title: Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.
abstract: OBJECTIVE
  To systematically review the risk of mortality associated with long term use of tiotropium delivered using a mist inhaler for symptomatic improvement in chronic obstructive pulmonary disease.
  
  
  METHODS
  Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and ClinicalTrials.gov for randomised controlled trials from inception to July 2010.
  
  
  METHODS
  Trials were selected for inclusion if they were parallel group randomised controlled trials of tiotropium solution using a mist inhaler (Respimat Soft Mist Inhaler, Boehringer Ingelheim) versus placebo for chronic obstructive pulmonary disease; the treatment duration was more than 30 days, and they reported data on mortality. Relative risks of all cause mortality were estimated using a fixed effect meta-analysis, and heterogeneity was assessed with the I(2) statistic.
  
  
  RESULTS
  Five randomised controlled trials were eligible for inclusion. Tiotropium mist inhaler was associated with a significantly increased risk of mortality (90/3686 v 47/2836; relative risk 1.52, 95% confidence interval, 1.06 to 2.16; P = 0.02; I(2) = 0%). Both 10 µg (2.15, 1.03 to 4.51; P = 0.04; I(2) = 9%) and 5 µg (1.46, 1.01 to 2.10; P = 0.04; I(2) = 0%) doses of tiotropium mist inhaler were associated with an increased risk of mortality. The overall estimates were not substantially changed by sensitivity analysis of the fixed effect analysis of the five trials combined using the random effects model (1.45, 1.02 to 2.07; P = 0.04), limiting the analysis to three trials of one year's duration each (1.50, 1.05 to 2.15), or the inclusion of additional data on tiotropium mist inhaler from another investigational drug programme (1.42, 1.01 to 2.00). The number needed to treat for a year with the 5 µg dose to see one additional death was estimated to be 124 (95% confidence interval 52 to 5682) based on the average control event rate from the long term trials.
  
  
  CONCLUSIONS
  This meta-analysis explains safety concerns by regulatory agencies and indicates a 52% increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, 1830 E Monument Street, Baltimore, MD 21287, USA. ssingh31@jhu.edu
authors.forename: Sonal
authors.initials: S
authors.lastname: Singh
authors.forename: Yoon K
authors.initials: YK
authors.lastname: Loke
authors.forename: Paul L
authors.initials: PL
authors.lastname: Enright
authors.forename: Curt D
authors.initials: CD
authors.lastname: Furberg
mesh_terms: D000280:Administration, Inhalation; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000069447:Tiotropium Bromide
chemical_list: D001993:Bronchodilator Agents; D012602:Scopolamine Derivatives; D000069447:Tiotropium Bromide