Genetic analysis can point to patients who are at increased risk of suffering from bleeding during treatment with the blood thinner warfarin, a study published in The Lancet
on 10 March 2015 confirms.
Based on the variation and combination of two genes, researchers identified patients who were sensitive or highly sensitive to warfarin. These two groups of patients had an increased frequency of overt bleeding in the first three months of treatment with warfarin and required a lower dose to achieve a therapeutic effect.
“In cases where there is a plan to use warfarin, genotyping could identify close to 40% of patients in whom there is an early increased risk of over-anticoagulation and bleeding with use of standard dosing practices,” says lead study author Jessica Mega, associate professor of medicine in cardiovascular medicine at Brigham and Women’s hospital, Boston.
Warfarin is the most widely used anticoagulant for the treatment or prevention of blood clots. Between individuals, the dose of warfarin that will produce the desired level of anticoagulation can vary greatly. This variability means that patients taking warfarin must be monitored with regular blood testing to get the dose right based on each person’s response.
Previous studies identified two genetic variants that influence how sensitive a person is to warfarin and the US Food and Drug Administration advises that genetic testing can assist in deciding the dose. But up until now it has not been known if these variants affected the bleeding risk associated with warfarin.
In a large randomised controlled trial that was designed to compare warfarin with the new oral anticoagulant edoxaban (n=21,105), a subset of patients were included in a genetic analysis (14,348). Researchers identified patient’s variant of the genes CYP2C9 and VKORC1, which respectively encode an enzyme responsible for the metabolism of the S-warfarin isomer and the vitamin K epoxide reductase, the molecular target of warfarin. Based on a patient’s version and combination of these genes, they were classified as normal responders (61.7%), sensitive responders (35.4%) and highly sensitive responders (2.9%).
Of the 4,833 patients assigned to warfarin, in the first 90 days of treatment the highly sensitive responders had more than two and half times the risk of overt bleeding as normal responders (hazard ratio [HR] 2.66, 95% confidence interval 1.69–4.19; P<0.0001). Sensitive responders also had an elevated risk (HR 1.31, 95% CI 1.05–1.64; P=0.0179). However, after three months the risk levelled out between the groups. As expected, the CYP2C9 and VKORC1 genes were not associated with an increased risk of bleeding from edoxaban.
“Compared with normal responders, the sensitive and highly sensitive responders required lower doses of warfarin to achieve a therapeutic [effect],” say the researchers. “As a result, edoxaban compared with warfarin reduced bleeding more so in sensitive and highly sensitive responders than in normal responders in this early period.” In the original study, edoxaban was found to be non-inferior to warfarin at preventing stroke or pulmonary embolism.
The studies were funded by the manufacturer of edoxaban, Daiicho Sankyo.
 Mega JL, Walker JR, Ruff CT et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. The Lancet 2015. doi:10.1016/S0140-6736(14)61994-2.