Pharmacogenetics in the Management of Coumarin Anticoagulant Therapy: The Way Forward or an Expensive Diversion?

W arfarin and related coumarin-based anticoagulants are the mainstay of pharmacological management for the long-term prevention of thromboembolism. It is estimated that over 1 million residents in the United Kingdom take warfarin; in excess of 20 million prescriptions for the anticoagulant are dispensed each year in the United States of America. Despite recent advances in the development of novel, alternative, oral antithrombotics it is likely that coumarins will be used widely for at least the next decade. Coumarins inhibit the posttranslational carboxylation of glutamate residues on proteins dependent on vitamin K, including coagulation factors II, VII, IX, and X. This carboxylation process is essential for their biological activity and requires the reduced form of vitamin K. Coumarins inhibit vitamin K epoxide reductase, the enzyme responsible for the recycling of vitamin K. The vitamin K epoxide reductase complex 1 (VKORC1) gene has been identifi ed only recently [1] and this has permitted study of the effect of polymorphisms on sensitivity to coumarins. The metabolism of warfarin depends principally upon the hepatic microsomal enzyme P450 2C9 (Cyp2C9), which catalyses degradation of the more potent S enantiomer to inactive metabolites. Coumarins have very few side effects. However, by far the most common unwanted effect, abnormal bleeding, may be lethal. Overall, the rate of life-threatening bleeding is around two per 100 patient years and more minor bleeding is common [2]. This is despite the widespread adoption of the International Normalised Ratio (INR) as the method for standardisation of the prothrombin time, the coagulation assay used to measure the anticoagulant effect of warfarin. For most clinical indications, dosing is aimed at achieving a target INR of 2.5 (range 2.0–3.0), which represents a level of anticoagulation associated with an optimal relationship between antithrombotic effi cacy and bleeding risk. However, even with the best available management, individual patients on warfarin are within the target INR range for only 50%–70% of the time, on average. Although the reasons for this imprecision of dose response are often not immediately apparent, important contributing factors include co-medication with interacting drugs [3] and incomplete adherence. In addition, the dietary content of vitamin K has a measurable effect on the INR in patients taking warfarin [4]. In addition to this variation in dose-response within individuals, the inter-individual dose range required to achieve and maintain the target INR is exceptionally wide—for example, in the case of warfarin, a maintenance dose of 1 to >10 …