A systematic search on the main databases Medline, Web of Science, and Embase until April 21, 2024 was performed. Only randomized trials were eligible for this analysis. As primary endpoint we analyzed major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, non-fatal myocardial infarction (MI) and non-fatal stroke. As secondary endpoints we investigated the individual primary endpoints as well as the rate of total and severe bleeding events. The analysis was carried out using the odds ratio (OR) as outcome measure. Due to the expected heterogeneity across studies, a random-effects model was fitted to the data.

In total, 6 randomized trials comprising 33,508 patients (16,824 on clopidogrel, 16,684 on aspirin) were analyzed. Clopidogrel as compared to aspirin significantly reduced MACE (OR 0.85 [95 %CI 0.77–0.94], p < 0.001, I2 = 26 %). The reduction was driven by a decrease in non-fatal MI (OR 0.73 [95 %CI 0.60–0.90], p = 0.01, I2 = 28 %) and stroke (OR 0.86 [95 %CI 0.74–1.00], p = 0.05, I2 = 8 %), without increasing the rates of total (OR 1.04 [95 %CI 0.83–1.31], p = 0.73, I2 = 72 %) or severe bleeding (OR 0.89 [95 %CI 0.83–1.18], p = 0.43, I2 = 50 %). No effect on all-cause mortality was detectable (OR 0.96 [95 %CI 0.87–1.06], p = 0.41, I2 = 0 %).