Genotype-Guided P2Y 12 -Inhibitor De-Escalation Strategy in Acute Coronary Syndrome: Observational Evidence From the POPular-GUIDE PCI

BACKGROUND: A genotype-guided de-escalation strategy—switching from a potent P2Y 12 inhibitor to clopidogrel—may reduce bleeding risk in patients with acute coronary syndrome (ACS). This analysis evaluated the safety and effectiveness of routine genetic testing to guide antiplatelet therapy in clinical practice. METHODS: In this investigator-initiated, prospective, multicenter implementation study, patients received either standard care, with antiplatelet therapy at the physician discretion, or genotype-guided therapy. In the genotype-guided group, physicians were recommended to switch to clopidogrel in noncarriers of CYP2C19 loss-of-function alleles. The coprimary end points were major adverse cardiac events, a composite of cardiovascular death, myocardial infarction, or stroke, and major or nonmajor clinically relevant bleeding, at 1 year of follow-up. Hazard ratios were adjusted for baseline differences between cohorts using multivariable Cox regression. Net adverse cardiac events comprised all-cause death, myocardial infarction, stroke, stent thrombosis, and major bleeding. A Bonferroni-adjusted significance level of α =0.025 was applied. RESULTS: A total of 9907 patients were included in the analysis. Of these, 1208 (12%) were included in the genotype-guided cohort, whereas 8699 (88%) were assigned to the standard care cohort. Major adverse cardiac events occurred in 107 patients (8.9%) in the genotype-guided cohort and 897 patients (10.3%) in the standard care cohort (adjusted hazard ratio, 1.05 95% CI, 0.85–1.29; P =0.64). Major or nonmajor clinically relevant bleeding was reported in 146 patients (12.1%) in the genotype-guided cohort compared with 1384 patients (15.9%) in the standard care cohort (adjusted hazard ratio, 0.79 95% CI, 0.67–0.94; P =0.01). There was no significant association with net adverse cardiac events (adjusted hazard ratio, 0.91 95% CI, 0.76–1.09; P =0.31). CONCLUSIONS: In patients with acute coronary syndrome receiving antiplatelet therapy, implementation of a CYP2C19 genotype-guided de-escalation strategy in clinical practice was associated with a significant reduction of major and nonmajor clinically relevant bleeding compared with standard care at 12 months, without increasing ischemic events. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03823547.