Several methods have been proposed to assess causality in drug-induced liver injury but none have been tested in the specific context of acute liver failure leading to transplantation (ALFT).
We took advantage of the Study of Acute Liver Transplant (SALT), a European case-population study of ALFT, to test different causality scales.
Causality was assessed by experts in SALT, a 7-country case-population study from 2005 to 2007 of adult otherwise unexplained ALFT, for all drugs found within 30 days prior to the date of initial symptoms of liver disease (index date), using information content, causality scales, and data circuit determined from a pilot study, Salome.
The consensus points from Salome were to provide full data on drugs including international non-proprietary name (INN) and doses except for non-steroidal anti-inflammatory drugs (NSAIDs) and to use the World Health Organization (WHO) causality scale. In SALT, among the 9,479 identified patients, 600 (6.3 %) were cases of ALFT, of which 187 had been exposed to drugs within 30 days, without overdose. In 130 (69.5 %) of these the causality score was possible, probable, or highly probable.
In ALFT cases, once other clinical causes have been excluded and drug exposure established within 30 days, the main discriminant characteristic for causality will be previous knowledge of possible hepatotoxicity.
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The authors wish to thank all the physicians and staff at the transplant centers and all the patients whose acceptance of this study made it possible, and the various persons in administrative positions, data protection, ethics, and the British research & development committees.
Nicholas Moore and Dominique Larrey had the original idea for the study several years ago and proposed it to the sponsor and to the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Nicholas Moore was the overall study supervisor, intervening when necessary for the smooth operation of the study. Dominique Larrey was chairman of the scientific committee and of the case adjudication committee (CAC) and was the everyday hepatology counsel for the study. George-Philippe Pageaux was the vice-chairman of the CAC and contributed enormously to case understanding and adjudication.
Sinem Ezgi Gulmez and Séverine Lignot were the scientific and operational study coordinators, devising the initial document generation under the control of the scientific committee, organizing negotiations with transplant centers, study data retrieval, writing the study reports and draft article, and verifying all contents. The study coordination team also included Sophie Micon and Fatima Hamoud, who coordinated the scientific and CAC activities. Régis Lassalle and Jérémy Jove provided data management and statistical analyses. Patrick Blin was the study epidemiological overseer, contributing to study design, operations, analysis, and understanding. Jacques Bernuau, Franco Bissoli, Yves Horsmans, Jean-Louis Montastruc, Bruno Stricker, and Douglas Thorburn were members of the CAC and performed causality assessments.
All authors contributed comments on the final version of this paper.
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Corresponding authors have completed and signed the copyright assessment.
Corresponding authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis, which was conducted independently from the financer.
Competing interest statement
All authors have completed the unified competing interest form, and declared their competing interest if any. Dr Bruno Stricker has received travel reimbursements. Drs Yves Horsmans and Franco Bissoli have declared being consultants for Helsinn Pharmaceutical Company.
No specific conflict of interest is declared with regard to this study, by any of the authors, inasmuch as for a number of the authors who are employees of the University of Bordeaux, the University of Bordeaux received compensation as described below. Authors participating in the committees received compensation from the University of Bordeaux for the time spent on the committees.
A contributorship statement is included in the manuscript.
The study was conducted at the request of the CHMP of the EMA, independently from the financer, Helsinn Healthcare SA (HHC), manufacturers of nimesulide. The financer had no role in the design of the study, which was submitted to and approved by the CHMP, or in the collection, management, analysis, or interpretation of the data. Nor did they have any role in the preparation or review of this manuscript. They were given the opportunity to read and comment on this paper before submission, but the content of the paper was entirely under the control and responsibility of the authors. HHC entered a contract with the University of Bordeaux for the conduct of the study. All contracts with experts or transplant centers were with the University of Bordeaux. HHC had no direct contact with any of the participants in the study.
The report of this study has been sent to the regulatory authorities and was presented to the CHMP on 17 May 2011.
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Gulmez, S.E., Moore, N., Pageaux, GP. et al. Causality of Drugs Involved in Acute Liver Failure Leading to Transplantation: Results from the Study of Acute Liver Transplant (SALT). Drug Saf 36, 757–764 (2013). https://doi.org/10.1007/s40264-013-0071-5
- Visual Analogue Scale
- Causality Assessment
- Causality Score
- Causality Classification