Safety and preliminary efficacy of one month glycoprotein IIb/IIIa inhibition with lefradafiban in patients with acute coronary syndromes without ST-elevation - A phase II study

Aims Oral glycoprotein IIb/IIIa inhibitors might enhance the early benefit of an intravenous agent and prevent subsequent cardiac events in patients w ith acute coronary syndromes. We assessed the safety and preliminary effica cy of 1 month treatment with three dose levels of the oral GP IIb/IIIa bloc ker lefradafiban in patients with unstable angina or myocardial infarction without persistent ST elevation. Methods The Fibrinogen Receptor Occupancy STudy (FROST) was designed as a d ose-escalation trial with 20, 30 and 45 mg lefradafiban t.i.d. or placebo. Five hundred and thirty-one patients were randomized in a 3:1 ratio to lefr adafiban or placebo in a double-blind manner, Efficacy was assessed by the incidence of death, myocardial infarction, coronary revascularization and r ecurrent angina. Safety was evaluated by the occurrence of bleeding classif ied according to the TIMI criteria and by measuring clinical laboratory par ameters. Results There was a trend towards a reduction in cardiac events with lefrad afiban 30 mg when compared with placebo and lefradafiban 20 mg. The benefit was particularly apparent in patients with a positive (greater than or equ al to0.1 ng.ml(-1)) troponin I test at baseline and less so in those with a negative test result. In patients receiving lefradafiban, the cardiac even t rate decreased with increasing minimal levels of fibrinogen receptor occu pancy. There was a dose-dependent increase in the incidence of bleeding: th e composite of major or minor bleeding occurred in 1% of placebo patients, 5% of patients receiving lefradafiban 20 mg and in 7% of patients receiving 30 mg, with an excessive risk (15%) in the 45 mg group which resulted in e arly discontinuation of this dose level. Gingival and arterial or venous pu ncture site bleedings were most common and accounted for more than 60% of a ll haemorrhagic events. There was an increased incidence of neutropenia (ne utrophils <1.5x10(9)/l) in the lefradafiban groups (5.2% vs 1.5% in the pla cebo group), which did not result from bone marrow depression but rather fr om a reversible redistribution of neutrophils by margination or clustering. Conclusion One month's treatment with the oral glycoprotein IIb/IIIa inhibi tor lefradafiban in patients with unstable angina and myocardial infarction without persistent ST elevation resulted in a decrease in cardiac events w ith lefradafiban 30 mg and a dose-dependent increase in haemorrhagic events . The observed favourable trend towards a reduction in cardiac events in pa tients with elevated troponin levels requires confirmation in a large clini cal trial. (C) 2000 The European Society of Cardiology.