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Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) TrialFox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S; Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial. Circulation. 2004 Sep 7;110(10):1202-8. Epub 2004 Aug 16.Reviewer: Hong Liu, MD
Background: Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Methods and Results: In the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial 12,562 patients were randomized to clopidogrel or placebo in addition to aspirin, and the primary outcome was cardiovascular (CV) death, myocardial infarction (MI), or stroke. The benefits were consistent among those undergoing percutaneous coronary intervention (PCI) [9.6% for clopidogrel, 13.2% for placebo; relative risk (RR), 0.72; 95% CI, 0.57 to 0.90], coronary artery bypass grafting (CABG) surgery (14.5% for clopidogrel 16.2% for placebo; RR, 0.89; 95% CI, 0.71 to 1.11), and medical therapy only (8.1% for clopidogrel, 10.0% for placebo; RR, 0.80; 95% CI, 0.69 to 0.92; test for interaction among strata, 0.53). For CABG during the initial hospitalization (530 for placebo, 485 for clopidogrel), the frequency of CV death, MI or stroke before CABG was 4.7% for placebo and 2.9% for clopidogrel (RR, 0.56; 95% CI, 0.29 to 1.08). For the entire study, there was a 1% excess of major bleeding but no significant excess of life-threatening bleeding. Among patients undergoing CABG, the rates of life-threatening bleeding were 5.6% for clopidogrel and 4.2% for placebo (RR, 1.30; 95% CI, 0.91 to 1.95; both nonsignificant). Conclusions: The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization. Comments: Clopidogrel therapy significantly reduced cardiovascular death, MI, or stroke in patients managed by medical therapy and in patients treated with revasculization (PCI or CABG). But bleeding during and post cardiopulmonary bypass (CPB) surgery remains a major potential problem especially with increase use of clopidogrel preoperatively although in the patients underwent CABG surgery there were overall no statistical differences in major and life-threatening bleeding between the two groups in this trial. When should the drug therapy be stopped preoperatively and when it will be safe to re-start the treatment postoperatively? The authors of this study further explored the relationship between the time of clopidogrel cessation prior to surgery and bleeding risk. The data suggested that there was no excess in any bleeding for those stopping clopidogrel for > 5 days before surgery (a period determined by the biological half-life of the drug), and a nonsignificant excess in major bleeding was seen for those who continued the clopidogrel within five days of surgery. Although the excess bleeding risk for those on clopidogrel within five days of CABG was not statistically significant, the consistency of this effect with the duration of effect of clopidogrel on platelet in the circulation suggests that there may be a modest excess risk, which is likely to be true. The rates of re-operation were also not increased in those who stopped clopidogrel equal and/or great than five days before surgery. For those who continued the drug within five days of surgery, there was a trend for excess in re-operation. It has been demonstrated that postoperative clopidogrel therapy is effective in reducing recurrent ischemic events. When should the clopidogrel therapy be restarted? Studies suggested that the drug therapy should be started seven days after surgery. However, the data in this study demonstrated that overall there was no excess in bleeding or in the need for re-operations within seven days after CABG in the clopidogrel group compared with the placebo group. In summary, for most patients who require non-urgent CABG after presentation with ACS, benefits may be maximized by initiating clopidogrel and aspirin on admission and then stopping clopidogrel five days before surgery to minimize the bleeding risk and the therapy can be restarted within seven days post-operatively. Table of Contents:
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