Beneficial Effects of Clopidogrel Combined With Aspirin in Reducing Cerebral Emboli in Patients Undergoing Carotid Endarterectomy

Abstract

Background-Postoperative thromboembolic stroke affects 2% to 3% of patients undergoing carotid endarterectomy (CEA) and is preceded by 1 to 2 hours of increasing cerebral embolization. Previous work has demonstrated that high rates of postoperative embolization are associated with increased platelet reactivity to adenosine 5Ј-diphosphate (ADP). Our hypothesis was that preoperative administration of the platelet ADP antagonist clopidogrel could reduce postoperative embolization. Methods and Results-One hundred CEA patients on routine aspirin therapy (150 mg) were randomized to 75 mg clopidogrel (nϭ46) or placebo (nϭ54) the night before surgery. Platelet response to ADP was assessed by whole-blood flow cytometry. The number of emboli detected by transcranial Doppler within 3 hours of CEA was independently quantified. Time taken from flow restoration to skin closure was used as an indirect measure of the time to secure hemostasis. In comparison with placebo, clopidogrel produced a small (8.8%) but significant reduction in the platelet response to ADP (PϽ0.05) while conferring a 10-fold reduction in the relative risk of those patients having Ͼ20 emboli in the postoperative period (odds ratio, 10.23; 95% CI, 1.3 to 83.3; Pϭ0.01, Fisher's exact test). However, in the clopidogrel-treated patients, the time from flow restoration to skin closure (an indirect marker of hemostasis) was significantly increased (Pϭ0.04, Fisher's exact test), although there was no increase in bleeding complications or blood transfusions. Conclusions-This is the first study to show that a CEA patient's postoperative thromboembolic potential can be significantly reduced by targeted preoperative antiplatelet therapy without increasing the risk of bleeding complications.

Therapeutic Benefit of Low-Dose Clopidogrel in Patients Undergoing Carotid Surgery Is Linked to Variability in the Platelet Adenosine Diphosphate Response and Patients’ Weight

“…We subsequently showed that a submaximal dose of clopidogrel (75 mg), given with aspirin, before carotid surgery resulted in a significant reduction in postoperative embolization (thus reducing the risk of postoperative embolic stroke) without a real increase in bleeding. 15 The question addressed here is how this low dose of clopidogrel can produce such an effective clinical outcome.…”

“…All patients enrolled were on long-term aspirin therapy, standardized to 150 mg aspirin for 4 weeks before surgery. The methodology has been described previously 15 and was a double-blind randomized control trial with patients receiving either a single 75-mg dose of clopidogrel or placebo 12 hours before surgery in addition to their aspirin. Patients were excluded from the trial if they had refused informed consent, reported aspirin intolerance, had not complied with aspirin administration, or were already taking other antiplatelet or antithrombotic therapy.…”

“…There were no significant differences in terms of age, male-to-female ratio, weight, atherosclerotic risk factors, presenting complaint, or degree of carotid stenosis between the groups. These patients represent an unselected subgroup of subjects entered into our randomized trial of clopidogrel reported previously, 15 and their demographic and clinical characteristics were comparable.…”

“…Completion angioscopy was performed before restoration of flow, and patients were monitored during and for 3 hours after the procedure with transcranial Doppler as described previously. 15 …”

“…Patients given a single 75-mg tablet of clopidogrel the night before surgery showed a significant 10-fold reduction in postoperative embolization compared with placebo with no increased risk of bleeding. 15 This low dose of clopidogrel was selected from previous studies in healthy volunteers 16 and in preliminary studies in patients as a dose with minimal risk of causing significant surgical bleeding.…”