Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy

Abstract

Genetic variants in CYP2C9 and VKORC1 strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1 genotypes 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 CYP2C9 and VKORC1 genotypes 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 (R(2)) from 0.05 to 0.42 and 0.19, respectively (full model, R(2) = 0.46). For first stable warfarin dose, adding either early INRs or genotypes to the baseline model increased the R(2) from 0.08 to 0.32 and 0.27, respectively (full model, R(2) = 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 CYP2C9 and VKORC1 genotypes during warfarin initiation is captured by the early INR response.

Figures

Figure 1

Comparison of goodness of fit (R2) among 4 models for each of the 3 outcome variables. (A) Time to INR ≥ the lower limit of therapeutic range. (B) Time to INR > 4. (C) Early stable warfarin dose. In each panel, the first bar (□) represents the baseline model (including age, ethnicity, sex, amiodarone use, target INR, and cumulative warfarin dose); second bar (), the baseline model + VKORC1 / CYP2C9 genotypes; the third bar (), the baseline model + early INR values; fourth bar (■), the full model. The difference between the last 2 bars (■ and ) in each panel represents the contribution of genotypes after adjustment for baseline covariates and INRearly.