Genetically defined warfarin sensitivity confirmed in study
Genetic polymorphisms in CYP2C9 and VKORC1 affect the pharmacology and safety of warfarin, and patients with venous thromboembolism (VTE) who carry the said polymorphisms spend more time overanticoagulated, require a lower drug dose and are at increased bleeding risk with the drug, according to a pharmacogenetic subanalysis of the Hokusai VTE trial.
The results of the current analysis extend that of the previous analysis of ENGAGE AF-TIMI 48*—a large study comparing edoxaban with warfarin for the prevention of stroke and systemic embolic events in patients with atrial fibrillation—demonstrating that patients on warfarin who were identified as sensitive or highly sensitive responders, based on CYP2C9 and VKORC1 genotypes, had higher warfarin-associated bleeding rates and spent more time overanticoagulated compared with normal responders. [Lancet 2015;385:2280–7]
In the present investigation using data from Hokusai VTE, a randomized noninferiority trial evaluating the safety and efficacy of edoxaban vs warfarin in VTE patients initially treated with heparin, the authors confirmed that patients with genetically defined warfarin sensitivity had indeed heightened risk of bleeding while receiving anticoagulant treatment with the vitamin K antagonist (VKA). [Heart 2017;doi:10.1136/heartjnl-2016-310901]
The risk of major bleeding was higher by 1.38 fold (95 percent CI, 1.11 to 1.71) among sensitive warfarin responders and by 1.79 fold (1.09 to 2.99) among highly sensitive warfarin responders in comparison with normal responders (p=0.0035 and p=0.0252). The two warfarin-sensitive patient groups also had an early discontinuation of heparin therapy (p<0.001), a decreased final weekly warfarin dose (p<0.001) and spent more time overanticoagulated (p<0.001).
The analysis included 3,956 of 8,292 (47.7 percent) adult patients in Hokusai VTE. Among the 1,978 randomized to warfarin, 63.04 percent were normal responders, 34.12 percent were sensitive responders and 2.84 percent were highly sensitive responders.
Despite the presence of limitations that could restrict the generalizability of the results, the data presented in the current analysis have the potential to influence the practical management of warfarin therapy for the treatment of VTE in patients who are sensitive or highly sensitive responders to the VKA, the authors said.
“Although the Food and Drug Administration recommends dose adjustments for warfarin in patients with warfarin-sensitive genotypes, in clinical practice, CYP2C9 and VKORC1 genotypes are not routinely assessed, and it has never been demonstrated that genotyping can reduce the risk of bleeding,” they pointed out.
Thus, further investigations into the potentially beneficial effects of genotyping prior to prescribing anticoagulation therapy in patients with AF or VTE are warranted, the authors said. “Genotype-informed dosing may be especially beneficial in those patients who are initiating therapy, as an individual’s genetic sensitivity could interact with existing clinical factors to exacerbate overall bleeding risk.”
*Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48