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Background: Early initiation of a new P2Y12 inhibitor in ST-elevation myocardial infarction (STEMI) patients prior to primary percutaneous coronary intervention (PCI) is recommended over clopidogrel. However, comparative data remain limited, especially in semi-rural regions with subsequent longer transfer times., Objectives: We aimed to assess the determinants, effectiveness, and safety of pretreatment with new P2Y12 inhibitors compared with clopidogrel in a primary PCI regional network., Methods: Outcomes of 1235 primary PCI patients pretreated with new P2Y12 inhibitors (n = 1050) or clopidogrel (n = 185) were evaluated using a prospective registry. Primary effectiveness endpoint was the composite of death, recurrent myocardial infarction, stroke, or new revascularization. Serious bleedings were defined as Bleeding Academic Research Consortium ≥ 2., Results: Clopidogrel was more likely to be used in older and female patients with more comorbidities. Mean transfer time was longer in the clopidogrel group (123.3 ± 67.3 vs. 102.3 ± 57.2 min; p < 0.01). The primary endpoint was less frequent with new P2Y12 inhibitors compared with clopidogrel (14.9 vs. 30.3%; odds ratio 0.58, 95% confidence interval [CI] 0.39-0.87; p < 0.01), mostly driven by a reduced rate of death (4.5 vs. 26% respectively; hazard ratio 0.25, 95% CI 0.16-0.38; p < 0.01). Bleeding rates did not differ between groups (1 vs. 0.5%, respectively; p = 0.96)., Conclusion: Compared with clopidogrel, pretreatment with new P2Y12 inhibitors seems to be associated with lower risks of mortality and ischemic outcomes, and similar risks of bleeding in a real-world registry. Our results are in line with the guidelines recommending the preferential pre-PCI administration of new P2Y12 inhibitors in STEMI patients referred for primary PCI., (Copyright © 2021 Elsevier Inc. All rights reserved.)