Original Articles
Vol. 5 No. 3 (2026): In memory of Armando D’Angelo
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
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 28 August 2026
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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.
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CRediT authorship contribution
All the authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.
Supporting Agencies
provided by an unrestricted grant to the St. Antonius Hospital, Nieuwegein, the Netherlands by Daiichi Sankyo Europe. Genotyping was provided by Genedrive® (Manchester, United Kingdom), the Department of Clinical Chemistry, Erasmus MC, University Medical Center (Rotterdam, the Netherlands), and the Azienda Ospedaliero–Universitaria Pisana (Pisa, Italy).Data Availability Statement
The datasets used and/or analyzed during the current study are available upon reasonable request from the corresponding author.
How to Cite
1.
Chiusolo S, Verburg A, Morizzo C, Van Schaik RH, Matic M, Coenen MJ, et al. 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. Bleeding Thromb Vasc Biol [Internet]. 2026 Aug. 28 [cited 2026 Aug. 28];5(3). Available from: https://www.btvb.org/btvb/article/view/421
Copyright (c) 2026 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
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