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.
- Martinez, F. J.
- Rabe, K. F.
- Ferguson, G. T.
- Wedzicha, J. A.
- Singh, D.
- Wang, C.
- Rossman, K.
- St Rose, E.
- Trivedi, R.
- Ballal, S.
- Darken, P.
- Aurivillius, M.
- Reisner, C.
- Dorinsky, P.
Keywords
- Aged
- Bronchodilator Agents/*therapeutic use
- Budesonide/*therapeutic use
- Cause of Death
- Double-Blind Method
- Drug Therapy, Combination
- Female
- Forced Expiratory Volume
- Formoterol Fumarate/*therapeutic use
- Glucocorticoids/*therapeutic use
- Glycopyrrolate/*therapeutic use
- Humans
- Kaplan-Meier Estimate
- Male
- Middle Aged
- *Mortality
- Muscarinic Antagonists/*therapeutic use
- Proportional Hazards Models
- Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology
- Severity of Illness Index
- *BGF metered-dose inhaler
- *chronic obstructive pulmonary disease
- *inhaled corticosteroids/long-acting muscarinic antagonist/long-acting β2-agonist
- *triple therapy