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

Li C, Schwarz UI, Ritchie MD, Roden DM, Stein CM, Kurnik D
Blood. 2009 113 (17): 3925-30

PMID: 19074728 · PMCID: PMC2673121 · DOI:10.1182/blood-2008-09-176859

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.

MeSH Terms (14)

Aryl Hydrocarbon Hydroxylases Cytochrome P-450 CYP2C9 Dose-Response Relationship, Drug Female Genotype Humans International Normalized Ratio Male Middle Aged Mixed Function Oxygenases Substrate Specificity Treatment Outcome Vitamin K Epoxide Reductases Warfarin

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