Genetic variations associated with worse outcomes with use of common antiplatelet drug for cardiac procedures
An analysis of data from previously published studies
indicates that use of the antiplatelet drug clopidogrel for patients who have
common genetic variants of a certain gene and are undergoing a procedure such
as coronary stent placement have an associated increased risk for major adverse
cardiovascular events, particularly development of blood clots in stents, according
to a study in the October 27 issue of JAMA.
Clopidogrel, one of the most commonly prescribed medications, has been shown
to reduce cardiovascular events in patients undergoing percutaneous coronary intervention.
"However, there is a large degree of interindividual variability in the pharmaco-dynamic
response to clopidogrel," the authors write. Data suggest its pharmacologic
effect varies based on variations of the gene CYP2C19, but there is uncertainty
regarding the clinical risk given by certain variations.
Jessica L. Mega, M.D., M.P.H., of Brigham and Women's Hospital and Harvard
Medical School, Boston, and colleagues conducted a meta-analysis to determine
the risk of major adverse cardiovascular outcomes among carriers of 1 or 2 reduced-function
CYP2C19 genetic variants in patients treated with clopidogrel. The analysis included
data from 9 studies and 9,685 patients (of whom 91.3 percent underwent PCI and
54.5 percent had an acute coronary syndrome), 863 experienced the composite outcome
of cardiovascular death, heart attack, or stroke; and 84 patients had stent thrombosis
among the 5,894 evaluated for such.
There were 6,923 patients (71.5 percent) with no CYP2C19 reduced-function alleles
(an alternative form of a gene), 2,544 (26.3 percent) with 1 reduced-function
CYP2C19 allele, and 218 (2.2 percent) with 2 reduced-function CYP2C19 alleles.
"Compared with CYP2C19 noncarriers, there was a significantly increased risk
of cardiovascular death, myocardial infarction, or stroke in the 26.3 percent
of the overall study population who carried only 1 reduced-function CYP2C19 allele.
Similarly, there was a significantly increased risk of cardiovascular death, myocardial
infarction, or stroke in the 2.2 percent of the overall study population who carried
2 reduced-function CYP2C19 alleles," the researchers write.
The authors also found that both carriers of only 1 reduced-function CYP2C19
allele and carriers of 2 alleles were at significantly increased risk of stent
thrombosis when compared with CYP2C19 noncarriers.
"In conclusion, the findings of this collaborative meta-analysis demonstrate
that common genetic variants in the CYP2C19 gene are associated with almost 1
in 3 patients not receiving ideal protection from ischemic events when treated
with standard doses of clopidogrel for PCI. Given how widely clopidogrel is used
to treat patients with cardiovascular disease, determination of the optimal antiplatelet
treatment doses or regimens for individual patients is needed to tailor therapy
appropriately," the authors write.
In an accompanying editorial, Valentin Fuster, M.D., Ph.D., of the Mount Sinai
School of Medicine, New York, and Joseph M. Sweeny, M.D., of the Mount Sinai Medical
Center, comment on the findings of this meta-analysis.
" … in patients treated with clopidogrel, the best genome-guided strategy
remains to be determined. The information obtained by CYP2C19 genetic testing
may be particularly useful in patients at risk of poor outcomes, either because
they have already had an adverse event (e.g., stent thrombosis) or other at-risk
characteristics such as diabetes mellitus, chronic renal failure, or angiographic
high-risk features."
They add that until other ongoing studies that are investigating the best genome-guided
strategy for higher-risk patients are completed, "clopidogrel and CYP2C19
genetic testing appear to be only a limited piece of the overall therapeutic puzzle
of clopidogrel therapy and personalized medicine."
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