Drug-eluting stents are the default treatment for acute coronary syndromes, unless concerns or contraindications preclude dual antiplatelet therapy (DAPT). Platelet microemboli and mediators from activated platelets can undermine the restoration of perfusion. Therefore, ST-segment elevation MI (STEMI) patients should receive antiplatelet treatments regardless of reperfusion strategy. This review offers an evidence-based comparison of the P2Y12 antagonists that have been evaluated in STEMI. While several studies support clopidogrel in STEMI, the benefits emerge several hours after administration and vary considerably reflecting genetic, cellular and clinical inter-individual differences. Although higher clopidogrel loading doses may improve outcomes, ticagrelor and prasugrel are more potent, produce less inter-individual variability, and show a faster onset of action. Ticagrelor and prasugrel improve outcomes compared to clopidogrel, with manageable bleeding risks, although further studies with a longer follow up are needed. Studies directly comparing ticagrelor and prasugrel are now needed. In the meantime, most current guidelines focus on clopidogrel and, therefore, need revision. While several polymorphisms influence platelet activity, CYP2C19 variants are the most consistently linked to clopidogrel responsiveness. Consensus groups should consider the studies needed to allow routine pharmacogenomic testing. The evidence-based use of P2Y12 antagonists in DAPT should further reduce the morbidity and mortality associated with STEMI.
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