Impact of CYP2C19 loss-of-function variants on outcomes in atrial fibrillation patients undergoing percutaneous coronary intervention: rationale and study design of the WOEST-3 genetic substudy

Background: The impact of CYP2C19 loss-of-function (LOF) variants on clopidogrel efficacy in atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI) remains uncertain. While clopidogrel is the preferred P2Y12 inhibitor in combination with oral anticoagulants, approximately one-third of patients carry CYP2C19 LOF alleles, known to reduce platelet inhibition and increase ischemic risk. Methods: The WOEST-3 genetic substudy is an observational pharmacogenetic investigation embedded within the randomized WOEST-3 trial (NCT04436978). Patients with AF undergoing PCI and providing additional consent for genetic testing will be included. CYP2C19 *2, *3, *4, *8 and *35 genotypes will be determined using both Genedrive® (Genedrive Diagnostics Ltd, Manchester, UK) point-of-care and laboratory-based assays. Genetic results will remain blinded to investigators and clinicians to avoid treatment bias. The primary endpoint is a 6-month composite of death, myocardial infarction, stroke, systemic embolism, and stent thrombosis. Approximately 30% of patients are anticipated to carry CYP2C19 LOF alleles. The study will determine whether concomitant direct oral anticoagulants therapy mitigates the impact of reduced clopidogrel activation in these carriers or whether genetic variability continues to confer excess ischemic risk. Conclusions: This protocol paper describes the rationale and design of a genetic substudy aimed at clarifying the prognostic relevance of CYP2C19 genotype in AF patients undergoing PCI and informing the design of future genotype-guided antithrombotic trials.