Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease

Background-Antiplatelet therapy is the mainstay of the treatment and second ary prevention of cardiovascular and cerebrovascular ischemic events. We as sessed the safety, tolerability, and pharmacodynamics of lotrafiban, an ora l platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strat egy in patients with cerebrovascular or cardiovascular disease. Methods and Results-Overall, 351 patients with a recent cardiovascular or c erebrovascular acute ischemic event were randomized in a double-blind fashi on to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregatio n and clinical events, The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated e arly because of excess major bleeding. Protocol-defined thrombocytopenia (< 100 000 platelets/mu L) occurred in 5 lotrafiban-treated patients (1.4%, 95 % CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three l otrafiban-treated patients had a nadir platelet count <20 000/mu L (0.9%, 9 5% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platele t aggregation; 5 mg lotrafiban did not differ significantly from placebo, w hereas 100 mg inhibited aggregation by nearly 100%. Conclusions-Lotrafiban provides dose-dependent platelet inhibition when adm inistered to a range of patients with atherosclerosis. The level of platele t inhibition appears to correlate with bleeding risk and drug tolerability.