Impact of Clopidogrel Therapy on Mortality and Cancer in Patients with Cardiovascular and Cerebrovascular Disease: A Patient-Level Meta-Analysis

Abstract

Background - Clinical trial data associate extended clopidogrel therapy with increased mortality and cancer. We sought to determine the impact of continued clopidogrel use on mortality and cancer within a patient-level meta-analysis of randomized clinical trials. Methods and Results - Meta-analytic clinical event rates for all-cause, cardiovascular, noncardiovascular, and cancer-related mortality; cancer; myocardial infarction; stroke; and fatal and major nonfatal bleeding were generated using patient-level data from 6 randomized trials comparing prolonged versus no or short-duration clopidogrel on a background of aspirin in patients with cardiovascular and cerebrovascular disease. Among 48 817 randomized patients (median follow-up 546 days), there was no difference in all-cause (7.23% versus 7.26%; P=0.97), cardiovascular (5.25% versus 5.22%; P=0.86), noncardiovascular (1.98% versus 2.03%; P=0.73), and cancer-related (0.93% versus 0.99%; P=0.59) mortality or in new cancer diagnoses (2.97% versus 2.96%; P>0.99). Rates of myocardial infarction (3.21% versus 4.05%; P<0.0001) and stroke (3.04% versus 3.75%; P<0.0001) were significantly lower in patients receiving continued clopidogrel. Fatal bleeding was more common with continued clopidogrel use (0.39% versus 0.27%; P=0.03), as were major nonfatal bleeding (4.06% versus 2.68%; P<0.0001) and intracranial hemorrhage (0.43% versus 0.30%; P=0.02). Conclusions - Across trials of cardiovascular and cerebrovascular disease, extended-duration clopidogrel on a background of aspirin has no overall effect on mortality or cancer but does reduce rates of myocardial infarction and stroke and increase rates of bleeding. These findings emphasize the need for selective use of extended clopidogrel therapy in patients in whom the risks of ischemia are not fully counterbalanced by the risks of bleeding.