Study seeks safer blood thinner used by millions

~ Warfarin users must carefully manage the doseage amount.

WASHINGTON -- It's the nation's most troublesome lifesaver. Every day, 2 million Americans swallow a blood thinner called warfarin that puts them on a tightrope: Too little, and they won't be protected from lethal blood clots. Too much, and they can bleed to death.

Something as simple as a big serving of spinach or stressful travel can alter how much of the drug stays in the body, putting patients in a danger zone.

Even picking the best dose in the first place is perilous, as doctors basically use trial-and-error for each patient.

That could soon change. Scientists have discovered two genes that help determine if someone can tolerate only a little warfarin or needs a lot. So the Food and Drug Administration is launching a major study to see if testing new patients' genes will dramatically reduce side effects during the critical first weeks of therapy.

Even before that study gets under way this fall, the FDA is about to alter the warning labels on generic warfarin and the brand-name version, Coumadin. The message to doctors: Be aware that some patients' genes dictate far lower doses than you usually prescribe, and stay tuned for more precise instructions.

"It's a very difficult drug," says Dr. Brian Gage of Washington University in St. Louis, who is leading a pilot study of the gene testing for another government agency, the National Institutes of Health. "Each person has a limited range where they have the right thinness of blood. ... It's hard to get right the first time."

The difficulty doesn't stop once doctors finally settle on an initial dose. Patients need regular blood tests -- daily at first, then weekly or monthly -- to check that their blood is clotting properly. Few get those checks at specialized clinics trained to recognize impending side effects and avert them.

And a recent survey by the National Consumers League suggests too few understand other basic steps they're supposed to take to avoid warfarin complications.

"Patients, some were absolutely clueless. It was scary how much they didn't know," said Rebecca Burkholder, health policy director at the consumer group, which has begun a patient-safety campaign to try to change that.

Among the leading myths: that warfarin users must avoid vitamin K-rich green, leafy vegetables. Warfarin works by blocking a step in the blood-clotting process that is largely regulated by vitamin K.

Actually, the key is consuming about the same amount of vitamin K all the time, learned Lynn Levitt, 32, of Highlands Ranch, Colo., who has used the drug for three years since developing a life-threatening clotting disorder.

Levitt initially thought if tests showed her blood wasn't too thin one week, "I could go celebrate with a big salad. Actually, I could eat salad every single day but I need to do it consistently," she now knows.

Warfarin is one of the most widely used medicines, and doctors' top choice in blood thinners to prevent heart attacks, strokes and other lethal blood clots. It cuts some patients' risk of death by up to 70 percent.

At the same time, warfarin is one of the most side-effect prone drugs. The FDA cites research suggesting warfarin alone accounts for 15 percent of severe drug side effects. For every 100 patients, there are anywhere from one to seven major bleeding episodes.

And most of the side effects occur in the first month of treatment, says FDA pharmacology chief Dr. Lawrence Lesko.

Enter the gene tests.

A gene known as CYP2C9 produces an enzyme that helps the body metabolize a variety of medicines. Variations in that gene can make people metabolize warfarin more slowly, so that they need a smaller dose.

But that's not the only factor. A vitamin K-related gene called VKORC1 produces the blood-clotting protein that warfarin blocks. People who produce less of that protein need less warfarin.

Say doctors start a 200-pound, 40-year-old man on 10 milligrams of warfarin. But if he had the warfarin-sensitive gene combination, he'd only need 3 mg -- the higher dose puts him at risk of a hemorrhage. Today, doctors would know that only once routine blood tests show the patient's clotting levels out of whack, and it can take days for a dose adjustment to kick in.

In November, FDA-funded researchers will begin enrolling up to 800 warfarin patients to see if gene testing gets them the right dose faster, with fewer side effects in that first month.

DNA-based prescribing is a fledgling science called pharmacogenetics. The FDA has put a little gene-based advice on the labels of a few medications so far, and will soon put preliminary advice on warfarin's. But if the new study pans out -- and Lesko's optimistic -- it would be the first to link specific gene results to exact doses of a widely used drug.

"It's a high-water mark in many ways," notes Lesko.

Still, gene tests won't eliminate warfarin problems. Initial dose aside, simple lifestyle changes -- stress, travel, or use of a host of other medicines, vitamins, herbs or foods -- can affect how the body processes warfarin, causing blood to suddenly become either too thin or not thin enough.

But the National Consumers League survey found less than a third of patients got reminders from their doctors to have their blood regularly tested, or knew if the tests signaled their warfarin dose needed adjusting. The FDA cites studies that show less than half of warfarin users maintain the right level of blood thinness most of the time.

To improve that patient monitoring, health insurance giant Kaiser Permanente has its more than 30,000 warfarin users enrolled in special pharmacist-run "anticoagulation management" programs. Patients get tested in the pharmacy that fills their prescription. Specially trained pharmacists telephone each with the result, questioning lifestyle changes if the blood levels aren't right -- and can change doses on the spot, speedier than tracking down a doctor to do it.

A study of the first such Kaiser program, recently published in the journal Chest, concluded it prevents one major side effect for every 52 warfarin users.

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EDITOR'S NOTE -- Lauran Neergaard covers health and medical issues for The Associated Press in Washington.

On the Net:

National Consumer League warfarin safety info: http://www.mybloodthinner.org