Platelet Glycoprotein IIb/IIIa Inhibitors in Cardiovascular Disease

372 Pages·1999·6.339 MB·English

by  Thaddeus R. Tolleson MD, Robert A. Harrington MD (auth.), A. Michael Lincoff MD, Eric J. Topol MD (eds.)

PLATELET GLYCOPROTEIN
lib/lila
INHIBITORS
IN CARDIOVASCULAR DISEASE
CoNTEMPORARY CARDIOLOGY
CHRISTOPHER P. CANNON
SERIES EDITOR
PlATELET GLYCOPROTEIN lib/lila INHIBITORS IN CARDIOVASCULAR DISEASE
Edited by A. Michael Lincoff, MD, and Eric J. Topol, MD, 1999
MANAGEMENT OF ACUTE CORONARY SYNDROMES
Edited by Christopher P. Cannon, MD, 1999
MINIMALLY INVASIVE CARDIAC SURGERY
Edited by Mehmet C. Oz, MD, and Daniel]. Goldstein, MD, 1999
ANNOTATED ATlAS OF ELECTROCARDIOGRAPHY
Edited by Thomas M. Blake, MD, 1999
PLA]'EI.ET
GLYCOPROTEIN
lib/lila
INHIBITORS
IN CARDIOVASCUlAR
DISFASE
Edited by
A.
MICHAEL LINCOFF, MD
J.
Eruc
ToPOL, MD
The Cleveland Clinic Foundation, Cleveland, Ohio
*
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
© 1999 Springer Science+ Business Media New York
Originally published by Humana Press Inc. in 1999
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Platelet glycoprotein lib/Ilia inhibitors in cardiovascular disease I edited by A. Michael Lincoff, Eric J. Topol.
p. em. --(Contemporary cardiology ; 2)
Includes index.
ISBN 978-1-4757-6202-0 ISBN 978-1-59259-724-6 (eBook)
DOI 10.1007/978-1-59259-724-6
I. Heart--Surgery--Miscellanea. 2. Coronary artery bypass--Miscellanea. 3. Operations, Surgical--
Miscellanea. I. Lincoff, A. Michael, MD II. Topol, Eric J., MD. III. Series: Contemporary cardiology
(Totowa, NJ) ; 2.
[DNLM: l. Heart Diseases--surgery. 2. Surgical Procedures, Minimally Invasive--methods. 3. Cardiac
Surgical Procedures--methods. 4. Vascular Surgical Procedures--methods. WG 169M665 1999]
RD598.M525 1999
617.4' 12--dc21
DNLM/DLC
for Library of Congress 98-30788
CIP
PREFACE
The last two decades have witnessed a burgeoning interest in the development and
application of antithrombotic approaches to the treatment of cardiovascular diseases,
based on recognition of the key roles played by the arterial platelet-thrombus in the
pathogenesis of acute coronary syndromes, ischemic complications of percutaneous
coronary revascularization, coronary artery bypass graft disease, and even de novo native
and peripheral artery atherosclerosis. Aspirin celebrated its 1O Oth anniversary as a thera
peutic agent in 1997, although only recently has some of its mechanism of action been
elucidated and its efficacy demonstrated in controlled studies. Heparin too has been
employed since its introduction in 1916 as an anticoagulant, but again with only recent
and relatively limited controlled evaluation for the treatment of cardiovascular disease.
In the last few years, the pharmacologic armamentarium directed against vascular throm
bosis has been substantially enriched, with introduction into practice of new fibrinolytic
agents, low molecular weight heparins, direct thrombin inhibitors, antagonists to various
pathways of platelet activation, and the platelet glycoprotein lib/Ilia inhibitors.
Despite this recent expansion in the number of alternatives for anti thrombotic therapy,
the clinical efficacy of such compounds in the management of cardiovascular disease has
been at times disappointing. Among the agents directed against the activity and genera
tion of thrombin, heparin has been used most broadly, but with unproven or limited
effectiveness in many settings. For example, although employed universally during
percutaneous coronary interventional procedures, heparin has never been tested in a
placebo-controlled fashion among these patients. Moreover, small trials ofheparin in the
settings of unstable angina or acute myocardial infarction have suggested only modest
efficacy of this agent in limiting ischemic complications. Hirudin and hirulog, potent
direct inhibitors of thrombin activity that overcome many of the intrinsic limitations of
heparin, have only modestly improved clinical outcome compared with heparin in large
scale trials of coronary intervention or acute ischemic syndromes. Similarly, despite the
theoretical advantages of!o w molecular weight heparins, the efficacy of these agents has
proven to be variable, with only enoxaparin showing evidence of clinical benefit over
unfractionated heparin in controlled studies. The strategy of clot lysis with fibrinolytic
or "thrombolytic" compounds has been clearly demonstrated in large-scale trials tore
duce mortality by reestablishing coronary patency during acute myocardial infarction.
Yet even the newest generation of these agents remains limited by an apparent "ceiling"
of reperfusion rates, as well as the consistent failure of these compounds to improve
clinical outcome (with trends toward more frequent ischemic and bleeding complica
tions) in the settings ofunstable angina or percutaneous coronary intervention.
Approaches to inhibition of the platelet have met with somewhat more uniform suc
cess in the treatment of arterial thrombosis, a finding that suggests that platelet deposi
tion, activation, and aggregation are the crucial initiating components of the response to
arterial injury. Placebo-controlled trials have consistently demonstrated that therapy
v
VI Preface
with aspirin will reduce the risk of ischemic events by up to 30-40% across the broad
spectrum of atherosclerotic diseases of the arterial tree. Through its irreversible inacti
vation of platelet cyclo-oxygenase, aspirin inhibits the thromboxane-mediated mecha
nism of platelet activation; compounds directed against other activation pathways of the
platelet have generally exhibited efficacy comparable but not markedly superior to that
of aspirin. The thienopyridines, ticlopidine and clopidogrel, prevent platelet activation
via inhibition of the adenosine diphosphate receptor, with a recent large-scale trial dem
onstrating modest benefit of clopidogrel over aspirin in reducing the long-term risk of
ischemic events among patients with cardiovascular, cerebrovascular, or peripheral vas
cular atherosclerosis. Clinical experience with the thienopyridines administered in ad
dition to aspirin among patients undergoing coronary stent implantation, however, has
suggested that clinical efficacy may be substantially enhanced when more than one
mechanism of platelet activation is inhibited.
The limitations of compounds directed against individual pathways of platelet activa
tion may therefore be overcome by approaches aimed at the "final common pathway" of
platelet aggregation, the surface glycoprotein lib/Ilia receptor. Multiple mechanisms of
platelet activation in response to different agonists all "converge" to render this trans
membrane complex competent to bind circulating adhesion molecules and crosslink
adjacent platelets. The clinical hemorrhagic syndrome caused by a rare inherited defect
in this receptor (Glanzmann's thrombasthenia), characterized by mucocutaneous 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. Following the initial devel
opment by Coller of a monoclonal antibody that blocks the interaction of this receptor
with adhesion molecules, peptide and nonpeptide synthetic molecules with similar activ
ity were also designed. Systematic programs of controlled clinical trial evaluation have
demonstrated that these agents are markedly effective and safe in reducing the risk of
adverse ischemic events among a broad spectrum of patients with atherosclerotic cardiac
disease. In 1995, the first glycoprotein lib/Ilia antagonist, abciximab, received market
ing approval as an adjunct to percutaneous coronary revascularization, with two addi
tional agents, eptifibatide and tirofiban, approved by the Food and Drug Administration
in 1998 for the management of patients with unstable angina. This class oft herapy is now
increasingly employed by physicians caring for patients with stable and unstable coro
nary syndromes.
Platelet Glycoprotein Ila/Illb Inhibitors in Cardiovascular Disease is a comprehen
sive, definitive, and detailed overview of the preclinical and clinical development of the
class of glycoprotein lib/Ilia receptor antagonists. The goal of the book is to elucidate
the theoretical basis for inhibition of platelet aggregation in the treatment of coronary
syndromes, to present and synthesize the evidence demonstrating the efficacy of glyco
protein lib/Ilia blockade in inhibiting ischemic complications of coronary intervention
and the acute coronary syndromes, to provide guidelines for the use oft his class of agents
in the clinical management of cardiovascular disease, and to provide a speculative view
Preface
Vll
of other potential applications of this class of therapy. In every case chapters have been
authored by acknowledged experts in the field, including the pioneers in the discovery
and characterization of cell surface adhesion molecules and the glycoprotein Ilb/IIIa
receptor and the principal investigators for the major clinical trials oft he receptor antago
nists. The most current data are included, producing a complete body of knowledge of
the contemporary "state of the art" in this field.
Part I ofthe book concentrates on the basic pathophysiology underlying the theoretical
usefulness and development of this class of agents. In Chapter 1, Drs. Tolleson and
Harrington provide the underpinnings for anti thrombotic therapy in cardiovascular dis
ease by reviewing the role of thrombosis and platelet activity in the pathophysiology of
acute ischemic syndromes or complications of coronary intervention. The function of
cell surface adhesion molecules in mediating platelet adhesion, the essential reaction for
the hemostatic function of platelets, is discussed by Dr. Plow in Chapter 2, followed by
a detailed description ofthe structure and functions of the glycoprotein lib/III receptor
by Drs. Law and Phillips. Dr. Coller then recounts the "bench to bedside" development
of the first agent directed against this receptor, the monoclonal antibody fragment
abciximab, and summarizes the pharmacologic properties of the currently available
compounds of this class.
Part II concentrates on the clinical setting in which the role of glycoprotein lib/Ilia
blockade has been most intensively studied thus far: percutaneous coronary
revascularization. The three agents that have been evaluated for this indication
(abciximab, eptifibatide, and tirofiban) are discussed in Chapters 5-8, focusing on data
derived from the pivotal Phase III and IV trials. In Chapter 5, I review the EPIC, EPILOG,
and EPISTENT trials, which together established the efficacy of abciximab among the
broad spectrum of patients undergoing coronary balloon angioplasty, atherectomy, or
stent implantation. Drs. O'Shea and Tcheng discuss the IMPACT II trial testing eptifibatide
among patients undergoing coronary intervention for a variety of indications in Chapter
6, whereas Drs. Salame, King, and Chronos summarize the RESTORE trial oftirofiban
in patients treated by revascularization for acute ischemic syndromes in Chapter 7.
Chapter 8 by Drs. van den Brand and Simoons focuses on the strategy tested in the
CAPTURE trial of pretreatment by glycoprotein Ilb/IIIa blockade with abciximab for
refractory unstable angina. Part II concludes with a summary chapter by Dr. Topol and
myself integrating the results of the major trials of glycoprotein lib/Ilia during coronary
intervention, comparing the different agents and providing practical guidelines for clini
cal use.
Part III focuses on the emerging role ofg lycoprotein lib/Ilia blockade during the acute
coronary ischemic syndromes of unstable angina and acute myocardial infarction. In
Chapter 10, Drs. Moliterno and White provide a comprehensive review and synthesis of
the results of the four major trials (PURSUIT, PRISM PLUS, PRISM, and PARAGON),
which demonstrated the role of empiric therapy with eptifibatide, tirofiban, or lamifiban
among patients with unstable angina or myocardial infarction without ST -segment eleva
tion. Drs. Greenbaum, Harrington, and Ohman discuss in Chapter II the applications of
Preface
Vlll
glycoprotein Ilb/IIIa blockade to the treatment of acute myocardial infarction with ST
segment elevation as an adjunct to mechanical or pharmacologic reperfusion.
Part IV provides a view into the future development and application of this class of
agents to the treatment of vascular disease. The medicoeconomic aspects of this therapy
in the settings of coronary intervention or acute ischemic syndromes are analyzed by Dr.
Mark in Chapter 12. Drs. Kleiman, Mazur, and Graziadei describe and evaluate the
various techniques of monitoring platelet function in Chapter 13, an issue that is becom
ing increasingly important for the optimization of platelet inhibitor dosing, particularly
with long-term oral therapy. The "new frontier" of chronic anti platelet therapy with oral
glycoprotein Ilb/IIla agents is discussed by Drs. Kereiakes and Cannon in Chapter 14, a
strategy that holds promise as a means of extending the efficacy of parenteral agents or
providing long-term protection against ischemic events in high-risk individuals. Dr. Sila
writes from the neurologist's viewpoint in Chapter 15, first summarizing the intracranial
hemorrhagic risk associated with these agents and then speculating on the potential
applications of this class of therapy to the treatment of cerebrovascular disease. Finally,
Dr. Califf summarizes his overview and perspective on the advances made in the man
agement of vascular thrombosis and new directions for progress in this field.
The pharmacologic inhibition of the platelet glycoprotein lib/Ilia receptor represents
one of the most exciting fields of cardiovascular research, with rapid, logical, evidence
based development from the laboratory to broad clinical use. The information described
in this book provides a compelling body of data supporting the effectiveness and safety
of these agents in the treatment of thrombotic vascular disease. In the setting of coronary
intervention, glycoprotein lib/Ilia blockade represents the most important advance in
pharmacotherapy since aspirin and, together with stenting, has established a new stan
dard ofe fficacy for this procedure. In the acute coronary syndromes, these agents provide
protection against important ischemic events among patients treated conservatively or by
revascularization. The rationale for application of these agents to reperfusion therapy
for myocardial infarction is sound, and data from Phase II studies in this setting are
encouraging. The potential clearly exists to extend these therapies to the management of
cerebrovascular and peripheral vascular disease. The field will continue to advance by
development of new parenteral and oral agents, refinement of techniques for platelet
function monitoring, and evaluation ofthe combination of glycoprotein lib/lila blockade
with novel inhibitors of thrombin or other components of the coagulation cascade.
I acknowledge and express my appreciation for the superb contributions by the chapter
authors of this book, who drew on their considerable expertise and first-hand experience
to produce a truly up-to-date and comprehensive discussion of this field. Additionally,
the publisher and production staff atH umana Press, including Paul Dolgert, Fran Lipton,
and Susan Giniger, made exceptional efforts for the timely completion of this project.
Robin Moss deserves recognition for her imaginative book cover artwork. My sincere
gratitude goes to my coeditor, Eric J. Topol, who not only provided experience and
Preface ix
counsel invaluable to the creation oft his book, but has led the clinical development oft his
field with vision and energy and has guided and facilitated my own participation in these
research activities.
Most importantly, I would like to recognize the support and patience of my wife,
Debra, and our children, Gabrielle, Aaron, and Jacob without whose tolerance and under
standing of conflicting time demands, no meaningful professional endeavors on my part
would be possible.
A. Michael Lincoff, MD
CoNTENTS
Preface ........................................................................................................ v
Contributors ........................................................................................... xiii
PART I BASIC PRINCIPLES
1 Thrombosis in Acute Coronary Syndromes and
Coronary Interventions ...................................................................... 3
Thaddeus R. Tolleson and Robert A. Harrington
2 Mechanisms of Platelet Adhesion ................................................. 21
Edward F. Plow
3 Glycoprotein lib-Ilia in Platelet Aggregation and Acute Arterial
Thrombosis ................................................................................ 3 5
Debbie A. Law and David R. Phillips
4 Glycoprotein lib/Ilia Antagonists: Development of Abciximab and
Pharmacology of Select Agents ................................................ 6 7
Barry S. Coller
lib/lila
PART II GLYCOPROTEIN BLOCKADE DURING
CoRONARY INTERVENTION
5 Abciximab in Coronary Intervention-The EPIC, EPILOG,
EPISTENT Trials ...................................................................... 93
A. Michael Lincoff
6 Eptifibatide in Coronary Intervention-The IMPACT Trials .... 115
Conor O'Shea and James E. Tcheng
7 Tirofiban in Coronary Intervention- The RESTORE Trial ........ 127
Mahomed Y Sa/arne, Spencer B. King, III,
and Nicolas A. Chronos
8 The Use of Abciximab in Therapy Resistant Unstable Angina:
Clinical and Angiographic Results of the CAPTURE Pilot and
the CAPTURE Study ................................................................. 143
Marcel J. B. M. van den Brand and Maarten L. Simoons
9 Overview of the Glycoprotein lib/Ilia Inhibitor Interventional Trials ...
................................................................................................... 169
A. Michael Lincoff and Eric J. Topol
lib/lila
PART III GLYCOPROTEIN BLOCKADE FOR
ISCHEMIC SYNDROMES
10 Unstable Angina: PURSUIT, PARAGON, PRISM, and
PRISM PLUS ........................................ _.. ..................................... 201
David J. Moliterno and Harvey D. White
Xl