In patients with
acute coronary syndromes, inhibition of platelet aggregation with parenteral alpha(IIb)/beta(III) antagonists has proven effective at preventing nonfatal
myocardial infarction and repeat
percutaneous coronary interventions. Paradoxically, the efficacy observed for acute indications and parenteral agents has not extended to oral agents and chronic prevention of secondary thrombotic events, despite robust antithrombotic properties in preclinical
thrombosis models. This report documents the preclinical data of
Lotrafiban, an oral alpha(IIb)/beta(III) antagonist that recently failed in a phase III clinical trial (
BRAVO) for the prevention of secondary
thrombosis.
Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of
lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of
coronary occlusion, size of the developing
thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose
lotrafiban (0.1ug/kg/min) and
aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of
lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the
ADP receptor antagonist clopidogrel was also assessed in the electrical injury model.
Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular
infarct areas, but lacked the overall efficacy of
lotrafiban. In the "Folts" model,
lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of
aspirin. Overall, the preclinical data demonstrated that alpha(IIb)/beta(III) antagonism with
lotrafiban was a well tolerated and effective strategy for attenuating acute arterial
thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial
BRAVO are unexplained. However, the combined evidence suggests that these acute canine
thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.