Warfarin genotyping reduces adverse events

Genetic testing can improve the safety of warfarin therapy for patients at high risk of VTE following hip or knee replacement surgery a new study has found.

The findings from the trial known as GIFT (Genetics Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis), could see use of genotype-guided warfarin dosing become more widespread, according to researchers in the US.

Published in JAMA this week the study results showed that precision-medicine based on clinical factors and three genes reduced the combined risk of major bleeding, an INR of four or more, venous thromboembolism or death among patients undergoing elective hip or knee arthroplasty compared with those who had clinically guided dosing.

But Australian expert, Professor Jon Emery from the University of Melbourne said he’s not convinced about the cost effectiveness of the test – especially if the findings from GIFT can’t be applied to other patient populations where warfarin is indicated such as in those with atrial fibrillation.

Writing in a linked editorial he noted that the benefit of genotyping would likely be smaller in AF patients, since the risk of VTE is higher in patients undergoing knee and hip surgeries.

He also pointed out that based on the study’s primary endpoint, a composite of major bleeding, INR of four or greater, VTE or death, some 26 patients would need to be genotyped to prevent one event – which would most commonly be an INR of four or more.

He argued that it would be ‘simpler and less expensive’ to push for the wider use of clinical dosing algorithms to reduce the harms of anticoagulation.

All 1,600 patients involved in the study were genotyped for three warfarin-related gene variants before being randomised to either genotype guided warfarin dosing or clinically guided dosing for the first 11 days after surgery.

Variants in the three genes singled out for the test can affect vitamin K recycling, warfarin sensitivity and warfarin metabolism in the liver, which can cause an overdose if the dose is not adjusted soon enough, the researchers said.

Patients randomised to genotype guided dosing had a reduced primary endpoint rate – 10.4% compared to 14.7% in the clinically guided group. There were no deaths in either group.

Investigators, led by Dr Brian Gage, Professor of Medicine at Washington University in the US, also reported that genotype guided dosing improved the percentage of time in the therapeutic range, up from 51.3% in the clinically guided group to 54.7% with genotype-guided dosing.

The study is the most detailed look yet at the effect of genotype-guided dosing say investigators who noted that earlier studies looking at whether genetic testing could improve warfarin dosing produced conflicting results mostly because they were smaller and considered fewer genes than GIFT.

And while many of those studies were carried out before other anti thrombotic therapies like DOACs became more widely adopted, Professor Gage and colleagues argued that the importance of the GIFT findings should not be overlooked.

They pointed out that many doctors continue to prescribe the non vitamin K antagonist because it is effective, inexpensive and reversible – that’s despite warfarin accounting for more medication-related emergency department visits among older patients than any other drug over the last decade.

“Strategies that optimise the risks and benefits of warfarin therapy are important despite the availability of alternatives,” they noted.

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