A pooled analysis of mortality in patients with COPD receiving dual bronchodilation with and without additional inhaled corticosteroid

Marc Miravitlles* (Corresponding Author), Katia M.C. Verhamme, Peter M. A. Calverley, Michael Dreher, Valentina Bayer, Asparuh Gardev, Alberto de la Hoz, Jadwiga A Wedzicha, David Price

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
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Background: Recent studies report a lower mortality rate during treatment with long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist LABA)/inhaled corticosteroid (ICS) versus LAMA/LABA in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations.
Objective: We compared time to all-cause mortality with LAMA/LABA versus LAMA/LABA/ICS in patients with mild-to-very-severe COPD and a predominantly low exacerbation risk.
Methods: Data were pooled from six randomized controlled trials (TONADO 1/2, DYNAGITO, WISDOM, UPLIFT and TIOSPIR; LAMA/LABA: n=3,156, LAMA/LABA/ICS: n=11,891). Analysis was on24 treatment and data were censored at 52 weeks. Patients on LAMA/LABA/ICS received ICS prior to study entry, which was not withdrawn at randomization. Patients on LAMA/LABA/ICS were propensity score (PS)-matched to patients on LAMA/LABA who had not previously received ICS; covariates included age, sex, geographical region, smoking status, post-bronchodilator forced expiratory volume in 1 second percent predicted, exacerbation history in previous year, body mass index and time since diagnosis. Time to all-cause mortality was assessed using Cox proportional hazard regression models.

Results: After PS matching, 3,133 patients on LAMA/LABA and 3,133 on LAMA/LABA/ICS were analyzed. Fewer than 20% of patientsreported ≥2 exacerbationsin the prior year(LAMA/LABA: 19.1%; LAMA/LABA/ICS: 19.0%). There were 41 (1.3%) deaths on LAMA/LABA and 45 (1.4%) on LAMA/LABA/ICS. No statistically significant difference in time to death was observed between
treatment arms (hazard ratio for LAMA/LABA 1.06; 95% confidence intervals 0.68, 1.64; P=0.806).

Sensitivity analyses conducted using different covariates or in an intent-to-treat population showed similar results.
Conclusion: This pooled analysis of over 6,000 patients with mild-to-very-severe COPD and predominantly low exacerbation risk showed no differences in mortality with LAMA/LABA versus LAMA/LABA/ICS, suggesting that the survival benefit of triple therapy seen in some recent studies may be specific to a high-risk population. This supports current Global Initiative for Chronic Obstructive
Lung Disease (GOLD) recommendations that triple therapy should be reserved for the subpopulations of patients who need it the most (eg, those with an eosinophilic phenotype and a high risk of exacerbations) to avoid ICS overuse.
Original languageEnglish
Pages (from-to)545—558
Number of pages14
JournalInternational journal of chronic obstructive pulmonary disease
Issue number17
Early online date11 Mar 2022
Publication statusPublished - 11 Mar 2022

Bibliographical note

Support for this project was provided by Boehringer Ingelheim International GmbH (BI). The authors did not receive payment related to the development of the manuscript. Medical writing assistance, in the form of the preparation and revision of the manuscript, was supported financially by BI and provided by Vicki Cronin of MediTech Media, under the authors’ conceptual direction and based on feedback from the authors. BI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The authors would like to thank Wenqiong Xue for her contributions to the statistical analysis.


  • COPD
  • exacerbation history
  • inhaled corticosteroid
  • long-acting β2-agonist
  • long-acting muscarinic antagonist
  • mortality


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