Sex Differences in Prognostic Implications of CYP2C19 Genotype After Drug-Eluting Stent Implantation

Abstract

Background Dual-antiplatelet therapy is standard after percutaneous coronary intervention, but clopidogrel responsiveness varies with CYP2C19 loss-of-function alleles. Whether the genotype conveys different prognostic significance between sexes is uncertain. Methods We analyzed 4630 East-Asian patients with acute coronary syndrome in the PTRG-DES (Platelet Function- and Genotype-Related Long-Term Prognosis in Drug-Eluting Stent-Treated Patients With Coronary Artery Disease) consortium with available CYP2C19 genotyping. Patients were classified as rapid/normal metabolizers versus intermediate/poor metabolizers. The primary end point was cardiac death, myocardial infarction, or definite stent thrombosis within 5 years. Results Among 4630 patients with acute coronary syndrome, 1708 (36.9%) were women. The prevalence of intermediate/poor metabolizer phenotypes was similar in women (61.8%) and men (62.5%). After multivariable adjustment for clinical, laboratory, and procedural confounders, intermediate/poor metabolizer carriers had a significantly higher risk of the 5-year primary outcome in men compared with rapid/normal metabolizer carriers (adjusted hazard ratio [HR], 3.27 [95% CI, 1.58-6.74]; P=0.001). In contrast, no significant association was observed in women (adjusted HR, 1.21 [95% CI, 0.58-2.52]; P = 0.615). Intermediate/poor metabolizer status was also associated with a higher risk of 5-year cardiac death in men only (adjusted HR, 7.01 [95% CI, 2.01-24.48]; P=0.002). Significant interactions between sex and CYP2C19 metabolizer status were observed for both the primary outcome (P for interaction=0.034) and cardiac death (P for interaction=0.049). Conclusions CYP2C19 loss-of-function allele status was a significant predictor of long-term adverse cardiovascular outcomes in men but not in women, suggesting a sex-specific prognostic difference in patients with acute coronary syndrome undergoing percutaneous coronary intervention.