Abstract 3739: Influence of Thienopyridines on Atherosclerotic Lesion Induced by Cholesterol Feeding in Two Animal Models
Purpose: Prasugrel is a novel thienopyridine antiplatelet prodrug with antiplatelet properties distinct from clopidogrel and which are consistent with results from its phase 3 evaluation (TRITON-TIMI38) demonstrating reduced rates of ischemic events compared to clopidogrel. Its influence on atherosclerotic lesion development has not been reported. In the present study, the effects of prasugrel on atherosclerotic lesion development in cholesterol-fed rabbits and guinea pigs were examined.
Methods: Japanese white rabbits (n=10/group) were fed a standard diet supplemented with 1% cholesterol with or without test drugs for 10 weeks. Platelet aggregation (PA) was measured by light transmission aggregometry (LTA) and total area of atherosclerotic lesions in the aorta were determined by the Xerographic method. Hartley guinea pigs (n=11–12/group) were likewise fed standard chow with 1% cholesterol with or without test drugs. After 20 weeks of feeding, ADP-induced PA was measured by LTA and lipid accumulation in aortic arch was evaluated by oil red O (ORO) staining.
Results: In the absence of the thienopyridines, cholesterol feeding resulted in enhanced ADP-induced platelet aggregation. Both prasugrel (3 mg/kg/day) and clopidogrel (10 mg/kg/day) resulted in significant decreases in PA induced by ADP in cholesterol-fed rabbits. Rabbits in the 3 mg/kg prasugrel-treated group had significantly less aortic lesions (p<0.05) compared to those in vehicle-treated group. Clopidogrel at 10 mg/kg resulted in a (non significant) trend towards reduced atherosclerotic lesions. In cholesterol-fed guinea pigs, prasugrel at 3 mg/kg/day significantly inhibited ADP-induced PA (p<0.05) and lipid accumulation in the aortic arch (p<0.01), while clopidogrel showed less inhibition of PA and lipid accumulation.
Conclusion: In parallel with effects on PA, prasugrel demonstrated more potent effects than clopidogrel on lesion development in cholesterol-fed rabbits and guinea pigs. It remains to be determined whether these activities contribute to the greater efficacy of prasugrel in prevention of ischemic events in patients with atherothrombotic disease.