Tiotropium Respimat inhaler and the risk of death in COPD.

BACKGROUND: Tiotropium delivered at a dose of 5 µg with the Respimat inhaler showed efficacy similar to that of 18 µg 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 µg or 5 µg, as compared with tiotropium HandiHaler at a once-daily dose of 18 µg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 µg or 2.5 µg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 µg 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 µg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 µg 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 µg 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 µg or 2.5 µg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 µg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.).

The Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationale.

BACKGROUND: Tiotropium bromide is an effective therapy for COPD patients. Comparing across programs tiotropium Respimat Soft Mist inhaler was at least as efficacious as tiotropium HandiHaler, however, concerns have been raised about tiotropium's safety when given via Respimat. METHODS: The TIOSPIR trial (NCT01126437) compares the safety and efficacy of tiotropium Respimat 5 µg once daily (marketed) and 2.5 µg once daily (investigational) with tiotropium HandiHaler 18 µ once daily (marketed). The hypotheses to be tested are 1). that tiotropium Respimat 5 µg once daily and Respimat 2.5 µg once daily are non-inferior to HandiHaler in terms of all-cause mortality, and 2). that tiotropium Respimat 5 µg once daily is superior to HandiHaler in terms of time to first exacerbation. A spirometry substudy evaluates the bronchodilator efficacy. The trial is a randomized, double-blind, double dummy, event-driven, parallel group study. Participants can use any background treatment for COPD except inhaled anticholinergic agents. The study encompasses a wide range of COPD patients, e.g. patients with stable cardiac diseases including arrhythmia can be included. Clinical sites are international and include both primary care as well as specialists. RESULTS: To date, over 17,000 participants have been randomized from over 1200 sites in 50 countries with an anticipated treatment duration of 2-3 years. CONCLUSION: TIOSPIR will provide precise estimates of the relative safety and efficacy of the Respimat and HandiHaler formulations of tiotropium, assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort.

Childhood appendicitis in the United Kingdom: fifty years of progress.

The number of in-hospital deaths in children aged 0 to 14 years from acute appendicitis in England and Wales has fallen from an annual average of 36.2 in 1963 through 1967 to 1.8 in 1993 through 1997, and the case-fatality rate from 1.06 to 0.16 per 1,000 discharges, a reduction of 85%. During these 4 decades, the child population has fallen by 8.5%, and the number of children discharged from the hospital with a diagnosis of acute appendicitis by 63%. These data highlight a trend noted in Scotland in the first 50 years of the 20th century. Approximately three quarters of the fall in the number of deaths from acute appendicitis since 1963 is accounted for by a lower incidence of appendicitis in a slightly reduced child population. A quarter of the fall is caused by a marked decline in the hospital case-fatality rate during the last 30 years, likely to be related to improvements in clinical care. Delay in diagnosis is the main contributory factor in the residual small number of deaths each year. Despite the availability of numerous diagnostic aids, clinical acumen remains a fundamental component of expert management of acute appendicitis in children.