Pharmacodynamics and safety of lefradafiban, an oral platelet glycoproteinIIb/IIIa receptor antagonist, in patients with stable coronary artery disease undergoing elective angioplasty

Objective-Lefradafiban is the orally active prodrug of fradafiban, a glycop rotein IIb/IIIa receptor antagonist. The present phase II study aimed to de termine the dose of lefradafiban that provides 80% blockade of the glycopro tein IIb/IIIa receptors by fradafiban, and to study the pharmacodynamics an d safety of different doses in patients with stable angina undergoing angio plasty. Design-A double blind, placebo controlled, dose finding study. Setting-Four academic and community hospitals in the Netherlands. Patients-64 patients with stable coronary artery disease undergoing electiv e percutaneous transluminal coronary angioplasty. Interventions-30 mg, 45 mg, and 60 mg of lefradafiban three times daily or placebo was given for 48 hours. Main outcome measures-The primary safety end point was the occurrence of bl eeding, classified as major, minor, or insignificant according to the throm bolysis in myocardial infarction (TIMI) criteria. Efficacy indices included per cent fibrinogen receptor occupancy (FRO), ex vivo platelet aggregation , and plasma concentrations of fradafiban. Results-Administration of lefradafiban 30, 45, and 60 mg three times daily resulted in a dose dependent increase in median FRO levels of 71%, 85%, and 88%, respectively. Inhibition of platelet aggregation was closely related to FRO. There were no major bleeding events. The 60 mg lefradafiban group h ad a high (71%) incidence of minor and insignificant bleeding. The incidenc e of bleeding was 44% in the 30 mg and 45 mg groups, compared with 9% in pl acebo patients. Puncture site bleeding was the most common event. The odds of bleeding increased by 3% for every 1% increase in FRO. Conclusions-Lefradafiban is an effective oral glycoprotein IIb/IIIa recepto r blocker. The clinical effectiveness of doses up to 45 mg three times dail y should be investigated.