This systemic review of the currently available randomised trials of tiotropium for stable COPD showed that tiotropium reduced COPD exacerbations and related hospitalisations compared with placebo or ipratropium. Increases in FEV1 and FVC from baseline were significantly larger with tiotropium than with placebo, ipratropium, and LABA. The decline in trough FEV1 from steady state was slower with tiotropium than with placebo or ipratropium, and pulmonary mortality was non‐significantly lower with tiotropium.
The benefits observed with tiotropium for exacerbations and related hospitalisations were large and clinically important. Consistent with these findings, tiotropium has been shown to be cost effective although not cost saving compared with ipratropium in Europe.22
The magnitude of the reduction in exacerbation related hospitalisations with tiotropium was similar in comparison with placebo, ipratropium and salmeterol, and was similar in large placebo controlled trials that did and did not permit use of LABA.
Changes in health related quality of life, symptom scales, and spirometric indices also appeared clinically significant. Compared with placebo and ipratropium, the mean change in the SGRQ across all participants was close to the clinically significant change in SGRQ of 4 units, and more participants on tiotropium achieved a clinically significant change in SQRQ and TDI compared with placebo and ipratropium. Improvements in spirometric indices from baseline were clinically significant compared with placebo and ipratropium at a threshold for FEV1
of 100 ml23
but not at a threshold of 225 ml.24
Improvements in spirometric indices from baseline were statistically but not clinically significant compared with salmeterol.
The results of this systemic review are consistent with a previous review of treatments for COPD25
which reported on exacerbations and quality of life but which was limited by double counting of patients randomised to tiotropium. Our results correct and extend that review with more than twice the number of randomised patients and additional outcomes of hospitalisations, mortality, symptom scales, spirometric indices, and adverse events.
We found that the decline in trough FEV1
from steady state was slower with tiotropium than with placebo or ipratropium. This difference was large relative to the difference observed in a meta‐analysis of inhaled corticosteroids in COPD26
and was consistent with a post hoc analysis of one of the tiotropium trials.27
However, this observation should be interpreted with caution as it might be due to (1) incomplete attainment of steady state of tiotropium at 8 days; (2) chance, given that multiple spirometric indices were measured and that the duration of the relevant trials was only 1 year; and (3) bias, given that most but possibly not all trial results for this measure were available for meta‐analysis. Larger longer term trials are necessary to assess the validity of this result, which would be of major clinical relevance if replicated.
Mortality from pulmonary causes was non‐significantly lower among those randomised to tiotropium compared with placebo or ipratropium. This finding suggests that observed benefits on exacerbations and hospitalisations might translate into reductions in pulmonary mortality, but requires evaluation in long term randomised trials designed specifically to examine pulmonary mortality. Estimates for disease‐specific mortality can be subject to more biases than all‐cause mortality, and we note that all‐cause mortality did not differ appreciably between tiotropium and placebo.
The trials included in this review were of good quality and used almost identical designs with regard to inclusion and exclusion criteria. The clinical homogeneity of the trials resulted in statistical homogeneity for most outcome measures across the trials. We calculated summary estimates of the effects of tiotropium compared with placebo and ipratropium. Heterogeneity would be introduced if ipratropium had an effect on the relevant outcomes, but ipratropium has been shown not to alter the long term decline in FEV1
hospitalisations or survival12
compared with placebo. LABA, on the other hand, may reduce exacerbations compared with placebo.25,28
Potential limitations of meta‐analyses include double counting of patients from overlapping publications, publication bias, reporting bias, and selection bias from differential inclusion of available trials. We avoided double counting by discussing trial overlap with the primary authors and the manufacturer of tiotropium, and evaluated for publication bias with funnel plots and statistical tests. Selective reporting of secondary end points and of non‐intention to treat reports in published manuscripts may bias results; we minimised this bias by obtaining supplemental data for five of the nine included studies, although complete intention to treat analyses were missing for most studies due to missing data. We avoided selection bias by pre‐specified inclusion and exclusion criteria, a systematic search, and independent evaluation of trial inclusion by two reviewers.
In conclusion, tiotropium reduced COPD exacerbations and exacerbation related hospitalisations compared with placebo or ipratropium. It also improved health related quality of life and symptom scores and can be recommended for the treatment of stable COPD. The results of this systematic review suggest that tiotropium may slow the decline in FEV1, although this finding requires confirmation in additional long term randomised clinical trials.