Early Aspirin Withdrawal Post-PCI Reduces Bleeding, No MI Increase with P2Y12 Monotherapy

BACKGROUND: Patients at high ischemic or bleeding risk after percutaneous coronary intervention (PCI) require protection against thrombotic events with dual antiplatelet therapy (DAPT) while avoiding bleeding. Although guidelines recommend 12-month DAPT after acute coronary syndrome (ACS), recent trials have tested the safety of early aspirin withdrawal with potent P2Y12-inhibitor monotherapy. METHODS AND FINDINGS: We performed a meta-analysis of randomized trials (from inception through August 2025) comparing early aspirin withdrawal (≤3 months) with transition to ticagrelor- or prasugrel-monotherapy versus continued DAPT. Co-primary outcomes were myocardial infarction (MI) and clinically relevant bleeding. Prespecified timing analyses stratified the comparison versus DAPT by aspirin timing: immediate (aspirin noninitiation or in-hospital cessation) and early (post-discharge discontinuation within 3 months). Bayesian models quantified risk-stratified probabilities of benefit and harm; trial sequential analysis (TSA) assessed conclusiveness of evidence. Seven trials (n = 27,743) were included. P2Y12-inhibitor monotherapy reduced bleeding (HR = 0.55, 95% CI [0.42, 0.71]; p < 0.001) without significantly increasing MI overall (HR = 1.11, 95% CI [0.91, 1.35]; p = 0.31), death, stroke, or stent thrombosis. Immediate aspirin noninitiation/cessation increased MI (HR = 1.41, 95% CI [1.01, 1.97]; p = 0.04), whereas early discontinuation did not (HR = 0.97, 95% CI [0.76, 1.24]; p = 0.82). TSA indicated conclusiveness for bleeding benefit and futility for an MI excess. Analyses restricted to ACS confirmed the overall results. Bayesian analyses corroborated these effects and identified risk-aligned timing: in high bleeding risk, ≤1-month aspirin discontinuation yielded a 100% posterior probability of bleeding benefit (NNT = 12) and 70% probability of MI-safety; in high ischemic risk, 3-month aspirin discontinuation yielded 100% probability of bleeding benefit (NNT = 57) and 86% probability of MI-safety. Limitations include aggregate data only and limited precision for the immediate aspirin withdrawal subgroup. CONCLUSIONS: Among high-risk post-PCI patients on ticagrelor/prasugrel, discontinuing aspirin within 3 months reduces bleeding without an ischemic trade-off versus DAPT. Immediate aspirin noninitiation or cessation should be avoided; timing should be individualized to bleeding and ischemic risk. PROSPERO: CRD420251167706.