Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR® trial

Robert A Wise,1 Peter MA Calverley,2 Kerstine Carter,3 Emmanuelle Clerisme-Beaty,4 Norbert Metzdorf,5 Antonio Anzueto6 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Respiratory Medicine, University Hospital Aintree, Liverpool, UK; 3Biostatistics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 4Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 5Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany; 6Department of Pulmonary Diseases and Critical Care Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX, USA Background: Although COPD exacerbations are known to occur more frequently in winter, there is little information on hospitalizations and cause-specific mortality. This study aimed to examine seasonal variations in mortality and exacerbations in patients with COPD during the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial. Patients and methods: TIOSPIR was a large-scale, multicenter trial, which assessed the safety and efficacy of tiotropium delivered via HandiHaler® (18 µg once daily) or Respimat® Soft Mist™ (2.5 or 5 µg once daily) inhaler in patients with COPD. Patients were aged ≥40 years, with a smoking history ≥10 pack-years, and post-bronchodilator forced expiratory volume in 1 second ≤70% and forced expiratory volume in 1 second/forced vital capacity ≤0.70. COPD exacerbations and deaths were monitored throughout the trial. The data were pooled to examine seasonal patterns. Southern hemisphere data were shifted by 6 months to align with northern hemisphere seasons. Results: TIOSPIR was conducted in 43 northern (n=15,968) and 7 southern (n=1,148) hemisphere (n=1,148) countries. The median duration of treatment was 835 days, with a mean follow-up of 2.3 years. Among 19,494 exacerbations, there were clear seasonal differences (winter, 6,646 [34.1%]; spring, 4,515 [23.2%]; summer, 3,198 [16.4%]; autumn, 5,135 [26.3%]). Exacerbations peaked in early winter (December in the northern hemisphere and June in the southern hemisphere), respiratory hospitalizations in midwinter, and respiratory deaths in early spring. Conclusion: Although winter poses a 2-fold hazard for COPD exacerbations vs summer, respiratory deaths peak in early spring. These data suggest that seasonal intensification of preventive treatments may impact COPD morbidity and mortality. Trial registration number: NCT01126437. Keywords: TIOSPIR, tiotropium, HandiHaler, Respimat Soft Mist inhaler, seasonality, preventive treatment, exacerbations