Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin

TLDR

Initiation of warfarin therapy using trial‑and‑error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the validation cohort, the pharmacogenetic‑dosing algorithm was prospectively applied to patients starting warfarin, and a nonprofit website (http://www.WarfarinDosing.org) was created to facilitate its use. The algorithm identified VKORC1, CYP2C9 variants, BSA, age, INR target, amiodarone, smoking, race, and thrombosis as independent predictors, explaining 53–54% of dose variability versus 17–22% for a clinical model (P < 0.001). Clinical Pharmacology & Therapeutics (2008); 84, 3, 326–331 doi:10.1038/clpt.2008.10.

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 m2), 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. Clinical Pharmacology & Therapeutics (2008); 84, 3, 326–331 doi:10.1038/clpt.2008.10