Platelet activation and aggregation are believed to be the primary causes of thrombus development following percutaneous transluminal coronary revascularization (PTCR). Platelet aggregation is mediated by the binding of fibrinogen to the platelet receptor glycoprotein IIb/IIIa. Published trials have shown that intravenous administration of glycoprotein IIb/IIIa receptor antagonists immediately before and up to 48 hours after angioplasty reduces the incidence of myocardial infarction and death, as well as the need for revascularization. However, platelet activation may persist for up to one month after an acute coronary syndrome, and occlusion may recur for up to 21 days following PTCR and stent placement. Use of oral antithrombotic agents such as ticlopidine has become common practice after PTCR, even though the U.S. Food and Drug Administration has not labeled the drug for this use, and ticlopidine has many associated adverse effects. O'Neill and colleagues evaluated whether oral xemilofiban, a glycoprotein IIb/IIIa receptor antagonist, would provide sustained protection from the need for revascularization, myocardial infarction or death following PTCR.
Patients with angiographic evidence of coronary artery disease who needed PTCR were enrolled in the double-blind randomized trial. Patients at high risk for ischemic events were specifically sought to increase the potential event rate and increase the chance of proving a therapeutic benefit of the study drug. Patients with a platelet count of less than 120,000 mm3, a history of bleeding disorders, active bleeding or a coagulation deficiency were excluded. Following diagnostic angiography but before PTCR, eligible patients were randomized to receive one of three regimens: (1) a single dose of 20 mg of oral xemilofiban preoperatively, followed by 20 mg given three times daily; (2) a single dose of 20 mg of oral xemilofiban preoperatively, followed by 10 mg given three times daily; or (3) an identical placebo. Those who received coronary stents with PTCR in the placebo group were also given ticlopidine in a dosage of 250 mg twice daily for 14 to 28 days. In addition, all patients received a daily dose of 80 to 325 mg of aspirin. Follow-up occurred between days 10 and 21 after PTCR and at day 60. The primary end point was event-free survival at six months. Events were defined as death, nonfatal myocardial infarction and the need for urgent revascularization on the basis of cardiac symptoms, ischemia, or both.
Over a one-year period, 7,232 patients were enrolled. Mean patient age was 59 years, and about 80 percent of the patients were men. Follow-up for all three groups averaged 205 days. A total of 332 events occurred in the 10-mg group, 306 in the 20-mg group, and 324 in the placebo group. There were no significant differences across groups at 30 or 213 days. More specifically, the incidence of death or myocardial infarction was essentially the same across groups. The measured treatment effects also were similar, regardless of stent placement. Episodes of bleeding occurred in 6.1 percent of the 10-mg group, 11.6 percent of the 20-mg group, but only 1.5 percent of the placebo group. Thrombocytopenia, defined as a platelet count of less than 80,000 mm3, occurred in 0.5 percent of the treatment groups and 0.1 percent of the placebo group.
The authors conclude that treatment with xemilofiban before PTCR and afterward for an extended period of time provided no observed improvement in clinical end points, specifically the incidence of early and late (six-month) myocardial infarction and mortality. For now, the benefit of this class of medications remains unproved.