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Genotyping Appears to Offer Warfarin Dosing Edge in New Clinical Trial

NEW YORK (GenomeWeb) – New research suggests that genotypes at a handful of informative SNPs can help dial in on the appropriate warfarin dose and reduce the risk of adverse events such as excessive bleeding, while providing blood clot control.

As part of a randomized clinical trial dubbed GIFT, researchers from Washington University in St Louis and elsewhere compared adverse events in nearly 1,600 knee or hip replacement patients randomized to receive warfarin dosed with either traditional clinical criteria or clinical criteria coupled with genotyping information for four variants in three genes coding for enzymes that influence warfarin metabolism or sensitivity.

The team's findings, published online today in the Journal of the American Medical Association, pointed to statistically significant decline in adverse events in the genotype-guided dosing group: just shy of 11 percent of individuals in that group experienced adverse events compared with nearly 15 percent of those in the traditional dosing arm.

In the hip and knee replacement group, the authors found that genotype-based dosing "reduced the combined risk of major bleeding, [international normalized ratio (INR)] of 4 or greater, venous thromboembolism, or death." Still, they cautioned that "[f]urther research is needed to determine the cost-effectiveness of personalized warfarin dosing."

Warfarin labels have urged genotype-guided dosing for roughly a decade, the team noted. Even so, prior clinical trials have produced somewhat conflicting results and the utility of genotype-based dosing for warfarin drugs is still up in the air.

"Widespread use of genotype-guided dosing will depend on reimbursement, regulations, and logistics," the authors wrote. "Although several commercial platforms for warfarin-related genes have been approved by the US [Food and Drug Administration] and the European Medicines Agency, routine genotyping is not yet recommended."

For the GIFT trial, investigators focused on elective hip and knee replacement patients 65 years old or older who were being treated with warfarin. The targeted INR in these individuals was 1.8 or 2.5, while an INR of 4 or more was considered an adverse event.

Of the 1,650 participants who were randomized in the study, 1,597 individuals completed the trial, receiving one or more warfarin doses. The latter group included 789 individuals who received traditional clinically guided warfarin doses and 808 individuals with genotype-guided doses based on four variants in the VKORC1, CYP2C9, and CYP4F2 genes that were assessed using a GenMark Diagnostics genotyping platform. All of the patients were receiving warfarin to prevent clots related to elective hip or knee surgeries.

Along with an overall dip in adverse events — which encompassed everything from bleeding or venous thromboembolism to INR levels that exceeded warfarin targets — the researchers saw major bleeding, specifically, in eight individuals from the clinically guided group and just two individuals in the genotype dosing arm of the study.

When it came to adverse events involving elevated INR values, the team reported 77 events in the clinically guided group and 56 in the genotype-based dosing group. Venous thromboembolism occurred in 38 individuals from the clinically guided dosing arm and 33 individuals who received warfarin doses informed by genotyping information.

In a related commentary article in JAMA, University of Melbourne researcher Jon Emery explained that further research is needed to determine how cost-effective and generalizable the results of the GIFT trial are to other patient populations.

Based on the GIFT trial composite primary outcome, 26 patients would need to be genotyped to prevent one event," Emery wrote, noting that "an updated meta-analysis of trial data should be applied to cost-effectiveness modeling to inform new policy."