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Conclusive link between genetics and clinical response to warfarin uncovered

Higher early rates of bleeding with warfarin linked to genetic differences; newer drug provides greater early safety for patients with these genetic variants

Brigham and Women's Hospital

In a study published in The Lancet on March 10, researchers from Brigham and Women's Hospital (BWH) report that patients with a genetic sensitivity to warfarin - the most widely used anticoagulant for preventing blood clots - have higher rates of bleeding during the first several months of treatment and benefited from treatment with a different anticoagulant drug. The analyses from the TIMI Study Group, suggest that using genetics to identify patients who are most at risk of bleeding, and tailoring treatment accordingly, could offer important safety benefits, particularly in the first 90 days of treatment.

"We were able to look at patients from around the world who were being treated with warfarin and found that certain genetic variants make a difference for an individual's risk for bleeding," said Jessica L. Mega, MD, MPH, a cardiologist at BWH, senior investigator in the TIMI Study Group and lead author of the paper. "For these patients who are sensitive or highly sensitive responders based on genetics, we observed a higher risk of bleeding in the first several months with warfarin, and consequently, a big reduction in bleeding when treated with the drug edoxaban instead of warfarin."

Warfarin has been in clinical use for 60 years and genetics has been thought to influence an individual's sensitivity to the drug. The FDA label for warfarin notes that genetic variants in two genes - CYP2C9 and VKORC1 - can assist in determining the right warfarin dosage for an individual. But a conclusive link between variation in these two genes and bleeding has been debated. By leveraging data from their ENGAGE AF-TIMI 48 trial - an international, randomized, double-blind trial in which patients with atrial fibrillation received either a higher dose of edoxaban, a lower dose of edoxaban or warfarin to prevent blood clots from forming in the heart and leading to stroke - the TIMI investigators were able to observe important connections between genetic differences and patient outcomes. The trial represents the largest study of this kind to date and included nearly three years of follow-up with participants.

In ENGAGE-TIMI 48, patients were randomly assigned treatment and followed over time. The research team divided 14,000 study participants into three categories based on genetic makeup: normal responders, sensitive responders or highly sensitive responders. During the first 90 days, sensitive and highly sensitive responders who received warfarin experienced significantly higher rates of bleeding compared to normal responders. As a result, during this early time period, edoxaban was more effective than warfarin at reducing bleeding in sensitive and highly sensitive responders.

"These findings demonstrate the power of genetics in personalizing medicine and tailoring specific therapies for our patients," said Marc S. Sabatine, MD, MPH, a cardiologist at BWH, Chairman of the TIMI Study Group and senior author of the paper.

Warfarin remains the most common anticoagulant in part due to economics and availability, but several novel oral anticoagulants (NOACs), including dabigatran, rivaroxaban and apixaban, have entered the market. Edoxaban, a Xa inhibitor, received FDA approval for stroke prevention in atrial fibrillation earlier this year based on the results of the ENGAGE AF-TIMI 48 trial.

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ENGAGE AF-TIMI 48 was supported by research grants from Daiichi Sankyo. Full funding information, including all author disclosures, can be found in the full text of the article.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 3.5 million annual patient visits, is the largest birthing center in Massachusetts and employs nearly 15,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 1,000 physician-investigators and renowned biomedical scientists and faculty supported by nearly $650 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH continually pushes the boundaries of medicine, including building on its legacy in transplantation by performing a partial face transplant in 2009 and the nation's first full face transplant in 2011. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials group. For more information, resources and to follow us on social media, please visit BWH's online newsroom.

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