ESPRIT in context: pharmacology matters!

One of the most notable advances in cardiology of the past decade has been the development and clinical application of a novel class of potent antiplatelet agents — the platelet glycoprotein (GP) IIb/IIIa integrin inhibitors. In the mid-1990s, large-scale, randomized, controlled clinical trials of these agents documented highly significant and clinically relevant reductions in the morbidity and mortality of percutaneous coronary intervention. Subsequently, GP IIb/IIIa inhibitors were found to prevent ischaemic events in patients admitted with the acute coronary syndromes of unstable angina or non-Q wave myocardial infarction. The first GP IIb/IIIa agent brought to market in the U.S.A. (1994) was abciximab (ReoPro, Centocor, Malvern, PA, U.S.A., and Eli Lilly, Indianapolis, IN, U.S.A.). Abciximab is the Fab fragment of a chimeric murine–human monoclonal antibody to the GP IIb/ IIIa integrin. Abciximab binds to GP IIb/IIIa with high affinity and has a slow receptor off-rate, resulting in a long biological half-life ( 12 h). In clinical trials, treatment with abciximab during percutaneous coronary intervention consistently provided impressive reductions in the incidence of ischaemic events across a series of trials including EPIC, EPILOG, CAPTURE, and EPISTENT. In 1998, eptifibatide (Integrilin, COR Therapeutics, South San Francisco, CA, U.S.A., and Schering-Plough, Kenilworth, NJ, U.S.A.) and tirofiban (Aggrastat, Merck, West Point, PA, U.S.A.) were approved for use by the U.S.A. Food and Drug Administration. These agents are distinguished from abciximab by a much shorter half-life ( 2–3 h), a rapid off-rate, and greater selectivity for the GP IIb/IIIa receptor complex. Results of pivotal clinical trials of these two agents in the percutaneous coronary intervention indication, however, were disappointing. In the IMPACT II trial of eptifibatide and the RESTORE trial of tirofiban, lower degrees of absolute and relative benefit were seen in comparison to the abciximab series of trials. Potential explanations for this disparity included both pharmacodynamic issues (particularly the extended duration of action of abciximab) and the potential role of receptor cross-reactivity of abciximab with other receptors beside GP IIb/IIIa. Based on the trial results, the clinical and commercial con-