Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide.1,2 Patients with COPD often experience exacerbations which are defined as periods of acute worsening of respiratory symptoms necessitating additional treatment.3 Exacerbations contribute to the overall disease burden experienced by patients with COPD, with patients with frequent or prolonged exacerbations shown to have worse health status and faster disease progression compared with patients with infrequent exacerbations.4 Additionally, exacerbations are also associated with increased medical costs and health care resource utilization, with the highest clinical and financial burden associated with severe exacerbations requiring hospitalization.5-8 Finally, as well as recent prior COPD exacerbations being a risk factor for future exacerbations,3,9,10 studies have indicated that exacerbations are associated with an increased risk of all-cause mortality,10-13 and adverse cardiovascular (CV) events.14-16

The InforMing the Pathway of COPD Treatment (IMPACT) trial evaluated once-daily single-inhaler triple therapy with inhaled corticosteroid (ICS) /long-acting muscarinic receptor antagonist (LAMA) /long-acting beta2-agonist (LABA), fluticasone furoate/umeclidinium/vilanterol versus dual therapy with ICS/LABA, fluticasone furoate/vilanterol, or LAMA/LABA, umeclidinium/vilanterol, in patients with symptomatic COPD and a history of exacerbations.17 Treatment with fluticasone furoate/umeclidinium/vilanterol significantly reduced the annual rate of moderate/severe exacerbations versus fluticasone furoate/vilanterol and umeclidinium/vilanterol,17 in addition to a significant reduction in all-cause mortality with fluticasone furoate/umeclidinium/vilanterol compared with umeclidinium/vilanterol.18 Despite these observed benefits, previous studies have indicated that the use of ICSs may be associated with an increased risk of pneumonia in patients with COPD.17,19-21 However, a recent post hoc analysis of IMPACT demonstrated an overall net benefit of triple therapy in this patient population as indicated by an overall decreased risk of death despite an increased risk of pneumonia in patients treated with ICS-containing therapies.18,22 An additional concern with the use of bronchodilators is their reported association in some studies with an increased risk of CV events,23 although data are conflicting regarding this finding.24 Therefore, it is of interest to consider the risk of cardiopulmonary events when performing benefit-risk assessments of treatments for patients with COPD.

Using the IMPACT trial population, this post hoc analysis aimed to investigate the risk of all-cause mortality during and following a moderate/severe exacerbation, and to further determine the benefit-risk profile of fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol and umeclidinium/vilanterol by using a cardiopulmonary composite endpoint including exacerbations, pneumonia, CV events, and death during the study period.