Although the FDA has recommended that CYP2C19 genotyping be considered before prescribing the drug clopidogrel to identify individuals who may be less responsive to the medication, a review and analysis of previous studies did not find an overall significant association between the CYP2C19 genotype and cardiovascular events, based on a study published Dec. 28, 2011 in the Journal of the American Medical Association.
Clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) is used by approximately 40 million patients worldwide to treat or prevent atherothrombotic events after PCI.
"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 background information in the article. Also, the American Heart Association and American College of Cardiology have argued that evidence is insufficient to support CYP2C19 genotype testing.
Michael V. Holmes, MBBS, MSc, of University College London, and colleagues conducted a systematic review and meta-analysis to assess the strength and quality of evidence on the association of CYP2C19 genotype with responsiveness to clopidogrel. The researchers identified 32 studies that met criteria, including studies that reported clopidogrel metabolism, platelet reactivity or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype.
The 32 studies included 42,016 patients reporting 3,545 CVD events, 579 stent thromboses and 1,413 bleeding events. Six studies were randomized trials (effect-modification design) and the remaining 26 reported individuals exposed to clopidogrel (treatment-only design).
In treatment-only analysis, individuals with one or more CYP2C19 alleles (an alternative form of a gene) associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding and higher risk of CVD events.
However, there was evidence of small-study bias, Holmes and colleagues reported. When analyses were restricted to studies with 200 or more events, the point estimate was lessened. In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD endpoints or bleeding. A limitation included selective outcome reporting.
“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," the researchers wrote. "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."
Holmes et al added that their findings are consistent with another recent meta-analysis (BMJ 2011;343:d4588), but it also differ in “several important ways,” such as:
- The current review included 17 more studies than the recent meta-analysis.
- The current review included analysis of the association between the CYP2C19 genotype and clopidogrel metabolites and platelet reactivity.
- The current review included analysis of individual outcomes as well as composite cardiovascular outcomes.
- The current review compared and contrasted findings from treatment-only and effect-modification study designs.
- Finally, Holmes et al placed the observed risk of cardiovascular outcomes in the context of the expected risk based on the observed effect of CYP2C19 genotype on active clopidogrel metabolites.
In the accompanying editorial, Steven E. Nissen, MD, of the Cleveland Clinic Foundation, wrote that several factors led to the unrealistic expectations of the effectiveness of CYP2C19 genotyping for clopidogrel, and that a large randomized controlled trial is needed to adequately test the clopidogrel pharmacogenomic hypothesis.
“In the absence of such a study, physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution,” Nissen wrote. “It is still likely that pharmacogenomics has a bright future in cardiovascular medicine, but the pharmacogenomics approach to drug therapy must undergo the same rigorous testing for efficacy and cost-effectiveness that is required