Do Pharmacogenetics Have a Role in the Dosing of Vitamin K Antagonists?

Bruce Furie, M.D.

November 19, 2013DOI: 10.1056/NEJMe1313682

Article
References: Vitamin K plays a single role in human biology — as a cofactor for the synthesis of γ-carboxyglutamic acid. This amino acid is a component of at least 14 proteins, including 4 blood-coagulation proteins (factor IX, factor VII, factor X, and prothrombin) and 2 regulatory proteins (protein C and protein S), and it is critical for the physiologic function of these proteins. Humans do not synthesize vitamin K. Rather, we ingest it in our diet. The vitamin K quinone is reduced to the semiquinone, and this reduced vitamin K is a cofactor that is required for the conversion of specific glutamic-acid residues on the vitamin K–dependent proteins to γ-carboxyglutamic acid by the vitamin K–dependent carboxylase. Vitamin K epoxide, a product of this reaction, is converted back to the vitamin K quinone by the vitamin K epoxide reductase, otherwise known as VKOR. This vitamin K cycle can be broken, and a state of vitamin K deficiency at the carboxylase level effected, by the inhibition of VKOR by vitamin K antagonists, including warfarin. Warfarin and its analogues have been used as oral anticoagulant agents for more than 50 years. By targeting VKOR, the post-translational modification of the vitamin K–dependent blood-coagulation proteins is impaired. A reduced functional level of factor IX, factor VII, factor X, and prothrombin leads to delayed blood coagulation. This inhibition is monitored in the clinical laboratory with the use of the prothrombin time and is corrected for the varied potencies of tissue factor used in the assay by means of a calibration factor, yielding the international normalized ratio (INR). The intensity of therapy with vitamin K antagonists varies according to the indication for anticoagulation, and the INR is adjusted by varying the dose of the vitamin K antagonist. The goal of therapy is to keep the INR in the therapeutic range, since patients with an INR that is subtherapeutic are at increased risk for thrombosis and patients with an INR that is supratherapeutic are at increased risk for bleeding. Keeping the INR within the therapeutic range can be challenging. Warfarin binds to albumin, and only about 3% is free and pharmacologically active. A number of medications can displace warfarin, leading to its increased activity and subsequent increased rate of degradation. Diet, specifically the intake of foods containing vitamin K, can offset the effect of the daily dose of the vitamin K antagonist. Age, weight, and sex are other factors that influence the dose. In addition, the catabolic rate of the vitamin K antagonists appears to have a genetic basis. Genetic polymorphisms in the cytochrome P-450 enzyme CYP2C9 include two variants, C144R in CYP2C9*2 and I359L in CYP2C9*3. These variants have substantially reduced activity, as compared with CYP2C9*1, and are associated with reduced clearance and thus a decrease in the warfarin-dose requirement.1 Similarly, mutations in VKOR, the target of the vitamin K antagonists, lead to various degrees of warfarin resistance. Polymorphisms in VKORC1, the gene encoding this protein, lead to variability in the sensitivity to vitamin K antagonists.2 Might genotyping of CYP2C9 and VKORC1 in patients initiating anticoagulant therapy with vitamin K antagonists lead to more precise dosing and, by extrapolation, reduce the risk of thrombotic and bleeding complications? Numerous anecdotal, observational, and small clinical trials have been published on the use of this information, with many authorities promoting this approach. The results of three large, randomized clinical trials that test this hypothesis have now been published in the Journal.3-5 Although they vary in organization and structure (duration of study, vitamin K antagonist used, double-blind vs. single-blind design, racial characteristics of the study group, and method for dosing in the control group), they are also similar (large, multicenter, randomized studies; primary end point of the time in the therapeutic range; genotyping of CYP2C9 and VKORC1; and the use of the INR target as a biomarker for the risk of bleeding and thrombosis). Importantly, these trials all examine the initiation of therapy with vitamin K antagonists and use as a primary end point the percentage of time that a patient is within the therapeutic range during the initial phase of treatment. The more important end point, the rate of bleeding and thrombotic complications, was beyond the power design of these trials. Despite design differences, the conclusions of the three studies are similar. In an initial period of 4 weeks of anticoagulation with warfarin, the randomized, double-blind study by Kimmel et al.3 showed results in the study group that included pharmacogenetic information to supplement clinically guided dosing that were nearly identical to the results in the group that used clinically guided dosing alone (percentage of time in the therapeutic INR range, 45.2% vs. 45.4%). In the 12 weeks after the initiation of anticoagulation with acenocoumarol and phenprocoumon, Verhoef et al.4 used a new point-of-care device and found that a genotype-guided algorithm that included clinical variables yielded results that were similar to those achieved with an algorithm based on clinical variables (61.6% vs. 60.2% at 12 weeks). Pirmohamed et al.5 compared genotype-guided dosing of warfarin, also using a point-of-care device, with standard dosing methods used in clinical practice. The results at 12 weeks were 67.4% and 60.3%, which are significantly different albeit similar, indicating a modest improvement. What can we conclude from these trials? First, we must recall that these trials address the process of the initiation of anticoagulant therapy — during the very first week — and not an approach to intermediate or long-term anticoagulation. Second, it would appear that, despite the variation in trial design, these trials indicate that this pharmacogenetic testing has either no usefulness in the initial dosing of vitamin K antagonists or, at best, marginal usefulness, given the cost and effort required to perform this testing. Improved safety with the use of vitamin K antagonists is nonetheless an important goal, and it remains so, despite the introduction of new oral anticoagulants. Perhaps we should concentrate on improvements in the infrastructure for INR testing, including better communication among the laboratory, the physician, and the patient (e.g., through social media); in the use of formal algorithms for dosing, without concern for genotype; in patient adherence to therapy and possibly more responsibility for dosing being assumed by the patient; and in increased diligence by medical and paramedical personnel in testing, monitoring, and dosing on the basis of the INR, given the high percentage of medical mismanagement associated with these anticoagulant agents.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org. This article was published on November 19, 2013, at NEJM.org.
Source Information
From Harvard Medical School and the Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center — both in Boston.