Tiotropium Inhaler Devices: Seeking Convenience When Mortality Is at Stake?

To the Editor:

In their very interesting study on the effect of switching tiotropium HandiHaler to Respimat Soft Mist inhaler, in patients with chronic obstructive pulmonary disease (COPD), Asakura et al.⁽¹⁾ showed that patients considered Respimat easier to use, while there was also a trend toward less adverse effects with Respimat. However, the major reservation on the new inhaler, regarding the possible increase in COPD mortality, is not taken into account. A large ongoing multicenter study is currently investigating this observation,⁽²⁾ while data from a recent meta-analysis of randomized controlled trials suggests that Respimat mist inhaler is associated with 52% increased risk of mortality compared with tiotropium HandiHaler, with a number needed to harm of 124 for Respimat 5 μg in patients with COPD.⁽³⁾ Furthermore, although lower doses of tiotropium are administered because of the improved lung drug deposition, and unlike the reasonable assumption that the lower tiotropium doses would result in lower circulating levels and adverse events, a recent study by van Noord et al. suggested that both 5- and 10-μg doses of tiotropium administered via Respimat mist inhaler are associated with higher peak plasma concentrations and higher urine excretion compared with 8-μg tiotropium HandiHaler.⁽⁴⁾ This finding could predict an increased rate of sudden cardiac deaths, as a result of the known arrhythmogenic properties of long-acting muscarinic antagonists. Consequently, large long-term studies are needed to access the comparative benefits of the different inhaler devices.