Wise_2013_N.Engl.J.Med_369_1491

BACKGROUND: Tiotropium delivered at a dose of 5 mug with the Respimat inhaler showed efficacy similar to that of 18 mug of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.
METHODS: In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 mug or 5 mug, as compared with tiotropium HandiHaler at a once-daily dose of 18 mug. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 mug or 2.5 mug vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 mug vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease.
RESULTS: During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 mug vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 mug vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 mug vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups.
CONCLUSIONS: Tiotropium Respimat at a dose of 5 mug or 2.5 mug had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 mug in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).