title: A prospective stratified case-cohort study on statins and multiple adverse events in Japan.
abstract: OBJECTIVE
  To assess the association between statins and diverse adverse events in Japanese population.
  
  
  METHODS
  New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009.
  
  
  RESULTS
  A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009).
  
  
  CONCLUSIONS
  Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ooba
authors.affiliation: Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan; Drug Safety Research Unit Japan, Tokyo, Japan.
authors.forename: Tsugumichi
authors.initials: T
authors.lastname: Sato
authors.affiliation: MSD K.K., Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Wakana
authors.affiliation: NTT Medical Center Tokyo, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Orii
authors.affiliation: Department of Pharmacy, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kitamura
authors.affiliation: EliLilly Japan, K.K., Hyogo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kokan
authors.affiliation: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kurata
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shimodozono
authors.affiliation: Office for Promoting Medical Research, Showa University, Tokyo, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsui
authors.affiliation: Department of Laboratory Medicine, The Jikei University Kashiwa Hospital, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kageyama
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kubota
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D002648:Child; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000201:enzymology / Q000652:urine; D005260:Female; D006417:Hematuria / Q000139:chemically induced; D006761:Hospitals / Q000706:statistics & numerical data; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects*; D007564:Japan; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000139:chemically induced; D012206:Rhabdomyolysis / Q000139:chemically induced; D055815:Young Adult
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase