Background and Purpose—We have previously shown that a single 75-mg tablet of clopidogrel, taken before carotid endarterectomy, significantly reduces postoperative embolization, a marker of thromboembolic stroke. This study explores the antiplatelet effect of this submaximal dose.

Methods—Fifty-six patients on long-term aspirin (150 mg) were randomized to 75 mg clopidogrel or placebo before carotid endarterectomy. Blood samples were taken pre- and postdrug administration and at the end of surgery to measure platelet activation and adenosine diphosphate (ADP) response by flow cytometry and aggregometry.

Results—Surgery produced a significant rise in platelet activation in vivo as evidenced by a rise in the percentage of monocyte–platelet aggregates in patients given placebo, but this was not seen in patients receiving clopidogrel. Before surgery, clopidogrel produced a significant reduction in the platelet response to ADP; for example, with 10^-6M ADP, 77.32±2.3% bound fibrinogen in placebo group compared with 67.16±3.1% after clopidogrel (P=0.01). This was accentuated after surgery when the percentage of platelets binding fibrinogen in response to ADP was 76.53±2.2% in patients given placebo and 62.84±3.3% in the clopidogrel group (P=0.002). Similar differences were seen over a range of ADP concentrations and by aggregometry. Platelet responsiveness before treatment was highly variable and was positively correlated with the inhibitory effect of clopidogrel; patients with the highest baseline response to ADP showed the greatest response to clopidogrel. A negative correlation was seen between the effect of clopidogrel and patients’ weight (r=0.57; P=0.002).

Conclusions—These results explain how a single 75-mg dose of clopidogrel produces a significant clinical impact on embolization.