Directing the Course of Treatment with Pharmacogenomics

Dual antiplatelet therapy using clopidogrel and aspirin improves cardiovascular outcomes in patients with acute coronary syndromes and after percutaneous coronary intervention (PCI) by reducing platelet aggregation.  However, inter-individual variation in response to these medications is widely recognized and is related to recurrent cardiovascular events.  In the Amish Pharmacogenomics of Antiplatelet Intervention (PAPI) study, we measured ex-vivo ADP-stimulated platelet aggregation before and after clopidogrel treatment and conducted a genome-wide association study of drug response (Shuldiner et al, JAMA 2009). We identified a common loss-of-function variant in cytochrome P450 2C19 (CYP2C19*2) as a major determinant of clopidogrel response, accounting for 12% of the variation in platelet aggregation. Subjects who carry the CYP2C19*2 variant do not metabolize clopidogrel into its active form as effectively as those with the *1/*1 genotype and thus respond less well to its anti-platelet effect. The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention and those with the CYP2C19*2 variant were more likely to have a cardiovascular ischemic event or death during 1 year of follow-up. Several (although not all) studies utilizing candidate gene approaches have confirmed the relationship between CYP2C19*2 and poorer outcomes in clopidogrel-treated patients, which led to an update of the clopidogrel label by the FDA suggesting that genetic testing may identify poor responders for consideration of alternate therapy. CYP2C19*2 is common in diverse population - approximately 1/3 of the U.S. population harbor at least one copy of this variant. Since alternative therapy (and possibly higher doses of clopidogrel) may be indicated in CYP2C19*2 carriers to improve outcomes, clinicians are now faced with the opportunity to translate these findings into more individualized anti-platelet therapy approaches. However, prospective randomized clinical trials, to provide the evidence base to change clinical practice will likely be necessary for widespread adoption.