Real-World Implementation of a Genotype-Guided P2Y12 Inhibitor De-Escalation Strategy in Acute Coronary Syndrome Patients

Background: CYP2C19 genotype–guided de-escalation from ticagrelor or prasugrel to clopidogrel may optimize the balance between ischemic and bleeding risk in patients with acute coronary syndrome (ACS). Objectives: This study sought to compare bleeding and ischemic event rates in genotyped patients vs standard care. Methods: Since 2015, ACS patients in the multicenter FORCE-ACS (Future Optimal Research and Care Evaluation in Patients with Acute Coronary Syndrome) registry received standard dual antiplatelet therapy (DAPT). Since 2021, genotype-guided P2Y ₁₂ inhibitor de-escalation was recommended at a single center, switching noncarriers of the loss-of-function allele CYP2C19∗3 or CYP2C19∗2 from ticagrelor or prasugrel to clopidogrel, whereas loss-of-function carriers remained on ticagrelor or prasugrel. The primary ischemic endpoint, a composite of cardiovascular mortality, myocardial infarction, or stroke, and the primary bleeding endpoint, Bleeding Academic Research Consortium 2, 3, or 5 bleeding, were compared between a genotyped cohort and a cohort treated with standard DAPT after 1 year. Results: Among 5,321 enrolled ACS patients, 406 underwent genotyping compared with 4,915 nongenotyped ACS patients on standard DAPT. In the genotyped cohort, 65.3% (n = 265) were noncarriers, 88.7% (n = 235) of whom were switched to clopidogrel. The primary ischemic endpoint occurred in 5.2% (n = 21) of patients in the genotyped cohort compared to 6.9% (n = 337) in the standard care cohort (adjusted HR: 0.82; 95% CI: 0.53-1.28). The primary bleeding rate was significantly lower in the genotyped cohort compared to the standard care cohort (4.7% vs 9.8%; adjusted HR: 0.47; 95% CI: 0.30-0.76). Conclusions: The implementation of a CYP2C19 genotype–guided P2Y ₁₂ inhibitor de-escalation strategy in a real-world ACS population resulted in lower bleeding rates without an increase in ischemic events compared to a standard DAPT regimen.