K. Drozda,1 Y. Lee,1 S. R. Patel,1 J. Lee,1 O. Pugach,1 J. D. Duarte,1 E. A. Nutescu,1 L. H. Cavallari2; 1University of Illinois, Chicago, IL, 2University of Florida, Gainesville, FL

BACKGROUND: Achieving therapeutic anticoagulation quickly after warfarin initiation is important because the risks for complications are highest early in therapy. Genotype is associated with time to therapeutic INR (TTR) and risk for over-anticoagulation. We aimed to determine if genotype-guided warfarin dosing eliminates differences in TTR and over-anticoagulation during warfarin initiation.
METHODS: A total of 117 warfarin naïve patients were genotyped for VKORC1 -1639G>A and CYP2C9*2,*3,*5,*6,*11 and*14. TTR, defined as time to first therapeutic INR, rate of INR rise, and INRs ≥4 over the first 31 days of warfarin were compared by genotype. Survival analysis was performed to evaluate genotype differences in TTR.
RESULTS: In the initial 31 days, TTR (days) was similar in CYP2C9 variant carriers [5.0(3.0-7.0)] and non-carriers [6.0(4.0-11.0), p=0.151] but shorter with VKORC1 AA [4.0(2.0-6.0)] vs. GA/GG [6.0(4.0-11.0)] genotype (p=0.015). In the first 10 days of warfarin, the hazard of achieving therapeutic INR was 2.39 higher with VKORC1 AA vs. GA/GG genotype (p=0.005), but not different by CYP2C9 genotype. The rate of INR increase (unit/day) was higher with VKORC1 AA vs. GA/GG genotype (0.40±0.34 vs. 0.21±0.16, respectively, p=0.052), and strengthened after adjusting for age and body size (p=0.0002). The proportion of INRs ≥4 was similar between all genotype groups.
CONCLUSION: Our data suggest that genotype-guided dosing leads to similar TTR by CYP2C9 genotype and eliminates the genotype-associated risk for supra-therapeutic anticoagulation. Further dosing adjustments may be necessary to reduce TTR with VKORC1 GA or GG genotype.