1. Does tiotropium lower exacerbation and hospitalization frequency in COPD patients?
Results of a meta-analysis
Van den Bruel A, Gailly J, Neyt M
CRD summary
The authors concluded that tiotropium reduced the number of exacerbations and hospitalisations of chronic obstructive
pulmonary disease (COPD) patients compared with placebo and ipratropium; compared with salmeterol, only the
exacerbation frequency was reduced. Given the variability across trials, the possibility of inappropriate pooling and the
poor quality of the evidence base, the authors’ conclusions should be interpreted with caution.
Authors' objectives
To estimate the effect of tiotropium (a long-acting anticholinergic inhalant) on exacerbation and chronic obstructive
pulmonary disease (COPD)-related hospitalisation frequency.
Searching
MEDLINE, EMBASE, INAHTA (International Network of Agencies for Health Technology Assessment), CRD
databases and the Cochrane Library were searched with no language restrictions up to November 2008; search terms
were reported. Websites of the US Food and Drug Administration, European Medicines Agency and NICE were
searched for unpublished studies, as were clinical trial registries. Experts in the field and the manufacturers of
tiotropium were also contacted to identify further studies.
Study selection
Randomised controlled trials (RCTs) that compared tiotropium with placebo, ipratropium bromide or long-acting
beta2-agonists in patients with stable chronic obstructive pulmonary disease (COPD) were eligible for inclusion. Stable
COPD was defined as no exacerbation one month prior to trial entry. Eligible trials had to have a follow-up of at least
12 weeks after randomisation. Concomitant medications were allowed including short-acting or long-acting
beta2-agonists, and oral or inhalant glucocorticosteroids. Only reviews with a sensitive search strategy in several
databases plus explicit criteria for inclusion and exclusion were eligible.
Outcomes comprised the number of exacerbations and the number of hospitalisations per patient year.
In the included trials, mean patient age ranged from 63.6 to 77.4 years; their baseline forced expiratory volume (FEV1)
ranged from 36 to 51% predicted. Included patients had smoked at least 10 pack years and suffered from moderate to
severe COPD. Most trials defined exacerbations as at least one or two new or increased respiratory symptoms (such as
cough, wheeze, dyspnoea, chest congestion, shortness of breath or sputum production) that necessitate a change in
treatment, although some trials a purely symptom-based definition not necessarily leading to change in treatment.
Papers were checked for eligibility by two reviewers; disagreements were resolved by consensus.
Assessment of study quality
Trial quality was assessed using the checklist of the Dutch Cochrane Centre. The checklist assessed: adequate
sequence generation and allocation concealment; blinding of patients, personnel and assessors; intention-to-treat
analysis; and absence of selective reporting.
The authors did not state how many reviewers performed the quality assessment.
Data extraction
Two reviewers independently extracted the number of exacerbations and the number of hospitalisations to calculate
mean differences and 95% confidence intervals (CIs). Where missing data was apparent, trial authors and drug
manufacturers were contacted.
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2. Methods of synthesis
Data were pooled using a fixed-effects model based on the generic inverse-variance approach (when no heterogeneity
was present, defined as I2
≤25%); a random-effects model was used when heterogeneity was present. Heterogeneity
was assessed using I2
. Sensitivity analysis was performed by removing the trials causing heterogeneity.
Publication bias was tested using funnel plots and Egger’s test.
Results of the review
Nine trials were included in the review (n=13,103 patients, range 142 to 5,992). Two trials reported adequate
concealment of allocation. Most trials did not perform an intention-to-treat analysis for all outcomes reported. All
trials were reported to be double blind, but none described blinded outcome assessment. All included trials were
sponsored by the pharmaceutical company marketing tiotropium or the comparator drug. Trial duration varied from six
to 48 months.
Exacerbation frequency: Tiotropium reduced the number of exacerbations per patient year by 0.31 (95% CI 0.46 to
0.17; seven trials; I2
=91%) compared with placebo and by 0.23 exacerbations per patient year (95% CI 0.31 to 0.15;
one study) compared with ipratropium. There was a significant difference in exacerbation frequency between
tiotropium and the long-acting beta2-agonist salmeterol (-0.16; 95% CI -0.29 to -0.03; one study). Removal of the trial
causing heterogeneity in the tiotropium versus placebo analysis did not significantly alter the results.
COPD-related hospitalisation frequency: Tiotropium reduced the number of hospitalisations per patient year compared
with placebo (-0.04, 95% CI -0.08 to -0.01; five trials; I2
=84%) and compared with ipratropium (-0.06, 95% CI -0.09
to -0.03; one trial).
Assessment of publication bias using funnel plots could not be performed as fewer than 10 trials were included.
Authors' conclusions
Statistically significant, but clinically small, effects were found for tiotropium compared with placebo and ipratropium.
The comparison with salmeterol was significant for exacerbation frequency but not for hospitalisation frequency;
however, this finding should be interpreted with caution.
CRD commentary
The review question and supporting inclusion criteria were clearly stated. The search strategy included relevant
sources and searches for unpublished studies. Attempts were made to minimise language bias. There was potential for
publication bias which could not be assessed due to the small number of included trials. Study selection and data
extraction was conducted with some attempt to minimise error and bias, but it was unclear whether this extended to
quality assessment.
An appropriate quality assessment tool was used to rate the included trials. Appropriate methods were used to assess
heterogeneity but, given its presence in the pooled analyses, it was questionable whether it was appropriate to pool the
trials. Ipratropium and salmeterol comparisons were assessed by only a single trial each; the authors acknowledged
that the finding for salmeterol should be interpreted with caution as the original trial showed a non-significant
difference, which was significance in this review.
Given the variability across trials, the possibility of inappropriate pooling and the poor quality of the evidence base,
the authors’ conclusions should be interpreted with caution.
Implications of the review for practice and research
The authors did not state any implications for practice or further research.
Funding
None.
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3. Bibliographic details
Van den Bruel A, Gailly J, Neyt M. Does tiotropium lower exacerbation and hospitalization frequency in COPD
patients? Results of a meta-analysis BMC Pulmonary Medicine 2010; 10:50
PubMedID
20858226
DOI
10.1186/1471-2466-10-50
Original Paper URL
http://www.biomedcentral.com/1471-2466/10/50/abstract/
Indexing Status
Subject indexing assigned by NLM
MeSH
Albuterol /analogs & derivatives /therapeutic use; Bronchodilator Agents /therapeutic use; Cholinergic Antagonists
/therapeutic use; Disease Progression; Hospitalization /statistics & numerical data; Humans; Ipratropium /therapeutic
use; Pulmonary Disease, Chronic Obstructive /drug therapy; Randomized Controlled Trials as Topic; Scopolamine
Derivatives /therapeutic use
AccessionNumber
12010007367
Database entry date
24/08/2011
Record Status
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract
contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on
the reliability of the review and the conclusions drawn.
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