Antiplatelet therapy in high-bleeding risk patients with acute coronary syndrome: pharmacogenomics in the era of precision medicine

The management of high-bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS) remains a significant challenge, requiring careful balancing of ischemic prevention and bleeding avoidance. Bleeding risk reduction in patients with HBR treated with newer-generation drug-eluting stents includes P2Y12 inhibitor intensity de-escalation, shortening of the dual antiplatelet therapy (DAPT) duration and monotherapy with a P2Y12 inhibitor. Although data for HBR patients are limited, an individualized approach is required. Preference for a short DAPT duration and use of clopidogrel where indicated may reduce bleeding incidence without incurring ischemic risk. Pharmacogenomic testing for CYP2C19 helps personalize antiplatelet therapy in specific patient subgroups. We herein discuss current data and limitations of DAPT strategies in the understudied HBR patient population with ACS undergoing PCI. A literature search of PubMed/MEDLINE and Embase (inception-January 2026) identified randomized trials, meta-analyses, registries, and major guidelines (ESC, ACC/AHA, JCS) on ACS, high-bleeding risk, CYP2C19-guided antiplatelet strategies, de-escalation, and monotherapy. Individualized antiplatelet therapy, genetic characteristics and clinical parameters, should be integrated in the management of such patients. Clopidogrel pharmacogenomics and modern monotherapy or short DAPT strategies promise improved safety and efficacy, with the patient at the center of the therapeutic decision.