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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. This Article Full Text (PDF) All Versions of this Article: blood-2007-01-069609v1 110/5/1511    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Millican, E. Articles by Gage, B. F Search for Related Content PubMed PubMed Citation Articles by Millican, E. Articles by Gage, B. F Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Possible requiem: trial-and-error warfarin Samuel Z. Goldhaber Blood 2007 110: 1404-1405. [Full Text] [PDF] This article has been cited by other articles: J. F. Meschia Pharmacogenetics and Stroke Stroke, November 1, 2009; 40(11): 3641 - 3645. [Abstract] [Full Text] [PDF] M. W. Linder, M. Bon Homme, K. K. Reynolds, B. F. Gage, C. Eby, N. Silvestrov, and R. Valdes Jr. Interactive Modeling for Ongoing Utility of Pharmacogenetic Diagnostic Testing: Application for Warfarin Therapy Clin. Chem., October 1, 2009; 55(10): 1861 - 1868. [Abstract] [Full Text] [PDF] M. H. Rosove and W. W. Grody Should We Be Applying Warfarin Pharmacogenetics to Clinical Practice? No, Not Now Ann Intern Med, August 18, 2009; 151(4): 270 - 273. [Abstract] [Full Text] [PDF] M. R. Langley, J. K. Booker, J. P. Evans, H. L. McLeod, and K. E. Weck Validation of Clinical Testing for Warfarin Sensitivity: Comparison of CYP2C9-VKORC1 Genotyping Assays and Warfarin-Dosing Algorithms J. Mol. Diagn., May 1, 2009; 11(3): 216 - 225. [Abstract] [Full Text] [PDF] C. Li, U. I. Schwarz, M. D. Ritchie, D. M. Roden, C. M. Stein, and D. Kurnik Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy Blood, April 23, 2009; 113(17): 3925 - 3930. [Abstract] [Full Text] [PDF] J. Shin, S. R. 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Med., June 19, 2008; 358(25): 2741 - 2744. [Full Text] [PDF] M. D. Caldwell, T. Awad, J. A. Johnson, B. F. Gage, M. Falkowski, P. Gardina, J. Hubbard, Y. Turpaz, T. Y. Langaee, C. Eby, et al. CYP4F2 genetic variant alters required warfarin dose Blood, April 15, 2008; 111(8): 4106 - 4112. [Abstract] [Full Text] [PDF] U. I. Schwarz, M. D. Ritchie, Y. Bradford, C. Li, S. M. Dudek, A. Frye-Anderson, R. B. Kim, D. M. Roden, and C. M. Stein Genetic Determinants of Response to Warfarin during Initial Anticoagulation N. Engl. J. Med., March 6, 2008; 358(10): 999 - 1008. [Abstract] [Full Text] [PDF] J. L. Anderson, B. D. Horne, S. M. Stevens, A. S. Grove, S. Barton, Z. P. Nicholas, S. F.S. Kahn, H. T. May, K. M. Samuelson, J. B. Muhlestein, et al. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation Circulation, November 27, 2007; 116(22): 2563 - 2570. [Abstract] [Full Text] [PDF] P. A Lenzini, G. R Grice, P. E Milligan, S. K Gatchel, E. Deych, C. S Eby, R S. J Burnett, J. C Clohisy, R. L Barrack, and B. F Gage Optimal Initial Dose Adjustment of Warfarin in Orthopedic Patients Ann. Pharmacother., November 1, 2007; 41(11): 1798 - 1804. [Abstract] [Full Text] [PDF]

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