Methodology for a multinational case–population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT)



The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multicentre, retrospective case–population study, named SALT (Study of Acute Liver Transplant), is documented here.


This was a multicentre, multinational retrospective case–population study performed in France, Italy, Portugal, Greece, Ireland, the Netherlands and the UK. The study period was 3 years (1 January 2005–31 December 2007). Cases were patients ≥18 years of age with ALF at the time of registration on the transplant list for liver transplantation who had been exposed to an NSAID within 30 days preceding the initial symptoms of liver disease (index date). Exposure was defined as exposure to any NSAID. Per country rates of NSAID-exposed transplantation-registered ALF were computed as the ratio of the number of cases identified in the country to total population exposure. Overall and per-drug sales for NSAIDs and for paracetamol were obtained from Intercontinental Marketing Services (IMS) Health for all participating countries. Population exposure was measured as the defined daily dose and as estimated annual number of patients exposed (primary endpoint) with 95 % confidence intervals.


The study protocol was approved by the CHMP. Of the 57 eligible liver transplant centres, 54 agreed to participate in the study. All national authorizations were received with relevant administrative burden, mainly due to bureaucracy.


The present study created a multinational research network to estimate population-based absolute rates of drug-exposed ALF leading to registration on the transplantation list. This study design was chosen to obtain a fast response to a public health issue, namely, that of an increased risk of a rare, very serious adverse reaction. This model could be used to study other drug-related issues in ALF.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Van Steenbergen W, Peeters P, De Bondt J, Staessen D, Buscher H, Laporta T, Roskams T, Desmet V (1998) Nimesulide-induced acute hepatitis: evidence from six cases. J Hepatol 29:135–141

    PubMed  Article  Google Scholar 

  2. 2.

    McCormick PA, Kennedy F, Curry M, Traynor O (1999) COX 2 inhibitor and fulminant hepatic failure. Lancet 353:40–41

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Schattner A, Sokolovskaya N, Cohen J (2000) Fatal hepatitis and renal failure during treatment with nimesulide. J Intern Med 247:153–155

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Weiss P, Mouallem M, Bruck R, Hassin D, Tanay A, Brickman CM, Farfel Z, Bar-Meir S (1999) Nimesulide-induced hepatitis and acute liver failure. Isr Med Assoc J 1:89–91

    PubMed  CAS  Google Scholar 

  5. 5.

    Andrade RJ, Lucena MI, Fernandez MC, Gonzalez M (2000) Fatal hepatitis associated with nimesulide. J Hepatol 32:174

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Macia MA, Carvajal A, del Pozo JG, Vera E, del Pino A (2002) Hepatotoxicity associated with nimesulide: data from the Spanish Pharmacovigilance System. Clin Pharmacol Ther 72:596–597

    PubMed  CAS  Google Scholar 

  7. 7.

    Merlani G, Fox M, Oehen HP, Cathomas G, Renner EL, Fattinger K, Schneemann M, Kullak-Ublick GA (2001) Fatal hepatoxicity secondary to nimesulide. Eur J Clin Pharmacol 57:321–326

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    (2007) Nimesulide withdrawal too little, too late? Irish Pharmacy J85

  9. 9.

    Finish Medicines Agency (2002) The sale of Nimed, an anti-inflammatory analgesic, is temporarily suspended due to its adverse liver effects. Available at:

  10. 10.

    Irish Medicines Board (IMB) (2007) IMB announces immediate suspension of the marketing of medicines containing nimesulide. IRB, Dublin

  11. 11.

    World Health Organization (WHO) (2007). Oral nimesulide: marketing suspended in Ireland due to reports of liver failure. WHO Information Exchange System Alert No 113 (23 May 2007). WHO, Geneva

  12. 12.

    European Medicines Agency (EMEA) (2004) Committee for proprietary medicinal products opinion following an article 31 referral. Nimesulide-containing products. EMEA Press Office, London

  13. 13.

    European Medicines Agency (EMEA) (2007) European Medicines Agency recommends restricted use of nimesulide-containing medicinal products. EMEA Press Office, London

  14. 14.

    European Medicines Agency (EMEA) (2007) Questions and answers on the CHMP recommendation on nimesulide-containing medicines. EMEA Agency Press Office, London

  15. 15.

    Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, Montastruc JL, Carvajal A (2006) Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 20:391–395

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Lee CH, Wang JD, Chen PC (2010) Increased risk of hospitalization for acute hepatitis in patients with previous exposure to NSAIDs. Pharmacoepidemiol Drug Saf 19:708–714

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, Venegoni M (2003) Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. Br Med J 327:18–22

    Article  CAS  Google Scholar 

  18. 18.

    Theophile H, Laporte JR, Moore N, Martin KL, Begaud B (2011) The case-population study design: an analysis of its application in pharmacovigilance. Drug Saf 34:861–868

    PubMed  Article  Google Scholar 

  19. 19.

    Benichou C, Danan G, Flahault A (1993) Causality assessment of adverse reactions to drugs—II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol 46:1331–1336

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Danan G, Benichou C (1993) Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 46:1323–1330

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Edwards IR, Biriell C (1994) Harmonisation in pharmacovigilance. Drug Saf 10:93–102

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Macedo AF, Marques FB, Ribeiro CF, Teixeira F (2003) Causality assessment of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert panel, according to different levels of imputability. J Clin Pharm Ther 28:137–143

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Meyboom RH, Hekster YA, Egberts AC, Gribnau FW, Edwards IR (1997) Causal or casual? The role of causality assessment in pharmacovigilance. Drug Saf 17:374–389

    Article  CAS  Google Scholar 

  24. 24.

    Methodology W.C.C.f.D.S (2010) Guidelines for ATC classification and DDD assignment 2011. WHO Collaborating Centre for Drug Statistics Methodology, Oslo

    Google Scholar 

  25. 25.

    Arimone Y, Begaud B, Miremont-Salame G, Fourrier-Reglat A, Molimard M, Moore N, Haramburu F (2006) A new method for assessing drug causation provided agreement with experts’ judgment. J Clin Epidemiol 59:308–314

    PubMed  Article  Google Scholar 

  26. 26.

    Arimone Y, Begaud B, Miremont-Salame G, Fourrier-Reglat A, Moore N, Molimard M, Haramburu F (2005) Agreement of expert judgment in causality assessment of adverse drug reactions. Eur J Clin Pharmacol 61:169–173

    PubMed  Article  Google Scholar 

  27. 27.

    Arimone Y, Miremont-Salame G, Haramburu F, Molimard M, Moore N, Fourrier-Reglat A, Begaud B (2007) Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions. Br J Clin Pharmacol 64:482–488

    PubMed  Article  Google Scholar 

  28. 28.

    Theophile H, Arimone Y, Miremont-Salame G, Moore N, Fourrier-Reglat A, Haramburu F, Begaud B (2010) Comparison of three methods (consensual expert judgement, algorithmic and probabilistic approaches) of causality assessment of adverse drug reactions: an assessment using reports made to a French pharmacovigilance centre. Drug Saf 33:1045–1054

    PubMed  Article  Google Scholar 

  29. 29.

    Gulmez SE, Lignot-Maleyran S, Devries CS, Sturkenboom M, Micon S, Hamoud F, Blin P, Moore N (2012) Administrative complexities for a European observational study despite directives harmonising requirements. Pharmacoepidemiol Drug Saf. doi:10.1002/pds.3204. [Epub ahead of print]. Available at:

  30. 30.

    Sanchez-Fueyo A (2011) Hot-topic debate on tolerance: immunosuppression withdrawal. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 17[Suppl 3]:S69–73

    Article  Google Scholar 

  31. 31.

    Tsochatzis E, Koskinas J, Manesis EK, Archimandritis AJ (2007) Liver transplantation in Greek patients: epidemiological data, morbidity, and mortality of 71 patients from a single center with 6 years of mean follow-up. Transplant Proc 39:1505–1507

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Benichou C (1990) Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 11:272–276

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    MIMS Publications (July 2007). IMB suspension of marketing of nimesulide containing medicines. IMB Notice Information: Human Medicines

Download references


The authors wish to thank all of the physicians and staff at the transplant centres and all of the patients whose acceptance of this study made it possible, as well as the various individuals in administrative positions, data protection, ethics and R&D committees.

Organizational aspects

The study protocol was submitted to the CHMP in 2007 and approved in November 2008.

The Department of Pharmacology of Université Bordeaux Segalen (UBS, France) was the international coordinating centre and had full control of all study operations and decisions, developed study methods and documents, retrieved, managed and is due to analyze the data independently from the financer. A scientific committee composed of international experts in pharmacoepidemiology, hepatology and statistics developed the protocol and oversaw the study. In each participating country a coordinator (National Case Selection Committee Hepatologist, NCSCH) was assigned to help with country-specific aspects and with the validation of cases from their own country. All drug-exposed cases of ALF were reviewed by a case adjudication committee (CAC) composed of hepatologists and pharmacoepidemiologists with the aim to assess causality.


This study was conducted at the request of the European Committee on Human Medicinal Products (CHMP) of the European Medicines Agency, independently from the financer, Helsinn Healthcare SA, manufacturers of nimesulide. The financer had no control of protocol, data retrieval, processing or analysis. Helsinn SA contracted with University of Bordeaux for the conduct of the study. All contracts with members of the committees, with the individual local investigators and with individual transplant centres were with the University of Bordeaux. Helsinn SA was given the opportunity to read and comment this paper before submission, but the content of the paper was entirely under the control and responsibility of the authors.

The report of this study has been sent to the regulatory authorities.

Conflict of interest statements

The authors declare that they have no conflict of interest.

Author contributions

Nicholas Moore (NM) and Dominique Larrey (DL) had the original idea for the study several years ago and proposed it to the financer and to the CHMP. NM was the overall study supervisor, intervening when necessary for the smooth operation of the study. DL was chairman of the scientific committee and of the case adjudication committee, and was the everyday hepatology counsel for the study. George-Philippe Pageaux was the vice-chairman of the case adjudication committee. Sinem Ezgi Gulmez (SEG) 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 centres and study data retrieval, writing the study reports and draft article and verifying all contents. SEG also finalized this article. Patrick Blin was the study epidemiological overseer, contributing to study design, operations, analysis and understanding. Corinne de Vries, Susana Perez-Gutthann, Miriam Sturkenboom and Jacques Bénichou provided considerable methodological input to the study scientific committee. Dominique Larrey, George-Philippe Pageaux, Jacques Bernuau, Franco Bissoli, Yves Horsmans, Bruno Stricker and Douglas Thorburn were the members of the case adjudication committee, developed the case adjudication process and performed causality assessments.

Author information



Corresponding author

Correspondence to Sinem Ezgi Gulmez.

Additional information

On behalf of all SALT study participants.

Appendix. Study participants

Appendix. Study participants

Coordinating centre

Department of pharmacology, University Bordeaux Ségalen, Bordeaux, France

Department head: Prof. Nicholas Moore

Scientific project manager: Assoc. Prof. S. Ezgi Gülmez

Consultant pharmacoepidemiologist:Dr. Patrick Blin

Unit director: Cécile Droz-Perroteau

Project team manager: Séverine Lignot-Maleyran

Assistant project managers: Fatima Hamoud, Sophie Micon

Statistician and data manager chief: Régis Lassalle

Statistician: Jérémy Jové

Data manager: Lydie Mahevo

Databases: Patrick Bouex, Ludovic Liège

CRAs: Gilles Thonï & Kendle CRO

Administrative personal: Aline Arnaiz, Caroline Florit, Sylvie Icart, Claude Masset

Scientific committee

Chairman: Prof. Dominique Larrey (Montpellier, France)

Prof. Jacques Bénichou (Rouen, France)

Prof. Achille Caputi (Messina, Italy)

Prof. Corinne S. de Vries (Bath, the UK)

Prof. Jean-Louis Montastruc (Toulouse, France)

Prof. James Neuberger (Birmingham, the UK)

Dr. Susana Perez-Gutthann (Barcelona, Spain)

Prof. Didier Samuel (Villejuif, France)

Prof. Miriam Sturkenboom (Rotterdam, the Netherlands)

Prof. Giampaolo P. Velo (Verona, Italy)

Case adjudication committee

Chairman: Prof. Dominique Larrey (Montpellier, France)

Prof. Jacques Bernuau (Clichy, France)

Dr. Franco Bissoli (Novara, Italy)

Prof. Yves Horsmans (Brussels, Belgium)

Prof. Jean-Louis Montastruc (Toulouse, France)

Prof. Georges-Philippe Pageaux (Montpellier, France)

Prof. Bruno Stricker (Rotterdam, the Netherlands)

Dr. Douglas Thorburn (London, the UK)

National case selection committee hepatologists

Prof. Georges-Philippe Pageaux (Montpellier, France)

Assoc. Prof. Irene Zouboulis-Vafiadis (Athens, Greece)

Prof. Aiden McCormick (Dublin, Ireland)

Prof. Angelo Gatta (Padova, Italy)

Prof. Estela Monteiro (Lisbon, Portugal)

Prof. Harold J. Metselaar (Rotterdam, the Netherlands)

Dr. Douglas Thorburn (London, the UK)

Local investigators at participating centres (in alphabetical order of cities)


Prof. Evrard Philippe (Besancon)

Dr. Neau-Cransac Martine (Bordeaux)

Prof. Chiche Laurence (Caen)

Prof. Buc Emmanuel (Clermont Ferrand)

Prof. Durand François (Clichy)

Prof. Laurent Alexis (Creteil)

Prof. Minello Anne (Dijon)

Prof. Leroy Vincent (Grenoble)

Prof. Dharancy Sébastien (Lille)

Dr Debette Gratien Marilyne (Limoges)

Prof. Boillot Olivier (Lyon)

Prof. Ducerf Christian (Lyon)

Prof. Le Treut Yves (Marseille)

Prof. Georges-Philip Pageaux (Montpellier)

Prof. Gugenheim Jean (Nice)

Prof. Carbonell Nicolas (Paris)

Prof. Calmus Yvon (Paris)

Prof. Compagnon Philippe (Rennes)

Prof. Wolf Philippe (Strasbourg)

Prof. Suc Bertand (Toulouse)

Prof. Ichai Philippe (Villejuif)


Prof. Efstathios Antoniou (Athens)

Prof. Dimitrios Takoudas (Salonica)


Prof. Aiden McCormick (Dublin)


Dr. Daniele Nicolini (Ancona)

Prof. Lupo Luigi.G (Bari)

Prof. Giovanna Gaffuri (Bergamo)

Dr. Cristina Morelli (Bologna)

Prof. Fausto Zamboni (Cagliari)

Prof. Luciano Gregorio De Carlis (Milano)

Dr. Barbara Antonelli (Milano)

Prof. Gerunda Giorgio Enrico, Dr. Roberto Ballarin (Modena)

Prof. Fulvio Calise, Dr. Marina Romano (Napoli)

Prof. Angelo Gatta, Prof. Umberto Cillo, Prof. Paolo Angeli (Padova)

Prof. Giovanni Vizzini (Palermo)

Prof. Paolo De Simone (Pisa)

Prof. Ginanni Corradini (Roma)

Prof. Giuseppe Ettorre (Roma)

Dr. Sabina Magalini (Roma)

Prof. Andrea Brunati, Dr. Alessandra Cibelli (Torino)

Prof. Umberto Baccarani (Udine)

Dr. Matteo Donataccio (Verona)


Prof. Estela Monteiro (Lisbon)

Dr. Helena Miranda (Porto)

The Netherlands

Prof. Bart van Hoek (Leiden)

Prof. Robert J. Porte (Groningen)

Prof. Herald Metselaar, Dr. Emine Sen (Rotterdam)


Chief investigators: Prof. Corinne de Vries, Dr. Alison Nightingale (Bath)

Dr. Drihaj Tripathi (Birmingham)

Dr. Murat Akyol (Edinburgh)

Dr. Mervyne Davies, Dr. Claire Corps (Leeds)

Dr. Douglas Thorburn (London)

Dr. William Bernal (London)

Dr. Mark Hudson (Newcastle)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gulmez, S.E., Larrey, D., Pageaux, GP. et al. Methodology for a multinational case–population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT). Eur J Clin Pharmacol 69, 605–616 (2013).

Download citation


  • Acute liver failure
  • Case–population
  • Liver transplantation
  • Non-steroidal anti-inflammatory drugs
  • Pharmacoepidemiology