A systematic review and meta-analysis found that in randomised controlled trials (RCT), use of the Respimat mist inhaler was associated with increased mortality compared to placebo in patients with chronic obstructive pulmonary disease (COPD).

Tiotropium is effective in providing symptomatic benefit in patients with COPD. It is available in two formulations, the Handihaler, which is a dry powder inhaler (DPI), and the Respimat device. The Respimat delivers the drug in solution as a fine mist, and is recommended for patients with difficulty in using the DPI. Bioavailability and peak blood levels from the Respimat are significantly higher than from the DPI. There evidence of an increased risk of cardiovascular adverse effects from inhaled anticholinergic drugs, and the authors of this study became aware of concerns over mortality differences in clinical trials of the Respimat device. This systematic review and meta-analysis was intended to examine the evidence behind these concerns. The authors carried out a comprehensive literature search for randomised placebo-controlled trials of tiotropium mist inhaler that lasted at least 30 days and where mortality data were reported. Fixed effect meta-analysis was used to estimate relative risks (RR) of all cause mortality, and heterogeneity was assessed with the I^2 statistic.

The initial search yielded 57 potentially relevant articles, of which 14 were reviewed in full (reason for exclusion, not RCT in COPD) and 5 (n=6,522; tiotropium 3,686, placebo 2,836) were eligible for the meta-analysis. A sixth study reported preliminary results and was used in a sensitivity analysis. Across the five trials, 137 patients died and tiotropium mist inhaler was associated with a significantly increased risk of mortality compared with placebo (90 vs. 47; RR 1.52; 95% CI, 1.06 to 2.16; P=0.02; I^2=0%). Both doses of tiotropium were associated with increased risk: 10 microg (RR 2.15;  95% CI 1.03 to 4.51; P=0.04; I^2=9%) and 5 microg (RR1.46;  95% CI 1.01 to 2.10; P=0.04; I^2=0%). The results were not substantially affected by sensitivity analyses.

Based on the average control event rate from the long term trials, the authors estimated a number needed to treat for a year with the 5 microg dose to see one additional death: this was 124, however because of the small numbers the confidence interval was wide (95% CI 52 to 5682). They conclude that in this analysis, there was an increased risk of death associated with use of the tiotropium mist inhaler compared to placebo. There was suggestion of a dose-response effect, however the numbers involved were too small for this to be robust. They note the limitations of their analysis, but comment that the trials were done in a standardised manner and there is biological plausibility. An ongoing trial that is comparing the two formulations will clarify some of the uncertainties, and other work will provide more information on the use of inhaled anticholinergic drugs in high-risk populations.

An accompanying Editorial comments on the study and while noting that the use of relative risks in studies of this type is valid, he emphasises that the absolute risks were low: mortality in trials that lasted a years was 1.8% vs. 2.6% to give a difference of 0.8% or 8 patients in 1,000. The NNT for harm form this estimate was 121, again with a wide confidence interval (95% CI 51 to 5,556). The point estimate was, however, considerably larger than that for salmeterol in asthma. He concludes that until the comparative trial data are available the DPI would be the safer option, and patients who prefer the mist inhaler should be counselled on the possible increased risk.

The journal ‘Evidence Based Medicine’ has featured a commentary on this research, noting the following:

• The comparison with placebo was clinically important and relevant; previous studies have used inappropriate controls (e.g. salmeterol in the POET-COPD study)

• Although a possible explanation for the increased mortality seen with Spiriva Respimat could be due to higher reported peak plasma concentrations compared with those achieved with the Handihaler device, this is at odds with research previously conducted by the authors

• Concern of a possible increased risk of cardiovascular mortality in association with long-acting anticholinergics in the treatment of COPD has consistently been reported in the literature and the authors say the results of this systematic review provide ‘conclusive evidence’, and that appropriate action should be urgently taken

• They call on the manufacturer to update and include a contraindication in the Spiriva Respimat SPC to inform all prescribers that patients with pre-existing arrhythmias are at the highest risk of death from its use. In the meantime, all prescribers should exercise caution in recommending tiotropium in the Respimat delivery system for patients with COPD.