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JAMA Study Questions Need for Genotype Testing for Clopidogrel

NEW YORK (GenomeWeb News) – Despite a recommendation from the US Food and Drug Administration that patients undergo genetic testing before being prescribed antiplatelet drug clopidogrel, researchers from the UK have published an analysis casting doubt on the effectiveness of such testing.

In the study published in the Dec. 28 issue of the Journal of the American Medical Association, the researchers reviewed previous genotyping studies of clopidogrel and concluded that though there was an "association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events."

Worldwide, clopidogrel, which also is sold under the brand name Plavix by Bristol-Myers Squibb and Sanofi, is used by about 40 million patients to treat or prevent strokes and heart attacks.

The drug prevents dangerous blood clots but has shown to be less effective in some patients because it relies on several enzymes in order to be activated, and variations in a patient's CYP2C19 gene can alter enzyme activity.

About two years ago, FDA issued a black box warning for the drug and recommended that patients undergo CYP2C19 genotyping before a physician prescribes the drug, but the American Heart Association and the American College of Cardiologists have questioned the need for such testing.

Aiming to determine the usefulness of such genotype testing, researchers from University College London and the London School of Hygiene and Tropical Medicine "conducted a systematic review and critical appraisal to assess the strength and quality of evidence on the association of CYP2C19 genotype with responsiveness to clopidogrel," they said.

In total, they looked at 32 earlier studies of more 42,016 patients reporting 3,545 cardiovascular events, 579 stent thromboses, and 1,413 bleeding events. Six of the studies were randomized trials, or effect-modification design, and the rest were studies with patients exposed to clopidogrel, or treatment-only design.

The main analysis compared patients with one or more copies of any CYP2C19 genetic variant associated with reduced enzyme function with patients who had no such genetic variants, or who had one or more CYP2C19*17 gain-of-function alleles.

They found that in the treatment-only design studies, patients with one or more variation of the CYP2C19 gene associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding, and higher risk of cardiovascular events. They also found, though, evidence of small-study bias.

"When studies were stratified by number of outcome events, there was a clear trend toward the null in larger studies," they wrote.

Also, they saw that in effect-modification studies no association existed between modification of the effect of clopidogrel with cardiovascular disease end points or bleeding.

Further, they identified "issues" with how pharmacogenetic studies on CYP2C19 were designed and analyzed. For example, only five studies of clopidogrel response that they reviewed "were nested within a randomized trial in which both treatment and comparator group were genotyped, a design that allows evaluation of the clopidogrel treatment effect overall … and an assessment of differential treatment response by CYP2C19 genotype."

Randomized trials reduce the risk of selective reporting bias, they said, and added that among the four effect-modification placebo-controlled trials they analyzed, they saw no evidence of a link between clopidogrel treatment and CYP2C19 genotype.

In particular, they were concerned about the small-study bias that they found. "Not all ascertained outcomes were reported either individually or as part of the [cardiovascular] composite," the researchers said.

"Moreover, if a particular *allele was not typed, the participant was presumed to lack the variant allele in that position. Thus, some individuals assigned to the *1 category (lacking all alternative alleles) may have been misclassified, simply because genotyping was not attempted for some * alleles. Taken together, these observations cast doubt on the association of CYP2C19 genotype with clinical cardiovascular end points," they concluded.

In an editorial also in JAMA, Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation, called for a large randomized controlled trial to test the effectiveness of genetic testing for CYP2C19.

"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 for other therapies," Nissen said. "Overzealous adoption based on limited biochemical data does not serve the public interest."

In response to the JAMA article and Nissen's editorial, cardiologists from Scripps Health, including Eric Topol, as well as colleagues from Vanderbilt University and Hôpital Pitié-Salpetrière in Paris, issued a letter pointing out what they see as flaws in the review analysis.

They especially take issue with a meta-analysis of stent thrombosis associated with CYP2C19 loss-of-function alleles, in which the London researchers concluded "an absolute increase of 14 stent thromboses per 1,000 individuals."

In addition to calling the figure "an underestimate given the methodological flaws of the analysis," Topol and his colleagues said that "[w]ith over 1 million patients undergoing coronary stenting per year in the United States, this extrapolates to over 14,000 stent thrombosis events per year."

They further said that the meta-analysis did not test for heterogeneity among patients who underwent stenting versus those who were medically treated. The Scripps Health cardiologists said that no data for genotype-by-patient interaction was provided, and the analysis included "a large number of patients from trials that had nothing to do with coronary stenting … and assess[ed] outcomes where the benefit of clopidogrel itself is dubious."

They go on to say that prior pharmacogenomic studies on clopidogrel have shown CYP2C19 loss-of-function variants "to be important in coronary stenting patients and does not show up in those medically treated. It makes perfect sense that a metal implant in a coronary artery would pose a particular vulnerability to inadequate platelet suppression."