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Patient genotyping identifies increased bleeding risk with warfarin treatment
Patients with a genetic sensitivity to warfarin and increased rates of bleeding in the first several months of treatment stand to benefit from use of an alternate anticoagulant drug, according to research published in The Lancet.
Findings from the TIMI Study Group suggest that identifying high-risk patients through genetic testing and tailoring treatment could improve safety, especially during the initial 90 days of therapy, according to investigators.
“We now demonstrate conclusively that genetics impacts a patient’s risk of bleeding when treated with warfarin,” Marc S. Sabatine, MD, MPH, a cardiologist at Brigham and Women’s Hospital and chairman of the study group, told Cardiology Today.
Marc S. Sabatine
Although the FDA label for warfarin lists genetic variants in CYP2C9 and VKORC1 as useful in determining appropriate individual dosage, the association between variation in these two genes and bleeding has to-date been debated.
“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,” Jessica L. Mega, MD, MPH, also a cardiologist at Brigham and Women’s Hospital and senior investigator in the study group, said in a news release.
From the randomized, double-blind ENGAGE AF-TIMI 48 trial comparing two once-daily edoxaban (Savaysa, Daiichi Sankyo) doses vs. warfarin for nonvalvular atrial fibrillation, 14,348 patients were included in a genetic analysis and genotyped for CYP2C9 and VKORC1 variants.
Patients receiving warfarin (n = 4,833) were categorized into three genotype functional bins based on drug response, with 2,982 (61.7%) classified as normal, 1,711 (35.4%) as sensitive and 140 (2.9%) as highly sensitive.
When compared with normal responders, sensitive and highly sensitive responders spent larger portions of time over-anticoagulated (median 2.2%, IQR 0-20.2; 8.4%, 0-25.8; and 18.3%, 0-32.6; P for trend < .0001) during the first 90 days of therapy.
Increased risks for bleeding with warfarin were also observed for sensitive responders (HR = 1.31; 95% CI, 1.05-1.64) and highly sensitive responders (HR = 2.66; 95% CI, 1.69-4.19).
During the same period, edoxaban reduced bleeding in sensitive and highly sensitive responders more than in normal responders (60-mg edoxaban, P for interaction = .0066; 30-mg edoxaban, P for interaction = .0036).
After 90 days, bleeding risk decreased similarly with edoxaban and warfarin across genotypes.
“For clinicians who are considering using warfarin to anticoagulate their [patients] with atrial fibrillation, genotyping could identify close to 40% of patients in whom there is an early increased risk of over-anticoagulation and bleeding,” Sabatine said. “This risk could be substantially mitigated by using a direct oral anticoagulant such as edoxaban instead of warfarin.”
Sabatine noted future research will focus on searching for additional genetic variants that impact a patient’s risk of bleeding and stroke. – by Allegra Tiver
For more information: Marc S. Sabatine, MD, MPH, can be reached at Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA; email: msabatine@partners.org.
Disclosure: Sabatine reports support from grants awarded to Brigham and Women’s Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, BRAHMS, Bristol-Myers Squibb/Sanofi-Aventis Joint Venture, Critical Diagnostics, Daiichi-Sankyo, diaDexus, Eisai, Genzyme, Gilead and GlaxoSmithKline. Please see the full study for a list of all other authors’ relevant financial disclosures.