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Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH)

Application of this Data Organization Approach to Phase III Clinical Trials of Rivaroxaban after Total Hip or Knee Replacement Surgery

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Abstract

Background: The most specific indicator of a drug-induced liver injury signal in a clinical trial database is believed to be the occurrence of subjects experiencing drug-associated elevations in both serum ALT and serum total bilirubin (TB) without a significant elevation in serum alkaline phosphatase (ALP). eDISH (evaluation of Drug-Induced Serious Hepatotoxicity) is a recently described tool that organizes liver laboratory data by graphically displaying peak serum ALT and TB levels for each subject, and can also provide direct links to the pertinent clinical and laboratory data for each subject.

Objective: To illustrate the usefulness of the eDISH approach in the presentation of liver safety data by using phase III clinical trial data for rivaroxaban.

Methods: Four randomized, active-controlled studies were conducted worldwide in subjects undergoing elective hip or knee replacement surgery to compare the efficacy and safety of the anticoagulant rivaroxaban, an oral, direct Factor Xa inhibitor, with the low-molecular-weight heparin, enoxaparin. Liver laboratory assessments, including ALT, AST, TB and ALP, were performed frequently during the studies. Data were incorporated into eDISH and linked data for selected subjects were analysed.

Results:In the pooled analysis of the four studies, a total of 12262 subjects (6131 rivaroxaban, 6131 enoxaparin) received at least one dose of study drug and had at least one central and/or local laboratory assessment during the study. A total of 143 (2.33%) rivaroxaban subjects and 223 (3.64%) enoxaparin subjects experienced a peak ALT >3 × upper limit of normal (ULN) but did not experience an elevation of TB >2 × ULN; these subjects are displayed in the right lower quadrant of the eDISH plot, termed the ‘Temple’s Corollary quadrant’. There were ten rivaroxaban and ten enoxaparin subjects with a peak ALT >3 × ULN and a peak TB >2 × ULN; these subjects were displayed in the right upper quadrant of the eDISH plot, termed the ‘Hy’s Law quadrant’. eDISH allowed efficient examination of the relevant data for each of these subjects.

Conclusions:The eDISH approach is an efficient and effective way to organize and examine large liver safety databases for randomized controlled clinical trials. It greatly facilitates a systematic and transparent examination of the relevant liver safety laboratory data. We believe eDISH should become a standard approach for assessing and studying liver safety issues in clinical trials.

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Acknowledgements

Bayer Schering Pharma AG and Johnson & Johnson Pharmaceutical Research & Development, LLC, provided funding for the RECORD studies. The sponsors were also involved in the design and conduct of the studies (including the collection, management, analysis and interpretation of the data). Dr Watkins has served as a compensated consultant for Johnson & Johnson Pharmaceutical Research & Development, LLC, but received no compensation for his lead role in preparing this manuscript. Dr Desai and Dr Peters are employees of Johnson and Johnson Pharmaceutical Research & Development, LLC. Dr Berkowitz is an employee of Bayer HealthCare Pharmaceuticals Inc. Dr Horsmans has served as a consultant for Bayer HealthCare and Johnson & Johnson Pharmaceuticals. Dr Larrey has been a consultant for analysing rivaroxaban liver safety in the phase III trials. Dr Maddrey has consulted with Johnson & Johnson and Bayer regarding the hepatic safety of rivaroxaban. The authors wish to thank a number of individuals for their help with the collection, preparation and review of the data discussed in this manuscript; specifically, Sabine Dittmar, Martin Homering, Emanuel Lohrmann, Eugene Schiff, and Torsten Westermeier. The authors would also like to acknowledge Seamus McMillan of Chameleon Communications International, who provided editorial support with funding from Bayer Schering Pharma AG and Johnson & Johnson Pharmaceutical Research & Development, LLC.

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Authors and Affiliations

  1. The Hamner-UNC Institute for Drug Safety Sciences, 6 Davis Drive, PO Box 12137 Research Triangle Park, North Carolina, 27709-2137, USA

    Paul B. Watkins MD

  2. Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey, USA

    Mehul Desai & Gary Peters

  3. Bayer HealthCare Pharmaceuticals, Montville, New Jersey, USA

    Scott D. Berkowitz

  4. Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Yves Horsmans

  5. Department of Hepatic Physiopathology and INSERM U632, Montpellier School of Medicine, Montpellier, France

    Dominique Larrey

  6. The University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Willis Maddrey

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  1. Paul B. Watkins MD
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  2. Mehul Desai
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  3. Scott D. Berkowitz
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  4. Gary Peters
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  5. Yves Horsmans
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  6. Dominique Larrey
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  7. Willis Maddrey
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Correspondence to Paul B. Watkins MD.

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Watkins, P.B., Desai, M., Berkowitz, S.D. et al. Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH). Drug-Safety 34, 243–252 (2011). https://doi.org/10.2165/11586600-000000000-00000

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  • DOI: https://doi.org/10.2165/11586600-000000000-00000

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