Genotype Testing for Clopidogrel Responsiveness May Not Predict Events

A meta-analysis finds no association between CYP2C19 genotype and cardiovascular outcomes in clopidogrel recipients, but concerns about stent thrombosis linger.


Variation in individual response to clopidogrel's antiplatelet activity is, in part, governed by genetic variation in the CYP2C19 activating enzyme. To examine the effect of genetic variants on clopidogrel responsiveness and cardiovascular events, investigators conducted a meta-analysis of 32 studies involving 42,016 patients (mean age, 63 years; 29% women). Included were 21 studies in patients with acute coronary syndromes, 8 in patients with stable coronary disease (recruited mostly at the time of stent implantation), and 3 in patients with unspecified disease status.

In a "treatment-only" analysis of 22 prospective, observational studies and the treatment arms of 4 randomized trials, any copy of a reduced-function CYP2C19 allele was associated with a significantly increased risk for cardiovascular events (relative risk, 1.18). The effect was smaller (nonsignificant) in larger studies (?200 outcome events) than in smaller ones, consistent with a small-study bias. Of all clinical outcomes, stent thrombosis was the most strongly associated with a reduced-function allele (RR, 1.75; absolute increase, 14 events per 1000 individuals). In four placebo-controlled, randomized trials, risk for cardiovascular events with clopidogrel was reduced to a similar degree in patients with and in those without reduced-function alleles (RR, 0.87 and 0.78, respectively; P for interaction, 0.37).


Citation(s):

Holmes MV et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: A systematic review and meta-analysis. JAMA 2011 Dec 28; 306:2704.

Nissen SE. Pharmacogenomics and clopidogrel: Irrational exuberance? JAMA 2011 Dec 28; 306:2727.