Clopidogrel Is Slightly More Effective Than Aspirin for the Secondary Prevention of Cardiovascular and Cerebrovascular Events

Is clopidogrel more effective than aspirin for the secondary prevention of cardiovascular and cerebrovascular events?

Based on the analysis of pooled individual participant data, clopidogrel is slightly more effective than aspirin in the secondary prevention of major cardiovascular and cerebrovascular events without increasing the risk of major bleeding. The main difference was in lower rates of subsequent myocardial infarction and stroke of any etiology. (Level of Evidence = 1a)

The authors searched four databases and the websites of various cardiology societies to identify published randomized trials that directly compared clopidogrel with aspirin monotherapy in adults with established coronary artery disease. The participants could be antiplatelet therapy naïve, have recently discontinued dual antiplatelet therapy, or have undergone dual antiplatelet therapy run-in before randomization. The authors pooled the individual participant data to evaluate benefits and harms. The main outcome of interest was major adverse cardiovascular and cerebrovascular events: cardiovascular death, myocardial infarction, or stroke. The main harm was major bleeding. The authors identified seven trials (N = 28,982) with a median of 2.3 years of follow-up. Four studies were at low risk of bias, and the others had some concerns about protocol deviations.

Using intention-to-treat analysis, the authors reported that the overall rate of major adverse cardiovascular and cerebrovascular events was lower in the participants treated with clopidogrel (2.6 vs 2.99 per 100 person-years; number needed to treat [NNT] = 257). They found no significant difference in the rate of major bleeding (0.71 vs 0.77 per 100 person-years). They also found no significant difference in death from any cause or in cardiovascular death (2 and 1.2 per 100 person-years, respectively).

For the individual major adverse cardiovascular and cerebrovascular events outcome, clopidogrel was more effective than aspirin alone for subsequent myocardial infarctions (0.99 vs 1.27 per 100 person-years; NNT = 358) and for stroke of any etiology (0.73 vs 0.88 per 100 person-years; NNT = 667). Although the authors detected no heterogeneity among the major adverse cardiovascular and cerebrovascular events data, they found significant heterogeneity among the data on major bleeding ( I² = 50.7%). They also provided statistics to look at event rates over time, and these supported the main findings. According to GoodRx, a 90-day supply of clopidogrel, 75 mg, costs between $14 and $31; a 90-day supply of aspirin, 81 mg, costs between $5 and $12.

Study Design: Meta-analysis (randomized controlled trials)

Funding Source: Government

Setting: Various (meta-analysis)

Reference: Valgimigli M, Choi KH, Giacoppo D, et al. Clopidogrel versus aspirin for secondary prevention of coronary artery disease: a systematic review and individual patient data meta-analysis. Lancet. 2025;406(10508):1091-1102.