CYP2C19 Genetic Testing Should Not Be Done in All Patients Treated With Clopidogrel Who Are Undergoing Percutaneous Coronary Intervention

Clopidogrel when added to aspirin reduces major vascular events in patients undergoing percutaneous coronary intervention (PCI).1 Recent reports have suggested that common genetic variants involving hepatic cytochrome P450 system enzymes that convert clopidogrel to its active metabolite are associated with an increased risk of cardiovascular events. Specifically, patients who are carriers of 1 or more loss-of-function CYP2C19 alleles (including the *2 and *3 alleles) have reduced conversion of clopidogrel to its active metabolite, decreased platelet inhibition, and an increased risk of myocardial infarction, death, and stent thrombosis compared with noncarriers. Based on these findings and on related pharmacokinetic and pharmacodynamic data (NCT01123824), the United States Food and Drug Administration (FDA) has issued a “black box” warning of reduced effectiveness of clopidogrel in patients who are carriers of 2 loss-of-function alleles (so-called poor metabolizers) and has suggested that affected individuals receive a higher dose of clopidogrel or an alternative antiplatelet agent. This warning has led some investigators to conclude that all patients undergoing PCI with planned clopidogrel therapy should undergo CYP2C19 genetic testing.Response by Sibbing, Bernlochner, and Kastrati on p 521 In this report, we critically review the evidence for routine CYP2C19 testing in patients undergoing PCI according to established criteria for the implementation of a screening test in clinical practice. Summary of the Evidence Linking CYP2C129 Loss-of-Function Alleles to Clopidogrel Response and Cardiovascular RiskClopidogrel is a prodrug that must undergo 2-step hepatic metabolism by enzymes of the CYP system to form the active moiety that inhibits the platelet P2Y12 receptor.2–4 Common loss-of-function variants involving the CYP2C19 gene have been conclusively demonstrated to influence clopidogrel active metabolite levels and levels of platelet inhibition5–7 (Figure 1), and an increasing number of clinical reports link loss-of-function alleles with adverse clinical outcomes.7–12Figure 1. Hypothesized causal chain leading from loss-of-function (LOF) allele carriage to increased ischemic events …