Mr. C, a 65-year-old male with a 30 pack-year smoking history and a cardiac arrhythmia, comes to your office for treatment of his COPD. He has been well controlled on a regimen including tiotropium delivered by a dry powder inhaler called a HandiHaler. He plans to move to Europe to be near his family, but wondered whether the tiotropium device commonly used in Europe, the Respimat was equivalent to his Handihaler. Until recently there had been some concerns about the safety of the Respimat inhaler; a post-hoc pooled analysis in 2011 showed an increased rate of mortality associated with the Respimat inhaler as compared with placebo. This effect was particularly significant in patients with underlying cardiac disease.
To address these concerns, the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial was initiated; the results are published in this week’s NEJM. The authors conducted a large-scale, randomized, prospective trial that evaluated the safety and efficacy of 2.5 ug or 5 ug of tiotropium delivered by Respimat inhaler vs. 18 ug of tiotropium delivered by HandiHaler; these doses have equivalent bronchodilator effects. The authors enrolled 17,135 patients with COPD, including many with concomitant stable cardiac disease, and followed them for over 2 years. In terms of the primary outcome, there was no significant difference in death from all causes between the three groups (hazard ratio for Respimat 5 ug vs. HandiHaler was 0.96; hazard ratio for Respimat 2.5 ug vs. HandiHaler was 1.00). Adjudicated causes of death did not significantly differ across the three groups, including cardiac causes. In addition, there was no significant difference in the risk of the first COPD exacerbation between the Respimat 5 ug and HandiHaler groups (hazard ratio of 0.98). These data show no differences in terms of efficacy or safety between the two formulations of tiotropium.
In an accompanying editorial, Christine R. Jenkins, M.D., praises this trial for its rigorous and inclusive nature. She notes that often large-scale, prospective trials are only performed to uncover statistical differences in efficacy but not in safety. In this case, the authors powered the trial such that they could test the assumption that the Respimat formula of tiotropium is associated with increased mortality. In addition, she commends the authors for including a heterogenous population of COPD patients, which is more representative of the typical patients that walk into clinic. This trial not only helps physicians breathe easier when treating their patients with the Respimat formulation of tiotropium, but also sets a high standard for clinical trials involving patients with COPD. Now, Mr. C need not worry as he picks up life and moves to Europe.