Systematic Review and Meta-analysis of Adverse Events of Low-dose Aspirin and Clopidogrel in Randomized Controlled Trials

Abstract Purpose We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel. Materials and methods Databases were searched for randomized controlled trials of low-dose aspirin (75-325 mg/dayay) or clopidogrel administered for cardiovascular prophylaxis. Relative risks (RR) were determined by meta-analysis of 22 trials for aspirin versus placebo and from single studies for aspirin versus clopidogrel, aspirin versus aspirin/clopidogrel, and clopidogrel versus aspirin/clopidogrel. Absolute risk increase was calculated by multiplying RR increase by the pooled weighted incidence of the control. Results Aspirin increased the risk of major bleeding (RR = 1.71; 95% confidence interval [CI], 1.41-2.08), major gastrointestinal (GI) bleeding (RR = 2.07; 95% CI, 1.61-2.66), and intracranial bleeding (RR = 1.65; 95% CI, 1.06-5.99) versus placebo. No difference between 75-162.5 mg/day and >162.5-325 mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, 0.08-0.20); major GI bleeding: 0.12% (95% CI, 0.07-0.19), intracranial bleeding: 0.03% (95% CI, 0.01-0.08). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-GI bleeding endpoints) with aspirin versus clopidogrel (RR = 1.45; 95% CI, 1.00-2.10). The absolute annual increase was 0.12% (95% CI, 0.00-0.28). Conclusions Low-dose aspirin increases the risk of major bleeding by 70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357-∞) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars.