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Gene Variants Tied to Poor Outcomes with Heart Drug

Heart patients taking a widely used anti-clotting drug are at increased risk for serious cardiovascular problems if they have 1 or 2 copies of a common gene variant. The finding adds critical information for personalizing medications based on genetic makeup.

The clot-busting drug clopidogrel (Plavix) is often prescribed for people at risk for heart attack or stroke. The drug is also used to prevent clot-related complications after coronary stenting, a procedure that opens blocked arteries in the heart. However, clopidogrel doesn't work for everyone. Recent studies suggest that it's less effective in people who have specific variants of the CYP2C19 gene. These "reduced-function" variants make it difficult or impossible to convert clopidogrel to its active form.

A warning label on clopidogrel’s packaging notes that patients who inherited variant versions of CYP2C19 from both parents might not get the full benefits of the drug. However, it's been unclear how having a single copy of a reduced-function variant affects patient outcome. About one-third of the population carries at least 1 reduced-function variant.

To learn more, Dr. Jessica Mega of Brigham and Women’s Hospital headed a research team that involved scientists from 9 earlier studies. In an approach called a meta-analysis, the investigators pooled and reanalyzed their previously collected data on 9,685 patients at high risk for heart attack or stroke. All participants had been taking clopidogrel, and their CYP2C19 genes had been analyzed. The new analysis was supported in part by NIH's ×îÐÂÂ鶹ÊÓƵ Heart, Lung and Blood Institute (NHLBI).

The researchers found that patients who had just 1 copy of a CYP2C19 reduced-function variant—as well as those with 2 copies—were at a significantly increased risk of heart attack, stroke or cardiovascular-related death. The results were reported in the October 27, 2010, issue of the Journal of the American Medical Association.

The researchers also took a separate look at 5,894 patients who had a coronary stent. Once again, patients with either 1 or 2 copies of reduced-function variants had a substantially greater risk of major cardiovascular complications than those who lacked the variants. This included a 3-fold increased risk for stent thrombosis—a potentially dangerous blood clot that forms inside the metal stent.

These findings suggest that the impact of genetics on clopidogrel response may be greater than initially realized. The drug's warning label addresses only the 2% to 4% of the population that carries 2 copies of reduced-function CYP2C19 variants. However, an additional 26% of the population with just 1 variant may also be at risk. These patients might benefit from taking higher doses of clopidogrel, or they might need to take a different anti-clotting medication.

Several studies are now under way to determine the best strategy for using genetics to tailor clopidogrel therapy for each patient. "As we move forward, integrating genetic information will be one way to ensure that all patients are on the right drug for them," says Mega.

—by Vicki Contie