2025 Acute Coronary Syndrome Guideline: Missing the Boat on CYP2C19 Genotyping.
The 2025 American College of Cardiology/American Heart Association/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome guideline focuses on strategies to reduce bleeding risk with antiplatelet therapy yet lacks any recommendation related to CYP2C19 genotyping. The impact of CYP2C19 loss-of-function alleles on the effectiveness of clopidogrel is well documented, and although prasugrel and ticagrelor more effectively reduce the risk for atherothrombotic events compared with clopidogrel in patients with a CYP2C19 loss-of-function allele, clopidogrel reduces bleeding risk without an increase in atherothrombotic events compared with prasugrel or ticagrelor in those without a loss-of-function allele. Accordingly, an American Heart Association Scientific Statement supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed. This commentary summarizes the evidence in support of CYP2C19-guided P2Y12 inhibitor selection in the context of other 2025 acute coronary syndrome guideline recommendations and urges future guidelines to incorporate recommendations for CYP2C19 genotyping, especially for those at high bleeding risk.