Warfarin Pharmacogenetics
Significant interest in the pharmacogenetics of warfarin therapy has been triggered with the recent package insert update that highlights the potential role of pharmacogenetics in improving the safety and effectiveness of warfarin. We review the evidence of the influence of the two key genes of interest, the cytochrome P450 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 gene, VKORC1, on warfarin response and discuss the implications of current knowledge for clinical practice. The influence of CYP2C9 and VKORC1 genotypes on warfarin dose requirements has been consistently demonstrated in diverse racial and ethnic patient groups in observational studies and randomized clinical trials. Dosing algorithms have been developed that incorporate clinical, demographic, and genetic information to help select a warfarin starting dose. Furthermore, CYP2C9 variant genotypes have been associated with a significantly increased risk of serious bleeding events. However, evidence to date from prospective, controlled studies has not demonstrated an added benefit of incorporating genotype-guided therapy in improving anticoagulation control or in preventing or reducing the risk of hemorrhagic or thromboembolic complications. Research efforts designed to evaluate the effectiveness of genotype-guided therapy in improving outcomes are under way. However, the routine use of CYP2C9 and VKORC1 genotyping in the general patient population who begin warfarin therapy is not supported by evidence currently available.

Ever since its discovery 66 years ago and its commercial introduction in 1954, warfarin has remained the mainstay of oral anticoagulant therapy. Despite its proven efficacy, and refine-ments and standardization in the monitoring of warfarin therapy, underutilization of this drug is widespread.

Clearly, the capricious nature of the response to any given dose of warfarin demands sophis-ticated and resource-intensive methods to determine the warfarin dose and maintain therapeutic anticoagulation. The intricacies of warfarin metabolism, the complexities of the coagulation system, and the multitude of factors affecting level of anticoagulation do not make this a straightforward task. Despite concerted efforts, development of dosing nomograms, and institution of specialized anticoagulation clinics, management of anticoagulation is far from optimal.

The evolution of our understanding of warfarin pharmacodynamics and pharmacokinetics and the recognition of genetic regulation of warfarin response have stimulated efforts aimed at quantifying this influence. Although investi-gations have identified the influence of several genes on warfarin response, the bulk of the evidence supports the influence of polymorphisms in two genes: the cytochrome P450 (CYP) 2C9 gene, CYP2C9, and the vitamin K epoxide reductase complex 1 (VKORC1) gene, VKORC1. This evidence provided the basis for the recent update to the warfarin package insert (http://www.fda.gov/cder/drug/infopage/warfarin/default.htm) mandated by the United States Food and Drug Administration (FDA).