Copyright © 2000 by the European Society of Cardiology.
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
a Thoraxcenter, Erasmus University and University Hospital Rotterdam, The Netherlands
c Städtische Kliniken Kassel, Germany
d Queen's Medical Centre, University Hospital Nottingham, United Kingdom
e Hopital Tenon, Paris, France
f Hopital de la Citadelle, Liege, Belgium
g Boehringer Ingelheim Pharma KG, Germany
h Boehringer Ingelheim BV, The Netherlands
b Cardialysis BV, Clinical Research Management and Core Laboratories, Rotterdam, The Netherlands
revised June 26, 2000; accepted June 28, 2000
Abstract
Aims Oral glycoprotein IIb/IIIa inhibitors might enhance the early benefit of an intravenous agent and prevent subsequent cardiac events in patients with acute coronary syndromes. We assessed the safety and preliminary efficacy of 1 month treatment with three dose levels of the oral GP IIb/IIIa blocker lefradafiban in patients with unstable angina or myocardial infarction without persistent ST elevation.
Methods The Fibrinogen Receptor Occupancy STudy (FROST) was designed as a dose-escalation trial with 20, 30 and 45mg lefradafiban t.i.d. or placebo. Five hundred and thirty-one patients were randomized in a 3:1 ratio to lefradafiban or placebo in a double-blind manner. Efficacy was assessed by the incidence of death, myocardial infarction, coronary revascularization and recurrent angina. Safety was evaluated by the occurrence of bleeding classified according to the TIMI criteria and by measuring clinical laboratory parameters.
Results There was a trend towards a reduction in cardiac events with lefradafiban 30mg when compared with placebo and lefradafiban 20mg. The benefit was particularly apparent in patients with a positive (
0·1ng.ml–1) troponin I test at baseline and less so in those with a negative test result. In patients receiving lefradafiban, the cardiac event rate decreased with increasing minimal levels of fibrinogen receptor occupancy. There was a dose-dependent increase in the incidence of bleeding: the composite of major or minor bleeding occurred in 1% of placebo patients, 5% of patients receiving lefradafiban 20mg and in 7% of patients receiving 30mg, with an excessive risk (15%) in the 45mg group which resulted in early discontinuation of this dose level. Gingival and arterial or venous puncture site bleedings were most common and accounted for more than 60% of all haemorrhagic events. There was an increased incidence of neutropenia (neutrophils <1·5x109/l) in the lefradafiban groups (5·2% vs 1·5% in the placebo group), which did not result from bone marrow depression but rather from a reversible redistribution of neutrophils by margination or clustering.
Conclusion One month's treatment with the oral glycoprotein IIb/IIIa inhibitor lefradafiban in patients with unstable angina and myocardial infarction without persistent ST elevation resulted in a decrease in cardiac events with lefradafiban 30mg and a dose-dependent increase in haemorrhagic events. The observed favourable trend towards a reduction in cardiac events in patients with elevated troponin levels requires confirmation in a large clinical trial.
Key Words: Unstable angina, myocardial infarction, lefradafiban, glycoprotein IIb/IIIa blockers, platelet aggregation inhibitors
f1 Correspondence: K. Martijn Akkerhuis, MD, Cardialysis BV, P.O. Box 2125, 3000 CC Rotterdam, The Netherlands.
f3 Professor Neuhaus has died since the acceptance of this paper.
f2 Investigators and study organization of the Fibrinogen Receptor Occupancy STudy are listed in the Appendix. 
Professor Neuhaus has died since the acceptance of this paper.
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