SS13 - Reduced Clopidogrel Metabolizers Have Increased Risk of Cardiac but Not Limb Events Following PAD Revascularization

Objectives: Clopidogrel remains the most prescribed antithrombotic therapy following peripheral artery disease (PAD) revascularization. However, 20-50% of the population are clopidogrel non-responders. Loss-of-function cytochrome P450 2C19 (CYP2C19) single-nucleotide polymorphisms (SNPs) decrease clopidogrel metabolism and activation, resulting in intermediate or poor metabolizer phenotypes. The association of these SNPs with adverse clinical outcomes with clopidogrel treatment is well-studied in coronary artery disease (CAD), leading to genotype-guided antiplatelet strategies following CAD interventions. However, the impact of these SNPs in PAD remains unclear. We evaluated the association of clopidogrel-related SNPs with PAD intervention outcomes.

Methods: We included adults with PAD treated at a multi-hospital institution and prescribed clopidogrel after extracranial, extremity, or visceral open/endovascular revascularization (2016-2024) who had pharmacogenomics data from prior percutaneous coronary intervention. Individuals were stratified into normal (normal, rapid, ultrarapid) and reduced (intermediate, poor) clopidogrel metabolizer phenotypes based on CYP2C19 SNPs. Entropy-balanced weights of pre-revascularization patient- and procedure-specific variables were generated ( <.1 standard mean difference threshold for adequate balance). Residual imbalances were addressed with covariate adjustment. Cox regression hazards models evaluated the association between phenotypes and risk of primary (major adverse limb event [MALE]) and secondary (major adverse cardiovascular events [MACE], major revascularizations, major amputations, any revascularization, major bleeding) adverse outcomes, generating balanced hazard ratios (bHR) with 95% confidence intervals (95%CI), censoring loss to follow-up or death. Negative binomial regression models evaluated the association between phenotypes and number of adverse outcomes.

Results: Among 185 patients (69±10yrs, 62% male, 8% extracranial, 81% extremity, 11% visceral revascularization), 19% were reduced clopidogrel metabolizers. There was no significant association between metabolizer phenotypes and MALE (bHR=0.70, 95%CI 0.35-1.40, p-value=.32) (Figure 1), its individual components (major revascularizations bHR=0.78, 95%CI 0.38-1.62, p-value=.50; major amputations bHR 0.44, 95%CI 0.12-1.67, p-value=.23), or any revascularizations (bHR=0.93, 95%CI 0.49-1.76, p-value=.82). Reduced metabolizer phenotype was significantly associated with increased risk of MACE (bHR=1.88, 95%CI 1.08-3.25, p-value=.03) (Figure 2) but not major bleeding events (bHR=0.80, 95%CI 0.37-1.73, p-value=.57). The reduced phenotype was also associated with an increased number of MACE (incidence rate ratio (IRR)=1.61, 95%CI 1.02-2.56, p-value=.04) but not with MALE (IRR=0.68, 95%CI 0.36-1.28, p-value=.23).

Conclusions: The reduced clopidogrel metabolizer phenotype from loss-of-function CYP2C19 SNPs was associated with an increased risk and number of MACE but not MALE events after PAD revascularization. Because MACE significantly impacts the outcomes of PAD patients undergoing intervention, prospective evaluation of genotype-guided antiplatelet therapy in these patients is essential to reduce cardiac morbidity and mortality and improve overall outcomes.