Classic Papers in Coronary Angioplasty

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Classic Papers in Coronary Angioplasty

medwedi.ru

Clive Handler and Michael Cleman (Eds)

Classic Papers in Coronary Angioplasty With 18 Figures

Clive Handler, MD, FACC, FESC Consultant Cardiologist and Physician The National Pulmonary Hypertension Unit The Royal Free Hospital London, UK and Consultant Cardiologist Highgate Hospital London, UK

Michael Cleman, MD, FACC Professor of Medicine Director Cardiac Catheterization Laboratory and Angioplasty Services Yale University School of Medicine/Yale-New Haven Hospital New Haven, Connecticut, USA

British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2006922470 ISBN-10: 1-84628-400-7 ISBN-13: 978-1-84628-400-7

e-ISBN: 1-84628-454-6

Printed on acid-free paper

© Springer-Verlag London Limited 2006 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Whilst we have made considerable efforts to contact all holders of copyright material contained in this book, we may have failed to locate some of them. Should holders wish to contact the Publisher, we will be happy to come to some arrangement with them. Printed in the United States of America

(EB)

9 8 7 6 5 4 3 2 1 Springer Science+Business Media springer.com

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Contents

Editors

vi

Contributors

vi

Acknowledgements

viii

Preface

ix

Foreword

xi 1

Chapter 1

Vascular biology of atherosclerosis Peter F. Bodary, Daniel T. Eitzman

Chapter 2

Quantification of coronary atherosclerosis for cardiovascular risk assessment: the hole in the doughnut? Paul Schoenhagen, Steven E. Nissen

21

Primary angioplasty (PPCI) in ST-elevation myocardial infarction Iqbal Saeed Malik, Rodney Foale

39

Chapter 3

Chapter 4

Coronary angioplasty for acute coronary syndromes Steven Pfau

Chapter 5

High-risk coronary intervention: a selective literature review of high-risk subsets Jeffrey J. Popma, Hung Ly

65

89

Chapter 6

Stenting in coronary angioplasty Jeptha P. Curtis, John F. Setaro

115

Chapter 7

Ancillary techniques in interventional cardiology John M. Lasala, George Chrysant, Adrian Messerli

141

Chapter 8

Anti-thrombotic management in interventional cardiology James Tcheng, Steve Kindsvater

163

Chapter 9

Coronary artery bypass grafts in the era of percutaneous coronary angioplasty Thanos Athanasiou, Brian Glenville

Chapter 10

Index

191

Epilogue Gerry Coghlan

217

Frequently cited papers in coronary angioplasty

229 231

Editors Clive Handler MD, FACC, FESC Consultant Cardiologist and Physician, The National Pulmonary Hypertension Unit, The Royal Free Hospital, London, UK and Consultant Cardiologist, Highgate Hospital, London, UK

Michael Cleman MD, FACC Professor of Medicine, Director, Cardiac Catheterization Laboratory and Angioplasty Services, Yale University School of Medicine/Yale-New Haven Hospital, New Haven, Connecticut, USA

Contributors Thanos Athanasiou MD, PhD, FETCS Consultant Cardiothoracic Surgeon, St. Mary’s Hospital, London, UK

Peter F. Bodary PhD Research Investigator of Internal Medicine/Cardiology, University of Michigan, Ann Arbor, Michigan, USA

George Steven Chrysant MD Director, Advanced Cardiac Imaging, Integris Heart Hospital, Oklahoma City, Oklahoma, USA

Gerry Coghlan MD, FRCP Consultant Cardiologist, The Royal Free Hospital, London, UK

Jeptha P. Curtis MD Instructor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

Daniel T. Eitzman MD, FACC Associate Professor of Internal Medicine/Cardiology, University of Michigan, Ann Arbor, Michigan, USA

Rodney Foale MBBS, FRCP, FACC, FESC, FCSANZ Consultant Cardiologist and Clinical Director of Surgery, Cardiovascular Science and Critical Care, Waller Department of Cardiology, St. Mary’s Hospital, London, UK

Brian Glenville BSc(Hons), MS Professor and Head of Department of Cardiothoracic Surgery, Hadassah University Hospital, Jerusalem, Israel

Steven Michael Kindsvater MD Keesler Medical Center, Keesler AFB, Mississippi, USA

John M. Lasala MD, PhD Associate Professor of Cardiology, Washington University School of Medicine, St Louis, Missouri, USA

Hung Ly MD Interventional Cardiology Fellow, Cardiology Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA

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Iqbal Saeed Malik MA, MRCP, PhD Consultant Interventional Cardiologist, Waller Department of Cardiology, St. Mary’s Hospital, London, UK

Adrian W. Messerli MD Cardiology Associates of Kentucky, Lexington, Kentucky, USA

Steven E. Nissen MD, FACC Medical Director, Cleveland Clinic Cardiovascular Research Coordinating Center, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Steven Pfau MD Associate Professor of Medicine, Yale University School of Medicine, Cardiology Section, New Haven, Connecticut, USA

Jeffrey J. Popma MD Director, Interventional Cardiology, Brigham and Women’s Hospital, Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts, USA

Paul Schoenhagen MD, FAHA Cardiovascular Imaging, Departments of Radiology and Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

John F. Setaro MD Associate Professor of Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

James E. Tcheng MD, FACC, FBCAI, FESC Associate Professor of Medicine; Associate Professor of Community & Family Medicine, Duke Clinical Research Institute, Duke University Medical Center Durham, North Carolina, USA

vii

Acknowledgements Both Clive Handler and Michael Cleman would like to thank Professor Lawrence Cohen for writing the foreword to this book and for arranging the transatlantic link between London and New Haven, which was essential for this project, and for his encouragement and wise counsel. Clive Handler would like to acknowledge the support of his wife, Caroline, and their three children, Charlotte, Sophie and Julius, during the production of this book. The idea for this book came from his colleague from school, Dr Neil Soni, who co-edited the first book in this series, Classic Papers in Critical Care. He is also grateful to his colleague from the Royal Free Hospital, Dr Gerry Coghlan, who not only contributed the final chapter but also proof read the book. Michael Cleman would like to acknowledge his wife Marilyn, and his children, Jake and Katie for their patience and support in this project. The support and expertise of his interventional colleagues at Yale has been invaluable in collating the material.

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Preface Percutaneous coronary intervention (PCI) is one of the most commonly performed cardiac procedures. Physicians, all healthcare professionals and healthcare managers, as well as patients and their families, the world over, are aware that it is a very useful and powerful tool to help improve the lives of patients with coronary heart disease. But how did we get here? Cardiologists of our generation were in training when PCI was in its infancy. There was no evidence base to guide us and we witnessed and practiced with comparatively primitive equipment. We all had to learn from our own successes and failures as well as from the experiences of colleagues. The residents and trainees of today may not fully appreciate the anxieties of interventionists during procedures during those early years. Inherent problems included imaging and evaluating the significance of a coronary artery lesion; lack of data on what constituted high risk lesions and patients which made case selection difficult (this, in turn added uncertainty when discussing and quantifying the procedural risks to patients); arterial access problems and bleeding (particularly during the anticoagulation era); primitive and traumatic hardware complicating target lesion access; the sinking feeling of dealing with abrupt vessel closure, dissection and haemodynamic collapse before the availability of stents; and the disappointment felt by patients and interventionists with a comparatively high incidence of restenosis. Subacute thrombosis was an infrequent but worrying and unpredictable complication. On-site backup coronary artery surgery was generally considered mandatory and this had a knock-on effect on the work and finances of hospitals and providers. Memories of those early days when our expectations of the procedure, performed mainly for accessible, proximal, comparatively simple lesions in patients with single vessel disease, were that plain old balloon angioplasty would keep our patients away from the surgeons for a little while longer, and that it could be used as a salvage procedure for “inoperable” patients, have faded and have been replaced with a different, more confident, evidence-based practice. The frontiers have been pushed back; PCI incorporating drug-eluting stents and modern antiplatelet treatments is a routine, low-risk, day-case procedure performed in patients of all ages and co-morbidity, with high patient and clinician expectations for both acute and chronic coronary artery disease, without the necessity of on-site surgery. PCI has changed the way we approach clinical problems. Physicians managing patients with known or suspected coronary heart disease, whether in their office, in the emergency room or in the coronary care unit, understand that prompt diagnosis and treatment are now available. We continually search for improvements and refinements in equipment and pharmacological therapies. We collaborate with our basic science colleagues to find answers to molecular and cellular biological obstacles. Our imaging and vascular colleagues are key members of the multidisciplinary approach to develop and expand the use of the technique and enhance the quality of service we provide our patients. These rapid developments in the management of coronary heart disease, which will eventually affect nearly all of us, have been possible only through the vision, persistence, intellectual curiosity, skill and discipline of our predecessors. Interventionists today have been handed the baton and continue the quest. The aim of this book is not intended to be a birthday party for PCI, although its publication coincides with the 25th anniversary of Grüntzig’s paper. We wanted to pause, take breath and try to produce a small, useful and enjoyable book that would remind all those involved in PCI, of some of the major contributions to the literature. Looking back often helps in seeing what may lie ahead.

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We have invited some of the world’s leading interventionists to help us and they have done a fine job. They were given a difficult task. We asked them to provide us with their personal choice of the papers that have most influenced their practice and understanding of PCI in a number of its components. As busy clinicians, we are not often (if ever) forced to identify the papers that have been the most influential in shaping our practice. It may be considered a somewhat artificial approach, but reading an expert’s personal, restricted choice of papers that he would take on a desert island (without internet or library access), is of interest. Dr Mitchell Fink MD, in his preface to “Classic Papers in Critical Care”, excused the personal choices of the contributors by likening them to the views of a San Francisco restaurant critic. We have also included citation indices for each paper so that our readers have the additional views of the wider PCI community. You may have your own personal choices and may disagree with the choice of our contributors. We would beg your tolerance with this, an inherent weakness of this book. But it is also a strength, because the very nature and enjoyment of this series is that leading world experts allow readers to peep at their academic proclivities and personal perspectives of papers they think are scientifically and clinically useful. We feel that it provides a useful reference for others and has educational and historical value. Our friend and teacher, the eminent Professor Lawrence Cohen, confessed in his foreword, that he “got it wrong” at his first attempt to 25 years ago. Even he could not have anticipated how things were to turn out. This collection of “Classic Papers in Coronary Angioplasty”, 25 years down the road, is an opportunity to look behind us as we enter an early lap of a long distance race. Together with our contributors, we hope that you will enjoy this coned-in snapshot of PCI in 2005. We have no doubt that the next quarter of a century will bring us more surprises and improved care for our patients. Clive Handler MD, FACC, FESC Michael Cleman MD, FACC

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Foreword I am particularly pleased to get a second chance. I refer to the fact that at the time of my first chance, I got it all wrong. The year was 1979 and Dr Andreas Grüntzig had recently published an article in The New England Journal of Medicine entitled Nonoperative Dilation of Coronary Artery Stenosis: Percutaneous Transluminal Coronary Angioplasty. I took the opportunity to write a Letter to the Editor in which I stated: “A method for relief of coronary obstructions that did not involve operations would obviously have a major impact on medical, surgical, economic and psychologic aspects of this disease...” “Although this report is of great interest, it would be wise for cardiologists to maintain a healthy skepticism... This operation is clearly not the answer for most patients with obstructive coronary lesions. It is appropriate for only a fraction of patients with coronary artery disease – perhaps between 3 and 10 per cent. It may be successful in some patients with intrinsic coronary lesions and even in some who have previously undergone bypass grafting with subsequent occlusion of the graft.” I further went on to say: “Even when the obstructive lesion can be reached by the catheter, in how many patients will the dilatation be successful and free from complications such as intimal dissection? Further, if a lesion can be dilated, will the obstruction remain open for an extended period or will it return in days, weeks or months?” Perhaps you can understand my relief at being given a second chance to visit the topic of coronary angioplasty. This excellent book explores the growth in our knowledge gleaned over a quarter of a century. It explores the field from perspectives ranging from that of the vascular biologist to that of the surgeon who must thoughtfully reassess the diminishing role of coronary artery bypass surgery now that a non-operative approach is not only possible but in many instances preferable. It would not be a stretch to say that coronary angioplasty is to cardiology as the Rosetta Stone was to Egyptian hieroglyphics, allowing the language to be translated. The opening chapter on “Vascular Biology of Atherosclerosis” begins with the seminal work of Ross which was the first to identify the vascular smooth muscle cell as playing a critical role in the development of the atherosclerotic plaque. In collaboration with L. Harker, Ross went on to point to the role of hyperlipidemia in causing endothelial injury. The chapter by Schoenhagen and Nissen chronicles our ability to quantify the extent of coronary plaquing and also estimate the composition of coronary plaques. Proudfit’s paper of 40 years ago reports on the correlation between clinical findings and selective cine coronary arteriography in 1000 patients. For the first time, a patient’s clinical symptoms could be evaluated alongside a picture of the coronary arterial tree. This chapter also contains the 1990 article by Nissen et al. describing the development of intravascular ultrasound (IVUS), a technique that is able not only to quantify the extent of plaque but also its morphology. As experience with coronary angioplasty grew in patients with stable angina, it is not surprising that clinicians would extend this technique to the patient who is in the midst of a myocardial infarction. This approach is compared to the previous gold standard, thrombolytic therapy. It is now generally agreed that although both procedures have their respective roles, primary

xi

Foreword

percutaneous coronary intervention (PPCI) is the preferable method if the patient can be brought to the catheterization laboratory in a timely manner. Coronary angioplasty has spawned a wealth of research directed at prevention of thrombosis. The work on platelet glycoprotein IIb/IIIa receptor inhibition was stimulated by the need to prevent thrombosis at the site of angioplasty. It is unlikely that this field of research would have been advanced as far as it is today had it not been for the needs brought about by angioplasty. Once balloon angioplasty became an established therapeutic procedure, the addition of coronary stenting was a natural sequence. It was hoped that stenting would help prevent restenosis, a complication that plagued up to 20 per cent of patients undergoing balloon angioplasty. Starting slowly 15 years ago, coronary stents are now placed in 80 per cent of patients undergoing balloon angioplasty. The latest improvement is the development of drug-eluting stents to further prevent smooth muscle proliferation leading to restenosis. Chapter 9 of this important book is a reflective commentary on the respective roles of angioplasty and coronary artery bypass surgery. From its slow beginnings in 1980 where there were about 1000 angioplasties performed, there are currently 900,000 angioplasties performed annually. Most of these angioplasties are performed in patients who could not have been considered candidates when the procedure was first introduced over 25 years ago. It has already become the primary treatment of patients with coronary artery disease. Finally, I want to commend the two editors Drs Clive Handler and Michael Cleman. I first met Dr Handler when I was a Visiting Professor at the Brompton Hospital in 1985. He was a member of the Junior Cardiac Club. We became colleagues and friends, a relationship that has been a mutual pleasure for the past 20 years. Dr Cleman is my respected colleague at Yale. I have watched him grow from the time he came to Yale as a Cardiology Fellow 25 years ago, to his becoming a Professor and Head of our Interventional Cardiology Team. As I indicated in the beginning of this piece, I am grateful to both of them for the opportunity of having a second chance to visit coronary angioplasty. This time I believe I got it right. Professor Lawrence S. Cohen The Ebenezer K. Hunt Professor of Medicine Yale University School of Medicine New Haven, CT USA Fellow, British Cardiac Society

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Chapter 1

Vascular biology of atherosclerosis Peter F. Bodary, Daniel T. Eitzman Introduction The pathogenesis of atherosclerosis has been the subject of thousands of articles published over the past several decades. Currently over 5000 papers per year are being published related to atherosclerosis. To identify only eight articles from this vast literature that have had great impact on our understanding of the biology of atherosclerosis is a difficult task. It will be impossible to do justice to the hundreds of investigators that have shaped the field as it is currently viewed. Most of the fundamental concepts shaping the field of atherosclerosis were generated by pathologists through observational studies. The current view of atherosclerosis probably began with the work of Rudolph Carl Virchow, a professor of pathology, who published “Cellular Pathology” in 1858. Virchow put forth the novel notion that cells were affected by outside stimuli and that diseased cells arose from other diseased cells. Virchow suggested that the atherosclerotic lesion resulted from lipid accumulation and cellular proliferation in the arterial wall. During the same time period (1852), von Rokitansky suggested that atherosclerotic lesion development was preceded by fibrin deposition and that persistence of fibrin deposits might contribute to the formation of an atherosclerotic lesion. Many other pathologists preceding and during this time period had made similar observations and it is difficult to determine who should be credited with the original observations. Suffice it to say, many pathologists have described atheromatous changes in the vasculature but experimental data to support specific hypotheses were lacking during this time period. This review will therefore focus on papers from the more “modern era” of vascular biology. The modern biology of atherosclerosis arguably began with a series of seminal primate studies described by Russell Ross. In 1973, Ross and Glomset described the cellular composition of atherosclerotic lesions and proposed a critical role for the vascular smooth muscle cell in atherogenesis. Ross and Harker went on to propose the “response to injury hypothesis” to explain the development of atherosclerotic plaques and establish the critical role of hyperlipidemia in the initiation and progression of atherosclerosis. In 1981, Ross Gerrity established the role of the monocyte in atherogenesis using a hypercholesterolaemic swine model. This work de-emphasized the contribution of the vascular smooth muscle cell in the growing atherosclerotic lesion and stressed the importance of foam cells derived from monocytes. In 1983, Erling Falk studied human autopsy specimens and demonstrated that coronary thrombosis developed when plaque rupture occurred at a site of pre-existing coronary stenosis. Further characterization of the “vulnerable plaque” composition was provided by Michael Davies from an autopsy series of patients who died suddenly of ischaemic coronary disease. Seymour Glagov and co-workers introduced the concept of vascular remodelling when he demonstrated that the vascular wall could actually enlarge to accommodate atherosclerotic lesion growth. Further elucidation of the complexity of atherosclerotic lesions was provided by Herbert Stary when he published results of an autopsy series that included infants through young adults. These studies demonstrated that growth of the atherosclerotic plaque begins very early in life and progresses through various stages of complexity. Following the establishment of the contribution of lipids to atherosclerosis by several investigators, Brown and Goldstein elucidated the major pathway responsible for cholesterol homoeostasis. This work would earn them the Nobel prize and lead to therapeutical breakthroughs towards the battle against atherosclerotic vascular disease.

Vascular biology of atherosclerosis

Title 1

Atherosclerosis and the arterial smooth muscle cell Author Ross R, Glomset J

Reference Science 1973; 180: 1332–1339

Abstract Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis.

Summary In this paper, Russell Ross reviews the current data regarding the vascular smooth muscle cell in atherosclerosis. “Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis”. At the time this paper was written, little was known about the genesis of atherosclerosis. Previous studies had demonstrated that blood pressure, smoking and plasma lipid concentrations could influence the development of clinical symptoms of atherosclerotic vascular disease but the sequence of pathological events at the cellular level was largely unknown. Focal accumulation of intimal smooth muscle cells was argued to be critical to the early stages of atherosclerosis. Ross argued that “the accumulation of smooth muscle cells necessarily precedes or accompanies both the deposition of lipid and the accumulation of extracellular connective matrix, because the lipid deposits occur either within smooth muscle cells or outside them in association with connective tissue matrix components which are secretory products of smooth muscle cells”. Ross stated that smooth muscle cell proliferation began when a breach of endothelial integrity occurred that would allow substances present in the plasma to stimulate cellular proliferation. Studies supporting these observations included the tendency of vascular smooth muscle cells to accumulate in the intima at arterial branch points, where endothelial permeability appeared to be increased. Stemerman and Ross had also demonstrated experimentally using macaques that vascular lesions could be induced by denuding the femoral artery vascular endothelium with balloon catheters. Three months after injury, the lesion contained as many as 15 layers of smooth muscle cells surrounded by collagen and immature elastic fibers. These lesions were described as identical in appearance to the “fibromusculoelastic” lesions seen in man. Ross also reviews evidence (in vitro and in vivo) that lipids appear to influence proliferation of vascular smooth muscle cells and that vascular smooth muscle cells are responsible for production of extracellular matrix.

Citation Count

986

Key message Vascular smooth muscle cell proliferation plays a critical role in the development and growth of atherosclerotic lesions.

Strengths The identification of vascular smooth muscle cells and the time course of proliferation and matrix production following vascular injury greatly enhanced the understanding of vascular lesion

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Classic Papers in Coronary Angioplasty

(a)

(b)

(c)

Figure 1 Light micrographs demonstrating (a) a normal primate iliac artery (Mecaca nemestrina) (⫻550); (b) an iliac artery 3 months after de-endothelialization, showing a marked increase in intimal thickness due to accumulation of smooth muscle cells and extracellular matrix (⫻500); and (c) an iliac artery 6 months after de-endothelialization, by which time the intimal thickness had returned to one to two layers (⫻500). This sequence demonstrated the relative reversibility of an experimentally induced lesion in a monkey on a normal diet with normal concentration of plasma lipid. formation. This work also identified the smooth muscle cell as a therapeutical target towards the prevention of vascular disease.

Weaknesses Conclusion regarding cell types and cellular proliferation in atherosclerosis were based on studies of femoral artery injury in primates. The lesions that develop following arterial injury with balloon catheters (neointima) are fibrous and are not the same as those that occur in naturally occurring atherosclerosis. In addition, accurate means of identifying cell types in atherosclerotic plaques were not available at the time of this paper.

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Vascular biology of atherosclerosis

Title 2

Hyperlipidemia and atherosclerosis Author Ross R, Harker L

Reference Science 1976; 193: 1094–1100

Abstract Chronic hyperlipidemia initiates and maintains lesions by endothelial cell desquamation and lipid accumulation.

Summary In this paper, Ross and Harker describe the effect of hyperlipidemia on the growth of vascular lesions, with and without mechanical injury, in primates. The article begins with an overview of the response to injury hypothesis to explain atherosclerosis development. According to this hypothesis (in 1976), everyone is susceptible to various forms of endothelial injury including mechanical, chemical, immunological and toxic sources. If the injury is a single event, the lesions would be reversible but continuous exposure to a toxic stimulus would lead to lesion progression which may be irreversible. Upon disruption of endothelial integrity, the vascular smooth muscle cells would be exposed to elements from the plasma that would stimulate proliferation. At the time of this paper, the principle mitogen present in blood serum responsible for the stimulation of smooth muscle cell growth was thought to be platelet-derived. In studies examining the effect of hyperlipidemia on vascular lesion formation, a group of monkeys were fed a hypercholesterolaemic diet and followed for up to 18 months after aorto-iliac balloon injury. At 6 weeks to 3 months following arterial injury, hypercholesterolaemic monkeys displayed thickened intima filled with lipidladen cells which were presumptively identified as vascular smooth muscle cells. The number of cells comprising the intima in a control group of normolipidemic monkeys following injury was similar but the amorphous lipid inclusions were lacking. Long-term follow-up revealed that the lesions in the hyperlipidemic group had progressed while those in the normolipidemic group had regressed. Thus, hyperlipidemia promoted intimal growth after injury. Critical observations were then made in the non-injured iliac artery. By 10 months following initiation of hyperlipidemia, there were no differences between the injured and non-injured iliac arteries. Both arteries (injured and non-injured) contained 10–15 layers of lipid-laden smooth muscle cells surrounded by extracellular lipid and large quantities of newly formed connective tissue matrix. To search for evidence that hyperlipidemia was causing endothelial injury, Ross examined endothelial integrity in the hyperlipidemic animals using special staining techniques. In all of the hyperlipidemic animals, there was focal loss of endothelial cells accounting for approximately 5% of the aorto-iliac endothelial surface. In some areas, the longitudinal shape of the endothelial cells had changed to a polyhedral or round configuration, indicating abnormal endothelial regeneration. Since platelet-derived factors were believed to be critical to the growth of vascular lesions following endothelial injury, measures of platelet activity were performed. Ross and Harker found that platelet survival was reduced from 8 days to 5.8 days in animals that were hyperlipidemic for more than 6 months. To determine whether the reduced platelet survival was due to increased platelet consumption at exposed endothelial surfaces or secondary to a direct effect of hyperlipidemia, labelled platelets were transfused from a normolipidemic animal into a hyperlipidemic

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animal and from a hyperlipidemic animal to a normolipidemic animal. Platelets from the hyperlipidemic animals survived normally in the normolipidemic animals while survival of platelets from the normolipidemic animals was reduced in the hyperlipidemic animals. The authors concluded that reduced platelet survival was due to increased platelet consumption on exposed subendothelium and they went on to demonstrate a correlation between the amount of endothelium removed and platelet survival.

Citation Count

543

Key message Hyperlipidemia is sufficient to cause endothelial injury, initiation, and growth of atherosclerotic plaques. This study also demonstrated the effect of the hyperlipidemic environment on the progression of vascular lesions following mechanical injury.

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Vascular biology of atherosclerosis

Strengths In a primate model, the authors clearly demonstrated a critical direct role for a hypercholesterolaemic diet in the initiation and progression of atherosclerosis. The implications of these studies were that understanding and targeting factors involved in lipid metabolism could lead to therapeutic breakthroughs.

Weaknesses The hypothesis that platelets or platelet products were essential to growth of the atherosclerotic plaque was not adequately tested. Thus the role of platelets in atherosclerotic lesion growth, based on in vitro vascular smooth muscle cell culture experiments and the transfusion experiments, was probably overemphasized.

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Classic Papers in Coronary Angioplasty

Title 3

The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions II. Migration of foam cells from atherosclerotic lesions Author Gerrity RG

Reference Am J Pathol 1981; 103: 181–190, 191–199

Abstract Paper I: In a previous publication the author and his co-workers demonstrated that atherosclerotic lesion development in the aorta of hypercholesterolemic pigs was preceded by intimal penetration of blood-borne mononuclear cells, and that medial smooth muscle cells were not involved in the formation of early fatty lesions in this model. The current study shows that aortic arch lesions do not progress beyond the fatty cell lesion stage for up to 30 weeks of a moderate cholesterol/lard diet, although they become more extensive in area. Mononuclear cells were found adherent to the endothelium, in endothelial junctions, and in the intima during this period, and were ultrastructurally identified as monocytes by the presence of peroxidase-positive granules (peroxisomes) in their cytoplasm. In addition, lesion areas with nonspecific esterase activity correlated well with Sudan IV staining. Intimal monocytes and altered intimal monocytes with an enlarged cytoplasm and containing a few lipid droplets were both shown to be phagocytic by their uptake of ferritin, which had penetrated the intima after intravenous injection. Circulating monocytes and those adherent to the endothelial surface did not contain ferritin in these animals. The results indicate that blood mononuclear cells associated with lesion formation in this model are, in fact, monocytes, which subsequently undergo transformation into macrophage foam cells in fatty streak lesions. The absence of medial cell involvement indicates that monocytes are the major foam cell precursor in these lesions. Paper II: A defined role in the atherogenic sequence is proposed for the circulating monocyte. The author has been able to demonstrate a “monocyte clearance system” in which large numbers of circulating monocytes invade the intima of lesion-prone areas in arteries, become phagocytic, and accumulate lipid. A fatty cell lesion results. Once lipid-laden, foam cells migrate back into the bloodstream by crossing the arterial endothelium. The ratio of penetrating monocytes to emerging foam cells decreases as fatty cell lesions develop until a one-to-one ratio is achieved in late fatty cell lesions, which do not progress further. Advanced fibroatherosclerotic plaques in the same animals do not show the same characteristics and have smooth muscle cell involvement. It would appear that advancement of the lesion is at least partially a result of failure of the monocyte clearance system to remove sufficient lipid. The invasion of monocytes and endothelial damage caused by foam cell clearance may, in late fatty lesions, contribute to plaque evolution by introducing growth factors from macrophages and platelets and allowing greater lipid influx. Elucidation of this system was facilitated by the examination of vessels from diet initiation onwards and by the observation of late nonprogressing fatty cell lesions. It is possible that this

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Vascular biology of atherosclerosis

(a)

(c)

(b)

(d)

Figure 1 (a) TEM of monocyte (M) trapped in junction of endothelium (E) from arch area of 12-week pig. Main body and nucleus of cell are in the lumen (Lu), with cellular extensions (arrows) spread below endothelium (uranyl acetate, lead citrate, ⫻12,400). (b) Monocyte (M) beneath endothelium (E) in a 15-week arch lesion from a pig injected with ferritin 15 min before death. Ferritin can be seen in phagocytotic vacuoles (arrows), one of which is open to the intimal space. Inset shows ferritin in vacuole in squared area (unstained, ⫻15,500; inset, ⫻61,000). (c) SEM of monocyte (M) adherent to endothelium (E). Cytoplasmic extensions from monocyte can be seen to indent endothelial plasma membrane (arrows); (d) TEM of “hypertrophied” monocyte (HM) beneath endothelium (E) in 30-week abdominal lesion. Peroxidase-positive granules (arrows) can be seen in the cytoplasm (uranly acetate, lead citrate; peroxidase-reacted, ⫻12,500). system exists in other models but has been overlooked by a predilection for the study of advanced lesions that prevails in the literature.

Summary In this paper, parts I and II, Ross Gerrity described the progression of atherosclerotic lesions in a hypercholesterolaemic pig model. At the time of these studies the predominant cell type in growing

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atherosclerotic plaques was controversial with much emphasis placed on the vascular smooth muscle cell. Although other authors had described monocytes in atherosclerotic lesions, this paper carefully studies the progression of atheroma at different time points and characterizes the lesion composition. Yorkshire pigs were fed a normal chow or high-fat chow and sacrificed at 6, 12, 15 and 30 weeks after the initiation of diet. At 15 weeks following high-fat chow, “lesions were always of a foam cell nature, confined to the intima, with no evidence of medial cell involvement in the intima or engorgement of smooth muscle cells with lipid”. Monocytes were identified using various histological criteria. At 30 weeks following high-fat diet, fibrous lesions were described as fibrous caps overlying necrotic lipid cores. Gerrity hypothesized, based on this and earlier studies from his group, that blood-derived monocytes adhere to the endothelium, which is not necessarily associated with endothelial damage, and then penetrate into the intima. He also demonstrated that intimal monocytes are phagocytic at a time that lipid droplets appear in their cytoplasm. Thus, early lesions of atherosclerosis consist of monocyte foam cells that actively accumulate lipid and may be a source of a growth factor. The author also suggests a role of the monocyte in lesion lipid efflux.

Citation Count

Paper I: 1132, Paper II: 354

Key message Blood-derived monocytes are the predominant cell type in early atherosclerotic lesions. This is a fundamental underpinning to our current understanding of atherosclerosis as an inflammatory disease.

Strengths A detailed histological examination with elegant electron micrographs of lesions at various stages of development using a hypercholesterolaemic pig model.

Weaknesses Primarily observational, descriptive data.

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Vascular biology of atherosclerosis

Title 4

A receptor-mediated pathway for cholesterol homoeostasis Author Brown MS, Goldstein JL

Reference Science 1986; 232: 34–47

Abstract Not available.

Summary Animal models of hypercholesterolaemia, as described in the preceding papers, as well as humans with familial hypercholesterolaemia indicated an enormous potential for the role of cholesterol metabolism in atherosclerosis. Brown and Goldstein embarked on their studies of cholesterol homoeostasis in 1972, in an attempt to understand the human genetic disease, familial hypercholesterolaemia (FH), a disease characterized by marked hypercholesterolaemia with premature myocardial infarction. FH heterozygotes, carrying a single copy of a mutant lowdensity lipoprotein (LDL) receptor gene, are common accounting for about 1 in 500 persons. LDL levels are approximately doubled in these individuals and myocardial infarctions begin to occur in the 30 s and 40 s. The homozygous FH frequency is about 1 in a million persons and is characterized by a 6–10-fold elevation in LDL and myocardial infarctions beginning in childhood. The existence of the homozygous state facilitated the discoveries of Brown and Goldstein as they could study effects of the mutant gene without confounding effects of the normal gene. The authors demonstrated that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase), the rate limiting step in cholesterol biosynthesis, was subject to negative regulation in cultured fibroblasts, i.e. activity was upregulated when lipoproteins were removed from the culture media and suppressed when they were added. This suppression only occurred with LDL, and at relatively low concentrations, suggesting the possibility of a high-affinity receptor. Homozygous FH cells had HMG CoA reductase activities that were extremely high and were not subject to regulation by LDL in the medium. This suggested that there may be a defect in the HMG CoA reductase gene that rendered it’s expression resistant to LDL. However, when cholesterol was dissolved in ethanol so that it could enter cells passively, suppression of HMG CoA reductase activity was achieved. These studies supported the hypothesis of a cell surface lipid receptor. This was proven with radiolabelled LDL, which bound to normal fibroblasts and not FH-homozygous fibroblasts. The investigators and associates went on to demonstrate that cholesterol generated from LDL within the lysosome was the second messenger responsible for suppressing HMG CoA reductase activity. Cholesterol acts at several levels to influence lipid homoeostasis including suppression of transcription of the HMG CoA reductase gene and acceleration of the degradation of the enzyme protein. The LDL-derived cholesterol also activates a cholesterol-esterifying enzyme, acyl-CoA: cholesterol acyltransferase (ACAT), and suppresses the synthesis of LDL receptors by lowering the concentration of LDL receptor mRNA. Thus, the cells can adjust the number of LDL receptors to provide adequate cholesterol for metabolic needs without causing cholesterol overaccumulation. At least 10 different mutations in the LDL receptor were identified by structural criteria and separated into 4 classes. These included mutations that lead to the absence of LDL receptors,

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1.

HMG CoA reductase

2.

ACAT

LDL receptors LDL

Cholesterol Cholesteryl linoleate 3. LDL receptors

Protein

Cholesteryl linoleate

Amino acids LDL binding

Lysosomal hydrolysis

Internalization

Regulatory actions

Figure 1 Sequential steps in the LDL receptor pathway of mammalian cells. Vertical arrows indicate the direction of regulatory effects. mutations that alter receptor transport from the ER to the Golgi, mutations that lead to abnormal binding to LDL and mutations leading to failure of LDL receptors to cluster in coated pits.

Citation Count

2878

Key message Cholesterol homoeostasis is under exquisite control by a complex cellular pathway initiated by a high-affinity LDL cell surface receptor.

Strengths The pathways elucidated by Brown and Goldstein not only explained the cause of many cases of hyperlipidemia but have also served as the foundation for pharmaceutical discovery platforms aimed at prevention of coronary artery disease.

Weaknesses None.

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Title 5

Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis Author Falk E

Reference Br Heart J 1983; 50: 127–134

Abstract Ruptured atheromatous plaques were identified by step-sectioning technique as responsible for 40 of 51 recent coronary artery thrombi and 63 larger intimal haemorrhages. The degree of preexisting luminal narrowing at the site of rupture was decisive for whether plaque rupture caused occlusive thrombosis or just intimal haemorrhage. If the pre-existing stenosis was greater than 90% (histologically determined) then plaque rupture nearly always caused occlusive thrombosis. Clearly indicating the primary role of plaque rupture in thrombus formation were the frequent finding of plaque fragments deeply buried in the centre of the thrombus and the nature of the thrombus at the site of rupture where it consisted predominantly of platelets. Thus, a severe chronic stenosis seems to be a prerequisite for occlusive thrombus formation, but the thrombotic process itself is triggered by an acute intimal lesion.

Summary At the time of this paper, there was general agreement that clinical complications of atherosclerotic vascular disease, such as myocardial infarction and stroke were due to thrombotic vascular occlusion. However, the underlying substrate or triggering mechanism for these thrombotic events was not well understood. In this paper, Erling Falk studied 47 patients with suspected fatal ischaemic heart disease. Postmortem angiography was performed along with detailed histological examination of the coronary arteries. Forty of 103 sites of plaque rupture identified were associated with significant recent luminal thrombosis, 95% of which were occlusive. In general, the greater the degree of underlying stenosis, the higher the risk of occlusive thrombosis. An underlying ruptured atheromatous plaque was identified in 82% of recently thrombosed coronary segments. No obstructions due to intimal haematoma (haemorrhage) were identified in this study.

Citation Count

548

Key message Thrombotic complications of coronary atherosclerosis are due to plaque rupture.

Strengths A combined postmortem angiographical and coronary histological study with excellent histological examples of plaque rupture and occlusive thrombosis.

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Classic Papers in Coronary Angioplasty

(c)

(a) 1

4

2

5

3

6

(d)

(e)

(b)

Figure 1 A case clearly illustrating the primary role of plaque rupture in the pathogenesis of occlusive coronary thrombosis. (a) Postmortem angiogram showing total occlusion of the left anterior descending artery at the arrow (original magnification ⫻0.6). (b) The thrombosed vascular segment is cut transversely at 2–3 mm intervals (white contrast medium in the non-thrombosed vascular lumen). Section no. 2 shows the disrupted fibrous cap (arrow), and it is seen that both a cap fragment and fatty atheromatous substance have been lost. The thrombotic process has started at the site of rupture (Section no. 2–4) and attains its occlusive property just distal to the rupture (Section no. 5). (c) Microscopy of Section no. 4 shows direct communication between the vascular lumen and the atheromatous “gruel” (big arrow) and mural thrombosis at one of the free edges of the torn fibrous cap which projects into the lumen (small arrow) (original magnification ⫻13). (d) Microscopy of Section no. 5 shows a detached fragment of the fibrous cap (small asterisk) and atheromatous material with cholesterol clefts (big asterisk) intimately mixed with aggregated platelets in the vascular lumen (original magnification ⫻15). (e) Histological section from the perfusion area of the left anterior descending artery showing an intramyocardial artery occluded by a platelet embolus containing atheromatous plaque material with cholesterol clefts from the ruptured plaque proximal in the artery (original magnification ⫻33).

Weaknesses A relatively small series. Thrombosis occurring at sites of less severe atherosclerotic lesions may have been less stable and more likely to be dislodged or lysed by the time histological examination was performed. Thus the conclusion that occlusive thrombosis occurs only at sites of severe underlying stenosis may have been overstated.

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Title 6

Compensatory enlargement of human atherosclerotic coronary arteries Author Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ

Reference N Engl J Med 1987; 316: 1371–1375

Abstract Whether human coronary arteries undergo compensatory enlargement in the presence of coronary disease has not been clarified. We studied histologic sections of the left main coronary artery in 136 hearts obtained at autopsy to determine whether atherosclerotic human coronary arteries enlarge in relation to plaque (lesion) area and to assess whether such enlargement preserves the cross-sectional area of the lumen. The area circumscribed by the internal elastic lamina (internal elastic lamina area) was taken as a measure of the area of the arterial lumen if no plaque had been present. The internal elastic lamina area correlated directly with the area of the lesion (r
0.44, p less than 0.001), suggesting that coronary arteries enlarge as lesion area increases. Regression analysis yielded the following equation: Internal elastic lamina area
9.26  0.88 (lesion area)  0.026 (age)  0.005 (heart weight). The correlation coefficient for the lesion area was significant ( p less than 0.001), whereas the correlation coefficients for age and heart weight were not. The lumen area did not decrease in relation to the percentage of

Figure 1 Photograph of a cross section of a typical left main coronary artery with an advanced atherosclerotic plaque (left panel), and a corresponding contour tracing of the artery (right panel). The lumen (Lu) is clearly demarcated by the intimal surface. The internal elastic lamina (arrowheads) is readily discernible for most of the vessel circumference and almost always beneath the plaque as well, despite underlying atrophy of the media where the plaque and arterial wall tend to bulge outward (between the arrows). The area occupied by the lesion (Le) is shaded. The cross-sectional stenosis is defined as the extent to which the area encompassed by the internal elastic lamina (i.e. the potential lumen area if no plaque were present) is occupied by the lesion (percentage of stenosis, lesion area/internal elastic area ⫻100). In this vessel, the cross-sectional stenosis is 46% (magnification, ⫻7.4).

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Classic Papers in Coronary Angioplasty

stenosis (lesion area/internal elastic lamina area  100) for values between zero and 40 percent but did diminish markedly and in close relation to the percentage of stenosis for values above 40 percent (r
0.73, p less than 0.001). We conclude that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40 percent of the internal elastic lamina area. The preservation of a nearly normal lumen cross-sectional area despite the presence of a large plaque should be taken into account in evaluating atherosclerotic disease with use of coronary angiography.

Summary The purpose of this study was to determine whether human coronary arteries undergo compensatory enlargement in the presence of atherosclerosis. Histological analysis of left main coronary arteries was performed on 136 human hearts. Among the specimens there was a wide range of lumen area and lesion sizes. Comparisons between specimens revealed that lesion area increased with age at a rate of 0.08 mm2 per year and lumen area decreased at a rate of 0.37 mm2 for each mm2 increase in lesion area. The internal elastic lamina area increased at a rate of 0.60 mm2 for each mm2 increase in lesion area. Thus, the vessel wall area increased with growth of the lesion, a relationship independent of age and heart weight. When a plot was made of lumen area vs. percentage of stenosis, there was no relationship of lumen area with stenosis up to 40% stenosis. However, as the stenosis increased above 40%, there was a marked reduction of lumen area. Thus, during early stages of plaque growth there is preservation of lumen size accomplished by expansion of the arterial wall.

Citation Count

1103

Key message Arterial remodelling occurs with growth of atherosclerotic plaques. Coronary angiograms that use contrast agents to opacify the arterial lumen may markedly underestimate atherosclerotic burden.

Strengths This was the first clear demonstration of vascular remodelling in humans. The implications of the concept of vascular remodelling with the accompanying necessary matrix turnover have generated an entire new field of study in vascular biology.

Weaknesses This was not a longitudinal study. Thus a diverse population with varying risk factors could have affected the results. Only the left main artery was studied. Different results may occur in smaller arteries.

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Title 7

Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults Author Stary HC

Reference Arteriosclerosis 1989; 9(Supp): I-19–I-32

Abstract In an autopsy study of the evolution of atherosclerotic lesions in young people, we obtained the coronary arteries and aortas of 1160 male and female subjects who died between full-term birth and age 29 years. In this article, we report the light and electron microscopic observations of the coronary arteries of 565 of these subjects in which we fixed the coronary arteries by perfusion with glutaraldehyde under pressure. From birth, the intima was always thicker in the half of the coronary artery circumference opposite the flow-divider wall of a bifurcation (eccentric thickening). In cases where we found lipid in the intima, there was always more in eccentric thickening. Isolated macrophage foam cells in the intima of infants were the earliest sign of lipid retention. These cells occurred in 45% of infants in the first 8 months of life but decreased subsequently. At puberty, more substantial accumulations of macrophage foam cells reappeared in more children. Foam cells were now accompanied by lipid droplets in existing smooth muscle cells and by thinly scattered extracellular lipid. Sixty-five percent of children between ages 12 and 14 years had such lesions. An additional 8% of children had progressed beyond this early stage and had developed advanced preatheroma or atheroma stages. Such advanced lesions, located only in areas of eccentric thickening, were characterized by the addition of massive extracellular lipid that displaced normal cells and matrix and, thus, damaged and weakened the arterial wall.

Summary This paper describes a large series of coronary histology data from 565 human subjects who died between full-term birth and 29 years of age. At the time of this study, there was controversy regarding the extent of atherosclerosis in the young and at what age dietary interventions to reduce atherosclerosis should be instituted. The left main, proximal left anterior descending and proximal circumflex arteries were analysed. Based on the findings of this series, a classification system was developed to characterize development of atherosclerotic lesions. Type 1 lesions consist of isolated macrophage foam cells in the proteoglycan layer with no extracellular lipid or vascular smooth muscle cells. These lesions were seen in some infants as early as the first week of life and appeared to be decreased after the first year. Type II lesions are fatty streaks composed of layers of cells with lipid droplet-inclusions. More macrophages are present than type I lesions. These lesions were noted beginning from late in the first decade of life. A type III lesion is a preatheroma that is intermediate between the fatty streak and the atheroma. These lesions contain all the components of a fatty streak with a marked increase in the number of extracellular lipid particles. They appear grossly as a small white elevation and are typically seen beginning in the mid second decade of life. Type IV lesions were seen in subjects beginning at the end of puberty

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(a)

(b)

Figure 1 (a) Outer wall at the level of the left main coronary artery just proximal to the main bifurcation. Extracellular lipid (arrows) is abundant and concentrated in the musculoelastic layer (me) of eccentric thickening and displaces some structural intimal smooth cells. Macrophage foam cells (fc) and lipid-laden smooth muscle cells are layered above the extracellular aggregates. Such lipid deposits were classified as preatheroma (type III lesion). From a 25-year-old white man who died in a motorcycle accident. (b) Outer wall at the LAD 1 level with eccentric thickening now metamorphosed into a lesion classified as atheroma (type IV lesion). Extracellular lipid now forms a confluent core in the musculoelastic layer of eccentric thickening. While this lipid deposit thickens the intima, it also weakens the wall as it displaces structural smooth muscle cells. From a 19-year-old white man who committed suicide. Pgc: proteoglycan intima; M: media; and A: adventitia.

and consisted of large lipid or necrotic cores. Macrophage foam cells were seen bordering the lipid core on the luminal aspect of the lesion. A type V lesion is a fibroatheroma in which the proteoglycan layer has changed in composition with an increased number of smooth muscle cells embedded in a dense matrix of collagen and capillaries. This layer of smoothmuscle cells becomes a fibrous cap. These lesions were typically seen beginning in the mid third decade of life. Stary described the frequency of the various lesions at different ages and this data established that vascular lesions are quite common even in young children. This study raised many questions regarding the sequence of events that would lead to a fatty streak at such young ages and subsequent progression of lesion complexity.

Citation Count

15

Key message Vascular lesions consistent with early atherosclerosis begin very early in life and appear to progress in complexity through a series of defined stages.

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Vascular biology of atherosclerosis

Strengths Detailed, extensive histological examination of very young human subjects. The idea that lesion growth occurs through predictable stages representing various cellular and molecular events set a framework for future investigations.

Weaknesses Descriptive study. Although this classification system has been useful to facilitate our understanding of atherogenesis, the staging of atherosclerotic lesions may be an oversimplification of the underlying pathophysiology and not take into account the marked heterogeneity of atherogenesis between individuals.

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Title 8

Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content Author Davies MJ, Richardson PD, Woolf N, Katz DR, Mann J

Reference Br Heart J 1993; 69: 377–381

Abstract OBJECTIVE: To assess the size of the lipid pool and the number of smooth muscle cells and monocyte/macrophages in human aortic plaques that were intact and to compare the results with those in aortic plaques undergoing ulceration and thrombosis. DESIGN: The lipid pool was measured as a percentage of the total cross sectional area of the plaque. Immunohistochemistry was used to identify cell types (monocytes/macrophages (M phi) by EBM11 and HAM56, smooth muscle cells by alpha actin). The area of the tissue occupied by each cell type was measured by quantitative microscopy in the peripheral (shoulder) area of the plaque and the plaque cap. Absolute counts of each cell type were expressed as the ratio of SMC:M phi. MATERIAL: Aortas were obtained at necropsy from men aged less than 69 years who died suddenly (within 6 hours of the onset of symptoms) of ischaemic heart disease. 155 plaques from 13 aortas were studied. Four aortas showed intact plaques only (group A, n
31). Nine aortas showed both intact plaques (group B, n
79) and plaques that were undergoing thrombosis (group C, n
45). RESULTS: In 41 (91.1%) of the 45 plaques undergoing thrombosis (group C) lipid pools occupied more than 40% of the cross sectional area of the plaque. Only 12 (10.9%) of the 110 intact plaques (groups

Figure 1 Contrast between an intact advanced aortic plaque (left), in which the surface is opaque and smooth, and early ulceration (right), in which thrombus has formed over the plaques. However, a large part of the plaque is not covered by thrombus.

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Vascular biology of atherosclerosis

A  B) had lipid pools of this size. The mean size of the lipid pool in plaques of groups A, B, and C was 12.7%, 27.3% and 56.7% respectively. Compared with intact plaques those undergoing thrombosis contained a smaller volume of smooth muscle cells (2.8% v 11.8%) and a larger volume of monocyte/macrophages (13.7% v 2.9%) in the plaque cap. The ratio of the number of smooth muscle cells to monocytes/macrophages was 7.8 in group A plaques, 4.1 in group B plaques, and 1.0 in group C plaques. This gradient was the result of an absolute increase in monocyte/macrophages and an absolute decrease in smooth muscle cells. CONCLUSIONS: In the aorta ulceration and thrombosis were characteristic of plaques with a high proportion of their volume occupied by extracellular lipid, and in which there was a shift toward a preponderance of monocyte/macrophages compared with smooth muscle cells in the cap.

Summary This study was one of the first to characterize the composition of atherosclerotic plaques at risk for thrombosis. To address this important issue, aortas were obtained at necropsy from adult males who died suddenly of ischaemic heart disease. 155 plaques from 13 aortas were analysed. In 41 of 45 disrupted plaques (91%) with thrombosis, the lipid pool occupied more than 40% of the cross-sectional area of the plaque whereas only 11% of intact plaques had lipid pools of this size. Compared with intact plaques, those with thrombosis also contained a smaller volume of smooth muscle cells (2.8 vs. 11.8%) and a larger amount of monocyte macrophages (13.7% vs. 2.9%) in the cap of the plaque.

Citation Count

397

Key message Atherosclerotic plaques at risk of thrombotic complications are characterized by large lipid pools, thin fibrous caps and increased macrophage activity.

Strengths These relatively simple observations have stood the test of time. Systemic indices of inflammation which probably correlate with plaque inflammation (i.e. macrophage activity) have proven potent indicators of cardiac risk. Potent lipid lowering therapies which appear to reduce large lipid pools and inflammatory activity have been shown to reduce cardiovascular events. Additional therapies targeting plaque stabilization are under development.

Weaknesses Only aortas were analysed in this study which may not exhibit identical pathology to coronary arteries. Since only autopsy specimens were analysed, it is difficult to prove whether the changes in plaque cellular composition observed in the setting of thrombosis were a cause or effect of the thrombus.

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Chapter 2

Quantification of coronary atherosclerosis for cardiovascular risk assessment: the hole in the doughnut? Paul Schoenhagen, Steven E. Nissen Introduction A tomographical section of a diseased coronary artery, which is characterized by the central lumen and the surrounding thickened vessel wall, roughly resembles a doughnut. Depending on the imaging modality used, this basic coronary anatomy is described from different perspectives. Angiographical techniques described the size and characteristics of the lumen. In contrast, tomographical techniques, including intravascular ultrasound (IVUS), computed tomography (CT), and magnetic resonance imaging (MRI), describe the plaque and the vessel wall. If the overall diameter of the coronary arteries were fixed (as is the case in a pipe of a water faucet), changes in plaque size would always be reflected in luminal dimensions. However, it has become obvious that coronary pathophysiology is far more complex than reflected in the historical comparison of diseased arteries with “rusty pipes”. This has important implications for the quantitative assessment of coronary artery disease. The following selection of eight articles, reflecting 50 years of research, will provide a review of this changing understanding of coronary atherosclerosis and the emerging role of contemporary atherosclerosis imaging for cardiovascular risk assessment. It is remarkable that two investigators, Crawford and Levene, already described the complexity of coronary pathology in 1953 (Paper no. 1). Based on the observations of pressuredistended and undistended aortic wall specimens, the authors stated that “ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media, which may bulge outwards”. Not surprisingly, these post-mortem observations did not find widespread clinical attention, because in vivo imaging of coronary arteries to confirm clinical significance, was not possible. A few years later, in the late 1950s, selective coronary angiography was the first imaging modality introduced to clinical cardiology. As described in the paper by Proudfit, Shirey, and Sones (Paper no. 2), the diagnosis of coronary disease in the pre-angiographical era relied solely on the elucidation of historical or clinical symptoms of ischaemia. The correlation of these ischaemic syndromes with angiographical findings naturally lead to the definition of disease by the severity of luminal stenosis. It therefore appeared logical to define changes of disease severity (progression/regression) by changes in luminal dimension. This became possible through quantitative coronary angiography, which allowed precise assessment of luminal dimensions in serial research protocols (Paper no. 3). Proudfit et al. had already described a correlation of disease severity and serum cholesterol levels in young patients (Paper no. 2), and subsequent serial studies using quantitative coronary angiography examined luminal changes during lipid-lowering treatment (Paper no. 4). These studies suggested less progression or greater propensity for regression in the treatment group and demonstrated the value of luminal dimensions in the assessment of disease severity. However, the changes in luminal size were surprisingly small in comparison to the observed large clinical benefit, demonstrated in a decreased event rate during follow-up. In order to explain this discrepancy, it has been suggested that changes in qualitative rather than quantitative plaque characteristics induce clinical disease stabilization.

Quantification of coronary atherosclerosis for cardiovascular risk assessment

However, emerging tomographical imaging modalities demonstrated limitations of the angiographical description of coronary disease. IVUS, performed during cardiac catheterization, for the first time allowed in vivo assessment of the vessel wall (Paper no. 5). The initial observations of atherosclerotic plaque characteristics coincided with a seminal post-mortem study of human coronary arteries reminiscent of Crawford and Levene’s observation. In this study, Dr Glagov, a pathologist at the University of Chicago, systematically described the relation between plaque size and luminal dimension, and suggested that early plaque accumulation was typically not reflected in luminal change because of an outward bulging or “remodelling” of the overall vessel size (Paper no. 6). In a clinical arena focused on luminal size and the paradigm that “bigger is better”, outward or “positive” remodelling was understood as a compensatory mechanism intended to maintain luminal size. However, subsequent post-mortem and imaging studies challenged that view by consistently demonstrating an association between outward remodelling of coronary lesions and unstable clinical presentation (Paper no. 7). These results suggest that plaque progression is initially accommodated by an expansion of vessel diameter rather than luminal stenosis. It appears that these outward remodelled but mildly stenotic lesions (vulnerable or high-risk plaques) have a particular tendency to rupture, initiating acute coronary events. It is an attractive hypothesis that changes of regression are also reflected mainly in plaque size rather than luminal dimension. These data provided the rational of using tomographical imaging for the quantitative assessment of disease progression and regression. Several invasive and non-invasive imaging modalities are used to assess disease burden in different areas of the vascular tree. In the last few years, IVUS has been developed into a reliable quantitative modality, allowing serial observation of coronary plaque volume during pharmacological treatment. A series of such studies are currently examining changes in plaque volume in non-intervened vessels of patients enrolled at the time of coronary intervention. The recently published results from the Apo A-I Milano Trial (Paper no. 8), demonstrate for the first time that disease regression in patients presenting with acute coronary syndromes can be induced by aggressive modification of high-density lipoprotein (HDL) levels. The response in the first weeks after the event emphasizes the highly dynamic nature of coronary artery disease. These serial studies will eventually allow to compare plaque burden, plaque characteristics, systemic markers of inflammation, and clinical outcome. These results will be important for disease prevention in primary setting but also for secondary prevention following the interventional treatment of symptomatic patients.

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Title 1

Medial thinning in atheroma Author Crawford T, Levene CI

Reference J Pathol Bacteriol 1953; 66: 19–23

Abstract The amount of medial thinning at atheromatous areas was measured from aortas and iliac arteries fixed in the usual way and in the distended state at arterial pressure. All but one of 134 plaques from undistended vessels and all 76 plaques from vessels fixed in distension showed definite medial thinning. In the distended vessels the ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media which may bulge outwards. Only advanced plaques with recent thrombotic accretions project noticeably into the lumen. The familiar intimal bulge is in fact a post-mortem artifact. Physical considerations rule out pressure as the cause of the medial thinning, and the occurrence of outward bulging of the media indicates that something more than a disuse atrophy is concerned. The early and constant appearance of the medial thinning supports the contention that it is not a secondary result of the atheromatous process but an essential part of it, and the lesion as a whole is comparable to a shallow aneurysm partially or completely filled by the plaque of intimal thickening.

Summary This paper from 1953 already described the complexity of coronary pathology. Based on observations of pressure-distended or undistended aortic wall specimens, the authors demonstrate that atherosclerotic plaque progression may occur without changes in luminal dimension, as “ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media, which may bulge outwards”.

Citation Count

99

Related References 1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990’s. Nature 1993; 362: 801–809. 2. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 104: 365–372. 3. Moreno PR, Purushothaman KR, Fuster V, O’Connor WN. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta: implications for plaque vulnerability. Circulation 2002; 105: 2504–2511. 4. Zarins CK, Xu C, Glagov S. Atherosclerotic enlargement of the human abdominal aorta. Atherosclerosis 2001; 155: 157–164.

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Quantification of coronary atherosclerosis for cardiovascular risk assessment

5. Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310: 1137–1140.

Key message The shape of the lumen of the distended vessels is of further interest in that it implies that the familiar centrally bulging plaques which are such a feature of the aorta in the autopsy room are in fact a post-mortem artefact produced by abnormal shortening of the medial fibres when the blood pressure falls at death. Our observations have been limited to the aorta and iliac arteries, but that the same holds for the coronary arteries is suggested by the work of Stewart, Birchwood and Wells (1935), and of Harrison and Wood (1949).

Why it’s important This paper challenges the role of luminal dimension as the sole predictor of disease significance at a time when coronary angiography was just emerging.

Strengths It is remarkable that Crawford and Levene made these observations based on a simple but original experiment in 1953, before the availability of in vivo imaging.

Weaknesses The lack of in vivo imaging did not allow confirmation in clinical studies.

Relevance This study emphasized that plaque development may be dissociated from luminal dimensions, a concept reappearing in later studies. However, it is not surprising that these post-mortem observations did not find widespread clinical attention, because in vivo imaging of coronary arteries was not possible.

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Title 2

Selective cine coronary arteriography: correlation with clinical findings in 1000 patients Author Proudfit WL, Shirey EK, Sones Jr FM

Reference Circulation 1966; 33: 901–910

Abstract Symptoms of coronary arterial disease generally occur in association with obstruction of the coronary arteries in the absence of valvular defects. Until recent years accurate information relative to obstructive lesions in the coronary arteries could not be obtained from the living patient. In the absence of definite electrocardiographic diagnosis of myocardial infarction, clinical diagnosis of coronary disease has been dependent principally on the elicitation and proper evaluation of the history, and therefore, the accuracy has varied with the care, ability, and experience of the physician. In other fields of medicine in which clinical diagnosis can be compared with those based on objective criteria, it is evident that errors in clinical diagnoses are common. The development of selective cine coronary arteriography has made possible the correlation of clinical syndromes and evidence of arterial obstruction during life. If this method of study is valid, there should be a close relationship between the typical clinical syndromes (angina pectoris and myocardial infarction) and the presence of significant arteriographic abnormality.

Summary Before the introduction of coronary angiography the diagnosis of coronary disease relied on elucidating historical or clinical symptoms of ischaemia. This and other papers correlated these ischaemic syndromes with angiographical findings based on the severity of luminal stenosis. These findings would subsequently revolutionize the field of cardiovascular medicine.

Citation Count

490

Related References 1. Forssmann W. Die Sondierung des rechten Herzens. Klin Wochenschr 1929; 8: 2085. 2. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography: a new technique. Acta Radiol 1953; 39: 368. 3. Judkins MP. Selective coronary arteriography: a percutaneous transfemoral technique. Radiology 1967; 89: 815. 4. Proudfit WL, Shirey EK, Sones Jr FM. Distribution of arterial lesions demonstrated by selective cinecoronary arteriography. Circulation 1967; 36: 54–62.

Key message One of the difficulties encountered in the correlation of clinical and arteriographical findings is the necessarily arbitrary separation of degrees of estimated arterial obstruction. It is apparent

25

Quantification of coronary atherosclerosis for cardiovascular risk assessment

that mild degrees of obstruction rarely cause angina pectoris or myocardial infarction. Arteriographical evidence of obstruction is almost always severe in symptomatic patients. Therefore, precise classification of relatively minor degrees of obstruction does not seem to be so important as it was considered to be during early progress of the study.

Why it’s important The correlation of ischaemic syndromes with angiographical findings defined the role of highgrade luminal stenosis in clinical coronary syndromes.

Strengths 1. Systematic correlation of clinical syndromes with angiographical findings. 2. Observation of role of risk factors (hypercholesterolemia) for angiographical disease manifestation.

Weaknesses Based on the understanding of coronary artery disease at the time, the role of mildly stenotic lesions for the initiation of acute coronary syndromes was underestimated.

Relevance The correlation of clinical, ischaemic syndromes with angiographical findings led to the definition of disease by the severity of luminal stenosis. This paradigm has been the basis for the enormous success of coronary revascularization of symptomatic patients.

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Title 3

Quantitative coronary arteriography: estimation of dimensions, hemodynamic resistance, and atheroma mass of coronary artery lesions using the arteriogram and digital computation Author Brown BG, Bolson E, Frimer M, Dodge HT

Reference Circulation 1977; 55: 329–337

Abstract More accurate characterization of coronary artery lesions is needed for evaluation of shortand long-term interventions in coronary disease. A method of segmental artery analysis has been developed to maximize the information obtained from coronary arteriograms. Coronary lesions are traced from two projected, perpendicular, 35 mm cineangiographic views and transmitted, in digital form, to a PDP 11/45 computer. Magnification and distortion of the image are compensated for in order to determine the actual vessel profiles, using the catheter and its location as a scaling device. The two views are matched; a spatial representation of the vessel centerline is constructed mathematically; and orthogonal vessel diameters are computed at increments along this centerline. Assuming an elliptical lumen, the absolute and percentage reduction in diameter and cross-sectional area in the stenosis are computed. More complex functions (integrated atheroma mass, Poiseuille resistance, and orifice resistance) are then calculated. The accuracy and variability of the different steps involved in lesion analysis have been determined. Dimensional accuracies of 150 microns (SD) are feasible. Examples are given of patients with Prinzmetal’s angina and with progressive coronary disease.

Summary The authors describe a quantitative method of describing disease severity applicable in clinical and research studies.

Citation Count

469

Related References 1. Reiber JH, Serruys PW, Kooijman CJ, et al. Assessment of short-, medium-, and long-term variations in arterial dimensions from computer-assisted quantitation of coronary cineangiograms. Circulation 1985; 71: 280–288. 2. Keane D, Haase J, Slager CJ, et al. Comparative validation of quantitative coronary angiography systems. Results and implications from a multicenter study using a standardized approach. Circulation 1995; 91: 2174–2183.

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Quantification of coronary atherosclerosis for cardiovascular risk assessment

Key message Estimates of minimum cross-sectional area appear to provide a sensitive means of determining progression of an atherosclerotic lesion. The computed Poiseuille resistance represents an integrated average of a function of lumen constriction, weighted by the nature of the function towards the most severely constricted portion of the lesion; it appears to provide an even more sensitive index of disease progression than diameter or area estimations alone. Resistance is also (in theory) a more relevant index of the physiological severity of the arterial stenosis.

Why it’s important Based on the definition of coronary disease by the severity of luminal stenosis it appeared logical to define changes of disease severity (progression/regression) by changes in luminal dimension as well. This became possible through quantitative coronary angiography.

Strengths Quantitative coronary angiography allowed precise assessment of luminal dimensions in serial research protocols.

Weaknesses The authors acknowledge the limitations of the angiographical description of coronary disease, which is based on a planar projection of the luminal silhouette.

Relevance These studies introduced the concept of imaging as endpoint in clinical and research studies.

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Classic Papers in Coronary Angioplasty

Title 4

Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B Author Brown G, Albers JJ, Fisher LD, et al.

Reference N Engl J Med 1990; 323: 1289–1298

Abstract BACKGROUND AND METHODS: The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2.5-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated). RESULTS: The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes, 7 and 5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (46 and 15 percent) or niacin and colestipol (32 and 43 percent). In the conventionaltherapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; p less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77). CONCLUSIONS: In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipidlowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.

Summary This study describes the change of angiographical lesion severity during lipid-lowering treatment concordant with clinical benefit.

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Quantification of coronary atherosclerosis for cardiovascular risk assessment

Citation Count

1347

Related References 1. Jukema JW, Bruschke AV, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528–2540. 2. Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic Changes with Lovastatin Therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med 1993; 119: 969–976. 3. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park J-S, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol 1995; 26: 1133–1139. 4. MAAS Investigators. Effect of Simvastatin on coronary atheroma: the Multicentre AntiAtheroma Study (MAAS). Lancet 1994; 344: 633–638. 5. Waters D, Higginson L, Gladstone P, et al. Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial. Circulation 1994; 89: 959–968.

Key message Our results show that quantitative arteriography is an effective method of assessing interventions against the atherosclerotic process. Although it answers different questions from those answered by clinical trials, arteriography permits a direct assessment of the vascular processes underlying clinical disorders, and it is currently the only reliable way to study the regression of lesions.

Why it’s important This and other studies demonstrated less progression or greater propensity for regression in the treatment group and demonstrated the value of luminal dimensions in the assessment of disease severity as a clinical endpoint.

Strengths Applies coronary angiography to the quantitative assessment of atherosclerosis progression and regression in clinical research.

Weaknesses The authors describe that other pathological processes including arterial remodelling, vasomotor tone, and endothelial function initiate changes of arterial architecture independent of changes in luminal dimension.

Relevance These studies demonstrate the dynamic nature of coronary artery disease (CAD) and the value of luminal dimensions in the assessment of disease severity.

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Classic Papers in Coronary Angioplasty

Title 5

Application of a new phased-array ultrasound imaging catheter in the assessment of vascular dimensions: in vivo comparison to cineangiography Author Nissen SE, Grines CL, Gurley JC, et al.

Reference Circulation 1990; 81: 660–666

Abstract Tomographic imaging techniques such as ultrasound can provide important information in the evaluation of vascular anatomy. Recent technical advances have permitted fabrication of a small (1.83 mm), phased-array, intravascular ultrasonic imaging catheter capable of continuous realtime, cross-sectional imaging of blood vessels. We used this imaging catheter to compare intraluminal ultrasound with cineangiography in the measurement of vascular dimensions in animals and to assess the intraobserver and interobserver variability of the technique. Segmental deformation of vessel anatomy was produced by stenoses created with a tissue ligature or by balloon dilation. The mean value for measurements of vessel diameter was 5.6 mm by cineangiography and 5.7 mm by intravascular ultrasound. The correlation between cineangiography and ultrasound was close (r
0.98). Mean cross-sectional area by angiography was 28.8 mm2 and 29.6 mm2 (r
0.96) by ultrasound. Percent diameter reduction produced by the stenoses averaged 48.4% by cineangiography and 40.1% by ultrasound, and the two methods correlated closely (r
0.89). Correlation between cineangiography and ultrasound for vessel diameter and area before balloon dilation was closer (r
0.92 and 0.88) than after balloon dilation (r
0.86 and 0.81). This difference reflected an increase in measured vessel eccentricity following balloon dilation. These data demonstrate that intravascular ultrasound is an accurate and reproducible method for measurement of vascular diameter and cross-sectional area in vivo. Intravascular ultrasound is capable of accurately identifying and quantifying segmental deformation of vascular dimensions produced by either stenoses or balloon dilation.

Summary This paper describes the development of intravascular ultrasound (IVUS) technology in an initial in vitro model.

Citation Count

199

Related References 1. St Goar FG, Pinto FJ, Alderman EL, Fitzgerald PJ, Stadius ML, Popp RL. Intravascular ultrasound imaging of angiographically normal coronary arteries: an in vivo comparison with quantitative angiography. J Am Coll Cardiol 1991; 18: 952–958.

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2. Yock PG, Linker DT, Angelsen BA. Two-dimensional intravascular ultrasound: technical developments and initial clinical experience. J Am Soc Echocardiogr 1989; 2: 296–304. 3. McPherson DD, Hiratzka LF, Lamberth WC, et al. Delineation of the extent of coronary atherosclerosis by high-frequency epicardial echocardiography. N Engl J Med 1987; 316: 304–309. 4. Ge J, Liu F, Gorge G, Haude M, Baumgart D, Erbel R. Angiographically “silent” plaque in the left main coronary artery detected by intravascular ultrasound. Coron Artery Dis 1995; 6: 805–810. 5. Schoenhagen P, Nissen S. Understanding coronary artery disease: tomographic imaging with intravascular ultrasound. Heart 2002; 88: 91–96 [Review].

Key message IVUS has the potential to be the most sensitive technique by which to define the progression or regression of atherosclerosis, and to study the response of intravascular size to pharmacological agents. The use of ultrasonic catheters also holds the enormous potential for anatomic definition of the vessel wall, and the possible assessment of the extent and composition of atherosclerotic plaque.

Why it’s important This and other early studies validated IVUS for subsequent in vivo assessment of the vessel wall.

Strengths Despite the initial limitation on comparison of luminal measurements between IVUS and angiography, these studies already realized the importance for vessel wall imaging.

Weaknesses These early in vitro studies were limited by many technical deficiencies of the IVUS technology, which were subsequently resolved allowing routine clinical imaging.

Relevance Intravascular ultrasound allowed for the first time in vivo assessment of the atherosclerotic plaque and directed the clinical interest to the vessel wall.

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Classic Papers in Coronary Angioplasty

Title 6

Compensatory enlargement of human atherosclerotic coronary arteries Author Glagov S, Weisenberg E, Zarins CK, et al.

Reference N Engl J Med 1987; 316: 1371–1375

Abstract Whether human coronary arteries undergo compensatory enlargement in the presence of coronary disease has not been clarified. We studied histological sections of the left main coronary artery in 136 hearts obtained at autopsy to determine whether atherosclerotic human coronary arteries enlarge in relation to plaque (lesion) area and to assess whether such enlargement preserves the cross-sectional area of the lumen. The area circumscribed by the internal elastic lamina (internal elastic lamina area) was taken as a measure of the area of the arterial lumen if no plaque had been present. The internal elastic lamina area correlated directly with the area of the lesion (r
0.44, p less than 0.001), suggesting that coronary arteries enlarge as lesion area increases. Regression analysis yielded the following equation: Internal elastic lamina area
9.26  0.88 (lesion area)  0.026 (age)  0.005 (heart weight). The correlation coefficient for the lesion area was significant (p less than 0.001), whereas the correlation coefficients for age and heart weight were not. The lumen area did not decrease in relation to the percentage of stenosis (lesion area/internal elastic lamina area  100) for values between zero and 40% but did diminish markedly and in close relation to the percentage of stenosis for values above 40% (r
0.73, p less than 0.001). We conclude that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40% of the internal elastic lamina area. The preservation of a nearly normal lumen cross-sectional area despite the presence of a large plaque should be taken into account in evaluating atherosclerotic disease with use of coronary angiography.

Summary In this seminal post-mortem study of human coronary arteries, Dr Glagov et al. systematically described the relation between plaque size and luminal dimension, and suggested that early plaque accumulation was frequently not reflected in luminal change because of an outward bulging or “remodelling” of the overall vessel size. The results are reminiscent of Crawford and Levene’s observation (Paper no. 1).

Citation Count

1103

Related References 1. McPherson DD, Sirna SJ, Hiratzka LF, et al. Coronary arterial remodeling studies by highfrequency epicardial echocardiography. J Am Coll Cardiol 1991; 17: 79–86.

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2. Hermiller JB, Tenaglia AN, Kisslo KB, et al. In vivo validation of compensatory enlargement of atherosclerotic coronary arteries. Am J Cardiol 1993; 71: 665–668. 3. Armstrong ML, Heistad DD, Marcus ML, Megan MB, Piegors DJ. Structural and hemodynamic responses of peripheral arteries of macaque monkeys to atherogenic diet. Arteriosclerosis 1985; 5: 336–346. 4. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002; 105: 939–943. 5. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002; 105: 297–303.

Key message Our findings do indicate that many persons have an adequate, if not normal, lumen crosssectional area in the presence of advanced atherosclerosis and that such a possibility should be taken into account in evaluating the extent and severity of disease with angiography. The arrest of progression and the stabilization of a plaque before cross-sectional stenosis exceeds 40% could be consistent with preservation of an adequate, if not normal lumen area in such patients. Identification of the clinical, functional and anatomical factors that influence plaque stabilization could have important clinical consequences, even if the disease is not reversible and regression is not achieved.

Why it’s important This and subsequent papers explained why plaque accumulation was not always associated with luminal stenosis.

Strengths 1. Systematic observation of early atherosclerotic lesions in human post-mortem arteries. 2. The authors suggest an explanation for the dissociation between plaque and lumen size, which subsequently will have significant influence on our current understanding of coronary artery disease (CAD).

Weaknesses Owing to the cross-sectional design of post-mortem studies, the findings regarding plaque development needed confirmation in serial studies.

Relevance The simultaneous description of the compensatory changes of vessel size during plaque development in post-mortem and imaging studies provided the rational for tomographical imaging of coronary atherosclerosis.

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Classic Papers in Coronary Angioplasty

Title 7

Relation of arterial geometry to luminal narrowing and histological markers for plaque vulnerability: the remodeling paradox Author Pasterkamp G, Schoneveld AH, van der Wal AC, et al.

Reference J Am Coll Cardiol 1998; 32: 655–662

Abstract OBJECTIVE: To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND: Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS: We obtained 1521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS: Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections. Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION: Intraindividually, pathohistologic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

Summary This study describes an association between outward “positive” remodelling and lesion characteristics associated with unstable clinical presentation. It suggests that outward remodelled but mildly stenotic lesions appear to have a particular tendency to rupture initiating acute coronary events (vulnerable plaques).

Citation Count

75

Related References 1. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study. Circulation 2000; 101: 598–603.

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2. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome. J Am Coll Cardiol 2000; 35: 106–111. 3. Kotani J, Mintz GS, Castagna MT, et al. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction. Circulation 2003; 107: 2889–2893.

Key message Both plaque and vessel area were geometrical determinants of the presence of markers related to plaque vulnerability. The type of arterial remodelling may have a dual impact on luminal narrowing. Compensatory enlargement will retard chronic luminal narrowing, but it might enhance the risk of plaque rupture and, hence, acute luminal narrowing or occlusion. Conversely, paradoxical shrinkage will accelerate chronic luminal narrowing, but it might reduce the risk of plaque rupture and, hence, acute luminal narrowing or occlusion. Future studies using intravascular ultrasound (IVUS) are needed to verify the inferred predictive value for unstable angina and acute myocardial infarction or compensatory enlarged lesions.

Why it’s important Glagov’s observations demonstrate that plaque progression is initially accommodated by an expansion of vessel diameter rather than luminal stenosis (arterial remodelling). Based on the studies correlating remodelling with clinical presentation, it has become obvious that these outward remodelled but mildly stenotic lesions appear to have a particular tendency to rupture initiating acute coronary events (vulnerable plaques). It is an attractive hypothesis that changes of regression are also reflected in plaque size rather than luminal dimension.

Strengths The careful comparison of lesion geometry with histological lesion characteristics allowed hypothesis about potential interactions between remodelling and plaque vulnerability/stability, which were later confirmed in clinical imaging studies.

Weaknesses These results from femoral vessels may not apply to coronary vessels in particular in the setting of acute coronary syndromes. Therefore clinical confirmation was needed.

Relevance This paper and subsequent post-mortem and IVUS studies of coronary arteries have modified the prevailing paradigm about high-risk lesions and focused attention to mildly stenotic but vulnerable plaques and overall plaque burden.

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Classic Papers in Coronary Angioplasty

Title 8

Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized placebo controlled pilot study Author Nissen SE, Tsunoda T, Tuzcu EM, et al.

Reference JAMA 2003; 290: 2292–2300

Abstract CONTEXT: Although low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano/phospholipid complexes produces rapid regression of atherosclerosis in animal models. OBJECTIVE: We assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS). DESIGN: The study was a double blind, randomized, placebo-controlled multicenter pilot study comparing the effects of ETC216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS). SETTING: Ten community and tertiary care hospitals in the United States. PATIENTS: Between November 2001 and March 2003, 123 patients consented, 57 were randomly assigned, and 47 completed the protocol. INTERVENTIONS: In a ratio of 1:2:2, patients received 5 weekly infusions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments. MAIN OUTCOME MEASURE: The primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy measures included the change in total atheroma volume and average maximal atheroma thickness. RESULTS: The mean (SD) percent atheroma volume decreased by 1.06% (3.17%) in the combined ETC-216 group (median, 0.81%; 95% confidence interval [CI], 0.34% to 1.53%; p
0.02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%) (median, 0.03%; p
0.97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was 14.1 mm3 or a 4.2% decrease from baseline ( p  0.001). CONCLUSION: A recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.

Summary This study describes the rapid regression of atherosclerotic plaque burden during treatment with an high-density lipoprotein (HDL) mimetic in patients with acute coronary syndromes.

Citation Count

119

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Quantification of coronary atherosclerosis for cardiovascular risk assessment

Related References 1. Takagi T, Yoshida K, Akasaka T, Hozumi T, Morioka S, Yoshikawa J. Intravascular ultrasound analysis of reduction in progression of coronary narrowing by treatment with pravastatin. Am J Cardiol 1997; 79: 1673–1676. 2. Matsuzaki M, Hiramori K, Imaizumi T, et al. Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART). J Am Coll Cardiol 2002; 40: 220–227. 3. Schartle M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001; 104: 387–392. 4. Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 2002; 287: 3215–3222. 5. Schoenhagen P, Tuzcu EM, Stillman AE, et al. Non-invasive assessment of plaque morphology and remodeling in mildly stenotic coronary segments: comparison of 16-slice computed tomography and intravascular ultrasound. Coron Artery Dis 2003; 14: 459–462.

Key message This initial trial of an exogenously produced HDL mimetic demonstrated significant evidence of rapid regression of atherosclerosis. The potential utility of the new approach must be fully explored in a larger patient population with longer follow-up, assessing a variety of clinical end points, including morbidity and mortality.

Why it’s important These results demonstrate for the first time that disease regression in patients presenting with acute coronary syndromes can be induced by aggressive modification of HDL levels.

Strengths First study showing regression of plaque burden after pharmacological treatment in acute coronary syndromes. The significant change in only 5 weeks is evidence of the highly dynamic nature of coronary artery disease (CAD).

Weaknesses Eventually, these new imaging endpoints will need to the compared to clinical endpoints of morbidity and mortality.

Relevance Serial imaging studies will eventually allow to compare plaque burden, plaque characteristics, systemic markers of inflammation, and clinical outcome. These results will be important for disease prevention in primary setting but also for secondary prevention following the interventional treatment of symptomatic patients.

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Chapter 3

Primary angioplasty (PPCI) in ST-elevation myocardial infarction Iqbal Saeed Malik, Rodney Foale Introduction Almost all acute ST-elevation myocardial infarction (STEMI) is due to thrombotic occlusion of the coronary artery. Non-STEMI (NSTEMI), diagnosed on the basis of subsequent cardiac troponin (c-Trop-T or c-Trop-I) or creatinine kinase (CPK) rise, but without initial ST elevation on the electrocardiography (ECG) is probably related to intermittent or incomplete coronary occlusion. This chapter deals specifically with the treatment of STEMI. The era of reperfusion as the mainstay of treatment was ushered in with the realization that the occlusive thrombus could be managed by use of a combination of a guidewire to mechanically initiate coronary blood flow and the intracoronary infusion of streptokinase. The recognition that the prompt restoration of flow salvages myocardium, reduces infarct size, and prolongs life has been the driving force behind a large number of clinical trials, assessing thrombolytic therapy for acute myocardial infarction (AMI). The results of these trials, done in the early 1980s and involving tens of thousands of patients, unequivocally showed that thrombolytic therapy resulted in preserved left-ventricular function and decreased mortality in patients with STEMI. Despite its proven efficacy, thrombolytic therapy has limitations. Many patients are ineligible for treatment due to risk factors for bleeding, and in addition, treatment beyond 12 hours of the onset of pain has no proven benefit. Of those given thrombolytic therapy, 10–15% have persistent occlusion or re-occlusion of the infarct-related artery. Normal flow, which is important for long-term survival, is only achieved in 60% of patients. Up to 40% of those who have initial thrombolysis end up having ischaemia-driven percutaneous transluminal coronary angioplasty (PTCA) in any case. Consequently, primary PTCA (primary angioplasty) or primary percutaneous coronary intervention (PPCI) has been advocated as a better treatment of ST-elevation myocardial infarction. Since time from symptom onset to administration of thrombolysis is a key determinant of success, prehospital thrombolysis has been suggested as a competitor for PPCI. However, only 4% of ambulance calls about chest pain are for patients with ST-segment elevation AMI who are eligible for thrombolysis. Half of all patients with ST-segment elevation AMI drive to hospital. For these reasons, prehospital thrombolysis has not been instituted in many communities, and is less available than PPCI. In addition up to one-third of cases need urgent percutaneous coronary intervention (PCI) prior to hospital discharge. PPCI is defined as balloon angioplasty plus stenting undertaken as the primary reperfusion strategy for STEMI without previous or concomitant thrombolytic therapy. It is not without its own limitations. In older clinical trials, major bleeding was significantly more frequent in the group who had PPCI than in those receiving thrombolytic therapy. Since most of these bleeds were localized to the access site, lower doses of intravenous heparin, smaller sheath sizes, and improved operator technique during PPCI probably contributed to the overall improved bleeding risk in the 13 most recent trials. Although no single trial has confirmed the mortality advantage of PPCI over thrombolysis, most have shown a trend in that direction. The latest meta-analysis suggests that there is a 2% absolute mortality reduction at 30 days with PPCI (5% vs. 7% with thrombolysis; p
0.0003). The benefit, in terms of death, non-fatal myocardial infarction, and stroke, is confirmed with the

Primary angioplasty (PPCI) in ST-elevation myocardial infarction

most recent randomized controlled trial (8.5% vs. 14.2% in the fibrinolysis group; p
0.002). Therefore, modern treatment of STEMI should be PPCI, facilitated by the use of strong antiplatelet agents such as glycoprotein IIb/IIIa receptor blockers and clopidogrel. A similar invasive approach can be used for NSTEMI, but does not need to be performed immediately. Mortality reduction with an early invasive strategy is not conclusively proven. The previous data suggesting an increased risk by intervening too early in NSTEMI appears to have been surpassed in the era of glycoprotein IIb/IIIa receptor blockers and clopidogrel. Research for the future will rest on whether stents coated in agents such as paclitaxel and sirolimus, which are known to reduce restenosis rates in stable coronary-artery disease, can be safely used in the context of STEMI and NSTEMI to provide even better long-term results. In addition, there will be continued development of adjunctive therapy to reduce the risk at the time of intervention still further.

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Classic Papers in Coronary Angioplasty

Title 1

Acute myocardial infarction: intracoronary application of nitroglycerin and streptokinase Author Rentrop KP, Blanke H, Karsch KR, et al.

Reference Clin Cardiol 1979; 2: 354–363

Abstract In five patients with acute myocardial infarction, the effects of both intracoronary nitroglycerin (NTG) and subsequent intracoronary streptokinase application were evaluated. In addition, transluminal recanalization was performed in one of these patients. Injection of NTG into the infarct-related coronary artery resulted in improved distal filling of the subtotally occluded left circumflex artery in one patient, and in transient patency of the completely occluded right coronary artery in a second patient. In a third patient patency of the totally occluded left anterior descending artery (LAD) was achieved by transluminal recanalization with a guide wire. In a fourth patient with occlusion of the LAD, there was no response to intracoronary NTG and mechanical recanalization was not attempted. Subsequent intracoronary infusion of streptokinase (1000–2000 U/min for 15–60 min) resulted in a further and long-term reduction of narrowing at the site of acute occlusion in patients I–III and in opening of the completely occluded LAD in patient IV. Improvement of lumen was paralleled by alleviation of symptoms. In a fifth patient, in whom the LAD was subtotally occluded, the degree of coronary obstruction could not be changed by intracoronary application of NTG or by lysis. In this patient, symptoms and ECG changes improved with reduction of pathologically elevated blood pressure values. The findings suggest that myocardial infarction had been caused by thrombotic occlusion in four patients, and that spasm of the infarct vessel could have been an additional factor in two of these patients. In the fifth patient, an increase of afterload in the presence of a subtotal lesion might have caused the critical imbalance between oxygen supply and demand, resulting in cell death.

Summary Acute myocardial infarction (AMI) is due to coronary occlusion with thrombus. Flow can be restored by passing a guidewire through the thrombus or by the use of streptokinase. Flow in a subtotally occluded vessel can be improved with nitrate therapy, whilst the effects of reduced flow can be ameliorated by reducing pathologically elevated blood pressure.

Citation Count

271

Related References 1. Davies MJ, Woolf N, Robertson WB. Pathology of acute myocardial infarction with particular reference to occlusive coronary thrombi. Br Heart J 1976; 38: 659–664. 2. Judkins MP. Selective coronary arteriography. Part 1: a percutaneous femoral technique. Radiology 1967; 89: 815.

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Key message Reperfusion therapy can be used to relieve symptoms and improve the coronary perfusion.

Why it’s important Although a small paper, this summarizes all that has since followed in the field of reperfusion therapy. The role of vasospasm is assessed with the use of intracoronary nitrates. The dispersion of thrombus with streptokinase was then attempted successfully. Finally, the current fervour with which primary percutaneous coronary intervention (PPCI) is pursued clearly has its origins in the mechanical dispersion of clot with an angioplasty wire in one of the five patients discussed. This paper clearly suggests several different methods to open the artery.

Strengths Its main strength is the foresight of the paper. This was published in 1979.

Weaknesses Only five patients were enrolled. This is not randomized controlled trial data!

Relevance This was the first report of mechanical reperfusion therapy in man. Although only a guidewire was passed, flow still improved, and symptoms and electrocardiographical (ECG) changes resolved.

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Classic Papers in Coronary Angioplasty

Title 2

A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction Author O’Neill W, Timmis GC, Bourdillon PD, et al.

Reference N Engl J Med 1986; 314: 812–818

Abstract METHODS: We randomly assigned 56 patients who presented within 12 hours of their first symptoms of acute myocardial infarction to treatment with either intracoronary streptokinase or coronary angioplasty. RESULTS: The mean (SD) duration of symptoms (3.0  1.2 hours in the group treated with angioplasty vs. 3.6  1.8 in the group treated with streptokinase; p not significant) and time to recanalization (4.1  1.4 hours vs. 4.8  1.7 hours; p not significant) were similar in both groups. Coronary recanalization was achieved in 83 percent of the patients treated with angioplasty and in 85 percent of those treated with streptokinase (p not significant). Residual luminal stenosis in the coronary artery was significantly decreased after angioplasty, as compared with streptokinase therapy (43  31 percent of patients vs. 83  17; p  0.001). Residual stenosis of 70 percent or more was present in 4 percent of the angioplasty-treated patients and in 83 percent of the streptokinase-treated patients (p  0.01). Ventricular function after therapy was assessed by serial contrast ventriculograms. Increases in both global ejection fraction (8  7 percent vs. 1  6; p  0.001) and regional wall motion (1.32  1.32 SD vs. 0.59  0.79 SD; p  0.05) were greater for the angioplasty group. CONCLUSION: We conclude that angioplasty and streptokinase produce similar rates of early coronary reperfusion during evolving transmural myocardial infarction. However, angioplasty is significantly more effective in alleviating the underlying coronary stenoses, and this may result in more effective preservation of ventricular function after therapy.

Summary The ground breaking trial to confirm the benefits of thrombolysis, Interventional Study of Infarct Survival-2 (ISIS-2) was published in 1988. The present trial was a randomized comparison of intravenous streptokinase vs. primary percutaneous coronary intervention (PPCI) in a very small group of (56) patients presenting early (approximately 3 h) after the onset of ST-elevation myocardial infarction (STEMI). There was a remarkably high rate of recanalization with thrombolysis, but not the normal flow (thrombolysis in myocardial infarction, TIMI, Grade 3) which is required for best prognosis. The similar rate of reperfusion with PPCI (83%) was acceptable for the techniques used at that time. Differences in mortality were never going to be realized, but there was evidence of improved regional wall function, presumably related to the improvement in coronary stenosis rather than reperfusion alone.

Citation Count

404

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

Related References 1. Ribeiro EE, Silva LA, Carneiro R, et al. Randomized trial of direct coronary angioplasty versus intravenous streptokinase in acute myocardial infarction. J Am Coll Cardiol 1993; 22: 376–380. 2. Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328: 680–684.

Key message PPCI may be equivalent or better than intravenous streptokinase.

Why it’s important To the enthusiasts, it suggested that PPCI was the way of the future. To the conservative majority it suggested that no lives were saved with PPCI compared to thrombolysis. The debate had begun, but only in the 21st century have most physicians accepted the correct answer.

Strengths The authors are to be commended for being able to take on the methodology of randomized trials and apply them to an important cardiological question. The major end points assessed remain the ones of interest in all subsequent studies.

Weaknesses The study was a small pilot, and was not designed to assess rates of major cardiac event. Thus it was hypothesis generating.

Relevance At the time of publication, streptokinase had not been widely accepted as a treatment choice for STEMI. The thought of percutaneous coronary intervention (PCI) in the midst of acute myocardial infarction (AMI) was felt to be too high risk. The trial stands at the very first randomized controlled trial to assess PPCI. It confirmed that PPCI did not increase risk.

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Title 3

Decreasing hospital mortality between 1994 and 1998 in patients with acute myocardial infarction treated with primary angioplasty but not in patients treated with intravenous thrombolysis: results from the pooled data of the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Registry and the Myocardial Infarction Registry (MIR) Author Zahn R, Schiele R, Schneider S, et al.

Reference J Am Coll Cardiol 2000; 36: 2064–2071

Abstract BACKGROUND: We investigated changes in the clinical outcome of primary angioplasty and thrombolysis for the treatment of acute myocardial infarction (AMI) from 1994 to 1998. Primary angioplasty for the treatment of AMI is a sophisticated technical procedure that requires experienced personnel and optimized hospital logistics. Growing experience with primary angioplasty in clinical routine and new adjunctive therapies may have improved the outcome over the years. METHODS: The pooled data of two German AMI registries: the Maximal Individual Therapy in AMI (MITRA) study and the Myocardial Infarction Registry (MIR) were analyzed. RESULTS: Of 10,118 lytic eligible patients with AMI, 1385 (13.7%) were treated with primary angioplasty, and 8733 (86.3%) received intravenous thrombolysis. Patients characteristics were quite balanced between the two treatment groups, but there was a higher proportion of patients with a prehospital delay of 6 h in those treated with primary angioplasty. The proportion of an in-hospital delay of more than 90 min significantly decreased in patients treated with primary angioplasty over the years ( p for trend
0.015, multivariate odds ratio [OR] for each year of the observation period
0.84, 95% confidence interval [CI]: 0.73–0.96) but did not change significantly in patients treated with thrombolysis. Hospital mortality decreased significantly in the primary angioplasty group (p
0.003 for trend; multivariate OR for each year
0.73, 95% CI: 0.58–0.93). However, for patients treated with thrombolysis, hospital mortality did not change significantly ( p for trend 0.175, multivariate OR for each year: 1.02, 95% CI: 0.94–1.11). CONCLUSIONS: Compared with thrombolysis the clinical results of primary angioplasty for the treatment of AMI improved from 1994 to 1998. This indicates a beneficial effect of the growing experience and optimized hospital logistics of this technique over the years.

Summary Hospital mortality in patients treated with primary percutaneous coronary intervention (PPCI) or thrombolysis was retrospectively assessed. There was no significant change in mortality over time in the patients treated with thrombolysis (n
8733, p
0.175 for trend), but significant reduction in those treated with PPCI in recent years (n
1385, p
0.003 for trend) (Figure 1).

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

30-day mortality (%)

16 Thrombolysis

14

PPCI

12 10 8 6 4 2 0 1994

1995

1996 Year

1997

1998

Figure 1 The 30-day mortality after thrombolysis has not improved over time, whilst the benefits of PPCI have increased with advancing technology over the course of 1994–1998. Adapted from Zahn et al.

Citation Count

26

Related References 1. Tiefenbrunn AJ, Chandra NC, French WJ, Gore JM, Rogers WJ. Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) for patients with acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 1998; 31: 1240–1245. 2. Every NR, Parsons LS, Hlatky M, Martin JS, Weaver WD. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. Myocardial Infarction Triage and Intervention Investigators. N Engl J Med 1996; 335: 1253–1260.

Key message By 1998, German patients treated with PPCI were doing dramatically better than those treated with thrombolysis.

Why it’s important Several previous registries had suggested that PPCI added no value in most ST-elevation myocardial infarction (STEMI) patients that are eligible for thrombolysis. Although thrombolytic treatment has advanced a little in the last 20 years, PPCI has advanced much more, based on experience and new technology. This study provided the data behind this statement.

Strengths No hospital took part in both the MITRA and the MIR registry. Thus a large part of Germany (over 270 hospitals) was assessed by combining both registries.

Weaknesses Registry data can be flawed by erroneous data collection and bias. Mortality in patients treated with thrombolysis (11.3%) was constantly higher than the mortality reported by other studies (5.4–7.6%). This difference in mortality may be caused by different patient selection: in the MITRA/MIR studies patients in cardiogenic shock were not excluded, and patients were 3 years older compared with the Second National Registry of Myocardial Infarction (NRMI-2 registry). Thus this was a high-risk group.

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In addition, no data was presented on which thrombolytic agent was used. This was left to the discretion of the hospital. There was also no information on the rate of usage of glycoprotein IIb/IIIa receptor blockers or stents for PPCI. Thus both lysis and PPCI groups may not have received the standard of care expected today.

Relevance Real-world scenarios are needed to confirm the benefits of treatments that have proven useful in trials. This registry collected data from smaller hospitals, suggesting that the improvements in PPCI can be achieved even in smaller units.

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

Title 4

Coronary angioplasty with or without stent implantation for acute myocardial infarction Author Grines CL, Cox DA, Stone GW, et al., The Stent Primary Angioplasty in Myocardial Infarction Study Group

Reference N Engl J Med 1999; 341: 1949–1956

Abstract BACKGROUND: Coronary-stent implantation is frequently performed for treatment of acute myocardial infarction. However, few studies have compared stent implantation with primary angioplasty alone. METHODS: We designed a multicenter study to compare primary angioplasty with angioplasty accompanied by implantation of a heparin-coated Palmaz–Schatz stent. Patients with acute myocardial infarction underwent emergency catheterization and angioplasty. Those with vessels suitable for stenting were randomly assigned to undergo angioplasty with stenting (452 patients) or angioplasty alone (448 patients). RESULTS: The mean (SD) minimal luminal diameter was larger after stenting than after angioplasty alone (2.56  0.44 mm vs. 2.12  0.45 mm, p  0.001), although fewer patients assigned to stenting had grade 3 blood flow (according to the classification of the Thrombolysis in Myocardial Infarction trial) (89.4 percent vs. 92.7 percent in the angioplasty group, p
0.10). After six months, fewer patients in the stent group than in the angioplasty group had angina (11.3 percent vs. 16.9 percent, p
0.02) or needed target-vessel revascularization because of ischemia (7.7 percent vs. 17.0 percent, p  0.001). In addition, the combined primary end point of death, reinfarction, disabling stroke, or target-vessel revascularization because of ischemia occurred in fewer patients in the stent group than in the angioplasty group (12.6 percent vs. 20.1 percent, p  0.01). The decrease in the combined end point was due entirely to the decreased need for targetvessel revascularization. The six-month mortality rates were 4.2 percent in the stent group and 2.7 percent in the angioplasty group ( p
0.27). Angiographic follow-up at 6.5 months demonstrated a lower incidence of restenosis in the stent group than in the angioplasty group (20.3 percent vs. 33.5 percent, p  0.001). CONCLUSIONS: In patients with acute myocardial infarction, routine implantation of a stent has clinical benefits beyond those of primary coronary angioplasty alone.

Summary In arteries suitable for stenting, primary percutaneous coronary intervention (PPCI) performed with stenting produces marginally lower rates of thrombolysis in myocardial infarction, grade 3 (TIMI-3), flow (89.4% vs. 92.7% in the angioplasty group; p
0.10). However, restenosis rates at 6 months are reduced with stents compared to balloon alone, driving down the overall 6-month major adverse cardiovascular event rates (12.6% vs. 20.1%; p  0.01).

Citation Count

305

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Related References 1. Serruys PW, van Hout B, Bonnier H, et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II). Lancet 1998; 352: 673–681. 2. Stone GW, Brodie BR, Griffin JJ, et al. Prospective, multicenter study of the safety and feasibility of primary stenting in acute myocardial infarction: in-hospital and 30-day results of the PAMI stent pilot trial. Primary Angioplasty in Myocardial Infarction Stent Pilot Trial Investigators. J Am Coll Cardiol 1998; 31: 23–30.

Key message Stents can be used safely in ST-elevation myocardial infarction (STEMI), and reduce restenosis as they do in patients undergoing elective percutaneous coronary intervention (PCI).

Why it’s important Thrombosis within the stent was a problem before the use of aspirin plus clopidogrel in elective PCI. In the face of acute myocardial infarction (AMI), where restoration of flow is key to success, and TIMI-3 flow is the goal, stenting might have had a disadvantage. This has proved to be unfounded.

Strengths To test the benefits of stents, without requiring large numbers of patients, only one type of stent was tested. This was heparin coated, with a theoretical advantage in reducing thrombosis rates. The results might not have been relevant to other stents, but at least were confirmed for the Palmaz–Schatz stent. The operators involved worked in high-volume centres used to performing PPCI.

Weaknesses Use of glycoprotein IIb/IIIa receptor blockers reduces the risk of peri-procedural events in both low- and high-risk patients during PCI with stenting. TIMI-3 flow rates might have been even better if these agents (which were not universally accepted at the time of the trial) had been used. The fact that patients were selected after angiography as being suitable for stenting means that a universal strategy of direct stenting was not tested. In the pilot phase, only 77% of cases were felt suitable for stenting.

Relevance Data from the early days of stenting suggested that TIMI flow rates may be lower after stenting. However, deployment of stents directly can simplify procedures, reduce the risk of dissection, and may reduce distal embolization. This trial confirmed the safety of this strategy.

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

Title 5

Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials Author Keeley EC, Boura JA, Grines CL

Reference Lancet 2003; 361: 13–20

Abstract BACKGROUND: Many trials have been done to compare primary percutaneous transluminal coronary angioplasty (PTCA) with thrombolytic therapy for acute ST-segment elevation myocardial infarction (AMI). Our aim was to look at the combined results of these trials and to ascertain which reperfusion therapy is most effective. METHODS: We did a search of published work and identified 23 trials, which together randomly assigned 7739 thrombolytic-eligible patients with ST-segment elevation AMI to primary PTCA (n
3872) or thrombolytic therapy (n
3867). Streptokinase was used in eight trials (n
1837), and fibrin-specific agents in 15 (n
5902). Most patients who received thrombolytic therapy (76%, n
2939) received a fibrin-specific agent. Stents were used in 12 trials, and platelet glycoprotein IIb/IIIa inhibitors were used in eight. We identified short-term and long-term clinical outcomes of death, non-fatal reinfarction, and stroke, and did subgroup analyses to assess the effect of type of thrombolytic agent used and the strategy of emergent hospital transfer for primary PTCA. All analyses were done with and without inclusion of the SHOCK trial data. FINDINGS: Primary PTCA was better than thrombolytic therapy at reducing overall short-term death (7% [n
270] vs 9% [360]; p
0.0002), death excluding the SHOCK trial data (5% [199] vs 7% [276]; p
0.0003), non-fatal reinfarction (3% [80] vs 7% [222]; p  0.0001), stroke (1% [30] vs 2% [64]; p
0.0004), and the combined endpoint of death, non-fatal reinfarction, and stroke (8% [253] vs 14% [442]; p  0.0001). The results seen with primary PTCA remained better than those seen with thrombolytic therapy during long-term follow-up, and were independent of both the type of thrombolytic agent used, and whether or not the patient was transferred for primary PTCA. INTERPRETATION: Primary PTCA is more effective than thrombolytic therapy for the treatment of ST-segment elevation AMI.

Summary A total of 23 trials comparing primary percutaneous coronary intervention (PPCI) to thrombolysis have been combined in one meta-analysis of 7739 patients. This has allowed a comparison of major end points of death, non-fatal myocardial infarction (MI), stroke, and bleeding. All were significantly lower in the PPCI group. In addition, analysis of subgroups suggested that use of fibrin-specific agents such as tissue plasminogen activator (tPA) did not alter the result. The SHOCK trial, with a comparison of a strategy of initial revascularization with initial medical therapy for cardiogenic shock was different from other trials as up to 36 h could have elapsed since the onset of symptoms. Exclusion or inclusion of this trial did not substantially alter the results (Figure 1).

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I lM -fa on

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ta

ea D

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Ha st ro em ke o rrh D ea ag th ic /n st on ro ke -fa ta lM I/s tro ke

Thrombolysis

th

30-day event rate (%)

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Figure 1 There are significant reductions in total mortality (p  0.0002), non-fatal MI (p  0.0001), stroke (p
0.0004), and the combined end point of death, non-fatal MI, and stroke (p  0.0001). Adapted from Keeley et al., 2003.

Citation Count

171

Related References 1. Weaver WD, Simes RJ, Betriu A, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997; 278: 2093–2098. 2. Dalby M, Bouzamondo A, Lechat P, Montalescot G. Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: a meta-analysis. Circulation 2003; 108: 1809–1814.

Key message PPCI is safer and more effective than thrombolysis.

Why it’s important No individual trial has managed to show a mortality advantage to PPCI. All published trials except Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) suggest this trend. Use of meta-analysis suggests that there is a morbidity and mortality advantage to PPCI as the treatment of ST-elevation myocardial infarction (STEMI).

Strengths This is the largest meta-analysis performed to date. It thus allowed some further questions to be addressed. Thus, for example, the presence of only off-site facilities, entailing transfer to another hospital for PPCI appeared to have little effect on safety.

Weaknesses A comparison of accelerated tPA vs. PPCI appears the best test of the effect of PPCI. Use of accelerated tPA was limited to 12 of the 23 trials, and if only these trials are used, then the amount of benefit for PPCI becomes non-significant. The absence of significance does not

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

exclude the presence of clinical benefit, however. A randomized trial to address the issue would need 4400 patients, and is unlikely to ever be done. The advantage of PPCI over prehospital thrombolysis also could not be assessed. An additional criticism that has been levelled at this trial is that there is no comparison of PPCI with stent and PPCI without stent. However, use of stents is now almost universal and has never been shown to be a disadvantage in terms of major adverse cardiac events compared to plain balloon angioplasty in any setting. Finally, although tests of heterogeneity were negative in the 23 trials, there could still have been a biased assessment (e.g. from publication bias).

Relevance Mortality reduction is the ultimate gold standard for any treatment modality. With the presence of trained interventionalists, and an increase in cardiac catheter laboratory capacity, PPCI will become feasible for a large number of patients with STEMI. Well-researched meta-analysis informs the debate to allow development of the service. This paper, in combination with the DANish trial in Acute Myocardial Infarction (DANAMI) and PRAGUE-2 studies, is the catalyst for major change in the treatment of STEMI.

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Title 6

Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: a randomised study Author Bonnefoy E, Lapostolle F, Leizorovicz A, et al., on behalf of the Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) Study Group

Reference Lancet 2002; 360: 825–829

Abstract BACKGROUND: Although both prehospital fibrinolysis and primary angioplasty provide a clinical benefit over in-hospital fibrinolysis in acute myocardial infarction, they have not been directly compared. Our aim was to find out whether primary angioplasty was better than prehospital fibrinolysis. METHODS: We did a randomised multicentre trial of 840 patients (of 1200 planned) who presented within 6 h of acute myocardial infarction with ST-segment elevation, initially managed by mobile emergency-care units. We assigned patients to prehospital fibrinolysis (n
419) with accelerated alteplase or primary angioplasty (n
421), and transferred all to a centre with access to emergency angioplasty. Our primary endpoint was a composite of death, non-fatal reinfarction, and non-fatal disabling stroke at 30 days. Analyses were by intention to treat. RESULTS: The median delay between onset of symptoms and treatment was 130 min in the prehospital-fibrinolysis group and 190 min (time to first balloon inflation) in the primary-angioplasty group. Rescue angioplasty was done in 26% of the patients in the fibrinolysis group. The rate of the primary endpoint was 8.2% (34 patients) in the prehospital-fibrinolysis group and 6.2% (26 patients) in the primary-angioplasty group (risk difference 1.96, 95% CI  1.53 to 5.46). In all, 16 (3.8%) patients assigned prehospital fibrinolysis and 20 (4.8%) assigned primary angioplasty died ( p
0.61). CONCLUSION: A strategy of primary angioplasty was not better than a strategy of prehospital fibrinolysis (with transfer to an interventional facility for possible rescue angioplasty) in patients presenting with early myocardial infarction.

Summary In a trial of 840 patients within 6 h of ST-elevation myocardial infarction (STEMI), it was found that 26% of the thrombolysis group needed rescue angioplasty for failed thrombolysis. Major adverse events (death, non-fatal myocardial infarction (MI), and stroke at 30 days) occurred in 8.2% of the thrombolysis group and 6.2% of the primary percutaneous coronary intervention (PPCI) group ( p
n.s.). No significant differences were seen in individual end points except bleeding, which was more common in the PPCI arm (Table 1).

Citation Count

84

Related References 1. Prehospital thrombolytic therapy in patients with suspected acute myocardial infarction. The European Myocardial Infarction Project Group. N Engl J Med 1993; 329: 383–389.

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

Table 1 Occurrence of primary end points at 30 days in CAPTIM trial End point

Prehospital lysis (n
419)

PPCI (n
421)

Risk difference (95% confidence interval)

p value

Combined Death Repeat MI Disabling stroke

34 (8.2%) 16 (3.8%) 15 (3.7%) 4 (1.0%)

26 (6.2%) 20 (4.8%) 7 (1.7%) 0

1.96 (1.53 to 5.46) 0.93 (3.67 to 1.81) 1.99 (0.27 to 4.24) 1.00 (0.02 to 1.97)

0.29 0.61 0.13 0.12

Adapted from Bonnefoy et al., 2002.

2. Rawles J. Halving of mortality at 1 year by domiciliary thrombolysis in the Grampian Region Early Anistreplase Trial (GREAT). J Am Coll Cardiol 1994; 23: 1–5.

Key message The Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) study group conclude that a strategy of primary angioplasty was not better than a strategy of prehospital fibrinolysis in patients with early MI.

Why it’s important Early treatment is essential to open the blocked artery in acute myocardial infarction (AMI). This is especially true for thrombolysis, since the clot organizes with time and becomes more resistant to dissolution. In meta-analysis, prehospital thrombolysis reduces mortality by 17% compared to in-hospital treatment. The mortality in the Grampian Region Early Anistreplase Trial (GREAT) trial was reduced by 50% by reducing time to thrombolysis by 130 min. On the basis of these trials it was clearly worthwhile assessing this against PPCI. Thus prehospital thrombolysis to reduce symptom-to-needle time needed assessment.

Strengths This is the only large randomized controlled trial of prehospital thrombolysis vs. PPCI. All factors involved in causing delay to treatment were assessed well.

Weaknesses The authors state that those with a history of coronary-artery bypass graft (CABG) were excluded, yet they seem to have included five such patients (1.2%) in the percutaneous transluminal coronary angioplasty (PPCI) group. Although this number is small, patients with such a history are known to have a higher adverse event rate than those without previous CABG. This difference might therefore have affected the results, and such patients should not have been included in the final analysis. There was also a higher rate of cardiogenic shock in the PTCA group than the fibrinolysis group, perhaps because of the increased delay to the start of therapy (190 vs. 130 min). The study protocol stated that those with left main-stem stenosis or critical three-vessel disease should be considered for CABG; 41 patients had angiography but not angioplasty for various reasons. However, the results indicate that not a single patient was referred for surgery, suggesting that PTCA was done on some patients with high risk, complex disease who might have done better with bypass surgery.

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Not surprisingly there was a high rate of thrombolysis in myocardial infarction (TIMI) 0 or 1 flow on baseline angiography (n
316, 80%). Of the 364 who had angioplasty, 303 had stent implantation (83%), and only 97 (27%) received glycoprotein IIb/IIIa antagonist therapy. There is evidence that aggressive anti-platelet therapy with abciximab together with stent implantation in primary angioplasty reduces the 6-month incidence of death, reinfarction, disabling stroke, and ischaemia-driven target-vessel revascularization.

Relevance This trial continues to provide ammunition for those against PPCI who argue that before adopting it as the best strategy, it should be tested properly against prehospital thrombolysis. Abciximab increases epicardial artery patency when given before primary angioplasty, suggesting that prehospital administration of glycoprotein IIb/IIIa inhibitors, rather than fibrinolysis, with subsequent primary angioplasty will be the future treatment of choice.

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Primary angioplasty (PPCI) in ST-elevation myocardial infarction

Title 7

Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction Author Montalescot G, Barragan P, Wittenberg O, et al.

Reference N Engl J Med 2001; 344: 1895–1903

Abstract BACKGROUND: When administered in conjunction with primary coronary stenting for the treatment of acute myocardial infarction, a platelet glycoprotein IIb/IIIa inhibitor may provide additional clinical benefit, but data on this combination therapy are limited. METHODS: We randomly assigned 300 patients with acute myocardial infarction in a double-blind fashion either to abciximab plus stenting (149 patients) or placebo plus stenting (151 patients) before they underwent coronary angiography. Clinical outcomes were evaluated 30 days and 6 months after the procedure. The angiographic patency of the infarct-related vessel and the left ventricular ejection fraction were evaluated at 24 hours and 6 months. RESULTS: At 30 days, the primary end point – a composite of death, reinfarction, or urgent revascularization of the target vessel – had occurred in 6.0 percent of the patients in the abciximab group, as compared with 14.6 percent of those in the placebo group (p
0.01); at 6 months, the corresponding figures were 7.4 percent and 15.9 percent (p
0.02). The better clinical outcomes in the abciximab group were related to the greater frequency of grade 3 coronary flow (according to the classification of the Thrombolysis in Myocardial Infarction trial) in this group than in the placebo group before the procedure (16.8 percent vs. 5.4 percent, p
0.01), immediately afterward (95.1 percent vs. 86.7 percent, p
0.04) and 6 months afterward (94.3 percent vs. 82.8 percent, p
0.04). One major bleeding event occurred in the abciximab group (0.7 percent); none occurred in the placebo group. CONCLUSIONS: As compared with placebo, early administration of abciximab in patients with acute myocardial infarction improves coronary patency before stenting, the success rate of the stenting procedure, the rate of coronary patency at 6 months, left ventricular function, and clinical outcomes.

Summary In the ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up) study, 300 patients with acute myocardial Infarction (AMI) within 12 h were randomly assigned to stent with placebo or stent plus abciximab. The primary end point of death/reinfarction/urgent target-vessel revascularization at 30 days was reached by 6.0% the abciximab group and 14.6% of the placebo group ( p
0.02). This benefit was maintained at 6 months with combined end point rates of 7.4% for abciximab and 15.9% for placebo ( p
0.02). Thrombolysis in myocardial infarction (TIMI) 3 flow was seen in 16.8% of the patients taking abciximab at the time of catheterization compared with 5.4% of those taking placebo ( p
0.01). The best flow rates were seen with the earliest abciximab administration. Diabetic patients appeared to gain most from glycoprotein IIb/IIIa blockade, with a significantly reduced 6-month mortality rate of 0% compared with 16.7% with placebo ( p
0.02).

Citation Count

249

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Related References 1. Stone GW, Grines CL, Cox DA, et al. Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Investigators. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002; 346: 957–966. 2. Lincoff AM, Califf RM, Van de Werf F, et al., for the GUSTO V Investigators. Mortality at 1 Year With Combination Platelet Glycoprotein IIb/IIIa Inhibition and Reduced-Dose Fibrinolytic Therapy vs Conventional Fibrinolytic Therapy for Acute Myocardial Infarction: GUSTO V Randomized Trial. JAMA 2002; 288: 2130–2135.

Key message Glycoprotein IIb/IIIa receptor blockers have been shown to reduce the risk of major adverse events after elective percutaneous coronary intervention (PCI). This trial confirmed that they were also beneficial in primary percutaneous coronary intervention (PPCI).

Why it’s important Despite the success of PPCI, there is still a 5–10% rate of non-TIMI-3 flow. This is related to poor outcome, and is probably the result of distal microvascular embolization with thrombus. TIMI-3 flow before PPCI begins is also associated with improved outcome. This trial confirms the acute and longer-term benefits of using abciximab early.

Strengths Patients were recruited and assigned to treatment rapidly, always before coronary angiography. Thus, in 25% of cases abciximab treatment could be started before getting to the catheterization laboratory. As a result there was no angiographical selection bias.

Weaknesses There is good data for the use of tirofiban, another glycoprotein IIb/IIIA receptor blocker, in nonST-elevation myocardial infarction (STEMI). This was not tested in this study. There are no major criticisms to make of this study.

Relevance Following this trial, the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial failed to show a significant benefit from abciximab in patients receiving stents with PPCI. This may have been due to the fact that the drug was given later than in the ADMIRAL trial, and that very-high-risk patients were excluded. Overall, if given early (before beginning PPCI), abciximab is likely to be useful.

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Title 8

A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction Author Andersen HR, Nielsen TT, Rasmussen K, et al., for the DANAMI-2 Investigators

Reference N Engl J Med 2003; 349: 733–742

Abstract BACKGROUND: For the treatment of myocardial infarction with ST-segment elevation, primary angioplasty is considered superior to fibrinolysis for patients who are admitted to hospitals with angioplasty facilities. Whether this benefit is maintained for patients who require transportation from a community hospital to a center where invasive treatment is available is uncertain. METHODS: We randomly assigned 1572 patients with acute myocardial infarction to treatment with angioplasty or accelerated treatment with intravenous alteplase; 1129 patients were enrolled at 24 referral hospitals and 443 patients at 5 invasive-treatment centers. The primary study end point was a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days. RESULTS: Among patients who underwent randomization at referral hospitals, the primary end point was reached in 8.5 percent of the patients in the angioplasty group, as compared with 14.2 percent of those in the fibrinolysis group ( p
0.002). The results were similar among patients who were enrolled at invasive-treatment centers: 6.7 percent of the patients in the angioplasty group reached the primary end point, as compared with 12.3 percent in the fibrinolysis group ( p
0.05). Among all patients, the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfarction (1.6 percent in the angioplasty group vs. 6.3 percent in the fibrinolysis group, p  0.001); no significant differences were observed in the rate of death (6.6 percent vs. 7.8 percent, p
0.35) or the rate of stroke (1.1 percent vs. 2.0 percent, p
0.15). Ninety-six percent of patients were transferred from referral hospitals to an invasive-treatment center within two hours. CONCLUSIONS: A strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes two hours or less.

Summary A total of 1572 patients with acute myocardial infarction were randomized with angioplasty or accelerated treatment with intravenous alteplase. Among patients who underwent randomization at referral hospitals, the primary end point of death/myocardial infarction/cerebrovascular accident was reached in 8.5% of the patients in the angioplasty group, as compared with 14.2% of those in the fibrinolysis group (p
0.002). Among all patients, the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfarction (1.6% in the angioplasty group vs. 6.3% in the fibrinolysis group; p  0.001); no significant differences were observed in the rate of death (6.6% vs. 7.8%; p
0.35) or the rate of stroke (1.1% vs. 2.0%; p
0.15). Only 4% were felt to be too sick to transfer. The benefits were attained despite median delay to start of transportation of 50 min, with travel 25 km for 70% of cases.

Citation Count

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Related References 1. Madsen JK, Grande P, Saunamaki K, et al., Danish multicenter randomized study of invasive versus conservative treatment in patients with inducible ischemia after thrombolysis in acute myocardial infarction (DANAMI). DANish trial in Acute Myocardial Infarction. Circulation 1997; 96: 748–755.

Key message Primary percutaneous coronary intervention (PPCI) can be offered to 62% of the Danish population safely and effectively by seven percutaneous coronary intervention (PCI) centres.

Why it’s important It shows the feasibility of a population-wide programme of PPCI, with safe transfer of patients between hospitals.

Strengths There was a high rate of randomization: nearly 1500 of the 4278 patients screened were entered into the study. This would reduce selection bias. This paper does not address the issue of rescue angioplasty after thrombolysis. By not doing this, the thrombolysis arm is fairly pure (3.4% PCI), unlike the CAPTIM (Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction) data, which had almost one-third of the thrombolysis patients undergoing PCI in hospital. Most of the difference in primary end point was due to a lower reinfarction rate (6.3% vs. 1.6%; p  0.001). Of the 62 patients with reinfarction, the 30-day mortality was much higher than the other patients with no reinfarction (24.4% vs. 6.5%; p  0.001). This suggests that early revascularization reduces in-hospital non-fatal events, leading to longterm mortality benefits.

Weaknesses No mortality advantage was found in this trial, despite a significant clinical event rate. This may have been as shock patients, diabetic patients on metformin, patients with renal impairment and patients with prior coronary-artery bypass grafting (CABG) were all excluded. These highrisk groups probably have the most to gain from PPCI. As in the field of lipid reduction, one large trial showing benefit (as in the Scandanavian, Simvastatin Survival Study) would convince the doubters. The power of the study to detect differences between thrombolysis and PPCI was also reduced as patients presented and were randomized remarkably quickly (randomization within 135 min from symptom onset).

Relevance Data from this trial were presented more than 1 year before its final publication. It has begun to shape health care policy. The most interesting part of the programme was that no patient was taken to emergency surgery, suggesting that almost any anatomy could be dealt with percutaneously.

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Title 9

Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction: final results of the randomized national multicentre trial – PRAGUE-2 Author Widimsky P, Budesinsky T, Vorac D, et al., “PRAGUE” Study Group Investigators

Reference Eur Heart J 2003; 24: 94–104

Abstract BACKGROUND: Primary percutaneous coronary intervention (PCI) is shown to be the most effective reperfusion strategy in acute myocardial infarction (AMI). The aim of this multicentre national randomized mortality trial was to test whether the nationwide change in treatment guidelines (transportation of all patients to PCI centres) was warranted. METHODS: The PRAGUE-2 study randomized 850 patients with acute ST elevation myocardial infarction presenting within 12 h to the nearest community hospital without a catheter laboratory to either thrombolysis in this hospital (TL group, n
421) or immediate transport for primary percutaneous coronary intervention (PCI group, n
429). The primary end-point was 30-day mortality. Secondary end-points were: death/reinfarction/stroke at 30 days (combined end-point) and 30day mortality among patients treated within 0–3 h and 3–12 h after symptom onset. Maximum transport distance was 120 km. RESULTS: Five complications (1.2%) occurred during the transport. Randomization-balloon time in the PCI group was 97  27 min, and randomizationneedle time in the TL group was 12  10 min. Mortality at 30 days was 10.0% in the TL group compared to 6.8% mortality in the PCI group ( p
0.12, intention-to-treat analysis). Mortality of 380 patients who actually underwent PCI was 6.0% vs. 10.4% mortality in 424 patients who finally received TL ( p  0.05). Among 299 patients randomized 3 h after the onset of symptoms, the mortality of the TL group reached 15.3% compared to 6% in the PCI group ( p  0.02). Patients randomized within 3 h of symptom onset (n
551) had no difference in mortality whether treated by TL (7.4%) or transferred to PCI (7.3%). A combined end-point occurred in 15.2% of the TL group vs 8.4% of the PCI group ( p  0.003). CONCLUSIONS: Long distance transport from a community hospital to a tertiary PCI centre in the acute phase of AMI is safe. This strategy markedly decreases mortality in patients presenting 3 h after symptom onset. For patients presenting within 3 h of symptoms, TL results are similar results to long distance transport for PCI.

Summary Taking a country-wide approach to primary percutaneous coronary intervention (PPCI), the Czech republic tested the possibility of long-distance transport for PPCI vs. streptokinase. In a randomized trial of 850 patients with ST-elevation myocardial infarction (STEMI), PPCI took 90 min whereas thrombolysis was delivered in 12 min. Despite this, there was a strong trend to mortality reduction (PPCI 6.8% vs. 10.0% for thrombolysis; p
0.12). The benefits were very marked in those presenting with 3 h of symptoms (PPCI 6% vs. 15.3% in the thrombolysis group; p  0.02). The distances between primary hospitals and PCI centres varied

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Thrombolysis

173

12

60

Pain – randomization Randomization – thrombolysis/transport Transport Door-to-balloon/lysis time

PPCI

183

0

50

20

100

150

200

48

26

250

300

30-day mortality (%)

Figure 1 The causes of delay in reperfusion with PPCI and thrombolysis in the PRAGUE-2 study. Transport between hospitals took 48 min on average. It has been assumed that streptokinase would take 60 min to work. Delays in the PPCI arm occurred due to randomization, transport, and door-to-balloon times. Modified from Widimsky et al., 2003. 18 16 14 12 10 8 6 4 2 0

Thrombolysis

All patients

PPCI

Patients 0–3 h

Patients 3–12 h

Figure 2 The 30-day mortality (%) amongst patients in the PRAGUE-2 study in all patients, early (3 h) and late presenters (3 h after symptom onset). Mortality benefits are not seen with PPCI compared to thrombolysis, if treatment is received very early. Modified from Widimsky et al., 2003.

between 5 and 120 km. There were two deaths and three ventricular fibrillations (successfully treated with defibrillation in the emergency ambulance car, their further course was uneventful) during the transport (i.e. complications during the transport occurred in 1.2%) (Figures 1 and 2).

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68

Related References 1. Widimsky P, Groch L, Zelizko M, Aschermann M, Bednar F, Suryapranata H. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE study. Eur Heart J 2000; 21: 823–831.

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2. Vermeer F, Oude Ophuis AJ, vd Berg EJ, et al. Prospective randomised comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: a safety and feasibility study. Heart 1999; 82: 426–431.

Key message When percutaneous coronary intervention (PCI) cannot be started within 60 min of the electrocardiographical (ECG) diagnosis, thrombolysis should be used, but only for patients presenting within 3 h of symptom onset. However, all patients presenting between 3 and 12 h from symptom onset should be transported for primary PCI and thrombolysis should not be used in this subset of patients. If the transfer time can be reduced to 60 min, then PPCI could be recommended for all patients.

Why it’s important A model for a regional PPCI service is available on the basis of this paper. Large distances and multiple centres can achieve worthwhile results.

Strengths The trial enrolled 850 of about 4000 patients presenting with any acute myocardial infarction (AMI) to participating centres. This represents an excellent recruitment rate, reducing the chances of bias.

Weaknesses Comparison of PPCI was made with streptokinase. This is inferior to fibrin-specific agents, but since it was still a commonly used drug in their population, the authors cannot be criticized too heavily for this. The primary outcome of the study was total death at 30 days. The analysis by intention to treat showed no significant reduction in death, 6.8% in PCI vs. 10.0% in TL group (p
0.12). However, the authors emphasize that per protocol analysis showed a significant reduction in death, 6.0% in PCI vs. 10.4% in TL group ( p  0.05). Per protocol analyses are prone to bias and are not recommended for reporting the primary outcome of the study. In addition they performed a post hoc subgroup analysis comparing patients randomized 3 h and 3 h after symptoms.

Relevance Transfer distances of up to 120 km (average transfer time 48 min) did not appear to reduce the benefits of PPCI and transport was safe, with 1% of cases suffering complications. Of note is that almost all patients were kept at the PCI centre for 24 h, rather than being transferred back acutely.

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Classic Papers in Coronary Angioplasty

Title 10

Clinical characteristics and outcome of patients with early (⬍2 h), intermediate (2–4 h) and late (⬎4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction Author Zijlstra F, Patel A, Jones M, et al.

Reference Eur Heart J 2002; 23: 550–557

Abstract AIMS: We examined the clinical characteristics and outcome of patients with early (2 h), intermediate (2–4 h) and late (4 h) presentation treated by primary angioplasty or thrombolytic therapy for acute myocardial infarction. METHODS AND RESULTS: We studied 2635 patients enrolled in 10 randomized trials of primary angioplasty (n
1302) vs thrombolytic therapy (n
1333) in acute myocardial infarction, and baseline characteristics of the two groups were comparable. Increase in presentation delay is associated with older age, female gender, diabetes and an increased heart rate. We classified the patients according to the time delay from symptom onset to presentation into three categories: early presentation (2 h), intermediate presentation (2–4 h), and late presentation (4 h). At 30 days the combined rate of death, nonfatal reinfarction and stroke in patients presenting early was 5.8% in the angioplasty group vs 12.5% in the thrombolysis group, in patients with intermediate presentation, 8.6% vs 14.2%, respectively, and in patients presenting late 7.7% vs 19.4%, respectively. With increasing time from symptom onset to presentation, all major adverse cardiac event rates show a trend to a larger increase in the thrombolysis group compared to the angioplasty group, both at 30 days and at 6 months after the acute event. CONCLUSIONS: Major adverse cardiac event rates are lower after angioplasty compared to thrombolysis, irrespective of time to presentation. With increasing time to presentation major adverse cardiac event rates increase after thrombolysis but appear to remain relatively stable after angioplasty.

Summary Although primary percutaneous coronary intervention (PPCI) offers advantages over thrombolysis, a further benefit may be in those who present later after ST-elevation myocardial infarction (STEMI). Using data from 10 randomized trials, median time to thrombolysis was 22 min, whilst median time to balloon was 69 min. About 25% of all patients presented 4 h after symptoms (Figure 1).

Citation Count

6

Related References 1. Boersma E, Maas ACP, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996; 348: 771–775.

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30-day mortality/MI/CVA

25 Thrombolysis 20

PPCI

15 10 5 0 Early (0–2 h)

Intermediate (2–4 h)

Late (4 h)

Figure 1 The 30-day event rate (death, non-fatal MI, and stroke) with PPCI and thrombolysis related to presentation early (2 h after symptoms) or late (4 h after symptoms). There was a strong trend towards worse outcomes after thrombolysis with 4 h time delay (p
0.01 for trend). No such trend was seen for PPCI (p
0.4) (MI: myocardial infarction; CVA: cerebral vascular accident). Modified from Zijlstra et al., 2002.

2. Zeymer U, Tebbe U, von Essen R, Haarmann W, Neuhaus KL. Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens. Am Heart J 1999; 137: 34–38. 3. Cannon CP, Gibson CM, Lambrew CT. Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000; 283: 2941–2947.

Key message The later after symptom onset you present after STEMI, the more likely it is that thrombolysis will not work effectively.

Why it’s important Many patients present more than 3–4 h after the onset of chest pain. This may be too late for thrombolysis to be truly effective. Although data exists for some benefit up to 12 h after onset of pain, this study suggests late presenters should get PPCI instead.

Strengths This is a rigorous meta-analysis focusing on a specific question: time.

Weaknesses Several publications have used pooled data from the available trials of PPCI. If enough questions are asked of the data, then spurious effects can be found to be significant by chance. The trend of diminishing benefit with increasing time from pain to treatment was not strongly significant.

Relevance One randomized trial showing a relationship between time from symptoms and benefits of PPCI over thrombolysis may be criticized, but if confirming a consistent effect over 10 trials is harder to dismiss. How late is too late for thrombolysis is not clear, but 4 h may be classed as too late if PPCI is available. This fits in with other data available, including the PRAGUE-2 study.

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Chapter 4

Coronary angioplasty for acute coronary syndromes Steven Pfau Introduction Acute coronary syndrome (ACS) is a term of relatively recent origin, encompassing all clinical conditions that are manifestations of acute myocardial ischaemia. The label of “unstable angina” was first applied in 1971, when it was recognized that patients with new or worsening angina were at increased risk for cardiovascular morbidity and mortality compared to those with more chronic symptoms. Further, it was obvious that there was a need to define diagnostic criteria for this group of patients in order to develop risk stratification and treatment strategies, particularly to identify those who would benefit from urgent surgical revascularization. A variety of terms have been associated with this clinical presentation, including preinfarction angina, crescendo angina, acute coronary insufficiency, and intermediate coronary syndrome. Among the large number of patients who receive these labels is a subgroup of patients at increased risk for acute myocardial infarction and cardiovascular death; careful evaluation is necessary to separate those who will benefit most from aggressive treatment, particularly coronary revascularization. The strategy of early revascularization in patients with unstable angina developed from the larger experience with surgical coronary revascularization for stable angina in the 1970s, and from the relative limitations of the available medical therapy. By the mid-1980s, coronary artery bypass surgery was a primary therapy for patients with unstable angina, with low operative mortality, and excellent short- and long-term results. Shortly after Greuntzig’s report of “non-operative” revascularization for stable angina in 1979, angioplasty emerged as an alternative to bypass surgery, particularly in patients with refractory symptoms, proximal lesions, and single vessel disease. Patients with ACS are quite diverse with regard to demographics, signs and symptoms, and the results of diagnostic testing at the time of their presentation. Once identified, however, the approach to treatment has been distilled to a fairly consistent set of principles. These principles have developed through careful observation, examination of the pathophysiology of this clinical entity and by large, prospective randomized trials. This chapter focuses specifically on the use of percutaneous revascularization in this patient group, a therapy which has now surpassed surgical coronary bypass as the mainstay of treatment. Angioplasty in patients with ACS is generally considered “high risk”, as it is associated with more complex lesion morphology, higher rates of acute closure, periprocedural creatinine kinase (CK) release, and restenosis. In spite of these complicating factors, the widespread acceptance of percutaneous coronary intervention (PCI) in patients with ACS has resulted from three important factors: 1. early evidence of the efficacy of angioplasty for symptom control; 2. the progressive improvement in patient selection, angioplasty techniques, device technology, and adjunctive pharmacotherapy that has improved the safety and durability of PCI in this patient subgroup; 3. the large body of evidence that early, aggressive revascularization in patients who present with signs and symptoms of acute ischaemia is associated with improved clinical outcomes.

Coronary angioplasty for acute coronary syndromes

This last factor has led to an emphasis on risk stratification and identification of those patients who will receive the most benefit from early invasive evaluation. In this chapter, I identify several papers which illustrate each of these developmental factors. Current American Heart Association/American College of Cardiology (AHA/ACC) guidelines reflect the rapid advancement in our understanding of the identification, risk stratification, and treatment of this diverse group of patients. At present we are able to control ischaemic symptoms effectively in almost all patients who present with ACS using a combination of medical therapy and percutaneous revascularization, reserving surgery for those with significant left main coronary obstruction or particularly diffuse three vessel disease. Furthermore, the phenomenal advancements in risk factor modification, in particular treatment of lipid disorders, begin during the index hospitalization and substantially alter the natural history of these patients in the months and years following discharge. In spite of the dramatic advances in the interventional treatment of unstable angina, our understanding of the pathophysiology remains incomplete. Evidence for the role of inflammation in acute manifestations of coronary atherosclerosis is relatively new. Immune competent cells reside within both healthy and diseased arteries, and respond to influences as diverse as hyperlipidemia, exercise, and emotion. Therapies which target these cells and the cytokines that regulate their behaviour are being tested in a variety of “immune-mediated” diseases, and undoubtedly these therapies will be translated to patients with unstable angina. The use of stents as platforms for local delivery of antiproliferative and immunosuppressive drugs is arguably the largest technological advance in interventional cardiology. The integration of data regarding atherosclerotic inflammation into risk stratification and interventional treatment of patients with acute coronary ischaemia will facilitate the next major set of advances in this exciting field.

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Classic Papers in Coronary Angioplasty

Title 1

Evaluation of the role of coronary angioplasty in patients with unstable angina pectoris Author Williams DO, Riley RS, Singh AK, Gewirtz H, Most AS

Reference Am Heart J 1981; 102: 1–9

Abstract Seventeen patients presenting with unstable angina pectoris underwent percutaneous transluminal coronary angioplasty (PTCA). Despite vigorous medical therapy, all patients were disabled with 10 experiencing refractory in-hospital angina. PTCA was judged successful in 13 patients and resulted in decreased coronary diameter narrowing from 80  16% to 34  13% and reduced transstenotic pressure gradient from 69  13 to 23  12 mmHg. Regional coronary blood flow (CBF) and myocardial metabolism were assessed at rest and during pacing tachycardia in six patients with left anterior descending coronary stenosis. Prior to PTCA, neither regional CBF increased nor coronary vascular resistance declined during pacing; myocardial lactate extraction fell, indicating a shift from aerobic to anaerobic metabolism. Following PTCA, however, rapid pacing resulted in increased regional CBF, decreased coronary vascular resistance, and preservation of aerobic metabolism. Following PTCA, successfully dilated patients demonstrated marked relief of angina symptoms, increase in functional capacity, and objective exercise EKG and thallium scintigraphic evidence of relief of previously ischemic myocardium. This investigation demonstrates that PTCA, when combined with medical therapy, can be performed safely and successfully in selected patients who present with otherwise refractory unstable angina, and indicates the procedure deserves further study as a therapeutic alternative in this condition.

Summary Seventeen carefully selected patients with unstable angina were treated by angioplasty after failure of medical therapy. In 13 of the 17, a satisfactory angioplasty result was obtained which resulted in resolution of angina; 12 of 13 remained symptom free at 2 years. In six patients with proximal left anterior descending artery (LAD) stenosis, coronary sinus catheterization, and rapid atrial pacing were used to demonstrate that in this acute setting the identified stenosis results in impaired regional blood flow and altered myocardial substrate use consistent with ischaemia. All parameters normalized after successful angioplasty of these LAD lesions.

Citation Count

118

Related References 1. Meyer J, Schmitz H-J, Kiesslich T, et al. Percutaneous transluminal coronary angioplasty in patients with stable and unstable angina pectoris: analysis of early and late results. Am Heart J 1983; 106: 973–980.

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2. de Feyter PJ, Serruys PW, van den Brand M, et al. Emergency coronary angioplasty in refractory unstable angina. N Engl J Med 1985; 313: 342–346. 3. Safian RD, Snyder LD, Snyder BA, et al. Usefulness of PTCA for unstable angina after non Q-wave acute myocardial infarction. Am J Cardiology 1987; 59: 263. 4. de Feyter PJ, Suryapranata H, Serruys PW, et al. Coronary angioplasty for unstable angina: immediate and late results in 200 consecutive patients with identification of risk factors for unfavorable early and late outcome. J Am Coll Cardiol 1988; 12: 324–333.

Key message This paper is the first demonstration that angioplasty, in addition to standard medical therapy, is a safe and effective in selected patients with unstable angina. In addition, Williams proves that stenosis on angiogram correlates with alterations in myocardial metabolism, coronary haemodynamics, stress testing parameters, and symptoms; and that angioplasty of the culprit stenosis returns these parameters to normal in addition to relief of symptoms. The results were durable, as only one patient had recurrent symptoms at 2 years.

Why it’s important Within 2 years of the publication of Gruentzig’s first case series, Williams and colleagues show that the technique of non-surgical coronary dilatation can be safely used to treat patients with medically refractory angina. This observation dramatically expands the number of patients who are candidates for angioplasty.

Strengths This study was remarkable (at the time) because it was the first publication of the application of angioplasty to this group of patients. It also elegantly demonstrates the functional consequences of proximal coronary stenosis relative to myocardial blood flow, haemodynamics and substrate utilization which are normalized after successful angioplasty.

Weaknesses By today’s standards, 17 patients is too small a cohort from which to draw any substantial conclusions.

Relevance This article is the first to demonstrate that coronary stenosis identified on angiography in patients with unstable angina can be safely treated by angioplasty, with excellent short- and long-term clinical outcomes. This observation is a seminal event in the field of interventional cardiology as it applies to patients with unstable angina.

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Title 2

Coronary angioplasty of the unstable angina related vessel in patients with multivessel disease Author de Feyter PJ, Serruys PW, Arnold A, et al.

Reference Eur Heart J 1986; 7: 460–467

Abstract This study is a retrospective analysis of the efficacy of percutaneous transluminal coronary angioplasty (PTCA) of the ischaemia-related vessel in patients with unstable angina. Forty-three patients had multivessel disease with dilatation of the ischaemia related vessel only (group I; partial revascularization) while 111 patients had single vessel disease only (group II; total revascularization). The initial success rate in both groups was identical (88% versus 88%). The need for emergency coronary artery bypass surgery was similar in the two groups (group I 12% versus group II 9%; NS). The total post PTCA myocardial infarction rate (despite urgent CABG) was also similar in the two groups (group I 9% versus group II 10%; NS). The results of electrocardiographic exercise testing and Thallium-201 scintigraphy provide objective evidence for incomplete revascularization in group I. The maximum workload achieved was lower, and the frequency of exercise induced angina, ST-segment depression and reversible perfusion defect was higher than in group II. Moreover, at 6 months follow-up the recurrence rate of angina pectoris rate was higher in group I than in group II (29% versus 16%; p less than 0.05). It is concluded that dilatation of the ischaemia related vessel only in patients with unstable angina and multivessel disease is as effective in the management of the acute phase of unstable angina as is dilatation of the ischaemia related vessel in patients with single vessel disease. However, due to only partial revascularization the recurrence rate of angina pectoris is higher.

Summary Over a period of 2 years in 1983 and 1984, de Feyter and colleagues studied a cohort of 154 patients with unstable angina who had angioplasty in addition to standard medical therapy. Of these, most had single vessel disease, but about one-third (43) had multivessel disease. In this group, only the “ischaemia-related vessel” was dilated; all patients were followed for clinical events, and the large majority had follow-up stress testing and angiography. Procedural success, periprocedural myocardial infarction (MI), emergent coronary artery bypass grafting (CABG), and subsequent restenosis rates were remarkably similar between those with single vessel disease and those with multivessel disease. The incidence of ischaemic defects on stress test at follow-up was slightly higher in the multivessel group (33% vs. 23%), and at 6 months the number with recurrent angina was also slightly higher in those with multivessel disease (29% vs. 16%).

Citation Count

47

Related References 1. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985; 5: 609–616.

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2. Wohlgelertner D, Cleman M, Highman HA, Zaret BL. Percutaneous transluminal coronary angioplasty of the “culprit lesion” for management of unstable angina pectoris in patients with multivessel coronary artery disease. Am J Cardiol 1986; 58: 460–464. 3. Dorros G, Sterzer SH, Cowley M, Myler RK. Complex coronary angioplasty: multiple coronary dilatations. Am J Cardiol 1984; 53: 126–130.

Key message While the ischaemic burden in patients with multivessel disease is related to all narrowed arteries, the authors argue that angioplasty of the single lesion which is responsible for an acute presentation can be safe and effective in selected patients with unstable angina. The data presented in the article, although retrospective and highly selected, bear this out. The authors acknowledge that this strategy leads to incomplete revascularization, yet was effective in controlling symptoms; most patients were discharged without the need for surgical revascularization.

Why it’s important At the time of this report, percutaneous transluminal coronary angioplasty (PTCA) was considered an appropriate treatment for about 5–10% of patients with chronic stable angina. Angioplasty was also evolving as a reasonable strategy in selected patients with unstable angina and single vessel disease who failed medical therapy. In the early 1980s, angiographical characteristics, such as ulceration and thrombus were correlated with acute clinical presentation. The concept of directing interventional treatment at these “active” lesions followed quickly. This paper attempts to prove that a strategy of selective revascularization in patients with multivessel disease is effective in the management of patients with acute coronary syndrome (ACS), expanding the applicability of angioplasty beyond those with single vessel disease. In fact, the authors state “We now believe that PTCA of only the ischaemia-related vessel should be regarded as an initial strategy which in most patients will have long term success …”.

Strengths Through their practice of aggressive angioplasty, the authors proved that selective revascularization, although incomplete, can be a valuable technique in the management of patients with multivessel disease. The strengths of this article are the thoroughness of the data presentation and the excellent follow-up data, including stress testing and repeat angiography which underline the safety of the selective revascularization concept.

Weaknesses This is a retrospective review of experience with a highly selected group of patients. The authors state that the ischaemia-related vessel was determined by location of spontaneous dynamic electrocardiogram (EKG) ST segments, but no information is offered regarding any angiographical characteristics of the treated arteries or lesions.

Relevance The authors introduce a number of unique concepts to the practice of angioplasty: ischaemiarelated artery, the success and appropriateness of selective revascularization, and staged angioplasty. Their arguments opened a new conceptual framework for the treatment of multivessel disease, both in patients with ACS and with stable angina. In contrast to coronary surgery (where results are best with complete revascularization), angioplasty can effectively control symptoms and improve outcomes by using a more selective revascularization strategy.

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Title 3

Restenosis after successful coronary angioplasty in patients with single-vessel disease Author Leimgruber PP, Roubin GS, Hollman J, et al.

Reference Circulation 1986; 73: 710–717

Abstract To determine risk factors for restenosis, we studied 998 patients who underwent elective coronary angioplasty (PTCA) to native coronary arteries between July 1980 and July 1984. Restenosis, defined as a luminal narrowing of greater than 50% at follow-up, was present in 302 patients (30.2%). Univariate analysis of 29 factors revealed seven factors related to restenosis: vessel dilated (circumflex coronary artery 18%, right coronary artery 27%, left anterior descending artery 34%; p less than 0.01), duration of angina greater than 2 months compared with angina of shorter duration (27% vs 35%, p
0.01), post-PTCA stenosis of 30% or less compared with 31% to 50% (28% vs 36%, p less than 0.025), stable vs unstable angina (26% vs 34%, p less than 0.05), presence vs absence of intimal dissection (26% vs 32%, p
0.07) and female gender vs male gender (25% vs 32%, p
0.08). Multivariate analysis revealed five factors independently related to increased risk of restenosis in the following order of importance: PTCA in the left anterior descending artery, absence of intimal dissection immediately after PTCA, final gradient greater than 15 mmHg, a large residual stenosis after PTCA, and unstable angina. Restenosis after PTCA is a multifactorial problem. The hemodynamic and angiographic result at the time of PTCA significantly influences long-term outcome, but additional measures aimed at reducing the rate of recurrence of atherosclerotic plaque are required.

Summary The authors report their experience with 1758 successful angioplasties at Emory between 1980 and 1984. The patients had single vessel disease, and the lesions dilated were in native coronary arteries; restenotic lesions and acute myocardial infarctions (MIs) were excluded. Repeat angiography was recommended at 6 months, and was completed in 998 (57%) of the patients. Follow-up angiograms were analysed at a core facility for angiographical evidence of restenosis, and univariate and multivariate analysis was performed to determine those clinical and lesion characteristics that predicted restenosis. Of the clinical variables included in the study, only unstable angina predicted restenosis.

Citation Count

615

Related References 1. Gruentzig AR, King SB III, Schlumpf M, Siegenthaler W. Long-term follow-up after percutaneous transluminal coronary angioplasty: the early Zurich experience. N Engl J Med 1987; 316: 1127–1132.

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2. Serruys PW, Luijten HE, Beatt KJ, et al. 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: 361–371. 3. de Groote P, Bauters C, McFadden EP, Lablanche J-M, Leroy F, Bertrand ME. Local lesionrelated factors and restenosis after coronary angioplasty. Circulation 1995; 91: 968–972. 4. Rensing BJ, Hermans WR, Vos J, et al., for the Coronary Artery Restenosis Prevention on Repeated Thromboxane Antagonism (CARPORT) Study Group. Luminal narrowing after percutaneous transluminal coronary angioplasty: a study of clinical, procedural, and lesional factors related to long-term angiographic outcome. Circulation 1993; 88: 975–985.

Key message Presentation with unstable angina is identified as the only clinical risk factor for restenosis early in the angioplasty experience (all other risk factors were angiographical).

Why it’s important This is one of the largest and most thorough of the early papers which attempt to understand which patient and lesion specific characteristics are related to restenosis after balloon angioplasty, and the first to identify unstable angina as an independent risk factor for restenosis. Almost all factors identified in this early description (unstable angina, residual stenosis, residual gradient, total occlusion, and proximal left anterior descending artery (LAD) location) have been subsequently validated in larger and prospective registries, in both the balloon and stent eras. From an analytic standpoint, a number of techniques used in this report became standard practice for angiographical restenosis trials. This is the first paper to use quantitative angiographical stenosis of 50% at the index lesion as the definition of restenosis, a definition that has become a standard in interventional trials.

Strengths This study was a large, systematic review of 1995 consecutive native coronary angioplasties at Emory between 1980 and 1984. All follow-up angiograms were reviewed at the same institution to allow consistency in interpretation, a concept that is behind angiographical core laboratories in most angioplasty clinical trials. The authors are among the most important thought leaders in the field, both in the earliest days of coronary angioplasty and continuing into the current era. The accuracy of their observations is apparent in the enduring nature of these risks for restenosis, even 18 years later.

Weaknesses While almost 1000 patients had follow-up angiograms available for review at a mean of 7 months, this represented only 57% of the original cohort, and so conclusions regarding risk factors for restenosis are incomplete. Although the authors argue that the lack of incomplete angiographical follow-up served only to overestimate restenosis rates (since those who were asymptomatic probably did not have restensosis), this is probably explains why diabetes, even insulin-dependent diabetes, was not recognized as a risk factor for restenosis. There was no attempt to assess for asymptomatic ischaemia or asymptomatic restenosis.

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Relevance This study is largely of historical interest, although it underscores the importance of unstable angina (among other factors) as a risk factor for restenosis; a risk that persisted into the modern stent era. With the advent of drug-eluting stents, the impact of unstable angina on restenosis rates may have been substantially reduced or eliminated.

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Title 4

Incidence and clinical significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty Author Klein LW, Kramer BL, Howard E, Lesch M

Reference J Am Coll Cardiol 1991; 17: 621–626

Abstract To assess the incidence and clinical significance of elevated total plasma creatine kinase (CK) and MB isoenzyme fraction after apparently successful coronary angioplasty, a prospective study of 272 consecutive elective procedures was undertaken. Total CK (normal  200 IU/liter) and CK MB isoenzyme (normal 4%) were measured immediately after successful completion of the procedure and every 6 h for 24 h. All nonelective procedures results not fulfilling all American Heart Association/American College of Cardiology Task Force guideline criteria for a successful result were excluded from analysis. Of the 272 elective procedures, 249 (92%) were successful; abnormally elevated CK or CK MB serum levels, or both, were found in 38 (15%) of the successful outcomes. Three patterns of abnormal enzymes were identified: 15 patients with CK 200 IU/liter and CK MB 5% (group 1), 4 patients with CK 200 IU/liter and CK MB 4% (group 2), and 19 patients with CK  200 IU/liter and CK MB 5% (group 3). The three groups were distinguishable by the nature of the complications causing the enzyme release (in particular, the etiology and clinical manifestations). There were significantly more clinically apparent events in group 1 than in other groups (13 of 15 versus 11 of 23, p  0.01) and more events associated with persistent electrocardiographic changes (p
0.05). However, no clinically important sequelae were recognizable in any group at hospital discharge. Thus, abnormal serum enzyme release after apparently successful coronary angioplasty is (1) relatively common; (2) has many possible causes, including both minor complications and reversibility of impending major complications; and (3) results in no permanent clinical sequelae.

Summary This study examined procedural details and in-hospital events in a series of elective angioplasties to establish the significance of post-angioplasty creatinine kinase (CK) and CK-MB elevation. All patients with major in-hospital events after angioplasty (death, cardiac arrest, Q wave myocardial infarction (MI) and emergency coronary artery bypass grafting, CABG) were excluded. Patients with elevated CK-MB (both those with normal total CK and elevated total CK) were more likely to have had a clinical event during the angioplasty or immediately after that would have explained elevated cardiac enzymes. These events included side-branch occlusion, prolonged ischaemic chest pain either during the procedure or within the first 72 h, saphenous vein graft embolism, large dissection, or transient coronary thrombosis.

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80

Related References 1. Abdelmeguid AE, Topol EJ. The myth of the myocardial ‘infarctlet’ during percutaneous coronary revascularization procedures. Circulation 1996; 94: 3369–3375. 2. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation 1996; 94: 1528–1536. 3. Tardiff BE, Califf RM, Tcheng JE, et al., for the IMPACT-II Investigators. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. J Am Coll Cardiol 1999; 33: 88–96. 4. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol 1998; 31: 241–251.

Key message The authors found that the vast majority of patients who have CK-MB elevation after “successful” angioplasty have events during the procedure that could explain the enzyme abnormalities. In those patients with prolonged ischaemic chest pain after angioplasty, the authors recognize that this may be related to subacute closure, but that this would represent only a minority of those studied. Since all of these patients were discharged to home after the CK-MB elevation, the authors conclude that “no apparently important clinical consequences are apparent after several days”.

Why it’s important Although the general conclusion from this report (that CK-MB elevation after angioplasty is benign) has subsequently been overturned by larger, more carefully done studies, this paper is generally credited as the first attempt to understand the potential implications of CK-MB elevation after coronary angioplasty.

Strengths The authors divided their patients into three categories, including one group which had CK-MB elevation without total CK elevation. The recognition that this may represent a group with small but important myocardial necrosis presaged the debate about what specific criteria should define periprocedural MI (2  normal CK, 5  normal CK, etc.) and the troponin era, where increasingly sensitive markers of myocardial injury are able to identify patients who are at longterm risk.

Weaknesses The authors excluded all patients with major in-hospital events, such as emergency bypass surgery, from the analysis. As they were drawing conclusions about in-hospital risk, all patients who had events should have been included. Similarly, the absence of post-discharge follow-up information is critical; the true value of cardiac enzyme markers at the time of angioplasty is to identify patients at risk in the short to intermediate term after discharge, rather than in the hospital.

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Relevance The importance of periprocedural myocardial necrosis has been confirmed in a large number of prospective observational studies; recognition of these events has changed the practice of angioplasty dramatically. The causes of these events have been, in part, identified and addressed: the efficacy of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors is in large part related to their ability to limit myocardial injury at the time of angioplasty. Distal embolism protection is now standard in saphenous vein graft angioplasty, and is extending into native coronary angioplasty where recognition of distal embolization is increasing (i.e. acute MI).

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Title 5

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. Thrombolysis in myocardial ischemia Author The TIMI IIIB Investigators

Reference Circulation 1994; 89: 1545–1556

Abstract BACKGROUND: Although coronary thrombosis plays a critical role in the pathogenesis of unstable angina and non-Q-wave myocardial infarction (NQMI), the effects of thrombolytic therapy in these disorders is not clear. Also, the role of routine early coronary angiography followed by revascularization has not been established. METHODS AND RESULTS: Patients (n
1473) seen within 24 hours of ischemic chest discomfort at rest, considered to represent unstable angina or NQMI, were randomized using a 2  2 factorial design to compare (1) TPA versus placebo as initial therapy and (2) an early invasive strategy (early coronary arteriography followed by revascularization if initial medical therapy failed). All patients were treated with bedrest, antiischemic medications, aspirin, and heparin. The primary end point for the TPA-placebo comparison (death, myocardial infarction, or failure of initial therapy at 6 weeks) occurred in 54.2% of the TPA-treated patients and 55.5% of placebo-treated patients (p
NS). Fatal and nonfatal myocardial infarction after randomization (reinfarction in NQMI patients) occurred more frequently in TPA-treated patients (7.4%) than in placebo-treated patients (4.9%, p
0.04, Kaplan-Meier estimate). Four intracranial hemorrhages occurred in the TPA-treated group versus none in the placebo-treated group (p
0.06). The endpoint for the comparison of the two strategies (death, myocardial infarction, or an unsatisfactory symptom-limited exercise test at 6 weeks) occurred in 18.1% of patients assigned to the early conservative strategy and 16.2% of patients assigned to the early invasive strategy (p
NS). In the latter, the average length of initial hospitalization, incidence of rehospitalization within 6 weeks, and days of rehospitalization were all significantly lower. CONCLUSIONS: In the overall trial, patients with unstable angina and NQMI were managed with low rates of mortality (2.4%) and myocardial infarction or reinfarction (6.3%) at the time of the 6-week visit. These results can be achieved using either an early conservative or early invasive strategy, the latter resulting in a reduced incidence of days of hospitalization and of rehospitalization and in the use of antianginal drugs. The addition of a thrombolytic agent is not beneficial and may be harmful.

Summary Between October 1989 and June 1992, 1473 patients were randomized according to two management strategies: either the use of tissue plasminogen activator (TPA) or placebo, and either routine catheterization, or catheterization guided by clinical evidence of ongoing ischaemia. This created four groups for analysis: TPA with early cath, TPA with ischaemia-guided cath, placebo with early cath, and placebo with ischaemia-guided cath. At the prespecified endpoint of 6 weeks, TPA was detrimental, with increased rates of myocardial infarction (MI) and intracranial

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haemorrhage. Routine catheterization had no advantage over ischaemia-guided catheterization with regard to death, MI, or positive stress test at 6 weeks, but it was not detrimental and it was associated with shorter hospital stay and less rehospitalization.

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438

Related References 1. DeWood MA, Stifter WF, Simpson CS, et al. Coronary arteriographic findings soon after nonQ-wave myocardial infarction. N Engl J Med 1986; 315: 417–423. 2. Luchi RJ, Scott SM, Deupree RH. Principle investigators and their associates of veterans administration cooperative study No. 28. Comparison of medical and surgical treatment for unstable angina pectoris. N Engl J Med 1987; 316: 977–984. 3. Mahoney EM, Jurkovitz CT, Chu H, et al., for the TACTICS-TIMI 18 Investigators. Cost and cost-effectiveness of an early invasive vs conservative strategy for the treatment of unstable angina and non-ST-segment elevation myocardial infarction. JAMA 2002; 288: 1851–1858.

Key message As many as 11 previous studies had failed to clearly answer whether thrombolytics were helpful in patients with unstable angina; thrombolysis in myocardial infarction (TIMI) 3b is generally cited as the study that clearly demonstrated an adverse effect. More importantly, this study ignited a debate over routine invasive evaluation and revascularization in patients with acute coronary syndrome (ACS) that would last for the next 7 years. Although the primary endpoints were not different between routine invasive and conservative arms, two powerful observations gave the invasive strategy momentum:(1) routine invasive evaluation shortened hospital stay and decreased readmission rates, and (2) invasive evaluation was performed in 64% of the conservative arm by 6 weeks. This study demonstrated unequivocally that invasive evaluation is an important part of the management of patients with unstable angina and non-Q-wave MI whether it is used early, or following provocative testing.

Why it’s important This study highlighted the frequency with which patients with this diagnosis will require invasive evaluation and revascularization. With the appropriate level of aggressiveness, this diagnosis can have excellent short and intermediate mortality and reinfarction rates. The findings in this study set the tone for the widespread use of percutaneous intervention in this patient population.

Strengths This carefully designed study provided a wealth of information regarding the appropriate use of invasive evaluation and percutaneous revascularization in patients with ACS. The study served as a template for a number of subsequent studies which examined the benefit of routine angiography and intervention in patients with unstable angina.

Weaknesses This study was extremely well designed and executed. Overall rates of mortality and reinfarction were relatively low; in part, this may reflect a relatively lower-risk group of patients (i.e. the average age was 60 years). Subsequent studies have demonstrated that invasive evaluation provides the most benefit to the highest-risk patients.

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Relevance Early diagnostic angiography and percutaneous coronary intervention is currently one of the foundations of treatment in patients with ACS. TIMI 3b established the utility of routine diagnostic study and the frequency with which revascularization is necessary in this patient population. No study before or since has had the same degree of impact on the practice of angioplasty in ACS.

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Title 6

Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty Author The EPIC Investigators

Reference N Engl J Med 1994; 330: 956–961

Abstract BACKGROUND: Platelets are believed to play a part in the ischemic complications of coronary angioplasty, such as abrupt closure of the coronary vessel during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal-antibody Fab fragment (c7E3 Fab) directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. This receptor is the final common pathway for platelet aggregation. METHODS: In a prospective, randomized, double-blind trial, 2099 patients treated at 56 centers received a bolus and an infusion of placebo, a bolus of c7E3 Fab and an infusion of placebo, or a bolus and an infusion of c7E3 Fab. They were scheduled to undergo coronary angioplasty or atherectomy in high-risk clinical situations involving severe unstable angina, evolving acute myocardial infarction, or high-risk coronary morphologic characteristics. The primary study end point consisted of any of the following: death, non-fatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intraaortic balloon pump for refractory ischemia. The numbers of end-point events were tabulated for 30 days after randomization. RESULTS: As compared with placebo, the c7E3 Fab bolus and infusion resulted in a 35 percent reduction in the rate of the primary end point (12.8 vs. 8.3 percent, p
0.008), whereas a 10 percent reduction was observed with the c7E3 Fab bolus alone (12.8 vs. 11.5 percent, p
0.43). The reduction in the number of events with the c7E3 Fab bolus and infusion was consistent across the end points of unplanned revascularization procedures and non-fatal myocardial infarction. Bleeding episodes and transfusions were more frequent in the group given the c7E3 Fab bolus and infusion than in the other two groups. CONCLUSIONS: Ischemic complications of coronary angioplasty and atherectomy were reduced with a monoclonal antibody directed against the platelet IIb/IIIa glycoprotein receptor, although the risk of bleeding was increased.

Summary Over 2000 patients undergoing high-risk angioplasty (42.5% had acute coronary syndrome, ACS) were randomized to placebo or one of two regimens of c7E3Fab (abciximab) in an attempt to reduce the 10–20% risk of periprocedural ischaemic complications that occur in this group. At 30 days, bolus plus infusion of abciximab was superior to placebo with a 35% reduction in those who reached the primary endpoint. The rates of death, intra-aortic balloon pump (IABP) placement, stent placement, and emergency coronary artery bypass grafting (CABG) were low and not different between groups. The primary endpoint was driven primarily through a decrease in non-fatal myocardial infarction (MI) (8.6% vs. 5.2%, p
0.013) and the need for emergent repeat percutaneous transluminal coronary angioplasty (PTCA) (4.5% vs. 0.8%, p  0.001). Major bleeding was higher in the abciximab group compared to placebo (14% vs. 7%, p
0.001).

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1223

Related References 1. 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 non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488–1497. 2. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436–443. 3. GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. Lancet 2001; 357: 1899–1900. 4. 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. Circulation 1999; 100: 2045–2048.

Key message In the balloon angioplasty era, abrupt vessel closure was related to a variety of factors, including local platelet activation and thrombus formation at the site of balloon injury. Profound inhibition of platelet function using an antibody against the IIb/IIIa inhibitor in patients at high risk for acute closure (including unstable angina) was associated with improved periprocedural ischaemic complications, but at a cost of increased bleeding.

Why it’s important This article heralded a phase of progressively more aggressive platelet inhibition during angioplasty as a mechanism to improve the results of coronary intervention. Patients with ACS were frequent targets of these therapies, because the pathophysiology was thought to include activated platelets and because of the relatively high event rates. This class of medications has had a profound effect on the way in which patients with ACS are managed; these insights were first obtained in this study involving patients undergoing angioplasty, many of whom had ACS.

Strengths The study was successful in enrolling a group of patients at high risk for serious ischaemic complications of coronary angioplasty: the placebo arm had almost a 13% event rate. In patients with unstable angina, the benefit was the greatest, with a 62% reduction in primary endpoint at 30 days. At 6 months, mortality was reduced from 6.6% in placebo to 1.8% ( p
0.018) in this group, indicating that prevention of creatine kinase (CK) release with this medication did have a favourable effect on intermediate term mortality.

Weaknesses A significant proportion of the combined endpoint was non-fatal MI (elevation of the creatinine phosphokinase (CPK)-MB). The cutoff for definition of non-fatal MI was elevation of CK-MB greater than three times normal; had less liberal definitions been used the benefit may have been larger.

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Relevance Careful observational and laboratory study had led to the understanding of the importance of platelets in the acute complications of angioplasty. Logical design of a drug to dramatically inhibit platelet function led to abciximab. In a single study of the first drug in this class, the EPIC trial dramatically changed the practice of angioplasty in patients considered to be at “high risk”. Future studies of these medications focused almost exclusively on patients with ACS, many of whom had percutaneous intervention. The largest benefits for IIb/IIIa inhibitors appear to be in patients undergoing angioplasty while hospitalized for ACS.

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Title 7

The TIMI risk score for unstable angina/non-ST elevation MI. A method for prognostication and therapeutic decision making Author Antman EM, Cohen M, Bernink PJLM, et al.

Reference JAMA 2000; 284: 835–842

Abstract Context patients with unstable angina/non-ST-segment elevation myocardial infarction (MI) (UA/NSTEMI) present with a wide spectrum of risk for death and cardiac ischemic events. OBJECTIVE: To develop a simple risk score that has broad applicability, is easily calculated at patient presentation, does not require a computer, and identifies patients with different responses to treatments for UA/NSTEMI. DESIGN, SETTING, AND PATIENTS: Two phase 3, international, randomized, double-blind trials (the Thrombolysis in Myocardial Infarction [TIMI] 11B trial [August 1996–March 1998] and the Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI trial [ESSENCE; October 1994–May 1996]). A total of 1957 patients with UA/NSTEMI were assigned to receive unfractionated heparin (test cohort) and 1953 to receive enoxaparin in TIMI 11B; 1564 and 1607 were assigned respectively in ESSENCE. The 3 validation cohorts were the unfractionated heparin group from ESSENCE and both enoxaparin groups. MAIN OUTCOME MEASURES: The TIMI risk score was derived in the test cohort by selection of independent prognostic variables using multivariate logistic regression, assignment of value of 1 when a factor was present and 0 when it was absent, and summing the number of factors present to categorize patients into risk strata. Relative differences in response to therapeutic interventions were determined by comparing the slopes of the rates of events with increasing score in treatment groups and by testing for an interaction between risk score and treatment. Outcomes were TIMI risk score for developing at least 1 component of the primary end point (all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization) through 14 days after randomization. RESULTS: The 7 TIMI risk score predictor variables were age 65 years or older, at least 3 risk factors for coronary artery disease, prior coronary stenosis of 50% or more, ST-segment deviation on electrocardiogram at presentation, at least 2 anginal events in prior 24 hours, use of aspirin in prior 7 days, and elevated serum cardiac markers. Event rates increased significantly as the TIMI risk score increased in the test cohort in TIMI 11B: 4.7% for a score of 0/1; 8.3% for 2; 13.2% for 3; 19.9% for 4; 26.2% for 5; and 40.9% for 6/7 (p  0.001 by 2 for trend). The pattern of increasing event rates with increasing TIMI risk score was confirmed in all 3 validation groups (p  0.001). The slope of the increase in event rates with increasing numbers of risk factors was significantly lower in the enoxaparin groups in both TIMI 11B (p
0.01) and ESSENCE (p
0.03) and there was a significant interaction between TIMI risk score and treatment (p
0.02). CONCLUSIONS: In patients with UA/NSTEMI, the TIMI risk score is a simple prognostication scheme that categorizes a patient’s risk of death and ischemic events and provides a basis for therapeutic decision making.

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Summary The authors report the design, testing, and clinical utility of a risk stratification algorithm for patients with unstable angina and non-Q wave myocardial infarction (MI). Using the databases of the thrombolysis in myocardial infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events (ESSENCE) trials, they developed a scoring system based on six variables that could be assessed at the bedside, plus serum markers of myocardial injury. Using these seven factors, event rates at 14 days were lowest (8.3%) in the groups with scores of 0 or 1 and gradually increased in a stepwise fashion to 40.9% in those with a score of 6 or 7. The risk score accurately predicted graded event rates for all-cause mortality, MI, urgent revascularization, and all-cause mortality/non-fatal MI.

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231

Related References 1. Farhi JI, Cohen M, Fuster V. The broad spectrum of unstable angina pectoris and its implications for future controlled trials. Am J Cardiol 1986; 58: 547–550. 2. Willich SN, Stone PH, Muller JE, et al. High-risk subgroups of patients with non-Q wave myocardial infarction based on direction and severity of ST segment deviation. Am Heart J 1987; 114: 1110–1119. 3. Zaacks SM, Liebson PR, Calvin JE, Parrillo JE, Klein LW. Unstable angina and non-Q wave myocardial infarction: does the clinical diagnosis have therapeutic implications? J Am Coll Cardiol 1999; 33: 107–118. 4. Lindahl B, Venge P, Wallentin L. Relation between troponin T and the risk of subsequent cardiac events in unstable coronary artery disease. Circulation 1996; 93: 1651–1657. 5. Calvin JE, Klein LW, VandenBerg BJ, et al. Risk stratification in unstable angina. Prospective validation of the Braunwald classification. JAMA 1995; 273: 136–141.

Key message Within minutes of their presentation, most patients will provide all the information necessary by history and physical examination to allow their physician to predict short-term risk. Patients with a diagnosis of acute coronary syndrome (ACS) represent a heterogeneous group, and the aggressiveness of treatment should be dictated by risk of future events. Once risk has been determined, the aggressiveness of therapy can be tailored to individual patients.

Why it’s important Coronary intervention in patients with ACS is beneficial, but because of the risks and expense, should be reserved for patients who are most at risk without intervention. Risk assessment and direction of therapy can be reliably performed at the bedside soon after presentation in most patients with ACS.

Strengths The study provides a practical and easy to use risk assessment tool for physicians evaluating patients with ACS. This analysis also compared the relative benefit of a new, more costly therapy (low-molecular-weight heparin) to standard therapy according to their risk score. The validity of the scoring system was confirmed in this analysis; the patients with the highest-risk scores received the most benefit from the new therapy.

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Weaknesses The databases use to create and test the scoring system were the same used for validation in a retrospective fashion. A prospective validation cohort from another group of investigators may have provided less chance for unrecognized biases. Subsequently other trials of ACS therapy have validated the scoring system; in TIMI 18 only those patients with intermediate and highrisk scores benefited from early invasive evaluation and revascularization.

Relevance In prospective, randomized trials the TIMI risk score has accurately predicted those patients in whom coronary intervention is most beneficial. Patients with unstable angina/non-Q-wave MI are a heterogeneous population where it is important to match the aggressiveness of therapy with level of risk. The TIMI risk score is an easy and rapid tool for assessment of those patients with ACS who are likely to benefit from invasive evaluation and percutaneous coronary intervention.

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Title 8

Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban Author Cannon CP, Weintraub WS, Demopoulos L, et al., for the TACTICS – Thrombolysis in Myocardial Infarction 18 Investigators

Reference N Engl J Med 2001; 344: 1879–1887

Abstract 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 myocardial infarction without ST-segment elevation. METHODS: We enrolled 2220 patients with unstable angina and myocardial infarction without ST-segment elevation 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 IIb/IIIa inhibitor tirofiban. They were 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 (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischemia or an abnormal stress test. The primary end point was a composite of death, nonfatal myocardial infarction, and rehospitalization for an acute coronary syndrome at six months. RESULTS: At six months, the rate of the primary end point was 15.9 percent with use of the early invasive strategy and 19.4 percent with use of the conservative strategy (odds ratio, 0.78; 95 percent confidence interval, 0.62 to 0.97; p
0.025). The rate of death or non-fatal myocardial infarction at six months was similarly reduced (7.3 percent vs. 9.5 percent; odds ratio, 0.74; 95 percent confidence interval, 0.54 to 1.00; p  0.05). CONCLUSIONS: In patients with unstable angina and myocardial infarction without ST-segment elevation who were treated with the glycoprotein IIb/IIIa 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 the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients.

Summary This is the largest study to date comparing an early, compulsory invasive management strategy (early invasive) to an ischaemia-driven invasive strategy (conservative) in patients hospitalized with unstable angina. Over 2000 patients were randomized, and all received contemporary adjunctive therapy with aspirin (ASA), heparin, and 2b3a inhibitors; the vast majority of patients undergoing angioplasty received stents. At 6 months, the invasive strategy was superior to the ischaemia-driven strategy as determined by a prespecified combined incidence of death, non-fatal myocardial infarction (MI), and

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rehospitalization for acute coronary syndrome (ACS). Patients with the highest-risk features (labile ST segments, elevated troponins) had the most benefit from the invasive strategy.

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468

Related References 1. Morrow DA, Cannon CP, Rifai N, et al., 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: 2405–2412. 2. 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 randomised trial. FRISC II Investigators. Fast revascularisation during instability in coronary artery disease. Lancet 2000; 356: 9–16. 3. Fox KA, Poole-Wilson PA, Henderson RA, et al.; Randomized Intervention Trial of unstable Angina Investigators. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized intervention trial of unstable angina. Lancet 2002; 360: 743–751.

Key message In patients with intermediate and high-risk profiles, 2b3as combined with an early invasive strategy improve outcome when compared to more conservative approaches. In those patients with acute coronary ischaemia, an aggressive approach to early revascularization is the best strategy.

Why it’s important Within a year, the invasive approach defined by this article was adopted into a revision of the American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines for patients with unstable angina. The question of immediate invasive vs. conservative, first raised by the thrombolysis in myocardial infarction (TIMI) IIIb study in 1994 was finally answered definitively.

Strengths The study was well designed, including the most up to date therapy available for both arms. The three similar studies which preceded all had design flaws which limited their general applicability: TIMI IIIB did not use stents or 2b/3a inhibitors, VANQWISH waited 3 days before randomization and excluded many high-risk patients, and FRISC II also had a prolonged period between randomization and invasive evaluation.

Weaknesses Although the primary endpoint was combined non-fatal MI, rehospitalization and death, there was no difference in mortality between the two strategies. Overall mortality was very low in this study, and event rates were primarily driven by non-fatal MI. In spite of the specific intent to enroll patients with ACS at “high risk”, 25% of enrolled subjects had a TIMI risk score of 0–2. A larger study that enrolled only high-risk patients may have been better able to establish a mortality advantage to the invasive strategy.

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Relevance This study defines our current understanding of the pathophysiology and treatment of patients with ACS. An unstable plaque with obstructive morphology and platelet activation is the hallmark of this entity; rapid identification of the culprit, inhibition of the platelets, and relief of the obstruction gives the best short- and long-term clinical outcomes.

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High-risk coronary intervention: a selective literature review of high-risk subsets Jeffrey J. Popma, Hung Ly Introduction The use of percutaneous coronary intervention (PCI) to treat ischaemic coronary artery disease (CAD) has expanded dramatically over the past 25 years. From its incipience as an alternative to coronary bypass surgery in selected patients with single-vessel disease, PCI has evolved into the preferred revascularization strategy in the 900,000 patients who undergo this procedure annually in the USA. The safety and durability of PCI have improved dramatically since 1979 [1], due to continual technological improvements (e.g. drug-stents, distal protection devices), refinements in peri-procedural adjunctive pharmacology (e.g. glycoprotein IIb–IIIa [GP IIb–IIIa] inhibitors, alternative thrombin inhibitors), and a better understanding of early and late outcomes associated with low- and high-risk patients. This review will focus on the pivotal literature that describes the clinical outcomes of patients undergoing “high-risk” coronary intervention. We begin with a description of the percutaneous transluminal coronary angioplasty (PTCA) of the National Heart, Lung, and Blood Institute (NHLBI) Registry (Paper no. 1), which was critical for the evaluation of the success rates associated with balloon angioplasty in high-risk patients. Detre and her colleagues at the University of Pittsburgh have documented the outcomes associated with PCI for the past 25 years in the NHLBI PTCA Registry [2], coronary bypass surgery or balloon angioplasty in patients with multivessel disease BARI (Bypass Angioplasty Revascularization Investigation) trial [3], new device angioplasty (New Approaches to Coronary Intervention, NACI, Registry) [4], and the ongoing DYNAMIC Registries [5]. Their work has allowed us to document temporal improvement in outcomes and practice strategies [6]. A number of “high-risk” subsets have been identified that predict both early complications and late clinical outcome. In the second manuscript of this series (Paper no. 2), Kip and colleagues characterize the long-term clinical outcome of patients with diabetes mellitus who underwent successful balloon angioplasty in the NHLBI PTCA Registry [7]. From this series, we find a sobering glimpse into the late mortality rates associated with the extensive atherosclerotic disease in diabetic patients. Improving the late-term prognosis in diabetic patients has been a major focus of recent therapies, but it is clear that interventional approaches need to be coupled with aggressive risk factor modification in diabetic patients. Ongoing trials, such as the FREEDOM trial, will address the benefit of surgical revascularization in diabetic patients with multivessel CAD. The endorgan effects of diabetes likely contributes to the recently identified risk of mild-to-moderate renal insufficiency on late procedural outcomes that is described by Best and colleagues at the Mayo Clinic (Paper no. 3). Using a more sophisticated index of renal function, creatinine clearance is related to late clinical events. Even a mild degree of renal dysfunction is associated with a heightened risk for an adverse event, with an incremental worse outcomes with increasing degrees of renal insufficiency [8]. Three other risk groups were identified in the early PTCA series. Cowley and colleagues describe the higher in-hospital mortality and complication rates noted in women compared with

High-risk coronary intervention

men when balloon angioplasty was the only option (Paper no. 4). It is likely that the arterial barotrauma occurring during balloon inflation contributed to this higher complication rate in women [9]. With improvements in equipment design and the frequent use of coronary stents, clinical outcomes of women undergoing PCI has improved substantially, now considered equally effective in men and women. Another potential high-risk group includes patients with reduced left ventricular function. Holmes and colleagues describe the outcome of patients with reduced left ventricular function treated with balloon angioplasty (Paper no. 5). Somewhat surprisingly, favourable outcomes were found in carefully selected patients with reduced left ventricular function [10]. The final clinical “high-risk” groups included in this series are patients who present with acute myocardial infarction that is complicated by cardiogenic shock. The historical mortality rate of patients with cardiogenic shock approached 80% in medically treated patients. Hochman and colleagues (Paper no. 6) found a modest reduction in the mortality rate in these patients using an early aggressive approach to revascularization, particularly in younger patients (75 years). As a result, revascularization therapy is now preferred to thrombolytic therapy in patients who present with cardiogenic shock. A number of angiographical risk factors that predict an unfavourable outcome after PCI have also been identified and are useful for the triage of patients to medical therapy, PCI, or coronary artery bypass graft (CABG) [11]. In a multicenter series of patients undergoing multivessel balloon angioplasty, Ellis and colleagues validate the empiric observations of the American College of Cardiology – American Heart Association PTCA Guidelines Writing Group (Paper no. 7). These observations showed that the angiographical criteria were important predictors of procedural outcome [12]. Three additional high-risk subsets that portend a great risk for failure or complications after PCI are then reviewed. Platko and colleagues describe the outcome of patients undergoing balloon angioplasty of saphenous vein stenoses (Paper no. 8) and identify the importance of saphenous vein graft age and its effect on the occurrence of distal embolization. Holmes and colleagues (Paper no. 9) describe the early NHLBI experience with total occlusions, setting the stage for a variety of innovative tools that are used to cross total coronary occlusions [13]. Despite these advances, total coronary occlusion remains the major reason for referral to coronary artery bypass surgery rather than recurrent intervention. In the final paper in this series, George and associates report the initial experience with “kissing balloon” inflation for bifurcation lesions (Paper no. 10). Although stand-alone balloon angioplasty is rarely performed for bifurcation lesions, “kissing balloon” inflation strategy is a critical component of all PCI bifurcation strategies [14]. In aggregate, coronary interventional has advanced dramatically over the past 25 years. Some initial risk factors are no longer important, whereas others, such as diabetes mellitus, total coronary occlusions, and complex saphenous vein graft disease remain important clinical challenges.

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Title 1

Percutaneous transluminal coronary angioplasty in 1985–1986 and 1977–1981: the National Heart, Lung, and Blood Institute Registry Author Detre K, Holubkov R, Kelsey S, et al.

Reference N Engl J Med 1988; 318: 265

Abstract In August 1985, the Percutaneous Transluminal Coronary Angioplasty Registry of the National Heart, Lung, and Blood Institute reopened at its previous sites to document changes in angioplasty strategy and outcome over time. The new registry entered 1802 consecutive patients who had not had a myocardial infarction in the 10 days before angioplasty. Patient selection, technical outcome, and short-term major complications were compared with those of the 1977 to 1981 registry cohort. The new-registry patients were older and had a significantly higher proportion of multivessel disease (53% versus 25%, p  0.001), poor left ventricular function (19% versus 8%, p  0.001), previous myocardial infarction (37% versus 21%, p  0.001), and previous coronary bypass surgery (13% versus 9%, p  0.01). The new-registry cohort also had more complex coronary lesions, and angioplasty attempts in these patients involved more multivessel procedures. Despite these differences, the in-hospital outcome in the new cohort was better. Angiographic success rates according to lesion increased from 67% to 88% ( p  0.001), and overall success rates (measured as a reduction of at least 20% in all lesions attempted, without death, myocardial infarction, or coronary bypass surgery) increased from 61% to 78% ( p  0.001). In-hospital mortality for the new cohort was 1%, and the nonfatal myocardial infarction rate was 4.3%. Both rates are similar to those for the old registry.

Summary The National Heart, Lung, and Blood Institute (NHLBI) Registry demonstrated that there were substantial improvements in operator experience and equipment design over the first decade of balloon angioplasty. More complex patients were treated, and procedural success rates increased from 61% to 78%. Despite more complex patients, overall complication rates were unchanged over the study period.

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644

Key message Investigators in the registry have performed angioplasty since before 1980 and thus rank as the most experienced. Certainly, with less experienced operators one would initially expect a less complex angioplasty strategy as well as lower success rates. However, some studies have suggested that improved technique have allowed recent beginners to learn faster.

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Why it’s important In the early days of balloon angioplasty, improvements in outcomes were generally documented using single-centre registries and operator anecdotes about their personal experience. The NHBLI Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry was the first to centralize the data collection mechanism, and provide independent and objective assessments of procedural outcome.

Strengths The standardized data collection forms and definitions used to characterize baseline clinical characteristics and procedural outcomes became the cornerstone for the evaluation of new devices used to treat more complex patient subsets.

Weaknesses With the rapid evolution of interventional technique and devices, the major limitation of the Registry was that the information was nearly outdated as soon as it is published, and many subtle changes in technique that affect outcome were not captured.

Relevance In the 25 years following the introduction of balloon angioplasty by Gruentzig and his colleagues, first in Zurich and later in Atlanta [1], the technique of non-surgical coronary artery revascularization has evolved so dramatically that vestiges of “plain ’ole balloon angioplasty” or POBA are barely recognizable. In the early days, a dedicated group of investigators formed the NHLBI PTCA Registry to provide objective analysis of the outcomes associated with balloon angioplasty. A 61% procedural success rate seems unacceptable using contemporary standards, but in the 1977–1981 PTCA Registry, it was viewed as a remarkable success. The subsequent comparisons of the 1985–1986 PTCA Registry results with the early series demonstrated that progress had been made, and more complex patients could be safely treated. This cited Registry also served as the backbone for the objective assessment of outcomes after balloon angioplasty and provided detailed information about early and late (up to 9 years) outcomes after PCI. With the introduction of new devices, the PTCA Registry gave rise to the New Approaches to Coronary Intervention (NACI) Registry that evaluated outcomes with directional, rotation, and extraction atherectomy, excimer laser angioplasty, and stent placement using the Palmaz–Schatz and Gianturco–Roubin stents [4]. Current practice is now captured using a series of time-limited DYNAMIC Registries that document the rapidly changing trends in stent use [5]. These registries series have been invaluable for tracking changes in outcomes in patients with complex lesion subsets [6,15].

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Title 2

Coronary angioplasty in diabetic patients: the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry Author Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW

Reference Circulation 1996; 94: 1818–1825

Abstract Patients with diabetes mellitus are at increased risk for cardiovascular disease. Data on baseline clinical and angiographic characteristics and short- and long-term outcomes of 281 diabetic and 1833 nondiabetic PTCA patients in the multicenter National Heart, Lung, and Blood Institute 1985–1986 PTCA Registry were analyzed. Diabetic patients were older, were more likely to be female, and had more co-morbid baseline conditions, triple vessel disease, and atherosclerotic lesions. Angiographic success and completeness of revascularization did not differ significantly, yet diabetic patients experienced more in-hospital death (women) and nonfatal myocardial infarction. Nine-year mortality was twice as high in diabetic patients (35.9% versus 17.9%). Similarly, 9-year rates of nonfatal myocardial infarction (29.0% versus 18.5%), bypass surgery (36.7% versus 27.4%), and repeat PTCA (43.7% versus 36.5%) were higher in diabetics than in nondiabetics. In multivariate analysis, diabetes remained a significant predictor of decreased 9-year survival and other untoward events.

Summary Compared with non-diabetic percutaneous transluminal coronary angioplasty (PTCA) patients, diabetic patients have more extensive and diffuse atherosclerotic disease. Despite similar probability of angiographical success, diabetic patients are more likely to suffer in-hospital death (women) and nonfatal myocardial infarction. Long-term survival and freedom from myocardial infarction and coronary revascularization are also reduced in diabetic PTCA patients.

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165

Key message A diabetic patients with single-vessel disease has the same 9-year mortality rate as a nondiabetic patient with three-vessel coronary artery disease.

Why it’s important The results of this long-term outcome study in diabetic patients demonstrated that the prognosis of diabetic patients is much worse than patients who do not have diabetes mellitus.

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Strengths Standardized data collection case reported forms and planned long-term follow-up render this registry unique amongst registries and provide a unique opportunity to characterize the natural history of patients successfully treated with balloon angioplasty.

Weaknesses This study was performed prior to the availability of a number of systemic therapies for diabetic patients that would favorably affect their long-term prognosis, including better agents for glycaemic control, lipid-lowering therapy with statins, angiotensin-converting enzyme inhibitors, and betablockers. This study was also performed before the availability of coronary stents, and now drugeluting stents, but these therapies are not useful in preventing late mortality in patients with coronary artery disease.

Relevance Controversy still exists about the appropriate revascularization strategy for diabetic patients with multivessel coronary artery disease [3]. This registry report delineates the challenges in the diabetic patient – long-term prognosis relates more to the underlying atherosclerotic disease than it does to the flow-limiting stenosis [16]. The protective effect of the left internal mammary artery (LIMA) graft to the left anterior descending, particularly in insulin-requiring diabetes, may relate to the ability to maintain perfusion of the anterior wall via the LIMA in the event of more proximal plaque rupture in the diabetic patient. Ongoing evaluation in the ongoing BARI (Bypass Angioplasty Revascularization Investigation) 2D trial in diabetic patients will evaluate late term outcomes in patients assigned to insulin-providing or insulin-sensitizing agents or to revascularization therapy (percutaneous or surgical) or aggressive medical therapy. The FREEDOM trial is also planned to evaluate the outcome of diabetic patients with multivessel disease to surgical or drug-eluting stents on the background of aggressive medical therapy.

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Title 3

The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions Author Best PJ, Lennon R, Ting HH, et al.

Reference J Am Coll Cardiol 2002; 39: 1113–1119

Abstract This study sought to determine the effect of varying degrees of renal insufficiency on death, and cardiac events during and after a percutaneous coronary intervention (PCI). Cardiac mortality and all-cause mortality were determined for 5327 patients undergoing PCI from January 1, 1994, to August 31, 1999, at the Mayo Clinic, based on the estimated creatinine clearance or whether the patient was on dialysis. In-hospital mortality was significantly associated with renal insufficiency ( p
0.001). Even after successful PCI, one-year mortality was 1.5% when the creatinine clearance was 70 ml per minute (n
2558), 3.6% when it was 50 to 69 ml per min (n
1458), 7.8% when it was 30 to 49 ml per minute (n
828) and 18.3% when it was 30 ml per minute (n
141). The 18.3% mortality rate for the group with 30 ml per min creatinine clearance was similar to the 19.9% mortality rate in patients on dialysis (n
46). The mortality risk was largely independent of all other factors.

Summary Renal insufficiency is a strong predictor of death and subsequent cardiac events in a dosedependent fashion during and after percutaneous coronary intervention (PCI). Patients with renal insufficiency have more baseline cardiovascular risk factors, but renal insufficiency is associated with an increased risk of death and other adverse cardiovascular events, independent of all other measured variables.

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83

Key message The principal finding of this study is that renal dysfunction significantly increases the risk of death and cardiac death during and after PCI in a dose-dependent manner. Even mild renal insufficiency (creatinine clearance 70 ml/min) has an important association with 1-year mortality (relative risk 1.46) and is nearly as predictive as diabetes mellitus.

Why it’s important The contribution of mild degrees of renal insufficiency on late mortality in patients undergoing coronary intervention is an important clinical finding, and may serve as an important marker of vascular disease. Creatinine clearance rather than use of the baseline serum creatinine should be determined, particular in low-weighted women.

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Strengths This is a large registry from the Mayo Clinic that has routine surveillance to assess late term mortality rates.

Weaknesses The limitation for this study was that therapies that may change the outcomes associated with renal insufficiency were not well characterized and there was limited insight into the precise mechanism by which renal insufficiency affected prognosis.

Relevance It has been recognized since the early 1990s that patients with end-stage renal disease and those on chronic dialysis are at increased risk of morbidity and mortality after percutaneous intervention [17–24]. A more recent report has described the outcomes of patients with mild degrees of renal insufficiency [25], and a report from the DYNAMIC Registry has also suggested that the baseline serum creatinine is an important predictor of late clinical events [26]. The significance of the current study is that the risk of late mortality is related to incremental reductions in creatinine clearance, beginning with mild degrees of renal dysfunction. This may also have important implications for patients who develop bleeding complications after intervention.

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Title 4

Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA Registry Author Cowley MJ, Mullin SM, Kelsey SF, et al.

Reference Circulation 1985; 71: 90–97

Abstract To assess whether gender influenced the outcome of percutaneous transluminal coronary angioplasty (PTCA), early outcomes were compared in 705 women and 2374 men enrolled in the NHLBI PTCA Registry. Women were older ( p  0.01) and had more unstable angina ( p  0.01), and class 3 or 4 angina ( p  0.01). Men had more multivessel disease ( p  0.01), prior bypass surgery ( p  0.01), and abnormal left ventricular function ( p  0.05). Women had a lower angiographic success rate (60.3% versus 66.2% in men; p  0.01) and had a lower clinical success rate (56.6% versus 62.2% in men; p  0.01). More women had complications (27.2% versus 19.4% in men; p  0.01), but overall frequency of major complications (death, myocardial infarction, emergency surgery) was not different (9.8% versus 9.3% in men). Women had a higher incidence of coronary dissection ( p  0.05) and higher in-hospital mortality (1.8% versus 0.7% in men; p  0.01). PTCA-related mortality was nearly six times higher in women (1.7% versus 0.3% in men; p  0.001) and mortality with emergency surgery was more than five times higher (17.4% versus 3.2% in men; p  0.001). Multivariate analysis indicated that female gender was an independent predictor for lower success ( p  0.05) and early mortality ( p  0.05) and was the only baseline predictor for PTCA-related mortality.

Summary In the 1977–1978 percutaneous transluminal coronary angioplasty (PTCA) Registry, women fared far worse than men after balloon angioplasty, with a six times higher PTCA-related mortality rate and a five times higher need for emergency coronary artery bypass surgery. There were differences in co-morbidities in men and women, but gender was the only independent predictor for in-hospital mortality.

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156

Key message PTCA in women is associated with a significantly lower success rate and a higher in-hospital mortality rate than in men. However, during follow-up after successful PTCA, women have a comparable symptomatic improvement, a lower incidence of additional revascularization procedures and restenosis, and improved survival compared with men.

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Why it’s important This 1977–1978 National Heart, Lung, and Blood Institute (NHLBI) Registry series was an extremely useful glimpse into the independently adjudicated early and late outcomes at multiple clinical sites proficient in PTCA. The Registry laid the foundation for the documentation of improved outcomes over time with advances in equipment design, operator experience, and with the availability of new devices.

Strengths This NHLBI Registry provided data collection using standardized definitions for baseline and procedural variables, and late clinical outcomes.

Weaknesses With rapid evolution of PTCA methods, the results of this Registry were outdated nearly as quickly as they were published. Nevertheless, documentation of the initial experience has proven invaluable to assess improvements over time.

Relevance The 1985–1986 NHLBI PTCA [27] and the Northern New England Cardiovascular Disease Study Group [28] also reported a higher in-hospital mortality and complication rates in women than men, due to a higher incidence of procedural complications, whereas the European experience reported similar outcomes for men and women [29]. Advances in equipment design and operator experience in the 1990s [30], coupled with the introduction of coronary stents, substantially improved the outcomes of coronary intervention in women [31–36]. It is now felt that men and women have comparable outcomes after percutaneous coronary intervention (PCI).

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Title 5

Long-term outcome of patients with depressed left ventricular function undergoing percutaneous transluminal coronary angioplasty: the NHLBI PTCA Registry Author Holmes DR, Detre KM, Williams DO, Kent KM, King SB, Yeh W, Steenkiste A

Reference Circulation 1993; 87 2002; 39: 21–29

Abstract Coronary revascularization with bypass has been shown to improve survival in patients with coronary artery disease and left ventricular dysfunction. The purpose of this investigation was to characterize the outcome of angioplasty in patients with decreased left ventricular function and contrast it with the results in patients with normal left ventricular function. In the 1985–1986 National Heart, Lung, and Blood Institute’s percutaneous transluminal coronary angioplasty (PTCA) Registry, of 1802 patients undergoing PTCA, 244 patients (13.5%) had an ejection fraction of 45% (mean, 39.6). These patients had a higher incidence of prior infarction, a longer and worse history of manifestations of coronary disease, and more extensive coronary artery disease than patients with wellpreserved function; 88% and 91%, respectively, had successful dilation of at least one lesion (non-significant difference). However, patients with decreased left ventricular function had a decreased frequency of successful dilation of all lesions in which PTCA was attempted (76% versus 84%, p  0.01). There were no statistically significant differences in in-hospital complications – death occurred in 0.8% and 0.7%, nonfatal myocardial infarction occurred in 4.9% and 4.5%, and emergency surgical revascularization was performed in 4.5% and 3.2%, respectively. Patients were followed for a mean of 4.1 years; during this time, patients with decreased left ventricular function had significantly worse survival and combined event-free survival. Despite this, at 4 years, 87% of the patients with a mean ejection fraction of 39.6% remained alive, and 77% were alive and had not experienced infarction or required bypass.

Summary Percutaneous transluminal coronary angioplasty (PTCA) is effective in selected patients with depressed left ventricular function. Initial outcome and risk–benefit ratio are excellent. Successful dilation of at least one vessel was achieved in 88% of patients with depressed left ventricular function and in 91% of patients with more normal left ventricular function. The former group, however, had a decreased incidence of successful dilation in all lesions in which dilation was attempted (76% vs. 84%, p  0.01). There was no significant difference in in-hospital complications between the two groups. During follow-up, patients with decreased left ventricular function had worse event-free survival, although 77% were alive without infarction or bypass grafting at 4 years.

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36

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Key message These multicenter data document the efficacy of PTCA in selected patients with suitable angiographical anatomy but depressed left ventricular function.

Why it’s important This study demonstrated that patients with reduced left ventricular function could safely undergo coronary intervention without an excess of complications.

Strengths This National Heart, Lung, and Blood Institute (NHLBI) Registry provided data collection using standardized definitions for baseline and procedural variables, and late clinical outcomes.

Weaknesses Patients with severe (left ventricular ejection fraction  0.20) were not well characterized in this study.

Relevance Transient occlusion of the epicardial vessel during percutaneous coronary intervention (PCI) is known to cause transient regional wall motion abnormalities. PCI in patients with reduced left ventricular function has the potential to worsen the heart failure and cause pulmonary oedema. On occasion, in patients with elevated pulmonary capillary wedge pressures, an intra-aortic balloon pump during PCI has proven useful [37]. Although one early report suggested that complications were increased in patients with reduced ventricular function [38], this cited report suggests that patients with reduced left ventricular function can be treated safely with PCI.

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Title 6

One-year survival following early revascularization for cardiogenic shock Author Hochman JS, Sleeper LA, White HD, et al.

Reference JAMA 2001; 285: 190–192

Abstract To assess the effect of early revascularization (ERV) on 1-year survival for patients with acute myocardial infarction (AMI) complicated by cardiogenic shock, the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial, an unblinded, randomized controlled trial was conducted from April 1993 through November 1998. Thirty-six referral centers with angioplasty and cardiac surgery facilities enrolled 302 patients with AMI and cardiogenic shock due to predominant left ventricular failure who met specified clinical and hemodynamic criteria. Patients were randomly assigned to an initial medical stabilization (IMS; n
150) group, which included thrombolysis (63% of patients), intra-aortic balloon counterpulsation (86%), and subsequent revascularization (25%), or to an ERV group (n
152), which mandated revascularization within 6 hours of randomization and included angioplasty (55%) and coronary artery bypass graft surgery (38%). One-year survival was 46.7% for patients in the ERV group compared with 33.6% in the IMS group (absolute difference in survival, 13.2%; 95% confidence interval [CI], 2.2–24.1%; p  03; relative risk for death, 0.72; 95% CI, 0.54–0.95). Of the 10 prespecified subgroup analyses, only age (75 versus 75 years) interacted significantly ( p  0.03) with treatment in that treatment benefit was apparent only for patients younger than 75 years (51.6% survival in ERV group versus 33.3% in IMS group). Eighty-three percent of 1-year survivors (85% of ERV group and 80% of IMS group) were in New York Heart Association class I or II.

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74

Key message Early revascularization (ERV) therapy resulted in a 39% improvement in 1-year survival compared with initial medical stabilization. The absolute benefit of early revascularization therapy for cardiogenic shock saves 132 lives for every 1000 patients treated, and is … is similar to the absolute benefit of coronary artery bypass grafting (CABG) for left main coronary artery disease at 1 year.

Why it’s important The study demonstrated the benefit of an early aggressive strategy in patients with cardiogenic shock who were 75-year old.

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Strengths This randomized, multicentre trial demonstrated a clear benefit of revascularization therapy in younger patients with cardiogenic shock with mortality rates with medical therapy that were similar to prior registries.

Weaknesses The study enrolled its 300 patients over several years due to challenges with recruitment. It is possible that some of the sickest patients with cardiogenic shock were excluded from the study.

Relevance Cardiogenic shock (CS) is the leading cause of death for patients hospitalized with acute myocardial infarction (AMI). Although a number of registry reports in the late 1980s and early 1990s suggested that revascularization therapy improved the prognosis compared with medical therapy [39–43], it also appeared that the sickest patients with cardiogenic shock never made it to the catheterization laboratory, and no randomized trials demonstrated the benefit of ERV. The importance of this clinical trial was that patients were assigned to an aggressive medical therapy arm or to revascularization therapy, and clear survival benefits were demonstrated in patients assigned to revascularization therapy. The age restriction of 75-year old may be revised with the recent report from Northern New England Registry. From 1990 to 2000, a total of 310 out of 52,418 patients (0.59%) had percutaneous coronary intervention (PCI) for cardiogenic shock, 24% of whom were elderly (75 years). Procedural characteristics were similar between the two groups. Independent predictors of mortality for both groups were older age and the absence of collaterals; during the stent era (1997–2000), significant predictors were lack of stent placement and diabetes mellitus. The mortality rate for elderly shock patients undergoing PCI was 46%, which is significantly less than previously reported in randomized clinical trials [44].

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Title 7

Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection: Multivessel Angioplasty Prognosis Study Group Author Ellis SG, Vandormael MG, Cowley MJ, et al.

Reference Circulation 1990; 82: 1193–1202

Abstract To assess the likelihood of procedural success in patients with multivessel coronary disease undergoing percutaneous coronary angioplasty, 350 consecutive patients (1100 stenoses) from four clinical sites were evaluated. Eighteen variables characterizing the severity and morphology of each stenosis and 18 patient-related variables were assessed at a core angiographic laboratory and at the clinical sites. Most patients had Canadian Cardiovascular Society class III or IV angina (72%) and two-vessel coronary disease (78%). Left ventricular function was generally well preserved and 1.9 stenoses per patient had attempted percutaneous coronary angioplasty. Procedural success ( 50% final diameter stenosis in one or more stenoses and no major ischemic complications) was achieved in 290 patients (82.8%), and an additional nine patients (2.6%) had a reduction in diameter stenosis by 20% or more with a final diameter stenosis 51–60% and were without major complications. Major ischemic complications (death, myocardial infarction, or emergency bypass surgery) occurred in 30 patients (8.6%). In-hospital mortality was 1.1%. Stepwise regression analysis determined that a modified American College of Cardiology/American Heart Association Task Force (ACC/AHA) classification of the primary target stenosis (with Type B prospectively divided into Type B1 [one Type B characteristic] and Type B2 [greater than or equal to two Type B characteristics]) and the presence of diabetes mellitus were the only variables independently predictive of procedural outcome (target stenosis modified ACC/AHA score; p less than 0.001 for both success and complications; diabetes mellitus: p
0.003 for success and p
0.016 for complications). Analysis of success and complications on a per stenosis dilated basis showed, for type A stenoses, a 92% success and a 2% complication rate; for Type B1 stenoses, an 84% success and a 4% complication rate; for Type B2 stenoses, a 76% success and a 10% complication rate; and for Type C stenoses, a 61% success and a 21% complication rate. The subdivision into Types B1 and B2 provided significantly more information in this clinically important intermediate risk group than did the standard ACC/AHA scheme. The stenosis characteristics of chronic total occlusion, high grade (80–99% diameter) stenosis, stenosis bend of more than 60 degrees, and excessive tortuosity were particularly predictive of adverse procedural outcome.

Summary This improved scheme may improve clinical decision making and provide a framework on which to base meaningful subgroup analysis in randomized trials assessing the efficacy of percutaneous coronary angioplasty.

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Citation Count

618

Key message Good short-term results can be obtained with coronary angioplasty performed by experienced operators in patients with multivessel disease in whom the important stenosis has Type A or B1 characteristics. However, when the important stenoses have Type B2 or C characteristics, other forms of therapy should be very strongly considered.

Why it’s important This study prospectively validated the empiric impression of the American College of Cardiology and American Heart Association Percutaneous Transluminal Coronary Angioplasty (ACC/AHA PTCA) Guidelines Committee that suggested that procedure success and complications rates could be estimated from assessing the baseline lesion morphology.

Strengths This study was one of the first to use an independent core laboratory assessment of procedural outcomes relating to the lesion morphology.

Weaknesses Despite standardized criteria, there was substantial variability in the identification of adverse lesion characteristics from the angiogram by clinical investigators. Some of the morphological features predicted procedural failure (e.g. total occlusion) whereas others predicted complications (e.g. thrombus, degenerated saphenous vein grafts).

Relevance In 1988, a joint task force of the ACC and AHA established an empiric classification system for lesion complexity [11]. These risk factors have subsequently been shown to be predictive in a number of single- and multicentre studies using other devices [45], including coronary stents [46]. Although overall success rates have increased and complication rates have lowered [47], the overall effect of lesion morphology on procedural outcomes has persisted in most studies [48–50].

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Title 8

Percutaneous transluminal angioplasty of saphenous vein graft stenosis: long-term follow-up Author Platko WP, Hollman J, Whitlow PL, Franco I

Reference J Am Coll Cardiol 1989; 14: 1645–1650

Abstract Percutaneous transluminal angioplasty was used to treat 101 patients with saphenous vein bypass graft stenosis at a mean of 50.1 months (range 2 to 196) after coronary artery bypass surgery. The patients presented between March 1981 and April 1987. A total of 107 saphenous vein grafts were dilated at 117 sites. The primary success rate was 91.8%. The incidence of cardiac complications was 7.1%. There were no cardiac complications in 53 patients with grafts implanted less than 36 months before angioplasty (Group 1). The 48 patients with grafts implanted for greater than 36 months (Group 2) had a 12.5% incidence rate of myocardial infarction, a 4% incidence rate of emergent bypass surgery and a 4% incidence rate of death for an overall cardiac complication rate of 14.9% ( p less than 0.01). Follow-up was obtained at a mean of 16.8  13.9 months (range 1 to 54) in 87 patients (97% of successful cases). Repeat coronary angiography was performed in 49 patients and revealed restenosis in 30 patients (61.2%), with no difference in recurrence rates for proximal, mid or distal graft sites. Clinical recurrence (defined as recurrence of symptoms, myocardial infarction, repeat angioplasty, surgery or death) was 33.1% for Group 1 patients and 64.1% for Group 2 patients ( p less than 0.01).

Summary The complication and recurrence rates of saphenous vein graft angioplasty are significantly higher when performed for late (36 months) vein graft failure. All therapeutic options should be carefully examined before proceeding with angioplasty for saphenous vein graft stenosis in this type of patient.

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146

Key message There is a 6% likelihood of myocardial infarction, 2% likelihood of emergency coronary bypass surgery, and a 2% mortality rate (associated with angioplasty of saphenous vein graft, SVGs) … All of these complications occurred after angioplasty on grafts implanted 36 months after the operation.

Why it’s important This work evaluated graft age and degeneration on the occurrence of procedural outcome after balloon angioplasty.

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Strengths This single-centre series was one of the first to describe the outcomes associated with SVG intervention.

Weaknesses The major limitation of the study was the failure to characterize the angiographical appearances of the SVG in an effort to identify predictors of risk. The addition of distal protection devices and coronary stents have markedly improved procedural outcomes in these patients.

Relevance SVG interventions remain a clinical challenge for the interventionalist. This study related the procedural outcome to SVG age, suggesting that older SVGs were more friable and susceptible to complications. Over the years, the prognostic importance of the complications occurring during SVG intervention was further characterized [51–57]. Distal embolization was later associated with substantial morbidity and mortality [58]. A number of distal protection devices have been designed to reduce these complications and have now become integrated in contemporary interventional practice.

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Title 9

Angioplasty in total coronary artery occlusion Author Holmes DR, Vlietstra RE, Reeder GS, et al.

Reference J Am Coll Cardiol 1984; 3: 845–849

Abstract Percutaneous transluminal coronary angioplasty was attempted without streptokinase in 24 patients with total coronary artery occlusion but without acute transmural myocardial infarction. The maximal duration of occlusion was estimated to be 1 week or less in 10 patients, more than 1 to 4 weeks in 6, more than 4 to 12 weeks in 3 and more than 12 weeks in 5. Dilation of the occluded artery was attempted in the left anterior descending coronary artery in 17 patients, in the right coronary artery in 4 and in the circumflex coronary artery in 3. Angioplasty was successful in 13 patients (54%): left anterior descending coronary artery in 59%, right coronary artery in 50% and circumflex coronary artery in 33%. In patients with successful dilation, there was a mean decrease in coronary artery stenosis from 100 to 23%. In the 19 patients whose occlusion was estimated to be of 12 weeks’ duration or less, angioplasty was successful in 68%. In the five patients whose occlusion was estimated to be of more than 12 weeks’ duration, dilation was not successful in any ( p
0.006).

Summary In selected patients with symptomatic coronary artery disease and recent coronary artery occlusion without associated acute myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) alone may be effective in restoring patency.

Citation Count

125

Key message Total occlusion is not by itself a contraindication to coronary angioplasty. Successful dilatation can be performed in approximately two-thirds of selected patients with recent (12 weeks) total occlusion.

Why it’s important This was one of the earliest reports of the success rates associated with the use of PTCA for total coronary occlusion.

Strengths This initial single-centre registry report provided important insight into a subset of patients who were deemed unsuitable for coronary angioplasty.

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Weaknesses In the early days of angioplasty, the equipment was much less sophisticated and precluded crossing the total occlusion in many cases.

Relevance Percutaneous intervention of total coronary occlusions remains of the major challenges. Several early series describe angiographical criteria that were deemed predictors of unlikely success with intervention in total occlusions, including bridging collaterals, flush occlusions, and the presence of a branch vessel arising from the occlusion [13,59–61]. A progressive improvement of the procedural success rates have been achieved, particularly with the use of new hydrophilic coronary guidewires, but total coronary occlusions remain the most frequent cause for referral for coronary artery bypass surgery.

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Title 10

Balloon angioplasty of coronary bifurcation lesions: the kissing balloon technique Author George BS, Myler RK, Stertzer SH, et al.

Reference Cathet Cardiovasc Diagn 1986; 12: 124–138

Abstract Initial experience with the technique of “kissing balloon” angioplasty is described in 52 patients undergoing coronary angioplasty. Guiding catheters employing both the femoral and brachial approach were used in all but two of the coronary angioplasties and, in addition, the bilateral femoral approach was used in the renal and peripheral angioplasties. Initial success was achieved in 51 (98%) patients. Abrupt closure requiring urgent coronary revascularization occurred in one patient six hours following the completion of the procedure. Another patient developed a new Q-wave on the electrocardiogram and moderate elevation of CPK-MB fraction following the procedure due to loss of a diagonal branch. No deaths occurred in this series. Angiographic restenosis developed in ten patients. In the recurrence group, five had repeat kissing balloon angioplasty, two had repeat single vessel angioplasty, and three patients chose elective surgical revascularization.

Summary Based on our experience, the technique of kissing balloon coronary angioplasty can be performed safely utilizing the brachio-femoral technique.

Citation Count

55

Key message The risk of major side branch occlusion can be minimized with this (kissing balloon) technique and the overall complication rate does not significantly differ from that of our experience in singlevessel coronary angioplasty.

Why it’s important This was one of the earliest reports of the “kissing” or simultaneous balloon inflation within the native coronary vessels, a technique that has persisted with the use of coronary stents.

Strengths The technique described uses two guiding catheters and simultaneous cannulation of the coronary artery with two angioplasty systems.

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Weaknesses Angioplasty equipment was bulky and difficult to steer at this time. These techniques have evolved substantially with the miniaturization of angioplasty equipment.

Relevance Coronary intervention of bifurcations in which the side branch has significant disease, has remained problematic, despite the use of coronary stents. The risk of side branch occlusion during intervention relates to the extent of the disease within the branch vessel [62], and is due to the snowplowing effect of shifting plaque from the parent vessel to the branch and vice versa. The simultaneous kissing balloon technique described in this series uses dual balloon inflations in the parent vessel and side branch to minimize this effect. Although two guiding catheters were needed with the prototype angioplasty devices, smaller caliber angioplasty catheter soon permitted this procedure to be performed from a single-guiding catheter [63]. Debulking techniques using directional or rotational atherectomy improved procedural success rates and reduced late recurrence [64], but these methods have largely been replaced with coronary stenting [65]. A number of innovative stenting techniques have been described [66,67], but most end with the performance of a kissing balloon inflation. Yet in contrast to the early days, bifurcation stenting can be performed with a single six French-guiding catheter.

References 1. Gruentzig A, Senning A, Siegenthaler W. Non-operative dilatation of coronary artery stenosis. Percutaneous transluminal coronary angioplasty. N Engl J Med 1979; 301: 61. 2. Detre K, Holubkov R, Kelsey S, et al. Percutaneous transluminal coronary angioplasty in 1985–1986 and 1977–1981. The National Heart, Lung, and Blood Institute Registry. N Engl J Med 1988; 318: p265–270. 3. BAR Investigators. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 1997; 96: p1761–1769. 4. Baim DS, Kent KM, King SB, et al. Evaluating new devices. Acute (in-hospital) results from the New Approaches to Coronary Intervention Registry. Circulation 1994; 89: p471–481. 5. Williams D, Holubkov R, Yeh W, et al. Percutaneous coronary intervention in the current era compared with 1985–1986: the National Heart, Lung, and Blood Institute Registries. Circulation 2000; 102: 2945–2951. 6. Srinivas V, Brooks M, Detre K, et al. A decade of improvement in the clinical outcomes of percutaneous coronary intervention for multivessel coronary artery disease. Circulation 2003; 107: e88. 7. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW. Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1996; 94: p1818–1825. 8. Best P, Lennon R, Ting H, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39: 1113–1119. 9. Cowley M, Mullin S, Kelsey S, et al. Sex differences in early and long-term results of coronary angioplasty in the NHLBI PTCA Registry. Circulation 1985; 71: 90–97. 10. Holmes D, Detre K, Williams D, et al. Long-term outcome of patients with depressed left ventricular function undergoing percutaneous transluminal coronary angioplasty. The NHLBI PTCA Registry. Circulation 1993; 87: 21–29.

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11. Ryan T, Faxon D, Gunnar R, et al. Guidelines for percutaneous transluminal coronary angioplasty: a report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Subcommittee on Percutaneous Transluminal Coronary Angioplasty). J Am Coll Cardiol 1988; 12: 529–545. 12. Ellis S, Vandormael M, Cowley M, et al. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Multivessel Angioplasty Prognosis Study Group. Circulation 1990; 82: 1193–1202. 13. Holmes D, Forrester J, Litvack F, et al. Chronic total obstruction and short-term outcome: the Excimer Laser Coronary Angioplasty Registry experience. Mayo Clin Proc 1993; 68: 5–10. 14. George B, Myler R, Stertzer S, et al. Balloon angioplasty of coronary bifurcation lesions: the kissing balloon technique. Cathet Cardiovasc Diagn 1986; 12: 124–138. 15. Popma J, Kuntz R, Baim D. A decade of improvement in the clinical outcomes of percutaneous coronary intervention for multivessel coronary artery disease. Circulation 2002; 106: 1592–1594. 16. Kuntz R. Importance of considering atherosclerosis progression when choosing a coronary revascularization strategy: the diabetes-percutaneous transluminal coronary angioplasty dilemma. Circulation 1999; 99: 847–851. 17. Kahn J, Rutherford B, McConahay D, Johnson W, Giorgi L, Hartzler G. Short- and longterm outcome of percutaneous transluminal coronary angioplasty in chronic dialysis patients. Am Heart J 1990; 119: 484–489. 18. Vaitkus P, Guidera S. Percutaneous transluminal coronary angioplasty in patients undergoing chronic dialysis. J Interv Cardiol 1993; 6: 293–296. 19. Ahmed W, Shubrooks S, Gibson C, Baim D, Bittl J. Complications and long-term outcome after percutaneous coronary angioplasty in chronic hemodialysis patients. Am Heart J 1994; 128: 252–255. 20. Reusser L, Osborn L, White H, Sexson R, Crawford M. Increased morbidity after coronary angioplasty in patients on chronic hemodialysis. Am J Cardiol 1994; 73: 965–967. 21. Koyanagi T, Nishida H, Kitamura M, et al. Comparison of clinical outcomes of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty in renal dialysis patients. Ann Thorac Surg 1996; 61: 1793–1736. 22. Marso S, Gimple L, Philbrick J, Di MJ. Effectiveness of percutaneous coronary interventions to prevent recurrent coronary events in patients on chronic hemodialysis. Am J Cardiol 1998; 82: 378–380. 23. Hang C, Chen M, Wu B, Wu C, Chua S, Fu M. Short- and long-term outcomes after percutaneous transluminal coronary angioplasty in chronic hemodialysis patients. Catheter Cardiovasc Interv 1999; 47: 430–433. 24. Herzog C, Ma J, Collins A. Long-term outcome of dialysis patients in the United States with coronary revascularization procedures. Kidney Int 1999; 56: 324–332. 25. Gruberg L, Weissman N, Waksman R, et al. Comparison of outcomes after percutaneous coronary revascularization with stents in patients with and without mild chronic renal insufficiency. Am J Cardiol 2002; 89: 54–57. 26. Naidu S, Selzer F, Jacobs A, et al. Renal insufficiency is an independent predictor of mortality after percutaneous coronary intervention. Am J Cardiol 2003; 92: 1160–1164. 27. Kelsey S, James M, Holubkov A, Holubkov R, Cowley M, Detre K. Results of percutaneous transluminal coronary angioplasty in women. 1985–1986 National Heart, Lung, and Blood Institute’s Coronary Angioplasty Registry. Circulation 1993; 87: 720–727. 28. Malenka D, O’Connor G, Quinton H, et al. Differences in outcomes between women and men associated with percutaneous transluminal coronary angioplasty. A regional prospective study of

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13,061 procedures. Northern New England Cardiovascular Disease Study Group. Circulation 1996; 94: II99–II104. 29. Ruygrok P, de JP, van DR, van dBM, Serruys P, de FP. Women fare no worse than men 10 years after attempted coronary angioplasty. Cathet Cardiovasc Diagn 1996; 39: 9–15. 30. Bell M, Grill D, Garratt K, Berger P, Gersh B, Holmes D. Long-term outcome of women compared with men after successful coronary angioplasty. Circulation 1995; 91: 2876–2881. 31. Jacobs A, Kelsey S, Yeh W, et al. Documentation of decline in morbidity in women undergoing coronary angioplasty (a report from the 1993–94 NHLBI Percutaneous Transluminal Coronary Angioplasty Registry). National Heart, Lung, and Blood Institute. Am J Cardiol 1997; 80: 979–984. 32. Jacobs A, Johnston J, Haviland A, et al. Improved outcomes for women undergoing contemporary percutaneous coronary intervention: a report from the National Heart, Lung, and Blood Institute Dynamic registry. J Am Coll Cardiol 2002; 39: 1608–1614. 33. Robertson T, Kennard E, Mehta S, et al. Influence of gender on in-hospital clinical and angiographic outcomes and on one-year follow-up in the New Approaches to Coronary Intervention (NACI) Registry. Am J Cardiol 1997; 80: 26K–39K. 34. Lansky A, Mehran R, Dangas G, et al. New-device angioplasty in women: clinical outcome and predictors in a 7372-patient registry. Epidemiology 2002; 13: S46–S51. 35. Malenka D, Wennberg D, Quinton H, et al. Gender-related changes in the practice and outcomes of percutaneous coronary interventions in Northern New England from 1994 to 1999. J Am Coll Cardiol 2002; 40: 2092–2101. 36. Ashby D, Mehran R, Aymong E, et al. Comparison of outcomes in men versus women having percutaneous coronary interventions in small coronary arteries. Am J Cardiol 2003; 91: 979–981, A4, A7. 37. Anwar A, Mooney M, Stertzer S, et al. Intra-aortic balloon counterpulsation support for elective coronary angioplasty in the setting of poor left ventricular function: a two center experience. J Invasive Cardiol 1990; 2: 175–180. 38. Kohli R, Di SG, Cowley M, Nath A, Goudreau E, Vetrovec G. Coronary angioplasty in patients with severe left ventricular dysfunction. J Am Coll Cardiol 1990; 16: 807–811. 39. Lee L, Erbel R, Brown T, Laufer N, Meyer J, O’Neill W. Multicenter registry of angioplasty therapy of cardiogenic shock: initial and long-term survival. J Am Coll Cardiol 1991; 17: 599–603. 40. Lee L, Bates E, Pitt B, Walton J, Laufer N, O’Neill W. Percutaneous transluminal coronary angioplasty improves survival in acute myocardial infarction complicated by cardiogenic shock. Circulation 1988; 78: 1345–1351. 41. Bengtson J, Kaplan A, Pieper K, et al. Prognosis in cardiogenic shock after acute myocardial infarction in the interventional era. J Am Coll Cardiol 1992; 20: 1482–1489. 42. Hibbard M, Holmes D, Bailey K, Reeder G, Bresnahan J, Gersh B. Percutaneous transluminal coronary angioplasty in patients with cardiogenic shock. J Am Coll Cardiol 1992; 19: 639–646. 43. Moosvi A, Khaja F, Villanueva L, Gheorghiade M, Douthat L, Goldstein S. Early revascularization improves survival in cardiogenic shock complicating acute myocardial infarction. J Am Coll Cardiol 1992; 19: 907–914. 44. Dauerman H, Ryan T, Piper W, et al. Outcomes of percutaneous coronary intervention among elderly patients in cardiogenic shock: a multicenter, decade-long experience. J Invasive Cardiol 2003; 15: 380–384. 45. Ellis S, Popma J, Buchbinder M, et al. Relation of clinical presentation, stenosis morphology, and operator technique to the procedural results of rotational atherectomy and rotational atherectomy-facilitated angioplasty. Circulation 1994; 89: 882–892.

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46. Kastrati A, Schomig A, Elezi S, et al. 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: 1285–1290. 47. Myler R, Shaw R, Stertzer S, et al. Lesion morphology and coronary angioplasty: current experience and analysis. J Am Coll Cardiol 1992; 19: 1641–1652. 48. Krone R, Laskey W, Johnson C, et al. A simplified lesion classification for predicting success and complications of coronary angioplasty. Registry Committee of the Society for Cardiac Angiography and Intervention. Am J Cardiol 2000; 85: 1179–1184. 49. Krone R, Kimmel S, Laskey W, et al. Evaluation of the Society for Coronary Angiography and Interventions’ lesion classification system in 14,133 patients with percutaneous coronary interventions in the current stent era. Catheter Cardiovasc Interv 2002; 55: 1–7. 50. Shaw R, Anderson H, Brindis R, et al. Development of a risk adjustment mortality model using the American College of Cardiology–National Cardiovascular Data Registry (ACC–NCDR) experience: 1998–2000. J Am Coll Cardiol 2002; 39: 1104–1112. 51. Famularo M, Vasilomanolakis E, Schrager B, Talbert W, Ellestad M. Percutaneous transluminal angioplasty of aortocoronary saphenous vein graft. Morphologic observations. JAMA 1983; 249: 3347–3350. 52. Marquis J, Schwartz L, Brown R, et al. Percutaneous transluminal angioplasty of coronary saphenous vein bypass grafts. Can J Surg 1985; 28: 335–337. 53. Platko W, Hollman J, Whitlow P, Franco I. Percutaneous transluminal angioplasty of saphenous vein graft stenosis: long-term follow-up. J Am Coll Cardiol 1989; 14: 1645–1650. 54. Shimshak T, Hartzler G. Percutaneous transluminal angioplasty in diffuse subtotally occluded vein grafts. Cathet Cardiovasc Diagn 1989; 17: 99–104. 55. Bartlett J, Tuzcu E, Simpfendorfer C, Dorosti K, Franco I, Whitlow P. Percutaneous transluminal coronary angioplasty of native coronary arteries via saphenous vein grafts. J Invasive Cardiol 1991; 3: 62–65. 56. Meester B, Samson M, Suryapranata H, et al. Long-term follow-up after attempted angioplasty of saphenous vein grafts: the Thoraxcenter experience 1981–1988. Eur Heart J 1991; 12: 648–653. 57. de FP, van SR, de JP, Topol E, Serruys P. Balloon angioplasty for the treatment of lesions in saphenous vein bypass grafts. J Am Coll Cardiol 1993; 21: 1539–1549. 58. Hong M, Popma J, Pichard A, et al. Clinical significance of distal embolization after transluminal extraction atherectomy in diffusely diseased saphenous vein grafts. Am Heart J 1994; 127: 1496–1503. 59. Holmes D, Vlietstra R, Reeder G, et al. Angioplasty in total coronary artery occlusion. J Am Coll Cardiol 1984; 3: 845–849. 60. Bell M, Berger P, Bresnahan J, Reeder G, Bailey K, Holmes D. Initial and long-term outcome of 354 patients after coronary balloon angioplasty of total coronary artery occlusions. Circulation 1992; 85: 1003–1011. 61. Bell M, Berger P, Menke K, Holmes D. Balloon angioplasty of chronic total coronary artery occlusions: what does it cost in radiation exposure, time, and materials? Cathet Cardiovasc Diagn 1992; 25: 10–15. 62. Meier B, Gruentzig A, King SI, et al. Risk of side branch occlusion during coronary angioplasty. Am J Cardiol 1984; 53: 10–14. 63. Oesterle S, McAuley B, Buchbinder M, Simpson J. Angioplasty at coronary bifurcations: single-guide, two-wire technique. Cathet Cardiovasc Diagn 1986; 12: 57–63. 64. Dauerman HL, Baim DS, Cutlip DE, et al. Mechanical debulking versus balloon angioplasty for the treatment of diffuse in-stent restenosis. Am J Cardiol 1998; 82: 277–284.

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65. Teirstein P. Kissing Palmaz–Schatz stents for coronary bifurcation stenoses. Cathet Cardiovasc Diagn 1996; 37: 307–310. 66. Lefevre T, Louvard Y, Morice M, et al. Stenting of bifurcation lesions: classification, treatments, and results. Catheter Cardiovasc Interv 2000; 49: 274–283. 67. Melikian N, Di MC. Treatment of bifurcation coronary lesions: a review of current techniques and outcome. J Interv Cardiol 2003; 16: 507–513.

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Chapter 6

Stenting in coronary angioplasty Jeptha P. Curtis, John F. Setaro Introduction The introduction of stents stands as one of the truly revolutionary steps in the history of interventional cardiology. Since worldwide approval of the balloon-expandable Palmaz–Schatz stent, the use of stents has become a routine part of percutaneous coronary interventions (PCI). In 2002 it was estimated that stents are used in more than 80% of all coronary interventions at a cost of over 1.6 billion dollars in the USA alone. These numbers do not factor in the increased costs associated with drug-eluting stents. Clearly stents have had a profound impact on the contemporary practice of interventional cardiology. This chapter will review the studies that served as critical steps in the development and adoption of coronary stents. The term “stent” is thought to come from the English dentist, Charles R. Stent, who developed a method of supporting misaligned teeth. Subsequently, stent (having permanently lost its capitalization) was adopted by surgeons to describe any device designed to support a bodily orifice or cavity during skin grafting or to immobilize a skin graft following placement. In modern medical literature, the definition of stent has come to encompass all hollow devices inserted into the tubular structures in order to provide support and maintain patency. Drs Dotter and Judkins initially proposed the development of intravascular stents in their seminal 1964 paper, “Transluminal Treatment of Arteriosclerotic Obstruction”. After describing the results achieved by serial coaxial arterial dilatations, they envisioned the use of an “endovascular (or, paravascular) splint [that] could maintain an adequate false lumen until the natural processes of fibrosis and re-intimalization had taken place”. Although it took only 5 years for Dr Dotter to implant coilspring tubes in canine femoral arteries, it would take almost two decades before technological innovations allowed the successful implantation of expandable metal stents in human arteries. The need for intracoronary stents was driven by the two persistent limitations of balloon angioplasty, namely restenosis and acute closure. In the pre-stent era, acute closure due to dissection or residual stenosis led to emergency bypass surgery in more than 1% of patients. Furthermore, 30–50% of patients had symptomatic restenosis requiring repeat interventions. Stents were unique among advanced interventional devices, having a capability to address both problems simultaneously. In cases of threatened acute closure, interventionalists could use stents to tack up a dissection flap. In addition, the greater acute gain in luminal diameter associated with the use of coronary stents led to clinically and statistically significant reductions in need for revascularization due to restenosis. Once approved for elective use in coronary interventions, the floodgates opened and stents swiftly became the rule rather than the exception. Subsequent studies demonstrated the utility of stents in a variety of patients and lesion subgroups including acute myocardial infarction, diabetics, total occlusions, saphenous vein grafts, and long lesions. Simultaneously, stent manufacturers have continuously improved their technology, creating stents with thinner struts, increased radial support, and improved deliverability. Undoubtedly the most important advance since the original introduction of coronary stents has been the development and approval of drug-eluting stents which have dramatically decreased the incidence of clinical and angiographical restenosis.

Stenting in coronary angioplasty

Collectively, these advances have allowed interventional cardiologists to approach higher-risk patients, and fewer patients are being sent for surgery or treated medically. This shift has led critics to question whether interventional cardiologists have gone too far and routinely use stents in situations where there is limited or no evidence of benefits associated with stent implantation. If there is truth to these charges, the challenge to interventional cardiologists will be to balance current evidence with the desire to advance the field of coronary intervention.

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Title 1

Transluminally-placed coilspring endarterial tube grafts: long-term patency in canine popliteal artery Author Dotter CT

Reference Invest Radiol 1969; 4: 329–332

Abstract Tubular prosthetic grafts introduced via carotid arteries were placed transluminally in femoralpopliteal arteries in 25 dogs using simple catheter techniques. While various impervious plastic tubes clotted promptly, the adoption of an open coilspring configuration has made possible long-term patency. Advantages of this potentially useful approach include freedom from the trauma usually associated with surgical vascular reconstruction.

Summary In this paper, Dr Dotter presents his group’s technique for the percutaneous transluminal placement of tubes in 25 undiseased canine arteries. While procedural success rate was high, maintaining patency proved difficult due to early thrombus formation. This was universally true in the 19 dogs who received plastic tubes, all of which clotted within 24 h. More promising was the experience of “coilspring tubular prosthethes” implanted in six dogs. These devices consisted of wound no. 5 gauge stainless-steel wire ranging in length from 1 to 10 cm. Heparin was given during stent implantation and continued for 4 days or until occlusion occurred. No antiplatelet therapies were employed. Of the metal prostheses implanted, three had occluded at 24 h. However, two stents remained patent for more than 2 years on follow-up angiography.

Citation Count

347

Related References 1. Dotter CT, Judkins MD. Transluminal treatment of arteriosclerotic obstruction. Description of a new technic and a preliminary report of its application. Circulation 1964; 30: 654–670. 2. Dotter CT, Buschmann RW, McKinney MK, Rosch J. Transluminal expandable nitinol coil stent grafting: preliminary report. Radiology 1983; 147: 259–260. 3. Cragg A, Lund G, Rysavy J, Castaneda G, Castaneda-Zuniga W, Amplatz K. Nonsurgical placement of arterial endoprostheses: a new technique using nitinol wire. Radiology 1983; 147: 261–263. 4. Palmaz JC, Sibbett RR, Reuter SR, Tio FO, Rice WJ. Expandable intraluminal graft: a preliminary study: work in progress. Radiology 1985; 156: 73–77. 5. Wright KC, Wallace S, Charsangavej C, Carrasco CH, Gianturco C. Percutaneous endovascular stents: an experimental evaluation. Radiology 1985; 156: 69–72.

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Key message This brief report was the first demonstration of the technical feasibility of transluminal tube placement in arterial vasculature. This paper also identified the importance of thrombus formation and established stainless steel as the preferred material for endovascular prostheses. Perhaps most exciting, Dr Dotter demonstrated the potential for long-term patency associated with these tubes.

Why it’s important This paper represented a significant milestone in the development of stent technology. Coming only 5 years after his initial call for the development of an “endovascular splint”, Dr Dotter succeeded in significantly pushing the entire field forward and stimulated additional efforts aimed at improving stent technology.

Strengths This was the first report of successful stent implantation and laid the groundwork for all future efforts.

Weaknesses While Dr Dotter demonstrated the potential for long-term patency, the small size and limited expandability of the coilspring tubes made them unsuitable for use in humans. As such, the field would essentially remain static until technological advances made self-expanding and balloonexpandable stents possible.

Relevance Although the technology and techniques developed by Dr Dotter, and described in this paper have no application to modern interventional cardiology, this paper established the feasibility of stent implantation and laid the foundation for further research. Moreover, the scientific ingenuity and intellectual curiosity embodied by Dr Dotter remains a standard for all interventionalists.

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Title 2

Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty Author Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L

Reference N Engl J Med 1987; 316: 701–706

Abstract Occlusion and restenosis are the most common reasons that transluminal balloon angioplasty may fail to provide long-term benefit. An intravascular mechanical support was therefore developed with the aim of preventing restenosis and sudden closure of diseased arteries after angioplasty. The endoprosthesis consists of a self-expandable stainless-steel mesh that can be implanted nonsurgically in the coronary or peripheral arteries. Experiments in animals showed complete intimal coverage within weeks and no late thrombosis during a follow-up period of up to one year. We performed 10 implantations in 6 patients for iliac or femoral arterial disease; 24 coronary-artery stents were implanted in 19 patients who presented with coronary-artery restenoses (n
17) or abrupt closure (n
4) after transluminal angioplasty or deterioration of coronary-bypass grafts (n
3). We observed three complications in the group with coronary disease. One thrombotic occlusion of a stent resulted in asymptomatic closure, a second acute thrombosis was managed successfully with thrombolysis, and one patient died after bypass surgery for a suspected but unfound occlusion. Follow-up in the patients has continued for nine months without evidence of any further restenoses within the stented segments. Our preliminary experience suggests that this vascular endoprosthesis may offer a useful way to prevent occlusion and restenosis after transluminal angioplasty. Long-term follow-up will be required to validate the early success of this procedure.

Summary In this paper, the investigators describe their experience deploying self-expanding stents in peripheral and coronary arteries. The authors used a canine model to demonstrate the feasibility of deploying self-expanding stents in the femoral and coronary arteries of mongrel dogs. Examination of the stents and arterial segments at 9 months demonstrated endothelialization of stent struts with a smooth neointimal layer. The authors then turned their attention to human subjects. In coronary arteries, procedural success was over 90%. In the four patients who received a stent for failed angioplasty, successful delivery of a stent restored coronary blood flow and averted the need for emergency coronary bypass surgery. During follow-up three patients developed stent thromboses (17%) and one patient died (6%). There were no cases of in-stent restenosis, though two patients developed new, symptomatic stenoses at sites remote from the coronary stent.

Citation Count

825

Related References 1. Serruys PW, Strauss BH, Beatt KJ, et al. Angiographic follow-up after placement of a selfexpanding coronary-artery stent. N Engl J Med 1991; 324: 13–17.

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2. Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stenting for acute and threatened closure complicating percutaneous transluminal coronary angioplasty. Circulation 1992; 85: 916–927.

Key message Implantation of stainless steel, self-expanding stents in human coronary arteries can be used to treat acute closure following balloon angioplasty, and may be associated with a lower rate of restenosis.

Why it’s important By 1987, the potential benefits and limitations of percutaneous balloon angioplasty had largely been identified. Although technical improvements permitted successful dilatation of most lesions, balloon angioplasty was limited in the short term by acute closure and in the long term by restenosis. Other technologies aimed at circumventing these problems included directional atherectomy, rotablation, and laser angioplasty. In this paper, Sigwart and colleagues established the technical feasibility and safety of the placement of intravascular stainless-steel stents in human peripheral and coronary arteries, and established stents as a potentially useful adjunct to balloon angioplasty.

Strengths This paper was another landmark in the application of stent technology and represented the largest series of patients successfully treated with self-expanding stent implantation.

Weaknesses As a case series, the investigators have no control group for comparison, and it is likely the majority of cases could have been treated successfully with simple balloon angioplasty. In addition, while starting to identify the periprocedural risks associated with stent implantation, the number of patients was too small and the clinical follow-up was too short to define fully the risks of stent thrombosis and in-stent stenosis.

Relevance This paper was the first to bring significant attention to the potential of intracoronary-stent implantation. It represents a pivotal moment in the history of interventional cardiology providing evidence that intravascular stents could be used to prevent or treat acute closure and hinting at the possibility of reducing restenosis. Nevertheless as the authors accurately stated, “further studies will determine with greater precision the benefits and risks of this new approach”.

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Title 3

A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease Author Fischman DL, Leon MB, Baim DS, et al., for the Stent Restenosis Study Investigators

Reference N Engl J Med 1994; 331: 496–501

Abstract BACKGROUND: Coronary-stent placement is a new technique in which a balloon-expandable, stainless-steel, slotted tube is implanted at the site of a coronary stenosis. The purpose of this study was to compare the effects of stent placement and standard balloon angioplasty on angiographically detected restenosis and clinical outcomes. METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz–Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later. RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who underwent standard balloon angioplasty (96.1 percent vs. 89.6 percent, p
0.011), a larger immediate increase in the diameter of the lumen (1.72  0.46 vs. 1.23  0.48 mm, p  0.001), and a larger luminal diameter immediately after the procedure (2.49  0.43 vs. 1.99  0.47 mm, p  0.001). At six months, the patients with stented lesions continued to have a larger luminal diameter (1.74  0.60 vs. 1.56  0.65 mm, p
0.007) and a lower rate of restenosis (31.6 percent vs. 42.1 percent, p
0.046) than those treated with balloon angioplasty. There were no coronary events (death; myocardial infarction; coronary-artery bypass surgery; vessel closure, including stent thrombosis; or repeated angioplasty) in 80.5 percent of the patients in the stent group and 76.2 percent of those in the angioplasty group ( p
0.16). Revascularization of the original target lesion because of recurrent myocardial ischemia was performed less frequently in the stent group than in the angioplasty group (10.2 percent vs. 15.4 percent, p
0.06). CONCLUSIONS: In selected patients, placement of an intracoronary stent, as compared with balloon angioplasty, results in an improved rate of procedural success, a lower rate of angiographically detected restenosis, a similar rate of clinical events after six months, and a less frequent need for revascularization of the original coronary lesion.

Summary To determine the effectiveness of coronary stents to prevent restenosis, investigators randomized 470 patients to compare a strategy of elective stent implantation with a strategy of balloon angioplasty with bail-out stenting for threatened closure or residual stenosis. Procedural success was significantly higher in the elective stent group with larger luminal diameters. Routine angiography at 6 months demonstrated a significantly lower rate of restenosis in the elective stent group compared with the balloon angioplasty group (31.6% vs. 42.1%). Revascularization for recurrent ischaemia was lower in the stent group, but there was a non-significant trend towards a higher risk of the combined end point of death, myocardial infarction, and vessel closure.

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Related References 1. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331: 489–495. 2. Erbel R, Haude M, Hopp HW, et al. Coronary-artery stenting compared with balloon angioplasty for restenosis after initial balloon angioplasty. N Engl J Med 1998; 339: 1672–1678. 3. Versaci F, Gaspardone A, Tomai F, et al. A comparison of coronary-artery stenting with angioplasty for isolated stenosis of the proximal left coronary artery. N Engl J Med 1997; 336: 817–822. 4. Buller CE, Vladimir D, Carere RG, et al. Primary stenting versus balloon angioplasty in occluded coronary arteries. Circulation 1999; 100: 236–242.

Key message The elective use of coronary stents improves procedural success and reduces rates of restenosis, but may be associated with slightly increased risk of major adverse cardiac events.

Why it’s important Previous studies had defined a role for stents to prevent acute closure consequent to dissection or inadequate balloon angioplasty result. Although there was accumulating evidence that stents might lower the rates of restenosis, there had been no randomized trials comparing elective vs. bail-out stenting for this indication. In this setting, the STRESS study, in conjunction with the Belgium–Netherlands Stent (BENESTENT) I trial, provided key evidence that stents significantly reduce (but do not eliminate) restenosis. Coronary stents were the first, and still the only, technology shown to decrease restenosis in randomized clinical trials. The STRESS and BENESTENT I studies served as the basis for the Food and Drug Administration’s (FDA’s) approval of elective coronary stenting in the USA, allowed the widespread adoption of stents, and to a large degree relegated other technologies to smaller, niche roles.

Strengths The STRESS study was a well-designed and implemented randomized multicentre clinical trial. Along with BENESTENT I, the STRESS investigators set the standard for trials of stents and other interventional devices.

Weaknesses The trial protocol specified that lesions had to be less than 15 mm, treatable with a single stent, with a reference lumen of at least 3 mm. As such, the investigators excluded the complex lesions associated with the worst outcomes using balloon angioplasty alone, and it was not known if the results of this trial could be extrapolated to more complex stenoses or patients.

Relevance In conjunction with the BENESTENT trial, the STRESS study laid the groundwork for approval of elective stenting. Additional studies demonstrated similar efficacy in saphenous vein graft stenoses, longer lesions, and for restenosis after balloon angioplasty. Collectively these trials established the use of coronary stents as the present day standard of care.

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Title 4

Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance Author Colombo A, Hall P, Nakamura S, et al.

Reference Circulation 1995; 91: 1676–1688

Abstract BACKGROUND: The placement of stents in coronary arteries has been shown to reduce restenosis in comparison to balloon angioplasty. However, clinical use of intracoronary stents is impeded by the risk of subacute stent thrombosis and complications associated with the anticoagulant regimen. To reduce these complications, the hypothesis that systemic anticoagulation is not necessary when adequate stent expansion is achieved was prospectively evaluated on a consecutive series of patients who received intracoronary stents. METHODS AND RESULTS: From March 1993 to January 1994, 359 patients underwent Palmaz–Schatz coronary stent insertion. After an initial successful angiographic result with 20% stenosis by visual estimation had been achieved, intravascular ultrasound imaging was performed. Further balloon dilatation of the stent was guided by observation of the intravascular ultrasound images. All patients with adequate stent expansion confirmed by ultrasound were treated only with antiplatelet therapy (either ticlopidine for 1 month with short-term aspirin for 5 days or only aspirin) after the procedure. Clinical success (procedure success without early postprocedural events) at 2 months was achieved in 338 patients (94%). With an inflation pressure of 14.9  3.0 atm and a balloon-tovessel ratio of 1.17  0.19, optimal stent expansion was achieved in 321 of the 334 patients (96%) who underwent intravascular ultrasound evaluation, with these patients receiving only antiplatelet therapy after the procedure. Despite the absence of anticoagulation, there were only two acute stent thromboses (0.6%) and one subacute stent thrombosis (0.3%) at 2-month clinical follow-up. Follow-up angiography at 3 to 6 months documented two additional occlusions (0.6%) at the stent site. At 6-month clinical follow-up, angiographically documented stent occlusion had occurred in 5 patients (1.6%). At 6-month clinical follow-up, there was a 5.7% incidence of myocardial infarction, a 6.4% rate of coronary bypass surgery, and a 1.9% incidence of death. Emergency intervention (emergency angioplasty or bailout stent) for a stent thrombosis event was performed in 3 patients (0.8%). The overall event rate was relatively high because of intraprocedural complications that occurred in 16 patients (4.5%). Intraprocedural complications, however, decreased to 1% when angiographically appropriately sized balloons were used for final stent dilations. There was one ischemic vascular complication that occurred at the time of the procedure and one ischemic vascular complication that occurred at the time of angiographic follow-up. By 6 months, repeat angioplasty for symptomatic restenosis was performed in 47 patients (13.1%). CONCLUSIONS: The Palmaz–Schatz stent can be safely inserted in coronary arteries without subsequent anticoagulation provided that stent expansion is adequate and there are no other flow-limiting lesions present. The use of high-pressure final balloon dilatations and confirmation of adequate stent expansion by intravascular ultrasound provide assurance that anticoagulation therapy can be safely omitted. This technique significantly reduces hospital time and vascular complications and has a low stent thrombosis rate.

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Summary The authors present data from 359 patients who had stent implantation guided by intravascular ultrasound. The authors demonstrated that traditional techniques resulted in underdeployed stents that often did not cover the entire lesion. They further showed that high-pressure inflations (14 atm) using balloons sized to the reference lumen were necessary to attain optimal stent expansion. Optimal stent expansion was attained in 321 patients (89.4%), and these patients received only ticlopidine or aspirin with no additional systemic anticoagulation. During follow-up of patients with optimal stent expansion, there were only five stent closures (1.6%).

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849

Related References 1. Nath FC, Muller DWM, Ellis SG, et al. Thrombosis of a flexible coil coronary stent: frequency, predictors, and clinical outcomes. J Am Coll Cardiol 1993; 21: 622–627. 2. Karrillon GJ, Morice MC, Benveniste E, et al. Intracoronary stent implantation without ultrasound guidance and with replacement of conventional anticoagulation by antiplatelet therapy. 30-day clinical outcome of the French Multicenter Registry. Circulation 1996; 94: 1519–1527. 3. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1997; 339: 1665–1671. 4. Schömig A, Neumann F-J, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334: 1084–1089.

Key message Optimal stent implantation can be achieved using intravascular ultrasound, appropriately sized stents, and high-pressure balloon inflations. Patients who receive optimal stent implantation do not require prolonged post-procedural systemic anticoagulation and can be safely treated with antiplatelet agents alone.

Why it’s important Early recognition of the risks of introducing thrombogenic materials into coronary arteries prompted investigators to use intraprocedural heparin, dextran, and thrombolytic agents followed by prolonged aspirin, dipyridamole, and warfarin. This regimen, however, was associated with significant risk of bleeding and necessitated prolonged hospitalization, both of which greatly increased costs. Furthermore, in spite of these precautions, the incidence of stent thrombosis was as high as 18% in early case series. These limitations significantly hindered the adoption of coronary stenting into routine clinical practice. Accordingly, the insights provided by Columbo and colleagues represented an important advance by offering both a practical method favouring high-pressure inflations and at the same time uncoupling stent implantation from the need for prolonged systemic anticoagulation.

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Strengths Although not a randomized clinical trial, the low 1.6% incidence of acute and subacute stent thrombosis in the absence of systemic anticoagulation was a remarkable finding that could almost stand on its own merit.

Weaknesses Once again there is no direct control group for comparison with this series of patients. However, previous studies had demonstrated at least a 3–4% incidence of stent thrombosis, and in this context the low 1.6% rate of stent thrombosis observed by Columbo and colleagues was extremely favourable. In addition, patients were enrolled at a high volume, referral centres, and it was initially unclear whether similar results could be attained in general interventional practice.

Relevance The insights of Columbo and colleagues completely changed the practice of stent implantation and ushered in the modern era interventional cardiology. Prior to this publication, stents provided an attractive bail-out option in the case of severe dissection and held promise for decreasing restenosis. Nevertheless the use of stents was limited by the very real and potentially life-threatening risk of acute stent thrombosis, as well as the requirement of prolonged hospitalizations to achieve systemic anticoagulation following stent implantation. Their findings led to the Stent Anticoagulation Restenosis Study (STARS) trial in which patients randomized to aspirin plus ticlopidine had a significantly lower risk of stent thrombosis (0.5%) than patients who received aspirin alone (2.9%) or aspirin plus coumadin (2.7%). Thus the work of Columbo and colleagues freed interventionalists from the need for prolonged anticoagulation and spurred the widespread adoption of routine coronary-stent use.

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Title 5

Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease Author Serruys PW, Unger F, Sousa JE, Jatene A, Bonnier HJRM, Schonberger JPAM, Buller N, Bonser R, van den Brand MJB, van Herwerden LA, Morel M-AM, van Hout BA, for the Arterial Revascularization Therapies Study (ARTS) Group

Reference N Engl J Med 2001; 344: 1117–1124

Abstract BACKGROUND: The recent recognition that coronary-artery stenting has improved the short- and long-term outcomes of patients treated with angioplasty has made it necessary to reevaluate the relative benefits of bypass surgery and percutaneous interventions in patients with multivessel disease. METHODS: A total of 1205 patients were randomly assigned to undergo stent implantation or bypass surgery when a cardiac surgeon and an interventional cardiologist agreed that the same extent of revascularization could be achieved by either technique. The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events at one year. The costs of hospital resources used were also determined. RESULTS: At one year, there was no significant difference between the two groups in terms of the rates of death, stroke, or myocardial infarction. Among patients who survived without a stroke or a myocardial infarction, 16.8 percent of those in the stenting group underwent a second revascularization, as compared with 3.5 percent of those in the surgery group. The rate of event-free survival at one year was 73.8 percent among the patients who received stents and 87.8 percent among those who underwent bypass surgery ( p  0.001 by the log-rank test). The costs for the initial procedure were $4212 less for patients assigned to stenting than for those assigned to bypass surgery, but this difference was reduced during follow-up because of the increased need for repeated revascularization; after one year, the net difference in favor of stenting was estimated to be $2973 per patient. CONCLUSIONS: As measured one year after the procedure, coronary stenting for multivessel disease is less expensive than bypass surgery and offers the same degree of protection against death, stroke, and myocardial infarction. However, stenting is associated with a greater need for repeated revascularization.

Summary The authors enrolled 1205 carefully selected patients with multivessel coronary-artery disease and preserved left ventricular function. Patients were then randomized to either percutaneous intervention with routine stenting or coronary-artery bypass surgery. The incidence of all major adverse clinical events at 1 year was higher in the stenting group than the surgery group (26.2% vs. 12.2%). However, the difference was entirely attributable to the need for repeat revascularization for in-stent restenosis, and the incidence of death, stroke, and myocardial infarction were comparable (9.3% stent vs. 8.8% surgery). Although angina was more frequent in the stent group due to restenosis, overall quality of life did not differ between the two groups. One-year medical costs including initial procedure were $2973 lower in patients randomized to stenting.

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216

Related References 1. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996; 335: 217–225. 2. King III SB, Lembo NJ, Weintraub WS, et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. Emory Angioplasty versus Surgery Trial (EAST). N Engl J Med 1994; 331: 1044–1050. 3. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. A comparison of coronaryartery stenting with angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. N Engl J Med 1997; 336: 817–822. 4. Legrand VMG, Serruys PW, Unger R, et al. Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease. Circulation 2004; 109: 1114–1120. 5. Stables RH, The SoS Investigators. Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet 2002; 360: 965–970.

Key message Among patients with coronary anatomy suitable to either procedure, a strategy of multivessel percutaneous intervention incorporating routine stenting yields similar 1-year incidence of death, stroke, and myocardial infarction compared with coronary-artery bypass surgery. However, patients treated with stenting required repeat revascularization much more often than patients who underwent bypass surgery.

Why it’s important While it has long been recognized that percutaneous intervention is preferable to coronary bypass surgery in the treatment of single-vessel coronary disease, the optimal method for multivessel disease has been to be a source of controversy for more than two decades. Randomized comparisons of balloon angioplasty vs. coronary-artery bypass surgery suggested these techniques were comparable, and that surgery resulted in less residual ischemia when compared with multivessel angioplasty. In addition, the Bypass Angioplasty Revascularization Investigation (BARI) trial raised the possibility of excess mortality associated with multivessel angioplasty. The emergence of routine stent implantation, however, made a new round of trials necessary to reevaluate this question in the stent era.

Strengths This is the largest randomized trial of routine stenting and coronary-artery bypass surgery. The study was well designed, and investigators managed to maintain excellent adherence to study protocol.

Weaknesses The 1-year follow-up was too short to provide a true comparison of the relative merits of stenting vs. surgery. For example, a longer follow-up interval may have revealed a tendency towards graft attrition in the surgical group. As in all trials comparing percutaneous coronary interventions

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(PCI) and surgery, the stringent clinical and angiographical characteristics required for enrolment greatly limits the generalizability of these results to the larger population of patients with multivessel coronary disease.

Relevance The results of the Arterial Revascularization Therapies Study (ARTS) trial provides additional evidence that among appropriately selected patients with multivessel coronary disease, percutaneous intervention with routine stenting offers results that are comparable to those of traditional bypass surgery. Nevertheless, the need for repeat revascularization among stent patients in the ARTS trial, as well the higher mortality among patients randomized to stenting in the Stent or Surgery trial leaves unanswered the question of which technique is superior. The emergence of drug-eluting stents further complicates the relative merits of multivessel angioplasty vs. bypass surgery and makes yet another round of clinical trials necessary.

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Title 6

Intracoronary Stenting and Angiographic Results: Strut Thickness Effect on REstenosis Outcome (ISAR-STEREO) Trial Author Kastrati A, Mehilli J, Dirschinger J, et al.

Reference Circulation 2001; 103: 2816–2821

Abstract BACKGROUND: Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results. METHODS AND RESULTS: A total of 651 patients with coronary lesions situated in native vessels 2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 m) and 325 patients to the thick-strut stent (strut thickness of 140 m). The primary end point was the angiographic restenosis (50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 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 to 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 to 0.99; p
0.03). No difference was observed in the combined 1-year rate of death and myocardial infarction. CONCLUSIONS: The use of a thinner-strut device is associated with a significant reduction of angiographic and clinical restenosis after coronary artery stenting. These findings may have relevant implications for the currently most widely used percutaneous coronary intervention.

Summary To determine the effect of strut thickness on the incidence of restenosis, the authors randomized 651 patients undergoing percutaneous coronary intervention (PCI) to receive either an Advanced Cardiovascular Systems (ACS) RX Multi-Link stent with 50- m thick struts or an ACS Multi-Link RX Duet with 140- m thick struts. Procedural success was high in both groups, but the thin-strut stent was less likely to be delivered successfully (92.6% vs. 96.9%) requiring crossover to the thick-strut stent. During follow-up, patients who received the thin-strut stent were significantly less likely to have angiographical restenosis (15.0% vs. 25.8%) or restenosis requiring target-vessel revascularization at 1 year (8.6% vs. 13.8%).

Citation Count

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Related References 1. Rogers C, Edelman ER. Endovascular stent design dictates experimental restenosis and thrombosis. Circulation 1995; 91: 2995–3001. 2. Garasic JM, Edelman ER, Squire JC, et al. Stent and artery geometry determine intimal thickening independent of arterial injury. Circulation 2000; 101: 812–818. 3. Lansky AJ, Roubin GS, O’Shaughnessy CD, et al. Randomized comparison of GR-II stent and Palmaz–Schatz stent for elective treatment of coronary stenoses. Circulation 2000; 102: 1364–1368. 4. Pache J, Kastrati A, Mehilli J, et al. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO-2) trial. J Am Coll Cardiol 2003; 41: 1283–1288.

Why it’s important As the use of coronary stents became routine, competition between an expanding number of stent manufacturers led to refinements in stent design. These innovations resulted in lower stent profile, increased visibility, improved deliverability, and decreased strut thickness. Despite these technological innovations, there was relatively little interest in determining whether differences in stent design would translate into clinically important differences in restenosis. The underlying assumption of many clinicians was that once delivered, all stents provided comparable reductions in restenosis. The Food and Drug Administration (FDA) reinforced this assumption by only requiring stent manufacturers to demonstrate comparable 30-day outcomes. The ISAR-STEREO investigators made a significant contribution to the literature when they demonstrated that stent design does impact on restenosis.

Strengths ISAR-STEREO was a randomized, multicentre clinical trial that was adequately powered to detect clinically meaningful differences in angiographical restenosis. The investigators used stents that had essentially identical design which minimized the chance that the observed differences in outcome were due to factors other than stent strut thickness.

Weaknesses Interventional cardiologists were not blinded to the stent type. Similarly, though quantitative coronary angiography (QCA) analysis was performed by investigators blinded to group assignment, differences in fluoroscopic appearance may have compromised blinding.

Relevance Although the ISAR-STEREO investigators definitively demonstrated that design impacts outcome, considerations of stent design have taken a backseat to the emergence of drug-eluting stents. Nevertheless, optimizing patient outcomes after PCI will require combining the best drug with the best stent platform. Accordingly additional innovations in stent design will no doubt play an important role in the future of interventional cardiology.

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Title 7

Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction Author Stone GW, Grines CL, Cox DA, et al., for the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Investigators

Reference N Engl J Med 2002; 346: 957–966

Abstract BACKGROUND: As compared with thrombolytic therapy, primary percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction reduces the rates of death, reinfarction, and stroke, but recurrent ischemia, restenosis, and reocclusion of the infarct-related artery remain problematic. When used in combination with PTCA, coronary stenting and platelet glycoprotein IIb/IIIa inhibitors may further improve outcomes. METHODS: Using a 2-by-2 factorial design, we randomly assigned 2082 patients with acute myocardial infarction to undergo PTCA alone (518 patients), PTCA plus abciximab therapy (528), stenting alone with the MultiLink stent (512), or stenting plus abciximab therapy (524). RESULTS: Normal flow was restored in the target vessel in 94.5 to 96.9 percent of patients and did not vary according to the reperfusion strategy. At six months, the primary end point – a composite of death, reinfarction, disabling stroke, and ischemia-driven revascularization of the target vessel – had occurred in 20.0 percent of patients after PTCA, 16.5 percent after PTCA plus abciximab, 11.5 percent after stenting, and 10.2 percent after stenting plus abciximab ( p  0.001). There were no significant differences among the groups in the rates of death, stroke, or reinfarction; the difference in the incidence of the primary end point was due entirely to differences in the rates of target-vessel revascularization (ranging from 15.7 percent after PTCA to 5.2 percent after stenting plus abciximab, p  0.001). The rate of angiographically established restenosis was 40.8 percent after PTCA and 22.2 percent after stenting ( p  0.001), and the respective rates of reocclusion of the infarcted-related artery were 11.3 percent and 5.7 percent ( p
0.01), both independent of abciximab use. CONCLUSIONS: At experienced centers, stent implantation (with or without abciximab therapy) should be considered the routine reperfusion strategy.

Summary Using a 2-by-2 factorial design, the investigators randomized 2082 patients with acute myocardial infarction to receive one of the following treatment strategies: balloon angioplasty alone; angioplasty with routine stent implantation; balloon angioplasty with the glycoprotein IIb/IIIa inhibitor abciximab; or angioplasty with routine stenting and abciximab. Patients were randomized after diagnostic angiography and before the start of the percutaneous intervention. As expected, patients randomized to receive a stent had larger luminal diameters and less residual stenoses, but this did not correspond to significant differences in epicardial blood flow. At 30 days, patients randomized to receive a stent, abciximab, or both had lower incidences of the composite end point of death, reinfarction, disabling stroke, or target-vessel revascularization. At 6 months, the need for revascularization among patients who received a stent was roughly half that of patients who had angioplasty alone with or without abciximab. However, there were no significant differences in the occurrence of death, reinfarction, or disabling stroke.

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221

Related References 1. Zjilstra F, de Boer MJ, Hoorntje JC, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993; 328: 680–684. 2. Stone GW, Brodie BR, Griffin JJ, et al. Clinical and angiographic follow-up after primary stenting in acute myocardial infarction: the PAMI Stent Pilot Trial. Circulation 1999; 99: 1548–1554. 3. Stone GW. Stenting in acute myocardial infarction: observational studies and randomized trials. J Invest Cardiol 1998; 10: 16a–28a. 4. Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. N Engl J Med 1999; 341: 1949–1956. 5. Cox DA, Stone GW, Grines CL, et al. Outcomes of optimal or “stent-like” balloon angioplasty in acute myocardial infarction: The CADILLAC trial. J Am Coll Cardiol 2003; 42: 971–977.

Key message When performing primary angioplasty for acute myocardial infarction, a strategy of routine stent implantation, with or without the use of glycoprotein IIb/IIIa inhibitors improves both angiographical and clinical outcomes.

Why it’s important Primary angioplasty has emerged as the treatment of choice for patients experiencing an acute myocardial infarction. A number of clinical trials have shown that, compared with thrombolytic therapy, primary angioplasty improves myocardial salvage and increases event-free survival primarily by reducing reinfarction and the need for target-vessel revascularization. Although pilot studies of stent implantation during primary angioplasty were promising, the first large randomized trial investigating the strategy of routine stent implantation suggested that stent use was associated with reductions in epicardial blood flow and increases in mortality. Based on these findings, it was recommended that stents be reserved for the treatment of suboptimal balloon angioplasty results. The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) investigators provided important information regarding the safety and efficacy of routine stent implantation during primary angioplasty when combined with platelet inhibition.

Strengths The investigators used relatively broad inclusion criteria to enrol patients who were representative of the broader population of patients with acute myocardial infarction and improve the generalizability of the study’s findings. In addition, approximately 90% of patients who were eligible for enrolment after diagnostic angiography were randomized.

Weaknesses Randomization took place after diagnostic coronary angiography. While it is unlikely that this affected the angioplasty vs. stent analysis, it may have limited the efficacy of abciximab in this setting.

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Relevance The number of hospitals performing primary angioplasty continues to increase. The CADILLAC trial provided strong evidence that the strategy of routine stent implantation provides superior clinical outcomes to patients undergoing primary angioplasty, and establishes this as the current standard of care. Nevertheless the design of the trial with initiation of IIb/IIIa inhibition in the catheterization laboratory leaves open the question of whether upstream use of IIb/IIIa inhibitors by paramedics or emergency physicians can lead to further improvements in patient outcomes. Moreover, additional studies will be needed to refine the technique of primary angioplasty and clarify the role of distal protection devices, thrombectomy, and the use of drug-eluting stents in this setting.

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Title 8

Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery Author Moses JW, Leon MB, Popma JJ, et al., for the SIRIUS Investigators

Reference N Engl J Med 2003; 349: 1315–1323

Abstract BACKGROUND: Preliminary reports of studies involving simple coronary lesions indicate that a sirolimus-eluting stent significantly reduces the risk of restenosis after percutaneous coronary revascularization. METHODS: We conducted a randomized, double-blind trial comparing a sirolimus-eluting stent with a standard stent in 1058 patients at 53 centers in the United States who had a newly diagnosed lesion in a native coronary artery. The coronary disease in these patients was complex because of the frequent presence of diabetes (in 26 percent of patients), the high percentage of patients with longer lesions (mean, 14.4 mm), and small vessels (mean, 2.80 mm). The primary end point was failure of the target vessel (a composite of death from cardiac causes, myocardial infarction, and repeated percutaneous or surgical revascularization of the target vessel) within 270 days. RESULTS: The rate of failure of the target vessel was reduced from 21.0 percent with a standard stent to 8.6 percent with a sirolimus-eluting stent ( p  0.001) – a reduction that was driven largely by a decrease in the frequency of the need for revascularization of the target lesion (16.6 percent in the standard-stent group vs. 4.1 percent in the sirolimus-stent group, p  0.001). The frequency of neointimal hyperplasia within the stent was also decreased in the group that received sirolimus-eluting stents, as assessed by both angiography and intravascular ultrasonography. Subgroup analyses revealed a reduction in the rates of angiographic restenosis and target-lesion revascularization in all subgroups examined. CONCLUSIONS: In this randomized clinical trial involving patients with complex coronary lesions, the use of a sirolimus-eluting stent had a consistent treatment effect, reducing the rates of restenosis and associated clinical events in all subgroups analyzed.

Summary The investigators randomized 1058 patients with significant coronary-artery disease to receive a sirolimus-eluting stent or a standard bare-metal stent. Over follow-up of 270 days, the use of sirolimus-eluting stents was associated with clinically and statistically significant reductions in both in-stent restenosis (3.2% vs. 35.4%) and in-segment restenosis (8.9% vs. 36.3%) compared with standard bare-metal stents. Although the rate of restenosis was considerably higher in patients with diabetes (about 18% in the sirolimus-stent group vs. about 51% in the standardstent group), the absolute benefits associated with sirolimus-eluting stents were preserved. Failure to cover the entire injured segment was the primary cause of restenosis in patients randomized to sirolimus-eluting stents.

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Related References 1. Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells. Circ Res 1995; 76: 412–417. 2. Suzuki T, Kopia G, Hayashi S, et al. Stent-based delivery of sirolimus reduces neointimal formation in a porcine coronary model. Circulation 2001; 104: 1188–1193. 3. Sousa JE, Costa MA, Abizaid A, 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: 192–195. 4. Morice M-C, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773–1780. 5. Park S-J, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the prevention of coronary restenosis. N Engl J Med 2003; 348: 1537–1545.

Key message Sirolimus-eluting stents significantly reduced restenosis and the need for target-vessel revascularization. There was no subgroup who did not benefit from use of sirolimus-eluting stents.

Why it’s important Since the original reports of complete suppression of neointimal proliferation by both oral and stent-delivered sirolimus, clinicians have eagerly awaited the arrival of drug-coated stents to achieve the ultimate goal of interventional cardiology – safe and effective coronary intervention with no risk of restenosis. These expectations were raised even further by the RAVEL trial in which sirolimus-eluting stents were associated with no restenoses and no repeat interventions. In this environment, the SIRIUS trial played an important role by confirming the promise of sirolimuseluting stents and serving as the pivotal trial for Food and Drug Administration (FDA) approval in the USA.

Strengths Another well-designed clinical trial, the SIRIUS trial, provided convincing evidence that sirolimus-eluting stents significantly reduces angiographical restenosis and prevents recurrent ischaemia.

Weaknesses A number of high-risk lesion subtypes such as total occlusions, long segments of disease, in-stent stenosis, and bifurcation lesions were excluded from the SIRIUS trial. The efficacy of drug-eluting stents in these lesion subtypes are being looked at in ongoing trials. Although the authors did not formally test for an interaction between insulin requiring diabetes and efficacy of sirolimuseluting stents, the relatively high rate of in-segment restenosis in this subgroup may be a cause for concern. Finally, the authors provide no information regarding the cost-effectiveness of sirolimus-eluting stents. Accordingly it is not known whether the incremental costs of drug-eluting stents, which cost more than three times the bare-metal stents, are offset by the decreased expenses attributable to lower rates of repeat revascularization.

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Relevance Since their introduction, drug-eluting stents have rapidly become the standard of care in both the USA and abroad. The SIRIUS trials, in combination with the results from RAVEL and TAXUS have demonstrated consistent reductions in restenosis. If drug-eluting stents prove similarly efficacious in all lesion subtypes, they will allow interventional cardiologists to approach more complex lesions and greatly expand the pool of patients who will benefit from percutaneous intervention.

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Title 9

Stenting of unprotected left main coronary artery stenoses: immediate and late outcomes Author Park S-J, Park S-W, Hong M-K, et al.

Reference J Am Coll Cardiol 1998; 31: 37–42

Abstract OBJECTIVES: We examined the immediate and long-term outcomes after stenting of unprotected left main coronary artery (LMCA) stenoses in patients with normal left ventricular (LV) function. BACKGROUND: Left main coronary artery disease is regarded as an absolute contraindication for coronary angioplasty. Recently, several reports on protected or unprotected LMCA stenting, or both, suggested the possibility of percutaneous intervention for this prohibited area. METHODS: Forty-two consecutive patients with unprotected LMCA stenoses and normal LV function were treated with stents. The post-stent antithrombotic regimens were aspirin and ticlopidine; 14 patients also received warfarin. Patients were followed very closely with monthly telephone interviews and follow-up angiography at 6 months. RESULTS: The procedural success rate was 100%, with no episodes of subacute thrombosis regardless of anticoagulation regimen. Six-month follow-up angiography was performed in 32 of 34 eligible patients. Angiographic restenosis occurred in seven patients (22%, 95% confidence interval 7% to 37%); five patients subsequently underwent elective coronary artery bypass graft surgery (CABG), and two patients were treated with rotational atherectomy plus adjunct balloon angioplasty. The only death occurred 2 days after elective CABG for treatment of in-stent restenosis. The other patients (without angiographic follow-up) remain asymptomatic. CONCLUSIONS: Stenting of unprotected LMCA stenoses may be a safe and effective alternative to CABG in carefully selected patients with normal LV function. Further studies in larger patient populations are needed to assess late outcome.

Summary The authors provide characteristics and clinical outcomes of 42 patients with preserved left ventricular function who underwent stenting of an isolated, unprotected left main stenosis. All but one patient were thought to be good candidates for coronary-artery bypass surgery but strongly preferred a percutaneous intervention. Stents were used electively in 38 patients and as bail-out therapy in four patients. Procedural success was 100% with no significant periprocedural complications and no stent thrombosis. Quantitative coronary angiography (QCA) revealed an increase in minimal luminal diameter from 1.1 mm to 4.2 mm. During follow-up, seven patients (17%) had symptomatic restenosis less than 2 months after the procedure. Among the 32 patients who underwent angiography at 6 months, restenosis occurred in seven patients. The only death occurred in a patient with in-stent stenosis who was referred for elective coronary bypass surgery.

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Related References 1. O’Keefe Jr JH, Hartzler GO, Rutherford BD, et al. Left main coronary angioplasty: early and late results of 127 acute and elective procedures. Am J Cardiol 1989; 64: 144–147. 2. Ellis SG, Tamai H, Nobuyoshi M, et al. Contemporary percutaneous treatment of unprotected left main coronary stenoses: initial results from a multicenter registry analysis 1994–1996. Circulation 1997; 96: 3867–3872. 3. Silvestri M, Barragan P, Sainsous J, et al. Unprotected left main coronary artery stenting: immediate and medium-term outcomes of 140 elective procedures. J Am Coll Cardiol 2000; 35: 1543–1550. 4. Park SJ, Park SW, Hong MK, et al. Long-term (three-year) outcomes after stenting of unprotected left main coronary artery stenosis in patients with normal left ventricular function. Am J Cardiol 2003; 91: 12–16.

Key message In carefully selected, low-risk patients with isolated stenosis of the left main coronary artery, percutaneous intervention with routine stenting may offer an alternative to coronary bypass surgery. However, patients are at significant risk of symptomatic restenosis and require close monitoring and routine angiography to identify recurrent ischaemia.

Why it’s important Left main lesions present a unique challenge to the interventional cardiologist. In the era of balloon angioplasty, patient outcomes were disappointing with high rates of symptomatic restenosis and the spectre of catastrophic acute closure. The arrival of coronary stents improved procedural success rates, but did not eliminate the risk of restenosis or stent thrombosis. In this setting, this case series provided an important first glimpse at both the promise and pitfalls of left main stenting. While initial procedural success was high, the 17% rate of restenosis presenting as unstable angina would give clinicians pause before adopting left main stenting as part of their interventional practice.

Strengths There are two major strengths to this study. First, stents were implanted in all patients, which was not the case in other registries of left main stenting. Second, the authors almost exclusively enrolled patients who were also candidates for bypass surgery. Accordingly, patients were more similar to patients in clinical practice who are referred for coronary bypass surgery than what has been reported in other registries.

Weaknesses This case series is far too small to determine the true risks and outcomes associated with stent implantation in unprotected left main stenosis. Although the authors excelled at identifying appropriate patients as evidenced by the high rate of procedural success, it may be difficult to replicate their decision-making process based on the description provided.

Relevance For patients with significant stenosis of the left main artery, coronary bypass surgery offers a proven therapy shown to provide a survival advantage over medical therapy. In part due to the risks

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identified by Park and colleagues, the interventional community has remained appropriately reluctant to perform percutaneous interventions on left main disease in the absence of a relative or absolute contraindication to surgery. Nevertheless, pharmacological advances and the low restenosis rates achieved with drug-eluting stents may allow left main stenting to offer a safe and efficacious alternative to coronary-artery bypass surgery. At present, however, stenting of the left main remains largely a therapy of last resort, one usually employed in the setting of a cardiac emergency, severe co-morbid disease, or a patient’s refusal to consider bypass surgery.

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Chapter 7

Ancillary techniques in interventional cardiology John M. Lasala, George Chrysant, Adrian Messerli Introduction The Ancillary Techniques in Interventional Cardiology Section will be diverse in covering a number of cutting balloon devices such as directional coronary atherectomy, rotational atherectomy, and distal embolic protection. Limitations on space prevent an elaborate discussion on other techniques that would qualify for the chapter. These three were chosen because they span over a decade and a half of interventional cardiology. Some are more historical in nature; all have had a substantial impact at one time during the development of interventional cardiology techniques. The rotational atherectomy system was developed by Dr David C Auth PhD, two decades ago. It consists of a nickel-plated brass elliptical burr coated on the leading edge with 20–30 micron diamond chips. The chips protrude from the nickel plating forming a cutting surface of approximately 5 microns, therefore ablating atherosclerotic plaque to the size of a red blood cell. The ablated material can then pass through the microcirculation and is consumed by the reticular endothelial system. The burr is attached to a long flexible drive shaft with a central core clearance of 0.009 inch stainless steel guidewire. The drive shaft is driven by compressed nitrogen and housed in a Teflon sheath that can be irrigated with a flush solution containing a cocktail of heparin, nitroglycerin or calcium channel blockers at the discretion of the operator. A fiber optic light probe helps rotate the shaft at 140–180,000 rpm. A higher speed may be necessary when encountering heavily calcified lesions. Reduction of friction of the drive shaft with the Teflon-coated sheath has recently been improved by the addition of Rotaglide TM solution consisting of a phospholipid emulsion constituting nature’s “10W40”. It minimizes heat and improves the efficiency of the drive shaft. Rotational atherectomy is a very operator dependent technique. Though comprising less than 10% of all procedures in the United States, it enables the operator to perform cases that involve heavy degrees of calcification to be performed where other technologies fail. The rotablator is capable of cutting into elastic plaque whether or not it is calcified, by applying the principle of differential cutting. The normal artery being more elastic in nature, will deflect from the burr itself, similar to shaving one’s face in the morning – the beard reflected off the skin is preferentially cut. Rotational atherectomy is successful only with diligent attention to technique and detail. The field has been advanced by a number of high volume practitioners who have previously published on optimal techniques, such as Maurice Buchbinder at La Jolla California; Mark Reisman at Swedish Hospital, Seattle Washington; Samin Sharma, Mount Sinai Medical Center in New York City; Gregory Braden, Winston Salem, North Carolina; and Ted Feldman at Abbott Northwestern Hospital Chicago, Illinois. Directional coronary atherectomy (DCA) was intended to improve the safety and efficacy of revascularization compared to balloon angioplasty by controlling plaque removal. The device was conceived and initially tested by Dr John B Simpson, MD at Sequoia Hospital in Redwood City, California. The debulking strategy was developed in response to the major problems of balloon angioplasty during the early 1980s and was designed to decrease the primary failure and abrupt closure rates while minimizing restenosis. The entire concept of atherectomy was introduced by Dr Simpson who developed the prototype known as the Simpson Coronary AtheroCath. This consists of a metal housing with a fixed balloon, a nose cone collection chamber and a hollow tube which accompanies a 0.014 inch

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guidewire. A cup-shaped cutter inside the housing is attached to a flexible drive shaft and is activated by a hand-held battery operated motor driver unit. The AtheroCath is advanced into the lesion with the cutting chamber directed into the plaque bulk. The blade is then withdrawn exposing the plaque to the chamber and cutting surface. When the balloon is inflated it will further push the cutting window into the plaque. The cutter is manually advanced while rotating the cutter at approximately 2000 rpm. The excised atheroma is then pushed forward and stored in the distal nose cone, allowing for collection. The development of directional coronary atherectomy and its practitioners, particularly Drs Donald Baim and Richard Kuntz of Harvard, devised effective debulking strategies in an optimal manner, proposing the “bigger is better hypothesis”. This hypothesis stated that although there is an obligatory late loss of lumen diameter that occurs after coronary intervention, a larger lumen would have a higher probability of avoiding restenosis and producing fewer symptoms. Directional arthrectomy with its controlled debulking was developed as a means of capitalizing on this hypothesis. Other operators, notably Chuck Simonton working at Charlotte, North Carolina, have demonstrated that ultrasound guidance of debulking can further perfect outcomes. In fact, directional coronary atherectomy, in common with stenting, is the only device tested in a prospective randomized manner, to demonstrate a reduction in angiographic rates of restenosis. Recovery of atheroma, unlike its destructive counter part, rotational atherectomy, also was helpful to vascular biologists, providing a biopsy specimen that could be evaluated for procoagulate activity, neointimal formation, and differences in the plaque composition in patients with stable and unstable angina. Today, the device has largely been superseded by intracoronary stenting which is considerably simpler and less operator dependent. It has found use in bulky areas such as bifurcation lesions in the coronary tree while an updated version of directional coronary artherectomy (Fox Hollow) has been employed in peripheral arteries to debulk large lesions in the lower extremity. Embolic protection devices round out the trio of ancillary technologies. This is the most recently developed and currently, the most commonly used in contemporary intervention. This is a rapidly burgeoning field with many major medical device companies currently pursuing FDA approval with an embolic protection device. The landmark papers regarding the SAFER Trial established embolic protection as the method of choice in reducing MB/CPK release related to saphenous vein graft intervention. Application into both the coronary tree, carotids and renal intervention will be helpful to protect against end-organ damage. The number of articles being reviewed and published in this field will fill a rather large book chapter over the next three years. The development of these techniques stand as testament to the ingenuity of the engineers, private industries and interventional cardiologists who have helped make these devices a reality. Necessity truly being the mother of invention has been the guiding force to the design and construction of ancillary techniques involved in interventional cardiology. All have given us important additions to our armamentarium in caring for our patients with coronary disease.

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Title 1

A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease (The CAVEAT Study Group) Author Topol EJ, Leya P, Pinkerton CA, et al.

Reference N Engl J Med 1993; 329: 221–227

Abstract BACKGROUND: Directional coronary atherectomy is a new technique of coronary revascularization by which atherosclerotic plaque is excised and retrieved from target lesions. With respect to the rate of restenosis and clinical outcomes, it is not known how this procedure compares with balloon angioplasty, which relies on dilation of the plaque and vessel wall. We compared the rate of restenosis after angioplasty with that after atherectomy. METHODS: At 35 sites in the United States and Europe, 1012 patients were randomly assigned to either atherectomy (512 patients) or balloon angioplasty (500 patients). The patients underwent coronary angiography at base line and again after six months; the paired angiograms were quantitatively assessed at one laboratory by investigators unaware of the treatment assignments. RESULTS: Stenosis was reduced to 50% or less more often with atherectomy than with angioplasty (89% vs. 80%, p  0.001), and there was a greater immediate increase in vessel caliber (1.05 vs. 0.86 mm, p  0.001). This was accompanied by a higher rate of early complications (11% vs. 5%, p  0.001) and higher in-hospital costs ($11,904 vs. $10,637; p
0.006). At six months, the rate of restenosis was 50% for atherectomy and 57% for angioplasty ( p
0.06). However, the probability of death or myocardial infarction within six months was higher in the atherectomy group (8.6% vs. 4.6%, p
0.007). CONCLUSIONS: Removing coronary artery plaque with atherectomy led to a larger luminal diameter and a small reduction in angiographic restenosis, though the latter was not statistically significant. However, atherectomy led to a higher rate of early complications, increased cost, and no apparent clinical benefit after six months of follow-up.

Summary The CAVEAT study was a randomized study that assigned 512 patients to directional coronary atherectomy (DCA) and 500 patients to percutaneous transluminal angioplasty (PTCA). Patients were enrolled at 35 sites in the USA and Europe, and underwent baseline and 6 month angiography to examine whether there was a difference in restenosis rates between the two modalities. The primary end-point of the study was angiographical restenosis (50%). A composite early clinical end point of death, MI, emergency coronary bypass surgery, and acute vessel closure were determined. Both DCA and PTCA had 96% angiographical success rates according to the site physicians; however, there was a slightly better reported success rate for DCA when evaluated by the core laboratory (89% vs. 80%, p  0.001). In terms of the clinical endpoints, there was no statistically significant difference in outcome (Table 1).

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Table 1 Cumulative clinical outcomes (values in number (%)) at 6 months (from Topol et al. N Engl J Med 1993; 329: 221–227) Outcome Death Myocardial infarction Coronary artery bypass surgery Need for subsequent non-surgical coronary intervention No adverse clinical end point

Atherectomy (n
512)

Angioplasty (n
500)

p-value

8 (1.6) 39 (7.6) 42 (8.2) 145 (28.3)

3 (0.6) 22 (4.4) 34 (6.8) 152 (30.4)

0.22 0.04 0.39 0.42

307 (60)

307 (63)

0.49

For the cumulative outcomes, patients may be included in more than one category. In addition, the 6-month composite clinical end point was prospectively defined as death, the worst outcome, followed in order of rank by myocardial infarction, coronary artery bypass surgery, and the need for subsequent coronary intervention. Patients were classified in the category that corresponded to the worst outcome they had experienced. By ordinal logistic regression, there was no significant difference between the two groups in the composite clinical end point (p
0.19).

Strengths This study was a large randomized study evaluating both angiographical success and clinical outcomes in patients undergoing two different accepted methods of treating obstructive coronary disease. The groups were equal in representation and both groups were treated with the same basic pharmacological agents before and after their procedures including aspirin and a calcium channel blocker prior to the baseline procedure with intracoronary nitroglycerin prior to the baseline angiogram, and at 6-month follow-up angiogram.

Weaknesses While the sites were chosen on the basis of their experience with DCA, the overall experience with this new device (at the time) was relatively small compared to the operator’s cumulative skill with PTCA. Each operator had to have experienced an 80% or higher success rate with a minimum of 400 PTCAs compared to an 85% success rate with a minimum of 50 DCAs. Also, 26% of the patients in the DCA arm crossed over to other technologies for revascularization, namely stents, perfusion balloons, or other atherectomy devices compared with 14% in the PTCA arm.

Relevance DCA was heralded as a potential replacement for PTCA due to the ability of DCA to excise and remove plaque and plaque debris compared to treating the plaque with balloon expansion and fracture. The trial was done on the heels of successful registry data and during a time when many operators were early on what is now known to be a steep learning curve. The operators in the trial were vastly more experienced with PTCA compared to DCA possibly hurting the outcome of the trial. As stenting became more widespread and was proven to drastically reduce restenosis rates, DCA faced a new challenge, which was not only to outperform PTCA, but also to outperform PTCA and stenting. Now with drug-eluting stent technology reducing the restenosis rates into the single digits, it is clear that DCA does not compare favourably and its use is restricted to a small number of centres.

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Title 2

“Optimal” directional coronary atherectomy, final results of the Optimal Atherectomy Restenosis Study (OARS) Author Simonton CA, Leon MB, Baim DS, et al.

Reference Circulation 1998; 97: 332–339

Abstract BACKGROUND: Previous clinical trials of directional coronary atherectomy (DCA) have failed to show significant improvement in early or late outcomes compared with balloon angioplasty (PTCA). The present study tested the hypothesis that more aggressive “optimal” atherectomy could be performed safely to produce larger initial lumen diameters and a lower late restenosis rate. METHODS AND RESULTS: The present study was a prospective multicenter registry of consecutive patients undergoing optimal DCA of de novo or restenotic lesions in 3.0- to 4.5-mm native coronary arteries. Optimal DCA was defined as using a 7F atherectomy device and adjunctive PTCA if necessary to achieve a 15% residual stenosis. Six-month angiographic and 1-year clinical follow-up was planned in all patients. A total of 199 patients with 213 lesions met eligibility criteria for enrollment. Short-term procedural success was achieved in 97.5%, with a major complication rate (death, emergency bypass surgery, or Q-wave myocardial infarction [MI]) of 2.5%. There were no early deaths. Non-Q-wave MI (CK-MB 3 times normal) occurred in 14% of patients. Mean reference vessel diameter was 3.28 mm. Mean diameter stenosis was reduced from 63.5% to a final stenosis of 7%. Late 1-year clinical follow-up revealed one cardiac death and a target lesion revascularization rate of 17.8%. The angiographic restenosis rate at 6 months was 28.9%, with the major predictor of restenosis being a smaller postprocedure lumen diameter. CONCLUSIONS: Optimal DCA produced a low residual % diameter stenosis and a lower restenosis rate than seen in previous trials without an increase in early or late major adverse events.

Summary The OARS (Optimal Atherectomy Restenosis Study) trial followed two large randomized trials (Coronary Angioplasty vs. Excisional Atherectomy Trial and Canadian Coronary Atherectomy [CAVEAT and CCAT]) that examined the efficacy of directional coronary atherectomy (DCA) as a method of treating obstructive atherosclerotic coronary disease versus standard balloon angioplasty. Both trials failed to show a significant benefit to using DCA. Moreover, there was a belief that these trials were conducted too early in the development of the DCA technique, which is to say that the operator’s experience was early on the learning curve. Another thought was that “optimal” atherectomy had not been performed. The OARS trial tested the “bigger is better” approach to atherectomy. The hypothesis was that more aggressive DCA would lead to a larger early lumen diameter; and subsequently, better late clinical and angiographical restenosis rates. The study involved 200 consecutive patients at four centres who underwent more aggressive atherectomy and who were followed at 6 months (angiography) and 12 months (clinical). The primary end-points were 6-month angiographical restenosis (50%) and 12 month target vessel failure rate (myocardial infarction (MI), target vessel revascularization (TVR), or death).

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(a)

100 90 80

Lesions (%)

70 60 DCAPTCA Ref

50

DCAPTCA Pre

40

DCAPTCA Post 30 DCA Only Ref 20

DCA Only Pre

10

DCA Only Post

0 0.0

0.5

1.0

1.5

2.0

2.5 3.0 MLD (mm)

3.5

4.0

4.5

5.0

100

(b)

90 80

Lesions (%)

70 60 50 40 30

DCAPTCA Pre

20

DCAPTCA Post DCA Only Pre

10 0 40 30 20 10

DCA Only Post 0

10

20

30

40

50

60

70

80

90

100

Diameter stenosis (%)

Figure 1 Baseline and acute angiographic results. (a) Cumulative distribution of reference vessel diameter and minimal luminal diameter (MLD) at baseline (preprocedure) and after final treatment (postprocedure). (b) Cumulative distribution of % diameter stenosis at baseline (preprocedure) and after final treatment (postprocedure).

The results for angiographical restenosis, death, MI, TVR and target vessel failure were 29%, 1%, 1.5%, 21% and 24%, respectively. A large initial lumen diameter was achieved with an average size of 3.16 mm (in vessels with reference diameters of 3.0–4.5 mm). The authors concluded that “optimal” DCA could be performed safely and would result in larger initial lumen diameters (Figure 1).

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66

Strengths The trial was conducted at experienced centres capable of performing more aggressive DCA. The follow-up included angiographical and clinical end points.

Weaknesses The trial was not randomized and 87% of patients underwent post-DCA percutaneous transluminal coronary angioplasty (PTCA); therefore, in most cases the result was not 100% attributable to DCA. There was a high incidence of periprocedural CK-MB elevation although this did not manifest in poorer clinical outcomes.

Relevance The overall benefit of DCA shown in this study is modest at best. Using a more aggressive DCA strategy did lead to a larger early lumen; however, this was at a cost of higher CK-MB levels and without a large clinical benefit. The OARS trial did collect early registry results of safety and efficacy, but did not improve greatly on the shortcomings of CAVEAT and CCAT, which were larger studies. Compared to PTCA, the restenosis rate of 29% achieved in this study compares favourably; however, it falls short of newer era bare metal stents and is clearly inferior to drugeluting stents in terms of angiographical restenosis rates.

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Title 3

Final results of the balloon vs. optimal atherectomy trial (BOAT) Author Baim DS, Cutlip DE, Sharma SK, et al.

Reference Circulation 1998; 97: 322–331

Abstract BACKGROUND: Previous directional coronary atherectomy (DCA) trials have shown no significant reduction in angiographic restenosis, more in-hospital complications, and higher 1-year mortality than conventional balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). DCA, however, has subsequently evolved toward a more “optimal” technique (larger devices, more extensive tissue removal, and routine postdilation to obtain diameter stenosis 20%). METHODS AND RESULTS: The Balloon vs. Optimal Atherectomy Trial (BOAT) was conducted to evaluate whether optimal DCA provides short- and long-term benefits compared with balloon angioplasty. One thousand patients with single de novo, native vessel lesions were randomized to either DCA or PTCA at 37 participating centers. Lesion success was obtained in 99% versus 97% ( p
0.02) of patients to a final residual diameter stenosis of 15% versus 28% ( p  0.001) for DCA and PTCA, respectively, the latter including stents in 9.3% of the patients. There was no increase in major complications (death, Q-wave myocardial infarction, or emergent coronary artery bypass graft surgery [2.8% versus 3.3%]), although creatine kinase – MB  3  normal was more common with DCA (16% versus 6%; p  0.001). Angiographic restudy (in 79.6% of eligible patients at 7.2  2.6 [median, 6.9] months) showed a significant reduction in the prespecified primary end point of angiographic restenosis by DCA (31.4% versus 39.8%; p
0.016). Clinical follow-up to 1 year showed nonsignificant 13 to 17% reductions in the DCA arm of the study for mortality rate (0.6% versus 1.6%; p
0.14), target vessel revascularization (17.1% versus 19.7%; p
0.33), targetsite revascularization (15.3% versus 18.3%; p
0.23), and targetvessel failure (death, Q-wave myocardial infarction, or target vessel revascularization, 21.1% versus 24.8%; p
0.17). CONCLUSIONS: Optimal DCA provides significantly higher short-term success, lower residual stenosis, and lower angiographic restenosis than conventional PTCA, despite failing to reach statistical significance for reducing late clinical events compared with PTCA with stent backup.

Summary BOAT (Balloon vs. Optimal Atherectomy Trial) was a randomized, comparative clinical study assessing late angiographic and clinical outcomes after directional atherectomy (DCA) vs. percutaneous transluminal coronary angioplasty (PTCA) in 986 patients with focal stenoses in native coronary arteries. BOAT demonstrated that acute lumen results and late angiographical restenosis could be significantly improved by DCA, without a concomitant increase in procedural complications or late cardiac events. Also, DCA resulted in lower rates of restenosis than PTCA. Mortality and Q-wave MI rates were equivalent. The authors hypothesized that DCA had performed poorly in prior trials because inexperienced operators had utilized less than “optimal” technique. In BOAT, larger 7 French devices were used in 95% of procedures and balloon postdilation was performed in 81% of the 486 lesions.

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Citation Count

115

Related References 1. Adelman AG, Cohen EA, Kimball BP, et al. A comparison of directional atherectomy with balloon angioplasty for lesions of the left anterior descending artery. N Engl J Med 1993; 329: 228–233. 2. Bersin RM, Simonton CA. Rotational and directional coronary atherectomy. Catheter Cardiovasc Interv 2003; 58: 485–499. 3. Holmes DR, Topol EJ, Adelman AG, Cohen EA, Califf RM. Randomized trials of directional coronary atherectomy: implications for clinical practice and future investigation. J Am Coll Cardiol 1994; 24: 431–439. 4. Topol EJ, Leya F, Pinkerton CA, et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993; 329: 221–227.

Strengths A clear strength of this trial in contrast to prior direct coronary atherectomy (DCA) trials was the operators’ intention to employ an aggressive “optimal” technique. As a result, the average coronary lumen was larger in BOAT than in CAVEAT.

Weaknesses The authors acknowledge that a conceivable limitation of the study was that atherectomy results might still be suboptimal. Intravascular ultrasound was not utilized routinely; had it been, even more effective plaque debulking could theoretically have been achieved. Another important caveat is that BOAT did not address the value of combining DCA with stenting. Larger lumen gains and lower rates of restenosis can be obtained by deployment of stents alone, and obviate the need for DCA.

Key message Although “optimal” DCA resulted in improved angiographical outcomes with lower rates of restenosis, TVR at 1 year was not statistically different. Also, the rate of peri procedural non-Q-wave MI (defined in BOAT as CK-MB elevation 3 times normal) was more than twice as frequent for DCA vs. for PTCA (16% and 6% respectively, p  0.001). Finally, as mentioned above, the role of provisional DCA in an era of nearly routine stent deployment has not been defined. This issue was to be addressed in a prospective randomized trial, the Atherectomy before Multilink Improves lumen Gain and clinical Outcomes (AMIGO) trial, in which excisional atherectomy combined with stenting will be tested against stenting alone. This trial did not show an overall benefit to debulking prior to stenting except in a few subsets such as bifurcation disease.

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Title 4

Saphenous vein graft angioplasty free of emboli randomized (SAFER) Trial Investigators: randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts Author Baim DS, Wahr D, George B, et al.

Reference Circulation 2002; 105: 1285–1290

Abstract BACKGROUND: Stents provide effective treatment for stenotic saphenous vein bypass grafts, but their placement carries a 20% incidence of procedure-related complications, potentially related to the distal embolization of atherosclerotic debris. We report the first multicenter randomized trial to evaluate use of a distal embolic protection device during stenting of such lesions. METHODS AND RESULTS: Of 801 eligible patients, 406 were randomly assigned to stent placement over the shaft of the distal protection device, and 395 were assigned to stent placement over a conventional 0.014-inch angioplasty guidewire (control group). The primary end point–a composite of death, myocardial infarction, emergency bypass, or target lesion revascularization by 30 days–was observed in 65 patients (16.5%) assigned to the control group and 39 patients (9.6%) assigned to the embolic protection device ( p
0.004). This 42% relative reduction in major adverse cardiac events was driven by myocardial infarction (8.6% versus 14.7%, p
0.008) and “no-reflow” phenomenon (3% versus 9%, p
0.02). Clinical benefit was seen even when platelet glycoprotein IIb/IIIa receptor blockers were administered (61% of patients), with composite end points occurring in 10.7% of protection device patients versus 19.4% of control patients (p
0.008). CONCLUSIONS: Use of this distal protection device during stenting of stenotic venous grafts was associated with a highly significant reduction in major adverse events compared with stenting over a conventional angioplasty guidewire. This demonstrates the importance of distal embolization in causing major adverse cardiac events and the value of embolic protection devices in preventing such complications.

Summary This randomized, multicentre study supports the efficacy of the Medtronic PercuSurge GuardWire for retrieval of plaque debris and prevention of atheromatous embolization in degenerated saphenous vein grafts (SVG). Use of the device during stenting of stenotic venous grafts was associated with significantly fewer major adverse cardiac events (MACE), including death, MI, emergency bypass, or target lesion revascularization at 30 days. Importantly, the Saphenous vein graft angioplasty free of emboli randomized (SAFER) cohort was in fact representative of the typical SVG population; their mean age was 68, about 35% had diabetes; 75% had class III or IV angina, and 40% had rest angina. Target lesion length averaged 16 mm and about 39% of lesions had angiographically noteworthy thrombus.

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Related References 1. Carlino M, De Gregorio J, Di Mario C, et al. Prevention of distal embolization during saphenous vein graft lesion angioplasty. Experience with a new temporary occlusion and aspiration system. Circulation 1999; 99: 3221–3223. 2. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation 2000; 101: 570–580. 3. Webb JG, Carere RG, Vermany R, et al. Retrieval and analysis of particulate debris following saphenous vein graft intervention. J Am Coll Cardiol 1999; 34: 461–467.

Strengths This well-powered randomized study included a “real-world” SVG patient cohort. Additionally, skilled operators performed the interventions under appropriate contemporary pharmacological cover; for instance, nearly 60% of the patients received glycoprotein IIb/IIla inhibitors.

Weaknesses An important initial concern was the reported 35% malfunction rate of the device. It was later reported that the majority of these complications were “minor”, and that results improved as operators gained experience. An original weakness of the trial design was the exclusion of patients with diffuse disease, including only those with relatively simple lesions (a maximum of two lesions within a single SVG which required treatment). Due to slow enrolment, the criteria were amended to include a more representative sample of SVG patients. Acute coronary syndrome patients, however, were not included.

Key message Percutaneous intervention of degenerated SVGs carries a high risk of distal embolization. Potential strategies to prevent or reduce embolization during treatment of SVGs have included extraction or directional coronary atherectomy, laser angioplasty, ultrasound thrombolysis, and intracoronary administration of urokinase. None of these have provided consistent benefit. The PercuSurge device is the first technique associated with a significant reduction in MACE in patients who undergo percutaneous intervention in an SVG. Perhaps more importantly, the SAFER trial underscores the important correlation between atheromatous embolization and adverse cardiac events, which should provide incentive for routine emboli protection during percutaneous intervention of SVGs.

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Title 5

Randomized comparison of distal protection with a filterbased catheter and a balloon occlusion and aspiration system during percutaneous intervention of diseased saphenous vein aorto-coronary bypass grafts Author Stone GW, Rogers C, Hermiller J, et al.

Reference Circulation 2003; 108: 548–553

Abstract BACKGROUND: The high rate of periprocedural complications resulting from atherothrombotic embolization after percutaneous intervention in diseased saphenous vein grafts is reduced by distal microcirculatory protection using a balloon occlusion and aspiration system. Whether filterbased catheters, which offer the inherent advantages of maintained perfusion and ease of use, are as effective for this purpose has not been established. METHODS AND RESULTS: A total of 651 patients undergoing percutaneous intervention of 682 saphenous vein graft lesions were prospectively randomized to distal protection with the filter-based Boston Scientific FilterWire EX versus the Medtronic GuardWire balloon occlusion and aspiration system. Device success was 95.5% and 97.2% with the FilterWire EX and GuardWire, respectively ( p
0.25). Postprocedural measures of epicardial flow and angiographic complications were similar between the 2 groups, although bailout IIb/ IIIa inhibitors were required slightly less frequently in the FilterWire EX group (0% versus 1.5%, p
0.03). The primary end point, the composite incidence of death, myocardial infarction, or target vessel revascularization at 30 days, occurred in 9.9% of FilterWire EX patients and 11.6% of GuardWire patients (difference [95% CI]
1.7% [6.4%, 3.1%]; p for superiority
0.53, p for noninferiority
0.0008). CONCLUSIONS: Distal protection with the FilterWire EX may be safely used as an adjunct to percutaneous intervention of diseased saphenous vein grafts and, compared with distal protection with the GuardWire balloon occlusion and aspiration system, results in similar rates of major adverse cardiac events at 30 days.

Summary Due to the fact that percutaneous coronary intervention (PCI) of diseased saphenous vein grafts (SVG) results in the distal embolization of atherosclerotic debris, a need arose for a device or devices that could protect the distal vessel during PCI from being showered with debris and resulting in periprocedural myocardial infarction (MI). A balloon occlusion and aspiration device, the Medtronic GuardWire, was developed and tested in a multicentre, randomized trial vs. no protection. The result was that the use of the GuardWire led to less periprocedural events and a higher angiographical and clinical success rate. Use of the GuardWire necessitates complete occlusion of the SVG, which has resulted in transient hypotension, angina, and left ventricular dysfunction. A new filter device, the Boston Scientific FilterWire EX, was developed to protect the microcirculation without having the SVG completely occluded. The primary end point was the 30-day composite incidence of major adverse cardiac events (MACE), including death, MI, or target vessel revascularization. A total of 332 patients with

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30 Filter Wire EX Guard Wire

Patients (%)

25 20 15 10 5 0 1

2

3

4

6 5 CK-MB

7

8

9

10

Figure 1 Cumulative frequency distribution curves of peak postprocedural CK-MB for patients randomized to FilterWire EX vs. the GuardWire. Each curve represents the percentage of patients whose CK-MB elevation exceeds the value on the x-axis.

348 grafts were randomized to the FilterWire EX compared to 319 patients with 334 grafts in the GuardWire group. All patients received 325 mg of aspirin and were loaded with either 300 mg of clopidogrel or 500 mg of ticlodipine within 4 h after the procedure. The use of glycoprotein IIb/IIIa inhibitors was left to the individual operator’s discretion. Device success rates for the devices were 95% for the FilterWire and 97% for the GuardWire. There was no statistically significant difference in the end point between the two devices (Figure 1). Postprocedural measures of epicardial coronary blood flow, procedural complications, and postprocedural creatine kinase myocardial band (CK-MB) release were similar between the two groups; however, the use of glycoprotein IIb/IIIa inhibitors for “bailout” was slightly higher in the GuardWire group.

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Strengths This was a well-designed randomized, controlled trial that demonstrated the benefit of using a new distal protection device for PCI of SVGs. This trial showed that the newer filter device was not inferior to the established balloon occlusion and aspiration device.

Weaknesses The trial could potentially expose weaknesses of the GuardWire system, namely the downsides of left ventricle (LV) dysfunction and angina that accompany total occlusion of a diseased SVG while undergoing PCI; however, the trial is not ambitious enough to prove a difference in terms of MI or LV function assessment postprocedure. Instead, they use a composite end point with the goal of being non-inferior.

Key message In a population similar to that used in the trial that established the GuardWire as the standard of care for PCI of SVGs, a new filter device was shown to be as safe and effective ( p for noninferiority
0.0008) as the established balloon occlusion and aspiration system. The benefit of

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Table 1 Procedural outcomes and acceleration index (AI). Circulation 2003; 108: 548–553

Number of patients, Number of lesions Procedure duration* (min) Device success (%) Failure to deliver device Failure to deploy filter Failure to inflate balloon Failure to maintain occlusion, or rupture Clinical success (%) GP IIB/GP IIA inhibitors used before intervention(%) GP IIB/GP IIA inhibitors used during procedure (%) Stents implanted (%) Number of stents implanted per lesion Total length of stents (mm) Maximal device size (mm) Maximal inflation pressure (atm) Reference vessel diameter after procedure (mm) In-stent minimal luminal diameter after procedure (mm) In-stent diameter stenosis after procedure (%) In-lesion minimal luminal diameter after procedure (mm) In-lesion diameter stenosis after procedure (%) TIMI flow post (%) 0/1 2 3 Thrombus (%) Dissection (%) Perforation (%) Distal embolus (%)

FilterWire EX

GuardWire

p

332, 348 59.0  30.5 95.5 3.9 0.6 – – 85.8 51.5 0 98.4 1.2  0.5 23.0  12.1 4.0  0.6 14.9  4.6 3.38  0.72 3.23  0.61

319, 334 62.1  30.3 97.2 0.6 – 0.9 1.2 86.2 53.3 1.5 98.2 1.2  0.6 24.4  13.3 4.2  0.9 13.7  4.7 3.39  0.63 3.21  0.64

– 0.21 0.25 0.005 – – – 0.89 0.65 0.03 0.99 0.14 0.13 0.05 0.03 0.84 0.64

3.3  12.0 2.96  0.63

4.6  13.6 2.91  0.58

0.21 0.36

12.9  9.5

13.7  10.7

0.05

0.3 4.0 95.7 3.1 0.6 0.9 2.5

0 2.3 97.7 6.3 2.3 1.0 2.0

0.99 0.26 0.19 0.06 0.10 0.99 0.79

* Time from arterial puncture to guide catheter removal.

using a distal protection device for PCI of SVG is further proven by this study. For operators concerned with the transient occlusion of a diseased SVG during PCI and the subsequent events that can occur, this trial shows that the non-occlusive filter device can be used with equal efficacy (Table 1).

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Title 6

Randomized comparison of angioplasty of complex coronary lesions at a single center: Excimer laser, Rotational atherectomy, and Balloon Angioplasty Comparison (ERBAC) Study Author Reifart N, Vandormael M, Krajcar M, et al.

Reference Circulation 1997; 96: 91–98

Abstract BACKGROUND: The purpose of this study was to test whether coronary revascularization with ablation of either excimer laser or rotational atherectomy can improve the initial angiographic and clinical outcomes compared with dilatation (balloon angioplasty) alone. METHODS AND RESULTS: At a single center, a total of 685 patients with symptomatic coronary disease warranting elective percutaneous revascularization for a complex lesion were randomly assigned to balloon angioplasty (n
222), excimer laser angioplasty (n
232), or rotational atherectomy (n
231). The primary end point was procedural success (diameter stenosis 50%, absence of death, Q-wave myocardial infarction, or coronary artery bypass surgery). The patients who underwent rotational atherectomy had a higher rate of procedural success than those who underwent excimer laser angioplasty or conventional balloon angioplasty (89% versus 77% and 80%, p
0.0019), but no difference was observed in major in-hospital complications (3.2% versus 4.3% versus 3.1%, p
0.71). At the 6-month follow-up, revascularization of the original target lesion was performed more frequently in the rotational atherectomy group (42.4%) and the excimerlaser group (46.0%) than in the angioplasty group (31.9%, p
0.013). CONCLUSIONS: Procedural success of rotational atherectomy is superior to laser angioplasty and balloon angioplasty; however, it does not result in better late outcomes. The role of plaque debulking before balloon dilatation in percutaneous coronary revascularization remains to be fully defined.

Summary The ERBAC (excimer laser, rotational atherectomy, and balloon angioplasty comparison) study was designed to compare procedural success rate and major in-hospital adverse events in 685 patients randomized to conventional percutaneous transluminal coronary angioplasty (PTCA), excimer laser angioplasty (ELCA) or rotational atherectomy. The trial was conducted at a single centre and included patients with type B or type C de novo stenoses. The patients who underwent rotational atherectomy enjoyed the highest rate of procedural success, but major in-hospital event rates were similar in all three arms. Despite better initial lurnen enlargement, neither ELCA nor rotational atherectomy resulted in reduced rates of restenosis when compared to PTCA. In fact, at 6 months patients who underwent ELCA or rotational atherectomy had significantly more ischaemic complications and higher target vessel revascularization rates than did those who underwent PTCA.

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Citation Count

83

Related References 1. Appelman YEA, Piek JJ, Strikwerda S, et al. Randomised trial of excimer laser angioplasty versus balloon angioplasty for treatment of obstructive coronary artery disease. Lancet 1996; 347: 79–84. 2. Bittl JA, Sanborn TA. Excimer laser-facilitated coronary angioplasty. Relative risk analysis of acute and follow-up results in 200 patients. Circulation 1992; 86: 71–80. 3. Litvack F, Eigler N, Margolis J, et al. Percutaneous excimer laser coronary angioplasty: results in the first consecutive 3,000 patients: the ELCA Investigators. J Am Call Cardiol 1994; 23: 323–329. 4. Stone GW, de Marchena E, Dageforde D, et al. Prospective, randomized, multicenter comparison of laser facilitated balloon angioplasty versus stand-alone balloon angioplasty in patients with obstructive coronary artery disease. The Laser Angioplasty Versus Angioplasty (LAVA) Trial Investigators. J Am Coll Cardiol 1997; 30: 1714–1721.

Strengths The ERBAC study was the first randomized comparison of PTCA with two contemporary alternative techniques. A noteworthy strength of the trial was the inclusion of patients with multivessel disease, and lesions with complex characteristics. Also, clinical follow-up was conducted to 6 months.

Weaknesses The study only enrolled at a single centre, and was unblinded. Follow-up angiography was performed in only 75% of patients. Stents were used only as a bailout option so their use was infrequent, calling into question the value of the results in the contemporary interventional era.

Key message The results of the ERBAC trial challenge the hypothesis that aggressive debulking will result in a lower restenosis and repeated revascularization rate. In general, the use of atheroablative techniques has not consistently translated into improved clinical outcomes. Since both rotational atherectomy and ELCA can increase procedural risk in inexperienced hands, fewer operators in the community use these techniques. Nevertheless, three clinical trials are currently underway to examine potential future applications for ELCA mostly in the periphery, such as the PELA trial of ELCA in occluded superficial femoral arteries, and the LACI trial of ELCA in limb-threatening ischaemia.

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Title 7

Comparison of rotational atherectomy with conventional balloon angioplasty in the prevention of small coronary arteries: results of the Dilatation vs. Ablation Revascularization Trial Targeting Restenosis (DART) Author Mauri L, Reisman M, Buchbinder M, et al.

Reference Am Heart J 2003; 145: 847–854

Abstract BACKGROUND: The optimum treatment of obstructive coronary disease in small (3.0 mm diameter) arteries remains unknown. Rotational atherectomy is an approved treatment that might reduce the vascular injury during percutaneous coronary intervention compared with angioplasty. We report on a multicenter, randomized, blinded end point trial comparing rotational atherectomy with balloon angioplasty in the prevention of restenosis of obstructed, noncalcified small coronary arteries. METHODS: A total of 446 patients with myocardial ischemia associated with an angiographic stenosis in a native coronary artery 2 to 3 mm in diameter and 20 mm in length without severe calcification were randomly assigned to receive rotational atherectomy (n
227) or balloon angioplasty (n
219). The primary end point was target vessel failure at 12 months (defined as the composite of death, Q-wave myocardial infarction, and clinically driven repeat revascularization of the target vessel). RESULTS: The mean reference vessel diameter was 2.46  0.40 mm, the mean lesion length was 9.97  5.59 mm, and the prevalence of diabetes mellitus was 32%. Acute procedural success (91.6% for rotational atherectomy, 94.1% for balloon angioplasty, p
0.36) and target vessel failure at 12 months were not significantly different (30.5% vs 31.2%, p
0.98). At 8 months, there were no significant differences in minimum lumen diameter (1.28  0.63 mm vs. 1.19  0.54 mm, p
0.26), % diameter stenosis (28%  12% vs. 29%  15%, p
0.59), binary restenosis rate (50.5% vs. 50.5%, p
1.0), or late loss index (0.57 vs. 0.62, p
0.7). No Q-wave myocardial infarctions occurred in either arm of the study, and non-Q-wave myocardial infarctions (defined as creatine kinase level 2 times normal with an elevated creatine kinase-myocardial band isoenzyme level) occurred in 2.2% and 1.4% of the patients in the rotational atherectomy and balloon angioplasty groups, respectively ( p
0.72). CONCLUSION: Rotational atherectomy was found to be safe in the treatment of obstructed small arteries, but lower rates of target vessel failure were not achieved compared with balloon angioplasty. Because the acute gain and loss index ratios of the 2 treatments were similar, there was no evident beneficial antirestenosis mechanism seen for rotational atherectomy.

Summary The advent of coronary stenting has led to successful percutaneous intervention of medium to large coronary (3.0 mm) coronary arteries with a reduction in restenosis of 33% compared to balloon angioplasty. The 30–50% of symptomatic coronary lesions in vessels less than 3.0 mm have not been treated as successfully with stenting. The results of prior trials comparing stenting with balloon angioplasty were varied with two of the trials (ISAR-SMART, SISA) showing no advantage to stenting over percutaneous transluminal coronary angioplasty (PTCA). The other

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two trials (BESMART, RAP) showed a modest reduction in restenosis with stenting. The restenosis rates for coronary arteries less than 3.0 mm are between 21% and 47%. Rotational atherectomy has been demonstrated to be a successful debulking device by reducing plaque volume through abrasion as opposed to radial plaque fracture. The DART (dilation vs. ablation revascularization trial) randomized 227 patients to rotational atherectomy and 219 patients to balloon angioplasty. The primary end point was target vessel failure (composite of death, QWMI, clinically driven revascularization of the target vessel) at 12 months. All patients received 325 mg of aspirin, a calcium channel antagonist, and intravenous heparin before the procedure. Intracoronary nitroglycerin was administered before baseline and after intervention angiography. A stepwise approach was employed in the rotational atherectomy group with a recommended burr-to-artery ratio of 0.70–0.85 and platform speeds of 160,000 rpm for burrs 2.0 mm and 180,000 rpm for burrs 2.0 mm. Success rates for rotational atherectomy and PTCA were 92% and 94%, respectively. Thrombolysis in myocardial infarction (TIMI-3) flow was established in 99% of patients in both arms. There was no difference in the end point between the two groups (Figure 1). There was a difference in acute procedural outcomes between the two groups. The rate of dissection (mostly non-flow-limiting type A, B, C) was higher in the PTCA group compared to the rotational atherectomy group (26% vs. 12%, p  0.001). In terms of other angiographical results, there was no statistically significant difference between the two groups in minimum lumen diameter, residual stenosis, acute gain, binary restenosis, or late loss (Table 3).

Freedom from TVF (%)

100 80 60 40 PTCA Rotablator®

20 0 0

30

60

90 120 150 180 210 240 270 300 330 360 Time after initial procedure (days)

Figure 1 Kaplan–Meier curve of survival free from target vessel failure (TVF) (p ⫽ 0.98).

Table 1 Acute Procedural Outcomes (from Mauri et al. Am Heart J 2003; 145: 847–854) Outcome Device success (%) Procedure success (%) TIMI-3 flow (%) Dissection (%) A B C D E F

Rotational atherectomy (n
227)

Balloon angioplasty (n
219)

212 (94) 207 (92) 224 (99) 28 (12) 0 13 (5.7) 13 (5.7) 2 0 0

210 (96) 206 (94) 217 (98) 56 (26) 5 (2.3) 24 (11) 24 (11) 2

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1 (0.2)

p 1 0.36 1 0.001

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3

Key message This trial demonstrates that there is no advantage to using rotational atherectomy instead of balloon angioplasty in non-calcified small coronary arteries. There is a slightly higher (not statistically significant) level of creatine kinase-myocardial band (CK-MB) release associated with rotational atherectomy. The dilemma of how to approach vessels 3.0 mm remains.

Strengths The trial was a well-designed randomized trial of two proven strategies.

Weaknesses The trial compares rotational atherectomy with balloon angioplasty for prevention of restenosis, which are both inferior to stenting. The trial was completed when routine stenting was becoming the norm. In the era of newer stent technology (both bare metal and drug-eluting stents), both of these options would be seen as adjunctive therapy as opposed to a primary strategy.

Relevance The trial compared two different accepted strategies for approaching smaller calibre coronary arteries. As the data on stenting lesions with bare stents in vessels 3.0 mm had been mixed, it was important to compare PTCA to another approach. Rotational atherectomy had been established as a method for debulking lesions, particularly calcified lesions; therefore, the comparison of the two strategies was reasonable. However, in the era of drug-eluting stents, it appears that both rotational atherectomy and PTCA will lose out in favour of newer drug-eluting stent technology.

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Title 8

Cutting balloon angioplasty for the prevention of restenosis: results of the cutting balloon global randomized trial Author Mauri L, Bonan R, Weiner BH, et al.

Reference Am J Cardiol 2002; 90: 1079–1083

Abstract The cutting balloon (CB) is a specialized device designed to create discrete longitudinal incisions in the atherosclerotic target coronary segment during balloon inflation. Such controlled dilatation theoretically reduces the force needed to dilate an obstructive lesion compared with standard percutaneous transluminal coronary angioplasty (PTCA). We report a multicenter, randomized trial comparing the incidence of restenosis after CB angioplasty versus conventional balloon angioplasty in 1238 patients. Six hundred seventeen patients were randomized to CB treatment, and 621 to PTCA. The mean reference vessel diameter was 2.86  0.49 mm, mean lesion length 8.9  4.3 mm, and prevalence of diabetes mellitus in patients was 13%. The primary end point, the 6-month binary angiographic restenosis rate, was 31.4% for CB and 30.4% for PTCA ( p
0.75). Acute procedural success, defined as the attainment of 50% diameter stenosis without in-hospital major adverse cardiac events, was 92.9% for CB and 94.7% for PTCA ( p
0.24). Freedom from target vessel revascularization was slightly higher in the CB arm (88.5% versus 84.6%, log-rank p
0.04). Five coronary perforations occurred in the CB arm only (0.8% versus 0%, p
0.03). At 270 days, rates of myocardial infarction, death, and total major adverse cardiac events for CB and PTCA were 4.7% versus 2.4% ( p
0.03), 1.3% versus 0.3% (p
0.06), and 13.6% versus 15.1% ( p
0.34), respectively. In summary, the proposed mechanism of controlled dilatation did not reduce the rate of angiographic restenosis for the CB compared with conventional balloon angioplasty. CB angioplasty should be reserved for difficult lesions in which controlled dilatation is believed to provide a better acute result compared with balloon angioplasty alone.

Summary In contrast to previous studies, this well-powered, 34-centre randomized trial, conducted in Europe and North America, failed to find a statistically significant difference in rates of angiographical stenosis after cutting balloon (CB) angioplasty as compared to conventional percutaneous transluminal coronary angioplasty (PTCA). The 270-day clinical follow-up major adverse cardiac event rates were also similar. Although the CB angioplasty cohort did have lower target vessel revascularization rates at 270 days, they also had a statistically significant higher incidence of myocardial infarction. Based on these data, one can conclude that CB angioplasty does not significantly reduce the proportional response to injury.

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Related References 1. Barath P, Fishbein MC, Vari S, Forrester JS. Cutting balloon: a novel approach to percutaneous angioplasty. Am J Cardiol 1991; 68: 1249–1252. 2. Ergene O, Seyithanoglu BY, Tastan A, et al. Comparison of angiographic and clinical outcome after cutting balloon and conventional balloon angioplasty in vessels smaller than 3 mm in diameter: a randomized trial. J Invasive Cardiol 1998; 10: 70–75. 3. Izumi M, Tsuchikane E, Funamoto M, et al. Final results of the CAPAS trial. Am Heart J 2001; 142: 782–789. 4. Kondo T, Kawaguchi K, Awaji Y, Mochizuki M. Immediate and chronic results of cutting balloon angioplasty: a matched comparison with conventional angioplasty. Clin Cardiol 1997; 20: 459–463. 5. Roguelov C, Eeckhout E, De Benedetti E, et al., RENO Registry Investigators. Clinical outcome following combination of cutting balloon angioplasty and coronary beta-radiation for in-stent restenosis: a report from the RENO Registry. J Invasive Cardiol 2003; 15: 706–709.

Strengths The obvious strengths of the trial include the size of the cohort, the large number of enrolling centres, and the well-designed trial design allowing for adequate statistical power. Additionally, greater than 80% of patients underwent repeat angiography at 6 months. Prior reports, many of which were smaller and conducted at a single centre, had earlier follow-up angiography rates.

Weaknesses Given the relatively small number of procedural complications, specifically coronary artery perforations (5 for CB, 0 for PTCA), it is difficult to draw any conclusions regarding overall procedural safety of the CB. Also, later reports suggested that the North American cohort may have derived benefit from CB angioplasty via a reduction in restenosis, but this benefit was diluted by the equivocal results seen in Europe. Unfortunately, subset analyses were not included or addressed in the manuscript.

Key message Despite the theoretical mechanistic benefit, supporting clinical data for the use of CB in the primary prevention in restenosis is scarce. Moreover, there is no consensus that suggests CB angioplasty provides greater lumen dimensions than conventional PTCA. Given the advent of newer anti-proliferative technologies such as drug-eluting stents, the role of the CB may become increasingly limited, such as difficult to dilate lesions. The greatest perceived benefit seems to be in the treatment of in-stent restenosis. Recently, a European study noted improved 6-month clinical outcome in patients with in-stent restenosis for CB angioplasty prior to coronary beta-radiation.

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Chapter 8

Anti-thrombotic management in interventional cardiology James Tcheng, Steve Kindsvater Introduction Since the dawn of the interventional age, the need for anti-thrombotic therapy during percutaneous coronary intervention (PCI) has been considered a given. To mitigate the potential for intra-procedural thrombosis, Andreas Gruentzig administered unfractionated heparin in the very first PCI procedure in 1977. Aspirin was recognized as a mainstay of therapy in the early 1980s. Another decade would elapse, however, before systematic evaluations of anti-thrombotic strategies identified new therapeutics that could further improve outcomes of PCI beyond that achieved with aspirin and heparin. Over the past two decades, literally thousands of papers had been authored evaluating antithrombotic therapies in PCI. Most of these reports represent small steps, or in some cases missteps, in the understanding and use of anti-platelet and anti-thrombin agents as adjuncts to PCI. A few studies stand out for their contributions to our understanding of basic principles, or because they resulted in paradigm shifts in our therapeutic strategies. We believe the following papers represent these “best of the best”. Where is the body of evidence today? By coupling the absolutes of molecular science with the powers of observations across hundreds of thousands of patients, our understanding of the anti-thrombotic environment can perhaps best be summarized diagrammatically (Figure 1). There is a complex interplay between the classic coagulation cascade and platelet activity that leads to thrombosis. Interruption of the coagulation cascade (left side of panel) is best accomplished relatively late in the pathway, either by inhibition of factor Xa, the factor Xa–V–calcium complex, or at the level of thrombin. While unfractionated heparin has traditionally been the therapeutic mainstay, both enoxaparin or bivalirudin are in positions to (and arguably should) replace heparin today during PCI. The platelet, on the other hand, turns out to be much more difficult to address (right side of panel). Platelet activity can be divided into four different

Intrinsic, extrinsic pathways

Coagulation cascade

Platelet agonists Aspirin

Plasma clotting cascade

ADP Thromboxane A2

Enoxaparin Unfractional Heparin Fondaparinux

Prothrombin Factor Xa Antithrombin III

Conformational activation of GPIIb/IIIa

Thrombin Bivalirudin Hirudin Argatroban Ximelagatran

Platelet aggregation Fibrinogen Thrombolytics

Figure 1 Sites of anti-thrombotic drug action.

Platelet cascade

Fibrin Thrombus

Ticlopidine Clopidogrel GPIIb/IIIa inhibitors

Anti-thrombotic management in interventional cardiology

functions: adhesion, activation, secretion, and aggregation. Both aspirin and the thienopyridines (ticlopidine and clopidogrel) target pathways that lead to platelet activation (and consequent secretion), and indirectly reduce (but do not eliminate) the capacity of platelets to aggregate. On the other hand, the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers prevent platelet aggregation, but they do not inhibit activation (or secretion). Thus the paradox is that inhibition of the “final common pathway” leading to platelet aggregation (with a GP IIb/IIIa inhibitor) is not sufficient to completely inhibit platelet function; in other words, the elaboration of vasoactive substrates and pro-inflammatory cytokines can occur despite treatment with these powerful agents. So where does this leave us? In the words of baseball great Casey Stengel, “It’s easy to get good players. Getting ’em to play together … that’s the hard part.” Even today, the ideal regimen has not been defined. As many of these agents are costly, and all increase bleeding, each patient must be approached individually. Therapeutic decisions depend on striking a balance among efficacy, safety, and cost/cost-effectiveness. There does not appear to be a single “cookbook” approach that can be universally applied. It would seem appropriate for lower-risk patients (those unlikely to develop a thrombotic complication) to be managed with less aggressive regimens, while higher-risk patients deserve the multifaceted, multiple therapeutic target approach. The direction of future research will thus include the continued development and evaluation of new therapeutics along with efforts to fine tune the inherent complexity of multiple pathways, multiple agents, and multiple opportunities in defining and determining optimal strategies.

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Title 1

Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty Author Califf RM, for the EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications) Study Group

Reference N Engl J Med 1994; 330: 956–961

Abstract BACKGROUND: Platelets are believed to play a part in the ischemic complications of coronary angioplasty, such as abrupt closure of the coronary vessel during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal-antibody Fab fragment (c7E3 Fab) directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. The receptor is the final common pathway for platelet aggregation. METHODS: In a prospective, randomized, double-blind trial, 2099 patients treated at 56 centers received a bolus and an infusion of placebo, a bolus of c7E3 Fab and an infusion of placebo, or a bolus and an infusion of c7E3 Fab. They were scheduled to undergo coronary angioplasty or atherectomy in high-risk clinical situations involving severe unstable angina, evolving myocardial infarction, or high-risk coronary morphologic characteristics. The primary study end point consisted of any of the following: death, nonfatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intraaortic balloon pump for refractory ischemia. The numbers of end-point events were tabulated for 30 days after randomization. RESULTS: As compared with placebo, the c7E3 Fab bolus and infusion resulted in a 35 percent reduction in the rate of the primary end point (12.8 vs. 8.3 percent, p
0.008), whereas a 10 percent reduction was observed with the c7E3 Fab bolus alone (12.8 vs. 11.5 percent, p
0.43). The reduction in the number of events with the c7E3 Fab bolus and infusion was consistent across the end points of unplanned revascularization procedures and nonfatal myocardial infarction. Bleeding episodes and transfusions were more frequent in the group given the c7E3 Fab bolus and infusion than in the other two groups. CONCLUSIONS: Ischemic complications of coronary angioplasty and atherectomy were reduced with a monoclonal antibody directed against the platelet IIb/IIIa glycoprotein receptor, although the risk of bleeding was increased.

Summary The EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) study was a multicentre, randomized, parallel group, placebo-controlled trial of 2099 patients undergoing percutaneous coronary intervention (PCI) who were felt to be at high risk for developing a thrombosis-mediated ischaemic complication. Treatment with a bolus plus infusion of the glycoprotein IIb/IIIa (GP IIb/IIIa) blocker abciximab (ReoPro) reduced the 30-day incidence of major adverse cardiac events (death, myocardial infarction (MI), or urgent revascularization) by 35% (12.8% vs. 8.3%, p
0.009). This was accomplished mainly by a reduction in MI (8.6% vs.

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5.2%, p
0.013), but was accompanied by a doubling in rates of major thrombolysis in myocardial infarction (TIMI) bleeding and blood transfusion requirements.

Citation Count

1223

Related References 1. Gruentzig AR, King III SB, Schlumpf M, Siegenthaler W. Long-term follow-up after percutaneous transluminal coronary angioplasty: the early Zurich experience. N Engl J Med 1987; 316: 1127–1132. 2. Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. N Engl J Med 1992; 326: 10–16. 3. Detre KM, Holmes Jr DR, Holubkov R, et al. Incidence and consequences of periprocedural occlusion: the 1985–1986 national heart, lung, and blood institute percutaneous transluminal coronary angioplasty registry. Circulation 1990; 82: 739–750. 4. Ellis SG, Roubin GS, King III SB, et al. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation 1988; 77: 372–379. 5. Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigators. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. JAMA 1997; 278: 479–484.

Key message In high-risk patients undergoing percutaneous revascularization, potent peri-procedural antiplatelet therapy with the GP IIb/IIIa antagonist abciximab reduces acute ischaemic events, primarily nonfatal MI and urgent repeat percutaneous or surgical revascularization, and this benefit is sustained up to 3 years. This reduction in ischaemic events is achieved at the cost of increased bleeding and need for transfusion.

Why it’s important The EPIC study was the first to demonstrate that the GP IIb/IIIa integrin was a logical clinical target for modulating the thrombosis cascade, and that potent blockade of this receptor during coronary intervention translated into improved clinical outcomes. Furthermore, benefit was imparted across the spectrum of major adverse cardiac events attributable to thrombosis (death, MI, and abrupt closure leading to repeat coronary revascularization). Prior to the EPIC study, acute vessel closure following angioplasty, often a thrombosis-mediated event, was a major cause of patient morbidity and mortality. This was the first major pharmacological breakthrough in PCI, and began the paradigm shift to focus on pharmacotherapies as critical adjuncts to PCI.

Strengths This was a large, well-designed, prospective randomized trial with sufficient power and provided detailed data and results describing the advantages and disadvantages of abciximab therapy as an adjunct to PCI. The study spawned a series of sub-analyses, which further extended the knowledge base for use of this class of drugs.

Weaknesses Patients with either ST elevation acute MI (n
42), or lesions within saphenous vein grafts (n
101) comprised only a small fraction of the trial. Lower-risk patients were excluded from

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the study, reducing the generalizability of the results. Intracoronary stents were placed for “procedural failure” of angioplasty in less than 2%, and the need for a stent was tracked as part of the composite primary endpoint.

Relevance In managing the high-risk patient undergoing PCI, this trial highlighted the central role of platelets in precipitating complications of PCI. The bolus and infusion approach of abciximab, directed against the platelet GP IIb/IIIa receptor, improved procedural success rates and reduced acute ischaemic events. Furthermore, this benefit of abciximab occurred in the setting of concomitant aggressive anticoagulation with unfractionated heparin with pre-specified goals for the activated clotting time (ACT) of 300–350 s. Despite dual anticoagulation and anti-platelet therapy, the rate of intracranial haemorrhage was not increased with the GP IIb/IIIa inhibitor. The results paved the way to acceptance of GP IIb/IIIa blockade as a mainstay of therapy in coronary intervention and the acute coronary syndromes.

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Title 2

Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3 Fab) during percutaneous coronary revascularization Author Lincoff MA, for the PROLOG (Precursor to EPILOG [Evaluation in PTCA to Improve Long-term Outcome with abciximab glycoprotein IIb/IIIa blockade]) Investigators

Reference Am J Cardiol 1997; 79: 286–291

Abstract Blockade of the platelet glycoprotein IIb/IIIa receptor by abciximab (c7E3 Fab) during coronary intervention reduces the incidence of ischemic complications, but has been associated with a doubling of the risk for bleeding complications. The present pilot study investigated whether modification of heparin dosing and/or early sheath removal would reduce the hemorrhagic complications associated with abciximab. One hundred three patients undergoing coronary intervention received abciximab (0.25 mg/kg bolus, 10 mg/min infusion for 12 hours) and aspirin and were randomized in a 2  2 factorial design to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. In the “standard-dose heparin” group, an initial bolus of 100 U/kg was administered to achieve a procedural activated clotting time (ACT) 300 seconds; in the “low-dose heparin” group, an initial bolus of 70 U/kg was administered without adjustment for ACT. In the “late sheath removal” arm, heparin infusion was continued for the 12-hour duration of the abciximab infusion, followed by sheath removal; in the “early sheath removal” group, heparin was stopped after the interventional procedure and sheaths were removed during the abciximab infusion. There were no apparent differences between patients randomized to the different treatment groups with regard to the occurrence of ischemic end points. Rates of bleeding and blood transfusion were reduced by low-dose heparin and early sheath removal and were lowest when both strategies were combined. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention may be useful in diminishing the incidence of hemorrhagic complications without loss of clinical efficacy.

Summary This study was a follow-on to the EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) trial, where a doubling in the rates of major bleeding and blood transfusions were observed with abciximab (ReoPro) treatment during high-risk percutaneous coronary intervention (PCI). In EPIC, bleeding correlated inversely with the activated clotting time and with body weight, which led to the hypothesis that less anticoagulation and/or early sheath removal would reduce bleeding without attenuating the benefits of glycoprotein IIb/IIIa (GP IIb/IIIa) blockade. In a randomized, parallel group, factorial design, 103 patients were randomized to late sheath removal after the completion of a 12 h abciximab and heparin infusion with either low- or highdose procedural heparin, or early sheath removal during the abciximab infusion (without further

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heparin by infusion) with either low- or high-dose procedural heparin. Bleeding complications and a composite endpoint of death, myocardial infarction, or urgent revascularization were tabulated at 7 days. The combined strategy of early sheath removal and low-dose heparin resulted in the lowest rate of bleeding without affecting the composite efficacy endpoint rate.

Citation Count

79

Related References 1. 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: 956–961. 2. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689–1696.

Key message When using abciximab as an adjunct to coronary intervention, rates of bleeding and transfusion can be reduced by a strategy of lower-dose peri-procedural heparin without subsequent heparin by intravenous infusion, along with sheath removal shortly after completion of the procedure.

Why it’s important PROLOG, the pilot study to the larger EPILOG (Evaluation in PTCA to Improve Long-term Outcome with abciximab Glycoprotein IIb/IIIa blockade) study, demonstrated that sheath haemostasis could be achieved while the patient was receiving a continuous infusion of the GP IIb/IIIa blocker abciximab. It provided sufficient evidence that substantially lower doses of heparin could also be safely evaluated in the subsequent EPILOG study.

Strengths This was a small, elegantly designed, prospective randomized pilot study which concisely demonstrated the safety of a strategy of reduced procedural and post-procedural use of heparin coupled with vascular sheath removal shortly after PCI.

Weaknesses This trial was (by design) underpowered to show definitive differences in either efficacy or in haemorrhagic complications, and thus could not be considered definitive despite the compelling trends. The observations required a larger follow-up trial (EPILOG) to confirm the findings.

Relevance Until the PROLOG study was conducted, the interventional community felt it to be heresy to substantially reduce heparin dosing during and after PCI. It was also unclear whether vascular haemostasis could be achieved with full GP IIb/IIIa blockade on board. PROLOG provided sufficient evidence to challenge conventional wisdom. This permitted the clinical trials community to move forward and conduct the definitive EPILOG trial.

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Title 3

Randomized placebo-controlled and balloon-angioplastycontrolled trial to assess the safety of coronary stenting with use of glycoprotein IIb/IIIa blockade Author Topol EJ, for the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) Investigators

Reference Lancet 1998; 352: 87–92

Abstract BACKGROUND: Coronary stenting with the use of heparin, aspirin, and ticopidine for thromboprophylaxis is performed in more than 500,000 patients per year worldwide. We did a randomized controlled trial to assess the role of platelet glycoprotein IIb/IIIa blockade for use in elective stenting. METHODS: At 63 hospitals in the USA and Canada, 2399 patients with ischemic heart disease and suitable coronary artery lesions were randomly assigned stenting plus placebo (n
809), stenting plus abciximab, a IIb/IIIa inhibitor (n
794), or balloon angioplasty plus abciximab (n
796). The primary endpoint was a combination of death, myocardial infarction, or need for urgent revascularization in the first 30 days. All patients received heparin, aspirin, and standard pharmacological therapy. FINDINGS: The primary endpoint occurred in 87 (10.8%) of 809 patients in the stent plus placebo group, 42 (5.3%) of 794 in the stent plus abciximab group (hazard ratio 0.48 [95% CI 0.33–0.69] p  0.001), and 55 (6.9%) of 796 in the balloon plus abciximab group (0.63 [0.45–0.88] p
0.007). The main outcomes that occurred less with abciximab were death and large myocardial infarction –7.8% in the placebo group, 3.0% for stent plus abciximab (p  0.001), and 4.7% for balloon angioplasty plus abciximab (p
0.01). Major bleeding complications occurred in 2.2% of patients assigned stent plus placebo, 1.5% assigned stent plus abciximab, and 1.4% assigned balloon angioplasty plus abciximab (p
0.38). INTERPRETATION: Platelet glycoprotein IIb/IIIa blockade with abciximab substantially improves the safety of coronary-stenting procedures. Balloon angioplasty with abciximab is safer than stenting without abciximab.

Summary By 1996, coronary stenting had been adopted as the desired technique for percutaneous intervention. Standard pharmacological prevention of stent thrombosis included heparin, aspirin, and the thienopyridine ticlopidine. The investigators hypothesized that a platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor, superimposed on standard pharmacological prevention, would further improve outcomes in coronary stenting. In a multicentre, randomized, double-blind, controlled, parallel group trial, 2399 patients were assigned to stenting plus placebo, stenting plus abciximab, or balloon angioplasty plus abciximab. The composite primary endpoint of death, myocardial infarction, or urgent revascularization was tabulated at 30 days. The primary endpoint was lowest in the stent plus abciximab group (5.3%, hazard ratio 0.48, p  0.001) and was also reduced in the balloon angioplasty plus abciximab group (6.9%, hazard ratio 0.63, p
0.007), compared with the stent plus placebo group (10.8%).

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Citation Count

838

Related References 1. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331: 489–495. 2. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331: 496–501. 3. Lincoff MA, Califf RM, Moliterno DJ, for the EPISTENT Investigators. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341: 319–327. 4. Topol EJ, Lincoff AM, Kereiakes DJ, for the EPISTENT Investigators. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization. Am J Med 2002; 113: 1–6.

Key message Even with stent implantation and aggressive anti-platelet therapy including aspirin and a thienopyridine, blockade of the platelet GP IIb/IIIa receptor with abciximab further reduces adverse cardiac events in patients undergoing placement of an intracoronary stent. This is accomplished primarily by reducing rates of death or large myocardial infarction (MI) (defined as new Q waves or creatinine kinase MB fraction greater than five times the upper limit of normal). Furthermore, balloon angioplasty plus abciximab is safer than the strategy of coronary stenting without the use of abciximab.

Why it’s important The BENESTENT and related studies had demonstrated the superiority of coronary stenting over balloon angioplasty primarily due to a reduction in the need for repeat revascularization. However, this benefit had come with a price tag, namely the problem of subacute stent thrombosis, occurring in 1–3% of patients. Furthermore, some in the interventional community did not believe platelet GP IIb/IIIa blockade to be relevant in the setting of stent implantation. EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) was the first to evaluate a GP IIb/IIIa receptor blocker, superimposed on the standard anti-thrombotic therapy, in patients undergoing elective coronary stenting, and demonstrated that abciximab reduced major events by more than 50% without an increase in bleeding complications. Furthermore, among 794 patients who received abciximab with stenting, there were no cases of sub-acute thrombosis. Lastly, the benefits of abciximab persisted at 6 months and at 1 year. A mortality benefit was also demonstrated at 1 year.

Strengths EPISTENT was a well-designed, large, randomized, prospective trial with clearly defined and relevant clinical endpoints. The study addressed an issue of high clinical relevance, namely the utility of GP IIb/IIIa blockade following the paradigm shift from balloon to stent technologies during percutaneous coronary intervention (PCI).

Weaknesses The number of patients undergoing vein graft angioplasty (n
51) was too small for definitive evaluation of this subgroup. Relevance of the MI component of the primary endpoint continues to be debated.

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Relevance Simply put, EPISTENT ushered in a new standard of care for prevention of major adverse cardiovascular events with PCI. Potent anti-platelet therapy with abciximab during coronary stenting or angioplasty reduces the likelihood of patient death or large MI, without causing an excess in bleeding complications.

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Title 4

Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (The PRIDE Study) Author Tcheng JE, Talley JD, O’Shea JC, et al.

Reference Am J Cardiol 2001; 88: 1097–1102

Abstract This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 g/kg bolus followed by a 0.75 g/kg/min infusion; eptifibatide as a 180 g/kg bolus with a 2.0 g/kg/min infusion; or eptifibatide as a 250 g/kg bolus with a 3.0 g/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 M adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone [PPACK]. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8–24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 g/kg bolus followed by a 2.0 g/kg/min infusion at steady state achieved 80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.

Summary In a series of seminal trials in coronary intervention, blockade of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor with abciximab was shown to reduce adverse cardiac event rates by 35–50%. A similar trial of eptifibatide (Integrilin), the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II) trial, showed only a marginal 14–22% benefit. The PRIDE trial was conducted to determine if the in vivo activity of eptifibatide might have been overestimated by the ex vivo assay conditions used to select the eptifibatide doses evaluated in IMPACT-II. Before elective percutaneous intervention, 127 patients were randomized to placebo or one of three combinations of an eptifibatide bolus and maintenance infusion. Samples were assayed for platelet aggregation (anticoagulants: sodium citrate and PPACK), receptor occupancy, and drug concentration. Clinical 30-day endpoints included bleeding complications, death, myocardial infarction, or urgent revascularization. Dose-dependent pharmacodynamics were observed, with citrate anticoagulation exaggerating the anti-platelet effects. The 180 g/kg bolus and 2.0 g/kg/min infusion achieved target

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platelet inhibition, but was associated with an equilibration/volume of distribution dependent transient decrement in inhibition in the 1–4 h time window.

Citation Count

20

Related References 1. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. Lancet 1997; 349: 1422–1428. 2. Phillips DR, Teng W, Arfsten A, et al. Effect of calcium on GP IIb/IIIa interactions with integrilin-enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997; 96: 1488–1494. 3. The PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436–443.

Key message The PRIDE study elegantly demonstrated that sodium citrate interferes with the assay for platelet aggregation in patients undergoing percutaneous coronary intervention (PCI), leading to an overestimation of the in vivo effects of eptifibatide. PRIDE suggested an appropriate dose of eptifibatide to achieve adequate platelet inhibition during the peri-PCI period. The PRIDE study also underscored the critical need for physiologically relevant assay parametres in pharmacodynamic evaluations of agents prior to the design of pivotal clinical trials.

Why it’s important In evaluating eptifibatide as an adjunct to percutaneous intervention, the IMPACT-II trial documented a reduction in the rate of major adverse events by 22% at 30 days. Although statistically significant, the magnitude of the observed benefit was less than expected based upon comparable studies of other GP IIb/IIIa receptor blockers. The PRIDE study revealed that the IMPACTII dose (135 g/kg bolus and 0.75 g/kg/min infusion) fell far short of its target of 80% inhibition of platelet aggregation. Furthermore, PRIDE showed that a 180 g/kg bolus and 2.0 g/kg/min infusion of eptifibatide, as used in the PURSUIT (Platelet IIb-IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial, was similarly inadequate, leading to an early dip below the 80% platelet inhibition benchmark. This led to further modelling of eptifibatide pharmacodynamics, eventually identifying a 180 g/kg double bolus coupled with a 2.0 g/kg infusion as the optimal regimen.

Strengths The PRIDE trial was a classic dose escalation, pharmacodynamic study with a novel twist (multiple anticoagulants and multiple platelet agonists) that assessed the effects of various doses of eptifibatide used in percutaneous intervention.

Weaknesses None of the doses utilized in the PRIDE trial actually achieved the goal of greater than 80% inhibition of platelet aggregation throughout the study period. Further study and computer-assisted modelling was thus required to identify the proper dose. Nonetheless, PRIDE did provide a

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pharmacodynamic blueprint for a sufficiently potent eptifibatide dose which could be used in future trials.

Relevance By demonstrating that the doses utilized in both the IMPACT-II and PURSUIT trials were too low, the PRIDE study underscored the importance of pharmacodynamic modelling. Furthermore, by providing a rationale for the marginal benefits observed in these two trials, PRIDE re-invigorated the debate that the platelet inhibition afforded by GP IIb/IIIa inhibitors might be a class effect.

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Title 5

Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial Author Tcheng JE, for The ESPRIT Investigators

Reference Lancet 2000; 356: 2037–2044

Abstract BACKGROUND: The platelet glycoprotein IIb/IIIa inhibitors, although effective in reducing ischemic complications of percutaneous coronary intervention, are used in few coronary stent implantation procedures. ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) is a randomized, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting. METHODS: We recruited 2064 patients undergoing stent implantation in a native coronary artery. Immediately before percutaneous coronary intervention, patients were randomly allocated to receive eptifibatide, given as two 180 g/kg boluses 10 min apart and a continuous infusion of 2.0 g/kg/min for 18–24 h, or placebo, in addition to aspirin, heparin, and a thienopyridine. The primary endpoint was the composite of death, myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 48 h after randomization. The key secondary endpoint was the composite of death, myocardial infarction, or urgent target vessel revascularization at 30 days. FINDINGS: The trial was terminated early for efficacy. The primary endpoint was reduced from 10.5% (108 of 1024 patients on placebo [95% CI 8.7–12.4%]) to 6.6% (69 of 1040 [5.1–8.1%]) with treatment ( p
0.0015). The key 30-day secondary endpoint was also reduced, from 10.5% (107 of 1024 patients on placebo [8.6–12.3%]) to 6.8% (71 of 1040 [5.3–8.4%]; p
0.0034). There was consistency in reduction of events across all components of the composite endpoint and among the major subgroups. Major bleeding was infrequent but arose more often with eptifibatide than placebo (1.3%, 13 of 1040 [0.7–2.1%] vs. 0.4%, 4 of 1024 [0.1–1.0%]; p
0.027). INTERVENTION: Routine glycoprotein IIb/IIIa inhibitor pretreatment with eptifibatide substantially reduces ischemic complications in coronary stent intervention and is better than a strategy of reserving treatment to the bailout situation.

Summary The ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) Trial evaluated a novel, higher-dose regimen of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blocker eptifibatide (Integrilin) than had been studied in two previous pivotal trials. ESPRIT was a multicentre, randomized, double-blind, parallel group trial that recruited 2064 patients undergoing nonurgent percutaneous coronary intervention (PCI) to placebo or eptifibatide (two 180 g/kg boluses 10 min apart and a 2.0 g/kg/min 18–24 h infusion) in addition to aspirin, unfractionated heparin, and a thienopyridine. Second and third generation stents were deployed in patients in ESPRIT. Endpoints included death, myocardial infarction (MI), and urgent revascularization at 48 h and 30 days, and “bailout” GP IIb/IIIa inhibitor therapy at 48 h. Eptifibatide treatment produced a significant 37% reduction in the 48 h primary endpoint which was maintained to 30 days and 1 year.

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Citation Count

262

Related References 1. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. Lancet 1997; 349: 1422–1428. 2. The PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436–443. 3. Tcheng JE, Talley JD, O’Shea JC, et al. Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study). Am J Cardiol 2001; 88: 1097–1102. 4. Topol EJ, for the EPISTENT Investigators. Randomized placebo-controlled and balloonangioplasty-controlled trial to assess the safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998; 352: 87–92.

Key message The high-dose, double-bolus regimen of eptifibatide in planned coronary stent implantation produced clinically relevant and statistically significant reductions in ischaemic complications. This suggests a dose-dependent class effect to the benefit of platelet GP IIb/IIIa integrin blockade. Also, benefit was observed with eptifibatide therapy despite the relative maturity of stent technologies.

Why it’s important The ESPRIT dosing strategy achieved greater than 90% inhibition of GP IIb/IIIa receptors throughout the dosing period. The lower dose of eptifibatide used in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II) trial (50–60% inhibition) reduced the composite of death, MI, or urgent revascularization from 11.6% to 9.1% (absolute difference

2.5%). In ESPRIT, high-dose eptifibatide reduced the composite endpoint from 10.5% to 6.9% ( 3.6%). Abciximab, the GP IIb/IIIa receptor from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, reduced the composite endpoint from 8.9% to 5.2% ( 3.7%). Taking trial differences into consideration, the findings of the ESPRIT trial are in accord with those of the EPISTENT trial, suggesting a class effect of the GP IIb/IIa receptor blockers.

Strengths The ESPRIT trial was a large scale, well-designed, randomized, placebo-controlled trial.

Weaknesses Emergency intervention patients (such as those with ongoing ischaemia or acute MI) were not included in the trial, nor were patients with a target lesion in a coronary bypass graft. A head-tohead comparison of eptifibatide to abciximab would have further advanced the field.

Relevance Although prior trials had shown a clear benefit of abciximab in PCI, at the time of the ESPRIT trial abciximab was only utilized in 25% of cases, likely secondary to the high costs of this agent. The ESPRIT data suggested that the benefits during coronary stent implantation afforded by eptifibatide are a class effect (provided proper dosing is achieved) of the GP IIb/IIIa receptor blockers. The lower cost of eptifibatide, consequently, has led to this agent’s emergence as the most common drug in its class utilized to improve the safety profile of coronary intervention procedures.

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Title 6

Comparison of enoxaparin versus unfractionated heparin in patients with unstable angina pectoris/non-ST-segment elevation acute myocardial infarction having subsequent percutaneous coronary intervention Author Fox KAA, Antman EM, Cohen M, Bigonzi F, for the ESSENCE/TIMI 11B Investigators

Reference Am J Cardiol 2002; 90: 477–482

Abstract Patients with unstable angina or non-ST-segment elevation myocardial infarction (MI) may undergo invasive revascularization procedures shortly after admission to hospital or after a brief period of stabilization. In the Thrombolysis in Myocardial Infarction (TIMI) 11B trial and Efficacy and Safety of Subcutaneous Enoxaparin in non-Q-Wave Coronary Events (ESSENCE) trial 1326 patients underwent percutaneous coronary intervention (PCI). A total of 924 patients underwent PCI during the initial hospitalization period, and of these, 445 patients did so while receiving treatment with unfractionated heparin (UFH) or the low-molecular-weight heparin, enoxaparin. This analysis compared efficacy and clinical events in the enoxaparin and UFH groups in patients who: (1) underwent PCI while on treatment versus those who did not, and (2) underwent PCI in hospital. We also compared those who did not undergo PCI. Treatment with enoxaparin (1 mg/kg given as twice daily subcutaneous injections) was beneficial and well tolerated in patients with unstable angina and non-ST-segment elevation MI who underwent PCI. Compared with UFH, enoxaparin significantly reduced the likelihood of clinical events (death and nonfatal MI after PCI) in patients who underwent PCI after 1 year (p
0.003 for in-hospital PCI); p
0.005 for on-treatment PCI), with a trend toward a reduced event rate at 43 days. In addition, patients treated with enoxaparin who did not undergo PCI also showed a reduction in the risk of death, nonfatal MI, and urgent revascularization when compared with those treated with UFH (significant at 43 days, with a trend persisting at 1 year). Study limitations were that PCI was nonrandomized, the analysis was post hoc, and the sample size was relatively small. Nevertheless, in the absence of large clinical trials, this study suggests that treatment with enoxaparin was well tolerated, and exhibited a similar risk of major hemorrhage to UFH in patients who underwent PCI.

Summary The authors performed a post hoc, post-randomization meta-analysis of the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in nonQ-Wave Coronary Events (ESSENCE) trials to evaluate enoxaparin vs. unfractionated heparin in patients who underwent percutaneous coronary intervention (PCI) during the initial hospitalization. A total of 924 patients underwent PCI, and 445 of these patients underwent PCI while on treatment with randomized therapy (enoxaparin or unfractionated heparin). Death, myocardial infarction (MI), and urgent revascularization were tabulated at 43 days and 1 year. A 50% reduction in the rate of death or MI was seen at 1 year for those “on therapy”; death or MI occurred in 4.98% (10/201) for enoxaparin vs. 13.11% (32/244) for unfractionated heparin (UFH) ( p
0.005).

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Citation Count

18

Related References 1. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337: 447–452. 2. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. The TIMI 11B Investigators. Circulation 1999; 100: 1593. 3. Young JJ, Keriakes DJ, Grines CL, et al. Low-molecular-weight heparin therapy in percutaneous coronary intervention: the NICE 1 and NICE 4 trials. J Invasive Cardiol 2003; 12(Suppl. E): E14–E18. 4. Ferguson JJ. The use of enoxaparin and IIb/IIIa antagonists in acute coronary syndromes, including PCI: final results of the NICE-3 study. J Am Coll Cardiol 2001; 37(Suppl. A): 365A. 5. Bhatt DL, Lee BI, Casterella PJ, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous intervention. J Am Coll Cardiol 2003; 41: 20–25.

Key message Treatment with enoxaparin is safe and efficacious in patients with unstable angina and nonST-elevation MI who undergo percutaneous intervention. In patients with an acute coronary syndrome, enoxaparin would appear to be at least as good, and perhaps better than heparin as an adjunct to PCI. Interestingly, the benefit of enoxaparin over unfractionated heparin did not become statistically significant until the period between 43 days and 1 year for the composite of death or MI or for the composite of death, MI, or urgent revascularization.

Why it’s important Regarding the pharmacological arsenal of anti-thrombotic agents to facilitate percutaneous intervention, much work has evaluated anti-platelet therapies including the glycoprotein IIb/IIIa inhibitors and the thienopyridines. Studies that directly challenge conventional wisdom that heparin anticoagulation is required are sparse. This post hoc analysis of the ESSENCE and TIMI 11B trials showed that the low-molecular-weight heparin, enoxaparin, was superior to heparin in the prevention of death, MI, or urgent revascularization at 1 year. Furthermore, the clinical efficacy of enoxaparin was achieved without an increase in major or minor haemorrhage.

Strengths The TIMI 11B and ESSENCE trials were the pivotal head-to-head comparisons of enoxaparin and UFH in the treatment of acute coronary syndromes. The meta-analysis of the use of enoxaparin as an adjunct to PCI was powered sufficiently and had adequate long-term follow-up to show meaningful differences in patient outcomes.

Weaknesses This was a retrospective meta-analysis of ESSENCE/TIMI 11B, where only a small percentage of patients underwent percutaneous intervention (13%). There was no randomization to receive or not receive percutaneous intervention, nor was the randomization performed at the time of

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PCI. Also, there was no monitoring of levels of anticoagulation in the enoxaparin arm. The use of heparin during intervention confounded the data in 56 patients who had previously received enoxaparin.

Relevance Various data support the use of low-molecular-weight heparin, particularly enoxaparin, in the medical management of the acute coronary syndromes. As the results of clinical trials emerge in routine clinical practice, cardiologists are ever more frequently confronted with the acute coronary syndrome patient receiving enoxaparin who subsequently require PCI. This analysis provides strong support for the use of low-molecular-weight heparin in percutaneous intervention and “bridges the gap” between the pre-intervention medical therapy of the acute coronary syndrome patient and management of anticoagulant therapy during PCI. Further guidance on this issue awaits the results of ongoing prospective, randomized trials.

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Title 7

Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention (REPLACE-2 randomized trial) Author Lincoff AM, Bittl JA, Harrington RA, et al., for the REPLACE-2 Investigators

Reference JAMA 2003; 289: 853–863

Abstract CONTEXT: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI). OBJECTIVE: To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned GP IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications. DESIGN, SETTING, AND PARTICIPANTS: The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community and referral hospitals in 9 countries from October 2001 through August 2002. INTERVENTIONS: Patients were randomly assigned to receive intravenous bivalirudin (0.75 mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional GP IIb/IIIa inhibition (n
2999), or heparin (65 U/kg bolus) with planned GP IIb/IIIa inhibition (abciximab or eptifibatide) (n
3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. MAIN OUTCOME MEASURES: The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization. RESULTS: Provisional GP IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs. 10% of patients in the heparin-plus-GP IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77–1.09; p
0.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs. 7.1% of patients in the heparin-plus-GP IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90–1.32; p
0.40). Prespecified statistical criteria for non-inferiority to heparin plus GP IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs. 4.1%; p  0.001). CONCLUSIONS: Bivalirudin with provisional GP IIb/IIIa blockade is statistically not inferior to heparin plus planned GP IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.

Summary In balloon angioplasty trials, bivalirudin was shown to have a favourable profile relative to heparin as a substitute anti-thrombin. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE) 2 was designed to test two hypotheses in contemporary stent

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percutaneous coronary intervention (PCI): (1) that bivalirudin would prove superior to heparin in historical controls, and (2) that bivalirudin (with “bailout” use of a glycoprotein IIb/IIIa (GP IIb/IIIa) blocker) would be non-inferior to a combination of unfractionated heparin and a GP IIb/IIIa inhibitor. Patients undergoing PCI were randomized to the bivalirudin with bailout GP IIb/IIIa inhibitor therapy or heparin with planned GP IIb/IIIa inhibitor therapy. Only 7% of patients in the bivalirudin group received “bailout” GP IIb/IIIa inhibitor. All patients received aspirin and 85% were pretreated with a thienopyridine. At 30 days, death, myocardial infarction (MI), urgent revascularization, and major bleeding events were tabulated. There was less bleeding in the bivalirudin arm. Furthermore, bivalirudin was found to be noninferior to unfractionated heparin plus planned GP IIb/IIIa blockade during PCI.

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Related References 1. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: 251–256. 2. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333: 764–769. 3. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ, for the Bivalirudin Angioplasty Study Investigators. Bivalirudin vx heparin during coronary angioplasty for unstable or post-infarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142: 952–959. 4. Antman EM. Should bivalirudin replace heparin during percutaneous coronary interventions? JAMA 2003; 289: 903–905.

Key message The direct thrombin inhibitor bivalirudin is a superior replacement to unfractionated heparin as an adjunct to PCI. Bleeding (both major and minor) is less common with bivalirudin, which makes bivalirudin particularly attractive in PCI patients who are at a high risk for bleeding. The strategy of bivalirudin with “bailout” GP IIb/IIIa inhibitor is non-inferior to the combination of unfractionated heparin plus a GP IIb/IIIa inhibitor in low-to-intermediate risk PCI patients, with the advantage of bivalirudin being imparted with reduced rates of bleeding (but not with improvements in efficacy).

Why it’s important Fundamentally, heparin is not a particularly good anti-thrombin. Also, despite their efficacy, the high cost of GP IIb/IIIa inhibitors and the risk of increased bleeding have limited their widespread use to approximately 50–60% of patients undergoing PCI. The REPLACE-2 trial established bivalirudin as an excellent replacement for heparin during PCI. In lower-risk patients, substitution of bivalirudin for GP IIb/IIIa inhibitors would result in lower rates of bleeding along with cost savings without compromising efficacy. Notably, bivalirudin has not been proven in higher-risk patients, including acute coronary syndrome patients and ST-elevation MI. Nonetheless, bivalirudin is an obvious choice for a PCI patient with heparin-induced thrombocytopenia or who is at high risk for bleeding complications.

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Strengths The REPLACE-2 trial was a well-designed, randomized, non-inferiority trial which established a role for the direct thrombin inhibitor bivalirudin in PCI.

Weaknesses Managing anticoagulation therapy in the pre-PCI hospital phase (where bivalirudin has not been established) with the subsequent use of bivalirudin in the catheterization lab is confusing at best, and was not evaluated in REPLACE-2. Patients enrolled in REPLACE-2 were in lower-risk categories, making the generalizability of the findings less certain. The criteria for non-inferiority was only marginally achieved. Whether additional benefit could be achieved with the combination of bivalirudin plus a GP IIb/IIIa inhibitor is not known.

Relevance The REPLACE-2 trial has resulted in substantial replacement of heparin alone, as well as heparin with a GP IIb/IIIa antagonist, in routine PCI. That unfractionated heparin, the standard of care in PCI for more than 25 years, will ultimately be replaced is not in question. Nonetheless, while bivalirudin is an attractive anticoagulant, additional data needs to be accrued before we will be able to identify the optimal anti-platelet and anti-thrombin cocktail that provides the safest, most efficacious, and most cost-effective approach for the entire spectrum of patients undergoing PCI.

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Title 8

Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Author Mehta SR, Yusuf S, Peters RJG, et al., for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Investigators

Reference Lancet 2001; 358: 527–533

Abstract BACKGROUND: Despite the use of aspirin, there is still a risk of ischemic events after percutaneous coronary intervention (PCI). We aimed to find out whether, in addition to aspirin, pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI. METHODS: 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been randomly assigned double-blind treatment with clopidogrel (n
1313) or placebo (n
1345). Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission, and for a median of 10 days overall. After PCI, most patients (80%) in both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or urgent target-vessel revascularization within 30 days of PCI. The main analysis was by intention to treat. FINDINGS: There were no drop-outs. 59 (4.5%) patients in the clopidogrel group had the primary endpoint, compared with 86 (6.4%) in the placebo group (relative risk 0.70 [95% CI 0.50–0.97], p
0.03). Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularization ( p
0.03), and of cardiovascular death or myocardial infarction ( p
0.047). Overall (including events before and after PCI) there was a 31% reduction in cardiovascular death or myocardial infarction ( p
0.002). There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group ( p
0.001). At follow-up, there was no significant difference in major bleeding between the groups ( p
0.64). INTERPRETATION: In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo.

Summary Ischaemic events following percutaneous coronary intervention (PCI) are largely plateletmediated adverse outcomes which are only partially attenuated by aspirin therapy. The authors hypothesized that clopidogrel, a thienopyridine anti-platelet agent, given prior to PCI (and continued long term) in addition to aspirin, would be superior to placebo in preventing major ischaemic events. The PCI Clopidogrel in Unstable angina to prevent Recurrent Events (PCI-CURE) analysis was a post hoc, post-randomization analysis of acute coronary syndrome patients undergoing PCI in the CURE study. Enrollees were treated with aspirin and randomized to either pre-treatment with clopidogrel or placebo for a mean of 6 days prior to PCI. Open-label clopidogrel was given

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for the first 4 weeks after PCI, and then the initial randomization resumed. Endpoints included cardiovascular death, myocardial infarction (MI), urgent revascularization, and bleeding at 30 days and at study termination (mean 8 months). Randomization to clopidogrel treatment was associated with a 30% reduction in adverse cardiac events through the end of the follow-up period.

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Related References 1. Clopidogrel in Unstable angina to prevent Recurrent Events (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. 2. Steinhubl SR, Ellis SG, Wolski K, et al. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events: data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial. Circulation 2001; 103: 1403–1409. 3. Chew DP, Bhatt DL, Sapp S, et al. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001; 103: 201–206. 4. Mehta SR, Yusuf S, for the CURE Investigators. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme: rationale, design, and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000; 21: 2033–2041. 5. Bhatt DL, Bertrand ME, Berger PB, L’Allier PL. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002; 39: 9–14.

Key message In high-risk acute coronary syndrome patients without ST-segment elevation MI, pretreatment with clopidogrel prior to PCI followed by long-term clopidogrel treatment reduces the 1-month and 1-year risk of cardiovascular death or MI by about 30%. The benefit observed with clopidogrel begins early after the initiation of treatment, and it continues to widen with prolonged clopidogrel therapy up to 8 months following PCI. Furthermore, clopidogrel had no adverse effect on major bleeding.

Why it’s important The PCI-CURE study was designed to test the value of clopidogrel in the context of a conservative approach to the management of patients with a non-ST-elevation acute coronary syndrome who subsequently require PCI. In fact, the use of glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers was discouraged, and centres routinely pursuing a strategy of early angiography were excluded from the trial. The PCI-CURE trial, however, extended the indication of clopidogrel by showing that the benefit derived from clopidogrel – mainly a reduction in myocardial infarction – was measurable very early after initiation of therapy (before PCI), with further benefits achieved even months after PCI.

Strengths The PCI-CURE study was a well-designed trial which supports the use of clopidogrel in acute coronary syndrome patients initially managed with a conservative approach who subsequently require a PCI.

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Weaknesses This was a post hoc, post-randomization analysis. No information was provided on patients who subsequently required surgical revascularization. The long wait prior to PCI in the trial does not reflect the growing validated practice for early angiography and intervention; thus this study should not be construed as an argument for early treatment in all patients. Still unanswered is the efficacy of clopidogrel initiated “on the table” in ad hoc PCI procedures. Furthermore, the use of GP IIb/IIIa receptor blockers, a proven therapy in the patient population studied in PCICURE, was largely ignored.

Relevance The key implications of the PCI-CURE data relate to the timing of the start and particularly the subsequent length of clopidogrel therapy. However, the scope and applicability of the PCICURE study are limited by the fact that data are derived from a large, simple drug trial focused on the conservative management of acute coronary syndrome patients. The trial ignored the important and growing role of GP IIb/IIIa inhibitors, the fact that some form of clopidogrel treatment prior to PCI was already the norm, and the excess bleeding associated with clopidogrel when cardiac surgery is indicated. Nevertheless, in many medical centres (particularly outside of the USA) where a conservative approach is preferred and GP IIb/IIIa agents are less often utilized, the PCI-CURE approach may be quite applicable.

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Title 9

Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial Author Steinhubl SR, Berger PB, Mann JT, for the Clopidogrel for the Reduction of Events During Observation (CREDO) trial Investigators

Reference JAMA 2002; 288: 2411–2420

Abstract CONTEXT: Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied. OBJECTIVES: To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy. DESIGN, SETTING, AND PARTICIPANTS: The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001. INTERVENTIONS: Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (1053) or placebo (n
1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. MAIN OUTCOME MEASURES: One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population. RESULTS: At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9–44.4%; p
0.02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, 14.2% to 41.8%; p
0.23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, 1.6% to 62.9%; p
0.051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; p
0.07). CONCLUSIONS: Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.

Summary Clopidogrel reduces rates of thrombotic complications after stent percutaneous coronary intervention (PCI), but the optimal timing of initiation of therapy and the length of therapy remained

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unclear. The Clopidogrel for the Reduction of Events During Observation (CREDO) trial was a multicentre, randomized, controlled trial that evaluated a loading dose (300 mg) given 3–24 h prior to PCI coupled with prolonged therapy (1 year) following PCI. Patients received both the clopidogrel loading dose and prolonged therapy or placebo. All received aspirin and clopidogrel in the 4 weeks following PCI. At 28 days and 1 year, the endpoints of death, myocardial infarction (MI), stroke, and urgent revascularization were tabulated. At 28 days, there was only a marginal efficacy favouring clopidogrel pre-treatment. By 1 year, however, the composite of death, MI, and stroke was reduced by 27%. There was a strong trend to benefit with 6 h of pretreatment, but ad hoc treatment was not evaluated. These benefits were accomplished without an increase in bleeding risk.

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Related References 1. Steinhubl SR, Lauer MS, Mukherjee DP, et al. The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions. J Am Coll Cardiol 1998; 32: 1366–1370. 2. Steinhubl SR, Ellis SG, Wolski K, et al. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events: data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial. Circulation 2001; 103: 1403–1409. 3. Mehta S, Yusuf S, Peters R, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527–533. 4. Muller I, Seyfarth M, Rudiger S, et al. Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001; 85: 92–93.

Key message The CREDO trial demonstrated that continuation of dual anti-platelet therapy with aspirin and clopidogrel for at least 1 year was associated with significant, clinically relevant decreases in thrombotic events. Interestingly, most of the benefit accrued after the first month of the trial. The longterm combination of aspirin and clopidogrel was safe. The CREDO trial did not support the routine administration of a 300 mg loading dose of clopidogrel given between 3 and 24 h prior to PCI. However, clopidogrel “loading” may be beneficial when the dose can be administered more than 6 h prior to PCI.

Why it’s important Despite the lack of rigorous data supporting pretreatment with clopidogrel, prior to the CREDO trial, a patient often proceeded directly from diagnostic angiography to intervention (particularly in the USA), receiving a 300 mg loading dose of clopidogrel at the time of PCI. The CREDO trial suggests that efficacy can be improved by treatment as far ahead in advance as possible relative to the time of PCI. More importantly, however, the real benefit of clopidogrel treatment is imparted with longer-term therapy; outcomes at 1 month were only marginally improved by pre-treatment.

Strengths The CREDO trial was a well-designed, blinded, randomized trial which had a major impact on the management of anti-platelet therapy in the PCI patient.

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Weaknesses Higher pretreatment loading doses (600 mg) were not studied. No conclusions can be drawn from CREDO regarding a potential concomitant benefit of adding a glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor to patients already adequately pretreated with clopidogrel. Still unanswered is the relative efficacy of “on the table” treatment, or post-PCI treatment with a loading dose, in ad hoc cases; in the control arm, only 75 mg of clopidogrel (without a loading dose) was given after PCI. Future trials should help to clarify the relative roles of clopidogrel and glycoprotein IIb/IIIa inhibitors as being complementary or duplicative during PCI.

Relevance The CREDO trial provided cardiologists with a guideline for anti-platelet therapy in PCI patients. It argues strongly for long-term treatment following PCI. For cardiology practices where intervention immediately follows angiography, the CREDO trial supports the role of the more immediate action of intravenous glycoprotein IIb/IIIa inhibitors during PCI, since the effects of clopidogrel in PCI seem to require at least 6 h following a loading dose. On the other hand, when the delay between angiography and intervention is prolonged, clopidogrel “loading” reduces thrombotic events. The critical finding remains, however, that long-term therapy following PCI with both aspirin and clopidogrel is warranted to improve cardiovascular outcomes.

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Chapter 9

Coronary artery bypass grafts in the era of percutaneous coronary angioplasty Thanos Athanasiou, Brian Glenville Introduction It seems a very long time ago that important stenoses of the coronary arterial tree, which were symptomatic and not controlled by medical management were automatically referred for surgical revascularization by coronary artery bypass grafting (CABG). The data that came through from the early trials of surgery vs. medical management also made us realize that that left main stem was prognostic regardless of symptomatology. That situation lasted for some 20 years. During those golden years for coronary surgeons and their patients, the results rapidly improved and the benefits became even clearer for all to see. Conduit choices were influenced by the enormous benefit that the left internal mammary artery conferred to the patient as clearly demonstrated by Loop. Different conduits, namely the right internal mammary, the gastroepiploic artery, the inferior epigastric and the latest version, the radial artery, have had their proponents. They were enthusiastically received and then underwent critical review. It is of interest that the latest fashion with the radial artery may, in the presence of statins, prove to be identical in 5-year graft survival to saphenous vein. There are increasing numbers of physicians forecasting the complete demise of the operation of CABG. Time will tell, but there are currently cardiac units in the British National Health Service, that had 1 year waiting lists who currently quote times from referral to operation in hours! This predicted demise of the speciality might be thought as unprecedented in the history of cardiothoracic surgery. They are wrong! In the late 1950s, antibiotics and improved housing conditions caused the rapid fall in the requirement for tuberculosis surgery. The surgeons who performed the operations including thoracoplasty, were highly skilled and produced fabulous results for their time. When their services were no longer required, cardiac surgery was evolving and it was anticipated that that these gifted surgeons would just move across and learn a new set of tricks. In fact remarkably few made the transition successfully and those outstanding thoracic surgeons either retired or stuck to lung cancer work. Another revolution came with the advent of coronary surgery. The skills that made excellent valve surgeons and reconstructive congenital surgeons were different to the more “vascular” type skills needed for good patency rates of the saphenous vein or the internal mammary artery. The surgeons who trained in the early 1980s will be familiar with the request of a number of their valve surgeon bosses to finish off the list, i.e. they did the valves and you did the bypass grafts. If the predictions are right, what will the coronary surgeons of today be doing tomorrow? Some will wait it out and cope with the diminishing numbers, some will retire and some, the minority, will reinvent themselves. That said, the story is not over yet and the promise of the drug eluting stents may not be as giant in actuality. We live, as the Chinese say, in interesting times. This chapter details many of the salient articles that helped to define the respective roles of angioplasty and surgery. The goal posts keep moving for both specialities as stenting and other catheter-based techniques improve for the cardiologists and beating heart surgery, and enhanced

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cardiac anaesthetic techniques and drugs help the surgical cause. All techniques have an unwanted complication rate and competition is one of the driving factors causing us to strive to reduce them. For instance, beating heart surgery, may be the single most important development in reducing the psychoneurological morbidity that can occur during CABG. One fundamental question that is much more difficult to answer is, whether a treatment modality that can be technically performed, should be performed; is it in our patients’ best long-term interests. The eight papers that we have selected have not always been the milestone publications along that decision tree. They may not even have been the sentinel papers at the time of publication but they served to clarify the perspective for both physicians and surgeons. Physicians and surgeons in the field will be well aware and have read the “famous” papers, such as randomised intervention treatment of angina (RITA) and Common Access to Biotechnological Resources and Information (CABRI). Papers like these, although heavily cited, can become dogma without full justification. They may either have come from well-known centres and wellknown practitioners, and have been less critically viewed even by experienced peer review systems. By positioning surgery and angioplasty head to head (an entirely appropriate thing to do), we force ourselves into a competitive arena that may lose some of that perspective. We should be viewing both revascularization strategies as complementary, selecting the right treatment for the right patient at the right time. We have tried to pick out eight papers, some of them with major design faults, but that have illustrated the right questions to be asked. Not all of the papers have provided a robust answer but together with the related references, we hope will provide the reader with a broad view. Patients and their doctors should realize that angioplasty may only be a temporizing technique before bypass grafts (which is also not a cure for coronary artery disease) and that patients who start with surgery may well require angioplasty to correct graft attrition or new native disease.

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Title 1

Percutaneous coronary intervention versus coronary bypass graft surgery for diabetic patients with unstable angina and risk factors for adverse outcomes with bypass the VA AWESOME multicentre registry: comparison with the randomised clinical trial Author Sedlis SP, et al.

Reference J Am Coll Cardiol 2002; 40: 1555–1566

Abstract OBJECTIVES: This study compared survival after percutaneous coronary intervention (PCI) with survival after coronary artery bypass graft surgery (CABG) among diabetics in the Veterans Affairs AWESOME (Angina With Extremely Serious Operative Mortality Evaluation) study randomized trial and registry of high-risk patients. BACKGROUND: Previous studies indicate that CABG may be superior to PCI for diabetics, but no comparisons have been made for diabetics at high risk for surgery. METHODS: Over five years (1995 to 2000), 2,431 patients with medically refractory myocardial ischemia and at least one of five risk factors (prior CABG, myocardial infarction within seven days, left ventricular ejection fraction 0.35, age 70 years, or an intra-aortic balloon being required to stabilize) were identified. A total of 781 were acceptable for CABG and PCI, and 454 consented to be randomized. The 1,650 patients not acceptable for both CABG and PCI constitute the physician-directed registry, and the 327 who were acceptable but refused to be randomized constitute the patient-choice registry. Diabetes prevalence was 32% (144) among randomized patients, 27% (89) in the patient-choice registry, and 32% (525) in the physician-directed registry. The CABG and PCI survival rates were compared using Kaplan-Meier curves and log-rank tests. RESULTS: The respective CABG and PCI 36-month survival rates for diabetic patients were 72% and 81% for randomized patients, 85% and 89% for patient-choice registry patients, and 73% and 71% for the physician-directed registry patients. None of the differences was statistically significant. CONCLUSIONS: We conclude that PCI is a relatively safe alternative to CABG for diabetic patients with medically refractory unstable angina who are at high risk for CABG.

Summary The AWESOME was a nationwide, prospective, randomized-clinical trial designed to compare coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) survival for patients with medically refractory unstable angina and at high risk of adverse outcomes with CABG. The difficulties of enrolling patients into such an ambitious study are well demonstrated in this paper; 2431 suitable patients were identified, of these 781 were acceptable for CABG and PCI but only 454 consented to be randomized. Previous studies showed a significant survival benefit for CABG at 5 years in treated diabetics. However, PCI has improved with stents and glycoprotein IIb/IIIa inhibitor drugs. The methods of the study are well described including the outcomes of patients who refused to be randomized to the study but were included in a registry. This paper reports the outcomes of the high-risk diabetic patients in the setting of a randomized-clinical trial.

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The conclusions show no survival advantage with CABG. Diabetes is associated with adverse outcomes for both CABG and PCI. It does show a reduction in recurrent angina and need for further revascularization in the surgical group vs. PCI. The article focuses on the important differences between its own trial design and the bypass angioplasty revascularization investigation (BARI) study and suggests reasons for the differing outcomes. It suggests that at least 50% of the survival benefit for CABG in diabetic patients could be explained by a lower mortality during Q-wave myocardial infarction (MI). The survival benefit was almost entirely limited to patients who received at least one internal artery graft. The paper concludes with other differences with other studies and their possible theoretical and therapeutic implications. It also outlines newer trials, using more advanced techniques and explains why some of them will be useful and others, which by nature of their patient inclusion criteria cannot be used for comparison or extrapolation.

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7

Related References 1. Morrison DA, Sethi G, Sacks J, et al. A multicenter, randomized trial of percutaneous coronary intervention versus bypass surgery in high-risk unstable angina patients. Controlled Clin Trials 1999; 20: 610–619. 2. Morrison DA, Sethi G, Sacks J, et al. Percutaneous coronary intervention versus coronary artery bypass graft surgery for patients with medically refractory myocardial ischemia and risk factors for adverse outcomes with bypass: a multicenter randomized trial. J Am Coll Cardiol 2001; 38: 143–149. 3. BARI investigators. Comparison of coronary artery bypass graft surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996; 335: 217–225.

Key message Surgery provides similar survival but less recurrent angina and less need for repeat revascularization in high-risk patients with diabetes and unstable angina.

Why it’s important There are many trials comparing CABG and PCI in similar settings but this paper focuses on the subset of diabetic patients who were at higher risk at surgery. Trials like BARI have not addressed this type of patient population.

Strengths Despite the inherent difficulties of patient recruitment in the setting of unstable angina and predicted high risk of adverse outcome of surgery, this was a prospective randomized trial and registry.

Weaknesses The paper produces 36 months’ data and was worth publishing at that point. Ischaemic heart disease is nonetheless progressive and most other studies demonstrate a diminution of effect of surgery with time. Therefore, a longer follow-up time will make this study more important and relevant for decision-makers in health care.

Relevance The authors have concentrated on difficult but real clinical dilemmas. We need answers to patients who are unstable, diabetic and predicted high adverse risk at surgery.

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Title 2

Clinical impact of drug-eluting stents in changing referral practices for coronary surgical revascularisation in a tertiary care center Author Ferreira AC, Peter AA, Salerno TA, et al.

Reference Ann Thorac Surg 2003; 75: 485–489

Abstract BACKGROUND: The long-term benefits of angioplasty are limited by the occurrence of restenosis. Drug-eluting stents with a projected restenosis rate of close to 0% are soon to become available. The short- and long-term consequences of this advance to the cardiac surgical volume remain unclear. METHODS: A total of 196 consecutive coronary angiograms and medical records of patients referred for coronary bypass surgery were reviewed. Considering the hypothetical premise of having drug-eluting stents with a near zero restenosis rate, we reviewed each case to determine if surgical revascularization was still the preferred option for revascularization. RESULTS: The mean age was 60 (10.6) years. Seventy-two percent of patients were male. Considering the availability of drug-eluting stents 154 (79%) would still have been sent to surgery, representing a 21% decrease in the number of surgical revascularizations. Angiographic characteristics predicting coronary bypass revascularization were the presence of chronic total occlusion (odds ratio [OR]: 9.1; confidence interval [CI]: 2.1 to 39), left main coronary artery stenosis (OR: 9.6; CI: 1.27 to 73), and need for valvular surgery (OR: 7.38; CI: 1.3 to 157). The most common predictors of a change in clinical management from surgical to percutaneous revascularization if drug-eluting stents were available were diffuse coronary narrowing (OR: 15.78), restenotic lesions (OR: 27.86), and small coronary arteries (OR: 26). CONCLUSIONS: Drug-eluting stents may have a significant impact on cardiac surgery volume (approximately a 21% decrease in our center). It may also direct patients with small vessels, diffuse narrowing, or restenotic lesions and diabetic patients to percutaneous therapy.

Summary This paper sets out to try and predict the changing surgical referral practice in the setting of better results from percutaneous coronary intervention (PCI) with drug eluting stents. The authors took 196 consecutive coronary angiograms and medical records of patients referred for coronary artery bypass grafting (CABG) to a centre by two interventional cardiologists. Having referred these patients for surgery, the cardiologists when then asked to reassess their decisionmaking, now assuming that drug eluting stents would produce a near zero restenosis rate. Each physician was also asked to state the main reason why surgical revascularization was chosen over PCI. Total coronary occlusion, left main stenosis, ejection fraction less than 25%, small coronary arteries, diffuse narrowings, lesion complexity, proximal vessel tortuosity, angioplasty failure or the need for combined surgical procedure such a valvular surgery were all accepted reasons for surgical preference.

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The results showed a 21% decrease in surgical referral. If combined surgical procedures patients were excluded, the decrease was 24.5%. Clinical characteristics did not predict significant utilization of coated stents. Only a history of left ventricular dysfunction predicted the use of surgical revascularization even if coated stents had been available. The presence of left main disease (19.5%), chronic total occlusion (31.8%) and combined valvular surgery (12.8%) did predict referral for surgery despite the presumed availability of coated stents. The authors state that interventional cardiologists throughout the USA are predicting a 50% decrease in surgery, which is more than twice the authors’ presumptive projections. They go on to say that the concern for restenosis is only one of many reasons for referring patients for surgical revascularization. The authors believe that their reduction will only be 21–25% and that characteristics, such as diffuse disease, chronic occlusion and complex anatomy still limit the PCI approach, and that these problems will not be solved by drug eluting stent technology alone. They conclude that the impact of drug eluting stents may well be less than commonly predicted by some interventionists. It may also direct more patients with small vessels, diffuse narrowing or restenotic lesions and diabetic patients to PCI. Time will of course tell!

Citation Count

10

Related References 1. Schunkert H, Harrell, L, Palacios, IF. Implications of small reference vessel diameter in patients undergoing percutaneous coronary revascularization. J Am Coll Cardiol 1999; 34: 40–48. 2. Holmes DR, Hirshfield J, Faxon D, et al. ACC expert consensus document on coronary artery stents. J Am Coll Cardiol 1998; 32: 1471–1482.

Key message The advent of drug eluting stents and the promise of close to zero restenosis will cause a predicted reduction of around 20% reduction in surgical referrals.

Why it’s important There is a major health care planning requirement to predict future trends for ischaemic heart disease. This could have a major impact on planning for both surgical centres and catheter-based facilities. It will also have a major effect on attracting trainees into the two specialities and the provision of training posts.

Strengths An imaginative paper trying to address the need to predict surgical volumes for the next few years. Using a setting of “high-volume” interventional cardiologists as their reference point is a good attempt to replicate standard clinical practice.

Weaknesses It remains a theoretical paper. It is based on assumptions including automatic referral for left main stem disease that will not be universally accepted. The authors do admit that this indication may change. Another assumption is a near zero restenosis rate; current data suggests this

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may be closer to 10%. Further the poorer “trackability” of the drug eluting stents may make deployment in the circumflex territory more challenging in the immediate future. The reasons for referral for PCI or CABG are from a centre, which may not be fully representative of other practice. The authors themselves highlight this potential weakness.

Relevance The issue of the balance between PCI and CABG is probably the single most current surgical consideration. How this balance actually pans out will have dramatic consequences for patients and providers. It will be fascinating to see how accurate the authors’ prediction will be. We think the changes will be much more dramatic than a 20% reduction.

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Title 3

Clinical and economic outcomes of multi vessel coronary stenting compared with bypass surgery: a single-center US experience Author Reynolds MR, Neil N, Ho KKL, et al.

Reference Am Heart J 2003; 145: 334–342

Abstract BACKGROUND: Randomized trials comparing multivessel stenting with coronary artery bypass surgery (CABG) have demonstrated similar rates of death and myocardial infarction but higher rates of repeat revascularization after stenting. The impact of these alternative strategies on overall medical care costs is uncertain, particularly within the US health care system. METHODS: We performed a retrospective, matched cohort study to compare the clinical and economic outcomes of multivessel stenting and bypass surgery. The stent group consisted of 100 consecutive patients who underwent stenting of 2 major native coronary arteries at our institution. The CABG group consisted of 200 patients who underwent nonemergent isolated bypass surgery during the same time frame, matched (2:1) for age, sex, ejection fraction, diabetes mellitus, and extent of coronary disease. Detailed clinical follow-up and resource utilization data were collected for a minimum of 2 years. Total costs were calculated by use of year 2000 unit prices. RESULTS: Over a median follow up period of 2.8 years, there were no significant differences in all-cause mortality rates (3.0% vs 3.0%), Q-wave myocardial infarction (5.1% vs 4.0%), or the composite of death or myocardial infarction (7.1% vs 7.0%) between the stent and CABG groups ( p
not significant for all comparisons). However, at 2-year follow up, patients with stents were more likely to require 1 repeat revascularization procedure (32.0% vs 4.5%, p  .001). The initial cost of multivessel stenting was 43% less than the cost of CABG (11,810 dollars vs 20,574 dollars, p  .001) and remained 27% less (17,634 dollars vs 24,288 dollars, p
.005) at 2 years. CONCLUSIONS: Multivessel stenting and CABG result in comparable risks of death and myocardial infarction. Despite a higher rate of repeat revascularization, multivessel stenting was significantly less costly than CABG through the first 2 years of follow-up.

Summary Keeping up with trials with the latest stents, the latest drug therapy or the latest surgical improvement is difficult. When a study is actually published in a journal, the inherent delay in the system means that clinical practice has often moved on. To some extent one can extrapolate costs knowing material costs and predicted outcomes but this is not substitute for actual studies. This is the first paper to look at the economic costs after stenting was widely introduced and glycoprotein IIb/IIIa inhibitors were used. Dated 2002, it is before the advent of drug eluting stents. The authors start by delineating some of the above medical changes but also make the point that although bypass surgery may have undergone less radical change, the US health care system and economic pressures have led to the development of critical pathways and quality improvement initiatives that have resulted in dramatic reductions in the length of stay and therefore hospital costs.

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The authors refer to three randomized trials comparing multi-vessel stenting with bypass surgery (see Related References). These were non-US studies and short-term results. This paper attempts to address these points by performing a retrospective, matched cohort study comparing long-term clinical and economic outcomes of coronary stenting with bypass surgery for the treatment of multi-vessel coronary disease within the US health care system. It consisted of 100 consecutive patients who underwent stenting of at least two native coronary arteries. They were matched for age, sex, ejection fraction, diabetes and extent of coronary disease, with 200 patients undergoing elective coronary artery bypass grafting (CABG). The study found that multi-vessel stenting and bypass surgery resulted in similar rates of death and major myocardial infarction (MI) over a median follow-up of nearly 3 years. These clinical findings are consistent with most previous randomized trials over follow-up periods ranging from 1 to 8 years. The study reported that repeat revascularization was more frequent among patients undergoing multi-vessel stenting and these results are broadly in line with previously published data. However, the authors found that although follow-up medical care costs were higher with stenting, after 2 years, overall medical costs remained around $6500 lower with stenting than with bypass surgery, a relative reduction of 27%. The authors wrote extensively on the attempts to compare their findings with other published series. They concluded that economic data from their study are not directly comparable to any previous study. One important factor that confounds comparison is the dollar exchange rate. Length of stay, medical infrastructure, reimbursement mechanisms, other practice patterns and cultural factors may all be factors that would be capable of materially changing the outcome of direct comparison. Differences from previous studies also extended to the time frame encompassed by the analysis. Randomized trials tabulated medical care costs beginning with the performance of the index revascularization procedure. This is appropriate for a randomized trial structure but not for observational studies where “ad hoc” procedures and timings will frequently occur. The authors argue that removing these ad hoc procedures will systematically underestimate the cost savings that could be achieved by percutaneous coronary intervention (PCI). The savings that the authors identified amounted to a significant $2500. These differences are crucial to their findings and an important discussion point. Nonetheless, whether these differences are indeed more relevant to a clinical situation is not unequivocally proven in this study. The authors conclude that larger studies will be necessary to determine whether specific patient subgroups will benefit from one or the other form of revascularization. In addition longer periods of follow-up are necessary to see of the costs–benefits that this paper has indicated with PCI extend beyond 2 years.

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5

Related References 1. Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 2001; 344: 1117–1124. 2. Rodriguez A, Bernardi V, Navia J, et al. Argentine randomised study: coronary angioplasty with stenting versus coronary bypass surgery in patients with multi-vessel disease (ERAC-II): 30 day and one year follow up results. J Am Coll Cardiol 2001; 37: 51–58. 3. The SoS Investigators. Coronary artery bypass surgery versus percutaneous intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial. Lancet 2002; 360: 965–970.

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Key message In this study PCI was less expensive than CABG over a 2-year period. (It should be noted that many other trials have not supported this finding.)

Why it’s important Although this paper has important limitations, it attempts to address the important issue of direct comparison of costs for PCI and CABG.

Strengths The study was a single US centre i.e. a setting where health costs are transparently and commercially accurate. The study was a 2-year study. The authors were well aware of the limitations of the study and did attempt to address them wherever possible.

Weaknesses It is an observational rather than retrospective study. It occurs before the era of drug eluting stents. The paper is unclear but implies that the bypass grafts were largely or totally performed using cardiopulmonary bypass. It is also unclear as the extent of IIa /IIIb usage. It is a relatively small study. The cases were restricted to elective cases, which may make for cleaner data but is less reflective of the standard situation.

Relevance Although patients will correctly demand the “right” treatment in any given setting, the health costs of varying procedures, matched with the outcomes cannot be ignored and this paper draws out many of the important issues.

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Title 4

A prospective randomized trial comparing stenting with off-pump coronary surgery for high-grade stenosis in the proximal left anterior descending coronary artery: three year follow up Author Drenth DJ, Veeger NJGM, Winter JB, et al.

Reference J Am Coll Cardiol 2002; 40: 1955–1960

Abstract OBJECTIVES: This study was done to identify the best treatment for an isolated high-grade stenosis of the proximal left anterior descending coronary artery (LAD). BACKGROUND: Percutaneous transluminal coronary angioplasty with stenting (PCI) and off-pump coronary artery bypass grafting (surgery) are used to treat single-vessel disease of a high-grade stenosis of the proximal LAD. Midterm results of both treatments are compared in this prospective randomized study. METHODS: In a single-center prospective trial, we randomly assigned 102 patients with a high-grade stenosis of the proximal LAD (American College of Cardiology/American Heart Association classification type B2 or C) to PCI (n
51) or surgery (n
51). Primary composite end point was freedom from Major Adverse Cardiac and Cerebrovascular Events (MACCE) at follow-up, including death, myocardial infarction, cerebrovascular accident, and repeat target vessel revascularization (TVR). Secondary end points were angina pectoris class and need for antianginal medication at follow-up. Analysis was by intention-to-treat (ITT) and received treatment (RT). RESULTS: Mean follow-up time was three years (90% midrange, two to four years). Incidence of MACCE was 23.5% after PCI and 9.8% after surgery; p
0.07 ITT (24.1% vs. 8.3%; p
0.04 RT). After surgery a significantly lower angina pectoris class ( p
0.02) and need for antianginal medication ( p
0.01) was found compared to PCI. Target vessel revascularization was 15.7% after PCI and 4.1% after surgery ( p
0.09). CONCLUSIONS: At three-year follow-up (range, two to four years), a trend in favor of surgery is observed in regard to MACCEfree survival with a significantly lower angina pectoris status and significantly lower need for antianginal medication.

Summary High-grade type B2- or C-lesion in the proximal left anterior descending artery (LAD) can be treated either by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). At the time this study was undertaken, PCI carried around a 25% chance of restenosis or occlusion. Surgical data suggested a 6 months patency of 95%. Whilst these results were thought to be clear, some may have felt that the surgical approach may be thought of as more invasive in regards to periprocedural morbidity and mortality. Therefore, the authors conducted a prospective randomized study to compare PCI and CABG in 102 patients with a high-grade stenosis of the proximal LAD. In summary, their findings showed a significantly higher restenosis in the PCI group at 6 months (29%) when compared to the CABG group (4%). There were no significant differences in the periprocedural adverse events. The study presented the 2–4-year follow-up comparing the clinical outcomes.

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The PCI patients had stent implantation after predilation. They were treated with 250 mg ticlopidine daily for a month after stenting. The CABG operations were all performed on a beating heart through a small left anterolateral thoracotomy with a stabilizer. The primary endpoint for the study was 3-year freedom from major adverse cardiac and cerebrovascular events (MACCE). The MACCE were death, myocardial infarction (MI), stroke and the need for repeat target vessel revascularization (TVR). The TVR was performed only in patients with angiographic restenosis of 50% in combination with objective evidence of ischaemia. Secondary endpoints were angina, use of antianginal medication, other clinical events and MACCE without revascularization. Almost all the MACCE occurred during the first 9 months after stenting and during hospitalization after surgery. Clinical outcome at 3-year follow-up for angina status and need for antianginal medication was significantly lower after CABG than PCI. The authors commented that despite a perception that surgery is thought to be a more invasive procedure, there was a higher peri-procedural complication rate after PCI. Three-year follow-up showed a trend in favour of better survival in the CABG group which was already apparent in the early post-procedural period. They correlated the increase in angina as a symptom and requirement for antianginal drugs with the increased (29%) restenosis rate in the PCI treated group. Other known risk factors for restenosis like diabetes and number of stents used could not be identified in the PCI group. This may be due to the relatively small study size. The authors conclude with the findings that long-term MACCE free and angina free survival can be expected after off-pump CABG with left internal mammary artery (LIMA) to LAD. PCI is a good alternative if the patient accepts a higher chance for repeated TVR. We think these conclusions are highly responsible and based on good evidence.

Citation Count

18

Related References 1. Drenth DJ, Winter JB, Veeger NJ, et al. Minimally invasive coronary artery bypass grafting versus percutaneous transluminal coronary angioplasty with stenting in isolated high-grade stenosis of the proximal left anterior descending coronary artery: six months’ angiographic and clinical follow up of a prospective randomised study. J Thorac Cardiovasc Surg 2002; 124: 130–135. 2. Jansen EW, Borst C, Lahpor JR, et al. Coronary artery bypass grafting without cardiopulmonary bypass using the octopus method: results in the first one hundred patients. J Thorac Cardiovasc Surg 1998; 116: 60–67. 3. Goy JJ, Kaufmann U, Goy-Eggenberger D, et al. A prospective randomised trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior descending coronary artery stenosis: the SIMA trial (Stenting vs. Internal Mammary Artery). Mayo Clin Proc 2000; 75: 1116–1123.

Key message Comparing PCI and CABG for proximal LAD disease showed significantly lower angina and need for antianginal medication with CABG. There was a trend to event free survival improvement with CABG.

Why it’s important This is an important example of a condition with two, markedly different treatments. Both cardiac surgeon and interventional cardiologist viewed the lesions as treatable by their techniques, and thus the question is should the patient have PCI and not can the patient have PCI?

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Strengths This is a prospective study with a good follow-up period. One hundred and two patients is the minimum number that could power such a study.

Weaknesses The stents used were not drug eluting and the study period was prior to the widespread use of glycoprotein IIa/IIIb receptor blockers. The two PCI main mechanisms of failure were restenosis and procedural. The former may well have changed with drug and stent advances.

Relevance This paper’s findings are of major relevance to clinical practice. The problem is the old one of how one can extrapolate these findings to the latest clinical practice. It would be of major interest and relevance to follow-up with a theoretical study (see Clinical Impact of Drug-Eluting Stents in Changing Referral Practices for Coronary Surgical Revascularization in a Tertiary Care Centre) modelling a low restenosis rate and trying to predict what impact this would have.

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Title 5

Long-term survival in 11,661 patients with multivessel coronary artery disease in the era of stenting: a report from the Alberta Provincial Project for the Outcome Assessment in Coronary Heart Disease (APPROACH) Investigators Author Dzavik V, Ghali WA, Norris C, et al.

Reference Am Heart J 2001; 142: 119–126

Abstract BACKGROUND: Studies of survival of patients with multivessel coronary artery disease (MVD) in the prestent era suggested that outcomes after coronary artery bypass surgery (CABG) are similar to those after percutaneous coronary intervention (PCI) in subsets of coronary severity. The purpose of this study of the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) was to examine the association between treatment and survival up to 5 years in patients with MVD enrolled from 1995 through 1998. METHODS AND RESULTS: Data on patient characteristics were obtained at the time of the initial coronary angiography. Survival was determined through data linkage to the provincial Bureau of Vital Statistics. Riskadjusted hazard ratios were calculated to compare different treatments. In the 11,661 patients with MVD, CABG was the initial therapy in 3782, PCI in 3540, and medical therapy in 4339. Cumulative 5-year survival was 91.4% with CABG, 91.9% with PCI, and 82.9% with medical therapy ( p  .001). Hazard ratios were CABG: medical 0.53 (95% confidence interval [CI] 0.46–0.71), PCI: medical 0.65 (95% CI 0.56–0.74), and CABG: PCI 0.81 (95% CI 0.68–0.96). Analysis across coronary severity groups revealed a benefit of CABG compared with PCI only in the group with severe left main CAD: 0.30 (95% CI 0.17–0.54). CONCLUSIONS: In a multicenter clinical setting, MVD patients treated with revascularization have significantly higher 5-year survival rate than do those treated medically. Risk-adjusted comparison reveals PCI treatment to be associated with long-term survival similar to treatment with CABG in all coronary severity subgroups except the group with severe left main coronary artery disease. Patient selection factors are likely to be contributing to these findings.

Summary The main aim of this study was to examine cumulative survival to 5 years in patients with multivessel disease (MVD) managed with medical therapy, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) who were prospectively enrolled in APPROACH to determine risk-adjusted hazard ratios for mortality, for each interventional treatment modality compared with medical management. The medical literature has always viewed the controlled prospective randomized clinical trial as the gold standard and observational studies as markedly inferior. There are many advantages with the randomization but equally many biases that make extrapolation to real clinical practice difficult. This prospectively collected observational study has all the caveats inherent in such a study but also many insights into the consequences of different management paths, albeit in different patient groups. The educated will, I believe,

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benefit as much from well documented observational studies as the “gold standard” randomized trial. This paper took place in a transitional period of increasing stent utilization. The early registries demonstrated a higher survival in patients treated with CABG compared with those treated medically, with survival in patients with three-vessel disease being linked to completeness of revascularization. Surgically treated patients in this study with three-vessel disease and left main disease clearly had a lower risk-adjusted mortality than those treated medically. There did not appear to be a survival benefit to initial treatment with CABG compared with medical therapy in those with two-vessel disease even in the presence of severe proximal left anterior descending artery (LAD) disease. This last finding is clearly surprising. These findings are similar to the Duke Medical Centre Registry of 9263 patients. At 5 years there was a significant survival benefit of CABG over medical therapy in patients with three-vessel disease as well as small survival advantage in those with two-vessel disease. The 10-year follow-up indicates that treatment with CABG showed survival outcome in all Duke severity subgroups except those without at least one 95% stenosis. Their observations with respect to the risk with PCI compared with medical treatment confirm those of the earlier Duke registry with respect to survival differences favouring PCI in all coronary severity groups up to three-vessel disease. The APPROACH study indicated an extension of risk reduction with PCI to those with three-vessel disease, including those with proximal LAD disease. This extension, they go on to say, is likely to be related to the introduction of stents reducing the rates of restenosis and abrupt closure. The lack of difference in patients with less severe two-vessel disease may relate to advances in medical therapy. The early randomized trials of CABG vs. PCI, reporting similar outcomes were all underpowered to detect differences in survival. One study [2] of 450 patients randomized to PCI vs. CABG in the stent era revealed a significantly higher survival in the PCI group at 18 months. However, the bypass angioplasty revascularization investigation (BARI) study showed that diabetic patients randomized to PCI had significantly lower survival than those patients randomized to CABG. As previously mentioned, these studies had highly selected study populations with exclusions, e.g. previous revascularization procedures or in some cases, total occlusions. The authors state that the high survival with the PCI groups in their study, may well be the reduction in major cardiac events, especially the need for target vessel revascularization (TVR). The hazard ratio favouring CABG was almost entirely a function of benefit in the left main stem disease group. However, they do admit one of the limitations of an observational study in that they cannot rule out the effect of clinical selection. It may well have been that the more favourable patients from the anatomical viewpoint went into the PCI group with the remaining patients going for CABG, unless their anatomy was extremely unfavourable.

Citation Count

4

Related References 1. Mark DB, Nelson CL, Califf RM, et al. Continuing evolution of therapy for coronary artery disease: initial results from the era of coronary angioplasty. Circulation 1994; 89: 2015–2025. 2. Rodrigues A, Bematdi V, Navia J, et al. Argentine randomised study: coronary angioplasty with stenting vs coronary bypass surgery in patients with multivessel disease. J Am Coll Cardiol 2001; 37: 51–58. 3. Feit F, Brooks M, Sopka G, et al. Long term clinical outcome in the Bypass Angioplasty Registry: comparison with the randomised trial. BARI investigators. Circulation 2000; 101: 2795–2802.

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Key message Patients with multi-vessel coronary disease have a significantly higher survival rate when treated with revascularization over medical management. Long-term survival after left main stem disease is better with CABG than PCI.

Why it’s important The techniques for PCI and CABG have improved vastly over the years. Medical management is also dramatically different from 30 years ago. A study (not trial) looking at these three treatment options is important since the messages may have changed over the years. The message from this observational study is that survival is better with revascularization whatever technique is used for most patients.

Strengths The data for this observational study was collected prospectively. Despite the caveats on the limitations of the study outlined by the authors and their caution not to extrapolate on treatment efficacy, their paper reflects true life management. In many ways it has less bias than a controlled randomized clinical trial where the inclusion/exclusion criteria will produce results on just a small proportion of the patients actually treated.

Weaknesses This was a non-randomized study, and reflected the patient population that was referred to this centre and the treatment modalities that were thought appropriate at the time. There was a waiting list of months for revascularization and unstable patients may have died.

Relevance It is responsible of the authors to caution that this paper should not be viewed for efficacy of treatment. The readers will judge for themselves whether, despite the patient bias of an observational study, there are relevant messages for their patients.

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Title 6

Comparison of coronary artery bypass surgery and stenting for the treatment of multivessel disease Author Serruys PW, Unger F, Souse JE, et al.

Reference N Engl J Med 2001; 344: 1117–1124

Abstract BACKGROUND: The recent recognition that coronary-artery stenting has improved the short- and long-term outcomes of patients treated with angioplasty has made it necessary to reevaluate the relative benefits of bypass surgery and percutaneous interventions in patients with multivessel disease. METHODS: A total of 1205 patients were randomly assigned to undergo stent implantation or bypass surgery when a cardiac surgeon and an interventional cardiologist agreed that the same extent of revascularization could be achieved by either technique. The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events at one year. The costs of hospital resources used were also determined. RESULTS: At one year, there was no significant difference between the two groups in terms of the rates of death, stroke, or myocardial infarction. Among patients who survived without a stroke or a myocardial infarction, 16.8 percent of those in the stenting group underwent a second revascularization, as compared with 3.5 percent of those in the surgery group. The rate of event-free survival at one year was 73.8 percent among the patients who received stents and 87.8 percent among those who underwent bypass surgery (p  0.001 by the log-rank test). The costs for the initial procedure were $4,212 less for patients assigned to stenting than for those assigned to bypass surgery, but this difference was reduced during follow-up because of the increased need for repeated revascularization; after one year, the net difference in favor of stenting was estimated to be $2,973 per patient. CONCLUSION: As measured one year after the procedure, coronary stenting for multivessel disease is less expensive than bypass surgery and offers the same degree of protection against death, stroke, and myocardial infarction. However, stenting is associated with a greater need for repeated revascularization.

Summary The setting of this study is clearly outlined in the introduction. It quotes [1] the writing that approximately 60% of patients treated with balloon angioplasty or bypass surgery have multivessel disease (MVD) that could be treated by either procedure. That the quoted paper was from 1997 makes the statement somewhat forward thinking or perhaps ambitious. It goes on, much less controversially, to state that earlier studies suggest that either procedure has similar outcomes as far as survival are concerned, but coronary artery bypass grafting (CABG) is associated with fewer interventions. The authors postulate that surgery may be more appropriate than conventional balloon angioplasty for MVD, but this may not be the case when stent placement is performed in conjunction with balloon angioplasty. This very reasonable postulate is the backdrop for their study. They go on to state that costs are also important when it comes to decision-making. The Arterial Revascularization Therapies Study (ARTS) was designed to compare not only clinical outcomes but also the costs to the hospital of the two procedures and the relative costeffectiveness of the procedures.

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Patients were randomized when both the surgeon and the interventional cardiologist accepted the patient for revascularization. Left main disease was excluded. Any occlusion had to be of less than 1 month’s duration. A poor left ventricle (below 30% ejection fraction), heart failure, and recent (within 1 week) MI were among the major exclusions. There was a delay of 27  39 days between randomization and treatment, and three patients died whilst awaiting CABG; 25 of the 1205 patients randomized to one treatment actually received the other. In the percutaneous coronary intervention (PCI) group, 40% of the major adverse events that occurred in the first 30 days after intervention were due to stent thrombosis (2.8% of patients); 21% of the stented group underwent additional revascularization as compared with 3.8% of the surgical group. At 1 year the CABG patients had a significantly higher proportion without angina and a lower rate of use of antianginals. Survival was similar. Costs of CABG were significantly higher than PCI primarily due to differences in the duration of the procedures and length of hospital stay. These differences reduced with time as the PCI patients received repeat procedures. The authors felt that their findings present physicians with a dilemma for treatment. However, they did conclude that although the most effective method of revascularization remains surgery, their findings tipped the scales of cost-effectiveness in favour of PCI, by demonstrating a substantial reduction in the outcomes of the procedures. One presumes that they were referring to cost alone because it is hard to understand or justify if they did in fact mean overall outcomes. The study was supported by Johnson & Johnson, a prominent manufacturer of stents.

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Related References 1. Rigter H, Meijler AP, McDonnell J, Scholma JK, Bernstein SJ. Indications for coronary revascularisation: a Dutch perspective. Heart 1997; 77: 211–218. 2. Cohen DJ, Breall JA, Ho KK, et al. Evaluating the potential cost effectiveness of stenting as a treatment for symptomatic single vessel coronary disease: use of a decision-analytical model. Circulation 1994; 89: 1859–1874. 3. Van den Brand M, van Halem C, van den Brink F, et al. Comparison of costs of percutaneous transluminal coronary angioplasty and coronary bypass surgery for patients with angina pectoris. Eur Heart J 1990; 11: 765–771. 4. Schulpher MJ, Seed RA, Henderson RA, et al. Health service costs of coronary angioplasty and coronary artery bypass surgery: the Randomised Intervention Treatment of Angina (RITA) trial. Lancet 1994; 344: 927–930.

Key message At 1 year PCI is less expensive than CABG and offers the same degree of protection against death, stroke and MI. PCI with stenting is associated with a greater need for repeated revascularization, and more recurrent angina and a higher requirement for antianginal medication.

Why it’s important This is a study conducted during the stenting era comparing PCI vs. CABG. It questions the accepted view prior to this and similar studies that CABG is more appropriate than PCI for MVD.

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Strengths This is a prospective randomized study that included a cost–benefit as well as survival and other end points. It assessed the relative cost-effectiveness of the procedures.

Weaknesses Like any randomized study the inclusion/exclusion criteria were strict. They therefore excluded patients with left ventricular ejection fractions of less than 30%. The vessels had to be amenable to PCI and if occluded, had to be of less than 1 month’s duration. These were stable patients who had not had a myocardial infarction (MI) in the previous week. The study period was only 1 year. There were 67 participating centres making true cost comparison exceedingly difficult.

Relevance This paper is of direct relevance to physicians making decisions on PCI vs. CABG. The cost analysis will be of interest to health economists.

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Title 7

Rescue percutaneous coronary intervention following coronary artery bypass graft: a descriptive analysis of the changing interface between interventional cardiologist and cardiac surgeon Author Adams MR, Orford JL, Gavin JB, Wainstein MV, et al.

Reference Clin Cardiol 2002; 25: 280–286

Abstract BACKGROUND: Despite decreasing rates of acute and subacute complications of percutaneous coronary intervention (PCI), these procedures are generally only performed in centers where it is possible for failed PCI to be treated by rescue coronary artery bypass graft (CABG). Case reports and case series have documented successful PCI following failed CABG. We sought to confirm this decrease in the need for rescue CABG following failed PCI and to examine trends in the utilization of rescue PCI following failed CABG. HYPOTHESIS: The interface between interventional cardiologist and cardiac surgeon is characterized by changing practice patterns and resource utilization. METHODS: We examined the medical records of all patients admitted to the Brigham and Women's Hospital over a 7-year period and identified 169 patients who required both PCI and CABG during the same hospital admission. We describe and compare three predetermined groups of patients defined by the sequence of, and indication for, the relevant myocardial revascularization procedures. RESULTS: In all, 100 patients required CABG for failed PCI, 46 patients had planned hybrid procedures involving both CABG and PCI, and 23 patients required PCI following failed CABG. There was a decrease in the need for rescue CABG following failed PCI, both in total numbers and as a percentage of total cases (2.5% in 1994 and 0.22% in 1999). There was a simultaneous increase in the utilization of rescue PCI following failed CABG (0% in 1994 and 1.6% in 2000). Hybrid procedures were identified as a source of innovative solutions to a variety of challenging clinical problems. CONCLUSIONS: Changing patterns of resource utilization should be considered when planning hospital facilities and patient triage, and these patients undergoing percutaneous or surgical revascularization may benefit from close cooperation between the cardiac surgeon and the interventional cardiologist.

Summary The introduction to the article states with references that both coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are effective in controlling the symptoms of myocardial ischaemia. It then continues telling the reader that both treatment modalities carry a small but significant risk of myocardial infarction (MI) and death. Nothing too controversial or ground-breaking so far! Rescue CABG appears to have become less frequent since the introduction of stenting and occasionally PCI is used to rescue failed CABG. The article sought to characterize the interface between interventional cardiologist and cardiac surgeon at Brigham,

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and Women’s Hospital, Boston, Massachusetts, USA. It also sought to examine the trends in utilization of rescue PCI following failed CABG. Between January 1994 and March 2000, 7529 PCI procedures and 6684 CABG operations were performed; 169 patients underwent both cardiac surgery and PCI on the same admission. These patients formed the basis of the study. There were 100 patients who underwent CABG following PCI, 61 with threatened or evolving infarction and 39 who were stable but unsuccessful. Reasons for urgent surgical intervention included abrupt vessel closure, dissection, perforation and delayed closure including stent thrombosis. Of those with threatened MI, just over 3% were in cardiogenic shock and 67% underwent placement of an intra-aortic balloon pump (IABP). These patients had a mean number of 2.6  1 grafts and left internal mammary artery (LIMA) usage was 58.5%; 46 patients had a planned hybrid procedure, 31 of whom required PCI as primary or rescue treatment for acute MI when the procedure was planned as a bridge to CABG due to left main or triple vessel disease. In nine cases, successful PCI was performed for a structural complication of the infarction. Four patients had complex hybrid procedures e.g. saphenous graft to left anterior descending artery (LAD) to facilitate protected left main stenting. The final group of 21 patients were those who had evolving MI following CABG and two patients who were stable but required PCI for important non-graftable vessels. PCI targets included native left main stems, all three coronary arteries, LIMA and saphenous grafts. Procedural success was achieved in 23 of the 25 lesions. Some centres have questioned the need for a surgical presence when performing PCI. The authors believe this is advantageous in some situations and life saving in others like left main occlusion or cardiac tamponade. They add that the prognosis following CABG for failed PCI is excellent and need not preclude the use of the internal mammary artery grafts. Compared with failed PCI when vessel occlusion and threatened MI may be obvious, graft occlusion after CABG may be less obvious. Graft failure may be suggested by localized ST segment elevation, haemodynamic instability or ventricular fibrillation. Coronary angiographical is commonly required to confirm graft problems. The authors state that novel approach, such as minimally invasive CABG increase the chance of early graft failure requiring PCI intervention. Rescue CABG continues to play an important role in the management of failed PCI but the need for it has decreased over the years with the widespread use of stents. It is now almost as common to have rescue PCI after failed CABG. Patients benefit from close co-operation between the cardiac surgeon and the interventional cardiologist.

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Related References 1. Rasmussen C, Thiis JJ, Clemmensen P, et al. Significance of early graft failure after coronary artery bypass grafting. Feasibility and results of acute angiography and revascularisation. Eur J Cardiothorac Surg 1997; 12: 847–852. 2. Schieman G, Cohen BM, Buchbinder M. Standby percutaneous coronary angioplasty for coronary artery bypass surgery. Cathet Cardiovasc Diagn 1990; 21: 151–161. 3. Seckler JI, Butte A, Harrell L, Palacios I, Jang IK. Acute occlusion during coronary interventions: the changing pattern in the era of stents. J Invas Cardiol 1998; 10: 208–212. 4. Talley JD, Weintraub WS, Roubin GS, et al. Failed elective percutaneous transluminal coronary angioplasty requiring coronary artery bypass surgery. In hospital and late clinical outcome at 5 years. Circulation 1990; 82: 1203–1213.

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Key message There are changing patterns of the requirements for CABG rescue after PCI failure and PCI rescue after CABG failure. Close co-operation between the two teams may be of benefit.

Why it’s important This paper brings the stark reality of the small failure rate of both CABG and PCI to the fore and discusses their implications. It stresses the necessity of considering these cases when planning hospital facilities.

Strengths An imaginative paper detailing urgent CABG and PCI failures. It also discusses the starts of hybrid procedures.

Weaknesses The retrospective paper is from one centre and can therefore reflect only the pattern of PCI and CABG failures in that centre. It may not be possible to extrapolate to other centres since the variables of physicians, case mix, etc. may be unrepresentative of wider areas.

Relevance As the case mix for both PCI and CABG continues to be more challenging, the failure rates for either or both procedures may change but the interface between cardiac surgeon and interventional cardiologist become even more important.

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Title 8

A meta-analysis of randomised controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one to eight year outcomes Author Hoffman SN, TenBrook Jr JA, Wolf MP, et al.

Reference J Am Coll Cardiol 2003; 41: 1293–1304

Abstract OBJECTIVES: We performed a meta-analysis of randomized trials comparing coronary artery bypass graft surgery (CABG) with percutaneous transluminal coronary angioplasty (PTCA) for the treatment of coronary artery disease, incorporating new trials and examining long-term outcomes. BACKGROUND: Previous meta-analyses of trials comparing CABG with PTCA have reported short- and intermediate-term outcomes, but since then longer term follow-up and newer trials have been published. METHODS: We performed a meta-analysis of 13 randomized trials on 7,964 patients comparing PTCA with CABG. RESULTS: We found a 1.9% absolute survival advantage favoring CABG over PTCA for all trials at five years ( p  0.02), but no significant advantage at one, three, or eight years. In subgroup analysis of multivessel disease, CABG provided significant survival advantage at both five and eight years. Patients randomized to PTCA had more repeat revascularizations at all time points (risk difference [RD] 24% to 38%, p  0.001); with stents, this RD was reduced to 15% at one and three years. Stents also resulted in a significant decrease in nonfatal myocardial infarction at three years when compared with CABG. For diabetic patients, CABG provided a significant survival advantage over PTCA at 4 years but not at 6.5 years. CONCLUSIONS: Our results suggest that, when compared with PTCA, CABG is associated with a lower five-year mortality, less angina, and fewer revascularization procedures. For patients with multivessel disease, CABG provided a survival advantage at five to eight years, and for diabetics, a survival advantage at four years. The addition of stents reduced the need for repeat revascularization by about half.

Summary Eligible studies for this meta-analysis were limited to randomized-controlled clinical trials comparing the initial strategies of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients with multi vessel or proximal left anterior descending artery (LAD) disease who were candidates for either procedure. Studies that utilized stents as one of the initial interventions were included; 13 trials met these criteria. AWESOME was excluded (see section Why it’s important below). Four trials were included reporting on subgroups of patients with diabetes mellitus. In the overall analysis with 7964 eligible patients, neither strategy provided a statistically significant survival advantage at 1, 3 or 8 years. At 5 years, there was a survival advantage with the CABG patients. Subgroup analysis of multi-vessel trials showed a similar survival advantage at 5 and 8 years. The authors stated that they viewed this long-term survival advantage as consistent

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with the observational studies that they read but did not include in the meta-analysis. They issue the caveat that these data were in the present era and could not be replicated when the 3-year data is reviewed. They agree that the long-term impact of stents and improvements in CABG are still not known. Their analysis of the diabetic subgroups reflects the heterogeneity in outcomes in the literature. CABG provides a statistically significant survival advantage at 4 years but 61⁄2, unless the randomised intervention treatment of angina (RITA) study is excluded. Angina and revascularization rates were higher following PCI in the overall analysis and in all subgroups. This increased with time despite the expected need for revascularization in CABG patients due to failure of bypass grafts. Stenting reduced this need by around 1⁄2 to 15% and perhaps drug-eluting stents will reduce this still further. The authors do caution that the revascularization results need to be interpreted carefully because of the degree of heterogeneity found in reported outcomes. In addition, the indications for repeat revascularization were not always specified and may have varied between the study centres. They speculate that higher revascularization rates with PCI may reflect less complete revascularization with PCI initially. Other sources of heterogeneity included definitions of outcomes such as post-procedural myocardial infarction (MI). They also tried to compare their findings with comparable other meta-analyses and found no major differences for 1 to 3 years outcomes. CABG patients had significantly fewer repeat revascularizations, less angina but no clear survival advantage or non-fatal MI at 1 to 3 years. The authors conclude their article asking, “How then does one decide between CABG and PCI?” They answer by saying that the decision to recommend CABG or PCI will be guided by the results of randomized trials, technical improvements, local expertise and period assessments such as their meta-analysis! The discussion continues.

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Related References 1. Barsness GW, Peterson ED, Ohman EM, et al. Relationship between diabetes mellitus and long term survival after coronary artery bypass and angioplasty. Circulation 1997; 96: 2551–2556. 2. Hannan EL, Racz MJ, McCallister BD, et al. A comparison of three year survival after coronary artery bypass graft surgery and percutaneous coronary angioplasty. J Am Coll Cardiol 1999; 33: 63–72. 3. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta analysis. JAMA 1999; 282: 1054–1060. 4. DerSimonian R, Laird N. Meta analysis in clinical trials. Control Clin Trials. 1986; 7: 177–188.

Key message When compared to PCI, CABG is associated with a lower 5-year mortality, less angina and fewer revascularization procedures. CABG provides a survival advantage at 5–8 years and for diabetics, a survival advantage at 4 years. The addition of stents reduced the need for repeat revascularization by about half.

Why it’s important This was a meta-analysis of 13 trials with 7964 patients from 1996 onwards. Only one major trial was excluded (AWESOME) because it enrolled patients with severe left ventricular function or recent MI. The meta-analysis provided many clear end points.

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Strengths A well constructed and argued paper. The data that would be nice to include in such a metaanalysis are often not included but this is pointed out at each stage. The conclusions are mature and not sensationalized.

Weaknesses Although it states that this is a meta-analysis of 13 trials, for some end points, e.g. 8-year outcome, only four trials were suitable for inclusion with smaller numbers of patients. As with all randomized trials in surgical studies, there is careful patient selection, which may mean that the results are not applicable to all patients. They estimate that the patients included represent typically 2–12% of those screened.

Relevance This paper attempts to address the fundamental question of which patient will benefit from PCI and which from CABG. It is not an easy question to answer and changes with differing time end points.

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Chapter 10

Epilogue Gerry Coghlan Introduction When interventional cardiology was born 28 years ago few could have foreseen its rapid growth and current dominant position in cardiology. In the late 1980s when percutaneous coronary intervention (PCI) had already become a significant player in the world of revascularization, “gut feeling” rather than knowledge underpinned the approach to hardware selection and adjunctive pharmacotherapy. The transformation of interventional cardiology from “eminence-based” to the most evidence-based speciality in medicine in just over 15 years has been truly remarkable. This collection of classic papers document this change, showing how ideas tested in vitro and in vivo, coupled with registry-based observations, helped formulate specific questions, which were refined by small scale studies and culminated in practice-changing randomized trials. These articles focus on studies that led to step changes in our understanding of coronary artery disease and the vascular and thrombotic responses to intervention, and our daily practice in revascularization. These articles allow those with little knowledge of interventional cardiology, to understand the place of PCI in 2005, while for those in the field it summarizes neatly that which one needs to know about the history of PCI to date. The first two chapters take the reader through the pivotal articles which led to our current understanding of the nature of atherosclerosis, the factors which cause progression, regression and clinical events, followed by the nature and limitations of imaging techniques which have contributed to this understanding. The next two chapters deal with studies that established the superiority of PCI in acute myocardial infarction and high risk acute coronary syndromes during a period of rapid evolution of medical therapies for the same conditions. Chapter 5 shows how registry studies identified high risk subgroups for PCI providing the kind of detailed real-life population analysis that is often missing from controlled randomized studies. Some of these risk factors have been overcome with advances in technology (female sex and type B lesions) and some remain significant challenges (chronic occlusions and left main stem lesions). Chapters 6 and 7 deal with technological advances, illustrating how many exciting techniques were shown not to improve outcomes (directional and rotational atherectomy, eximer laser and cutting balloons) and have thus become niche products, while others such as stents have become part of routine practice. The pace of progress in our understanding of the haemostatic systems and how to safely manipulate them is particularly gratifying and perfectly illustrated by the articles in chapter 8. In chapter 9, the potential of a world without cardiac surgery is considered; it is clear from the articles presented that coronary artery bypass grafting (CABG) though in retreat, is not yet dead. To close I would simply like to add a few articles which did not in themselves change the world, but which foreshadowed greater works. These are in essence the articles that set the scene for further investigation down a line that ultimately changed practice. The authors, with the exception of Essed et al. (Title 4) who simply made a fortuitous observation, are the visionaries who saw well beyond the limitations of current practice, they are in essence the pioneers without whom PCI would not have evolved as it has.

Epilogue

Title 1

The percutaneous dilatation of chronic coronary stenoses – experiments and morphology Author Grüntzig A, Schneider HJ

Reference Schweiz Med Wochenschr 1977; 107(44): 1588

Abstract Since 1971, percutaneous transluminal angioplasty of peripheral arteries has been performed in 225 patients. There was an overall patency rate of 70–80% after 2 years. Our technique was then adapted and modified to perform coronary dilatation. This was performed successfully in 8 dogs in which selective coronary artery stenosis was induced by silk ligature and secondary inflammatory changes. The technique was then applied to the coronary lesions in postmortal humans and tested in the operating room during A–C bypass to evaluate vessel patency, peripheral debris, etc.

Summary This study describes the process of adapting peripheral angioplasty for use in human coronaries. Proof of concept in carefully designed animal studies followed by work in humans in controlled circumstances opened the way for Grüntzig’s definitive work that was published 2 years later.

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Related References One could simply list all work published on coronary angioplasty. A Medline search yields over 16,000 articles, while PubMed search yields nearly 25,000.

Key message Non-operative revascularization of human coronaries is possible.

Why it’s important This is the article that led to the development of coronary angioplasty as we know it today.

Strengths Careful and logical exploration of the feasibility and safety of the technique.

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Weaknesses No procedures performed in pigs. Unlike dogs, pigs lack collaterals, this would have provided greater insight into the likely tolerance of brief periods of ischaemia required for percutaneous coronary angioplasty.

Relevance This article reports the first successful work in coronary angioplasty, the methodology demonstrated the essential safety of the technique in controlled circumstances. As a forerunner of their 1979 article on PCI in patients, it set the framework and neutralized many of the potential worries which might have been expressed, and thus set the scene for the very rapid adoption of the technique that followed.

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Title 2

Treatment of unstable angina pectoris with percutaneous transluminal coronary angioplasty (PTCA) Author Meyer J, Schmitz H, Erbel R, Kiesslich T, Bocker-Josephs B, Krebs W, Braun PC, Bardos P, Minale C, Messmer BJ, Effert S

Reference Cathet Cardiovasc Diagn 1981; 7(4): 361–371

Abstract Percutaneous transluminal coronary angioplasty (PTCA) was performed in 40 patients (34 male, 6 female; 51.0  8.5 years) with the typical clinical picture of unstable angina. All had a short history of pain (2.9  2.0 months), angina at rest, transient ST and/or T-wave changes during this period, and little or no enzyme elevations. The patients had a total of 41 stenoses (39 single, one double; one main-stem, 26 left anterior descending, 14 right coronary artery). The degree of the stenoses was 95.5  4.9% (area method) and 81.8  10.7% (diameter method). PTCA was successfully performed in 26 cases (63%), reducing the stenoses to 61.5  12.4% (area method) and 39.1  10.0% (diameter method). One patient (2.5%) received an immediate bypass operation because of an acute vessel occlusion. Eleven of the 14 not successfully treated patients received an aortocoronary bypass within the next three to 35 days. All still had symptoms of unstable angina. Three patients refused operation. Their treatment consisted of nitroglycerin, beta-blockers and nifedipine. Seventeen of the 26 successfully treated patients were restudied after 4.9  1.7 months. The degree of stenosis had risen to 69.2  17.4% (area method). While the stenoses in 12 patients were equal or less than before PTCA, stenosis recurred in five cases. Two patients were successfully retreated. PTCA can be performed with a good early success rate and a low complication rate in patients with unstable angina. Relief of pain and improvement of blood supply to the jeopardized myocardium can be provided immediately and with a limited amount of expense. The method can therefore be regarded as firststage treatment in such patients.

Summary This is the first article to detail the successful application of coronary angioplasty in a high-risk population. Two-thirds of patients responded to intervention alone, leaving only one-third needing operation. Follow-up angiography suggested that restenosis was not uncommon.

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Related References 1. Faxon DP, Detre KM, McCabe CH, Fisher L, Holmes DR, Cowley MJ, Bourassa MG, Van Raden M, Ryan TJ. Role of percutaneous transluminal coronary angioplasty in the treatment of unstable angina. Report from the National Heart, Lung, and Blood Institute Percutaneous

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Transluminal Coronary Angioplasty and Coronary Artery Surgery Study Registries. Am J Cardiol 1984; 53(12): 131C–135C. 2. Strauss WE, Fortin T, Hartigan P, Folland ED, Parisi AF. A comparison of quality of life scores in patients with angina pectoris after angioplasty compared with after medical therapy. Outcomes of a randomized clinical trial. Veterans Affairs Study of Angioplasty Compared to Medical Therapy Investigators. Circulation 1995; 92(7): 1710–1719. 3. Morrison DA, Sacks J, Grover F, Hammermeister KE. Effectiveness of percutaneous transluminal coronary angioplasty for patients with medically refractory rest angina pectoris and high risk of adverse outcomes with coronary artery bypass grafting. Am J Cardiol 1995; 75(4): 237–240. 4. Morrison DA, Bies RD, Sacks J. Coronary angioplasty for elderly patients with “high risk” unstable angina: short-term outcomes and long-term survival. J Am Coll Cardiol 1997; 29(2): 339–344.

Key message PTCA can be performed safely and successfully in most patients with unstable angina, leading to relief of ischaemia.

Why it’s important Patients with unstable angina spent weeks to months in hospital, and had a significant likelihood of progressing to myocardial infarction. Conservative practitioners treated this population with bed rest and drug therapies, regarding operative intervention as risky and unproven in this subpopulation. The advent of a less “traumatic” interventional approach, rapidly converted many of these physicians, though absolute proof of the superiority of an interventional approach was still many years away.

Strengths Though PCI had only been practiced for 2 years at the time of publication, this article describes a relatively large homogenous population. In many countries the management of this population was backward. Meyer and colleagues were describing a potentially efficient method of addressing the needs of this population which captured the imagination of cardiologists throughout the world.

Weaknesses This was a registry, there was no control population, and thus no evidence that any of the established techniques (medical or surgical) were inferior to this new technique.

Relevance One of the most successful applications of PCI has been in managing acute coronary syndromes. The management of such patients has been revolutionized in the past two decades. This article represents an early application of the technique to this difficult population, yet despite many trials it would be nearly two decades before unequivocal evidence for the superiority of PCI over medical management of this population was established.

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Title 3

Percutaneous transluminal coronary angioplasty with and without thrombolytic therapy for treatment of acute myocardial infarction Author Hartzler GO, Rutherford BD, McConahay DR, Johnson WL Jr, McCallister BD, Gura GM Jr, Conn RC, Crockett JE

Reference Am Heart J 1983; 106(5 Pt 1): 965–973

Abstract Successful percutaneous transluminal coronary angioplasty (PTCA) was performed during evolving acute myocardial infarction (AMI) in 41 patients. Catheterization was performed within 1 hour of presentation, from 1 to 12 hours (mean 3.3) following symptom onset. In 17 of 29 patients with a totally occluded coronary artery, successful thrombolytic therapy was followed by PTCA of a residual high-grade atheromatous stenosis. Successful PTCA without prior thrombolytic therapy was employed in 11 of 12 subtotal coronary stenoses producing acute infarction syndromes and in two patients having critical coronary stenoses not immediately responsible for AMI. Three patients experienced early in-hospital reocclusion with reinfarction. One death occurred in a patient presenting with cardiogenic shock. All remaining patients had prompt pain relief, subsequent stable clinical courses, and no clinical or late angiographic evidence of coronary reocclusion. Dramatic improvement of regional and global left ventricular function was evident in 22 of 27 patients undergoing late left ventricular angiography. At followup, 94% of patients remained free of angina although three required repeat dilatation of recurrent stenoses. We concluded that PTCA may be performed with or without thrombolytic therapy in selected patients with AMI and may reduce the likelihood of late reocclusion following successful thrombolytic therapy.

Summary This study describes the acute catheterization of patients presenting with acute myocardial infarction, followed by intracoronary thrombolysis and subsequent angioplasty for occlusions, and angioplasty alone for those with residual flow. Early improvement of left ventricular function was documented in most patients.

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Related References 1. Lee G, Amsterdam EA, Low R, Joye JA, Kimchi A, DeMaria AN, Mason DT. Efficacy of percutaneous transluminal coronary recanalization utilizing streptokinase thrombolysis in patients with acute myocardial infarction. Am Heart J 1981; 102(6 Pt 2): 1159–1167.

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2. Pepine CJ, Prida X, Hill JA, Feldman RL, Conti CR. Percutaneous transluminal coronary angioplasty in acute myocardial infarction. Am Heart J 1984; 107(4): 820–822. 3. Grbic M, Sigwart U, Goy JJ, Maendly R, Essinger A, Perret C, Nicod P, Sadeghi H. Mechanical recanalization and dilatation of coronary arteries in the acute stage of myocardial infarction. Schweiz Med Wochenschr 1985; 115(45): 1583–1586. 4. Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. New Engl J Med 1993; 328(10): 680–684. 5. Zijlstra F, de Boer MJ, Ottervanger JP, Liem AL, Hoorntje JC, Suryapranata H. Primary coronary angioplasty versus intravenous streptokinase in acute myocardial infarction: differences in outcome during a mean follow-up of 18 months. Coron Artery Dis 1994; 5(8): 707–712. 6. Liem AL, Zijlstra F. Favorable long-term results of primary percutaneous transluminal coronary angioplasty in acute myocardial infarction compared to intravenous streptokinase treatment; a randomized study. Ned Tijdschr Geneeskd 1995; 139(49): 2564–2567. 7. Zeymer U, Uebis R, Vogt A, Glunz HG, Vohringer HF, Harmjanz D, Neuhaus KL, ALKK-Study Group. Randomized comparison of percutaneous transluminal coronary angioplasty and medical therapy in stable survivors of acute myocardial infarction with single vessel disease: a study of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte. Circulation 2003; 108(11): 1324–1328.

Key message Thrombolysis is not essential when establishing reperfusion in patients with acute myocardial infarction.

Why it’s important Although the final step of mechanical disobliteration of occlusive thrombus was not taken in this study, it showed for the first time that thrombotic lesions responded to mechanical therapy in the absence of adjunctive thrombolytic therapy.

Strengths At the time of this study not even systemic thrombolysis had been established as a proven therapy. The open artery hypothesis was accepted by most, but it was believed that thrombus required thrombolytic therapy. This article shows that in the presence of thrombus equivalent results can be obtained with or without thrombolysis. Importantly the study shows that left ventricular function improves if one successfully opens the artery.

Weaknesses The essential step of comparing mechanical recanalization with and without adjuvant thrombolytic therapy in a single population was not taken.

Relevance Primary PCI for myocardial infarction is now recognized as the treatment of choice for ST elevation MI. At the time the work reported here was performed, the concept was truly groundbreaking, while thrombolysis was used as adjunctive therapy in patients with complete occlusions, the direction of thinking is clear. Direct angioplasty for myocardial infarction was being reported within a year of this publication.

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Title 4

Transluminal coronary angioplasty and early restenosis. Fibrocellular occlusion after wall laceration Author Essed CE, Van den Brand M, Becker AE

Reference Br Heart J 1983; 49(4): 393–396

Abstract Transluminal coronary angioplasty was performed in a 51 year old man with a localised narrowing of the proximal segment of the left anterior descending coronary artery. Initial inflations with a small size balloon catheter were unsuccessful. A second attempt, during the same procedure, using a larger calibre catheter relieved the obstruction but produced a dissection. Angina pectoris reappeared approximately three months later. Another attempt to relieve the obstruction by angioplasty, five months after the initial procedure, induced ST segment elevation before angioplasty, followed by ventricular fibrillation and death. The necropsy showed a split in the preexistent sclerotic plaque and a dissecting aneurysm of the media. A proliferation of fibrocellular tissue filled the false channel and almost totally occluded the pre-existent arterial lumen. The observation suggests that wall laceration with exposure of smooth muscle cells to blood may have initiated the excessive fibrocellular tissue response. This event may be the underlying pathogenetic mechanism for the occurrence of early restenosis after transluminal coronary angioplasty.

Summary Post mortem evaluation of a restenotic plaque showed that fibrocellular proliferation, rather than recoil, thrombus or atherosclerosis was responsible for luminal occlusion.

Citation Count

263

Related References 1. Schwartz RS, Huber KC, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DR. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol 1992; 19(2): 267–274. 2. MacLeod DC, Strauss BH, de Jong M, Escaned J, Umans VA, van Suylen RJ, Verkerk A, de Feyter PJ, Serruys PW. Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human coronary atherosclerotic and restenotic lesions. J Am Coll Cardiol 1994; 23(1): 59–65. 3. Orford JL, Selwyn AP, Ganz P, Popma JJ, Rogers C. The comparative pathobiology of atherosclerosis and restenosis. Am J Cardiol 2000; 86(4B): 6H–11H. 4. Chorny M, Fishbein I, Golomb G. Drug delivery systems for the treatment of restenosis. Crit Rev Ther Drug Carrier Syst 2000; 17(3): 249–284.

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5. Waksman R, Cheneau E, Ajani AE, White RL, Pinnow E, Torguson R, Deible R, Satler LF, Pichard AD, Kent KM, Teirstein PS, Lindsay J. Intracoronary radiation therapy improves the clinical and angiographic outcomes of diffuse in-stent restenotic lesions: results of the Washington Radiation for In-Stent Restenosis Trial for Long Lesions (Long WRIST) Studies. Circulation 2003; 107(13): 1744–1749. 6. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation 2003; 108(14): 1701–1706. 7. Indolfi C, Pavia M, Angelillo IF. Drug-eluting stents versus bare metal stents in percutaneous coronary interventions (a meta-analysis). Am J Cardiol 2005; 95(10): 1146–1152.

Key message Intimal proliferation in response to arterial wall injury may explain early restenosis.

Strengths The anatomical and histopathological detail.

Weaknesses This is a case report. Larger series followed, but reliance on post-mortem data always raised the possibility that the restenosis seen in the population who died, might be different from general restenosis. Only with the advent of atherectomy was this issue finally decided.

Relevance While merely a case report, this article managed to identify the true nature of coronary restenosis for the first time. Throughout the 1980s and early 1990s a much greater understanding of the process was developed, but yet many of the treatments tried showed scant regard for the essential pathobiological nature of balloon/stent injury and the fibrocellular response which followed. Only with the advent of antimitotic drug eluting stents has any real impact on this process been made.

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Title 5

Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty Author Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L

Reference New Engl J Med 1987; 316(12): 701–706

Abstract Occlusion and restenosis are the most common reasons that transluminal balloon angioplasty may fail to provide long-term benefit. An intravascular mechanical support was therefore developed with the aim of preventing restenosis and sudden closure of diseased arteries after angioplasty. The endoprosthesis consists of a self-expandable stainless-steel mesh that can be implanted nonsurgically in the coronary or peripheral arteries. Experiments in animals showed complete intimal coverage within weeks and no late thrombosis during a follow-up period of up to one year. We performed 10 implantations in 6 patients for iliac or femoral arterial disease; 24 coronary-artery stents were implanted in 19 patients who presented with coronary-artery restenoses (n
17) or abrupt closure (n
4) after transluminal angioplasty or deterioration of coronary-bypass grafts (n
3). We observed three complications in the group with coronary disease. One thrombotic occlusion of a stent resulted in asymptomatic closure, a second acute thrombosis was managed successfully with thrombolysis, and one patient died after bypass surgery for a suspected but unfound occlusion. Follow-up in the patients has continued for nine months without evidence of any further restenoses within the stented segments. Our preliminary experience suggests that this vascular endoprosthesis may offer a useful way to prevent occlusion and restenosis after transluminal angioplasty. Longterm follow-up will be required to validate the early success of this procedure.

Summary Endovascular stainless-steel stents were tested in animal models, and implanted in human peripheral and coronary arteries. Coronary patients included those with restenosis after plain old balloon angioplasty (POBA), a group known for high rates of recurrent restenosis and those with abrupt occlusion, for whom there was at this time no effective intravascular solution. This report consists of evidence of deployability and a low rate of early stent thrombosis.

Citation Count

827

Related References All 8887 studies of coronary stenting published since.

Key message Stents can be placed in human coronary arteries percutaneously without substantial risks of acute occlusion, and with some evidence to suggest that restenosis is ameliorated.

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Why it’s important Sigwart and colleagues addressed two of the fundamental problems of coronary angioplasty, dissection and recoil, and applied a logical solution.

Strengths The structure of the study is logical, moving from animal studies to peripheral arterial studies and finally to high-risk coronary lesions. Follow up is excellent, with repeat angiography at a time when restenosis is likely to have occurred.

Weaknesses This is only a pilot study. No evidence of the superiority of stenting over conventional management is presented, and the problems of early stent occlusion are clear, but cannot be evaluated in such a small population.

Relevance Stenting is now regarded as an essential component of PCI. Yet when Sigwart and colleagues performed this work, it was by no means clear that placing and leaving a lump of metal in a coronary artery was sensible or safe. By this time many adjunctive techniques were being explored, most have since disappeared or become niche products. Of all the ideas generated only stenting has truly stood the test of time.

The future So what is the future of PCI? This brief trip through history shows that the future lies in identifying the important clinical problems of PCI and using the imagination and creativity of interventionists harnessed with the expertise of our colleagues in basic science, imaging and technology, to help solve the remaining issues and the as yet, unknown, problems that may emerge. We will need to be as inventive, bold and brave as our predecessors if we are to make another quantum leap in our ability to make further progress in helping our patients. Unsolved problems include bifurcation lesions, chronic occlusions, restenosis in the drugeluting stent era, and the absence of long term outcome comparisons of current practices and strategies versus CABG, both in terms of mortality and cost per quality adjusted life-years. None of the bifurcation stents currently being tested seem user-friendly enough to have a great future, but this may simply be a matter of time. Guidewires capable of forcing their way through fibrous tissue have been developed, and can now provide directional control, but as yet, no system allowing completely safe luminal tracking, has been developed. Whether multislice computerized tomography (MSCT), intracoronary ultrasound and systems which can detect the change in electrical parameters between media and intima, will become part of routine PCI is unclear. Healthcare organizations and others who fund cardiovascular care will want evidence that PCI and adjunctive therapies and pre and post PCI investigations, are necessary and cost effective. So, we may have the technology, the skills, the enthusiasm and the capacity to provide an increasing PCI service for all presentations and types of coronary heart disease, but not the sanction of those who have to pay for these effective but costly treatments. Whether increasingly effective primary and secondary prevention will reduce the need for PCI is also not known, but it is likely that these therapies will merely delay, rather than remove the need for PCI. Our patients will be older with co-morbidity and the procedure will be more

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technically demanding and have a greater risk. Increasing patient age and morbidity does not appear to reduce their expectations or those of their families and this is common to nearly all medical and surgical specialities. Indeed, as a result of our enthusiasm, efforts and capability to offer myocardial revascularization and effective secondary prevention to our patients, we are largely responsible for increasing the average age of the patients operated on by our surgical colleagues. Comparisons of drug eluting stenting for multivessel disease versus CABG are underway. Few doubt that this will show equivalence, but will this be cost effective? Advances in medical therapy may also change the character and presentation of coronary heart disease. The greatest challenge for the interventionalist, is not the lesions that we treat, it is those that we leave. We rely on antiplatelet drugs, statins and angiotensin-converting enzyme (ACE) inhibitors to pacify these lesions. As our therapies improve, will there is any need for the interventionalist in the future? I think we are safe from extinction for the next 20 years, but after that all bets are off.

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Frequently cited papers in coronary angioplasty Serruys PW, De Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. New England Journal of Medicine 1994; 331(8): 489–495.

2350

Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. New England Journal of Medicine 1994; 331(8): 496–501.

2253

Shadoff N, Valett N, Bates E, Galeana A, Knopf W, Shaftel J, et al. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. New England Journal of Medicine 1994; 330(14): 956–961.

1613

Topol EJ. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352(9122): 87–92.

850

Frye RL, Alderman EL, Andrews K, Bost J, Bourassa M, Chaitman BR, et al. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease: The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. New England Journal of Medicine 1996; 335(4): 217–225.

669

Zijlstra F, De Boer MJ, Hoorntje JCA, Reiffers S, Reiber JHC, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. New England Journal of Medicine 1993; 328(10): 680–684.

607

King III SB. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96(5): 1445–1453.

579

Ellis SG. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. New England Journal of Medicine 1997; 336(23): 1621–1628.

490

Weaver WD, Simes RJ, Betriu A, Grines CL, Zijlstra F, Garcia E, et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review. Journal of the American Medical Association 1997; 278(23): 2093–2098.

483

Mintz GS, Popma JJ, Pichard AD, Kent KM, Satter LF, Wong SC, et al. Arterial remodeling after coronary angioplasty: A serial intravascular ultrasound study. Circulation 1996; 94(1): 35–43.

467

Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, et al. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease: Implications for patient selection. Circulation 1990; 82(4): 1193–1202.

435

Pitt B, Waters D, Brown WV, Van Boven AJ, Schwartz L, Title LM, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. New England Journal of Medicine 1999; 341(2): 70–76.

398

Grines CL, Cox DA, Stone GW, Garcia E, Mattos LA, Giambartolomei A, et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. New England Journal of Medicine 1999; 341(26): 1949–1956.

380

Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. Journal of the American College of Cardiology 1985; 5(3): 587–592.

380

Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary artery stenosis. Percutaneous transluminal coronary angioplasty. New England Journal of Medicine 1979; 301(2): 61–68.

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Frequently cited papers in coronary angioplasty

Serruys PW, Van Hout B, Bonnier H, Legrand V, Garcia E, MacAya C, et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II). Lancet 1998; 352(9129): 673–681.

365

Holmes Jr. DR, Vlietstra RE, Smith HC. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): A report from the PTCA Registry of the National Heart, Lung, and Blood Institute. American Journal of Cardiology 1984; 53(12): 77C–81C.

353

King III SB, Lembo NJ, Weintraub WS, Kosinski AS, Barnhart HX, Kutner MH, et al. A randomized trial comparing coronary angioplasty with coronary bypass surgery. New England Journal of Medicine 1994; 331(16): 1044–1050.

344

Serruys PW, Luijten HE, Beatt KJ, Geuskens R, De Feyter PJ, Van Den Brand M, et al. 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(2): 361–371.

337

Ming Wei Liu, Roubin GS, King III SB. Restenosis after coronary angioplasty: Potential biologic determinants and role of intimal hyperplasia. Circulation 1989; 79(6): 1374–1387.

335

Nobuyoshi M, Kimura T, Nosaka H, Mioka S, Ueno K, Yokoi H, et al. Restenosis after successful percutaneous transluminal coronary angioplasty: Serial angiographic follow-up of 229 patients. Journal of the American College of Cardiology 1988; 12(3): 616–623.

331

Afridi I, Kleiman NS, Raizner AE, Zoghbi WA. Dobutamine echocardiography in myocardial hibernation: Optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation 1995; 91(3): 663–670.

326

Topol EJ, Leya F, Pinkerton CA, Whitlow PL, Hofling B, Simonton CA, et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. New England Journal of Medicine 1993; 329(4): 221–227.

323

Hampton JR, Henderson RA, Julian DG, Parker J, Pocock SJ, Sowton E, et al. Coronary angioplasty versus coronary artery bypass surgery: The Randomised Intervention Treatment of Angina (RITA) trial. Lancet 1993; 341(8845): 573–580.

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Index Indexer: Dr Laurence Errington References are in chapter and paper number form except for those with numbers in brackets e.g. 3(39) which indicates the page number in the introductory section to each chapter. Abbreviations used; CABG, coronary artery bypass graft; MI, myocardial infarction; PCI, percutaneous coronary intervention abciximab (ReoPro; monoclonal antibody to gpIIb/IIIa receptor; c7E3 Fab) in coronary stenting in acute MI, 3.7, 6.7 compared with PTCA and abciximab, 6.7, 8.3, 8.5 heparin dose lowering in patients treated with, 8.2 in high-risk PTCA, 4.6, 8.1 ACC/AHA PTCA guidelines, 5.7 acute coronary syndromes PTCA, 4.1–8 aspirin  clopidogrel in, pre- and postprocedural, 8.8 unfractionated vs LMW heparin preceding, 8.6 recombinant ApoA-1 Milano effects on atherosclerosis in patients with, 2.8 ADMIRAL study, 3.7 Alberta Provincial Project for the Outcome Assessment in Coronary Heart Disease, 9.5 alteplase vs thrombolytic therapy in acute MI, 3.8 prehospital, 3.6 American College of Cardiology/American Heart Association PTCA guidelines, 5.7 ancillary techniques, 7.1–8 angina, CABG vs stenting in left anterior disease and symptoms, 9.4 angina, unstable, 4(65) early invasive and conservative strategies compared in, 4.8 PTCA (and PCI in general), 4.1, 10.2 aspirin  clopidogrel before and after, 8.8 CABG vs, in diabetics, 9.1 heparin preceding, unfractionated vs LMW forms, 8.6

in multivessel disease, 4.2 restenosis risk, 4.3 TIMI risk score for, in prognostication and therapeutic decision-making, 4.7 Angina With Extremely Serious Operative Mortality Evaluation Study, 9.1 angiography/arteriography (coronary) quantitative atheroma mass estimation, 2.3 haemodynamic resistance estimation, 2.3 lipid-lowering therapy effects on disease regression via, 2.4 luminal dimensions in, 2.3 luminal dimensions in, correlations with ischaemic syndromes, 2.2 restenosis assessed by in directional atherectomy, 7.1, 7.2, 7.3 in PTCA (vs directional atherectomy), 7.1, 7.3 in stenting, strut thickness effects, 6.6 angiography/arteriography (peripheral vessels in general), luminal dimensions in, compared with intravascular ultrasound, 2.5 Angiomax (bivalirudin)  planned gpIIb/IIIa inhibitor compared with heparin and provisional gpIIb/IIA inhibitor, 8.7 animal studies of PTCA, 10.1 anticoagulants, intravascular ultrasoundguided stenting without, 6.4 see also specific anticoagulants antiplatelet agents dual (in PCI), long-term postprocedural, 8.9 preprocedural and, 8.8 in intravascular ultrasound-guided stenting, 6.4 see also specific (types of) agents antithrombotics, 8.1–9 sites of action, 8(163)

Index

apolipoprotein A-1 Milano, recombinant, effects on atherosclerosis in patients with acute coronary syndromes, 2.8 apolipoprotein B, elevated, lipid-lowering therapy and effects on coronary artery disease regression with, 2.4 APPROACH study, 9.5 Arterial Revascularization Therapies Study Group, 6.5 arteries coronary see coronary arteries smooth muscle cell see smooth muscle cell arteriography see angiography ARTS Group, 6.5 aspirin, 8(164) clopidogrel with see clopidogrel in intravascular ultrasound-guided stenting, 6.4 atherectomy, 7(141–2) directional, 7(141), 7(142) compared with PTCA, 7.1 “optimal”, 7.2, 7.3 rotational, 7(141) excimer laser ablation vs, 7.6 PTCA vs, 7.6, 7.7 atheroma formation (atherogenesis), monocyte role, 1.3 mass estimation in quantitative coronary angiography, 2.3 medial thinning, 2.1 atheromatous plaque see plaque atherosclerosis coronary see coronary arteries vascular biology, 1.1–8 AWESOME study, 9.1 Balloon vs Optimal Atherectomy Trial (BOAT), 7.3 bifurcation lesions, kissing balloon technique, 5.10 bivalirudin  planned gpIIb/IIIa inhibitor compared with heparin and provisional gpIIb/IIA inhibitor, 8.7 BOAT, 7.3 Boston Scientific FilterWire EX, 7.5 brachio-femoral technique of kissing balloon PTCA, 5.10 bypass graft (coronary artery; CABG), 9.1–8 PCI rescue of, 9.7 PCI vs for diabetics with unstable angina and risk factors for adverse outcomes, 9.1

meta-analysis of randomized controlled trials, 9.8 multivessel disease see multivessel coronary disease stenting see stenting referral for, drug-eluting stents reducing, 9.2 saphenous vein, stenosis see saphenous vein bypass graft c7E3 Fab see abciximab CADILLAC study, 6.7 CAPTIM study, 3.6 cardiogenic shock, 5.6 cardiovascular risk assessment, quantification of coronary atherosclerosis in, 2.1–8 CAVEAT study, 7.1 children, atherosclerotic lesions, 1.7 cholesterol homeostasis, receptor-mediated pathway, 1.4 see also hypercholesterolaemia cine-angiography, luminal dimensions in comparisons with assessment by intravascular ultrasound, 2.5 coronary, correlations with ischaemic syndromes, 2.2 clopidogrel, 8(164) aspirin and (in PCI), long-term postprecedural, 8.9 preprocedural and, 8.8 clotting see anticoagulants; coagulation coagulation (clotting) cascade, site of anti-thrombotic drug action, 8(163) see also anticoagulants coilspring tubes, 6.1 colestipol, elevated apoB and effects on coronary artery disease regression of, 2.4 Comparison of Angioplasty and Prehospital Thrombolysis in Acute myocardial Infarction (CAPTIM) study, 3.6 complications, risk factors for see high-risk patients Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications, 6.7 coronary arteries angiography see angiography atherosclerotic in children/young adults, 1.7 enlargement/remodelling, 1.6, 2.6, 2.7

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lipid-lowering therapy with elevated apoB and effects on, 2.4 plaque rupture precipitating thrombosis, 1.5 quantification for cardiovascular risk assessment, 2.1–8 recombinant ApoA-1 Milano effects on, in patients with acute coronary syndromes, 2.8 bifurcation lesions, kissing balloon technique, 5.10 bypass graft see bypass graft left see left anterior descending coronary artery disease; left main coronary artery stenosis luminal dimensions see luminal dimensions; occlusion; stenosis multivessel disease see multivessel coronary disease stenting see stenting thrombosis see thrombosis coronary syndromes, acute see acute coronary syndromes cost (economic) of CABG vs stenting in multivessel disease, 6.5, 9.3, 9.6 creatine kinase elevation after PTCA, transient, incidence and clinical significance, 4.4 CREDO trial, 8.9 CURE study, PCI in, 8.8 cutting balloon angioplasty, 7.8 Czeck PRAGUE-2 study, 3.9 Danish trial in Acute MI (DANAMI), 3.8 DART study, 7.7 death see mortality diabetes, PCI (incl. PTCA), 5.2 CABG vs, in patients with unstable angina, 9.1 Dilatation vs. Ablation Revascularization Trial, 7.7 directional atherectomy see atherectomy drug-eluting stents, restenosis with, 9.2 sirolimus-eluting vs standard stents, 6.8 very low rates, 9.2 drug therapy see pharmacological therapy dyslipidaemia see hyperlipidaemia

non-Q wave MI (ESSENCE) trial, 4.7, 8.6 embolic protection devices (in PCI), 7(142) stenotic saphenous vein bypass graft, 7.4, 7.5 endovascular techniques see entries under intravascular Enhanced Suppression of the Platelet IIb/IIIa Receptor with Itegrilin Therapy (ESPRIT), 8.5 enoxaparin, 4.7, 8.6 EPIC investigators, 4.6, 8.1 EPISTENT, 8.3, 8.5 eptifibatide (Integrilin) ESPRIT study, 8.5 IMPACT-II and PURSUIT studies, 8.4 PRIDE study, 8.4 ERBAC study, 7.6 ESPRIT study, 8.5 ESSENCE trial, 4.7, 8.6 ETC-216 (recombinant apoA-1 Milano), effects on atherosclerosis in patients with acute coronary syndromes, 2.8 Evaluation of 7E3 for the Prevention of Ischaemic Complications, 4.6, 8.1 Evaluation of Platelet IIb/IIIa Inhibitor for Stenting, 8.3, 8.5 excimer laser angioplasty, 7.6 experimental studies of PTCA, 10.1 Fab fragment to gpIIB/IIIa receptor, monoclonal see abciximab fatty cell lesions, monocytes and, 1.3 female–male differences in outcome, 5.4 femoro–brachial technique of kissing balloon PTCA, 5.10 fibrocellular occlusion following PTCA, 10.4 FilterWire EX, 7.5 foam cells, monocyte transition into, 1.3 gender and outcome in PTCA, 5.4 German acute MI registries, mortality in primary angioplasty vs thrombolysis, 3.3 glyceryl trinitrate in acute MI, intracoronary application, 3.1 glycoprotein IIb/IIIa inhibitors, 8(164), 8.1–5 in coronary stenting, 8.3 in acute MI, 3.7, 6.7 in high-risk PTCA, 4.6, 8.1 in saphenous vein graft angioplasty with embolic protection device, 7.4 in unstable coronary syndromes (unstable angina and non-ST elevation MI), 4.8

economic cost of CABG vs stenting in multivessel disease, 6.5, 9.3, 9.6 Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and

233

Index

GuardWire, Medtronic, 7.4, 7.5 guidewire passage through coronary thrombus, 3.1

ischaemic syndromes, luminal stenosis (assessed by angiography) correlations with, 2.2

haemodynamic resistance estimation in quantitative coronary angiography, 2.3 HDL mimetic effects on coronary atherosclerosis in patients with acute coronary syndromes, 2.8 heparin (in PCI), unfractionated enoxaparin compared with, in acute coronary syndromes, 8.6 with gpIIb/IIIa inhibitor, 8.7 abciximab and lowering dose of heparin, 8.2 compared with bivalirudin and gpIIb/III inhibitor, 8.7 heparin-coated stents, 3.4 high-density lipoprotein mimetic effects on coronary atherosclerosis in patients with acute coronary syndromes, 2.8 high-risk patients CABG, diabetic patients with unstable angina, 9.1 PCI (incl. PTCA), 5.1–10, 10.2 abciximab in, 4.6, 8.1 histological markers of plaque vulnerability to rupture, 2.7 hypercholesterolaemia, animal models, atherosclerosis in, 1.2–4 hyperlipidaemia atherosclerosis and, 1.2 LDL receptor and, 1.4

kidney dysfunction, outcome associated with, 5.95 kissing balloon technique, bifurcation lesions, 5.10

IMPACT-II study, 8.4 infants, atherosclerotic lesions, 1.7 injury/trauma, mechanical fibrocellular tissue response in PTCA to, 10.4 vascular lesions following, 1.2 Integrelin see eptifibatide intimal proliferation in atherosclerosis, 1.1 in post-angioplasty restenosis, 10.4 Intracoronary Stenting and Angiographic Results: Strut Thickness effect on REstenosis Outcome trial, 6.6 intravascular stents see stenting intravascular ultrasound see ultrasound ISAR-STEREO trial, 6.6 ischaemia, myocardial, thrombolysis in, 4.5 ischaemic complications, post-angioplasty, abciximab in prevention of, 4.6, 8.1

laser angioplasty, excimer, 7.6 LDL receptor and cholesterol homeostasis, 1.4 left anterior descending coronary artery disease, CABG vs stenting, 9.4 left main coronary artery stenosis, unprotected, stenting, 6.9 left ventricular dysfunction and outcome, 5.5 lipid, elevated blood levels see hyperlipidaemia lipid-lowering therapy with elevated apolipoprotein B and effects on coronary artery disease regression, 2.4 lovastatin, elevated apoB and effects on coronary artery disease regression of, 2.4 low-density lipoprotein and cholesterol homeostasis, 1.4 luminal dimensions (vascular) coronary angiographic assessment see angiography ischaemic syndrome correlation with, 2.2 narrowing of see restenosis; stenosis plaque progression without changes in, 2.1, 2.6 intravascular ultrasound compared with angiography in assessment of, 2.5 male–female differences in outcome, 5.4 Maximal Individual Therapy in Acute MI (MITRA) registry, mortality in primary angioplasty vs thrombolysis, 3.3 mechanical injury see injury medial thinning in atheroma, 2.1 Medtronic GuardWire, 7.4, 7.5 men and women, differences in outcome, 5.4 meta-analysis, PTCA primary, vs thrombolytic therapy in acute MI, 3.5 vs CABG, 9.8 metallic stents, earliest use, 6.1

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Index

MIR (Myocardial Infarction Registry), mortality in primary angioplasty vs thrombolysis, 3.3 MITRA registry, mortality in primary angioplasty vs thrombolysis, 3.3 monoclonal antibody to gpIIb/IIIa inhibitors see abciximab monocyte in atherogenesis, 1.3 morbidity, risk factors for see high-risk patients morphological determinants of PTCA outcome in multivessel disease, 5.7 mortality primary angioplasty vs thrombolysis, 3(39–40), 3.3 risk factors in PCI for, 5.1–10 multivessel coronary disease CABG vs PCI, 9.5 CABG vs stenting, economic and clinical outcomes, 6.5, 9.3, 9.6 PTCA diabetics with three-vessel disease, 5.2 morphological and clinical determinants of outcome, 5.7 of unstable angina-related vessel, 4.2 myocardial infarction non-Q wave early invasive and conservative strategies compared in, 4.5 post-angioplasty, diagnosis, 4.4 non-ST segment elevation early invasive and conservative strategies compared in, 4.8 heparin (unfractionated vs LMW) preceding PCI for, 8.6 TIMI risk score for, in prognostication and therapeutic decision-making, 4.7 ST-elevation, primary angioplasty in, 3.1–10 stenting see stenting thrombolytic therapy in see thrombolytic therapy Myocardial Infarction Registry (MIR), mortality in primary angioplasty vs thrombolysis, 3.3 myocardial ischaemia see ischaemia; ischaemic syndromes National Heart, Lung, and Blood Institute (NHLBI) PTCA Registry 1985–1986 and 1977–1981, 5.1 diabetic patients, 5.2

235

left ventricular dysfunction in, 5.5 sex differences in results, 5.4 niacin, elevated apoB and effects on coronary artery disease regression of, 2.4 nitroglycerin in acute MI, intracoronary application, 3.1 OARS trial, 7.2 occlusion, coronary fibrocellular, following PTCA, 10.4 partial see stenosis stents in prevention after angioplasty of, 6.2 total, angioplasty, 5.9 see also restenosis Optimal Atherectomy Restenosis Study, 7.2 outcome, adverse, risk factors see high-risk patients PCI-CURE study, 8.8 pharmacological therapy in coronary artery disease apoB elevated-patients, 2.4 with HDL mimetic (recombinant apoA-1), 2.8 with PCI, 8.1–9 plaque, coronary atheromatous/atherosclerotic intravascular ultrasound assessment, 2.5 luminal dimensions and size of, 2.1, 2.6 medial thinning, 2.1 rupture precipitating thrombosis, 1.5 vulnerability to, histological markers, 2.7 vascular remodelling in response to growth of, 1.6, 2.6, 2.7 platelet glycoprotein IIb/IIIa inhibitors see glycoprotein IIb/IIIa inhibitors sites of drug action, 8(163) survival in hyperlipidaemia, 1.2 popliteal artery, coilspring tubes, 6.1 PRAGUE-2 study, 3.9 prehospital thrombolysis vs primary angioplasty, 3.6 PRIDE study, 8.4 primary angioplasty in acute MI, 3.1–10 definition, 3(39) stenting in see stenting thrombolytic therapy vs see thrombolytic therapy PURSUIT study, 8.4

Index

Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE) 2 study, 8.7 receptor-mediated pathway in cholesterol homeostasis, 1.4 referral for CABG, drug-eluting stents reducing, 9.2 renal insufficiency, outcome associated with, 5.95 ReoPro see abciximab REPLACE-2 study, 8.7 restenosis directional atherectomy, 7.1, 7.2, 7.3 post-angioplasty, 10.4 cutting balloon and prevention of, 7.8 directional atherectomy restenosis compared with, 7.1, 7.2, 7.3 excimer laser ablation restenosis compared with, 7.6 risk factors, 4.3 rotational atherectomy restenosis compared with, 7.6, 7.7 stent prevention of, 6.2 stent restenosis compared with, 6.3 stent angioplasty restenosis compared with, 6.3 drug-eluting stents see drug-eluting stents strut thickness effects, 6.6 risk factors see high-risk patients rotational atherectomy see atherectomy SAFER trial, 7.4 saphenous vein bypass graft stenosis, angioplasty, 5.8 embolic protection device, 7.4, 7.5 self-expanding stents in prevention of postangioplasty occlusion/restenosis, 6.2 sex differences in PTCA results, 5.4 SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial, 3.5, 5.6 shock, cardiogenic, 5.6 Simpson Coronary AtheroCath, 7(141–2) sirolimus-eluting stents (SIRIUS trial), 6.8 smooth muscle cell, arterial in atherosclerosis, 1.1 in restenosis following PTCA, 10.4 ST elevation MI with, primary angioplasty in, 3.1–10 MI without see myocardial infarction, non-ST segment elevation

statins, elevated apoB and effects on coronary artery disease regression of, 2.4 stenosis/narrowing coronary ACC/AHA PTCA classification of primary target stenosis, 5.7 left anterior descending, CABG vs stenting in high-grade stenosis, 9.4 left main, unprotected, stenting, 6.9 plaque accumulation and, 2.1, 2.6 plaque rupture with severe pre-existing, precipitating thrombosis, 1.5 severity (assessed by angiography), correlations with ischaemic syndromes, 2.2 coronary saphenous vein graft see saphenous vein bypass graft see also occlusion; restenosis Stent Primary Angioplasty in MI Study Group, 3.4 Stent Restenosis Study Group, 6.3 stenting, 6.1–9 abciximab with see abciximab CABG vs in left anterior descending disease, 9.4 in left main coronary artery stenosis, 6.9 in multivessel disease, cost and clinical outcomes, 6.5, 9.3, 9.6 drug-eluting stents see drug-eluting stents earliest developments, 6(115), 6.1 eptifibatide with, 8.5 intravascular ultrasound guidance, without anticoagulation, 6.4 in primary angioplasty (in acute MI), 3(39), 3.4 meta-analysis, 3.5 platelet glycoprotein IIb/IIIa inhibitors with, 3.7, 6.7 PTCA compared with, 6.7, 8.3 randomized study, 6.3 strut thickness effects on restenosis, 6.6 streptokinase in acute MI, 3.1 primary angioplasty vs, 3.2 long-distance transport for, 3.9 STRESS study, 6.3 strut thickness effects on stent restenosis, 6.6 surgical referral for CABG, drug-eluting stents reducing, 9.2 TACTICS – TIMI 18 investigators, 4.8 thienopyridines see clopidogrel; ticlopidine

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thrombin inhibitor  planned gpIIb/IIIa inhibitor compared with heparin and provisional gpIIb/IIA inhibitor, 8.7 thrombolytic (fibrinolytic) therapy in acute MI, 3(39), 3.1, 4.5, 10.3 limitations, 3(39) primary angioplasty vs, 3(39–40), 3.2, 3.8 clinical characteristics and outcome related to time to presentation treated by, 3.10 long-distance transport for, 3.9 meta-analysis, 3.5 mortality comparisons, 3(39–40), 3.3 prehospital thrombolysis vs primary angioplasty, 3.6 see also TIMI trials thrombolytic (fibrinolytic) therapy in unstable angina, 4.5 thrombosis, coronary guidewire passage through thrombus, 3.1 plaque rupture precipitating, 1.5 see also antithrombotics ticlopidine in intravascular ultrasound-guided stenting, 6.4 TIMI (Thrombolysis in Myocardial Infarction) trials TIMI IIB and heparin (unfractionated vs LMW) before PCI for unstable angina and non-ST elevation MI, 8.6

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and risk score for unstable angina and non-ST elevation MI, 4.7 TIMI IIIB, 4.5 see also TACTICS – TIMI 18 investigators tirobifan in unstable angina and non-ST elevation MI, 4.8 tissue plasminogen activator (tPA) in MI, vs other strategies, 4.5 primary angioplasty vs, 3.5 in unstable angina, 4.5 trauma, mechanical see injury trinitroglycerin in acute MI, intracoronary application, 3.1 ultrasound, intravascular compared with cineangiography in assessment of vascular dimensions, 2.5 stent guidance without anticoagulation, 6.4 VA AWESOME study, 9.1 vascular angiography see angiography vascular biology of atherosclerosis, 1.1–8 ventricular dysfunction, left, outcome in, 5.5 Veterans Affairs AWESOME study, 9.1 women and men, differences in outcome, 5.4

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