Cardiovascular Trials Review

Eighth Edition
Acute Myocardial Infarction Acute Treatment of Stroke Unstable Angina/Non-Q-Wave Infarction Stable Angina Pectoris and Silent IschemiaMedical Therapy Interventional Cardiology Hypertension Congestive Heart Failure Lipid-Lowering Studies Arrhythmia Anticoagulation for Atrial Fibrillation Deep Vein Thrombosis/Pulmonary Embolism Coronary Artery Disease, Atherosclerosis, Prevention of Progression Valvular Heart Disease Preliminary Reports EDITORS: ROBERT A. KLONER, MD, PhD YOCHAI BIRNBAUM, MD
& Jason S. Chi, BS

Cardiovascular Trials Review

8th Edition
Edited by: Robert A. Kloner, MD, PhD Yochai Birnbaum, MD Studies compiled by: Robert A. Kloner, MD, PhD Yochai Birnbaum, MD Contributions by: Jason S. Chi, BS
Robert A. Kloner, MD, PhD Director of Research, Heart Institute, Good Samaritan Hospital Professor of Medicine, Cardiovascular Division University of Southern California Los Angeles, CA Yochai Birnbaum, MD Medical Director, Cardiac Intensive Care Unit Medical Director, Heart Station Professor of Medicine, Division of Cardiology, University of Texas Medical Branch Galveston, TX Jason S. Chi, BS University of Illinois at Chicago College of Medicine, Chicago, IL

Dedicated to the memory of Philip Kloner 19251997

Cardiovascular Trials Review, 8th Edition Copyright 2003 by Le Jacq Communications, Inc. All rights reserved. 1st Edition Copyright 1996, 2nd Edition Copyright 1997, 3rd Edition Copyright 1998, 4th Edition Copyright 1999, Millenium (5th) Edition Copyright 2000, 6th Edition Copyright 2001, 7th Edition Copyright 2002 by Le Jacq Communications, Inc. Reproduction or translation of any part of this work without permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, Le Jacq Communications, Inc., 3 Parklands Drive, Darien, CT 06820. The facts, opinions, and ideas expressed in this book are those of the authors and do not necessarily reflect those of the publisher. The opinions and information presented in this book are attributed to the authors and not to the publisher. No responsibility is assumed by the publisher for any damage and/or injury of any nature occurring from any use, misuse, or omission of any of the information contained in this book.

ISBN 1-929660-13-8
Printed in the United States of America.

ii

Contents

Contents

Table of Contents

Subjects Trials Listing Introduction Trials Trials Index (in alphabetical order)

-v-vii-xxxiii1 1205

Contents

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Contents

Subjects
Section Page

1.

Acute Myocardial Infarction a. Thrombolytic Therapy b. Percutaneous Transluminal Coronary Angioplasty vs Stenting vs Thrombolytic Therapy c. Anticoagulation/Antiplatelet d. Early vs Late Intervention After Acute Myocardial Infarction e. Remodeling After Infarction f. Miscellaneous and Adjunctive Therapy Acute Treatment of Stroke

1 31 71 139 143 157 193

2. 3.

Unstable Angina/Non-Q-Wave Infarction/Non-ST-Elevation 207 Myocardial Infarction or Acute Coronary Syndrome Stable Angina Pectoris and Silent IschemiaMedical Therapy 307 Interventional Cardiology a. Percutaneous Transluminal Coronary Angioplasty (and/or stenting) vs Coronary Artery Bypass Graft Surgery b. Percutaneous Transluminal Coronary Angioplasty vs Stenting vs Other Percutaneous Devices, IVUS Guided Stenting c. Medical Therapy, Brachytherapy, Drug-Eluting Stents to Prevent Restenosis and/or Complications After Intracoronary Interventions or Occlusion After Coronary Artery Bypass Grafting d. Other Therapy Including Transmyocardial Laser Revascularization Hypertension Congestive Heart Failure Lipid-Lowering Studies Arrhythmia

4. 5.

339 367 467 595 615 697 783 905

6. 7. 8. 9.

Contents

Section

Page

10. 11. 12.

Anticoagulation for Atrial Fibrillation Deep Vein Thrombosis/ Pulmonary Embolism Coronary Artery Disease, Atherosclerosis, Prevention of Progression Valvular Heart Disease Preliminary Reports a. Acute Myocardial Infarction b. Unstable Angina, Non-Q-Wave Myocardial Infarction c. Hypertension d. Congestive Heart Failure e. Arrhythmia f. Interventional Cardiology

1009 1019 1055

13. 14.

1145

1157 1163 1169 1173 1181 1189

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Contents

Trials Listing
Page Acronym/Title

1a.
2 4

Acute Myocardial Infarction Thrombolytic Therapy

GUSTO-III (1 Year) Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries-III SPEED (GUSTO-IV Pilot) Early Percutaneous Coronary Intervention Strategies for Patency Enhancement in the Emergency Department. Global Use of Strategies to Open Occluded Coronary Arteries IV SPEED Strategies for Patency Enhancement in the Emergency Department. Global Use of Strategies to Open Occluded Arteries (GUSTO-IV Pilot) GUSTO V Global Utilization of Strategies to Open Occluded Coronary Arteries V GUSTO V Global Utilization of Strategies to Open Occluded Coronary Arteries V TIMI-4 Thrombolysis in Myocardial Infarction-4 InTIME-II Intravenous nPA for Treatment of Infarcting Myocardium Early-II ASSENT (Substudy) Assessment of the Safety and Efficacy of a New Thrombolytic Agent ASSENT-2 Assessment of the Safety and Efficacy of a New Thrombolytic-2 ASSENT-3 Assessment of the Safety and Efficacy of a New Thrombolytic Regimen-3 TUCC Randomized Trial Confirming the Efficacy of Reduced Dose Recombinant Tissue Plasminogen Activator in a Chinese Myocardial Infarction Population and Demonstrating Superiority to Usual Dose Urokinase ER-TIMI Results of the Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 Trial

8 11 13 15 18 20 22 25

27

1b.

Acute Myocardial Infarction Percutaneous Transluminal Coronary Angioplasty vs Stenting vs Thrombolytic Therapy
Stent-PAMI Stent-Primary Angioplasty in Myocardial Infarction Long-Term Benefit of Primary Angioplasty as Compared with Thrombolytic Therapy for Acute Myocardial Infarction

32 34

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Page 36 38 40

Acronym/Title PACT Plasminogen Activator Angioplasty Compatibility Trial CCP Cooperative Cardiovascular Project PRAGUE Primary Angioplasty in Patients Transferred from General Community Hospitals to Specialized PTCA Units with or Without Emergency Thrombolysis STOPAMI Stent vs Thrombolysis for Occluded Coronary Arteries in Patients with Acute Myocardial Infarction STAT Stenting vs Thrombolysis in Acute Myocardial Trial SHOCK Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock? Stenting vs Balloon Angioplasty for Acute Myocardial Infarction Randomized Comparison of Direct Stenting with Conventional Stent Implantation in Selected Patients with Acute Myocardial Infarction STENTIM-2 Stenting in Acute Myocardial Infarction-2 C-PORT The Atlantic Cardiovascular Patient Outcomes Research Team TIMI Frame Count Air PAMI Air Primary Angioplasty in Myocardial Infarction Study Randomized Comparison of Primary Angioplasty and Thrombolytic Therapy CAPTIM Comparison of Angioplasty and Prehospital Thrombolysis in Acute Myocardial Infarction PRAGUE-2 Primary Angioplasty in Patients Transported from General Community Hospitals to Specialized PTCA Units with or Without Emergency Thrombolysis-2

43 45 47 50 52 54 57 59 61 63 65 68

1c.

Acute Myocardial Infarction Anticoagulation/ Antiplatelet

CARS (Substudy) Coumadin Aspirin Reinfarction Study (Substudy) TIMI-14 (Substudy) Thrombolysis in Myocardial Infarction-14 MINT Myocardial Infarction with Novastan and tPA ESCALAT Efegatran and Streptokinase to Canalize Arteries Like Accelerated Tissue Plasminogen Activator ISAR-2 Intracoronary Stenting and Antithrombotic Regimen-2 HEAP Heparin in Early Patency
Contents

72 74 76 78 81 83

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Page 85 87 89 91 93 95 98 100 102 104

Acronym/Title HIT-4 Hirudin for the Improvement of Thrombolysis-4 TIM Triflusal in Myocardial Infarction Eptifibatide vs Placebo in Patients Receiving Thrombolytic Therapy JAMIS Japanese Antiplatelet Myocardial Infarction Study STAMI Study of Ticlopidine vs Aspirin in Myocardial Infarction ADMIRAL Abciximab Before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-Up INTRO AMI Integrilin and Low-Dose Thrombolysis in Acute Myocardial Infarction Study CHAMP Combination Hemotherapy and Mortality Prevention HART II Second Trial of Heparin and Aspirin Reperfusion Therapy ENTIRE-TIMI-23 Enoxaparin and TNK-tPA With or Without GP IIIb/IIIa Inhibitor as Reperfusion Strategy in ST Evaluation MI Thrombolysis in Myocardial Infarction-23 HERO-2 Hirulog and Early Reperfusion or Occlusion-2 Trial PENTALYSE Pentasaccharide, as an Adjunct to Fibrinolysis in ST Elevation Acute Myocardial Infarction CADILLAC Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications PRIME Promotion of Reperfusion in Myocardial Infarction Evolution VITAL Vasoflux International Trial for Acute Myocardial Infarction Lysis Enoxaparin vs Unfractionated Heparin After Thrombolytic Therapy for Acute Myocardial Infarction ASPECT-2 Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 AMI-SK Acute Myocardial Infarction Streptokinase ASSENT Plus Assessment of the Safety and Efficacy of a New Thrombolytic Plus TIGER-PA Tirofiban Given in the Emergency Room Before Primary Angioplasty Pilot Trial Intracoronary vs Intravenous Abciximab in Acute Coronary Syndromes APRICOT-2 Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis Trial-2 Warfarin, Aspirin, or Both After Myocardial Infarction

106 108 111 115 118 120 122 124 127 129 131 133 136

Contents

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Page

Acronym/Title

1d.

Acute Myocardial Infarction Early vs Late Intervention After Acute Myocardial Infarction
Early Revascularization in 14-Day Survivors of Acute Myocardial Infarction

140

1e.

Acute Myocardial Infarction Remodeling After Infarction

GISSI-3 Substudy Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico-3 TRACE (Update) Trandolapril Cardiac Evaluation TRACE (Diabetic Substudy) Trandolapril Cardiac Evaluation Study CAPRICORN Carvedilol Post-Infarct Survival Control in LV Dysfunction OPTIMAAL Optimal Trial In Myocardial Infarction with the Angiotensin II Antagonist Losartan SMILE-2 Survival of Myocardial Infarction Long-Term Evaluation-2

144 146 148 150 152 155

1f.

Acute Myocardial Infarction Miscellaneous and Adjunctive Therapy

DECREASE Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group NEHDP National Exercise and Heart Disease Project AMISTAD Acute Myocardial Infarction Study of Adenosine Trial INTERCEPT Incomplete Infarction Trial of European Research Collaborators Evaluating Progress Post-Thrombolysis Cariporide in Patients with Acute Anterior Myocardial Infarction EMIP-FR European Myocardial Infarction ProjectFree Radicals LIMIT AMI Limitation of Myocardial Infarction Following Thrombolysis in Acute Myocardial Infarction Study GISSI-Prevenzione Trial Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto Miocardico GISSI-Prevenzione Gruppo Italiano per lo Studio della Sopravvivenza nellInfarto MiocardicoPrevenzione
Contents

158 160 162 164 166 168 170 172 174

Contents

Page 176 179 181 184 186 189

Acronym/Title ESCAMI Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction Does Angina Pectoris the Week Before Protect Against First Acute Myocardial Infarction in Patients with Diabetes Mellitus? HALT-MI Hu23F2G Anti-Adhesion to Limit Cytotoxic Injury Following AMI MAGIC Magnesium in Coronaries FLORIDA Fluvastatin on Risk Diminishment After Acute Myocardial Infarction SADHART Sertraline Antidepressant Heart Attack Randomized Trial

2.
194 196 198 200 203 205

Acute Treatment of Stroke

NINDS Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study STAT Stroke Treatment with Ancord Trial ATLANTIS Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke PROCAT II Prolyse in Acute Cerebral Thromboembolism II Aptiganel Hydrochloride in Acute Ischemic Stroke WARSS Warfarin Aspirin Recurrent Stroke Study

3.

Unstable Angina/Non-Q-Wave Infarction/ Non-ST-Elevation Myocardial Infarction or Acute Coronary Syndrome

HASI (Update) Bivalirudin Angioplasty Study (Hirulog Angioplasty Study) PRISM-PLUS Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms PRISM-PLUS (Angiographic Results) Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms PRISM-PLUS (Diabetic Substudy) Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms

208 211 213

215

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Page 217

Acronym/Title VANQWISH Trial (Non-Q-Wave Myocardial Infarction Following Thrombolysis) Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital PARAGON B Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B PARAGON B (Troponin T Substudy) Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy PURSUIT (Substudy) Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy PURSUIT (Substudy) Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy PURSUIT (Substudy) Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy PURSUIT (Subanalysis) Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy FRISC II Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II FRISC II (Substudy) Fragmin and Fast Revascularization During Instability in Coronary Artery Disease II FRAX.I.S Fraxiparine in Ischemic Syndrome TIMI-11B Thrombolysis in Myocardial Infarction-11B Randomized Trial Comparing IV Nitroglycerin and Heparin for Treatment of Unstable Angina Secondary to Restenosis After Coronary Artery Angioplasty Efegatran in Unstable Angina SYMPHONY Sibrafiban vs Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes 2nd SYMPHONY Sibrafiban vs Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-Acute Coronary Syndromes OPUS-TIMI-16 Oral Glycoprotein IIb/IIIa Inhibition with Orbofiban in Patients with Unstable Coronary Syndromes ESSENCE (ST Segment Monitoring Substudy) Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events ESSENCE (1-Year Results) Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events
Contents

219 221

223 225 227 229 231 233 238 240 243 245

247 250 252 254 256 258

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Page 260 262 264 267 270 272

Acronym/Title APLAUD Antiplatelet Useful Dose GUARDIAN Guard During Ischemia Against Necrosis FROST Fibrinogen Receptor Occupancy Study GUSTO IV-ACS Global Utilization of Strategies to Open Occluded Coronary Arteries IVAcute Coronary Syndromes GUSTO IV Global Use of Strategies to Open Occluded Coronary Arteries IVAcute Coronary Syndrome (1-Year Follow-Up) TACTICS-TIMI-18 Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction-18 TACTICS-TIMI 18 (Substudy) Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction-18 CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events CURE Clopidogrel in Unstable Angina To Prevent Recurrent Events (Substudy) CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (Substudy) PCI-CURE Clopidogrel in Unstable Angina to Prevent Recurrent EventsPercutaneous Coronary Intervention Substudy VINO Value of First Day Coronary Angiography/Angioplasty in Evolving Non-ST Segment Elevation Myocardial Infarction. An Open Multicenter Randomized Trial ACE Inhibitors in Acute Coronary Syndrome INTERACT Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment Women Do Have an Improved Long-Term Outcome After Non-STElevation Acute Coronary Syndromes Treated Very Early and Predominantly with Percutaneous Coronary Intervention ACUTE 2 Antithombolic Combination Using Tirofiban and Enoxaparin RITA 3 Randomized Intervention Trial of Unstable Angina NUT-2 The Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 Pilot Study AZACS Azithromycin in Acute Coronary Syndrome

275

277 280 282 285 288

290 292 295

297 299 302 305

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Page

Acronym/Title

4.

Stable Angina Pectoris and Silent IschemiaMedical Therapy

EMIT European Mivazerol Trial New Pharmacological Treatment for Intermittent Claudication: Results of a Randomized, Multicenter Trial MUST-EECP Multicenter Study of Enhanced External Counterpulsation QUO VADIS Quinapril on Vascular ACE and Determinants of Ischemia PATCH Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health FIRST FGF Initiating Revascularization Trial TRIMPOL II Trimetazidine in Poland II PISA Persantin in Stable Angina TIME Trial of Invasive vs Medical Therapy in Elderly Patients IONA Impact of Nicorandil in Angina Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Antianginal and Anti-Ischemic Effects of Ivabradine, an If Inhibitor, in Stable Angina CAPE II Trial Circadian Anti-Ischemic Program in Europe II Effects of Oral Magnesium Therapy on Exercise Tolerance, ExerciseInduced Chest Pain, and Quality of Life in Patients with Coronary Artery Disease

308 310 312 314 316 318 320 322 324 326 328 330 333 336

5a.

Interventional Cardiology Percutaneous Transluminal Coronary Angioplasty (and/or stenting) vs Coronary Artery Bypass Graft Surgery
Cognitive Outcome After Off-Pump and On-Pump Coronary Artery Bypass Graft Surgery. A Randomized Trial Octopus Study Octopus Study BHACAS (1 & 2) Beating Heart Against Cardioplegic Arrest Studies 1&2
Contents

340 342 344 346

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Page 348 350 352 354

Acronym/Title EAST (8-Year Mortality Data) Emory Angioplasty vs Surgery Trial BARI (7-Year Outcome, Diabetics) Bypass Angioplasty Revascularization Investigation Arterial Revascularization Therapies Study ERACI II Argentine Randomized Trial of Percutaneous Transluminal Coronary Angioplasty vs Coronary Artery Bypass Surgery in Multivessel Disease II ARTS Arterial Revascularization Therapy Study AWESOME Angina with Extremely Serious Operative Mortality Evaluation Comparison of Stenting with Minimally Invasive Bypass Surgery for Stenosis of the Left Anterior Descending Coronary Artery SOS Stent or Surgery

357 359 361 364

5b.

Interventional Cardiology Percutaneous Transluminal Coronary Angioplasty vs Stenting vs Other Percutaneous Devices, IVUS Guided Stenting
BENESTENT-I (5-Year Follow-Up) Belgium Netherlands Stent STRESS (Diabetic Substudy) Stent Restenosis Study TOSCA Total Occlusion Study of Canada START (Stent vs Atherectomy) Stent vs Directional Coronary Atherectomy Randomized Trial START (Stenting vs PTCA) Stent Implantation and Balloon Angioplasty in the Treatment of De Novo Coronary Artery Lesions ABACAS Adjunctive Balloon Angioplasty After Coronary Atherectomy Study FROST French Randomized Optimal Stenting Trial Comparison of GR-II Stent and Palmaz-Schatz Stent CRUISE Can Routine Ultrasound Influence Stent Expansion? COBRA Comparison of Balloon Angioplasty vs Rotational Atherectomy PARAGON Stent Study Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Stent Implantation in Small Coronary Arteries

368 370 372 374 376 378 380 382 384 386 388

390
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Page 392 394 396 399 401 403 405 407 409 411 413 415 417 419 421 423 425 427 429 431 433 435 437 439 441

Acronym/Title High-Pressure Stenting vs Balloon Angioplasty NIRVANA NIR Vascular Advanced North American Trial STRATAS Study to Determine Rotablator and Transluminal Angioplasty Strategy BET Benefit Evaluation of Direct Coronary Stenting BET Benefit Evaluation of Direct Coronary Stenting ASCENT ACS MultiLink Stent Clinical Equivalence in De Novo Lesions Trial DESTINI Doppler End Point Stenting International Investigation DEBATE II Doppler End Points Balloon Angioplasty Trial Europe II DEBATE II (Substudy) Doppler End Points Balloon Angioplasty Trial Europe II ISAR-SMART Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries ISAR-SMART Trial (Substudy) Intracoronary Stenting or Angioplasty for Restenosis Reduction in Small Arteries WIDEST Wiktor Stent in De Novo Stenosis OPUS-1 Optimum Percutaneous Transluminal Coronary Angioplasty vs Routine Stenting-1 ADVANCE Additional Value of NIR Stents for Treatment of Long Coronary Lesions ARTIST Angioplasty vs Rotational Atherectomy for Treatment of Diffuse In-Stent Restenosis Trial ARTIST (Substudy) Angioplasty Versus Rotational Atherectomy for the Treatment of Diffuse In-Stent Restenosis Trial SISA Stent in Small Arteries OPTICUS Optimization with ICUS (Intracoronary Ultrasound) to Reduce Stent Restenosis Cutting Balloon Angioplasty SCORES Stent Comparative Restenosis BESMART Bestent in Small Arteries SAFE Saphenous Vein Graft Angioplasty Free of Emboli Magic 5L Magic 5L Wallstent Study CAPAS Cutting Balloon Angioplasty vs Plain Old Balloon Angioplasty Randomized Study in Type B/C Lesions SISCA Stenting in Small Coronary Arteries
Contents

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Page 443 446 449 452 455 458 460 462 464

Acronym/Title PREDICT Predilatation vs Direct Stenting in Coronary Treatment DIRECT Comparison of Direct Stenting vs Stenting with Predilation for the Treatment of Selected Coronary Narrowings SWIBAP Stent Without Balloon Predilation Cutting Balloon Global Randomized Trial Direct Coronary Stenting Versus Predilatation Followed by Stent Placement ISAR-STEREO-2 Intracoronary Stenting and Angiographic Results: Strut Thickness Effect on Restenosis Outcome Trial DANSTENT The Danish Multicenter Stent Study TENISS The Tenax vs NIR Stent Study MultiLink Long Stents for Long Coronary Lesions

5c.

Interventional Cardiology Medical Therapy, Brachytherapy, Drug-Eluting Stents to Prevent Restenosis and/or Complications After Intracoronary Interventions or Occlusion After Coronary Artery Bypass Grafting
IMPACT-II (Substudy) Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II EPISTENT Evaluation of Platelet IIb/IIIa Inhibition in Stenting EPISTENT (6-Month Outcome) Evaluation of Platelet IIb/IIIa Inhibition in Stenting EPISTENT (Diabetic Substudy) Evaluation of Platelet IIb/IIIa Inhibition in Stenting ERASER The Evaluation of ReoPro and Stenting to Eliminate Restenosis 3-Year Clinical and Angiographic Follow-Up After Intracoronary Radiation VIP Visipaque in Percutaneous Transluminal Coronary Angioplasty EXCITE Evaluation of Oral Xemilofiban in Controlling Thrombotic Events Clopidogrel as Adjunctive Antiplatelet Therapy During Coronary Stenting Clopidogrel vs Ticlopidine After Intracoronary Stent Placement Minimal Heparinization in Coronary Angioplasty

468 470 472 474 476 478 480 482 484 486 488
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Page 490 492 495 498 500 502 504 506 508 510 512 515 517 519 521 523 525 527 529 531 533 535 537 539 541

Acronym/Title TREAT Tranilast Restenosis Following Angioplasty Trial TREAT-2 Tranilast Restenosis Angioplasty Trial-2 CAPARES Coronary Angioplasty Amlodipine Restenosis Study WRIST Washington Radiation for In-Stent Restenosis Trial COURT Contrast Media Utilization in High-Risk PTCA Gamma-1 Trial Gamma-1 Study (Intravascular Ultrasound Analysis) -Radiation TherapyDose-Finding Study CLASSICS Clopidogrel Aspirin Stent International Cooperative Study PREVENT (Radiotherapy) Proliferation Reduction with Vascular Energy Trial ESPRIT Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy ESPRIT (Substudy) Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy ESPRIT (Substudy) Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy IMPRESS Intramural Infusion of Low-Molecular-Weight Heparin to Prevent Restenosis After Stent Implantation PRICE Prairie ReoPro vs Integrilin Cost Evaluation NICOLE Nisoldipine in Coronary Artery Disease in Leuven PARIS Effect of ACE Inhibitors on Angiographic Restenosis from PARIS Investigators POLONIA Study Polish-American Local Lovenox NIR Assessment Study ISAR Intracoronary Stenting and Antithrombotic Regimen ISAR-3 Intracoronary Stenting and Antithrombotic Regimen-3 Brachytherapy for Femoropopliteal Angioplasty TARGET Do Tirofiban and ReoPro Give Similar Efficacy Trial TARGET (Subanalysis) Do Tirofiban and ReoPro Give Similar Efficacy Outcomes? TARGET Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial Sirolimus-Eluting Stents

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Page 543 545 547

Acronym/Title Intravascular Gamma Radiation for In-Stent Restenosis in Saphenous Vein Bypass Grafts ITALICS Randomized Investigation by the Thoraxcenter of Antisense DNA Using Local Delivery and IVUS After Coronary Stenting Trial RAVEL Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions RAVEL Randomized Study with the Sirolimus-Eluting Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions RAVEL (Angiographic Findings) Randomized Study with the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent RAVEL Randomized, Double-Blind Study with the Sirolimus-Eluting Bx Velocity Balloon Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions. (Substudy) TRAPIST Trapidil for Prevention of In-Stent Stenosis ATLAST Randomized, Placebo-Controlled Trial of Enoxaparin After High-Risk Coronary Stenting Homocysteine and Restenosis VeGAS 2 Vein Graft AngioJet Study 2 CART-1 Canadian Antioxidant Restenosis Trial COAST Heparin-Coated Stents in Small Coronary Arteries Trial CREDO Clopidogrel for the Reduction of Events During Observation IMPRESS Immunosuppressive Therapy for the Prevention of Restenosis After Coronary Artery Stent Implantation TOPSTAR Troponin in Planned PTCA/Stent Implantation with or Without Administration of the Glycoprotein IIb/IIIa Receptor Antagonist Tirofiban The Swiss Heart Study ASPECT Asian Paclitaxel-Eluting Stent Clinical Trial ASPECT (Substudy) Asian Paclitaxel-Eluting Stent Clinical Trial BAAS Balloon Angioplasty and Anticoagulation Study ESPRIT Esapent for Prevention of Restenosis Italian Study PRESTO Prevention of Restenosis with Tranilast and Its Outcomes

549

552 554

557 559 562 564 566 569 572 575 578

581 583 585 587 590 592

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Acronym/Title

5d.

Interventional Cardiology Other Therapy Including Transmyocardial Laser Revascularization

LARS Laser Angioplasty of Restenosed Stents ATLANTIC Angina TreatmentsLasers and Normal Therapies in Comparison Transmyocardial Revascularization with CO2 Laser in Patients with Refractory Angina Pectoris. Clinical Results from the Norwegian Randomized Trial TOTAL Total Occlusion Trial with Angioplasty by Using Laser Guide Wire PACIFIC Potential Angina Class Improvement from Intramyocardial Channels Norwegian Randomized Trial with Transmyocardial Revascularization Percutaneous Transmyocardial Lasers in Chronic Total Occlusion A Randomized, Controlled Trial of the Use of Pulmonary Artery Catheters in High-Risk Surgical Patients

596 598 601

603 605 607 609 611

6.
616 618 620 623 625 627 629 631 634 639

Hypertension
SHEP (Subanalysis) Systolic Hypertension in the Elderly Program STOP-Hypertension-2 (Update) Swedish Trial in Old Patients with Hypertension-2 Syst-Eur Systolic Hypertension-Europe Syst-Eur (Substudy) Systolic Hypertension-Europe TONE Trial of Nonpharmacologic Interventions in the Elderly ARIC Atherosclerosis Risk in Communities DRASTIC Dutch Renal Artery Stenosis Intervention Cooperative Study ALLHAT Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Comparison of ACE Inhibitors, Calcium Antagonists, -Blockers, and Diuretic Agents on Reactive Hyperemia in Patients with Essential Hypertension: A Multicenter Study
Contents

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Page 641 643 645 647 649 651 653 655 657 659 662 666 668 670 672 674 677 679 682 684 686 689

Acronym/Title CANDLE Candesartan vs Losartan Efficacy Comparison Study Long-Term Effects of Weight Loss and Dietary Sodium Reduction on Incidence of Hypertension NORDIL Nordic Diltiazem Study INSIGHT International Nifedipine GITS Study: Intervention as a Goal in Hypertensive Treatment DASH Dietary Approaches to Stop Hypertension(Reduced Dietary Sodium Study) Drug Classes in Black Hypertensives CASTLE Candesartan and Amlodipine for Safety, Tolerability and Efficacy ABC Trial Association of Black Cardiologists TOHP-II Trials of Hypertension Prevention-II AASK African American Study of Kidney Disease and Hypertension AASK The African American Study of Kidney Disease and Hypertension IRMA II Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study II RENAAL Reduction of End Points in NIDDM (Non-Insulin Dependent Diabetes Mellitus) with Angiotensin II Antagonist Losartan IDNT Irbesartan Diabetic Nephropathy Trial IDNT Irbesartan Diabetic Nephropathy Trial PROGRESS Perindopril Protection Against Recurrent Stroke Study PROGRESS (Substudy) Perindopril Protection Against Recurrent Stroke Study LIFE Losartan Intervention for End Point Reduction LIFE (Diabetes Mellitus Substudy) Losartan Intervention for End Point Reduction LIFE Losartan Intervention for End Point Reduction (Substudy) A Comparison of Outcomes with Angiotensin-Converting-Enzyme Inhibitors and Diuretics for Hypertension in the Elderly COOPERATE Combination Treatment of Angiotensin-II Receptor Blocker And Angiotensin-Converting-Enzyme Inhibitor in Non-Diabetic Renal Disease SUCCESS-VII Successive Celecoxib Clinical Efficacy and Safety Studies

691

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Page 694

Acronym/Title MARVAL Microalbuminuria Reduction with Valsartan

7.
698 701 703 705 707 709 711 713 715 717 721 723 725 727 729 731 733 735 737 739

Congestive Heart Failure

PRAISE Prospective Randomized Amlodipine Survival Evaluation PRAISE (Substudy) Prospective Randomized Amlodipine Survival Evaluation ELITE II Evaluation of Losartan in the Elderly II DIAMOND-CHF Danish Investigations of Arrhythmia and Mortality on Dofetilide in Congestive Heart Failure RALES Randomized Aldactone Evaluation Study Investigators ATLAS Assessment of Treatment with Lisinopril and Survival RESOLVD Randomized Evaluation of Strategies for Left Ventricular Dysfunction RESOLVD (Metoprolol Study) Randomized Evaluation of Strategies for Left Ventricular Dysfunction STRETCH Symptom, Tolerability, Response to Exercise Trial of Candesartan Cilexetil in Heart Failure MERIT-HF Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure MERIT-HF (Substudy) Metoprolol CR/XL Randomized Intervention Trial in Heart Failure MERIT-HF (Substudy) Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure Metoprolol vs Carvedilol in Heart Failure MUSTIC Multisite Stimulation in Cardiomyopathies MUSTIC (Long-Term Analysis) The Multisite Stimulation In Cardiomyopathies IMPRESS Inhibition of Metalloproteinase BMS-186716, Omipatrilat, in a Randomized Exercise and Symptom Study with Heart Failure High Enalapril Dose Study MACH 1 Mortality Assessment in Congestive Heart Failure 1 COPERNICUS Carvedilol Prospective Randomized Cumulative Survival Study COPERNICUS Carvedilol Prospective Randomized Cumulative Survival
Contents

xxii

Contents

Page 741 744 746 748 750 752 754 756 758 760 762 764 766 768 770

Acronym/Title COPERNICUS Carvedilol Prospective Randomized Cumulative Survival Study BEST The -Blocker Evaluation of Survival Trial BREATHE-1 Bosentan Randomized Trial of Endothelin Antagonist Therapy-1 VMAC Vasodilation in the Management of Acute Congestive Heart Failure OPTIME-CHF Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure Dobutamine vs Nesiritide on Arrhythmias Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy ALPHABET Arterial Pulmonary Hypertension and Beraprost European Trial MIRACLE Multicenter InSync Randomized Clinical Evaluation Val-HeFT Valsartan Heart Failure Trial Val-HeFT Echocardiographic Study Valsartan Benefits Left Ventricular Structure and Function in Heart Failure REMATCH Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure SOLVD Studies of Left Ventricular Dysfunction (Substudy) LIDO Levosimendan Infusion Versus Dobutamine RUSSLAN Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarct The MIRACLE ICD Trial The Multicenter InSync Randomized Clinical Evaluation-Implantable Cardioverter Defibrillator Trial RITZ-4 Randomized Intravenous Tezosentan Study-4 OVERTURE Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events EPHESUS Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study

773 775 777 780

8.
784

Lipid-Lowering Studies
HATS HDL-Atherosclerosis Treatment Study

Contents

xxiii

Page 786

Acronym/Title Comparison of the Effects of Atorvastatin Versus Simvastatin on Subclinical Atherosclerosis in Primary Prevention as Determined by Electron Beam Tomography 4S Scandinavian Simvastatin Survival Study 4S (Substudy) Scandinavian Simvastatin Survival Study WOSCOPS Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia: West of Scotland Coronary Prevention Study WOSCOPS (Substudy) West of Scotland Coronary Prevention Study CARE Cholesterol and Recurrent Events CARE (Substudy) Cholesterol and Recurrent Events CARE (Substudy) Cholesterol and Recurrent Events AFCAPS/TexCAPS AFCAPS/TexCAPS C-Reactive Protein Substudy: Air Force/Texas Coronary Atherosclerosis Prevention Study LIPID (Substudy) Long-Term Intervention with Pravastatin in Ischemic Disease LIPID Substudy (Effect In Women) Long-Term Intervention with Pravastatin in Ischemic Disease LIPID (Incidence of Stroke) Long-Term Intervention with Pravastatin in Ischemic Disease VA-HIT Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VA-HIT (Update) Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VA-HIT (Stroke Substudy) Veterans Affairs HDL Intervention Trial VA-HIT Veterans Affairs High-Density Lipoprotein Intervention Trial (Substudy) Cerivastatin in Primary Hypercholesterolemia Extended Release Niacin vs Gemfibrozil for the Treatment of Low Levels of High-Density Lipoprotein Cholesterol LISA Lescol in Severe Atherosclerosis BIP Bezafibrate Infarction Prevention Post-CABG Post-Coronary Artery Bypass Graft Trial (7.5-Year FollowUp) ASAP Atorvastatin vs Simvastatin on Atherosclerosis Progression

788 793 795

798 800 804 806 808 810 813 815 817 819 821 822 825 827 829 831 833 835

xxiv

Contents

Contents

Page 837 839 841 843 845 847 849 851 853

Acronym/Title MIRACL Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering MIRACL Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (Substudy) RIKS-HIA Register of Information and Knowledge About Swedish Heart Intensive Care Admissions ASSET Atorvastatin Simvastatin Safety and Efficacy Trial Statin, Restenosis and the PlA2 Polymorphism of the Platelet Glycoprotein IIIa Gene ADMIT Arterial Disease Multiple Intervention Trial L-CAD Lipid-Coronary Artery Disease Study WATCH Womens Atorvastatin Trial on Cholesterol Comparison of Effects on Low-Density Lipoprotein Cholesterol and High-Density Lipoprotein Cholesterol with Rosuvastatin vs Atorvastatin in Patients with Type IIa or IIb Hypercholesterolemia Atorvastatin vs Cerivastatin PRINCE Pravastatin Inflammation CRP Evaluation GAIN German Atorvastatin Intravascular Ultrasound Study Vascular Basis for the Treatment of Myocardial Ischemia GREACE Greek Atorvastatin and Coronary Heart Disease Evaluation CHALLENGE Comparison of Efficacy and Safety of Atorvastatin and Simvastatin in Patients with Dyslipidemia With and Without Coronary Heart Disease Niacin-ER/Lovastatin Combination for Hyperlipidemia FAST Fukuoka Atherosclerosis Trial ALLHAT-LLT The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack TrialLipid Lowering Trial ADVENT The Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial Efficacy and Safety of a Potent New Selective Cholesterol Absorption Inhibitor, Ezetimibe, in Patients with Primary Hypercholesterolemia Efficacy and Safety of Ezetimibe Added to Ongoing Statin Therapy for Treatment of Patients with Primary Hypercholesterolemia Long-Term Persistence in Use of Statin Therapy in Elderly Patients STRRIDE Studies of Targeted Risk Reduction Interventions Through Defined Exercise (Substudy)

855 857 859 861 863 865

868 870 873 876 880 882 885 887

Contents

xxv

Page 890 892 895 897 899 901 903

Acronym/Title ASCOT-LLA Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm ADVOCATE The Advicor Versus Other Cholesterol-ModulatingAgents Trial Evaluation Ezetimibe Ezetimibe-Pravastatin Rosuvastatin vs Pravastatin and Simvastatin Rosuvastatin vs Atorvastatin PROSPER Prospective Study of Pravastatin in the Elderly at Risk

9.
906 908 910 912 914 916 918 920 923 925 927 929 931

Arrhythmia
MADIT-II Multicenter Automatic Defibrillator Implantation Trial-II AVID Antiarrhythmics vs Implantable Defibrillators AVID (-Blocker Substudy) Antiarrhythmics vs Implantable Defibrillators Prevention of Implantable Defibrillator Shocks by Treatment with Sotalol Facilitating Transthoracic Cardioversion of Atrial Fibrillation with Ibutilide Pretreatment French Active Compression-Decompression Cardiopulmonary Resuscitation Study MUSTT Multicenter Unsustained Tachycardia Trial Investigation MUSTT Multicenter Unsustained Tachycardia Trial (Substudy) CTAF Canadian Trial of Atrial Fibrillation CIDS Canadian Implantable Defibrillator Study TRACE (Atrial Fibrillation Substudy) Trandolapril Cardiac Evaluation ARCH Amiodarone Reduction in Coronary Heart Trial Oral d,1 Sotalol Reduces the Incidence of Postoperative Atrial Fibrillation in Coronary Artery Bypass Surgery Patients: A Randomized, Double-Blind, Placebo-Controlled Study Efficacy and Safety of Ibutilide Fumarate for the Conversion of Atrial Arrhythmias After Cardiac Surgery GEMICA Grupo de Estudios Multricentricos en Argentina

933 936

xxvi

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Contents

Page 939 941 943 945 947 949 951 954 957 960 962 964 966 968 970 972 974 976 978 980 982 984 987 990
Contents

Acronym/Title CTOPP Canadian Trial of Physiologic Pacing Effective Prevention of Atrial Fibrillation by Continuous Atrial Overdrive Pacing After Coronary Artery Bypass Surgery Atrial Pacing for the Prevention of Atrial Fibrillation After Cardiovascular Surgery Cardiopulmonary Resuscitation by Chest Compression Alone or with Mouth-to-Mouth Ventilation ARREST Amiodarone in Out-of-Hospital Resuscitation of Refractory Sustained Ventricular Tachyarrhythmias CASH Cardiac Arrest Study: Hamburg PIAF Pharmacologic Intervention in Atrial Fibrillation AFIST Atrial Fibrillation Suppression Trial DIAMOND Danish Investigations of Arrhythmia and Mortality on Dofetilide DIAMOND (Substudy) Danish Investigations of Arrhythmia and Mortality on Dofetilide Metoprolol CR/XL to Maintain Sinus Rhythm After Conversion from Atrial Fibrillation SVA-3 Azimilide Supraventricular Arrhythmia Program-3 Amiodarone for Prevention of Atrial Fibrillation Post-CABG SAFIRE-D Symptomatic Atrial Fibrillation Investigative Research on Dofetilide Study ORCA Optimized Response to Cardiac Arrest CAT Cardiomyopathy Trial tPA in Cardiac Arrest Hypothermia After Cardiac Arrest Study Hypothermia in Cardiac Arrest MOST Mode Selection Trial in Sinus-Node Dysfunction ALIVE Amiodarone vs Lidocaine in Prehospital Ventricular Fibrillation Evaluation AFFIRM The Atrial Fibrillation Follow-up Investigation of Rhythm Management Delaying Defibrillation to Give Basic Cardiopulmonary Resuscitation to Patients with Out-of-Hospital Ventricular Fibrillation ERAFT European Rythmol/Rytmonorm Atrial Fibrillation Trial

xxvii

Page 993 995 997 999 1001 1003 1005 1007

Acronym/Title UKPACE United Kingdom Pacing and Cardiovascular Events Trial BLOS The -Blocker Length of Stay DAVID Dual Chamber and VVI Implantable Defibrillator Trial DEBUT Defibrillator vs -Blocker for Unexplained Death in Thailand VPS II Second Vasovagal Pacemaker Study STAF The Strategies of Treatment of Atrial Fibrillation AIRCRAFT Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial AMIOVIRT Amiodarone vs Implantable Cardioverter-Defibrillator

10.
1010 1012 1014 1017

Anticoagulation for Atrial Fibrillation

AFASAK 2 Copenhagen Atrial Fibrillation, Aspirin and Anticoagulation 2 ACUTE Assessment of Cardioversion Using Transesophageal Echocardiography PATAF Primary Prevention of Arterial Thromboembolism in Nonrheumatic Atrial Fibrillation SPORTIF II Stroke Prevention by Oral Thrombin Inhibitors in Atrial Fibrillation

11.
1020 1022 1024

Deep Vein Thrombosis/ Pulmonary Embolism

MEDENOX Prophylaxis in Medical Patients with Enoxaparin Study NAFT-North American Fragmin Trial Low-Molecular-Weight Heparin Prophylaxis vs Warfarin in Hip Arthroplasty NAFT-North American Fragmin Trial Dalteparin Extended Outof-Hospital vs In-Hospital Warfarin/Out-of-Hospital Placebo, in Hip Arthroplasty DOTAVK Duree Optimale du Traitement Antivitamines K ENOXACAN II Enoxaparin and Cancer Pentasaccharide in Hip-Fracture Surgery Group Ximelagatran Prophylaxis Against Venous Thromboembolism Pentasaccharide in Major Knee Surgery Study Warfarin Optimal Duration Italian Trial
Contents

1026 1028 1030 1032 1034 1036

xxviii

Contents

Page 1038 1040 1043 1046 1048 1050 1052

Acronym/Title PENTATHLON 2000 Fondaparinux vs Enoxaparin for Prevention of Venous Thromboembolism After Hip-Replacement Surgery EPHESUS European Pentasaccharide Hip Elective Surgery Study METHRO II Melagatran for Thrombin Inhibition in Orthopaedic Surgery Prolonged Thromboprophylaxis with Oral Anticoagulants After Total Hip Arthroplasty SACRE Study Comparing Oral Anticoagulants with Reviparin PREVENT Prevention of Recurrent Venous Thromboembolism Heparin Plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism

12.

Coronary Artery Disease, Atherosclerosis, Prevention of Progression

ACADEMIC Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia Study AVERT Atorvastatin vs Revascularization Treatment HOPE (Ramipril Study) Heart Outcomes Prevention Evaluation HOPE (Substudy) Heart Outcomes Prevention Evaluation HOPE (Substudy) Heart Outcomes Prevention Evaluation HOPE Heart Outcomes Prevention Evaluation Study (Substudy) HOPE Heart Outcomes Prevention Evaluation (Substudy) HOPE (Vitamin E Study) Heart Outcomes Prevention Evaluation MICRO-HOPE Microalbuminuria, Cardiovascular and Renal Outcomes Heart Outcomes Prevention Evaluation APRES ACE Inhibition Post-Revascularization Study Physicians Health Study (Post-Trial Aspirin Substudy) QUIET (Angiographic Study) Quinapril Ischemic Event Trial QUIET Quinapril Ischemic Event Trial Estrogen Replacement and Atheroclerosis Trial BCAPS -Blocker Cholesterol-Lowering Asymptomatic Plaque Study SCAT Simvastatin/Enalapril Coronary Atherosclerosis Trial PREVENT Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial

1056 1058 1060 1062 1064 1066 1068 1070 1072 1075 1077 1079 1081 1083 1085 1087 1089

Contents

xxix

Page 1091 1093 1095 1098 1100 1102 1104 1106 1108 1110 1112 1114 1116 1118 1121 1124 1127 1129 1132 1134 1136 1138 1140 1142

Acronym/Title PREVENT (Post Hoc Analysis) Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial PART-2 Prevention of Atherosclerosis with Ramipril Trial-2 PPP Primary Prevention Project SECURE Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E DAIS Diabetes Atherosclerosis Intervention Study ETICA Exercise Training Intervention After Coronary Angioplasty MORE Multiple Outcomes of Raloxifene Evaluation (Secondary Analysis) CLARIFY Clarithromycin Acute Coronary Syndrome Patients in Finland ADAM Aneurysm Detection and Management Veterans Affairs Cooperative Study United Kingdom Small Aneurysm Trial Participants TPT (Angina) Thrombosis Prevention Trial CUDAS Perth Carotid Ultrasound Disease Assessment Study CAPRIE Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (Substudy) ELSA European Lacidipine Study on Atherosclerosis ENCORE I Evaluation of Nifedipine and Cerivastatin on Recovery of Coronary Endothelial Function Womens Health Initiative Observational Study VEAPS The Vitamin E Atherosclerosis Prevention Study WAVE Womens Angiographic Vitamin and Estrogen Trial Indo-Mediterranean Diet Heart Study SUAVISArterial Arm Sulodexide Arterial Venous Italian Study Arterial Arm PACIFIC Prevention with a Combined Inhibitor and Folic Acid in Coronary Heart Disease HERS II Heart and Estrogen/Progestin Replacement Substudy HERS II Heart and Estrogen/Progestin Replacement Study Follow-up WHI Womens Health Initiative

xxx

Contents

Contents

Page

Acronym/Title

13.
1146 1148

Valvular Heart Disease

Low-Molecular-Weight Heparin After Mechanical Heart Valve Replacement Early and Long-Term (1 Year) Effects of the Association of Aspirin and Oral Anticoagulant on Thrombi and Morbidity After Replacement of the Mitral Valve with the St. Jude Medical Prosthesis SCT Smoking Cessation Therapy (Fenfluramine Analysis) Mechanical vs Bioprosthetic Valves Clinical and Echocardiographic Follow-up of Patients Previously Treated with Dexfenfluramine or Phentermine/Fenfluramine

1150 1152 1154

14a.
1158 1160

Preliminary Reports Acute Myocardial Infarction

ANTIBIO (Preliminary Report) Antibiotic Therapy in Patients After an Acute Myocardial Infarction TETAMI Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction

14b.

Preliminary Reports Unstable Angina, Non-Q-Wave Myocardial Infarction

A-to-Z Aggrastat to Zocor SYNERGY Superior Yield of the New Strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors

1164 1166

14c.
1170

Preliminary Reports Hypertension

INVEST International Verapamil SR/Trandolapril Study

14d.
1174

Preliminary Reports Congestive Heart Failure

EARTH (Preliminary Report) Endothelin A Receptor Antagonist Trial in Heart Failure

Contents

xxxi

Page 1176 1178

Acronym/Title XSOLVD Extended Studies of Left Ventricular Dysfunction Preliminary Report COMPANION Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure

14e.
1182 1184 1186

Preliminary Reports Arrhythmia

PAFAC (Preliminary Report) Prevention of Atrial Fibrillation After Cardioversion SPORTIF III Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation AF-CHF The Atrial Fibrillation and Congestive Heart Failure Trial

14f.
1190 1192 1194 1196 1198 1200 1202

Preliminary Reports Interventional Cardiology

X-TRACT X-Sizer for Treatment of Thrombus and Atherosclerosis in Coronary Interventions Trial BRITE II Beta Radiation to Reduce In-Stent Restenosis II OctoStent Abciximab in Patients Undergoing Stenting After Loading with HighDose Clopidogrel DELIVER The RX ACHIEVE Drug-Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Lesions TAXUS II Paclitaxel-Eluting Stent Study FACIT Folate After Coronary Intervention Trial

xxxii

Contents

Introduction
The purpose of Cardiovascular Trials Review, Eighth Edition, is to review those trials that have made a major impact on the practice of clinical cardiology within the last 5 years. We have included only studies that were published in English and concentrated mainly on publications that have appeared since 1999 and have studied either pharmacological or device therapy. The text is divided into major headings of diseases such as myocardial infarction and unstable angina. In general, we gave priority to prospective randomized trials with preference to multicenter studies. In this eighth edition, we have added more than 130 new entries and concentrated on trials from 20022003. We have included some smaller studies that describe the new drug-eluting stents. The front section of the book concentrates on articles already in print. The preliminary reports section concentrates on studies that have been presented or discussed in abstract or other form at major cardiology meetings within the last year. Some of these studies are ongoing clinical trials. The Trials Listing sets forth studies by disease categories, which are in the Subjects section. The Trials Index at the back of the book alphabetically lists acronyms and the corresponding pages on which the trials can be found, followed by the names of trials without acronyms. We continue to be amazed by the increasing number of new, large clinical trials in the literature. Since the early 90s there has been a virtual explosion of growth in the number of these trials. An article by Cheng (Am Heart J. 1999;137:726765) listed more than 2250 cardiology trials with acronyms. It is common for some acronyms to be used for more than one study (example: PREVENT). Because the seventh edition exceeded 1500 pages, we had to eliminate many studies prior to 1999 to make room for those published in the last 12 years. These earlier studies can be found in the seventh edition of Cardiovascular Trials Review. Unfortunately, we were not able to include all studies in this text. There are many excellent studies that may not appear in this book. However, a review of the trials included in this book should give readers a flavor of the types and designs of major clinical trials that have influenced the practice of clinical cardiology. The drugs, indications for drugs, and drug dosages may or may not be approved for general use by the US Food and Drug Administration. Physicians should consult the package inserts and/or the Physicians Desk Reference for drug indications, contraindications, side effects, and dosages as recommended. Robert A. Kloner, MD, PhD Yochai Birnbaum, MD Jason S. Chi, BS Los Angeles, July 2003

xxxiii

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MIRACL
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (Substudy)

Title

Effects of atorvastatin on stroke in patients with unstable angina or non-Q-wave myocardial infarction. Waters DD, Schwartz GG, Olsson AG, et al. Circulation 2002;106:16901695. Hypercholesterolemia; unstable angina, non-Q-wave myocardial infarction; stroke. To determine whether aggressive lowering of lipid levels with a statin reduces the incidence of nonfatal stroke in patients who have had an acute coronary syndrome. Substudy of a randomized, placebo-controlled trial. As per MIRACL. 16 weeks. Patients were randomized to atorvastatin (n=1538) 80mg/d or placebo (n=1548) for 16 weeks. All patients were counseled on adherence to the National Cholesterol Education Program Step I diet.

Authors Reference Disease

Purpose

Design Patients Follow-up Regimen

Section 8

8. Lipid-Lowering Studies

839

MIRACL
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (Substudy) (continued)
Results The end point of this substudy was the incidence of fatal and nonfatal stroke. At study entry, the lipid levels between the two groups were similar; the mean level of total cholesterol was 206 mg/dL, 124 mg/dL for LDL cholesterol, 46 mg/dL for HDL cholesterol, and 182 mg/dL for triglycerides. The total and LDL cholesterol had increased slightly in the placebo group at the end of the study. LDL cholesterol had increased 12% in the placebo group, and decreased by 40% in the atorvastatin group. Nonfatal stroke occurred in 22 patients in the placebo group and 9 in the atorvastatin group (relative risk [RR] 0.40; 95% CI=0.190.88; p=0.02). Fatal and nonfatal stroke occurred in 24 patients in the placebo group and 12 in the atorvastatin group (RR 0.49; 95% CI=0.240.98, p=0.04). 3 strokes were classified as hemorrhagic; all were in the placebo group. 8 strokes were classified as either hemorrhagic or undetermined; 5 of these were in the placebo group. All other strokes were either thrombotic or embolic. Patients who developed stroke were older than those who did not, were more likely to be women, and more likely to have a history of heart failure, cerebrovascular disease, or MI. Lipid levels at baseline were similar in patients who developed stroke and those who did not. Cox proportional hazards analysis revealed that 2 variables were associated with an increased risk of nonfatal stroke: history of cerebrovascular disease (RR 3.44; 95% CI=1.507.87; p=0.004); and previous MI (RR 1.99; 95% CI=0.964.15; p=0.065). Treatment with atorvastatin had a RR of 0.41 (95% CI=0.190.89; p=0.024) and current smoking had a RR of 0.28 (95% CI=0.080.92; p=0.36). However, further analysis showed that current smokers in the study were younger and less likely to have diabetes, hypertension, history of heart failure, or previous coronary revascularization, which may account for this finding. Aggressive lowering of lipid levels with atorvastatin in patients with an acute coronary syndrome was associated with a significantly reduced risk of stroke in the shortterm (16 weeks) follow-up period.

Conclusions

840

8. Lipid-Lowering Studies

ASCOT-LLA
Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm

Title

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-thanaverage cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes TrialLipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Sever PS, Dahlof B, Poulter NR, et al. Lancet 2003;361:11491158. Hypertension, hypercholesterolemia (mild). To study the cardiovascular effects of atorvastatin in hypertensive patients with total cholesterol of 6.5 mmol/L. Randomized, 2 2 factorial design, double-blind, multicenter. The antihypertensive arm is designed as Prospective Randomized Open Blinded end points (PROBE) trial. 10,305 patients, 4079 years old, with untreated hypertension (160/100 mm Hg) or treated hypertension with blood pressure 140/90 mm Hg, who had also serum total cholesterol of 6.5 mmol/L and were not currently taking a fibrate or a statin. In addition, patients had to have 3 of the following risk factors (left ventricular hypertrophy, abnormal ECG, type 2 diabetes, peripheral vascular disease, previous TIA or stroke, male sex, age 55 years, microalbuminuria or proteinuria, smoking, total cholesterol/HDL cholesterol ratio of 6, or premature family history of coronary heart disease). Patients with previous myocardial infarction, angina, a stroke within the preceding 3 months, serum triglycerides >4.5 mmol/L, congestive heart failure, uncontrolled arrhythmia or any routine laboratory test showing important hematological or biochemical abnormality were excluded.
8. Lipid-Lowering Studies

Authors Reference Disease Purpose

Design

Patients

890

ASCOT-LLA
Anglo-Scandinavian Cardiac Outcomes TrialLipid Lowering Arm (continued)
Follow-up Regimen Median 3.3 years. After a 4-week run-in phase, 19,342 patients were randomized to -blockers diuretics or to amlodipine ACE inhibitor. In addition, the eligible patients for the lipid-lowering arm were randomized to atorvastatin 10 mg/d (n=5168) or placebo (n=5137). The study was terminated prematurely by the Data and Safety Monitoring Board. Compared with placebo, atorvastatin reduced total cholesterol by 1.3 mmol/L, LDL cholesterol by 1.2 mmol/L, and triglycerides by 0.3 mmol/L at 1 year. HDL cholesterol levels were comparable between the groups. The primary end point of the study (nonfatal MI or coronary heart disease death) occurred in 1.9% in the atorvastatin group and in 3.0% in the placebo group (hazard ratio [HR] 0.64; 95% CI= 0.500.83; p=0.0005). All-cause mortality was 3.6% and 4.1%, respectively (p=0.165). Cardiovascular mortality was 1.4% and 1.6%, respectively (p=0.51). Stroke occurred in 1.7% and 2.4%, respectively (HR 0.73; 95% CI=0.560.96; p=0.024), and MI in 1.7% and 2.7%, respectively (HR 0.62; 95% CI= 0.470.81; p=0.0005). Total cardiovascular events and procedures occurred in 7.5% and 9.5% of the patients, respectively (HR 0.79; 95% CI=0.690.90; p=0.0005). Coronary events occurred in 3.4% in the atorvastatin and 4.8% in the placebo group (HR 0.71; 95% CI=0.590.86; p=0.0005). The rates of serious adverse events and liver-enzyme elevation were comparable between the atorvastatin and placebo groups. Atorvastatin 10 mg/d reduced major cardiovascular events and stroke in hypertensive patients with high-risk features for cardiovascular disease and normal or only mildly elevated serum cholesterol levels.

Results

Section 8

Conclusions

8. Lipid-Lowering Studies

891

Comparison of the Effects of Atorvastatin Versus Simvastatin on Subclinical Atherosclerosis in Primary Prevention as Determined by Electron Beam Tomography

Title

Comparison of the effects of atorvastatin versus simvastatin on subclinical atherosclerosis in primary prevention as determined by electron beam tomography. Hecht HS, Harman SM. Am J Cardiol 2003;91:4245. Coronary artery disease. To determine the comparative effects of atorvastatin and simvastatin on progression of calcified plaque as determined by electron beam tomography (EBT) in patients without symptomatic coronary artery disease. Observational. 103 patients in the atorvastatin group and 46 in the simvastatin group. No patients had a history of symptomatic CAD. In each group, mean age was approximately 59 years, approximately 27% had hypertension, approximately 5% were smokers, and 60% had a family history of CAD. 2% and 9% of patients in the atorvastatin and simvastatin groups were diabetic, respectively. All differences between the 2 groups were nonsignificant. Total cholesterol and LDL cholesterol were significantly higher in the atorvastatin group at study start than in the simvastatin group (p<0.05). Dosages of the statins and niacin were determined by the treating physicians of the patients and were not established in the protocol. The mean dose of atorvastatin was 14.28.1 mg and simvastatin was 23.711.8 mg. Approximately half of all patients were taking niacin, and the average dose was 1890 and 1875 mg in the atorvastatin and simvastatin groups, respectively.

Authors Reference Disease Purpose

Design Patients

786

8. Lipid-Lowering Studies

Comparison of the Effects of Atorvastatin Versus Simvastatin on Subclinical Atherosclerosis in Primary Prevention as Determined by Electron Beam Tomography (continued)
Follow-up Regimen 1.2 years. Statin treatment to lower LDL cholesterol as described above and niacin treatment to increase HDL and lower triglycerides as above. Diet, weight loss, exercise, smoking cessation, and aspirin were recommended to all patients. The EBT calcium score and volume score at study start were similar between the 2 groups. The baseline LDL cholesterol, total, and non-HDL cholesterol levels were significantly higher in the atorvastatin group. The EBT percentile was significantly higher in the atorvastatin cohort. The change in total cholesterol in the atorvastatin and simvastatin groups, respectively, was 26.2% and 22.2%; for LDL cholesterol: 39.8% and 34.7%; for HDL: +15.6% and +14.9%; for triglycerides: 22.1% and 18.8%; none of these differences were significant between the statin groups. The change in calcium scores was +10.8% and +7.5%, and the change in volume scores was +8.5% and +7.8% in the atorvastatin and simvastatin groups, respectively, with no significant differences between the groups. The calcium score and volume score were similar between the groups at the end of the study. Treatment with atorvastatin and simvastatin in patients who are asymptomatic for CAD produced an equal progression of calcified plaques as determined by EBT.

Results

Conclusions

Section 8

8. Lipid-Lowering Studies

787

CAPE II Trial
Circadian Anti-Ischemic Program in Europe II

Title

Medical treatment of myocardial ischemia in coronary artery disease: effect of drug regime and irregular dosing in the CAPE II trial. Deanfield JE, Detry J-M, Sellier P, et al. J Am Coll Cardiol 2002;40:917925. Coronary artery disease. To determine the efficacy of amlodipine and diltiazem in preventing ischemia when an irregular dosing pattern is used. Double-blind, randomized, multicenter.

Authors Reference Disease Purpose

Design Patients

Section 4

250 patients, 128 in the amlodipine group, 122 in diltiazem group. Patients age 2180 years were eligible if they had a history of stable angina (2 attacks/week and no change in symptoms for 1 month), positive exercise test, and at least one other objective finding of coronary artery disease. Exclusion criteria were: congestive heart failure, uncontrolled arrhythmia or hypertension, standing systolic blood pressure <100 mm Hg, heart rate <50 beats/min, heart block greater than 1 AV-block, or abnormal ECG that would potentially impair the interpretation of study findings. 14 weeks. The study began with a 2-week placebo run-in period during which patients underwent ambulatory ECG monitoring and exercise testing. Patients were then randomized to 6 weeks of treatment with 5 mg amlodipine or 180 mg diltiazem once a day. Two weeks later, the dosages were increased to 10 mg and 300 mg, respectively. 72-hour 333

Follow-up Regimen

4. Stable Angina Pectoris and Silent IschemiaMedical Therapy

CAPE II Trial
Circadian Anti-Ischemic Program in Europe II (continued)
ambulatory ECG monitoring and exercise testing were performed two weeks after the dosage increase. Both groups were given a placebo pill on the third day of ECG monitoring to simulate a missed dose, with exercise testing performed again thereafter. Atenolol, 50 mg once a day, was then added to patients in the amlodipine group and isosorbide 5-mononitrate, 50 mg once a day, was added to patients in the diltiazem group. After 2 weeks of this combined treatment, the dosages of atenolol and isosorbide were each increased to 100 mg daily. At 14 weeks, (total 6 weeks combined treatment) patients underwent 72-hour ambulatory ECG monitoring and exercise testing, with a placebo pill again given for the last 24 hours. Results Age, gender, angina history, incidence of previous MI or revascularization, heart rate, or BP were not significantly different between the 2 groups. Many of the patients were already being treated with aspirin and ACEIs, and use of lipid-lowering drugs was common. The primary outcome measures determined by the ECG records were: total number of ST-segment episodes, total duration of such episodes, and peak ST-segment depression, all recorded during the 48-hour monitoring period while on active drug therapy. Secondary outcome measures were: ECG records from the 24-hour off-medication period, exercise test results, and daily angina diary data. Ischemic events at baseline were similar between the 2 groups. Among the primary outcome measures, there was a significant reduction in transient ST-segment depression events in both groups when compared with baseline, and there was no significant difference between the 2 groups. During the medication-free period, ischemic suppression was maintained in the amlodipine group; patients in the diltiazem group showed a significantly higher number (p<0.0001), duration (p=0.0002), and peak ST depression (p<0.0001) of ischemic episodes than patients in the amlodipine group. Outcome measures of ischemia determined by ECG were reduced further with the addition of atenolol to amlodipine (p<0.0001) for number, duration, and peak ST depression of ischemic episodes. The combination of
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isosorbide 5-mononitrate and diltiazem resulted in a nonsignificant reduction in these measures. During the drug holiday, the amlodipine/atenolol group showed less ischemia than the diltiazem/isosorbide 5-mononitrate group, demonstrated by fewer episodes of ST segment depression (p=0.02) and peak ST segment depression (p=0.02). The atenolol/amlodipine combination resulted in a significant reduction in ischemia in the 24-hour drug holiday period (p<0.001). However, the addition of isosorbide to diltiazem resulted in only a small benefit vs monotherapy. There was significant improvement in ischemia during exercise testing for both amlodipine and diltiazem (time to 1 mm ST depression, amlodipine [477 seconds] vs baseline [430 seconds] and diltiazem [477 seconds] vs baseline [428 seconds], p<0.01 for both). However, diltiazem was much less effective during the medication-free period; (474 seconds for amlodipine vs 443 seconds for diltiazem, p=0.03). During active therapy, the amlodipine/atenolol group showed a significantly increased total exercise time, time to angina onset, and 1 mm ST-segment depression vs the diltiazem/isosorbide group (time to 1mm ST-segment depression 520 seconds on amlodipine/atenolol vs 478 seconds on diltiazem/isosorbide, p<0.05). The drug-free day produced the same results (502 seconds vs 434 seconds, p<0.002). Both monotherapies were highly effective in reducing angina attacks and nitroglycerin consumption (p<0.0001), and combination therapy was more effective than monotherapy in reducing both of these (p<0.0001). Frequently reported adverse effects were edema (12.5% in the amlodipine group, 4.1% in diltiazem), and headache (7.0% and 20.5%, respectively). Conclusions Amlodipine and diltiazem are effective in reducing ischemic episodes when used as monotherapy. The addition of atenolol and isosorbide 5-mononitrate, respectively, further augments this effect. Amlodipine, alone or in combination therapy, is more likely than diltiazem to be beneficial in patients who miss doses, or dose irregularly.

Section 4

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