title: Clinical importance of the drug interaction between statins and CYP3A4 inhibitors: a retrospective cohort study in The Health Improvement Network.
abstract: OBJECTIVE
  To compare the relative hazard of muscle toxicity, renal dysfunction, and hepatic dysfunction associated with the drug interaction between statins and concomitant medications that inhibit the CYP3A4 isoenzyme.
  
  
  BACKGROUND
  Although statins provide important clinical benefits related to mitigating the risk of cardiovascular events, this class of medications also has the potential for severe adverse reactions. The risk for adverse events may be potentiated by concomitant use of medications that interfere with statin metabolism.
  
  
  METHODS
  Data from The Health Improvement Network (THIN) from 1990 to 2008 were used to conduct a retrospective cohort study. Cohorts were created to evaluate each outcome (muscle toxicity, renal dysfunction, and hepatic dysfunction) independently. Each cohort included new statin initiators and compared the relative hazard of the outcome. The interaction ratio (I*R) was the primary contrast of interest. The I*R represents the relative effect of each statin type (statin 3A4 substrate vs. statin non-3A4 substrate) with a CYP3A4 inhibitor, independent of the effect of the statin type without a CYP3A4 inhibitor. We adjusted for confounding variables using the multinomial propensity score.
  
  
  RESULTS
  The median follow-up time per cohort was 1.5 years. There were 7889 muscle toxicity events among 362,809 patients and 792,665 person-years. The adjusted muscle toxicity I*R was 1.22 (95% confidence interval [CI] = 0.90-1.66). There were 1449 renal dysfunction events among 272,099 patients and 574,584 person-years. The adjusted renal dysfunction I*R was 0.91 (95%CI = 0.58-1.44). There were 1434 hepatic dysfunction events among 367,612 patients and 815,945 person-years. The adjusted hepatic dysfunction I*R was 0.78 (95%CI = 0.45-1.31).
  
  
  CONCLUSIONS
  Overall, this study found no difference in the relative hazard of muscle toxicity, renal dysfunction, or hepatic dysfunction for patients prescribed a statin 3A4 substrate versus a statin non-3A4 substrate with CYP3A4 inhibitor concomitancy.
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. crowan@outcome.com
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Rowan
authors.forename: Steven M
authors.initials: SM
authors.lastname: Brunelli
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Munson
authors.forename: James
authors.initials: J
authors.lastname: Flory
authors.forename: Peter P
authors.initials: PP
authors.lastname: Reese
authors.forename: Sean
authors.initials: S
authors.lastname: Hennessy
authors.forename: James
authors.initials: J
authors.lastname: Lewis
authors.forename: Daniel
authors.initials: D
authors.lastname: Mines
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Barrett
authors.forename: Warren
authors.initials: W
authors.lastname: Bilker
authors.forename: Brian L
authors.initials: BL
authors.lastname: Strom
mesh_terms: D000368:Aged; D015331:Cohort Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D016208:Databases, Factual; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D007674:Kidney Diseases / Q000453:epidemiology / Q000209:etiology; D008107:Liver Diseases / Q000453:epidemiology / Q000209:etiology; D008297:Male; D008875:Middle Aged; D009135:Muscular Diseases / Q000453:epidemiology / Q000209:etiology; D012189:Retrospective Studies; D006113:United Kingdom
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors