Clopidogrel inhibition of stent, graft, and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates

Background-A recent study showed that clopidogrel reduces thrombo-occlusive complications in patients with symptomatic atherosclerosis more effectivel y than aspirin. Methods and Results-The effects of clopidogrel and aspirin have been compar ed, singly and in combination, for measurements of In-111-labeled platelets and I-125-labeled fibrin deposition in baboon models of arterial thrombosi s and related to platelet aggregation and expression of activation epitopes induced by ADP, collagen, and thrombin receptor agonist peptide (TRAP) and to template bleeding times (BTs). Low-dose oral clopidogrel (0.2 mg.kg(-1) .d(-1)) produced cumulative (1) intermediate decreases in In-111-platelet a nd I-125-fibrin deposition for segments of prosthetic vascular graft, deplo yed endovascular metallic stents, and endarterectomized aorta (P<0.009 in a ll cases); (2) elimination of ADP-induced platelet aggregation (P<0.001); ( 3) modest inhibition of collagen-induced platelet aggregation (P<0.01); (4) no reduction in TRAP-induced platelet aggregation; and (5) minimal prolong ation of BTs (P=0.03). High-dose oral clopidogrel (greater than or equal to 2 mg/kg) produced the same effects within 3 hours. The effects of clopidog rel dissipated over 5 to 6 days. Aspirin 10 mg.kg(-1).d(-1) alone did not d ecrease In-111-platelet and I-125-fibrin deposition on segments of vascular graft but detectably decreased In-111-platelet and I-125-fibrin accumulati on on stents (P<0.01), minimally inhibited ADP- and collagen-induced platel et aggregation (P<0.05 in both cases), and minimally prolonged BTs (P=0.004 ). Within 3 hours of aspirin administration, the antithrombotic effects of acute high-dose or chronic low-dose clopidogrel were substantially enhanced , and BTs were modestly prolonged without inhibiting platelet aggregation i nduced by TRAP (P<0.001 in all cases compared with clopidogrel alone). Conclusions-Clopidogrel produces irreversible, dose-dependent, intermediate reduction in thrombosis that is substantially enhanced by the addition of aspirin. The effects of combining aspirin and clopidogrel need to be evalua ted in patients at risk of vascular thrombosis.