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J Am Coll Cardiol, 2000; 36:2028-2035
© 2000 by the American College of Cardiology Foundation
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REVIEW ARTICLE

A critical appraisal of platelet glycoprotein IIb/IIIa inhibition

Derek P. Chew, MB, BSa and David J. Moliterno, MD, FACCa

a Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Manuscript received December 23, 1999; revised manuscript received May 23, 2000, accepted July 13, 2000.

Reprint requests and correspondence: Dr. David J. Moliterno, Cleveland Clinic Foundation, Department of Cardiology, Desk F25, 9500 Euclid Avenue, Cleveland, Ohio 44195
Molited{at}ccf.org

Despite the success of abciximab in preventing ischemic events after percutaneous coronary interventions, attempts to develop intravenous, small-molecule glycoprotein IIb/IIIa antagonists and diversify the clinical indications for these agents have produced varied results. The 30-day ischemic event reduction in the percutaneous coronary intervention trials has ranged by over three-fold (16% to 56%) and is greater among the acute coronary syndrome trials. The phase III trials exploring the role of oral glycoprotein IIb/IIIa inhibition have been consistently disappointing, with evolving evidence of increased mortality. Mechanisms contributing to these heterogeneous results may include normal variation in platelet or receptor number, differences in receptor activity, interpatient variation in pharmacological dose-response and the possibility of prothrombotic or nonglycoprotein IIb/IIIa effects. Plausibility of "suboptimal" effect is suggested by several recent studies. Trials investigating the role of intravenous small-molecule IIb/IIIa antagonists highlight the importance of effective dosing. The increase in bleeding and mortality observed in the oral glycoprotein IIb/IIIa studies indicate the consequences of suboptimal dosing on safety on one hand, while raising the possibility of important prothrombotic, counterregulatory or other sudden cardiac events. This article will undertake a review of the relevant platelet biology, discuss the mechanisms that may contribute to suboptimal antiplatelet efficacy with these agents and examine insights from the clinical trials supporting these concepts.

Abbreviations and Acronyms
  ACS = acute coronary syndrome
  CAPTURE = c7E3 FAB Antiplatelet Therapy in Unstable Refractory Angina trial
  EPIC = Evaluation of c7E3 for the Prevention of Ischemic Complications trial
  EPILOG = Evaluation in Percutaneous Transluminal Coronary Angioplasty to Improve Long-term Outcome With Abciximab Glycoprotein IIb/IIIa Blockade
  EPISTENT = Evaluation of IIb/IIIa Platelet Inhibitor for Stenting
  ESPRIT = Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor Using Integrelin Therapy trial
  EXCITE = Evaluation of Xemilofiban in Controlling Thrombotic Events
  GOLD = Au-Assessing Ultegra
  IMPACT II = Integrelin to Manage Platelet Aggregation To Combat Coronary Thrombosis-II trial
  MI = myocardial infarction
  OPUS TIMI 16 = Orbofiban in Patients With Unstable Coronary Syndromes Thrombolysis In Myocardial Infarction 16 trial
  PARAGON = Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial
  PCI = percutaneous coronary intervention
  PRISM = Platelet Receptor Inhibition in Ischemic Syndrome Management trial
  PRISM-PLUS = Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial
  RESTORE = Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis trial
  SYMPHONY = Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post Acute Coronary Syndromes trial
  TARGET = Do Tirofiban And Reopro Give Similar Efficacy Outcomes Trial




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