Editors' ChoicePharmacogenomics

Antiplatelet Therapy: To Genotype or Not?

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Science Translational Medicine  22 Sep 2010:
Vol. 2, Issue 50, pp. 50ec147
DOI: 10.1126/scitranslmed.3001693

Clopidogrel, an antiplatelet drug, is a cornerstone in the management of patients receiving coronary stents in whom it is used to prevent clotting inside stents, myocardial infarction, and death. It is the second-most highly prescribed drug in the world, with global sales exceeding $8 billion. In 2008, patients with stents who were also heterozygote carriers of common loss-of-function polymorphisms in the hepatic cytochrome 2C19 (CYP2C19) system were found to have a near twofold increase in risk for myocardial infarction and death and a greater than threefold increase in risk for stent thrombosis. Clopidogrel, a prodrug, is activated via the CYP2C19 system with loss-of-function carriers having reduced clopidogrel bioavailability. Importantly, one-third of Europeans and close to half of African Americans and Asians carry the at-risk alleles.

Now, Paré et al. publish results from a genetic substudy of two cohorts—one of patients with acute coronary syndromes (ACS) and another with atrial fibrillation (AF)—that suggest that CYP2C19 polymorphisms are in fact not useful in predicting the risk for myocardial infarction, stroke, and death. In this study, over 6000 patients with AF and ACS were genotyped for a common gain-of-function and two loss-of-function CYP2C19 polymorphisms. Notably, the gain-of-function CYP2C19 variant did confer a significant protective effect, which is consistent with previously reported data (hazard ratio 0.55; 95% confidence interval, 0.42 to 073). In contrast, the loss-of-function allele status did not predict an increased risk for adverse cardiovascular events. Nevertheless, on closer inspection of the data, several explanations for the discrepancy between current and previous data linking CYP2C19 genotype to adverse CV events become clear. Foremost, fewer than 14% of patients from the current study received stents, and less than one-quarter of the patients had an actual myocardial infarction. Second, drug-eluting stents, which have a greater tendency toward stent thrombosis, were not used. Third, the benefit of clopidogrel in AF is not well established, making genotyping for CYP2C19 alleles in this population a moot point.

Conversely, CYP2C19 genotype status has been highly predictive of infarction and death in patient groups that had received stents and in most cases had biomarker evidence of myocardial injury (>80%). Accordingly, although the study by Pare et al. may indicate that genotyping for CYP2C19 loss-of-function polymorphisms may not be necessary in ACS patients managed conservatively, those undergoing percutaneous intervention with coronary stents do appear to be at a heightened risk for adverse events. Thus, for the vast majority of patients, genotyping should remain the method of choice for individualizing therapy according to one’s unique biologic makeup.

G. Paré et al., Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. 29 August 2010 (10.1056/NEJMoa1008410). [Abstract]

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