Drug Evaluation in Angina Pectoris

261 Pages·1994·14.747 MB·English

by  Giuseppe Specchia, Stefano Ghio (auth.), Diego Ardissino M.D., Lionel H. Opie M.D., Ph.D., Stefano Savonitto M.D. (eds.)

DRUG EVALUATION IN ANGINA PECTORIS
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DRUG EVALUATION
IN ANGINA PECTORIS
Ediltd by
Diego Ardissino, M. D.
Lionel H. Opie, M.D., Ph.D.
Stefano Savonitto, M. D.
~.
"
Springer Science+Business Media, LLC
Library of Congress Cataloging-in-Publication Data
Dcug evaluation in angina pectoris/edited by Diego Ardissino,
Lionel H. Opie, Stefano Savonino.
p. cm.-(Oevelopments in cardiovasculat medicine; v. 158)
Includes index.
ISBN 978-1-4613-6127-5 ISBN 978-1-4615-2628-5 (eBook)
DOI 10.1007/978-1-4615-2628-5
1. Myocardial depressants-Effectiveness. 2. Angina pectoris
Chemothetapy. 1. Ardissino, Diego. 11. Opie, Lionel H.
III. Savonitto, Stefano. IV. Series.
[ONLM: 1. Angina Pectoris-dcug thetapy. 2. Anti-Arrhythmia
Agents-thetapeutic U5e. Wl DE997VME v. 158 1994/WG 298
0794 1994}
RM347.078 1994
616.1 '22061-dc20
DNLMIDLC
for Libtary of Congress 94-12345
CIP
©
Copyrtght 1994 by Springer Science+Business Media New York
OriginaUy published by Kluwer Academic Publishers in 1994
Softcover reprint ofthe hardcover Ist edition 1994
All rights reserved. No part of this publicanon may be reproduced, stored in a retrievaI system
or ttanSmitted in any form or by any means, mechanical, photo-copying, recordlng,
or otherwise, without ehe prior wrinen permission of the publisher,
Springer Science+Business Media, LLC.
Prmtoo on acid-free paper.
Dedicatedto myparents, Rosa andLuigi.
Diego Ardissino
Dedicated to Professor Albrecht Fleckenstein (1917
1992), who did so much to establish the antianginal
mechanisms ofcalciumantagonists.
Lionel H. Opie
Dedicated to the former Head of the 2nd Division of
Cardiology of the Ospedale Niguarda Ca' Granda,
Professor Carlo Belli, and to my father, Doctor
Faustino Savonitto, both recently retired after having
servedthezrpatientsfor 40 years in Milan.
Stefano Savonitto
CONTENTS
Contributing Authors IX III. PLANNING, CONDUCTING, AND
EVALUATING CLINICAL TRIALS IN
Foreword XI ANGINA PECTORIS 119
Preface XIII
9. PatientSelectionandDefinitionofStudy
Endpoints 121
I. PATHOPHYSIOLOGY, CLINICAL
PRESENTATION, AND PROGNOSIS OF PeterSchulmanandDaVIdWaters
ANGINA PECTORIS 1
10. ControllingPotentialSourcesofBiasinClinical
1. Pathophysiology, ClinicalPresentation, and
TrialsofAntianginalAgents 129
PrognosisofAnginaPectoris 3
MartoMotolese
GIuseppeSpecchlaandStefanoGh,o
11. Parallel-GroupandCrossoverDesignsforDrug
II. EVALUATION OF THE PATIENT WITH EvaluationintheVariousFormsofAngina
ANGINA PECTORIS 13
Pectoris 139
StefanoSavomlto
2. ClinicalValueofAnginalSymptomsand their
AssessmentinDrugTrials 15
StefanoSavomltoandP,eraA. Merllnl 12. Dose-ResponseRelationshipsandCombination
StudieswithAntianginalAgents 151
3. QualityofLifeAssessmentsinClinicalTrialsof UdhoThadam
AnginaPectoris 31
IngelaWIklund 13. SampleSizeandPowerofClinical
Trials 157
4. OptimizingtheExerciseTestfor ErmannoEleuterlandDIegoArdmlno
PharmacologicalStudiesinPatientswith
AnginaPectoris 41 14. MulticenterTrials:Designand
jonathanMyersandVIctorF. Froeltcher Conduct 167
AndreaMcNeIllandjacobusLubsen
5. EvaluationofTransientMyocardialIschemiaby
HolterMonitoring 53
IV. CRITICAL ISSUES RELATED TO SPECIFIC
ArshedA.Quyyuml
ANTIANGINAL AGENTS 183
6. RadionuclideMethodsfortheEvaluationof
15. ExperimentalEvaluationandClinicalRelevance
VentricularFunctionandThrombolytic
ofTolerancetoNitrates 185
Therapy 73
johna. ParkerandjohnD. Parker
PaoloMarzullo, AlemaG,mell" andAntomoL'Abbate
7. ProvocativeTestingofCoronary 16. ClinicalEvaluationofBeta-blockersinVarious
Vasoconstriction 85 FormsofAnginaPectoris 195
MartoPrevltalt, PaoloBarbem,andDIegoArdmlno NinaRehnqvlst
8. PharmacologicalInvestigationUsingInvasive 17. EfficacyandSafetyofCalciumAntagonistsas
Methods 103 AntianginalAgents 201
EzlOBramuCClandOtegoArdmlno LIOnelH. aple
VII
V11I CONTENTS
18. EffectsofAntithromboticAgentsonMortality 20. CommentsontheFoodandDrug
andNonfatalCardiacEvents 213 Administration(FDA)CardiacandRenalDrugs
PurreTherollxandRosa-MartaLldon AdvisoryCommitteeRecommendedGuidelines
fortheConductofAntianginalDrug
19. TheChallengeofThrombolyticTherapyin Trials 251
UnstableAnginaPectoris 233 UdhoThadam
johnA. VendlltoandjohnA. Ambrose
21. EuropeanCommunities'Committeefor
ProprietaryMedicinalProducts(CPMP)
v. REGULATORY ASPECTS RELATED TO THE
WorkingPartyonEfficacyofMedicinal
EVALUATION OF NEW ANTIANGINAL
AGENTS 249 Products 255
BernardDIIPIIIS
Index 259
CONTRIBUTING AUTHORS
JohnA. Ambrose, MD, FACC Arshed A. Quyyumi, MD, MRCP
DivisionofCardiology National Heart, Lung, and Blood Institute
DepartmentofMedicine National Institutes ofHealth
MountSinaiMedicalCenter Bethesda, MD, USA
NewYork, NY, USA
Antonio L'Abbate, MD, FACC
DiegoArdissino, MD, FESC Institute ofClinical Physiology
DivisionofCardiology National Research Council
I.R.C.C.SPoliclinicoSanMatteo Pisa, Italy
UniversityofPavia
Rosa Maria Lid6n, MD
Pavia, Italy
Montreal Heart Institute
PaoloBarberis, MD Montreal, Quebec, Canada
DivisionofCardiology
Jacobus Lubsen, MD
I.R.C.C.SPoliclinicoSanMatteo
Societe' pour la Recherche Cardiologique (SOCAR)
UniversityofPavia
SA
PaVia, Italy
Givrins, Switzerland, and
EzioBramucci, MD Erasmus Ufilversity
DIvisionofCardiology Rotterdam, The Netherlands
I.R.C.C.SPoliclinicoSanMatteo Andrea MacNeill, Msc
UniversityofPavia Societe' pour la Recherche Cardiologique (SOCAR)
Pavia, Italy SA
Givrins, Switzerland
Bernard Dupuis, MD, PhD
Institute ofPharmacology Paolo Marzullo, MD, FESC, FACC
University ofLille Institute ofClinical Physiology
Lille, France National Research Council
Pisa, Italy
Ermanno Eleuteri, MD
Division ofCardiology Piera Angelica Merlini, MD
I.R.C.C.S Policlinico San Matteo Second Division ofCardiology
University ofPavia Dipartimento Cardiologico "A. De Gasperis"
Pavia, Italy Ospedale Niguarda Ca' Granda
Milan, Italy
Victor F. Froelicher, MD, FACC
Division ofCardiovascular Medicine Mario Motolese, MD, FESC
Stanford University School ofMedicine Second Postgraduate School ofCardiology
Department ofVeterans Affairs Medical Center University "LaSapienza"
Palo Alto, CA, USA Rome, Italy
Stefano Ghio, MD, FESC Jonathan Myers, PhD
Division ofCardiology Division ofCardiovascular Medicine
I.R.C.C.S Policlinico San Matteo Stanford University School ofMedicine
University ofPavia Department ofVeterans Affairs Medical Center
Pavia, Italy Palo Alto, CA, USA
Alessia Gimelli, MD Lionel H. Opie, MD, DPhil, FRCP, FACC
Institute ofClinical Physiology MRClUCT Ischemic Heart Research Unit
National Research Council University ofCape Town Medical School
Pisa, Italy Capetown, South Africa
IX
x PREFACE
John D. Parker, MD Giuseppe Specchia, MD, FACC
Mount Sinai Hospital Division ofCardiology
Toronto, Ontario, Canada I.R.C.C.S Policlinico San Matteo
University ofPavia
John O. Parker, MD, FACC Pavia, Italy
Cardiovascular Laboratory
Pierre Theroux, MD, FACC
Kingston General Hospital
Montreal Heart Institute
Kingston, Ontano, Canada
Montreal, Quebec, Canada
Mario Previtali, MD
Udho Thadani, MBBS, MRCP, FRCPC
Division ofCardiology
Department ofCardiology
I.R.C.C.S Policlinico San Matteo
University ofOklahoma
University ofPavia
Health Sciences Center
Pavia, Italy
Oklahoma City, OK, USA
Nina Rehnqvist, MD, FESC, FACC
John A. Venditto
Department ofMedicine
Division ofCardiology
Danderyd Hospital
Department ofMedicine
Danderyd, Sweden
Mount Sinai Medical Center
New York, NY, USA
Stefano Savonitto, MD, FESC
Second Division ofCardiology David Waters, MD, FACC
Dipartimento Cardiologico "A. De Gasperis" Division ofCardiology
Ospedale Niguarda Ca' Granda Department ofMedicine
Milan, Italy The University ofConnecticut Health Center
Hartford, CT, USA
Peter Schulman, MD, FACC
Department ofMedicine Ingeia Wiklund, MSc
Univer~ity ofConnecticut Health Center Department ofMedicine
John Dempsey Hospital and Hartford Hospital astra Hospital
Hartford, CT, USA Goteborg, Sweden
FOREWORD
Over the past few decades, there has been consider the endpoint of exercise tolerance be paramount,
able advance in our approach to the patient with or should the prevention of death and myocardial
angina pectoris, with an increasing array ofpharma infarction be a key future goal? How should new,
cologicinterventionsthataresuitableincludingbeta putative antianginal therapies be pursued?
blockers, calciumchannel blockers, nitrates, aspirin, In the future it is clear that new opportunities
and, for unstable angina, intravenous heparin. are arising to potentially have a major impact in
Although this armamentarium may, on the surface, improving the efficacy of therapy in patients with
seem impressive, it is quite common to see patients anginapectoris. Thesecan bedivided intotheagents
who have incapacitating angina or at least have had with the potential for prevention ofplaque rupture,
to significantly change their life-style. Furthermore, such as antioxidants, angiotensinconverting enzyme
exceptfor improvingexercisetoleranceandqualityof inhibitors, and the cholesterol-lowering drugs, and
life, it remains unclear that medical therapy has newagents thatstimulateangiogenesis, suchas basIC
drasticallyaltered the natural historyofpatientswith fibroblastgrowthfactor. Throughthecarefulanalytic
angina. approach outlined in this book, a proper template
In Drug Evaluation m Angma PectortS, Ardissino, canbedevelopedforsuchagents, characterizingtheir
Opie, and Savonitto have provided a very com effects and eventually transforming the interventIOn
prehensive and thoughtful approach to the improve from the theoretical to the actual, practical level.
ment in antianginal therapy for the future. In 21 Drug EvaluatIOn in Angina Pectoris is an exception
chapters prepared by 31 expert contributors, the ally well-written and carefully edited text. For all
pathophysiology is first reviewed, a systematic internists and cardiologists caring for patients with
evaluation of the patient with angina is presented, angina, particularly those with a desire to capture
and following thisfoundation therearethreesections state-of-the-art management today and to define
for the refinement oftherapy in the future-clinical therapeutic progress in the future, this book wdl
trials, critical issues on specific antianginals, and be an invaluable educational tool. The editors and
health care policy issues with respect to regulatory authors should be congratulated on pulling together
review and practice guidelines. this important field of clinical practice and inves
The book serves as a valuable template for the tigation, tightly integrated in a unique monograph.
consideration ofmany crucial questions in the man It is clear that this book will have a positive impact
agement of angina pectoris. Now that the field of on the treatmentofanginapectorisandpatientswith
agents is beginning to get crowded, how can we ischemic heart disease for years to come.
differentiate them, especially with respect to func
tionaloutcomesandqualityoflife?Howaggressively EricJ. Topol
should asymptomatic ischemia be inhibited? Should Cleveland, Ohio, USA
XI