Impact of CYP2C19 and CYP3A4 Inhibitor Use on Clopidogrel Clinical Effectiveness in CYP2C19 Genotyped Patients...

CYP2C19 and CYP3A4 contribute to clopidogrel bioactivation. CYP2C19 no-function alleles diminish clopidogrel's antiplatelet effects and clinical effectiveness. Coadministration of either a CYP2C19 or a CYP3A4 inhibitor may also reduce clopidogrel's antiplatelet effects and lead to phenoconversion in patients without a CYP2C19 no-function allele (normal/rapid/ultrarapid metabolizers: NM/RM/UMs). However, the impact of CYP2C19 or CYP3A4 inhibitor use on clopidogrel clinical effectiveness remains unclear. Rates of major atherothrombotic events (MAE) over 12 months after percutaneous coronary intervention (PCI) were evaluated in 3,242 patients across three sites who underwent CYP2C19 genotype testing and received P2Y₁₂ inhibitor therapy. Overall, 6.8% of patients were co-prescribed a moderate or strong inhibitor of either CYP2C19 or CYP3A4, as defined by the U.S. Food and Drug Administration. In CYP2C19 genotype-predicted NM/RM/UMs treated with clopidogrel (n = 1,624), the MAE rates were numerically higher, but not significantly different in patients receiving either a CYP2C19 or a CYP3A4 inhibitor vs. no inhibitor (18.4 vs. 12.8 events/100 patient-years, adjusted hazard ratio (HR) 1.51, 95% confidence interval (CI), 0.85-2.68, P = 0.155). When evaluating CYP2C19 inhibitor and CYP3A4 inhibitor use separately, MAE rates were higher in clopidogrel-treated NM/RM/UMs receiving a CYP2C19 inhibitor compared to no inhibitor (adjusted HR 2.22, 95% CI 1.01-4.91, P = 0.048), but no significant difference was observed in those receiving a CYP3A4 inhibitor compared to no inhibitor (adjusted HR 1.26, 95% CI 0.57-2.75, P = 0.569). These results suggest that concomitant use of a CYP2C19 inhibitor, but not a CYP3A4 inhibitor, may contribute to phenoconversion and decreased clopidogrel clinical effectiveness after PCI in CYP2C19 genotype-predicted NM/RM/UMs.