Genetic testing can make warfarin doses safer

Considering a patient’s genetic makeup when prescribing warfarin—a blood thinner commonly prescribed to prevent life-threatening blood clots—can mean fewer adverse side effects like hemorrhage, a new study shows.

Warfarin has been in use for decades, but dosing remains tricky: Too much can cause internal bleeding; too little fails to prevent blood clots.

“Physicians have been prescribing warfarin since the Eisenhower administration,” says Brian F. Gage, a professor of medicine at Washington University School of Medicine in St. Louis and first author of the study in the Journal of the American Medical Association.

“Thousands of patients end up in the emergency department…But we continue to prescribe it because it is highly effective, reversible, and inexpensive.”

“It’s a widely used anticoagulant, but it causes more major adverse events than any other oral drug. Thousands of patients end up in the emergency department or hospital because of warfarin-induced bleeding. But we continue to prescribe it because it is highly effective, reversible, and inexpensive. So our goal is to make warfarin safer.

“GIFT (Genetics Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis) showed that precision-medicine based on clinical factors and three genes improves the safety of initiating warfarin therapy.”

Patients in the trial were randomly assigned to one of two groups. One group received warfarin dosing based on standard factors such as age, height, and weight. The second group was dosed based on these clinical factors plus genetic variants.

Participating sites included Washington University School of Medicine, Hospital for Special Surgery in New York, Intermountain Healthcare, University of Utah, and Rush University Medical Center.

Of the 789 patients who were dosed in the traditional manner, 116 experienced at least one adverse event (14.7 percent). Of the 808 patients whose warfarin dosing was guided by genetic testing, 87 experienced an adverse event (10.8 percent). Compared with patients receiving traditional warfarin dosing, patients dosed with the genetic approach had a 27 percent reduction in adverse events, which was statistically different.

The adverse events were bleeding, formation of blood clots in the veins, and warfarin overdoses. No patient died during the trial.

Three genes

Earlier studies looking at whether genetic testing could improve warfarin dosing had produced conflicting results. However, these studies were smaller and considered fewer genes than GIFT. GIFT enrolled 1,600 patients age 65 and older at high risk of blood clots because they underwent hip- or knee-replacement surgeries.

Unlike prior studies, GIFT took into account genetic variants in three genes for 11 days of warfarin therapy. Genetic variants were assessed on a commercial platform called GenMarkDx.

Variants in one gene affect vitamin K recycling. Variants in another gene affect warfarin sensitivity. Variants in the third gene alter warfarin metabolism in the liver and can cause an overdose if the dose is not adjusted soon enough.

“There are additional genetic variants that may help to guide warfarin dosing, especially among patients with African ancestry,” Gage says. In the future, we hope to quantify how these variants affect warfarin.”

Warfarin isn’t best for balancing bleeding and stroke risk

Gage also notes how health-care costs relate to dosing warfarin in a genetically guided manner.

“Although genetic testing is more expensive than clinical dosing, the cost is falling,” he says. “In our study, we estimated that genetic testing costs less than $200 per person, which is less than one month of a newer anticoagulant.”

The National Heart, Lung and Blood Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health; the Centers for Medicare and Medicaid Services; and GenMarkDx funded the work.

Source: Washington University in St. Louis

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