, Mafrici A, Cavallini C, Melandri G, Thompson TD, Vahanian A, Ohman EM, Califf RM, Van de Werf F, Topol EJ. Prognostic value of the admission electrocardiogram in acute coronary syndromes. JAMA 1999; 281:707–13. Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA, Hamm CW, O’Hanesian MA, Wagner GS, Kleiman NS, Harrell FE Jr, Califf RM, Topol EJ. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996; 335:1333–41. Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996; 335:1342–9. Ohman EM, Armstrong PW, White HD, Granger CB, Wilcox RG, Weaver WD, Gibler WB, Stebbins AL, Cianciolo C, Califf RM, Topol EJ. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. Am J Cardiol 1999; 84: 1281–6.

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Fig. 1.10 Association between the BNP level and the mortality rate at 10 months, according to the index diagnosis. The quartiles were recalibrated for each of the subgroups. Quartile 1 represents the lowest level of BNP, and quartile 4 the highest level. The P values shown are for the trend within each subgroup. Source: de Lemos et al. (2001). 7.

8.

9.

10.

11.

12. 13.

14.

Newby LK, Christenson RH, Ohman EM, Armstrong PW, Thompson TD, Lee KL, Hamm CW, Katus HA, Cianciolo C, Granger CB, Topol EJ, Califf RM. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. The GUSTO-IIa Investigators. Circulation 1998; 98: 1853–9. Alexander JH, Sparapani RA, Mahaffey KW, Deckers JW, Newby LK, Ohman EM, Corbalan R, Chierchia SL, Boland JB, Simoons ML, Califf RM, Topol EJ, Harrington RA. Association between minor elevations of creatine kinase-MB level and mortality in patients with acute coronary syndromes without ST-segment elevation. JAMA 2000; 283:347–53. Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999; 354:1757–62. Hamm CW, Heeschen C, Goldmann B, Vahanian A, Adgey J, Miguel CM, Rutsch W, Berger J, Kootstra J, Simoons ML. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 1999; 340:1623–9. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with unstable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. J Am Coll Cardiol 1997; 29: 43–8. The PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/ IIIa inhibitor), heparin, or both in unstable angina. Circulation 1998; 97:2386–95. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIB Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335: 775–82. Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase: clinical findings through hospital discharge. Circulation 1987; 76:142–54.

RISK STRATIFICATION IN ACUTE CORONARY SYNDROMES

15.

16.

17.

18. 19. 20. 21. 22. 23. 24.

25. 26.

27.

28.

29.

30.

19

Heeschen C, van den Brand MJ, Hamm CW, Simoons ML, for the CAPTURE Investigators. Angiographic findings in patients with refractory unstable angina according to troponin T status. Circulation 1999; 100: 1509–14. deFilippi CR, Tocchi M, Parmar RJ, Rosanio S, Abreo G, Potter MA, Runge MS, Uretsky BF. Cardiac troponin T in chest pain unit patients without ischemic electrocardiographic changes: angiographic correlates and longterm clinical outcomes. J Am Coll Cardiol 2000; 35:1827–34. Lindahl B, Diderholm E, Lagerqvist B, Venge P, Wallentin L, and the FRISC-II Investigators. Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC-II substudy. J Am Coll Cardiol 2001; 38:979–86. Antman EM. Troponin measurements in ischemic heart disease: more than just a black and white picture [letter; comment]. J Am Coll Cardiol 2001; 38:987–90. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340:115–26. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:973–9. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000; 342:836–43. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000; 101:1767–72. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. N Engl J Med 2000; 343:1139–47. Omland T, Aakvaag A, Bonarjee VV, Caidahl K, Lie RT, Nilsen DW, Sundsfjord JA, Dickstein K. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide brain natriuretic peptide. Circulation 1996; 93:1963–9. Arakawa N, Nakamura M, Aoki H, Hiramori K. Plasma brain natriuretic peptide concentrations predict survival after acute myocardial infarction. J Am Coll Cardiol 1996; 27:1656–61. Richards AM, Nicholls MG, Yandle TG, Frampton C, Espiner EA, Turner JG, Buttimore RC, Lainchbury JG, Elliott JM, Ikram H, Crozier IG, Smyth DW. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 1998; 97: 1921–9. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann FJ, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM, Braunwald E; TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)—Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344:1879–87. Bayes-Genis A, Conover CA, Overgaard MT, Bailey KR, Christiansen M, Holmes DR Jr, Virmani R, Oxvig C, Schwartz RS. Pregnancy-associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med 2001; 345:1022–9. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) Investigators. Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II Prospective Randomized Multicentre Study [published erratum appears in Lancet 1999; 354:1478]. Lancet 1999; 354:701–7. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II Prospective Randomized Multicentre Study. Lancet 1999; 354:708–15.

2 Use of glycoprotein IIb/IIIa inhibitors before percutaneous coronary intervention

Introduction The management of patients with ischaemic heart disease during the last two decades has been characterized by recognition of the dynamic nature of coronary arterial atherosclerosis and in particular by the importance of atherosclerotic plaque rupture and thrombosis. A particularly important aspect of this growing body of knowledge has centred on the importance of localized thrombosis as a mediator of ischaemic complications of percutaneous coronary interventions (PCI) and of the central role of the platelet as an initiating factor in the development of arterial thrombi. In the early 1980s the physiology of platelet aggregation was elucidated by description of the cell surface protein now know as glycoprotein IIb/IIIa |1,2|. Simultaneously, studies began to reveal that aspirin, a relatively mild antiplatelet agent, was able to reduce the rate of periprocedural myocardial infarction (MI) after coronary angioplasty |3,4|. In the mid 1990s it became apparent that further platelet blockade with abciximab, a monoclonal antibody directed at platelet glycoprotein IIb/IIIa, led to further reductions in periprocedural ischaemic events (predominantly MI and emergency revascularization) in patients undergoing coronary balloon angioplasty and in those receiving intracoronary stents |5–7|. Several remaining issues of great importance have undergone significant resolution within the past year. The reduction in ischaemic events achieved with abciximab consisted predominantly of non-Q wave MI; the low short-term mortality associated with PCI has precluded primary mortality trials of IIb/IIIa inhibitors during PCI. Thus, whether this reduction is paralleled by lower long-term mortality, as might be predicted if the MIs are significant, has remained an issue. The investigators of eight studies of abciximab in PCI address this question in the first paper presented in this chapter. Whether the newer generation of less expensive synthetic and semi-synthetic IIb/IIIa inhibitors could also provide protection against periprocedural MI was addressed by the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) Investigators and the Do Tirofiban and ReoPro Give Similar Efficacy (TARGET) Investigators. The design of the latter study was particularly interesting since it included early treatment with the thienopyridine, clopidogrel, and thus asked whether the additional action of this compound against platelet aggregation as well as platelet activation could serve as an ‘equalizer’ between two treatment regimens. Another of the remaining issues concerned the safety of readministration of abciximab. This drug is a monoclonal chimeric antibody, and studies during its development indicated that human antichimeric antibodies developed in 6–7% of patients receiving the drug for the first time.

© Clinical Publishing Services Ltd

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Consequently, a registry was established to describe the efficacy of the drug when readministered and to catalogue the number of events that were presumed to be immunologically mediated. Finally, perhaps the most important issue concerns the degree to which IIb/IIIa inhibitor use has become integrated with the use of an invasive management strategy in patients with acute coronary syndromes. The Treat Angina With Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) Investigators performed an initial assessment of this strategy. Patients in TACTICS-TIMI 18 received intravenous tirofiban for 4–48 hours and were then randomized to an early invasive strategy or an early conservative management strategy with tirofiban continued through the invasive procedure and for as long as 24 hours afterwards. In an attempt to refine this approach further for the benefit of practitioners who may not have easy access to cardiac catheterization facilities, this group evaluated the benefit of an early invasive strategy according to gradations of risk, and reported that the benefit was most pronounced in patients with elevated troponin levels at the time of admission |8|. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. K M Anderson, R M Califf, G W Stone, et al. J Am Coll Cardiol 2001; 37: 2059–65. BACKGROUND. Studies of PCI suggest that MI after intervention is predictive of mortality. Abciximab has consistently reduced the incidence of MI among PCI patients in several trials. The presumed mechanism is prevention of platelet thrombus associated with vessel wall injury and downstream embolization into the microcirculation. The goals of this study were to test: 1) if IIb/IIIa inhibition with an abciximab bolus and 12-hour infusion reduces mortality after PCI; 2) if prevention of early MI after PCI is a mechanism for reducing mortality; and 3) for risk factors for mortality after PCI. In eight trials, 5154 patients were randomized to a regimen comprising conventional therapy plus a bolus of abciximab within 1 hour before PCI followed by a 12-hour infusion, while 4136 controls were randomized to conventional therapy alone. Patient follow-up from 6 months to 3 years was available. Survival differences were examined using proportional hazards regression and survival curves. A hazard ratio of 0.71 (95% confidence interval [CI] 0.57–0.89, P=0.003) suggested a mortality benefit with abciximab. The absolute reduction in mortality was estimated to be 0.5% through 30 days, 0.7% through 6 months, 0.9% through 1 year and 1.8% through 3 years. Early MI explained 18% of the observed mortality benefit at 1 year.

Multivariate regression suggested that patients with advanced cardiovascular disease may derive the greatest mortality benefit from abciximab. INTERPRETATION. The evidence from 9290 randomized PCI patients showed that mortality was reduced in patients who received an abciximab bolus and 12-hour infusion.

Comment While mortality at one year was reported to be reduced among stented patients treated with abciximab in the Evaluation of Platelet IIb/IIIa Inhibition in Stenting (EPISTENT) trial |7|, this manuscript is the first published report of reduced long-term mortality associated with IIb/IIIa inhibition using abciximab. There was a concordant reduction in mortality across all the trials included in the analysis, with nearly identical mortality reductions among patients who did or did not receive an intracoronary stent. It is interesting to note that the mortality curves (Fig. 2.1) diverged rather than remained parallel, consistent with the mechanism of myocardial preservation resulting from prevention of MI. However, this manuscript also points out for the

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Fig. 2.1 Mortality over 6 months for all eight studies |5–7,9–12| combined. Patients received either standard therapy (placebo) or standard therapy plus an abciximab bolus within 1 hour before PCI followed by a 12-hour infusion. Source: Anderson et al. (2001).

first time that only a fraction (18%) of deaths at one year occurred in patients who had had an early event detected within the trials. Whether this was a result of non-Q wave MIs occurring after hospital discharge (and thus after the period of intense surveillance had ended), or was due to another mechanism remains to be determined. Nonetheless, the paper provides added impetus for aggressive use of IIb/IIIa inhibitors during PCI. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. The ESPRIT Investigators. Lancet 2000; 356:2037–44. BACKGROUND. Although llb/llla inhibitors are effective in reducing ischaemic complications of PCI, they are used in few coronary stenting procedures. ESPRIT was designed to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting. The study enrolled 2064 patients undergoing stent implantation in a native coronary artery. Immediately before PCI, the patients were randomly allocated to receive eptifibatide (given as two 180 μg/ kg boluses 10 minutes apart followed by a continuous infusion of 2.0 μg/kg/minute for 18–24 hours) or a placebo. All patients also received aspirin, heparin and a thienopyridine. The primary end-point of the study was a composite of death/MI/urgent target vessel revascularization/thrombotic bailout IIb/IIIa inhibitor therapy within 48 hours after randomization. The key secondary end-point was a composite of death/MI/urgent target vessel revascularization within 30 days. The trial was terminated early after interim results showed that eptifibatide reduced the primary composite end-point from 10.0% to 6.6% (P=0.0015). The key 30-day secondary end-point was also reduced from 10.5% to 6.8% (P=0.0034). There was consistency in the reduction of events across all components of the composite end-point and among the major subgroups. Major bleeding was infrequent, but occurred more often with eptifibatide than with placebo (1.3% versus 0.4%, P=0.027). INTERPRETATION. Routine pre-treatment with eptifibatide substantially reduced ischaemic complications in coronary stent intervention and was better than a strategy of reserving treatment to the bailout situation.

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Fig. 2.2 Kaplan-Meier plots of the probability of death/MI (upper panel) and of death/MI/urgent target vessel revascularization (lower panel) within 30 days. RR=risk ratio. Source: ESPRIT Investigators (2000).

Comment This trial was the first to show that treatment with a semi-synthetic IIb/IIIa inhibitor (eptifibatide) reduces periprocedural ischaemic events (Fig. 2.2). While previous trials of tirofiban and eptifibatide had shown trends toward preventing ischaemic events, the trends were weak and did not achieve statistical significance in either case. The ESPRIT Investigators selected a dosing regimen that was modelled on pharmacokinetic and pharmacodynamic properties of eptifibatide discovered after the previous trials had been completed |13|. Unlike patients in the former trials, those enrolled in ESPRIT were scheduled for non-emergency coronary stenting. Ninety-eight per cent received stents as planned, and received clopidogrel following the procedure. The trial was also important as it demonstrated that IIb/IIIa inhibition is still effective in the age of modern stent implantation techniques, and in low-risk as well as high-risk patients. While it is tempting to compare the relative event reduction observed in this trial with that observed in other studies (particularly the EPISTENT trial of abciximab), this temptation should be avoided. Although the control group event

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rates were similar, other factors such as physician selection bias (since other IIb/IIIa inhibitors were available at the time of the trial), use of a core creatine kinase laboratory, and differing use of ticlopidine and heparin between the two trials confound such speculation. Nonetheless, ESPRIT confirmed that the use of eptifibatide is effective in reducing periprocedural ischaemic complications of PCI. Recent publications in abstract form have confirmed that the observed benefit was sustained over at least a one-year period |14|. Comparison of two platelet glycoprotein llb/llla inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. E J Topol, D J Moliterno, H C Herrmann, et al. N Engl J Med 2001; 344: 1888–94. BACKGROUND. In the setting of PCI, llb/llla inhibitors have significantly reduced the risk of death/ non-fatal MI within 30 days. This trial was designed to assess whether there are differences in safety or efficacy between tirofiban and abciximab. Using a double-blind, double-dummy design at 149 hospitals in 18 countries, patients were randomly assigned to receive either tirofiban or abciximab before undergoing PCI with the intent to perform stenting. The primary end-point was a composite of death/ non-fatal MI/urgent target vessel revascularization within 30 days. The trial was designed and statistically powered to demonstrate the non-inferiority of tirofiban as compared with abciximab. The primary end-point occurred more frequently among the 2398 patients in the tirofiban group than among the 2411 patients in the abciximab group (7.6% versus 6.0%; hazard ratio 1.26; one-sided 95% CI 1.51 demonstrating lack of equivalence; two-sided 95% CI 1.01–1.57 demonstrating the superiority of abciximab over tirofiban, P=0.038). The magnitude and direction of the effect were similar for each component of the composite end-point (hazard ratio for death 1.21; hazard ratio for MI 1.27; hazard ratio for urgent target vessel revascularization 1.26), and the difference in the incidence of MI between the tirofiban group and the abciximab group was significant (6.9% and 5.4% respectively, P=0.04). The relative benefit of abciximab was consistent regardless of age, sex, the presence or absence of diabetes, or the presence or absence of pre-treatment with clopidogrel. There were no significant differences in the rates of major bleeding complications or transfusions, but tirofiban was associated with a lower rate of minor bleeding episodes and thrombocytopenia. INTERPRETATION. Although the trial was intended to assess the non-inferiority of tirofiban as compared with abciximab, the findings demonstrated that tirofiban offered less protection from major ischaemic events than did abciximab.

Comment This trial represents the first and thus far the only direct randomized comparison between two IIb/IIIa inhibitors. Conceived with the intention of establishing noninferiority for tirofiban compared with abciximab, TARGET ultimately showed that abciximab provided superior reduction of a composite of ischaemic events (hazard ratio 1.26; 95% CI 1.01–1.57) (Fig. 2.3), largely as a result of a reduction in MI (from 6.9% to 5.4%, P=0.04). The dose of tirofiban used in TARGET was taken from the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE), and had originally been ‘calibrated’ against a less potent platelet agonist than was used in the dose-finding trials of abciximab. An important concept tested in TARGET was that the early use of a loading dose of clopidogrel in addition to tirofiban would provide clinical efficacy similar to that seen with abciximab. Should this fail to occur, it would provide indirect evidence that clopidogrel alone is unlikely to afford the same degree of protection against periprocedural MI as does a IIb/ IIIa inhibitor. When treatment is started 48 hours prior to cardiac catheterization, tirofiban has been shown to be useful in preventing ischaemic events in patients hospitalized with an acute coronary syndrome who

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Fig. 2.3 Incidence of the primary composite end-point (death/non-fatal MI/urgent target vessel revascularization) in the first 30 days after enrolment. After 30 days, the incidence of the primary end-point was 7.6% in the tirofiban group and 6.0% in the abciximab group (hazard ratio 1.26; 95% CI 1.01–1.57; P=0.038). Source: Topol et al. (2001).

are likely to undergo PCI |15|. However, TARGET would imply that for ‘downstream’ use in the cardiac catheterization laboratory, a standard dose of abciximab is more efficacious than tirofiban at preventing periprocedural ischaemic complications. Abciximab readministration: results of the ReoPro Readministration Registry. J E Tcheng, D J Kereiakes, A M Lincoff, et al. Circulation 2001; 104: 870–5. BACKGROUND. IIb/IIIa inhibition with abciximab improves the clinical outcomes of PCI. This registry was conducted to characterize the effects of repeated

administration of abciximab during intervention. Twenty-two centres in the United States recruited 500 consecutive patients who were receiving abciximab for at least a second time during PCI. Safety was measured as the incidence of hypersensitivity reactions, major bleeding, and thrombocytopenia. Efficacy was assessed as event-free clinical success. Human antichimeric antibody (HACA) responses were also characterized. There were no cases of hypersensitivity (95% upper CI 0.3%), major bleeding or death. The clinical success rate was 94.4%. Thrombocytopenia occurred in 23 patients (4.6%; 95% CI 2.8–6. 4%), including 12 (2.4%; 95% CI 1.1–3.7%) who developed profound thrombocytopenia (<20×109 cells/ I). In two patients (0.4%) profound thrombocytopenia did not develop until after hospital discharge; in four (0.8%) profound thrombocytopenia recurred despite platelet transfusion. Before the first readministration, a positive HACA titre was present in 22 of 454 patients (4.8%); after the first readministration, an additional 82 of 432 (19.0%) became HACA-positive. HACA did not neutralize the in vitro inhibition of platelet aggregation by abciximab or correlate with clinical events. INTERPRETATION. The results, including the overall rates of thrombocytopenia, were consistent with randomized clinical trials of first abciximab treatment. However, there was a shift from mild to profound thrombocytopenia, and cases of delayed presentation and of recurrent thrombocytopenia were seen. These findings suggest that indications and guidelines for first-time use apply to retreatment, and that systematic monitoring for thrombocytopenia is particularly important.

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Comment PCI is often viewed as a short-term response to a long-term disease. Restenosis occurs in a substantial proportion of patients who have had intracoronary stents implanted, and atherosclerosis frequently progresses in previously unaffected or unrecognised areas of the coronary circulation. Consequently PCI is frequently performed several times during the lifetime of the patient with coronary artery disease. Since abciximab is a chimeric antibody, there has been concern about repeated administration in patients undergoing PCI. The registry thus provides reassuring evidence that severe immunological consequences are unlikely to result from the readministration of abciximab. In vitro assays of platelet inhibition appeared to be unaffected as well, suggesting that the antibody was not neutralized. The 2.4% incidence of profound thrombocytopenia (<20×109 cells/l) is greater than that reported in studies of first-time administration of abciximab. In addition, several of the cases of profound thrombocytopenia had more prolonged courses than are usually seen in patients receiving a first dose of abciximab. Thus, although extra vigilance may be required after readministering abciximab, the results of the registry indicate that readministration is a reasonably safe approach in the patient who is undergoing a second PCI and who has had prior exposure to abciximab. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. C P Cannon, W S Weintraub, L A Demopoulos, et al. N Engl J Med 2001; 344:1879–87. BACKGROUND. There is continued debate as to whether a routine early invasive strategy is superior to a conservative strategy for the management of unstable angina and non-ST elevation MI. The TACTICS-TIMI 18 trial enrolled 2220 patients who had unstable angina or non-ST elevation MI with ST or T wave changes, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. All patients were treated with aspirin, heparin and tirofiban, and randomly assigned to an early invasive strategy, which included routine catheterization within 4 to 48 hours and revascularization as appropriate, or to a more conservative strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischaemia or an abnormal stress test. The primary end-point was a composite of death/non-fatal MI/rehospitalization for an acute coronary syndrome within 6 months. At 6 months, the rate of the primary end-point was 15.9% with use of the early invasive strategy and 19.4% with use of the conservative strategy (odds ratio 0.78; 95% CI 0.62–0. 97; P=0.025) (Fig. 2.4). The rate of death/non-fatal MI within 6 months was similarly reduced (7.3% versus 9.5%, odds ratio 0.74; 95% CI 0.54–1.00; P<0.05) (Table 2.1).

INTERPRETATION. In patients with unstable angina or non-ST elevation MI who received tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of early IIb/IIIa inhibition in combination with an early invasive strategy in such patients.

Comment This study provides landmark information for the management of patients with acute coronary syndromes. Previous studies had failed to provide evidence that a strategy of early angiography and revascularization was beneficial to patients with acute coronary syndromes. Although the Fragmin and Fast Revascularization During Instability in Coronary Artery Disease (FRISC) study provided the first indication that modern

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Fig. 2.4 Cumulative incidence of death/non-fatal MI/rehospitalization for an acute coronary syndrome within 6 months. Source: Cannon et al. (2001).

medical stabilization techniques (using low molecular weight heparin) and interventional approaches reduced reinfarction and mortality |16,17|, the 5-day stabilization period in that trial did not represent ‘early’ intervention as most practitioners think of it. In TACTICS-TIMI 18, patients underwent a brief stabilization period using tirofiban. Tirofiban was then continued through the duration of the procedure. Viewed in the context of previous trials of PCI, one would conclude that administration of ‘upstream’ and periprocedural tirofiban reduced the early hazard associated with revascularization, and may have played Table 2.1 Clinical outcomes of patients assigned to invasive or conservative management in TACTICS-TIMI 18

At 30 days Death/non-fatal MI/ rehospitalization for an acute coronary syndrome Death/non-fatal MI Death Fatal or non-fatal MI Rehospitalization for an acute coronary syndrome At 6 months Death/non-fatal MI/ rehospitalization for an acute coronary syndrome Death/non-fatal MI Death Fatal or non-fatal MI

Invasive strategy Conservative strategy Odds ratio (n=1114) (n=1106) (95% CI)

P value

82 (7.4%)

116 (10.5%)

0.67 (0.50–0.91)

0.009

52 (4.7%) 25 (2.2%) 34 (3.1%) 38 (3.4%)

77 (7.0%) 18 (1.6%) 64 (5.8%) 61 (5.5%)

0.65 (0.45–0.93) 1.40 (0.76–2.59) 0.51 (0.33–0.77) 0.61 (0.40–0.92)

0.02 0.29 0.002 0.018

177 (15.9%)

215 (19.4%)

0.78 (0.62–0.97)

0.025

81 (7.3%) 37 (3.3%) 53 (4.8%)

105 (9.5%) 39 (3.5%) 76 (6.9%)

0.74 (0.54–1.00) 0.93 (0.58–1.47) 0.67 (0.46–0.96)

<0.05 0.74 0.029

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Rehospitalization for an acute coronary syndrome Source: Cannon et al. (2001).

Invasive strategy Conservative strategy Odds ratio (n=1114) (n=1106) (95% CI)

P value

123 (11.0%)

0.054

152 (13.7%)

0.78 (0.60–1.00)

a major role in facilitating the benefit associated with an early invasive strategy. Although the study was designed to detect a reduction in the composite end-point of death/MI/rehospitalization (and thus to test whether there is economic benefit to an early invasive strategy), the composite end-point of death/MI was also significantly reduced at 6 months. There was also significant internal consistency, as the mortality reduction was greatest in high-risk groups as defined using a clinical risk score or using troponin assays. A significant question left unanswered by this trial concerns very early intervention. Patients randomized to the early invasive strategy underwent angiography between 4 and 48 hours after randomization. The study was not designed to test whether urgent revascularization (i.e. within the first few hours after presentation) in patients with a non-ST elevation acute coronary syndrome is advantageous or disadvantageous compared with angiography after several hours of antithrombin and antiplatelet therapy. Nonetheless, TACTICSTIMI 18 provides a major step forward in deciding how to triage patients with acute coronary syndromes. References 1. 2. 3.

4.

5. 6. 7. 8.

9.

10. 11.

Marguerie GA, Plow EF, Edgington TS. Human platelets possess an inducible and saturable receptor specific for fibrinogen. J Biol Chem 1979; 254:5357–63. Marguerie GA, Thomas-Maison N, Larrieu MJ, Plow EF. The interaction of fibrinogen with human platelets in a plasma milieu. Blood 1982; 59:91–5. Barnathan ES, Schwartz JS, Taylor L, Laskey WK, Kleaveland JP, Kussmaul WG, Hirshfeld JW Jr. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circulation 1987; 76:125–34. Schwartz L, Bourassa MG, Lesperance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bonan R, David PR. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988; 318: 1714–19. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330:956–61. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689–96. The EPISTENT Investigators. Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoproteinIIb/IIIa blockade. Lancet 1998; 352:87–92. Morrow DA, Cannon CP, Rifai N, Frey MJ, Vicari R, Lakkis N, Robertson DH, Hille DA, DeLucca PT, DiBattiste PM, Demopoulos LA, Weintraub WS, Braunwald E; TACTICS-TIMI 18 Investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA 2001; 286:2405–12. Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA, Cohen ED, Gainey PC, White HJ, Cheek HB, Moses JW, Moliterno DJ, Effron MB, Topol EJ. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. Circulation 1998; 98:734–41. The ERASER Investigators. Acute platelet inhibition with abciximab does not reduce in-stent restenosis (ERASER study). Circulation 1999; 100:799–806. Neumann FJ, Kastrati A, Schmitt C, Blasini R, Hadamitzky M, Mehilli J, Gawaz M, Schleef M, Seyfarth M, Dirschinger J, Schomig A. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and

USE OF GLYCOPROTEIN IIB/IIIA INHIBITORS

12.

13.

14.

15.

16.

17.

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angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. J Am Coll Cardiol 2000; 35:915–21. Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, Boulenc JM, Morice MC, Maillard L, Pansieri M, Choussat R, Pinton P; ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up) Investigators. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344:1895–903. Gilchrist IC, O’Shea JC, Kosoglou T, Jennings LK, Lorenz TJ, Kitt MM, Kleiman NS, Talley D, Aguirre F, Davidson C, Runyon J, Tcheng JE. Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention. Circulation 2001; 104:406–11. O’Shea JC, Hafley GE, Greenberg S, Hasselblad V, Lorenz TJ, Kitt MM, Strony J, Tcheng JE; ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy trial) Investigators. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001; 285:2468–73. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-Plus) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and nonQ-wave myocardial infarction. N Engl J Med 1998; 338:1488–97. Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II Prospective Randomized Multicentre Study. Lancet 1999; 354:708–15. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomized trial. Lancet 2000; 356:9–16.

3 Use of antithrombin therapy in patients undergoing percutaneous coronary intervention

Introduction In recent years, several novel approaches to anticoagulation have been developed and tested as adjunctive therapy in patients undergoing percutaneous coronary intervention (PCI). Besides unfractionated heparin, other indirect thrombin inhibitors now available include low molecular weight heparins such as dalteparin and enoxaparin. Direct thrombin inhibitors such as lepirudin, bivalirudin and argatroban have also been introduced. Other emerging therapeutic options that are yet to reach phase III clinical testing in PCI include the pentasaccarides |1|. Initial studies of glycoprotein IIb/IIIa receptor antagonists used in conjunction with unfractionated heparin have been instrumental in highlighting the key issues surrounding the use of these agents in the catheterization laboratory. As seen within the context of abciximab therapy, an excess bleeding risk associated with high levels of thrombin inhibition can be ameliorated by reducing the heparin dose without compromising overall efficacy |2|. These observations support the need for monitoring and dose individualization in patients undergoing PCI. However, to what extent these observations apply to the newer anticoagulants, or to patients not receiving glycoprotein IIb/IIIa inhibition, requires further clarification. In addition, the evidence supporting pre-treatment with thienopyridines in patients undergoing invasive treatment for acute coronary syndromes suggest that the optimal antithrombin-antiplatelet combination for patients undergoing PCI is likely to differ according to patient acuity. This requires careful re-evaluation. However, compared with the substantial evidence on platelet inhibition for the prevention of periprocedural and late ischaemic events after PCI, studies of anticoagulation have been relatively few in number and of smaller magnitude. While several important large-scale studies addressing these questions are currently in progress, initial studies of these agents have suggested that there is a role for them to be used either alone or possibly in combination with antiplatelet therapies. Unfractionated heparin therapy and the optimal activated clotting time Despite extensive clinical experience of unfractionated heparin used as adjunctive therapy for PCI, few studies have addressed the issue of the optimal level of anticoagulation with this agent. More recently, there has been a trend for clinicians to use lower doses of heparin without concurrent glycoprotein IIb/IIIa inhibition in the absence of well-controlled data |3|. This change in practice patterns reflects the clinical

© Clinical Publishing Services Ltd

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recognition that greater levels of anticoagulation appear to be associated with an excess bleeding risk, and is reinforced by observations from abciximab trials reporting that bleeding complications were reduced without compromising efficacy when concurrent thrombin inhibition was reduced |2|. To what extent this applies to patients not receiving abciximab is uncertain. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. D P Chew, D L Bhatt, A M Lincoff, et al. Circulation 2001; 103:961–6. BACKGROUND. The clinical outcomes of patients with differing activated clotting times (ACTs) in the heparin and aspirin comparator arms of 6 large-scale PCI trials, which used similar dosing regimens and clinical end-points, were analysed in order to define the optimal ACT during PCI. With the ACT values examined as 25 second ranges, the minimum ACT around the time of initial device activation was correlated with 7-day rates of death, myocardial infarction (MI) and urgent revascularization, while the maximal ACT during the procedure was correlated with major and minor hemorrhage. While the efficacy analysis was based on ACT data from a total of 5216 patients, the bleeding analysis was based on only 3485 patients as the bleeding end-point definition differed in one trial, necessitating its exclusion. With ACT values extending from <200 seconds to >450 seconds, a ‘U-shaped’ relationship between the ACT and the ischaemic outcome was evident. The lowest ischaemic event rate was observed in patients with an ACT of 350–375 seconds. ACT values within this range were associated with a 34% reduction in ischaemic events compared with values in the 275–300 second range. As expected, bleeding complications with heparin alone increased in association with increasing ACT levels, with the lowest rates of bleeding being observed in the 300–325 second range, although wide confidence intervals were evident around the lowest ACT intervals. Analysis of patients receiving heparin and abciximab confirmed previous observations |2|. A similar low rate of ischaemic complications across the entire range of ACT values was documented, but a substantial increase in bleeding complications was associated with high ACT values (Fig. 3.1). INTERPRETATION. Contrary to recent reports, the optimal suppression of ischaemic events with unfractionated heparin therapy in patients undergoing PCI, demands

treatment to ACT levels that are substantially higher than currently appreciated. These data define a goal for heparin dosing within coronary interventions and establish a benchmark of optimal unfractionated heparin therapy against which future trials of novel antithrombotic regimens in percutaneous interventions can be compared.

Comment While this analysis represents the largest compiled dataset of patients examining the relationship between the ACT and outcome following PCI, it is important to highlight the retrospective nature of this analysis and therefore the potential for several sources of confounding. Firstly, while the target ACT levels and clinical end-points specified within these trials were similar, ACT measurement was not a principal component of the study question, and therefore documentation of these values was incomplete. Secondly, the relationship between the ACT and clinical events may also have been confounded by several clinical and procedural factors including body weight, female gender and the duration of the procedure. While the relationship persisted after adjustment for many of these factors in multivariate analysis, there is a potential for residual confounding by unmeasured factors within observational analyses |4|. Thirdly, the relevance of these

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Fig 3.1 Relationship between the activated clotting time and ischaemic and bleeding events with heparin, used alone and in conjunction with abciximab. Source: Chew et al. (2001).

observations within the context of current interventional practice remains somewhat uncertain. While the widespread application of stenting has brought a reduction in the need for urgent repeat revascularization and a commensurate increase in the rate of periprocedural MI, the relative impact of greater anticoagulation on these end-points is uncertain. Specifically, only 766 patients within this analysis, drawn largely from the EPISTENT trial |5|, received coronary stents. While a similar trend towards reduced ischaemic events associated with higher ACT values was suggested within this analysis, the relatively small number of patients prevents definitive conclusions. Despite these limitations, this study reinforces the observations from previous investigations suggesting a reduction in ischaemic event rates associated with higher levels of anticoagulation, supporting previously proposed ACT levels |6|. Furthermore, the tight balance between bleeding and ischaemic risk argues in favour of clinical monitoring. Lastly, this analysis again illustrates that while the addition of abciximab mitigates the suboptimal suppression of ischaemic events at low levels of anticoagulation, there is an excess bleeding risk without additional benefit associated with the targeting of higher ACT levels. Low molecular weight heparin Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. D J Kereiakes, C Grines, E Fry, et al. J Invas Cardiol 2001; 13:272–8. BACKGROUND. While studies have begun to examine the relative efficacy of the low molecular weight heparins in patients undergoing PCI, there are few direct comparative data available. The National Investigators Collaborating on Enoxaparin (NICE) Study Group have recently published registry studies of enoxaparin used without abciximab (NICE-1) and with abciximab (NICE-4) in patients undergoing PCI. In the NICE-1 registry, 828 patients undergoing PCI received enoxaparin (1.0 mg/kg) intravenously prior to coronary intervention, and in the NICE-4 registry, 818 patients received enoxaparin (0.75 mg/kg) and abciximab (0.25 mg/kg bolus followed by a 0.125 μg/kg/minute infusion).

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The primary end-point of both studies was major haemorrhage in-hospital or within 30 days. Secondary end-points assessed at the same time points included the incidence of minor bleeding, the need for transfusion, and a composite ischaemic end-point of death, MI and urgent revascularization. The exclusion criteria in these studies were acute MI within 24 hours, fibrinolysis within 3 days, prior low molecular weight heparin within 12 hours, serum creatinine >2.5 mg/dl, and thrombocytopenia of <100000 cc. All patients received aspirin, and 85% and 88% of patients received at least one stent in NICE-1 and NICE-4 respectively. All patients undergoing stenting also received either clopidogrel or ticlopidine. Sheaths were removed 4–6 hours after the end of the procedure, and the use of vascular closure devices was not permitted in either study.

In the absence of concurrently compiled comparator arms in these studies, a planned comparison with the EPILOG |2| and EPISTENT |5| studies of unfractionated heparin and abciximab was undertaken. Specifically, this permitted comparison of these enoxaparin strategies with standard-dose heparin without abciximab and low-dose heparin plus abciximab, therefore the end-point definitions used in the registries were identical to those in the randomized trials of abciximab |2,5|. Major haemorrhage occurred in 1.1% of patients in the NICE-1 registry, and minor haemorrhage and transfusions occurred in 6.2% and 2.7% respectively. By 30 days, the composite ischaemic end-point of death, MI and urgent revascularization had occurred in 7.7% of patients, with MI occurring in 5.4% of cases (Table 3.1). Similar event rates were observed in NICE-4, with major haemorrhage occurring in 0. 4% of patients, minor bleeding in 7.0% and transfusions in 1.8%. The composite ischaemic event rate in NICE-4 was 6.8%. INTERPRETATION. In the dose regimens studied, enoxaparin with or without abciximab appeared to provide safe and effective anticoagulation during PCI. The combination of reduced-dose enoxaparin and abciximab was associated with a low incidence of adverse outcomes (bleeding or ischaemic events). Additional studies may be required to establish the relative safety and efficacy of this new adjunctive pharmacologic strategy when compared with the combination of low-dose, weight-adjusted unfractionated heparin and abciximab.

Comment A substantial degree of caution should be exercised when interpreting these data, given the differences in exclusion criteria used in the trials, the temporal dissociation between the study and comparator groups, and possibly the limited sample size of the comparisons. In addition, since neither of these comparisons were randomized or blinded, these studies are limited by clinical selection bias. Firstly, Table 3.1 Comparative 30-day results of low molecular weight heparin trials in patients undergoing PCI NICE-1 trial |11| (n=828)

NICE-4 trial |11| (n=818)

Heparin 100 U/kg (n=809)

Heparin 70 U/kg +abciximab (n=794)

Dalteparin trial |12| (n=103)

EPISTENT |5|

Enoxaparin 1.0 mg/kg Enoxaparin 0.75 mg/kg Dalteparin 40–60 IU/kg +abciximab Death, MI, URV (%) Major bleed (%)

7.7 1.1

6.8 0.4

15.5 2.8

10.0 2.2

5.3 1.5

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NICE-1 trial |11| (n=828)

NICE-4 trial |11| (n=818)

Heparin 100 U/kg (n=809)

Heparin 70 U/kg +abciximab (n=794)

Dalteparin trial |12| (n=103)

EPISTENT |5|

Enoxaparin 1.0 mg/kg Enoxaparin 0.75 mg/kg Dalteparin 40–60 IU/kg +abciximab Minor bleed (%) 6.2 7.0 Transfusion (%) 2.7 1.8 MI=myocardial infarction, URV=urgent revascularization. Source: Kereiakes et al. (2001).

10.3 2.8

1.7 2.2

2.9 2.8

given that planned abciximab was not permitted within the NICE-1 study, selection of a lower-risk population of patients is inherent in the trial design. Secondly, the exclusion of patients with renal impairment differs from the abciximab studies, further reducing the comparability of the respective patient populations. Thirdly, with evolving clinical practice, bleeding event rates within clinical trials have continued to decline over time, thereby clouding the comparability of these studies and limiting the interpretation of the relative benefit of enoxaparin compared with heparin. On the other hand, while neither of these studies was large enough to determine statistical superiority or non-inferiority, they do provide promising evidence that bleeding event rates are not substantially worse from a clinical standpoint, and suggest that these agents may be safely administered among selected patients undergoing PCI. This series of studies provides the first steps towards validation of a clinical dose of enoxaparin for patients undergoing PCI. The patients enrolled in these studies had similar anti-factor-Xa levels to those seen with unfractionated heparin, providing a putative ACT of approximately 300 seconds. Dalteparin in combination with abciximab during percutaneous coronary intervention. D J Kereiakes, N S Kleiman, E Fry, et al. Am Heart J 2001; 141:348–52. BACKGROUND. In a dose-ranging study, the use of dalteparin in conjunction with abciximab was tested in 107 patients undergoing PCI. Four patients received dalteparin (120 U/kg) <8 hours prior to PCI, one of these patients then received a further 40 U/kg at the start of the procedure. The remaining patients were randomized to receive either 40 U/kg intravenously (27 patients) or 60 U/kg intravenously (76 patients) at the start of the procedure. However, due to three thrombotic events during enrolment, the blinding was broken and the 40 U/kg arm of the study was terminated, with these patients subsequently enrolled to the 60 U/kg arm. All patients received aspirin and abciximab. Prolongation of the ACT was observed with the 60 U/kg dose (approximately 240 seconds), and anti-factor-lla activity of approximately 1.0 was commonly seen at 30 minutes during the procedure. While this study was not designed to adequately evaluate clinical outcomes, death, MI (defined as a creatine kinase level of >3 times the upper limit of normal) or urgent revascularization occurred in 15.5% of patients overall. Major haemorrhage and transfusion each occurred in 2.8% of patients. INTERPRETATION. These event rates are somewhat higher than expected, and relevant interpretation for clinical practice recommendations awaits adequately powered randomized studies.

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Comment Despite the fact that this study lacks a control group, ischaemic events observed within this study appear greater than observed in recent randomized trials, driven largely by events occurring in the initial lower dose dalteparin group. These findings suggest that further evaluation of the appropriate dose of dalteparin among patients undergoing PCI is required before phase III trials are undertaken. However, caution should be exercised when considering these results within the context of the NICE registries studying enoxaparin. In particular, these data do not necessarily support the superiority of one low molecular weight heparin over another. Such conclusions require direct comparative trials. Furthermore, collectively these studies are not an adequate substitute for well-designed and adequately powered randomized comparisons between unfractionated heparin and low molecular weight heparin, and therefore do not provide sufficient evidence on which to base recommendations for routine clinical use of low molecular weight heparin. Given that low molecular weight heparins are substantially more expensive that unfractionated heparin, such recommendations require direct comparative trials in which the true superiority of this treatment approach can be adequately assessed. Direct thrombin inhibition Bivalirudin versus heparin during coronary angioplasty for unstable or post-infarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. J A Bittl, B R Chaitman, F Feit, W Kimball, E J Topol. Am Heart J 2001; 142: 952–9. BACKGROUND. While new clinical trial data are awaited from the Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE) Part 2 trial, the data from the initial bivalirudin trial in patients undergoing coronary angioplasty, published in 1995 |7|, has recently been reanalysed. Table 3.2 Analysis differences between the initial report |7| and the final report of the Bivalirudin Angioplasty Study Initial report

Final report

Per-protocol analysis Clinical and angiographic end-points Variable time point (patient discharge) Partial adjudication of data Death or MI: 158 events Major haemorrhage: 292 events Source: Bittl et al. (2001).

Intention-to-treat analysis Clinical end-points Fixed time points (7 days, 90 days, 180 days) Complete adjudication of data Death or MI: 171 events Major haemorrhage: 275 events

This re-evaluation of a clinical trial is highly unusual, but arises from peculiar circumstances. Upon the completion of the initial trial, the sponsors of bivalirudin (then known as hirulog) terminated development of this agent. With the data incompletely evaluated, the trial was published with a per protocol analysis incorporating both clinical and angiographic end-points. Subsequent acquisition of bivalirudin by another sponsor led to re-evaluation and publication of the results, using an intention-totreat analysis and clinical outcomes consistent with contemporary trials. Furthermore, events were assessed at a fixed time point (7 days) rather than in-hospital, as originally published. The key differences between the original analysis and the final report are presented in Table 3.2. Despite the

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atypical nature of such a reanalysis, these data form the basis for the US Food and Drug Administration’s approval of bivalirudin as an anticoagulant for patients undergoing PCI. Despite the unusual circumstances, this study represents one of the largest studies of anticoagulant therapy in PCI. A total of 4312 patients were randomized to receive either bivalirudin (1.0 mg/kg bolus followed by 2.5 mg/kg/hour throughout the procedure and for 4 hours afterwards, followed by 0.2 mg/ kg/hour for 18–24 hours), or heparin (175 IU/kg bolus followed by 15 IU/kg/hour for 18–24 hours). All patients received aspirin and underwent coronary angioplasty. Stenting was not performed in this study, and glycoprotein llb/llla inhibitors were not used. At 7 days, the composite ischaemic end-point of death, MI or revascularization had occurred in 6.2% of the patients who had received bivalirudin and in 7.9% of those who had received heparin (P=0.039). In addition to this ischaemic benefit, there was a reduction in bleeding. Clinically significant bleeding was observed in 3.5% of the bivalirudin treatment group and in 9.3% of the heparin treatment group (P<0.001), and 2.0% and 5.7%, respectively, received red cell transfusions (≥ 2 units). The most striking benefit was observed in patients with post-infarction angina (within 7 days). Studied under a stratified randomization design, these patients had a 42% reduction in their composite ischaemic event rate (11.7% vs 20.2%, P<0.001) and an 80% reduction in the rate of major haemorrhage (2.4% vs 11.8%, P<0.001). Considering ischaemic and bleeding end-points collectively, the benefit of bivalirudin remained evident at 90 days and 6 months. INTERPRETATION. This analysis supports the hypothesis that bivalirudin reduces ischaemic complications and bleeding after angioplasty. Further trials are needed to evaluate bivalirudin versus heparin in conjunction with platelet-glycoprotein IIb/IIIa inhibitors and for coronary stenting.

Comment While these results suggest that bivalirudin is superior to heparin in patients undergoing angioplasty, some caution should be exercised in interpreting these data. It was argued that the reanalysis of this study using end-points consistent with those of current PCI trials enabled the evaluation of this agent within the context of data on other therapies—specifically the glycoprotein IIb/IIIa receptor antagonists. However, such reclassification does not overcome the issue of non-contemporary practice. Most illustrative of this point are the rates of bleeding and revascularization observed within the study. The bleeding and transfusion rates with heparin were substantially higher than those seen in more contemporary trials, which have been in the range of 3–4%. Likewise, these days, the need for early surgical revascularization has been markedly reduced by the widespread use of coronary stenting. Hence, considering the large number of patients studied and the robust benefit seen particularly in the post-infarction angina group, these data provide strong, but not conclusive, evidence for the superiority of bivalirudin in patients undergoing PCI. Specifically, while these results suggest an improvement in outcomes even within the context of current event rates, the relative and absolute benefits of bivalirudin in current practice remain uncertain. These questions are currently being addressed within the context of stenting, thienopyridines and glycoprotein IIb/IIIa inhibition by a 6000 patient trial. Key issues regarding anticoagulation in PCI While none of the studies presented provide pivotal evidence to support a change in anticoagulant practice in patients undergoing PCI, they do illustrate the continued evolution of antithrombin therapy. Firstly, they highlight the important clinical questions that will need to be addressed if further development in this area is to continue. Specifically, with the progressive reduction in ischaemic complications now seen in clinical trials, bleeding complications have become a significant consideration for the interventional cardiologist. As

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seen with the use of heparin alone, optimization of therapy may be possible by increasing the degree of anticoagulation, but these benefits may be achieved at the cost of increased bleeding complications. With these new approaches to antithrombin therapy, the balance between suppression of ischaemic events and bleeding complications will need to be carefully weighed, particularly in high-risk groups such as the elderly, women and patients with renal impairment. In this regard, the reduction in ischaemic and bleeding events with bivalirudin is promising, but requires further validation. Secondly, with the availability of several antiplatelet and antithrombin options, a new complexity in treatment choices for antithrombotic therapy in the catheterization laboratory is emerging. Considering the bleeding risk and the substantial costs associated with these agents, it is unlikely that all therapies will be justifiable for all patients, and choices individualized to the patient’s risk profile remain of principal importance. In particular, the routine use of glycoprotein IIb/IIIa inhibition in PCI needs to be reconsidered given the reanalysis of the Bivalirudin Angioplasty Study data and the results of the Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (PCI-CURE) study, where pretreatment of clopidogrel was associated with a 30% reduction in ischaemic complications |8|. This question forms the basis of the REPLACE Part 2 trial, which is comparing bivalirudin plus provisional glycoprotein IIb/IIIa inhibition with heparin plus planned glycoprotein IIb/IIIa inhibition in patients undergoing PCI on a background of aspirin plus clopidogrel therapy. Alternatively, considering the heightened ischaemic risk borne by patients presenting with high-risk acute coronary syndromes, a therapeutic combination that includes a novel antithrombin agent, clopidogrel and glycoprotein IIb/IIIa inhibition may be warranted in this setting. Nevertheless, considering the concomitant burden of bleeding complications in these patients, this will need to be validated prospectively. The observations drawn from patients treated with heparin also strongly argue for point-of-care monitoring of the anticoagulant effect. The extent to which this principle applies to the low molecular weight heparins when used either in isolation or in combination with antiplatelet therapy remains uncertain. If optimization of antithrombin therapy is required, development of a point-of-care test and definition of an optimal therapeutic range will be needed, and indeed this is the focus of current research. Furthermore, clinical interpretation of measures of anticoagulation such as the ACT clearly differs across the different agents. For example, the ACT does not reflect the degree of anticoagulation with enoxaparin, and is somewhat prolonged with dalteparin; the lower bleeding complication rates seen with bivalirudin with similar levels of ACT prolongation argue against the discriminatory utility of this test. Hence, interpretation of point-of-care testing needs to be agent-specific, and this will require further clarification. Thirdly, emerging evidence acquired within the context of modern antithrombotic therapies appears to support the invasive approach in patients with acute coronary syndromes |9,10|. This heralds the increased use of angiography for the stratification of clinical management. Consequently, such practices place new demands on antithrombin (and antiplatelet) therapies used in the ‘upstream’ treatment of acute coronary syndromes among patients destined for early invasive management. This issue is particularly relevant to the low molecular weight heparins, where the absence of a point-of-care test and a relatively long half-life raises concern about their relative safety and efficacy in patients undergoing urgent PCI. This question is being prospectively addressed in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial of enoxaparin, the results of which are expected in late 2002. If similar or superior clinical efficacy and safety is demonstrated, this trial promises to streamline the care of acute coronary syndrome patients undergoing invasive management.

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Conclusion Despite extensive clinical experience comparing heparin with antiplatelet therapies in patients undergoing PCI, relatively few studies have addressed the question of optimizing antithrombin therapy. Issues that require clarification include the balance between ischaemic and bleeding complications, the optimal clinical application of antithrombin therapies within the context of currently available antiplatelet therapies, and the utility of point-of-care testing. While the initial steps in this process appear very promising, important conclusions regarding the efficacy, safety and overall cost-effectiveness of these novel antithrombin treatments await the results of several large-scale multi-centre randomized trials currently in progress. References 1. 2. 3. 4. 5.

6. 7.

8

9.

10.

Hirsh J. New anticoagulants. Am Heart J 2001; 142:S3–S8. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689–96. Garachemani A, Meier B. Heparin for coronary angioplasty: high dose, low dose, or no dose? [editorial]. Heart 1998; 80:3–4. Hanratty CG, Ward M. Optimal activated clotting time during percutaneous coronary intervention [letter]. Circulation 2001; 104:e83. Lincoff AM, Califf RM, Moliterno DJ, Ellis SG, Ducas J, Kramer JH, Kleiman NS, Cohen EA, Booth JE, Sapp SK, Cabot CF, Topol EJ. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341:319–27. Narins CR, Hillegass WB Jr, Nelson CL, Tcheng JE, Harrington RA, Phillips HR, Stack RS, Califf RM. Relation between activated clotting time during angioplasty and abrupt closure. Circulation 1996; 93:667–71. Bittl JA, Strony J, Brinker JA, Ahmed WH, Meckel CR, Chaitman BR, Maraganore J, Deutsch E, Adelman B. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333:764–9. Mehta SR, Yusuf S, Peters RJG, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE Study. Lancet 2001; 358:527–33. Fragmin and fast revascularization during instability in coronary artery disease (FRISC II) Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II Prospective Randomized Multicentre Study. Lancet 1999; 354: 708–15. Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Bertrand M, Neumann FJ, Stone GW, DiBattiste PM, Demopoulos L; TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Trial) Investigators. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001; 344: 1888–94.

4 Drug management post-percutaneous coronary intervention

Introduction Over the last decade, coronary stent deployment has become standard treatment during percutaneous coronary interventional (PCI) procedures. Aspirin combined with a 2–4 week course of ticlopidine is more effective than a combination of aspirin and anticoagulation in preventing platelet-rich thrombotic occlusion of the stent post-procedure. Unfortunately, ticlopidine therapy is frequently associated with skin rashes and gastrointestinal symptoms, and infrequently with more serious blood dyscrasias including thrombotic thrombocytopenic purpura. Clopidogrel is a newer thienopyridine with fewer reported side effects, which compared favourably to aspirin in preventing vascular events in the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial |1|. Two trials comparing clopidogrel with ticlopidine in patients undergoing stent deployment are reviewed in this chapter, along with data on those patients undergoing PCI in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial |2|, which compared aspirin plus clopidogrel with aspirin alone in patients with vascular disease. While there has been much interest in the effects of glycoprotein IIb/IIIa inhibitors in preventing periprocedural myocardial necrosis, established antiischaemic therapy may also have a cardioprotective role at the time of PCI. A non-randomized evaluation of β-blocker therapy in such patients is discussed below. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). M E Bertrand, H-J Rupprecht, P Urban, A H Gershlik, F T Investigators. Circulation 2000; 102:624–9. BACKGROUND. Aspirin combined with ticlopidine (an adenosine diphosphate [ADP] antagonist) is more effective than aspirin plus anticoagulation in preventing thrombosis after intracoronary stent deployment. Clopidogrel is a newer ADP antagonist with fewer side effects than ticlopidine. 1020 patients with successful stent deployment were allocated within six hours of stenting to receive four weeks of treatment with ticlopidine 250 mg twice daily clopidogrel given as a 300 mg loading dose followed by 75 mg/day, or clopidogrel 75 mg/day with no loading dose. All patients received aspirin 325 mg/day. Primary end-point events (major bleeding/blood dyscrasia/early study drug discontinuation for non-cardiac reasons) occurred in 9.1% of those taking ticlopidine and 4.6% of those taking clopidogrel (P=0.005). Major cardiac events (defined as cardiac death, myocardial infarction [MI] or target lesion revascularization) occurred in 0.9% of those given ticlopidine, 1.2% of those given clopidogrel with a

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loading dose, and 1.5% of those given clopidogrel without a loading dose. The differences between the groups were not significant. INTERPRETATION. Clopidogrel produced fewer major adverse side effects and was better tolerated than ticlopidine, in combination with aspirin, in patients undergoing stent deployment. Adverse cardiac events were infrequent and did not differ significantly between the treatment groups.

Comment This study showed a benefit of clopidogrel therapy following stent deployment in a relatively low-risk population. A successful stenting procedure was required prior to enrolment. The inclusion criteria of singlevessel stenting, a reference vessel diameter of >2.8 mm, no residual stenosis, thrombus or dissection following stent deployment, and the exclusion criteria of slow reflow, vein graft lesions or need for IIb/IIIa inhibitors before or after the procedure excluded most higher-risk patients. The safety end-point difference was entirely due to increased early discontinuation of ticlopidine for skin rash, gastrointestinal symptoms or ‘allergy’, rather than any difference in bleeding rates. There were no reported cases of thrombotic thrombocytopenic purpura. Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. M Taniyuchi, H I Kurz, J M Lasala. Circulation 2001; 104:539–43. BACKGROUND. Antiplatelet therapy after stent deployment was also evaluated in this single-centre study. 1016 patients with successful stent implantation were assigned to receive ticlopldine or clopidogrel, in combination with aspirin 325 mg/day. The first dose of ticlopidine (500 mg) or clopidogrel (300 mg) was administered within 60 minutes of completing the procedure. The primary endpoint of failure to complete two weeks of thienopyridine therapy occurred in 3.6% of ticlopidine patients and 1.6% of clopidogrel patients (P=0.04). Most medication discontinuation was due to skin rash. At 30 days a major adverse cardiac event (cardiac death, Q wave MI, stent thrombosis or target vessel revascularization) had occurred in 4.6% of ticlopidine patients and 3.8% of clopidogrel patients (P=0. 55). The patient population differed from CLASSICS in that there were few clinical or angiographic exclusion criteria. Those enrolled included patients with acute MI (41%), angiographic thrombus (21%), diabetes (29%) and vein graft lesions (9%). Almost half the patients were given periprocedural IIb/IIIa inhibitors. INTERPRETATION. Clopidogrel is an effective thienopyridine which is better tolerated than ticlopidine in patients undergoing PCI with stent deployment.

Comment This study found that clopidogrel was better tolerated than ticlopidine following stent deployment, even when the thienopyridine was administered for only two weeks. The study population more closely represents patients undergoing ‘real world’ PCI than the CLASSICS population, except that the use of IIb/ IIIa inhibitors was higher than in most non-US countries. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. S R Mehta, S Yusuf, R J G Peters, et al. Lancet 2001; 358:527–33.

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BACKGROUND. Patients undergoing PCI are at risk of periprocedural and later ischaemic events. This study was a prospective subgroup analysis of 2658 patients undergoing PCI in the CURE study. Patients with non-ST elevation acute coronary syndromes were treated with aspirin and randomly assigned to receive either clopidogrel or placebo. At enrolment almost all patients had abnormal troponin levels or electrocardiographic (ECG) changes. The study drugs were administered for a median of 6 days prior to PCI if it was performed during the initial hospital admission

(about two thirds of patients), or longer (10 days overall median treatment) if it was performed later (one third of patients). Most patients in both groups received open-label clopidogrel for 4 weeks postintervention, before reverting to blinded clopidogrel or placebo for a mean of 8 months. At 30 days postPCI the primary composite end-point of cardiovascular death/MI/urgent target vessel revascularization was reduced from 6.4% with placebo to 4.5% with clopidogrel (a 30% relative risk reduction, P=0.03) (Fig. 4.1). The beneficial effect of clopidogrel pretreatment may have been underestimated because openlabel thienopyridine was actually administered to one quarter of patients prior to PCI. Beyond 30 days post-intervention, the composite end-point of death/MI was non-significantly reduced from 4.0% with placebo to 3.1% with clopidogrel over the next 8 months.

INTERPRETATION. Pre-treatment with clopidogrel reduces the incidence of adverse cardiac events occurring in the periprocedural period and subsequent 30 days. There may be some additional benefit of lesser magnitude from longer-term clopidogrel administration.

Comment Although this study has the limitation of being a subgroup analysis, it provides good evidence for starting patients with acute coronary syndromes on clopidogrel at the time of initial presentation if they might undergo PCI. The only patients potentially disadvantaged by this strategy are those undergoing angiography who subsequently need urgent cardiac surgery (e.g. for critical disease, haemodynamic instability, or as a complication of PCI). While there was no excess of bleeding in those who had discontinued clopidogrel for five days or more, there was a 50% increase in the relative risk of major bleeding in patients who had received clopidogrel within the previous five days. Cardioprotective effect of prior β-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention: benefit is extended to improvement in intermediate-term survival. S K Sharma, A Kini, J D Marmur, V Fuster. Circulation 2000; 102:166–72. BACKGROUND. β-blockers have cardioprotective effects, including prevention of reinfarction, when administered post-MI. A prospective registry of 1675 consecutive patients undergoing PCI was used to compare the 643 (38%) who were on β-blocker therapy with the remainder who were not, with regard to periprocedural creatine kinase (CK)-MB elevations and subsequent clinical outcomes. Those on βblockers prior to the procedure were significantly less likely to have elevated CK-MB levels (13% vs 22%, P<0.001) (Fig. 4.2), and had less chest pain and a lower periprocedural heart rate and blood pressure. The difference was largely in ‘minor’ enzyme elevation (1–3 times normal). At a mean follow-up of 15 months, mortality was lower in those on β-blockers (0.8% vs 2.0%, P=0.04), although the difference was not related to the reduction in CK-MB.

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Fig. 4.1 Kaplan-Meier cumulative hazard rates for the primary composite end-point of cardiovascular death/MI/urgent target vessel revascularization within 30 days after PCI in the PCI-CURE study. Source: Mehta et al. (2001). INTERPRETATION. Pre-procedural β-blocker therapy may reduce periprocedural ‘minor’ myocardial necrosis occurring during and after PCI.

Comment This prospective registry found that patients on β-blockers prior to PCI were less likely to have elevation of CK-MB post procedure. The major limitation of this study is that it was non-randomized and there were considerable differences between those taking β-blockers and the remainder. Patients on β-blockers were more likely to be male and to have hypertension, angina at rest, multivessel disease, a history of prior MI, or a history of coronary bypass graft surgery. Many of those factors were associated with an increased likelihood of CK-MB elevation. On multivariate analysis, prior β-blocker use was the only predictor of lack of CK-MB elevation. One unusual feature of the study population, compared with most centres, was the use of rotational atherectomy in over half of the patients. Approximately half of the patients received stent

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Fig. 4.2 Incidence and magnitude of CK-MB elevation in patients receiving prior β-blocker therapy versus those receiving no prior β-blocker therapy. Source: Sharma et al. (2000).

deployment, and β-blocker therapy appeared to be of greatest benefit in patients in whom a stent was deployed. Conclusion Clopidogrel and ticlopidine have now been compared in three randomized trials of patients with successful stent deployment (Table 4.1) |3–5|. All of the patients were also taking aspirin, and the thienopyridine was commenced immediately after the procedure. All three studies confirmed the better tolerability of clopidogrel, with therapy consistently more likely to be completed with clopidogrel than with ticlopidine. The major adverse cardiac event rates were low, thus all three studies were underpowered to detect any potential difference in antithrombotic efficacy. It was of some concern that adverse cardiac event rates were slightly higher with clopidogrel than with ticlopidine in the Müller |3| and CLASSICS |4| studies (particularly in the group not given a loading dose of clopidogrel). However, when the Table 4.1 Major adverse cardiac events within 30 days post-stent deployment

Müller et al. |3| CLASSICS |4| Taniuchi et al. |5|

n

Treatment period

Ticlopidine

Clopidogrel 75 mg/day

Clopidogrel 300 mg+75 mg/day

700 1020 1016

4 weeks 4 weeks 2 weeks

1.7% 0.9% 4.6%

3.1% 1.5% –

– 1.2% 3.8%

data from all three studies are combined, the 30-day major adverse cardiac event rates were 2.7% with ticlopidine and 2.6% with clopidogrel (P=0.85). The findings of these three trials, combined with earlier non-randomized data, have led to clopidogrel replacing ticlopidine during coronary stent procedures. Would better outcomes be achieved if patients were

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pre-treated with clopidogrel prior to their interventional procedure? PCI-CURE provides evidence that this would indeed be the case. There are some unresolved issues. How long should clopidogrel treatment be continued? The risk of recurrent ischaemic events in patients with acute coronary syndromes decreases over time, and long-term treatment is expensive. Beyond 30 days post-intervention, clopidogrel reduced the composite end-point of death/ MI by approximately 0.1% per month of treatment. How should the use of clopidogrel be integrated with that of intravenous IIb/IIIa inhibitors? The use of IIb/IIIa inhibitors was discouraged in PCI-CURE, and they were significantly less likely to be used in those assigned to clopidogrel (26.6%) than those on placebo (20.9%, P=0.001). Because the patients in this study received open-label thienopyridines after PCI, any increased risk of bleeding with combined therapy could not be assessed in this study. The magnitude of reduction in the composite end-point of death/MI at 30 days (approximately 20% in the whole CURE study population and 30% in those undergoing PCI) compared very favourably with that achieved by IIb/IIIa inhibitors (9% in a recent meta-analysis) |6|. While considerable attention has focused on the use of IIb/IIIa inhibitors to reduce periprocedural myocardial necrosis during PCI, other anti-ischaemic medications have received less attention. β-blockers may be effective at reducing ‘minor’ myocardial damage, particularly in patients with high-risk clinical features. The mechanism of benefit is uncertain. While there appeared to be no difference in the incidence of side branch closure or distal embolism, vasospasm and slow flow were possibly reduced in those treated with β-blockers. The long-term clinical importance of modest elevations of CK-MB or troponin early after intervention remains uncertain. While such elevations are associated with a worse clinical outcome, cause and effect remain unresolved as patients who have an elevated CK-MB level are more likely to have adverse clinical and angiographic features than those who do not. A randomized trial of β-blocker therapy is needed to determine whether it should be routinely administered prior to PCI in the absence of contraindications. References 1. 2.

3. 4.

5. 6.

CAPRIE Steering Committee. A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet1996; 348:1329–39. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med2001; 345:494–502. Müller C, Büttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation2000; 101:590–3. Bertrand ME, Rupprecht H-J, Urban P, Gershlik AH, FT Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000; 102:624–29. Taniuchi M, Kurz HI, Lasala JM. Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation 2001; 104:539–43. Boersma E, Harrington RA, Moliterno DJ, White H, Theroux P, Van de Werf F, de Torbal A, Armstrong PW, Wallentin LC, Wilcox RG, Simes J, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomized clinical trials. Lancet2002; 359:189–98.

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Section conclusion The studies reviewed in this section support the use of troponins for risk stratification and targeting of treatments, the use of IIb/IIIa inhibitors with PCI and upstream prior to revascularization, and the use of clopidogrel long-term after PCI. Before the use of low molecular weight heparins and bivalirudin can be widely adopted, several important issues will need to be resolved. These include the need for examination of the balance between bleeding and ischaemic complications associated with these anticoagulants—especially within the context of early invasive therapy for acute coronary syndromes, the clinical need for monitoring and the validity of surrogate therapeutic targets. It is also important to assess the relative clinical benefit of these agents within the context of other modern therapies, and their place among current antithrombotic regimens in patients undergoing PCI.

Part II Percutaneous coronary mtervention in acute coronary syndromes

5 Percutaneous coronary intervention persistent in ST-segment elevation myocardial infarction

Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York State. B A Vakili, R Kaplan, D L Brown. Circulation 2001; 104:2171–6. BACKGROUND. A rapidly increasing proportion of patients with acute ST-segment elevation myocardial infarction is treated with primary angioplasty. Numerous studies involving thousands of patients undergoing predominantly elective procedures, have shown an inverse relationship between both physician and hospital angioplasty volumes and adverse outcomes. It has been shown that hospitals with the most experience at treating myocardial infarction patients, have the lowest mortality. No previous study to date has examined the separate and potentially interactive effects of both operator and hospital primary angioplasty volume. This information may have important consequences for regional planning of triage and acute treatment of patients presenting with acute ST-segment elevation myocardial infarction. INTERPRETATION. Data were analyzed from the 1995 New York State Coronary Angioplasty Reporting System Registry. Patients (n=1342) who underwent angioplasty within 23 hours of onset of acute myocardial infarction (AMI) without preceding thrombolytic therapy were included (Table 5.1). From these data it can be concluded that physicians and/or hospitals that performed a higher volume of primary angioplasty procedures had a lower mortality rate.

Comment Multiple factors may contribute to the association between the volume of primary angioplasty procedures and clinical outcome. The patient with AMI is often experiencing active ischaemia, manifested by chest pain, arrhythmias and haemodynamic instability. Therefore, stabilization of the patients while achieving timely and complete reperfusion requires expertise in an array of pharmacological and mechanical therapies. Improved skill and judgment of physicians and other hospital

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Table 5.1 Unadjusted and adjusted relative risk of in-hospital death among patients who underwent primary angioplasty for AMI according to physician and hospital volume Model*

Relative risk (95% CI) High-volume vs low-volume physicians

High-volume vs low-volume hospitals

Unadjusted 0.50 (0.3–0.77) 0.67 (0.4–1.1) Adjusted for demographics 0.53 (0.31–0.91) 0.67 (0.4–1.1) Adjusted for demographics and 0.56 (0.32–0.91) 0.67 (0.42–1.1) medical history Adjusted for demographics, medical 0.43 (0.21–0.83) 0.56 (0.29–1.1) history, haemodynamic status, and time to treatment *Demographics include age and sex. Medical history includes smoking, diabetes, previous MI, and previous cardiac surgery. Haemodynamic status refers to patients requiring pharmacological support or the presence of systolic blood pressure <80 mm Hg or a cardiac index <2 L/m2 despite pharmacological or mechanical support before commencement of procedure. Time to treatment refers to <6 hours or from 6 to 23 hours after symptom onset. Source: Vakili et al. (2001).

staff derive from greater experience, ultimately resulting in improved outcomes for patients. Thus, based on these data, patients selected for primary angioplasty should, if possible, be directed to high volume physicians in high volume hospitals. Importance of time to reperfusion on outcomes of primary coronary angioplasty for acute myocardial infarction: results from the Stent Primary Angioplasty in Myocardial Infarction (PAMI) Trial. B R Brodie, G W Stone, M C Morice, et al. Am J Cardiol 2001; 88: 1085–90. BACKGROUND. Time to treatment has a profound effect on clinical outcome in patients treated with thrombolysis. Several recent studies have suggested that time to treatment may be less important with primary angioplasty than with thrombolytic therapy, and there are several possible reasons why this may be the case. First, TIMI (Thrombolysis In Myocardial Infarction) 2 or 3 flow is achieved less often with increasing time to treatment with thrombolysis, but in many studies it has been found that TIMI 3 flow was achieved in a high percentage of patients treated with primary angioplasty, regardless of time to treatment. Second, in patients treated with thrombolysis, mortality rates from myocardial rupture increase with increasing time to treatment, whereas rupture after primary angioplasty is a rare event. Finally, the Table 5.2 An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction Time to reperfusion

Final TIMI 3 flow 1 month Death (%) Reinfarction (%)

<2 hours n=73 (5.9%)

2–4 hours n=518 (42%)

4–6 hours n=311 (25%)

>6 hours n=330 (27%)

91%

92%

89%

92%

4.1 0.0

3.3 0.4

3.5 1.6

3.0 0.6

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Time to reperfusion <2 hours n=73 (5.9%)

2–4 hours n=518 (42%)

6 months Death (%) 5.5 4.6 Reinfarction (%) 0 1.4 Source: The GUSTO Investigators. N Eng J Med 1993; 329:673–82.

4–6 hours n=311 (25%)

>6 hours n=330 (27%)

4.5 4.2

4.2 3.0

incidence of intracranial bleeding after thrombolysis may increase with increasing time to treatment, as found in the Global Utilization of Streptokinase and Tpa to Open arteries (GUSTO)-1 trial. INTERPRETATION. In this analysis of 1232 patients from the Stent PAMI trial there was no correlation between time to treatment and mortality suggesting that the survival benefit of primary angioplasty may be related principally to factors other than myocardial salvage (Table 5.2).

Comment Patients with cardiogenic shock were not included in this analysis, and in the SHOCK trial |1| mortality increased with increasing time to treatment in patients with AMI and cardiogenic shock. Nevertheless, these data have implications regarding the triage of patients with AMI for primary angioplasty. Predictors and prognosis of suboptimal coronary blood flow after primary coronary angioplasty in patients with acute myocardial infarction. F A Cura, P L I’Allier, S R Kapadia, et al. on behalf of the GUSTO llb and RAPPORT Investigators. Am J Cardiol 2001; 88:124–8. BACKGROUND. The goal of primary angioplasty is the prompt restoration of normal flow in the infarct related epicardial coronary artery, in order to achieve effective reperfusion of the myocardium. Suboptimal epicardial coronary flow after primary angioplasty can occur due to distal embolization of thrombus and atheromatous

debris, microvascular damage and oedema, reperfusion injury or an inadequate angioplasty result with a flow limiting mechanical obstruction in the epicardial artery based on residual stenosis, dissection or thrombosis. Early identification of patients at risk for suboptimal coronary blood flow may aid further management and direct additional therapeutic measures. INTERPRETATION. Clinical and angiographic data from 891 patients enrolled in the GUSTO IIB and RAPPORT studies were analyzed. The mortality at 30 days in patients with TIMI 3 flow (81% of patients) was 1.5%, compared to 10.2% in patients with TIMI ≥ 2 flow (19% of patients) after primary angioplasty. Multivariate analysis of clinical and angiographic data showed that the presence of thrombus on the initial angiogram, increasing age, and increasing heart rate were independent predictors of TIMI grade ≥ 2 flow after primary angioplasty. Two factors were associated with a higher rate of post-procedural TIMI 3 flow, namely anterograde flow at presentation and treatment of the circumflex artery. Diabetes, the use of bail-out stents, and time from symptom-onset to treatment did not influence the final TIMI flow grade after primary angioplasty.

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Comment Easily obtainable clinical and angiographic characteristics are helpful to predict suboptimal coronary blood flow after primary angioplasty for AMI. The presence of coronary thrombus on the initial angiogram identifies a population at risk of distal embolization and poor runoff. Additional pharmacological procedures, thrombectomy or embolic protection should be considered. The mortality of elderly patients with acute STsegment elevation myocardial infarction remains high in spite of primary angioplasty. This seems related to a lower clinical success rate, as even after adjustment for baseline demographic, clinical and angiographic characteristics, increasing age was still a strong predictor of a final TIMI ≥ 2 flow after primary angioplasty. Long-term recovery of left ventricular function after primary angioplasty for acute myocardial infarction. J P Ottervanger, A W J van’t Hof, S Reiffers, et al. Eur Heart J 2001; 22: 785–90. BACKGROUND. In survivors of acute myocardial infarction, left ventricular function is the most important predictor of long-term prognosis. However, left ventricular function may change during the months after myocardial infarction, by mechanisms such as remodelling and gradual relief of stunning or hibernation. Determinants of a change in left ventricular function may have prognostic significance, give insight into the mechanisms of the changes in ventricular function, and may have important implications for the therapeutic approach.

INTERPRETATION. Changes in the left ventricular function were studied in 600 consecutive patients with acute myocardial infarction treated with primary angioplasty who underwent radionuclide ventriculography at day 4 and after 6 months. There was a mean relative improvement during the 6 months of 6%, from 43.7±11.4% to 46.3±11.5%, (P<0.01). Improvement in left ventricular function was observed in 48% of patients, whereas a decrease was noted in 25%. Anterior infarct location, ejection fraction at day 4≥ 40% and single vessel disease were significant predictors of left ventricular functional recovery. Multivessel disease was associated with absence of recovery.

Comment After AMI, expansion of the infarct zone is followed by compensatory hypertrophy of non-infarcted segments. Infarct size and patency of the infarct related artery are the principal factors affecting this early remodelling process. Effective reperfusion therapy limits infarct size and preserves some viable myocardium within the infarct zone. This viable myocardium may however have a depressed function for a prolonged period of time: ‘stunning’ or ‘hibernation’. This has been demonstrated in particular in patients with anterior infarction. Multivessel disease is associated with a decrease in left ventricular function. These patients have more extensive coronary artery disease and probably limited collateral blood flow. This may be related to prolonged and/or profound myocardial ischaemia, causing more severe hibernation. Further studies, investigating the impact of more complete revascularization, are therefore needed to demonstrate whether revascularization of potentially ischaemic myocardium distant from the infarct zone is of clinical benefit. Primary stent implantation compared with primary balloon angioplasty for acute myocardial infarction: a meta-analysis of randomized clinical trials. M M Zhu, A Feit, H Chadow, M Alam, T Kwan, L T Clark. Am J Cardiol 2001; 88:297–301.

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BACKGROUND. Primary angioplasty is used as reperfusion therapy in an increasing proportion of patients with AMI. Although balloon angioplasty is effective in restoring anterograde flow in the infarct related coronary artery, recurrent myocardial ischaemia and restenosis may occur in subsequent months. With the development of effective post-stenting antithrombotic regimens and safe stent implantation techniques, coronary stenting is no longer contraindicated in thrombus containing lesions and has gained considerable popularity in the treatment of AMI. Individual randomized trials have shown variable results. Therefore, the data from 9 randomized trials were pooled in this analysis. INTERPRETATION. Data from Zwolle, Fresco, Grami, Pasta, Stent-Pami, Stentim-2, Psaami, Prisami and Cadillac studies were used. A total of 2050 patients were

Table 5.3 Outcomes at 6–12 months Stent versus Balloon Odds ratio

95% Confidence interval

Death 1.04 0.75–1.44 Reinfarction 0.71 0.47–1.08 TVR 0.43 0.36–0.52 MACE 0.52 0.44–0.62 TVR=target vessel revascularization. MACE=major adverse cardiac event, a combination of death, reinfarction and TVR. Source: Zhu et al. (2001).

P 0.9 0.13 <0.001 <0.001

randomized to stenting and 2070 to balloon-angioplasty. Crossover rates ranged from 0–3% in the stent group, and from 0–36% in the balloon group (Table 5.3).

Comment Although the results of the individual trials showed some variations in inclusion criteria, design, and outcome measures, statistical analysis excluded significant heterogeneity across the studies. Taken together, these trials did not show a mortality difference between the 2 treatment strategies. It is important to realize that patients were enrolled after angiography, and that only a few trials enrolled patients in cardiogenic shock. With these caveats in mind, we can conclude that the benefit of stenting is due to prevention of restenosis, with a lower rate of target vessel revascularization and as a consequence a lower rate of major adverse coronary events, without an influence on death and reinfarction, 6–12 months after primary angioplasty. Predictive value of the Killip classification in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. V S DeGeare, J A Boura, L L Grines, W W O’Neil, C L Grines. Am J Cardiol 2001; 87:1035–8. BACKGROUND. In 1967, Killip and Kimball |2| reported the clinical outcome of 250 patients with AMI and described that findings from simple physical examination had a strong predictive value for early mortality. Over the past decades many advances in the care of patients with AMI have been implemented in routine clinical practice. A rapid and simple tool, available immediately upon hospital

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admission/presentation to identify patients at higher risk of death may assist in the acute management of patients treated with primary angioplasty. Following successful angioplasty, low-risk Table 5.4 Killip class versus outcome in 3032 patients treated with primary angioplasty for AMI related to mortality and reinfarction rates for primary angioplasty patients Killip

Mortality In-hospital

6 months

I 2.4% II 7% III 19% Source: DeGeare et al. (2001).

4% 10% 28%

patients can be admitted to a step-down unit instead of to the Coronary Care Unit (CCU) and they are candidates for early (2–3 days) discharge from the hospital. Additional therapeutic measures can be considered for patients at increased risk of untoward events. INTERPRETATION. In this study of 3032 patients, enrolled in one of the PAMI-trials, Killip class was a predictor both of in-hospital and of 6 months mortality (Table 5.4). After multivariate analyses to correct for confounding variables, Killip classification remained a predictor of mortality, both in hospital and at 6 months follow-up.

Comment Killip class was associated with several clinical and angiographic variables, such as age, gender, diabetes, heart rate, blood pressure, ejection fraction, multivessel disease and infarct location. Nevertheless, it is still an excellent way to risk stratify patients who present with an AMI. Multivariate analysis showed that together with age and left ventricular ejection fraction, Killip class is an important predictor of mortality. Advancing Killip class was also associated with increased use of intraaortic balloon pump, post-procedural renal failure, major arrhythmia and more bleeding complications. The exact mechanism(s) by which this classification remains a predictor is unknown, and this study is a post hoc analysis. Furthermore, patients with cardiogenic shock were excluded. Nevertheless, it can be concluded that the Killip classification is still of great clinical value, even with modern invasive management of AMI. Primary percutaneous coronary interventions in patients with acute myocardial infarction and prior coronary artery bypass grafting. J Al-Suwaidi, J L Velianou, P B Berger, et al. Am Heart J 2001; 142:452–9. BACKGROUND. Large numbers of patients undergo coronary artery bypass grafting and the number of patients in whom ischaemia recurs after surgery is increasing. It is estimated that 2–3% per year suffer from a myocardial infarction over the first 5 years, with slightly higher rates thereafter. Although success rates of primary angioplasty in patients with AMI after bypass surgery seem to be higher than those for thrombolytic therapy, the outcome for these patients is not as good as observed in infarct patients without prior bypass surgery. INTERPRETATION. From the Mayo Clinic percutaneous transluminal coronary angioplasty registry, 128 patients were identified and treated with primary angioplasty for AMI with previous bypass surgery. They were compared with 944 primary angioplasty patients without previous bypass surgery. The treated vessel was a native coronary artery in 65 patients and a vein graft in 63 patients. Patients with previous surgery were older,

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more often male, had a higher incidence of heart failure, a lower left ventricular ejection fraction and a higher rate of multivessel coronary artery disease. There was a trend towards a lower procedural success rate in patients after surgery, that was significant if the treated vessel was a vein graft, 80% versus 96%, P<0.001, and distal embolization occurred more often in vein grafts. In a multivariate analysis, previous surgery had no significant effect on mortality but treatment of a vein graft was associated with a significantly increased risk of death: Relative risk 1.74, 95% confidence interval 1.16–2.61, P=0.008.

Comment These data confirm that primary angioplasty for the treatment of AMI in patients with previous coronary artery bypass surgery is associated with lower success than in patients without prior surgery, in particular when the treated vessel is a vein graft. This appears to be largely related to adverse baseline clinical characteristics in combination with difficulty in obtaining an optimal angioplasty result in vein graft lesions, despite the use of stents and abciximab. Even when a vein graft is the infarct related vessel, it seems therefore preferable to perform angioplasty of the native artery when it is feasible to do so. Furthermore, these data show that even after successful angioplasty, the frequency of adverse events remains relative high. This underscores the importance of aggressive medical management with antiplatelet drugs, lipidlowering therapy, β-blockers and angiotensin-converting enzyme inhibitors, all of which have been shown to reduce mortality. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. G Montalescot, P Barragan, O Wittenberg, et al. ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up) Investigators. N Engl J Med 2001; 344:1895–1903. BACKGROUND. The glycoprotein llb/llla receptor has binding domains for fibrinogen, fibronectin and von Willebrand factor, representing the common pathway for platelet aggregation. Current approaches to glycoprotein llb/llla inhibition include a monoclonal antibody (abciximab) and competitive inhibition with small molecular antagonists. The recent shift in focus away from thrombin inhibition towards potent platelet inhibition has made a profound impact on the practice of percutaneous coronary interventions for stable as well as unstable ischaemic syndromes. Although many patients seem to benefit from glycoprotein llb/llla antagonists, most benefit is seen in certain high risk subgroups. For instance, in patients with an acute ischaemic syndrome, elevated troponins identify patients who derive greater benefit from this antiplatelet therapy. INTERPRETATION. As compared with placebo, early administration of abciximab resulted in a higher patency rate before stenting, a higher procedural success rate and improved clinical outcome, with a low rate of major bleeding (Table 5.5).

Comment The potential benefit of adjunctive use of abciximab in AMI patients treated with primary balloon angioplasty and/or stenting are improved flow before and after the procedure, treatment of lesion-associated thrombus and thrombotic embolism, protection against the ‘no reflow’ phenomenon and, by maintaining the integrity of the distal circulatory bed, improved clinical outcome. Although the results of the much larger CADILLAC trial |3| do not confirm the findings of this trial, there

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Table 5.5 300 patients treated with stenting for acute myocardial infarction Abciximab

P

Placebo

TIMI 3 before stent 16.8% 0.01 5.4% TIMI 3 after stent 95.1% 0.04 86.7% TIMI 3 at 6 months 94.3% 0.04 82.8% MACE at 30 days 6.0% 0.01 14.6% MACE at 6 months 7.4% 0.02 15.9% MACE=major adverse coronary events, defined as the combination of death, reinfarction or urgent revascularization of the target vessel. Source: Montalescot et al. (2001).

is an important difference in the design of these two trials: in the ADMIRAL study a quarter of the patients were randomized and treated with the study drug in the ambulance. These patients were treated early after symptom-onset and they were pre-treated compared to the adjunctive or concomitant use of the study drug in the other patients and in the CADILLAC trial. In these pre-treated patients there was marked benefit, in terms of patency and outcome, of abciximab. Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define subgroups of patients benefiting most from primary angioplasty? Results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction Registry and the Myocardial Infarction Registry. R Zahn, R Schiele, S Schneider, et al. J Am Coll Cardiol 2001; 37: 1827–35. BACKGROUND. Although it is clear that in expert hands and in expert centres, primary angioplasty is the reperfusion treatment of choice, several non-randomized comparisons of angioplasty and thrombolysis from large registries have failed to confirm improved outcome in community patients treated with primary angioplasty in comparison with thrombolytic therapy. This has cast some doubt as to whether the results of randomized trials that favoured angioplasty over thrombolysis, could be obtained in the ‘real world’. The MITRA (Maximal Individual Therapy in acute myocardial infarction Registry) and MIR (Myocardial Infarction Registry) registries were German prospective multicentre observational studies of patients with AMI. In the MITRA 54 hospitals participated and the MIR was a nationwide 217 mainly community hospital registry. Taken together they represent the ‘real world’ in an excellent way. INTERPRETATION. A total of 10895 patients underwent reperfusion therapy. After exclusion of patients with contraindications for thrombolysis (active bleeding, stroke <3 months, trauma <14 days) or a pre-hospital delay of >12 hours, 1327 patients treated with primary angioplasty could be compared to 8579 patients treated with thrombolysis. Median in-hospital time to treatment was 70 minutes for angioplasty compared to 30 minutes for start of lytic therapy. Hospital mortality was 6.4% after angioplasty and 11.3% after thrombolysis. After corrections in a multivariate model for baseline characteristics the odds ratio was 0.58, with 95% confidence intervals 0.44–0.77. This benefit of angioplasty was evident in all subgroups and was of comparable magnitude, irrespective of age, gender, infarct location, resuscitation, heart failure, cardiogenic shock and prior myocardial infarction. There was a significant correlation between mortality and absolute risk reduction (r=0.82, P<0.0001) in the different subgroups: as mortality increased, there was an increase in absolute benefit of primary angioplasty compared with thrombolysis.

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Comment These data confirm, for the first time, in registry data from the ‘real world’, a clear superiority of primary angioplasty over intravenous thrombolysis. Mortality in both treatment groups was higher than observed in the randomized trials, probably related to inclusion of a relatively large proportion of patients >75 years of age and with cardiogenic shock. The large numbers of patients at many different centres, and the uniform results in all subgroups, confirm the data of the randomized studies, and strengthen the results in favour of primary angioplasty for treatment of AMI in the ‘real world’. Closing remarks The management of acute ST elevation myocardial infarction (MI) is constantly evolving. It is now clear that primary PTCA is superior to thrombolysis. This is not only the case in highly selected patients, but also holds for ‘real world’ myocardial infarctions seen in community hospitals. It should be noted that mortality is higher in these ‘real world’ patients compared to well-defined trial patients, which is probably due to the inclusion of more elderly (>75 years) and cardiogenic shock patients. A meta-analysis (n=4120) demonstrated that primary stenting was superior to balloon angioplasty for treatment of AMI with respect to a decrease in target vessel revascularization due to restenosis, but not for outcomes judged by death and repeat myocardial infarction. The ‘golden hour’ is a well-established phenomenon in thrombolysis for acute ST elevation MI, i.e. the sooner the vessel is opened, the better the outcome. However, quite surprisingly this does not seem to be the case in primary stenting, where there appears to be no relation between time to treatment and mortality: i.e. myocardial salvage does not appear to be the principal factor of long term survival. I believe that time still is an important factor and would encourage practitioners to act as quickly as possible to open the vessel, but if sometimes there is ‘inevitable’ considerable delay in treatment it may be preferable to perform PCI. Regional establishment of an AMI centre to offer treatment is being planned in many countries and it should be kept in mind that primary angioplasty procedures should preferably be performed by physicians and/or hospitals with a high volume of patients treated, which results in a significantly lower mortality rate. In the era of percutaneous catheter treatment of AMI simple clinically obtained percutaneous parameters (Killip classification) are also highly predictive of progress in patients undergoing primary PTCA AMI. Improvement of the left ventricular function was seen in patients with anterior wall infarction and single vessel disease but not with multi-vessel disease. This may be a plea for a more aggressive approach by achieving complete revascularization. The role of platelet glycoprotein GP IIb/IIIa inhibitors as adjunctive treatment to PCI in AMI is still controversial. The relatively small ADMIRAL trial showed a benefit, in particular when the drug is given as soon as possible (i.e. in the ambulance before PCI) but the results of the larger CADILLAC trial were negative. Not all patients do well after PCI. Those with the presence of a thrombus, an acute occlusion of a vein graft and very elderly patients appear to have a worse prognosis. This may require another approach. In the case of a thrombus adjunctive treatment with a platelet GP IIb/ IIIa inhibitor in elderly patients one should possibly strive for complete revascularization while in cases of vein graft occlusion one might attempt to treat the native coronary artery supplying the ischaemic territory.

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References 1.

2. 3.

Hochman JS, Sleeper LA, White HD, Dzavik V, Wong SC, Menon V, Webb JG, Steingart R, Picard MH, Menegus MA, Boland J, Sanborn T, Buller CE, Modur S, Forman R, Desvigne-Nickens P, Jacobs AK, Slater JN, LeJemtel TH. One-year survival following early revascularization for cardiogenic shock. JAMA 2001; 285: 190–2. Killip T, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two-year experience with 250 patients. Am J Cardiol 1967; 20:457–64. Stone GW, Grines CL, Cox DA, et al. A prospective, randomized trial comparing primary balloon angioplasty with or without abciximab to primary stenting with or without abciximab in acute myocardial infarction: primary endpoint analysis from the CADILLAC trial. Circulation2000; 102:11–664.

6 Early invasive versus early conservative strategy in non-ST elevation acute coronary syndromes

Introduction Non-ST elevation acute coronary syndrome (formerly known as unstable angina [UA] non-Q wave myocardial infarction) is the most common cardiac cause for hospital admission in the western world. It is not a harmless disorder since the risk for major complications in the first period after the initial event is substantial. Cannon reported a 1 year incidence of death or myocardial infarction (MI) between 7.3% (Braunwald class I) and 18.5% (Braunwald class IIIc) |1|. If a combination of risk factors is present, the event rate can be as high as 40% |2|. Advances in antiplatelet (GP IIb/IIIa blockers, clopidogrel) and antithrombin therapy (low molecular weight heparins, hirudin) have considerably improved prognosis but there is still a need for further improvement. Whether early invasive diagnostic work-up of patients presenting with an acute coronary syndrome has a benefit over initial medical stabilization has lately been the subject of much clinical research |3–10|. The dilemma is that a strategy of early coronary angiography and subsequent revascularization can probably prevent clinical events (death, MI, stroke and bleeding) but on the other hand is also a cause of these very events. Until recently the standard of care was medical stabilization with antiplatelet therapy (aspirin, clopidogrel, GP IIb/IIIa blocker), antithrombin therapy (heparin, low molecular weight heparins, hirudin), β blockers, nitrates and calcium antagonists. Coronary angiography and revascularization was reserved for medically refractory unstable patients and patients with provocable ischaemia at functional diagnostic tests. This approach was based on the findings of the Thrombolysis In Myocardial Infarction (TIMI) IIIb |3,4|, Veterans Affairs Non-Q Wave Infarction Strategies in Hospital (VANQUISH) |5|, and Medicine versus Angiography in Thrombolytic Exclusion (MATE) |6| trials, performed at the beginning of the nineties. All three showed a lack of benefit from a routine invasive strategy in patients admitted with UA or an evolving non-Q wave MI. The VANQUISH results were flawed by a low revascularization rate in the invasive group, only 44% of invasive management patients were revascularized during the initial hospitalization, which was not very different from the patients allocated to a conservative strategy (33%). Furthermore there was a very high mortality in the surgically treated patients in the invasive group (11.6%). The MATE trial enrolled a diverse group of patients with suspected acute MI, ineligible for thrombolytic therapy because of lack of electrocardiogram (ECG) criteria or contraindications. A difference in in-hospital recurrent angina in favour of the invasive strategy group was found, but no short- and long-term difference in mortality or occurrence of MI.

© Clinical Publishing Services Ltd

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The findings of these randomized trials were recently underscored in the large prospective Organization to Assess Strategies for Ischaemic Syndromes (OASIS) registry |7|. Unstable patients admitted to hospitals with a high early angiography rate (60%) in Brazil and the USA had a similar rate of death and MI at six months to that of patients admitted in countries with a low (20%) early angiography rate. An optimistic observation was that lower rates of refractory angina and readmissions for UA during follow-up were found for the more aggressively managed patients. On the other hand, an unexplained excess of stroke and bleeding complications in the first six months of follow-up was apparent in this group. Data from a 1988– 1994 MITI (Myocardial Infarction Triage and Intervention) registry cohort added to the confusion |8|. NonQ wave infarction patients admitted to hospitals favouring early angiography had a lower early (30 days) and late (4 year) mortality as compared to patients admitted to hospitals favouring an initial conservative approach. An even larger early and late mortality benefit was noted if coronary angiography was carried out very early (<6 hours from admission). This was however a retrospective analysis and the patients admitted to the hospitals favouring an initial conservative strategy were older and sicker. To clear up the confusion a well conducted randomized trial using state of the art interventional techniques and modern antithrombotic therapy was necessary. In their landmark randomized trial, the Fast Revascularization during Instability in Coronary artery disease (FRISC) II investigators did just that and recently reported |9,10| that an initial invasive management strategy reduced the incidence of MI, readmissions and angina pectoris at six months and even reduced mortality at one-year follow-up. This trial differed from VANQUISH, TIMI IIIB and MATE in several ways. Firstly, patients included were at higher risk of complications. They had to have dynamic ECG abnormalities, CKMB rise or positive troponin T. Secondly, the patients allocated to a conservative strategy in FRISC II were truly treated conservatively with only 10% coronary angiographies and 9% revascularizations at ten days as compared to 98% and 71% in the invasive group. For comparison: in TIMI IIIB, early angiography was performed in 58% of the patients in the conservative group, this was 48% in VANQUISH and 60% in MATE. Finally, stents were used liberally in the percutaneous transluminal coronary angioplasty (PTCA) patients of the invasive strategy arm in FRISC II. In 61% of patients at least 1 stent was implanted. Coronary stenting is known to improve short-and medium-term outcome after percutaneous coronary intervention (PCI) by reducing the need for emergency surgery and reducing restenosis rate. The results of the FRISC II trial triggered a renewed interest in the early invasive management strategy for patients suffering a non-ST elevation acute coronary syndrome. Most important in this respect is the publication of the Treat Angina with aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial in June 2001 discussed in the first paper of this chapter. In this randomized trial again an early invasive strategy was compared to a conservative approach. In an attempt to further improve outcome, all patients received adjunctive treatment with the GP IIb/IIIa receptor blocker tirofiban. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein llb/llla inhibitor tirofiban. C P Cannon, W S Weintraub, L A Demopoulos, et al. for the TACTICS-Thrombolysis in Myocardial Infarction (TIMI) 18 Investigators. N Engl J Med 2001; 344:1879–87. BACKGROUND. There is continued debate as to whether a routine, early invasive strategy is superior to a conservative strategy for the management of UA and MI without ST-segment elevation. 2220 patients with UA and MI without ST-segment elevation were enrolled who had electrocardiographic evidence of changes in the ST-segment or T wave, elevated levels of cardiac markers, a history of coronary artery disease, or all three findings. All patients were treated with aspirin, heparin, and the glycoprotein llb/llla inhibitor tirofiban. They were randomly assigned to an early invasive strategy, which included routine catheterization within 4 to 48 hours and revascularization as

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appropriate (percutaneous coronary intervention [PCI] or surgery), or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischaemia or an abnormal stress test. The primary end-point was a composite of death, non-fatal MI, and rehospitalization for an acute coronary syndrome at six months. At six months, the rate of the primary end-point was 15.9% with use of the early invasive strategy and 19.4% with use of the conservative strategy (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.62–0. 97; P=0.025). The rate of death or non-fatal MI at six months was similarly reduced (7.3% vs 9.5%; OR 0.74; 95% CI 0.54–1.00; P<0.05). INTERPRETATION. In patients with UA and MI without ST-segment elevation who were treated with the glycoprotein llb/llla inhibitor tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of an early invasive strategy in combination with the early inhibition of glycoprotein IIb/IIIa.

Comment This very important trial shows that using modern day technology (stents in 85% of patients treated with PCI) an early invasive approach under an umbrella of GP IIb/IIIa blockade is safe and has a clear treatment benefit over initial medical stabilization. In contrast to the FRISC II study, the invasive strategy in TACTICS was accompanied by a lower incidence of MI in the first week after the initial episode, which can probably be attributed to the well documented protective effect of GP IIb/IIIa receptor blockers during coronary interventions. However, to really prove the added value of tirofiban in the early invasive strategy, a second randomization would have been necessary. Given the overwhelming evidence of clinical efficacy of GP IIb/IIIa blockade in patients with unstable coronary syndromes and during coronary interventions, this probably would have been unethical. Another difference with the FRISC II trial was the higher rate of angiography and revascularization in the conservative strategy group. Coronary angiography and revascularization during the initial hospitalization was performed in 10% and 9% of patients in the conservative group of FRISC II, this was 51% and 37% in the conservative group of TACTICS. The conservative group in TACTICS was therefore clearly less conservative than the conservative arm in FRISC II. Despite this smaller difference in baseline risk in TACTICS, the treatment effect of the invasive strategy on death or non-fatal MI at six months was of the same magnitude as in FRISC II; 7.3% vs 9.3% in the conservative arm in TACTICS (OR 0.74; 95% CI 0. 54–1.0; P<0.05), 9.4% vs 12.1% in FRISC II (risk ratio 0.78; 95% CI 0.62–0.98; P=0.032). It is tempting to conclude that the protective effect of tirofiban in the invasive group compensated for the smaller difference in baseline risk. Early coronary angiography improves long-term survival in unstable angina. V Mathew, M E Farkouh, B J Gersh, et al. Am Heart J 2001; 142:768–74. BACKGROUND. The role of early coronary angiography in the evaluation of patients with UA has been controversial. This study was designed to determine the effect of early coronary angiography on long-term survival in patients with UA. We reviewed the Olmsted County Acute Chest Pain Database, a population-based epidemiological registry that includes all patients residing within Olmsted County who were seen for emergency department evaluation of acute chest pain from 1985 to 1992. Patients with symptoms consistent with

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myocardial ischaemia qualifying as UA were classified as undergoing early (≥ 7 days of index presentation) angiography or not. A total of 2264 patients with symptoms consistent with UA were identified with a mean duration of follow-up of six years; 892 underwent early angiography. Early angiography patients were younger, less likely to have heart failure; more likely to be male, hypercholesterolaemic, and smokers; had prior coronary revascularization; and had an MI at the index presentation. After baseline differences were controlled, early angiography was associated with a reduction in all-cause long-term mortality (relative

risk [RR] 0.63; 95%; CI 0.53–0.74). Patients at intermediate or high risk for death or MI at presentation were most likely to benefit from early angiography. INTERPRETATION. Early angiography in the evaluation of patients with UA was associated with a reduction in all-cause mortality, particularly in intermediate-and high-risk patients, in this retrospective population-based study.

Comment This study is a retrospective analysis of a population based registry. Taking into account the shortcomings of a retrospective analysis this study makes a useful contribution to the literature. It confirms that early assessment of coronary anatomy in unstable patients has a major impact on long-term survival (Fig. 6.1). It will not only lead to necessary revascularization procedures to avert early complications, but knowledge of coronary atherosclerotic changes is likely to encourage physicians and patients to adhere to risk factor modification and medical treatment. The latter may partly explain the improved survival in the early angiography group. Secondly the findings underscore the importance of risk stratification since high-risk patients had more to gain from early angiography. The study further suggests that the earlier coronary angiography has been performed, the better the long-term prognosis. Patients undergoing angiography within two days of the initial event had a better long-term survival than patients who had their angiogram performed between day three and seven. Events tend to occur early in the course of UA and can probably be prevented by early knowledge of coronary anatomy. Improving outcome over time of percutaneous coronary interventions in unstable angina. M Singh, C S Rihal, P B Berger, et al. J Am Coll Cardiol 2000; 36:674–8. BACKGROUND. An early invasive strategy has not been shown to be superior to conservative treatment in patients with UA. Earlier studies had utilized older technology. Interventional approaches have changed in the recent past but, to our knowledge, no large studies have addressed the impact of these changes on the outcome of coronary interventions. In-hospital and intermediate-term outcome in 7632 patients with UA who underwent coronary interventions in the last two decades were analysed. The study population was divided into three groups: group 1, n=2209 who had coronary intervention from 1979 to 1989; group 2, n=2212 with interventions from 1990 to 1993; and group 3, n=3211 treated from 1994 to 1998. Group 2 and 3 patients were older and sicker compared with group 1 patients. The clinical success improved significantly in group 3 (94.1%) compared with group 2 (87%) and group 1 (76.5%) (P<0.001). There was a significant reduction in in-hospital mortality, Q wave MI and need for emergency bypass surgery in group 3 compared with the earlier groups. One-year event-free survival was also significantly higher in the recent group compared with the earlier groups: 77% in group 3, 70% in group 2 and 74% in group 1 (P<0.001). With the use of multivariate models to adjust for clinical and angiographic

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Fig. 6.1 Adjusted survival curves for patients undergoing early coronary angiography versus patients who did not undergo early coronary angiography (P<0.00001). Source: Mathew et al. (2001). variables, treatment during the most recent era was found to be independently associated with improved in-hospital and intermediate-term outcomes. INTERPRETATION. There has been significant improvement in the in-hospital and intermediate-term outcome of coronary interventions in patients with UA in recent years; newer trials comparing conservative and invasive strategies are therefore needed.

Comment This retrospective analysis clearly shows that both early, procedure-related, complications and long-term (Fig. 6.2) complications have dramatically decreased in patients treated with PCI for UA. This improvement in outcome can be attributed to several factors: The percentage of stenting increased from 0% in the 1979–1989 group to 51% in the 1994–1998 group. Further, the use of GP IIb/IIIa receptor blockers rose from 0% in the early cohorts to 34.5% in the 1994–1998 group. It is known that both stenting and GP IIb/IIIa blockers prevent acute, ischaemic events in patients with UA. By reducing restenosis, stenting also improves intermediate term outcome. These results suggest that using modern angioplasty equipment and adjunctive antithrombotic treatment, early coronary angiography with provisional PCI might be a better alternative than initial medical stabilization for patients presenting with UA. Use of risk stratification to identify patients with unstable angina likeliest to benefit from an invasive versus conservative management strategy. D H Solomon, P H Stone, R J Glynn, et al. J Am Coll Cardiol 2001; 38: 969–76. BACKGROUND. Risk stratification may offer a method for identifying which patients with UA or non-Q wave myocardial infarction (NQMI) are the most likely to benefit from invasive management strategies. The analysis was based on data from a randomized controlled trial that enrolled 1473 patients presenting with UA or NQMI who were randomly assigned to an early invasive or early conservative (medical) management strategy. We constructed a risk-stratification score for each patient based on adjusted odds ratios for clinical variables likely to predict adverse outcomes. We stratified all trial

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Fig. 6.2 Estimated event-free survival curves for death, MI, coronary artery bypass surgery or repeat revascularization (revasc): 1994–1998 relative to 1979–1989 is 0.85, P=0.002. Risk of 1990–1993 relative to 1979–1989 is 1.07, P=0.14. Source: Singh et al. (2000). subjects by their risk scores and studied the rates of death or MI of the early invasive management strategy in each stratum. The final multivariate model included older age, ST-segment depression on presentation, history of complicated angina before presentation, and elevation in baseline creatine kinase-MB fraction. Although patients with a higher risk score had an increased rate of death or MI within 42 days and 365 days (P<0. 001) in both management strategies, early invasive management for patients in the high-and very highrisk categories was associated with a lower rate of death or MI within 42 days

compared with conservative management. No such benefit was seen in patients in the larger group of patients in the very low-, low-or moderate-risk categories (P=0.03 for the interaction between risk category and management assignment). INTERPRETATION. Risk stratification may be an effective method for identifying those patients with UA or NQMI most likely to benefit from early invasive management. Selective use of early invasive management can have a substantial impact in reducing morbidity and mortality in higher-risk patients, but may not be warranted in lower-risk patients.

Comment Renewed interest in early coronary angiography for patients presenting with UA triggered this post hoc analysis of the TIMI IIIb trial data. The TIMI IIIb trial enrolled patients from 1989–1992, well before stents and GP IIb/IIIa blockers became available. The study was published in 1994 and showed no difference in six weeks and one year outcome (death or MI) between an early invasive and an early conservative treatment strategy. Despite this, Solomon et al. could identify a subset of high-risk patients who benefited from an early invasive strategy. The risk score they developed shows a remarkable similarity with the recently published TIMI risk score that was developed from data of non-ST elevation acute coronary syndrome patients enrolled in clinical

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trials from 1994–1998 |2|. The TIMI risk score contains all the variables of the present risk score expanded with current aspirin use, known coronary artery disease and the presence of≥ 3 risk factors for coronary artery disease. This similarity underscores the robustness of variables such as ST deviation, serum markers for myocardial damage, and age for prediction of worse outcome. In the FRISC II and TACTICS-TIMI 18 trials, patients had to have ST deviation and/or positive serum markers for enrolment in the study. A highrisk population was thus selected and this might explain the fact that both these trials showed an overall benefit of an invasive strategy. Therefore application of an invasive strategy to a high-risk population might be beneficial whereas an initially conservative approach seems more justified in low-risk patients. ST depression in ECG at entry indicates severe coronary lesions and large benefits of an early invasive treatment strategy in unstable coronary artery disease. The FRISC II ECG substudy. E Diderholm, B Andrén, G Frostfeldt, et al. Eur Heart J 2002; 23:41–49. BACKGROUND. In unstable coronary artery disease, ST-segment depression indicates a poor prognosis. We evaluated whether the effect of early revascularization and the extent of coronary lesions were related to ST-segment and T wave changes on admission. 2457 patients with unstable coronary artery disease were randomized to an early invasive strategy with coronary angiography/ revascularization within seven

days or to a non-invasive strategy with coronary procedures only when symptoms or severe ischaemia recurred. ST depression of ≥ 0.05 mV was present in 1114 (45.5%) patients. In the invasive group, 45% of the patients with ST depression had three-vessel disease or left main stenosis compared with 22% if no ST-segment depression was present, P<0.001. In patients with ST-segment depression, the invasive strategy reduced death/MI at twelve months from 18.2 to 12.0%, (RR 0.66; 95% CI 0.50–0.88; P=0.004) (Fig. 6.3), while mortality was changed from 5.8 to 3.3%, P=0.050. In patients without ST-segment depression, the corresponding rates concerning death/MI were 10.4 and 8.9, and for mortality 2.0 and 1. 2% (nonsignificant). INTERPRETATION. In unstable coronary artery disease, ST-segment depression is associated with a 100% increase in the occurrence of three-vessel/left main disease and an increased risk of subsequent cardiac events. In these patients an early invasive strategy substantially decreases death/MI.

Comment ST depression on an admission ECG for UA is an ominous sign. It predicts severe coronary artery disease and these patients fare worse than those without ECG changes or with isolated T wave inversion irrespective of an initial invasive or conservative approach (Fig. 6.3). An early invasive approach reduced the risk for death or MI at one year by a spectacular 34% in patients with ST depression on their admission ECG. The patients with no ST depression on their first ECG did not benefit from an invasive approach in terms of mortality or MI. However, the number of readmissions at twelve months and the proportion of patients with angina pectoris at three months was significantly reduced in the group without ST changes. It should be remembered that these are soft end-points in a non-blinded trial set-up and that during initial hospitalization very strict criteria were applied before coronary angiography could be performed in the conservative group. The latter is likely to shift invasive procedures (with hospital admission) for residual anginal complaints to the follow-up period. This study again makes a case for risk stratification in patients with non-ST elevation acute coronary syndromes. Based on ST changes on an early ECG, a group of high-risk patients can be selected who will

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Fig. 6.3 Probability of death or MI in relation to strategy and occurrence of ST-segment depression on admission. ST dep=ST depression. Source: Diderholm et al. (2002).

benefit from early angiography and prompt revascularization. The role of serum markers such as troponin T is unclear in FRISC II. In patients with troponin T levels ≥ 0.1 μg/l an invasive strategy reduced the rate of death or MI at six months from 13.4% to 10.2% (RR 0.73; 95% CI 0.56–1.02; P=NS). At twelve months the reduction from 15,6% to 11.0% was statistically significant (RR 0.70; 95% CI 0.53–0.93). At one year, mortality was also reduced by an invasive approach in the troponin T-positive patients 4.4% vs 2.2% (RR 0. 51; 95% CI 0.28–0.94). However in multivariate analysis only ST depression and an invasive strategy were retained in the model, implying that troponin T is not an independent predictor of death/MI in FRISC II. It would therefore be of interest to know the outcome of patients with a positive troponin T level without ST depression on their admission ECG. Unfortunately, these data were not provided in the report. The troponin levels were measured from blood drawn at study entrance. It is likely that a number of highrisk patients had still not reached seroconversion at that time and were thus not detected as troponin Tpositive. Serial measurements of troponin T would have identified these patients and probably would have made troponin a stronger predictor of poor outcome in multivariate analysis. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. D A Morrow, C P Cannon, N Rifai, et al. for the TACTICS-TIMI 18 Investigators. JAMA 2001; 286:2405– 12. BACKGROUND. Cardiac troponins I (cTnl) and T (cTnT) are useful for assessing prognosis in patients with UA and non-ST-segment elevation MI. However, the use of cardiac troponins for predicting benefit of an invasive versus conservative strategy in this patient population is not clear.

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The objective of the study was to prospectively test whether an early invasive strategy provides greater benefit than a conservative strategy in acute coronary syndrome patients with elevated baseline troponin levels. A total of 2220 patients were enrolled. Baseline troponin level data were available for analysis in 1821, and 1780 completed the six-month follow-up. Patients were randomly assigned to receive (1) an early invasive strategy of coronary angiography between 4 and 48 hours after randomization and revascularization when feasible based on coronary anatomy (n=1114) or (2) a conservative strategy of medical treatment and, if stable, pre-discharge exercise tolerance testing (n=1106). Conservative strategy patients underwent coronary angiography and revascularization only if they manifested recurrent ischaemia at rest or on provocative testing. Patients with a cTnI level of ≥ 0.1 ng/ml (n=1087) experienced a significant reduction in the primary end-point of death, MI, or rehospitalization for acute coronary syndrome at six months with the invasive versus conservative strategy (15.3% vs 25.0%; OR 0.54; 95% CI 0.40–0.73). Patients with cTnI levels of less than 0.1 ng/ml had no detectable benefit from early invasive management (16.0% vs 12.4%; OR 1.4; 95% CI 0.89–2.05; P<0.001 for interaction). The benefit of invasive vs conservative management through 30 days was evident even among patients with low-level (0.1–0.4 ng/ml) cTnI elevation (4.4% vs 16.5%; OR 0.24; 95% CI 0.08–0.69). Directionally similar results were observed with cTnT. INTERPRETATION. In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy.

Comment This substudy of the TACTICS-TIMI 18 trial clearly shows that baseline troponins in patients admitted with a non-ST elevation acute coronary syndrome can accurately identify those who are likely to benefit from an invasive strategy (Fig. 6.4). Contrary to the findings in FRISC II, a positive troponin assay was still an independent predictor of worse outcome in the invasive strategy group after controlling for ST depression, age and CKMB (multivariate analysis). There is no readily available explanation for this divergent finding. It can be speculated that the additional treatment with tirofiban in TACTICS made an invasive strategy in troponin-positive patients safer (more divergence of the event curves) and thus made troponin a stronger predictor of worse outcome. The lack of a control group without tirofiban treatment prevents us from making definite conclusions on this. Conclusion Several randomized trials comparing an invasive with a conservative treatment strategy for patients admitted with an acute coronary syndrome have been executed and published in the last ten years; the early TIMI IIIB, VANQUISH and MATE trials with an equivocal or negative outcome for the invasive strategy and the more recent FRISC II and TACTICS-TIMI 18 trials that showed a clear clinical benefit for an invasive strategy. For several reasons, the results of the early studies are no longer applicable to current patient care. First, aggressive antithrombotic therapy with GP IIb/IIIa receptor blockers and clopidogrel has clearly improved outcome in these patients whether they are treated medically or with additional PCI |11–13|. A second factor is the introduction of coronary stents which has not only made the PCI procedure safer with less need for bail-out surgical procedures but has also improved long-term outcome by a decrease in restenosis. The third important factor is an improved triage of patients based on ECG findings and troponin measurements, which

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Fig. 6.4 Probability of death or MI in relation to treatment and serum markers. Source: Morrow et al. (2001).

allows only those patients who are most likely to benefit to be exposed to the risks of invasive procedures. Indeed, the FRISC and TACTICS studies recruited patients on the basis of ECG changes and/or elevation of serum markers for myocardial necrosis. The advantage of the ECG as a risk stratification tool is its immediate availability at the time of presentation or during chest pain, while troponin measurements generally take more time to become positive. This might delay clinical decision-making. Another advantage of risk stratification is cost control. An early invasive strategy is an expensive strategy and performing invasive procedures only in selected patients who will benefit from these procedures will favourably influence the costbenefit ratio. Finally, with the advent of drug eluting stents the restenosis problem will be a thing of the past. The invasive treatment of non-ST elevation acute coronary syndromes will therefore undoubtedly shift more and more towards PCI, even for multivessel, diffuse, and small vessel disease. PCI is logistically easier to apply

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than CABG (coronary artery bypass graft) in these non-elective patients and can therefore be performed earlier. This is likely to prevent complications that tend to cluster early in the course of UA. Closing remarks Non-ST elevation acute coronary syndrome is the most frequent cause of hospital admission in our Western society. It is a serious disease with a high frequency of cardiac death and (re-) infarction. Earlier studies have shown that an aggressive approach (i.e. high frequency of early revascularization: PTCA or CABG) was not better than conservative medical strategy. However, new treatments such as stent implantation, combined with adjunctive treatment with platelet GP IIb/IIIa inhibitors and post-stent implantation treatment with thienopyridines is clearly more effective. Indeed this approach has shown in two important major trials (FRISC II and TACTICS) that an aggressive invasive approach is significantly better than conservative medical management. Not all patients do better with an aggressive approach. Patients with no ST depression and a normal troponin level do equally well with either an aggressive or a conservative strategy. However, high-risk patients with elevated troponin levels, ST depression or diabetes appear to fare significantly better with an aggressive invasive approach. Therefore, risk-stratification with cardiac troponins should be part of the management of non-ST-segment elevation acute coronary syndrome patients for triage to an early invasive treatment or conservative treatment. An open question remains: how soon is ‘early’: within 24h, 48h or a week? Several trials are underway to investigate whether a very early (i.e. 24h) aggressive invasive strategy is more efficacious than an early (48h-1 week) strategy. References 1.

2.

3.

4.

5.

6.

Cannon CP, McAbee CH, Stone PH, et al. Prospective validation of the Braunwald classification of unstable angina: results from the Thrombolysis In Myocardial Ischemia (TIMI) III registry (abstract). Circulation1995; 92: 1–19. Antman EM, Cohen M, Bernink PJLM, McCabe CH, Horacek T, Papuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for unstable angina/ non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000; 284:835–42. The TIMI IIIB investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB trial. Circulation 1994; 89:1545 -56. Anderson HV, Cannon CP, Stone PH, Williams DO, McCabe CH, Knatterud GL, Thompson B, Willerson JT, Braunwald E. One year results of the thrombolysis in myocardial infarction (TIMI) IIIB clinical trial. A randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol 1995; 26: 1643–50; erratum J Am Coll Cardiol 2000; 35:263. Boden WE, O’Rourke RA, Crawford MH, Blaustein AS, Deedwania PC, Zoble RG, Wexler LF, Kleiger RE, Pepine CJ, Ferry DR, Chow BK, Lavori PW. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared to a conservative management strategy. VANQUISH trial. N Engl J Med 1998; 338:1785–92. McCullough PA, O’Neill WW, Graham M, Stomel RJ, Rogers F, David S, Farhat A, Kazlauskaite R, Al-Zagoum M, Grines CL. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy. Results of the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Am Coll Cardiol 1998; 32:596–605.

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Yusuf S, Flather M, Pogue J, Hunt D, Varigos J, Piegas L, Avezum A, Anderson J, Keltai M, Budaj A, Fox K, Ceremuzynski L. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. OASIS registry. Lancet1998; 352:507–14, 533. Scull GS, Martin JS, Weaver WD, Every NR. Early angiography versus conservative treatment in patients with non-ST elevation acute myocardial infarction: MITI investigators. Myocardial Infarction Triage and Intervention. J Am Coll Cardiol 2000 15; 35: 895–902. FRISC II investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicenter study. Lancet 1999; 354:708–15. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomized trial. Lancet 2000; 356:9–16. Boersma E, Akkerhuis KM, Théroux P, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation1999; 100:2045–8. The CURE trial investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST segment elevation. N Engl J Med 2001; 345: 494–502. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, Copland I, Fox KA; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet2001; 358:527–33.

7 Percutaneous coronary intervention after thrombolytic therapy

Introduction In the 1980s, several randomized thrombolytic trials were performed, in which patients underwent urgent percutaneous coronary intervention (PCI). In these studies, PCI was done during or early after treatment with thrombolytic therapy. In none of these trials PCI was studied in a randomized fashion. Further, PCI was performed in occluded as well as in open vessels. The outcome of these interventions did not show any benefit in favour of the angioplasty. Also thereafter, several case reports indicated the poor outcome of PCI after failed thrombolysis. One has to keep in mind that there was an important selection: Usually PCI was performed in cases of severe complications like profound shock and the intervention was made many hours after thrombolytic therapy had failed. The Rescue study from Ellis et al. in 1994 |1| was the first prospective randomized trial that at least showed some moderate benefit of a catheter intervention. In that study, the left ventricle was better in the PCI group, especially during exercise, and mortality halved from 10% to 5%. Due to the low number of patients in this trial (n=150) mortality reduction was not significantly different. In addition, the patients included in the Rescue study were highly selected: patients with extensive acute myocardial infarction (AMI) were frequently not included in the study, because the investigators felt it to be unethical to randomize such patients to a potentially conservative approach. In that study also, the time delay from onset of pain to PCI was considerable. In this study, the first step was taken towards the proof that rescue PCI is of value. The outcome of the Rescue trial fitted with the experience of several groups that performed PCI routinely in cases of failed thrombolysis. Later, some non-randomized reports in small sample sizes indeed confirmed the potential value of rescue PCI after failed thrombolysis. At the moment, many interventionalists cannot resist the temptation to dilate an already open artery after successful thrombolysis, which is frequently found during angiography. So far there is no scientific basis for this approach. In the meantime, several smaller randomized studies have been published showing a superior outcome after primary PCI when compared to thrombolytic therapy without further intervention. These results have persuaded many interventional hospitals to switch from thrombolytic treatment to primary PCI. Gradually, also more and more patients with AMI have been referred for primary PCI. A larger study (Global Use of Strategies to Open Occluded coronary arteries [GUSTO] IIB) confirmed that primary PCI was better than thrombolysis |2|. The difference in mortality, however, was clearly less than that found in the initial studies.

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In contrast, in some registries, no superiority of primary PCI over thrombolysis could be shown. It is likely that primary PCI is the best treatment in dedicated centres, but in ‘real life’ the advantage of this therapy is less or even absent. The advocators of rescue PCI feel that the time needed to prepare the catheterization laboratory can be used to try to re-open the vessel with reasonably successful results. Outside office hours, it usually takes at least one hour before angiography can start. With modern thrombolytic agents, the chance of opening up the vessel within that hour is approximately 60%. In the last two years, several studies have been published focusing on early PCI following AMI. In the present chapter, new data are given on the outcome of rescue PCI with and without stenting after failed thrombolysis. Further, the approach of adjunct PCI after successful thrombolysis, and delayed PCI in the first days after thrombolysis is compared to conservative treatment. In addition, the outcome of rescue PCI is compared to the results after primary PCI. Also the problem of bleeding complications is addressed in case rescue PCI is performed in conjunction with a GP IIb/IIIa receptor blocker. Finally, the outcomes of failed rescue PCI and failed primary PCI are compared. Failure of thrombolysis: experience with a policy of early angiography and rescue angioplasty for electrocardiographic evidence of failed thrombolysis. A G Sutton, P G Campbell, E D Grech, et al. Heart 2000; 84:197–204. BACKGROUND. In a cohort study, the outcome after coronary angiography with or without rescue PCI was assessed in AMI patients with electrocardiograph evidence of failed reperfusion after thrombolytic therapy. The electrocardiographic evidence of failed thrombolysis was diagnosis in case of persistence of ST-segment elevation >50%. This electrocardiographic criterion was observed in 197 patients. Of the 197 patients, 156 had immediate rescue PCI. This resulted in Thrombolysis in Myocardial Infarction (TIMI) 3 flow in 124 patients (79%) and TIMI 2 flow in 11 patients (7%), while the remaining 21 patients (14%) had no reperfusion. In-hospital mortality of the 135 patients with reasonable or good flow was 5.9%, while 48% of the patients with no reperfusion died. In 41 of the initial 197 patients no rescue PCI was carried out because of reasonable flow in 6 patients or good flow in 35 patients. INTERPRETATION. A policy of emergency angiography and rescue PCI when appropriate reduces mortality in a high-risk population to a level that can be expected in cases of successful thrombolysis. Unsuccessful PCI is associated with a high mortality.

Comment It becomes more and more evident that the electrocardiogram (ECG) is a very useful and reliable tool to predict reperfusion. The ECG is also of value to predict the prognosis after the event. In the present nonrandomized analysis, absence of significant changes in the ST-segment elevation parameter was used to predict nonreperfusion. The ECG was correct in 79%. The ECG two hours after start of the thrombolytic therapy was used for this assessment. Timing of the registration of the ECG in relation to the angiographic outcome was not mentioned. It is conceivable that in several other patients the vessel reopened before the angiogram was taken. Time delay from onset of symptoms to arrival in the catheterization laboratory was in general very long (approximately 8 hours). This can be partially explained by the two hour waiting period before the decision to perform angiography was taken. In addition, another two hours were needed to start the catheterization.

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To make it even worse, the longer the delay the poorer the PCI outcome was. It is likely that these long delays have negatively influenced the outcome. If PCI was performed within 8 hours mortality was 10.5%. In the patients where the PCI delay exceeded 8 hours, mortality was 13.7%. Angiography in this study was performed to calculate the value of various electrocardiographic criteria needed to detect inadequate reperfusion. In daily practice, a decrease of >50% of the ST-segment elevation can be trusted as a true sign of reperfusion. The prognosis in these cases is excellent although late interventions are quite common because of recurrent ischaemia. In the absence of these electrocardiographic signs of reperfusion, the angiographic reperfusion status is less predictable. The vessel is usually occluded. Less frequently, the vessel is widely open, but distal plugging or embolization is present, resulting in an inadequate myocardial perfusion. In contrast to failed PCI, successful PCI (TIMI 3 flow but also TIMI 2 flow) did have an excellent prognosis (mortality: 48% and 5.9% respectively). Re-infarction in the rescue group was rare and comparable to primary PCI data given in the literature. In summary, ECG findings should be used to detect the reperfusion status. Ten-year experience with early angioplasty in 759 patients with acute myocardial infarction. F Bär, J Vainer, J Stevenhagen, et al. J Am Coll Cardiol 2000; 36:51–8. BACKGROUND. Primary PCI has been shown to be beneficial in terms of clinical outcome. In contrast, the value of rescue PCI has been insufficiently established. In a retrospective analysis the angiographic and clinical outcome of 317 consecutive patients who had rescue PCI ~90 min. after failed thrombolysis and 442 patients treated with primary PCI were compared. Baseline characteristics were comparable for most variables. Treatment delay was longer for the patients with rescue PCI ~240 min. vs ~195 min. in the primary PCI group. Coronary patency after PCI

was comparable: 90.2% for the rescue PCI group and 91.4% for the primary PCI group (P=0.67). Inhospital mortality rates were 4.7% and 6.6% respectively (P=0.37). Also the other complication rates were fairly similar during the hospital phase and the one-year follow-up. Predictors of death were: age, infarct size, location of AMI, failed PCI, and left main occlusion. Failed PCI resulted in a poor outcome for both strategies: after failed rescue PCI 22.6% and after failed primary PCI 26.3% of the patients died. In this analysis of 759 patients with AMI, rescue PCI early after failed thrombolysis seems to be as effective and safe as primary PCI. INTERPRETATION. Although the study is retrospective in nature and the outcome data have to be weighted, the outcome of rescue PCI is remarkably good. These results are comparable to the outcome of primary PCI, which is as expected. Patency is high and mortality and morbidity relatively low considering the population is at high risk.

Comment In contrast to previous observations, rescue PCI frequently failed. In these reports, rescue PCI was usually performed many hours after the start of thrombolysis. The drive to intervene was the occurrence of complications. In the present study, rescue PCI after failed thrombolysis is good and comparable to the results of primary PCI. The explanation for this difference is probably the early start (90 min) of the intervention after failure of thrombolysis, independent of whether complications had already occurred. The lesson of this study is the consistency of early intervention after failed thrombolysis. This intervention is not to treat complications, but to prevent them.

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Table 7.1 Clinical outcome during hospitalization Total population

Rescue PTCA

Primary PTCA

P value

Number of patients 759 (100) 317 (100) 442 (100) Death 44 (5.8) 15 (4.7) 29 (6.6) 0.37 Re-infarction 45 (5.9) 16 (5.1) 29 (6.6) 0.47 Re-PTCA 68 (9.0) 29 (9.2) 39 (8.8) 0.99 CABG 32 (4.2) 12 (3.8) 20 (4.5) 0.75 Any of the above 135 (17.8) 53 (16.7) 82 (18.6) 0.58 Recurrent angina 100 (13.2) 44 (13.9) 56 (12.7) 0.70 CVA 6 (0.8) 3 (0.9) 3 (0.7) 1.00 Blood transfusion 19 (2.5) 13 (4.1) 6 (1.4) <0.05 Maximal ASAT 255 (17–2000) 312 (43–1537) 215 (17–2000) <0.01 Ejection fraction* 46 (11.8) 45.4 (11.4) 46 (12.1) 0.54 Hospital stay (days) 8.1 (8.6) 8.2 (7.5) 8.1 (9.7) 0.46 * By echocardiography. Data presented are numbers (%) of patients or mean value±SD or median (range). ASAT=aspartate aminotransferase; CABG=coronary artery bypass graft; CVA=cerebrovascular accident; PTCA=percutaneous transluminal coronary angioplasty. Source: Bär et al. (2000). Table 7.2 Predictive factors of the one-year mortality of 759 patients who underwent acute PTCA: a univariate analysis Deaths

Survivors

P value

Number of patients 67 (100) 681 (100) Males 46 (68.7) 506 (74.3) 0.39 Age (years) 68.7 (11.0) 59.7 (11.5) <0.001 Thrombolysis 23 (34.3) 287 (42.1) 0.27 Failed PTCA 17 (25.4) 52 (7.6) <0.001 Myocardial infarction: Anterior 41 (61.2) 330 (48.5) 0.06 Inferior 28 (41.8) 349 (51.3) 0.18 Maximal ASAT 334 (52–2000) 253 (17–1555) 0.07 Culprit lesion: LAD 32 (47.8) 324 (47.6) <0.001 RCA 19 (28.4) 246 (36.1) CX 5 (7.5) 91 (13.4) LMCA 5 (7.5) 1 (0.2) Graft 6 (9.0) 19 (2.8) Data presented are number of patients or mean value±SD or median (range). ASAT=aspartate aminotransferase; CX=circumflex coronary artery; LAD=left anterior descending coronary artery; LMCA=Left main coronary artery; PTCA=Percunateous transluminal coronary angioplasty; RCA=right coronary artery. Source: Bär et al. (2000).

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The advantages of the strategy of thrombolysis, careful observation for the presence of reperfusion, and early rescue PCI in case of persistent occlusion are that the time needed to transport a patient to an interventional hospital or to prepare the catheterization laboratory is used effectively: a thrombolytic agent might already have reopened the vessel during this waiting period. The burden for the catheterization laboratory is greatly reduced and the clinical outcome seems the same. Many reports have been published indicating the high risk of failed rescue PCI. This observation is also made in the present study: mortality was 22.6%. Some investigators suggested that the rescue PCI procedure itself was to blame. This suggestion is rather unlikely because a similar high mortality (26.3%) is found after failed primary PCI in the present study. Bleeding risks with abciximab after full-dose thrombolysis in rescue or urgent angioplasty for acute myocardial infarction. P Jong, E Cohen, W Batchelor, et al. Am Heart J 2001; 141(2):218–25. BACKGROUND. The bleeding risk associated with GP llb/llla inhibitor treatment in patients undergoing early PCI after thrombolysis for AMI is unclear. The risk of and predictors for bleeding complications were studied in 147 consecutive patients. All patients underwent PCI within 48 hours after full-dose thrombolysis. Abciximab was given in 57 patients, while 90 patients did not receive this therapy. The decision to use abciximab and the choice of the dose were at the discretion of the cardiologist. Low dosages of procedural heparin were administered in the abciximab group. Bleeding complications from onset of AMI to discharge were compared. Baseline characteristics of both groups were comparable. The incidence of all bleedings (major or minor) was nearly double in the reopro group (63% vs 39%; P=0.004). Severity of bleeding complications were also much higher: 12% vs 3% (P=0.04) respectively. In the abciximab patients one intra-cranial and one other fatal bleeding occurred. Multivariate regression analysis identified abciximab therapy as the most powerful predictor of bleeding complications. INTERPRETATION. In the setting of rescue or urgent PCI after full-dose thrombolysis, bleeding complications are frequently encountered. The adjunctive use of abciximab further increases the bleeding risk considerably.

Comment In this retrospective non-randomized analysis, 70% of all patients included had rescue PCI within 12 hours of failed thrombolysis. The remainder of patients had urgent PCI between 12 and 24 hours after onset of AMI. Bleeding complications were quite frequent and severe. One of the explanations for a high risk of bleeding is the type of thrombolytic agent used. In the TIMI 14 study it was shown, that the combination of abciximab and streptokinase is rather dangerous. In the present study only 11% of patients received streptokinase. All others had alteplase, which in this setting is regarded as much safer. The investigators do not mention whether there were any differences in bleeding complications between the two thrombolytic agents. Remarkably, early abciximab therapy within 12 hours had bleeding risks identical to those of the late group (12–24 hours). Success of PCI was independent of abciximab treatment, although more stents were used in that group (79% vs 51%). In the abciximab group, early sheath removal (within 12 hours of PCI) was more common (39% vs 17%). This partially explains the excess of bleeding complications: puncture bleeding was seen in 40% vs 28% in the control group (P=0.16). Obviously, the higher risk of bleeding complications should be

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Fig. 7.1 Bleeding risks in patients treated with abciximab or placebo. Source: Jong et al. (2001).

counterbalanced by an improved outcome. However, in the present article no data were given on the clinical outcome. Even when such data were presented, the number of patients would probably be too low to make firm conclusions. Based on the present data, the use of abciximab after the full dose of a thrombolytic agent cannot be advocated. Review of immediate angioplasty after fibrinolytic therapy for acute myocardial infarction: insights from the rescue 1, rescue 2, and other contemporary clinical experiences. S Ellis, E Ribero da Silva, C Spaulding, M Nobuyoshi, B Weiner, J D Talley. Am Heart J 2000; 136(6): 1046–53. BACKGROUND. After fibrinolytic therapy, restoration of TIMI 3 flow is seen in 40–50% of patients. In this meta-analysis of 1456 patients from 9 randomized trials and 977 patients from 4 registries all treated with fibrinolytic therapy, rescue PCI was compared to conservative treatment. Rescue PCI after failed thrombolysis (TIMI 0–1 flow) reduced severe heart failure: 3.8% vs 11.7% in the conservative group. In patients with more extensive AMI, one-year mortality was lower in the rescue group: 8% and 13% (P=0.001) respectively. Re-infarction was also lower: 4.3% vs 11.3%. Due to the low numbers of patients with TIMI 2 flow after thrombolysis but before an intervention, the value of an intervention in this group is unclear. In patients with TIMI 3 flow before catheter intervention, facilitated PCI is shown to be safe: in two registries, mortality was 2.0% and 4.6% respectively. Compared to the early PCI studies carried out at the beginning of the 1980s, the outcome of rescue PCI

after failed thrombolysis or facilitated PCI after successful thrombolysis is clearly much improved now. INTERPRETATION. The data of the meta-analysis of 9 randomized studies and 4 registries suggests a benefit of rescue PCI. The role of mechanical intervention in this setting should be more extensively explored.

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Comment This is a rather complex meta-analysis of the value of acute PCI after thrombolysis in patients with different TIMI flows. Based on data gathered in patients with TIMI 0–1 flows, a significant improvement in outcome after rescue PCI is found when compared with a conservative strategy. An important progress in outcome is obvious when results of trials performed in the 1980s are compared with those in the 1990s. Even facilitated PCI after successful thrombolysis seems to be no longer contra-indicated because of lesser re-infarction rates. This can partially be explained by better skills and knowledge of the interventionalist. Further, the materials used for angioplasty are of much higher quality, smaller, and more flexible. Finally, the use of modern more effective medication like platelet aggregation inhibitors is important for the acute as well as the sub-acute phase. The additional use of GP IIb/IIIa inhibitors after a full dose of thrombolysis might improve the outcome. However, severe bleeding complications are reported and counterbalance the potential angiographic and clinical improvement. Angiographic and clinical outcome after rescue coronary stenting. H Dauerman, R Prpic, C Andreou, M Vu, J Popma. Cath and Cardiovasc Interv 2000; 50:269–75. BACKGROUND. The role of coronary stenting after failed thrombolysis to improve outcome is not well established. In a 3-year registry, the acute angiographic outcome was evaluated in 108 consecutive patients with AMI. All had rescue PCI because of failed thrombolysis: in 63 patients balloon angioplasty was performed and in 45 patients coronary stenting. Residual stenosis after the intervention was 31±22% for balloon angioplasty and 15±10% for stenting (P<0.001). Overall in-hospital mortality was 5.5%. Morbidity was also comparable except for re-PCI: 9.5% vs 0% (P=0.08). INTERPRETATION. The angiographic and clinical outcome after stenting in stable and unstable angina is usually significantly better when compared to balloon angioplasty only. The same observation has now been made in a rescue PCI setting.

Comment In this retrospective rather small sized analysis on the value of rescue PCI with or without stenting, excellent mortality and morbidity data are shown. Also in this setting, stenting shows an even better outcome than balloon angioplasty alone. The chance of repeat target vessel intervention was importantly lower (0%!) compared to ballooning (9.5%). This suggests that in the AMI, sub-acute thrombotic occlusion after stenting is uncommon in spite of the very thrombogenic environment. As expected, in the stent group a lot more GP IIb/IIIa inhibitors were administered: all patients had ticlopidin 2×250 mg daily for one month and 47% were treated with abciximab. In the balloononly group percentages were 0% and 16% respectively. In spite of this aggressive regimen, bleeding complications were not different. Early coronary intervention following pharmacologic therapy for acute myocardial infarction (the combined TIMI 10B–14 experience). M Schweiger, C Cannon, S Murphy, et al. Am J Cardiol 2001; 88:831–6. BACKGROUND. Earlier studies have suggested that immediate PCI following thrombolytic therapy for AMI is associated with an increase in adverse cardiac events and routine PCI in this setting has offered no advantage over a conservative strategy. In the present retrospective analysis of two angiographic thrombolysis studies 1938 patients were evaluated. Patients in the TIMI 10B study were

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randomized to receive one of the two thrombolytic agents: alteplase or TNK. In the TIMI 14 study, patients were randomized to thrombolytic therapy with or without abciximab. All patients underwent angiography 90 min after the start of medication. In many of the patients angiography was followed by a PCI. PCI was classified as being rescue PCI; in case TIMI 0–1 flow was seen just prior to the intervention. In case TIMI 2–3 flow was observed, PCI was classified as being an adjunct procedure if the PCI was performed immediately after the 90 min angiography. A delayed PCI was defined as a procedure >150 min after the onset of angiography (median 2.75 days). A clear trend to a lower 30-day mortality was observed in the rescue PCI group of 296 patients compared to those 55 patients who had no PCI: 6% vs 17% (P=0.01, adjusted P=0.28). The 424 patients who underwent adjunctive PCI had similar 30-day mortality (3%) to the 481 patients who underwent delayed PCI (3%). This was importantly better then the 683 patients with TIMI 2–3 flow without further catheter intervention (6%) (P=0.02). INTERPRETATION. Early PCI following AMI is associated with excellent outcomes. Randomized trials of early invasive strategies following thrombolysis are warranted.

Comment The PCI studies from the 1980s suggested that early intervention shortly after thrombolytic therapy is not beneficial for the patients in terms of clinical outcome. One of the problems of these early non-randomized observations was that no distinction was made in the degree of TIMI flow before the intervention and the outcome. In addition, in many patients PCI was performed during the infusion of the thrombolytic agent. At that time, only streptokinase was used. Since that period, treatment has substantially changed. New thrombolytic agents are used, which are more effective for opening up the artery. Usually, an intervention is postponed until it becomes clear that the thrombolytic agent is ineffective (±90 min after start of the medication). Further, pathophysiology of the disease, intervention materials, medication, and skills has been dramatically improved. Therefore, it is not very surprising that the outcome of the more recent rescue interventions is Table 7.3 Thirty-day clinical end-points compared to medical therapy with patent artery Patent Artery

Death Medical therapy with TIMI 2/3 flow at 90 min Medical therapy with occluded artery at 90 min Rescue PCI Adjunctive PCI Delayed PCI Adjunctive or delayed PCI CABG during hospitalization Recurrent AMI Medical therapy with TIMI

OR

95% CI

P value

1.0

Reference group

3.35

1.2–9.2

0.02

1.85 0.69 0.28 0.48 0.54

0.9–3.9 0.28–1.7 0.09–0.9 0.21–1.1 0.19–1.5

0.10 0.42 0.03 0.09 0.24

1.0

Reference group

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Patent Artery OR

95% CI

P value

2/3 flow at 90 min Medical therapy with –† –† –† occluded artery at 90 min Rescue PCI 0.21 0.06–0.75 0.02 Adjunctive PCI 0.49 0.18–1.3 0.15 Delayed PCI 0.39 0.15–1.0 0.06 Adjunctive or delayed PCI 0.43 0.18–1.03 0.06 CABG during 1.16 0.51–2.65 0.72 hospitalization Death or recurrent AMI Medical therapy with TIMI 1.0 Reference group 2/3 flow at 90 min Medical therapy with 1.74 0.7–4.3 0.24 occluded artery at 90 min Rescue PCI 0.81 0.43–1.5 0.51 Adjunctive PCI 0.55 0.27–1.1 0.10 Delayed PCI 0.34 0.16–0.73 0.01 Adjunctive or delayed PCI 0.44 0.24–0.83 0.01 CABG during 0.88 0.45–1.7 0.72 hospitalization Logistic regression analysis for 30-day clinical outcomes comparing PCI to medical therapy in patients with a patent artery (at 90-minute angiography) controlling for age, location of AMI, prior AMI, smoking, gender, history of diabetes, history of hypertension, single-vessel disease, pulse on admission, systolic blood pressure on admission, abciximab use, stent use, and time from symptom onset to treatment. There was 1 patient with an occluded artery at 90 minutes who was treated medically (no PCI performed) who had a recurrent MI. This patient underwent CABG and was in the CABG group for multivariate analysis. CI=confidence intervals; CABG=coronary artery bypass grafting; OR=odds ratio. Source: Schweiger et al. (2001).

importantly better. In spite of these newer developments, in the present studies TIMI 2–3 flow was reached in 85% and TIMI 3 flow in only 78%. This was significantly less when compared to PCI in open vessels: In their studies a TIMI 3 flow of 89% was reached. Obviously, rescue PCI remains a rather difficult procedure, which should be kept in the hands of experts. This was recently underlined by the clear-cut relationship between the number of PCIs in the setting of AMI and the clinical outcome. The more experience the interventionalist had the better the outcome |3|. As in the present observation, several other more recent randomized and non-randomized studies have indicated that rescue PCI in the case of TIMI 0–1 flow is favourable for the patient. The most important part of this study is the finding that an adjunct PCI or a delayed PCI results in an importantly better outcome when compared to the conservative approach. The current American College of Cardiology/American Heart Association guidelines for the management of AMI conclude that routine angiography and PCI following thrombolytic therapy may be harmful. The current data suggests otherwise. The procedure is not only safe but also results in an improved outcome.

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The authors underline that the present observations do have a number of limitations. Therefore, they stress that randomized trials are needed to prove that an early intervention is indeed superior to a conservative approach. Primary versus rescue percutaneous coronary intervention in patients with acute myocardial infarction. G Gimelli, A Kaldry, M Sabatine, I Jang. Acta Cardiol 2000; 55(3):187–92. BACKGROUND. This study was carried out to compare the angiographic and clinical outcome of 60 patients with AMI who underwent primary PCI and 45 patients treated with rescue PCI after failed thrombolysis. In this observational study, time delay to reperfusion was significantly longer in the rescue PCI group (354 min) vs the primary group (189 min) (P<0.001). Nearly all patients received a stent (93%) after primary PCI and after rescue PCI (93%). GP llb/llla inhibitors were given in 53% of patients treated with primary PCI, and in 20% of the rescue PCI group. TIMI 3 flow was achieved in 93.3% after primary PCI and in 88.8% of the rescue group (P=0.08). Post-procedure ejection fraction was 53% in the primary PCI and 47% in the rescue patients (P=0.014). The composite end-point of death, reinfarction, re-PCI, coronary artery bypass graft (CABG), or recurrent angina during a six-month followup period was observed in 35% of the primary PCI group and in 26.7% of the rescue group (P=0.36). INTERPRETATION. In the patients treated with rescue PCI, a significantly longer delay in reperfusion, a somewhat lower angiographic success, and a lower post-procedural ejection fraction was observed compared to patients with primary PCI. Despite this, the long-term clinical outcome of patients treated with rescue PCI appeared to be at least similar or even better.

Comment The present data show that rescue PCI after failed thrombolysis results in nearly similar patency and clinical outcome when compared to primary PCI. Rescue PCI is a safe and effective procedure. Although the results of this study are in line with other recent observations, the data have to be interpreted with some caution, because it is a rather small sized retrospective analysis. Many of the patients involved in this study were transported from other hospitals. In that group, transportation to the interventional hospital was shown to be safe even in patients with cardiogenic shock. The authors even claim that thrombolysis and rescue PCI is the treatment of choice for patients in cardiogenic shock. This statement is, however, insufficiently founded, because of the relatively low number of shock patients in their study. Still, the strategy of thrombolysis and rescue PCI might indeed be an excellent option for patients with extensive AMI admitted in a non-interventional hospital. In this group the most important goal is to achieve reperfusion as early as possible. In this non-interventional setting, thrombolytic therapy will, in the majority of patients, result in reperfusion within a 90 min period. Such rapid time to reperfusion can never be reached when using a primary PCI strategy, because then all patients have to be transported first which will take a considerable amount of time.

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Cardiogenic shock and catheter interventions Introduction Cardiogenic shock during AMI is associated with a very high mortality of 50% or more. In recent years, more insight has been gained into what mechanisms can cause cardiogenic shock. In addition, treatment has become more aggressive: for example, angiography, intra-aortic balloon pump (IABP), thrombolysis, or immediate primary or rescue PCI is available and these are used increasingly if this complication occurs. The focus of this chapter is whether the outcome of patients with cardiogenic shock has indeed improved after an early PCI or CABG. For the first time, not only are data available of retrospective analyses but also of the prospective randomized ‘SHOCK’ trial |4|. From that particular trial one-year outcome is given, which is shown to be crucially different from the 30-day outcome. Such randomized trials are extremely significant, because an important selection bias can be expected in the type of treatment for the patients with cardiogenic shock. It is likely that such selection bias will be in favour of PCI or CABG, because the patients who are most likely to recover will undergo an intervention while terminal patients are likely to be treated more conservatively. Some of the studies in this chapter will give insight into the incidence of cardiogenic shock during AMI. The influence of pre-treatment with thrombolytic therapy or IABP is also addressed. Severity of coronary disease, age of the patient, and TIMI flow before and after the interventions are shown to be of importance in the outcome of the patients. Will intra-coronary stenting improve outcome in cardiogenic shock? In some of the trials cited, data are available on the influence of the delay between onset of pain and the start of PCI. This point is of vital importance to answer the question of what the best strategy is for patients admitted in a noninterventional hospital. Is it worthwhile to refer shock patients for an intervention? Comparison of impact of primary percutaneous transluminal coronary angioplasty and primary stenting on short-term mortality in patients with cardiogenic shock and evaluation of prognostic determinants. H Yip, C Wu, H Chang, et al. Am J Cardiol 2001; 87:1184–8. BACKGROUND. Whether primary stenting is better than primary PCI of cardiogenic shock in the setting of AMI is not yet clear. Since cardiogenic shock remains the most deadly complication of AMI, it is crucial that we try to optimize treatment. The investigators of the present study conducted a prospective, non-randomized trial in one hospital in Taiwan during the years 1993–2000. Cardiogenic shock developed on admission or in less than 2 hours after arrival in the hospital. Cardiogenic shock was defined by certain specific criteria. By examining the effect on in-hospital and 30-day mortality, they compared primary PCI and primary stenting in patients with cardiogenic shock complicating AMI. From 740 patients with AMI, in whom emergency revascularization was performed during the mentioned period, 95 patients (12.8%) had cardiogenic shock. Six of these patients were not eligible for PCI; they were excluded from the analysis. The remaining 89 patients formed the two groups studied here. The first group of 42 patients underwent primary PCI. This consists of the first years of the trial. The second group treated with primary stenting enrolled 47 patients. These patients were included during the last years. The stent group received additionally ticlopidin for a 2 week period after the procedure. In-hospital mortality was not different for the two groups (PCI group 31% and stent group 31.9%; P=0.92). After univariate analysis of the risk factors for in-hospital mortality, profound shock (systolic blood pressure <75 mmHg despite I.V. inotropics and use of IABP, associated with clinical signs of hypoperfusion) had the worst prognostic factor (71.4% mortality with profound shock versus 22.1% without profound shock; P=0.001). Other significant risk factors were: age <70 years or ≥ 70 years (mortality 54.8% for ≥ 70 years versus mortality 22.4% for <70 years; P=0.002), multi-vessel disease

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(mortality for multivessel 40.9% versus mortality for single vessel 13.0%; P=0.001) and unsuccessful reperfusion (mortality for unsuccessful reperfusion 64.3% versus mortality for successful reperfusion 28. 0%; P=0.008). When early reperfusion was achieved ≥ 4.7 hours, mortality was significantly lower (59. 3% for reperfusion >4.7 hours versus 22.6% for reperfusion ≥ 4.7 hours; P=0.001). INTERPRETATION. This study showed that for treatment of patients who developed cardiogenic shock in the setting of AMI, primary stenting was not superior to primary PCI

in terms of in-hospital and 30-day mortality. Factors that significantly increased mortality were: profound shock, age ≥ 70 years, unsuccessful PCI and multivessel disease. Early reperfusion (≥ 4.7 h) significantly decreased mortality.

Comment The authors tested the strategies of primary stenting and of primary PCI prospectively in two consecutive periods. This approach allowed an accurate and reasonably reliable study. Selection bias between the two treatments was probably minimal because of the specific design of the trial. There are, nevertheless, some limitations. The study was not randomized, it was conducted in one hospital and the enrolment period was relatively long (7 years). Also the eligibility criteria excluded patients with cardiogenic shock occurring 2 hours or more after arrival at the hospital. That criterion will probably exclude many patients developing cardiogenic shock at a later phase, because this is a complication that usually occurs at a later stage. At the same time, the number of patients defined as suffering from cardiogenic shock is surprisingly high (12.8%). The patients enrolled do have more chances of surviving the shock, because part of the myocardium might still be viable only a few hours after onset of AMI. Perhaps that is why the overall in-hospital mortality of these cardiogenic shock patients was relatively low: 31.5%. For example: in the randomized SHOCK trial and the prospective SHOCK trial registry in-hospital mortality was 46.4%. The no-reflow phenomenon was related to a poor outcome: 70.0% of patients died vs 29.1% of patients with good distal perfusion. In 23.6% profound shock developed. The haemodynamics of these patients deteriorated rapidly, followed by respiratory failure, altered mental state, and sudden death due to ventricular tachyarrhythmia that required defibrillation. Although the coronary reperfusion rate of patients with profound shock was similar to that of patients without profound shock (81.0% vs 85.3%), they had a higher mortality rate and usually died within a few hours after admission. Whether the use of GP IIb/IIIa agents, which was not given in this study, could improve the clinical outcome remains to be determined. Table 7.4 Multivariate predictors of in-hospital and 30-day mortality Variables

OR

95% CI

P value

Profound shock Unsuccessful reperfusion Multivessel disease Reperfusion time >4.7 h Source: Yip et al. (2001).

16.7 5.1 5.2 0.16

3.9–70.1 1.1–24.8 1.1–25.3 0.1–0.6

0.001 0.042 0.044 0.004

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Effect of early revascularization on mortality from cardiogenic shock complicating acute myocardial infarction in California. M Edep, D Brown. Am J Cardiol 2000; 85:1185–8. BACKGROUND. In this retrospective, multicentre study, the investigators examined patients with cardiogenic shock complicating AMI. All patients were admitted in non-federal hospitals in California. The effect of early revascularization on overall in-hospital mortality was tested. From 63 964 patients with AMI, 1122 (1.8%) were defined as having cardiogenic shock. Overall in-hospital mortality for patients with cardiogenic shock was 56%. Early revascularization (day 0 or day 1 after admission) was carried out in 259 patients. These 259 patients had the best risk profile: patients undergoing early revascularization had a 33% in-hospital mortality compared to 68% in those not treated with early revascularization. Later revascularization (PCI or CABG) after day 1 was performed in 344 cardiogenic shock patients. After multivariate adjustment, the benefit of early intervention was still present: the odds ratio was 0.20 (P=0.0001). INTERPRETATION. Results from this study suggest that early revascularization in patients with AMI complicated by cardiogenic shock, reduces in-hospital mortality, even when adjustments for risk factors are made.

Comment The incidence of cardiogenic shock (1.8%) in patients with AMI in this study appears to be very low when compared to the literature. For example, in the GUSTO I 7.4% patients had shock and in the GUSTO III the percentage was 5.5. The reason for this low incidence is probably that patients in the cardiogenic shock group were mostly registered using the admission diagnosis. In the GUSTO I study only 0.8% of patients already had cardiogenic shock on admission. This means that most of the patients who developed cardiogenic shock during admission did not enter this registry. In addition, the definition ‘cardiogenic shock’ was more rigid than in other trials. The fact that the data were collected retrospectively is another limitation. In these shock patients, thrombolytic therapy was applied in only 12% of cases. IABP was utilized in 28%, which is also lower than, for example, the GUSTO I study (35%). However, the patients in whom an IABP was used had a significantly better mortality outcome (40%) than the patients not treated with counterpulsation (62%) (P=0.001). In a multivariate analysis, advanced age >60 years, female gender, diabetes, and prior AMI or CABG were all shown to be independently associated with an increased risk of death from cardiogenic shock. In contrast, like early reperfusion (see above), a history of hypertension was found to confer protection against in-hospital mortality, with an odds ratio of 0.70 (P=0.01). Table 7.5 Baseline characteristics of all patients

Age (yrs) Women Caucasian Hypertension Diabetes Prior AMI Prior coronary angioplasty

Early revascularization (n=259)

No early revascularization (n=863)

P value

66 39% 82% 34% 20% 4.6% 3.5%

72% 48% 77% 32% 30% 6.0% 7.8%

0.001 0.008 NS NS 0.002 NS 0.02

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Prior coronary bypass Q-wave AMI Anterior wall AMI Source: Edep and Brown (2000).

Early revascularization (n=259)

No early revascularization (n=863)

P value

4.3% 95% 46%

8.3% 91% 39%

0.03 0.02 0.04

Despite the presence of several limitations in this study, the better in-hospital outcome of early revascularization in cardiogenic shock is consistent with the results found in other non-randomized trials. Lack of progress in cardiogenic shock: lessons from the GUSTO trials. V Menon, J Hochman, A Stebbins, et al. for the GUSTO Investigators. Eur Heart J 2000; 21:1928–36. BACKGROUND. Data from the GUSTO I (1990–1993) and from the GUSTO III (1995–1997) trials were examined in order to find the possible progress made in treatment of cardiogenic shock complicating AMI. These two large trials tested different thrombolytic regimens in AMI. GUSTO I enrolled 41021 patients while GUSTO III included 15059 patients. For the purpose of this study, the investigators examined only patients enrolled in countries common to both trials. In that selection of patients, 2814 of the 37892 patients (7.4%) in GUSTO I developed cardiogenic shock, while 695 of the 12572 patients (5.5%) in GUSTO III had this complication. Patients with cardiogenic shock in GUSTO III had a higher overall 30-day mortality than those in GUSTO I (62% vs 54%; P=0.001). Even after adjustment for baseline characteristics this difference remained at one year after AMI. Re-infarction rates were also higher in GUSTO III (14% vs 11%; P=0. 013) as well as recurrent ischaemia (35% vs 27%; P=0.00001). An explanation for the differences in outcome was that patients in GUSTO III had a higher risk profile than the ones in GUSTO I: They were older and more likely to have diabetes or hypertension, more anterior MI, and higher Killip class on presentation. Patients treated with PCI had a mortality of 32% in the GUSTO I study, while death rate in GUSTO III was 37% (P=0.28). When the patients

with cardiogenic shock treated with altepase (tPA) were compared, mortality was also lower in the GUSTO I (55%) compared to the GUSTO III (62%). The US group treated with PCI had 29% mortality in GUSTO III and 30% mortality in GUSTO I. At the same time, in the non-US PCI group mortality was higher as well in GUSTO I (45%) and in GUSTO III (52%). INTERPRETATION. The investigators demonstrated that patients with cardiogenic shock complicating AMI have a higher mortality rate when treated with thrombolysis only than with additional PCI. This is probably due to differences in baseline characteristics between both trials, mortality has not improved with time. Due to a more aggressive treatment with PCI or CABG, survival is better in the USA when it is compared to other countries.

Comment This is the largest database of patients with cardiogenic shock. Although these trials were not specifically designed to study cardiogenic shock, the patients with this complication were prospectively identified in these two trials. Therefore, they contain extremely valuable information concerning the treatment of cardiogenic shock.

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Although GUSTO III was conducted some years later, mortality in cardiogenic shock was higher than in GUSTO I. The differences in baseline characteristics have Table 7.6 Profile of patients with cardiogenic shock enrolled in GUSTO I and GUSTO III GUSTO I

GUSTO III

P value

n (overall) 2814 695 n (U.S.A.) 1891 (67%) 271 (39%) Age (years)* 68 (60, 75) 71 (61, 77) 0.0001 Males 1775 (63%) 434 (63%) 0.758 Weight (kg) 75 (65, 85) 75 (65, 85) 0.684 Height (cm) 170 (163, 177) 170 (162, 176) 0.148 Hypertension 1216 (44%) 335 (49%) 0.025 Diabetes 522 (19%) 160 (23%) 0.009 Hypercholesterolaemia 794 (31%) 223 (33%) 0.231 Current smokers 943 (34%) 208 (31%) 0.220 Former smokers 1688 (60%) 256 (37%) 0.001 Previous angina 1179 (42%) 355 (51%) 0.001 Prior myocardial infarction 690 (25%) 196 (28%) 0.059 Previous angioplasty 100 (4%) 30 (4%) 0.356 Previous bypass surgery 188 (7%) 36 (5%) 0.138 Time to treatment (h) 2.8 (2.0, 4.0) 2.8 (1.8, 3.8) 0.099 Index anterior infarction 1405 (50%) 414 (60%) 0.001 *Presented as median (25th, 75th percentiles). Presented as numbers (percentages) except where indicated. Source: Menon et al. (2000).

already been pointed out. Another reason explaining the difference in the incidence of cardiogenic shock between the two trials is that ‘only’ 5.5% had cardiogenic shock in GUSTO III compared to 7.4% in GUSTO I. The higher cardiogenic shock percentage in GUSTO I was mainly due to higher rates in US centres that participated in that trial (8.2% in US vs 6.2% in non-US centres). Probably, patients were characterized as having cardiogenic shock more easily in the US. The enrolment of less ill patients might at least partially explain the better outcome in the US patients. This statement is not covered by the GUSTO III trial. In that trial, the cardiogenic shock criteria were followed more strictly in the US (5.7% in US vs 5. 4% in non-US centres). Still, a significant difference in the 30-day mortality of 29% and 52% was found between the PCI groups for US and non-US centres, respectively. This difference in mortality clearly speaks in favour of an aggressive interventional treatment as is more common in the US: PCI or CABG in the GUSTO III study was 50% in US patients vs only 13% in non-US patients. The same figures can be given for the use of IABP. The conclusion that early revascularization with PCI or bypass surgery is beneficial for patients with cardiogenic shock in the setting of AMI is consistent with the results of other non-randomized studies. Percutaneous coronary intervention for cardiogenic shock in the shock trial registry. J Webb, T Sanborn, L Sleeper, et al. Am Heart J 2001; 141(6):964–70.

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BACKGROUND. In this article the investigators present results from the registry of the SHOCK trial. This was one of the only two randomized trials ever conducted (only the SHOCK trial was completed). In the present study, the hypothesis was tested that in patients with cardiogenic shock complicating AMI, early revascularization improves the outcome when compared to medical treatment without further intervention. The SHOCK trial registry prospectively enrolled patients from 36 multinational centres. These patients were not suitable for the randomized trial mentioned above. From 1190 patients in the registry (April 1993 to August 1997) 226 were excluded. Reasons for exclusion were mechanical or iatrogenic causes of shock, or PCI or CABG before the occurrence of shock. The remaining 884 patients in the registry had cardiogenic shock in the setting of AMI, predominantly due to left ventricular failure. 276/884 (31.2%) patients underwent PCI, 499 patients (56.5%) had medical treatment and 109 (12.3%) CABG. Patients treated medically had higher in-hospital mortality (78%) than ones treated with PCI (46.4%) or CABG (23.9%). Most of the patients, who went through angiography, had multi-vessel disease (78%). The greater the number of diseased arteries involved, the worse the prognosis (34.2% mortality for 0- and 1-vessel disease, 40.7% for 2-vessel disease, and 51.2% for 3-vessel disease). In this registry, the significance of flow after PCI was also examined: in-hospital mortality rose, when instead of grade III TIMI flow (33.3% mortality), only grade II (50.0 % mortality) or grades 0 and I (85. 7% mortality) were achieved. Change in the pre- and post-procedural TIMI flow was also correlated with in-hospital mortality:

38.8% mortality for improved flow, 58.8% for unchanged flow, and 81.8% for reduced flow after the PCI. A successful PCI (<50% residual stenosis and TIMI II or III flow) greatly influenced in-hospital mortality: 36.1% mortality for successful vs 82.5% for unsuccessful intervention. INTERPRETATION. Patients with AMI and cardiogenic shock due to left ventricular failure do have significantly lower in-hospital mortality when treated with PCI than with medical treatment. The degree of coronary flow and presence or absence of patency post-PCI have an important influence on outcome. Measures to promote early and rapid reperfusion appear critically important in improving the otherwise poor outcome associated with cardiogenic shock.

Comment This is a registry which included 3 times more patients than the randomized SHOCK trial. Patients in the registry were probably more similar to members of the general population than those enrolled in the SHOCK trial who were older and more ill. In the SHOCK registry, patients assigned to the PCI group, had a significantly better in-hospital survival than the ones assigned to medical treatment, even when adjustments for patients’ differences and other survival biases were made. This result in favour of revascularization was, at 30 days, not obvious in the randomized SHOCK trial. Nevertheless, also in the SHOCK trial an improved outcome after successful PCI was observed at six months and at one year. We must not forget that this registry was not a randomized trial and has resulted in a selection bias. For example, PCI and CABG patients were less sick and younger than those assigned to medical treatment. They were also less likely to have a history of previous myocardial infarction, heart failure, CABG, or peripheral vascular disease. It partially explains the differences in inhospital mortality between the medically treated group (78%), the PCI group (46.4%) and the CABG group (23.9%). Such differences were not found in the randomized trial. Median time from onset of complaints to admission was 4 hours, AMI to PCI was 8.7 hours, and shock to PCI was 3.3 hours. There was a trend to poorer mortality rates related to these time intervals: 40.2% for PCI

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Fig. 7.2 Mortality of patients after successful or unsuccessful PCI. Source: Webb et al. (2001).

within 6 hours from onset of AMI, 50.9% if the PCI was performed between 6 and 12 hours after onset of AMI, and 60.5% if the delay was 12–24 hours. These long intervals are partially explained by the 42.5% referral patients, arriving 11.7 hours (median) after AMI onset. PCI in that group was performed a median of 4.4 hours later. This is reflected in the clinical outcome: 48.4% mortality for transferred patients versus 31. 1% for non-transferred patients. Patients, who died already before any revascularization was started, were put into the medically treated group. It is clear that this arbitrarily chosen approach negatively influenced the outcome in that category. Patients of this registry were included between 1993 and 1997. Since then further knowledge and several new therapeutic options have become available. For example: In patients undergoing PCI, stents were used in 24% and GP IIb/IIIa agents in only 7%. There was no obvious benefit in survival from using stents or GP IIb/IIIa inhibitors, but the number of patients treated was relatively small. During the period of the study, the use of coronary angiography increased from 45% to 67%. Although CABG rates remained relatively stable, PCI rates exhibited a trend upward from 24% to 36%, resulting in an increased overall rate of revascularization (from 36% to 48%). Over the registry period from 1993–1997, the use of stents increased from 0% to 32%, and that of GP IIb/IIIa inhibitors from 0% to 12%. In current practice these new therapeutic options might positively influence the outcome. Despite the mentioned limitations, this large registry provides a powerful tool for understanding and optimizing treatment for cardiogenic shock in the setting of AMI. This is especially true when the data of this registry are combined with the data of the randomized SHOCK trial. One-year survival following early revascularization for cardiogenic shock. J Hochman, L Sleeper, H White, et al. J Am Medical Ass 2001; 285(2): 190–2. BACKGROUND. Cardiogenic shock is one of the most dramatic complications of AMI. It is related to a very high mortality. In this article, the investigators of the SHOCK trial present the 1-year survival, which was one of the secondary end-points in that study.

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The SHOCK trial was a multicentre, randomized, unblinded study, which tested the strategy of early revascularization versus the initial medical stabilization strategy, for patients with AMI complicated by cardiogenic shock. The study was performed from April 1993 to November 1998. Thirty-six referral centres participated. All centres had facilities and the capability to perform emergency angioplasty and cardiac surgery when needed. Cardiogenic shock was predominantly due to left ventricular failure in the 302 patients included in the study. Eligible patients, according to pre-specified clinical and haemodynamic criteria, were randomly assigned to two groups: A) Early revascularization (<6 hours) treatment with either angioplasty (55%) or CABG (38%), depending on the patient’s coronary anatomy (n=152). B) Initial stabilization with medical treatment including thrombolysis (63%) and intra-aortic balloon pump (86%). These patients were allowed to undergo angiography and if necessary revascularization (25%) only 54 hours after randomization (n=150). The primary end-point of the study was all-cause 30-day mortality. At that time, there was a nonsignificant difference in 30-day mortality between the early interventional group and the initial conservative group. However, at one year there was a significant survival difference in favour of the early interventional group (46.7% vs 33.6%; P<0.03). This benefit in survival of the invasive strategy was present only in patients below the age of 75 years. The sub-group of patients above 75 years of age seemed to do better with medical treatment. Of the survivors at one year, 83% (85% of group A and 80% of group B) were in New York Heart Association (NYHA) class I or II. INTERPRETATION. This study demonstrated that, in the setting of AMI, younger patients with cardiogenic shock due to left ventricular failure do have a better 1-year survival if they undergo early revascularization. A rapid transfer of these patients to medical centres capable of providing early angiography and revascularization procedures is recommended.

Comment This article is the 12-month report from the SHOCK trial; the only randomized and completed trial that tested prospectively the effect of early revascularization compared to initial medical stabilization in patients with cardiogenic shock complicating AMI. Considering the enormous difficulties of conducting such study, we must compliment the investigators on their achievements. The results favouring invasive therapy were already observed in previous nonrandomized studies. In view of the initial non-significant mortality difference at 30 days, a surprisingly high 39% relative mortality difference was observed at one year. There is an absolute benefit of 132 lives saved for every 1000 patients treated with invasive therapy. The results were also hiding some more surprises: interventional therapy was only effective in patients younger than 75 years of age. However, one has to keep in mind that the study was not designed to investigate the influence of age differences. In this trial, all centres that participated were properly equipped for coronary interventions and had welltrained staff. They achieved a median time from treatment to the first revascularization attempt of 0.9 h for angioplasty and 2.7 h for bypass surgery. In the real world, it will be quite difficult to reach these short treatment periods. The relatively low mortality rate, observed in patients who followed medical treatment, is probably due to the natural selection (median time of randomization: 12 h after infarction) in addition to the extensive use of IABP (86%), as well as the use of thrombolysis (63%) and delayed revascularization (25%). Data from other large retrospective studies usually show a much more limited use of these therapies.

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Fig. 7.3 Survival estimates for early revascularization (n=152) and initial medical stabilization (n=149) groups. Logrank test P=0.04. ERV indicates early revascularization group: IMS, initial medical stabilization group. Source: Hochman et al. (2001).

The outcome of the present study should urge cardiologists to be as aggressive as possible in AMI patients with cardiogenic shock. Recent magnitude of and temporary trends (1994–1997) in the incidence and hospital death rates of cardiogenic shock complicating acute myocardial infarction: the second National Registry of Myocardial Infarction. R Goldberg, J Gore, C Thompson, J Gurwitz. Am Heart J 2001; 141(1): 65–71. BACKGROUND. The authors present data from the Second National AMI (US) Registry and analyse the incidence, in-hospital mortality and treatment of cardiogenic

shock complicating AMI. This registry is very large and observational. It was conducted in the years 1994–1997 and enrolled 426 253 patients with AMI. These patients were admitted in 1662 US hospitals. The incidence of cardiogenic shock after AMI was 6.2% (n=26 280). A small reduction of the shock incidence was observed during these years: from 6.6% in 1994 to 6% in 1997. Patients admitted in the later years also had a lower risk profile of developing shock during admission. A marked difference in mortality was seen between the patients not in shock (10%) and those in shock (74%). Patients who developed shock had a significant, albeit small, absolute difference in the risk of dying after cardiogenic shock over time (76% mortality in 1994 to 72% mortality in 1997). When adjusting for risk factors, the improvement appeared to be more significant (odds ratio 0.79, 95% confidence interval 0.71–0.87). Of the patients dying from cardiogenic shock (n=19 467), only 12.8% had PCI, while of those patients surviving this complication (n=6 813), 43.9% underwent PCI (P<0.001). INTERPRETATION. In this registry, a small decline in the incidence of cardiogenic shock and some reduction of the in-hospital mortality was found during years 1994 to 1997. Despite these trends, it remains of considerable importance to prevent this clinical syndrome, given its high lethality.

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Comment The very large number of patients and centres included in this registry ensures that the results represent daily practice. Nearly 1/4 of all US hospitals participated in this registry. The incidence of cardiogenic shock was 8.1% for patients with ST-segment elevation and 4.9% for patients with non-ST-segment elevation (6.2% overall). This is consistent with other non-randomized trials in US and the randomized GUSTO I in the US centres (8.2%), but is significantly higher than that found in nonUS centres in GUSTO I (6.2%), and in GUSTO III (US, 5.7% and non-US centres, 5.4%). One has to realize that the GUSTO trials included only patients with ST-segment elevation (or bundle branch block) and not with ST-segment depression. Among the 26 280 patients with cardiogenic shock, 7317 (28%) had shock at the time of admission while the remainder developed shock thereafter. The patients dying due to cardiogenic shock were significantly older, more likely to be female, and had selected co-morbidities present. In terms of treatment, these patients were less likely to have received angiotensin-converting enzyme (ACE) inhibitors, aspirin, beta blockers, and calcium channel blockers. Patients surviving cardiogenic shock had an almost three times higher chance of having undergone PCI than the ones who died. Thrombolytic agents were given to a significantly lower proportion of patients dying than those surviving cardiogenic shock. The reasons for the progressive improvement in hospital survival (especially after adjustment) remain unclear. It might be explained by changes in the natural history of AMI or cardiogenic shock with less severely ill cases identified earlier in the course of the illness. Indirect evidence suggests that the more aggressive treatment and especially PCI is at least partly responsible for that improvement. The fact that patients surviving cardiogenic shock underwent revascularization much more often than the ones who died (67.8% vs 19.3%) points towards this explanation but at the same time, the outcome difference is severely hampered by the strong selection bias. IABP therapy has been shown to result in initially favourable clinical and haemodynamic responses; however, in the majority of the studies in which this intervention was used, death among patients was merely delayed. In the present study, there was a small increase in the use of IABP over time. Early coronary angioplasty for acute myocardial infarction complicated by cardiogenic shock: have novel therapies led to better results? R Moreno, E Garcia, M Abeytua, et al. J Invasive Cardiol 2000; 12(12): 597–604. BACKGROUND. The progress made in patients with AMI and cardiogenic shock treated with PCI is examined during the years 1991–1999. Also the role of adjuvant therapies and operators’ experience in the improvement made is assessed. From 1991 to 1999, in Gregorio Hospital in Madrid, Spain, 792 patients were treated with PCI within 12 hours of symptom initiation, 94 of them had cardiogenic shock not caused by mechanical complications. These 94 patients are the subject of this study. The only baseline characteristics, that significantly changed from patients treated before 1994 and after 1997, was age (an age increase from 65.7±11.9 years before 1994 to 68.3±11.5 years in 1998–1999, P<0. 004) and location of the infarction (from 80% anterior location before 1994 to 59% anterior in 1998– 1999, P<0.01). The operators’ experience also increased progressively. Before 1994, a successful angiographic procedure (<50% residual stenosis and TIMI 2 or 3 flow) was achieved in 72.3% (<50% stenosis and TIMI 3 flow in 36.4%). During 1998 and 1999 there was an impressive improvement in angiographic outcome observed: 94.1% TIMI 2 or 3 flow and 76.5% TIMI 3 flow. An important increase was observed in the use of stents and GP llb/llla agents (mainly abciximab) during the years. There was no significant change in the use of IABP (68.1% overall).

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Despite this, in-hospital mortality did not change significantly for the periods examined. Overall mortality was 63.8%. There was also no statistically important difference in mortality between stenting (used in 51.1% of patients) and balloon angioplasty. In a univariate analysis, patients treated with abciximab (8.5%) had statistically significant lower in-hospital mortatity, but in a multivariable analysis this was not independently associated with a better in-hospital survival. In the multivariable analysis, the factors, which independently influenced in-hospital mortality, were: age >60 years (mortality for patients ≥ 50 years, 16.7%; 50–60 years, 45.5%; >60 years, 72.7%), multivessel disease, non-inferior location and TIMI grade <3 flow after angioplasty (55.7% mortality for TIMI 3 flow vs 78.8% for TIMI <3 flow, P=0.023).

INTERPRETATION. In patients with AMI and cardiogenic shock, the adjuvant therapies like stenting and abciximab combined with improved operators’ experience have led to higher rates of angiographic success and TIMI 3 flow. However, these did not result in a better in-hospital survival.

Comment The overall in-hospital mortality observed is relatively high compared to other retrospective trials. This can partly be explained by the more strict enrolment of a blood pressure criterion of <80 mmHg in this study (commonly, a blood pressure of <90 mmHg is used to define shock). It would be useful to know the percentage of patients with AMI that developed shock, as well as the mortality in patients with cardiogenic shock not treated by PCI, but such data were not given in the article describing this study. Limitations of the study are the non-randomized, retrospective nature, the single centre participation and the small number of patients enrolled: For example, the shock group admitted before 1994 consisted of 11 patients and the shock group admitted in 1998 or 1999 of 17 patients. Nevertheless, the results are in general consistent with those of other non-randomized trials. They indicate that in cardiogenic shock patients no important decrease in mortality is achieved in spite of optimizing catheter-based interventions. References 1.

2.

3. 4.

Ellis SG, Ribeiro da Silva E, Heyndrickx G, Talley JD, Cernigliaro C, Steg G, Spaulding C, Nobuyoshi M, Erbel R, Vassanelli C, et al. for the Rescue Investigators. Randomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 1994; 90: 2280–4. Global Use of Strategies To Open occluded arteries (GUSTO) IIb Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336:1621–8. Vakili B, Kaplan R, Brown D. Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York State. Circulation 2001; 104:2171–6. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, Buller CE, Jacobs AK, Slater JN, Col J, McKinlay SM, LeJemtel TH, for the SHOCK (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK) Investigators. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. N Engl J Med 1999; 341:625–34.

Part III Stents

8 Stent versus angioplasty: indication for stents in stable

Introduction In recent years technological advances in stent design and pharmacological developments in antithrombotic regimens has lead to the widespread use of stenting in interventional cardiology for patients with stable coronary artery disease. As a result of two landmark clinical trials in stable coronary artery disease |1,2|, the elective use of stenting in focal de novo lesions (>3 mm diameter) iae seen proven to be superior to percutaneous transluminal coronary angioplasty (PTCA) in terms of increased procedural success, lower rates of angiographic restenosis and target vessel revascularization up to one year of follow-up. However, whether these early benefits may be extrapolated to the long term is unknown. Review of the interventional literature in 2001 sees the publication of long-term follow-up data of the outcome of stenting versus angioplasty in the Benestent-I trial and the database of the Department of Veterans Affairs medical centres. The use of elective stenting in small coronary arteries (<3 mm diameter) remains controversial because of lower primary success and more frequent major cardiac adverse events with PTCA alone due to higher rates of restenosis and thrombosis |3|. This, together with uncertainty about the long term results of stents in small vessels, has led thus far to a recommendation that stents should not be used in small vessels to improve long-term results |4|. However, as small coronary arteries may represent over a half of interventional practice in some series |5| a clear rationale exists for the potential benefit of stenting in this clinical group to improve outcome. The year 2001 has seen the publication of three randomized trials to try and clarify this area further. The three papers are first individually discussed and then the results of all three are compared and contrasted in a linking final paragraph. Although coronary stents clearly reduce the rates of clinical and angiographic restenosis in selected patients they remain costly and are associated with in-stent restenosis which remains difficult to treat. Despite a move in recent years towards elective stenting for stable coronary disease there still remains a role for provisional stenting as the achievement of a stent-like balloon result in a low-risk patient may yield equivalent clinical results to stenting. Indeed, the Benestent-I trial investigators showed that patients with stent-like angiographic results, defined as residual stenosis≥ 30% with no major dissection, had clinical and angiographic outcomes similar to stented patients |6|. This important concept is explored further in the paper by Cantor and colleagues which analyses how baseline and angiographic characteristics may be used to

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select a sub-group of patients for whom a provisional stenting strategy would be most appropriate with significant cost-saving implications. Finally, this chapter includes the European Antiplatelet Stent Investigation (EASI) group experience with the Cordis Tantalum Coil Stent comparing results to conventional angioplasty from pooled PTCA and Benestent-I data. Continued benefit of coronary stenting versus balloon angioplasty: five-year clinical follow up of Benestent-I trial. F Kiemeneij, P Serruys, C Macaya, et al. J Am Coll Cardiol 2001; 37(6): 1598–1603. BACKGROUND. The Benestent-I trial was a randomized study comparing elective Palmaz-Schatz stent implantation with balloon angioplasty in patients with stable angina pectoris and a single de novo lesion in a native coronary artery. In 516 patients at seven months there was a lower incidence of restenosis and major adverse cardiac events and a reduced need for repeat interventions was found at one-year follow-up. This study sought to establish whether the favourable early results were maintained at five-year follow-up. Patients were followed up and clinical information obtained at the outpatient clinic, by telephone interview or via the referring physician. Primary clinical end-points included death (regardless of cause), cerebrovascular accident, Q wave myocardial infarction (MI), non-Q wave MI (twice upper limit of normal rise in serum creatine kinase), coronary artery bypass surgery (CABG) or a repeat percutaneous coronary intervention (PCI) involving the target lesion. Secondary clinical end-points were anginal class and current medication use. Five year follow-up data were available from 511 patients included in the study: 256 were randomized to stent implantation and 256 to PTCA (one patient lost to follow-up). There was no statistical difference in combined primary clinical end-points between groups at five years. However, the reduced need for repeat PTCA was maintained in the stent group (17. 2% vs 27.3%; relative risk [RR] 0.63; 95% confidence interval [CI] 0.45 to 0.88; P=0.008). There was no difference in anginal class or medication usage between the two groups except for the use of nitrates which was significantly lower in the stent group (P=0.002). INTERPRETATION. The main conclusion of the five-year follow-up of this landmark study is that the early one-year advantage in reduced need for repeat PTCA is maintained at long-term follow-up. However, there was no difference between the two groups in terms of major adverse cardiac or cerebrovascular events or mortality.

Comment The Benestent-I trial is the longest follow-up of elective stenting so far reported and is a testimony to the long-term stability of coronary stenting once the ‘risk period’ for clinical restenosis is over. The importance of this ‘risk period’ is highlighted by the fact that the initial reduction in major adverse cardiac events seen in stented patients at seven months was not maintained at twelve months. The results are even more striking when one considers that stent implantation was performed before newer generation antiplatelet agents, e.g. ticlopidine or clopidogrel, were available. All patients receiving stents in the Benestent-I study were anticoagulated with warfarin for 3 months. Five-year event-free survival Kaplan-Meier curves for patients enrolled in the Benestent-1 trial are shown in Figure 8.1. Comparison of outcomes of coronary stenting versus conventional coronary angioplasty in the Department of Veterans Affairs medical centres. F Maynard, S M Wright, N R Every, J L Ritchie. Am J Cardiol 2001; 87: 1240–5.

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Fig. 8.1 Five-year event-free survival Kaplan-Meier curves for patients enrolled in the Benestent-1 trial assigned to stenting (white line) versus balloon angioplasty (black line). Source: Kiemeneij et al. (2001). BACKGROUND. This study compared the short-and long-term benefit of coronary stenting versus conventional angioplasty in 27 355 patients from the Department of Veterans Affairs medical centres undergoing PCI during a five-year period between October 1994 and September 1999. The study population was divided into two groups of patients, one with a primary diagnosis of acute MI (n=6072), and a non-MI group. 52% of patients in the MI group and 48% in the non-MI group received stents. More multivessel procedures were performed in the stented MI and non-MI groups (P<0.00019). The

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non-MI group included patients with a clinical diagnosis of both stable and unstable angina. Stepwise logistic regression was used to compare hospital mortality, same admission CABG, rehospitalization and survival. In the non-MI group hospital mortality did not differ between stent and PTCA groups but same admission CABG was significantly less in the stented group (1.2% vs 3.3%, P<0.0001) after adjustment for age and comorbidity. Two-year rehospitalization rates for PCI, CABG and unstable angina were lower in the stent group (P<0.0001). Two-year survival was also better for stenting in veterans 92% vs 91% (P=0.008). INTERPRETATION. In veterans without a clinical admission diagnosis of MI those who underwent coronary stenting had the same in-hospital mortality, reduced rates of same-admission CABG, and at two years marginally better survival and lower rates of rehospitalization.

Comment This retrospective analysis of registry data from the Veterans Affairs medical centres gives an interesting historical perspective on the elective use of stents during a five year period between 1994 and 1999 in lowand high-risk patients. The enormous numbers of patients involved in this study leads to a number of significant P values which clearly need to be interpreted with caution. For the purpose of the chapter title the focus of the results of the paper is with the lower-risk non-MI group which included patients with stable angina pectoris. Unfortunately clinical Table 8.1 Two-year rehospitalization rates for patients without MI undergoing PCI in the Veterans Affairs medical centres’ database between 1994 and 1999 Outcome

Stent

No Stent

Unadjusted P value

Adjusted P value

PCI Coronary artery bypass surgery AMI Unstable angina Congestive heart failure Any rehospitalization Source: Maynard et al. (2001).

14.1% 5.0% 7.0% 22.1% 11.8% 54.6%

16.7% 7.7% 7.3% 28.7% 12.7% 65.9%

<0.0001 <0.0001 0.24 <0.0001 0.002 <0.0001

<0.0001 <0.0001 0.21 <0.0001 0.053 <0.0001

details of patient sub-groups in the non-MI group are not available for scrutiny. However, the two-year results of reduced rehospitalization for repeat PCI, CABG or unstable angina are in keeping with the Benestent-I five-year follow up study. This is shown in Table 8.1. An important criticism of this study is the small number of women (<2%) included in the study so that the conclusions may not be extrapolated to the female population. Stenting in small coronary arteries (SISCA) trial. A randomized comparison between balloon angioplasty and the heparin-coated beStent. R Moer, Y M Myreng, P Molstad, et al. J Am Coll Cardiol 2001; 38(6): 1598–1603. BACKGROUND. Problems associated with small vessel stenting may be overcome by the use of modern technology stents and effective antiplatelet therapy. The SISCA trial is a randomized, controlled trial involving 5 Scandinavian centres comparing elective stenting with PTCA in small coronary arteries with a reference diameter of 2.1–3.0 mm.

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145 patients were randomly assigned to elective stenting (n=74) with the heparin (Hepamed)-coated 15 mm beStent or PTCA (n=71). Patients with stable angina comprised 74% and 78.9% of stent and PTCA groups respectively. Repeat angiography was performed at 6 months. The primary end-point was the minimal luminal diameter (MLD) derived by on-line quantitative coronary angiography (QCA) at follow-up. Secondary end-points included the restenosis rate, event free survival and angina status. Ten patients in the PTCA group (14%) crossed over to stenting because of a residual stenosis after PTCA of >50%. Primary end-point results showed a non-significant trend toward greater MLD (1.69±0.52 vs 1.57 ±0.44, P=0.096) and restenosis (9.7% vs 18.8%, P=0.15) in the stented group than the PTCA group at six months. Event-free survival at follow-up was significantly higher in the stent group (90.5% vs 76.1%, P=0.016).

INTERPRETATION. Stenting and PTCA of small coronary arteries is associated with a good clinical outcome. Moreover, stenting is associated with superior event-free survival at six-month follow-up despite a non-significant trend toward angiographic improvement.

Comment This study planned to recruit 200 patients in each arm but was terminated prematurely because of expiration of the biological activity of the heparin coating. Intention to treat analysis of the angiographic outcome at follow-up showed a significant benefit of stenting, with respect to net gain and diameter stenosis and the authors interpret this as a possible Type II error in statistical analysis related to the premature trial termination. What is remarkable in this trial is the very low reported rates of angiographic restenosis, much lower than previously published in small stent trials |7|. The authors attribute this to the ‘clinical and lesionspecific characteristics of the study group’ which excluded type C lesions and total occlusions. The point is also made that the pre-procedural baseline diameter stenosis of the lesions was mild at most (stent 59.4±9.9, PTCA 57.4±8.9). However, as there is no evidence to suggest that the degree of restenosis is related to the initial lesion diameter stenosis these results remain surprising. Stent placement compared with balloon angioplasty for small coronary arteries trial. In-hospital and six-month clinical and angiographic results. R Koning, H Eltchaninoff, P Commeau, et al. for the BESMART (BeStent in small arteries) trial investigators. Circulation 2001; 104:1604–8. BACKGROUND. This French large-scale multicentre (21), prospective randomized trial compared the outcome of stenting small vessels (<3 mm diameter) with standard balloon angioplasty. A total of 381 symptomatic patients were randomized to either stent implantation (192 patients, 197 lesions) or PTCA (189 patients, 198 lesions) for de novo lesions in native coronary arteries. Patients with stable angina comprised 38.5% and 41.2% in stent and PTCA groups respectively. Patients with ostial and/or bifurcation lesions and an ejection fraction <30% were excluded. Crossover to stenting occurred in 22. 7% in the PTCA group. The BeStent Small (Medtronic Inc) was used in all cases and all lesions to be stented were first pre-dilated with a 2.5 mm or 2.75 mm non-compliant balloon. The primary end-point was the angiographic restenosis rate at 6 months as determined by QCA. Secondary endpoints included procedural success (angiographic success without significant major adverse cardiac event [MACE]) and MACE at six-month follow-up. After the procedure a larger acute gain was achieved in the stent group resulting in a greater MLD. In-hospital clinical events did not differ between stent and PTCA groups. Results at six months showed a significant reduction in restenosis in the stent group (21% vs 47%, P=0.

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0001). Target vessel revascularization rate at six months was also less frequent in the stent group (13% vs 25%, P=0.0006).

INTERPRETATION. Elective small vessel stenting of de novo lesions is safe and effective resulting in a marked reduction in restenosis and target vessel revascularization at six months.

Comment This study provides convincing data for the use of elective stenting for de novo lesions <3 mm in diameter. The impressive results with stenting occur despite the fact that diabetics were over-represented in the stent group (22% vs 12%, P=0.008) and the inclusion of type C lesions in the study group. This study also included a significant number of high-risk patients with a clinical diagnosis of unstable angina (50% in the stent group, 42.8% in the PTCA group). Stent placement to prevent restenosis after angioplasty in small coronary arteries. S Doucet, M J Schalji, M C M Vrolix, et al. for the Stent In Small Arteries (SISA) Trial Investigators. Circulation 2001; 104:2029–33. BACKGROUND. This is another multicentre randomized controlled trial of stenting versus PTCA in small vessels <3 mm diameter using the heparin coated beStent. This study organized from the Montreal Heart Institute only included patients with stable angina, stabilized unstable angina or documented silent ischaemia requiring PCI of one de novo lesion with reference-vessel diameter >2.3 mm and <2.9 mm by QCA. 351 patients were randomly assigned to PTCA alone (n=182) or stent implantation (n=169). Follow-up angiography was performed at six months. The primary end-point was angiographic restenosis at six months. Secondary end-points included MACE (death, MI, CABG and target vessel revascularization) in-hospital and at six months. Crossover to stent occurred in 37 (20.3%) of the PTCA group. Despite an immediate post-intervention gain in luminal diameter the MLD at six months did not differ between groups. There was a non-significant reduction in restenosis in the stented group compared to the PTCA group (28% vs 32.9%, P=0.36). Rates of in-hospital and six month MACE did not differ between groups although there was a trend toward fewer in-hospital events in the stent group (3% vs 7.1% in PTCA group, P=0.076). INTERPRETATION. Stenting and PTCA are associated with equal rates of angiographic restenosis at six months without significant differences in early (in-hospital) or late MACE.

Comment This is essentially a negative study which concludes that both stenting or PTCA of small lesions is safe (low in-hospital clinical events) but with equivalence in terms of angiographic restenosis or MACE. The continued controversy of small vessel stenting Two previously published randomized studies of small vessel stenting yielded conflicting results in terms of anti-restenotic potential |7,8| so with the publication in 2001 of these 3 studies outlined above are we any wiser? Unfortunately these studies fail to clarify the situation further. All three (SISCA, BESMART and SISA) are similar in their design with follow-up angiography in the majority at six months. The end-points although defined differently in the studies are essentially the same, comprising six month angiographic

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restenosis as the primary end-point and early and late MACE as the secondary. The clinical, lesion-specific characteristics and outcomes of these three trials are summarized in Table 8.2. BESMART and SISA enrolled similar patient numbers but SISCA had to be terminated early with fewer patient numbers which is its major weakness. BESMART included considerably more high-risk patients with unstable angina than the other two studies. Lesion length appears similar in all three studies. However, in BESMART lesions undergoing PCI were smaller in reference diameter with a more significant baseline diameter stenosis than in SISCA and SISA. SISA is essentially a negative study. So what can we deduce from these findings? BESMART provides convincing evidence for the superiority of stenting small arteries of about 2.2 mm in diameter of at least moderate degree stenosis but perhaps there is an additional as yet poorly understood benefit of small vessel stenting in the context of unstable angina. Unfortunately the results from SISCA and SISA mean that this area will remain controversial but worthy of further investigation. Achieving optimal results with standard balloon angioplasty: can baseline and angiographic variables predict stent-like outcomes? W Cantor, A S Hellkamp, E D Peterson, et al. J Am Coll Cardiol 2001; 37(7): 1883–90. BACKGROUND. Coronary stents reduce the need for repeat revascularization but are costly and can lead to in-stent restenosis which is difficult to treat. However, achieving a stent-like result from standard PTCA in patients at low risk of repeat revascularization may remove the need for a stent. The authors pooled data from five interventional trials (CAVEAT, EPIC, IMPACT-II, MARCATOR and PBC) and analysed patients with an optimal PTCA result (<30% residual stenosis without dissection) in order to determine the multivariable predictors of repeat revascularization. Clinical follow-up data for the five trials was available for at least six months. A total of 5146 patients who underwent standard PTCA were available for analysis. Multivariate logistic regression was performed to determine independent predictors of repeat revascularization at six months in 18% of cases in which there was an optimal (stent-like) PTCA result. The repeat revascularization rate was lower for patients with a stent-like PTCA result (20% vs 26%, P<0.001). Independent predictors of repeat Table 8.2 Comparison of clinical, lesion-specific characteristics and outcome of the SISCA, BESMART and SISA trials. Year rehospitalization rates for patients without MI undergoing PCI in the Veterans Affairs medical centers’ database between 1994 and 1999 SISCA

No. of patients Unstable angina Lesion characteristics

Crossover to stent Angiographic restenosis

RD DS Length

BESMART

SISA

STENT

PTCA

STENT

PTCA

STENT

PTCA

74 26% 2.44±0.35 59.4±9.9 11.8±4.5

71 21% 2.38±0.32 57.4±8.9 10.8±4.3 14% 19%

192 50% 2.23±0.36 68±12 9.1±4.0

189 43% 2.24±0.34 66±12 9.6±4.6 23% 50%

169 29% 2.5±0.37 62.8±10.9 10.8±4.2

182 34% 2.45±0.34 61.9±11.1 10.2±4.1 20% 33%

10% 24% NS P=0.0001 MACE early NS NS late P=0.016 P=0.0006 RD=reference diameter (mm), DS=diameter stenosis (%), Length=lesion length (mm). Source: Moer et al. (2001), Koning et al. (2001), Doucet et al. (2001).

28% NS NS NS

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revascularization included female gender, lesion length >10 mm and proximal left anterior descending coronary artery lesions. In the study cohort only 8% of patients had an optimal PTCA result without these risk factors, with repeat revascularization and target vessel revascularization rates of 14% and 8% respectively, similar to the rates seen in stent trials. The authors went on to perform a cost-effectiveness analysis comparing the six month costs of an elective stenting strategy (all patients stented) versus PTCA in this sub-group. They concluded that this strategy of patient selection based on clinical and angiographic criteria could represent a potential saving of $78 million based on current stent costs. INTERPRETATION. Optimal (stent-like) PTCA in a small sub-group of patients defined by clinical criteria associated with a low risk of repeat revascularization leads to an equivalent outcome when compared to elective stenting. This strategy of selection of patients for PTCA alone can lead to a significant cost saving over a six month period without the potential hazards of in-stent restenosis associated with elective stent deployment.

Comment This is a very interesting study which argues that in up to 8% of patients where a stent-like result is achieved in the absence of three simple clinical criteria, the outcome can be equivalent to that of elective stenting. Table 8.3. shows six month clinical outcomes with and without stents and Table 8.4. shows the predictors of repeat revascularization examined at six months. This provides useful practical advice to the clinical cardiologist working in the ‘real world’ where in many countries financial restraints on stent usage are an important concern in clinical practice. However, a word of caution may be extrapolated from the long-term stent versus PTCA data from Benestent-I. Although there is an equivalence at six month followup in this study the message from Benestent-I is of a superiority of stents over PTCA in terms of long-term freedom from repeat revascularization. An important question therefore is whether this sub-group is also equivalent to stenting in terms of long-term follow-up. This remains to be seen. Table 8.3 Six month clinical outcomes with and without stent-like results

Death Myocardial infarction Repeat angioplasty Bypass surgery Any repeat revascularization Composite of above Data are presented as percentage (95% CI). Source: Cantor et al. (2001).

Stent-like result (n=938)

No stent-like result (n=4208)

P value

0.4% (0.0–0.9) 3.6% (2.4–4.8) 17.1% (14.7–19.5) 4.4% (3.1–5.8) 20.0% (17.5–22.6) 22.0% (19.3–24.6)

0.6% (0.3–0.8) 5.6% (4.9–6.3) 21.0% (19.7–22.2) 6.6% (5.8–7.3) 25.5% (24.1–26.8) 27.6% (26.3–29.0)

0.6 0.009 0.007 0.11 <0.001 <0.001

Table 8.4 Predictors of repeat revacularization at six months Univariable

Multivariable

Factor

Odds ratio (95% CI)

P value Odds ratio (95% CI)

P value

Age (per 10-year increase) Female gender Diabetes

1.12 (0.97–1.30) 1.88 (1.34–2.64) 1.14 (0.77–1.69)

0.13 <0.001 0.50

0.01

1.67 (1.12–2.48)

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Odds ratio (95% CI)

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Multivariable P value Odds ratio (95% CI)

Congestive heart failure 0.63 (0.26–1.53) 0.31 Unstable angina 1.16 (0.80–1.66) 0.44 Prior infarction 0.71 (0.52–0.99) 0.04 0.68 (0.46–1.01 Multivessel disease 1.09 (0.78–1.53) 0.62 Proximal left anterior descending lesion 1.46 (1.01–2.12) 0.04 1.62 (1.06–2.47) Ostial lesion 0.99 (0.58–1.70) 0.97 0.87 (0.50–1.52)† Total occlusion 0.79 (0.35–1.82) 0.59 Calcification 1.26 (0.86–1.86) 0.24 1.11 (0.71–1.73)† Length ≥ 10 mm 1.61 (1.05–2.47) 0.03 1.62 (1.04–2.51) Reference vessel diameter* 1.10 (0.76–1.61) 0.61 Pre-procedural minimum luminal diameter* 1.02 (0.54–1.93) 0.95 Pre-procedural percent diameter stenosis* 1.00 (0.99–1.01) 0.95 Post-procedural minimum luminal diameter* 1.03 (0.61–1.73) 0.91 Post-procedural percent diameter stenosis* 1.02 (0.99–1.04) 0.14 1.02 (0.99–1.04)† *Per one-unit increase in the covariate value. †Variables ‘forced’ into multivariate model. Source: Cantor et al. (2001).

P value

0.05 0.03 0.63 0.66 0.03

0.27

Angiographic and clinical one-year follow-up of the Cordis Tantalum Coil Stent in a multicentre international study demonstrating improved restenosis rates when compared to pooled PTCA and BENESTENT-I data: the European Antiplatelet Stent Investigation. M T Rothman, P W Serruys, G Grollier, et al. Cathet Cardiovasc Intervent 2001; 52:249–59. BACKGROUND. This is a prospective non-randomized multicentre observational study designed to evaluate the use of the new Cordis Tantalum coil stent. The authors indicate that this stent has the distinct advantage of being clearly visible under fluoroscopy, facilitating its safe deployment. 275 patients were enrolled from centres from western Europe; 47% had stable angina, 44% had unstable angina, and 9% had evidence of silent ischaemia. Follow-up angiograms were performed at six months and clinical follow-up was available for one year. Primary end-points were MACE defined as

cardiac death, MI (Q wave and non-Q wave), and target vessel revascularization (re-PTCA or CABG) at 1, 7 and 13 months. Secondary end-points were MLD and restenosis rates. Clinical and angiographic outcomes with the Cordis Tantalum stent were compared with PTCA results from a pooled database of the Carport, Mercator, Marcator, and Park studies (CMMP), and the Benestent-I balloon and stent groups. MACE rates at 1, 7 and 13 months were low at 3%, 14%, and 17%, respectively. Procedural success was 96% and subacute thrombosis rate 1.5% in a group of 60% of patients who had American Heart Association/American College of Cardiology (AHA/ACC) type B2 or C lesions. 6 month restenosis rate was 17.3% which is significantly better than that in CMMP (41%, P<0.0001) and the Benestent-I balloon group (33.2%, P<0.0001) and equivalent to the Benestent-I stent group (21.6%, not significant). INTERPRETATION. The Cordis Tantalum coil stent is safe and effective with acceptable long-term outcomes. The angiographic results with this stent are superior when compared to pooled PTCA data from randomized trials and equivalent to trials incorporating a slotted-tube stent.

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Comment This observational study confirms the feasibility of the use of this coil stent in a heterogeneous clinical group of patients who have complex coronary lesions and gives acceptable clinical and angiographic outcome. Previous experience with coil stents has indicated inferiority compared to the slotted-tube variety so it was important to show equivalence in this study. The weakness of course is that this study was not randomized and there are clearly some methodological concerns regarding the evaluation of MLD in the context of a radio-opaque stent. However these are discussed in detail by the authors. Table 8.5 shows the comparison of the Cordis Tantalum coil stent with pooled PTCA and Benestent-I data. Table 8.5 Comparison of restenosis with the Cordis Tantalum coil stent with pooled PTCA (CMMP) series and Benestent-I EASI

CMMP

BENESTENT-I balloon group

BENESTENT-I stent group

Number Vessel size (mm) MLD pre (mm) MLD follow-up (mm)

249 2.91±0.44 1.07±0.28 1.99±0.69

Diameter stenosis follow-up (%) Restenosis rate (%)

35.5±19

244 2.90±0.43 1.06±0.27 1.52±0.56 (P<0.0001) 47.7±18.1 (P<0.0001) 41.0 (P<0.0001)

229 3.01±0.46 1.07±0.31 1.72±0.56 (P<0.0001) 43.5±15.9 (P<0.0001) 33.2 (P<0.0001)

236 2.98±0.45 1.08±0.33 1.82±0.64 (P<0.0002) 38.4±18.5 (P<0.0029) 21.6

17.3

*Values are mean±SD. Source: Rothman et al. (2001).

Conclusion So what are the main messages from research into the angioplasty versus stent debate in stable coronary artery disease? What is clear is that the ongoing evolution in stent technology, particularly with the exciting development in drug-eluting stents to prevent restenosis, will increasingly shift the paradigm toward stenting and this is broadly backed up by the data. As shown in the Benestent-I study, stents have been proven to be safe, are easy to use and as shown in the five-year follow-up study in this chapter, derive longterm benefit in terms of a reduced need for target vessel revascularization. This is supported by the two-year follow-up data in the Veterans Affairs study which, although it included stable and unstable angina patients, showed a reduced need for rehospitalization and even a marginal but significant beneficial effect on mortality. The debate about small vessel stenting versus angioplasty remains ongoing despite data from three randomized studies. The two comparable studies BESMART and SISA are clearly in conflict despite subtle differences in study characteristics. Despite the statistically negative findings in SISA there was a trend toward fewer in-hospital events. Longer-term data and further studies may yet yield a definitive answer. The message from the study by Cantor et al. is that there still remains a place for provisional stenting in a sub-group of patients with a stent-like result who may be further divided into low-risk by adopting simple clinical criteria. The result is clinical equivalence in terms of outcome with important potential financial implications.

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Finally, will 2001 herald the comeback of the coil stent? Scepticism based on initial data implying inferiority of the original Wiktor coil stent compared to its slotted-tube counterparts |9| may be dispelled by the findings of the EASI study investigators who cite very acceptable outcomes in their evaluation of the Cordis Tantalum coil stent. However, what is now needed is a randomized controlled trial to further test these encouraging results. References 1.

2.

3. 4. 5. 6. 7.

8.

9.

Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med1994; 331:489–95. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994; 331:496–501. Schunkert H, Harrel L, Palacios IF. Implications of small reference vessel diameter in patients undergoing percutaneous coronary revascularization. J Am Coll Cardiol 1999; 34:40–8. Holmes DR Jr, Hirshfeld J Jr, Faxon D, Vlietstra RE, Jacobs A, King SB 3rd. ACC expert consensus document on coronary artery stents. J Am Coll Cardiol 1998; 32:1471–82. Foley DP, Melkert R, Serruys PW. Influence of coronary vessel size on renarrowing process and late angiographic outcome after successful balloon angioplasty. Circulation 1994; 90:1239–51. Foley DP, Serruys PW. Provisional stenting—stent-like balloon angioplasty: evidence to define the continuing role of balloon angioplasty for percutaneous coronary revascularization. Semin Intervent Cardiol 1999; 1:269–73. Kastrati A, Schomig A, Dirschinger J, Mehilli J, Dotzer F, von Welser N, Neumann FJ. A randomized trial comparing stenting with balloon angioplasty in small vessels in patients with symptomatic coronary disease. Circulation 2000; 102:2593–8. Park SW, Lee CW, Hong MK, Kim JJ, Cho GY, Nah DY, Park SJ. Randomized comparison of coronary stenting with optimal balloon angioplasty for treatment of lesions in small coronary arteries. Eur Heart J 2000; 21: 1785–9. Buchwald A, Unterberg C, Werner G, Voth E, Kreuzer H, Wiegand V. Initial clinical results with the Wiktor stent in acute complications and restenosis after coronary angioplasty. J Intervent Cardiol 1991; 14:374–9.

9 Stent design and coatings

Introduction Coronary artery stents have emerged as the preferred tool for percutaneous coronary interventions during the past decade. Their ubiquitous acceptance results from the ease and speed of applicability, the improved safety by elimination of abrupt closure and the need for urgent coronary artery bypass grafting, and the angiographically pleasing result. The basic principle underlying their therapeutic value is common to all coronary artery stents and consists of: 1. increasing the arterial lumen by scaffolding the arterial vessel wall; 2. tagging of intimal flaps between the stent surface and vessel wall; 3. sealing of dissections. Early efforts in stent development aimed at improving flexibility and deliverability to allow access to an ever-broader array of anatomical lesions without loss of radial strength. Care to deploy stents with circumferential apposition to the vessel wall and the introduction of dual antiplatelet therapy were rewarded by a significant reduction in early stent thrombosis. However, in-stent restenosis emerged as an iatrogenic adverse event in 10–30% of patients and proved therapy resistant with high relapse rates. The pathobiology of restenosis in response to stent implantation became increasingly understood using experimental restenosis models. Stent struts elicit vascular injury by endothelial denudation, intima laceration and media penetration. This results first in platelet and fibrin deposition on the subendothelial matrix within the first 1–3 days, and the extent of vascular injury determines the local thrombotic response. Activated platelets release cytokines and adhesion molecules, which perpetuate inflammatory cell recruitment and migration across the endothelium into the arterial wall during the second phase on days 3–7 after stent implantation. The third phase is characterized by intimal proliferation mediated by migration and proliferation of monocytes and medial smooth muscle cells, production of metalloproteinases degrading the extracellular matrix and thereby facilitating cell migration. The vasculoproliferative cascade following stent implantation observed in experimental restenosis models has been confirmed in human atherosclerotic lesions. Thus, early after stent implantation, fibrin and acute inflammatory cells are omnipresent around stent struts. Beginning 2 weeks after stent implantation a neointima composed of macrophages and α-actin negative spindle cells is formed. This is followed by staged redifferentiation and extracellular matrix

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formation. The healing process is completed by re-endothelialization occurring weeks to months after stent implantation. Two therapeutic avenues emerged from these insights into the pathobiology of vascular repair following stent implantation: 1. Changes in stent design to reduce vascular injury during stent deployment; 2. Coating of the stent surface to attenuate the vasculoproliferative repair cascade. This chapter will review reports relevant to these two strategies published during the last year. Stent design Stent design related neointimal tissue proliferation in human coronary arteries: an intravascular ultrasound study. R Hoffmann, C Jansen, A König, et al. Eur Heart J 2001; 22:2007–14. BACKGROUND. Histological restenosis models in animals have indicated that stent design has a significant impact on vessel trauma during stent implantation and on the amount of subsequent neointimal tissue proliferation. The impact of different stent designs on intimal hyperplasia in human atherosclerotic coronary arteries has not been determined. Angiographic and intravascular ultrasound studies were performed at the six-month follow-up in 131 consecutive native coronary lesions of 131 patients treated with 50 Multi-Link stents, 40 InFlow stents and 41 Palmaz-Schatz stents. Lumen and stent cross-sectional areas (CSA) were measured at 1 mm axial increments. Mean intimal hyperplasia cross-sectional area (stent CSA-lumen CSA) and mean intimal hyperplasia thickness were calculated. Intravascular ultrasound demonstrated different levels of intimal hyperplasia proliferation for the three stents. Mean intimal hyperplasia thickness was 0.16±0.08 mm for Multi-Link stents, 0.26±0.19 mm for Palmaz-Schatz stents and 0.39±0.1 mm for Inflow stents (P<0.001). Multivariate analysis proved that stent type was the only independent predictor of intimal hyperplasia thickness at follow-up (P<0.001). INTERPRETATION. Coronary stent design has a significant impact on subsequent intimal hyperplasia after implantation into atherosclerotic human coronary arteries. The corrugated ring design of the Multi-Link stent proved to result in less tissue proliferation at six-month follow-up than the tubular slotted design of Palmaz-Schatz and InFlow stents.

Comment Less neointimal hyperplasia has been observed in experimental restenosis models following implantation of stents with a corrugated-ring design compared with tubular slotted stents. This finding has been related to the more complex and closed strut area of corrugated-ring stents causing less balloon-mediated endothelial denudation between stent struts and lower surface-contact stress and contact area, suggesting minimized arterial injury compared with the more simple and open slotted-tube stent structure |1|. The present study investigated whether these experimental results with different stent designs could be reproduced in human atherosclerotic arteries. Previous clinical stent-versus-stent equivalency trials using angiography failed to demonstrate significant differences between newer generation stents compared with the reference PalmazSchatz, a tubular slotted stent, except for the less coil resistant Gianturco-Roubin II stent. The investigators of the present study employed intravascular ultrasound allowing for a direct assessment of intimal hyperplasia rather than indirect angiographic measures based on luminal dimensions and late loss. Although

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Fig. 9.1 Plot of the mean±SD of the follow-up intravascular ultrasound intimal hyperplasia CSA over the entire stent length in 1 mm axial increments for the three stent types. Source: Hoffmann et al. (2001).

the study was not randomized and used different stent deployment techniques, the following findings are noteworthy. First the authors demonstrated for the first time in human atherosclerotic arteries that a corrugated-ring design appears to induce less neointimal hyperplasia than tubular slotted stents and therefore translates into clinically relevant differences, which should drive stent selection (Fig. 9.1). Second, the study nicely illustrates the advantages of the more sensitive and specific intravascular ultrasound over angiographic measures of restenosis. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISARSTEREO) trial. A Kastrati, J Mehilli, J Dirschinger, et al. Circulation 2001; 103:2816–21. BACKGROUND. Increased thrombogenicity and the proliferative response of smooth muscle cells induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicentre study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results. A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive one of two commercially available stents of comparable design but different thickness: 326 patients were assigned to the thin-strut stent (strut thickness of 50 μm) and 325 patients to the thick-strut stent (strut thickness of 140 μm)). The primary end-point was the angiographic restenosis (≥ 50% diameter stenosis at followup angiography). Secondary end-points were the incidence of reinterventions due to restenosis-induced ischaemia and the combined rate of death and myocardial infarctions at one year. The incidence of angiographic restenosis was 15.0% in the thin-strut group and 25.8% in the thick-strut group (relative risk, 0.58; 95% CI 0.39–0.87; P=0.003). Clinical restenosis was also significantly reduced, with a reintervention rate of 8.6% among thin-strut patients and 13.8% among thick-strut patients (relative risk, 0.62; 95% CI 0.39–0.99; P=0.03). No difference was observed in the combined one-year rate of death and myocardial infarction (MI). INTERPRETATION. The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting.

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Fig. 9.2 Cumulative distribution curves of diameter stenosis immediately after procedure and at six-month follow-up angiography in both study groups. Although final result in thin-strut group was less optimal than that achieved in thickstrut group (rightward displacement of curve of diameter stenosis immediately after stenting, P=0.03), diameter stenosis at follow-up was significantly reduced in thin-strut vs thick-strut group (leftward displacement of respective curve, P=0. 002). Source: Kastrati et al. (2001).

Comment The number and thickness of the struts of stainless steel stents are important determinants of radial strength, longitudinal flexibility and arterial geometry during deployment |2|. Thus, thicker stent struts are stiffer and provide more radial force for resisting elastic vessel recoil. However, these advantages of thicker stent struts may be offset by a greater degree of vascular injury provoking more neointimal hyperplasia. In addition, experimental data indicate impaired endothelial cell coverage and thus vessel healing of metal surfaces thicker than 75 μm, a phenomenon which has been related to flow disturbances impairing cell attachment. The present study investigated the effect of stent strut thickness on neointimal hyperplasia in human atherosclerotic arteries using angiography. Patients were randomly assigned to either a thin (50 μm) or thick (140 μm) strut stent. The two stents employed in this study were the ACS Rx Multi-Link (thin strut) and ACS MultiLink RX Duet (thick strut), devices with similar design (decreased number of inter-ring articulations for the thick strut stent) and slightly different lengths manufactured by the same company (Guidant). Although the thin-strut stents provided slightly worse acute results with respect to residual stenosis and featured somewhat longer stent lengths, angiographic and clinical restenosis were significantly reduced (by 42%) for these stents (Fig. 9.2). Thus, stent strut thickness emerges as a clinically meaningful determinant of neointimal hyperplasia and target vessel revascularization. Although the study does not provide a mechanism for this beneficial effect, improved vessel healing by means of re-endothelialization and reduced vascular injury is a potential cause. Importantly, the reduced radial force of thin-strut stents did not have a negative impact on subsequent outcome.

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Stent Coatings Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. T Suzuki, G Kopia, S Hayashi, et al. Circulation 2001; 104:1188–93. BACKGROUND. The purpose of this study was to determine the efficacy of stentbased delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits smooth muscle cell (SMC) proliferation by blocking cell cycle progression. Stents were coated with a non-erodable polymer containing 185 μg SRL, 350 μg DEX, or 185 μg SRL and 350 μg DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, n=13; SRL, n=13; DEX, n=13; SRL and DEX, n=8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97±13 ng/artery, with a stent content of 71±10 μg at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47±1.04 mm2 for the SRL alone and 2.42±1.04 mm2 for the combination of SRL and DEX compared with the metal (5.06±1.88 mm2, P<0.0001) or DEX-coated stents (4.31±3.21 mm2, P<0.001), resulting in a 50% reduction of in-stent stenosis. INTERPRETATION. Stent-based delivery of SRL via a non-erodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.

Comment The major long-term limitation of stent implantation into coronary arteries remains neointimal hyperplasia resulting in in-stent restenosis. Experimental data indicate that cell cycle progression is an attractive therapeutic target to address vasculoproliferative disease processes. SRL is a potent immunosuppressive drug and acts as a cell cycle inhibitor of vascular smooth muscle cells by blocking cell progression at the G1/S transition |3|. SRL binds to the cytosolic FK506 binding protein (FKBP12) and forms the SRLFKBP12 complex, which inhibits the kinase called the mammalian target of rapamycin (mTOR). Through an unknown pathway retinoblastoma protein (pRb) phosphorylation is inhibited, while the cyclindependent kinase (CDK) inhibitor p27kip1 is increased. Upregulation of p27kip1 has been recognized as an important mechanism by which SRL inhibits vascular smooth muscle proliferation and migration. While systemic administration of SRL has been shown to significantly reduce neointimal hyperplasia after balloon angioplasty in pig coronary arteries, this route of application is limited by the adverse effects of the drug such as leukopaenia, thrombocytopaenia and hyperlipidaemia. The present study investigated the feasibility of stent-based SRL delivery using a non-erodable polymer matrix and is remarkable for the following findings. First, the non-erodable polymer matrix is biocompatible and does not show signs of excessive inflammation or thrombus formation, previous shortcomings associated with some stent polymers. Second, therapeutic arterial wall concentrations of SRL can be achieved at exceedingly low systemic drug levels utilizing a stent-based delivery. Chronic tissue retention of SRL is enhanced by its lipophilicity and affinity to the FKBP12 cytosolic receptor. Third, SRL results in 50% less neointimal hyperplasia and less inflammation compared with controls at similar degrees of arterial injury (Fig. 9.3). Fourth, stent-based delivered SRL reduces PCNA (proliferating cell nuclear antigen) expression and pRb phosphorylation in the arterial wall, the likely mechanism on cell cycle signalling and proliferation. These findings form the basis of the recent clinical investigation of sirolimus-coated stents in human atherosclerotic arteries.

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Fig. 9.3 Low-and high-power photomicrographs 28 days after oversized stent placement in normal porcine coronary arteries. (a) and (b) (high power) are a bare metal stent with neointimal formation typical for degree of strut-induced medial injury. (c), SRL-coated stent has significantly less neointima vs bare metal stent despite a similar degree of vessel injury. High-power photomicrograph of SRL-eluting stent (d) demonstrates neointima consisting of SMCs and proteoglycans. Note strut-induced focal medial compression without medial necrosis or intimal haemorrhage. Hematoxylin-eosin stain. Magnification: (a) and (c)×2, (b) and (d)×40. Source: Suzuki et al. (2001).

Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. J E Sousa, M A Costa, A C Abizaid, et al. Circulation 2001; 104: 2007–11. BACKGROUND. We have previously reported a virtual absence of neointimal hyperplasia four months after implantation of SRL-eluting stents. The aim of the present investigation was to determine whether these results are sustained over a period of one year. Forty-five patients with de novo coronary disease were successfully treated with the implantation of a single SRL-eluting Bx VELOCITY stent in Sao Paulo, Brazil (n=30, 15 fast release [group I, GI] and 15 slow release [GII]) and Rotterdam, The Netherlands (15 slow release, GIII). Angiographic and volumetric intravascular ultrasound (IVUS) follow-up was obtained at 4 and 12 months (GI and GII) and 6 months (GIII). In-stent minimal lumen diameter and percent diameter stenosis remained essentially unchanged in all groups (at 12 months, GI and GII; at 6 months, GIII). Follow-up in-lesion minimal lumen diameter was 2.28 mm (GIII), 2.32 mm (GI), and 2.48 mm (GII). No patient approached the ≥ 50% diameter stenosis at one year by angiography or IVUS assessment, and no edge restenosis was observed. Neointimal hyperplasia, as detected by IVUS, was virtually absent at 6 months (2±5% obstruction volume, GIII) and at 12 months (GI=2±5% and GII=2±3%). INTERPRETATION. This study demonstrates a sustained suppression of neointimal proliferation by SRLeluting Bx VELOCITY stents 1 year after implantation.

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Comment This study extends the experimentally derived data of SRL-coated stents discussed in the previous paper to the clinical arena. It is the first application of SRL-coated stents to human atherosclerotic arteries and reports angiographic and IVUS investigations beyond the initial assessment after four months reported earlier by the same group of investigators to include data |4| for up to one year. Notably, no single patient reached the>50% diameter restenosis limit at one year. Even more impressive was the near absence of neointimal hyperplasia as assessed by IVUS with a mere 2±5% luminal volume obstruction and virtually no change in intimal hyperplasia compared with the four month results. In contrast to previous experiences with intravascular brachytherapy, no evidence of edge restenosis became apparent. Compared with the 51% reduction in neointimal hyperplasia using SRL-coated stents in healthy porcine coronary arteries, the near complete absence of neointimal hyperplasia as assessed by IVUS in human atherosclerotic arteries is unexpected. While it may simply reflect the reality that even the best experimental model cannot accurately mimic the human condition, temporal differences in the vasculoproliferative process between species also have to be considered.

Fig. 9.4 In-lesion per cent diameter stenosis (%DS) and MLD over a period of 1 year. Angiographic follow-up was performed at 4 and 12 months in group I (GI) and GII and at 6 months in GIII. Source: Sousa et al. (2001).

Although the study population of this pilot investigation was small, the magnitude of therapeutic efficacy in preventing in-stent restenosis in humans is unparalleled and has recently been buttressed by the results of the randomized RAVEL trial enrolling 238 patients (not yet published). These findings are certainly the most important advance since the introduction of coronary artery stents to the armentarium of percutaneous coronary interventional techniques and may well lead to the cure of the self-inflicted restenotic process. The enthusiasm for these findings cannot be overestimated reflecting the relief from despair after nearly a quarter century of inconclusive research efforts. Nevertheless, some limitations and cautions emerge. Looking closely at the minimal luminal diameter, there is a temporal (non-significant) trend towards some late lumen loss at 12 months (Fig. 9.4). One wonders if this trend could become more apparent with longer follow-up periods or be prevented by different drug release kinetics. In this study, one case of late (14 months) stent thrombosis was observed. Although the investigators make the case of an unstable plaque rupture based on intravascular observations during followup examinations, other possible mechanisms such as delayed re-endothelialization cannot be disregarded.

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Finally, only long-term investigations will be able to determine other potential adverse effects such as positive arterial remodelling resulting in aneurysms, perforations, late thrombosis or fibrosis. Gene expression profiling of human stent-induced neointima by cDNA array analysis of microscopic specimens retrieved by helix cutter atherectomy: detection of FK506-binding protein 12 upregulation. D Zohlnhöfer, C A Klein, T Richter, et al. Circulation 2001; 103: 1396–1402. BACKGROUND. Restenosis due to neointima formation is the major limitation of stent-supported balloon angioplasty. Despite abundant animal data, molecular mechanisms of neointima formation have only been investigated on a limited basis in patients. This study sought to establish a method for profiling gene expression in human in-stent neointima and to identify differentially expressed genes that may serve as novel therapeutic targets. We retrieved tissue specimens from patients with symptomatic in-stent restenosis using a novel helix cutter atherectomy device. cDNA samples prepared from neointima (n=10) and, as a control, from the media of normal arteries (n=14) were amplified using a novel polymerase chain reaction protocol and hybridized to cDNA arrays. Immunohistochemistry characterized the atherectomy material as neointima. cDNA arrays readily identified differentially expressed genes. Some of the differentially expressed genes complied with expected gene expression patterns of neointima, including downregulation of desmin and upregulation of thrombospondin-1, cyclooxygenase-1, and the 70kDa heat shock protein B. Additionally, we discovered previously unknown gene expression patterns, such as downregulation of mammary-derived growth inhibitor and upregulation of FK506-binding protein 12 (FKBP12). Upregulation of FKBP12 was confirmed at the protein level in neointimal smooth muscle cells. INTERPRETATION. Gene expression patterns of human neointima retrieved by helix-cutter atherectomy can be reliably analysed by cDNA array technology. This technique can identify therapeutic targets in patients, as exemplified by the findings regarding FKBP12. FKBP12 is the receptor for rapamycin (sirolimus), which in animal models reduced neointima formation. Our study thus yields a rationale for the use of rapamycin to prevent restenosis in patients.

Comment This study demonstrated for the first time in humans the retrieval of in-stent neointimal tissue suitable for subsequent gene expression analysis. Histological analysis of material retrieved from stented coronary arteries showed characteristics of human neointima consisting of smooth muscle cells and loose extracellular matrix-like collagen. Using polymerase chain reaction and cDNA array analysis the expression of 2345 known genes was then compared between neointima derived

Fig. 9.5 Transcription profiles of human neointima and control media. Each column represents a gene expression analysis of a single specimen for 8 highly expressed housekeeping genes (top) and 6 selected genes that show significant upregulation or downregulation in neointima versus control (bottom). Grey values correspond to signal intensities shown at bottom of figure. HLA indicates human leucocyte antigen. Source: Zohlnhöfer et al. (2001).

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from stented coronary arteries and media from control arteries. Twenty-three of the 2345 examined genes met the criteria for differential expression. Fig. 9.5 shows the gene expression profile for six differentially expressed genes with putative relevance to the pathogenesis of neointimal proliferation. Thus, upregulation was found for thrombospondin-1, the 70kDa heat shock protein B, cyclooxygenase-1, and FKBP12, whereas downregulation was present for desmin, and mammary-derived growth inhibitor (MDGI). FKBP12 is the FK506 binding protein and target of rapamycin (SRL). As discussed in two previous articles of this review, rapamycin has been shown to be effective in reducing neointimal hyperplasia in animal models and in humans after coronary stent implantation. Thus, the upregulation of FKBP12 as evidenced in the present study provides a rationale for using rapamycin to prevent in-stent restenosis in humans. This example illustrates the potential of the described technique to identify other therapeutic targets relevant to neointimal proliferation after stent implantation in humans. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. A Farb, P F Heller, S Shroff, et al. Circulation 2001; 104:473–9. BACKGROUND. Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored. Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulphate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 μg of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 μg of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher dose (42.0 and 20.2 μg) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal haemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth to that of uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 μg of paclitaxel. INTERPRETATION. CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days.

Comment Paclitaxel is a promising therapeutic agent for stent-based drug delivery in the prevention of neointimal hyperplasia currently undergoing clinical evaluation. Paclitaxel causes polymerization of tubulin and therefore formation of abnormally stable and non-functional microtubules resulting in cell cycle arrest in the G0/G1 and G1/M phases. In vitro studies demonstrated inhibition of vascular smooth muscle cell proliferation and migration by paclitaxel. The present study investigated the effect of a chondroitin-sulphate and gelatin polymer-coated stent containing 4 different doses of paclitaxel with an uncoated, stainless steel stent and a CSG polymer-coated stent without paclitaxel in rabbit iliac arteries. The CSG polymer was biocompatible without evidence of

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Fig. 9.6 Neointimal thickness 28 days after deployment of CSG-coated stents containing various doses of paclitaxel, CSG-coated stents without paclitaxel, and uncoated bare stents without paclitaxel. Source: Farb et al. (2001).

Fig. 9.7 No reduction in neointimal thickness 90 days after deployment of CSG-coated stents containing 42.0 or 21.0 μg of paclitaxel. Source: Farb et al. (2001).

stent thrombosis or an exaggerated inflammatory response. After 28 days, there was a dose-dependent reduction in neointimal thickness corresponding to a 49% and 36% decrease for the two highest paclitaxel dose regimens, respectively, compared with both stainless steel and CSG-coated stents (Fig. 9.6). However, after 90 days intimal thickness was similar for all surface coatings irrespective of drug dose (Fig. 9.7). Histological studies showed signs of incomplete healing as evidenced by intimal fibrin deposition, intimal and adventitial inflammation, medial necrosis, and increased intimal proliferation for the high dose

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paclitaxel-coated stents. Impaired vascular healing was not present for stainless steel and CSG-coated stents and resolved after 90 days for the high dose paclitaxel-coated stents. The important theme of the present study is that the therapeutic efficacy of paclitaxel in terms of reduced neointimal hyperplasia was associated with vascular toxicity and incomplete vascular healing. Furthermore, the therapeutic effect of paclitaxel was lost at 90 days paralleled by resolution of vascular toxicity. These findings suggest that paclitaxel delays rather than prevents neointimal hyperplasia in response to stent deployment with the tested polymer and dose regimens. The study also underlines the complexity of stentbased drug delivery requiring assessment of the effects of polymers, drug pharmacokinetics and toxicity in addition to efficacy measures. Comparison of the heparin-coated versus the uncoated Jostent: no influence on restenosis or clinical outcome. J Wöhrle, E Al-Khayer, C Schindler, M Kochs, V Hombach, M Höher. Eur Heart J 2001; 22:1808–16. BACKGROUND. Heparin coating of stents is thought to reduce stent thrombosis and restenosis rates. However, clinical data comparing coated and uncoated stents of the same model are lacking. We compared the heparin-coated (C) and the uncoated (U) version of the Jostent® stent with regard to the clinical and angiographic outcome

after six months. Provisional stenting was done in 277 patients and 306 lesions; only 40 were Benestent-II-like lesions. Delivery success rate was 98.4%. Both groups (C/U: n=156/150 lesions) were comparable in clinical and procedural data. Post-stenting, reference diameter (C/U: 2.68±0.56/2.66±0.53 mm) and minimal lumen diameter did not differ (C/U: 2.48±0.47/2.48±0.52 mm). During follow-up the rate of subacute stent thrombosis (C/U: 1.9%/1.3%) and MI did not differ. Angiography at the sixmonth follow-up (79.4%) revealed no difference in restenosis rate (C/U: 33.1%/30.3%). Risk factors for restenosis were a type B2/C lesion (P<0.02), a stented segment longer than 16 mm (P<0.006) and a stent inflation pressure <14 bar (P<0.0063). INTERPRETATION. Corline heparin coating of the Jostent® has no impact on the in-hospital complication rate, stent thrombosis or restenosis. The Jostent® design gives a high procedural success rate and satisfying result at 6 months in an everyday patient population undergoing provisional stenting.

Comment Heparin binds via a specific pentasaccharide sequence on antithrombin (AT) III and acts as a catalyst for accelerating the neutralization of thrombin by AT III. Beyond its potent antithrombotic effects, heparin is also a strong inhibitor of smooth muscle cell proliferation and migration in vitro and has been shown to reduce neointimal hyperplasia in several animal models. The latter property has been attributed to an antiinflammatory effect of heparin. Thus, it has been shown that intravenous heparin infusion reduces early leucocyte infiltration and subsequent neointimal growth following both balloon- and stent-mediated arterial injury. Based on its antithrombotic and antiproliferative properties heparin appears to be the drug of choice for stent-based delivery to both reduce the incidence of subacute stent thrombosis, and reduce in-stent restenosis by its antiproliferative properties. Heparin-coated stents have been investigated in humans in the Benestent-II |5| and Primary Angioplasty in Myocardial Infarction (PAMI)-II studies. They have shown encouraging results with respect to subacute stent thrombosis and reinfarction even in high-risk populations such as those presenting with acute MI, and give acceptable results with respect to restenosis. However, these studies compared a heparin-coated stent

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Fig. 9.8 Cumulative frequency of event-free survival from death, MI or need for revascularization, indicating no difference between the groups with heparin coated and with uncoated stents. Source: Wöhrle et al. (2001).

against balloon angioplasty, and the present study is therefore the first to compare a heparin-coated stent directly to an uncoated, stainless steel stent of identical design in humans. Although the study was not randomized, but compared the coated with the uncoated stent in alternating lots of 50 consecutive stentimplantation procedures, both groups were similar with respect to clinical and angiographic characteristics. Somewhat surprisingly, the heparin-coated stents had no impact on stent thrombosis (1.9% vs 1.3%), major adverse cardiac events (25.2% vs 25.7%), or restenosis (33% vs 30.3%) (Fig. 9.8) compared with uncoated stents. There are several possible explanations for this observation. Firstly, heparin is covalently bound to a stent-based polymer, which prevents its release and diffusion into neighbouring tissue and has a lower ATIII binding capacity. Secondly, all patients were treated with a dual antiplatelet regimen consisting of acetylsalicylic acid and ticlopidine resulting in a low subacute stent thrombosis rate. Thus, the study was underpowered to detect a potentially small difference in stent thrombosis, which might have become more apparent with the use of aspirin alone. Third, the lack of effect of heparin with respect to restenosis could be related to the low heparin activity present on the stent (<1 unit heparin per stent). The role of heparin as a drug for stent-based delivery will require further study of dose and delivery mode. Patients at high risk of reinfarction or stent thrombosis such as those presenting with acute coronary syndromes or coagulation abnormalities might become potential beneficiaries of heparin-coated stents alone or used in conjunction with other drugs. Gold-coated NIR stents in porcine coronary arteries. E R Edelman, P Seifert, A Groothuis, A Morss, D Bornstein, C Rogers. Circulation 2001; 103:429–34. BACKGROUND. As endovascular stents are altered to add functionality, e.g. by adding radiopaque coatings, biocompatibility may suffer. We examined the vascular

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response in porcine coronary arteries to stainless steel gold-coated NIR stents (7-cell, Medinol, Inc). Stents, 9 and 16 mm in length, were left bare or coated with a 7 μm layer of gold. Physical and material effects were examined in four different gold-coated stent types, two at each length that either had the coating applied to the standard strut, i.e. gold coating thicker than controls, or had the coating applied to thinned struts, i.e. gold coating of the same thickness as control struts. Simple gold coating exacerbated intimal hyperplastic and inflammatory reactions over 28 days, but postplating thermal processing smoothed the coating surface and negated the adverse tissue response to gold. The relative amounts of base steel and gold coating and their resistances to expansion and collapse determined the extent of stent recoil. INTERPRETATION. Gold coatings enhance the radiopacity of steel stents, but not without effects on vascular repair. Material effects predominate and can be eliminated by heating coated stents to alter surface finish and material purity. Clinical results may suffer unless consideration is given to material and physical effects of gold.

Comment Gold is a biocompatible element used as a prosthetic material for various implants. Gold coating of stainless steel stents has been shown to reduce platelet adhesion and thrombus mass in vitro, and to result in thinner neointima formation of aortic wall specimens. In addition, gold is more radiopaque than stainless steel and thereby provides improved visibility during fluoroscopy and more precise stent positioning in the target lesion. The present study compared the vascular response of porcine coronary arteries to implantation of uncoated stainless steel stents with gold-coated stents. In all experiments gold-coated stents produced a greater degree of neointimal hyperplasia than their stainless steel counterparts regardless of stent length and strut thickness (standard vs thinned to accommodate additional gold layer). The increased neointimal thickness was accompanied by a higher degree of inflammation as evidenced by the number of multinucleated giant cells and CD45 positive cells. Of note, post-plating thermal processing of gold-coated stents resulted in a smoothed surface structure as shown by atomic force microscopy (Fig. 9.9) and negated the increase in neointimal hyperplasia and inflammation (Fig. 9.10). These findings have been recently corroborated in a clinical study comparing the gold-coated InFlow stent with an uncoated stainless stent of identical design |6|. Of note, the gold-coated stent featured the same strut thickness and width as the uncoated stainless stent. There was no difference in the 30-day major adverse cardiac event rate between gold-coated and uncoated, stainless steel stents (7.9% vs 5.8%) attesting to equivalent technical success and an acceptable incidence of thrombosis events. However, angiographic restenosis was significantly worse for the gold-coated stent (49.7%) compared with the uncoated, stainless steel stent (38.1%). Possible explanations for the adverse vascular response to gold-coated stents include surface breaks and cracks, surface contaminations introduced by the coating process, and removal of the protective oxide layer from stainless steel stents. The adverse effects of gold-coated stents with respect to restenosis and inflammation certainly outweigh the benefit of improved visibility due to enhanced radiopacity and disqualify gold as a stent-coating material unless it undergoes special surface processing. Conclusion Stent coatings were proposed to attenuate the vasculoproliferative repair cascade following stent implantation. Passive coatings provide a biologically inert barrier between the injured vessel wall, the stent

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Fig. 9.9 Extent of neointimal thickness ((a) mm), and degree of inflammation ((b) % porcine CD45-positive cells in neointima) 28 days after implantation of 9-mm stainless steel stents left intact (Bare; open bars), gold-coated NIR stents (Royal; solid bars), and flash-heated post-plated NIR stents (Baked; grey bars). Source: Edelman et al. (2001).

surface and the bloodstream, thus reducing platelet deposition and inflammatory cell invasion thought to be prerequisite for subsequent smooth muscle cell proliferation and migration. They encompass polymers and inorganic coatings such as silicon carbide, gold, titanium-nitride-oxide etc. Active coatings contain drugs released from polymers or directly bound to metal surfaces, which aim to prevent smooth muscle cell proliferation and migration. The obvious advantage of stent-based drug delivery is the direct delivery of the therapeutic agent to the site of action, thus reducing systemic adverse effects. Initial setbacks in developing stent-based drug delivery related mainly to difficulties in developing suitable carrier molecules. However, recent polymer molecules proved suitable for drug binding and elution as well as being biocompatible without provoking an exaggerated inflammatory response of the vascular wall. The most promising therapeutic agents are directed at cell cycle regulating proteins to prevent smooth muscle cell proliferation. Rapamycin (SRL), paclitaxel and actinomycin D induce cell cycle arrest at various stages of the cell cycle. These agents have proved efficacious in animal models of restenosis and are currently under clinical investigation. Most human experience is currently available for rapamycin (sirolimus), which actually outperformed experimental observations with zero percent restenosis at up to one-year follow-up without apparent adverse events. If this is confirmed in larger scale clinical trials, stentbased drug delivery will have a dramatic impact on interventional cardiology. The absence of restenosis would be a tremendous relief for patients, who could not previously be sure of the durability of the intervention. The main shortcoming compared with surgical revascularization, the need for target lesion revascularization, would be eliminated. This would undoubtedly broaden the indications for a percutaneous revascularization strategy, particularly in patients previously considered at high risk of restenosis such as those with small vessel disease, diabetes, long lesions, bifurcations, saphenous vein graft lesions and left main stenosis.

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Fig. 9.10 Three-dimensional atomic force micrographs demonstrate surface topography of gold-coated NIR stents before (a) and after (b) heat treatment. Average roughness of heat-treated stents was less than half of non-heated gold stents (59.9±22.4 vs 154.6±5.4), and mean maximum peak-to-valley excursion was >3-fold lower (86.4±7.7 vs 284.4±3. 9). Source: Edelman et al. (2001).

References 1. 2. 3. 4.

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Rogers C, Edelman ER. Endovascular stent design dictates experimental restenosis and thrombosis. Circulation 1995; 91:2995–3001. Garasic JM, Edelman ER, Squire JC, Seifert P, Williams MS, Rogers C. Stent and artery geometry determine intimal thickening independent of arterial injury. Circulation 2000; 101:812–8. Marx SO, Marks AR. The development of rapamycin and its application to stent restenosis. Circulation 2001; 104:852–5. Sousa JE, Costa MA, Abizaid A, Abizaid AS, Feres F, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001; 103:192–5. Serruys PW, van Hout B, Bonnier H, Legrand V, Garcia E, et al. Randomized comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II). Lancet 1998; 352:673–81.

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Kastrati A, Schömig A, Dirschinger J, Mehili J, von Welser N, et al. Increased risk of restenosis after placement of gold-coated stents: results of a randomized trial comparing gold-coated with uncoated steel stents in patients with coronary artery disease. Circulation 2000; 101:2748–83.

10 Carotid and renal artery stenting

Carotid stenting for ischaemic stroke prevention Stroke is one of the leading causes of disability in the western countries and third only to cardiovascular disease and cancer as the leading cause of mortality. In the Unites States each year, more than 600 000 Americans suffer an acute ischaemic stroke, which results in more than 150 000 deaths. Of those who survive, the majority suffer permanent disability or residual neurological impairment and about 25% have another stroke. The cost to society exceeds $50 billion each year, and the cost to individuals and their family members is immeasurable |1|. It has been said that prevention of stroke is infinitely more effective and less costly than stroke treatment and rehabilitation. Numerous risk factors for stroke have been identified, and modification of these factors is the crux of prevention |2|. Most cerebrovascular accidents (CVAs) (about 60%) are caused by atherosclerotic emboli, usually arising from the aortic arch, neck vessels or cardiac chambers. Another 20–30% are caused by carotid arterial occlusive disease arising from stenosis |3|. The clinical spectrum of carotid stenosis ranges from asymptomatic bruits discovered on physical examination, to transient ischaemic attacks (TIAs) related to embolization or hypoperfusion, to ischaemic stroke. The progression from carotid artery stenosis to occlusion is in turn inconsistent and unpredictable. A disabling stroke may be the first manifestation in 20% of cases |4,5|. Meanwhile, in asymptomatic patients with haemodynamically significant carotid artery disease, the annual stroke rate ranges from 2–5%. Carotid revascularization is performed to reduce the risk of stroke and it can be performed either by carotid endarterectomy (CEA) or carotid stenting (CS). The advantage of CEA over medical therapy in patients with significant carotid stenoses has been established in recent randomized studies |6–9|. CEA for carotid artery stenosis is valuable for some patients, but not all. Practical accepted guidelines for stroke prevention include CEA for selected asymptomatic patients with carotid artery stenosis greater than 60% and CEA for patients with symptomatic carotid artery stenosis of 50% or more. For both symptomatic and asymptomatic carotid artery stenosis, the surgeon should be experienced in performing CEA and should have surgical outcomes similar to those of the surgeons who participated in the CEA trials |10|. Clinical trials have shown that carotid surgery prevents stroke, but also has a significant risk of morbidity |11–13|. CS can also be used to treat carotid stenosis. There has been considerable interest in recent years in performing carotid angioplasty, with or without stenting, instead of CEA in patients with asymptomatic or symptomatic carotid artery stenosis. CS has been under investigation in the United States since 1994. It is

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now being performed in many centres around the world with low complication rates. Even though most of the data published so far have been from case series, and little information has come from controlled clinical trials, CS continues to proliferate as a therapy for carotid occlusive disease. What has motivated the continued growth of CS? First of all, its popularity is due to the perceived advantages of a less invasive and apparently simple treatment for extracranial carotid occlusive disease and the advantage of avoiding some of the perioperative complications of CEA including cranial nerve injury, general anaesthesia, and the discomforts of surgery. The potential advantages of CS over CEA include avoidance of neck wound complications and cranial nerve palsies and a reduction in periprocedural myocardial infarction. In contrast, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) study |6| reported a 3.9% myocardial infarction rate, an 8.9% wound complication rate, and a 7.6% cranial nerve palsy rate. In addition, observational evidence and one randomized trial (CAVATAS) |14| have provided physicians with a sense that the procedure is both safe and effective. Preliminary reports suggest that CS can be performed with an acceptable 30-day complication rate. The most reliable data have come from the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), which found that carotid angioplasty can be performed with the same perioperative morbidity and mortality as CEA. Results are available from 504 patients with carotid stenosis randomized to surgery or endovascular treatment. Endovascular treatment was carried out by percutaneous transluminal angioplasty using balloon catheters with the adjunct use of stents in 26%. Complication rates for all strokes and deaths for the angioplasty and surgery groups were the same even though relatively high in both groups (10% and 9.9%, respectively). Both treatments appeared equally effective at preventing stroke recurrence with no difference in the rates of stroke during follow-up for up to 3 years. The large published case series of carotid endovascular treatments suggest a similar major morbidity rate to surgery |15–22|, but a small single centre randomized trial reported very poor results in stented patients |23|. Recommendations of the American Heart Association (AHA) published in 1998 state: ‘Use of carotid stenting should be limited to well-designed, well-controlled randomized studies with careful dispassionate oversight’. CS may provide an alternative to CEA, especially in those patients deemed to be at higher risk for endarterectomy. These patients include those with 1) previous history of CEA, 2) hostile neck secondary to radiation, total laryngectomy, or creation of a tracheotomy, 3) high lesions that are located above the mandible, low lesions below the clavicle, or 4) contralateral internal carotid artery (ICA) occlusion |24|. Techniques of carotid angioplasty and stenting improved over the course of CAVATAS, and new designs of stents, filters and protection devices are being developed. However, valid data that contrast the efficacy of carotid artery stenting (CAS) and CEA, the gold standard for the treatment of symptomatic carotid stenosis, are not available. Further large, multicentre randomized trials are therefore being started which will evaluate primary stenting of carotid artery stenosis in patients with cerebrovascular disease. Until the results are available, it will remain uncertain whether angioplasty and stenting are safe and effective therapeutic alternatives to surgery. Clinical trials in both Europe and North America (Carotid Revascularization Endarterectomy versus Stent Trial, CREST, and Carotid Revascularization with Endarterectomy or Stenting Systems, CARESS) will assess the ultimate role for carotid angioplasty and stenting in the management of both asymptomatic and symptomatic carotid artery stenosis. Until clinical trial data are available (CREST and CARESS), an argument can be made that in unique circumstances where CEA would be associated with a high perioperative complication rate, angioplasty and stenting may have a role in reducing the risk of ipsilateral stroke. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis.

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G S Roubin, G New, S S Iyer, et al. Circulation 2001; 103(4):532–7. BACKGROUND. CS is a less invasive percutaneous procedure than CEA for the treatment of carotid stenosis. Reports suggest that it can be performed with periprocedural complication rates similar to those of CEA. The purpose of this study was to determine short- and long-term outcomes in the largest prospective cohort of CS patients. This study followed 528 consecutive patients (604 hemispheres/ arteries) undergoing CS. There was a 0.6% (n=3) fatal stroke rate and 1% (n=5) non-stroke death rate at 30 days. The major stroke rate was 1% (n=6), and the minor stroke rate was 4.8% (n=29). The overall 30-day stroke and death rate was 7.4% (n=43). Over the 5-year study period, the 30-day minor stroke rate improved from 7.1% (n=7) for the first year to 3.1% (n=5) for the fifth year (P<0.05 for trend). The best predictor of 30-day stroke and death was age 80 years or more. After the 30-day period, the incidence of fatal and non-fatal stroke was 3.2% (n=31). On Kaplan-Meier analysis, the 3-year freedom from ipsilateral or fatal stroke was 92±1%. INTERPRETATION. Experience from a single group of operators demonstrates that CS can be performed with an acceptable 30-day complication rate. Late follow-up also demonstrates a low rate of fatal and non-fatal stroke. These results suggest that CS may be comparable to CEA, and it underscores the clinical equipoise and premise for the National Institute of Health-supported, randomized CREST comparing CS with CEA.

Comment This prospective study on outcomes after CS was undertaken to better define the incidence of immediate and late stroke in a large series of patients. The findings of this study suggest that CS can be carried out with acceptable procedural outcomes. The high freedom from ipsilateral stroke at three years suggests that CS is durable and efficacious. Symptomatic patients and asymptomatic patients had similar periprocedural complication rates after CS. The results in asymptomatic patients appear to be higher than that reported in the Asymptomatic Carotid Atherosclerosis Study (ACAS) |9|. However, although criteria for symptom status are the same, differences may exist in other criteria, such as patient age and comorbidity, between the asymptomatic patients in this series and the patients in the CEA trials. Consequently, these results cannot be directly compared with the results of CEA. In the latter part of the present study, complication rates for symptomatic patients fell within AHA/Society of Vascular Surgery guidelines, whereas procedural outcomes for asymptomatic patients exceeded the recommended 3% upper limit based on ACAS results. During the last two years of the study, asymptomatic patients <80 years of age had a periprocedural complication rate of 3.5%. This prospective study cannot be comparable to reported trials and series of CEA because of confounding factors that may make patients at higher or lower risk. In particular, a large proportion of symptomatic patients in this study were NASCET ineligible |6|. Nonetheless, stroke rates after CS appear to be in a range similar to those observed in randomized trials of CEA for symptomatic patients. Meaningful comparison of the results of CEA vs CS will ultimately be tested in randomized trials. The longterm durability of CS has been examined as well. Long-term survival curves in the symptomatic patients in this present series demonstrate an 11% fatal and non-fatal stroke rate estimated at three years. In CAVATAS |14|, in which 96% of patients were symptomatic, the three-year freedom from ipsilateral stroke and death was similar between the angioplasty and CEA groups. NASCET, on the other hand, reported a 15. 8% two-year any stroke or death rate and an 8.0% major stroke or death rate. Long-term survival curves in the asymptomatic group in this study demonstrated a 14% fatal and non-fatal stroke rate at three years. In asymptomatic patients, ACAS reported a five-year stroke or death rate of 20.7%. Moreover, in this study, symptom status was not a predictor of periprocedural or late neurological events. Of importance, the need

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for repeated intervention was low in this cohort. This is consistent with the low angiographic restenosis rates reported by our group and that of others. Similar periprocedural and late outcomes were observed for men and women in this study. This is in contrast to randomized and observational reports of CEA, which have consistently demonstrated poorer outcomes for women. This study included patients who were 80 years of age. Age 80 years was a predictor of periprocedural events and late stroke. No comparison from randomized CEA trials can be made because age 80 years was one of the exclusion criteria. Observational data reported for CEA, however, concur with our results and demonstrate an increased risk of stroke for patients >75 years of age. Seventy-six patients had bilateral stenting, with the potential for bilateral neurological complications to occur. This is in contrast to CEA trials in which patients were usually excluded if a bilateral procedure was required, thereby reducing the possibility of bilateral neurological events. Selection criteria in trials of CEA typically precluded patients with any serious illness deemed to be life limiting. The present study did not exclude patients with other life-threatening diseases, such as cancer, lung disease, and coronary ischaemia. Procedural safety and short-term outcome of ambulatory carotid stenting. N Al-Mubarak, G S Roubin, J J Vitek, G New, S S Iyer. Stroke 2001; 32(10): 2305–9. BACKGROUND. Ambulatory procedures increase patient comfort and enhance cost-effectiveness. Feasibility and safety of ambulatory CS was sought to be determined in a selected group of patients admitted and discharged the same day after the CS procedure. Immediate and short-term outcomes were reported. A total of 98 ambulatory CS procedures (98 hemispheres in 92 patients) were performed. There were 66 men (72%), and the mean age was 70±9 years. Of the patients, 28% had neurological symptoms related to the treated artery within 3 months before the procedure. Sixteen per cent of the patients had prior CEA, 4% had prior ipsilateral neck radiation, and 8% had complete occlusion of the contralateral internal carotid artery. Successful access site haemostasis was ensured in all patients with suturemediated vascular closure devices in 96 (98%) and manual compression in 2. Clinical follow-up was available for 96% of the patients at a mean time of 6±4 months. There were no neurological events, deaths, repeated procedures, or major access site complications. INTERPRETATION. Ambulatory CS is both safe and feasible. This approach will enhance the applicability of the procedure by increasing patient comfort and potentially reducing procedural costs.

Comment Suitable carotid stent patients can be discharged on the same day with no adverse outcomes. This paper illustrates one of the most important advantages of CS over CEA. Experience from a single tertiary referral centre shows that the low invasiveness of the procedure allows CS to be performed as an ambulatory procedure in selected individuals with very good results and great patient comfort. CAS would appear to be ideally suited for outpatient delivery. This minimally invasive technique is associated with an acceptable periprocedural complication rate in experienced centres. By comparison, CEA usually requires general anaesthesia, and in the case of repeat procedures, a more difficult neck dissection with a greater risk of cranial nerve injury. Moreover, patients with post-surgical restenosis also experience a greater complication rate and sometimes a longer hospital stay. Hence, outpatient CAS using a percutaneous closure device may prove to be an economical and attractive alternative to conventional CEA. Emergency stenting to treat neurological complications occurring after carotid endarterectomy. A Anzuini, C Briguori, G S Roubin, et al. J Am Coll Cardiol 2001; 37(8): 2074–9.

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BACKGROUND. CEA has been proven safe and effective in reducing the risk of stroke in symptomatic and asymptomatic patients with >60% carotid artery stenosis. However, perioperative stroke has been reported in 1.5% to 9% of CEA cases. The management of such a complication is challenging. Recently, percutaneous transluminal carotid angioplasty with stent deployment has emerged as a valuable and alternative strategy for the treatment of carotid artery disease. The purpose of this study was to assess the efficacy of emergency stent implantation for the treatment of perioperative stroke after CEA. Between April 1998 and February 2000, 18 of the 995 patients (1.8%) who had undergone CEA experienced perioperative major or minor neurological complications. Of these, 13 patients underwent emergency carotid angiogram and eventual stent implantation, whereas the remaining five had surgery reexploration. Carotid angiogram was performed within 20±10 min and revealed vessel flow-limiting dissection (five cases) or thrombosis (eight cases). Percutaneous transluminal carotid angioplasty with direct stenting (self-expandable stent) was performed in all 13 cases. Angiographic success was 100%. Complete remission of neurological symptoms occurred in 11 of the 13 patients treated by stent implantation and in one of the five patients treated by surgical reexploration (P=0.024). INTERPRETATION. Stent implantation seems to be a safe and effective strategy in the treatment of perioperative stroke complicating CEA, especially when carotid dissection represents the main anatomic problem.

Comment This is a very provocative paper which focuses on one of the possible indications for CAS. Carotid artery occlusive disease is responsible for 20% to 30% of stroke cases. CEA has been proven safe and effective in reducing the risk of stroke in symptomatic and asymptomatic patients with >60% carotid artery stenosis. However, perioperative stroke has been reported in 1.5% to 9% of CEA cases. Several early reports describe poor neurological results after surgery for acute carotid artery thrombosis. In this series, emergency CS for peri-CEA stroke was performed in all cases with excellent angiographic success (100%). The impressive rate of complete remission of neurological symptoms (11 out of 13 patients) clearly underscore the importance of a very short surgical-to-cath time related to the luxury of having a skilled on-site cath lab suite. This preliminary experience with primary stenting for the treatment of post-CEA stroke is encouraging and needs to be tested further in a larger sample size. Thrombosis after CEA is the most common cause of perioperative stroke, accounting for up to 75% of cases. Distal intimal flap, furthermore, represents another important cause of such a complication. The results of this study confirm the prevalent role of thrombosis (56% of cases) and underline the importance of a flow-limiting dissection (44% of cases) as the cause of the perioperative stroke. Identification of vessel dissection is very accurate by angiographic examination. However, it has been reported that angiography requires at least one hour to perform. This additional time required to reach a diagnosis is justified if the diagnostic procedure (carotid angiography) has a therapeutic counterpart. The main finding of this study was that stent implantation seems to be more effective than surgical re-exploration in the treatment of perioperative stroke, especially when the problem is due to vessel dissection. This result suggests that stent implantation is an expeditious technique to treat carotid dissection occurring after eversion CEA. Even with immediate surgical re-exploration, the result may be unsuccessful when dealing with carotid dissection. In particular, it may be especially troublesome when dissection arises above the angle of the mandible. The necessity for greater exposure often means that more time is needed for dissection or other manoeuvres at a point of considerable inconvenience during the operation. The encouraging clinical results of this trial may be also explained by the fact that the interval between onset of neurological symptoms and stent implantation was kept to a minimum. For this reason, we

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think that a meticulous neurological monitoring and a prompt availability of a catheterization laboratory emergency team are crucial for the efficacy of such a strategy for the treatment of perioperative stroke. In-stent restenosis after carotid angioplasty-stenting: incidence and management. E Y Chakhtoura, R W Hobson 2nd, J Goldstein, et al. J Vasc Surg 2001; 33(2):220–5; discussion 225–6. BACKGROUND. Carotid angioplasty-stenting (CAPS) has been advocated as an alternative to CEA in patients with restenotic lesions after prior CEA, primary stenoses with significant medical comorbidities, and radiation-induced stenoses. The incidence of restenosis after CAPS and its management remains ill defined. Chakhtoura et al. evaluated the incidence and management of in-stent restenosis after CAPS. Patients with asymptomatic (61%) and symptomatic (39%) carotid stenosis of ≥ 80% underwent CAPS between September 1996 and May 2000; there were 50 procedures and 46 patients (26 men and 20 women). All patients were followed up clinically and underwent duplex ultrasonography (DU) at 3- to 6-month intervals. In-stent restenoses ≥ 80% detected with DU were further evaluated by means of angiography for confirmation of the severity of stenosis. No periprocedural or late strokes occurred in the 50 CAPS procedures during the 30-day follow-up period. One death (2.2%) that resulted from myocardial infarction was observed 10 days after discharge following

CAPS. During a mean follow-up period of 18±10 months (range, 1–44 months), in-stent restenosis was observed after four (8%) of the 50 CAPS procedures. Angiography confirmed these high-grade (≥ 80%) in-stent restenoses, which were successfully treated with balloon angioplasty |3| or angioplasty and restenting |1|. No periprocedural complications occurred, and these patients remained asymptomatic and without recurrent restenosis over a mean follow-up time of 10±6 months. INTERPRETATION. In-stent restenoses occurred after 8% of CAPS procedures and were managed without complications with repeat angioplasty or repeat angioplasty and restenting.

Comment According to data from CAVATAS |14| available from 504 patients with carotid stenosis randomized to surgery or endovascular treatment, restenosis in the endovascular group was significantly more common. In CAVATAS endovascular treatment was carried out by percutaneous transluminal angioplasty using balloon catheters with the adjunct use of stents in 26%. At present, the rate of stenting is much higher (almost universal) and consequently restenosis rate is lower. CAPS restenosis seems to be quite easily treatable by repeated percutaneous technique (mainly only with balloon angioplasty) and is not a major clinical issue. Carotid artery stenting in patients with high-risk anatomy for carotid endarterectomy. G Dangas, J R Laird Jr, R Mehran, et al. J Endovasc Ther 2001; 8(1): 39–43. BACKGROUND. Dangas et al. report the results of CAS in patients considered to have high-risk anatomical characteristics for CEA. CAS was performed in 39 carotid arteries of 37 consecutive patients (26 men; mean age 72±8 years, range 56–88) who met the criteria for high-risk surgical anatomy: previous ipsilateral CEA (20/39, 51.3%), common carotid bifurcation above the mandibular angle (5/39, 12.8%), contralateral carotid artery occlusion (15/39, 38.5%), or previous radiation therapy to the neck (1/39, 2.6%). Palmaz, Integra, or Wallstents were deployed via a percutaneous femoral artery access. Independent neurological evaluation was performed at specified time points, and a dedicated committee adjudicated all clinical events. Procedural success was 100%, with no major in-hospital complications. Neurological events were rare. Only one (2.6%) transient ischaemic attack occurred prior to discharge;

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at 30 days, one (2.6%) additional minor stroke had been observed, giving a 2.6% cumulative 30-day ‘death plus any stroke’ rate. Over a mean 11±6-month follow-up, two (5.4%) patients died of nonneurological causes, but there were no strokes.

INTERPRETATION. CAS is a viable endovascular revascularization technique that can be performed safely and effectively in patients with high-risk anatomy for CEA.

Comment Carotid artery balloon angioplasty with or without stenting has been investigated for the past two decades, primarily for the treatment of patients with carotid stenosis who have been considered to be at high risk for CEA |12,13|. These patients include those with 1) previous history of CEA, 2) hostile neck secondary to radiation, total laryngectomy, or creation of a tracheotomy, 3) high lesions that are located above the mandible, low lesions below the clavicle, or 4) contralateral ICA occlusion. This paper confirms that even in a setting of high-risk anatomy CAS can be performed with an acceptably low complication rate. Traditionally these are patients in whom CEA has higher complication rate. These patient subsets have been largely excluded from the CEA randomized trials |6|. One group consists of patients with recurrent disease after CEA. Surgical repair of restenotic lesions has a 3% perioperative mortality and a perioperative stroke rate up to 12%. Neck irradiation is another factor that appears to increase operative risk (7% perioperative stroke rate), as is the presence of an occluded contralateral carotid artery. Subset analysis of the NASCET trial indicated that patients with contralateral carotid occlusion had significantly greater risk for CEA complications (14.3%) compared to patients with a patent contralateral carotid artery (5.1%). Last, a common carotid bifurcation above the level of the second cervical vertebral body hinders surgical access to the ICA distal to the lesion. The present study investigated the results of CAS in a patient group with high-risk anatomy for CEA, which incorporated patient groups that have typically been excluded from CEA trials because of the potential for increased complications, regardless of medical comorbidity. This cohort represented 28% of CAS cases during this study period. In this patient series, all the arteries were successfully stented, with few neurological sequelae. At the well-accepted safety window of 30 days, no deaths or disabling strokes had been observed, and only isolated incidences of TIA and minor stroke were seen (2.6% overall ‘all cause death plus any stroke’ rate). Thus, the endovascular approach appears to be specifically helpful in the treatment of carotid stenoses with anatomical features predisposing to a higher surgical risk. Although randomized trials will be needed to determine the superior carotid revascularization method in routine cases, the authors believe that results from CAS series such as this one will strengthen the ultimate impact of the results of the major randomized studies. Role of conventional angiography in evaluation of patients with carotid artery stenosis demonstrated by Doppler ultrasound in general practice. A I Qureshi, M F Suri, Z Ali, et al. Stroke 2001; 32(10):2287–91. BACKGROUND. Previous studies have suggested that patients with carotid stenosis who are candidates for endarterectomy can be effectively identified on the basis of carotid Doppler ultrasound alone. Before widespread acceptance of this policy, the accuracy of carotid Doppler ultrasound outside selected centres and clinical trials needs to be evaluated. Dr. Qureshi et al. performed a 12-month prospective study to evaluate the accuracy of Doppler ultrasound in identifying patients for carotid intervention in general practice settings. Each patient referred to the endovascular service for diagnostic

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angiography to evaluate for carotid stenosis was interviewed and examined by a neurologist. Subjects consisted of symptomatic patients with ≥ 50% stenosis and asymptomatic patients with ≥60% stenosis by Doppler ultrasound. Information pertaining to demographic and cerebrovascular risk factors and the results of the carotid Doppler ultrasound were recorded. The severity of stenosis on angiograms was measured with NASCET criteria by a blinded observer. The results of both studies were compared to determine the relative accuracy of ultrasound results. Of 130 patients (mean age 69±8.8 years) who met Doppler ultrasound criteria, 22 (17%) and 8 patients (6%) were found to have 30% to 49% or <30% stenosis by angiography, respectively. The positive predictive value of carotid Doppler ultrasound for identifying appropriate symptomatic candidates for carotid intervention (angiographic stenosis ≥ 50%) was 80%, with a false-positive value of 20%. The positive predictive value of carotid Doppler ultrasound for identifying appropriate asymptomatic candidates for carotid intervention (angiographic stenosis ≥ 60%) was 59%, with a false-positive value of 41%. CEA or angioplasty and stent placement were undertaken subsequently in 60 (46%) of the patients. In 94 patients who underwent cerebral angiography alone, no complications were observed. INTERPRETATION. The present accuracy of carotid Doppler ultrasound in general practice does not justify its use as the sole basis of selecting appropriate patients for carotid intervention. Given the relatively low rate of associated morbidity with present day techniques, additional confirmatory studies such as angiography should be performed in every patient before a decision regarding intervention is made.

Comment The present study underscores an important, and yet not applied, issue in terms of carotid intervention planning. Is it justified to perform CEA on the sole basis of carotid ultrasound (Duplex scan) |25|? Carotid disease is responsible for 30% of cerebral infarctions or TIAs in the anterior circulation. Appropriate use of ultrasound (US), magnetic resonance angiography (MRA), computed tomographic angiography (CTA), conventional angiography, can help identify the presence and cause of disease |26,27|. Carotid US has an 89% specificity and a 93% sensitivity in determining 60% or greater stenosis and is less expensive than MRA. In addition, it can provide information on plaque morphology and ulceration. US may be falsely positive for complete occlusion of the carotid artery in 2% of cases, so confirmatory testing with angiography may be necessary. MRA has the potential to image the intracranial circulation simultaneously with the extracranial carotid circulation. Its sensitivity is similar to that of duplex US, but its specificity is slightly lower, with overestimation of the degree of stenosis. Unlike duplex US, conventional MRA has poor capability of discerning ulcers in plaques. However, the combination of MRA and carotid US has very high sensitivity and specificity for degree of stenosis. Newer MRA technologies are evolving, such as multiple overlapping slab acquisition and MRA with gadolinium bolus, which may prove to have higher sensitivity and specificity for stenosis and plaque characterization. CTA is an evolving technology that correlates well with MRA in determining the degree of extracranial carotid stenosis and is superior to carotid US in determining complete occlusion. Disadvantages of CTA in the extracranial circulation include small risks of radiation and intravenous contrast reaction and limitations from bony artifact and overlapping jugular veins. Conventional angiography is not without risk. Non-neurological risks include acute renal failure, hypersensitivity or allergic reaction, and development of infection, haematoma, or pseudoaneurysm at the site of entry. The risk of transient neurological deficit is about 0.5%, and complications may result from thrombus formation at the catheter tip, endothelial flap caused by the guidewire, and site of dissection. The risk of persistent neurological deficit is about 0.1%. In common practice, if carotid US or MRA reveals significant stenosis, further angiography (conventional or MRA) may be performed before CEA is undertaken. However, many surgeons proceed on

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the basis of non-invasive imaging, precluding the need for standard angiography and its associated morbidity and cost. Of course, conventional angiography is performed as a part of the procedure itself before CS is undertaken. Cerebral protection with filter devices during carotid artery stenting. B Reimers, N Corvaja, S Moshiri, et al. Circulation 2001; 104(1):12–15. BACKGROUND. Distal embolization of debris during percutaneous CAS may result in neurological deficit. Filter devices for cerebral protection potentially reduce the risk of embolization. Elective carotid stent implantation using three different types of distal filter protection devices was attempted in 88 consecutive lesions (84 patients) in the ICA that had >70% diameter stenosis (mean, 78.7±10.7%). Procedures were performed in three different centres. The mean age of the patients was 69±8 years, 75% were men, and 35.7% had neurological symptoms. In 86 lesions, a stent was successfully implanted (97. 7%). In 83 of these 86 procedures (96.5%), it was possible to position a filter device. In 53% of filters, there was macroscopic evidence of debris. Collected material consisted of lipid-rich macrophages, fibrin material, and cholesterol clefts. Neurological complications during the procedure, in the hospital, and at

30 days of clinical follow-up occurred in only one patient (1.2%). This patient suffered a minor stroke that resolved within one week. Two major adverse cardiac events (2.3%) occurred during the 30 days of follow-up. INTERPRETATION. Filter protection during CAS seems feasible and safe. In the present series, the incidence of neurological complications was low.

Comment Recently, the indication for CS has been expanded to include those patients who are not necessarily considered to be at high surgical risk. However, CS has not received widespread acceptance primarily because of the availability of excellent results from CEA, and also due to the risk of embolic stroke associated with CS. Since it has been shown that the long-term patency and stroke prevention rates of CS are promising, if perioperative stroke can be prevented, CS may gain popularity by virtue of its less invasive nature. Strokes, both major and minor, are acknowledged complications of CS, and the mechanism now seems to be embolic, rather than the acute occlusion or dissection that was observed during early experiences of balloon angioplasty. The main cause of perioperative neurologic deficits following CS are thought to be embolic particles released from the carotid plaque during balloon dilatation and stent deployment. If protection devices can prevent these embolic events without causing additional problems, there is no reason why they should not be used on a routine basis during CS. Although the safety and efficacy of the protection devices in the carotid system must be proven in clinical trials, the early results are promising. This paper reports experience of carotid stent implantation with the aid of filter devices. A much larger investigation will be required to determine whether stroke is less likely with distal protection than without it. Could stroke develop even if these devices successfully trap all macroscopic material? Yes. Any instrumentation of the aortic arch and of the epiaortic vessels required to perform the procedure might be the cause of emboli |28|. Current status of carotid bifurcation angioplasty and stenting based on a consensus of opinion leaders. F J Veith, M Amor, T Ohki, et al. J Vasc Surg 2001; 33(2 Suppl):S111–6.

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BACKGROUND. Carotid bifurcation angioplasty and stenting (CBAS) has generated controversy and widely divergent opinions about its current therapeutic role. To resolve differences and establish a unified view of CBAS’ present role, a consensus conference of 17 experts, world opinion leaders from five countries, was held on November 21, 1999. These 17 participants had previously answered 18 key questions on current CBAS issues. At the conference these 18 questions and participants’ answers were discussed and in some cases modified to determine points of agreement (consensus), near consensus, (prevailing opinion), or divided opinion (disagreement). Conference discussion added two modified questions, placing a total of 20 key questions before the participants, representing four specialties (interventional

radiology, seven; vascular surgery, six; interventional cardiology, three; neurosurgery, one). It is interesting that consensus was reached on the answers to 11 (55%) of 20 of the questions, and near consensus was reached on answers to 6 (30%) of 20 of the questions. Only with the answers to 3 (15%) of the questions was there persisting controversy. Moreover, both these differences and areas of agreement crossed speciality lines. INTERPRETATION. The conference decided that CBAS should not currently undergo widespread practice but should await results of randomized trials. CBAS is currently appropriate treatment for patients at high risk in experienced centres. CBAS is not generally appropriate for patients at low risk. Neurorescue skills should be available if CBAS is performed. When cerebral protection devices are available, they should be used for CBAS. Adequate stents and technology for performing CBAS currently exist. There were divergent opinions regarding the proportions of patients presently acceptable for CBAS treatment (5% to 100%, mean 44%) and best treated by CBAS (3% to 100%, mean 34%). These and other consensus conclusions will help physicians in all specialities deal with CBAS in a rational way rather than by being guided by unsubstantiated claims.

Comment Clinical trials in both Europe and North America (CREST and CARESS) will assess the ultimate role for carotid angioplasty and stenting in the management of both asymptomatic and symptomatic carotid artery stenosis and will set the basis for final consensus. Carotid angioplasty with stenting in post-carotid endarterectomy restenosis. J J Vitek, G S Roubin, G New, N Al-Mubarak, S S Iyer. J Invasive Cardiol 2001; 13(2):123–5; discussion 158–70. BACKGROUND. Recurrent stenosis post-CEA is not a solitary or unusual phenomenon. Compared to the initial CEA, the reoperation is often more technically challenging and frequently results in local and neurological complications. Carotid artery angioplasty with stenting (CAAS) is currently being investigated as an alternative to CEA. In Vitek et al. series, ninety-nine patients underwent CAAS in 110 arteries. Procedural success was 99% (109/110). Our results show that CAAS treatment in post-CEA restenosis, especially with improved technique and distal protection, is safe with a low neurological complication rate, without any ‘local’ complications and without any cranial nerve palsies. INTERPRETATION. This study suggests that the future primary mode of treatment of post-CEA restenosis might be CS rather than surgery.

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Comment Reports of the natural history of carotid artery disease after CEA vary, with restenosis rates ranging from 1. 2% to 36%. The aetiology of recurrent disease takes two forms. The early onset type, i.e. arising within two years of operation, is commonly due to intimal hyperplasia or residual disease (4%). Late recurrences typically result from the ongoing atherosclerotic process. Repeat CEA for recurrent stenosis is more challenging than a primary procedure. Complex neck dissection through scar tissue and interposition of a graft to permit closure is often required. CS is a less invasive percutaneous technique that may avoid the anaesthetic and neck complications associated with an open surgical procedure. In most cases, restenotic lesions are asymptomatic, with a low risk of vascular events. A recent meta-analysis calculated a 1.88 relative risk of stroke in patients with recurrent disease compared to those without restenosis, although the authors did note a marked heterogeneity among studies. Results of some investigations suggest that the incidence of symptomatic recurrent stenosis ranges from 0% to 8%. The appropriateness of treating recurrent stenosis is an important issue. Justification of treatment requires that an intervention have a low periprocedural risk and provide long-term freedom from stroke. Higher morbidity and mortality rates (8%– 20%) following repeat endarterectomy versus primary surgery have been well documented, although some recent results suggest that the risk has improved. The subgroup of patients with carotid artery disease and recurrent stenosis also appears to have a higher prevalence of atherosclerotic risk factors and coronary heart disease. Hence, a minimally invasive approach may be more appropriate with this potentially higher surgical risk group. No randomized trials are currently comparing repeat CEA to medical therapy or CS. Patients with previous CEA have consistently been excluded from carotid artery disease trials because of their perceived increased risk. Overall, these data and previous multi-centre registry experience results suggest that CAS can be performed for post-surgical restenosis with complication rates similar to those for stenting of primary lesions, as well as most published rates for repeat endarterectomy. Conclusion CS is still being evaluated in clinical trials to determine its role in reducing the risk of stroke in patients with carotid artery stenosis (symptomatic and asymptomatic carotid occlusive disease). Over the last half decade, a large number of endovascular specialists have gained considerable experience with CS. This expertise, along with the introduction of dedicated carotid stents and neuroprotection devices, has set the stage for the vascular, interventional, and neurological communities to commit to a rigorous evaluation of this promising therapy. The National Institute of Health/National Institute of Neurological Disorders and Stroke recently approved funding for CREST |29|, a multicentre, randomized trial, to compare these two techniques. This multicentre randomized trial will compare the efficacy of CS against CEA in symptomatic patients with carotid stenosis. CREST is a pivotal study of paramount importance because it evaluates CS in a subset of patients that has been shown to gain the most benefit from carotid revascularization. Candidates for CREST will be carotid stenosis patients who have experienced a non-disabling stroke, transient ischaemic attack, or amaurosis fugax within six months of enrolment. Originally restricted to high-grade symptomatic lesions, the CREST protocol has been revised to lower the threshold symptomatic lesion to 50% stenosis, in accordance with the latest findings of NASCET. The primary end-points will be 30-day death, stroke, and myocardial infarction, and ipsilateral stroke during the four-year follow-up period. Secondary analyses will compare periprocedural mortality and economic and quality of life measures between the two procedures. Moreover, CREST’s commitment to evaluate differential efficacy of CEA and CS according to gender will constitute a major secondary analysis. It is anticipated that neuroprotection will be used in stent procedures. In order to have meaningful and comparable results in the two CREST groups of patients, both surgeons and

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stent operators have been selected carefully to ensure ‘state of the art’ techniques and patient care. The CREST study will require 2500 randomized patients to be adequately powered to show a difference between the two therapies. This will represent the largest trial of its kind and will require a massive recruitment effort involving 50 centres. If each centre could average a modest recruitment of two to three patients per month, this phase could be completed in two years! For FDA purposes, analysis of results could begin twelve months after enrolment of the last patients. A twelve-month analysis is likely to provide the most valuable information. However, additional clinical follow-up to four years is a crucial component of CREST. Priority must be given to recruitment efforts for the CREST study. However, for a variety of logistical, scientific, and ethical reasons, many patients with significant carotid stenoses will not be eligible for participation in CREST. This will represent a very large population of asymptomatic patients, the elderly (80 years), and people at higher risk for CEA owing to comorbidities. For many reasons, these CRESTineligible patients should not be lost to rigorous prospective evaluation. The International Society of Endovascular Specialists (ISES) recently submitted an Investigational Device Exemption (IDE) to the FDA for approval of the CARESS study so that symptomatic patients excluded from CREST may be studied. In addition, some asymptomatic patients will be included in the CARESS clinical cohort, but patients eligible for CREST will be excluded from CARESS. The threshold lesion for symptomatic patients will be a duplex-defined 50% stenosis; asymptomatic patients will require a 75% stenosis to be included in CARESS. In the majority of high-volume centres, it is likely that more than one stent/protection system will be available. CARESS is designed as an observational study to demonstrate the effectiveness of CS with cerebral protection compared to a contemporaneous group of CEAs. The primary end-points are similar to those in CREST. Surgical outcomes will be obtained from a concurrent prospective registry of CEAs undertaken at the study sites. Once underway, CARESS will provide adjunctive information on the management of patients with carotid occlusive disease. The less rigorous, observational design of CARESS will generate outcome data on patients treated with CS and CEA who fall outside the closely defined inclusion and exclusion criteria for CREST. Data from randomized clinical trial like CREST and an observational study such as CARESS are likely to provide the information the medical community requires to evaluate the usefulness of CS properly |30|. Renal artery stenting Renal artery stenosis (RAS) has long been recognized as a cause of systemic hypertension |31,32|, and has more recently been identified as a cause of progressive renal insufficiency |33,34|. Less than 10% of hypertensive patients have secondary causes; most patients with secondary hypertension have kidney disease. The most common cause of secondary hypertension is chronic renal insufficiency. RAS is the next most common cause of secondary hypertension. Atherosclerotic RAS has a prevalence of about 1% in hypertensive patients |35,36|. The most useful clues to the presence of renovascular disease are patient age of less than 30 or more than 50 years, systolic or diastolic epigastric bruit, and renal insufficiency that is unexplained or induced by angiotensin-converting enzyme (ACE) inhibitor therapy. Hypertension is often accelerated or malignant, of abrupt onset, accompanied by diffuse vascular disease, and refractory to tripledrug therapy. Most commonly identifiable secondary causes of refractory hypertension are renal artery stenosis and chronic renal parenchymal disease. RAS often results in hypertension that is difficult to control and resistant to treatment (refractory hypertension). Systematic evaluation of each patient with refractory hypertension is necessary to identify conditions or altered mechanisms of hypertension that are amenable to targeted therapy. After completion of evaluation, resistance to antihypertensive therapy should be found in

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no more than 3% to 5% of patients. As a matter of fact, one of the most common and underdiagnosed causes of refractory hypertension is renovascular disease, which is more common than previously recognized. Severe arterial artery stenosis may also lead to inadequate blood flow and impair the excretory function of the kidney |33,34|. A number of different patterns of presentation of ischaemic renal disease exist. These presentations include acute renal failure, often in association with use of angiotensin-converting enzyme (ACE) inhibitor; progressive renal dysfunction in a patient with previously identified renovascular hypertension; progressive renal dysfunction in an elderly patient with refractory hypertension; and unexplained progressive renal dysfunction in an elderly patient. Flash pulmonary oedema constitutes an important new pattern of clinical presentation in patients with RAS. Patients who present with flash pulmonary oedema out of proportion to the degree of myocardial dysfunction may have severe bilateral RAS or high-grade occlusion of a solitary main renal artery. Bilateral RAS, or stenosis to a solitary functioning kidney, has resulted in recurrent episodes of ‘flash’ pulmonary oedema and unstable angina pectoris. Flash pulmonary oedema in the absence of critical myocardial or valvular heart disease constitutes yet another clue to the presence of this disorder. The sudden onset of pulmonary oedema in patients with RAS is an increasingly recognized entity. Patients with bilateral RAS have increased intravascular volume. The release of renin observed in bilateral RAS results in subsequent elevation of the angiotensin II concentration, which in turn causes systemic vasoconstriction, thus increasing the myocardial afterload. Both hypervolaemia and increased myocardial afterload contribute to recurrent acute pulmonary oedema. Significant changes have occurred in the treatment of renal artery disease over the past few years. Invasive therapy (endovascular percutaneous transluminal angioplasty, with or without stent deployment; surgical revascularization) has generated significant interest among interventional physician specialists |37–41|. Angioplasty and stents can successfully lower blood pressure in many of these patients and reduce the need for antihypertensive therapy |42,43|. These measures have resulted in significant decreases in blood pressure, although data on long-term outcome are lacking. Percutaneous transluminal angioplasty of the renal artery can also be used for salvaging the function of the ischaemic kidney |44|. Primary renal artery stenting: characteristics and outcomes after 363 procedures. R J Lederman, F 0 Mendelsohn, R Santos, H R Phillips, R S Stack, J J Crowley. Am Heart J 2001; 142(2): 314–23. BACKGROUND. Stenting improves the acute results of percutaneous balloon angioplasty for atherosclerotic RAS. Predictors of benefit and angiographic restenosis are not well understood. We describe the technical and clinical success of renal artery stenting in a large consecutive series of patients with hypertension or renal insufficiency. We identify clinical, procedural, and anatomic factors that might influence outcome, restenosis, and survival. Primary renal artery stenting was performed in 300 consecutive patients who underwent 363 stent procedures in 358 arteries. Angiograms were analysed quantitatively. Clinical and angiographic follow-up data were available after a median of 16.0 months. At baseline, 87% of patients had hypertension, and 37% had chronic renal insufficiency. The mean age was 70 years (interquartile range 63.1–74.6 years). The stenosis was unilateral in 49% and bilateral in 48% and involved a solitary functioning kidney in 3.6%. The stenting procedure was successful in all attempts. There were no procedural deaths or emergency renal surgical procedures. Post-procedure azotaemia was seen in 45 of 363 (12%) procedures but persisted in only six patients (2%), all of whom had baseline renal insufficiency. Systolic and diastolic blood pressures were significantly reduced (systolic blood pressure from 164.0±28.7 to 142.4±19.1 mmHg, P<0.001). At follow-up, 70% of patients had improved blood pressure control regardless of renal function. In patients with baseline renal insufficiency, 19% had improvement in serum creatinine levels at follow-up, 54% had stabilization, and

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27% had deterioration. Follow-up mortality was 10% and was predicted by baseline creatinine levels (odds ratio 1.72 for each 1 mg/dL creatinine increment, 95% confidence interval 1.13–2.49) and extent of coronary artery disease (odds ratio 1.66 for each diseased coronary artery, 95% confidence interval 1.03– 2.67). Angiographic restenosis was found in 21% of 102 patients overall and was less common (12%) in arteries with a reference caliber

>4.5 mm (P<0.01 vs calibre <4.5 mm). Neither post-stenotic dilation nor severity of angiographic stenosis predicted clinical outcome. INTERPRETATION. Primary renal artery stenting can be performed safely with nearly uniform technical success. The majority of patients with hypertension or renal insufficiency derived benefit. Follow-up mortality was five-fold higher in patients with baseline renal insufficiency. Clinical and angiographic features did not predict blood pressure or renal functional outcome. Restenosis was more common in renal arteries with a reference calibre less than 4.5 mm.

Comment The technical expertise and tools required to treat renovascular obstruction have become commonplace, and many series of patients revascularized with surgery, balloon angioplasty or endovascular stenting have been reported. Percutaneous transluminal angioplasty of the renal artery has been increasingly used over the past 20 years for treating renovascular hypertension. In patients with atherosclerotic RAS the cure rate after percutaneous transluminal angioplasty of the renal artery is 8–10% although 40–50% still improve. Although excellent clinical results can be obtained with surgery, percutaneous transluminal renal angioplasty and stenting has proved similarly efficacious and is now the treatment of choice for atherosclerotic stenoses and fibromuscular dysplasia. The lesions are quite amenable to angioplasty and stenting. The best factor in predicting the response to percutaneous angioplasty/stenting or surgical treatment in patients with hypertensive disease still remains the duration of the hypertension (or resistant hypertension). The longer the hypertension has been present, the less chance there is for improvement or cure. This observation also applies to most forms of secondary hypertension. Since percutaneous transluminal angioplasty of the renal artery is associated with possible complications and restenosis |45|, it is obvious that in patients with atherosclerotic RAS the decision to attempt this procedure must be taken after careful selection of those who may actually benefit from the dilation. Effective antihypertensive therapy may be a reasonable option in certain scenarios. Percutaneous transluminal angioplasty of the renal artery can be used more extensively for salvaging the function of the ischaemic kidney than for treating hypertension because of the progressive nature of the atherosclerotic RAS and the lack of effective agents against such progression. After percutaneous transluminal angioplasty of the renal artery, 35% of patients have some improvement in renal function and another 35% are stabilized. Yet most studies addressing the renal effects of percutaneous transluminal angioplasty of the renal artery suffer the limitation of having used serum creatinine levels as an indicator of glomerular filtration rate (GFR). More recent studies which used radioisotopic techniques to evaluate the changes of GFR induced by percutaneous transluminal angioplasty of the renal artery in the stenotic kidney indicate that after a successful procedure the increase is, on average, 8–10 ml/min. Interestingly it appears that this improvement is slower in the kidneys of patients with atherosclerotic RAS than in those with fibromuscular RAS. Long-term effects of arterial stenting on kidney function for patients with ostial atherosclerotic renal artery stenosis and renal insufficiency.

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J J Beutler, J M Van Ampting, P J Van De Ven, et al. J Am Soc Nephrol 2001; 12(7):1475–81. BACKGROUND. It is uncertain whether renal artery stent placement in patients with atherosclerotic renovascular renal failure can prevent further deterioration of renal function. Therefore, the effects of renal artery stent placement, followed by patency surveillance, were prospectively studied in 63 patients with ostial atherosclerotic RAS and renal dysfunction (i.e. serum creatinine concentrations of >120 μmol/ l (median serum creatinine concentration, 171 μmol/l; serum creatinine concentration range, 121 to 650 μmol/l). Pre-stent renal (dys) function was stable for 28 patients and declining for 35 patients (defined as a serum creatinine concentration increase of ≥ 20% in 12 months). The median follow-up period was 23 months (interquartile range, 13 to 29 months). Angioplasty to treat restenosis was performed in 12 cases. Five patients reached end-stage renal failure within 6 months, and this was related to stent placement in two cases. Two other patients died or were lost to follow-up monitoring within 6 months, with stable renal function. For the remaining 56 patients, the treatment had no effect on serum creatinine levels if function had previously been stable; if function had been declining, median serum creatinine concentrations improved in the first year [from 182 μmol/l (135 to 270 μmol/l) to 154 μmol/l (127 to 225 μmol/l); P=0.05] and remained stable during further follow-up monitoring. INTERPRETATION. Stent placement, followed by patency surveillance, to treat ostial atherosclerotic RAS can stabilize declining renal function. For patients with stable renal dysfunction, the usefulness is less clear. The possible advantages must be weighed against the risk of renal failure advancement with stent placement.

Comment Atherosclerotic RAS may result in chronic renal insufficiency, and although controversial, probably leads to end-stage renal failure in a subset of patients. How often it is the primary cause of end-stage renal disease (ESRD) is not yet certain. Atherosclerotic vascular occlusive disease of the renal arteries does progress, but current rates of progression and occlusion are lower than those reported a decade ago. Severe renal artery stenosis may lead to inadequate blood flow and impair the excretory function of the kidney. Bilateral RAS is a common cause of renal failure. The associated hypertension is often unusual in its severity or it escapes from good control. Methods of identifying patients whose renal function is at true risk from vascular occlusive disease and determining who will benefit from intervention remain elusive. Functional tests that predict the change in renal function after revascularization are not yet available. However, a renal length of greater than 7.5 cm in the absence of renal cysts and a short history of renal functional deterioration indicate a good prognosis. Patients with recent deterioration in renal function, those with bilateral RAS or stenosis to a single functioning kidney, those with flash pulmonary oedema, advanced chronic renal failure, or ESRD (who have much to gain), those with reversible azotaemia during ACE inhibitor or angiotensin receptor antagonist therapy, and those whose conditions cannot be managed medically should be considered for revascularization. Results from recent controlled clinical trials of the response to percutaneous transluminal renal artery angioplasty (PTRA) and stenting indicate that improvement in blood pressure control or renal function is not a predictable outcome of renal revascularization. In azotaemic groups, 25%-30% of patients achieve important recovery of renal function. Thus, significant progress has been made recently in determining whether RAS is a frequent, treatable cause of renal failure. The decision to recommend revascularization remains a difficult balance between the risks and expense of the procedure and the undoubted benefits that accrue if renal function is successfully stabilized. Ostial renal artery stent placement in patients 75 years of age or older. M J Bloch, D A Trost, J Whitmer, T G Pickering, T A Sos, P August. Am J Hypertens 2001; 14(10):983–8.

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BACKGROUND. Renal artery stent placement has been shown to improve blood pressure (BP) and stabilize renal function in patients with atherosclerotic renovascular disease. However, limited data are available in patients ≥ 75 years of age. We analysed the pre-stent characteristics and clinical outcomes of patients aged ≥ 75 years who underwent renal artery stenting at our institution. We compared these data with those from the remainder of our stent cohort. Nineteen of 89 (21.3%) stent patients were ≥ 75 years old. Before intervention, those ≥ 75 years were significantly more likely to be women (84.2% vs 55%; P=0.02), current or former smokers (78.6% vs 36.8%; P=0.002), and on a greater number of antihypertensive medications (3.68 vs 2.80; P=0.048). Average clinical follow-up was similar in both groups (23.9 vs 23.2 months; P>0.05). At last available follow-up, there were more deaths in those ≥ 75 years (7/19 vs 5/70; P=0.038). No significant difference was found in the incidence of dialysis after intervention (3/19 vs 7/70). Seventy-four per cent of those ≥ 75 years had improved BP, 21% were stable, and 5% were worse. Renal function was improved in 26%, stable in 53%, and worse in 21%. INTERPRETATION. Among those ≥ 75 years, there was a significant decrease in systolic BP. Patients ≥75 years of age with atherosclerotic renovascular disease have a higher incidence of mortality two years after renal artery stent placement, but they seem to derive clinical benefit comparable to younger patients.

Comment RAS is a cause of systemic hypertension, and may also result in chronic renal insufficiency. Most cases in the elderly are atherosclerotic in origin. Chronic azotaemic renovascular disease is common in patients with atherosclerosis. Its prevalence appears to be increasing in the aging population. Some studies suggest that 10%–40% of elderly hypertensive patients with newly documented ESRD and no demonstrable primary renal disease have significant RAS. Endovascular treatment of renal artery stenosis. G Geroulakos, C Missouris, A Mitchell, R M Greenhalgh. J Endovasc Ther 2001; 8(2):177–85. BACKGROUND. Significant changes have occurred in the treatment of renal artery disease over the past few years. Although excellent clinical results can be obtained with surgery, percutaneous transluminal renal angioplasty has proved similarly efficacious and is now the treatment of choice for non-ostial atherosclerotic stenoses and fibromuscular dysplasia. The introduction of stents has become a valuable adjunctive therapy for post-angioplasty restenosis and dissection.

Comment This is a key review and overview article on the topic of renal stenting. The authors reviewed in depth current literature results in terms of procedural success and complications. They also reviewed current results of outcome both in terms of effect on hypertension and on renal function. Renal artery stenosis: duplex ultrasonography after angioplasty and stent placement. M J Sharafuddin, C A Raboi, M Abu-Yousef, W J Lawton, J A Gordon. Radiology 2001; 220(1):168–73. BACKGROUND. The purpose of this study was to evaluate the haemodynamic outcome of technically successful percutaneous transluminal renal artery angioplasty and stent placement (PTRAS) with duplex ultrasonography (DU). Eighteen patients who underwent PTRAS in 22 renal arteries were prospectively examined. All had abnormal pre-procedural DU findings. Those who had significant RAS (>70%) at angiography and underwent technically successful percutaneous interventions were enrolled. Standard intrarenal DU parameters (acceleration index [Al], acceleration time, waveform morphology

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grade, and resistive index) were compared before and after interventions. A significant Al increase occurred after PTRAS (9.02 m/sec2±4.85 [SD]), as compared with before intervention (2.34 m/sec2±2.03; P=0.001). Acceleration time significantly decreased from 0.084 second±0.049 to 0.032 second±0.008 (P=0. 01). There was also a significant resistive index increase from 0.69±0.12 to 0.79±0.12 (P=0.01). Abnormal waveform morphology (modified Halpern waveform grade 3–6) was present in 19 (86%) of 22 intrarenal arteries prior to intervention, as compared with one (5%) after PTRAS (P=0.001). In the instance in which an abnormal waveform persisted after intervention, waveform morphology improved from grade 6 to grade 3, with a concomitant Al increase from 0.96 to 5.1 m/sec2.

INTERPRETATION. The findings suggest an important potential role for DU in non-invasive assessment of the immediate haemodynamic outcome and long-term follow-up of PTRAS.

Comment In addition to the specific role pointed out in the present study in terms of haemodynamic follow-up postrenal artery angioplasty/stenting, the important role of Duplex scan in the diagnosis of renal artery stenosis is also emphasized. Recent advances in duplex ultrasound have allowed easier visibility of the renal vessels. The presence of RAS in an azotaemic patient can be assessed with non-invasive and risk-free radiologic techniques, including Duplex scan (Doppler US can detect increased velocity in the renal arteries, which is indicative of stenosis). Doppler imaging of the renal arteries (results are operator-dependent) was recently shown to be sensitive in detecting radiologically confirmed RAS in patients with arteriosclerotic renal disease |46|. The diagnosis of RAS has often been overlooked because of the difficulty in establishing the diagnosis. Most cases in the elderly are atherosclerotic in origin. When previously well-controlled hypertension has recently become resistant to therapy, patients older than 50 years of age with evidence of generalized vascular disease should be examined for renovascular disease. An abdominal bruit that lateralizes to one side should increase suspicion. A renal US is a good non-invasive screening measure. RAS may be suspected if one kidney is atrophic or smaller than the other. A renal arteriogram is diagnostic. Recent advances in imaging modalities, particularly duplex US and MRA, have allowed easier visibility of the renal vessels. Captopril-induced renograms are useful, unless the serum creatinine level is higher than 2 mg/ dl. In the absence of a history of ureteral disease, a significant discrepancy in the size of the kidneys on US warrants an angiogram in patients with generalized arteriosclerosis. Conclusion A secondary cause of hypertension should be suspected when the onset is sudden and severe or when blood pressure levels remain significantly elevated despite the administration of three or four different antihypertensive agents. Because renovascular hypertension is a potentially curable form of hypertension it should be considered in young white women (fibromuscular hyperplasia) and older hypertensive patients with recent onset of hypertension or refractory hypertension and the presence of other evidence for advanced atherosclerosis or an abdominal bruit. It is recommended evaluation for renovascular hypertension in young females (less than 25 years old) with marked hypertension, patients with new-onset hypertension and evidence of advanced atherosclerosis, patients with resistant hypertension and patients with malignant hypertension (especially white patients). PTRAS can successfully lower blood pressure in many hypertensive patients and reduce the need for antihypertensive therapy, although data on long-term outcome

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are lacking. From the experience gathered so far it is justified to state that this technique is the first choice for patients with fibromuscular RAS because their cure rate is 50% while 42% improve. In patients with atherosclerotic RAS the cure rate after percutaneous transluminal angioplasty of the renal artery is 8–10% although 40–50% still improve. Since percutaneous transluminal angioplasty of the renal artery is associated with possible major/minor complications and restenosis |45|, it is obvious that in patients with atherosclerotic RAS the decision to attempt this procedure must be taken after careful selection of those who may actually benefit from the dilation. ESRD, which is often related to diabetes or hypertension, is a serious medical and economic public health problem throughout the world. The incidence of ESRD is increasing dramatically, and it has become a significant public health problem both medically and economically. Although renal replacement therapies have revolutionized the management of renal failure, the morbidity and mortality associated with this condition remain substantial. Despite the progress made in improving renal dialysis and kidney transplantation, the extraordinary mortality of ESRD points to the need for new strategies that prevent, delay, or halt progression of renal disease. The primary care physician can play an important role by providing early intervention. As a result, diagnosis and therapy are increasingly directed towards the preservation of renal function, and the future of renal revascularization will depend on how well potential therapies address this goal |47|. Diabetes and hypertension are often implicated in development of ESRD, and better control of these disorders is an important goal in primary care medical practice. Percutaneous transluminal angioplasty of the renal artery can be used more extensively for salvaging the function of the ischaemic kidney than for treating hypertension because of the progressive nature of the atherosclerotic RAS and the lack of effective agents against such progression. After percutaneous transluminal angioplasty of the renal artery 35% of patients have some improvement in renal function and another 35% are stabilized. Prevention of chronic renal failure should be a primary healthcare goal in the new millennium. Better control of blood pressure, blood glucose, and lipid levels shows promise for slowing and perhaps even preventing renal dysfunction. Protein-sparing diets may also prove to be important. While it is not yet known whether combining interventions to treat each of these factors will have additive or synergistic effects, it seems prudent to approach these problems aggressively. References 1. 2. 3. 4. 5. 6. 7.

American Heart Association: 2000 Heart and Stroke Statistical Update. Dallas, Texas. American Heart Association, 1999. Elkind MS, Sacco RL. Stroke risk factors and stroke prevention. Semin Neurol 1998; 18(4):429–40. Prati P, Vanuzzo D, Casaroli M, Di Chiara A, De Biasi F, Feruglio GA, Touboul PJ. Prevalence and determinants of carotid atherosclerosis in a general population. Stroke 1992; 23(12):1705–11. Brown RD Jr, Evans BA, Wiebers DO, Petty GW, Meissner I, Dale AJ. Transient ischaemic attack and minor ischaemic stroke: an algorithm for evaluation and treatment. Mayo Clin Proc 1994; 69(11):1027–39. Whisnant JP. Natural history of transient ischaemic attack and ischaemic stroke. In: Whisnant JP (ed.) Stroke: Populations, Cohorts, and Clinical Trials. Oxford: Butterworth Heinemann, 1993; 135–53. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325(7):445–53. Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998; 339(20):1415–25.

CAROTID AND RENAL ARTERY STENTING

8.

9. 10.

11. 12. 13. 14. 15. 16. 17. 18. 19.

20. 21. 22.

23. 24.

25. 26. 27.

137

European Carotid Surgery Trialists’ Collaborative Group. Randomized trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial. Lancet 1998; 351(9113): 1379–87. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273(18):1421–8. Wennberg DE, Lucas FL, Birkmeyer JD, Bredenberg CE, Fisher ES. Variation in carotid endarterectomy mortality in the Medicare population: trial hospitals, volume, and patient characteristics. JAMA 1998; 279(16): 1278–81. Chaturvedi S, Femino L. Are carotid endarterectomy complication rates being monitored? Neurology 1998; 50 (6):1927–8. Rothwell PM, Slattery J, Warlow CP. Clinical and angiographic predictors of stroke and death from carotid endarterectomy: systematic review. BMJ 1997; 315:1571–77. McCrory DC, Goldstein LB, Samsa GP, Oddone EZ, Landsman PB, Moore WS, Matchar DB. Predicting complications of carotid endarterectomy. Stroke 1993; 24: 1285–91. Brown MM. Vascular Surgical Society of Great Britain and Ireland: results of the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). Br J Surg 1999; 86:710–11. Yadav JS, Roubin GS, Iyer SS, Vitek J, King P, Jordan WD, Fisher WS. Elective stenting of the extracranial carotid arteries. Circulation 1997; 95:376–81. Mathias K, Jager H, Sahl H, Hennigs S, Gissler HM. Interventional treatment of arteriosclerotic carotid stenosis. Radiology 1999; 39:125–34. Theron JG, Payelle GG, Coskun O, Huet HF, Guimaraens L. Carotid artery stenosis: treatment with protected balloon angioplasty and stent placement. Radiology 1996; 201: 627–36. Henry M, Amor M, Masson I, Henry I, Tzvetanov K, Chati Z, Khanna N. Angioplasty and stenting of the extracranial carotid arteries. J Endovasc Surg 1998; 5:293–304. Bergeron P, Becquemin JP, Jausseran JM, Biasi G, Cardon JM, Castellani L, Martinez R, Fiorani P, Kniemeyer P. Percutaneous stenting of the internal carotid artery: the European CAST I Study: Carotid Artery Stent Trial. J Endovasc Surg 1999; 6:155–9. New G, Roubin GS, lyer SS, Vitek JJ. Carotid artery stenting: rationale, indications, and results. Compr Ther 1999; 25:438–45. Diethrich EB, Ndiaye M, Reid DB. Stenting in the carotid artery: initial experience in 110 patients. J Endovasc Surg 1996; 3:42–62. Wholey MH, Wholey M, Mathias K, Roubin GS, Diethrich EB, Henry M, Bailey S, Bergeron P, Dorros G, Eles G, Gaines P, Gomez CR, Gray B, Guimaraens J, Higashida R, Ho DS, Katzen B, Kambara A, Kumar V, Laborde JC, Leon M, Lim M, Londero H, Mesa J, Musacchio A, Myla S, Ramee S, Rodriquez A, Rosenfield K, Sakai N, Shawl F, Sievert H, Teitelbaum G, Theron JG, Vaclav P, Vozzi C, Yadav JS, Yoshimura SI. Global experience in cervical carotid artery stent placement. Cathet Cardiovasc Interv 2000; 50: 160–7. Naylor AR, Bolia A, Abbott RJ, Pye IF, Smith J, Lennard N, Lloyd AJ, London NJ, Bell PR. Randomized study of carotid angioplasty and stenting versus carotid endarterectomy: a stopped trial. J Vasc Surg 1998; 28:326–4. Biller J, Feinberg WM, Castaldo JE, Whittemore AD, Harbaugh RE, Dempsey RJ, Caplan LR, Kresowik TF, Matchar DB, Toole JF, Easton JD, Adams HP Jr, Brass LM, Hobson RW 2nd, Brott TG, Sternau L. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation 1998; 97:501–9. De Marco JK, Schonfeld S, Wesbey G. Can noninvasive studies replace conventional angiography in the preoperative evaluation of carotid stenosis? Neuroimaging Clin North Am 1996; 6(4):911–29. Brant-Zawadzki M, Heiserman JE. The roles of MR angiography, CT angiography, and sonography in vascular imaging of the head and neck. AJNR Am J Neuroradiol 1997; 18(10):1820–5. Jackson MR, Chang AS, Robles HA, Gillespie DL, Olsen SB, Kaiser WJ, Goff JM, O’Donnell SD, Rich NM. Determination of 60% or greater carotid stenosis: a prospective comparison of magnetic resonance angiography and duplex ultrasound with conventional angiography. Ann Vasc Surg 1998; 12(3):236–43.

138

28. 29. 30.

31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42. 43.

44. 45. 46. 47.

III · STENTS

Williams DO. Carotid filters: new additions to the interventionalist’s toolbox. Circulation 2001; 104:2–3. Hobson RW 2nd, Brott T, Ferguson R, Roubin G, Moore W, Kuntz R, Howard G, Ferguson J. CREST: Carotid Revascularization Endarterectomy versus Stent Trial. Cardiovasc Surg 1997; 5:457–8. Roubin GS, New G, Iyer SS, Vitek JJ, Al-Mubarak N, Liu MW, Yadav J, Gomez C, Kuntz RE. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001; 103(4):532–7. Mann SJ, Pickering TG. Detection of renovascular hypertension: state of the art: 1992. Ann Intern Med 1992; 117:845–53. Derkx FHM, Schalekamp MADH. Renal artery stenosis and hypertension. Lancet 1994; 344:237–9. Dean RH, Tribble RW, Hansen KJ, O’Neil E, Craven TE, Redding JFH. Evolution of renal insufficiency in ischaemic nephropathy. Ann Surg 1991; 213(5):446–55; discussion 455–6. Hansen KJ. Prevalence of ischaemic nephropathy in the atherosclerosic population. Am J Kidney Dis 1994; 24: 615–21. The Joint National Committee. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997; 157(21):2413–46. National High Blood Pressure Education Program Working Group. 1995 update of the working group reports on chronic renal failure and renovascular hypertension. Arch Intern Med 1996; 156(17):1938–47. Gruntzig A, Kuhlmann U, Vetter W, Lutolf U, Meier B, Siegenthaler W. Treatment of renovascular hypertension with percutaneous transluminal dilatation of a renal artery stenosis. Lancet 1978; 1:801–2. van de Ven PJ, Kaatee R, Beutler JJ, Beek FJ, Woittiez AJ, Buskens E, Koomans HA, Mali WP. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomized trial. Lancet 1999; 353: 282–6. Dorros G, Jaff M, Mathiak L, Dorros II, Lowe A, Murphy K, He T. Four-year follow-up of Palmaz-Schatz stent revascularization as treatment for atherosclerotic renal artery stenosis. Circulation 1998; 98:642–7. Henry M, Amor M, Henry I, Ethevenot G, Tzvetanov K, Courvoisier A, Mentre B, Chati Z. Stents in the treatment of renal artery stenosis: long-term follow-up. J Endovasc Surg 1999; 6:42–51. White CJ, Ramee SR, Collins TJ, Jenkins JS. Renal artery stent placement. J Endovasc Surg 1998; 5:71–7. Plouin PF, Chatellier G, Darne B, Raynaud A. Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis. A randomized trial. Hypertension 1998; 31:823–9. van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J, Postma CT, Dees A, Woittiez AJ, Bartelink AK, Man in ‘t Veld AJ, Schalekamp MA. The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis. N Eng J Med 2000; 342:1007–14. Harden PN, MacLeod MJ, Rodger RS, Baxter GM, Connell JM, Dominiczak AF, Junor BJ, Briggs JD, Moss JG. Effect of renal artery stenting on progression of renovascular renal failure. Lancet 1997; 349:1133–6. Plouin PF, Darne B, Chatellier G, Pannier I, Battaglia C, Raynaud A, Azizi M. Restenosis after a first percutaneous transluminal renal angioplasty. Hypertension 1993; 21:89–96. Olin JW, Piedmonte MR, Young JR, DeAnna S, Grubb M, Childs MB. The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995; 122(11):833–8. Mackenzie HS, Brenner BM. Current strategies for retarding progression of renal disease. Am J Kidney Dis 1998; 31(1):161–70.

Part IV Restenosis

11 Pathophysiology, pharmacology and patient factors in restenosis

Introduction Restenosis has plagued angioplasty since its inception. Despite remarkable advances in the technique, the restenosis rate has remained relatively unchanged for more than 20 years. Over the past few years, however, greater understanding of the pathophysiology of restenosis, the development of stents and now, drugeluding stents, as well as radiation therapy, have all added significant armamentarium to the prevention of this problem. The increased understanding of the pathophysiology of restenosis has led to an appreciation of the importance of inflammation and the genetic factors regulating arterial wall proliferation. The prior concepts of restenosis involved a series of events that parallel wound healing. Following the stretch injury of angioplasty, elastic recoil of the artery, platelet accumulation and thrombosis occur, particularly if there was a significant dissection. Intimal proliferation is evident several days later and in experimental animal models peaks at two to three weeks. However, clinical and experimental studies have shown that unfavourable remodelling (either constriction or lack of adequate compensatory dilation) is largely responsible for restenosis following balloon angioplasty or angioplasty using laser or atherectomy devices. These older concepts are no longer appropriate in the modern stent era. While each of these components is clearly operative in angioplasty, stents have effectively eliminated elastic recoil and the problem of unfavourable remodelling. It is now widely recognized that intimal hyperplasia dominates the pathophysiology of balloon angioplasty. It is important, however, to recognize the lesser but important role that thrombosis plays in enhancing intimal hyperplasia, by providing a scaffold for the infiltration of circulating blood cells and arterial smooth muscle cells. Within the stent, there is no appreciable recoil and no significant degree of remodelling, but at the edges of the stent, the process of remodelling can be a significant contributor to edge restenosis. The important studies conducted over this past year were largely based upon solid basic research that has emphasized the growing role of both early and chronic inflammation and oxidant stress on inducing intimal proliferation. While not referenced below, many studies have shown that patients with restenosis have elevated levels of c-reactive protein (CRP) and other markers of inflammation, such as IL6 and TNF alpha, consistent with a generalized inflammatory process and an acute inflammatory reaction to angioplasty.

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Patient factors have not been very valuable in predicting restenosis. The one exception has been diabetes, where the rate of restenosis is two-fold greater. As noted below, the outcome of patients with diabetes and restenosis is quite unfavourable. Angiographic factors or intravascular ultrasound measurements of lumen diameter are still the most predictive of a favourable outcome. Therapeutic options to prevent restenosis have been largely disappointing. This past year, a number of clinical trials have shown that drugs that either inhibit the inflammatory response or effectively inhibit neointimal proliferation following stenting are generally effective. Most importantly, the introduction of drug-eluding stents will allow the use of agents that are effective in high doses experimentally, but toxic when given systemically. This should allow the development of many new and effective pharmacological approaches to restenosis. Pathophysiology and patient factors Elevated circulating levels of monocyte chemo-attractant protein-1 in patients with restenosis after coronary angioplasty. F Cipollone, M Marini, M Faza, et al. Arterioscler Thromb Vasc Biol 2001; 21(3):327–34. BACKGROUND. Inflammation plays a pathogenic role in the development of restenosis. Monocyte chemoattractant factor or MCP-1 is a highly potent chemoattractant to monocytes. Monocytes can be seen histologically early in the development of intimal hyperplasia and may, through cytokine and growth factors, contribute to the process. In addition, MCP-1 induces free oxygen radicals in circulating monocytes. This study measured plasma levels of MCP-1 in 50 patients before, 1, 5, 15, and 180 days after angioplasty. MCP-1 levels in those patients who developed angiographic evidence of restenosis were significantly higher than in those who did not. In contrast other chemokines did not correlate. By multivariate analysis an elevated MCP-1 level 15 days after the procedure was the only independent predictor of restenosis. INTERPRETATION. The important role of monocytes in the chronic inflammatory response during restenosis has not been fully appreciated before. This study not only emphasizes the importance of chronic inflammation, it provides a potential method to follow patients in order to determine the risk of restenosis (Fig. 11.1).

Comment The earliest cellular changes that occur following vascular injury in experimental animals are platelet adhesion and aggregation followed by thrombosis. Shortly thereafter, polymorphonuclear cells can be seen to infiltrate the injured area, as well as the developing thrombus. The major inflammatory cells, however, are the monocytes that can be seen within the first day but peak much later and parallel the intimal hyperplasia. Human studies show that CD68 or HAM56 staining cells are present in atherectomy specimens and at autopsy. This study verifies much of what has already been described experimentally and confirms the importance of the monocytes in this process. The stimulus for monocyte recruitment is the transient burst of MCP-1, but as shown, the chronic recruitment from autocrine and paracrine perpetuation may be equally important. The source of MCP-1 may not only be from the monocytes, but also from endothelial cells and smooth muscle cells. The study suggests that oxygen radical formation within circulating monocytes may be increased and could also contribute to the process. The study also shows the time course to be prolonged and suggests that interventions to reduce inflammation need to be present for at least two weeks. The important and unresolved question is why some

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Fig. 11.1 Scatterplot showing association of plasma MCP-1 measured in 50 patients 15 days after percutaneous transluminal coronary angioplasty (PTCA) with the degree of luminal renarrowing expressed as RLOSS at 6 months after treatment. Source: Cipollone et al. (2001).

patients responded to angioplasty with such an exaggerated inflammatory response, while others did not. Understanding this may allow better selection or pre-treatment of patients. The major limitation of the study is that it was performed in patients receiving balloon angioplasty and not stents. It seems likely that the same phenomenon is present with stents, but further study is clearly necessary to confirm this. Clinical and quantitative coronary angiographic predictors of coronary restenosis. A comparative analysis from the balloon-to-stent era. N Mercado, E Boersma, W Wijns, et al. J Am Coll Cardiol 2001; 38(3): 645–52. BACKGROUND. This study examined the clinical and angiographic predictors of restenosis in patients with and without coronary stents. The authors utilized the extensive database available at the Thorax centre in Rotterdam from 19 registries and randomized trials. The data from 8156 patients were analysed. The restenosis rate was 35% for PTCA and 19% for stenting. The multivariate predictors were largely the same for both with the only clinical predictors being diabetes and prior coronary artery bypass graft (CABG). Multivariate analysis showed that stent use, a large post-minimal luminal diameter (MLD), and lesion length were also predictive. INTERPRETATION. This study is one of the largest in the literature and continues to confirm that the most potent predictors of restenosis are angiographic rather than clinical (Table 11.1). The study also shows that in the stent era, the predictors are not significantly different from those described for balloon angioplasty.

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Comment While the findings initially are not surprising, the differing mechanisms responsible for restenosis with each technique and the recognized lack of benefit of stenting in small vessels or long lesions might have been expected to yield different results. The study emphasizes the importance of an adequate lumen following either procedure. As has been shown in the past, stents more reliably result in large lumens than balloon angioplasty. The study also continues to support the ‘bigger is better’ concept that has dominated angioplasty for the last 10 years. Larger lumens result in less restenosis but not because there is less intimal hyperplasia. In fact, the larger the lumen following angioplasty, the greater the absolute amount of intimal Table 11.1 Multivariate analysis: clinical and quantitative coronary angiographic predictors of coronary restenosis Variable

OR

95% CI

P value

Intercept coefficient=0.22 Stent use Lesion length Post-MLD Previous CABG Diabetes mellitus Stent use post-MLD Source: Mercado (2001).

0.83 1.05 0.53 0.69 1.33 0.34

0.72–0.97 1.04–1.06 0.46–0.61 0.53–0.9 1.16–1.54 0.31–0.39

0.0193 <0.001 <0.001 0.006 <0.001 0.002

hyperplasia. Fortunately, the degree of renarrowing is 40 to 60% of the initial gain in lumen. Thus, a larger gain results in a larger lumen, since it can better accommodate a 50% loss in lumen enlargement. This study in fact emphasizes this phenomenon even more for stenting, presumably because the stent not only eliminates unfavourable remodelling but also does away with compensatory enlargement that can help accommodate for the intimal hyperplasia seen with balloon angioplasty. This study also importantly demonstrates that certain variables thought to influence restenosis no longer have an effect. For instance, it has been long believed that lesion location, particularly a proximal left anterior descending (LAD) lesion, was an important predictor of restenosis. In this analysis, lesion location was not predictive. Patency of percutaneous transluminal coronary angioplasty sites at six-month angiographic followup. A key determinant of survival in diabetics after coronary balloon angioplasty. E Van Belle, R Ketelers, C Bauters, et al. Circulation 2001; 103:1218–24. BACKGROUND. Diabetes is a potent risk factor for adverse outcomes including restenosis. In this study the authors followed 603 patients with diabetes who had successful balloon angioplasty. All patients underwent angiography at 6 months and were followed for an average of 6.5 years. The overall actuarial 10-year mortality rate was 36%. When the group was divided into three groups based on the results of the 6-month angiogram, 162 patients were found to have no restenosis, 257 had non-occlusive restenosis and 94 had occlusive restenosis. The actuarial 10-year mortality was 24%, 35%, and 59% respectively. Multivariate analysis showed that occlusive restenosis was a potent predictor of mortality (odds ratio of 2.16). INTERPRETATION. Prior studies have shown that while restenosis adds to the morbidity of the procedure, it does not add to the long-term mortality. The finding that restenosis, particularly occlusive

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restenosis, has an important impact on long-term mortality in diabetic patients is of great significance and may well help to explain the poor outcome recognized to occur in these patients (Figure 11.2).

Comment Diabetic patients are at increased risk of developing coronary artery disease (CAD) and nearly three quarters die of heart disease. A diabetic with CAD is twice as likely to die as a patient with CAD but without diabetes. This holds true for both angioplasty and CABG as well. Since diabetic patients comprise 20–25% of all patients undergoing revascularization, an understanding of the factors responsible for the poor outcome is critical. Randomized trials, particularly the Bypass Angioplasty Revascularization Investigation (BARI) study, have shown that diabetic patients with PTCA or CABG have a significantly worse mortality than non-diabetics undergoing revascularization. Diabetic patients who underwent PTCA or CABG with saphenous vein graft (SVG) only had twice the mortality of patients with CABG with internal mammary artery (IMA) grafts. The mechanism for this less favourable outcome is not clear, but those that did best with surgery were those with the most extensive disease. The benefit was also most dramatic in those who sustained a myocardial infarction (MI) during follow-up. The mortality in diabetic patients with an MI who underwent CABG with a left interior mammary artery (graft) (LIMA) had a 5-year mortality of 10% compared to 66% and 36% for SVG only and PTCA. The investigators have interpreted this improved outcome to be due to the greater patency of the LIMA graft that protected against mortality following an MI during follow-up. The study by Van Belle et al. adds considerable insights into the poor outcome in diabetic patients. First, it demonstrates that diabetics have a higher rate of occlusive restenosis than non-diabetics (14% vs 3%). This is not surprising since it is well recognized that diabetes results in an increase in thrombosis due in part to reduced thrombolysis. In experimental studies, diabetes results in increased PAI-1 synthesis in the arterial wall following angioplasty. Secondly, the study showed an astounding restenosis rate of 63% in this unselected group of diabetics. Finally and most significantly, the study shows that restenosis has a major impact on mortality in these patients. The high rate of occlusion and of non-occlusive restenosis helps to validate the interpretation of the BARI study and indicates the importance of vessel patency in long-term outcome in these patients. The study, however, does have a number of limitations. Most importantly, the patients had only balloon angioplasty and not stenting. It has been shown by a number of investigators, including these investigators, that stenting reduces restenosis in patients with diabetes. However, the results of the Arterial Revascularization Therapy (ARTS) trial, which compared stenting to CABG, showed that diabetic patients undergoing surgery had a better outcome than those undergoing stenting. The impact of platelet IIb/IIIa antagonists, intravascular radiation and drug eluding stents in the diabetic are all relevant and could provide sufficient patency and absence of restenosis to make the outcome of angioplasty equivalent to that of surgery. Future studies will be necessary to evaluate these techniques in this high-risk population. Pharmacologic therapy Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. G Schnyder, M Roffi, R Pin, et al. N Engl J Med 2001; 345:1593–600.

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Fig. 11.2 Kaplan-Meier survival curves for long-term total (top panel) and cardiac (bottom panel) mortality as function of vessel patency at repeated angiography in dilated vessels. Source: Van Belle et al. (2001). BACKGROUND. Homocysteine levels have been shown to correlate with cardiovascular risk, the severity of CAD and restenosis. In this double blind controlled study, the benefit of folic acid, vitamin B12 and pyridoxine on restenosis was evaluated

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in 205 patients undergoing angioplasty or stenting. Treatment significantly lowered homocysteine levels. At 6 months, angiographic restenosis was 19.6% in the treatment group and 37.6% in the control group. In addition the rate of repeat revascularization was also lower in the treated patients. INTERPRETATION. This study not only demonstrates that a simple regimen of vitamins can reduce restenosis, but also supports the concept that homocysteine is an important contributor to restenosis. Ongoing studies will also evaluate the benefit in reducing the progression of disease as well. In comparison to more expensive methods to reduce restenosis, the simplicity and safety of this therapy makes it practical for nearly all patients.

Comment Homocysteine levels are the result of pryridoxal phosphate-dependent cystathionine β-sythetase pathways or vitamin B12-folate-dependent remethylation to methionine. Deficiencies of critical enzymes can lead to mild to moderate elevations of plasma homocysteine. The abnormally low enzymes can be inherited or can be acquired by deficiencies in folate, vitamin B12 or pyridoxine. It can also occur in renal failure. Homocysteinaemia can lead to vascular disease and mild forms have been felt to be associated with the acceleration of atherosclerosis. While homocysteine levels correlate with atherosclerosis, it still needs to be shown that vitamin treatment can reduce progression of atherosclerosis. In contrast, this study by Schnyder shows that the combination of folate, vitamin B12 and pyridoxine can reduce restenosis substantially. It is noteworthy that the patients were not selected on the basis of initial homocysteine levels and that the authors do not report a correlation between the level and the degree of lowering of homocysteine and outcome. This could mean that the mechanism of benefit is not through a reduction of homocysteine and is more likely due to the small sample size of the study. Those patients undergoing only balloon angioplasty had greater benefit than those undergoing stenting and this again raises issues concerning the mechanism of benefit. Since restenosis in balloon angioplasty is more related to unfavourable remodelling than intimal hyperplasia, it suggests that the vitamin therapy had an influence on remodelling as well. The study did not determine whether all three vitamins were necessary to achieve a reduction in restenosis. Many studies have shown that folate alone is sufficient in many patients with elevated homocysteine levels to lower the level of restenosis effectively. Local delivery of enoxaparin to decrease restenosis after stenting: results of initial multicentre trial. R S Kiesa, P Buszman, J L Martin, et al. Circulation 2001; 103:26–31. BACKGROUND. Local delivery of pharmacologic agents has been suggested as a means of reducing restenosis. Enoxaparin, a low molecular weight heparin, has been

shown to not only reduce thrombosis but also to inhibit smooth muscle cell proliferation and restenosis experimentally. A hundred patients undergoing coronary stenting were randomized to either local delivery of enoxaparin or routine therapy with systemic heparin. Local delivery was accomplished by use of a transport catheter. INTERPRETATION. This was the first study to show that local delivery of the drug enoxaparin is effective in reducing restenosis after angioplasty and stenting. The findings support the concept of local drug delivery. The study also shows the potential role of heparin and its derivatives in inhibiting restenosis.

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Comment Heparin is a complex mixture of polysaccharides that possess anticoagulant and antiproliferative actions. Heparin binds with antithrombin III to form a complex, which in turn binds with factors V and 10A to prevent fibrin formation. LMW heparins possess much greater activity toward factor 10A than unfractionated heparins. In addition, non-anticoagulant heparins also can inhibit smooth muscles cell proliferation, a property also seen with LMW heparins. Finally, these agents are more diffusible through the arterial wall. These properties suggest that LMW heparin might be effective in preventing restenosis. Unfortunately, clinical trials of enoxaparin, fragmin and heparin have not shown a reduction in restenosis, despite considerable experimental data to support the effectiveness of heparins. One explanation has been that the amount of drug delivered to the angioplasty site when given systemically is insufficient. The results of this trial would support this idea. With the advent of drug eluding stents, a long list of potential drugs that have been shown to reduce restenosis experimentally at high doses may now be clinically effective if delivered locally. Genetic manipulation of human coronary artery bypass grafts with E2F decoy (GT003) reduces graft failure, Nov 12, 2001. E Grube, T Felderhoff, P J Fitzgerald, et al. Results of the randomized, controlled prevent II trial AHA scientific sessions, late breaking trial presentation. Anaheim, California, 2001. BACKGROUND. Graft failure is recognized to occur over 10 years in 50–60% of saphenous vein grafts used for coronary bypass surgery. The mechanism of failure is due to intimal hyperplasia and to acceleration of atherosclerosis. The process has some parallels to restenosis. In this study, 200 patients undergoing CABG were randomized to placebo or to incubation of the vein graft in E2F decoy before implantation. E2F decoy is an inhibitor of a critical cell cycle gene necessary for smooth muscle cell replication. At 12 months, quantitative angiography and intravascular ultrasound (IVUS) in 136 patients showed a 30% reduction in vein graft failure (>75% stenosis) or death (P=0.034). IVUS also showed less intimal hyperplasia.

INTERPRETATION. This is the first randomized controlled study of gene therapy to prevent saphenous vein failure. While the study evaluated SVG disease, the findings are applicable to restenosis since intimal hyperplasia is similar between the two conditions and raises the possibility that gene therapy may have a role in restenosis prevention.

Comment The findings of this study give strong support to the field of vascular gene therapy. While the use of gene therapy for vascular disease has been reported before, this is the first investigation to show that cell cycle inhibition can reduce intimal hyperplasia. Prior studies have shown that genetic material can be transferred into the arterial wall by transfusion or by direct transfer. Randomized trials have not been positive or not yet conducted. The technique of gene transfer in this study was simple: incubation of the graft prior to insertion. This also prevents systemic exposure and allows for adequate transfer of the genetic material. The techniques necessary for application to prevention of restenosis will be much more difficult. Importantly, the study showed no adverse effects from exposure of the agent. Canadian antioxidant restenosis trial (CART-1).

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J C Tardif. AHA scientific sessions, late breaking trials. Anaheim California, 2001. BACKGROUND. The MVP study, a randomized clinical trial, demonstrated that probucol, a cholesterol-lowering agent with antioxidant properties, reduced restenosis. This study extends those observations by comparing, placebo, probucol and three doses of AGI-1067, an equipotent antioxidant. Patients were treated for two weeks prior to angioplasty. Stents were used in 81% of patients. The study showed that probucol and AGI-1067 resulted in larger lumen diameters at 6-month follow-up. There was also a dose response relationship with AGI-1067. The study also showed that the reference segments enlarged over time suggesting a possible effect on regression of the underlying atherosclerosis. INTERPRETATION. This study confirms the benefit of antioxidant therapy in reducing restenosis and confirms the important role that oxidant stress plays in the process.

Comment Oxidant stress in the arterial wall is recognized to occur during intimal thickening from hypertension and atherosclerosis. In addition, injury from angioplasty can significantly increase the production of free oxygen radical that can overwhelm the natural antioxidant enzymes within the wall. Oxidant stress can lead to further release of cytokines and growth factors and accelerate intimal hyperplasia. The MVP study and now the CART-1 study clearly demonstrate that inhibition of oxidant stress can reduce intimal hyperplasia. The agent studied has a number of advantages over probucol. The drug was well tolerated and had a significant dose response relationship to lumen diameter. It also had no effect on QT corrective interval, unlike probucol. Since the drug has no lipid effect, it can be assumed that the mechanism of action was through its antioxidant affect rather than by other mechanisms. PRESTO Trial. Tranilast for restenosis D Holmes. AHA scientific sessions, late breaking trials. Anaheim, California, 2001. BACKGROUND. Tranilast is an antikeloid agent with anti-allergic properties. It has been shown to inhibit smooth muscle cell proliferation and restenosis in experimental models. This study was a multicentre double-blind randomized trial of four dose regimens of tranilast versus placebo. The study enrolled 11 500 patients. The primary end-point was major cardiac events (death, MI, or ischaemic driven revascularization) at 6 months. Secondary end-points included quantitative angiographic and ultrasound measurements of the stenosis. The study showed that there was no difference in the primary end-point of major adverse cardiac event averaging 15–16% in each group and a low rate of death (1.2%), MI (1.4%) and target vessel revascularization (14.5%). Angiographic restenosis was 32–35% and there was similarly no difference between the groups. Analysis of a number of sub-groups also failed to identify any group of patients who benefited from the therapy. INTERPRETATION. This is the largest restenosis trial yet reported. It clearly shows that tranilast in four regimens failed to reduce clinical events and target vessel revascularization. Although the results of the quantitative coronary angiography (QCA) and IVUS were not reported, the negative clinical and initial angiographic findings are convincing. The data collected on this very large cohort of patients should be a valuable source of information for further understanding of restenosis in the stent era.

Comment The negative results of this study are surprising given the positive results reported in four previous randomized clinical trials. The previous studies were small and single centre studies, except for the TREAT trial. In this study 255 patients were studied. The restenosis rate fell from 47% to 15% in the high-dose

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tranilast group. Importantly, stents were not used in this study but were used in the PRESTO trial (85%). This difference may be one explanation for the negative results in the latter trial. The agent would be expected to have a significant benefit in restenosis. It has been shown to decrease smooth muscle cell proliferation through inhibition of platelet derived growth factor and transforming growth factor-β, decrease collagen synthesis, and improve nitric oxide (NO) production. The lack of effect and the demonstrated benefit of other agents with more potent anti-inflammatory and antiproliferative actions could also be an explanation. Finally, the dosages used could be insufficient and again, this suggests that local drug delivery may be critical for benefit from agents like tranilast. Conclusion The central theme of all of the new therapeutic approaches for prevention of restenosis is that high local concentration of drugs during the critical time period of healing are essential and that anti-inflammatory agents and anti-proliferative agents can be effective. As shown by the currently reported drug eluding trials, effective delivery of these agents can nearly eliminate restenosis. The future of the pharmacological therapy for restenosis will be to identify the best agents for local delivery and/or drug eluding stents. Based on experimental studies, many agents may be highly effective.

12 Management of in-stent restenosis

Introduction The introduction of stents lowered the incidence of restenosis in the most suitable lesions, the ones included in major randomized trials |1,2|, in the meantime extended the percutaneous treatment of lesions not considered suitable for angioplasty. This fact means that a number of non-ideal lesions are now effectively treated with a stent with optimal immediate result but without any clear guarantee of sustained long-term patency. If we examine the incidence of restenosis in the ‘real world’ type of lesions it seems that no progress has been made |3,4|. The incidence of in-stent restenosis (ISR) is approximately 20–35% and a repeat intervention is needed in 15–20%. Considering that stents are used in approximately 80% of 1000000 percutaneous interventions worldwide each year, more than 120000 patients will require a repeat procedure |5|. The treatment, however, of ISR has become a ‘Vicious cycle’ for interventional cardiologists. The limited tools we had until recently could not counterbalance the increasing incidence of restenosis with the accompanying requirement for target lesion revascularization. Mechanism of in-stent restenosis After percutaneous interventions three different mechanisms of restenosis have been identified: elastic recoil, intimal hyperplasia and vascular remodelling. It is now widely accepted that ISR is entirely attributed to intimal hyperplasia, as contemporary stent designs eliminate negative remodelling and elastic recoil |6|. This fact was initially shown by angiographic analyses |7,8| and by gross inspection and pathologic studies of stents removed at autopsy |9–12| demonstrating proliferating smooth muscle cells and extracellular matrix as the predominant components of ISR. The only mechanical problem which may still contribute to ISR is inadequate stent expansion. This problem was recognized at the early stages of stent usage. Several intravascular ultrasound (IVUS) criteria have been established to evaluate the complete apposition of the stent at the arterial wall and the achievement of the largest possible lumen according to the reference vessel size. The achievement of the IVUS criteria following stent implantation is reported to be 32–82% |13–15|. This fact means that adequate stent expansion is not achieved in a considerable percentage of stented lesions and this problem adds to that of tissue proliferation to increase the risk of ISR. Other mechanical complications leading to ISR are:

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missing the lesion, especially in aorto-ostial lesions, ‘crushed’ stents, and stent stripping off the balloon during the implantation procedure. These three complications were reported in 4.5% of the restenotic lesions (Castagna et al. (2001)). Time course of ISR Restenosis after stent implantation peaks by 1–3 months, reaches a plateau within 3–6 months and is unusual after 12 months |16,17|. Several angiographic studies have shown a further increase in lumen diameter six months to three years after stent implantation suggesting that six month angiography may overestimate the risk of restenosis |18|. The development of intimal hyperplasia leading to restenosis is not necessarily accompanied by symptoms. Asymptomatic restenosis diagnosed by scheduled repeat angiography is frequently observed. In a metanalysis of ten studies including 2690 patients with complete clinical and angiographic follow-up data following stent implantation, clinical silent restenosis was found in 55% of the patients with ISR. The only predictors for silent ISR at 6 months were male sex, greater diameter at follow-up, and a lesser lesion severity on follow-up angiography (Ruygrok et al. (2001)). Patterns of ISR The need to classify ISR in different patterns comes from the fact that each specific pattern has a different prognosis. ISR can be divided as focal or diffuse: Focal ISR is a stenosis≥ 10 mm in length; this type of ISR is found in about 42% of lesions |19|, diffuse ISR is any other type of restenotic lesion. The diffuse pattern of restenosis can be further divided into classes: ‘in-stent’ if confined to the stent, ‘proliferative’ if the ISR extends beyond the margins of the stent and ‘total occlusion’ if the stent is completely occluded. Of the 58% of diffuse ISR, intrastent restenotic lesions account for 21%, the ‘proliferative’ for 30% and total occlusions for 7% |19|. Predictors for diffuse pattern of ISR are: diabetes mellitus, recurrent ISR, small lumen diameter before and after stent implantation, final cross sectional area from IVUS, lesion and stent length, treatment of total occlusion and type of stents (coil) (Goldberg et al. (2001)). Our group has also introduced the concept of an aggressive pattern of restenosis defined as an increase in lesion length from the original lesion or as a restenotic narrowing tighter than the original. Aggressive ISR is more common in females, following implantation of Wallstents, and with long stent to lesion length ratios. Interestingly, aggressive restenosis occurs earlier and is more closely associated with symptoms and myocardial infarction than non-aggressive restenosis (Goldberg et al. (2001)). Treatment options for ISR The mechanical approach Balloon angioplasty for ISR Repeat balloon angioplasty (PTCA) has been the first approach for the treatment of ISR. PTCA is an easy and safe procedure with a high procedural success rate |20|. Initial angiographic measurements showed that

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lumen enlargement after angioplasty for ISR results primarily from compression or extrusion of intimal hyperplasia through the stent struts, or both, rather than from further stent expansion |7|. Subsequent studies with IVUS demonstrated that the mechanism of PTCA for ISR is a combination of additional stent expansion and tissue extrusion from the stent. Recent observations demonstrate that there is significant tissue re-intrusion shortly after PTCA treatment of ISR resulting in early lumen loss |21|. The angiographic re-restenosis rate following PTCA for ISR is 22–83% and depends on the pattern of restenosis and the percentage of stenosis |22–26|. PTCA for diffuse or severe stenotic ISR lesions is associated with higher restenosis rate. Bauters et al. showed that for diffuse ISR the re-restenosis rate was 42% versus 14% for focal ISR, and for stenosis diameter ≥ 70%, recurrence of restenosis was observed in 33% versus 11% of cases with stenosis <70% |25|. A prohibitive recurrence rate of 83% has been reported when ISR presents as a total occlusions and it is treated with PTCA |27|. The results of these studies suggest that PTCA should not be the method of choice for the treatment of diffuse ISR. However, for lesions with inadequate stent expansion of the stent and for focal ISR, balloon dilatation can be an effective solution, both immediately and in the long term |28,29|. Atheroablation These techniques aim to remove part of the hyperplasia formed inside the stent increasing the final lumen dimensions compared to PTCA |30,31|. Rotational atherectomy (ROTA), directional atherectomy (DCA), and excimer laser atherectomy (ELCA), have been be used to remove neointimal tissue during treatment of ISR. 1. Rotablation Atherectomy. The use of ROTA to treat ISR aims to partially remove tissue from inside the stent with a versatile system able to reach a number of lesions. Despite good immediate angiographic results this approach did not prove successful in the long term. The target lesion revascularization (TLR) rate after ROTA as a treatment for ISR ranged from 21% to 56%, with an angiographic restenosis rate up to 45% |30,32–37|. In the large randomized ARTIST trial (Angioplasty versus Rotational atherectomy for Treatment of diffuse In-stent Restenosis) 298 patients with diffuse ISR (lesion length 10–50 mm) were included |38|. This study failed to show any superiority of ROTA with additional PTCA over PTCA in the treatment of ISR. One important limitation of most of the studies using ROTA to treat ISR is the fact that additional PTCA was not used in an attempt to achieve the largest final diameter (large balloons and high pressure). A conservative approach was employed in order to limit any additional injury. 2. Directional Coronary Atherectomy. Although DCA is the only true ‘debulking’ technique a small amount of data are available on its use for the treatment of ISR. The insertion of large profile, rigid catheters is a concern unless straight arterial segments with large reference diameter are treated. Initial results with DCA were unfavourable as stent disruption was observed |20,39|. The complexity of the technique, the risk of damaging the stent and the lack of convincing data on its efficacy contributed to the lack of usage of DCA to treat ISR. Despite these limitations, the possibility of removing most of the hyperplasia is an appealing method for treating ISR. In order to be practical and effective, new low profile, flexible and easy to use catheters are needed |40|. This approach, which gives optimal immediate results, may prove quite useful to avoid additional re-stenting, an option to be avoided for patients also undergoing radiation therapy. 3. Excimer Laser Angioplasty. In an effort to accomplish successful debulking of restenotic tissue ELCA has been used in conjunction with PTCA. IVUS volumetric analysis showed that tissue ablation during

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ELCA contributed 29% to the overall lumen gain, tissue extrusion by PTCA contributed 31%, and additional stent expansion 40%. ELCA results in greater lumen gain, more intimal hyperplasia ablation, larger final lumen cross sectional area compared to PTCA (Mehran et al. (2000)). Although ELCA achieves better short-term angiographic results the long-term outcome is not favourable. In a large study Lauer et al. compared the efficacy of ELCA, ROTA and PTCA in 576 patients (682 lesions) with ISR. Although the larger immediate lumen enlargement was achieved by ELCA and ROTA, at six months the ELCA group had the lowest minimal lumen diameter (ROTA: 1. 62±0.89, ELCA: 1.35±0.93, PTCA: 1.53±0.87 mm) |41|. The LARS (Laser Angioplasty for Restenotic Stents) study was conducted for assessing the angiographic and clinical outcomes of 157 consecutive procedures in 146 patients with ISR treated with either PTCA alone (n=64) or ELCA (n=93). Lesions selected for ELCA were longer, more complex, and with compromised anterograde flow compared to PTCA-treated patients. ELCA-treated patients had a similar rate of procedural success (98.9% vs 98.4%) and major clinical complications (1.1% vs 1. 6%). At one year, ELCA-treated patients had similar rates of major cardiac events (39.1% vs 45.2%; P=0.456) and TLR (30.0% vs 32.3%; P=0.646) (Giri et al. (2001)). In a single centre study 96 patients were randomized to ELCA plus PTCA versus PTCA alone. In the laser group the angiographic restenosis rate was 77% versus 48% of the PTCA group |42|. These data suggest that ELCA in patients with ISR does not provide any benefit over PTCA alone for the prevention of recurrence of restenosis. Cutting balloon for ISR The use of a cutting balloon to treat ISR is unique because it cannot be considered similar to PTCA or as a truly ablating device. The cutting balloon catheter is a relatively novel device. This balloon has microblades that incise the neointimal tissue and develop a controlled fault line along which dilation occurs. When the balloon is inflated the blades incise the restenotic plaque up to the metallic stent edge. Therefore, the blades facilitate the maximum extrusion of the neointimal tissue, separated in 3 or 4 quadrants |43|. The cutting balloon achieves a better final result than conventional PTCA, by making the tissue more amenable to being pushed outwards through the stent struts |44|. The possible mechanisms of cutting balloon angioplasty for ISR are probably related to plaque extrusion through the stent struts, probably with less tissue injury compared to other techniques |44|. The greatest experience with cutting balloon in ISR has been gained in the Japanese Multicentre Registry which included 194 lesions. The angiographic restenosis was 29% and TLR was required in 22% of the lesions |45|. In a recent non-randomized study Adamian et al. compared the efficacy of cutting balloon with PTCA, restenting and rotablation atherectomy. Patients treated with cutting balloon had the lowest angiographic restenosis and TLR rates, despite the fact that lumen size after cutting balloon angioplasty was not as large as after re-stenting. The minimal lumen diameter at follow-up, however, was significantly larger in the cutting balloon group compared to that obtained with other techniques (Adamian et al. (2001)). The preliminary results of a randomized study including 282 patients did not show any difference in TLR between ROTA and cutting balloon angioplasty for the treatment of diffuse ISR (21.4% for ROTA vs. 34. 2% for cutting balloon, P=NS) |37|. The results of the RESCUT study (REStenosis CUTting balloon evaluation) are expected to provide insights regarding the efficacy of cutting balloon angioplasty compared to PTCA. RESCUT is a multicentre, randomized study comparing cutting balloon angioplasty to PTCA in patients with ISR. The

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enrolment phase of the study has been completed with a total of 420 patients included. In the RESCUT study, there is an ancillary IVUS sub-study, in which IVUS examination is performed 15–30 minutes after the procedure, for the detection of possible differences in the mechanisms between cutting balloon angioplasty and conventional PTCA in restenotic lesions. Additional stenting for ISR Re-stenting has also been proposed for the treatment of ISR in order to address the problems of elastic recoil and neointimal tissue reintrusion after PTCA |21|. The results after re-stenting do not completely support these theoretical advantages. The implantation of a second stent may be advantageous only in selected conditions. PTCA and stenting were evaluated in a comparative study, which included 135 patients with ISR. There was no benefit from re-stenting, although a larger lumen (2.95 mm vs 2.23 mm, P<0.01) and a smaller residual diameter stenosis (11% vs 23%, P=0.04) were achieved by the implantation of a new stent. Periprocedural cardiac enzyme elevation was more frequent in the stent group and at one year the cumulative mortality and the target lesion revascularization rates were similar (Mehran et al. (2001)). The overall effectiveness of re-stenting seems comparable to PTCA. A recent randomized study, the RIBS trial (Restenosis Intra-stent: Balloon angioplasty versus elective Stenting) |46|, showed a benefit of additional stenting for ISR when applied in vessels with diameter >3 mm. Thus the routine use of stents for the management of ISR is not supported by the current experience. The only rationale for the elective use of a second stent is the presence of stent compression or severe tissue prolapse in a vessel with a reference diameter >3 mm or in some selected cases of restenosis limited to the edge of a stent or in areas not fully covered by the previous stent. B. Biological approach The mechanical interventions for the treatment of ISR have not been associated with a clear long-term benefit except for the focal pattern. Device selection does not seem to influence late outcomes especially in most of the diffuse ISR |47,48|. In recent years new fields in Interventional Cardiology have been introduced utilizing a biological approach for preventing the recurrence of ISR Brachy therapy for ISR The use of radiations (gamma or beta) delivered at a close distance (inside the vessel lumen) has been shown to be an effective approach for treating ISR following luminal gain obtained with a mechanical approach. This method will be discussed in a separate chapter. Sonotherapy for ISR Therapeutic ultrasound has long been used in medicine. Catheter delivered ultrasound has been used since the 1980s in interventional cardiology for clot lysis in the setting of acute myocardial infarction and peripheral thrombembolism. However it was not until recently that the favourable properties of ultrasound for the inhibition of intimal hyperplasia were appreciated. Low frequency ultrasound has been shown to restore normal endothelial cell lining function and thus inhibit neointimal thickening due to smooth muscle

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proliferation. Although several methods inhibit smooth muscle proliferation, intravascular ultrasound is associated with a rapid re-endothelialization process and preservation of normal endothelium function. These properties theoretically reduce the risk of long-term side effects, such as late thrombosis and aneurysm formation, after intravascular sonotherapy. These preliminary encouraging observations were confirmed in experimental models. The application of intravascular sonotherapy (700 MHz) in a canine model of restenosis resulted in 35% reduction of intimal hyperplasia |49–52|. Other advantages of IVUS as an energy source compared with ionizing sources include: 1. The delivery of ultrasound does not require shielding in the catheterization laboratory; 2. Catheter-based therapeutic ultrasound has been shown not to damage the normal vessel wall; 3. Sonotherapy seems to cause transient vessel relaxation and may help limit ischaemia during the dwell time of the catheter; 4. Ultrasound has been shown to enhance drug delivery as well as gene transfection, suggesting it has the potential for further augmentation in conjunction with pharmacological approaches. Whether these expectations will be confirmed in clinical studies is still questionable. The efficacy of intravascular sonotherapy to prevent recurrence of ISR will be evaluated in the SPLASH study (Sonotherapy Prevention of Late Arterial in-Stent Hyperplasia), which is a double blind safety and efficacy study evaluating sonotherapy as an adjunctive treatment for ISR. In this study 600 patients with ISR will be enrolled in 50 centres. Sonotherapy following PTCA will be compared to a control group treated only with angioplasty, to reduce the recurrence of rerestenosis. Drug-eluting stents for ISR Lately, the implantation of drug-eluting stents in experimental models and in de novo atherosclerotic lesions was associated with complete abolition of neointimal hyperplasia |53–58|. The elimination of angiographic restenosis in de novo lesions |59,60| lead to the use of drug-eluting stents for the treatment of ISR. In a pilot study, 21 patients with ISR were treated with a single 60 μg paclitaxel-eluting stent. All patients received combined antiplatelet therapy for 3 months. There were no major in-hospital complications. Two patients experienced a subacute thrombotic occlusion of the stented artery at 14 days and at 4 months following the procedure. Angiographic follow-up in the first seven patients showed no significant narrowing of the paclitaxel-eluting stent |61|. Sousa et al. reported the initial experience of sirolimus-eluting stents for the treatment of ISR. Thirty patients with ISR were treated with sirolimus-eluting stents and four month angiographic follow-up was completed in 17 patients. Restenosis was not detected in any patient and the percentage of obstruction was only 5% |62|. Predictors of diffuse and aggressive intra-stent restenosis. S L Goldberg, A Loussararian, J De Gregorio, C Di Mario, R Albiero, A Colombo. J Am Coll Cardiol 2001; 37(4):1019–25. BACKGROUND. The characterization of ISR according to the pattern and the relationship of a specific pattern with the prognosis has been well documented by Mehran et al. |19| It is usually assumed that ISR is a clinical event not associated with acute myocardial infarction. This new report introduces the concept of aggressive ISR and brings out important clinical consequences of this type of ISR. A consecutive series of 456 coronary lesions with in-stent restenosis were evaluated for the type of restenosis using quantitative coronary angiography. Restenosis was defined as ≥ 50% diameter stenosis at follow-up angiography, diffuse restenosis as a follow-up lesion length ≥ 10 mm and aggressive

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Fig. 12.1 Relationship of type of restenosis with time to follow-up, presented as mean ±6 standard errors of the mean. The more aggressive the restenotic process, the earlier the patient presented with restenosis. P<0.05 compared with the non-aggressive group. Source: Goldberg et al. (2001). restenosis as either an increase in lesion length from the original lesion or a restenotic narrowing tighter than the original. Clinical, anatomic and procedural characteristics were evaluated for lesions associated with these types of restenosis. Diffuse restenosis was associated with a smaller reference artery diameter, longer lesion length, female gender, longer stent length and the use of coil stents. Aggressive restenosis was more common in women, with the use of Wallstents and with long stent to lesion length ratios. Aggressive restenosis occurred earlier and was more closely associated with symptoms and myocardial infarctions than non-aggressive restenotic lesions. Markers for diffuse restenosis were also important markers for the presence of any restenosis. A long stent to lesion length ratio is an important marker for aggressive restenosis. When severe forms of in-stent restenosis occur, they tend to present earlier and with more symptoms, including myocardial infarction. INTERPRETATION. This study introduces important new concepts: – restenotic lesion following stenting can be worse than the original lesion. This is an aggressive ISR. This means that the interventional cardiologist can make the original coronary stenosis tighter and longer at followup. Implanting long stents, especially if longer than the original lesion and achieving a small final lumen are factors which contribute to this type of complication. – an aggressive ISR tends to occur at an earlier time (as shown in Fig. 12.1), usually before 4 months, and can be associated with an adverse event such as acute myocardial infarction (6%). These findings are very important to guide the practice of any interventional cardiologist and mean that there is a clinical reason to try to avoid very long stents, provided the angiographic and functional results are acceptable, and to optimize the immediate results.

Comment Any interventional cardiologist should guide his practice keeping in mind not only the immediate outcome but also the long term. The introduction of stents, long stents and stents for small vessels has made the above statement very contemporary. The above study and the classical paper from Mehran et al. |19| should be well known and be used for decision making.

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Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention. P Ruygrok, M Webster, V de Valk, et al. Circulation 2001; 104:2289–94. BACKGROUND. Angiographic restenosis after percutaneous coronary interventional procedures is not always associated with symptoms. Most commonly Interventional Cardiologists treat symptomatic ISR. However, a substantial percentage of patients have silent ISR which is more common than recurrent angina. Clinical and angiographic factors associated with asymptomatic versus symptomatic restenosis after percutaneous coronary intervention were compared. All patients with angiographic restenosis from the BENESTENT I, BENESTENT II pilot, BENESTENT II, MUSIC, WEST 1, DUET. FINESS 2, FLARE, SOPHOS, and ROSE studies were analysed. Multivariate analysis evaluated 46 clinical and angiographic variables, comparing those with and without angina. The studies recruited 2690 patients who underwent percutaneous revascularization and 6-month follow-up angiography of those eligible. Restenosis (>50% diameter stenosis) occurred in 607 patients and was clinically silent in 335 males (P<0.008), the absence of antianginal therapy with nitrates

(P<0.0002) and calcium channel blockers (P<0.02) at 6 months, greater reference diameter after the procedure (P<0.04), greater reference diameter at follow-up (P<0.004), and lesser lesion severity (per cent stenosis) at 6 months (P<0.0004) were univariate predictors of asymptomatic restenosis. By multivariate analysis, only the male sex (P<0.04), greater reference diameter at follow-up (P<0.002), and lesser lesion severity at 6 months (P<0.0001) were associated with restenosis without angina. INTERPRETATION. Approximately half of patients with angiographic restenosis have no symptoms. Predictors of silent restenosis at 6 months were male sex, greater reference diameter at follow-up, and lesser lesion severity on follow-up angiography. The authors did not investigate the relationship between inducible ischaemia and angiographic restenosis or asymtomatic restenosis.

Comment This analysis of several studies demonstrates that>50% of patients with angiographic restenosis have no symptoms of angina 6 months after the intervention. An analysis was also performed on patients who were treated with stents. Of the 1469 patients who received stents, 16% developed restenosis, of whom 58% were asymptomatic. By multivariate analysis, unstable angina at the time of screening and absence of nitrate use at 6 months were associated with silent ISR. The first predictor (unstable angina) shows that stents may have a ‘plaque-stabilizing’ effect in the relief of symptoms in acute coronary syndromes. The fact that we do not know how many patients with asymptomatic restenosis did not have any demonstrable ischaemia is a major limitation of this study. The clinical message is that the absence of symptoms does not confirm the absence of angiographic restenosis. The contribution of ‘mechanical’ problems to in-stent restenosis: an intravascular ultrasonographic analysis of 1090 consecutive in-stent restenosis lesions. M T Castagna, G S Mintz, B O Leiboff, et al. Am Heart J 2001; 142(6):970–4. BACKGROUND. Several studies have shown that many restenotic stents were inadequately deployed. Other mechanical problems that lead to ISR include failure to cover the entire lesion by the stent, damage of stent configuration and stent stripping off the delivery balloon. In this study IVUS was used to determine the incidence of mechanical problems contributing to ISR. The authors studied 1090 consecutive patients with ISR treated at the Washington Hospital Centre. In all patients pre-intervention IVUS imaging was performed. IVUS measurements included 1) proximal and distal reference lumen

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areas and diameters and 2) stent minimum lumen, and intimal hyperplasia (stent minus lumen) areas; and burden. In 49 ISR lesions (4.5%), there were morphologic findings that contributed to the restenosis. These were termed mechanical complications. Examples include (1) missing the

lesion (e.g. an aorto-ostial stenosis) (12 cases), (2) ‘crushed’ stent (27 cases) and (3) having the stent stripped off the balloon during the implantation procedure (10 cases). Excluding mechanical complications, stent underexpansion was common. In 20% of the ISR cases the stents had a crosssectional area at the site of the lesion <80% of the average reference lumen area. The MUSIC (Multicentre Ultrasound Stenting in Coronaries) study had in-stent minimal CSA ≥ 80% of the average reference vessel cross sectional lumen. Twenty per cent of lesions had a minimum stent area <5.0 mm2 and an additional 18% had a minimum stent area of 5.0–6.0 mm2. In 80% the intimal hyperplasia burden was <75%, and in 24% of lesions it was <60%. INTERPRETATION. Mechanical problems related to stent deployment procedures contribute to a significant minority of ISR lesions (approximately 25%). Stent misplacement should be considered in particular settings as in aorto-ostial lesions, and other problems such as stent ‘crush’ (Fig. 12.2) are very rare. The most frequent mechanical problem is

Fig. 12.2 An example of a crushed stent is shown. Note that the distal half of the stent is crushed to one side (A and B), whereas the proximal half of the stent is distorted (C). During the stent implantation procedure, the operator lost wire position. In recrossing the freshly placed stent, the wire went through the diamond-shaped cells of the stent. During post-dilation, the distal half of the stent was crushed against the arterial wall. Source: Castagna et al. (2001). the under-expansion of the stent, and it is found in 20% of ISR lesions. The fact that 20% of the lesions had a final in-stent CSA <5 mm2 support the frequent presence of stent under-expansion. This conclusion would not

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be valid if the study was dealing with truly small vessels. In a vessel with a reference diameter of 2.5 mm the achievement of a final in-stent CSA of 5 mm2 constitutes a 0% residual stenosis. The reality is that this small final in-stent CSA was achieved in 40% of vessels with a reference diameter >2.5 mm.

Comment Although several factors contribute to the development of ISR, the mechanical problems should not be forgotten. These problems are the easiest to correct at the time of stent implantation. In order to maximize the appropriate and cost-effective use of resources like IVUS, we suggest it would be valuable to evaluate the immediate result post-stenting in specific settings as aorto-ostial lesions, some types of coronary ostial lesions and in lesions located in the proximal part of major epicardial vessels with an angiographic reference diameter ≥ 2.5 mm (pseudo-small vessels). We are perfectly aware that the use of IVUS will not be a major solution to the problem of restenosis, however a selective application of this tool can produce a modest but significant clinical improvement detected at the time of follow-up |63|. Clinical and angiographic outcome in the laser angioplasty for restenotic stents (LARS) multicenter registry. S Giri, S Ito, A J Lansky, et al. Catheter Cardiovasc Interv 2001; 52(1): 24–34. BACKGROUND. Ablating the hyperplastic neointimal tissue in ISR lesions prior to PTCA is an attractive alternative. ELCA has been evaluated in previous studies, but the late clinical outcome is not well studied. The LARS (Laser Angioplasty for Restenotic Stents) study is a multicentre case control study in which the investigators assessed the angiographic and clinical outcomes of 157 consecutive procedures in 146 patients with ISR at nine institutions treated with either PTCA alone (n=64) or ELCA (n=93) for ISR. Lesions selected for ELCA were longer (16.8 mm vs 11.2 mm; P<0.001), more complex (ACC/AHA type C: 35.1% vs 13.6%; P<0.001), and with compromised anterograde flow (Thrombolysis in Myocardial Infarction (TIMI) flow <3:18.9% vs 4.5%; P=0.008) compared to PTCA-treated patients. The balloon/artery ratio was greater in the ELCA group (1.02 vs 1.10, P=0.005), but it did not result in larger minimal lumen diameter post-procedure. The procedural success rate (98.9% vs 98.4%, P=NS) and the incidence of in-hospital adverse cardiac events (1.1% vs 1.6%, P=NS) were similar between the 2 groups. At 1 year, ELCA-treated patients had similar rates of major cardiac events (39.1% vs 45.2%; P=NS) and TLR (30.0% vs 32.3%; P=NS).

INTERPRETATION. These data suggest that ELCA in patients with complex in-stent restenosis is as safe and effective as PTCA alone. Despite higher lesion complexity and increased lesion length in ELCA-treated patients, no increase in event rates was observed and there was no clinical advantage.

Comment This study is important in the context of the evaluation of ELCA for the treatment of ISR. The number of patients enrolled in the study, the long-term follow-up and the concentration of multicentre experience provide enough information for the safety and efficacy of ELCA in the setting of ISR. The lack of randomization, however, does not permit the detection of any advantage of ELCA compared with PTCA. The equivalence of in-hospital and long-term results between ELCA and PTCA, despite the fact that the lesions treated with ELCA would be expected to have higher recurrence of restenosis, may rationalize the

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performance of a randomized trial. The only drawback, however, is the 30% TLR in the ELCA group which is still too high to support the extended usage of this complex and expensive modality. Six-month clinical and angiographic outcome after successful excimer laser angioplasty for in-stent restenosis. R Koster, J Kahler, W Terres, et al. J Am Coll Cardiol 2000; 36(1): 69–74. BACKGROUND. In research of the optimal mechanical treatment of ISR the application of atheroablative techniques is still attractive. ELCA provides several theoretical benefits as ablation can be accomplished with limited procedural complexity. This study evaluated the clinical and angiographic six-month follow-up after ELCA for restenosed coronary stents. ELCA has recently been shown to be safe and efficient for the treatment of in-stent restenosis. Ninety-six consecutive patients successfully treated with ELCA within 141 stents were included in a six-month clinical and angiographic follow-up. During follow-up there was one sudden death and one patient sustained myocardial infarction. Angina pectoris classified as ≥ Canadian Cardiovascular Society II recurred in 49 patients. Follow-up angiography was obtained in 89 patients (93%) with 133 stents. Quantitative coronary angiography revealed a mean diameter stenosis of 77±10% before intervention, 41±12% after laser treatment and 11 ±12% after adjunctive percutaneous transluminal coronary angioplasty (P<0.001). Six months after ELCA the mean diameter stenosis had increased to 60±26% (P<0.001). A ≥ 50% diameter stenosis was present in 48 patients (54%); in 24 of these patients diameter stenosis was ≥ 70%. Total occlusions occurred in an additional 10 patients (11%). There was a trend toward an increased recurrent restenosis rate in patients with diabetes mellitus and long lesions or total occlusions (P=0.059). Forty-eight patients (50%) received medical treatment after six months. Reinterventions were necessary in

30 patients (31%), and coronary artery bypass surgery was performed in 17 patients (18%). Eventfree survival was 50%. INTERPRETATION AND COMMENT. Excimer laser angioplasty for in-stent restenosis was associated with a high incidence of recurrent restenosis in this group of patients, suggesting that this technique is unlikely to reduce recurrent in-stent restenosis and that other approaches are necessary.

Treatment of in-stent restenosis with excimer laser coronary angioplasty versus rotational atherectomy: comparative mechanisms and results. R Mehran, G Dangas, G S Mintz, et al. Circulation 2001; 101(21): 2484–9. BACKGROUND. We compared the mechanisms and clinical results of ELCA versus ROTA, both followed by adjunct PTCA; 119 patients (158 ISR lesions) were treated with ELCA+PTCA and 130 patients (161 ISR lesions) were treated with ROTA+PTCA. Quantitative coronary angiographic and planar IVUS measurements were performed routinely. In addition, volumetric IVUS analysis to compare the mechanisms of lumen enlargement was performed in 28 patients with 30 lesions (16 ELCA +PTCA, 14 ROTA+PTCA). There were no significant differences between groups in pre-intervention or final post-intervention quantitative coronary angiographic or planar IVUS measurements of luminal dimensions. Angiographic success and major in-hospital complications with the two techniques were also similar. Volumetric IVUS analysis showed significantly greater reduction in intimal hyperplasia volume after ROTA than after ELCA (43±14 vs 19±10 mm3, P<0.001) because of a significantly higher ablation efficiency (90±10% vs 76±12%, P=0.004). However, both interventional strategies had similar long-term clinical outcome. One year target lesion revascularization rate was 26% with ELCA+PTCA vs 28% with ROTA+PTCA (P=NS). Despite certain differences in the mechanisms of lumen enlargement, both ELCA +PTCA and ROTA+PTCA can be used to treat diffuse ISR with similar clinical results.

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INTERPRETATION AND COMMENT. Similarly to the other studies, this investigation sets a final negative evaluation on the role of laser angioplasty to treat ISR.

Treatment of focal in-stent restenosis with balloon angioplasty alone versus stenting: short-and longterm results. R Mehran, G Dangas, A Abizaid, et al. Am Heart J 2001; 141(4): 610–4. BACKGROUND. Although several small studies have been performed to evaluate PTCA and restenting for the treatment of focal ISR, no large-scale comparative data on the clinical outcomes after these interventional procedures have been reported. In

this study the in-hospital and one-year clinical outcome of the two treatment strategies were evaluated. PTCA alone was performed in 266 patients (364 lesions) and re-stenting in 135 patients (161 lesions) for the treatment of focal ISR, defined as a lesion length ≥ 10 mm. PTCA was much less effective than stenting in achieving tissue extrusion and therefore the final lumen dimensions were significantly greater with stenting. The in-hospital rate of death, Q wave myocardial infarction and TLR were higher in the PTCA group (5.6% vs 0.7%, P=0.02). Non-Q wave myocardial infarction, evaluated by the increase of CK-MB >5 times normal was more frequent with stent (18.5% vs 9.7%, P=0.05). At one year the two interventional strategies had similar cumulative mortality (4.6% PTCA vs 5.1% stent, P=NS) and TLR rate (24.6% PTCA vs 26.5% stent, P=NS). By multivariate analysis, the only predictor of TLR was diabetes mellitus (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2–4.7, P=0.01). INTERPRETATION. Repeat stenting for the treatment of focal ISR is associated with greater acute lumen gain and less incidence of in-hospital adverse cardiac events. However, in the stent group a higher postprocedure creatine kinase myocardial band elevation rate and similar long-term clinical results were found compared with PTCA alone.

Comment This study supports the view that re-stenting for the treatment of ISR is not a viable strategy except for selected cases. It shows that, unlike native lesions, in the setting of ISR, post-intervention dimensions (when achieved with re-stenting) are of no value for predicting the recurrence of restenosis. This fact was supported by the similar long-term results despite the achievement of larger post-procedural minimal luminal diameters (MLDs) with re-stenting. Finally, this paper indicates that ISR is still an unsolved problem, since the TLR rate in both groups was approximately 25%, although only patients with focal ISR were included and routine angiographic follow-up was not performed. Cutting balloon angioplasty for the treatment of in-stent restenosis: a matched comparison with rotational atherectomy, additional stent implantation and balloon angioplasty. M Adamian, A Colombo, C Briguori, et al. J Am Coll Cardiol 2001; 38(3): 672–9. BACKGROUND. Among the mechanical interventions available to treat ISR, the controversies exist regarding optimal treatment for ISR. Recently, cutting balloon angioplasty (CBA) emerged as a tool in the management of ISR. Even if this device is not an ablative tool there is IVUS evidence |64| that a significant amount of tissue is removed by being pushed behind the stent struts. Compared to other devices the cutting balloon is easier to use and does not require any additional

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Fig. 12.3 Cumulative frequency distribution of the late lumen loss at follow-up in CBA, PTCA, ROTA, and additional stenting (STENT) groups. Significantly lower lumen loss noticed in CBA group compared to ROTA and STENT groups (0.63±0.6 mm, 1.30±0.8 mm, and 1.36±0.8 mm; P<0.0001). Source: Adamian et al. (2001).

dedicated equipment. A total of 648 lesions treated for ISR were divided into four groups according to the treatment strategy: CBA, ROTA, additional stenting (STENT), and PTCA. Following the matching process, 258 lesions were entered into the analysis. Baseline clinical and angiographic characteristics were similar among the groups (P=NS). Acute lumen gain was significantly higher in the STENT group (2.12±0.7 mm), whereas in the CBA group the gain was similar to that achieved following ROTA and following PTCA (1.70±0.6 vs 1.79±0.5 mm and 1.56±0.7 mm, respectively; P=NS). The lumen loss at follow-up was lower for the CBA versus ROTA and versus STENT (0.63±0.6 vs 1.30±0.8 mm and 1.36±0. 8 mm, respectively; P<0.0001), yielding a lower recurrent restenosis rate (20% vs 35.9% and 41.4%, respectively; P<0.05). By multivariate analysis, CBA (OR 0.17; CI 0.06–0.51; P=0.001) and diffuse restenosis type at baseline (OR 2.07; CI 1.15–3.71; P=0.02) were identified as predictors of TLR. INTERPRETATION. Despite the fact this study it is not randomized the four groups are well matched. Among the most important parameters that may affect the recurrence of restenosis (presence of diffuse ISR, small reference vessel size and long lesions) there was a good comparability of these parameters among the groups. As also predicted from

prior studies, the usage of cutting balloon resulted in a larger final MLD compared to PTCA and similar to ROTA followed by PTCA. Only the implantation of a new stent gave a final MLD larger than any other approach. The novel finding is that the late loss expressed as loss index was significantly lower (0.38) for the cutting balloon compared to any other device (Fig. 12.3). The fact that the cutting balloon does not move during the dilatation is another added benefit because it limits injury to the segment to be treated. This attribute

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is particularly important when the Interventionist plans to perform brachytherapy, a setting where controlling the relationship between radiated segment and injured segment is particularly important. The major limitation of the cutting balloon is the presence of rigid blades which prevent its advancement through bends.

Comment While awaiting more conclusive results from randomized studies, there is a considerable amount of data to support the usage of cutting balloon to treat most focal ISR as a stand alone device and diffuse ISR as a tool to prepare the lesions for brachytherapy. An important unanswered question is about the value of IVUS to optimize the result by helping the operator to select the appropriate size of the cutting balloon. Intravascular ultrasound assessment of the mechanism of lumen enlargement during cutting balloon angioplasty treatment of in-stent restenosis. J M Ahmed, G S Mintz, M Castagna, et al. Am J Cardiol 2001; 88(9): 1032–4. BACKGROUND. Cutting balloon is a novel coronary dilatation catheter with 3–4 microtomes mounted longitudinally on the surface of the stent. It has been used in calcified lesions and lately it has been used for the treatment of ISR. A defined observation is that CBA for ISR gives a better immediate result compared to PTCA. The exact mechanism through which this added benefit is obtained is not fully elucidated. Despite the limitation due to the small number of patients evaluated this study gives useful information about the mechanism of action of the cutting balloon during dilatation of ISR lesions. In this study 10 patients with ISR were included and IVUS examination was performed before and after CBA. Inflations were at a maximum of 10 atmospheres. The authors found an increase in lumen cross sectional area and a decrease of intimal hyperplasia area after CBA. Moreover, they observed an increase in persistent external elastic membrane area, in persistent plaque + media cross sectional areas and a trend toward additional stent expansion. However, they also found a decrease in lumen and an increase in plaque + media cross sectional areas at the adjacent reference segments.

INTERPRETATION. The results of this study suggest that most of the lumen enlargement after CBA is due to intimal hyperplasia extrusion through stent struts and axial redistribution of intimal hyperplasia into adjacent reference segments with minimal additional stent expansion.

Comment The main mechanisms recognized for lumen enlargement in ISR lesions are the neointimal tissue ablation, extrusion, and additional stent expansion. This paper shows that cutting balloon differs from conventional PTCA. The observed intimal hyperplasia extrusion can possibly be attributed to the microtomes that divide the neointimal tissue into small particles. Similar findings were reported by an earlier observational study |44|. The fact that the authors did not use information obtained by IVUS to properly select the size of the cutting balloon may not have fully evaluated the optimal performance of this device. Percutaneous and surgical interventions for in-stent restenosis: long-term outcomes and effect of diabetes mellitus. A Moustapha, A Assali, S Sdringola, et al. J Am Coll Cardiol 2001; 37:1877–82. BACKGROUND. ISR remains a challenging problem, and its optimal management is still unknown.

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In this study the long-term outcomes of patients with ISR were examined. These patients underwent different percutaneous interventions at the discretion of individual operators: balloon angioplasty, repeat stent or ROTA. We also examined long-term outcomes of patients with ISR who underwent coronary artery bypass surgery (CABG). Symptomatic patients (n=510) with ISR were identified using cardiac catheterization laboratory data. Management for ISR included PTCA (169 patients), repeat stenting (117 patients), ROTA (107 patients) or CABG (117 patients). Clinical outcome events of interest included death, myocardial infarction, target vessel revascularization (TVR) and a combined end-point of these major adverse cardiovascular events (MACE). Mean follow-up was 19±12 months. Patients with ISR treated with repeat stent had significantly larger average post-procedure MLD compared with PTCA or ROTA (3.3±0.4 vs 3.0±0.4 vs 2.9±0.5 mm, respectively, P<0.05). Incidence of TVR and MACE were similar in the PTCA, stent and ROTA groups (39%, 40%, 33% for TVR and 43%, 40%, 33% for MACE, P=NS). Patients with diabetes who underwent ROTA had similar outcomes to patients without diabetes, while patients with diabetes who underwent PTCA or stent had worse outcomes than patients without diabetes. Patients who underwent CABG for ISR, mainly because of the presence of multivessel disease, had significantly better outcomes than any percutaneous treatment (8% for TVR and 23% for MACE). Table 12.1 Incidence of TVR and MACE in different treatment groups according to diabetes status. The incidence of TVR and MACE was the same in patients with diabetes who underwent PTCA or repeat stent and was significantly higher than it was in patients without diabetes. Patients with diabetes who underwent ROTA had a lower incidence of TVR and MACE than patients with diabetes who underwent PTCA or repeat stenting, and their outcome was similar to that of patients without diabetes who underwent percutaneous interventions. There were no significant differences in the incidence of TVR or MACE in patients without diabetes regardless of the percutaneous intervention used Patients with diabetes

TVR (%) Death (%) MACE (%)

Balloon angioplasty (n=36)

Stent (n=30)

Rotational atherectomy (n=37)

CABG (n=36)

33 7 53

33 6 53

22 5 32

11 3 28

Stent (n=76)

Rotational atherectomy (n=65)

CABG (n=75)

Patients without diabetes Balloon angioplasty (n=109)

TVR (%) 22* 18† 21 Death (%) 7 7 6 MACE (%) 40* 38† 34 *P<0.05 compared with diabetics treated with balloon angioplasty. †P<0.05 compared with diabetics treated with stent. Source: Moustapha et al. (2001).

7 5 29

INTERPRETATION AND COMMENT. This study reports the medium-term clinical outcome of different mechanical techniques and CABG applied to an unselected population according to the clinical judgement of the Interventional Cardiologist. Among the mechanical procedures the authors did not evaluate cutting balloon. The important points are that the 510 patients group with ISR studied is quite large and that the institution reporting is a large tertiary care centre. This study shows several important points:

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• When the operator can select the strategy to use to treat ISR the long-term results are similar whatever technique was chosen. This is because the operator selects appropriately not because any technique is similar to any other. • Patients with diabetes have an inferior clinical outcome compared to non-diabetics. The advantage of ROTA in diabetics is an intriguing finding (I would like to know more about the details of the technique used) (Table 12.1). The small number of patients in each sub-group is a major concern. • CABG maintains superiority in terms of TVR for ISR as demonstrated for native lesions. Without any specific biological intervention (radiations or drug-eluting stents),

it is unlikely that percutaneous coronary interventions applied for ISR will be able to give superior or equivalent results to CABG. Despite all the above limitations most clinicians will choose repeat percutaneous coronary interventions with a mechanical approach, or with additional brachytherapy in selected cases, rather than CABG when dealing with a patient without diabetes and if the culprit lesion is not located in the proximal left anterior descending artery and there is diffuse ISR. Acute outcome with the flexicut directional coronary atherectomy catheter for the treatment of coronary in-stent restenosis. E R O’Brien, C Glover, M Labinaz. J Invasive Cardiol 2001; 13(9):618–22. BACKGROUND. ISR is a growing problem that is without a practical, efficacious treatment strategy. The purpose of this study was to determine the acute outcome of 17 patients with ISR who were treated with the new 8 French (Fr), guide-catheter compatible Flexicut directional atherectomy catheter (Guidant Corporation, Santa Clara, California). Failure to deliver the device occurred in 2 out of 17 ISR lesions. The remaining 15 ISR lesions were successfully debulked (e.g. minimum lumen diameter preprocedure: 0.30±0.16 mm; post-atherectomy plus adjuvant therapy: 2.16±0.57 mm). Of note, the reference vessel diameter was only 2.62±0.63 mm. In 11 out of 15 tissue specimens, macroscopic or microscopic particles consistent with stent material were found. There was an absence of acute closure or elevations of creatinine phosphokinase levels. Apart from one patient who developed recurrent restenosis, all other patients demonstrated either clinical improvement or lack of restenosis during early clinical follow-up (mean, 5 months). INTERPRETATION. The use of the Flexicut catheter provides satisfactory debulking and early clinical outcomes in patients with ISR. Long-term follow-up of these and additional patients will be helpful in determining the efficacy of the Flexicut atherectomy catheter for the treatment of ISR.

Comment Although DCA is the only technique providing true debulking of the neointimal tissue, the preliminary experience with previous DCA devices was not satisfactory as several complications were observed. The main shortcomings were: the use of large profile catheters, stent disruption and lack of convincing data for its efficacy. This study demonstrates the safety of a new catheter with smaller profile for the treatment of

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ISR. The increase of lumen dimensions post DCA shows that debulking of the hyperplastic tissue is indeed feasible with this device. However, the considerations of failure to deliver the device (2 out of 17 cases) and retrieval of stent material (73% of the treated segments) remain unresolved. Despite these problems this study rationalizes the evaluation of this approach for the management of ISR in a large, multicentre registry. The availability of more user-friendly atherectomy devices may bring more attention to this field. Conclusion The introduction of stents revolutionized Interventional Cardiology as acute complications and restenosis rate were reduced compared to the other methods. Despite stenting, restenosis did not disappear and introduced the new entity of ISR. Treatment of ISR with traditional methods is not always effective and there is the perception that some types of diffuse ISR may be more difficult to treat (to achieve favourable long-term results) compared to restenosis following PTCA. Intracoronary brachytherapy was the first method to reduce the rate of recurrence of ISR, but with several limitations. In the era of drug-eluting stents we expect that the incidence of ISR will decrease. Whether these new devices will prove effective to treat ISR is still an open question. At the present time the most important steps are: prevention of diffuse ISR by avoiding implanting long stents in unfavourable lesions and treatment of diffuse ISR with other modalities besides PTCA. References 1.

2.

3.

4.

5.

6.

7. 8.

Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994; 331:489–95. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994; 331:496–501. Kastrati A, Schomig A, Elezi S, Dirschinger J, Mehilli J, Schuhlen H, Blasini R, Neumann FJ. Prognostic value of the modified American College of Cardiology/American heart association stenosis morphology classification for long-term angiographic and clinical outcome after coronary stent placement. Circulation 1999; 100:1285–90. Finci L, Ferraro M, Nishida T, Albiero R, Corvaja N, Vaghetti M, Stankovic G, Recchia M, Di Mario C, Colombo A. Coronary stenting beyond standard indications. Immediate and follow-up results. Ital Heart J 2000; 1:739–48. Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, Kuntz RE, Popma JJ, Schaff HV, Williams DO, Gibbons RJ, Alpert JP, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G, Russell RO, Smith SC Jr; American College of Cardiology. American Heart Association Task Force on Practice Guidelines. Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)— executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2001; 37:2215–38. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996; 94: 1247–54. Gordon PC, Gibson CM, Cohen DJ, Carrozza JP, Kuntz RE, Baim DS. Mechanisms of restenosis and redilation within coronary stents—quantitative angiographic assessment. J Am Coll Cardiol 1993; 21:1166–74. Haude M, Erbel R, Issa H, Meyer J. Quantitative analysis of elastic recoil after balloon angioplasty and after intracoronary implantation of balloon-expandable Palmaz-Schatz stents. J Am Coll Cardiol 1993; 21:26–34.

MANAGEMENT OF IN-STENT RESTENOSIS

9. 10.

11.

12. 13. 14.

15.

16.

17.

18. 19.

20. 21

22.

23.

24. 25. 26.

167

Komatsu R, Ueda M, Naruko T, Kojima A, Becker AE. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation 1998; 98:224–33. Schatz RA, Baim DS, Leon M, Ellis SG, Goldberg S, Hirshfeld JW, Cleman MW, Cabin HS, Walker C, Stagg J, et al. Clinical experience with the Palmaz-Schatz coronary stent. Initial results of a multicenter study. Circulation 1991; 83:148–61. van Beusekom HM, van der Giessen WJ, van Suylen R, Bos E, Bosman FT, Serruys PW. Histology after stenting of human saphenous vein bypass grafts: observations from surgically excised grafts 3 to 320 days after stent implantation. J Am Coll Cardiol 1993; 21:45–54. Anderson PG, Bajaj RK, Baxley WA, Roubin GS. Vascular pathology of balloon-expandable flexible coil stents in humans. J Am Coll Cardiol 1992; 19:372–81. Schiele F, Meneveau N, Vuillemenot A, Gupta S, Bassand JP. Treatment of in-stent restenosis with high speed rotational atherectomy and IVUS guidance in small <3.0 mm vessels. Cathet Cardiovasc Diagn 1998; 44:77–82. Mudra H, di Mario C, de Jaegere P, Figulla HR, Macaya C, Zahn R, Wennerblom B, Rutsch W, Voudris V, Regar E, Henneke KH, Schachinger V, Zeiher A; OPTICUS (OPTimization with ICUS to reduce stent restenosis) Study Investigators. Randomized comparison of coronary stent implantation under ultrasound or angiographic guidance to reduce stent restenosis (OPTICUS Study). Circulation 2001; 104:1343–9. Moussa I, Moses J, Di Mario C, Albiero R, De Gregorio J, Adamian M, Di Francesco L, Colombo A. Does the specific intravascular ultrasound criterion used to optimize stent expansion have an impact on the probability of stent restenosis? Am J Cardiol1999; 83: 1012–17. Serruys PW, Luijten HE, Beatt KJ, Geuskens R, de Feyter PJ, van den Brand M, Reiber JH, ten Katen HJ, van Es GA, Hugenholtz PG. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation 1988; 77: 361–71. Nobuyoshi M, Kimura T, Nosaka H, Mioka S, Ueno K, Yokoi H, Hamasaki N, Horiuchi H, Ohishi H. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988; 12:616–23. Kimura T, Nosaka H, Yokoi H, Iwabuchi M, Nobuyoshi M. Serial angiographic followup after Palmaz-Schatz stent implantation: comparison with conventional balloon angioplasty. J Am Coll Cardiol 1993; 21:1557–63. Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, Pichard AD, Kent KM, Stone GW, Leon MB. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation 1999; 100:1872–8. Macander PJ, Roubin GS, Agrawal SK, Cannon AD, Dean LS, Baxley WA. Balloon angioplasty for treatment of in-stent restenosis: feasibility, safety, and efficacy. Cathet Cardiovasc Diagn 1994; 32:125–31. Shiran A, Mintz GS, Waksman R, Mehran R, Abizaid A, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Early lumen loss after treatment of in-stent restenosis: an intravascular ultrasound study. Circulation 1998; 98: 200–3. Eltchaninoff H, Koning R, Tron C, Gupta V, Cribier A. Balloon angioplasty for the treatment of coronary instent restenosis: immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998; 32:980–4. Reimers B, Moussa I, Akiyama T, Tucci G, Ferraro M, Martini G, Blengino S, Di Mario C, Colombo A. Longterm clinical follow-up after successful repeat percutaneous intervention for stent restenosis. J Am Coll Cardiol 1997; 30:186–92. Mehran R, Mintz GS, Popma JJ, Pichard AD, Satler LF, Kent KM, Griffin J, Leon MB. Mechanisms and results of balloon angioplasty for the treatment of in-stent restenosis. Am J Cardiol 1996; 78:618–22. Bauters C, Banos JL, Van Belle E, Mc Fadden EP, Lablanche JM, Bertrand ME. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998; 97:318–21. Schomig A, Kastrati A, Dietz R, Rauch B, Neumann FJ, Katus HH, Busch U. Emergency coronary stenting for dissection during percutaneous transluminal coronary angioplasty: angiographic follow-up after stenting and after repeat angioplasty of the stented segment. J Am Coll Cardiol 1994; 23:1053–60.

168

27. 28. 29.

30.

31. 32. 33.

34.

35. 36.

37. 38.

39. 40. 41. 42. 43. 44. 45. 46. 47.

IV · RESTENOSIS

Mintz GS, Hoffmann R, Mehran R, Pichard AD, Kent KM, Satler LF, Popma JJ, Leon MB. In-stent restenosis: the Washington Hospital Centre experience. Am J Cardiol 1998; 81:7E–13E. Mehran R, Dangas G, Mintz GS, et al. PTCA alone versus stent alone therapy for focal in-stent restenosis: Acute and long-term results. J Am Coll Cardiol 1999; 33: 1037–52. Wolf A, Schwarz F, Hofmann M, Gohring S, Storger H, Reifart N. Repetitive balloon angioplasty for recurrent in-stent restenosis: Results of first and second PTCA in focal and diffuse stenosis. J Am Coll Cardiol 1999; 33: 1037–51. Lee SG, Lee CW, Cheong SS, Hong MK, Kim JJ, Park SW, Park SJ. Immediate and long-term outcomes of rotational atherectomy versus balloon angioplasty alone for treatment of diffuse in-stent restenosis. Am J Cardiol 1998; 82:140–3. Mahdi NA, Pathan AZ, Harrell L, Leon MN, Lopez J, Butte A, Ferrell M, Gold HK, Palacios IF. Directional coronary atherectomy for the treatment of Palmaz-Schatz instent restenosis. Am J Cardiol 1998; 82:1345–51. Bottner RK, Hardigan KR. High-speed rotational ablation for in-stent restenosis. Cathet Cardiovasc Diagn 1997; 40:144–9. vom Dahl J, Radke PW, Haager PK, Koch KC, Kastrau F, Reffelmann T, Janssens U, Hanrath P, Klues HG. Clinical and angiographic predictors of recurrent restenosis after percutaneous transluminal rotational atherectomy for treatment of diffuse in-stent restenosis. Am J Cardiol 1999; 83:862–7. Goldberg SL, Berger P, Cohen DJ, Shawl F, Buchbinder M, Fortuna R, O’Neill W, Leon M, Braden GA, Teirstein PS, Reisman M, Bailey SR, Dauerman HL, Bowers T, Mehran R, Colombo A. Rotational atherectomy or balloon angioplasty in the treatment of intrastent restenosis: BARASTER multicenter registry. Catheter Cardiovasc Interv 2000; 51: 407–13. Sharma SK, Duvvuri S, Dangas G, Kini A, Vidhun R, Venu K, Ambrose JA, Marmur JD. Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases. J Am Coll Cardiol 1998; 32:1358–65. Radke PW, Klues HG, Haager PK, Hoffmann R, Kastrau F, Reffelmann T, Janssens U, vom Dahl J, Hanrath P. Mechanisms of acute lumen gain and recurrent restenosis after rotational atherectomy of diffuse in-stent restenosis: a quantitative angiographic and intravascular ultrasound study. J Am Coll Cardiol 1999; 34:33–9. Nakamura S, Yokoyama J, Kudou T, et al. Cutting balloon angioplasty versus rotablator atherectomy for treatment of diffuse in-stent restenosis. Circulation 2001; 104:2411. vom Dahl J, Dietz U, Silber S, et al. Angioplasty Versus Rotational Atherectomy for Treatment of Diffuse InStent Restenosis: Clinical and Angiographic Results From a Randomized Multicenter Trial (ARTIST Study). J Am Coll Cardiol 2000; 35:7. Bowerman RE, Pinkerton CA, Kirk B, Waller BF. Disruption of a coronary stent during atherectomy for restenosis. Cathet Cardiovasc Diagn 1991; 24:248–51. Di Mario C, Marsico F, Adamian M, Karvouni E, Albiero R, Colombo A. New recipes for in-stent restenosis: cut, grate, roast, or sandwich the neointima? Heart 2000; 84:471–5. Lauer B, Schmidt E, Amrosch H, et al. Rotational atherectomy, excimer laser angioplasty or balloon angioplasty for therapy of in-stent restenosis? J Am Coll Cardiol 2000; 35:89A. Haase J, Storger H, Hoffmann M, Schwartz F. Excimer laser angioplasty with adjunctive balloon dilation versus balloon dilation alone for the treatment of in-stent restenosis. J Intervent Cardiol 1999; 12:513–18 Barath P, Fishbein MC, Vari S, Forrester JS. Cutting balloon: a novel approach to percutaneous angioplasty. Am J Cardiol 1991; 68:1249–52. Albiero R, Nishida T, Karvouni E, Corvaja N, Vaghetti M, Di Mario C, Colombo A. Cutting balloon angioplasty for the treatment of in-stent restenosis. Catheter Cardiovasc Interv 2000; 50:452–9. Nakamura M, Suzuki T, Matsubara T, et al. Results of cutting balloon for stent restenosis. Japanese Multicenter Registry. J Am Coll Cardiol 1998; 31:1087–90. DiMarco J. Results from late-breaking clinical trials session at ACC 2001. J Am Coll Cardiol2001; 38:595–612. Waksman R, Zimarino M, Mehran R, et al. Device influence on outcome in the treatment of in-stent restenosis with and without radiation. J Am Coll Cardiol 2000; 2:21A.

MANAGEMENT OF IN-STENT RESTENOSIS

48. 49.

50. 51. 52. 53.

54.

55.

56.

57.

58.

59.

60.

61. 62. 63.

64.

169

Mehran R, Dangas G, Mintz GS, et al. In-stent restenosis: the great equalizer-disappointing clinical outcomes with all interventional strategies. J Am Coll Cardiol 1999; 33:63A. Lawrie A, Brisken AF, Francis SE, Tayler DI, Chamberlain J, Crossman DC, Cumberland DC, Newman CM. Ultrasound enhances reporter gene expression after transfection of vascular cells in vitro. Circulation 1999; 99: 2617–20. Fitzgerald PJ, Takagi A, Moore MP, Hayase M, Kolodgie FD, Corl D, Nassi M, Virmani R, Yock PG. Intravascular sonotherapy decreases neointimal hyperplasia after stent implantation in swine. Circulation 2001; 103:1828–31. Alter A, Rozenszajn LA, Miller HI, Rosenschein U. Ultrasound inhibits the adhesion and migration of smooth muscle cells in vitro. Ultrasound Med Biol 1998; 24: 711–21. Lejbkowicz F, Zwiran M, Salzberg S. The response of normal and malignant cells to ultrasound in vitro. Ultrasound Med Biol 1993; 19:75–82. Honda Y, Grube E, de La Fuente LM, Yock PG, Stertzer SH, Fitzgerald PJ. Novel drugdelivery stent: intravascular ultrasound observations from the first human experience with the QP2-eluting polymer stent system. Circulation 2001; 104:380–3. Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky R, Klugherz BD, Papandreou G, Narayan P, Leon MB, Yeung AC, Tio F, Tsao PS, Falotico R, Carter AJ. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104:1188–93. Gregory CR, Huang X, Pratt RE, Dzau VJ, Shorthouse R, Billingham ME, Morris RE. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995; 59:655–61. Heldman AW, Cheng L, Jenkins GM, Heller PF, Kim DW, Ware M Jr, Nater C, Hruban RH, Rezai B, Abella BS, Bunge KE, Kinsella JL, Sollott SJ, Lakatta EG, Brinker JA, Hunter WL, Froehlich JP. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001; 103: 2289–95. Hong MK, Kornowski R, Bramwell O, Ragheb AO, Leon MB. Paclitaxel-coated Gianturco-Roubin II (GR II) stents reduce neointimal hyperplasia in a porcine coronary in-stent restenosis model. Coron Artery Dis 2001; 12: 513–15. Signore PE, Machan LS, Jackson JK, Burt H, Bromley P, Wilson JE, McManus BM. Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in balloon-injured rat carotid arteries. J Vasc Interv Radiol 2001; 12:79–88. Grube E, Silber S, Eugen K. TAXUS I: Prospective, randomized, double-blind comparison of NIR-X stents coated with paclitaxel in a polymer carrier in de novo coronary lesions with uncoated controls. Circulation 2001; 104:2197. Sousa J, Morice M, Serruys PW, et al. The RAVEL study: A randomized study with the sirolimus coated BX velocity balloon expandable stent in the treatment of patients with de novo coronary artery lesions. Circulation 2001; 104:463. De Scheerder I, Huang Y, Dens J, Wang L. Treatment of in-stent restenosis using paclitaxel eluting stents: a single centre pilot trial. Circulation 2001; 104:3503. Sousa E, Abizaid A, Sousa A, et al. Sirolimus-coated for the treatment of in-stent restenosis: The first in-man experience. Circulation 2001; 104:2958. Fitzgerald PJ, Oshima A, Hayase M, Metz JA, Bailey SR, Baim DS, Cleman MW, Deutsch E, Diver DJ, Leon MB, Moses JW, Oesterle SN, Overlie PA, Pepine CJ, Safian RD, Shani J, Simonton CA, Smalling RW, Teirstein PS, Zidar JP, Yeung AC, Kuntz RE, Yock PG. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation 2000; 102:523–30. Albiero R, Nishida T, Karvouni E, Corvaja N, Vaghetti M, Di Mario C, Colombo A. Cutting balloon angioplasty for the treatment of in-stent restenosis. Cathet Cardiovasc Interv 2000; 50:452–9.

13 Vascular brachytherapy for restenosis

Introduction Vascular brachytherapy using beta and gamma radiation has revolutionized the treatment of percutaneous coronary interventions (PCI), particularly in-stent restenosis (ISR). In an ever-ageing population, the striking magnitude of this problem is likely to expand, with projected increases in the number of coronary interventions being performed. Annually, there are 450000 coronary angioplasties performed on de novo and restenotic lesions in the US alone. Despite the widespread application of stent implantation to reduce restenosis (approximately 70–80% of cases), 15–35% of these patients still develop restenosis, usually within 6–9 months of the procedure. While treatment of ISR with conventional therapy is simple, the longevity of the patent artery is short, with angiographic restenosis rates between 50% and 85%. Vascular brachytherapy is a promising technology with the potential to reduce the restenosis rate. Brachytherapy is now used for the treatment of coronary ISR with approval granted based on multiple trials of both gamma and beta energy, which show treatment efficacy and safety (Fig. 13.1). Typical results for gamma brachytherapy suggest a reduction of angiographic ISR by 50% or more, and major adverse cardiovascular event (MACE) reduction of 40% or more. The GAMMA I trial showed a beneficial reduction in angiographic restenosis in radiation-treated diabetics from 76% to 36%. Five-year data from the Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS) I trial and four-year data from the Washington Radiation for In-Stent restenosis Trial (WRIST) trials show persistence of benefits. Beta radiation also shows promising results. Using beta radiation, the Stents and Radiation Therapy (START) trial showed a 31% and 34% reduction in MACE and target lesion revascularization (TLR) respectively, while the Intimal Hyperplasia Inhibition with Beta In-stent Trial (INHIBIT) trial showed a similar reduction in cardiac events (Table 13.1). However, ionizing radiation can also induce vigorous coronary atherosclerosis, typically appearing 6–8 years after radiation. Animal data suggest a similar catchup phenomenon at six months, with atherosclerotic-like changes developing in porcine and canine arteries. The only serious complication to arise has been late thrombosis in both gamma and beta treatment, but this appears to be controlled by avoiding new stent placement at radiated sites and by continuing antiplatelet agents long-term (six or twelve months).

© Clinical Publishing Services Ltd

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Fig. 13.1 Relative risk and 95% CI of MACE |1|. Table 13.1 Randomized clinical trials: 1245 patients |1| Trial

n

P

Rx

% decrease

SCRIPPS WRIST GAMMA START INHIBIT

55 130 252 476 332

54 58 69 44 48

17 19 25 14 16

69% 67% 64% 61% 67%

Brachytherapy is the first effective treatment for ISR in the short term. Whether the excellent early results will persist for several years, and whether it will show efficacy in less cellular de novo lesions, remain in question for careful observation. To date, over 4000 patients have been enrolled in clinical trials that evaluate the effectiveness and safety of this technology. Initial clinical studies recognized the limitations of gamma radiation; including high activity and radiation exposure, long treatment times, the need for special shielding, and the mandatory need to remove staff from the patient’s side during the dwell time. These factors have driven the development of intracoronary radiation using beta emitters. The rapid progress of this technology is apparent, with recent FDA approval of the 90/Sr/Y Beta-Cath (Novoste, Norcross, GA) and the P32 Galileo (Guidant, Santa Clara, CA) systems for ISR. Despite these advances, many questions remain regarding the utility of vascular brachytherapy and its dissemination as a friendly tool to prevent restenosis. The risk of complications such as late thrombosis, edge effect, late restenosis, and aneurysm formation, along with the logistic issues associated with the use of this technology in the catheterization laboratory environment, are delaying the acceptance for routine use. Other indications such as treatment of de novo lesions and peripheral arteries are awaiting further supporting data from ongoing clinical trials.

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Intracoronary β-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries. P K Coussement, H D Leon, T Ueno, et al. Circulation 2001; 104: 2459–64. BACKGROUND. Long-term biological effects of ionizing radiation on coronary arteries remain poorly defined. This study examined late arterial responses six months after balloon angioplasty and βradiation in normal pig coronary arteries. In the study, coronary arteries of 25 adult pigs were randomized to receive 20 Gy (n=8) or 30 Gy (n=9) of 186Re (β-radiation) or sham radiation (n=8) immediately after balloon angioplasty. Aspirin was given daily during follow-up. The study vessels were analysed histopathologically at six months. β-radiation decreased lumen area (20 Gy, 1.55±0.99 mm2; 3 Gy, 1.03±0.82 mm2; and 0 Gy, 2.05±0.80 mm2; P<0.05) but not overall vessel area. The neointimal area was significantly larger within the injured segment with β-radiation (20 Gy, 1.92±1.23 mm2; 30 Gy, 1.51 ±0.97 mm2; and 0 Gy, 0.89±0.31 mm2; 0 Gy vs 20 Gy, P<0.05), and a significant increase of edge stenosis was observed with β-radiation. Irradiated vessels also had larger thrombus areas within the neointima (30 Gy, 0.24±0.61 mm2; 20 Gy, 0.98±1.57 mm2; and 0 Gy, 0.00±0.01 mm2; P<0.05) and larger adventitial areas (20 Gy, 2.25±0.75 mm2; 30 Gy, 2.38±0.98 mm2; and 0 Gy, 1.23±0.29 mm2; 0 Gy vs 20 or 30 Gy, P<0. 05) that showed substantial collagen accumulation. INTERPRETATION. Intracoronary β-radiation did not inhibit neointima formation in balloon-injured normal pig coronary arteries six months after the interventional procedure. Unresorbed thrombus contributed to, but was not the sole component of, augmented neointima formation. Irradiated vessels demonstrated more adventitial thickening and fibrosis. These observations may have relevance for long-term clinical outcomes after intracoronary β-radiation.

Comment In the present study, Coussement et al. describe an unfavourable 6-month outcome after catheter-based βirradiation in a porcine coronary model. The results described may provide some insights into the biology of restenosis inhibition with brachy-therapy, or they may be a finding limited by the idiosyncrasies of this particular animal model and not directly relevant to humans. In this study, normal pig coronary arteries exposed to 20 or 30 Gy of β-irradiation delivered by a 186Reliquid filled balloon after over-distension balloon injury demonstrated greater neointimal areas and thrombosis at six months compared with nonirradiated vessels. On the basis of the discrepancy between the six-month outcomes in clinical trials and these animal data, the investigators have proposed that the ‘direct extrapolation of the long-term outcome of endovascular irradiation in the pig coronary artery preparation of restenosis to the human setting is not appropriate’. How do we further reconcile differences between clinical and experimental studies? Another possible explanation for the conflicting results among species is that there is a differential rate of healing. This differential rate may be proportional to the longevity of the species. Humans have a life span of >70 years (72.8 years for men and 79.6 years for women). In contrast, pigs have a life span of 16 years, and rabbits have a life span of 5 to 6 years. Human coronary arteries take longer to heal after injury than normal pig or rabbit arteries. Finally, how do we put the current study in an appropriate perspective for the practice of interventional cardiology? First, it is clear that for patients with ISR, both γ- and β-irradiation-based intracoronary brachytherapy offer reasonably safe and effective means to reduce the risk of further ISR. In multiple controlled and randomized clinical trials, the beneficial results for this clinically challenging patient group are apparent at six months and, in a small subset of patients, at three years. The broader application of

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intracoronary brachytherapy for high-risk de novo lesions should be discouraged until late safety and efficacy outcomes can be validated in carefully controlled clinical trials. Long-term effects of intracoronary β-radiation in balloon- and stent-injured porcine coronary arteries. G L Kaluza, A E Raizner, W Mazur, et al. Circulation 2001; 103:2108–13. BACKGROUND. The data on the long-term safety and efficacy of intracoronary β-radiation in animal models are limited. A total of 30 coronary arteries in 15 swine were subjected to balloon or stent injury followed by β-radiation from a centred 32P source (2000 cGy to 1 mm beyond lumen surface) or a sham radiation procedure. The animals received aspirin for 6 months and ticlopidine for 30 days. Five of the 10 animals subjected to radiation died (at 5 days, 7 days, 3 months [n=2], and 4 months) as a result of layered, occlusive thrombus at the intervention site (3 stent and 2 balloon injury sites). No deaths occurred in the control group. In the surviving animals, balloon-injured and irradiated vessels showed a trend toward larger lumens than controls (2.15±0.17 vs 1.80±0.08 mm2, P=0.06) and larger external elastic lamina areas (3.32±0.21 vs 2.62±0.10 mm2, P=0.003). In the stent-injured vessels from surviving animals, lumen, neointimal, and external elastic lamina areas were 3.58±0.33, 3.16±0.35, and 8.12±0.42 mm2 for irradiated vessel segments; these values were not different from those in controls (3.21±0.15, 2. 84±0.27, and 7.76±0.28 mm2, respectively). Histologically, healing was

complete in most survivors, although intramural fibrin and haemorrhage were occasionally seen. INTERPRETATION. In the long-term (six month) porcine model of restenosis, the inhibition by intracoronary β-radiotherapy of the neointimal formation that is known to be present at one month is not sustained. This lack of effect on neointimal formation after balloon and stent arterial injury is accompanied by subacute and late thrombosis that lead to cardiac death on a background of continuous aspirin but relatively brief ticlopidine treatment.

Comment This study confirms the lack of beneficial effects of intravascular radiation in both the stented- and ballooninjured porcine arteries at six months. It also stresses the excess of thrombus in the irradiated arteries compared to control. The balloon-injured irradiated arteries had larger lumen compared to controls due to vascular remodelling while the stented-irradiated vessels did not differ in lumen or perimeter compared to the stented control arteries. Again, these findings are worrisome since they raise two problems with the use of radiation therapy; late thrombosis and late catch-up. While late thrombosis may be controlled with prolonged treatment of antiplatelet therapy, the late catch-up phenomenon needs to be kept in perspective, because all of our catheter-based treatments for atherosclerotic coronary disease are palliative and not curative. If and when these patients present with late recurrent restenosis, revascularization with bypass surgery or, in the not too distant future, drug-eluting stents, should be considered. It is thus incumbent upon us to continue efforts to reduce, reverse, or prevent the systemic disease of atherosclerosis. Two-year follow-up after beta and gamma intracoronary radiation therapy for patients with diffuse in-stent restenosis. R Waksman, A E Ajani, R L White, et al. Am J Cardiol 2001; 88:425–8. BACKGROUND. The two-year outcome data from Beta WRIST and the original WRIST cohort have recently been published in the American Journal of Cardiology. The long-term impact and safety of radiation for ISR is unknown. Clinical follow-up of the Beta and Gamma WRIST cohorts was compared

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Fig. 13.2 MACE event-free survival. WRIST 4-year follow-up |1|. to the placebo group of the WRIST study. The study population included 50 patients in each of three study groups, (1) Beta WRIST (90-yttrium, 90Y), (2) Gamma radiation arm (192Iridium) of WRIST and (3) placebo arm of WRIST. Clinical follow-up was assessed at six months, one year and two years. The procedure was successful in all cases without adverse events. Baseline clinical, angiographic and procedural characteristics were similar between groups except for shorter lesions with 90Y (17.2±9.8 vs 23.7±11.2 mm in placebo WRIST, P=0.004). The benefit of radiation compared to placebo was evident at all time

intervals assessed, with no differences detected between 90Y and 192 Iridium emitters. At two years, target vessel revascularization (90Y 46 % vs 192Iridium 44% vs placebo WRIST 72%, P=0.009) and composite MACE (90Y 46 % vs 192Iridium 48% vs placebo WRIST 72%, P=0.008) were reduced with radiation. Coronary radiation therapy using 90Y and 192Iridium for ISR demonstrated significant reductions in rates of clinical restenosis with an acceptable safety profile at two years. Treatment with beta emitters appears to be as effective as that with gamma emitters. INTERPRETATION. The WRIST is a double-blinded, randomized study assessing the effects of intracoronary radiation therapy (IRT) in patients (pts) with ISR. The two-year follow-up published this year supports the longevity of vascular brachytherapy patients over a period of two years in terms of a reduction for the need for repeat revascularization for patients with ISR.

Comment This paper reflects the current status of the long-term follow-up of patients that have undergone vascular brachytherapy treatment. Despite late events that occurred primarily in the irradiated group, the overall events were still lower compared to the control group. This has been shown now in several trials; among them SCRIPPS with five year follow-up and reduction in the TLR at five years in the irradiated group compared to controls and the WRIST study where these results are holding at 4 years (Fig. 13.2). It appears that the majority of the events occur up to 18 months. From 18 months to 5 years, there are few events in either the irradiated or the control groups. Reports from the beta trials show START at two years

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demonstrated that the durability of the effect is also seen with the use of beta emitters. More importantly, at the present time, the treated arteries do not show evidence of accelerated atherosclerosis, fibrosis, or perforation. If continued for an additional 5 years, we will be able to support the safety of brachytherapy. ‘Edge effect’ of 32P radioactive stents is caused by the combination of chronic stent injury and radioactive dose falloff. W J van der Giessen, E Regar, M S Harteveld, et al. Circulation 2001; 104: 2236–41. BACKGROUND. Radioactive stents have been reported to reduce in-stent neointimal thickening. An unexpected increase in neointimal response was observed, however, at the stent-to-artery transitions, the so-called ‘edge effect’. To investigate the factors involved in this edge effect, we studied stents with one radioactive half and one regular non-radioactive half, thereby creating a mid-stent radioactive dosefalloff zone next to a non-radioactive stent-artery transition at one side and a radioactive stent-artery transition at the other side. Half-radioactive stents (n=20) and non-radioactive control stents (n=10) were implanted in the coronary arteries of Yucatan micropigs. Animals received aspirin and clopidogrel as antithrombotics. After four weeks, a significant mid-stent stenosis was observed by angiography in the half-radioactive stents. Two animals died suddenly because of coronary occlusion at this mid zone at eight and ten weeks. At twelve-week follow-up angiography, intravascular ultrasound and histomorphometry showed a significant neointimal thickening at the mid-stent dose-falloff zone of the half-radioactive stents, but not at the stent-to-artery transitions at both extremities. Such a mid-stent response (mean angiographic late loss 1.0 mm) was not observed in the non-radioactive stents (mean loss 0.4 to 0.6 mm; P<0.01). INTERPRETATION. The study identifies two mechanisms for the reduction of edge effect with the use of radioactive stents. The edge effect of high-dose radioactive stents in porcine coronary arteries is associated with the combination of stent injury and radioactive dose falloff. These limitations raise the question of whether radioactive stents are a viable option for the prevention of restenosis.

Comment Over the last few years numerous attempts have been made to improve the performance of radioactive stents, among those was the use of high activity stents using cold ends or hot ends. Unfortunately none of these attempts was successful in eliminating the edge effect phenomenon (Fig. 13.3). The lack of success can simply be explained by the basic physics of a radioactive line source (RLS). Along the long axis of an RLS, the prescribed isodose extends beyond both source ends for a variable distance. However, what is of real interest is the length of the prescription isodose (in relation to the length of the RLS) at the prescribed distance from the RLS. This is the length that is available to us for treating the ‘injured segment’ of the artery. This length is always shorter than the RLS because, as we move away from the RLS (in a radial direction), the isodoses ‘bow inward’ (i.e. they curve toward the RLS as one approaches the ends). Thus, if the RLS length was selected to be exactly equal to the length of the vessel that we wanted to treat to a given dose (as is the case with the radioactive stent), the ends of that vessel length would always be under-dosed. In most of these studies the neointima begins to increase just within the ends of the stent, and this increase extends for the first millimetre or so on either side. This would mean an underdosing of the two ends. However, the predominance of negative remodelling observed beyond the first millimetre on either side of the stent probably reflects a restenotic process occurring in the non-stented segment of the artery, which has sustained an occult injury, due to either the pre-dilation balloon or the extension of medial fractures (which may have originated in the stented egment). The very effective inhibition of neointimal proliferation within the stent results in the minimal luminal diameter shifting to these edges, with the appearance of edge

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Fig. 13.3 The Hot End and Cold End studies |2|.

Fig. 13.4 Schematic diagram of geographic miss.

restenosis. The paper of van der Giessen demonstrates that the trauma associated with the stent implantation can by itself contribute to the edge phenomenon. ‘Geographic miss’ is a radiation oncology term extended to interventional cardiology, denoting circumstances when coronary injury, lesion, and stent sites are not adequately treated with radiation (Fig. 13.4). Sabate and colleagues |3| evaluated 50 consecutive lesions treated with beta radiation and looked for edges not receiving complete beta coverage. They found significantly higher late loss in geographic miss regions than in radiated segments (0.84±0.6 and 0.15±0.4 respectively), and concluded that angioplasty injury and low-dose beta radiation induce a worse procedural outcome. Recent sub-group results of the Beta-Cath trial (higher restenosis in stented and radiated segments) might similarly be explained by the

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geographic miss phenomenon. The edge effect appears to be real, with radiation potentially inducing neointimal formation in injured regions when associated with inadequate radiation doses. The use of radioactive stents is associated with nearly 100% of geographic miss and it will therefore be impossible to eliminate the edge effect with this technology. Treatment of long, diffuse, in-stent restenotic lesions with beta radiation using strontium 90 and sequential positioning ‘pullback’ technique: procedural details and clinical outcomes. I Crocker, M Joyal, T Fox, A Arsenault, R Bonan. J Invasive Cardiol 2001; 13(12):782–7. BACKGROUND. Long, diffuse, in-stent restenotic lesions have been problematic for many patients, necessitating the need for multiple repeat PCI. The need for repeat PCI

has been significantly reduced in patients since the advent of vascular brachytherapy. ISR resulting in long lesions (>30 mm) presents even more of a challenge. The interventional injury length created during PCI is usually greater than 30 mm and the vascular brachytherapy systems available in most hospitals are 30 mm or 40 mm in length. The purpose of this paper was to determine the safety and efficacy of a pullback technique to cover diffuse ISR lesions using the Beta-Cath system. The database of patients enrolled in the Compassionate Use registry between August 1999 and July 2000 was reviewed. In the database, 23 consecutive patients were treated with the pullback technique to cover diffuse lesions with a mean lesion length of 49.4±19.8 mm. A dose of 23 Gy at 2 mm from the centre of the source was prescribed for each step. At six month clinical follow-up, three patients (13%) underwent target vessel revascularization. Angiographic follow-up was obtained in eighteen patients (78%). Seven patients (38. 8%) showed angiographic restenosis (50% luminal re-narrowing). No aneurysms or zones of ectasia were noted. INTERPRETATION. This paper supports the safety of the pullback technique to cover diffuse lesions with beta source 90Sr/Y, without documented angiographic or clinical adverse events. Despite the pullback technique, the restenosis rate was still high compared to previously non-diffuse lesions treated with the same system.

Comment The present paper demonstrates the pullback radiation technique used to cover diffuse lesions (longer than the available train sources). The study demonstrates the feasibility and safety of the technique with high binary restenosis rates of nearly 40%. In the Long WRIST study when gamma radiation was utilized for long lesions >56 mm in length, the restenosis rate was higher compared to the WRIST study, which had a mean lesion length of 20 mm. It is possible that longer lesions require higher doses of radiation. The Beta-Cath catheter is a non-centred system, thus overlap of the dose with the pullback technique can result in doses exceeding 100 Gy to the wall. However on angiogram there was no evidence of angiographic adverse effects. Serial intravascular ultrasound assessment of the efficacy of intracoronary gamma-radiation therapy for preventing recurrence in very long, diffuse, in-stent restenosis lesions. J M Ahmed, G S Mintz, R Waksman, et al. Circulation 2001; 104(8): 856–9. BACKGROUND. The efficacy of coronary gamma-irradiation in preventing recurrent ISR is well established. However, brachytherapy may be less effective in very long, diffuse ISR lesions. In the

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present study, the authors analysed serial intravascular ultrasound (IVUS) in patients with long, diffuse ISR lesions (length, 36 to 80 mm)

who were enrolled in (1) Long WRIST, a double-blind, placebo-controlled trial of intracoronary gamma-irradiation where the prescribed doses were (15 Gy at 2 mm from the source) and (2) high-dose (HD) Long WRIST, a registry that used a dose prescription of 18 Gy at 2 mm from the source. IVUS was performed using automated pullback (0.5 mm/s). Stent, lumen, and intimal hyperplasia were measured at 2 mm intervals. Complete post-intervention and follow-up IVUS imaging was available in 30 irradiated and 34 placebo patients from Long WRIST and in 25 patients from HD Long WRIST. Stent length was longer in HD Long WRIST than in placebo or treated patients in Long WRIST (P=0. 0064 and P=0.0125, respectively). Otherwise, baseline measurements were similar. At follow-up, the minimum lumen area was largest in the HD Long WRIST patients (4.0±1.4 mm2); areas were 2.9±1.0 mm2 in irradiated patients in Long WRIST and 1.9±1.1 mm2 in placebo patients in Long WRIST (P<0. 005 for all comparisons). INTERPRETATION. Serial IVUS analysis shows that gamma-irradiation reduces recurrent in-stent neointimal hyperplasia in long, diffuse ISR lesions; however, it is even more effective when given at a higher dose.

Comment The present study demonstrates that long lesions are associated with higher tissue at follow-up compared to focal lesions. In addition, higher doses are associated with larger lumen and there is a linear dose response. Increase of the dose was associated with further reduction of the overall major cardiac events at six months. Another important observation was the lack of heterogeneity in the tissue volume at follow-up in the Long WRIST study suggesting that long lesions required higher doses to obtain a homogenous therapeutic effect across the entire length of the lesion. Gamma radiation continues to be effective for the treatment of long lesions and the vessels can tolerate even higher doses approved for use. Based on the results of the Long WRIST HD study we recommend a dose of at least 18 Gy at 2 mm for the Chekmate™ gamma system for the treatment of diffuse in-stent restenotic lesions. Liquid-filled balloon brachytherapy using 68Ga is effective and safe because of the short 68-minute half-life results of a feasibility study in the porcine coronary overstretch model. H P Stoll, G D Hutchins, W L Winkle, et al. Circulation 2001; 103:1793–8. BACKGROUND. Liquid-filled balloons for coronary brachytherapy provide significant advantages over solid sources in dose homogeneity but carry the risk of life-threatening radiointoxication after balloon rupture and laboratory contamination in case of a spill. The authors hypothesized that the positron emitter 68Ga, with a half-life of only 68 minutes, was well suited to overcome these safety obstacles while providing full therapeutic efficacy. The feasibility, efficacy, and safety of 68Ga liquid-filled balloon brachytherapy were investigated in the porcine coronary overstretch model. Four groups of five ballooninduced coronary lesions were irradiated with 8, 12, 16, and 24 Gy targeted to the adventitia. Ten unirradiated lesions served as controls. Segments treated with 16 or 24 Gy exhibited marked suppression of neointimal proliferation at 28-day follow-up, with quantitative parameters of intraluminal proliferation reduced to <20%. This beneficial effect was not compromised by untoward edge effects. Uninjured but irradiated vessels did not show histological signs of radiation damage. The 68Ga whole-

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body dose due to balloon rupture was estimated to be 5 rem/50 mCi treatment activity and compared favourably with that of 188Re (78 rem/50 mCi). INTERPRETATION. 68Ga positron radiation suppresses neointimal proliferation at doses of 16 and 24 Gy. This biological efficacy, coupled with the attractive safety profile, suggests the selection of 68Ga as an attractive isotope for liquid-filled balloon brachytherapy.

Comment When compared with wire-based beta sources, liquid- or gas-filled balloon technology has the potential advantages of homogenous delivery of radiation and the minimization of the distance from a beta source to the vessel wall and adventitia. One of the potential disadvantages of these systems is the potential leakage and spillage of the isotope. The advantage of the system used in the paper is the short half-life of the isotope; only 68 minutes. This feature can provide safety in case of balloon rupture. Overall, the liquid filled balloon systems utilizing the Re-188 isotope proved to be safe and effective in human clinical use. In clinical trials performed in the US, Korea, and Germany, the restenosis rates were<20%. Other systems of hot balloons with solid sources can provide similar advantages of centring and homogenous delivery of the radiation system to the target vessel. The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with chronic renal failure. L Gruberg, R Waksman, A E Ajani, et al. J Am Coll Cardiol 2001; 38(4): 1049–53. BACKGROUND. Patients with chronic renal failure (CRF) are at a higher risk than the general population of accelerated atherosclerotic cardiovascular disease and for restenosis after PCI. Previous studies have shown the effectiveness of both beta and gamma radiation in preventing recurrent restenosis in patients with ISR. This study was designed to analyse the in-hospital and six-month clinical and angiographic outcomes of patients with CRF treated with intracoronary radiation for the prevention of recurrence of ISR. The authors studied the in-hospital and six-month clinical and

angiographic outcomes of 118 patients with CRF and 481 consecutive patients without CRF who were treated with intracoronary radiation for the prevention of recurrence of ISR in native coronaries and saphenous vein grafts. Patients with CRF were usually older, women, hypertensive and diabetic, with multivessel disease and with reduced left ventricular function. In-hospital outcome for patients with CRF was marred by a higher incidence of death, non-Q wave myocardial infarction and major vascular and bleeding complications. At six-month follow-up, the mortality rate was higher in patients with CRF, 7.6% compared with 1.9% in non-CRF patients (P=0.003). Restenosis, TLR, and target vessel revascularization (TVR) rates were similar in the two groups. In patients with CRF, radiation therapy compared to placebo reduced restenosis (53.8% vs 22.6%, P=0.04), TLR (71.4% vs 15.3%, P<0.0001), and TVR (78.6% vs 23.7%, P=0.0002) (Fig. 13.5). INTERPRETATION. Intracoronary radiation for the prevention of recurrence of ISR achieved similar rates of restenosis and revascularization procedures in patients with and without CRF. Despite this benefit, patients with renal dysfunction continued to have significantly higher in-hospital and six-month adverse outcomes.

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Fig. 13.5 TVR at 6 months |4|.

Comment This study supports the hypothesis that vascular brachytherapy continues to be effective in patients with a high risk of recurrences. Similar observations were reported in patients with diabetes when radiation therapy proved to be an equalizer for those patients. The stented diabetic patient generally has 30%–40% restenosis rates in de novo lesions, compared to 15–20% in non-diabetics. Repeat percutaneous intervention for diabetic ISR may recur at rates as high as 80%. Diabetics in the GAMMA I (ISR) trial had a 36% ISR rate compared to 76% in those not receiving brachytherapy. Gamma brachytherapy thus appears to be highly effective in reducing recurrent diabetic ISR. In-lesion restenosis in non-diabetics was reduced from 47% to 33%. In diabetic patients, the START 30 ISR rate in the radiated group was 19% compared to 37% for controls. The diabetic sub-group (124 patients) showed in-stent analysis restenosis at 37% in the control group and 19% in radiated lesions (P=0.02). As in diabetic patients, the rate of TVR was striking, at nearly 80%, with conventional therapy. Despite its ability to reduce the restenosis rate, radiation therapy did not affect the high rates of mortality seen in the group with chronic renal failure and at most was associated with improvement in quality of life. Nevertheless, the study suggests that brachytherapy should be the treatment of choice for all patients with chronic renal failure. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary γ-radiation in patients with in-stent restenosis; Washington Radiation for In-stent restenosis Trial Plus 6 months of clopidogrel (WRIST PLUS). R Waksman, A E Ajani, R L White, et al. Circulation 2001; 103:2332–5. BACKGROUND. Intracoronary γ-radiation reduces recurrent ISR. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. WRIST PLUS, which involved six months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis. A total of 120 consecutive patients with diffuse ISR in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive 192Ir seeds was positioned to cover the treated site, and a

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dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for six months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the γ-radiation-treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only one month of antiplatelet therapy). At six months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active γ-radiation group and similar to those in the placebo historical control group. INTERPRETATION. Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with ISR treated with γ-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only one month of clopidogrel and aspirin.

Comment Late thrombosis is considered to be one of the major complications of vascular brachytherapy. In the early clinical trials utilizing the technology, the rate of late thrombosis was reported in up to 14% of the patients. Higher subacute and late stent thrombosis rates occurred in GAMMA-I for radiated compared to control patients (6.9% vs 1.7%). All radiated patients with stent thrombosis had new stents placed at the restenosis site. Autopsy evaluation from a few stents suggested arrested healing, with neither endothelium nor neointima covering new stents even at late time points. IVUS studies suggest that positive arterial remodelling at the radiated site caused separation of the stent from the vessel wall. This situation is analogous to earlier procedures of incomplete stent expansion. While late thrombosis is also a problem with beta radiation, most occurred before aspirin and ticlopidine or clopidogrel was continued for longer time periods. The thrombosis rate appears acceptable when these antiplatelet agents are continued long term. Data from the START trials suggest that late occlusions occurred equally in radiated and placebo groups (3.3% vs 3.0% respectively), and relate to new stent placement with 3/42 (7.1%) new stent patients vs 5/156 (3.2%) with no new stent. Prolonged antiplatelet therapy was associated with a reduction in late thrombosis, as shown in Table 13.2. Late thrombosis also occurs with other vascular brachytherapy strategies, and almost certainly relates to the healing arrest and lack of stent cover by cells. Current recommendations include extended antiplatelet therapy with clopidogrel and aspirin, and avoiding new stent placement at radiated sites. Other solutions may include using a heparin-coated stent to limit late thrombosis. Late thrombosis occurred primarily in patients that underwent stenting. WRIST PLUS was the first to examine whether prolonged antiplatelet therapy reduced the risk of late thrombosis. The study demonstrates that six months of clopidogrel and aspirin, and minimizing stent use significantly reduced the rate of late thrombosis seen in patients treated with gamma radiation for in-stent restenosis. Only one patient in this cohort developed late thrombosis while on clopidogrel. Few patients Table 13.2 Late thrombosis rate in clinical radiation trials with prolonged antiplatelet therapy Study

#PTS

Antiplatelet regimen clopidogrel

Thrombosis rate at 9 months

SCRIPPS III START INHIBIT GALILEO INHIBIT

500 245 166 125

6–12 months 1–6 months 1–6 months 6 months

0% 0% 3.2% 1.5%

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Study

#PTS

Antiplatelet regimen clopidogrel

Thrombosis rate at 9 months

BETA-CATH WRIST PLUS WRIST 12

450 120 120

2–6 months 6 months 12 months

1.8% 4.2% 2.5%

developed late thrombosis more than six months after cessation of the antiplatelet therapy. These findings raised the question of whether six months is enough to reduce the late thrombosis after radiation therapy. A recent study performed by the same group (WRIST 12) demonstrated that 12 months of clopidogrel is associated with further reduction of the thrombosis and revascularization rate. Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARIS feasibility clinical trial. R Waksman, J R Laird, C T Jurkowitz, et al. J Vasc Interv Radiol 2001; 12: 915–21. BACKGROUND. Pre-clinical studies with endovascular radiation have suggested that this technology would be efficacious in the peripheral arteries also undergoing intervention. The purpose of this study was to assess the feasibility, safety, and outcome of endoluminal gamma radiation therapy after balloon angioplasty of superficial femoral artery (SFA) lesions. Forty patients with claudication were enrolled in the study and underwent percutaneous transluminal angioplasty (PTA) of SFA lesions with a mean lesion length of 9.8±3.0 cm and a mean reference vessel diameter of 5.2±3.1 mm. After successful PTA, a segmented centring balloon catheter was positioned to cover the PTA site. The patients were then transported to the radiation oncology suite and treated with a microSelectron HDR afterloader with an Ir-192 source with a prescribed dose of 14 Gy, 2 mm into the vessel wall. Ankle-brachial index (ABI) and Rutherford score were evaluated at one, six and twelve months after the procedure and angiographic follow-up was conducted at six months. In the study, radiation was delivered successfully to 35 of 40 patients. There were no procedural complications. Exercise and rest ABI were higher at one year (0.72 ±0.26 and 0.89±0.18, respectively) compared to baseline (0.51±0.25 and 0.67±0.17, respectively). Maximum walking time on a treadmill increased from 3.41±2.41 min to 4.43±2.49 min at 30 days and was 4.04±2.8 min at 12 months. The angiographic binary restenosis rate at 6 months was 17.2% and the clinical restenosis rate at 12 months was 13.3%. There were no angiographic or clinical adverse events related to the radiation therapy. INTERPRETATION. Intra-arterial radiation after PTA of SFA lesions with the use of high-dose rate gamma radiation is feasible and safe. The angiographic and clinical improvements are sustainable at 1 year and represent a potent antirestenotic therapy for the treatment of narrowed peripheral arteries.

Comment The potential of expanding the use of vascular brachytherapy beyond coronary arteries and the treatment of ISR is demonstrated in this paper. The use of endovascular radiation was initiated a decade ago with encouraging results. In 2000, Minar et al. published a randomized study with the use of intravascular gamma

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Fig. 13.6 PARIS pilot study. Table 13.3 SFA radiation trials Study

Frankfurt Vienna 1 Vienna 2

#Pts

40 10 113

Random.

– – Yes

Centre cath.

– – –

Dose

Patency

Gy

at mm

%

12 12 12

3 3 3

82 60 72

183

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radiation as adjunct therapy to angioplasty of lesions in superficial femoral arteries. Their randomized study demonstrated significant reduction with the use of radiation compared to placebo. Several considerations should be addressed with the use of vascular brachytherapy in peripheral arteries; among them are the use of centring catheter, dose, and the treatment of long lesions. The Peripheral Artery Radiation Investigational Study (PARIS) pilot study demonstrated the lowest restenosis rates published thus far, which can be attributed to more accurate dosimetry and the use of centring catheters. If the randomized study duplicates these results, it is anticipated that vascular brachytherapy will be expanded for the use of de novo lesions in SFA lesions (Fig. 13.6). A list of radiation trials in SFA lesions is shown in Table 13.3. Conclusion Intracoronary radiation is a new and exciting area in interventional cardiology that, after many careful and meticulous designed clinical studies, has recently been approved by the FDA for the prevention of the recurrence of ISR. Currently, vascular brachytherapy is the only proven and available treatment for ISR. It is currently used in nearly 500 catheterization laboratories all over the world. There are still pending issues that will eventually be clarified. Long-term results and experiences made available from ongoing trials happening in centres all over the world will help clarify these issues. Prolonged antiplatelet therapy coupled with no new stent implantation immediately preceding radiation appears to be the solution to preventing the incidence of late thrombosis. The next step includes resolving the issues of edge effect and delayed restenosis. These obstacles will probably be surmounted by improving operators’ techniques and by ensuring careful and adequate lesion coverage with the radioactive source. In addition, the multidisciplinary approach has to be adopted in the catheterization laboratory with the integration of the radiation therapists and physicists in the procedure. However, regulatory authorities are delaying the implementation of this technology especially in Europe. A psychological barrier also remains that will need to be overcome by physicians, patients, and caregivers before intravascular radiation becomes standard therapy. A more thorough understanding of the technology will lead to greater acceptance and integration of this new therapeutic alternative for the benefit of all patients. Initiating vascular brachytherapy into a clinical practice requires substantial work and training. New staffing must be arranged for the procedures; including radiation oncologists, radiation physicists, and radiation safety personnel trained in the unique issues of brachytherapy. Other issues include licensing, shielding, scheduling times and patient throughput, and additional lab expenses for all of these features. References 1

Ajani AE, Kim H, Waksman R. Clinical trials of vascular brachytherapy for in-stent restenosis: update. Cardiovasc Radiat Med 2001; 2(2):107–13.

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Wardeh AJ, Albiero R, Kay IP, Knook AHM, Wijns W, Kozuma K, Nishida T, Ferrero V, Levendag PC, van der Giessen WJ, Colombo A, Serruys PW. Angiographical follow-up after radioactive ‘cold ends’ stent implantation —a multicenter trial. Circulation 2002; 105:550–3. Sabate M, Costa MA, Kozuma K, Kay IP, van der Giessen WJ, Coen VL, Ligthart JM, Serrano P, Levendag PC, Serruys PW. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation 2000; 101: 2467–71. Gruberg L, Waksman R, Ajani AE, Kim H-S, White RL, Pinnow E, Deible R, Satler LF, Pichard AD, Kent KM, Lindsay J. The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with chronic renal failure. J Amer Coll Card 2001; 38(4):1049–53. Waksman R (Ed). Vascular Brachytherapy. Third edition. New York: Futura Publishing Company, 2001.

Part V Cardiac imaging outside the cardiac catheter lab

Cardiac imaging outside the cardiac catheter lab

Introduction In the last five years, the speciality of percutaneous coronary intervention (PCI) has come of age. With the routine use of coronary stents and potent platelet inhibitors, PCI can be performed with predictable procedural results in the vast majority of cases. The further development of coated stents promises predictable intermediate and long-term results and thus finally even the most sceptical cardiac surgeon will have to accept the advantages of a percutaneous approach to treating coronary artery disease. As these developments are introduced into clinical practice many long held beliefs about the role and timing of PCI will be challenged. Recent publication of the FRISC II (Fast Revascularization during Instability in Coronary artery disease) and TACTICS (Treat Angina with aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy) studies has confirmed the benefits of early intervention in patients with acute coronary syndromes. This benefit is observed in the early period following treatment and is maintained in the subsequent months despite the incidence of restenosis and graft occlusion. Combined with advances in secondary prevention, particularly aggressive lipid lowering with statins and the protective effects of angiotensin-converting enzyme (ACE) inhibition, the management of atheromatous coronary disease will be transformed in the next five years. In this new era, the modalities of echocardiography, computed tomography (CT) and magnretic resonance imaging (MRI) will play an important and increasing role. Imaging has also undergone a major technological advance and clinical application of these improved techniques will provide both novel noninvasive imaging of obstructive atheromatous disease and promises assessment of vulnerable atheromatous plaque and coronary risk. Although enthusiasts for each noninvasive technique might suggest that their technology offers the ultimate imaging, it seems more likely that each modality will mature to provide slightly different and hopefully additive information. Potential roles for these modalities include: Screening symptom-free individuals for evidence of coronary disease As discussed by Dr McGuire later in this section, for any screening test for coronary disease to be applicable it must a) be safe and inexpensive, b) be minimally invasive, c) be reliable and reproducible, d) be able to detect the extent of atheroma, and e) have a high positive and negative predictive value for clinical events. Measurement of coronary artery calcification using electron beam computed tomography is being validated against coronary angiography in symptomatic and symptom-free individuals with

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encouraging results. In symptom-free individuals particularly, identification of occult atheroma in the coronaries facilitates the prescription of proven treatments capable of improving prognosis, e.g. statins. Using this targeted approach to therapy in the community is much more likely to be cost effective than prescribing drugs based on population statistics alone. Excluding ischaemic heart disease in patients with chest pain Although the risks of diagnostic cardiac catheterization have been reduced substantially by the use of improved contrast media and smaller catheters, there remains a small finite risk, particularly of emboli and ostial dissection related to catheter engagement. A truly reliable, non-invasive test which could rule out atheromatous disease would carry no risk. This would facilitate appropriate management at an earlier stage in the diagnostic process and, by reducing the number of normal coronary angiograms, it would also increase the catheter lab time available for PCI. Use of nuclear stress testing to detect ischaemia in this patient group has well documented limitations particularly in female patients. Both multislice spiral CT and MRI offer the potential to directly image the coronary arteries. Comparative studies with angiography have been undertaken with encouraging preliminary results and it seems likely that both techniques will be soon be able to state that some patients have absolutely normal epicardial coronary arteries. Detection of culprit lesions in patients with multivessel coronary disease A coronary angiogram gives only anatomical information about the presence (or absence) of stenoses within the coronary arterial tree. Despite this, in experienced hands and when combined with clinical information, the culprit coronary lesion can usually be identified and treated. However, in cases of multiple stenoses and particularly when disease is moderate rather than severe, identification of culprit stenoses can be difficult and it is in these cases that use of the Doppler pressure wire has been advocated. This technology measures the gradient across the lesion and the response of the vessel to vasodilation with adenosine—the coronary flow reserve. In the future, MRI may also offer this information. As described later in this section by Dr Neubauer, early MRI studies have used dipyridamole infusion to measure a myocardial perfusion index before and after PCI with encouraging initial results. Extrapolating these data to their full potential allows speculation that in the future anatomical and functional data may be available to interventionalists before they put on their lead coats and enter the catheter laboratory! Detection of vulnerable plaques Although high grade obstructive atheromatous lesions cause ischaemia and resultant angina, it is lipid rich, minimally occlusive lesions which rupture and cause myocardial infarction. The limited ability of coronary angiography to detect these types of lesions is well documented and although intracoronary ultrasound has improved imaging of apparently disease-free segments, detection of the ‘vulnerable’ plaque remains limited using contemporary technology. Multi-slice CT and MRI are now being used to detect mural atheromatous plaque. In this application, the ability of these techniques to image the coronary wall rather than the coronary lumen per se is an advantage (in contrast to the situation with high grade stenoses). When combined with the technology to label specific molecular targets such as fibrin or macrophage adhesion molecules and subsequent imaging with either PET or MRI the opportunity to prevent imminently impending coronary events may become a reality.

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Plaque composition Although enthusiasm for adjunctive devices to balloon dilatation remains mixed, most interventionalists would welcome improved information about plaque characteristics. Currently, detection of calcification during angiography may be augmented by recognition of subtle density variation around the stenosis and by clinical information. Intracoronary ultrasound does provide extra data but acquisition of intracoronary ultrasound data before intervention has generally been less valuable than data acquired during the procedure allowing optimization of stent deployment. Multislice CT in particular may be useful in detecting a high calcific content within the lesion allowing the opportunity for pre-procedure discussion of alternative strategies to balloon dilatation. Improved lesion characterization would also enable more appropriate comparisons to be made between alternative interventional devices and strategies. Monitoring the response to therapy following drug treatment i.e. response of plaque to lipid lowering agents In the pre-statin era there was extensive debate about the issue of atheromatous plaque regression. Expensive, ambitious studies were undertaken using serial coronary angiograms to attempt to assess the impact not only of drug interventions but also more dramatic interventions like haemofiltration. These studies were inconclusive partly because the magnitude of the treatment effect was modest, but more importantly because the methods used to measure the effects were both insensitive and lacked reproducibility. MRI and CT are able to reproducibly image atheroma within static large non-cardiac vessels such as the carotid artery and there is early data to suggest that statins can alter plaque composition advantageously. As outlined above, coronary imaging is already possible and with this improved technology and reproducibility the number of patients that must be recruited for these longitudinal prognostic studies is likely to be substantially reduced. Monitoring development of in-stent restenosis Exercise testing has many limitations in patients that have undergone PCI. In many patients there is little alternative to repeat angiography when symptoms recur, even when the pain is atypical. The extent of flow restriction caused by moderate in-stent restenosis can also be difficult to assess angiographically and intracoronary ultrasound may be required. Both CT and MRI may be able to visualize stented segments. Imaging with multi-slice CT has been used for assessment of coronary vein graft patency and early experience with MRI may show the benefit of serial scanning, particularly in those patients at high clinical risk of restenosis. Determination of long-term prognosis in patients with coronary disease With the excitement and pace of change in the practice of PCI, it is easy to forget that the coronary anatomy alone does not predict mortality in patients with coronary disease. Global left ventricular systolic function remains the principal determinant of event-free survival and it is clear that left ventricular angiography will soon be completely abandoned as part of a standard diagnostic coronary angiogram. Assessment of the left ventricle by standard two dimensional echocardiography (at rest and/or with dobutamine stress) has clear advantages but as discussed by Dr Becher the development of three dimensional echocardiography promises to remove many of the limitations of the two dimensional echocardiographic approach. Enhanced

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reproducibility and improved spatial orientation are obvious initial benefits, but accurate bedside assessment of left ventricular volumes may also be particularly useful. Simultaneous imaging of ventricular perfusion and function Resting myocardial perfusion imaging with concomitant assessment of ventricular function can be carried out using single-photon-emission computed tomography (SPECT) nuclear techniques but the development of myocardial perfusion echocardiography represents an exciting development particularly as it can be carried out at the patient’s bedside and is readily applicable to the emergency situation. Intermittent accelerated imaging allows simultaneous assessment of myocardial perfusion and wall motion in real time. Use of this technology in the emergency room may become standard when patients are admitted with acute myocardial infarction. Not only will an ‘at risk’ area be identified but serial imaging will also monitor the impact of interventions such as thrombolysis. Earlier and more accurate selection of those patients likely to benefit most from mechanical intervention seems an achievable goal. Viability and hibernation As discussed above, patients with resting left ventricular systolic dysfunction caused by ischaemic heart disease represent a high-risk group. Intervention by PCI and particularly by surgery carries a higher than normal risk but this is balanced by increased benefit in those patients with substantial hibernating myocardium which will improve in function with enhanced perfusion. Selecting which patients and which areas of myocardium will benefit from revascularization has been hampered by problems of study reproducibility and spatial resolution. Using dobutamine enhancement to study contractile reserve appears to be more sensitive than standard viability imaging using resting injection of perfusion tracers and radionuclide imaging. The effects of dobutamine can be imaged using echocardiography, SPECT or MRI. All three techniques appear to offer substantial advantages. As discussed by Dr Kelion, recent studies appear to have answered some of the outstanding questions about which segments of myocardium will benefit from revascularization. However, further study remains necessary to provide the specificity for definite improvement in prognosis which both patient and physician require to facilitate decision making when considering high-risk revascularization strategies.

14 Nuclear cardiology and stress echocardiography

Introduction Functional imaging using radionuclide techniques or stress echocardiography has an established role in the assessment of patients with known or suspected coronary disease. An extensive literature demonstrates the prognostic value of radionuclide myocardial perfusion imaging, and similar data is now accumulating for stress echocardiography |1,2|. These methods are also finding an increasing role in the identification of hibernating myocardium in patients with ischaemic left ventricular dysfunction, who might benefit from revascularization. Despite the clinical interest in this indication, there remains a striking degree of uncertainty about which technique and protocol should be used, what constitutes significant hibernating myocardium, and what end-point should be used to assess the outcome of treatment. Radionuclide techniques are also showing promise in imaging aspects of myocardial physiology and metabolism. Such imaging was once the exclusive province of positron emission tomography (PET), but is becoming more feasible using single-photon-emission-computed tomography (SPECT) following labelling of biologically relevant molecules with appropriate radioisotopes |3|. Stress echocardiography is also likely to be revolutionized as myocardial contrast echocardiography becomes easier and more widely available. Prognosis in coronary disease Prognosis in coronary disease: gated SPECT Introduction The prognostic value of radionuclide myocardial perfusion imaging in patients with known or suspected coronary disease is well-established. Most large studies avoid the use of multiple ‘soft’ cardiac events in favour of the ‘hard’ irreversible events of cardiac death or non-fatal myocardial infarction (MI) |1|. However, even these hard end-points may not necessarily be predicted by the same scintigraphic variables. The risks of cardiac death and non-fatal MI respond differently to different management approaches. Mortality is reduced in certain patient groups by coronary artery bypass surgery |4|. However, the rate of non-fatal MI is not affected by revascularization, although it may be improved by aggressive medical

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therapy. The ability to differentiate between patients at risk of cardiac death and those only at risk of nonfatal MI has clear management implications. Prediction of myocardial infarction versus cardiac death by gated myocardial perfusion SPECT: Risk stratification by the amount of stress-induced ischaemia and the post-stress ejection fraction. T Sharir, G Germano, X Kang, et al. J Nucl Med 2001; 42:831–7. BACKGROUND. The combination of myocardial perfusion and post-stress ejection fraction (EF) provides incremental prognostic information. This study assessed predictors of non-fatal MI versus cardiac death (CD) by gated myocardial SPECT and examined the value of integrating the amount of ischaemia and poststress EF data in risk stratification. We identified 2686 patients who underwent resting 201TI/stress 99mTc-sestamibi gated SPECT and were monitored for >1 year. Patients who underwent revascularization ≥ 60 days after the nuclear test were censored from the prognostic analysis. Visual scoring of perfusion images used 20 segments and a scale of 0–4. Post-stress EF was automatically generated. INTERPRETATION. Cox regression analysis showed that after adjusting for pre-scan data, the most powerful predictor of CD was post-stress EF, whereas the best predictor of MI was the amount of ischaemia (summed difference score [SDS]). Integration of the EF and SDS yielded effective stratification of patients into low-, intermediate-, and high-risk subgroups. Patients with EF >50% and a large amount of ischaemia were at intermediate risk (2%–3%), whereas those with mild or moderate ischaemia were at low risk of CD (<1%/ year). Patients with EF between 30% and 50% were at intermediate risk even in the presence of only mild or moderate ischaemia. In patients with EF <30%, the CD rate was high (>4%/year) irrespective of the amount of ischaemia. Post-stress EF is the best predictor of CD, whereas the amount of ischaemia is the best predictor of non-fatal MI. Integration of perfusion and function data improves stratification of patients into low, intermediate, and high risk of CD.

Comment This study provides an elegant insight into the prognostic value of modern myocardial perfusion imaging, reinforcing some old lessons. Thus global left ventricular function emerges as the key determinant of cardiac mortality, whilst the severity of reversible ischaemia, a reflection of the severity of underlying coronary disease, is the main predictor of non-fatal MI. This study was retrospective, and the management of patients following perfusion imaging will inevitably have been influenced by the results. The authors attempted to compensate for this by censoring from followup the 13% of patients who underwent early revascularization. However, these patients may have rep resented a particularly high-risk group selected on the basis of uncertain factors, and their removal from follow-up may have influenced the results of the prognostic analysis. It should be made clear that the value of ejection fraction used in the study was derived from the gated stress SPECT acquisition, which may reflect not only resting left ventricular function, but also any stunning following severe ischaemia. Whether the EF derived from a gated resting acquisition would perform as well was not addressed. Prognosis in coronary disease: dobutamine stress echocardiography Introduction There is a large body of evidence demonstrating the value of radionuclide myocardial perfusion imaging in the prediction of hard cardiac end-points over several years of follow-up, independently of the prognostic

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information supplied by clinical assessment or even coronary angiography |5,6|. In comparison, the prognostic data on stress echocardiography are less robust, based on much smaller patient populations with relatively short follow-up times and composite end-points |7|. Prediction of mortality using dobutamine echocardiography. T H Marwick, C Case, S Sawada, et al. J Am Coll Cardiol 2001; 37: 754–60. BACKGROUND. We sought to find out whether dobutamine echocardiography (DbE) could provide independent prediction of total and cardiac mortality, incremental to clinical and angiographic variables. Existing outcome studies with DbE have examined composite end-points, rather than death, over a relatively short follow-up. Clinical and stress data were collected in 3156 patients (age 63±12 years, 1801 men) undergoing DbE. Significant stenoses (>50% diameter) were identified in 70% of 1073 patients undergoing coronary angiography. Total and cardiac mortality were identified over nine years of follow-up (mean 3.8±1.9). Cox models were used to analyze the effect of ischaemia and other variables, independent of other determinants of mortality. INTERPRETATION. The dobutamine echocardiogram was abnormal in 1575 patients (50%). Death occurred in 716 patients (23%), 259 of whom (8%) were thought to have died from cardiac causes. Patients with normal DbE had a total mortality of 8% per year and a cardiac mortality of 1% per year over the first four years of follow-up. Ischaemia and the extent of abnormal wall motion were independent predictors of cardiac death, together with age and heart failure. In sequential Cox models, the predictive power of clinical data alone (model chi-square 115) was strengthened by adding the resting left ventricular function (model chi-square 138) and the results of DbE (model chi-square 181). In the subgroup undergoing coronary angiography, the power of the model was increased to a minor degree by the addition of coronary anatomy data. Dbe is an independent predictor of death, incremental to other data. While a normal dobutamine

echocardiogram predicts low risk of CD (of the order of 1% per year), this risk increases with the extent of abnormal wall motion at rest and stress.

Comment These results nicely parallel those of large studies of radionuclide myocardial perfusion imaging. A normal study is associated with a very low annual event-rate for the first few years of follow-up, but the risk increases subsequently, presumably due to the progression of coronary disease. A progressive increase in risk is observed with increasing extent of abnormality during stress. Global left ventricular (LV) function and evidence of reversible ischaemia are both important independent predictors of mortality. The response to stress adds prognostic information even when clinical and resting imaging data are taken into account. As the authors discuss, this study may be overestimating the risk of a normal stress echocardiogram as currently performed, whilst underestimating the risk of an abnormal study. Protocols for dobutamine stress echocardiography (DSE) have improved since the patients in this report underwent the investigation. Boluses of atropine are now routinely given to ensure that the target heart rate is achieved. Echocardiographic image quality has improved, and harmonic imaging allows better definition of the endocardial and epicardial boundaries. In addition, the use of echocardiographic contrast agents to opacify the left ventricular cavity is now routine practice in patients with suboptimal acoustic windows. These developments have increased the sensitivity of the investigation for detecting coronary disease. As a result, a normal stress echocardiographic

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study performed in 2001 may carry an even better prognosis than this paper suggests. The fact that referring physicians were not blinded to the result of the stress echocardiogram makes it likely that patients with an abnormal study were preferentially referred for coronary angiography, with a higher likelihood of subsequent revascularization than those who had a normal study. The 11% of the patient population who underwent revascularization would have been at relatively high cardiac risk, but were censored from subsequent follow-up. This may have reduced the apparent adverse prognostic impact of an abnormal stress echocardiogram. Assessment of hibernating/viable myocardium Assessment of hibernating/viable myocardium: technetium-99m-sestamibi SPECT Introduction Considering the time and money invested in the detection and treatment of hibernating myocardium, there is remarkably little prognostic data to support revascularization over conservative therapy. Most of the outcome data are based on the questionable surrogate end-point of recovery of segmental myocardial function |8|. SPECT imaging following injection of technetium-99m-sestamibi at rest, usually in combination with nitrates, is becoming increasingly popular for the assessment of hibernating myocardium. Acquisitions can be gated to assess myocardial function at the same time as perfusion/viability |9|. However, there is even less prognostic information to support the use of this method than there is for alternative techniques. Prognostic implications of Tc-99m-sestamibi viability imaging and subsequent therapeutic strategy in patients with chronic coronary artery disease and left ventricular dysfunction. R Sciagra, M Pellegri, A Pupi, et al. J Am Coll Cardiol 2000; 36:739–45. BACKGROUND. The aim of the study was to verify the prognostic implications of viability detection using baseline-nitrate sestamibi imaging in patients with LV dysfunction due to chronic coronary artery disease (CAD) submitted to different therapeutic strategies. The prognostic meaning of preserved viability in these patients is still debated. Sestamibi is increasingly used for myocardial perfusion scintigraphy and is being accepted also as a viability tracer, but no data are available about the relationship between viability in sestamibi imaging, subsequent treatment, and patient’s outcome. Follow-up data were collected in 105 CAD patients with LV dysfunction who had undergone baseline nitrate sestamibi perfusion imaging for viability assessment and had been later treated medically (group 1), or submitted to revascularization, which was either complete (group 2A) or incomplete (group 2B). INTERPRETATION. Eighteen hard events (CD or non-fatal MI) were registered during the follow-up. A significantly worse event-free survival curve was observed in the patients of group 1 (P<0.0002) and group 2B (P<0.03) compared to those of group 2A. Using a Cox proportional hazard model, the most powerful prognostic predictors of events were the number of non-revascularized asynergic segments with viability in sestamibi imaging (P<0.003, risk ratio [RR]=1.4), and the severity of CAD (P<0.02, RR=1.28). Viability detection in sestamibi imaging has important prognostic implications in CAD patients with LV dysfunction. Patients with preserved viability kept on medical therapy or submitted to incomplete revascularization represent high-risk groups.

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Comment The results suggest that patients with a significant number of viable (hibernating) myocardial segments have an improved prognosis with complete revascularization compared with medical therapy or incomplete revascularization. Unfortunately, this study illustrates many of the methodological flaws which have affected most previous studies of hibernating myocardium. The terms ‘Viable’ and ‘hibernating’ are used in different ways by different authors. In this study, the chosen definition of viability (resting dysfunction with preserved uptake of sestamibi at rest) will have included both segments with subendocardial infarction, as well as truly hibernating segments. Only hibernating segments are likely to demonstrate improved function following revascularization (by definition), although prognostic benefit might also arise from revascularization of partially infarcted segments supplied by stenosed coronary arteries if there is evidence of inducible ischaemia. The authors do not provide information about perfusion during stress or functional recovery following revascularization, and their results apply only using their definition of viability. This is a relatively small retrospective study in which the management of patients was not randomized and was influenced by the result of the imaging investigation being evaluated. Revascularized patients tended to have a lower New York Heart Association (NYHA) functional class than medically treated patients, and were therefore a less frail and lower risk group from the outset. This may have biased the prognostic results in favour of revascularization. Compared with completely revascularized patients, incompletely revascularized patients tended to have more extensive coronary disease, and yet were more likely to have been managed percutaneously than with bypass surgery. They may have been selected as being too frail for full surgical revascularization, which may have contributed to their poor outcome. Only six patients had no viable myocardial segments according to the authors’ definition. The study therefore offers no insight into the clinically important issue of whether the presence or absence of viable myocardium influences the prognostic benefit of revascularization over medical therapy. This is the latest of a small number of retrospective studies investigating the effect of management strategy on prognosis in patients with impaired LV function but significant myocardial viability. It is also the first to use technetium-99m-sestamibi SPECT as the imaging investigation. A prospective randomized study of the prognostic impact of revascularization on patients with ischaemic cardiomyopathy, with and without significant hibernating myocardium, is long overdue. Assessment of hibernating/viable myocardium: dobutamine stress echocardiography Introduction DSE is commonly used to assess the amount of hibernating myocardium in patients with impaired LV function and coronary disease |10|. Improvement of a dysfunctional myocardial segment at a low dose of dobutamine (5–10 mcg/kg/min) predicts functional recovery following revascularization. Subsequent deterioration at a high dose of dobutamine (‘biphasic response’) suggests inducible ischaemia as well as viability, and has an even higher positive predictive value. Assessment of regional wall motion in patients with impaired global LV function is difficult and subjective, making DSE a highly operator-dependent technique. EF is a universally understood index of global LV function, and can readily be calculated from an echocardiogram (or indeed from a gated radionuclide study). The response of EF to dobutamine is an

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indicator of global LV contractile reserve. This might represent a simple and reproducible way of assessing the overall extent of myocardial viability using DSE. Usefulness of the ejection fraction response to dobutamine infusion in predicting functional recovery after coronary artery bypass grafting in patients with left ventricular dysfunction. G Rocchi, D Poldermans, J J Bax, et al. Am J Cardiol 2000; 85:1440–4. BACKGROUND. Quantification of dysfunctional but viable myocardium has high prognostic value for improvement of LV function after coronary artery bypass grafting (CABG). DSE can assess viable myocardium by segmental wall motion changes during stress. However, analysis of wall motion is subjective with only moderate interinstitutional agreement (70%) and frequently overestimates functional improvement after CABG. In contrast, calculation of EF is less subjective and allows a more precise quantification of global contractile reserve. The aim of the study was to compare the prognostic value of EF response and segmental wall motion changes during DSE for the prediction of LV functional recovery after CABG. Forty patients underwent DSE before CABG. EF responses were assessed at rest, low-dose dobutamine, and at peak stress using the biplane disk method. Wall motion was scored using a 16-segment 5-point model. Resting radionuclide ventriculography (RNV-LVEF), performed before and 8±2 months after CABG, was used as an independent reference. INTERPRETATION. Five patients were excluded because of perioperative infarction or poor echo images. In 11 of 35 patients, RNV-LVEF recovered >5%. Improvement in EF during dobutamine infusion predicted RNV-LVEF recovery after CABG significantly better than segmental wall motion changes (72% vs 53%, P=0.03). A biphasic EF response (i.e. improvement in ≥ 10% at low dose and subsequent worsening at peak stress) had the highest predictive value (80%) for late functional recovery. In conclusion, EF response to dobutamine infusion was superior to segmental wall motion changes in predicting RNV-LVEF recovery after CABG.

Comment This study demonstrates that the presence of contractile reserve, as assessed from the response of EF to lowdose dobutamine, predicts recovery of global LV function following bypass surgery. The occurrence of a biphasic response, indicating the presence of inducible ischaemia as well as contractile reserve, is the best predictor. Calculation of EF at each level of dobutamine infusion may help to make DSE a more robust and reproducible method of assessing viability. The authors emphasize, however, that regional assessment of viability continues to be important to guide revascularization of appropriate coronary territories. This study may also be relevant to radionuclide protocols for assessing myocardial viability, which usually include RNV-LVEF or gated SPECT to provide a reproducible measure of EF. The addition of a low-dose dobutamine infusion to such protocols, with measurement of the response of EF, would provide an assessment of viability complementary to the evaluation of tracer uptake. Assessment of hibernating/viable myocardium: low-dose dobutamine gated SPECT Introduction Radionuclide imaging reveals myocardial viability as the uptake of a perfusion tracer injected at rest |11|. In contrast, stress echocardiography relies on the demonstration of contractile reserve during inotropic stimulation with dobutamine |10|. The techniques therefore evaluate different aspects of viability, and neither are perfect predictors of the response to revascularization. Gated SPECT is now a well validated

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technique for the assessment of regional and global LV function in patients undergoing radionuclide myocardial perfusion imaging |9|. It is an established part of many viability protocols, providing information about myocardial function alongside tracer distribution. The combination of gated SPECT with low dose dobutamine offers the potential to assess both contractile reserve and tracer uptake from the same study, greatly increasing the information available to guide further management. Low-dose dobutamine electrocardiograph-gated myocardial SPECT for identifying viable myocardium: Comparison with dobutamine stress echocardiography and PET. K Yoshinaga, K Morita, S Yamada, et al. J Nucl Med 2001; 42:838–44. BACKGROUND. The identification of severely dysfunctional but viable myocardium is of particular importance for the selection of patients with depressed LV function who will benefit from coronary revascularization. Assessment of inotropic reserve with dobutamine has recently been used for this purpose. This study compared the accuracy of low-dose dobutamine stress gated myocardial SPECT (DS SPECT) with the accuracy of DSE and resting perfusion SPECT for the identification of viable myocardium in patients with previous myocardial infarction. Resting and low-dose dobutamine (7.5 μg/ kg/min) gated (99m) Tc-tetrofosmin SPECT and echocardiography and resting (18) F-FDG PET were prospectively studied in 23 patients with previous MI and severely depressed regional function. Twentyone of them were successfully studied with each technique. The LV wall was divided into 14 segments to assess wall motion using a 5-point scale. PET viability was defined as FDG uptake ≥ 50% of the maximum uptake in a region with normal wall motion. For DS SPECT and DSE studies, viable myocardium was defined as hypokinetic areas with ≥ 1 point improvement in wall motion. For resting perfusion SPECT, viable myocardium was defined as hypokinetic areas with a relative uptake ≥ 50% of the maximum uptake. INTERPRETATION. Of a total of 294 segments, 55 had severe resting dyskinesis. Thirty-four segments were identified as viable on FDG PET, and 21 segments were identified as non-viable. Eleven segments were inadequately visualized with DSE, including five segments in the apex. Sensitivities (78% vs 76%) and specificities

(94% vs 100%) were similar for DSE and DS SPECT, with a concordance of 86% (kappa=0.72). DS SPECT and perfusion SPECT did not significantly differ with respect to sensitivities (76% vs 85%, respectively). However, specificity was significantly higher for DS SPECT than for perfusion SPECT (100% vs 52%, respectively, P<0.05). This study indicated that DS SPECT correlates well with DSE in the assessment of viability. In addition, gated SPECT can evaluate regional wall motion, even in areas inadequately assessed by echocardiography. DS SPECT may also provide additional information for identifying viable myocardium, which is often overestimated by routine perfusion scans.

Comment The study concluded that dobutamine gated SPECT is equivalent to DSE in the detection of viable myocardium. Moreover, it is a more specific technique than routine perfusion imaging. The use of FDG PET as a gold standard for viability has to be viewed with caution: ultimately, only functional recovery following revascularization provides confirmation of hibernation. Technetium-99m-sestamibi has been much more extensively evaluated as a viability tracer than technetium-99m-tetrofosmin. Moreover, it is generally agreed that nitrates should be given prior to injection of a technetium-99m based

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radiopharmaceutical to optimize tracer uptake. Thus the assessment of resting perfusion performed in the study may have been based on a suboptimal imaging protocol with some loss of sensitivity, although this should not have affected the main findings of the study. The patients in this study were recruited solely on the basis of previous Q wave MI. They tended to have preserved global LV function, and all but five had EF greater than 40%. It remains to be seen whether dobutamine gated SPECT would perform as well in a more typical population referred for assessment of viability, with severe LV impairment and extensive perfusion defects. Assessment of hibernating/viable myocardium: FDG SPECT Introduction Revascularization in coronary disease has been extensively demonstrated to improve symptoms, and in certain cases prognosis, in patients presenting with angina |4|. However its role in the management of patients with heart failure as the main presenting problem remains controversial. In patients who have a significant amount of hibernating myocardium as opposed to scar, left ventricular ejection fraction (LVEF) may improve following revascularization |12|. The minimum amount of hibernating myocardium required to ensure such recovery remains poorly defined. Moreover, the relevance of an often modest increase in EF to improvement of symptoms of heart failure is unclear. Fluorodeoxyglucose (FDG) is an analogue of glucose which is taken up by cardiomyocytes, but once phosphorylated cannot be metabolized further. It therefore becomes trapped in the cytosol where it acts as a marker of metabolic viability. Fluorine-18 is a positron emitting isotope, and FDG PET has long been an accurate method for the assessment of viable myocardium, albeit at small number of centres. FDG SPECT has also been shown to be feasible, but requires heavy high-energy collimators with specially thick lead septa to allow imaging of the 511 keV positron-annihilation photons |3|. The technique has yet to achieve widespread everyday use despite being available for at least five years. Fluorine-18 has a relatively long half-life (110 minutes), and although it must be centrally generated in a cyclotron it can be transported to nuclear cardiology laboratories on other sites. With appropriate distribution networks for the radiopharmaceutical, FDG SPECT may in time become a more routine investigation. Relationship between pre-operative viability and post-operative improvement in LVEF and heart failure symptoms. J J Bax, F C Visser, D Poldermans, A Elhendy, J H Cornel et al. J Nucl Med 2001; 42:79–86. BACKGROUND. The presence of myocardial viability is predictive of improvement in regional LV function after revascularization. Studies on predicting improvement in global LV function are scarce, and the amount of viable myocardium needed for improvement in LVEF after revascularization is unknown. Moreover, whether the presence of viability is associated with relief of heart failure symptoms after revascularization is uncertain. Hence, the aims were to define the extent of viable myocardium needed for improvement in LVEF and to determine whether pre-operative viability testing can predict improvement in heart failure symptoms. Patients (n=47) with ischaemic cardiomyopathy (mean LVEF ±SD, 30%±6%) undergoing surgical revascularization were studied with 18F-FDG SPECT to assess viability. Regional and global function were measured before and 3–6 months after revascularization. Heart failure symptoms were graded according to the New York Heart Association (NYHA) criteria, before and 3–6 months after revascularization. INTERPRETATION. The number of viable segments per patient was directly related to the improvement in LVEF after revascularization (r=0.79, P<0.01). Receiver operating characteristic curve analysis revealed

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that the cut-off level of four viable segments (representing 31% of the left ventricle) yielded the highest sensitivity and specificity (86% and 92%, respectively) for predicting improvement in LVEF. Furthermore, the presence of four or more viable segments predicted improvement in heart failure symptoms after revascularization, with positive and negative predictive values of 76% and 71%, respectively. The presence of substantial viability (four or more viable segments, 31% of the left ventricle) on FDG SPECT is predictive of improvement in LVEF and heart failure symptoms post-operatively.

Comment This study shows that the extent of viability as defined using FDG SPECT predicts improvement in EF and functional status following revascularization. In particular, a cut-off of four or more viable segments appeared to be a good working definition of significant viability for clinical use. An increase in EF per se is not an adequate reason to subject a patient with heart failure and coronary disease to a high-risk bypass operation, unless this translates into improved symptomatic status or survival. The lack of studies using such clinically relevant end-points has been an important weakness of the literature on hibernating myocardium. Matters are further complicated by the fact that patients with ischaemic cardiomyopathy might benefit from revascularization for reasons other than a simple increase in LV systolic function, or not directly related to the presence or absence of hibernating myocardium. Functionally, some of the breathlessness experienced by patients may be related to inducible ischaemia (‘angina-equivalent’) or the ischaemic myocardial dysfunction it produces. This would improve with revascularization independently of changes in resting LV function, but the inducibility of ischaemia was not assessed in this study. This may in part explain why as many as one third of patients with no improvement in EF nevertheless improved functionally following surgery in this study. Prognostically, revascularization might reduce the incidence of fatal MI or malignant ventricular arrhythmias whether or not EF improves. The revascularization of viable myocardium might even be valuable not because systolic function improves, but because it halts deterioration via progression to scar and subsequent adverse remodelling. Novel approaches Novel approaches: imaging apoptosis with technetium-99m-labelled annexin-V Introduction Radionuclide imaging in cardiology is widely performed to assess myocardial perfusion and LV function. The assessment of more subtle aspects of cellular metabolism and physiology has usually involved PET |3|. The labelling of ligands with technetium-99m offers the potential to image aspects of cellular function on a standard gamma camera system, broadening any potential clinical application. Apoptosis (programmed cell death), as distinct from necrosis, is an important cause of cardiomyocyte death in MI following reperfusion, as well as in myocarditis and transplant rejection |13|. The ability to image this process without having to resort to endomyocardial biopsy would be clinically valuable, whether in patient surveillance or to assess the value of novel therapeutic strategies. The normal sarcolemmal lipid bilayer is asymmetrical, with phosphatidylserine actively maintained on the inner leaflet; in apoptosis, phosphatidylserine is externalized. Annexin V is an endogenous intracellular protein which binds to membrane-bound phosphatidylserine with high affinity. It has been shown to target

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apoptotic cells in a murine model of reperfusion injury. Annexin V labelled with technetium-99m might find a use for imaging apoptosis of cardiomyocytes in patients in vivo. Visualization of cell death in vivo in patients with acute myocardial infarction. L Hofstra, I H Liem, E A Dumont, et al. Lancet 2000; 356:209–12. BACKGROUND. In vivo visualization and quantification of the extent and time-frame of cell death after acute myocardial infarction (AMI) would be of great interest. We studied in vivo cell death in the hearts of patients with an AMI using imaging with technetium-99m-labelled annexin-V—a protein that binds to cells undergoing apoptosis. Seven patients with an AMI and one control were studied. All patients were treated by percutaneous transluminal coronary angioplasty (six primary and one rescue), resulting in thrombolysis in myocardial infarction (TIMI) III flow of the infarctrelated artery. Two hours after reperfusion, 1 mg annexin-V labelled with 584 MBq Tc-99m was injected intravenously. Early (mean 3±4 h) and late (mean 20±5 h) SPECT images of the heart were obtained. Routine myocardial resting-perfusion imaging was also done to verify infarct localization. INTERPRETATION. In six of the seven patients, increased uptake of Tc-99m-labelled annexin-V was seen in the infarct area of the heart on early and late SPECT images. No increased uptake was seen in the heart outside the infarct area. All patients with increased Tc-99m-labelled annexin-V uptake in the infarct area showed a matching perfusion defect. In a control individual, no increased uptake in the heart was seen. Increased uptake of Tc-99m-labelled annexin-V was present in the infarct area of patients with an AMI, suggesting that programmed cell death occurs in that area. The annexin-V imaging protocol might allow us to study the dynamics of reperfusion-induced cell death in the area at risk and may help to assess interventions that inhibit cell death in patients with an AMI.

Comment This pilot study demonstrates the feasibility of using technetium-99m-labelled annexin V to image MI in patients following reperfusion. Further work is required to demonstrate that all myocardial uptake of technetium-99m-labelled annexin V represents true apoptosis as in mice. The value of this technique in the ‘measurement of the efficacy of therapies targeting cell death’ in AMI, one aim of the authors, is likely to be limited by difficulties in quantification of tracer uptake. A more realistic clinical use might be noninvasive monitoring of cardiac transplant recipients for rejection, though whether the density of apoptotic cells would be sufficient for imaging in this setting remains to be seen. Novel approaches: imaging sympathetic innervation with iodine-123-MIBG Introduction Radionuclide myocardial perfusion imaging is finding an increasing role in the assessment of patients with possible acute myocardial ischaemia. However in the absence of frank MI, a perfusion defect is only likely to be identified if the radiotracer is injected within 3–4 hours of chest pain. A technique which could be used to identify an area at risk even after the resolution of ischaemia would be clinically valuable. The radiopharmaceutical iodine-123-metaiodobenzylguanidine (123I-MIBG) is a catecholamine analogue which is taken up by sympathetic nerve terminals but not metabolized. It is finding a role in nuclear cardiology for the assessment of patients with chronic heart failure |14|. Sympathetic neurones may be more vulnerable to ischaemia than cardiomyocytes, and cardiac denervation as assessed by 123I-MIBG has been

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observed in patients even in the absence of significant MI. 123I-MIBG imaging following an acute coronary syndrome might reveal the original ‘area at risk’, independently of the extent of any MI. Extent of cardiac sympathetic neuronal damage is determined by the area of ischaemia in patients with acute coronary syndromes. Matsunari I, Schricke U, Bengel F M, et al. Circulation 2000; 101: 2579–85. BACKGROUND. Prior studies have demonstrated that acute ischaemic injury causes sympathetic neuronal damage exceeding the area of necrosis. The aim of this study was to test the hypothesis that sympathetic neuronal damage measured by 123I-MIBG imaging would be determined by the area of ischaemia as reflected by area at risk in patients undergoing reperfusion therapy for acute coronary syndromes. In 12 patients, the myocardium at risk was assessed by (99m) Tc-sestamibi SPECT before reperfusion, and infarct size was measured by follow-up (99m) Tc-sestamibi SPECT 1 week later. All patients also underwent 123I-MIBG SPECT within a mean of 11 days after onset. The SPECT image analysis was based on a semiquantitative polar map approach. Defect size on the 123I-MIBG or (99m) Tcsestamibi SPECT was measured for the LV with the use of a threshold of −2.5 SD from the mean value of a normal database and was expressed as %LV. INTERPRETATION. The 123I-MIBG defect size (47±18%LV) was larger than the infarct size (27±23%LV, P<0.001) but was similar to the risk area (49±18%LV, P=NS). Furthermore, the 123I-MIBG defect size was closely correlated with the risk area (r=0.905, P<0.001). Sympathetic neuronal damage measured by 123I-MIBG SPECT is larger than infarct size and is closely related to risk area, suggesting high sensitivity of neuronal structures to ischaemia compared with myocardial cells.

Comment This was a largely physiological study in a group of patients almost all of whom had an infarct on standard criteria. However as a clinical tool 123I-MIBG imaging might prove to be more valuable in the assessment of patients presenting with less clearcut acute chest pain. The study was not designed to demonstrate the time scale over which such imaging would be meaningful. No patient was reperfused in less than 2.5 hours from the onset of chest pain, and so the minimum period of continuous ischaemia required to produce neuronal damage is undefined. 123I-MIBG imaging was performed more than a week after presentation, and so its potential value as a diagnostic test acutely in the emergency room cannot be assessed. The time period over which sympathetic reinnervation—and hence recovery of an 123I-MIBG defect —occurs is unclear, although this is likely to be several months. Notwithstanding the uncertainties, this study suggests a method of demonstrating previously ischaemic myocardium even after reperfusion has occurred. 123I-MIBG imaging might therefore prove useful in the initial assessment of patients presenting with acute chest pain syndromes. Novel approaches: stress myocardial contrast echocardiography Introduction Myocardial contrast echocardiography (MCE) represents an important advance in stress echocardiography, providing an assessment not only of wall motion but also myocardial perfusion in the same study |15|. Intermittent harmonic imaging is required to optimize myocardial opacification, as continuous imaging

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causes excessive destruction of microbubbles. Wall motion must therefore be assessed from a separate image acquisition. Where possible, dynamic exercise is utilized to provide optimal cardiovascular stress. Its use in stress echocardiography is technically challenging, not least because of the brief time window in which adequate images must be obtained at peak stress. The addition of MCE to ‘standard’ echocardiography prolongs the time needed for image acquisition, and is therefore particularly difficult during exercise. Accelerated Intermittent Imaging (AII) is a novel ultrasound modality which uses low mechanical index and frame rates. This reduces destruction of microbubbles whilst allowing simultaneous assessment of myocardial contrast and wall motion in real time |16|. Real-time assessment of myocardial perfusion and wall motion during bicycle and treadmill exercise echocardiography: comparison with single photon emission computed tomography. S Shimoni, W A Zoghbi, F Xie, et al. J Am Coll Cardiol 2001; 37:741–7. BACKGROUND. We sought to determine the feasibility and accuracy of real-time imaging of MCE in detecting myocardial perfusion defects during exercise echocardiography compared with radionuclide tomography. Ultrasound imaging at a low mechanical index and frame rate (10 to 20 Hz) after intravenous injections of perfluorocarbon containing microbubbles has the potential to evaluate myocardial perfusion and wall motion (WM) simultaneously and in real time. One hundred consecutive patients with intermediate-to-high probability of coronary artery disease

underwent treadmill (n=50) or supine bicycle (n=50) exercise echocardiography. Segmental perfusion with MCE and WM were assessed in real time before and at peak exercise using low mechanical index (0.3) and frame rates of 10 to 20 Hz after 0.3 ml bolus injections of intravenous Optison (Mallinckrodt Inc., San Diego, California). All patients had a dual isotope (rest thallium-201, stress sestamibi) study performed during the same exercise session, and 44 patients had subsequent quantitative coronary angiography. INTERPRETATIOIN. In the 100 patients, agreement between MCE and SPECT was 76%, while it was 88% between MCE and WM assessment. Compared with quantitative angiography, sensitivity of MCE, SPECT and WM was comparable (75%), with a specificity ranging from 81% to 100%. The combination of MCE and WM had the best balance between sensitivity and specificity (86% and 88%, respectively) with the highest accuracy (86%). The real-time assessment of myocardial perfusion during exercise stress echocardiography could be achieved with imaging at low mechanical index and frame rates. The combination of WM and MCE correlates well with SPECT and is a promising important addition to conventional stress echocardiography.

Comment These results demonstrate the feasibility of simultaneous assessment of myocardial perfusion and wall motion during exercise stress echocardiography. This is a challenging technique which places great demands on the echocardiographer. It remains to be seen to what extent it could become a reliable everyday clinical tool in less expert centres. MCE correlated well with SPECT, the best established technique for assessing myocardial perfusion in everyday clinical practice. The correlation demonstrated between MCE and WM is perhaps of less interest because they were assessed from the same image acquisition which is likely to have biased the observers. Reduced agreement between MCE and SPECT was observed in the right coronary territory (76%) compared with the left anterior descending territory (89%). This is likely to represent a combination of factors: higher

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background inferiorly, difficulty distinguishing between perfusion defects and attenuation in basal and mid LV segments, and relative shielding of the inferior wall from microbubble destruction. The patients who underwent coronary angiography represent a small, selected population. Moreover, it is increasingly recognized that angiographic stenoses may not represent an appropriate gold standard for functional imaging. Nevertheless, the diagnostic sensitivity and specificity of MCE, and in particular its combination with WM, were very encouraging. Novel approaches: dobutamine stress echocardiography in aortic stenosis Introduction Patients with severe LV dysfunction and aortic stenosis with a low pressure gradient represent a difficult, if relatively unusual, clinical problem. It is often uncertain whether a patient has a primary cardiomyopathy with coincident mild aortic stenosis, or whether the aortic stenosis is the primary pathology but the left ventricle is no longer capable of generating a high transvalvular flow velocity. In the latter case, prognosis is poor without aortic valve replacement, but surgery carries a high risk. DSE is sometimes used to assess these patients, primarily to confirm that the aortic valve area calculated from the continuity equation remains low despite an increase in flow velocity. However, the ability of the left ventricle to generate an increase in stroke volume reflects underlying contractile reserve which might itself be an important prognostic indicator. Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients. Risk stratification by low-dose dobutamine echocardiography. J-L Monin, M Monchi, V Gest, A-M Duval-Moulin, J-L Dubois-Rande, P Gueret. J Am Coll Cardiol 2001; 37:2101–7. BACKGROUND. We sought to assess risk stratification by using DSE in patients with aortic stenosis (AS) and severe LV dysfunction. Few data are available on risk stratification for valve replacement in patients with AS, LV dysfunction and low transvalvular gradients. Low-dose DSE was performed in 45 patients (16 women and 29 men; median [quartile range] age in years: 75 [69 to 79]; left ventricular ejection fraction: 0.29 [0.23 to 0.32]; aortic valve area [cm2]: 0.7 [0.5 to 0.8]; mean transaortic gradient [mm Hg]: 26 [21 to 33]). Patients were classified into two groups: group I (n=32, LV contractile reserve on DSE) and group II (n=13, no contractile reserve). Valve replacement was performed in 24 and 6 patients in groups I and II, respectively. INTERPRETATION. Perioperative mortality was 8% in group I and 50% in group II (P=0.014). Survival at five years after the operation was 88% in group I. Compared with medical therapy, valve surgery was associated with better long-term survival in group I (hazard ratio for death [HR-D] 0.13, 95% confidence interval [CI] 0.002 to 0.49) and reduced survival in group II (HR-D 19.6, 95% CI 2.7 to 142). The effect of valve surgery on survival remained significant in both groups after adjustment for age, diabetes, respiratory disease and hypertension. Medical therapy had the same effect in both groups. In patients with AS, LV dysfunction and low transvalvular gradients, contractile reserve on DSE was associated with a low operative risk and good long-term prognosis after valve surgery. In contrast, operative mortality remained high in the absence of contractile reserve.

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Comment This study confirms that patients with severe aortic stenosis and poor LV function have a poor outlook with conservative treatment. The demonstration of an increase in stroke volume with dobutamine predicts a good outcome with aortic valve replacement, whilst its absence predicts a high operative mortality with little clinical benefit even in survivors of surgery. The interpretation of this study is inevitably affected by the relatively small number of patients. As the authors state, the patient group included in this study represented only 5% of all patients referred to their laboratory for assessment of AS and took more than six years to recruit. Only six patients without contractile reserve underwent surgery, presumably as a result of selection bias on the part of the referring physicians who were not blinded to the results of the DSE. Striking though their 50% operative mortality appears, it is based on three deaths only. Moreover, the longer-term functional and survival data is based on the three survivors. References 1. 2.

3. 4.

5.

6.

7. 8.

9.

10. 11.

12.

Iskander S, Iskandrian AE. Risk assessment using single-photon emission computed tomographic technetium-99m sestamibi imaging. J Am Coll Cardiol 1998; 32:57–62. Krivokapich J, Child JS, Walter DO, Garfinkel A. Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease. J Am Coll Cardiol 1999; 33:708–16. Dilsizian V, Bacharach SL, Khin MM, Smith MF. Fluorine-18-deoxyglucose SPECT and coincidence imaging for myocardial viability: clinical and technological issues. J Nucl Cardiol 2001; 8:75–88. Yusuf S, Zucker D, Peduzzi P, Fisher LD, Takaro T, Kennedy JW, Davis K, Killip T, Passamani E, Norris R, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994; 344:563–70. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico JA, Wang FP, Friedman JD, Germano G, Van Train K, Diamond GA. Incremental value of prognostic testing in patients with known or suspected ischemic heart disease: a basis for optimal utilization of exercise technetium-99m sestamibi myocardial perfusion single-photon emission computed tomography. J Am Coll Cardiol 1995; 26:639–47. Pavin D, Delonca J, Siegenthaler M, Doat M, Rutishauser W, Righetti A. Long-term (10 years) prognostic value of a normal thallium-201 myocardial exercise scintigraphy in patients with coronary artery disease documented by angiography. Eur Heart J 1997; 18: 69–77. Marwick TH. Use of stress echocardiography for the prognostic assessment of patients with stable chronic coronary artery disease. Eur Heart J 1997; 18 Suppl D:97–101. Bax JJ, Poldermans D, Elhendy A, Boersma E, Rahimtoola SH. Sensitivity, specificity, and predictive accuracies of various non-invasive techniques for detecting hibernating myocardium. Curr Probl Cardiol 2001; 26(2): 141–86. Berman DS, Germano G. Evaluation of ventricular ejection fraction, wall motion, wall thickening, and other parameters with gated myocardial perfusion single-photon emission computed tomography. J Nucl Cardiol 1997; 4:S169–71. Cornel JH, Bax JJ, Fioretti PM. Assessment of myocardial viability by dobutamine stress echocardiography. Curr Opinion Cardiol 1996; 11:621–6. Ragosta M, Beller GA, Watson DD, Kaul S, Gimple LW. Quantitative planar rest-redistribution 201Tl imaging in detection of myocardial viability and prediction of improvement in left ventricular function after coronary bypass surgery in patients with severely depressed left ventricular function. Circulation 1993; 87:1630–41. Vanoverschelde J-LJ, D’Hondt A-M, Marwick T, Gerber BL, De Kock M, Dion R, Wijns W, Melin JA. Head-tohead comparison of exercise-redistribution-reinjection thallium single-photon emission computed tomography

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13. 14.

15.

16.

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and low dose dobutamine echocardiography for prediction of reversibility of chronic left ventricular ischemic dysfunction. J Am Coll Cardiol 1996; 28:432–42. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio Pulkki LM. Apoptosis in human acute myocardial infarction. Circulation 1997; 95:320–3. Zhao C, Shuke N, Yamamoto W, Okizaki A, Sato J, Ishikawa Y, Ohta T, Hasebe N, Kikuchi K, Aburano T. Comparison of cardiac sympathetic nervous function with left ventricular function and perfusion in cardiomyopathies by (123) I-MIBG SPECT and (99m) Tc-tetrofosmin electrocardiographically gated SPECT. J Nucl Med 2001; 42: 1017–24. Kaul S, Senior R, Dittrich H, Raval U, Khattar R, Lahiri A. Detection of coronary artery disease with myocardial contrast echocardiography: comparison with 99mTc-sestamibi single-photon emission computed tomography. Circulation 1997; 96:785–92. Porter TR, Li S, Jiang L, Grayburn P, Deligonul U. Real-time visualization of myocardial perfusion and wall thickening in human beings with intravenous ultrasonographic contrast and accelerated intermittent harmonic imaging. J Am Soc Echocardiogr 1999; 12:266–71.

15 3D echocardiography

Introduction Limitations of two-dimensional echocardiography In recent years, three-dimensional echocardiography has evolved as a new diagnostic tool in cardiac imaging. Although it is still used more in research than in clinical practice, some recent developments suggest that 3D echocardiography (3D echo) will become more and more a reality in clinical practice within the next years. There is a clear role for 3D echo due to limitations related especially to geometric assumptions of two-dimensional echocardiography (2D echo) in important clinical situations. Assessment of systolic cardiac function and left ventricular mass are the most frequent indications for a twodimensional echocardiogram—approximately 50% of the requests for performing an echocardiographic examination are focused on the evaluation of left ventricular function. 2D echo has been criticized because of only moderate reproducibility and only differences in left ventricular (LV) ejection fraction of at least 10% are regarded as indicative for a real change in cardiac function while performing serial investigations |1|. The same is true for LV volumes. Thus follow-up studies, the assessment of medical therapy or interventions and monitoring in patients with valvular heart disease or dilatative cardiomyopathy are limited using 2D echo. Impact of 3D echo for assessment of LV function and mass The introduction of harmonic imaging and the use of ultrasound contrast agents have been shown to improve endocardial border delineation and therefore to improve the assessment of LV function |2,3|. However, even with optimal acoustic windows the complex geometry of the heart cannot be fully evaluated with two-dimensional echocardiography. Moreover scanplanes depend on positioning of the transducers, and minor changes in tilting or rotation of a scanhead result in major changes of the cross-sectional area of a heart chamber. This is the most important limitation for performing follow up studies. Without a 3D data set it is impossible to reproduce the scanplanes exactly. Recently, cardiac magnetic resonance imaging (MRI) has become more popular for the measurement of cardiac function parameters (i.e. volumes, ejection fraction and mass) because of the acquisition of volumetric data and its reproducibility |4|. 3D imaging with MRI or computed tomography (CT) has achieved an advanced state of development, and these modalities have been applied widely in clinical practice.

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Table 15.1 Benefits of 3D echo compared to 2D echo LV function, ejection fraction LV volumes, LV mass Regional wall motion/perfusion

Less observer dependent Better reproducibility Increased sensitivity for detecting IHD more accurate spatial delineation of infarcted tissue or ‘area at risk’ Valvular/congenital heart disease Better understanding of complex lesions, guiding interventions

Impact of 3D echo on assessment of valvular and congenital heart disease In valvular heart disease a three-dimensional assessment seems to be of particular value regarding the complex anatomy of, for instance, a mitral valve. A series of clinical studies has suggested that having a three-dimensional dataset provides incremental information over 2D echo recordings |5|. However, assessment of valvular morphology and function with 2D echo is already excellent in many patients, particularly those undergoing transoesophageal echocardiography and it has been questioned what a 3D display really does add to the available 2D images. For description of some valvular lesions like aortic stenosis the need for a 3D dataset is not as urgent as for assessment of LV function and mass. In comparison to other established 3D imaging technologies like MRI or CT, 2D echo has some advantages such as better spatial and temporal resolution. These advantages are lost with current 3D echo technology and a 3D display is indicated primarily when the exact geometry of a lesion is of clinical relevance |6–8|. An example where this is the case is in mitral valve disease where 3D studies have been helpful in providing a better understanding of the pathophysiology of and guiding the repair of mitral regurgitation |9,10|. Technology: the need for real-time imaging Most of the previous clinical studies have been performed using a transoesophageal probe but most advances have been made in transthoracic imaging. There are already some commercially available scanners, which can be upgraded for transoesophageal echocardiography. However, the technique still is cumbersome and far from being routinely used in clinical practice. To acquire a 3D data set a series of 2D images are recorded by rotating the scanplane in increments of 2 degrees or more, resulting in acquisition times of 30 and more seconds with off-line, timeconsuming reconstruction for a 3D display. During the acquisition time there should be no major respiratory movement of the heart. This may be achieved with a stable position of a transoesophageal probe, but it seems unlikely that this is feasible for the average sonographer using a transthoracic probe. More challenging is manually moving the scanhead to acquire a 3D dataset (‘free hand scanning’). It is obvious that this approach will not succeed in echocardiography unlike its applica Table 15.2 3D echo technology *Free Hand

The sonographer holds the 2D probe and moves it in an unrestricted fashion to obtain unlimited views, the probe position is tracked either magnetically, sonographically or optically *Automatic Scanplane Rotation Scanplane rotation by a motor within the 2D probe

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Real-time 3D

Beam forming to scan a pyramidal volume in real-time; no ECG, respiratory gating and reconstruction *ECG, respiratory gating and off-line reconstruction techniques.

tion in radiology or gynaecology where free hand scanning is an option. For 3D imaging of the heart a technique is desirable which acquires and displays the 3D data in real-time and this technology is now available! |11| A novel imaging system has been introduced which uses a special echo probe for rapid beam forming to scan a pyramidal volume in real-time (Fig. 15.1). Real-time 3D uses 2D phased array matrix grid instead of the linear unidimensional phased arrays of conventional two-dimensional transducers. Also, with the help of 16:1 parallel processing, more returning scan lines are acknowledged per transmit line than in the previous 1:1 transmit-receive scanners. Thus a 60°×60° pyramidal volume can be scanned during just one cardiac cycle. The present image display consists of intersecting B-sector scans with C-scan planes, adjustable in depth and orientation. Real-time is the breakthrough for 3D echo; theoretically the complete 3D dataset can be acquired without the need for electrocardiogram (ECG) or respiratory gating and no reconstruction is necessary for display of 3D images. Meanwhile, one of the big manufacturers for ultrasound equipment has presented their prototype for realtime 3D imaging and it is foreseeable that realtime 3D will become the option for upgrading of a commercially available system within the next two years. The following selection of peer reviewed papers gives an overview of some remarkable papers published during the last 18 months. These papers highlight both the usefulness of 3D echocardiography and the work in progress, which still is necessary to make 3D echo a practical tool. Assessment of left ventricular function by real-time 3-dimensional echocardiography compared with conventional non-invasive methods. S Takuma, T Ota, T Muro, et al. J Am Soc Echocardiogr 2001; 4: 275–84. BACKGROUND. Quantitative assessment of LV ejection fraction is an essential component of cardiac evaluation. We performed real-time 3D echo in 56 consecutive

patients who underwent multigated radionuclide angiography. Thirteen patients were excluded for the following reasons: 5 for large size of left ventricle required for image acquisition, 5 for suboptimal image quality in real-time 3D echo, and 3 for atrial fibrillation. Finally, we compared LV ejection fraction assessed by real-time 3D echo and conventional 2D echo with that obtained by multigated radionuclide angiography in 43 patients. LV ejection fraction was determined by real-time 3D echo with the use of parallel plane-disks and sector plane-disks summation methods. A good correlation was obtained between both real-time 3D echo methods and multigated radionuclide

angiography (r=0.87 and 0.90, standard error of estimate=3.7% and 4.2%), whereas the relation between the 2D echo method and radionuclide angiography demonstrated a significant departure from the line of identity (P<0.001). In addition, interobserver variability was significantly lower (P<0.05) for the real-time 3D echo methods than that by the 2D echo method. Real-time 3D echo may be used for quantification of LV function as an alternative to conventional methods in patients with adequate image quality. INTERPRETATION. This paper clearly demonstrates the usefulness of real-time 3D echo for assessing LV volumes. An excellent agreement of 3D echo with multigated radionuclide angiography was found. Like most

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Fig. 15.1a Transducer types for 3D imaging. of the other work on 3D echo, the variability of 3D measurements was significantly lower than that of 2D echo.

Comment Comparable results have been published using a continuously internally rotating transthoracic transducer |1,2|. However, for this transducer the acquisition time of about 6 s is still long and makes this approach susceptible to artefacts. For transthoracic imaging real-time 3D echo seems the way to go. This technology provides simultaneous acquisition of multiple views and has been evaluated in several studies. It may be that the spatial image resolution is still better using a rotating transducer, but this limitation has already been addressed using different approaches (see below).

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Fig. 15.1b Scanning of a pyramidal volume for real-time 3D echo (courtesy of Philips ultrasound).

Fig. 15.2 Volumetric scanning and images of the left ventricle. Source: Takuma et al. (2001).

Three-dimensional echocardiography with tissue harmonic imaging shows excellent reproducibility in assessment of left ventricular volumes. W Y Kim, P Sogaard, H Egeblad, N T Andersen, B Kristensen. J Am Soc Echocardiogr 2001; 14(6):612– 17.

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BACKGROUND. We studied the reproducibility of repeated measurements of LV volumes by 2D (biplane method of disks) and 3D echo (coaxial scanning) with tissue harmonic imaging. Ten healthy subjects underwent estimation of LV volumes by transthoracic echocardiography twice within 1 week by 2 different operators to investigate interexamination and operator variance. In addition, the analysis of LV volume was done manually by 2 observers to assess both interobserver and intraobserver variances. With 3D echo, observer variation had the greatest impact on variance. Operator variability showed important contributions to total variance with the use of 2D echo. The reproducibility of 3D echo and tissue harmonic imaging is excellent and comparable to MRI techniques; 3D echo therefore should provide a powerful tool for noninvasive LV volume estimation.

Measurement of left ventricular volumes by 3-dimensional echocardiography with tissue harmonic imaging: a comparison with magnetic resonance imaging. W Y Kim, P Sogaard, B O Kristensen, H Egeblad. J Am Soc Echocardiogr 2001; 14(3):169–79. BACKGROUND. We hypothesized that tissue harmonic imaging (THI) in comparison with fundamental imaging (FI) would improve endocardial border detection, and therefore in combination with 3D echo, it would be a precise method for LV volume measurement. Ten healthy subjects and 18 consecutive patients with dilated hearts underwent estimation of LV volumes by MRI and transthoracic 3D echo with THI and FI. In patients, the agreement between MRI and 3D echo was closer with THI in comparison with FI for assessment of LV volumes. Thus the mean ±2 SD of differences between MRI and 3D echo with THI versus FI, respectively, was −6.4±40.0 ml vs −17.4±57.6 ml (P<0.01) for the enddiastolic volume (EDV), and 0.0±26.6 ml vs −8.1±35.6 ml (P<0.01) for the end-systolic volume (ESV). In patients, THI in comparison with FI approximately halved observer variation on EDV and ESV. In healthy subjects, only ESV showed significantly reduced observer variation by THI. In conclusion, because THI demonstrated a clinically relevant reduction in observer variation and a closer agreement to the MRI technique in patients with dilated hearts, it should replace FI in LV volume measurements. INTERPRETATION (PREVIOUS TWO PAPERS). Both studies from the same group demonstrate that THI improves endocardial border definition in comparison to FI; this is similar to the data from previous studies using 2D echo. This improvement in image quality translates into and gives a closer agreement to the MRI technique and a better reproducibility of the echocardiographic measurements. The reproducibility of 3D echo and THI is comparable to MRI techniques.

Comment (previous two papers) The introduction of harmonic imaging has provided a dramatic improvement of image quality in 2D echo |2|. Harmonic imaging was becoming more popular at the same time as the first scanner for transthoracic real-time 3D echo was presented. The difference in image quality between a 2D plane of the threedimensional data set and a corresponding recording obtained by THI was striking. 3D image quality was inferior to 2D echo, because at the beginning harmonic imaging was not used. Once this is used and the probe is rotated, the image quality should have exactly the same resolution as 2D imaging; this is of course not valid for RT3D where the whole probe is different. Improvement of image quality will be crucial to make real-time 3D attractive for clinical use. Now THI is available for 3D reconstruction echocardiography. This is not only necessary for image quality but also needed for contrast echocardiography. Modern applications in contrast echocardiography such myocardial perfusion imaging cannot be performed without harmonic imaging modalities.

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Three-dimensional echocardiographic measurement of left ventricular mass: comparison with magnetic resonance imaging and two-dimensional echocardiographic determinations in man. M L Chuang, R A Beaudin, M F Riley, et al. Int J Card Imaging 2000; 16(5): 347–57. BACKGROUND. This study was performed to compare a novel 3D echo system to clinical 2D echo and MRI for determination of left ventricular mass (LVM) in humans. LVM is an independent predictor of cardiac morbidity and mortality. Echocardiography is the most widely used clinical method for assessment of LVM, as it is non-invasive, portable and relatively inexpensive. However, when measuring LVM, 2D echo is limited by assumptions about ventricular shape which do not affect 3D echo. A total of 25 unselected patients underwent 3D echo, 2D echo and MRI. 3D echo used a magnetic scanhead tracker allowing unrestricted selection and combination of images from multiple acoustic windows. Mass by quantitative 2D echo was assessed using seven different geometric formulas. LVM by MRI ranged from 91 to 316 g. There was excellent agreement between 3D echo and MRI (r=0.99, SEE=6.9 g). Quantitative 2D methods correlated well with but underestimated MRI (r=0.84−0.92) with SEEs over threefold greater (22.5–30.8 g). Interobserver variation was 7.6% for 3D echo vs 17.7% for 2D echo. These results show that LVM in humans can be measured accurately, relative to MRI, by transthoracic 3D echo using magnetic tracking. Compared to 2D echo, 3D echo significantly improves accuracy and reproducibility. INTERPRETATION. The poor accuracy and reproducibility of 2D echo for assessment of LVM is demonstrated in this paper. With the novel use of 3D echo, LV measurements are comparable to those obtained with MRI, which is the current gold standard for assessment of LVM |13,14|.

Comment Like LV volumes, LVM is a crucial clinical parameter which cannot be adequately evaluated using 2D echo. Numerous studies have been published using M mode or two-dimensional measurements to stratify patient groups or to evaluate antihypertensive therapy. However, it has been difficult to evaluate changes in LVM in individual patients because of the poor reproducibility of 2D images. Meanwhile MRI has become the gold standard for assessing myocardial mass, but 3D echo has the potential to provide comparable results. However, the data acquisition and the analysis still is cumbersome. Using transthoracic imaging, a single window often does not allow unrestricted acquisition of the data needed for 3D reconstruction, thus, 3D images were composed from multiple acoustic windows (see also Fig. 15.3). Improved 3D-echocardiographic endocardial border delineation using the contrast agent FS069 (Optison(R)): transoesophageal studies in a porcine model. M Handke, D M Schafer, G Heinrichs, et al. Ultrasound Med Biol 2001; 27(9): 1185–90. BACKGROUND. 3D echo has the potential for quantitative assessment of regional wall motion. However, the 3D procedures used to date do not provide the same spatial and temporal resolution as 2D echo, which results in problems with border delineation of the endocardium. There are, as yet, few studies testing whether the use of contrast agent can improve endocardial definition in the 3D data set. FS069 (Optison(R)) was used for the first time for this purpose in the present study. A total of 12 mechanically-ventilated pigs were examined by transoesophageal 3D echo, firstly using fundamental

imaging and secondly following left-atrial injection of FS069 (Optison(R)). The left ventricle was analysed using an 18-segment model. Scores with the value 0 (not visible), 1 (moderately visible) and 2 (well defined) were used to rate endocardial definition. All segments were assessed both end-diastolic and end-systolic. Various LV regions were examined by grouping segments (anterior/lateral/inferior and

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Fig. 15.3 LV reconstruction using information from the long axis (a), short axis (b) and combined acoustic windows (c), respectively. Source: Xujiong and Noble (2001) |15|. basal/ mid-ventricular/apical). Using the contrast agent, the proportion of non-visible segments fell for diastolic from 40 (18.5%) to 15 (6.9%), and for systolic from 26 (12.0%) to 11 (5.1%). The proportion of well defined segments increased for diastolic from 62 (28.7%) to 108 (50%) and for systolic from 73 (33. 8%) to 123 (56.9%). The mean visibility score increased for diastolic from 1.10±0.68 to 1.43±0.62 (P<0. 001), and for systolic from 1.22±0.64 to 1.52±0.59 (P<0.001). The benefit was greatest in regions where the visibility score was lowest without contrast: in the area of the lateral wall and systolic near the apex. In conclusion, the use of FS069 (Optison(R)) results in significantly better endocardial delineation in the 3D data set. This could be important in future for the 3D echocardiographic assessment of regional wall motion. INTERPRETATION. This paper highlights the limited image quality of current transoesophageal probes using fundamental 3D echo. The number of segments with poor or moderate endocardial definition was rather high—more than 50%! With contrast enhancement the image quality was dramatically improved.

Comment Application of ultrasound contrast has been successfully used in 2D echo to ‘salvage’ studies which otherwise were non-diagnostic. In patients with suboptimal windows contrast echocardiography is an

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established method according to guidelines of the American Society of Echocardiography |3|. In 2D echo the contrast agent is used to opacify the cavity. In this paper the contrast agent was used to increase the grey level of the myocardium and the recordings were started after the contrast agent was washed out of the LV cavity. Image quality is still limited in 3D echo compared to 2D echo and several approaches have been used to improve image quality in 3D echo. Harmonic imaging and contrast echocardiography are complementary in this respect. To fully exploit the potential of ultrasound contrast media, contrast specific imaging modalities like harmonic imaging are needed. Contrast specific imaging technologies will also allow the use of intravenously administered contrast agent for myocardial perfusion imaging. Three-dimensional echocardiography documents haemodynamic improvement by biventricular pacing in patients with severe heart failure. W Y Kim, P Sogaard, P T Mortensen, et al. Heart 2001; 85(5):514–20. BACKGROUND. The objectives of this study were to quantify the short-term haemodynamic effects of biventricular pacing in patients with heart failure and left

bundle branch block by using 3D echo. 3D echo was performed in 15 consecutive heart failure patients (New York Heart Association functional class III or IV) with an implanted biventricular pacing system. Six minute walk tests were performed to investigate the effect of biventricular pacing on exercise capacity. Data were acquired at sinus rhythm and after short term (2–7 days) biventricular pacing. Compared with baseline values, biventricular pacing significantly reduced LV EDV by mean (SD) 4.0 (5. 1)% (P<0.01) and ESV by 5.6 (6.4)% (P<0.02). Mitral regurgitant fraction was significantly reduced by 11 (12.1)% (P<0.003) and forward stroke volume (FSV) increased by 13.9 (18.6)% (P<0.02). Exercise capacity was significantly improved with biventricular pacing by 48.4 (43.3)% (P<0.00001). Regression analyses showed that the percentage increase in FSV independently predicted percentage improvement in walking distance (r(2)=0.73, P<0.0002). Both basal QRS duration and QRS narrowing predicted pacing efficacy, showing a significant correlation with %DeltaEDV, %DeltaESV, and %DeltaFSV. The results show that in five of 15 consecutive patients with heart failure and left bundle branch block, biventricular pacing induced a more than 15% increase in FSV, which predicted a more than 25% increase in walking distance and was accompanied by an immediate reduction in LV chamber size and mitral regurgitation. INTERPRETATION. Like several previous studies this trial demonstrated the benefit of biventricular pacing. The resynchronization of both ventricles has been beneficial in some patients with heart failure and left bundle branch block. The improvement in exercise capacity by biventricular pacing is correlated to the reduction in LV volumes.

Comment Echocardiography is the ideal method to assess the haemodynamic changes because it is repeatable and portable. However, using 2D echo it has been difficult to assess the minor changes following new medication or pacing in patients with heart failure. 3D echo provides more accurate and reproducible measurements of LV volumes which might be used to optimize pacemacker settings or dosing of drugs |16|. It is likely that patients with heart failure will have at least a symptomatic improvement from this echocardiographically guided ‘fine tuning’ of therapy, but further studies are needed to prove this hypothesis. These studies have to include other ultrasound technologies like Doppler Tissue Imaging which has been used in other trials to optimize biventricular pacing or even look at changes in myocardial perfusion.

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Real-time three-dimensional dobutamine stress echocardiography in assessment stress echocardiography for the assessment of ischemia: comparison with two-dimensional dobutamine stress echocardiography. M Ahmad, T Xie, M McCulloch, G Abreo, M Runge. J Am Coll Cardiol 2001; 37(5):1303–9.

BACKGROUND. This study was designed to test the feasibility and efficacy of using real-time threedimensional echocardiography (RT-3D) to detect ischaemia during dobutamine-induced stress (DSE) and compares the results with conventional 2D echo. RT-3D echo, a novel imaging technique, offers rapid acquisition with multiple simultaneous views of the left ventricle. These features make it attractive for application during stress. Of 279 consecutive patients screened for image quality by 2D echo, 253 patients with adequate images underwent RT-3D and 2D echo within 30 s of each other at baseline and at peak DSE. RT-3D echo and 2D echo showed good concordance in detection of abnormal left ventricle wall motion at baseline (84%: Kappa=0.59) and at peak DSE (88.9%: Kappa=0.72). LV wall motion scores were similar at baseline and peak DSE using both techniques. Interobserver agreements for detection of ischaemia at peak DSE were superior for RT-3D, 92.7% compared with 84.6% for 2D echo (P<0.05). Mean scanning time at peak stress by RT-3D in 50 randomly selected patients was shorter, 27.4 ±10.7 s compared with 62.4±20.1 s by 2D echo (P<0.0001). In 90 patients with coronary angiograms, RT-3D had a sensitivity of 87.9% in the detection of coronary artery disease (CAD) compared with 79. 3% by 2D. This shows that real-time three-dimensional dobutamine stress echocardiography is feasible and sensitive in the detection of CAD. The procedure offers shorter scanning time, superior interobserver agreements and unique new views of the left ventricle. INTERPRETATION. This study is remarkable because it is based on the experience in 279 patients whereas most other studies evaluating 3D echo include far fewer patients. The study demonstrates the feasibility of real-time 3D echo during a stress test and shows better sensitivity in the detection of CAD compared to routine 2D echo. Obviously real-time 3D stress echo is feasible in a high volume echo lab. However, with current equipment for real-time 3D echo it is crucial to include only patients with good acoustic windows!

Comment Stress echocardiography using two-dimensional imaging has become the most important method to assess inducible myocardial ischaemia in clinical practice. The sensitivity and specificity are between 76% and 90% according to a recent meta-analysis |17|. The limited sensitivity of stress echo was partly related to the fact that no three-dimensional data set was available and only a limited number of two-dimensional scanplanes can be evaluated. Therefore it is likely that stress induced ischaemia may be missed in some areas which are not fully represented by the existing scanplanes. Moreover the use of real-time 3D can shorten the time needed to scan the patient. Particularly during peak stress it may be very challenging to acquire all scanplanes with adequate image quality. RT-3D echo needs only one good loop per window! This paper nicely demonstrated that the scanning time was less than half of that needed for 2D echo. Therefore, the use of a 3D technique will make stress echo more reliable and avoid other more expensive or invasive procedures (myocardial scintigraphy, coronary angiography). It is however of note that the current RT-3D technology allows for a lesser spatial resolution (approx 3 mm), especially in the C-sector scans and the frame rate at the depths required in clinical use is lower than routine 2D imaging—which becomes very relevant for stress testing.

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Real-time three-dimensional colour Doppler echocardiography for characterizing the spatial velocity distribution and quantifying the peak flow rate in the left ventricular outflow tract. H Tsujino, M Jones, T Shiota, et al. Ultrasound Med Biol 2001; 27(1):69–74. BACKGROUND. Quantification of flow with pulsed-wave Doppler assumes a ‘flat’ velocity profile in the left ventricular outflow tract (LVOT), which observation refutes. Recent development of real-time, three-dimensional (3D) colour Doppler allows one to obtain an entire cross-sectional velocity distribution of the LVOT, which is not possible using conventional 2D echo. In an animal experiment, the crosssectional colour Doppler images of the LVOT at peak systole were derived and digitally transferred to a computer to visualize and quantify spatial velocity distributions and peak flow rates. Markedly skewed profiles, with higher velocities toward the septum, were consistently observed. Reference peak flow rates by electromagnetic flow meter correlated well with 3D peak flow rates (r=0.94), but with an anticipated underestimation. Real-time 3D colour Doppler echocardiography was capable of determining crosssectional velocity distributions and peak flow rates, demonstrating the utility of this new method for better understanding and quantifying blood flow phenomena. INTERPRETATION. This experimental study shows that 3D Doppler echocardiography is feasible. The authors found skewed profiles of the cross-sectional velocity distributions in the LVOT, which are not taken into account by the regular 2D colour Doppler analysis. Based on the 3D velocity distribution blood flow was accurately quantified.

Comment 3D colour Doppler echocardiography is another exciting application where 3D ultrasound can improve current imaging |18|. Measurements of intracardiac flow (cardiac output etc.) are often inaccurate and poorly reproducible because of two limitations: Firstly the current Doppler technique does not consider the real geometry of the intracardiac and intravascular velocity profiles which may change with the haemodynamic status. Most of current Doppler measurements of intracardiac flow are still based on simplifications such as a flat or parabolic profile. Secondly, the cross-sectional area of the flow is not adequately assessed with current 2D echo. Both issues are addressed by 3D echo and 3D Doppler imaging which ideally should be combined. Further studies are needed in humans to validate this approach, but is likely that 3D Doppler will have the same impact on assessment of cardiac output as 3D echo has on LV volumes. Mechanism of ischaemic mitral regurgitation with segmental left ventricular dysfunction: threedimensional echocardiographic studies in models of acute and chronic progressive regurgitation. Y Otsuji, M D Handschumacher, N Liel-Cohen, et al. J Am Coll Cardiol 2001; 37(2):641–8. BACKGROUND. This study aimed to separate proposed mechanisms for segmental ischaemic mitral regurgitation (MR), including LV dysfunction versus geometric distortion by LV dilation, using models of acute and chronic segmental ischaemic LV dysfunction evaluated by 3D echo. Dysfunction and dilation —both mechanisms with practical therapeutic implications—are difficult to separate in patients. In seven dogs with acute left circumflex (LCX) coronary ligation, LV expansion was initially restricted and then permitted to occur. In seven sheep with LCX branch ligation, LV expansion was also initially limited but became prominent with remodelling over eight weeks. 3D echo reconstruction quantified mitral apparatus geometry and MR volume. In the acute model, despite LV dysfunction with ejection fraction=23±8%, MR was initially trace with limited LV dilation, but it became moderate with subsequent prominent dilation. In the chronic model, MR was also initially trace, but it became moderate over eight weeks as the LV dilated and changed shape. In both models, the only independent predictor of MR volume was increased tethering distance from the papillary muscles (PMs) to the anterior annulus, especially medial and posterior shift of the ischaemic medial PM, measured by 3D

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reconstruction (r2=0.75 and 0.86, respectively). MR volume did not correlate with LV ejection fraction or dP/dt. This work shows that segmental ischaemic LV contractile dysfunction without dilation, even in the PM territory, fails to produce important MR. The development of MR relates strongly to changes in the 3D geometry of the mitral apparatus, with implications for approaches to restore a more favourable configuration. INTERPRETATION. This well-designed animal study demonstrates that ischaemic dysfunction of the PM itself is not as harmful as it was suggested to be from previous studies. It is the remodelling of the left ventricle following inferior myocardial infarction that results in more severe MR. The tethering distance from the PMs to the anterior annulus measured by 3D reconstruction seems to be crucial for the competence of the mitral valve.

Comment Ischaemic MR is a typical example of the usefulness for a three-dimensional display of a valvular lesion. The mechanism and potential therapeutic measures of ischaemic MR have been published in several papers by this group |9,10|. The authors emphasize the importance of LV volume and remodelling for development of ischaemic MR. This again underlines the need for an accurate and highly reproducible method for volume measurements, which is 3D echo and not 2D echo. Of course the morphology of the valve is crucial too, and the 3D visualization enhances the understanding of the underlying mechanisms and the information of the cardiac surgeon. In the future, 3D echo will play an incremental role for pre-operative evaluation of the patients, intraoperative guidance of interventions and postoperative follow-up studies. Conclusion Where are we now? For the major clinical applications there is a growing number of convincing studies which demonstrate both the usefulness of 3D information and the feasibility of this approach. Although there is still only a small number of patients evaluated with 3D echo, it is evident that the expectations of 3D echo can be fulfilled (see Table 15.1). However, most of the studies presented in this review were performed with sophisticated methods and there is a clear need for more simple and user-friendly devices to translate these results into daily clinical practice. This may be best achieved with real-time 3D echo which will upgrade 2D echo scanners in the near future. At this point in time, the clinical application of 3D ultrasound is likely to advance rapidly, as improved 3D rendering technology becomes more widely available. What has to be done to make 3D echo a clinical tool? Improvement of image quality A major issue will be the image quality. As shown in the reviewed abstracts great effort has been applied to improve image quality. The introduction of harmonic imaging and contrast echocardiography have already resulted in significant improvement but further work is needed. Having excellent spatial and temporal resolution in 2D echo and MRI, 3D echo must improve to be able to compete with other 3D imaging techniques.

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Acquisition of a complete 3D data set Using transoesophageal 3D echo, it is usually possible to acquire a complete 3D data set. Transthoracic windows may be limited by ribs or pulmonary tissue and thus the 3D data set can be incomplete. For some indications such as the evaluation of a specific valve, an incomplete 3D data set may be sufficient as long as the valve is displayed. For measurements of chamber volumes and myocardial mass, however, a complete 3D data set is mandatory. With the newer RT-3D imaging technology a limitation is the 60°×60° pyramid shaped data set rendered by the current transthoracic probes, which does not allow scanning of dilated hearts so far. Thus, wider sectors are needed but also a combination of images from multiple acoustic windows will be necessary to acquire a complete 3D data set. Who needs a 3D echo? With current equipment, a transoesophageal 3D study may be considered in patients with complex congenital heart disease and in mitral insufficiency. In the future every echocardiogram will probably be performed with a 3D echo scanner just as every conventional echo today is performed with a twodimensional echo scanner. The advantages of having a 3D data set are so obvious—particularly the option for getting reproducible measurements—the encouraging work of recent years should continue. The big manufacturers of ultrasound equipment have invested a lot in 3D echo development and meanwhile prototype devices are available which can cope with the specific requirements of imaging a moving organ— real-time 3D echo. There is still some engineering work to be done to optimize the systems, but the fundamental work has been completed. Further stimulus comes from the exciting developments in MRI, which shows us what a 3D imaging system can provide. Seeing the quality of MRI images one may be frustrated in continuing echo. However, echo cannot be abandoned even if MRI becomes widely available. Echocardiography has some unique features (high spatial and temporal resolution, portability, low costs), which make it a useful tool in a MRI environment provided a 3D data set is available. In patients with good acoustic windows 3D echo can do the same job as MRI for most indications. In patients with poor acoustic windows MRI will probably be the primary imaging method in the future. References 1. 2. 3. 4. 5. 6. 7. 8.

Gordon EP, Schnittger I, Fitzgerald PJ, Williams P, Popp RL. Reproducibility of left ventricular volumes by twodimensional echocardiography. J Am Coll Cardiol 1983; 2: 506–13. Becher H, Tiemann K, Schlosser T, Pohl C, Nanda NC, Averkiou M, Powers J, Lüderitz B. Improvement of endocardial border delineation using tissue harmonic imaging. Echocardiography 1998; 15(5):511–16. Becher H, Burns P. Handbook of Contrast Echocardiography. Springer, Heidelberg, New York, Tokyo, 2000. Sechtem U, Pflugfelder PW, Gould RG, Cassidy MM, Higgins CB. Measurement of right and left ventricular volumes in healthy individuals with cine MR imaging. Radiology 1987; 167:425–30. Lange A, Palka P, Burstow DJ, Godman MJ. Three-dimensional echocardiography: historical development and current applications. J Am Soc Echocardiogr 2001; 14(5): 403–12. Cooke JC, Gelman JS, Harper RW. Echocardiologists’ role in the deployment of the Amplatzer atrial septal occluder device in adults. J Am Soc Echocardiogr 2001; 14(6): 588–94. Mizelle KM, Rice MJ, Sahn DJ. Clinical use of real-time three-dimensional echocardiography in paediatric cardiology. Echocardiography 2000; 17(8):787–90. Marx GR, Sherwood MC, Fleishman C, Van Praagh R. Three-dimensional echocardiography of the atrial septum. Echocardiography 2001; 18(5):433–43.

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9.

10.

11.

12.

13.

14.

15. 16.

17. 18.

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Messas E, Guerrero JL, Handschumacher MD, Chow CM, Sullivan S, Schwammenthal E, Levine RA. Paradoxic decrease in ischaemic mitral regurgitation with papillary muscle dysfunction: insights from three-dimensional and contrast echocardiography with strain rate measurement. Circulation 2001; 104(16):1952–7. Messas E, Guerrero JL, Handschumacher MD, Conrad C, Chow CM, Sullivan S, Yoganathan AP, Levine RA. Chordal cutting: a new therapeutic approach for ischaemic mitral regurgitation. Circulation 2001; 104(16): 1958–63. Kisslo J, Firek B, Ota T, Kang DH, Fleishman CE, Stetten G, Li J, Ohazama CJ, Adams D, Landolfo C, Ryan T, von Ramm O. Real-time volumetric echocardiography: the technology and the possibilities. Echocardiography 2000; 17(8):773–9. Belohlavek M, Tanabe K, Jakrapanichakul D, Breen JF, Seward JB. Rapid three-dimensional echocardiography: clinically feasible alternative for precise and accurate measurement of left ventricular volumes. Circulation 2001; 103(24):2882–4. Schmidt MA, Freidlin RZ, Ohazama CJ, Jones M, Laurienzo JM, Brenneman CL, Norman JE, von Ramm OT, Panza JA. Anatomic validation of a novel method for left ventricular volume and mass measurements with use of real-time 3-dimensional echocardiography. J Am Soc Echocardiogr 2001; 14(1):1–10. Frielingsdorf J, Franke A, Kuhl HP, Hess OM, Flachskampf FA. Evaluation of septal hypertrophy and systolic function in diseases that cause left ventricular hypertrophy: a 3-dimensional echocardiography study. J Am Soc Echocardiogr 2001; 14(5):370–7. Xujiong Y, Noble AJ. 3D freehand ultrasound left ventricle reconstruction from multiple acoustic windows. Proceedings of MIUA 2001; 41–44. Chamoun AJ, Lenihan DJ, McCulloch M, Ahmad M, Sheahan RG. Resynchronization therapy in dilated cardiomyopathy: confirmation of haemodynamic improvement with real-time three-dimensional echocardiography. Circulation 2001; 103(19):E98–8. Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the diagnosis of coronary artery disease. Ann Intern Med 1999; 130(9):719–28. Ishii M, Hashino K, Eto G, Tsutsumi T, Himeno W, Sugahara Y, Muta H, Furui J, Akagi T, Ito Y, Kato H. Quantitative assessment of severity of ventricular septal defect by three-dimensional reconstruction of colour. Doppler-imaged vena contracta and flow convergence region. Circulation 2001; 103(5):664–9.

16 Magnetic resonance imaging in coronary artery disease

Introduction Although magnetic resonance imaging (MRI) methods have for over a decade played a major role in diagnostic imaging of organs that can be immobilized, such as the brain or joints, high resolution cardiac MRI, and, in particular, MRI in coronary artery disease has only been made feasible in recent years, through technical progress in hardware (magnets, gradients, magnetic resonance (MR) coils) and software (sequence) development. A number of landmark studies have been published in the past 18 months, which clearly demonstrate the enormous potential of MR methods for the diagnosis of coronary artery disease (CAD). While currently employed imaging methods, such as echocardiography, nuclear imaging and catheter-based techniques, all provide information on only a small number of parameters, the main advantage of cardiovascular MR (CMR) is its great versatility: In theory, CMR can provide information on cardiac anatomy, function, perfusion, tissue characteristics, viability, coronary artery anatomy and physiology, and cardiac ion homeostasis and energetics. The long-term goal is to implement all these measurements in one single examination lasting less than one hour (the so-called ‘one-stop-shop’), characterizing anatomic, functional and physiological aspects of the heart in CAD. Such a multiparametric, multifunctional understanding may lead to refined treatment strategies and improved outcomes in CAD. With regard to quantification of cardiac volumes and mass, the prime advantage of CMR is that the method is intrinsically three-dimensional, i.e., unlike echocardiography, does not rely on geometric assumptions of left ventricular shape, provides high spatial resolution with excellent image contrast, and does not require appropriate acoustic windows. Thus, CMR is ideal for precisely quantifying ventricular remodelling post-myocardial infarction. While such advantages have, in theory, been known previously, one study has now demonstrated the superiority of CMR compared to echocardiography for quantification of left ventricular volumes and mass, leading to a dramatic reduction of the number of study subjects required to power clinical studies of remodelling. Myocardial perfusion can be measured with CMR by imaging the passage of a bolus of MR contrast agent (Gd-DTPA) through the cardiac chambers and heart muscle before and after the use of a vasodilator (adenosine or dipyridamole). This measurement does not add more than a few minutes to the protocol of a CMR study. While currently, the technique is typically applied to obtain relative perfusion information (perfusion reserve index; absolute quantification of perfusion is being developed |1|). The images obtained are of high spatial resolution, allowing identification of transmural perfusion differences (i.e. subendocardial

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versus transmural perfusion deficits). One study has recently applied this technique to demonstrate the effects of balloon versus stent repeat balloon angioplasty (PTCA) on regional perfusion of the formerly ischaemic territory. It is anticipated that such studies will further our understanding of the haemodynamic consequences of different types of coronary intervention, and may be used to test the efficacy of interventional treatment strategies in clinical trials. Probably the most significant recent development in CMR is the assessment of myocardial viability and micronecrosis. Inversion recovery gradient echo MR images, obtained 10–15 min after application of a bolus of MR contrast agent (Gd-DTPA), depict viable (i.e. normal, stunned and hibernating) myocardium as dark, and non-viable (i.e. necrotic or scarred) myocardium as bright areas. While this concept is, in principle, not a new one, state of the art hardware, combined with new optimized MR sequences, now allow for both high spatial resolution and high contrast (>6SD difference) for imaging myocardial (non-) viability. Two landmark studies herald the utility of this technique both for a new era of clinical studies of viability and micro-necrosis and for immediate routine clinical application. One major goal for CMR in CAD is imaging of the coronary artery lumen with high spatial resolution, thus allowing for the non-invasive diagnosis and quantification of coronary artery stenoses. Unfortunately, this is the aspect of CMR that is still furthest away from routine clinical application: Current MR coronary angiography techniques allow for a maximum spatial resolution of ~0.7 mm, while invasive coronary angiography provides 0.1–0.2 mm resolution, which is required to determine the extent of luminal obstruction with confidence. Accordingly, a series of previous studies |2| have reported that the sensitivity and specificity of MR coronary angiography for detecting significant coronary stenoses are ~80–90%, i.e. they are currently insufficient for clinical use. Over the past 18 months, no clinical study on this subject has appeared that would significantly overcome these limitations. Thus, MR coronary luminography is, for the time being, back to technical development, where, however, novel promising concepts are being explored |3,4|. It is likely that high resolution MR coronary angiography can only be implemented on a future generation of MR scanners. However, several breakthrough studies have been reported that move beyond the information derived from luminography, suggesting areas where the unique strength of coronary MRI may lie in the future. One study (Hundley et al. (2000)) used phase contrast MRI to measure coronary flow velocities, and demonstrated that it was possible to accurately predict re-stenosis post-angioplasty, providing functional information on the haemodynamic severity of a coronary lesion, otherwise accessible only with invasive coronary Doppler flow wires. Another study (Botnar et al. (2000)) reported, for the first time, non-invasive quantitative MRI measurements of the coronary vessel wall and demonstrated significant alterations in patients with CAD. We have also recently seen the first report (Corti et al. (2001)) describing non-invasive quantitative MRI analysis of the beneficial effect of chronic cholesterol-lowering therapy on arterial (carotid and aortic) vessel wall morphology, heralding the use of MRI for monitoring anti-atherosclerotic treatment strategies. A most promising new application of MRI for patients with unstable CAD is the development of targeted MR contrast agents, and one recent paper (Flacke et al. (2001)) reported on the use of a nanoparticle agent, loaded with Gd3+ molecules and targeted to fibrin, which may become useful for imaging the location of unstable plaques at a stage when luminal obstruction by either coronary stenosis or acute luminal thrombosis due to plaque rupture are not yet present. Finally, one of the most fascinating aspects of CMR is that the method can provide information on the metabolic state of cardiac tissue in CAD. While such applications have been slow to evolve due to enormous technical challenges, two recent studies have demonstrated the utility of 23Na-MRI for imaging of subacute and chronic myocardial infarction and the feasibility of stress-31P-MR spectroscopy to detect the derangement of myocardial energetics, reflecting myocardial tissue ischaemia, in female patients with chest pain but normal epicardial coronary arteries.

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Cardiac function and mass Reduction in sample size for studies of remodelling in heart failure by the use of cardiovascular magnetic resonance. N G Bellenger, L C Davies, J M Francis, A J Coats, D J Pennell. J Cardiovasc Magn Reson 2000; 2(4):271– 8. BACKGROUND. Fast breathhold CMR has become a reference standard for the measurement of cardiac volumes, function, and mass. The implications of this for sample sizes for remodelling studies in heart failure (HF) have not been elucidated. This study determined the reproducibility of CMR in HF and calculated the sample size requirements and compared them with published values for echocardiography. Breathhold gradient echo films of the left ventricle were acquired in 20 patients with HF and 20 normal subjects. Sample size values were calculated from the interstudy standard deviation of the difference. The percentage variability of the measured parameters in our HF group of intraobserver (2.0–7.4%), interobserver (3.3–7.7%), and interstudy (2.5–4.8%) measurements was slightly larger than for the normal group (1.6–6.6%, 1.6–7.3%, and 2.0–7.3%, respectively) but remained comparable to previous studies in normal subjects. The calculated sample sizes in patients with HF for CMR to detect a 10 ml change in end-diastolic volume (n=12) and end-systolic volume (n=10), a 3% change in ejection fraction (n=15), and a 10 g change in

mass (n=9) were substantially smaller than recently published values for two-dimensional echocardiography (reduction of 81–97%). CONCLUSION. Breathhold CMR is a fast comprehensive technique for the assessment of cardiac volumes, function, and mass in HF that is accurate but also highly reproducible. This allows a considerable reduction in the patient numbers required to prove a hypothesis in research studies, which suggests a potential for important research cost savings.

Comment While the potential of CMR for quantification of cardiac volumes and mass has long been recognized, this study firmly establishes the fact that for precise quantitative measurements, CMR is highly superior to current standard echocardiographic techniques. The contrast-to-noise of state-of-the-art cardiac MR images is ~ one order of magnitude higher than that of corresponding echocardiographic images, and, thus, the number of patients required to demonstrate a significant change of volumes or mass in a clinical study, is ~ one order of magnitude lower. It is for this reason that the pharmaceutical industry is rapidly discovering the utility of CMR, and almost all major new heart failure/remodelling studies now include at least a sub-study employing cardiac MR. Myocardial perfusion Improvement of myocardial perfusion reserve early after coronary intervention: assessment with cardiac magnetic resonance imaging. N Al-Saadi, E Nagel, M Gross, et al. J Am Coll Cardiol 2000; 36:1557–64. BACKGROUND. The purpose of this study was to determine the potential value of MR myocardial perfusion in the follow-up of patients after coronary intervention.

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In some patients a residual impairment of myocardial perfusion reserve (MPR) early after successful coronary intervention has been observed. This study evaluated an MPR index before and after intervention with MR. Thirty-five patients with single and multivessel coronary artery disease were studied before and 24 h after intervention. The signal intensity (SI) time curves of the first pass of a gadolinium-diethylene triamine pentacetic acid bolus injected via a central vein catheter were evaluated before and after dipyridamole infusion. The upslope was determined using a linear fit. MPR index was estimated from the alterations of the upslope. The MPR index in segments perfused by the stenotic artery was significantly lower than in the control segments (1.07±0.24 vs 2.18±0.35, P<0.001) and improved significantly after intervention (1.89±0.39, P<0.001) but did not normalize completely (P<0.01).

After intervention the MPR index remained significantly lower in the balloon percutaneous transluminal coronary angioplasty group (1.72±0.38; n=13) in comparison with the stent group (1.99±0. 36, n=18, P<0.05; Figure 16.1). In the stent group a complete normalization of the MPR index was found 24 h after stenting. INTERPRETATION. MR perfusion measurements allow a reliable assessment of MPR index. An improvement of MPR index can be observed after coronary intervention, which is more pronounced after stenting. MR perfusion measurements allow the assessment and may be useful for the follow-up of patients with CAD after coronary intervention.

Comment This study demonstrates how MR perfusion measurement using a first pass technique can quantify the effect which interventions on stenosed epicardial coronary arteries have on perfusion of the associated myocardial tissue. It was shown that both balloon PTCA and stent led to a significant increase of perfusion, but stenting resulted in a significantly larger improvement, corresponding with a larger increase in luminal diameter. Since improved tissue perfusion is physiologically more relevant than the formal increase in coronary artery luminal diameter, future studies of interventional strategies are likely to include measurement of regional perfusion to assess whether perfusion may predict long-term interventional outcome better than quantitative coronary angiography (QCA) measurements. Myocardial viability and micronecrosis The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. R J Kim, E Wu, A Rafael, et al. N Engl J Med 2000; 343:1445–53. BACKGROUND. Recent studies indicate that MRI after the administration of contrast material can be used to distinguish between reversible and irreversible myocardial ischaemic injury regardless of the extent of wall motion or the age of the infarct. This study tested whether the results of contrast-enhanced MRI can be used to predict whether regions of abnormal ventricular contraction will improve after revascularization in patients with CAD. Gadolinium-enhanced MRI was performed in 50 patients with ventricular dysfunction before they underwent surgical or percutaneous revascularization. The transmural extent of hyperenhanced regions was postulated to represent the transmural extent of nonviable myocardium. The extent of regional contractility at the same locations was determined by cine MRI before and after revascularization in 41 patients. Contrast-enhanced MRI showed hyperenhancement of myocardial tissue in 40 of 50 patients before revascularization. In all patients with hyperenhancement the difference in image intensity between hyperenhanced regions and regions

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Fig. 16.1 Improvement of myocardial perfusion reserve index (MPRI) after intervention in patients treated with stents compared with balloon PTCA. Values are presented as single values, mean ± one standard deviation and percentage increment of MPRI. Source: Al-Saadi et al. (2000). without hyperenhancement was more than 6 SD (Figure 16.2). Before revascularization, 804 of the 2093 myocardial segments analysed (38%) had abnormal contractility, and 694 segments (33%) had some areas of hyperenhancement. In an analysis of all 804 dysfunctional segments, the likelihood of improvement in regional contractility after revascularization decreased progressively as the transmural extent of hyperenhancement before revascularization increased (P<0.001). For instance, contractility increased in 256 of 329 segments (78%) with no hyperenhancement before revascularization, but in only 1 of 58 segments with hyperenhancement of more than 75% of tissue. The percentage of the left ventricle that was both dysfunctional and not hyperenhanced before revascularization was strongly related to the degree of improvement in the global mean wall-motion score (P<0.001) and the ejection fraction (P<0. 001) after revascularization. INTERPRETATION. Reversible myocardial dysfunction can be identified by contrast-enhanced MRI before coronary revascularization.

Fig. 16.2 Typical contrast-enhanced images obtained by MRI in a short-axis view (upper panels) and a long-axis view (lower panels) in three patients. Hyperenhancement is present (arrows) in various coronary-perfusion territories—the left anterior descending coronary artery, the left circumflex artery and the right coronary artery—with a range of transmural involvement. Source: Kim et al. (2000).

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Comment This is a landmark study demonstrating the capability of MRI to image myocardial viability with a spatial resolution of 16 μl, resulting in an almost histologic depiction of the extent of myocardial necrosis/scar. Such resolution is currently unachievable with any other method including positron emission tomography (PET). Taking advantage of the high spatial resolution for viability detection, the study demonstrates a close inverse relationship between the transmural extent of nonviability and the likelihood of regional recovery of contractility post-revascularization, and shows, for the first time, that segments, for which more than 75% of the LV wall is non-viable, cannot recover regional function. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation. M J Ricciardi, E Wu, C J Davidson, et al. Circulation 2001; 103:2780–3. BACKGROUND. Mild elevations in creatine kinase-MB (CK-MB) are common after successful percutaneous coronary interventions and are associated with future adverse cardiac events. The mechanism for CK-MB release remains unclear. A new contrast-enhanced MRI technique allows direct visualization of myonecrosis. Fourteen patients without prior infarction underwent cine and contrastenhanced MRI after successful coronary stenting; 9 patients had procedure-related CK-MB elevation, and 5 did not (negative controls). The mean age of all patients was 61 years, 36% had diabetes, 43% had multivessel CAD, and all had a normal ejection fraction. Twelve patients (86%) received an intravenous glycoprotein llb/llla inhibitor; none underwent atherectomy, and all had final Thromboysis in Myocardial Infarction (TIMI) 3 flow. Of the 9 patients with CK-MB elevation, 5 had a minor side branch occlusion during stenting, 2 had transient electrocardiogram (ECG) changes, and none developed Q waves. The median CK-MB was 21 ng/ml (range, 12–93 ng/ml), which is 2.33 times the upper limit of normal. Contrast-enhanced MRI demonstrated discrete regions of hyperenhancement within the target vessel perfusion territory in all 9 patients (Fig. 16.3). Only one developed a new wall motion abnormality. The median estimated mass of myonecrosis was 2.0 g (range, 0.7 to 12.2 g), or 1.5% of left ventricular mass (range, 0.4% to 6.0%). Hyperenhancement persisted in 5 of the 6 who underwent a repeat MRI at 3 to 12 months. No control patient had hyper-enhancement. CONCLUSION. Contrast-enhanced MRI provides an anatomical correlate to biochemical evidence of procedure-related myocardial injury, despite the lack of ECG changes or wall motion abnormalities. Mild elevation of CK-MB after percutaneous coronary intervention is the result of discrete microinfarction.

Comment Using an MRI protocol identical to the one from the previous study, allowing the imaging of small volumes of necrotic myocardium, this study demonstrates that small increases of myocardial-specific enzymes following percutaneous intervention are not a benign phenomenon but do result from necrosis of small amounts (mean value 2 g) of myocardial tissue. This method provides an attractive new research tool which can be applied in future studies evaluating interventional strategies and their associated risk of peripheral micronecrosis due to microembolization. Coronary arteries and atherosclerosis Assessment of coronary arterial restenosis with phase-contrast magnetic resonance imaging measurements of coronary flow reserve.

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Fig. 16.3 Contrast-enhanced MRI views of two patients demonstrating discrete hyper-enhancement (solid arrows) immediately adjacent to the stent (open arrows), both early and late after percutaneous coronary intervention. A: patient had a stent in the proximal left anterior descending artery; B: patient had a stent in the mid-posterior descending artery. Both patients had minor side-branch occlusion. Source: Ricciardi et al. (2001). W G Hundley, L D Hillis, C A Hamilton, et al. Circulation 2000; 101: 2375–81. BACKGROUND. After successful percutaneous coronary arterial revascularization, 25% to 60% of subjects have restenosis, a recurrent coronary arterial narrowing at the

site of the intervention. At present, restenosis is usually detected invasively with contrast coronary angiography. This study was performed to determine if phase-contrast MRI (PC-MRI) could be used to detect restenosis non-invasively in patients with recurrent chest pain after percutaneous revascularization. Seventeen patients (15 men, 2 women, age 36–37 years) with recurrent chest pain >3 months after successful percutaneous intervention underwent PC-MRI measurements of coronary artery flow reserve followed by assessments of stenosis severity with computer-assisted quantitative coronary angiography. The intervention was performed in the left anterior descending coronary artery in 15 patients, one of its diagonal branches in 2 patients, and the right coronary artery in 1 patient. A PCMRI coronary flow reserve value <2.0 was 100% and 82% sensitive and 89% and 100% specific for detecting a luminal diameter narrowing of >70% and >50%, respectively. INTERPRETATION. Assessments of coronary flow reserve with PC-MRI can be used to identify flowlimiting stenoses (luminal diameter narrowings >70%) in patients with recurrent chest pain in the months after a successful percutaneous intervention.

Comment Non-invasive phase contrast MRI measurement of coronary flow velocity can potentially replace the invasive Doppler flow wire technique. The study demonstrates that MRI-measured coronary flow reserve is progressively reduced as the severity of luminal narrowing of a coronary stenosis increases. It is conceivable that, in the future, this method may contribute to interventional decision making in situations

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where the haemodynamic significance of a coronary stenosis remains uncertain from its angiographic appearance. Non-invasive coronary vessel wall and plaque imaging with magnetic resonance imaging. R M Botnar, M Stuber, K V Kissinger, W Y Kim, E Spuentrup, W J Manning. Circulation 2000; 102:2582– 7. BACKGROUND. Conventional x-ray angiography frequently underestimates the true burden of atherosclerosis. Although intravascular ultrasound allows for imaging of coronary plaque, this invasive technique is inappropriate for screening or serial examinations. This study therefore sought to develop a non-invasive free-breathing MR technique for coronary vessel wall imaging. It was hypothesized that such an approach would allow for in vivo imaging of coronary atherosclerosis. Ten subjects, including 5 healthy adult volunteers (aged 35±17 years, range 19 to 56 years) and 5 patients (aged 60±4 years, range 56 to 66 years) with x-ray confirmed CAD, were studied with a T2-weighted, dual-inversion, fast spinecho MR sequence. Multiple adjacent 5 mm cross-sectional images of the proximal right coronary artery were obtained with an in-plane resolution of 0.5×1.0 mm. A right hemidiaphragmatic navigator was used to facilitate free-breathing MR acquisition. Coronary vessel wall images were readily acquired in all subjects (Fig. 16.4). Both coronary vessel wall thickness (1.5±0.2 vs 1.0±0.2 mm) and wall area (21.2±3.1 vs 13.7±4.2 mm2) were greater in patients with CAD (both P<0.02 compared to healthy adults). INTERPRETATION. In vivo free-breathing coronary vessel wall and plaque imaging with MR has been successfully implemented in humans. Coronary wall thickness and wall area were significantly greater in patients with angiographic CAD. The presented technique may have potential applications in patients with known or suspected atherosclerotic CAD or for serial evaluation after pharmacological intervention.

Comment This important study represents the first MRI quantification of diseased human coronary artery wall characteristics in vivo, showing increased coronary wall thickness and area in CAD patients, pointing towards the cardiologists’ dream of noninvasive characterization of human coronary artery plaques. As a word of caution, major advances in spatial resolution are still required to achieve this goal. While the resolution of the current study (1.0×0.5 mm) allows detection of significant differences between mean values of groups of volunteers and CAD patients, the fact that the pixel size was similar to the absolute difference between normals and CAD (0.5 mm, i.e. corresponding to ~ one pixel) currently still precludes reliable conclusions on coronary morphology in individual patients. With further improvement of resolution, however, the implications of non-invasive coronary plaque characterization would be far-reaching. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions. A longitudinal study by high-resolution, non-invasive magnetic resonance imaging. R Corti, Z A Fayad, V Fuster, et al. Circulation 2001; 104:249–52. BACKGROUND. This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions. Eighteen asymptomatic hypercholesterolaemic patients with documented aortic and/or carotidatherosclerotic plaques were selected for the study. A total of 35 aortic and 25 carotid artery plaques were detected. Serial black-blood MRI of the aorta and carotid artery of the patients was performed at baseline and 6 and 12 months after lipid-lowering therapy with simvastatin. The effects of the treatment on atherosclerotic lesions were measured as changes in lumen area, vessel

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Fig. 16.4 Patient with occlusive CAD in mid right coronary artery (RCA). Display of MR slice positions/orientations proximal, within, and distal to 100% occlusion of mid RCA as seen on conventional x-ray angiogram (E). Crosssectional magnified views of RCA wall at these 4 different locations. Proximal (A, B) and distal (D) RCA appears to be patent, whereas at location of suspected 100% stenosis (C), no lumen is visible, suggestive of total occlusion. Source: Botnar et al. (2000). wall thickness, and vessel wall area, a surrogate of atherosclerotic burden. Simvastatin induced a significant (P<0.01) reduction in total and low density lipoprotein cholesterol levels at 6 weeks that was maintained thereafter. At 6 months, no changes in lumen area, vessel wall thickness, or vessel wall area were observed. However, at 12 months, significant reductions in vessel wall thickness and vessel wall area, without changes in lumen area, were observed in both aortic and carotid arteries (P<0.001; Fig. 16.5). INTERPRETATION. This in vivo human study demonstrates that effective and maintained lipid-lowering therapy by simvastatin is associated with a significant regression of atherosclerotic lesions. This observation suggests that statins induce vascular remodelling, as manifested by reduced atherosclerotic burden without changes in the lumen.

Comment This study demonstrates for the first time that CMR can be used to quantify treatment effects on human atherosclerosis regression in vivo, andundoubtedly will spawn numerous similar investigations. Furthermore, the study demonstrates that even with the most potent anti-atherosclerotic agent currently available for clinical use, CMR-detectable morphologic differences can only be demonstrated after one year of treatment. This suggests that, currently, for carotid and aortic atherosclerosis, the morphologic results of major long-term treatments can be quantified, but subtle and more short-term treatment effects will likely be undetectable with current CMR techniques. Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques.

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Fig. 16.5 Data on vessel wall area (top), lumen area (middle), and maximal vessel wall thickness (bottom) at baseline and 6 and 12 months after simvastatin therapy for aortic (left) and carotid plaques (right). The error bars indicate 1 SD. Source: Corti et al. (2001). S Flacke, S Fischer, M J Scott, et al. Circulation 2001; 104:1280–5. BACKGROUND. Molecular imaging of a thrombus within fissures of vulnerable atherosclerotic plaques requires sensitive detection of a robust thrombus-specific contrast agent. In this study, we

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report the development and characterization of a novel ligand-targeted paramagnetic molecular imaging agent with high avidity for fibrin and the potential to sensitively detect active vulnerable plaques. The nanoparticles were formulated with 2.5 to 50 mol% Gd-DTPA-BOA, which corresponds to >50000 Gd3+ atoms/particle. Paramagnetic nanoparticles were characterized in vitro and evaluated in vivo. In contradistinction to traditional blood-pool agents, T1 relaxation rate as a function of paramagnetic nanoparticle number was increased monotonically with Gd-DTPA concentration from 0.18 ml s−1 pmol −1 (10% Gd-DTPA nanoparticles) to 0.54 ml s−1 pmol−1 for the 40 mol% Gd-DTPA formulations. Fibrin clots targeted in vitro with paramagnetic nanoparticles presented a highly detectable, homogeneous T1weighted contrast enhancement that improved with increasing gadolinium level (0, 2.5, and 20 mol% Gd). Higher-resolution scans and scanning electron microscopy revealed that the nanoparticles were present as a thin layer over the clot surface. In vivo contrast enhancement under open-circulation conditions was assessed in dogs. The contrast-to-noise ratio between the targeted clot (20 mol% Gd-DTPA nanoparticles) and blood was ~118±21, and that between the targeted clot and the control clot was 131 ±37. INTERPRETATION. These results suggest that molecular imaging of fibrin-targeted paramagnetic nanoparticles can provide sensitive detection and localization of fibrin and may allow early, direct identification of vulnerable plaques, leading to early therapeutic decisions.

Comment While molecular imaging with PET, where specific molecular target agents are labelled with a positron emitting isotope, has been available for some time, this report suggests that molecular imaging may also be feasible with the radiation-free CMR method. Nanoparticles were created, consisting of a ligand targeted to fibrin and a large number of Gd-DTPA molecules, which bind to fibrin molecules both in vitro and in vivo. As fibrin is formed at the site of unstable coronary plaques, this targeted contrast agent, by substantially shortening relaxation times at sites of local accumulation, may allow to specific imaging of such plaques. If this were feasible reliably and within a short measurement time, the method would have major clinical implications. Molecular imaging with CMR is a most promising area of research for coming years, and the list of potential molecular targets is long. Ion homeostasis and energy metabolism Assessment of myocardial infarction in humans with 23Na MR imaging: comparison with cine MR imaging and delayed contrast enhancement. J J W Sandstede, T Pabst, M Beer, et al. Radiology 2001; 221:222–8 BACKGROUND. The purpose of this work was to demonstrate the feasibility of sodium 23 (23Na) MRI for assessment of subacute and chronic myocardial infarction and to compare results with cine, late enhancement, and T2-weighted imaging. Thirty patients underwent MRI 8 days ±4 (subacute, n=15) or more than 6 months (chronic, n=15) after myocardial infarction by using a 23Na surface coil with a double angulated electrocardiogram-triggered three-dimensional gradient-echo sequence at 1.5 T. In addition, cine, inversion-recovery gradient-echo, and, in the subacute group, T2-weighted images (n=9) were obtained. Myocardial infarction mass was depicted as elevated SI or wall motion abnormalities and expressed as a percentage of total left ventricular mass for all modalities (Fig. 16.6). Correlations were tested with correlation coefficients. All patients after subacute infarction and 12 of 15 patients with chronic infarction had an area of elevated 23Na SI that significantly correlated with wall motion abnormalities (subacute; r=0.96, P<0.001, and chronic; r=0.9, P<0.001); three patients had no wall motion abnormalities or elevated 23Na SI. Only 10 patients in the subacute and nine in the chronic group

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Fig. 16.6 Three MR modalities depict a 3-year-old anteroseptal myocardial infarction in a 42-year-old man in the left ventricular short-axis view. A, End-diastolic cine image; B, End-systolic cine image shows a wall motion defect (arrowheads in B and C) of the anteroseptal wall; C, T1-weighted image obtained 15 minutes after administration of gadopentetate dimeglumine depicts a corresponding subendocardial late enhancement; D-F, Three contiguous sections from 23Na MRI reveal elevated SI of a midventricular section in the septum and a small part of the anterior wall (arrowheads); Source: Sandstede et al. (2001). revealed late enhancement; significant correlation with 23Na MRI occurred only in subacute group (r=0. 68, P<0.05). Myocardial oedema in subacute infarction correlated (r=0.71, P<0.05) with areas of elevated 23Na SI but was extensively larger. INTERPRETATION. 23Na MRI demonstrates dysfunctional myocardium caused by subacute and chronic myocardial infarction.

Comment 23Na

Experimental studies have shown that content is increased in necrotic and scarred myocardium, but remains normal in stunned and hibernating myocardium14, and thus, 23Na MRI may allow imaging of myocardial viability without requiring injection of an i.v. contrast agent. This study, for the first time, shows in vivo 23Na MR images of infarcted human myocardium. The main challenge remains further improvement of spatial resolution, which is currently still two orders of magnitude lower than that of 1H MRI late enhancement techniques. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. S D Buchthal, J A den Hollander, C N Bairey Merz, et al. N Engl J Med 2000; 342:829–35.

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BACKGROUND. After hospitalization for chest pain, women are more likely than men to have normal coronary angiograms. In such women, myocardial ischaemia in the absence of clinically significant coronary artery obstruction has long been suspected. Most methods for the detection of the metabolic effects of myocardial ischaemia are highly invasive. Phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy

is a non-invasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischaemia. This study enrolled 35 women, who were hospitalized for chest pain but who had no angiographically significant coronary artery obstructions, and 12 age-and weightmatched control women with no evidence of heart disease. Myocardial high-energy phosphates were measured with 31P-NMR spectroscopy at 1.5 Tesla before, during, and after isometric handgrip exercise at a level that was 30% of the maximal voluntary grip strength. We measured the change in the ratio of phosphocreatine to ATP during exercise. Seven (20%) of the 35 women with chest pain and no angiographically significant stenosis had decreases in the phosphocreatine: ATP ratio during handgrip that were more than 2 SD below the mean value in the control subjects without chest pain. There were no significant differences between the two groups with respect to haemodynamic variables at rest and during handgrip, risk factors for ischaemic heart disease, findings on MRI and radionuclide perfusion studies of the heart, or changes in brachial flow during the infusion of acetylcholine. INTERPRETATION. These results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain consistent with the occurrence of myocardial ischaemia but no angiographically significant coronary stenoses.

Comment The pathophysiological relevance of chest pain in women with normal coronary arteries remains debated. This study uses 31P-NMR spectroscopy to non-invasively measure one direct biochemical consequence of myocardial ischaemia, a loss of the high-energy phosphate compound phosphocreatine (measured as PCr/ ATP ratio). It is demonstrated that a significant percentage of such women develop demonstrable myocardial ischaemia during handgrip exercise, as evidenced by a decrease of the PCr/ATP ratio, probably due to microvascular dysfunction. The study shows that 31P-NMR spectroscopy is a powerful technique that can clearly demonstrate exercise-induced ischaemia even when epicardial coronary arteries appear morphologically normal. The technique may also aid evaluation of treatment strategies in this group of patients. Conclusion The past 18 months have seen major new developments in the field of cardiac MR. CMR is now the accepted gold standard technique for quantification of cardiac function and mass, allowing design of clinical studies of, e.g. ventricular remodelling, with much smaller numbers of patients. (Semi-) quantitative CMR analysis of myocardial perfusion is now feasible with a spatial resolution that is highly superior to any other imaging method. However, large, multicentric studies demonstrating prognostic relevance of CMR perfusion measurements, in analogy to the large nuclear perfusion database, remain to be reported. Highresolution assessment of myocardial viability and micronecrosis is now feasible on all modern MR scanners, and is likely to have immediate and widespread clinical impact. Implementation of high-resolution MR coronary angiography remains elusive, but new strategies employing analysis of coronary flow velocities, vessel wall characteristics, new contrast agents targeted to components of unstable coronary plaques, and

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metabolic assessment of cardiac ion homeostasis and energetics, show great promise for adding new dimensions to our methodological armamentarium for diagnosing CAD and its functional consequences. In the future, CMR is likely to become a major diagnostic modality for CAD. References and further reading 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14.

15.

16. 17.

18.

Zenovich A, Muehling OM, Panse PM, Jerosch-Herold M, Wilke N. Magnetic resonance first-pass perfusion imaging: overview and perspectives. Rays 2001; 26(1):53–60. Botnar RM, Stuber M, Danias PG, Kissinger KV, Bornert P, Manning WJ. Coronary magnetic resonance angiography. Cardiol Rev 2001; 9(2):77–87. Gatehouse PD, Keegan J, Yang GZ, Mohiaddin RH, Firmin DN. Tracking local volume 3D-echo-planar coronary artery imaging. Magn Reson Med 2001; 46(5):1031–6. Nayak KS, Rivas PA, Pauly JM, Scott GC, Kerr AB, Hu BS, Nishimura DG. Real-time black-blood MRI using spatial presaturation. J Magn Reson Imaging 2001; 13(5): 807–12. Pennell D. Cardiovascular magnetic resonance. Heart 2001; 85(5):581–9. Reichek N. MRI myocardial tagging. J Magn Reson Imaging 1999; 10(5):609–16. von Kienlin M, Beer M, Greiser A, Hahn D, Harre K, Kostler H, Landschutz W, Pabst T, Sandstede J, Neubauer S. Advances in human cardiac 31P-MR spectroscopy: SLOOP and clinical applications. J Magn Reson Imaging 2001; 13(4):521–7. Neubauer S. Cardiac magnetic resonance spectroscopy: potential clinical applications. Herz. 2000; 25(4):452–60. Pohost GM, Meduri A, Razmi RM, Rathi VK, Doyle M. Cardiac MR spectroscopy in the new millennium. Rays 2001; 26(1):93–107. Saeed M, Wendland MF, Watzinger N, Akbari H, Higgins CB. MR contrast media for myocardial viability, microvascular integrity and perfusion. Eur J Radiol 2000; 34(3): 179–95. Gatehouse PD, Firmin DN. The cardiovascular magnetic resonance machine: hardware and software requirements. Herz. 2000; 25(4):317–30. Kramer CM. Current and future applications of cardiovascular magnetic resonance imaging. Cardiol Rev 2000; 8 (4):216–22. van Rossum AC. MR coronary angiography—fact or fiction? MAGMA 1998; 6(2–3): 181–3. Horn M, Weidensteiner C, Scheffer H, Meininger M, de Groot M, Remkes H, Dienesch C, Przyklenk K, von Kienlin M, Neubauer S. Detection of myocardial viability based on measurement of sodium content: a 23Na-NMR study. Magn Reson Med 2001; 45(5): 756–64. Lorenz CH, Walker ES, Morgan VL, Klein SS, Graham TP Jr. Normal human right and left ventricular mass, systolic function, and gender differences by cine magnetic resonance imaging. J Cardiovasc Magn Reson 1999; 1 (1):7–21. Yang X, Atalar E, Dechun Li, Serfaty JM, Wang D, Kumar A, Cheng L. Magnetic resonance imaging permits in vivo monitoring of catheter-based vascular gene delivery. Circulation 2001; 104:1588–90. de Roos A, Kunz P, Lamb H, Kroft L, Langerak S, Doornbos J, van der Wall E. Magnetic resonance imaging of ischaemic heart disease: why cardiac magnetic resonance imaging will play a significant role in the management of patients with coronary artery disease. J Comput Assist Tomogr 1999; 23 Suppl 1:S135–41. Frank H. Characterization of atherosclerotic plaque by magnetic resonance imaging. Am Heart J 2001; 141(2 Suppl):S45–8.

17 Coronary artery imaging using electron beam CT and multislice CT

Introduction Coronary heart disease is the major cause of death throughout the Western world. For many people, the first and only symptom of coronary heart disease is a fatal heart attack. Between 30 and 50 per cent of all deaths from acute myocardial infarction are sudden and without warning. The reliable non-invasive assessment of coronary artery disease would therefore constitute an important step forward in clinical cardiology. Coronary artery calcium scoring (CACS) programs have been historically developed and validated with Electron Beam Computed Tomography (EBCT), a form of ultra-fast CT. CACS is a non-invasive screening test for the early detection of coronary atherosclerosis. Until the last two to three years, helical CT has not been fast enough to successfully image the heart without blurring of the images caused by cardiac motion. This has changed with the introduction of multislice CT (MSCT) scanners. EBCT was introduced over 15 years ago. Virtually all this time has been needed for long-range studies and to gain credibility for this technique. EBCT is a cross-sectional x-ray imaging modality that does not require mechanical movement of an x-ray tube around the patient. EBCT uses an electron gun and a stationary tungsten ‘target’ rather than a standard x-ray tube to generate x-rays, permitting very rapid scanning times. EBCT has a temporal resolution of 100 milliseconds, and images can be acquired with prospective electrocardiographic triggering. EBCT has a high in-plane spatial resolution at a slice thickness of 3 mm. Mechanical computed tomography has made two major evolutionary leaps during the last decade. The first of these occurred in the early 1990s with the introduction of spiral or helical CT. The second leap occurred at the end of the decade with the introduction of multirow detector CT or MSCT. MSCT scanners can acquire four spiral slices simultaneously in 500 milliseconds (full rotation). Images however can be captured in less than 250 milliseconds with a partial rotation. In fact, down to 125 millisecond maximum temporal resolution can be achieved with segmented reconstruction. Four 0.5 mm slices can be achieved on some scanners. The increased scan speed and reduced slice thickness of MSCT results in improved resolution, which is necessary for CACS and CT angiography of the coronary arteries. Although EBCT is faster than MSCT, it does have limitations in resolution because of image acquisition in a fan shaped fashion. Mechanical CT shows a marked improvement in low-density resolution compared to EBCT. Visual inspection of comparable images from the same patient using both techniques, shows

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obvious improved clarity for helical CT over EBCT. MSCT, with the use of prospective and retrospective ECG-gating, shows a very high correlation with EBCT in the order of 0.96–0.99. CACS is based on the finding that precipitates of calcium phosphate in the coronary arteries always indicate the presence of atherosclerosis. Calcium is deposited early in the formation of atherosclerotic plaque, and calcification can be used as a marker for the atherosclerotic process. A number of studies, including Rumburger et al. |1|, report that the calcific plaque represents approximately 20% of the total plaque burden along the vessel and therefore coronary calcification can be regarded as a reliable correlate of total coronary atherosclerosis. The atherosclerotic process begins early in life. There is a very long presymptomatic phase with the clinical presentation of obstructive coronary artery disease usually not occurring until later in life. Symptomatic coronary artery disease is considered premature if it occurs before the age of 55. Atherosclerotic plaques can occupy around 40% of the cross-sectional area of the artery with minimal or no luminal stenosis |2|. This is explained by the phenomenon of vascular remodelling. As the plaque grows, the lumen remains the same. Therefore, although there may be minimal luminal stenosis, there is often a very large mural plaque. Although coronary angiography is still the ‘gold standard’ for the diagnosis of obstructive coronary artery disease, it is not an accurate measure of the total atherosclerotic plaque burden. A number of studies indicate that CACS with EBCT or MSCT is a highly sensitive method for assessing atherosclerotic burden. It is also a moderately specific test to predict stenotic disease. The extent and site of calcification, however, does not equate with site-specific stenosis. The exclusion of coronary calcification (i.e. calcification score=0) is associated with an extremely low probability of significant stenosis (>50%) |3|. In fact, a negative scan has a negative predictive value for fixed ‘significant’ coronary lumen obstructive disease of 95 to 100%. Patients with a calcium score of >400 have a high likelihood of at least one ‘significant’ coronary stenosis (>50% diameter). Although currently recognized risk factors for coronary artery disease are helpful to predict the development of atherosclerosis, their ability to identify individual patients at risk of events is limited. The weight of literature, particularly over the last few years, suggests that CACS is a proven indicator of future cardiac events and is currently the best non-invasive method to determine utilization of risk factor modification. There have been several arguments against CACS which have delayed its widespread acceptance as a screening tool. Firstly, only the calcified plaque is identified, and a full assessment of plaque morphology cannot be made (i.e. soft plaque is not imaged). The risk of plaque rupture seems to depend on plaque composition. Therefore the detection of vulnerable plaques is of major importance for risk stratification and early treatment to prevent plaque rupture. Secondly, there is continuing debate regarding the use of CACS as a long-term prognostic tool. The correlation between arterial mineralization and the probability of plaque rupture is still unknown. The majority of prognostic studies performed to date, however, have shown statistical significance for the detection of cardiac events (while not a direct marker of the vulnerable plaque at risk of rupture, the greater the CACS, the greater the potential for increased numbers of potentially lipidrich plaques, which are widely thought to be the culprit lesions of acute coronary syndromes). There are limited studies to date which have examined the prognostic role of CACS in symptomatic patients. Two excellent articles on this subject, however, were published in 2001, and these have been reviewed in this chapter. There has been a great deal of interest, particularly in the last year or two, in the development of CT angiography of the coronary arteries MSCT. CT angiography offers, in addition to the non-invasive documentation of high-grade stenoses, the possibility to differentiate plaque morphology and hopefully identify rupture-prone soft coronary lesions. In 2001, articles began appearing in the literature reporting initial experiences with MSCT angiography of the coronary arteries.

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Coronary artery calcification measured at electron beam CT: agreement in dual scan runs and change over time. L F Bielak, P F I I Sheedy, P A Peyser. Radiology 2001; 218(1):224–9. BACKGROUND. While investigators have reported changes in the quantity of coronary artery calcification (CAC) over time in a group, there has been concern about the ability to identify change over time in any given individual. This concern is due to the reported limited repeatability of EBCT results. 1376 asymptomatic research participants, who were not selected because they were at high risk of coronary artery disease, were examined for the quantity of CAC with two consecutive acquisitions (dual scan runs) at EBCT. A recently described regression approach was used to evaluate agreement in the quantity of CAC. With the data obtained, 95% limits of agreement were established and used to evaluate differences between scan runs performed approximately 3.5 years apart in 81 participants. The 95% limits of agreement depended on the mean quantity of CAC in the dual scan runs. Of the 81 participants whose examinations were approximately 3.5 years apart, 59 (73%) had no apparent change in CAC between the two examinations, 21 (26%) had large increases suggesting progression of CAC, and one (1%) had a large decrease suggesting regression of CAC. INTERPRETATION. The prevalence and mean quantity of CAC in the study group were not significantly different between the dual scan runs, but differences in the quantity of CAC existed in individuals. Reasons for differences between consecutive scan runs include image noise, artefact, motion, partial volume effect, patient positioning, triggering, accuracy of table movement, and breath holding. The regression approach described in this study can be used to evaluate agreement between dual scan runs.

Additionally and importantly, it can also be used to evaluate change in the quantity of CAC overtime in an individual.

Comment This study emphasizes the need for all centres performing CACS to have a quality-control program to ensure accurate reproducible results. It also demonstrates the appealing application of EBCT and MSCT for monitoring progression of coronary artery disease. A number of studies have been performed following disease progression with EBCT. In general, the continued accumulation of coronary artery calcium appears to portend a negative outcome |4|. In several studies, untreated patients showed a significant score progression over time. In these studies, patients with significant calcium score progression were more likely to have a cardiovascular event compared with patients showing stabilization or minimal progression of disease. The majority of aggressively treated patients (treated with statins) showed stabilization and even regression of the calcium volume score after a year. These studies indicate that EBCT and MSCT calcium scores can be gainfully employed to assess response to medical therapy for atherosclerosis. At the present time there is no evidence that repeating EBCT scans before 12 months have elapsed from the time of screening may show any significant change in calcium score. Ongoing clinical studies are needed to evaluate the ideal inter-scan interval. Coronary artery calcium measurement: agreement of multirow detector and electron beam CT. C R Becker, T Kleffel, A Crispin, et al. Am J Roentgen 2001; 176: 1295–8. BACKGROUND. A large number of multi-slice CT scanners have now been installed around the world. Many of these machines are involved in CACS programs. There is an obvious need to determine

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Fig. 17.1 Diagram shows receiver operating characteristic curves for EBCT (black line) and multirow detector CT (grey line). Difference of areas under receiver operating characteristic curves did not achieve statistical significance. Source: Becker et al. (2001). the agreement of coronary calcium measurements with EBCT and multirow detector CT. In this study coronary artery screening was performed in 100 patients with both EBCT and multirow detector CT. The images were transferred to a dedicated workstation for determination of the calcium score, volume, mass, density, and number of lesions. Due to the better signal to noise ratio of mechanical CT scanners, in addition to the traditional threshold of 130 Hounsfield Units (HU), the score of MSCT studies was reevaluated at a threshold of 90 HU. Fifty-nine of the patients underwent conventional coronary catheterization. The correlation between EBCT and multirow detector CT was high for every quantification algorithm. The areas under the curve in the receiver operating characteristic curve analyses for electron beam and multirow detector CT were similar for the score, volume and mass, whereas they were lower for the density. No significant difference was found for the areas under the curve between scores using 130 HU and those using a 90 HU threshold. Forty-five of the 59 patients who underwent conventional coronary angiography showed at least one significant stenosis.

INTERPRETATION. The agreement of the coronary artery calcium measurement between EBCT and MSCT is high. The volume and mass indices are superior to the traditional score, density, and number of lesions for comparing the results of EBCT and MSCT and for determining significant coronary artery disease.

Comment Coronary calcification is quantified via a score calculated according to the Agatston method |5|. The area of a calcified plaque is multiplied by a coefficient estimated on the basis of the peak density of the calcified lesion (set at 130 HU). Some studies have shown that the main limitation of the Agatston score is its limited

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Fig. 17.2 Diagram compares receiver operating characteristic curves of multirow detector CT scores re-evaluated with thresholds of 130 (black line) and 90 (grey line) HU. Area under curve, sensitivity, and specificity are same for both quantification algorithms. Source: Becker et al. (2001).

reproducibility |4|. For this reason, another scoring method was recently introduced—the calcium volume score—which demonstrates very low inter-scan variability. The authors of this article found that the volume score is superior to the traditional score when comparing the results of EBCT and MSCT. This article also demonstrates that the higher signal to noise ratio of MSCT allows a lower density threshold to be set which should increase the sensitivity for detection of calcified plaques. Despite the higher sensitivity with the threshold set at 90 HU, the area under the curve, sensitivity, and specificity were the same for the scores obtained with a density threshold set at 130 HU. This article also highlights another potential advantage of MSCT performed with retrospective ECGgating. MSCT scans are performed with a finer slice thickness than EBCT scans. This should allow detection of smaller calcified plaques. Using the helical data set, images can also be reconstructed at any desired slice position which may also help to reduce the number of small plaques missed. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1764 patients. R Haberl, A Becker, A Leber, et al. J Am Coll Cardiol 2001; 37(2): 451–7. BACKGROUND. This study correlates the EBCT calcium scores with the results of coronary angiography in symptomatic patients, in order to assess the value of CACS in predicting or excluding significant coronary artery disease (CAD). There is no doubt,

given the extensive literature, that EBCT is a sensitive method for detection of coronary calcium. It is, however, unclear whether it plays a role as a filter before invasive procedures in symptomatic patients. A

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total of 1764 patients from a single centre (1225 men and 539 women) with suspected CAD were included in the study. All patients underwent calcium screening with EBCT and conventional coronary angiography. All patients had typical or atypical chest pain and/or signs of myocardial ischaemia on noninvasive tests (bicycle stress tests, in most cases) and a clinical indication for cardiac catheterization. 41% of the individuals were smokers. Patients were excluded if they had CAD documented by previous cardiac catheterization or were specifically referred for coronary interventions. Therefore, at the time of angiography, the patient’s diagnosis was unclear. 56% of men and 47% of women revealed significant coronary stenoses greater than or equal to 50%. 25% of men and 41% of women had normal coronary angiograms. Total exclusion of coronary calcium (14% of the study group) was associated with an extremely low probability of stenosis (<1%). With calcium scores ≥ the 20th, the 100th, or the 75th percentile of age groups, the sensitivity to detect stenoses decreased to 97%, 93% and 81%, respectively, in men and to 98%, 82% and 76%, respectively, in women. At the same time, the specificity increased up to 77% in men and women. The mean score in men was significantly higher than that in women in each age class. There was a significant increase in calcification with age for both genders. The variability of scores within each age class was high; this was caused by a minority of patients with excessive calcification. The difference between patients with and without significant CAD was highly significant for the total group of patients and within each age group. INTERPRETATION. Exclusion of coronary calcium was associated with a very low risk of significant CAD (<1%). Eleven per cent of men and 22 per cent of women, although symptomatic with a high pre-test probability of CAD and an indication for coronary angiography, did not show any coronary calcium; this variable appears to be helpful as a filter before invasive procedures. Higher calcium score values are associated with decreased sensitivity to detect significant CAD, but increased specificity of the method. The quantification of calcium allowed exclusion of atherosclerotic disease in a subset of patients, and strongly predicted obstructive disease in others. The diagnostic benefit of calcium screening is maintained for all age groups.

Comment This study is the largest published. Its conclusions are that calcium screening with EBCT is a highly sensitive and moderately specific test to predict stenotic disease. Exclusion of coronary calcium defines a substantial sub-group of patients, albeit symptomatic, with a very low probability of significant stenosis. On the basis of these results, there may well be an indication for calcium screening in patients with atypical chest pain, especially if non-invasive tests are not feasible or inconclusive. CACS has the potential as a filter in symptomatic patients to reduce the number of invasive procedures which do not lead to intervention. This could decrease the ‘normal’ cardiac catheterization rate, which in many hospitals is approximately 40% (angiography is not the gold standard to validate the significance of coronary calcification; major discrepancies have been found between the angiographic severity of lesions and post-mortem examinations, with angiography underestimating the extent of atherosclerosis). This could lead to a significant improvement in the cost-effectiveness of cardiac diagnosis (and a reduction in radiation dose for a number of patients). The diagnostic accuracy of CACS has been found to be superior to conventional risk factor analysis and equal to or better than conventional stress tests. The exercise stress test is characterized by a wide variability of sensitivity, specificity and diagnostic accuracy, and is not free from complications. Stress radionuclide scintigraphy has been proposed as an alternative test by some, but this test is limited by variable sensitivity and specificity, high radiation exposure and a time-consuming protocol.

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Fig. 17.3 Diagnostic yield of calcium screening in symptomatic men. Source: Haberl et al. (2001).

EBCT and MSCT give the opportunity to combine calcium scanning and CT angiography in a single session. This would allow evaluation of the morphology of coronary plaque. No data, however, are available on a combined approach at this time. To maximize the specificity of this technology, calcium screening should be performed in pre-defined age cohorts. Calcium screening is best employed in asymptomatic subjects at intermediate risk of CAD to address the presence of atherosclerotic disease and to assess the risk of the individual patient. Specifically, men should undergo screening between the ages of 40 to 60 or 70 years of age, whereas women should be subjected to screening between the ages of 50 to 70 or 75 years of age |4|. Do conventional risk factors predict subclinical coronary artery disease? Results from the prospective army coronary calcium project. A Taylor, I Feuerstein, H Wong, W Barko, M Brazaitis, P G O’Malley. Am Heart Journal 2001; 141(3):463– 8. BACKGROUND. Recent guidelines issued by the American Heart Association recommended against the routine use of EBCT as a screening test in asymptomatic patients, because the additive value over clinical prediction tools is uncertain. In this study CAC, identified with EBCT, was compared with conventional clinical and serologic coronary risk factors, for the identification of patients with increased risk of coronary heart disease. 630 active-duty US Army personnel (39–45 years old) without known CAD were studied. These personnel were undergoing a routine physical examination as required by regulations. Each participant underwent clinical and serologic risk factor screening and EBCT. The cohort (mean age 42 ± two years, 82% male) had a low predicted risk of coronary events (using the Framingham risk index).

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Fig. 17.4 Diagnostic yield of calcium screening in symptomatic women. Source: Haberl et al. (2001).

The prevalence of coronary calcification was 17.6% (male 20.6%, female 4.3%). An abnormal CAC score was defined as the presence of any detectable CAC (CAC score greater than zero). Significant univariate correlates of CAC were total and low-density lipoprotein (LDL) cholesterol, triglycerides, systolic blood pressure, and body mass index. However, only LDL cholesterol was independently associated with CAC. There was a significant but weak relationship between CAC and the Framingham risk index, which was not different from the relationship between CAC and LDL cholesterol alone. Other risk factors (family history, homocysteine, insulin, lipoprotein (a), and fibrinogen) were not related to CAC. INTERPRETATION. In this age-homogeneous, low-risk screening cohort, conventional coronary risk factors significantly underestimated the presence of premature, subclinical calcified coronary atherosclerosis. These data support the potential of CAC detection as an anatomic, plaque-burden diagnostic test to identify patients who may require more intensive risk-reduction therapies, independent of predicted clinical risk.

Comment The relationship between CAC and cardiovascular risk factors in asymptomatic screening populations has been the subject of several prior studies. In contrast to

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Table 17.1 Relationships between coronary artery calcification and cardiovascular risk factors Variable

EBCT results CAC positive (n=111)

BMI (kg/m2) 28.2±3.2 Total cholesterol (mg/dL) 214±37 LDL cholesterol (mg/dL) 140±35 HDL cholesterol (mg/dL) 50±13 Triglycerides (mg/dL) 142±102 Systolic blood pressure (mm Hg) 124±13 Diastolic blood pressure (mm Hg) 77±9 Hypertension (%) 27.0 Tobacco use (%) Former 25.2 Current 8.3 Diabetes mellitus (%) 0 Glycosylated haemoglobin (%) 5.6±0.5 Serum insulin (μU/mL) 8.4±6.1 5-year FRI (%) 1.9±1.1 Family history of CAD (%) 20.7 Homocysteine (μmol/L) 9.8±2.8 Fibrinogen (mg/dL) 309±61 Lipoprotein(a) (mg/dL) 40.5±44.1 Values are mean±SD. HDL, High-density lipoprotein. Source: Taylor et al. (2001).

CAC negative (n=519)

Statistical significance

27.2±3.4 200±35 126±32 52±14 122±85 121±13 75±9 22.0

P=0.005 P<0.001 P<0.001 P=0.18 P=0.04 P=0.01 P=0.09 P=0.25 P=0.84

22.8 7.5 2.1 5.6±0.7 8.1±8.2 1.5±1.2 22.4 9.6±2.6 304±56 34.6±38.7

P= 0.12 P=0.85 P=0.73 P=0.004 P=0.71 P=0.46 P=0.46 P=0.16

earlier studies in which the prevalence of cardiovascular risk factors has generally been greater, the only risk factor in this study found to have an independent relationship to CAC was LDL cholesterol. The importance of this finding, consistent with the strong and primary relationship between lipids and early atherosclerosis, lies in the availability of safe and effective therapies for the reduction of LDL cholesterol. The major controversy currently surrounding EBCT and MSCT is the relationship between CAC, clinical risk prediction, and cardiovascular prognosis. The rationale for anatomic screening tests, such as EBCT, lies in the incomplete identification by risk modelling of patients who have clinical cardiovascular events. In this study, cardiovascular risk factors have been isolated from the effect of age. The study demonstrated that the majority of CAC in a screening cohort is not explained by standard cardiovascular risk factors. There is therefore limited overlap between CAC measurements of plaque burden and the Framingham risk index assessment. Because these methods do not identify the same patients as being ‘at risk’ in many cases, the routine measurements of plaque burden with CAC can meaningfully alter the treatment and potentially the outcomes of patients traditionally considered as low risk, primarily by intensifying efforts at LDL reduction. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography.

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P C Keelan, L F Bielak, K Ashai, et al. Circulation 2001; 104(4): 412–7. BACKGROUND. As discussed earlier, the scientific statement on CACS issued by the American Heart Association identifies the need for data collection about future cardiac events to determine the clinical significance of CACS. This ‘follow-up’ study was performed to determine whether CAC extent measured by EBCT predicts future hard cardiac events. The potential of selected CAD risk factors, prior CAD event history, and angiographic findings was also assessed to predict subsequent hard events. 288 patients underwent both coronary angiography and EBCT assessment within a four-week period between 1989 and 1995. Clinically stable patients undergoing coronary angiography were invited to participate. The indication for angiography was evaluation of chest pain in almost 90% of cases. Patients were not selected for angiography on the basis of the EBCT examination results, and most had EBCT after angiography, usually the next day. Patients were questioned by two of the authors during a telephone interview using a customized questionnaire a mean of 6.9 years after initial evaluation. Vital status and history of myocardial infarction during follow-up were determined. Selected risk factors were abstracted from medical records at the time of hospital discharge. The median CACS was 160. Twenty-two patients experienced hard cardiac events during follow-up. These patients were older and had more extensive CAC and angiographic disease. Only one of the 87 patients with a CAC score less than 20

experienced a subsequent hard event during follow-up. Event-free survival was significantly higher for patients with CAC scores less than 100 than for those with scores ≥ 100. When a stepwise multivariable model was used, only age and CAC extent predicted hard events. INTERPRETATION. CACS is highly predictive of future hard cardiac events and provides more prognostic information than angiography in symptomatic patients. In this study, no conventional coronary risk factors other than age predicted events, although measures of cholesterol levels at baseline were not available for 28 patients. Surprisingly, a history of myocardial infarction or revascularization was not associated with an increased likelihood of subsequent hard events. The benefits of aggressive risk factor modification and revascularization techniques might explain this observation. Future hard events were very rare in patients with minimal calcification, even though the clinical suspicion of CAD in these patients was sufficient to warrant angiography. When available, CACS should be considered in all patients with indications for angiography.

Comment It is widely believed that the existence of vulnerable plaque, which leads to hard cardiac events, is closely related to atherosclerotic burden. As I have discussed earlier, there is a strong correlation between the extent of vessel calcification and overall plaque burden. The remodelling phenomenon |2| results in a disparity between plaque burden and angiographic stenosis. This limits the information that may be gleaned from a coronary angiogram regarding disease burden and the likelihood of vulnerable plaque (i.e. the angiogram provides no information on plaque burden other than the extent of luminal obstruction). Therefore, in patients with a minimally abnormal coronary angiogram, the physician may erroneously conclude that Table 17.2 Stepwise multivariable Cox proportional hazards regression models for survival free of hard events with risk factors, CAD event history, CAC, and angiographic results.

Risk factors and CAD event history Age Risk factors, CAD event history, and CAC Age Log (CAC Score+1)

RR* 95% CI

P

2.15 (1.35, 3.45) 1.72 (1.02, 2.91) 1.88 (1.02, 3.48)

0.001 0.043 0.044

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Risk factors, CAD event history, and angiographic results Age Risk factors, CAD event history, angiographic results, and CAC Age Log (CAC score+1) *For 1-SD increase in continuous variables. Source: Keelan et al. (2001).

RR* 95% CI

P

2.15 (1.35, 3.45) 1.72 (1.02, 2.91) 1.88 (1.02, 3.48)

0.001 0.43 0.044

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the overall disease burden is mild. In these patients, a high CAC score may add important prognostic information and identify the need for aggressive medical therapy and regular patient follow-up. Detection of coronary artery stenoses by contrast-enhanced, retrospectively electrocardiographicallygated, multislice spiral computed tomography. S Achenbach, T Giesler, D Ropers, et al. Circulation 2001; 103(21): 2535–8. BACKGROUND. CT angiography using MSCT with retrospective- ECG gating was compared with invasive coronary angiography (quantitative coronary angiography), to investigate the ability of this method to identify high-grade coronary artery stenoses and occlusions. Sixty-four consecutive patients referred for invasive coronary angiography were studied using MSCT. Results were then compared with invasive coronary angiograms. The MSCT technique used was as follows: 4×1 mm slices; 500 millisecond gantry rotation; table feed 1.5 mm/rotation; 160 mls of intravenous contrast agent injected at 4 ml/sec; retrospective ECG gating. Thin-slab maximum-intensity projections and 3-D reconstructions were rendered on a Sclmage workstation. All coronary arteries and side-branches with a luminal diameter of ≥ 2 mm were assessed regarding evaluability and the presence of high-grade stenoses (>70% diameter stenosis) or occlusions. A vessel diameter of 2 mm or greater was chosen as stenoses in smaller vessels rarely constitute targets for revascularization. Of 256 coronary arteries (left main, left anterior descending, left circumflex and right coronary artery, including their respective side branches), 174 could be evaluated (68%). In 19 patients (30%), all arteries were evaluable. The most frequent reasons for impaired evaluability were motion artefacts (39 arteries) and severe vessel calcification (27 arteries). The right coronary artery was most frequently affected by degraded image quality (33 patients). Overall, 32 of 58 high-grade stenoses and occlusions were detected by MSCT (58%). In evaluable arteries, 32 of 35 lesions were detected, and the absence of stenosis was correctly identified in 117 of 139 arteries (sensitivity=91%; specificity=84%). INTERPRETATION. MSCT with retrospective ECG gating permits the detection of coronary artery stenoses with high accuracy if image quality is sufficient. Image quality however was degraded in a substantial number of cases, mainly due to rapid coronary motion. This may limit its current clinical use, however the encouraging results obtained in this study justify further research to improve the accuracy and evaluate the clinical usefulness of MSCT.

Comment The image quality that can be obtained by MSCT angiography is impressive. At this early stage in its development, however, image quality does not reach that of selective coronary angiography. Measures need to be taken to reduce the number of arterial segments that cannot be evaluated. Because most of the segments that could not be evaluated were affected by coronary motion, further shortening the image acquisition window would appear mandatory. Partial scan-reconstruction techniques, which apply a 90–180 degree reconstruction algorithm (partial segmented reconstruction) can improve temporal resolution to 125 milliseconds. Given the rapid technological advances in MSCT, further improvement in temporal resolution

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Fig 17.5 MSCT and coronary angiography in a patient with a stenosis of the left anterior descending (LAD) coronary artery. A, Cross-sectional image in axial orientation obtained by MSCT. The proximal LAD coronary artery shows a lumen narrowing (arrow). B, Sliding thin slab maximum intensity projection (slab thickness: 10 mm) of the left main and LAD coronary artery (arrow: stenosis). C, 3-dimensional reconstruction of the heart and contrast-enhanced coronary arteries showing the LAD stenosis (arrow). D, Invasive coronary angiography confirms the stenosis (84% diameter reduction, reference diameter 3.5 mm). Source: Achenbach et al. (2001).

appears inevitable. One manufacturer has already released an 8 slice system. By the end of 2002, several manufacturers will have 16 slice systems available. Manufacturers are spending a lot of money on further MSCT advances including 32 slice systems, and eventually large flat panel detectors capable of 256 simultaneous slices. Coronary angiography with multi-slice computed tomography. K Nieman, M Oudkerk, BJ Rensing, et al. Lancet 2001; 357(9256): 599–603.

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Fig 17.6 A, Cross-sectional image showing a motion artifact of the right coronary artery (arrows) which renders the artery unevaluable. B, Severe calcifications of the LAD coronary artery (arrows) which render the artery unevaluable concerning the presence of stenoses. C, Sliding thin slab maximum intensity projection (slab thickness: 10 mm) which shows a high-grade stenosis of a large diagonal branch (arrow). D, Corresponding coronary angiogram (arrow: stenosis of diagonal branch with 76% diameter reduction, reference diameter 2.5 mm). E, 3-dimensional reconstruction of the heart and coronary arteries in a patient without coronary artery stenoses. F, Corresponding coronary angiogram (in E and F, large arrow: LAD coronary artery, small arrow: diagonal branch, arrowhead: left circumflex coronary artery). Source: Achenbach et al. (2001). BACKGROUND. This is an early report on the potential value of MSCT angiography compared to conventional coronary angiography. Thirty-five patients were studied, including 11 who had undergone percutaneous transluminal coronary angioplasty and four who had had coronary-artery bypass grafts. MSCT Technique: 4×1 mm collimation; total scan time was between 30 and 40 seconds; 150 mls of

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Fig. 17.7 Left anterior projection with cranial angulation by MSCT coronary angiography (A) and conventional coronary angiography (B). Source: Nieman et al. (2001). contrast was injected; retrospective ECG gating was used; multiplanar reconstructions were performed. The proximal and middle segments of the coronary-artery tree were investigated. In the 31 patients without previous coronary surgery, 173 (73%) of the 237 proximal and middle coronary segments were assessable. In the assessable segments, 17 of 21 significant stenoses (>50% reduction of vessel diameter) were correctly diagnosed. The non-assessable segments included four lesions. The segments of the left main and left anterior descending arteries were visualized in most cases (90%), and six of eight stenoses were correctly detected. Visualization of the right coronary artery was more sensitive to motion artefacts, which resulted in a lower proportion of interpretable segments (71%). Nevertheless, all seven lesions were correctly diagnosed. The left circumflex artery was the most difficult to examine mainly due to its small size and adjacent contrast-filled structures such as the great cardiac vein and the left atrium. Only 51% of the circumflex segments were assessable, and two of four stenoses were detected. Misinterpretations were also the result of severe calcification of the vessel wall. Segments with implanted stents were poorly visualized, but spent patency could be assessed in all cases. Fifteen of the 17 segments of bypass grafts were assessable and four of five grafts lesions were detected. Two cases of anomalous coronary anatomy could be visualized. INTERPRETATION. MSCT allows non-invasive imaging of coronary artery stenoses and has the potential to develop into a reliable clinical technique.

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Comment This study, like the previous one, demonstrates the need for increased temporal resolution to reduce coronary motion artefact. The presence of extensive calcification also complicates assessment of the lumen of the coronary arteries. Intracoronary stents present imaging problems due to high-density artefact, however, patency can be assessed if enhancement by contrast medium is observed in the vessel segment distal to the stent. There are also some inherent problems with CT angiography using EBCT, as the in-plane spatial resolution is slightly lower than in MSCT. The entire heart cannot be covered when a 1.5 mm slice thickness is used. The entire heart can be covered with a 3 mm protocol at the cost of a reduction in Z-axis resolution. By comparison, magnetic resonance coronary angiography is still hampered by poor spatial resolution, long scan times and motion artefacts, image degradation by metallic stents and sternal wires, and other contra-indications to magnetic resonance imaging. For these reasons, non-invasive coronary angiography methods are unlikely to replace conventional coronary angiography in the near future for diagnosis of obstructive CAD. Nevertheless, as discussed in the previous study, exciting technical developments proposed for MSCT in the near future could change this situation. If these non-invasive methods, demonstrate the ability to reliably rule out the presence of significant coronary stenoses in those segments of the coronary arteries that would be potential targets for revascularization therapy, they may be useful to avoid ‘negative’ invasive coronary angiograms in selected patient groups |6|. Non-invasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography. S Schröder, A F Kopp, A Baumbach, et al. J Am Coll Cardiol 2001; 37(5): 1430–5. BACKGROUND. The risk of acute coronary syndromes caused by plaque disruption and thrombosis depends on plaque composition rather than stenosis severity. The reliable non-invasive assessment of plaque configuration would constitute an important step forward for risk stratification in patients with known or suspected CAD. The aim of this study was to evaluate the accuracy of the determination of coronary plaque configuration by MSCT. The results were compared with the findings of intracoronary ultrasound (ICUS). Fifteen patients with chronic stable angina due to at least one high-grade stenosis in the LAD or right coronary artery were included in this prospective study. The patients were scheduled for ICUS-guided percutaneous transluminal coronary angioplasty. Plaque composition was analysed according to ICUS criterion (plaque echogenicity: soft, intermediate, calcified) and MSCT criteria (plaque density expressed by Hounsfield Units [HU]). Thirtyfour plaques were analysed. With ICUS, 12 plaques were classified as soft, five as intermediate, and 17 as calcified. The density of these thirty-four plaques was measured in the MSCT angiogram studies. Soft plaques had a density of 14±26 HU, intermediate plaques had a density of 91±21 HU and calcified plaques had a density of 419±194 HU. There was no overlap in the mean density values among the three groups of plaques. Soft plaques with a presumably lipid-rich core might therefore be identified by density values less than 50 HU.

INTERPRETATION. The characterization of coronary lesion configuration, which is presently the domain of ICUS, might be reliably performed by non-invasive MSCT. Since rupture-prone soft plaques can be detected by MSCT, this non-invasive method might become an important diagnostic tool for risk stratification in patients with known or suspected CAD.

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Fig. 17.8 Conventional and MSCT angiography of LAD artery. Source: Nieman et al. (2001).

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Fig. 17.9 Conventional coronary angiography (A, B, C) and MSCT angiography (D, E) of a patient with previous coronary-artery bypass grafting. Source: Nieman et al. (2001).

Comment MSCT angiography offers the possibility to differentiate plaque configuration noninvasively with a high accuracy. There is a strong correlation of tissue density measurements within the plaque and the qualitative ultrasound classification of soft, intermediate and calcified plaque. Identifying plaque morphology, in particular the early detection of rupture-prone soft plaques, would be extremely useful in assessing future risk of hard cardiac events in patients with known or suspected CAD. This technology also offers the possibility to monitor plaque stabilization in patients receiving lipid-lowering therapy. Conclusion The search for more effective screening strategies for CAD is mostly attributable to the low sensitivity and specificity of currently available tests. Testing based on functional assessment has a reasonably good predictive value, but depends on the presence of significant coronary luminal narrowing for diagnosis and is therefore not useful for early detection of subclinical CAD in high risk subjects. A significant proportion of

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Fig. 17.10 Soft plaque as assessed by MSCT and ICUS. Source: Schröder et al. (2001).

Fig. 17.11 Intermediate plaque as assessed by MSCT and ICUS. Source: Schröder et al. (2001).

myocardial infarctions are due to rupture of non-obstructive atherosclerotic plaques that would not be detected by any functional test. The most valuable use of CACS in symptomatic patients is to exclude CAD in those patients with a negative test. A calcium score of zero excludes CAD with an accuracy greater than any other non-invasive test. Further cardiac diagnostic tests can be avoided in most patients with associated cost savings |7|. Patients with a high calcium score of >400 have a high incidence of obstructive disease. The requirements for an ideal screening test for coronary atherosclerosis were discussed in an editorial in the New England Journal of Medicine |8|. These requirements are that the test:

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Fig. 17.12 Calcified plaque as assessed by MSCT and ICUS. Source: Schröder et al. (2001).

Fig. 17.13 Comparison of plaque configuration and plaque density. Source: Schröder et al. (2001).

1. 2. 3. 4. 5.

be safe and inexpensive; be non-invasive or minimally invasive; be reliable and reproducible; correlates with the extent of atherosclerosis; has a high positive and negative predictive value for clinical events.

CACS appears to meet all of these criteria with some qualifications, particularly regarding point no. 5 as there is still debate about the long-term prognostic value of coronary calcification (the article by Keelan et al. found that CACS is highly predictive of future hard cardiac events).

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As seen in several of the articles in this chapter, MSCT angiography of the coronary arteries is an exciting and promising field. With further development, it offers the potential to non-invasively identify significant coronary stenoses and differentiate plaque morphology. With the large number of installed MSCT and EBCT scanners throughout the world and the rapid technological improvements in cardiac imaging with MSCT, it is to be hoped that this technology can assist in cardiovascular disease screening, and reduce the impact of cardiovascular disease on our society and worldwide. References and further reading 1.

2. 3. 4. 5. 6.

7. 8. 9. 10. 11.

Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium areas by electron beam computed tomography and coronary atherosclerotic plaque area: a histopathologic correlative study. Circulation 1995; 92:2157–62. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. New Engl J Med 1987; 316: 1371–5. Stanford W. Coronary artery calcification as an indicator of preclinical coronary artery disease. Radiographics 1999; 19:1409–19. Raggi P. Coronary calcium on electron beam tomography imaging as a surrogate marker of coronary artery disease. Am J Cardiol 2001; 87(4A):27A–34A. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15:827–32. Achenbach S, Ropers D, Regenfus M, Pohle K, Giesler T, Moshage W, Daniel WG. Non-invasive coronary angiography by magnetic resonance imaging, electron-beam computed tomography, and multislice computed tomography. Am J Cardiol 2001; 88 (2-A):70E–73E. Janowitz WR. CT imaging of coronary artery calcium as an indicator of atherosclerotic disease: an overview. J Thoracic Imaging 2001; 16(1):2–7. Celermajer DS. Non-invasive detection of atherosclerosis. N Engl J Med 1998; 329: 2014–15. Janowitz WR. Current status of mechanical computed tomography in cardiac imaging. Am J Cardiol 2001; 88(2A):35E–38E. Thompson BH, Stanford W. Imaging of coronary calcium: a case for electron beam computed tomography. J Thoracic Imaging 2001; 16(1):8–15. Carr JJ. Coronary Calcium. The Case for helical computed tomography. J Thoracic Imaging 2001; 16(1):16–24.

Section conclusion Review of this breaking data from imaging techniques complementary to angiography highlights the pace of change of technology. Our ability to image the heart and its function have changed dramatically and the situation is akin to opening Pandora’s box on many long standing clinical conundrums. These may include unlocking the mutifactorial causes behind the no-reflow phenomenon, which is seen particularly during intervention in degenerate coronary vein grafts and during salvage angioplasty, determining the mechanisms involved in acute ischaemic mitral regurgitation and optimizing strategies to release hibernating myocardium. MRI appears to be particularly poised to provide supplementary data in many clinical scenarios associated with ischaemic heart disease. Accurate and reproducible measurement of left ventricular mass and volume will help investigators to answer questions using information from much smaller groups of patients. The ability of MRI to detect plaque and particularly plaque composition in a reproducible way will facilitate drug development and additive secondary prevention measures. Combining data on flow with

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anatomical detail will reduce the need for diagnostic catheterization and performing interventional procedures under MRI guidance rather then X-ray screening seems likely in the future. Although CT scanning uses ionizing radiation it does appear that its ability to detect coronary calcification may be on the verge of clinical applicability as a screening test. Using a CT scan to rule out coronary disease may become a standard strategy rather than exercise testing in the outpatient assessment of patients with chest pain. Appreciation of the potential for MRI and CT particularly, appears to threaten the role of echocardiography as the most commonly used imaging technique. How-ever, major developments in echocardiography combined with its key asset—its ability to image a patient anywhere—are likely to maintain its key role. Certainly the development of perfusion imaging and 3D echocardiography are likely to expand indications for echocardiography and once 3D imaging can be provided in real time, it is conceivable that this may become the standard initial imaging technique for the majority of patients. Developments in these other techniques are likely to reduce the number of patients undergoing investigation with nuclear techniques. Increasingly the role of nuclear cardiology is likely to be restricted to answering specific research based questions but developments like technetium labelling of annexin V to measure the extent of cell death and apoptosis show that it will continue to have a role particularly in the assessment of viability and hibernation. After some years of ‘false starts’ we do appear to be on the verge of a major breakthrough in the management of ischaemic heart disease. These imaging modalities offer the essential tools to facilitate translation of data from the basic science laboratory bench into clinical practice. Translating these data into improvements in quality of life and prognosis are the challenge for clinical researchers in the next decade.

Part VI Contrast agents in interventional cardiology

18 Recent trial results

Introduction Over the past decade there has been an ongoing discussion about which type of contrast medium should be used in patients undergoing coronary interventions. Nowadays both ionic (dimeric strucure) and non-ionic (monomeric structure) low-osmolality contrast media are used in clinical routine. Recently, an isoosmolar non-ionic dimer has become available, while ionic monomeric, high-osmolality contrast media have been completely replaced in most countries. From 1991–2000, ten randomized studies comparing the effects of non-ionic versus ionic contrast media have been published |1–10|. A total of 6249 patients have been included in these trials. Randomized trials In the very first trial from Emory University, Atlanta, 913 patients undergoing 1058 separate percutaneous transluminal coronary angioplasty (PTCA) procedures were prospectively randomized to receive either diatrizoate, an ionic monomer, or iopamidol, a non-ionic monomer |1|. The overall incidence of ventricular tachycardia or fibrillation, or both, during the procedure occurred more frequently when diatrizoate was used compared to iopamidol (2.5% vs 1.0%, P=0.045). In the following seven trials, ioxaglate, an ionic dimer, was compared to the nonionic monomers iopamidol, iohexol, and iomeron |2–8|. A total of 3115 patients were randomized in these trials. Due to historic reasons, no antiplatelet agents (like abciximab) were used and coronary stenting was performed in one study only. The pre-defined end-points varied considerably among the trials. According to the respective authors, ioxaglate seemed to be ‘better’ than the non-ionic contrast medium in five of these six studies |2–7|. In only one trial the non-ionic contrast medium, iomeron, performed ‘better’ |8|. However, there were no significant differences observed in the incidence of emergent bypass surgery, myocardial infarction, and cardiac death between both types of contrast media in any of these trials. Among the 1555 patients randomized to receive ioxaglate 17 patients underwent emergent bypass surgery, 24 patients suffered myocardial infarction, and 9 patients died. Among the 1555 patients receiving non-ionic contrast media, the respective numbers were 19 for emergent bypass surgery, 28 for myocardial infarction,

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Fig. 18.1 Meta-analysis of 10 randomized contrast media trials in patients undergoing PTCA: Incidence of emergency coronary artery bypass surgery (CABG), myocardial infarction (MI), cardiac death (Death), and combined major adverse cardiac events (MACE) in 3230 patients receiving ionic and 3164 patients receiving non-ionic contrast media.

and 8 for death. In total, major adverse cardiac events (MACE) occurred in 50 patients (3.2%) in the ionic contrast medium group and in 55 patients (3.5%) in the non-ionic contrast medium group. Recently, 2 studies were published comparing the ionic dimer ioxaglate 320 and the non-ionic dimer iodixanol 320: In the VIP-trial (Visipaque In PTCA) 1411 patients with stable (49%) or unstable (51%) angina were randomized |9|. There were no significant differences regarding the end-points death, stroke, myocardial infarction, emergent bypass surgery, and repeat-PTCA (ioxaglate 3.9%, iodixanol 4.7%; P=0.45). Two patients died in the ioxaglate group and there were no deaths in the iodixanol group. Contrast medium related adverse drug reactions were more frequent in the ioxaglate group (3.5% vs 1.0%; P=0.002). In the COURT trial (COntrast media Utilization in high-Risk PTCA Trial) 815 patients with acute myocardial infarction (33%), post-infarction ischaemia (13%), and unstable angina (54%) were randomized |10|. In-hospital major adverse cardiac events occurred more often in those receiving ioxaglate compared with those receiving iodixanol (9.5% vs 5.4%; P=0.027). There were, however, 5 deaths in the iodixanol group as opposed to one death in the ioxaglate group. Moreover, in the 345 patients receiving abciximab, the composite primary clinical outcomes occurred in 18 (10.5%) of the iodixanol cohort and in 20 (11.5%) of the ioxaglate cohort (P=0.77). A meta-analysis of the 10 randomized studies comparing the effects of non-ionic versus ionic contrast media in patients undergoing PTCA that have been performed and published during the recent decade is shown in Fig. 18.1. A total of 6249 patients were enrolled. However, there were no significant differences observed in the incidence of emergent bypass surgery (non-ionic vs ionic, 1.3% vs 1.1%), myocardial infarction (3.0% vs 3.1%), and cardiac death (0.4% vs 0.4%) between both types of contrast media in any of these trials. The incidence of these endpoints combined (major adverse cardiac events) was 4.6% in the ionic as opposed to 4.7% in the non-ionic group. None of these differences between the contrast medium groups was significant. Trials from the year 2001 A study with a unique design was published by Scheller et al. |11|. A total of 3990 consecutive patients were enrolled over an inclusion period of 4.5 years. In all patients, diagnostic coronary angiography was performed using various non-ionic contrast media (5 monomers and 1 dimer). For the interventional procedure, the patients received either the same non-ionic contrast medium or ioxaglate, depending on the daily availability in the allocated cathlab room. Both acute and subacute stent occlusion occurred more

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frequently in the non-ionic (i.e. 5 monomers, 1 dimer) group (acute: 1.3% vs 0.3%, P=0.001; subacute: 2.4% vs 0.7%, P=0.001). Within 12 months, the incidence of the combined clinical end-point (coronary artery bypass graft (CABG), target vessel revascularization, overall mortality) was significantly reduced in the ionic (i.e. non-ionic/ionic) group (22.9% vs 16.3%, P=0.001). Due to the unique design with sequential contrast medium use, it seems to be difficult to attribute the clinical differences observed to a specific contrast medium. Neither Scheller nor Legrand in his related editorial |12| discussed the theoretical and pharmacological problems arising from ‘contrast medium mixture’ during coronary angiography and intervention. This trial leaves us with the question whether it is scientifically sound to compare data from patients receiving various non-ionic contrast media and patients receiving a mixture of non-ionics and ioxaglate. However, the trial prompted an interesting debate in the ‘letters to the editor’ section of the European Heart Journal: Batchelor |13| gave another interpretation of the COURT data, stating that the difference between the iodixanol and the ioxaglate group might be attributable to the higher procedural success rate (92% vs 86%, P=0.004) in the former and a more frequent use of laser or directional coronary atherectomy (3% vs 12%, P=0.039) in the latter cohort of patients. In a reply to Schräder’s letter |14|, Scheller explained in detail the unique features of his protocol of sequential use of contrast media. According to his theory, the non-ionic contrast medium that had been used during the initial diagnostic procedure should have undergone systemic dilution and excretion via the kidneys at the time of a subsequent coronary intervention |15|. However, it has been demonstrated that the effects of contrast media on blood and plasma volume may last for up to 60 minutes |16|. Therefore, the interventional cardiologist either has to wait almost an hour before starting the interventional procedure or he or she has to accept that ‘sequential use’ of contrast media results in a mixture of different types of contrast media within the intravascular compartment. Sutton et al. reported the incidence of early and late reactions after use of different contrast media in patients undergoing cardiac catheterization |17|. Early reactions occurred in 22.2% of those receiving ioxaglate, 7.6% of those receiving iodixanol, and 8.8% of those receiving iopamidol (P<0.0001). Late skin reactions occurred in 12.2% of those receiving iodixanol, 4.3% of those receiving ioxaglate, and 4.2% of those receiving iopamidol (P<0.0001). The authors concluded that there are significant differences between contrast agents used in diagnostic cardiac catheterization. These should be taken into account when selecting an agent and when obtaining informed patient consent. Conclusion A meta-analysis of ten randomized trials reveals no clinically significant correlation between the type of contrast medium and major adverse cardiac events after percutaneous coronary interventions. Due to methodological problems, the clinical value of ‘sequential contrast medium use’ remains open to debate. Non-ionic monomers reduce the risk of both early and late adverse drug reactions while non-ionic dimers increase the incidence of late skin reactions. Meanwhile, we should not forget the main purpose of iodinized contrast media in the catheterization laboratory: excellent opacification of the coronary arteries is an important prerequisite of excellent clinical results in interventional cardiology. Therefore, an ideal contrast medium should provide the highest diagnostic quality together with the lowest rate of side-effects. References 1.

Lembo NJ, King SB III, Roubin GS, Black AJ, Douglas JS Jr. Effects of non-ionic versus ionic contrast media on complications of percutaneous transluminal coronary angiophsty. Am J Cardiol 1991; 67:1046–50.

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4.

5.

6.

7.

8.

9.

10.

11. 12. 13. 14. 15. 16.

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Esplugas E, Cequier A, Jara F, Mauri J, Soler T, Sala J, Sabate X. Risk of thrombosis during coronary angioplasty with low osmolality contrast media. Am J Cardiol 1991; 68: 1020–4. Piessens JH, Stammen F, Vrolix MC, Glazier JJ, Benit E, De Geest H, Willems JL. Effects of an ionic versus a non-ionic low osmolar contrast agent on the thrombotic complications of coronary angioplasty. Cathet Cardiovasc Diagn 1993; 28:99–105. Lefevre T, Bernard A, Bertrand M, Lablanche JM, Cequier A, Espuglas E, Gayet JL, Gosselin G, Bonan R. Comparison by scanning electron microscopy of the antithrombotic potential of two low osmolality iodine contrast media during percuataneous coronary angioplasty. Arch Mal Coeur 1994; 87:225–33. Grines CL, Schreiber TL, Savas V, Jones DE, Zidar FJ, Gangadharan V, Brodsky M, Levin R, Safian R, Puchrowicz-Ochocki S, Castellani MD, O’Neill WW. A randomized trial of low osmolar ionic versus non-ionic contrast media in patients with myocardial infarction or unstable angina undergoing percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1996; 27:1381–6. Qureshi NR, den Heijer P, Crijns HJGM. Percutaneous coronary angioscopic comparison of thrombus formation during percutaneous coronary angioplasty with ionic and non-ionic low osmolality contrast media in unstable angina. Am J Cardiol 1997; 80: 700–4. Malekianpour M, Bonan R, Lespérance J, Gosselin G, Hudon, Doucet S, Laurier J, Duval D. Comparison of ionic and non-ionic low osmolar contrast media in relation to thrombotic complications of angioplasty in patients with unstable angina. Am Heart J 1998; 135:1067–75. Schräder R, Esch I, Ensslen R, Fach WA, Merle H, Scherer D, Sievert H, Spies HF, Zeplin HE. A randomized trial comparing the impact of a non-ionic (iomeprol) versus an ionic (ioxaglate) low osmolar contrast medium on abrupt vessel closure and ischemic complications after coronary angioplasty. J Am Coll Cardiol 1999; 33: 395–402. Bertrand ME, Esplugas E, Piessens J, Rasch W, for the Visipaque in Percutaneous Transluminal Coronary Angioplasty (VIP) Trial Investigators. Influence of a non-ionic, ios-osmolar contrast medium (iodixanol) versus an ionic, low-osmolar contrast medium (ioxaglate) on major adverse cardiac events in patients undergoing percutaneous transluminal coronary angioplasty. Circulation 2000; 101:131–6. Davidson CJ, Laskey WK, Hermiller JB, Harrison JK, Matthai W Jr, Vlietstra RE, Brinker JA, Kereiakes DJ, Muhlestein JB, Lansky A, Popma JJ, Buchbinder M, Hirshfeld JW Jr. Randomized trial of contrast media utilization in high-risk PTCA. The COURT trial. Circulation 2000; 101:2172–77. Scheller B, Hennen B, Pohl A, Schieffer H, Markwirth T. Acute and subacute stent occlusion—risk reduction by ionic contrast media. Eur Heart J 2001; 22:385–391. Legrand V. Ionic or non-ionic contrast media during coronary intervention: does it make a difference? Eur Heart J 2001; 22:353–4. Batchelor WB. From COURT to HOMBURG: in search of the optimal contrast agent. Eur Heart J 2001; 22: 2026–8. Schräder R. Ionic or non-ionic contrast media in stent placement. Eur Heart J 2001; 22: 2029. Scheller B. A reply. Eur Heart J 2001; 22:2029–31. Schräder R, Geigle P, Lemperle M, Fischer H, Kober G, Kaltenbach M. Veränderungen des Blut-und Plasmavolumens während einer diagnostischen Angiokardiographie. Unterschiede zwischen Kontrastmitteln mit hoher und niedriger Osmolalität. Dtsch Med Wschr 1991; 116:1937–42. Sutton AG, Finn P, Grech ED, Hall JA, Stewart MJ, Davies A, de Belder MA. Early and late reactions after the use of iopamidol 340, ioxaglate 320, and iodixanol 320 in cardiac catheterization. Am Heart J 2001; 141:677–83.

Abbreviations

2D echo 3D echo ABI ACAS ACC ACE ACT ADMIRAL ADP AHA AI AII AMI ARB ARTIST ARTS AS ASAT AT BARI BNP BP CAAS CABG CACS CAD CAPRIE CAPS

two-dimensional echocardiography three-dimensional echocardiography Ankle-brachial index Asymptomatic Carotid Atherosclerosis Study American College of Cardiology angiotensin-converting enzyme activated clotting time Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up adenosine diphosphate American Heart Association acceleration index accelerated intermittent imaging acute myocardial infarction angiotensin receptor antagonist Angioplasty versus Rotational atherectomy for Treatment of diffuse In-Stent Restenosis Arterial Revascularization Therapy Study aortic stenosis aspartate aminotransferase antithrombin Bypass Angioplasty Revascularization Investigation B-type natriuretic peptide blood pressure carotid artery angioplasty with stenting coronary artery bypass graft coronary artery calcium scoring coronary artery disease Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events carotid angioplasty-stenting

262

ABBREVIATIONS

CAPTURE CARESS CART-1 CAS CAVATAS CBA CBAS CCU CD CDK CEA CHF CI CK CLASSICS CMMP CMR COPD COURT CREST CRF CRP CRUISE CS CSA CSG CT CTA CURE CVA CVD CX DbE DCA DEX DSE DU EASI

c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina Carotid Revascularization with Endarterectomy or Stenting Systems Canadian antioxidant restenosis trial carotid artery stenting Carotid and Vertebral Artery Transluminal Angioplasty Study cutting balloon angioplasty carotid bifurcation angioplasty and stenting coronary care unit cardiac death cyclin-dependent kinase carotid endarterectomy congestive heart failure confidence interval creatine kinase CLopidogrel ASpirin Stent International Cooperative Study Carport, Mercator, Marcator, and Park studies cardiovascular MR chronic obstructive pulmonary disease COntrast media Utilization in high-Risk PTCA Trial Carotid Revascularization Endarterectomy versus Stent Trial chronic renal failure C-reactive protein Can Routine Ultrasound Influence Stent Expansion carotid stenting cross sectional areas chondroitin sulphate and gelatine computed tomography computed tomographic angiography Clopidogrel in Unstable angina to prevent Recurrent Events cerebrovascular accident cerebrovascular disease circumflex coronary artery dobutamine echocardiography directional atherectomy dexamethasone dobutamine stress echocardiography duplex ultrasonography European Antiplatelet Stent Investigation

ABBREVIATIONS

EBCT ECG EDV EF ELCA EPILOG EPISTENT ESPRIT ESRD ESV FDG FI FRISC GFR GP GUSTO HACA HD HDR HF HLA HU IABP ICA ICUS IDE IMA INHIBIT IRT ISES ISR IVUS LAD LARS LCX LDL

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electron beam CT electrocardiogram end-diastolic volume ejection fraction excimer laser atherectomy Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa blockade Evaluation of Platelet IIb/IIIa Inhibition in Stenting Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy end-stage renal disease end-systolic volume fluorodeoxyglucose fundamental imaging Fast Revascularization during InStability in Coronary artery disease glomerular filtration rate glycoprotein Global Utilization of Streptokinase and Tpa to Open arteries Global Use of Strategies To Open Occluded Coronary Arteries human antichimeric antibody high dose high dose rate heart failure human leucocyte antigen Hounsfield units intra-aortic balloon pump internal carotid artery intracoronary ultrasound investigational device exemption internal mammary artery INtimal Hyperplasia Inhibition with Beta In-stent Trial intracoronary radiation therapy International Society of Endovascular Specialists in-stent restenosis intravascular ultrasound left anterior descending laser angioplasty for restenotic stents left circumflex low density lipoprotein

264

ABBREVIATIONS

LIMA LMCA LV LVM LVOT MACE MATE MCE MCP-1 MDGI MI MIR MITI MITRA MLD MR MR MRA MRI MSCT mTOR MUSIC NASCET NICE NO NQMI NYHA OASIS OPTICUS OPUS OR PAMI PARAGON PARIS PCI PCI-CURE PC-MRI

left interior mammary artery left main coronary artery left ventricular left ventricular mass left ventricular outflow tract major adverse cardiac event Medicine versus Angiography in Thrombolytic Exclusion myocardial contrast echocardiography monocyte chemoattractant factor mammary-derived growth inhibitor myocardial infarction Myocardial Infarction Registry Myocardial Infarction Triage and Intervention Maximal Individual Therapy in acute myocardial infarction Registry minimal luminal diameter mitral regurgitation magnetic resonance magnetic resonance angiography magnetic resonance imaging multislice CT mammalian target of rapamycin Multicentre Ultrasound Stenting In Coronaries North American Symptomatic Carotid Endarterectomy Trial National Investigators Collaborating on Enoxaparin nitric oxide non-Q wave myocardial infarction New York Heart Association Organization to Assess Strategies for Ischaemic Syndromes OPTimization with ICUS to reduce stent restenosis Orbofiban in Patients with Unstable coronary Syndromes odds ratio Primary Angioplasty in Myocardial Infarction Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network Peripheral Artery Radiation Investigational Study percutaneous coronary intervention Clopidogrel in Unstable angina to prevent Recurrent Events trial phase contrast magnetic resonance imaging

ABBREVIATIONS

PCNA PET PM PRISM PTA PTCA PTRA PTRAS PVD QCA QTc RAS Rbp RCA REPLACE RESCUT RESTORE RIBS RLS RNV ROTA RR RT-3D SCRIPPS SD SDS SFA SHOCK SI SISA SMC SPECT SPLASH SRL ST START SVG

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proliferating cell nuclear antigen positron emission tomography papillary muscle Platelet Receptor inhibition in Ischaemic Syndrome Management percutaneous transluminal angioplasty percutaneous transluminal coronary angioplasty percutaneous transluminal renal artery angioplasty percutaneous transluminal renal artery angioplasty and stent placement peripheral vascular disease quantitative coronary angiography QT-corrective renal artery stenosis retinoblastoma protein right coronary artery Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events restenosis cutting balloon evaluation Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis Restenosis Intra-stent: Balloon angioplasty versus elective Stenting radioactive line source radionuclide ventriculography rotational atherectomy relative risk or risk ratio real-time three-dimensional echocardiography Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting standard deviation summed difference score superficial femoral artery SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK signal intensity Stent In Small Arteries smooth muscle cell single-photon-emission computed tomography Sonotherapy Prevention of Late Arterial in-Stent Hyperplasia sirolimus sinus tachycardia STents And Radiation Therapy saphenous vein graft

266

ABBREVIATIONS

SYNERGY TACTICS TIMI TARGET THI TIA TIMI TLR tPA TVR UA URV US VANQUISH VIP WM WRIST

Superior Yield of the New strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa trial Treat Angina with aggrastat and determine cost of Therapy with an Invasive or Conservative Strategy— Thrombolysis in Myocardial Infarction Do Tirofiban And ReoPro Give similar Efficacy Trial tissue harmonic imaging transient ischaemic attack Thrombolysis in Myocardial Infarction target lesion revascularization alteplase target vessel revascularization unstable angina urgent revascularization ultrasound Veterans Affairs Non-Q Wave Infarction Strategies in Hospital Visipaque In PTCA wall motion Washington Radiation for In-Stent restenosis Trial

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Index of Papers Reviewed

S Achenbach, T Giesler, D Ropers, S Ulzheimer, H Derlien, C Schulte, E Wenkel, W Moshage, W Bautz, WG Daniel, WA Kalender, U Baum. Detection of coronary artery stenoses by contrast-enhanced, retrospectively electrocardiographically-gated, multislice spiral computed tomography. Circulation 2001; 103(21):2535–8. 311 M Adamian, A Colombo, C Briguori, T Nishida, F Marsico, C Di Mario, R Albiero, I Moussa, JW Moses. Cutting balloon angioplasty for the treatment of in-stent restenosis: a matched comparison with rotational atherectomy, additional stent implantation and balloon angioplasty. J Am Coll Cardiol 2001; 38 (3):672–9. 203 M Ahmad, T Xie, M McCulloch, G Abreo, M Runge. Real-time three-dimensional dobutamine stress echocardiography in assessment stress echocardiography assessment of ischemia: comparison with two-dimensional dobutamine stress echocardiography. J Am Coll Cardiol 2001; 37(5):1303– 9. 271 JM Ahmed, GS Mintz, M Castagna, NJ Weissman, AD Pichard, LF Satler, KM Kent. Intravascular ultrasound assessment of the mechanism of lumen enlargement during cutting balloon angioplasty treatment of in-stent restenosis. Am J Cardiol 2001; 88 (9):1032–4. 205 JM Ahmed, GS Mintz, R Waksman, R Mehran, B Leiboff, AD Pichard, LF Satler, KM Kent, NJ Weissman. Serial intravascular ultrasound assessment of the efficacy of intracoronary gamma-radiation therapy for preventing recurrence in very long, diffuse, in-stent restenosis lesions. Circulation 2001; 104(8): 856–9. 224 N Al-Mubarak, GS Roubin, JJ Vitek, G New, SS lyer. Procedural safety and short-term outcome of

ambulatory carotid stenting. Stroke 2001; 32(10):2305– 9. 153 N Al-Saadi, E Nagel, M Gross, B Schnackenburg, I Paetsch, C Klein, E Fleck. Improvement of myocardial perfusion reserve early after coronary intervention: assessment with cardiac magnetic resonance imaging. J Am Coll Cardiol 2000; 36:1557– 64. 282 J Al-Suwaidi, JL Velianou, PB Berger, V Mathew, KN Garratt, GS Reeder, DE Grill, DR Holmes Jr. Primary percutaneous coronary interventions in patients with acute myocardial infarction and prior coronary artery bypass grafting. Am Heart J 2001; 142:452–9. 66 KM Anderson, RM Califf, GW Stone, FJ Neumann, G Montalescot, DP Miller, JJ Ferguson 3rd, JT Willerson, HF Weisman, EJ Topol. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2001; 37: 2059–65. 26 A Anzuini, C Briguori, GS Roubin, P Pagnotta, S Rosanio, F Airoldi, M Carlino, P Pagnotta, C Di Mario, I Sheiban, G Magnani, A Jannello, G Melissano, R Chiesa, A Colombo. Emergency stenting to treat neurological complications occurring after carotid endarterectomy. J Am Coll Cardiol 2001; 37(8): 2074–9. 154 F Bär, J Vainer, J Stevenhagen, K Neven, R Aalbregt, TO Ophuis, V van Ommen, H de Swart, E de Muinck, W Dassen, H Wellens. Ten-year experience with early angioplasty in 759 patients with acute myocardial infarction. J Am Coll Cardiol 2000; 36:51– 8. 89 JJ Bax, FC Visser, D Poldermans, A Elhendy, JH Cornel, E Boersma, R Valkema, A Van Lingen, PM Fioretti, CA Visser. Relationship between preoperative viability and post-operative improvement in

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LVEF and heart failure symptoms. J Nucl Med 2001; 42: 79–86. 252 CR Becker, T Kleffel, A Crispin, A Knez, J Young, UJ Schoepf, R Haberl, MF Reiser. Coronary artery calcium measurement: agreement of multirow detector and electron beam CT. Am J Roentgen 2001; 176:1295– 8. 302 NG Bellenger, LC Davies, JM Francis, AJ Coats, DJ Pennell. Reduction in sample size for studies of remodelling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000; 2 (4):271–8. 281 ME Bertrand, H-J Rupprecht, P Urban, AH Gershlick, FT Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000; 102: 624–9. 50 JJ Beutler, JM Van Ampting, PJ Van De Ven, HA Koomans, FJ Beek, AJ Woittiez, WP Mali. Longterm effects of arterial stenting on kidney function for patients with ostial atherosclerotic renal artery stenosis and renal insufficiency. J Am Soc Nephrol 2001; 12(7): 1475–81. 167 LF Bielak, PFII Sheedy, PA Peyser. Coronary artery calcification measured at electron beam CT: agreement in dual scan runs and change over time. Radiology 2001; 218(1):224–9. 301 JA Bittl, BR Chaitman, F Feit, W Kimball, EJ Topol. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952–9. 43 MJ Bloch, DA Trost, J Whitmer, TG Pickering, TA Sos, P August. Ostial renal artery stent placement in patients 75 years of age or older. Am J Hypertens 2001; 14(10):983–8. 168 RM Botnar, M Stuber, KV Kissinger, WY Kim, E Spuentrup, WJ Manning. Non-invasive coronary vessel wall and plaque imaging with magnetic resonance imaging. Circulation 2000; 102: 2582–7. 288 BR Brodie, GW Stone, MC Morice, DA Cox, E Garcia, LA Mattos, J Boura, WW O’Neill, TD Stuckey, S Milks, AJ Lansky, CL Grines; Stent Primary Angioplasty in Myocardial Infarction Study Group. Importance of time to reperfusion on outcomes of primary coronary angioplasty for acute myocardial infarction: results from the Stent Primary Angioplasty

in Myocardial Infarction (PAMI) Trial. Am J Cardiol 2001; 88:1085–90. 60 SD Buchthal, JA den Hollander, CN Bairey Merz, WJ Rogers, CJ Pepine, N Reichek, BL Sharaf, S Reis, SF Kelsey, GM Pohost. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med 2000; 342:829–35. 294 CP Cannon, WS Weintraub, LA Demopoulos, R Vicari, MJ Frey, N Lakkis, FJ Neumann, DH Robertson, PT DeLucca, PM DiBattiste, CM Gibson, E Braunwald; TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy) —Thrombolysis in Myocardial Infarction (TIMI) 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879–87. 33, 73 W Cantor, AS Hellkamp, ED Peterson, JP Zidar, PA Cowper, MH Sketch Jr, JE Tcheng, RM Califf, EM Ohman. Achieving optimal results with standard balloon angioplasty: can baseline and angiographic variables predict stent-like outcomes? J Am Coll Cardiol 2001; 37(7): 1883–90. 122 MT Castagna, GS Mintz, BO Leiboff, JM Ahmed, R Mehran, LF Satler, KM Kent, AD Pichard, NJ Weissman. The contribution of ‘mechanical’ problems to in-stent restenosis: an intravascular ultrasonographic analysis of 1090 consecutive in-stent restenosis lesions. Am Heart J 2001; 142(6):970–4. 198 EY Chakhtoura, RW Hobson 2nd, J Goldstein, GT Simonian, BK Lal, PB Haser, MB Silva Jr, FT Padberg Jr, PJ Pappas, Z Jamil. In-stent restenosis after carotid angioplasty-stenting: incidence and management. J Vasc Surg 2001; 33(2): 220–5; discussion 225–6. 155 DP Chew, DL Bhatt, AM Lincoff, DJ Moliterno, SJ Brener, KE Wolski, EJ Topol. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. Circulation 2001; 103:961–6. 38 ML Chuang, RA Beaudin, MF Riley, MG Mooney, WJ Mannin, PS Douglas, MG Hibberd. Threedimensional echocardiographic measurement of left ventricular mass: comparison with magnetic resonance imaging and two-dimensional echocardiographic

INDEX OF PAPERS REVIEWED

determinations in man. Int J Card Imaging 2000; 16(5): 347–57. 268 F Cipollone, M Marini, M Fazia, B Pini, A Iezzi, M Reale, L Paloscia, G Materazzo, E D’Annunzio, P Conti, F Chiarelli, F Cuccurullo, A Mezzetti. Elevated circulating levels of monocyte chemoattractant protein-1 in patients with restenosis after coronary angioplasty. Arterioscler Thromb Vasc Biol 2001; 21(3): 327–34. 178 R Corti, ZA Fayad, V Fuster, SG Worthley, G Helft, J Chesebro, M Mercuri, JJ Badimon. Effects of lipidlowering by simvastatin on human atherosclerotic lesions. A longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001; 104:249–52. 290 PK Coussement, HD Leon, T Ueno, MY Salame, SB King 3rd, NA Chronos, KA Robinson. Intracoronary β-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries. Circulation 2001; 104:2459–64. 217 I Crocker, M Joyal, T Fox, A Arsenault, R Bonan. Treatment of long, diffuse, in-stent restenotic lesions with beta radiation using strontium 90 and sequential positioning ‘pullback’ technique: procedural details and clinical outcomes. J Invasive Cardiol 2001; 13(12):782– 7. 223 FA Cura, PL l’Allier, SR Kapadia, PL Houghtaling, LM Dipaola, SG Ellis, EJ Topol, SJ Brener; on behalf of the GUSTO IIb and RAPPORT Investigators. Predictors and prognosis of suboptimal coronary blood flow after primary coronary angioplasty in patients with acute myocardial infarction. Am J Cardiol 2001; 88: 124–8. 61 G Dangas, JR Laird Jr, R Mehran, LF Satler, AJ Lansky, G Mintz, LH Monsein, R Laureno, MB Leon. Carotid artery stenting in patients with high-risk anatomy for carotid endarterectomy. J Endovasc Ther 2001; 8(1):39–43. 156 HL Dauerman, R Prpic, C Andreou, MA Vu, JJ Popma. Angiographic and clinical outcome after rescue coronary stenting. Cath and Cardiovasc Interv 2000; 50:269–75. 94 VS DeGeare, JA Boura, LL Grines, WW O’Neil, CL Grines. Predictive value of the Killip classification in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol 2001; 87: 1035–8. 64 JA de Lemos, DA Morrow, JH Bentley, T Omland, MS Sabatine, CH McCabe, C Hall, CP Cannon, E

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Braunwald. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345: 1014–21. 17 E Diderholm, B Andrén, G Frostfeldt, M Genberg, T Jernberg, B Lagerqvist, B Lindahl, Wallentin and the Fast Revascularization during InStability in Coronary artery disease (FRISC L 2nd). ST depression in ECG at entry indicates severe coronary lesions and large benefits of an early invasive treatment strategy in unstable coronary artery disease. The FRISC II ECG substudy. Eur Heart J 2002; 23:41–9. 78 S Doucet, MJ Schalji, MC Vrolix, D Hilton, P Chenu, B de Bruyne, W Udayachalerm, A Seth, L Bilodeau, JH Reiber, F Harel, J Lesperance, for the Stent In Small Arteries (SISA) Trial investigators. Stent placement to prevent restenosis after angioplasty in small coronary arteries. Circulation 2001; 104:2029–33. 121 ER Edelman, P Seifert, A Groothuis, A Morss, D Bornstein, C Rogers. Gold-coated NIR stents in porcine coronary arteries. Circulation 2001; 103:429– 34. 144 M Edep, D Brown. Effect of early revascularization on mortality from cardiogenic shock complicating acute myocardial infarction in California. Am J Cardiol 2000; 85:1185–8. 101 S Ellis, E Ribero da Silva, C Spaulding, M Nobuyoshi, B Weiner, JD Talley. Review of immediate angioplasty after fibrinolytic therapy for acute myocardial infarction: insights from the rescue 1, rescue 2, and other contemporary clinical experiences. Am Heart J 2000; 136(6):1046–53. 93 The ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. Lancet 2000; 356:2037–44. 28 A Farb, PF Heller, S Shroff, L Chneg, FD Kolodgie, AJ Carter, DS Scott, J Froehlich, R Virmani. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation 2001; 104: 473–9. 140 S Flacke, S Fischer, MJ Scott, RJ Fuhrhop, JS Allen, M McLean, P Winter, GA Sicard, PJ Gaffney, SA Wickline, GM Lanza. Novel MRI contrast agent for molecular imaging of fibrin: implications for detecting vulnerable plaques. Circulation 2001; 104: 1280–5. 292 G Geroulakos, C Missouris, A Mitchell, RM Greenhalgh. Endovascular treatment of renal artery stenosis. J Endovasc Ther 2001; 8(2):177–85. 169

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E Giannitsis, M Muller-Bardorff, S Lehrke, U Wiegand, R Tolg, B Weidtmann, F Hartmann, G Richardt, HA Katus. Admission troponin T level predicts clinical outcomes, TIMI flow, and myocardial tissue perfusion after primary percutaneous intervention for acute ST-segment elevation myocardial infarction. Circulation 2001; 104:630–5. 9 G Gimelli, A Kaldry, M Sabatine, I Jang. Primary versus rescue percutaneous coronary intervention in patients with acute myocardial infarction. Acta Cardiol 2000; 55(3):187–92. 97 S Giri, S Ito, AJ Lansky, R Mehran, J Margolis, P Gilmore, KN Garratt, F Cummins, J Moses, P Rentrop, S Oesterle, J Power, KM Kent, LF Satler, AD Pichard, H Wu, A Greenberg, TA Bucher, W Kerker, AS Abizaid, J Saucedo, MB Leon, JJ Popma. Clinical and angiographic outcome in the laser angioplasty for restenotic stents (LARS) multicenter registry. Catheter Cardiovasc Interv 2001; 52(1):24–34. 200 R Goldberg, J Gore, C Thompson, J Gurwitz. Recent magnitude of and temporary trends (1994–1997) in the incidence and hospital death rates of cardiogenic shock complicating acute myocardial infarction: the second National Registry of Myocardial Infarction. Am Heart J 2001; 141(1):65–71. 108 SL Goldberg, A Loussararian, J De Gregorio, C Di Mario, R Albiero, A Colombo. Predictors of diffuse and aggressive intra-stent restenosis. J Am Coll Cardiol 2001; 37(4):1019–25. 196 E Grube, T Felderhoff, PJ Fitzgerald, et al. Genetic manipulation of human coronary artery bypass grafts with E2F decoy (GT003) reduces graft failure. Results of the random-ized, controlled prevent II trial AHA scientific sessions, late breaking trial presentation. Anaheim, California, Nov 12, 2001. 185 L Gruberg, R Waksman, AE Ajani, HS Kim, RL White, E Pinnow, R Deible, LF Satler, AD Pichard, KK Kent, J Lindsay Jr. The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with chronic renal failure. J Am Coll Cardiol 2001; 38(4):1049–53. 226 R Haberl, A Becker, A Leber, A Knez, C Becker, C Lang, R Bruning, M Reiser, G Steinbeck. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1764 patients. J Am Coll Cardiol 2001; 37(2): 451–7. 304

M Handke, DM Schafer, G Heinrichs, E Magosaki, G Lutter, P Dern, C Bode, A Geibel. Improved 3Dechocardiographic endocardial border delineation using the contrast agent FS069 (Optison(R)): transoesophageal studies in a porcine model. Ultrasound Med Biol 2001; 27(9): 1185–90. 269 JS Hochman, LA Sleeper, HD White, V Dzavik, SC Wong, V Menon, JG Webb, R Steingart, MH Picard, MA Menegus, J Boland, T Sanborn, CE Buller, S Modur, R Forman, P Desvigne-Nickens, AK Jacobs, JN Slater, TH LeJemtel; SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) Investigators. One-year survival following early revascularization for cardiogenic shock. J Am Medical Ass 2001; 285(2): 190–2. 106 R Hoffmann, C Jansen, A König, PK Haager, G Kerckhoff, J Vom Dahl, V Klauss, P Hanrath, H Mudra. Stent design related neointimal tissue proliferation in human coronary arteries: an intravascular ultrasound study. Eur Heart J 2001; 22: 2007–14. 130 L Hofstra, IH Liem, EA Dumont, HH Boersma, WL van Heerde, PA Doevendans, E De Muinck, HJ Wellens, GJ Kemerink, CP Reutelingsperger, GA Heidendal. Visualization of cell death in vivo in patients with acute myocardial infarction. Lancet 2000; 356: 209–12. 254 D Holmes. PRESTO (Prevention of restenosis with tranilast and its outcomes) Trial. AHA scientific sessions, late breaking trials. Anaheim, California, 2001. 187 WG Hundley, LD Hillis, CA Hamilton, RJ Applegate, DM Herrington, GD Clarke, GA Braden, MS Thomas, RA Lange, RM Peshock, KM Link. Assessment of coronary arterial restenosis with phasecontrast magnetic resonance imaging measurements of coronary flow reserve. Circulation 2000; 101: 2375– 81. 287 P Jong, EA Cohen, W Batchelor, C Lazzam, C Kreatsoulas, MK Natarajan, BH Strauss. Bleeding risks with abciximab after full-dose thrombolysis in rescue or urgent angioplasty for acute myocardial infarction. Am Heart J 2001; 141(2):218–25. 92 GL Kaluza, AE Raizner, W Mazur, DG Schulz, JM Buergler, LF Fajardo, FO Tio, NM Ali. Long-term effects of intracoronary ß-radiation in balloon-and stentinjured porcine coronary arteries. Circulation 2001; 103:2108–13. 218

INDEX OF PAPERS REVIEWED

A Kastrati, J Mehilli, J Dirschinger, F Dotzer, H Schühlen, FJ Neumann, M Fleckenstein, C Pfafferott, M Seyfarth, A Schömig. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation 2001; 103:2816–21 132 P Kaul, Y Fu, W-C Chang, RA Harrington, GS Wagner, SG Goodman, CB Granger, DJ Moliterno, F Van de Werf, RM Califf, EJ Topol, PW Armstrong; PARAGON-A and GUSTO IIb Investigators. Platelet IIb/IIIa antagonism for the reduction of acute global organization network. Prognostic value of ST segment depression in acute coronary syndromes: insights from PARAGON-A applied to GUSTO-IIb. J Am Coll Cardiol 2001; 38:64– 71. 6 PC Keelan, LF Bielak, K Ashai, LS Jamjoum, AE Denktas, JA Rumberger, PF Sheedy II, PA Peyser, RS Schwartz. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation 2001; 104(4):412–7. 309 DJ Kereiakes, C Grines, E Fry, P Esente, D Hoppensteadt, M Midei, L Barr, W Matthai, M Todd, T Broderick, R Rubinstein, J Fareed, E Santoian, A Neiderman, B Brodie, J Zidar, JJ Ferguson, M Cohen; NICE 1 and NICE 4 Investigators. National Investigators Collaborating on Enoxaparin. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invas Cardiol 2001; 13: 272–8. 40 DJ Kereiakes, NS Kleiman, E Fry, G Mwawasi, R Lengerich, K Maresh, ML Burkert, JW Aquilina, M DeLoof, TM Broderick, TM Shimshak. Dalteparin in combination with abciximab during percutaneous coronary intervention. Am Heart J 2001; 141:348–52. 42 F Kiemeneij, P Serruys, C Macaya, W Rutsch, G Heyndrickx, P Albertsson, J Fajadet, V Legrand, P Materne, J Belardi, U Sigwart, A Colombo, JJ Goy, CM Disco, MA Morel. Continued benefit of coronary stenting versus balloon angioplasty: five-year clinical follow up of Benestent-I trial. J Am Coll Cardiol 2001; 37(6): 1598–1603. 116 RS Kiesa, P Buszman, JL Martin, E Deutsch, MM Rozek, E Gaszewska, M Rewicki, P Seweryniak, M Kosmider, M Tendera. Local delivery of enoxaparin to decrease restenosis after stenting: results of initial multicentre trial. Circulation 2001; 103:26–31. 184

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RJ Kim, E Wu, A Rafael, EL Chen, MA Parker, O Simonetti, FJ Klocke, RO Bonow, RM Judd. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000; 343:1445–53. 284 WY Kim, P Sogaard, H Egeblad, NT Andersen, B Kristensen. Three-dimensional echocardiography with tissue harmonic imaging shows excellent reproducibility in assessment of left ventricular volumes. J Am Soc Echocardiogr 2001; 14(6):612–7. 266 WY Kim, P Sogaard, B O Kristensen, H Egeblad. Measurement of left ventricular volumes by 3dimensional echocardiography with tissue harmonic imaging: a comparison with magnetic resonance imaging. J Am Soc Echocardiogr 2001; 14(3):169–79. 267 W Y Kim, P Sogaard, P T Mortensen, H K Jensen, A K Pedersen, BO Kristensen, H Egeblad. Threedimensional echocardiography documents haemodynamic improvement by biventricular pacing in patients with severe heart failure. Heart 2001; 85(5): 514–20. 270 R Koning, H Eltchaninoff, P Commeau, K Khalife, M Gilard, J Lipiecki, P Coste, M Bedossa, T Lefevre, P Brunel, MC Morice, L Maillard, P Guyon, J Puel, A Cribier; BESMART (BeStent in Small Arteries) trial investigators. Stent placement compared with balloon angioplasty for small coronary arteries trial. Inhospital and six-month clinical and angiographic results. Circulation 2001; 104: 1604–8. 120 R Koster, J Kahler, W Terres, J Reimers, S Baldus, D Hartig, J Berger, T Meinertz, CW Hamm. Six-month clinical and angiographic outcome after successful excimer laser angioplasty for in-stent restenosis. J Am Coll Cardiol 2000; 36(1): 69–74. 201 RJ Lederman, FO Mendelsohn, R Santos, HR Phillips, RS Stack, JJ Crowley. Primary renal artery stenting: characteristics and outcomes after 363 procedures. Am Heart J 2001; 142(2):314–23. 165 E Lindmark, E Diderholm, L Wallentin, A Siegbahn. Relationship between interleukin-6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or non-invasive strategy. JAMA 2001; 286:2107–13. 12 TH Marwick, C Case, S Sawada, C Rimmerman, P Brenneman, R Kovacs, L Short, M Lauer. Prediction of mortality using dobutamine echocardiography. J Am Coll Cardiol 2001; 37:754–60. 245

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V Mathew, ME Farkouh, BJ Gersh, CS Rihal, GS Reeder, DE Grill, LH Urban, SL Kopecky, JH Chesebro, DR Holmes Jr. Early coronary angiography improves long-term survival in unstable angina. Am Heart J 2001; 142:768–74. 74 I Matsunari, U Schricke, FM Bengel, H-U Haase, P Barthel, G Schmidt, SG Nekolla, A Schoemig, M Schwaiger. Extent of cardiac sympathetic neuronal damage is determined by the area of ischaemia in patients with acute coronary syndromes. Circulation 2000; 101: 2579–85. 255 F Maynard, SM Wright, NR Every, JL Ritchie. Comparison of outcomes of coronary stenting versus conventional coronary angioplasty in the Department of Veterans Affairs medical centres. Am J Cardiol 2001; 87:1240–5. 118 R Mehran, G Dangas, A Abizaid, AJ Lansky, GS Mintz, AD Pichard, LF Satler, KM Kent, R Waksman, GW Stone, MB Leon. Treatment of focal in-stent restenosis with balloon angioplasty alone versus stenting: short- and long-term results. Am Heart J 2001; 141(4):610–4. 202 R Mehran, G Dangas, GS Mintz, R Waksman, A Abizaid, LF Satler, AD Pichard, KM Kent, AJ Lansky, GW Stone, MB Leon. Treatment of in-stent restenosis with excimer laser coronary angioplasty versus rotational atherectomy: comparative mechanisms and results. Circulation 2001; 101(21): 2484–9. 202 SR Mehta, S Yusuf, RJG Peters, ME Bertrand, BS Lewis, MK Natarajan, K Malmberg, H Rupprecht, F Zhao, S Chrolavicius, I Copland, KA Fox; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) investigators. Effects of pretreatment with clopidogrel and aspirin followed by longterm therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527–33. 51 V Menon, J Hochman, A Stebbins, M Pfisterer, J Col, RD Anderson, D Hasdai, DR Holmes, ER Bates, EJ Topol, RM Califf, EM Ohman; for the GUSTO investigators. Lack of progress in cardiogenic shock: lessons from the GUSTO trials. Eur Heart J 2000; 21: 1928–36. 102 N Mercado, E Boersma, W Wijns, B J Gersh, CA Morillo, V de Valk, GA van Es, DE Grobbee, PW Serruys. Clinical and quantitative coronary angiographic predictors of coronary restenosis. J Am Coll Cardiol 2001; 38(3):645–52. 180

R Moer, YM Myreng, P Molstad, P Albertsson, P Gunnes, B Lindvall, R Wiseth, K Ytre-Arne, J Kjekshus, S Golf. Stenting in small coronary arteries (SISCA) trial. A randomized comparison between balloon angioplasty and the heparin-coated beStent. J Am Coll Cardiol 2001; 38(6): 1598–1603. 119 J-L Monin, M Monchi, V Gest, A-M Duval-Moulin, JL Dubois-Rande, P Gueret. Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients. Risk stratification by low-dose dobutamine echocardiography. J Am Coll Cardiol 2001; 37:2101–7. 258 G Montalescot, P Barragan, O Wittenberg, P Ecollan, S Elhadad, P Villain, JM Boulenc, MC Morice, L Maillard, M Pansieri, R Choussat, P Pinton. ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up) Investigators. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001; 344: 1895–1903. 67 R Moreno, E Garcia, M Abeytua, J Soriano, J Acosta, L Perez De Isla, E Lopez De Sa, R Rubio, J LopezSendon. Early coronary angioplasty for acute myocardial infarction complicated by cardiogenic shock: have novel therapies led to better results? J Invasive Cardiol 2000; 12(12): 597–604. 110 DA Morrow, CP Cannon, N Rifai, MJ Frey, R Vicari, N Lakkis, DH Robertson, DA Hille, PT DeLucca, PM DiBattiste, LA Demopoulos, WS Weintraub, E Braunwald; for the TACTICS-TIMI 18 investigators. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA 2001; 286: 2405–12. 80 A Moustapha, A Assali, S Sdringola, W Vaughn, R Fish, O Rosales, G Schroth, Z Krajcer, RW Smalling, HV Anderson. Percutaneous and surgical interventions for in-stent restenosis: long-term outcomes and effect of diabetes mellitus. J Am Coll Cardiol 2001; 37:1877–82. 206 LK Newby, EM Ohman, RH Christenson, DJ Moliterno, RA Harrington, HD White, PW Armstrong, F Van De Werf, M Pfisterer, V Hasselblad, RM Califf, EJ Topol. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin T-positive status: the

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PARAGON B troponin T substudy. Circulation 2001; 103:2891–6. 10 K Nieman, M Oudkerk, BJ Rensing, P van Ooijen, A Munne, RJ van Geuns, PJ de Feyter..Coronary angiography with multi-slice computed tomography. Lancet 2001; 357(9256):599–603. 314 ER O’Brien, C Glover, M Labinaz. Acute outcome with the flexicut directional coronary atherectomy catheter for the treatment of coronary in-stent restenosis. J Invasive Cardiol 2001; 13(9): 618–22. 208 Y Otsuji, MD Handschumacher, N Liel-Cohen, H Tanabe, L Jiang, E Schwammenthal, JL Guerrero, LA Nicholls, GJ Vlahakes, RA Levine. Mechanism of ischaemic mitral regurgitation with segmental left ventricular dysfunction: three-dimensional echocardiographic studies in models of acute and chronic progressive regurgitation. J Am Coll Cardiol 2001; 37(2):641–8. 274 JP Ottervanger, AWJ van’t Hof, S Reiffers, JCA Hoorntje, H Suryapranata, MJ de Boer, F Zijlstra. Long-term recovery of left ventricular function after primary angioplasty for acute myocardial infarction. Eur Heart J 2001; 22:785–90. 62 AI Qureshi, MF Suri, Z Ali, SH Kim, RD Fessler, AJ Ringer, LR Guterman, JL Budny, LN Hopkins. Role of conventional angiography in evaluation of patients with carotid artery stenosis demonstrated by Doppler ultrasound in general practice. Stroke 2001; 32(10): 2287–91. 158 B Reimers, N Corvaja, S Moshiri, S Sacca, R Albiero, C Di Mario, P Pascotto, A Colombo. Cerebral protection with filter devices during carotid artery stenting. Circulation 2001; 104(1):12–15. 159 MJ Ricciardi, E Wu, CJ Davidson, KM Choi, FJ Klocke, RO Bonow, RM Judd, RJ Kim. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation. Circulation 2001; 103:2780–3. 286 G Rocchi, D Poldermans, JJ Bax, R Rambaldi, E Boersma, A Elhendy, P van der Meer, W Vletter, JR Roelandt. Usefulness of the ejection fraction response to dobutamine infusion in predicting functional recovery after coronary artery bypass grafting in patients with left ventricular dysfunction. Am J Cardiol 2000; 85:1440–4. 249 MT Rothman, PW Serruys, G Grollier, J Hoorntje, A van Den Bos, W Wijns, A Gershlick, G Van Es, R Melkert, M Eijgelshoven, T Lenderink, G Richardson, C Dille-Amo; European Antiplatelet

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Stent Investigation. Angiographic and clinical oneyear follow-up of the Cordis Tantalum Coil Stent in a multicentre international study demonstrating improved restenosis rates when compared to pooled PTCA and BENESTENT-I data. Cathet Cardiovasc Intervent 2001; 52:249–59. 125 GS Roubin, G New, SS lyer, JJ Vitek, N Al-Mubarak, MW Liu, J Yadav, C Gomez, RE Kuntz. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001; 103(4):532–7. 151 P Ruygrok, M Webster, V de Valk, G van Es, J Ormiston, MA Morel, PW Serruys. Clinical and angiographic factors associated with asymptomatic restenosis after percutaneous coronary intervention. Circulation 2001; 104: 2289–94. 197 JJW Sandstede, T Pabst, M Beer, C Lipke, K Baurle, F Butter, K Harre, W Kenn, W Voelker, S Neubauer, D Hahn. Assessment of myocardial infarction in humans with 23Na MR imaging: comparison with cine MR imaging and delayed contrast enhancement. Radiology. 2001; 221(1):222–8. 293 G Schnyder, M Roffi, R Pin, Y Flammer, H Lange, FR Eberli, B Meier, ZG Turi, OM Hess. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345: 1593– 600. 183 S Schröder, AF Kopp, A Baumbach, C Meisner, A Kuettner, C Georg, B Ohnesorge, C Herdeg, CD Claussen, KR Karsch. Non-invasive detection and evaluation of atherosclerotic coronary plaques with multislice computed tomography. J Am Coll Cardiol 2001; 37(5): 1430–5. 318 M Schweiger, C Cannon, S Murphy, CM Gibson, JR Cook, RP Giugliano, HU Changezi, EM Antman, E Braunwald; TIMI 10B and TIMI 14 Investigators. Early coronary intervention following pharmacologic therapy for acute myocardial infarction (the combined timi 10B–14 experience). Am J Cardiol 2001; 88: 831– 6. 95 R Sciagra, M Pellegri, A Pupi, L Bolognese, G Bisi, V Carnovale, GM Santoro. Prognostic implications of Tc-99m sestamibi viability imaging and subsequent therapeutic strategy in patients with chronic coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2000; 36: 739–45. 247 MJ Sharafuddin, CA Raboi, M Abu-Yousef, WJ Lawton, JA Gordon. Renal artery stenosis: duplex US

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after angioplasty and stent placement. Radiology 2001; 220(1): 168–73. 169 T Sharir, G Germano, X Kang, HC Lewin, R Miranda, I Cohen, RD Agafitie, JD Friedman, DS Berman. Prediction of myocardial infarction versus cardiac death by gated myocardial perfusion SPECT: risk stratification by the amount of stress-induced ischaemia and the post-stress ejection fraction. J Nucl Med 2001; 42: 831–7. 244 SK Sharma, A Kini, JD Marmur, V Fuster. Cardioprotective effect of prior β-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention: benefit is extended to improvement in intermediate-term survival. Circulation 2000; 102:166– 72. 53 S Shimoni, WA Zoghbi, F Xie, BS Kricsfeld, S Iskander, L Gobar, IA Mikati, J Abukhalil, MS Verani, EL O’Leary, TR Porter. Real-time assessment of myocardial perfusion and wall motion during bicycle and treadmill exercise echocardiography: comparison with single photon emission computed tomography. J Am Coll Cardiol 2001; 37:741–7. 256 M Singh, CS Rihal, PB Berger, MR Bell, DE Grill, KN Garratt, GW Barseness, DR Holmes Jr. Improving outcome over time of percutaneous coronary interventions in unstable angina. J Am Coll Cardiol 2000; 36:674–678. 76 DH Solomon, PH Stone, RJ Glynn, DA Ganz, CM Gibson, R Tracy, J Avorn. Use of risk stratification to identify patients with unstable angina likeliest to benefit from an invasive versus conservative management strategy. J Am Coll Cardiol 2001; 38: 969– 76. 77 JE Sousa, MA Costa, AC Abizaid, BJ Rensing, AS Abizaid, LF Tanajura, K Kozuma, G Van Langenhove, AG Sousa, R Falotico, J Jaeger, JJ Popma, PW Serruys. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104:2007–11. 136 HP Stoll, GD Hutchins, WL Winkle, AT Nguyen, D Hou, CR Appledorn, B Romeike, KL March. Liquidfilled balloon brachytherapy using 68Ga is effective and safe because of the short 68-minute half-life results of a feasibility study in the porcine coronary overstretch model. Circulation 2001; 103:1793–8. 225 AG Sutton, PG Campbell, ED Grech, DJ Price, A Davies, JA Hall, MJ Stewart, MA de Belder. Failure

of thrombolysis: experience with a policy of early angiography and rescue angioplasty for electrocardiographic evidence of failed thrombolysis. Heart 2000; 84: 197–204. 88 T Suzuki, G Kopia, S Hayashi, LR Bailey, G Llanos, R Wilensky, BD Klugherz, G Papandreou, P Narayan, MB Leon, AC Yeung, F Tio, PS Tsao, R Falotico, AJ Carter. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104: 1188–93. 134 S Takuma, T Ota, T Muro, T Hozumi, R Sciacca, MR Di Tullio, DK Blood, J Yoshikawa, S Homma. Assessment of left ventricular function by real-time 3dimensional echocardiography compared with conventional non-invasive methods. J Am Soc Echocardiogr 2001; 4: 275–84. 263 M Taniyuchi, HI Kurz, JM Lasala. Randomized comparison of ticlopidine and clopidogrel after intracoronary stent implantation in a broad patient population. Circulation 2001; 104:539–43. 51 JC Tardif. Canadian antioxidant restenosis trial (CART-1). AHA scientific sessions, late breaking trials. Anaheim, California, 2001. 186 A Taylor, I Feuerstein, H Wong, W Barko, M Brazaitis, PG O’Malley. Do conventional risk factors predict subclinical coronary artery disease? Results from the prospective army coronary calcium project. Am Heart Journal 2001; 141(3):463–8. 307 JE Tcheng, DJ Kereiakes, AM Lincoff, BS George, NS Kleiman, DC Sane, DB Cines, RE Jordan, MA Mascelli, MA Langrall, L Damaraju, A Schantz, MB Effron, GA Braden. Abciximab readministration: results of the ReoPro Readministration Registry. Circulation 2001; 104:870–5. 31 EJ Topol, DJ Moliterno, HC Herrmann, ER Powers, CL Grines, D J Cohen, EA Cohen, M Bertrand, FJ Neumann, GW Stone, PM DiBattiste, L Demopoulos; TARGET Investigators. Do Tirofiban and ReoPro Give Similar Efficacy Trial. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001; 344:1888–94. 30 H Tsujino, M Jones, T Shiota, JX Qin, NL Greenberg, LA Cardon, AJ Morehead, AD Zetts, A Travaglini, F Bauer, JA Panza, JD Thomas. Real-time threedimensional colour Doppler echocardiography for characterizing the spatial velocity distribution and quantifying the peak flow rate in the left ventricular

INDEX OF PAPERS REVIEWED

outflow tract. Ultrasound Med Biol 2001; 27(1): 69–74. 273 BA Vakili, R Kaplan, DL Brown. Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York State. Circulation 2001; 104:2171–6. 59 E Van Belle, R Ketelers, C Bauters, M Perie, K Abolmaali, F Richard, JM Lablanche, EP McFadden, ME Bertrand. Patency of percutaneous transluminal coronary angioplasty sites at six months: angiographic follow-up. Circulation 2001; 103:1218– 24. 181 WJ van der Giessen, E Regar, MS Harteveld, VL Coen, R Bhagwandien, A Au, PC Levendag, J Ligthart, PW Serruys, A den Boer, PD Verdouw, E Boersma, T Hu, HM van Beusekom. ‘Edge effect’ of 32P radioactive stents is caused by the combination of chronic stent injury and radioactive dose falloff. Circulation 2001; 104:2236–41. 221 FJ Veith, M Amor, T Ohki, HG Beebe, PR Bell, A Bolia, P Bergeron, JJ Connors 3rd, EB Diethrich, RD Ferguson, M Henry, RW Hobson 2nd, LN Hopkins, BT Katzen, K Matthias, GS Roubin, J Theron, MH Wholey, SS Yadav. Current status of carotid bifurcation angioplasty and stenting based on a consensus of opinion leaders. J Vasc Surg 2001; 33(2 Suppl): S111–6. 160 JJ Vitek, GS Roubin, G New, N Al-Mubarak, SS lyer. Carotid angioplasty with stenting in post-carotid endarterectomy restenosis. J Invasive Cardiol 2001; 13 (2):123–5; discussion 158–70. 161 R Waksman, AE Ajani, RL White, E Pinnow, R Dieble, AB Bui, M Taaffe, L Gruberg, GS Mintz, LF Satler, AD Pichard, KK Kent, J Lindsay. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary γ-radiation in patients with in-stent restenosis; Washington Radiation for In-stent restenosis Trial Plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001; 103:2332–5. 228 R Waksman, AE Ajani, RL White, E Pinnow, R Mehran, AB Bui, R Deible, L Gruberg, GS Mintz, LF Satler, AD Pichard, KM Kent, J Lindsay. Twoyear follow-up after beta and gamma intracoronary radiation therapy for patients with diffuse in-stent restenosis. Am J Cardiol 2001; 88:425–8. 219 R. Waksman, JR Laird, CT Jurkowitz, AJ Lansky, F Gerrits, AS Kosinski, N Murrah, WS Weintraub; Peripheral Artery Radiation Investigational Study (PARIS) Investigators. Intravascular radiation therapy

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after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARIS feasibility clinical trial. J Vasc Interv Radiol 2001; 12: 915–21. 230 JG Webb, TA Sanborn, LA Sleeper, RG Carere, CE Buller, JN Slater, KW Baran, PT Koller, JD Talley, M Porway, JS Hochman; SHOCK Investigators. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial registry. Am Heart J 2001; 141(6): 964–70. 104 J Wöhrle, E Al-Khayer, C Schindler, M Kochs, V Hombach, M Höher. Comparison of the heparin coated versus the uncoated Jostent: no influence on restenosis or clinical outcome. Eur Heart J 2001; 22: 1808–16. 142 H Yip, C Wu, H Chang, MC Chen, CL Hang, CY Fang, YK Hsieh, CH Yang, KH Yeh, M Fu. Comparison of impact of primary percutaneous transluminal coronary angioplasty and primary stenting on short-term mortality in patients with cardiogenic shock and evaluation of prognostic determinants. Am J Cardiol 2001; 87:1184–8. 99 K Yoshinaga, K Morita, S Yamada, K Komuro, C Katoh, Y Ito, Y Kuge, T Kohya, A Kitabatake, N Tamaki. Low-dose dobutamine electrocardiographgated myocardial SPECT for identifying viable myocardium: comparison with dobutamine stress echocardiography and PET. J Nucl Med 2001; 42:838– 44. 250 R Zahn, R Schiele, S Schneider, AK Gitt, H Wienbergen, K Seidl, T Voigtlander, M Gottwik, G Berg, E Altmann, W Rosahl, J Senges. Primary angioplasty versus intravenous thrombolysis in acute myocardial infarction: can we define sub-groups of patients benefiting most from primary angioplasty? Results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction Registry and the Myocardial Infarction Registry. J Coll Cardiol 2001; 37: 1827–35. 68 MM Zhu, A Feit, H Chadow, M Alam, T Kwan, LT Clark. Primary stent implantation compared with primary balloon angioplasty for acute myocardial infarction: a meta-analysis of randomized clinical trials. Am J Cardiol 2001; 88: 297–301. 63 D Zohlnhöfer, CA Klein, T Richter, R Brandl, A Murr, T Nuhrenberg, A Schomig, PA Baeuerle, FJ Neumann. Gene expression profiling of human stentinduced neointima by cDNA array analysis of microscopic specimens retrieved by helix cutter

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atherectomy: detection of FK506-binding protein 12 upregulation. Circulation 2001; 103:1396–1402. 138

© Clinical Publishing Services Ltd

Index

A abciximab 3, 37 bleeding risk after thrombolytic therapy 92–3 CAPTURE study 11, 12 comparison with tirofiban 30–1 readministration 26 ReoPro Readministration Registry results 31–2 use after alteplase 92 use with dalteparin 42–3 use in percutaneous coronary intervention 25,26–7, 30– 1, 40–3 use in rescue PCI and stent implantation 95 use in stent implantation procedures (ADMIRAL) 67– 8 use after streptokinase 92 ACAS (Asymptomatic Carotid Atherosclerosis Study) 152 Accelerated Intermittent Imaging (AII) 256–7 actinomycin D, use in stent coatings 148 activated clotting time (ACT) clinical interpretation 46 optimal for PCI 38–40 acute coronary syndrome, non-ST elevation see non-ST elevation acute coronary syndrome acute coronary syndromes, risk stratification 3,5–21 ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-term Follow-up) study 67–8, 70 Agaston method (calculation of CACS) 303 age and predicted outcome of angioplasty 62 AGI-1067, role in prevention of restenosis (CART-1) 186 alteplase 92 American Heart Association (AHA) recommendations on carotid stent implantation 150 angina indication for stent implantation 115–127 see also non-ST elevation acute coronary syndrome angiography

cerebral 158–9 complications 238 in non-ST elevation acute coronary syndrome 72–5, 83 predictors of restenosis 180–1 see also computed tomography: angiography angioplasty comparison with intravenous thrombolysis 68–9 comparison with stent implantation 115–21, 127 effect of time to treatment on outcome 60–1, 69 for myocardial infarction following bypass grafting 66, 70 prediction of stent-like outcomes 122, 124–5 prediction of suboptimal coronary blood flow 61–2 recovery of left ventricular function 62–3, 69 of renal artery 168 vascular response 177 volume-outcome relation 59–60, 69 see also balloon angioplasty; cutting balloon angioplasty; percutaneous coronary interventions annexin V 242, 254–5 anticoagulation in PCI 45–6 see also antithrombin therapy, glycoprotein IIb/IIIa inhibitors; heparin; low molecular weight heparins antioxidants, role in prevention of restenosis (CART-1) 186 antiplatelet therapy 3 after brachytherapy 228–30 see also glycoprotein IIb/IIIa inhibitors; abciximab; aspirin antithrombin therapy 4, 37 optimisation 38–40, 45–6 277

278

INDEX

use in percutaneous coronary intervention 37–47 aortic stenosis, dobutamine stress echocardiography 258– 9 apoptosis, imaging with technetium-99m-labelled annexin V 253–5 argatroban 37 see also thrombin inhibitors ARTIST (Angioplasty versus Rotational atherectomy for Treatment of diffuse In-stent Restenosis) trial 192 ARTS trial 183 aspirin combination with ticlopidine or clopidogrel 49, 50–1 in prevention of late thrombosis after brachytherapy 228–9 use before coronary angioplasty 25 atheroablation for in-stent restenosis 191–3 atherosclerosis and homocysteine levels 184 induction by ionizing radiation 215 atherosclerotic lesions, imaging of effects of simvastatin 290–1 atherosclerotic renal artery stenosis see renal artery stenosis; renal artery stent implantation atypical chest pain, calcium screening 305 B B-type natriuretic peptide (BNP) 6, 21 prognostic value 17–20, 21 balloon angioplasty comparison with stent implantation 63–4, 69,116–18, 119–121 in in-stent restenosis 202–3, 206–8 in rescue PCI 94–5 effect on myocardial perfusion reserve index 282–4 for in-stent restenosis (ISR) 191 prediction of stent-like outcomes 122, 124–5 see also angioplasty; cutting balloon angioplasty; percutaneous coronary interventions balloon pumps, intra-aortic 98, 101–2, 110 balloons, liquid filled in brachytherapy 225–6 BARI study 181, 183 baseline ECG, prognostic significance 5, 6–8, 21 BENESTENT-I trial 115–118, 124, 126, 127 BENESTENT-II trial 143 BESMART (BeStent in Small Arteries) trial 120–1, 122, 123, 127 BeStent Small 120

beta-blockers, effect on CK-MB levels post PCI 53–4, 55– 6 beta brachytherapy 215, 216 long-term effects on pig coronary arteries 217–19 in treatment of long lesions 223–4 use of 68Ga in liquid-filled balloons 225–6 Beta-Cath catheter, use in pullback radiation technique 224 beta-cath trial 223 BETACATH, late thrombosis rate 229 biphasic response in dobutamine stress echocardiography 248, 249 bivalirudin 4, 37 and activated clotting time 46 Bivalirudin Angioplasty Study 43–4, 45 REPLACE Part 2 trial 45 see also thrombin inhibitors biventricular pacing, assessment by three dimensional echocardiography 270–1 bleeding risk with abciximab after thrombolytic therapy 92–3 brachytherapy 215–17, 232–3 in chronic renal failure 226–8 in diabetic patients 227–8 edge effect in radioactive stents 221–3 for in-stent restenosis (ISR) 194 long term effects on pig coronary arteries 217–19 in peripheral arteries 230–2 pullback technique for diffuse in-stent restenosis 223– 5 use of liquid-filled balloons 225–6 WRIST study 219–21 WRIST PLUS study 228–30 breathhold cardiovascular magnetic resonance 281–2 Bx VELOCITY stents, sirolimus-eluting 136 bypass surgery see coronary artery by pass grafting C C-reactive protein 6 CABG see coronary artery bypass grafting CADILLAC trial 67–8, 70 calcification see coronary artery calcification; coronary artery calcium scoring calcium screening 305, 306–9, 320–1 calcium volume score 303 CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events) trial 49 captopril-induced renograms 170

INDEX

CAPTURE (c7E3 Fab Antiplatelet Therapy in Unstable Angina) study 11, 12 cardiogenic shock 98–9 comparison of primary PCI with primary stent implantation 99–100 outcome of early revascularization 101–8, 110–11 Second National AMI (US) Registry data 108–10 cardiovascular magnetic resonance (CMR) 279–96, 295–6 in assessment of myocardial perfusion 282–4 contrast-enhanced imaging of myocardial viability 280, 284–6 coronary vessel wall and plaque imaging 288–90 imaging of atherosclerosis regression 290–1 imaging of microinfarction 286–7 measurement of cardiac volume, function and mass 281–2 molecular imaging of fibrin 292 23Naimaging 293–4 31P spectroscopy 294–5 phase contrast imaging of restenosis 287–8 see also magnetic resonance imaging cardiovascular risk factors and coronary artery calcification 308–9 CARESS (Carotid Revascularization with Endarterectomy or Stenting Systems) 151, 161, 163–4 carotid artery stent implantation 150–1 ambulatory 153–4 analysis of outcomes 151–3 comparison with endarterectomy (CREST and CARESS) 151, 161, 163–4 filter protection 159–60 in-stent restenosis 15 5–6 in patients with high risk anatomy for endarterectomy 156–7 in post CEA restenosis 161–2 for post-CEA stroke 154–5 carotid bifurcation angioplasty and stenting (CBAS) 160– 1 carotid Doppler ultrasound 158–9 carotid endarterectomy (CEA) 149, 152–3 complications 150, 153 perioperative stroke 154–5 management of restenosis 161–2 risk factors for 150, 156, 157 CART-1 (Canadian antioxidant restenosis trial) 186 CAVATAS (Carotid and Vertebral Artery Transluminal Angioplasty Study) 150–1, 152, 156 cerebral angiography 158–9 cerebrovascular accidents (CVA) see stroke

279

Chekmate™ gamma system 225 cholesterol, relationship to coronary artery calcification 308, 309 chondroitin sulphate and gelatin (CSG), use in stent coatings 140–2 chronic renal failure, use of brachytherapy 226–8 CLASSICS (Clopidogrel Aspirin Stent International Cooperative Study) 50, 54–5 clopidogrel 4, 28, 31, 49, 82 CAPRIE trial 49 CLASSICS 50, 54–5 comparison with ticlopidine 50–1, 54–5 PCI-CURE study 4, 45, 51–3, 55 in prevention of late thrombosis after brachytherapy 228–30 TARGET study 26 coil stents 125–6, 127 complications of percutaneous coronary interventions 25 computed tomography 241 angiography (CTA) 238, 239, 240, 301, 311–20, 321 carotid 158, 159, coronary 301 311–20, 321 multi-slice 299–300 angiography 238, 239, 240, 301, 311–20, 321 coronary artery calcium scoring 302–4 see also electron beam computed tomography (EBCT); single-photon-emission computed tomography (SPECT) congenital heart disease, three dimensional echocardiography 262 contrast echocardiography 246, 269–70 FS069 (Optison(R)) contrast in three dimensional echocardiography 269–70 see also dobutamine echocardiography contrast media 327–30 see also gadolinium contrast agents Cordis Tantalum coil Stent, evaluation 125–6, 127 coronary angiography magnetic resonance 239, 241, 280–1, 288–90 multi-slice computed tomography 311–20, 321 coronary artery bypass grafting (CABG) and angioplasty for subsequent myocardial infarction 66, 70 for in-stent restenosis, long term outcome 206–8 coronary artery bypass grafting (continued)outcome in diabetes 181, 183 as predictor for restenosis 180 reduction of graft failure by E2F Decoy 185–6

280

INDEX

use of glycoprotein IIb/IIIa inhibitors 3 value in cardiogenic shock 102–4 coronary artery calcification, and cardiovascular risk factors 308–9 coronary artery calcium scoring (CACS) 299, 300–2 comparison of EBCT and angiography 304–7 comparison of EBCT and MSCT 302–4 prognostic value 309–11 scoring methods 303 coronary atheroma detection of vulnerable plaques 238–9 screening for 238 coronary stenting see stent implantation coronary thrombus and outcome of angioplasty 61–2 corrugated-ring design of stents 131 COURT (COntrast media Utilization in high-Risk PTCA Trial) 328, 329 creatine kinase (CK)-MB elevation, imaging of microinfarction 286–7 creatine kinase (CK)-MB levels effect of β-blockers prior to PCI 53–4, 55–6 prognostic significance 5–6 CREST (Carotid Revascularization Endarterectomy Versus Stent Trial) 151,161, 163 CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial 49 cutting balloon angioplasty (CBA) in in-stent restenosis 193, 203–5 intravascular ultrasound assessment 205–6 D dalteparin 14, 41 and activated clotting time 46 use with abciximab in PCI 42–3 see also low molecular weight heparins dexamethasone, use in stent coatings 134 diabetic patients coronary artery disease mortality 181–3 long term outcomes of interventions for in-stent restenosis 206–8 and restenosis 178, 180, 181–3 use of brachytherapy 227–8 diatrizoate 327 diffuse in-stent restenosis 190, 196–7 pullback radiation technique 223–5 see also in-stent restenosis directional coronary atherectomy (DCA) 192 outcome with Flexicut catheter 208–9 dobutamine enhancement imaging techniques 240–1

echocardiography in aortic stenosis 258–9 in assessment of myocardial hibernation/viability 248–51 prognostic value 245–6 real time three dimensional echocardiography 271–3 Doppler pressure wire 238 Doppler ultrasonography carotid 158–9 echocardiography, real time colour 3D imaging 273–4 in evaluation of renal artery angioplasty and stenting 169–70 drug-eluting stents 195 Duplex ultrasonography see Doppler ultrasonography E E2F Decoy, reduction of graft failure in CABG 185–6 EASI (European Antiplatelet Stent Investigation) 125–6, 127 ECG see electrocardiography echocardiography 241 in assessment of left ventricular function 240 contrast agents 246, 269–70 exercise stress 256–8 free hand scanning 262–3 myocardial perfusion 240 rotating transthoracic transducer 266 two dimensional 261 see also dobutamine echocardiography; stress echocardiography edge effect in radioactive stents 221–3 ejection fraction, as index of global left ventricular function 249–50 electrocardiography in assessment of thrombolytic therapy 88–9 use in risk stratification 5, 21, 78–80, 83 electron beam computed tomography (EBCT) 299, 300 coronary artery calcium scoring 301–7 prognostic value of coronary artery calcium scoring 309–11 use in calcium screening 238, 305, 306–9, 320–1 embolic strokes, prevention during carotid artery stent implantation 159–60 end stage renal disease (ESRD) 171–2 enoxaparin and activated clotting time 46 in prevention of restenosis 184–5 SYNERGY trial 46 use in PCI 40–2

INDEX

see also low molecular weight heparins EPISTENT (Evaluation of Platelet IIb/IIIa Inhibition in Stenting) trial 27, 41 eptifibatide 3 use in coronary stent implantation 28–9 see also glycoprotein IIb/IIIa inhibitors ESPRIT study 3, 25, 28–9 exercise stress test 306 see also dobutamine echocardiography; stress echocardiography; stress radionuclide scintigraphy; stress-31P-MR spectroscopy eximer laser angioplasty (ELCA) 192–3, 200–2 F FDG SPECT, in assessment of myocardial hibernation/ viability 251–3 femoropopliteal artery lesions, brachytherapy 230–2 fibrin targeting with contrast agents 281, 292 fibromuscular renal artery stenosis 166, 167, 169, 171 filter protection during carotid artery stent implantation 159–60 FKBP-12 (FK 506-binding protein 12) 138–40 flash pulmonary oedema 165 Flexicut directional atherectomy catheter 208–9 fluorine-18 252 folic acid in prevention of restenosis 183–4 Frankfurt SFA radiation trials 232 FRISC-II (Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease) study 14–15, 34, 72, 73–4, 78, 82, 83 ECG study 78–80 FS069 (Optison(R)) contrast in three dimensional echocardiography 269–70 G 68Ga in liquid-filled balloon brachytherapy 225–6 gadolinium contrast agents in cardiovascular magnetic resonance 279–80, 282 imaging of myocardial viability 284–6 in molecular imaging of fibrin 292 GALILEO INHIBIT, late thrombosis rate 229 gamma brachytherapy 215, 216 in treatment of long lesions 224–5 WRIST PLUS trial 228–30 GAMMA I trial 215, 216 late thrombosis rate 229 outcome in diabetic patients 227–8

281

gated myocardial perfusion SPECT, prognostic value 244– 5 Gd-DTPA (gadolinium-diethylene triamine pentacetic acid) 279–80, 282 see also gadolinium contrast agents gene expression in neointimal hyperplasia 138–40 gene therapy, in reduction of intimal hyperplasia 185–6 geographic miss 222–3 Gianturco-Roubin II stent 131 global left ventricular function and ejection fraction 249–50 prognostic significance 240, 244, 246 glycoprotein IIb/IIIa inhibitors 3, 6, 37, 82 and troponin status 10–12, 13–14 use in non-ST elevation acute coronary syndrome 73– 4, 76 use in percutaneous coronary intervention 25–35, 45, 55 use in stent implantation procedures 28–9, 67–8, 69– 70 see also eptifibatide; lamifiban, orbofiban, tirofiban gold, use in stent coatings 144–6, 147 golden hour 69 graft failure, reduction by E2F Decoy 185–6 GUSTO (Global Utilization of Streptokinase and Tpa to Open arteries) trials 6–7, 61–2, 88, 101, 102–4, 109 H haemodynamic changes, assessment by three dimensional echocardiography 270–1 harmonic imaging in echocardiography 266–8, 270 heart failure, use of breathhold cardiovascular magnetic resonance 281–2 helical computed tomography 299 heparin 4, 38 mechanism of action 185 point-of care monitoring 46 see also low molecular weight heparins heparin-coated stents 119, 121, 142–4 hibernation, myocardial see myocardial hibernation history, role in risk stratification 5, 21 homocysteine levels and restenosis 183–4 hypertension, renal artery stenosis 164–5, 171 stent implantation 165–72 I IABP (intra-aortic balloon pumps) in cardiogenic shock 98, 101–2, 110

282

INDEX

imaging techniques 237–42 see also computed tomography; magnetic resonance imaging; Doppler ultrasonography; echocardiography inducible ischaemia 253 inflammatory markers 21 C-reactive protein 6 interleukin 6 12, 14–17 and restenosis 177–8 InFlow stent 130, 131 gold-coated 145 INHIBIT trial 215, 216 late thrombosis rate 229 in-stent restenosis (ISR) 129, 209 aggressive 190–1, 196–7 asymptomatic 190, 197–8 in carotid artery 155–6 diffuse 190, 196–7, 223–5 drug-eluting stents 195 focal 190 imaging techniques 239–40 intravascular ultrasound assessment of cutting balloon angioplasty 205–6 incidence 189 long term outcomes after intervention 206–8 mechanism 189–190 mechanical problems 198–200 predictors of 196, 197–8 reduction by sirolimus 134–8 and strut thickness 132–3 time course 190 treatment atheroablation 191–3 balloon angioplasty 191, 202–3 brachytherapy 194, 215–30, 232–3 cutting balloon angioplasty 193, 203–6 eximer laser angioplasty (ELCA) 192–3, 200–2 Flexicut directional coronary atherectomy 208–9 LARS (Laser Angioplasty for Restenotic Stents) study 200–1 pullback technique for long lesions 223–5 re-stenting 193–4, 202–3 sonotherapy 194–5 interleukin 6 (IL-6), prognostic significance 12, 14–17 intimal hyperplasia 129, 130–1, 177 effects of beta irradiation in pig coronary arteries 217– 19 effect of gold 144–6, 147

effect of heparin 142–4 effect of paclitaxel 140–2 gene expression 138–40 inhibition by ultrasound 194–5 reduction by antioxidants 186 reduction by sirolimus 134–8 role in in-stent restenosis 189 role of gene therapy 18 5–6 and strut thickness 132–3 intra-aortic balloon pumps (IABP), use in cardiogenic shock 98, 101–2, 110 intravascular ultrasonography (IVUS) 239 in analysis of in-stent restenosis 198–200 in assessment of brachytherapy for long lesions 224–5 in assessment of cutting balloon angioplasty 205–6 iodine-123-metaiodobenzylguanidine (MIBG) 255–6 iodixanol 328, 330 iohexol 327 iomeron 327 ionizing radiation, induction of atherosclerosis 215 iopamidol 327, 330 ioxaglate 327, 328, 329, 330 ISAR-STEREO trial 132 ischaemic mitral regurgitation, three dimensional echocardiography 274–5 J Jostent®, evaluation of heparin coating 142–4 K Killip classification and outcome of percutaneous coronary intervention 64–5, 69 L lamifiban, in treatment of non-ST elevation acute coronary syndrome 11 see also glycoprotein IIb/IIIa inhibitors LARS (Laser Angioplasty for Restenotic Stents) study 192, 200–1 late thrombosis after brachytherapy 228–30 LDL cholesterol, relationship to coronary artery calcification 308, 309 left ventricular function assessment 261 imaging techniques 240 recovery after acute myocardial infarction 62–3, 69 left ventricular mass, measurement by three dimensional echocardiography 268–9

INDEX

left ventricular outflow tract, imaging with real time 3D colour Doppler 273–4 left ventricular volumes, assessment by 3D echocardiography 263–8 lepirudin 37 see also thrombin inhibitors liquid-filled balloons, use in brachytherapy 225–6 Long WRIST study 224, 225 low dose dobutamine gated SPECT 250–1 low molecular weight heparins 4, 6, 37 in PCI 40–3, 46 in prevention of restenosis 184–5 see also dalteparin; enoxaparin M magnetic resonance imaging 241, 279–96 carotid angiography 158, 159 coronary angiography 238, 239, 240 markers of myocardial necrosis 5–6 MATE trial 71, 72, 81–2 microinfarction, contrast-enhanced magnetic resonance imaging 280, 286–7 MIR (Myocardial Infarction Registry) 68 MITI registry 72 MITRA (Maximal Individual Therapy in acute myocardial infarction Registry) 68 mitral regurgitation, three dimensional echocardiography 274–5 monocyte chemoattractant factor (MCP-1) as predictor of restenosis 178–9 mortality of cardiogenic shock 98, 99, 100, 110–11 Second National AMI (US) Registry data 108–9 of percutaneous coronary intervention 89, 91 mTOR (mammalian target of rapamycin) 134 Multi-Link stent 130, 131 multi-slice computed tomography (MSCT) 299–300 angiography 238, 239, 240, 301, 311–20, 321 coronary artery calcium scoring 302–4 multi-vessel coronary disease detection of culprit lesions 238 and left ventricular function 63, 69 MUSIC (Multicentre Ultrasound Stenting in Coronaries) study 199 myocardial contrast echocardiography (MCE) 256–8 myocardial hibernation 63 imaging techniques 240–1, 242, 243 cardiovascular magnetic resonance 280

283

dobutamine stress echocardiography 248–51 SPECT imaging 246–8, 251–3 see also myocardial viability myocardial infarction 69–70 angioplasty after prior bypass grafting 66, 70 comparison of angioplasty with intravenous thrombolysis 68–9 comparison of rescue PCI with primary PCI 89–91 comparison of stent implantation with balloon angioplasty 63–4 effect of time to angioplasty treatment on outcome 60– 1, 69 percutaneous coronary intervention in failed thrombolysis 88–91 prediction of suboptimal coronary blood flow after angioplasty 61–2 predictive value of Killip classification 64–5, 69 prevention of periprocedural MI 3–4, 25–31 recovery of left ventricular function 62–3, 69 volume-outcome relation for angioplasty 59–60, 69 myocardial infarction, non Q wave see non-ST elevation acute coronary syndrome myocardial necrosis, markers of 5–6 myocardial perfusion assessment by cardiovascular magnetic resonance 282– 4 measurement with cardiovascular magnetic resonance 279–80 myocardial perfusion echocardiography 240, 241 myocardial perfusion imaging 243 myocardial perfusion reserve index 282–4 myocardial remodelling post infarction 63 myocardial stunning see myocardial hibernation myocardial viability contrast-enhanced magnetic resonance imaging 280, 284–6 sodium-23 magnetic resonance imaging 281, 293–4 see also myocardial hibernation N 23Na magnetic resonance imaging 281, 293–4 NASCET (North American Symptomatic Carotid Endarterectomy Trial) 150, 152, 157, 163 neointimal formation, long term effects of beta irradiation in pig coronary arteries 217–19 neointimal hyperplasia see intimal hyperplasia neurohormonal markers see B-type natriuretic peptide NICE (National Investigators Collaborating on Enoxaparin) studies 40–2

284

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NIR stents, gold-coated 144–6, 147 nitrate sestambi imaging 247–8 non Q wave myocardial infarction see non-ST elevation acute coronary syndrome non-ST elevation acute coronary syndrome comparison of early invasive and conservative strategies 73–4 early angiography 74–5 risk stratification 77–8, 80 improving outcome of percutaneous coronary interventions 76–7 management 71–3 prognostic value of troponins 80–1, 82 risk stratification 3, 77–8 significance of ST depression 78–80 studies on early invasive strategy 71–83 O OASIS registry 72 Olmstead County Acute Chest Pain Database 74 orbofiban (OPUS-TIMI-16) 17 see also glycoprotein IIb/IIIa inhibitors oxidant stress, role in intimal hyperplasia 186 P 31P

magnetic resonance imaging 294–5 p27kip1 134 paclitaxel-eluting stents 140–2, 147–8, 195 Palmaz-Schatz stent 116, 130, 131 PAMI (Stent Primary Angioplasty in Myocardial Infarction) trial 60–1, 143 PARAGON A trial 6–8 PARAGON B troponin T substudy 10–12 paramagnetic nanoparticles in molecular imaging of fibrin 292 PARIS pilot study (SFA radiation) 230–2 PCI see percutaneous coronary interventions PCI-CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial 4, 45, 51–3, 55 pentasaccharides 37 percutaneous coronary interventions (PCI) adjunct 95–7 after thrombolytic therapy 87–111 anticoagulation 45–6 antithrombin therapy 4, 37–46 Bivalirudin Angioplasty Study 43–4 low molecular weight heparin 40–3 unfractionated heparin 38–40

comparison of early revascularization and conservative policy (TACTICS-TIMI-18 trial) 33–5 comparison of rescue PCI with primary PCI 89–91, 97–8 comparison with stent implantation in cardiogenic shock 99–100 delayed 95–7 effect of β-blockers on CK-MB levels 53–4, 55–6 glycoprotein IIb/IIIa inhibitors 3, 25–6, 45, 67–8, 70 eptifibatide 28–9 comparison of tirofiban with abciximab 30–1 imaging of procedure-related microinfarction 286–7 Killip classification, predictive value 64–5, 69 mortality 89, 91 in non-ST elevation acute coronary syndrome 76–7 prognostic significance of time to treatment 89, 90 use of abciximab 25, 26–7, 30–1, 40–3 value in cardiogenic shock 101–8, 110–11 see also angioplasty; balloon angioplasty; cutting balloon angioplasty; stent implantation percutaneous coronary interventions, rescue 88–9, 93–4 comparison with primary PCI 89–91, 97–8 role of stent implantation 94–5 timing and outcome 95–7 percutaneous transluminal coronary angioplasty (PTCA) see angioplasty percutaneous transluminal renal artery angioplasty (PTRA) 168 in end stage renal disease 171–2 percutaneous transluminal renal artery angioplasty and stent placement (PTRAS) evaluation by Duplex ultrasound 169–70 see also renal artery stent implantation phosphorus-31 magnetic resonance imaging 294–5 physical examination, role in risk stratification 5, 21 plaques composition 239 development 300 effects of statins 239 magnetic resonance imaging 288–90 targeted magnetic resonance contrast agents 281, 292 vulnerable 301, 310 imaging techniques 238–9 pregnancy-associated plasma protein-A 21 PRESTO trial 187 PREVENT trial 216

INDEX

PRISM (Platelet Receptor Inhibition in Ischaemic Syndrome Management) study 11 probucol, role in prevention of restenosis (CART-1) 186 prognosis in coronary disease, role of imaging techniques 243–6 prognostic factors age 62, 70 B-type natriuretic peptide (BNP) 17–20, 21 coronary artery calcium scoring 309–11 coronary thrombus 61–2 ECG changes 5, 6–8, 21 global left ventricular function 240, 244, 246 imaging techniques 243–6 interleukin 6 12, 14–17 Killip classification 64–5, 69 reversible ischaemia 244, 246 serum markers 5–6 ST depression 6–8, 21, 78–80 troponin levels 80–1, 82, 83 vein graft occlusion 66, 70 pullback radiation technique for diffuse in-stent restenosis 223–5 pyridoxine, in prevention of restenosis 183–4 R radioactive line source (RLS), physics of 221–2 radioactive stents, edge effect 221–3 rapamycin see sirolimus-eluting stents RAVEL trial 137 real-time three dimensional echocardiography 262–6, 271– 3 refractory hypertension 164 renal artery stenosis 164–5 diagnosis 170 renal artery stent implantation 164–5, 169, 171–2 evaluation by Doppler ultrasound 169–70 outcome 165–7 in atherosclerotic renal artery stenosis 167–8 in patients≥ 75 years 168–9 renal failure, use of brachytherapy 226–8 renal function assessment 168 renograms, captopril-induced 170 reperfusion, electrocardiographic signs of 89 reperfusion therapy, eligibility for 5 REPLACE Part 2 trial 45 rescue percutaneous coronary intervention 88–91, 93–4 comparison with primary PCI 89–91, 97–8 role of stent implantation 94–5 timing and outcome 95–7

285

RESCUE study 87 RESCUT (REStenosis CUTting balloon evaluation) study 193 restenosis 177–78, 188 Canadian antioxidant restenosis trial (CART-1) 186 clinical and angiographic predictors 180–1 in diabetes 178, 180, 181–3 in-stent see in-stent restenosis (ISR) and monocyte chemoattractant factor (MCP-1) 178–9 phase contrast magnetic resonance imaging 287–8 and plasma homocysteine levels 183–4 reduction by enoxaparin 184–5 reduction by vitamins 183–4 role of gene therapy 18 5–6 trial of tranilast (PRESTO trial) 187 re-stenting for in-stent restenosis (ISR) 193–4 comparison with balloon angioplasty 202–3 comparison with cutting balloon angioplasty 203–5 long term outcome 206–8 RESTORE (Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis) 30 reversible ischaemia, prognostic significance 244, 246 RIBS (Restenosis Intra-stent: Balloon angioplastyversus elective Stenting) 194 risk stratification in acute coronary syndromes 5–21 in aortic stenosis 258–9 ECG changes 83 in non-ST elevation acute coronary syndrome 3, 77–8, 83 troponin levels 80–1, 82, 83 rotational atherectomy (ROTA) comparison with cutting balloon angioplasty in in-stent restenosis 203–5 comparison with eximer laser angioplasty (ELCA) 202 for in-stent restenosis (ISR) 191–2, 193 long term outcome 206–8 S screening for coronary disease 237–8 coronary artery calcium scoring 305, 306–9, 320–1 SCRIPPS trials 215, 216, 220 late thrombosis rate 229 Second National AMI (US) Registry, cardiogenicshock 108–10 sestambi imaging 247–8 SHOCK trial 61, 98, 100 one-year survival 106–8 registry 104–6

286

INDEX

silicon carbide, use as stent coating 146 simvastatin, imaging of effects on atherosclerotic lesions 290–1 single-photon-emission computed tomography (SPECT) 240 assessment of myocardial hibernation/viability 246–8, 251–3 low dose dobutamine gated SPECT 250–1 prognostic value 244–5 use of iodine-123-metaiodobenzylguanidine (MIBG) 255–6 use of technetium-99m-labelled annexin V 253–5 sirolimus-eluting stents 134–8, 147–8, 195 SISA (Stent in Small Arteries) trial 121, 122, 123, 127 SISCA (Stenting in Small Coronary Arteries) trial 119– 120, 122, 123 sodium-23 magnetic resonance imaging 281, 293–4 sonotherapy for in-stent restenosis (ISR) 194–5 spiral computed tomography 299 SPLASH (Sonotherapy Prevention of Late Arterial inStent Hyperplasia) study 194 ST changes, prognostic significance 5, 6–8, 21, 78–80 ST elevation, changes in reperfusion 89 stable angina, indication for stent implantation 115–127 START trial 215, 216, 221 late thrombosis rate 229 outcome for diabetic patients 228 statins, effect on plaque composition 239 stent expansion, inadequate, 199–200 stent implantation 82–3 in carotid arteries 150–64 comparison with angioplasty 115–21, 127 comparison with balloon angioplasty 63–4, 69 comparison of clopidogrel with ticlopidine 50 comparison with percutaneous coronary intervention in cardiogenic shock 99–100 in diabetic patients 183 effect of beta-blockers on CK-MB levels 53–4 effect on myocardial perfusion reserve index 282–4 effect on outcome of time to treatment 60–1, 69 evaluation of Cordis Tantalum coil Stent 125–6 use of glycoprotein IIb/IIIa inhibitors 67–8, 70 indication in stable angina 115–127 NICE studies 40–2 in non-ST elevation acute coronary syndrome 72, 73, 76 in renal arteries 164–72 role in failed thrombolysis 94–5 small vessel 119–22, 123, 127

use of abciximab (EPISTENT trial) 27 use of eptifibatide 28–9 vascular response 28–9, 129–30 stent-like outcomes in angioplasty 122, 124–5 stents coatings actinomycin D 148 chondroitin sulphate and gelatin (CSG) 140–2 dexamethasone 134 gold 144–6, 147 heparin 142–4 paclitaxel 140–2, 147–8 passive 146 sirolimus 134–8, 147–8 design 129, 130–1 drug-eluting 195 edge restenosis 177 effect of strut thickness on restenosis 132–3 function 129 in-stent restenosis (ISR) 189–209 mechanical problems 198–200 misplacement 198–200 radioactive edge effect 221–3 underexpansion 199–200 vascular response to implantation 129–30 streptokinase 92 stress echocardiography 243, 256–8 prognostic value 245–6 real time three dimensional echocardiography 271–3 see also dobutamine echocardiography stress radionuclide scintigraphy 306 stress-31P-MR spectroscopy 281 stress testing 238 stroke 149 post-CEA, use of carotid stent implantation 154–5 prevention by carotid artery stent implantation 150–64 prevention during carotid artery stent implantation 159–60 strut thickness, effect on instent restenosis 132–3 stunning of myocardium 63 see also myocardial hibernation; myocardial viability superficial femoral artery (SFA) lesions, brachytherapy 230–2 Swiss SFA radiation trials 232 sympathetic innervation imaging with iodine-123-MIBG 255–6

INDEX

SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/ IIIa Inhibitors) trial 46 T TACTICS TIMI 18 trial 3, 26, 33–572–4, 78, 82, 83 substudy of troponins 80–1, 82 TARGET study 3, 25–6, 30–1 technetium-99m-imaging 242, 250, 251 of apoptosis 253–5 viability imaging 247–8 thienopyridines 37 see also clopidogrel; ticlopidine three dimensional echocardiography (3D echo) 240, 241, 261–76 acquisition of complete 3D data set 276 advantages 276 in assessment of haemodynamic changes 271–2 FS069 (Optison(R)) contrast 269–70 image quality 276 of ischaemic mitral regurgitation 274–5 measurement of left ventricular mass 268–9 real-time imaging 262–6 tissue harmonic imaging 266–8, 271 three dimensional stress echocardiography real time 271–3 see also dobutamine echocardiography thrombin inhibitors 4, 37 see also antithrombin therapy; argatroban; bivalirudin; lepirudin thrombocytopaenia, and abciximab readministration 3, 32 thrombolysis bleeding risk with subsequent use of abciximab 92–3 in cardiogenic shock 101–2 comparison with angioplasty 68–9 ECG assessment of 88–9 and subsequent PCI 87–111 thrombolysis, failed rescue percutaneous coronary intervention 88–91 role of stent implantation 94–5 timing of rescue percutaneous coronary intervention 95–7 thrombosis, late after brachytherapy 228–30 thrombus, coronary, and outcome of angioplasty 61–2 ticlopidine 4 comparison with clopidogrel 49, 50–1, 54–5

287

side effects 49 use in rescue PCI and stent implantation 95 time to treatment and outcome of angioplasty 60–1, 69 prognostic significance in percutaneous coronary intervention 89, 90 TIMI 10B and TIMI 14 studies 95–7 TIMI IIIb trial 71, 72, 78, 81–2 TIMI flow and outcome of rescue PCI 93–4, 95–7 TIMI-3 flow and troponin-positivity 9–10 tirofiban 3, 26, 81 comparison with abciximab 30–1 TACTICS-TIMI-18 trial 33–5, 73–4 and troponin status 11, 12, 13 use in non-ST elevation acute coronary syndrome 73– 4 tissue harmonic imaging in echocardiography 266–8, 271 titanium-nitride-oxide, use as stent coating 146 tranilast 187 transoesophageal three dimensional echocardiography 276 transthoracic three dimensional echocardiography 266, 276 TREAT trial 187 triage see risk stratification troponin status and use of glycoprotein IIb/IIIa inhibitors 10–12, 13–14 troponins 3 prognostic significance 5–6, 9–10, 21, 26 in non-ST elevation acute coronarysyndrome 80–1, 82 tubular slotted stents 131 tubulin, effect of paclitaxel 141 two dimensional echocardiography, limitations 261, 262 U ultrasonography in analysis of in-stent restenosis 198–200 in assessment of cutting balloon angioplasty 205–6 in evaluation of renal artery angioplasty and stent implantation 169–70 sonotherapy for in-stent restenosis (ISR) 194–5 unfractionated heparin see heparin unstable angina see non-ST elevation acute coronary syndrome V valvular heart disease, three dimensional echocardiography 262 VANQUISH trial 71–2, 81–2

288

INDEX

vascular brachytherapy see brachytherapy vascular injury cellular response 178–9 stent-induced 129 vascular response to angioplasty 177 vascular smooth muscle, effect of paclitaxel 140, 141 Veterans Affairs Medical Centres registry, comparison of stent implantation with angioplasty 118–19, 127 Vienna SFA radiation trials 232 VIP (Visipaque In PTCA) trial 328 vitamin B12, in prevention of restenosis 183–4 W Wallstents 191, 196 Wiktor coil stent 127 women, phosphorus-31 magnetic resonance imaging 294– 5 WRIST (Washington Radiation for In-Stent restenosis Trials) 215, 216, 219–21, 224, 225 WRIST 12 230 WRIST PLUS trial 228–30

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