Gly/Form/Bud Triple Therapy Reduces All-Cause Mortality versus Dual Therapy in COPD: ETHOS Study

27 Apr, 21

Introduction

Triple therapy with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ?₂-agonist (LABA) has been associated with a reduction in all-cause mortality as compared to LAMA/LABA as demonstrated by two long-term phase 3 trials – ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) and IMPACT (Informing the Pathway of COPD Treatment). In the ETHOS study, triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 out of 8509 intent-to-treat (ITT) population were missing vital status data at week 52. It is necessary to evaluate the mortality outcomes thoroughly given the clinical importance of this endpoint.

Aim

The robustness of the ETHOS mortality findings was evaluated after additional data retrieval for patients missing week 52 vital status in the original analyses.

Patient Profile

Age 40 to 80 years with symptomatic COPD (defined as a score of ≥10 on the COPD Assessment Test)
A postbronchodilator FEV₁ of 25 to 65% of the predicted normal value
Smoking history of at least 10 pack-years
History of >1 moderate or severe COPD exacerbation (if their FEV₁ was <50% of the predicted normal value) or >2 moderate or >1 severe COPD exacerbation (if their FEV₁ was ≥50% of the predicted normal value) in the year before screening

Method

Study Design

Randomized, double-blind, parallel-group, 52-week, phase 3 trial

Treatment Strategy

Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 ?g of BGF (BGF 320), 160/18/9.6 ?g of BGF (BGF 160), 18/9.6 ?g of GFF, or 320/9.6 ?g of budesonide/formoterol fumarate (BFF).

End Points

Time to death (all-cause)

Results

The intent-to-treat (ITT) population comprised 8509 patients.
The final retrieved dataset included week 52 vital status for 99.6% of the ITT population.
The risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; unadjusted P = 0.0035) in the final retrieved dataset, which was consistent with the findings in the original dataset.
As in the original dataset, BGF 320 reduced numerically the mortality as compared to BFF (hazard ratio, 0.72; p = 0.1721)
There were no significant differences in mortality with BGF 160 vs GFF and BFF.
Two tipping-point analyses using imputation of HRs showed that the post-withdrawal hazards for BGF 320 would have to be more than 230 and 227 times higher than pre-withdrawal hazards, respectively, for the comparison with GFF to lose significance in the final retrieved dataset.
Similar results were observed when the first 30, 60, or 90 days of treatment were excluded from the analysis.
HR for BGF 320 versus GFF remained relatively stable throughout the duration of the study when all deaths before each time point were excluded; suggesting a persistent effect even throughout the second half of the treatment period, in which the impact of acute ICS withdrawal would have been anticipated to be minimal.
A risk reduction of at least 34% (prior ICS subgroup) or 27% (overall population) was demonstrated throughout the study up to Day 350, indicating a robust risk reduction that was not driven by an early period of acute withdrawal effects.
Deaths attributed to 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.
The rates of moderate or severe exacerbations and severe exacerbations were higher in patients who died (2.20 and 0.80 per year respectively) than whose who did not die
Among the patients who died on treatment in the BGF 320 group, 36.0% and 60.0% had not experienced a moderate or severe exacerbation or severe exacerbation, respectively.
The benefit of BGF 320 versus GFF was shown across all subgroups of prior exacerbation history and baseline post-bronchodilator FEV₁% predicted, with numerically larger effect sizes in patients with two or more exacerbations in the previous year or a post-bronchodilator FEV₁ ≥50% predicted.

Conclusions

Triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) 320 resulted in reduction of all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF), in patients with moderate to severe COPD and a history of exacerbations.
Triple therapy with BGF 320 lowered, but not significantly, the risk of death compared with budesonide/formoterol fumarate (BFF).
There was no significant difference in the risk of death with triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) versus the dual therapy comparators.

Am J Respir Crit Care Med. 2021 Mar 1; 203(5): 553–564. Doi: 10.1164/rccm.202006-2618OC.