Background: Recent clinical trials have demonstrated that clopidogrel monotherapy is superior to aspirin for long-term maintenance after percutaneous coronary intervention (PCI). However, evidence remains limited regarding whether the clinical benefit of chronic clopidogrel monotherapy differs according to CYP2C19 genotype. Objectives: The study sought to investigate the prognostic impact of CYP2C19 genotype in patients with clopidogrel monotherapy for long-term maintenance following PCI. Methods: From the SMART-CHOICE 3 (SMart Angioplasty Research Team: CHoice of Optimal Anti-Thrombotic Strategy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents 3) trial and the nationwide PTRG-DES (Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients) consortium, we analyzed patients with CYP2C19 genotyping who completed the standard duration of dual antiplatelet therapy after PCI without cardiovascular events. Patients were classified according to CYP2C19 loss-of-function allele status: rapid or normal metabolizer vs intermediate or poor metabolizer (IM/PM). The primary outcome was a composite of all-cause death, myocardial infarction, and stroke at 3 years after switching to clopidogrel monotherapy. Results: Of 1,352 patients, 807 patients were carriers of a loss-of-function allele (IM/PM). The risk of primary outcome did not differ between the IM/PM and rapid or normal metabolizer groups (1.2% vs 2.2%; adjusted HR: 0.53; 95% CI: 0.20-1.44; P = 0.215). Likewise, the risk of major bleeding was comparable between the groups (1.1% vs 2.0%; adjusted HR: 0.40; 95% CI: 0.14-1.14; P = 0.086). Subgroup analyses consistently showed no significant interaction between CYP2C19 genotype and primary outcome. Conclusions: In patients who completed the standard duration of dual antiplatelet therapy following PCI, clinical effects of clopidogrel monotherapy were consistent across CYP2C19 genotypes. These findings provide clinical reassurance that clopidogrel monotherapy can be used effectively for long-term maintenance, regardless of CYP2C19 genotype. (SMart Angioplasty Research Team: CHoice of Optimal Anti-Thrombotic Strategy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents 3 [SMART-CHOICE 3]; NCT04418479 ; Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients [PTRG-DES]; NCT04734028 )
