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

Robert A Wise, Peter Ma Calverley, Kerstine Carter, Emmanuelle Clerisme-Beaty, Norbert Metzdorf, Antonio Anzueto, Robert A Wise, Peter Ma Calverley, Kerstine Carter, Emmanuelle Clerisme-Beaty, Norbert Metzdorf, Antonio Anzueto

Abstract

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: HandiHaler; Respimat Soft Mist inhaler; TIOSPIR; exacerbations; preventive treatment; seasonality; tiotropium.

Conflict of interest statement

Disclosure RAW reports personal fees and grants from Boehringer Ingelheim during the conduct of the study. He reports personal fees from AstraZeneca, Boehringer Ingelheim, ContraFect, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Pulmonx, Roche, Spiration, Sunovion, Teva, Theravance, Verona, and Vertex; and grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Pearl Therapeutics outside the submitted work. PMAC reports grants and personal fees from GlaxoSmithKline and Takeda; personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Zambon, and Recipharm; and non-financial support from Boehringer Ingelheim outside the submitted work. KC and EC-B are employees of Boehringer Ingelheim Pharmaceuticals, Inc. NM is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. AA reports grants and personal fees from GlaxoSmithKline, and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Numbers of exacerbations and incidence rates per 1,000 patient-months of exposure adjusted by hemisphere. Note: (A) Number of all exacerbations, (B) occurrence of first exacerbation, (C) number of all severe exacerbations, (D) occurrence of first severe exacerbation, and (E) exacerbation incidence rates. Abbreviations: NH, northern hemisphere; SH, southern hemisphere.
Figure 2
Figure 2
Mean frequency of all-cause deaths (per month as a percentage of the total deaths occurring over the study) and incidence rates of all-cause deaths per 1,000 patient-months of exposure. Note: (A) Northern hemisphere: percentage of deaths, (B) northern hemisphere: incidence rate, (C) southern hemisphere: percentage of deaths, (D) southern hemisphere: incidence rate, (E) hemisphere adjusted percentage of deaths, and (F) hemisphere adjusted incidence rate. Abbreviations: NH, northern hemisphere; SH, southern hemisphere.
Figure 2
Figure 2
Mean frequency of all-cause deaths (per month as a percentage of the total deaths occurring over the study) and incidence rates of all-cause deaths per 1,000 patient-months of exposure. Note: (A) Northern hemisphere: percentage of deaths, (B) northern hemisphere: incidence rate, (C) southern hemisphere: percentage of deaths, (D) southern hemisphere: incidence rate, (E) hemisphere adjusted percentage of deaths, and (F) hemisphere adjusted incidence rate. Abbreviations: NH, northern hemisphere; SH, southern hemisphere.
Figure 3
Figure 3
Mean numbers and incidence rates per 1,000 patient-months of exposure for cause-specific deaths adjusted for hemisphere. Note: (A) Number of MACE-related deaths, (B) incidence rate of MACE-related deaths, (C) number of respiratory-related deaths, (D) incidence rate of respiratory-related deaths, (E) number of neoplasm-related deaths, (F) incidence rate of neoplasm-related deaths, (G) number of other-related deaths, (H) incidence rate of other-related deaths. Abbreviations: MACE, major adverse cardiac event; NH, northern hemisphere; SH, southern hemisphere.
Figure 3
Figure 3
Mean numbers and incidence rates per 1,000 patient-months of exposure for cause-specific deaths adjusted for hemisphere. Note: (A) Number of MACE-related deaths, (B) incidence rate of MACE-related deaths, (C) number of respiratory-related deaths, (D) incidence rate of respiratory-related deaths, (E) number of neoplasm-related deaths, (F) incidence rate of neoplasm-related deaths, (G) number of other-related deaths, (H) incidence rate of other-related deaths. Abbreviations: MACE, major adverse cardiac event; NH, northern hemisphere; SH, southern hemisphere.

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Source: PubMed

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