Early Oral P2Y12 Inhibitor Loading in Patients with ST-segment Eleva-tion Myocardial Infarction Undergoing Primary PCI: A Systematic Re-view and Meta-analysis

Introduction: Whether oral P2Y12 inhibitor loading should be given before hospital arrival or deferred until angiography remains uncertain in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). We compared the efficacy and safety of early loading with later in-hospital, catheterization-laboratory, downstream, or no pretreatment. Methods: PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched from inception through July 2026 without a language restriction. Randomized and nonrandomized comparative studies of adults with STEMI undergoing primary PCI were eligible. Primary random-effects meta-analyses used restricted maximum likelihood (REML) when at least three independent studies were available. A direct prehospital analysis was defined in the working analysis plan before final pooling. Because the review was not prospectively registered, these analytical decisions are described as predefined rather than as claims of prospective protocol registration. Results: Twenty-six studies were included, comprising three randomized trials and 23 nonrandomized studies. In the primary REML analysis, early P2Y12 loading was associated with higher pre-PCI thrombolysis in myocardial infarction (TIMI) 2/3 flow (8 studies; odds ratio (OR): 1.37, 95% confidence interval (CI): 1.03 to 1.83; p=0.032; I²=87.5%) and pre-PCI TIMI 3 flow (9 studies; OR: 1.39, 95% CI: 1.03 to 1.88; p=0.029; I²=83.5%), but neither association retained nominal significance after Knapp–Hartung adjustment. Thirty-day recurrent myocardial infarction/re-infarction was lower in the primary model (10 studies; OR: 0.70, 95% CI: 0.50 to 0.96; p=0.029), although Egger testing suggested possible small-study effects (p=0.079) and leave-one-out analyses were not uniformly stable. Thirty-day stroke was also lower (6 studies; OR: 0.69, 95% CI: 0.56 to 0.85; p<0.001), but this estimate lost significance in sensitivity analysis. Six-month mortality was higher in a three-study primary analysis (OR: 1.18, 95% CI: 1.09 to 1.29; p<0.001), but the Knapp–Hartung CI included the null (0.99 to 1.41) and one registry contributed 99.6% of the random-effects weight. Major bleeding was not increased (14 studies; OR: 1.05, 95% CI: 0.86 to 1.28; p=0.655). Conclusions: The certainty of evidence was very low for every pooled outcome-time stratum. Primary analyses suggested possible improvements in pre-PCI patency and selected ischemic outcomes without a detectable increase in major bleeding, but several positive estimates were not robust to Knapp–Hartung or influence analyses. The isolated six-month mortality signal was likewise statistically fragile. Further studies are needed, yet current evidence does not establish a routine pretreatment benefit for oral P2Y12 inhibitor use in all patients with STEMI undergoing primary PCI.