March 2, 2009

Genetic Tests Help Optimize Doses of Blood-Thinning Drug

Image of clotted blood cells Electron micrograph of red blood cells and a single white blood cell entangled in a clot. IDavid Gregory and Debbie Marshall. All rights reserved by Wellcome Images.

Genetic tests can help doctors fine-tune the dosing of the widely prescribed blood-thinner warfarin for individual patients, according to a new study. The research may ultimately help patients avoid the life-threatening dangers of too-high or too-low doses of the drug.

Each year about 2 million Americans with certain heart conditions or other risk factors start taking warfarin, also known as Coumadin. It's often prescribed to prevent blood clots that can lead to heart attack, stroke or even death. But determining how much warfarin each patient needs can be difficult. The ideal dosage varies widely, with some patients needing about 10 times more than others. Yet finding the appropriate dosing is crucial. Too much can lead to excess bleeding, and too little can fail to prevent dangerous blood clots.

Scientists already knew that variations in 2 genes can influence warfarin's effectiveness. One gene, called CYP2C9, deactivates warfarin. The other, VKORC1, activates vitamin K, which is essential for blood clotting. However, it's been unclear whether these 2 genes could help doctors predict the ideal warfarin dosage for a wide range of patients with race, ethnicity or other genetic differences.

To investigate, researchers from 9 countries pooled their data on more than 5,000 people taking stable doses of warfarin. The team first analyzed data from about 4,000 of the patients, including demographic information like age, gender and race; CYP2C9 and VKORC1 variants; and initial, as well as optimized, warfarin dosages. Each patient’s optimal dosing had already been determined by gradually adjusting the doses based on blood tests. The study was funded in part by NIH’s National Institute of General Medical Sciences (NIGMS) and 3 other NIH components.

Based on their analysis, the scientists developed a mathematical formula, or algorithm, that uses both clinical and genetic data to predict the ideal warfarin dosage for each patient. They also made dose predictions using a different algorithm based only on clinical information. To test the validity of the 2 algorithms, the researchers then analyzed how well their computational predictions matched the actual, clinically derived optimal dosages of warfarin for the remaining 1,000 patients.

The results—described in the February 19, 2009, New England Journal of Medicine—showed that when genetic information was included, the predictions of ideal dosages were more accurate, especially for patients at the low or high ends of the dosing range. This is important because nearly half of those on warfarin are at the extremes of the range, and these patients are often at greatest risk for excessive bleeding or clotting.

"It appears that up to 46% of people will require a warfarin dose that is significantly higher or lower than average," says study co-author Dr. Russ Altman of the Stanford University School of Medicine. "We're hoping that our research will help clinicians get it right on the first try."

NIH’s National Heart, Lung and Blood Institute (NHLBI) is now launching a large clinical trial to evaluate a gene-based strategy for selecting initial warfarin doses based on blood test results. The trial, scheduled to begin in April 2009, will enroll 1,200 participants of diverse backgrounds and ethnicities at 12 clinical sites.

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