October 27th, 2010

Meta-Analysis Examines Risk Associated with CYP2C19 Genotypes

There has been widespread debate and disagreement over the clinical significance of people with reduced function CYP2C19 genotypes who take clopidogrel. In an effort to shed light on the topic, Jessica Mega and colleagues analyzed data from 9685 patients enrolled in nine clinical trials. Some 26% of patients had 1 reduced-function allele, and 2% had 2 reduced-function alleles.

In a paper in JAMA, the investigators report a “directionally consistent risk for all of the components of the composite end point associated with carriage of 1 or 2 reduced-function CYP2C19 alleles.” The hazard ratios for cardiovascular death, nonfatal MI, and stroke among those with 1 or 2 alleles were 1.84, 1.45, and 1.73, respectively. The researchers conclude that, given the widespread use of clopidogrel, “determination of the optimal antiplatelet treatment doses or regimens for individual patients is needed to tailor therapy appropriately.”

In an accompanying editorial, Valentin Fuster and Joseph Sweeny write that the presence of at least one loss-of-function allele in nearly 30% of the population “confirms that the prevalence of reduced-function alleles might not be as insignificant as previously thought.” On the other hand, “it is uncertain whether these new findings in high-risk patients actually support the use of … genetic testing,” since platelet reactivity depends on multiple genetic and nongenetic factors. They conclude that “in patients treated with clopidogrel, the best genome-guided strategy remains to be determined.”

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