Pharmacogenetics Testing: Implications for Cardiovascular Therapeutics with Clopidogrel and Warfarin

Abstract

The recent US Food and Drug Administration (FDA) boxed warning [1] for the antiplatelet agent clopidogrel urging caution that poor metabolizers may not derive the full potential protection from heart attacks, stroke, and cardiovascular death is the latest in a series of recent developments that highlight the possible future role of pharmacogenetics testing in clinical decision making. The FDA advisory also states that “healthcare professionals consider alternative dosing of Plavix for these patients, or consider using other antiplatelet medications. Tests are available to assess CYP2C19 genotype to determine if a patient is a poor metabolizer.” Several large clinical trials such as CURE [2] and CAPRIE [3] have shown the therapeutic benefit of clopidogrel in reducing cardiovascular events in at-risk cohorts. It is now established as a therapeutic agent in acute coronary syndromes (ACSs) in various European and American guidelines [4,5] with loading doses up to 600 mg in clinical use. Clopidogrel is a prodrug that requires primarily cytochrome (CYP) P450 2C19 enzyme for its activation with its subsequent mechanism of action being the inhibition of the P2Y12 ADP receptor on the platelet surface and consequent platelet inhibition. There has been recent recognition that genetic polymorphism can influence the level of 2C19 activity [6,7]. Carriers of the ∗2, ∗3, ∗4, and ∗5 alleles have reduced enzymatic activity and therefore reduced levels of clopidogrel-induced platelet inhibition. According to a study by Mega et al., among clopidogrel-treated subjects in the TRITON-TIMI 38 trial, carriers of these alleles had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; P = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; P = 0.02) [8]. Conversely, carriers of the ∗17 allele have a higher level of CYP2C19 activity and therefore platelet inhibition [6]. As the frequency of these variants differs widely in different populations, the efficacy of clopidogrel is likely to vary depending on the ethnic mix of the study population. Proton pump inhibitors (PPIs) are often coprescribed with clopidogrel for gastroprotection but these two