P2y12 inhibitors versus aspirin monotherapy for secondary prevention in patients with established atherosclerotic cardiovascular disease: a systematic review and meta-analysis
N Ktenopoulos, K Karampinos, A Apostolos, P Vlachakis, I Kachrimanidis, T Theodoropoulou, N Tsiamis, L Koliastasis, S Tsalamandris, G Benetos, M Drakopoulou, A Synetos, G Latsios, K Tsioufis, K ToutouzasAbstract
Background
Aspirin has long been the standard antiplatelet agent for secondary prevention in atherosclerotic cardiovascular disease (ASCVD), although emerging evidence suggests that P2Y12 inhibitor monotherapy may provide improved ischemic protection without increased bleeding risk.
Purpose
The comparison of clinical outcomes between P2Y12 inhibitors and aspirin monotherapy for long-term secondary prevention in patients with established ASCVD and to provide evidence for clinical decision-making.
Methods
This systematic review and meta-analysis was conducted in compliance with the updated PRISMA guidelines. A comprehensive electronic search of three major bibliographic databases (Cochrane, MEDLINE and Scopus) was performed to identify to identify randomized controlled trials (RCTs) comparing P2Y12 inhibitors and aspirin monotherapy in CAD patients, published through February 15th, 2026. Eligible studies included patients with established ASCVD comparing P2Y12 inhibitors (clopidogrel, ticagrelor and prasugrel) with aspirin. Studies that were non-RCTs, did not focus on monotherapies with these agents, involved patients under 18 years old, or included non-ASCVD patients were excluded. The primary outcome was myocardial infarction (MI). Secondary outcomes included any stroke, haemorrhagic and ischemic stroke, all-cause and cardiovascular mortality, any bleeding and major bleeding events. Relative risks (RR) with 95% confidence intervals (CI) were pooled using random-effects models.
Results
A total of 31,956 patients with established ASCVD were included (P2Y12 inhibitors: 15,725; aspirin: 16,231). P2Y12 inhibitors monotherapy was associated with a significantly lower risk of MI compared with aspirin (RR 0.76, 95% CI 0.62–0.93, I²=0%) and decreased risk of haemorrhagic stroke (RR 0.53, 95% CI 0.30-0.93, I²=19.5%). No significant differences were observed in all-cause mortality (RR 0.98, 95% CI 0.89-1.08, I²=30%), cardiovascular mortality (RR 0.80, 95% CI 0.62-1.02, I²=0%), major bleeding (RR 0.91, 95% CI 0.68-1.23, I²=60%), any bleeding (RR 1.01, 95% CI 0.80-1.27, I²=61%), ischemic stroke (RR 0.92, 95% CI 0.79-1.06, I²=39%) and any stroke (RR 0.81, 95% CI 0.59-1.11, I²=48%). No significant publication bias was documented. Significant heterogeneity was observed only for any bleeding outcome.
Conclusions
Among patients with established ASCVD receiving long-term antiplatelet monotherapy, P2Y12 inhibitors were associated with reduced MI and haemorrhagic strokes compared with aspirin without an increase in bleeding, ischemic stroke or mortality. These findings support P2Y12 inhibitor monotherapy as a potential alternative strategy for secondary prevention across the spectrum of ASCVD and warrant investigation in larger, randomized settings to better inform current evidence.Figure 1Figure 2