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Gene Mutations Can Make Heart Drugs Go Haywire

Carriers may have deadly response to warfarin

TUESDAY, April 2, 2002 (HealthDayNews) -- Variations in a gene that helps the body break down certain drugs greatly magnify the effects of blood thinners and raise the risk of potentially deadly bleeding disorders.

The gene, CYP2C9, makes an enzyme that is directly responsible for the metabolism of warfarin, one of the most common drugs for heart patients, new research says.

Between 2 million and 3 million Americans -- mainly people with an abnormal heart rhythm, a history of strokes or an enlarged heart -- take warfarin (known commercially as Coumadin) to help keep their blood from clotting. However, the amount they need varies widely; some patients may require only one milligram a day, others 30 times as much. Calculating the correct dose starts as a matter of trial and error.

Previous research has revealed that CYP2C9 comes in different flavors, and that these appear to determine how well a person's blood handles warfarin. Scientists have now found almost a half-dozen altered forms of this gene, each of which enhances the blood-thinning action of the drug.

In the latest study, appearing in tomorrow's Journal of the American Medical Association, David Veenstra and his colleagues at the University of Washington looked for the effects of warfarin in 185 men and women. Fifty-eight (about 31 percent) had at least one copy of two variants of CYP2C9.

Those with the variants were about 2.4 times as likely as people with the normal form of the gene to suffer serious bleeding complications while taking warfarin, the group found. The risk was four times greater in the first three months on the treatment.

"We're not just looking at bleeding gums. These were clinically significant events," Veenstra said.

People with the gene alterations also took much longer to reach a stable dose of the drug -- about three months longer, on average -- than did the others. "We were surprised that it took that much longer," Veenstra said. "That could be five, six, or seven visits to the doctor before they get them to a stable dose."

Dr. Brian Gage, a St. Louis warfarin expert who directs the Barnes-Jewish Hospital blood thinner clinic, said CYP2C9 may help doctors better administer it. "Despite its popularity, it's a very dangerous drug," Gage said. "A little bit is good, and too much can cause bleeding, even fatal bleeding."

But at least to date, Gage said, genetic testing is too time-consuming to be clinically practical. "You have to have a rapid turnaround. I'm not going to wait till next Tuesday" before starting a patient who needs to be on blood thinners today, he said. "That's wholly impractical."

Gage said he knows of at least two companies that are working on quicker screening technologies, but none is yet available.

Until then, he said, doctors will rely on the current standard of care a formula called INR -- to calibrate their warfarin regimens. INR reflects whether a person is taking the right amount of the drug.

Dr. Michael Stein, a clinical pharmacologist at Vanderbilt University who has studied CYP2C9, said the latest work "brings out what people would have predicted would have happened" in patients based on earlier findings.

But Stein said it's too soon to offer gene screening to blood thinner patients. After all, scientists don't know if altering a warfarin dose based on a person's CYP2C9 profile (their genotype) will in fact help them better tolerate the drug.

Dr. Valentin Fuster, director of the cardiovascular institute at Mount Sinai School of Medicine, said most cardiologists will want more evidence that these gene alterations truly matter before they embrace screening as a way to improve warfarin dosing. "This is not going to be used at all by any of us" until then, he said.

In an unrelated study also appearing in the Journal of the American Medical Association, University of Washington researchers report another instance of gene variants influencing cardiac therapy.

The finding hinges on a gene called alpha-adducin, which codes for an important protein involved in cell membranes. About a third of people have a variation in alpha-adducin, known as Gly460Trp, that forces the kidneys to retain salt. As a result, those with the mutation who develop high blood pressure are at a much greater risk of heart attacks and strokes than other hypertension patients.

The new study found that patients with the Gly460Trp mutation slashed their risk of these bad outcomes if they took diuretics to dry themselves out. Indeed, their odds of a heart attack or stroke were cut in half compared to those with the mutation who were taking other blood pressure medications, the researchers said.

"Here is a sub-group of people for whom diuretics may be very effective," said Dr. Bruce Psaty, who led the work.

Psaty said it's too soon for doctors to consider offering the test. "We found something that's very interesting and may become part of the translation of the work of the human genome to public health," he said. "We're not to the point where people should be asking for this genetic test."

What To Do

To learn more about blood thinners, try the Texas Heart Institute or the American Academy of Family Physicians.

For more on high blood pressure and how to prevent it, try the National Heart, Lung, and Blood Institute.

SOURCES: David Veenstra, Pharm.D., Ph.D., assistant professor, University of Washington School of Pharmacy, Seattle; Brian Gage, M.D., assistant professor of medicine, Washington University School of Medicine, St. Louis; Michael Stein, M.D., associate professor of medicine and pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.; Bruce Psaty, M.D., Ph.D., professor of medicine, epidemiology and health services, University of Washington, Seattle; Valentin Fuster, M.D., director of the cardiovascular institute, Mount Sinai School of Medicine, New York; April 3, 2002, Journal of the American Medical Association
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