Assessment of clopidogrel discontinuation rates following pharmacogenomic testing in a high-risk patient population : an interim analysis of the UPGRADE Registry

Background: Advancements in the science and technology of pharmacogenomics (PGx) offer a unique opportunity for clinicians to improve care efficiency. Clopidogrel is an antiplatelet agent commonly used for treatment of complications from coronary artery disease (CAD). Clopidogrel is a pro-drug and keenly dependent on cytochrome P450 enzymes for bioactivation to exert its antiplatelet effects. Poor CYP2C19 metabolic activity has been associated with reduced antiplatelet effects and worse cardiovascular outcomes. As a result, the FDA requires a warning of this association be included in the drug label for clopidogrel. This thesis work examined whether clinicians adhere to FDA recommendation of using an alternative antiplatelet therapy when persons taking clopidogrel were identified as CYP2C19 poor metabolizers. Methods: This retrospective, interim analysis of the UPGRADE Registry identified subjects taking clopidogrel prior to undergoing PGx testing. Clopidogrel discontinuation rates were then assessed by medication reconciliation reports at follow-up in the 90-days following receipt of PGx results. Discontinuation rates of subjects identified as CYP2C19 poor metabolizers (PM) were compared to those identified as non-poor metabolizers (non-PM) (ultrarapid, extensive, or intermediate). Results: Overall, 1,753 subjects were included in the analysis. The median age of subjects was 75 years, and distribution of CYP2C19 phenotypes mirrored global estimates. Forty-three subjects were identified as PM (2.5%), and 1,710 were identified as non-PM (97.5%). No difference in discontinuation rates was observed between PM and non-PM subjects (2.3% vs. 1.9%; OR=0.37, 95% CI 0.05-2.98). Furthermore, discontinuation rates were not affected by concomitant proton-pump inhibitor (PPI) use. Conclusion: Despite relatively robust evidence associating poor CYP2C19 function with worse outcomes in subjects taking clopidogrel, clinical uptake of related recommendations appears poor in the primary care setting. Multiple barriers to clinical uptake of the FDA’s recommendations exist. This finding maintains significant implications for future PGx recommendations.