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Wash U, Partners Kick off Five-Year Warfarin PGx Dosing Trial

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A group of hospitals led by Washington University School of Medicine in St. Louis has begun a clinical trial to determine how well genetic variants can customize dosing for the blood thinner warfarin.

The National Heart, Lung, and Blood Institute is funding the five-year, $3.7 million Genetics Informatics Trial of Warfarin, or GIFT, which will test a warfarin-dosing formula that takes three genetic variants into account.

The study follows another warfarin pharmacogenomics trial that NHLBI began last year called Clarification of Optimal Anticoagulation through Genetics, or COAG, a 1,200-patient prospective, randomized-controlled trial that is comparing clinical outcomes of one group of patients given warfarin based on just clinical factors and another cohort administered the anticoagulant based on clinical factors and genotype.

In addition to Wash U, GIFT collaborators include Barnes-Jewish Hospital, the University of Utah, Intermountain Health Care, and the Hospital for Special Surgery in New York.

The trial will enroll 1,600 patients recovering from hip or knee replacement surgery, which will enable the researchers to study the challenges facing doctors who are planning warfarin doses.

“Without any anticoagulant, orthopedic patients have a nearly 50 percent chance of having a blood clot after hip or knee replacement,” explained Brian Gage, a professor at WU-STL and lead investigator of the trial, in a statement.

Blood clots contribute to the death of 100,000 people in the US each year, with most of these deaths occurring suddenly, so prevention with a blood thinner or anticoagulant is viewed as the best protection available.

“These are 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,” Gage explained.

Warfarin dosing is challenging due to variable drug response between individuals and a narrow therapeutic range for the drug: doses that are too high can lead to bleeding, but too low of a dose can cause clotting. Consequently, the US Food and Drug Administration has updated warfarin's label to recommend dosing for individuals based on their genetic variants.

In the GIFT trial, all of the participants will be treated with warfarin, but for half of them the dose will be decided based solely on clinical formulas based on age, body size, medications, and smoking status, and for the other half the dose will be based on all of these factors plus genetics.

The patient groups also will be split another way, with each group trying to reach different targets of international normalized ratios, or INR, which measures the risk of a patient developing clotting or bleeding.

“There are only a few drugs that are at this stage of incorporating genetics into clinical use, Petra Lenzini, a research statistician in WU-STL’s division of General Medical Sciences, said in a statement.

“How we conduct this trial will set the stage for future research in relating genetics to pharmacology,” Lenzini added.

A recent prospective study led by Medco Health Solutions and the Mayo Clinic found that genetic testing for variants related to warfarin treatment response decreased hospitalization rates by almost one third.

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