Genetic testing can help determine safest dose of warfarin

Genetic testing may help doctors determine the proper dosage of the common blood thinner warfarin in joint replacement patients, according to a study published in JAMA.

In a trial of 1,597 patients undergoing hip or knee arthroplasty, 14.7 percent of patients who received dosage according to traditional guidelines experienced at least one adverse cardiovascular effect. When genotype-guided dosing was used, adverse effects dropped to 10.8 percent.

"Warfarin is very effective in preventing blood clots, but it’s very difficult to regulate,” study co-author Anne R. Bass, MD, a rheumatologist at Hospital for Special Surgery in New York City, said in a press release.

"About half of the population, because of genetic variants, is very sensitive to warfarin or has a very unpredictable or delayed response to the drug. This is the first study to show that adjusting the dose based on these genetic variants makes warfarin safer for patients."

The authors pointed out warfarin has accounted for more medication-related emergency room visits among older adults than any other drug over the last decade. Too much of it can lead to internal bleeding, while an insufficient dose can leave patients susceptible to blood clots.

About half of the study population received dosing based on clinical factors including age, height and weight, gender, race and other medications. Genetic variations were added to these factors to determine proper dosing for the other half of the study population.

The mean age of the overall sample was 72.1. Ninety-one percent of the trial population was white, and 63.6 percent were women.

Researchers analyzed the effects of warfarin dosage related to a composite of the following adverse events: major bleeding, international normalized ratio (INR) of 4 or greater or death within 30 days; and venous thromboembolism confirmed by testing within 60 days of joint replacement.

None of the participants died, but the genotype-guided dosage group showed lower rates of the other three endpoints. However, only INR of 4 or greater—which accounted for 2.8 percent of the 3.9 percent absolute reduction in the composite outcome—achieved independent statistical significance.

The authors said further studies are needed to analyze the cost-effectiveness of personalized genetic testing for warfarin dosing.

“Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics,” wrote the researchers, including principal investigator Brian F. Gage, MD, with Washington University in St. Louis. “Although several commercial platforms for warfarin-related genes have been approved by the U.S. FDA and the European Medicines Agency, routine genotyping is not yet recommended. The Centers for Medicare & Medicaid Services used its Coverage with Evidence Development program to fund genotyping in this trial and will review the results to determine future coverage.”