title: High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort.
abstract: OBJECTIVE
  Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment.
  
  
  METHODS
  The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions.
  
  
  RESULTS
  Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4-2.6]. High dose was classified as 40-80mg daily and low dose 10-20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2-12.7] for HDA, 1.4 [0.9-2.0] for LDA and 1.5 [1.0-2.2] for HDS.
  
  
  CONCLUSIONS
  The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small.
authors.affiliation: Dept. of Gastroenterology, Queen Elizabeth University Hospital, Glasgow, United Kingdom.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Clarke
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.|Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Paul C D
authors.initials: PC
authors.lastname: Johnson
authors.affiliation: Grimsdyke House London, London, United Kingdom.
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Hall
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: Dept. of Gastroenterology, Gartnavel General Hospital, Glasgow, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mills
mesh_terms: D000368:Aged; D000069059:Atorvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D006113:United Kingdom
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000069059:Atorvastatin; D019821:Simvastatin