Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin
P. Lenzini, J. A. Johnson, Howard L. McLeod, M. J. Rieder, Brian F. Gage, L. Grosso, D. L. Veenstra, C. Eby, R. J. Glynn, D. Voora, T. Langaee, G. Grice, L. E. Farnett, Christina L. Aquilante, S. Marsh, P. M. Ridker, P. E. Milligan, A. E. Rettie, E. Deych, A. Barrett
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.