Genetic testing for clopidogrel (Plavix) resistance offers no real advantage in cardiovascular outcomes for patients on the antiplatelet drug, a meta-analysis suggested.
Carrying one or more alleles associated with lower drug metabolism did correlate significantly with less platelet inhibition and lower risk of bleeding in clopidogrel-only studies analyzed by Michael V. Holmes, MBBS, MSc, of University College London, and colleagues.
But the 18% higher risk of cardiovascular disease events among these individuals lost significance and disappeared after controlling for small study bias, the group reported in the December 28 issue of the Journal of the American Medical Association.
Action Points
- Having one or more alleles associated with lower drug metabolism of clopidogrel (Plavix) correlated significantly with less platelet inhibition and lower risk of bleeding in clopidogrel-only studies.
- The 18% higher risk of cardiovascular disease events among these individuals lost significance and disappeared after controlling for small study bias.
Looking only at studies based on at least 200 events, the relative risk of cardiovascular events among patients predicted to be poor responders based on CYP2C19 genotype was essentially neutral at 0.97 (95% confidence interval 0.86 to 1.09).
In the studies that included both clopidogrel and comparator arms, CYP2C19 genotype had no impact on the effect of clopidogrel on cardiovascular disease events or bleeding (both P>0.05 for interaction).
Despite a good case for CYP2C19 genotyping based on clopidogrel metabolism and platelet aggregation, the "meta-analysis does not demonstrate a clinically important association of genotype with cardiovascular outcomes with the possible exception of stent thrombosis," Holmes' group concluded.
Stent thrombosis had the strongest overall link with reduced-function alleles (RR 1.75, 95% CI 1.50 to 2.03), corresponding to an absolute increase of 14 stent thromboses per 1,000 individuals.
But even for this measure, the larger studies showed a trend toward the null.
These results compellingly point to overly enthusiastic expectations for pharmacogenomics in personalizing clopidogrel dosing, Steven E. Nissen, MD, of the Cleveland Clinic, argued in an accompanying editorial.
The FDA issued a black box warning of diminished clopidogrel effectiveness in poor metabolizers that suggested testing for CYP2C19 genotype.
Although the American Heart Association and American College of Cardiology quickly countered that there was insufficient evidence for such a warning, the FDA subsequently approved tests for CYP2C19 genotype and for platelet reactivity.
"The consequences of the FDA's leap to judgment regarding CYP2C19 testing cannot be underestimated," Nissen wrote, pointing to clopidogrel as one of the most widely used drugs in all of medicine.
Until a large randomized controlled trial adequately tests the strategy, "physicians should use CYP2C19 or platelet reactivity testing rarely, if ever, and interpret the results with caution," he recommended in the editorial.
The meta-analysis included 32 studies (six randomized trials) with a total of 42,016 patients who had 3,545 cardiovascular disease events, 579 stent thromboses, and 1,413 bleeding events in all.
Most of the studies were done in the setting of acute coronary syndrome. Eight were in stable heart disease patients, largely those undergoing stenting.
When the researchers examined the 26 studies that included only individuals exposed to clopidogrel, reduced-function alleles cut the absolute risk of bleeding events by five to eight events per 1,000 individuals, but at the expense of eight to 12 more cardiovascular disease events per 1,000.
"The net potential clinical benefit of genotyping to adjust dose may therefore not be as great as initially assumed," Holmes' group wrote.
They also pointed to small-study bias as a problem (P=0.001) along with concerns over selective outcome reporting and the potential for misclassifying CYP2C19 genotype because of problems with nomenclature.
The meta-analysis was limited by lack of patient-level data, differences in composite cardiovascular disease endpoints used across the studies included, and inclusion of both acute and stable heart disease studies, which might dilute associations if the magnitude of effect of clopidogrel was greater in acute than stable cases, the group acknowledged.
source:- Medpagetoday
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