Table Of ContentC O N T E M P O R A R Y C A R D I O L O G Y
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LATELET LYCOPROTEIN B A NHIBITORS
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IN ARDIOVASCULAR ISEASE
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C C
ONTEMPORARY ARDIOLOGY
CHRISTOPHER P. CANNON, MD
SERIES EDITOR
Platelet Glycoprotein IIb/IIIa Inhibitors in Essentials of Bedside Cardiology: With A
Cardiovascular Disease, Second Edition, Complete Course in Heart Sounds and
edited by A. Michael Lincoff, MD, 2003 Murmurs on CD, Second Edition, by
Nuclear Cardiology Basics: How to Set Up Jules Constant, MD, FACC, 2003
and Maintain a Laboratory, edited by Primary Angioplasty in Acute Myocardial
Frans J. Th. Wackers, MD, Wendy Bruni, Infarction, edited by James E. Tcheng,
CNMT, and Barry L. Zaret, MD, 2003 MD, 2002
Minimally Invasive Cardiac Surgery, Second Cardiogenic Shock: Diagnosis and Treatment,
Edition, edited by Mehmet C. Oz, MD, edited by David Hasdai, MD, Peter B.
and Daniel J. Goldstein, MD, 2003 Berger, MD, Alexander Battler, MD, and
Cardiovascular Health Care Economics, edited David R. Holmes, Jr., MD, 2002
by William S. Weintraub, MD, 2003 Management of Cardiac Arrhythmias, edited
Heart Failure: A Clinician's Guide to Ambula- by Leonard I. Ganz, MD, 2002
tory Diagnosis and Treatment, edited by Diabetes and Cardiovascular Disease, edited
Mariell L. Jessup, MD, FACC, FAHA, and by Michael T. Johnstone, MD
Evan Loh, MD, FACC, FAHA, 2003 and Aristidis Veves, MD, DSC, 2001
Cardiac Repolarization: Basic and Clinical Blood Pressure Monitoring in Cardiovascular
Research, edited by Ihor Gussak, MD, Medicine and Therapeutics, edited by
PhD, Charles Antzelevitch, PhD, co-edited William B. White, MD, 2001
by Stephen C. Hammill, MD, Win-Kuang Vascular Disease and Injury: Preclinical
Shen, MD, and Preben Bjerregaard, MD, Research, edited by Daniel I. Simon, MD,
DMSc, 2003 and Campbell Rogers, MD 2001
Management of Acute Coronary Syndromes, Preventive Cardiology: Strategies for the
Second Edition, edited by Christopher Prevention and Treatment of Coronary
P. Cannon, MD 2003 Artery Disease, edited by JoAnne Micale
Aging, Heart Disease, and Its Management: Foody, MD, 2001
Facts and Controversies, edited by Niloo Nitric Oxide and the Cardiovascular System,
M. Edwards, MD, Mathew S. Maurer, MD, edited by Joseph Loscalzo, MD, PhD and
and Rachel B. Wellner, MPH, 2003 Joseph A. Vita, MD, 2000
Peripheral Arterial Disease: Diagnosis and Annotated Atlas of Electrocardiography: A
Treatment, edited by Jay D. Coffman, MD Guide to Confident Interpretation, by
and Robert T. Eberhardt, MD, 2003 Thomas M. Blake, MD, 1999
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P G
LATELET LYCOPROTEIN
II /III I
B A NHIBITORS
C D
IN ARDIOVASCULAR ISEASE
Second Edition
Edited by
A. M L ,
ICHAEL INCOFF MD
Department of Cardiovascular Medicine,
The Cleveland Clinic Foundation,
Cleveland, OH
H P
UMANA RESS
T , N J
OTOWA EW ERSEY
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© 2003 Humana Press Inc.
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Library of Congress Cataloging-in-Publication Data
Platelet glycoprotein IIb/IIIa inhibitors in cardiovascular disease / edited by A. Michael
Lincoff.-- 2nd ed.
p. ; cm. -- (Contemporary cardiology)
Includes bibliographical references and index.
ISBN 1-58829-185-5 (alk. paper) eISBN 1-59259-376-3.
1. Coronary heart disease--Chemotherapy. 2. Coronary heart disease--Pathophysiology.
3. Platelet glycoprotein GPIIb-IIIa complex--Inhibitors--Therapeutic use--Testing. I.
Lincoff, A. Michael. II. Contemporary cardiology (Totowa, N.J. : unnumbered)
[DNLM: 1. Cardiovascular Diseases--drug therapy. 2. Platelet Glycoprotein GPIIb-IIIa
Complex--antagonists & inhibitors. WG 166 P716 2003]
RC685.C6P585 2003
616.1'061--dc21
2002191923
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P
REFACE
One of the most important developments in the field of cardiovascular medicine over
the last two decades has been recognition of the key role played by arterial thrombosis
in the pathogenesis of acute coronary syndromes, ischemic complications of percutane-
ous coronary revascularization, and coronary and peripheral atherosclerosis. The phar-
macologic armamentarium directed against vascular thrombosis has thus expanded
substantially during that time, with development of new fibrinolytic agents, low-molecu-
lar-weight heparins, direct thrombin inhibitors, antagonists to platelet activation, and the
platelet glycoprotein IIb/IIIa inhibitors. Though clinical investigations of these com-
pounds have been marked by failures as well as successes, there is little doubt that
enhanced antithrombotic therapies have markedly improved the outcome of patients
undergoing coronary revascularization or with acute coronary syndromes.
Glycoprotein IIb/IIIa receptor antagonists were introduced into clinical practice to
overcome the limitations of approaches that inhibit only individual pathways of platelet
activation. Multiple mechanisms of platelet activation in response to different agonists
converge on the platelet membrane glycoprotein IIb/IIIa complex, the “final common
pathway” of platelet aggregation. The clinical hemorrhagic syndrome caused by a rare
inherited defect in this receptor (Glanzmann’s thrombasthenia), characterized by muco-
cutaneous and postsurgical bleeding, but infrequent spontaneous organ (particularly
central nervous system) bleeding, suggested that therapeutic inhibition of this receptor
might be a potent, yet well-tolerated means of treating thrombotic disorders. The first
agent directed against the receptor, a monoclonal antibody fragment developed by Coller
that blocks the interaction of glycoprotein IIb/IIIa with adhesion molecules, received
marketing approval in 1995. On the basis of unequivocal efficacy demonstrated during
extensive systematic controlled clinical trial evaluations, three parenteral glycoprotein
IIb/IIIa inhibitors are presently available for the management of patients undergoing
percutaneous coronary revascularization or with unstable ischemic syndromes.
In 1999, we published the first edition of this text, a comprehensive, definitive, and
detailed overview of the preclinical and clinical development of the class of glycoprotein
IIb/IIIa receptor antagonists. Since that time, new trials have evaluated the relative effi-
cacy of different agents, expanded our understanding of the roles of these drugs in the
management of acute coronary syndromes, critically assessed the efficacy of oral agents,
and explored the interaction between glycoprotein IIb/IIIa antagonists and other
antithrombotic and mechanical interventional therapies. The goals of this second edition,
as with the first, are to elucidate the theoretical basis for inhibition of platelet aggregation
in the treatment of coronary syndromes, to synthesize the evidence demonstrating the
efficacy of glycoprotein IIb/IIIa blockade in inhibiting ischemic complications of coro-
nary intervention and the acute coronary syndromes, and to provide guidelines for the use
of this class of agents in the clinical management of cardiovascular disease. In every case,
chapters have been contributed by acknowledged experts in the field, including the
pioneers in the discovery and characterization of cell surface adhesion molecules and the
glycoprotein IIb/IIIa receptor, as well as the principal investigators of the major clinical
trials. The most current data are included, with the intent to provide a comprehensive
body of knowledge of the contemporary “state of the art” in this field.
v
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vi Preface
The first section of Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular
Disease, Second Edition outlines the basic pathophysiology underlying the theoretical
usefulness and development of this class of agents. In Chapter 1, the role of thrombosis
and platelet activity in the pathophysiology of acute ischemic syndromes or complications
of coronary intervention are reviewed, providing the underpinnings for antithrombotic
therapy in cardiovascular disease. Platelet adhesion, the essential reaction for the hemo-
static function of platelets, is discussed in Chapter 2, followed by a detailed description of
the structure and functions of the glycoprotein IIb/IIIa receptor in Chapter 3. The “bench
to bedside” development of the first agent directed against this receptor is recounted in
Chapter 4, along with a summary of the pharmacologic properties of the other parenteral
compounds of this class.
The second section concentrates on the adjunctive use of glycoprotein IIb/IIIa block-
ade during percutaneous coronary revascularization. The three agents that have been
evaluated for this indication (abciximab, eptifibatide, and tirofiban) are discussed in
Chapters 5–7, focusing on data derived from the pivotal Phase III and IV studies. A
summary overview then follows, integrating the results of the major trials in this setting,
comparing the different agents, and providing practical guidelines for clinical use.
The third section focuses on glycoprotein IIb/IIIa blockade in the management of the
acute coronary ischemic syndromes. Chapters 9–11 detail the roles of these agents as
adjuncts to medical and revascularization therapies for unstable angina. Chapters 12 and
13 discuss the use of glycoprotein IIb/IIIa antagonists with mechanical or pharmacologic
(fibrinolytic) reperfusion therapies for ST-segment-elevation myocardial infarction.
The fourth section explores practical issues with the use of these agents and provides
a view into future applications in the treatment of vascular disease. Medico-economic
aspects are analyzed in Chapter 14. Chapters 15 and 16 describe techniques for monitor-
ing the efficacy of platelet inhibition and provide preliminary data regarding the interac-
tion of glycoprotein IIb/IIIa antagonists with other inhibitors of platelet function or the
coagulation cascade. The unexpected failure of chronic oral glycoprotein IIb/IIIa therapy
in a series of large-scale trials is discussed in Chapter 17. Chapter 18 speculates on the
possibility that clinical benefit may be derived from these agents through mechanisms
other than platelet inhibition, such as antiinflammatory effects. The potential efficacy
and established risks of glycoprotein IIb/IIIa blockade in relation to cerebrovascular
disease are explored in Chapters 19 and 20. Finally, advances made in the management
of vascular thrombosis and new directions for progress in this field are summarized in
Chapter 21.
I am most appreciative of the superb contributions by the chapter authors of this book,
who drew on their considerable expertise, first-hand experience, and perspectives to
produce a truly comprehensive discussion of this field. Additionally, the publisher and
production staff at Humana Press made exceptional efforts for the timely completion of
this project. Marion Tomasko and Robin Moss deserve recognition for their imaginative
book cover artwork.
I would also like to recognize the continued support, tolerance, and understanding of
my wife Debra and our children, Gabrielle, Aaron, and Jacob.
A. Michael Lincoff, MD
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C
ONTENTS
Preface............................................................................................................................v
Contributors...................................................................................................................ix
P I B P
ART ASIC RINCIPLES
1 Thrombosis in Acute Coronary Syndromes and Coronary
Interventions.................................................................................3
Thaddeus R. Tolleson and Robert A. Harrington
2 Platelet Adhesion............................................................................23
Edward F. Plow
3 Glycoprotein IIb/IIIa in Platelet Aggregation and Acute
Arterial Thrombosis....................................................................39
Patrick Andre and David R. Phillips
4 Glycoprotein IIb/IIIa Antagonists: Development of Abciximab
and Pharmacology of Abciximab, Tirofiban,
and Eptifibatide ..........................................................................73
Barry S. Coller
P II G II /III B D C
ART LYCOPROTEIN B A LOCKADE URING ORONARY
I
NTERVENTION
5 Abciximab During Percutaneous Coronary Intervention:
EPIC, EPILOG, and EPISTENT Trials...................................105
A. Michael Lincoff
6 Eptifibatide in Coronary Intervention: The IMPACT
and ESPRIT Trials....................................................................125
Jean-Pierre Dery, J. Conor O’Shea, and James E. Tcheng
7 Tirofiban in Interventional Cardiology: The RESTORE
and TARGET Trials..................................................................147
Nicholas Valettas and Howard C. Herrmann
8 Overview of the Glycoprotein IIb/IIIa Interventional Trials.......167
A. Michael Lincoff and Eric J. Topol
P III G II /III B A
ART LYCOPROTEIN B A LOCKADE FOR CUTE
I S
SCHEMIC YNDROMES
9 The Use of Abciximab in Therapy-Resistant Unstable Angina:
Clinical and Angiographic Results of the CAPTURE Pilot
Trial and the CAPTURE Study...................................................203
Marcel J. B. M. van den Brand and Maarten L. Simoons
10 Unstable Angina Trials: PARAGON, PURSUIT, PRISM,
PRISM-PLUS, and GUSTO-IV.................................................233
David J. Moliterno
vii
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viii Contents
11 Platelet Glycoprotein IIb/IIIa Inhibitors and an Invasive
Strategy.....................................................................................263
Christopher P. Cannon
12 Glycoprotein IIb/IIIa Receptor Blockade in Myocardial
Infarction: Adjunctive Therapy to Percutaneous
Coronary Interventions ............................................................275
Franz-Josef Neumann
13 Glycoprotein IIb/IIIa Receptor Blockade in Acute Myocardial
Infarction: Adjunctive Therapy to Fibrinolysis .......................289
Sorin J. Brener
P IV P I F A
ART RACTICAL SSUES AND UTURE PPLICATIONS
14 Economics of Glycoprotein IIb/IIIa Inhibition............................305
Daniel B. Mark
15 Platelet Monitoring and Interaction of Glycoprotein IIb/IIIa
Antagonists with Other Antiplatelet Agents............................321
Steven R. Steinhubl
16 Platelet Glycoprotein IIb/IIIa Antagonists: Their Interaction
with Low-Molecular-Weight Heparins and Direct
Thrombin Inhibitors..................................................................341
Amol S. Bapat, Naji Yazbek, and Neal S. Kleiman
17 Oral Agents ...................................................................................365
L. Kristin Newby
18 Platelet Glycoprotein IIb/IIIa Inhibitors: Effects Beyond
the Platelet................................................................................383
Dean J. Kereiakes and Pascal J. Goldschmidt-Clermont
19 Cerebrovascular Interventions......................................................397
Leslie Cho and Jay S. Yadav
20 Cerebrovascular Aspects of Glycoprotein IIb/IIIa Receptor
Inhibitors...................................................................................409
Cathy A. Sila
21 Evolution of Drug Development in Evidence-Based Medicine:
Summary and the Future..........................................................425
David E. Kandzari, David F. Kong, and Robert M. Califf
Index...........................................................................................................................459
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C
ONTRIBUTORS
PATRICK ANDRE, PhD • Millennium Pharmaceuticals Inc., South San Francisco, CA
AMOL S. BAPAT, MD • The Methodist DeBakey Heart Center, Baylor College
of Medicine, Houston, TX
SORIN J. BRENER, MD • Department of Cardiovascular Medicine, The Cleveland Clinic
Foundation, Cleveland, OH
ROBERT M. CALIFF, MD • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
CHRISTOPHER P. CANNON, MD • Cardiovascular Division, Department of Medicine,
Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
LESLIE CHO, MD • Department of Cardiovascular Medicine, The Loyola University
Medical Center, Chicago, IL
BARRY S. COLLER, MD • Laboratory of Blood and Vascular Biology, Rockefeller
University, New York, NY
JEAN-PIERRE DERY, MD • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
PASCAL J. GOLDSCHMIDT-CLERMONT, MD • Division of Cardiology, Duke University
Medical Center, Durham, NC
ROBERT A. HARRINGTON, MD • Division of Cardiology, Duke Clinical Research Institute,
Duke University Medical Center, Durham, NC
HOWARD C. HERRMANN, MD • Cardiovascular Division, Hospital of the University
of Pennsylvania, University of Pennsylvania Health System, Philadelphia, PA
DAVID E. KANDZARI, MD • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
DEAN J. KEREIAKES, MD • The Lindner Center for Research and Education, Ohio Heart
Health Center, Ohio State University, Cincinnati, OH
NEAL S. KLEIMAN, MD • The Methodist DeBakey Heart Center, Baylor College
of Medicine, Houston, TX
DAVID F. KONG, MD • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
A. MICHAEL LINCOFF, MD • Department of Cardiovascular Medicine, The Cleveland
Clinic Foundation, Cleveland, OH
DANIEL B. MARK, MD, MPH • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
DAVID J. MOLITERNO, MD • Department of Cardiovascular Medicine, The Cleveland
Clinic Foundation, Cleveland, OH
FRANZ-JOSEF NEUMANN, MD • Heart Center, Bad Krozingen, Germany
L. KRISTIN NEWBY, MD • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
J. CONOR O’SHEA, MD • Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC
DAVID R. PHILLIPS, PhD • Millennium Pharmaceuticals Inc., South San Francisco, CA
ix
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