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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1511-1515.
Prepublished online as a Blood First Edition Paper on March 26, 2007; DOI 10.1182/blood-2007-01-069609.
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Submitted January 22, 2007
Accepted February 26, 2007
Genetic-based dosing in orthopaedic patients beginning warfarin therapy
Eric Millican, Petra A Jacobsen-Lenzini, Paul E Milligan, Leonard Grosso, Charles Eby, Elena Deych, Gloria Grice, John C Clohisy, Robert L Barrack, R. Stephen J Burnett, Deepak Voora, Susan Gatchel, Amy Tiemeier, and Brian F Gage*
Department of Medicine, Washington University in St. Louis, St. Louis, MO
Department of Pathology, St. Louis University, St. Louis, MO
Department of Pathology, Washington University in St. Louis, St. Louis, MO
St. Louis College of Pharmacy, St. Louis, MO
Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO
* Corresponding author; email: bgage{at}im.wustl.edu.
High variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and International Normalized Ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and pre- and post-operative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four-fifths of the variability in therapeutic dose (R2adj of 79%). Significant (P<0.05) predictors were INR value after 3 doses (47% reduction per 0.25 unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (-38% and -17% per allele), estimated blood loss (interacting with INR3), smoking status (+20% in current smokers), and VKORC1 (-11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating warfarin therapy.
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