Spiriva Respimat inhaler as safe as HandiHaler (TIOSPIR)
Tiotropium: Safe In Either Form
Tiotropium (Spiriva) comes in two devices: the Respimat in Europe delivers a mist, while the Handihaler in the U.S. delivers a dry powder. The Respimat has been bronchodilating under a dark cloud in Europe for the past 2 years, since a BMJ meta-analysis suggested there was a 52% increased risk of death -- particularly from cardiovascular disease -- among people using the Respimat. The theory went that the mist could expose people to higher concentrations of drug that had pro-arrhythmogenic or other adverse cardiovascular effects. It was reported that the Respimat was denied FDA approval in the U.S. based on initial negative safety data (which had not impressed the European regulators unduly). There were calls for a worldwide recall of the Spiriva Respimat. Boehringer Ingelheim and Pfizer rebutted these charges with their own patient-level meta-analysis, but the safety concerns didn't go away. Now Spiriva's makers and marketers are having what looks like the last laugh, with the publication of the TIOSPIR trial in the September 2013 New England Journal of Medicine, showing no difference in safety outcomes between the Respimat and Handihaler forms of Spiriva. This trial was reportedly mandated by the FDA to answer the lingering questions about safety. Investigators randomized a staggering 17,135 people with COPD (including many with heart disease) to receive the Respimat or Handihaler forms of Spiriva and followed them for 2 years. There was no difference in death from any cause, the primary outcome (hazard ratios of ~1.00), nor were there any differences in deaths from cardiac causes or major cardiovascular events. Efficacy appeared equivalent as well, with a hazard ratio of 0.98 for having a COPD exacerbation during the trial.

Tiotropium Respimat
(source: Boehringer-Ingelheim) Tiotropium HandiHaler
(source: Boehringer-Ingelheim) Regarding tiotropium's cardiovascular safety in general, a 2008 JAMA meta-analysis argued that anticholinergics (including trials of tiotropium and ipratropium) increased cardiovascular death, as did one in Annals of Internal Medicine. However, the UPLIFT trial data (in which the U.S. Handihaler was used) showed no excess risk from tiotropium over placebo for death or cardiac events. A meta-analysis in Chest 2010 including 19,000 patients showed a risk reduction of 0.77 for death among those taking tiotropium. The UPLIFT randomized trial data more than assuaged the FDA's concerns about tiotropium's safety in general. The TIOSPIR trial may do the same for the Respimat inhaler in Europe, and conceivably open the door to regulatory approval of the Respimat for U.S. use. Robert A. Wise, et al. Tiotropium Respimat Inhaler and the Risk of Death in COPD. NEJM 2013; 369:1491-1501.