Therapeutic benefit of low-dose clopidogrel in patients undergoing carotid surgery is linked to variability in the platelet adenosine diphosphate response and patients' weight.
OBJECTIVE
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(-6)M 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.
Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK.
David A
DA
Payne
Chris I
CI
Jones
Paul D
PD
Hayes
A Ross
AR
Naylor
Alison H
AH
Goodall
D000244:Adenosine Diphosphate / Q000378:metabolism*; D001241:Aspirin / Q000627:therapeutic use; D001792:Blood Platelets / Q000378:metabolism*; D001835:Body Weight; D000077144:Clopidogrel; D016894:Endarterectomy, Carotid / Q000009:adverse effects; D006801:Humans; D010919:Placebos; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000188:drug therapy / Q000517:prevention & control; D013223:Statistics as Topic; D013927:Thrombosis; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D010919:Placebos; D010975:Platelet Aggregation Inhibitors; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin