Abstract
Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33–0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44–1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.
Highlights
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally (1)
All-cause mortality was a secondary endpoint in ETHOS, which evaluated triple therapy at two different inhaled corticosteroid (ICS) doses versus dual therapy with glycopyrrolate/formoterol fumarate metered dose inhaler (GFF; LAMA/LABA) or budesonide/formoterol fumarate metered dose inhaler (BFF; ICS/LABA) (7)
In the 52-week ETHOS trial, triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) 320 reduced the risk of death versus GFF and numerically reduced risk versus BFF in patients with moderate-to-very severe COPD and a history of exacerbations (7)
Summary
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally (1). Pharmacological treatments for COPD include bronchodilators (long-acting muscarinic antagonist [LAMA] and/or long-acting β2-agonist [LABA]), which may be combined with an inhaled corticosteroid (ICS) (2). These medications improve lung function and symptoms, and reduce the frequency of COPD exacerbations; to date, clinical trial data have provided inconsistent evidence of benefits on mortality (2). Two long-term trials that assessed ICS/LABA therapy in moderate or moderate-to-very severe COPD failed to demonstrate a significant difference in all-cause mortality versus placebo, despite trends in favor of the active treatments (4, 5). For the all-cause mortality endpoint in ETHOS, which included deaths that occurred on- and off-treatment, there was a 46% risk reduction with the 320-μg budesonide dose (and a non-significant, 22% reduction with the 160-μg dose) versus GFF, suggesting a possible dose-response effect of ICS therapy on mortality. In the IMPACT trial, which assessed all-cause mortality as a pre-specified other endpoint, there was a 29% risk reduction with fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 μg (ICS/LAMA/LABA) versus umeclidinium/vilanterol 62.5/25 μg (LAMA/LABA), including on- and off-treatment deaths (6)
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