CYP2C19 Loss-of-Function Carriers Have Increased Risk of Cardiac but Not Limb Events Following Clopidogrel Treatment for PAD Revascularization

Objective Clopidogrel remains the most prescribed antiplatelet medication following occlusive atherosclerotic revascularization. However, 20-50% of the population are clopidogrel non-responders. Loss-of-function (LOF) cytochrome P450 2C19 ( CYP2C19 ) single-nucleotide polymorphisms (SNPs) decrease clopidogrel metabolism and activation, resulting in intermediate or poor metabolizer phenotypes reducing formation of clopidogrel's active metabolite. The association of these SNPs with adverse clinical outcomes with clopidogrel treatment following coronary artery disease (CAD) revascularization is well-studied, but the impact of these SNPs in non-CAD revascularization outcomes remains unclear. We evaluated the hypothesis that CYP2C19 LOF carrier status is associated with worse cardiovascular and limb adverse events with clopidogrel treatment following peripheral arterial revascularization. Methods We included adults with peripheral artery disease (PAD) undergoing open and endovascular extracranial, extremity, or visceral arterial revascularization (2016-2024) at a multi-hospital institution who were also prescribed post-revascularization clopidogrel and had known pharmacogenetic data. Individuals were stratified into CYP2C19 LOF carriers and non-carriers based on CYP2C19 SNPs. Entropy-balanced weights of pre-revascularization patient- and procedure-specific variables were generated. Residual imbalances were addressed with covariate adjustment in Cox hazards models evaluating the association between CYP2C19 LOF genotype carrier status and risk of adverse outcomes, generating weighted hazard ratios (wHR) with 95% confidence intervals (95%CI), censoring loss to follow-up or death. The primary outcome was major adverse limb event (MALE), and secondary outcomes were major adverse cardiovascular events (MACE), major revascularizations, major amputations, any revascularization, and major bleeding. Results Among 211 patients (69.2±10.0 years, 64.0% male, 7.1% extracranial, 83.4% extremity, 9.5% visceral revascularization procedures), 42 (19.9%) were CYP2C19 LOF carriers. There was no significant association between LOF carrier status and MALE (wHR=0.76, 95%CI 0.40-1.45, p-value=.41), its individual components (major revascularization wHR=0.81, 95%CI 0.41-1.59, p-value=.54; major amputation wHR=0.40, 95%CI 0.10-1.52, p-value=.18), or any revascularizations (wHR=1.10, 95%CI 0.68-1.77, p-value=.70). Having a LOF genotype was significantly associated with a 79% increased risk of MACE (wHR 1.79, 95%CI 1.08-2.99, p-value=.03), but not major bleeding events (wHR=0.70, 95%CI 0.30-1.64, p-value=.41). Conclusion CYP2C19 LOF carriers were associated with an increased risk of MACE but not MALE or its components after PAD revascularization. Because MACE significantly impacts the outcomes of PAD patients undergoing intervention, prospective evaluation of genotype-guided antiplatelet therapy may reduce cardiac morbidity and mortality and improve overall outcomes.