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REVIEW ARTICLE

A critical appraisal of platelet glycoprotein IIb/IIIa inhibition

^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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