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Warfarin Dose Modification by Genotyping

Patients’ genotypes affect their responses to warfarin therapy.

Decisions about initial dosing of warfarin are influenced by patient age, concurrent medications, diet, and comorbid diseases. Despite dose modifications based on these considerations, many patients receive initial dosing that is too high or too low and can experience serious consequences, such as bleeding or new thrombi. During the past few years, researchers have reported that polymorphisms in the genes whose products interact with warfarin can have marked clinical effects. For example, vitamin K epoxide reductase C1 (VKORC1) is critical for the formation of functional clotting factors and is inhibited by warfarin, and cytochrome P-2C9 (CYP2C9) degrades warfarin.

To assess the effects of these genetic variations on warfarin management, investigators from Vanderbilt University School of Medicine genotyped 297 patients who were beginning warfarin therapy. Patients’ ages, sex, racial or ethnic backgrounds, indications for warfarin therapy, target international normalized ratio (INR) ranges, initial warfarin doses, and concomitant medications were noted at baseline. Subsequent INR values and warfarin doses, frequency of monitoring, and bleeding events were recorded for as long as 168 days (median, 43 days).

Target INRs for most patients were 2 to 3, and the average warfarin dose was 4.8±0.8 mg. About 12% of white patients and no black patients were homozygous for polymorphisms in VKORC1 (VKORC1-A). INRs rose into the therapeutic range 2.4x faster and became excessively high (>4) 2.5x times faster in VKORC1-A homozygotes than in non-A–haplotype patients (P=0.02 and P=0.003, respectively). INRs were above the therapeutic range for a greater percentage of time in VKORC1-A homozygotes (18.8% vs. 9.1%; P=0.02). VKORC1-A heterozygotes also had higher risk for having INRs >4 than did non-A–haplotype patients. Among all patients, 12% and 4.8% had polymorphisms for CYP2C9 type *2 and type *3, respectively. Whereas CYP2C9 genotype did not affect the time needed for INRs to rise into the therapeutic range, patients with *2 or *3 alleles did reach INRs >4 more rapidly than did those without CYP2C9 mutations (P=0.03); CYP2C9 mutations also were associated with more time above the therapeutic INR range, although this did not reach significance (P=0.09). Eight major and five minor bleeding events occurred, but these were not limited to patients with the genetic polymorphisms and were not significantly higher in any one group.

Comment: Recently, the FDA recommended that the labeling of warfarin include a statement about initial lower doses for patients with genetic variations in the CYP2C9 or the VKORC1 gene. The results of the present study confirm that people with these mutations are more sensitive to the effects of warfarin and that VKORC1 mutations have a greater effect than do mutations in CYP2C9. However, whether lowering warfarin doses will lower the incidence of bleeding is unknown and will be difficult to demonstrate, because even people whose INRs are within the therapeutic range occasionally bleed. The National Heart, Lung, and Blood Institute currently is supporting a large, multicenter, double-blind, randomized trial of genotype-guided warfarin therapy designed to determine whether this strategy improves patient outcomes.

— David Green, MD, PhD

Published in Journal Watch Oncology and Hematology April 1, 2008

Citation(s):

Schwarz UI et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008 Mar 6; 358:999.

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