PHARMACODYNAMIC EFFICACY, CLINICAL SAFETY, AND OUTCOMES AFTER PROLONGED PLATELET GLYCOPROTEIN IIB IIIA RECEPTOR BLOCKADE WITH ORAL XEMILOFIBAN - RESULTS OF A MULTICENTER, PLACEBO-CONTROLLED, RANDOMIZED TRIAL/

Background-Parenteral administration of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers can reduce ischemic complications of coronary angioplasty. Orally active GP IIb/IIIa blockers may allow mor e sustained receptor antagonism with the potential for long-term secon dary prevention. The pharmacodynamic efficacy, clinical safety, and ou tcomes after prolonged receptor blockade with an orally active GP IIb/ IIIa antagonist are not known. The Oral Glycoprotein IIb/IIIa Receptor Blockade to Inhibit-Thrombosis (ORBIT) Trial is a multicenter, placeb o-controlled, randomized trial of xemilofiban, an oral platelet GP IIb /IIIa blocking agent, administered to patients after percutaneous coro nary intervention. Methods and Results-After successful;elective percu taneous coronary intervention, 549 patients were randomized to receive either placebo or xemilofiban in-a dose of 15 or 20 mg, Stented patie nts randomized to placebo also received ticlopidine 250 mg orally BID for 4 weeks. Patients who received abciximab during the coronary inter vention and who were randomized to receive xemilofiban were administer ed a reduced dosage (10 mg TID for 2 weeks) followed by the randomized maintenance dose of 15 or 20 mg BID for 2 more weeks. All patients re ceived 325 mg aspirin PO QD. Ex vivo platelet aggregation in response to 20 mu mol/L ADP and 4 mu g/mL collagen was measured over time after the initial dose of study drug and at days 14 and 28 of long-term the rapy in 230 patients. All patients were followed clinically for 90 day s. Xemilofiban inhibited platelet aggregation to both ADP and collagen with peak levels of inhibition that were similar at 14 and 28 days of long-term oral therapy. Plasma levels of xemilofiban correlated with the degree of platelet inhibition. Peak platelet inhibition on day 1 c orrelated with the subsequent occurrence of insignificant or mild blee ding events. Although this study was not powered to evaluate differenc es in clinical outcomes, a trend (P=0.04) was observed for reduction o f. cardiovascular events at 3 months in patients not treated with abci ximab who received the highest dose (20 mg) of xemilofiban studied. Co nclusions-Xemilofiban inhibited platelet aggregation and was well tole rated during 28 days of long-term oral therapy. The observed trend in reduction of cardiovascular events in follow-up awaits confirmation in the larger-scale phase III study (EXCITE trial) currently in progress .