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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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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Genetic-based dosing in orthopedic patients beginning warfarin therapy
Eric A. Millican1,
Petra A. Lenzini1,
Paul E. Milligan1,
Leonard Grosso2,
Charles Eby1,3,
Elena Deych1,
Gloria Grice1,4,
John C. Clohisy5,
Robert L. Barrack5,
R. Stephen J. Burnett5,
Deepak Voora1,
Susan Gatchel1,
Amy Tiemeier1,4, and
Brian F. Gage1
1 Department of Medicine, Washington University in St Louis, MO;
2 Department of Pathology, St Louis University, MO;
3 Department of Pathology, Washington University in St Louis, MO;
4 St Louis College of Pharmacy, MO;
5 Department of Orthopaedic Surgery, Washington University in St Louis, MO
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 preoperative and postoperative 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 > .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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