title: Excess deaths associated with tigecycline after approval based on noninferiority trials.
abstract: BACKGROUND
  On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death.
  
  
  METHODS
  PubMed, EMBASE, Scopus, and ClinicalTrials.gov were searched using the terms "tigecycline" and "randomized controlled trial (RCT)" through April 2011. Excess deaths and noncure rates for both approved and nonapproved indications were examined using meta-analysis.
  
  
  RESULTS
  Ten published and 3 unpublished studies met inclusion criteria (N = 7434). No significant heterogeneity was seen for mortality (I(2 )= 0%; P = .99) or noncure rates (I(2 )= 25%; P = .19). Across randomized controlled trials, tigecycline was associated with increased mortality (risk difference [RD], 0.7%; 95% confidence interval [CI], 0.1%-1.2%; P = .01) and noncure rates (RD, 2.9%; 95% CI, 0.6%-5.2%; P = .01). Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (I(2 )= 0%; RD, 0.6%; P = .04). A pooled analysis of the 5 trials completed by early 2005 before tigecycline was approved would have demonstrated a similar harmful effect of tigecycline on survival (I(2 )= 0%; RD, 0.7%; P = .06).
  
  
  CONCLUSIONS
  Pooling noninferiority studies to examine survival may help ensure the safety and efficacy of new antibiotics. The association of tigecycline with excess deaths and noncure includes indications for which it is approved and marketed. Tigecycline cannot be relied on in serious infections.
authors.affiliation: Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland, USA. paritosh.prasad@nih.gov
authors.forename: Paritosh
authors.initials: P
authors.lastname: Prasad
authors.forename: Junfeng
authors.initials: J
authors.lastname: Sun
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Charles
authors.initials: C
authors.lastname: Natanson
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D017277:Drug Approval; D006801:Humans; D008911:Minocycline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D000078304:Tigecycline; D017211:Treatment Failure; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline