The Creating an Optimal Warfarin Nomogram (CROWN) Study

Todd S. Perlstein; Samuel Z. Goldhaber; Kerrie Nelson; Victoria Joshi; T. Vance Morgan; Lawrence J. Lesko; Joo-Yeon Lee; Jogarao Gobburu; David Schoenfeld; Raju Kucherlapati; Mason W. Freeman; Mark A. Creager

doi:10.1160/TH11-08-0568

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 107(01): 59-68
DOI: 10.1160/TH11-08-0568

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

The Creating an Optimal Warfarin Nomogram (CROWN) Study

Todd S. Perlstein

¹Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

,

Samuel Z. Goldhaber

¹Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

,

Kerrie Nelson

²Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA

,

Victoria Joshi

⁵Departments of Pathology, Massachusetts General Hospital and Brigham and Women’s Hospital, Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA

,

T. Vance Morgan

⁶Center for Personalized Genetic Medicine, Harvard Medical School, Boston, Massachusetts, USA

,

Lawrence J. Lesko

⁷Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

,

Joo-Yeon Lee

⁷Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

,

Jogarao Gobburu

⁷Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

,

David Schoenfeld

²Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA

³Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

,

Raju Kucherlapati

⁶Center for Personalized Genetic Medicine, Harvard Medical School, Boston, Massachusetts, USA

,

Mason W. Freeman

⁴Lipid Metabolism Unit and Endocrine Division, Massachusetts General Hospital, Boston, Massachusetts, USA

,

Mark A. Creager

¹Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

› Author Affiliations

Abstract

Summary

A significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, –1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3, 1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2. A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A to Algorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion.

Clinical Trial Registration: ClinicalTrials.gov (NCT00401414)

Keywords

Pharmacogenetics - warfarin - clinical trial

Full Text

References

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