Before Prescribing Clopidogrel Should Genetic Testing Occur? Apparently Not

A study in the December issue of JAMA reports that despite the U.S. Food and Drug Administration’s (FDA) recommendation that a certain type of genetic testing for the genotype CYP2C19 should be considered before prescribing clopidogrel to identify those individuals who may be less responsive to the medication, a review and analysis of earlier studies did not establish an overall significant link between the CYP2C19 genotype and cardiovascular events.

About 40 million patients worldwide take Clopidogrel, an antiplatelet drug for the treatment or prevention of blood clots from thickening of inner lining of arteries (atherothrombotic events), and after percutaneous coronary revascularization, such as balloon angioplasty for example.

Background information in the article states that:

“Despite the overall benefit, some individuals may be less responsive to clopidogrel than others because clopidogrel is a prodrug activated by several enzymes, including CYP2C19, and common genetic variation in CYP2C19 alters enzyme activity.”

According to arguments of The American Heart Association and American College of Cardiologists, there is insufficient evidence to support CYP2C19 genotype testing.

Michael V. Holmes, M.B.B.S., M.Sc., of University College London and team decided to perform a systematic review and meta-analysis to determine CYP2C19 genotype strength and quality in relation to its responsiveness to clopidogrel. They identified 32 studies from medical literature that met their criteria, which consisted of studies reporting clopidogrel metabolism, platelet reactivity or clinically relevant outcomes, such as cardiovascular disease [CVD] events and bleeding as well as information on CYP2C19 genotype.

A total of 42,016 patients were included in the 32 studies of which 3,545 reported CVD events, 579 reported stent thromboses and 1,413 bleeding events. Of the 32 studies six consisted of randomized trials (“effect-modification” design), whilst the other 26 consisted of individuals exposed to clopidogrel (“treatment-only” design).

They discovered that in the treatment-only analysis, those with 1 or more CYP2C19 alleles, an alternative form of a gene, linked to lower enzyme activity displayed lower active clopidogrel metabolite levels, lower risk of bleeding, less platelet inhibition, and higher risk of CVD events. The researchers highlighted the evidence of small-study bias and noted that when they restricted their evaluation to studies that contained 200 or more events, the point estimate was lessened.

They noted that CYP2C19 genotype was not linked to changes of clopidogrel’s effect on CVD end points or bleeding in effect-modification studies and stated that a limitation included selective outcome reporting.

The researchers conclude:

“Despite associations between CYP2C19 genotype, clopidogrel metabolism, and platelet aggregation, this systematic review and meta-analysis does not demonstrate a clinically important association of genotype with cardiovascular outcomes with the possible exception of stent thrombosis. Our appraisal has identified issues pertaining to the design and analysis of pharmacogenetic studies that are important in the understanding of the significance of the CYP2C19 genotype.”