Editors' ChoiceHuman Genetics

When a Clot Buster Doesn't Work So Well

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Science Translational Medicine  24 Nov 2010:
Vol. 2, Issue 59, pp. 59ec182
DOI: 10.1126/scitranslmed.3001945

The anticlotting drug clopidogrel is a cornerstone of treatment for patients who have received stents to open up blocked coronary arteries. In 2009, global sales for clopidogrel exceeded $8 billion, making it the second-most widely prescribed drug in the world. However, approximately one-third of Europeans, 40% of African Americans, and over half of those of Asian ancestry are poor metabolizers of clopidogrel and show a reduced anticlotting response to the drug. These individuals carry a common single-nucleotide polymorphism (SNP) in the liver enzyme CYP2C19 (part of the cytochrome system) that results in the diminished ability of this enzyme to convert the prodrug clopidogrel into its active form. Strikingly, carriers of this allele have a three- to sixfold increased risk of forming blood clots in stents (stent thrombosis), resulting in reduced blood flow and serious, sometimes fatal, cardiovascular sequelae.

To date, most studies that have linked hepatic CYP2C19 variants to adverse clinical outcomes have involved highly heterogeneous populations, making definitive conclusions regarding the extent of risk for stent thrombosis problematic. Now, in a comprehensive meta-analysis of published studies, Mega and colleagues clearly demonstrate that individuals carrying the high-risk variant CYP2C19*2 show an increase in adverse cardiovascular events, including stent thrombosis. Of 31 potentially relevant studies, 22 were excluded because of lack of data about coronary stent use and clinical outcome. Of the remaining nine studies, clinical outcome data for all patients were obtained, and a total of 9685 patients who had received coronary stents were analyzed for their CYP2C19 status. Remarkably, the authors found that carriers of the CYP2C19*2 high-risk allele had a consistent threefold increase in risk for stent thrombosis. Moreover, those patients who were homozygous for the at-risk variant (~4 to 14%) had a fourfold increase in stent thrombosis. Given that over 1 million stents are implanted annually in the United States alone, these data suggest that thousands of deaths could be prevented by using a different anticlotting drug in patients carrying the CYP2C19*2 high-risk allele. However, few hospitals use genetic screening to identify those patients who are poor metabolizers of clopidogrel and who would benefit from treatment with alternative anticlotting agents, a practice that should soon change given the convincing meta-analysis of Mega and colleagues.

J. L. Mega et al., Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: A meta-analysis. JAMA 304, 1821–1830 (2010). [Abstract]

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