Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin by Gage B F, Eby C, Johnson J A, Deych E, Rieder M J, Ridker P M, Milligan P E, Grice G, Lenzini P, Rettie A E, Aquilante C L, Grosso L, Marsh S, Langaee T, Farnett L E, Voora D, Veenstra D L, Glynn R J, Barrett A, McLeod H L in Clinical pharmacology and therapeutics (2008).

[PMID: 18305455] PubMed

Abstract

Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.

[ hide abstract ]

Discussed In Paper

Loading...

Variant Annotations

Sign in to see variant annotations.

Rx Annotations

Rx Annotation for warfarin, CYP2C9 and VKORC1

Main findings

The authors develop and validate a pharmacogenetic algorithm for warfarin dosing. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%).

Dosing protocol

Estimated daily warfarin dose (mg/day) = Exp (0.9751 - 0.3238 x VKOR_1639 + 0.4317 x BSA - 0.4008 x CYP2C9*3 - 0.00745 x Age - 0.2066 x CYP2C9*2 + 0.2029 x Target INR - 0.2538 x Amiodarone + 0.0922 x Smokes -0.0901 x AA_Race + 0.0664 x Prior_DVT_PE) where exp is the exponential function, BSA is in m2, the SNPs are coded 0 if absent, 1 if heterozygous, and 2 if homozygous, and race is coded as 1 if African American and 0 otherwise.

Additional findings

This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation (N=1015) and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001).

Additional information

  • Ethnicity: Mixed
  • Study size: Derivation cohort: 1015; validation cohort: 292