The Role of Pharmacogenomics in the Management of Traditional and Novel Oral Anticoagulants

Abstract

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 inter-patient variability in anticoagulant effects. Over the past decade, there has been substantial progress in our understanding of genetic contributions to variable warfarin response, particularly in regard to warfarin dose requirements. The genes encoding for cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 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 Americans compared to other racial groups, but this is the focus of on-going research. Several warfarin pharmacogenetic dosing algorithms and FDA-cleared genotyping tests are available for clinical use. Clinical trials are on-going 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. Currently, there is a lack of pharmacogenetic data with the newly approved oral anticoagulant, dabigatran, and with other oral anticoagulants in the research and development pipeline.