Optimizing selection of P2Y ₁₂ inhibiting therapy: clopidogrel, prasugrel or ticagrelor

INTRODUCTION: Antiplatelet therapy is key for secondary prevention in patients with atherosclerotic cardiovascular disease, particularly those undergoing percutaneous coronary intervention (PCI). While aspirin has historically been the standard of care agent, oral P2Y₁₂ inhibitors - namely clopidogrel, prasugrel and ticagrelor - have emerged as key adjunctive therapies as well as treatment alternatives. Given their differing pharmacodynamic, pharmacogenomic, and safety - efficacy profiles, the optimal selection of these agents remains an area of investigation. AREAS COVERED: This review provides a comprehensive overview of the pharmacologic profiles of oral P2Y₁₂ inhibitors, clopidogrel, prasugrel and ticagrelor, and their comparative effects when used with or without aspirin. MEDLINE, Cochrane, Web of Science, and Scopus were searched until August 5, 2025. Special attention is given to high-risk subgroups (e.g. clopidogrel poor-responders, diabetics, East Asians, females, and patients requiring concomitant oral anticoagulation), and to strategies involving platelet function or genetic testing. EXPERT OPINION: The selection of oral P2Y₁₂ inhibiting therapy should be tailored to the individual patient, taking into consideration clinical, procedural, demographic, and genetic factors, as well as the dynamic nature of ischemic and bleeding risks over time. Specific considerations are warranted for certain patient subgroups, as well as those with clopidogrel poor responsiveness, or patients with contraindications to ticagrelor or prasugrel.