title: Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT).
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service de Pharmacologie, Université Bordeaux, 33000 Bordeaux, France. sinemezgi.gulmez@u-bordeaux2.fr
authors.forename: Sinem Ezgi
authors.initials: SE
authors.lastname: Gulmez
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Georges-Philippe
authors.initials: GP
authors.lastname: Pageaux
authors.forename: Séverine
authors.initials: S
authors.lastname: Lignot-Maleyran
authors.forename: Corinne
authors.initials: C
authors.lastname: de Vries
authors.forename: Miriam
authors.initials: M
authors.lastname: Sturkenboom
authors.forename: Susana
authors.initials: S
authors.lastname: Perez-Gutthann
authors.forename: Jacques
authors.initials: J
authors.lastname: Bénichou
authors.forename: Franco
authors.initials: F
authors.lastname: Bissoli
authors.forename: Yves
authors.initials: Y
authors.lastname: Horsmans
authors.forename: Jacques
authors.initials: J
authors.lastname: Bernuau
authors.forename: Bruno
authors.initials: B
authors.lastname: Stricker
authors.forename: Douglas
authors.initials: D
authors.lastname: Thorburn
authors.forename: Patrick
authors.initials: P
authors.lastname: Blin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Moore
mesh_terms: D000208:Acute Disease; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology* / Q000601:surgery*; D003299:Cooperative Behavior; D005060:Europe / Q000453:epidemiology; D006801:Humans; D007391:International Cooperation; D016031:Liver Transplantation / Q000706:statistics & numerical data; D016017:Odds Ratio; D017891:Pharmacoepidemiology / Q000379:methods* / Q000706:statistics & numerical data; D012107:Research Design / Q000706:statistics & numerical data; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014850:Waiting Lists
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal