Genotype-Guided Dosing of Warfarin

Vitamin K antagonists (VKAs)2 have been used to treat thromboembolic disease for over 60 years, and they continue to be the most commonly prescribed anticoagulants worldwide. However, VKAs such as warfarin have a narrow therapeutic index, and the mean daily dose of warfarin varies widely from patient to patient. Underdosing can leave patients undertreated for their thromboembolic diseases; overdosing can result in bleeding. As such, patients are forced to undergo frequent blood testing, and dose adjustments are made on the basis of the resulting international normalized ratio (INR) values. To achieve a therapeutic INR, which is defined as a value between 2.0 and 3.0 for conditions such as atrial fibrillation and venous thromboembolism, the daily dosing of warfarin can range over 20-fold, from <1 to over 20 mg (1).The variability in warfarin dosing depends on several factors, including demographics, the environment, and genetics. Specifically, variants in the genes that encode an enzyme responsible for the metabolism of warfarin [cytochrome P450, family 2, subfamily C, polypeptide 9 ( CYP2C9 )3] and the molecular target of warfarin [vitamin K epoxide reductase complex, subunit 1 ( VKORC1 )] influence warfarin dosing. The Food and Drug Administration has noted these findings, and the warfarin label recommends that if a patient's genotype is known, then this information should be considered when initiating therapy. Nonetheless, debate continues about the utility of routine genetic testing in this setting, a topic that has been addressed by several studies, including the EUropean Pharmacogenetics of AntiCoagulant Therapy (EU-PACT) and Clarification of Optimal Anticoagulation through Genetics (COAG) trials (2, 3).The EU-PACT trial enrolled 455 patients initiating warfarin treatment, of whom approximately 72% had atrial fibrillation and 28% venous thromboembolism. In this open-label study, patients were randomized to either warfarin dosing based on an algorithm that included …