Publications (3)9.01 Total impact
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Article: Transplantation for Acute Liver Failure in Patients Exposed to NSAIDs or Paracetamol (Acetaminophen) : The Multinational Case-Population SALT Study.
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ABSTRACT: BACKGROUND: Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. OBJECTIVES: The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). RESULTS: In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. CONCLUSIONS: ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.Drug Safety 01/2013; · 3.63 Impact Factor -
Article: Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France.
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ABSTRACT: PURPOSE: The effect of denominator options on event rates was tested on the French part of the Study of Acute Liver Transplant (SALT). METHODS: SALT is a case population study of acute liver failure registered for transplantation (ALFT), exposed to non-steroidal anti-inflammatory drugs (NSAIDs) or non-overdose paracetamol, from 2005 to 2007. Population exposure was computed from the Intercontinental Medical Services' (IMS) and the French national healthcare insurance system's data as the number of defined daily doses (DDDs) sold or dispensed and the number of exposed patients. RESULTS: Nine ALFT cases were exposed to 10 NSAIDs and 49 to non-overdose paracetamol. NSAID sales ranged from 0.04 billion (niflumic acid) to 0.5 billion (ibuprofen) DDDs, amounting to 2.5 billion DDDs for all NSAIDs. The mean per-person exposure ranged from 13.1 (niflumic acid) to 43.2 (ketoprofen) DDDs, reaching 60.5 DDDs for any NSAID. The number of users ranged from 2 million (niflumic acid) to 13 million (ibuprofen), which was 26.6 million for all NSAIDs. The ALFT rates per billion DDDs ranged from 0 to 26 for individual NSAIDs and amounted to 4.6 for all NSAIDs. The ALFT rates per billion DDDs were inversely correlated with the average per-patient exposure (R(2) = 0.935, p = 0.0016). The ALFT rates per million users ranged from 0.31 to 0.49, which was 0.41 for all NSAIDs, with no difference between drugs and no effect of mean per-patient exposure (R(2) = 0.01, p = 0.9). Whether measured per DDD or per user, the event rate with paracetamol was three to five times higher than with NSAIDs. CONCLUSION: ALFT risk with NSAID seems to be user dependent rather than person-time (exposure) dependent. Choosing the wrong denominator in case population studies might give erroneous results. Copyright © 2012 John Wiley & Sons, Ltd.Pharmacoepidemiology and Drug Safety 11/2012; · 2.53 Impact Factor -
Article: Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT).
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ABSTRACT: PURPOSE: 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. CONCLUSION: 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.European Journal of Clinical Pharmacology 08/2012; · 2.85 Impact Factor
