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 warfarin-dose requirement. 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.
This study is one of three large RCTs published in the New England Journal of Medicine testing the hypothesis that genotyping of CYP2C9 and VKORC1 in patients initiating anticoagulation with vitamin K antagonists lead to more precise dosing. The studies varied in organisation and structure but all examined the initiation of therapy with vitamin K antagonists, used the same primary end point, and came to similar conclusions in that 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. However, the more important end point, the rate of bleeding and thrombotic complications, was beyond the power design of these trials.
An accompanying editorial suggests that perhaps the focus should be on improvements in the infrastructure for INR testing, including better communication among the laboratory, clinician and the patient; the use of formal algorithms for dosing without concern for genotype; improved patient adherence to therapy and possibly more responsibility for dosing being assumed by the patient; and also increased diligence by healthcare personnel in testing, monitoring, and dosing on the basis of the INR, given the high percentage of medical mismanagement associated with these agents.