A Genotype-Guided P2Y12-Inhibitor De-Escalation Strategy in Acute Coronary Syndrome: Observational Evidence from the POPULAR-GUIDE PCI

Background and Aims A genotype-guided de-escalation strategy - switching from a potent P2Y12-inhibitor to clopidogrel - may represent an effective and safe approach to reducing bleeding risk in patients with acute coronary syndrome (ACS). This analysis aimed to evaluate the safety and effectiveness of routine genetic testing to guide antiplatelet therapy in clinical practice. Methods In this investigator-initiated, prospective, multicentre implementation study, patients were divided into a standard care cohort, where antiplatelet therapy was prescribed at the physician's discretion (with a potent P2Y12 inhibitor as the default choice), and a genotype-guided cohort. In the genotype-guided group, physicians were recommended to switch to clopidogrel in noncarriers of CYP2C19 loss-of-function alleles during hospital admission. The primary endpoints were major adverse cardiac events (MACE), defined as a composite of cardiovascular death, myocardial infarction, or stroke, and major or non-major clinically relevant bleeding (Bleeding Academic Research Consortium types 2, 3, or 5), at one year of follow-up. Hazard ratios were adjusted for baseline differences between cohorts using multivariable Cox regression. Results A total of 9,907 patients were included in the analysis. Of these, 1,208 (12%) were included in the genotype-guided cohort, while 8,699 (88%) were assigned to the standard care cohort. MACE occurred in 107 patients (8.9%) in the genotype-guided cohort and 897 patients (10.3%) in the standard care cohort (adjHR 1.05; 95% CI 0.85-1.29; P = 0.64). Major or non-major clinically relevant bleeding was reported in 146 patients (12.1%) in the genotype-guided cohort compared to 1,384 patients (15.9%) in the standard care cohort (adjHR 0.79; 95% CI 0.67?0.94; P = 0.01). Conclusion In patients with ACS receiving antiplatelet therapy, implementation of a CYP2C19 genotype-guided de-escalation strategy in clinical practice significantly reduced major and non-major clinically relevant bleeding compared to standard care at 12 months, without increasing ischemic events.