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

Deepak Voora; Charles Eby; Mark W. Linder; Paul E. Milligan; Bonny L. Bukaveckas; Howard L. McLeod; William Maloney; John Clohisy; Steven R. Burnett; Leonard Grosso; Susan K. Gatchel; Brian F. Gage

doi:10.1160/TH04-08-0542

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

,

Charles Eby

¹Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

,

Mark W. Linder

⁴Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky, USA

,

Paul E. Milligan

¹Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

,

Bonny L. Bukaveckas

⁴Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, Kentucky, USA

,

Howard L. McLeod

¹Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

,

William Maloney

²Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

,

John Clohisy

²Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

,

Steven R. Burnett

²Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA

,

Leonard Grosso

³Department of Pathology, Saint Louis University School of Medicine, St. Louis, Missouri, USA

,

Susan K. Gatchel

¹Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

,

Brian F. Gage

¹Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

› Author Affiliations

Abstract

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

Full Text

References

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