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Thromb Haemost 2005; 93(04): 700-705
DOI: 10.1160/TH04-08-0542
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype

Deepak Voora
1   Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
,
Charles Eby
1   Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
,
Mark W. Linder
4   Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky, USA
,
Paul E. Milligan
1   Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
,
Bonny L. Bukaveckas
4   Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky, USA
,
Howard L. McLeod
1   Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
,
William Maloney
2   Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
,
John Clohisy
2   Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
,
Steven R. Burnett
2   Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
,
Leonard Grosso
3   Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
,
Susan K. Gatchel
1   Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
,
Brian F. Gage
1   Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
› Author AffiliationsFinancial support Supported by grants R01 HL074724 and R01 HL71083.
Further Information

Publication History

Received 25 August 2004

Accepted after resubmission 18 January 2005

Publication Date:
14 December 2017 (online)

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Summary

Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4–9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R2 = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.

Keywords

Polymorphism - prospective studies - cytochrome P-450 enzyme system/genetics - warfarin/administration and dosage
 

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