Pharmacogenetic Testing Identifies Patients at Highest Bleeding Risk from Warfarin
Bruce Soloway, MD reviewing Mega JL et al. Lancet 2015 Mar 10. Wu AHB. Lancet 2015 Mar 10.
Such patients are good candidates for the newer anticoagulants.
Polymorphisms in two genes, CYP2C9 and VKORC1, account for about 40% of the variability in patients' warfarin responses. FDA-approved initial-dosing recommendations, based on these genetic parameters, increase time in the therapeutic range; however, because genotype-based dosing haven't been shown to improve clinical outcomes, these test are not reimbursed by Medicare. New oral anticoagulants, such as the recently licensed factor Xa inhibitor edoxaban (Savaysa), are as effective as warfarin, with more predictable pharmacodynamics and lower risk for bleeding.
In a previous trial, 21,105 adults with nonvalvular atrial fibrillation were randomized to receive warfarin (titrated to an international normalized ratio [INR] of 2.0–3.0) or daily edoxaban (30 or 60 mg) for a median 2.8 years (NEJM JW Gen Med Jan 15 2014 and N Engl J Med 2013 Nov 19; [e-pub]). CYP2CP and VKORC1 genotypes were determined for >14,000 of these patients, who then were stratified as normal, sensitive, or highly sensitive warfarin responders (62%, 35%, and 3%, respectively).
In the first 90 days of treatment, highly sensitive and sensitive responders spent a greater proportion of time overanticoagulated (18.3% and 8.4%, respectively) than did normal responders (2.2%), and they were at excess risk for bleeding complications (hazard ratios, 2.66 and 1.31). In highly sensitive and sensitive responders, bleeding risk was reduced more in those who received edoxaban (compared with warfarin) than it was in normal responders. After 90 days, the difference in bleeding risk between edoxaban and warfarin was similar in all genotype groups.
CITATION(S):
Mega JL et al. Genetics and the clinical response to warfarin and edoxaban: Findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015 Mar 10; [e-pub].
Wu AHB.Pharmacogenomic testing and response to warfarin. Lancet 2015 Mar 10; [e-pub].
