Relative contribution of CYP2C9and VKORC1genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy

Genetic variants in CYP2C9and VKORC1strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1genotypes provide information about warfarin sensitivity additional to that provided by early INR responses. In 214 patients starting warfarin with INR-guided dose adjustments, we determined whether CYP2C9and VKORC1genotypes were associated with early measures of warfarin sensitivity (time to INR ≥ lower limit of therapeutic range; time to INR > 4; and first stable warfarin dose) after adjusting for early (days 4-6) and week 1 (days 7-9) INR values. Early INRs were associated with all outcomes (all P< .001) and were more informative than genotypes. For time to INR more than or equal to the lower limit of therapeutic range, adding either early INRs or genotypes to a baseline model (clinical variables only) increased the goodness-of-fit (R2) from 0.05 to 0.42 and 0.19, respectively (full model, R2= 0.46). For first stable warfarin dose, adding either early INRs or genotypes to the baseline model increased the R2from 0.08 to 0.32 and 0.27, respectively (full model, R2= 0.40). After inclusion of week 1 INRs, CYP2C9(P= .08) and VKORC1(P= .30) were not associated with stable warfarin dose. Thus, much of the information provided by CYP2C9and VKORC1genotypes during warfarin initiation is captured by the early INR response.