JAMA: CYP2C19 loss-of-function alleles equate to higher risk of CV events

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Carriers of the CYP2C19 loss-of-function allele are at an increased risk for a major adverse cardiovascular events (MACE), and it is estimated that one in three of these patients do not receive ideal protection from ischemic events when treated with clopidogrel for PCI, according to a meta-analysis published in the Oct. 27 issue of the Journal of the American Medical Association.

“[T]here is a large degree of interindividual variability in the pharmaco-dynamic response to clopidogrel,” the authors wrote.

In March, the FDA added a black box warning to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) after it found that 2 to 14 percent of the population may not be able to effectively metabolize the drug and may not receive its full benefits.

Jessica L. Mega, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues conducted a meta-analysis of nine previous studies to determine the risk for MACE among carriers of the one or two reduced-function CYP2C19 genetic variants in 9,685 patients administered clopidogrel.

Of the patient cohort, 71.5 percent of patients had no CYP2C19 reduced-function alleles while 26.3 percent had one reduced-function allele and 2.2 percent had two reduced-function alleles.

Of the 9,685 patients, 91.3 percent underwent PCI. The researchers found that 863 patients experienced the composite outcome of CV death, MI or stroke and 84 patients had stent thrombosis among the 5,894 evaluated for bleeding events. During the study, 272 patients died of a CV cause, 575 experienced a nonfatal MI and 68 experienced a non-fatal stroke.

The patients who carried either one or two reduced-function alleles held a higher risk for stent thrombosis.

“With respect to treatment options, there are some early data suggesting that increasing the dose of clopidogrel in carriers of a CYP2C19 reduced-function allele may enhance the degree of platelet inhibition,” the authors wrote.

"Understanding the ability to treat patients effectively with clopidogrel across CYP2C19 genotypes will be particularly important from a healthcare cost perspective, as the drug is already off patent in some countries and anticipated to go off patent in the U.S. and elsewhere in the near future," the authors wrote.

“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 concluded.

In an accompanying JAMA editorial, Valentin Fuster, MD, PhD, and Joseph M. Sweeny, MD, of the Mount Sinai School of Medicine in New York City, wrote that for 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.”