A five-year, $3.7 million clinical trial will investigate how to balance the benefits and risks of warfarin, a drug that helps prevent potentially deadly blood clots.

The multicenter study, led by researchers at Washington University School of Medicine in St. Louis, will evaluate customized warfarin dosage based on patient genetics and will test which range of blood clotting is optimal in orthopedic patients.

Blood clots contribute to the death of 100,000 Americans every year. Most of these deaths occur suddenly, so prevention with a blood thinner, or anticoagulant, such as warfarin (Coumadin) is widely regarded to be the best form of protection. However, a number of factors including drug interactions and genetics can interfere dangerously with warfarin, making it tricky to pinpoint the correct dose.

To help determine the best way to establish the right dose, knee or hip replacement surgery patients at Barnes-Jewish Hospital and several other institutions will be eligible to enroll in the Genetics InFormatics Trial of Warfarin (GIFT).

"Without any anticoagulant, orthopedic patients have a nearly 50 percent chance of having a blood clot after hip or knee replacement," says Brian Gage, MD, associate professor of medicine at Washington University and lead investigator of the trial. "These are the people at highest risk for blood clots, and because they've just had surgery they are also at high risk for bleeding. This balance is why this question of warfarin dosing is critical. Finding the right dose is like walking a tightrope."

The National Heart, Lung, and Blood Institute will fund the study. Collaborating institutions include the University of Utah, Intermountain Health Care, and the Hospital for Special Surgery in New York. Gage and colleagues hope to enroll 1,600 patients recovering from hip or knee replacement surgery, which will allow them to investigate two problems that make determining optimal warfarin dosage challenging.

First, individual genetic variation affects how warfarin is tolerated and broken down by the body. Based on years of research, the team has developed several formulas that take genetic information into account when calculating warfarin dosage. The newest of these formulas has been published online in Clinical Pharmacology and Therapeutics.

In the GIFT trial, they will use a formula that includes three gene variations that have been shown to influence a person's warfarin sensitivity or metabolism. They have made these formulas available to physicians through the Web site warfarindosing.

"What's special about warfarin is that there are only a few drugs that are at this stage of incorporating genetics into clinical use," says Petra Lenzini, a research statistician in the Division of General Medical Sciences and coordinator of the GIFT trial. "How we conduct this trial will set the stage for future research in relating genetics to pharmacology."

The second problem GIFT will tackle is the long-standing debate concerning appropriate target levels of clotting ability in the blood, a quantity known as the International Normalized Ratio (INR). INR refers to blood clotting speed: the higher the number, the longer blood takes to clot. A higher INR increases the chances that a patient will start bleeding, but also decreases the chances that a patient will develop a clot.

The American Academy of Orthopedic Surgeons currently recommends an INR of less than 2.0. However, the American College of Chest Physicians has set forth a recommended target INR of 2.0 to 3.0. Until now, no study has attempted to compare these two guidelines of warfarin treatment to determine which strikes the best balance between bleeding and clot risk.

All participants in GIFT will receive warfarin treatment. For half of the patients, warfarin dose will be decided based on clinical formulas that account for age, body size, medications and smoking status. The other half will receive a warfarin estimate based on these factors plus genetics. Each group will also be split, with one half trying to reach a target INR of less than 2.0 and the other half striving for an INR of 2.5. The researchers anticipate that after the initial two weeks of treatment, patients will have reached an appropriate level of warfarin with little adjustment needed thereafter.

"The first aim is a test of the paradigm of personalized medicine," Gage says. "We have been working in the field for eight years. Now, it's exciting to go see that results of these efforts will be used to care for thousands of patients."

Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen Al, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB, Angchaisuksiri P, Bass AR, Chen J, Eriksson N, Rane A, Lindh JD, Carlquist JF, Horne BD, Grice G, Milligan PE, Eby C, Shin J, Kim H, Kurnik D, Stein CM, McMillin G, Pendleton RC, Berg RL, Deloukas P, Gage BF. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clinical Pharmacology and Therapeutics. April 7, 2010 (advance online publication).

Funding from National Heart, Lung, and Blood Institute supports this research.

Gwen Ericson
Washington University School of Medicine

View drug information on Warfarin Sodium tablets.

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