Couma-Gen - Couma-Gen
The goal of the trial was to evaluate the ability to maintain optimal warfarin dosing with standard dosing regimen compared with a genotype-guided warfarin dosing regimen among an array of patients requiring oral anticoagulation.
Patients Enrolled: 206
Mean Follow Up: Mean 46 days
Mean Patient Age: Mean age 61 years
Starting chronic outpatient warfarin therapy with a target INR of 2-3 for one of the following reasons: atrial fibrillation; emergency treatment of clotting of veins and pulmonary embolism; hospitalized for ≥1 month after orthopedic surgery; or heart failure.
Rifampin within 3 weeks; co-morbidities precluding standard warfarin dosing
Percent out-of-range (OOR) INRs
Patients were randomized in a double-blind manner to standard dosing warfarin regemin (n = 99) or genotype-guided warfarin dosing regimen, with the dose initiation and management algorithm based on the results of the genotyping (n = 101). The personalized management regimen was based on pharmacogenetic variants CYP2C9 and VKORC1, as well as clinical characteristics of age, weight and gender. INRs were evaluated at baseline, and day 3, 5, 8, 21, 60 and 90.
Indication for warfarin was preoperative orthopedic surgery in 60% of patients, deep vein thrombosis and/or pulmonary embolism in 24%, and atrial fibrillation in 14%. Mean number of INRs checked was 7.6 per patient. The average warfarin dose per week decreased as the number of variants increased, with the highest does in those with wild type variant (44.7 mg for wild type variant, 37.4 mg for 1 variant, 26.3 mg for 2 variants, 17.6 for 3 variants, and 8 mg for 4 variants; p < 0.001 for trend).
The initial to final stable dose change in patients with a wild type variant (n = 56) was significantly lower in the genotype-guided warfarin regimen compared with the standard dose regimen (-0.5 mg/wk vs. +13.6 mg/wk, p = 0.001), showed no difference in patients with 1 variant (n = 75) (1.9 mg/wk vs. 2.4 mg/wk, p = 0.85) and was significantly higher in patients with >1 variant (n = 44) (-0.6 mg/wk vs. -10 mg/wk, p < 0.001). The primary endpoint of percent out-of-range INRs did not differ between the randomized groups (30.7% for the genotype-guided warfarin regimen vs. 33.1% for the standard dose regimen, p = 0.47). In a subgroup analysis, the percent out-of-range INRs were less frequent in the genotype-guided warfarin group than the standard group among patients with either wild type or multiple variants (29.3% vs. 39.1%, p = 0.03) but the results went the opposite direction in patients with a single variant (33.6%vs. 27%, p = 0.14). There were fewer dose changes per patient in the genotype-guided warfarin group than the standard group (mean 3.0 vs. 3.6, p = 0.035). There was no significant difference in the frequency of INR ≥4 between groups (34 vs. 42). INRs ≥4 were more common in multiple variant allele carriers (46% vs. 29%, p = 0.029 in the pooled population).
Among patients requiring oral anticoagulation, use of a genotype-guided warfarin dosing regimen was not associated with a difference in the percentage of out of range INRs compared with standard warfarin dosing. However, a reduction in out of range INRs was observed with genotype-guided warfarin dosing among patients with either wild type or multiple variants.
Warfarin has a wide interpatient variability, which can result in excessive dosing within an individual patient when only guided by INR. Half of the dose variability has been shown to be due to variants CYP2C9 and VKORC1 and age, weight and gender. While the overall primary endpoint of the trial was negative, benefits were observed in those with either wild type or multiple variants, suggesting targeted application of pharmacogenetic testing may be warranted. Patients who are wild type carriers require higher than average doses while carriers of multiple variant alleles require a lower dose on average. The FDA recently changed the labeling of warfarin to include the genetic impact of its dosing.
Anderson et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116:epub before print.
Presented by Dr. Jeffrey L. Anderson at the American Heart Association Annual Scientific Session, Orlando, FL, November 2007.
Keywords: Blood Coagulation, Pulmonary Embolism, Warfarin, Heart Failure, Venous Thrombosis, Orthopedics, Genotype, Pharmacogenetics, Emergency Treatment
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