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An individual’s genetic makeup can have a profound effect on the required dose of warfarin, the most widely used anticoagulant drug in the world, regardless of race, ethnicity or other differences.

February 18, 2009

• Warfarin dose related to two genes

• Personalized medicine precursor: dose adjusted to patient's genetic makeup

• UAB part of International Warfarin Pharmacogenetics Consortium

BIRMINGHAM, Ala. - An individual's genetic makeup can have a profound effect on the required dose of warfarin, the most widely used anticoagulant drug in the world, regardless of race, ethnicity or other differences. These findings are reported in the Feb. 19th issue of the New England Journal of Medicine by the International Warfarin Pharmacogenetics Consortium (IWPC). Treatment with warfarin is challenging because the ideal dosage for each person varies widely and is hard to predict, yet is crucial for the patient's safety.

The IWPC, organized by the National Institutes of Health (NIH), includes researchers from 21 research teams in nine countries, including researchers from UAB (University of Alabama at Birmingham). By pooling data on about 5,700 patients from around the world, investigators developed a warfarin dosing strategy that can help determine warfarin dose more accurately for patients of different racial, ethnic or geographic background.

Investigators compared different methods of warfarin dosing, one that relied on standard clinical information and one that included information on patient genotype for two genes: CYP2C9 and VKORC1. Dose predictions were more accurate when genetic information was included, especially for patients who require either lower or higher than standard doses. Nearly half of all patients on warfarin are at the extremes of the dosing range, and these patients may be at the greatest risk for excessive bleeding or clotting complications.

"Finding each patient's proper warfarin dose is extremely challenging," says Nita Limdi, Pharm.D., Ph.D., MSPH, assistant professor of neurology at UAB. "Physicians use an initial dose based on standard clinical factors and then fine-tune that dose until the proper level is reached. Genetic information can help doctors quickly optimize dose for a large proportion of patients and this in turn may minimize dangerous complications and improve the effectiveness of warfarin treatment."

In an important step toward putting these finding into clinical practice, the National Heart, Lung and Blood Institute (NHLBI) is launching the largest prospective, randomized clinical trial involving 1,200 patients in the United States to test gene-based warfarin dosing. The trial will begin next month and will examine whether genetoype-based prescribing strategy will improve patient outcomes.

Limdi says this approach is one application of what is being called personalized medicine. Perhaps with a better understanding of the role of genetics, physicians will one day be able to tailor an individual's treatment with the right drug at the right dose.

The consortium is supported by the National Institute of General Medical Sciences, the National Heart, Lung and Blood Institute, the National Institute of Neurological Disorders and Stroke and the National Center for Research Resources.

Proper Warfarin Dose Affected by Genetics