CYP2C19 genotype-guided P2Y12 inhibitor therapy optimization in patients at high bleeding risk: existing evidence and future directions.

INTRODUCTION: Use of CYP2C19 genotype to optimize oral P2Y12 inhibitor therapy can reduce major adverse cardiovascular events (MACE) after percutaneous intervention (PCI) in acutecoronary syndrome (ACS) patients. Interest in guided strategies to reduce bleeding risk by 'de-escalation' of antiplatelet therapy, particularly in high bleeding risk (HBR) patients, has increased. AREAS COVERED: This review (1) discusses existing antiplatelet therapy de-escalation strategies to reduce bleeding risk in ACS patients, (2) evaluates the representation of HBR patients and bleeding outcomes in clinical trials and real-world studies evaluating CYP2C19 genotype-guided approaches to optimize P2Y12 inhibitor therapy, and (3) identifies knowledge gaps and future research directions to determine the clinical utility of this strategy in real-world settings. A literature search was performed across PubMed, Embase and Google Scholar (inception-April 2026). CYP2C19: genotype-guided P2Y12 inhibitor de-escalation can reduce bleeding risk without increasing MACE risk post-PCI. However, this strategy's clinical utility in HBR patients, who may derive greatest benefit, has not been well-studied. Future research evaluating the impact of genotype-guided de-escalation strategies on post-PCI clinical outcomes in HBR patients is needed. Integrating clinical decision support tools, real-world evidence, and multidisciplinary approaches offer potential to optimize P2Y12 inhibitor therapy and improve outcomes in HBR patients.