New research offers more evidence for the connection between CYP2C9 and VKORC1 variants and increased bleeding risk in patients taking warfarin.
A large-scale study published in the March edition of the Lancet found that atrial fibrillation patients whose CYP2C9 and VKORC1 genetic variations made them highly sensitive to warfarin were nearly three times more likely to experience bleeding than those with normal sensitivity. Those who were still sensitive to warfarin, but less seriously so, were 1.3 times more likely to experience bleeding compared to normally sensitive patients while initiating therapy with the drug.
“…We showed clear and significant associations between CYP2C9 and VKORC1 genotypes and bleeding outcomes with warfarin,” study authors Mega et al. wrote.
Variations in the genes CYP2C9 and VKORC1 are both involved in how individuals respond to warfarin and account for about 40 percent of response variability, the study authors reported. In August 2007 and 2010, the U.S. Food and Drug Administration revised the drug labeling for Coumadin, a brand name of warfarin, to add that patients with certain CYP2C9 and VKORC1 variants may need non-standard warfarin doses at the beginning of treatment.
Mega et al. genotyped more than 14,000 patients who took part in the study—almost 5,000 of whom were assigned to be on warfarin—and followed the patients for three years.
The authors compared clinical outcomes of patients on warfarin to those on edoxaban (Savaysa®), a newly approved anticoagulant medication that does not rely on the same genetically variable pathways as warfarin. Overall, the researchers found edoxaban treatment was associated with reduced rates of bleeding, including potentially life-threatening types of bleeding.
“This genetic analysis revealed that during the early time period, the reduction in bleeding seen with edoxaban versus warfarin was more pronounced in sensitive and highly sensitive responders than normal responders,” the authors concluded.
Despite increasingly clear evidence showing varied warfarin dosing levels are needed for patients with variations in the CYP2C9 and VKORC1 genes, patient genotyping to guide warfarin therapy has not become the standard of care. Though the study itself stops short of calling for genotyping before patients begin anticoagulant treatment, study lead author Dr. Jessica Mega told GenomeWeb the research could change clinical practice in favor of adopting pharmacogenetic testing to advise best anticoagulant options for patients starting such treatment.
This study gels with the results of a September 2014 meta-analysis that found the pharmacogenetic-guided dosing of warfarin and other similar medications (collectively referred to as VKAs) reduced major bleeding episodes by 52.5 percent.