Abstract 2378: Genetics of the Initial Anticoagulant Response to Warfarin - a Prospective Study
Objective Several genetic variants contribute to inter-individual differences in steady state warfarin dose requirements; however, their role in determining the time course of warfarin effect is less clear.
Methods A prospective follow up study was conducted in patients starting warfarin therapy managed in anticoagulation clinics at Vanderbilt University. We determined cytochrome P450 2C9 (CYP2C9) genotype (CYP2C9*2; CYP2C9*3) and two major haplotype groups of the vitamin K epoxide reductase gene (VKORC1). Since 96%–99% of Caucasians belong to VKORC1 haplotype group A and B (Rieder et al. N Engl J Med 2005), carriers not assigned to A were defined as NonA. Demographic variables, INR, dose, bleeding events, interacting drugs and co-morbidity were recorded. Primary analysis variables were
time to therapeutic INR (international normalized ratio),
time to first above-range INR (INR > 4),
INR response over time, and
time outside the therapeutic INR range.
Results Analysis included 297 patients (61 years, 46% women, 90% European-Americans) with a mean follow up time of 66 ± 56 days and an average of 11 ± 6 INR measurements. VKORC1 genotypes were NonA/NonA 46%, NonA/A 43%, and A/A 11%. CYP2C9 genotypic frequencies were 69%, 27%, and 4% for *1/*1 (wildtype), *1/*2, *1/*3 and *2/*2, *3/*3, *2/*3, respectively. VKORC1 haplotype groups showed a significant difference in time to reaching their first therapeutic INR (p=0.002) with A/A patients reaching first therapeutic INR faster, as well as time to experiencing an above-range INR (p=0.007) with A/A patients being earlier than the other haplotype groups. Moreover, VKORC1 haplotype groups showed a significant difference in days with INR values above their therapeutic range (p = 0.03); patients with A/A haplotype had more days than the other two groups. By contrast, CYP2C9 genotype was not a significant predictor for these outcomes except CYP2C9*3 for time above therapeutic INR (p=0.014). VKORC1 haplotype was significantly associated with the anticoagulation response in the first two weeks of warfarin treatment, but not in weeks 3 and 4 as measured by mean daily and peak INR values.
Conclusions Initial variability of INR appears to be predominantly associated with VKORC1 rather than CYP2C9 genotype.