THE ANTIAGGREGATING AND ANTITHROMBOTIC ACTIVITY OF CLOPIDOGREL IS POTENTIATED BY ASPIRIN IN SEVERAL EXPERIMENTAL-MODELS IN THE RABBIT

It is unknown whether the addition of aspirin might increase both the efficacy and the potency of clopidogrel, a potent and selective ADP bl ocker. For that purpose, the efficacy of clopidogrel (1-20 mg/kg, p.o. ) administered orally to rabbits alone or: in combination with aspirin (0.1-10 mg/kg, p.o.) was determined in several experimental models. A potent synergistic effect of the clopidogrel/aspirin association was demonstrated with regard to collagen-induced platelet aggregation meas ured ex vivo. Similarly, aspirin potentiated the antithrombotic activi ty of clopidogrel measured with regard to experimental thrombosis indu ced by a silk thread or an stents placed in an arteriovenous shunt, th rombus formation following electrical stimulation of the rabbit caroti d artery and with regard to In-111-labeled platelet deposition on a st ent implanted in an arteriovenous shunt or on the subendothelium follo wing air drying injury of the rabbit carotid artery. A similar potenti ating effect of aspirin was obtained with regard io myointimal prolife ration (restenosis) in the femoral arteries of atherosclerotic rabbits which occurred as a consequence of stent placement. The clopidogrel/a spirin combination showed only additive-h pe effects on bleeding rime prolongation induced by ear transection in the rabbit, therefore showi ng that combined inhibition of cyclooxygenase and ADP's effects provid e a marked enhanced antithrombotic efficacy, Such a combination may pr ovide substantial protection against platelet aggregation leading to t hrombotic occlusion at sites of endothelial injuries and coronary arte ry stenosis in humans.