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

Chun Li, Ute I. Schwarz, Marylyn Deriggi Ritchie, Dan M. Roden, C. Michael Stein, Daniel Kurnik

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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 (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 R2 from 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 CYP2C9 and VKORC1 genotypes during warfarin initiation is captured by the early INR response.

Original languageEnglish (US)
Pages (from-to)3925-3930
Number of pages6
JournalBlood
Volume113
Issue number17
DOIs
StatePublished - Nov 17 2009

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International Normalized Ratio
Warfarin
Genotype
Therapeutics
Warfarin Sensitivity
Cytochrome P-450 CYP2C9

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Li, Chun ; Schwarz, Ute I. ; Ritchie, Marylyn Deriggi ; Roden, Dan M. ; Michael Stein, C. ; Kurnik, Daniel. / Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. In: Blood. 2009 ; Vol. 113, No. 17. pp. 3925-3930.
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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 (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 R2 from 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 CYP2C9 and VKORC1 genotypes during warfarin initiation is captured by the early INR response.",
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Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. / Li, Chun; Schwarz, Ute I.; Ritchie, Marylyn Deriggi; Roden, Dan M.; Michael Stein, C.; Kurnik, Daniel.

In: Blood, Vol. 113, No. 17, 17.11.2009, p. 3925-3930.

Research output: Contribution to journalArticle

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