Ticlopidine, Platelets and Vascular Disease

166 Pages·1993·4.858 MB·English

by  William K. Hass, J. Donald Easton (auth.), Professor William K. Hass MD, Professor J. Donald Easton MD (eds.)

Ticlopidine, Platelets and Vascular Disease
Ticlopidine Hydrochloride
-Hel
5-(2-chlorophenyl)methyl]-4,5, 6, 7 -tetrahydrothieno
[3,2-c] pyridine hydrochloride.
William K. Hass J. Donald Easton
Editors
Ticlopidine, Platelets
and Vascular Disease
With 20 Illustrations
Springer-Verlag
New York Berlin Heidelberg London Paris
Tokyo Hong Kong Barcelona Budapest
William K. Hass, MD 1. Donald Easton, MD
Department of Neurology Department of Neurology
New York University School of Medicine Brown University Medical Center
New York, NY 10016 Providence, RI 02903
USA USA
Library of Congress Cataloging-in-Publication Data
Ticlopidine, platelets and vascular disease / William K. Hass,
J. Donald Easton, editors.
p. cm.
Includes bibliographical references and index.
ISBN-13 :978-1-4613-8308-6 e-ISBN -13 :978-1-4613-8306-2
DOl: 10.1007/978-1-4613-8306-2
1. Ticlopidine-Testing. 2. Blood-platelets-Aggregation.
3. Cerebrovascular disease-Chemotherapy. 4. Myocardial infarction
Chemotherapy. I. Hass, William K., 1929-. II. Easton, J. Donald.
{DNLM: 1. Blood Platelets-physiology. 2. Ticlopidine
therapeutic use. 3. Vascular Diseases-drug therapy. WG 500 T557
1993]
RM666.T55T53 1993
616.1061-dc20
DNLMlDLC
for Library of Congress 92-48386
Printed on acid-free paper.
© 1993 Springer-Verlag New York Inc.
Softcover reprint of the hardcover 1st edition 1993
All rights reserved. This work may not be translated in whole or in part without the written
permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New York,
NY 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis.
Use in connection with any form of information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed
is forbidden.
The use of general descriptive names, trade names, trademarks, etc., in this publication, even
if the former are not especially identified, is not to be taken as a sign that such names, as
understood by the Trade Marks and Merchandise Marks Act, may accordingly be used freely
by anyone.
While the advice and information in this book are believed to be true and accurate at the date
of going to press, neither the authors nor the editors nor the publisher can accept any legal
responsibility for any errors or omissions that may be made. The publisher makes no warranty,
express or implied, with respect to the material contained herein.
Production coordinated by Chernow Editorial Services, Inc. and managed by
Henry Krell; manufacturing supervised by Jacqui Ashri.
Typeset by Typographic Specialties, Bozeman, MT.
98765 4 3 2 1
ISBN -13 :978-1-4613-8308-6
Preface
Blood platelets lack a nucleus. As a result their life span is short and they cannot
reproduce themselves. Platelets share these qualities with the red blood cell. Plate
lets and red blood cells, nevertheless, serve vital roles in the body. One major
function of the platelet is its capacity to aggregate and thereby initiate intravas
cular coagulation which often underlies such major diseases as myocardial infarc
tion, cerebral infarction, and pulmonary embolism. For this reason in recent years,
medical attention has been directed to drugs that inhibit platelet aggregation.
Aspirin was the first drug to be proven effective in this area. Since then other
drugs that share aspirin's fundamental biochemical action, inhibition of platelet
cyclooxygenase, have also been studied. Very recently, ticlopidine, the first of
what promises to be a new class of drugs inhibiting platelet aggregation and
coagulation via an entirely different biochemical mechanism, has been exten
sively studied and clinically shown to be as effective or more effective than
aspirin in the prevention of ischemic cardiovascular and cerebrovascular disease.
The medical world knows and understands aspirin well. It has been widely
available to physicians and patients for almost a century. Ticlopidine, on the
other hand, is novel and has not been the subject of a formal and rigorous textbook
review. Increasingly widespread use of ticlopidine throughout the world now
requires such an effort. Having been assured of the cooperation of the authors
of the individual chapters, all of whom enjoy international reputations for their
expertise in their assigned areas of review, the editors undertook this effort fully
aware that books so designed are not read like novels. Most physicians will, no
doubt, approach this book with specific questions in mind and address themselves
largely to one or two chapters of immediate interest. This makes some repetition
from chapter to chapter necessary. Efforts have been made, however, to minimize
repetition for those who would like to peruse this volume in depth.
The book is, therefore, dedicated to a wide spectrum of physicians consider
ing treatment of patients with ticlopidine, perhaps for the first time, who will
find herein an in-depth presentation of information necessary for confident
medical care.
William K. Hass, M.D.
J. Donald Easton, M.D.
vii
Contents
Preface . . . vii
Contributors xi
Chapter 1. Changing Concepts of the Pathophysiology
of Cerebral and Myocardial Infarction . 1
WILLIAM K. HASS and J. DONALD EASTON
Chapter 2. Overview of Ticlopidine's Development 13
EDOUARD PANAK and MONIQUE VERRY
Chapter 3. Pharmacodynamics and Pharmacokinetics
of Ticlopidine .. .. . ... ...... . 27
PHILIP TEITELBAUM
Chapter 4. Ticlopidine's Mechanism of Action on
Human Platelets ............ . 41
LAURENCE A. HARKER and JOHN J. BRUNO
Chapter 5. Clinical Studies of Stroke Prevention with
Ticlopidine in Man . . . 61
WILLIAM PRYSE-PHILLIPS
Chapter 6. Clinical Trials of Ticlopidine in Patients with
Intermittent Claudication .. .. . ..... . 75
LARS JANZON
Chapter 7. Clinical Trials of Ticlopidine in Patients with
Coronary Artery Disease. . . . . . . . . . 85
FRANCESCO BALSANO and FRANCESCO VIOLI
ix
x Contents
Chapter 8. A Systematic Overview of Randomized Trials of
Antiplatelet Agents for the Prevention of Stroke,
Myocardial Infarction, and Vascular Death 99
MICHAEL GENT
Chapter 9. An Analysis of the Side Effects of Tic10pidine 117
BASIL A. MOLONY
Chapter 10. The Role of Tic10pidine in Prevention of Ischemic
Stroke: A Benefit-Risk Assessment ....... . 141
J. DONALD EASTON
Index ... ... .. ... . . . 157
Contributors
Francesco Balsano, MD, Universita degli Studi di Roma "La Sapienza," Istituto
di I Clinica Medica, 00161 Rome, Italy.
John Bruno, PH.D, Consultant in Thrombosis and Atherosclerosis Research, Palo
Alto, CA 94304, USA.
J. Donald Easton, MD, Professor, Department of Neurology, Brown University,
Providence, RI 02903, USA.
Michael Gent, Professor, McMaster University and the Hamilton Civic Hospitals
Research Centre, Hamilton, Ontario L8V 1C3, Canada.
Laurence A. Harker, MD, Professor, Division of Hematology and Oncology,
Emory University School of Medicine, Atlanta, GA 30322, USA.
William K. Hass, MD, Professor, Department of Neurology , New York University
Medical Center, New York, NY 10016, USA.
Lars Janzon, MD, Department of Community Health Sciences, Lund University,
Malmo General Hospital, Malmo, Sweden.
Basil A. Molony, MD, Internist, Clinical Trialist, Los Altos, CA 94024, USA.
Edouard Panak, Sanofi Pharma, 32-34 Rue Marbeuf 7500, 75008 Paris, France.
William Pryse-Phillips, MD, Professor, Department of Medicine, Division of
Neurology, St. Johns, Newfoundland AlB 3V6, Canada.
Philip Teitelbaum, PH.D, Head, Department of Drug Metabolism, Syntex Dis
covery Research, Palo Alto, CA 94304, USA.
Monique Verry, PH.D, Sanofi Pharma, 32-34 Rue Marbeuf 7500, 75008 Paris,
France.
Francesco Violi, MD, Universita degli Studi di Roma, "La Sapienza," Istituto di
I Clinica Medica, 00161 Rome, Italy.
xi
1
Changing Concepts of the Pathophysiology
of Cerebral and Myocardial Infarction
WILLIAM K. BAss and J. DONALD EASTON
Introduction
In this volume we shall review the current status of antiplatelet therapy for
vascular occlusive disease. Specific attention will be paid to the first of a new
class of antiplatelet agents, ticlopidine hydrochloride. Our observations will be
timebound and therefore imperfect. Imperfection, however, has its virtues. In
1991 Ordinas1 noted that a fully suppressive antiplatelet agent would be so
effective, so perfect, that the adverse effect of severe bleeding would be the likely
result of its administration. A perfect drug, in fact, is more likely to be classified
as a poison than as a proper and safe medication.
In contrast to such a fully suppressive agent, ticlopidine at physiologic doses
does not completely inhibit platelet activity. In humans on a relatively small
dail y dose of 375 mg, there is only a 60-70% diminution of AD P-induced platelet
aggregation, only a moderate increase in template bleeding time, and incomplete
(therefore imperfect) protection against A-V shunt occlusion2 (Figure 1.1).
Progressing further on the trail of imperfection, we shall present in detail
three recently reported major clinical trials3-5 showing that ticlopidine: 1) is
more effective than a placebo in the prevention of recurrent stroke, myocardial
infarction, and vascular death in patients who suffered a completed stroke
(Canadian American Ticlopidine Study-CATS); 2) is significantly more effec
tive than aspirin for reducing the risk of stroke after transient ischemic attacks,
amaurosis fugax, and minor stroke (Ticlopidine Aspirin Stroke Study-TASS);
and 3) is strikingly effective in reducing the risk offatal and nonfatal myocardial
infarction in patients with unstable angina (STAI).
In none of the cited studies, however, does risk reduction even approach
perfection, i.e., 100% risk reduction. Given the incomplete suppression of platelet
aggregation by ticlopidine at physiologic doses and the less-than-total reduction
in stroke risk, it is not surprising that the usefulness of ticlopidine in contrast to
aspirin in the prevention of stroke or myocardial infarction has excited commen
tary from medical editorialists.6•7 Thus FitzGerald has asked, "Is ticlopidine
merely a 'more expensive aspirin' for use in unstable angina?" He has also
correctly pointed out that adverse drug effects were relatively uncommon with
2 W.K. Hass and J.D. Easton
High d ose: 375 mg/d
90 ...--,.--y---.--.--r--...,..--..--.----,;---,---,----, 2.8
80 2.6
70 ~4
60 2.2
Percent Bleeding
Inhibition 50 2.0 Time
of 40 1.6 Prolongation
Aggregation Factor
30- 1.6
20 1.4
10 1.2
o
L---"L..--L_-'----'-_ .1...---L_"--'-_L-....I...----lL........J 1.0
o 2 3 4 5 3 5 7 9
Days of Dosing Days After Last Dose
FIGURE 1.1. Patterns of aggregation inhibition in percent or bleeding time prolongation
as a time multiple of normal during a tic10pidine onset-offset study in humans. (Courtesy
of Dr. David Ellis.)
both ticlopidine and aspirin. Warlow's critique in the Journal of Neurology,
Neurosurgery, Psychiatry was limited to the problem of stroke prevention. He
was bothered by the primary employment of efficacy analysis in the CATS,
pointing out that efficacy studies provide the most optimistic estimate of treat
ment effect. Thus, in the CATS findings risk reduction (ticlopidine vs. placebo
of the composite endpoint-stroke, myocardial infarction, vascular death) was
23.3%, a statistically significant level with, however, a wide confidence interval
of 1.0-40.5%. The wide confidence level, the fact that 12% of patients stopped
taking ticlopidine because of side effects, and the probable cost of the drug in
comparison to over-the-counter aspirin led Warlow to opt for aspirin. The
Antiplatelet Trialists Collaboration8 found aspirin to have a mean composite
vascular endpoint risk reduction when compared to placebo of 25% with narrow
confidence intervals as evaluated by the technique of meta-analysis, which will
be examined in detail in a later chapter.
Thus, forcing a choice between ticlopidine and aspirin is fast becoming a kind
of parlor game having little bearing on the real problem-the specific patient
with specific risks of an arterial occlusive event. Aspirin, like ticlopidine, is
significantly and also incompletely effective. It, too, is imperfect. In head-on
comparisons for reducing risk of stroke, ticlopidine wins, but not by an over
whelming margin. In short, both drugs are imperfect but both will serve. Both