Timing matters: impact of early oral p2y12 pretreatment on ischemic outcomes and reperfusion in stemi patients undergoing primary pci

Background Early coronary reperfusion with primary percutaneous coronary intervention (PCI) combined with dual antiplatelet therapy (DAPT) is the standard of care in ST-segment elevation myocardial infarction (STEMI). Although oral P2Y12 inhibitors are routinely administered, the optimal timing of pretreatment remains debated, with inconsistent evidence regarding ischemic benefit and bleeding risk. Purpose To evaluate the clinical impact of early oral P2Y12 pretreatment prior to primary PCI in patients with STEMI. Methods We systematically searched PubMed, Embase, and the Cochrane Library from inception through November 5, 2025, for randomized controlled trials (RCTs) and cohort studies comparing early oral P2Y12 pretreatment versus no pretreatment in STEMI patients undergoing primary PCI. The primary outcomes were myocardial infarction (MI) and all-cause mortality. Secondary outcomes included post-PCI TIMI 3 flow and major bleeding. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using random-effects models. Risk of bias was assessed using ROB2 and ROBINS-I tools, and certainty of evidence was appraised using the GRADE framework. Results Twenty-four studies encompassing 110,326 patients (3 RCTs and 21 observational studies) were included. Pretreatment with oral P2Y12 inhibitors showed heterogeneous but overall favorable ischemic outcomes without a consistent increase in bleeding risk. Early P2Y12 pretreatment was associated with a significant reduction in recurrent MI at 30 days (RR = 0.84, 95% CI 0.73–0.96; p=0.01) with non-significant trends toward lower target vessel revascularization, mortality, stroke, stent thrombosis, MACE, and bleeding events. At 12 months, pretreatment was associated with a significant reduction in recurrent MI (RR = 0.73, 95% CI 0.57–0.95; p=0.02). No significant differences were observed in all-cause mortality or achievement of post-PCI TIMI 3 flow. Overall certainty of evidence was moderate. In prespecified subgroup analyses according to P2Y12 inhibitor type, differential treatment effects were observed across agents. Clopidogrel pretreatment reduced 30-day myocardial infarction (RR = 0.68, 95% CI 0.48–0.98; p=0.04), improved TIMI flow, and reduced bleeding risk (RR = 0.80, 95% CI 0.68–0.94; p=0.006). Ticagrelor pretreatment showed neutral effects across early and pooled follow-up analyses. Conclusions In patients with STEMI undergoing primary PCI, early oral P2Y12 pretreatment was associated with reduced recurrent myocardial infarction at short and long term follow-up, without a consistent increase in bleeding risk. No mortality benefit was demonstrated. Subgroup analyses suggested variability according to P2Y12 inhibitor type, with clopidogrel showing early ischemic and safety benefits. Further adequately powered randomized trials are needed to refine patient selection and optimal timing strategies.OutcomesINFOGRAPHIC