Abstract and Introduction
Warfarin is the most commonly prescribed oral anticoagulant. However, it remains a difficult drug to manage mostly because of its narrow therapeutic index and wide interpatient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly with regard to warfarin dose requirements. The genes encoding for cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are the major genetic determinants of warfarin pharmacokinetics and pharmacodynamics, respectively. Numerous studies have demonstrated significant contributions of these genes to warfarin dose requirements. The CYP2C9 gene has also been associated with bleeding risk with warfarin. The CYP4F2 gene influences vitamin K availability and makes minor contributions to warfarin dose requirements. Less is known about genes influencing warfarin response in African-American patients compared with other racial groups, but this is the focus of ongoing research. Several warfarin pharmacogenetic dosing algorithms and United States Food and Drug Administration–cleared genotyping tests are available for clinical use. Clinical trials are ongoing to determine the clinical utility and cost-effectiveness of genotype-guided warfarin dosing. Results from these trials will likely influence clinical uptake and third party payer reimbursement for genotype-guided warfarin therapy. There is still a lack of pharmacogenetic data for the newly approved oral anticoagulants, dabigatran and rivaroxaban, and with other oral anticoagulants in the research and development pipeline. These data, once known, could be of great importance as routine monitoring parameters for these agents are not available.
Warfarin is the most commonly prescribed oral anticoagulant and is widely used for the prevention of thromboembolism or stroke in patients with previous thromboembolism, recent orthopedic surgery, atrial fibrillation, heart valve replacement, or other diseases that increase the risk for thrombosis. Dabigatran and rivaroxaban are the only warfarin competitors on the market in the United States. However, dabigatran is approved only for the prevention of stroke in patients with atrial fibrillation. Rivaroxaban is approved for prophylaxis of venous thromboembolism after orthopedic surgery. Little is known about the pharmacogenetics of dabigatran, rivaroxaban, or other oral anticoagulants in the drug development pipeline. Thus, most of this review focuses on warfarin, with a brief discussion of potentially important genes related to dabigatran.
One of the primary challenges with warfarin therapy is determining the dosing regimen necessary to achieve therapeutic anticoagulation for an individual patient. Dose requirements vary as much as 20-fold among patients. Failure to achieve optimal anticoagulation significantly increases the risk for adverse sequelae.[2,3] Clinical factors, including age, body size, diet, and drugs that interfere with warfarin metabolism, are well known to influence warfarin dose requirements. There is also recent evidence that decreased renal function reduces warfarin dose requirements and increases the risk for warfarin-related bleeding.[5,6] Dose requirements also vary significantly by race, with higher mean maintenance doses in African-Americans and lower mean doses in Asians compared with doses in Caucasians. Whereas clinical factors are obviously important considerations when dosing warfarin, factors such as age, body size, and interacting drugs account for only 15–20% of the overall variability in warfarin dose.[1,7,8] It is now widely accepted that an individual's genotype significantly influences the warfarin dose required to attain optimal anticoagulation.
Pharmacotherapy. 2011;31(12):1192-1207. © 2011 Pharmacotherapy Publications