A Pooled Analysis of Mortality in Patients with COPD Receiving Dual Bronchodilation with and without Additional Inhaled Corticosteroid

Abstract

Marc Miravitlles,1 Katia Verhamme,2 Peter MA Calverley,3 Michael Dreher,4 Valentina Bayer,5 Asparuh Gardev,6 Alberto de la Hoz,6 Jadwiga Wedzicha,7 David Price8,9 1Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 2Department of Medical Informatics, Erasmus MC, Rotterdam, the Netherlands; 3Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; 4Department of Pneumology and Intensive Care Medicine, University Hospital Aachen, Aachen, Germany; 5Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 6Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 7Head Respiratory Division, National Heart and Lung Institute, Imperial College London, London, UK; 8Observational and Pragmatic Research Institute, Singapore; 9Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UKCorrespondence: Marc Miravitlles, Pneumology Department, Hospital Universitari Vall d’Hebron, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, CIBER de Enfermedades Respiratorias (CIBERES), P° Vall d’Hebron 119-129, Barcelona, 08035, Spain, Email [email protected]: 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 = 3156, LAMA/LABA/ICS: n = 11,891). Analysis was on-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 Patients on LAMA/LABA/ICS received ICS prior to study entry, which was not withdrawn at randomization.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, 3133 patients on LAMA/LABA and 3133 patients on LAMA/LABA/ICS were analyzed. Fewer than 20% of patients reported ≥ 2 exacerbations in 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%) deaths 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 6000 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 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.Graphical Abstract: Keywords: COPD, exacerbation history, inhaled corticosteroid, long-acting β2-agonist, long-acting muscarinic antagonist, mortality

Keywords

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