NEW YORK (Reuters Health) – While the CYP2C19 genotype is associated with platelet response to clopidogrel, that does not equate with any meaningful effect on clinical outcomes, according to the findings of a meta-analysis reported in the Journal of the American Medical Association for December 28th.

“This study identified no clinically significant interaction of CYP2C19 genotype with the association of clopidogrel therapy and cardiovascular events,” the authors conclude.

Dr. Michael V. Holmes, at University College London, and colleagues note that clopidogrel is metabolized by several enzymes including CYP2C19, and that loss-of-function alleles reduce enzyme activity.  This led the US Food and Drug Administration to recommend “consideration of CYP2C19 genotype” before prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have said there is insufficient evidence for this.

The authors therefore conducted a systematic review and identified 32 relevant studies of CYP2C19 genotype and clopidogrel metabolism for a meta-analysis.

Six of the studies were randomized trials, in five of which both the clopidogrel and comparator groups were genotyped.  The pooled data from these studies indicated that the CYP2C19 genotype did not significantly influence the effect of clopidogrel on cardiovascular endpoints (p=0.37 for interaction) or bleeding risk (p=0.07 for interaction).

The other 26 studies were either prospective cohorts in which all the participants received clopidogrel, or retrospective case-control studies.  The pooled analysis did indicate that individuals with loss-of-function CYP2C19 alleles had less platelet inhibition and a higher risk of cardiovascular events (relative risk 1.18).  However, there was strong evidence of small-study bias.  When the analysis was restricted to larger studies, the relative risk was attenuated to 0.94.

The clinical outcome with the strongest association with CYP2C19 loss-of-function alleles was stent thrombosis “but a trend toward the null was observed in larger studies,” Dr. Holmes and colleagues found.

They conclude, “Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events.”

In a related editorial, Dr. Steven E. Nissen of the Cleveland Clinic Foundation, Ohio, advises physicians to use CYP2C19 testing rarely, if ever, until a large randomized controlled trial has tested the clopidogrel pharmacogenomic hypothesis.

“The pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required for other therapies,” the states.  “Overzealous adoption based on limited biochemical data does not serve the public interest.”