Concept and clinical application of platelet glycoprotein IIb/IIIa inhibition with abciximab (c7E3 fab; ReoPro) for the prevention of acute ischemic syndromes

The platelet membrane glycoprotein (GP) IIb/IIIa integrin receptor is the final common pathway leading to plate let aggregation. Local aggregation commonly occurs following atherosclerotic plaque rupture or other injury to the vascular wall. When GP IIb/IIIa is activated, fibrinogen and von Willebrand factor bind to the receptor with high affinity, crosslinking platelets and locking them to the vessel surface and to each other. This process is central to arterial thrombus formation and consequent acute coronary syndromes, such as myocardial infarction (MI), unstable angina, and abrupt closure following revascularization procedures. Abciximab (c7E3 Fab; ReoPro) is a chimeric monoclonal antibody fragment developed specifically to inhibit GP IIb/IIIa receptor activity and thus prevent platelet aggregation and thrombosis. Abciximab has been evaluated in several clinical studies, the largest of which was the Evaluation of Abciximab for the Prevention of Ischemic Complications (EPIC) trial. This randomized, multicenter, placebo-controlled trial enrolled 2,099 patients at high risk for ischemic complications following coronary revascularization. The patients were randomized into three treatment groups: placebo, abciximab bolus (0.25 mg/kg), or abciximab bolus plus 12-h infusion (10 mu g/min). Patients in the abciximab bolus plus infusion group had significant reductions, compared with placebo, in a composite end point of death, nonfatal MI, and urgent coronary intervention within 30 days. These positive, short-term findings were maintained at 6 months of follow-up. Bleeding complications and transfusions were significantly increased in abciximab patients, although there was no increase in bleeding-related death, stroke, or surgery. Retrospective secondary analyses suggested that many of the bleeding events observed in the EPIC trial may have been associated with concomitant high-dose heparin therapy, particularly in lighter weight patients. Subsequent clinical trials have shown that bleeding events can be reduced in patients treated with abciximab by using weight-adjusted heparin dosing without affecting the efficacy of the abciximab bolus plus infusion regimen. Examination of health economic data from the EPIC trial showed that abciximab bolus plus infusion is cost effective as well as clinically beneficial. These results confirm the importance of platelet GP IIb/ma receptor blockade in the treatment of acute thrombotic syndromes.