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02-01-2012 | Cardiology | Article

Insufficient evidence to support genetic testing before clopidogrel use


Free abstract

MedWire News: There is insufficient evidence to support genetic testing before prescribing clopidogrel, say UK researchers whose review found no conclusive proof of a clinically important association between CYP2C19 genotype and the effect of clopidogrel on cardiovascular outcomes.

Their findings contrast with the US Food and Drug Administration (FDA) recommendation that CYP2C19 genotype should be ascertained before prescribing clopidogrel.

Michael Holmes, from University College London, and colleagues conducted a systematic review and meta-analysis of 32 studies to appraise evidence on the association between the CYP2C19 genotype and clopidogrel response.

The studies included 42,016 patients and reported on 3545 cardiovascular (CV) events, 579 stent thromboses, and 1413 bleeding events. Six studies were randomized trials with an effect-modification design, and the remaining 26 reported outcomes for individuals exposed to clopidogrel, with a treatment-only design.

In treatment-only analysis, patients with one or more CYP2C19 alleles associated with low enzyme activity (any copy of *2 through *8 alleles) had a 16% lower risk for any bleeding than individuals carrying the *1 or *17 alleles. Patients with any copy of the low-activity CYP2C19 alleles also had lower levels of active clopidogrel metabolites, less platelet inhibition, and an 18% higher risk for CV events. However, there was evidence for small-study bias in this analysis.

Furthermore, when the analysis was restricted to studies with 200 or more events, the summary risk ratio was attenuated, the authors note in the Journal of the American Medical Association.

In the effect-modification studies, the CYP2C19 genotype was not significantly associated with modification of clopidogrel's effects on CV endpoints or bleeding.

"Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with CV events," write the authors.

In a related commentary, editorialist Steven Nissen (Cleveland Clinic Foundation, Ohio, USA) calls the results of the current study "compelling" and states 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 result with caution," he adds.

Pharmacogenomics could have a future in CV medicine, but must undergo further testing for efficacy and cost-effectiveness, he continues.

"Overzealous adoption based on limited biochemical data does not serve the public interest," he concludes.

By Piriya Mahendra

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