Warfarin Pharmacogenetics

Abstract

Warfarin has been in clinical use for nearly 60 years, and in 2010 there were over 25 million prescriptions for warfarin in the U.S. While warfarin is highly efficacious, it has a narrow therapeutic window to achieve desired anticoagulation without excess risk of bleeding. Anticoagulation status is monitored with the International Normalized Ratio (INR), where the most common target INR is 2 to 3. Not only does warfarin exhibit a narrow therapeutic index, but there can be 10 to 20-fold differences in the warfarin dose required to achieve target INR. Thus the early period after warfarin therapy initiation requires frequent INR monitoring to determine the proper dose for the patient, is often associated with multiple dose adjustments, and many patients experience prolonged periods of over- or underanticoagulation while the appropriate dose is identified. These challenges lead warfarin to be a leading cause of emergency room visits and hospitalizations for an adverse drug reaction, and lead to significant underuse of the drug in patients for whom it is strongly indicated, particularly those with atrial fibrillation. 1 The difficulties associated with warfarin use led to great enthusiasm for the new oral anticoagulants. Dabigatran and rivaroxaban were approved in the last 18 months, yet they have made only a small dent in the market share for oral anticoagulants, with warfarin remaining the predominant anticoagulant used clinically. For example, in the first year of use in the US, approximately 1.1 million dabigratran prescriptions were dispensed, in contrast to the 25 million per year for warfarin. 2 Reasons for the lack of uptake may include recent concerns about excess bleeding risk with dabigatran, 2 lack of reversibility of the anticoagulation, twice daily dosing, challenges with dosing in renally impaired patients, bothersome adverse effects (particularly gastrointestinal adverse effects with dabigatran), cost, among others. Overall, these new agents have not been widely embraced in the manner anticipated, suggesting that warfarin will remain the mainstay of oral anticoagulant therapy for the foreseeable future. Thus there remains a need to identify ways to more safely and effectively utilize warfarin. That genetic polymorphisms might influence the variability in warfarin dose requirements was first recognized in 1999, and since then there has been a vast body of literature