PI-049 - IMPACT OF CYP2C19 AND CYP3A INHIBITORS ON CLOPIDOGREL CLINICAL EFFECTIVENESS IN CYP2C19 GENOTYPED PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION (PCI) IN A REAL-WORLD SETTING.

D. Shao¹, N. Le², J. Mosha¹, J. Rossi¹, G. Stouffer¹, L. Cavallari³, C. Lee¹; ¹University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, ²University of North Carolina at Chapel Hill & United Therapeutics, Chapel Hill, NC, United States, ³University of Florida, Gainesville, FL, United States.

Background: Clopidogrel (a prodrug) requires CYP2C19 and CYP3A4/5 for bioactivation. CYP2C19 no function alleles diminish clopidogrel’s antiplatelet effects and clinical effectiveness. Co-administration of CYP2C19 and CYP3A inhibitors can also diminish clopidogrel’s antiplatelet effects and may lead to phenoconversion (a mismatch between the genotype-predicted and actual metabolic phenotype). However, the impact of CYP2C19/CYP3A inhibitor use on clinical outcomes in clopidogrel-treated patients with and without a CYP2C19 no function allele remains unclear.

Methods: A single-center retrospective cohort study included 1,138 clopidogrel-treated PCI patients who were clinically genotyped for CYP2C19. Data were abstracted from electronic health records. Moderate and strong inhibitors of CYP2C19 or CYP3A4/5 defined by the FDA Examples of Drugs that Interact with CYP Enzymes and/or the Indiana University (IU) Drug Interaction Flockhart Table™ were considered. Major atherothrombotic event (MAE: death, acute coronary syndrome, stent thrombosis, or ischemic stroke) incidence was compared across patients receiving vs. not receiving a CYP2C19/CYP3A inhibitor over 1-year post-PCI by multivariable Cox regression after stratifying by CYP2C19 genotype.

Results: Among the 31 drugs defined as moderate/strong CYP2C19/CYP3A inhibitors, 11 were co-prescribed with clopidogrel; the most common were omeprazole (19.9%), amlodipine (17.1%), esomeprazole (5.3%), diltiazem (2.7%), and fluoxetine (2.1%). Overall, 464 (40.8%) patients received at least one inhibitor; 83 (7.3%) received multiple inhibitors. MAE incidence did not significantly differ across patients receiving vs. not receiving an inhibitor (Table). In CYP2C19 no function allele carriers, MAE rates were similar across groups. In non-carriers, MAE rates were numerically higher but not significantly different in patients co-prescribed an inhibitor; a sensitivity analysis considering only moderate/strong inhibitors defined by FDA yielded similar results.

Conclusion: There was no clear association between CYP2C19/CYP3A inhibitor use and higher MAE risk in clopidogrel-treated PCI patients who underwent CYP2C19 genotyping. Larger studies are needed to evaluate the impact of each inhibitor on clopidogrel clinical effectiveness.