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Review
. 2011 Jun 14:342:d3215.
doi: 10.1136/bmj.d3215.

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

Sonal Singh  1 , Yoon K Loke, Paul L Enright, Curt D Furberg
Affiliations
Review

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

Sonal Singh et al. BMJ. .

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.

Data sources: 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.

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 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.

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Conflict of interest statement

Competing interests. All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (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.

Figures

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Fig 1 Flow of participants through review
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Fig 2 Fixed effects meta-analysis of tiotropium delivered by mist inhaler (Respimat Soft Mist Inhaler; Boehringer Ingelheim) and risk of mortality in randomised controlled trials of chronic obstructive pulmonary disease
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Fig 3 Meta-analysis of tiotropium delivered by mist inhaler (Respimat Soft Mist Inhaler; Boehringer Ingelheim) 5 µg and 10 µg and risk of mortality in randomised controlled trials of chronic obstructive pulmonary disease
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Fig 4 Sensitivity analysis of tiotropium delivered by mist inhaler (Respimat Soft Mist Inhaler; Boehringer Ingelheim) and risk of mortality in randomised controlled trials of chronic obstructive pulmonary disease after including data from additional trial
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Fig 5 Meta-analysis of tiotropium delivered by mist inhaler (Respimat Soft Mist Inhaler; Boehringer Ingelheim) and risk of cardiovascular death in randomised controlled trials
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