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Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials

BMJ 2011; 342 doi: (Published 14 June 2011) Cite this as: BMJ 2011;342:d3215
  1. Sonal Singh, assistant professor1,
  2. Yoon K Loke, senior lecturer2,
  3. Paul L Enright, professor3,
  4. Curt D Furberg, professor4
  1. 1Department of Medicine, Johns Hopkins University School of Medicine, 1830 E Monument Street, Baltimore, MD 21287, USA
  2. 2School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK
  3. 3College of Public Health, University of Arizona, Tucson, AZ, USA
  4. 4Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA
  1. Correspondence to: S Singh ssingh31{at}
  • Accepted 8 April 2011


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.

Data sources Medline, Embase, the pharmaceutical company clinical trials register, the US Food and Drug Administration website, and for randomised controlled trials from inception to July 2010.

Study selection 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 I2 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; I2=0%). Both 10 µg (2.15, 1.03 to 4.51; P=0.04; I2=9%) and 5 µg (1.46, 1.01 to 2.10; P=0.04; I2=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.


  • Contributors: SS and YKL conceived and designed the study, drafted the manuscript, acquired the data, and carried out the statistical analysis. All authors analysed and interpreted the data and critically revised the manuscript for important intellectual content. CDF supervised the study. SS had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and is guarantor. SS and YKL contributed equally to this work.

  • Funding: SS is supported by a grant from the National Center for Research Resources, a component of the National Institutes of Health (No 1KL2RR025006-03), and National Institutes of health Roadmap for Medical Research. The contents of this study are solely the responsibility of the authors and do not necessarily represent the official view of National Center for Research Resources or the National Institutes of Health. The design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript was independent of any sources of funding.

  • Competing interests. All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any companies for the submitted work; PE has received about $30 000 (£18 000; €21 000) from Pfizer to review the quality of spirometry tests done for an international study of varenicline for smoking cessation in patients with chronic obstructive pulmonary disease; no author has non-financial interests that may be relevant to the submitted work; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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