Prognostic Implication of <i>CYP2C19</i> Genotype According to Clinical Risk Stratification After Drug‐Eluting Stent Implantation

The impact of CYP2C19 genotype in relation to clinical risk is unclear during clopidogrel treatment following drug-eluting stent (DES) implantation. This study aimed to evaluate the prognostic significance of CYP2C19 genotypes based on clinical risk stratification in DES-treated patients. From the nationwide multicenter PTRG-DES (Platelet function and genoType-Related long-term progGosis in DES-treated patients) consortium, patients were classified according to the presence of CYP2C19 loss-of-function (LoF) allele: rapid or normal metabolizers (RMs/NMs) vs. intermediate or poor metabolizers (IMs/PMs), and clinical risk was stratified using the CHADS-P₂A₂RC and TRS 2°P scores. The primary endpoint (1°EP) was a composite of cardiac death, myocardial infarction, and stent thrombosis during a 3-year follow-up. Among clopidogrel-treated patients with CYP2C19 genotyping (n = 8,163), IMs/PMs (62.1%) demonstrated an increased risk of 1°EP compared with RMs/NMs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.05-2.07; Log-rank P < 0.001), Most notable in those with high CHADS-P2A2RC (≥ 4) and TRS 2°P (≥ 3) scores (HR_adj: 1.68; 95% CI: 1.01-2.80; P = 0.047 and HR_adj: 1.63; 95% CI: 1.05-2.54; P = 0.029, respectively). In patients with low scores, there was no difference in 1°EP between IMs/PMs vs. RMs/NMs; however, an interaction was observed between acute and chronic coronary syndromes for both low CHADS-P₂A₂RC (HR_adj: 2.12; 95% CI: 1.11-4.03 and HR_adj: 0.68; 95% CI: 0.34-1.36; P_interaction = 0.017) and TRS 2°P scores (HR_adj: 2.34; 95% CI: 1.07-5.12 and HR_adj: 0.52; 95% CI: 0.22-1.17; P_interaction = 0.008). Among clopidogrel-treated patients, the carriage of the CYP2C19 LoF allele was associated with higher ischemic risk, particularly in those with high clinical risk or an acute coronary syndrome presentation.