P2Y12 Inhibitor Monotherapy Following Short-Duration Dual Antiplatelet Therapy After PCI

Background: Dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) reduces ischemic risk but imposes a haemorrhagic burden associated with increased morbidity. Major bleeding complicates long-term management across acute coronary syndromes (ACS) and chronic coronary syndromes, underscoring the need for safer antithrombotic strategies. P2Y12 inhibitor monotherapy following short-term DAPT has been proposed as a safer alternative, yet reported outcomes across individual randomized trials have been inconsistent, and the optimal strategy remains incompletely defined. Methods: PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched through April 2026 for randomized trials comparing P2Y12 inhibitor monotherapy after short-term DAPT with standard DAPT (6 to 12 months) in adult patients undergoing PCI with drug-eluting stents for ACS or CCS. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Trial sequential analysis (TSA), prespecified subgroup analyses, and GRADE certainty assessment were performed. Results: Twelve trials enrolling 48,778 patients were included. P2Y12 inhibitor monotherapy significantly reduced major bleeding (1.2% vs. 2.0%; RR 0.50, 95% CI 0.37–0.68; P<0.001), all bleeding (3.1% vs. 4.8%; RR 0.51, 95% CI 0.40–0.65; P<0.00001), and net adverse clinical events (NACE) (6.0% vs. 7.2%; RR 0.79, 95% CI 0.70–0.89; P<0.0002). No significant differences were observed in Major adverse cardiac and cerebrovascular events (MACCE), myocardial infarction, stroke, all-cause mortality, cardiovascular mortality, stent thrombosis, or target vessel revascularization. Trial sequential analysis confirmed the robustness of bleeding and NACE reductions and crossed the futility boundary for MACCE, providing reassurance against meaningful ischemic harm. The bleeding benefit was predominantly driven by ACS patients (P for interaction <0.0001), consistent across both early and delayed aspirin withdrawal strategies, and observed with all P2Y12 agent subtypes, though ticagrelor monotherapy uniquely demonstrated significant reductions in both NACE and MACCE. GRADE certainty was moderate for mortality and low for remaining outcomes, driven by open-label designs and heterogeneity. Conclusions: P2Y12 inhibitor monotherapy after short-duration DAPT significantly reduced bleeding and improved net clinical outcomes without increasing ischemic events. These findings support P2Y12 inhibitor monotherapy as an evidence-based antiplatelet de-escalation strategy after PCI, though the predominant bleeding benefit in ACS patients and the clinical superiority of ticagrelor underscore the necessity of individualized patient selection and deliberate agent choice in clinical practice.