Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study

Martínez, Fernando J.; Rabe, Klaus F.; Ferguson, Gary T.; Wedzicha, Jadwiga A.; Singh, Dave; Wang, Chen; Rossman, Kimberly; Rose, Elizabeth L.; Trivedi, Roopa; Ballal, Shaila; Darken, Patrick; Aurivillius, Magnus; Reisner, Colin; Dorinsky, Paul

doi:10.1164/rccm.202006-2618oc

Cited by 163 publications

(153 citation statements)

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“…The LAMA/LABA treatment, GFF, was associated with 53% and 48% improvement in untrimmed siVaw and siRaw, respectively. The significant increase in airway volume (9%) of BGF versus GFF further supports the benefit of budesonide in patients with moderate-to-severe COPD versus LAMA/LABA [ 3 , 22 ]. The smaller benefit of BGF in reducing of airway resistance relative to GFF (3%), could indicate a plateau effect.…”

Section: Discussionmentioning

confidence: 83%

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids

et al. 2021

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Background For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. Methods Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. Results A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. Conclusions As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component’s contribution in patients with moderate-to-severe COPD. Trial registration: ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677

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Section: Discussionmentioning

confidence: 83%

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids

et al. 2021

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“…Although there are studies showing a relationship between exacerbations and coronary events, 21 , 22 reduction in all-cause mortality could not be completely attributed to a reduced risk of exacerbations, and when deaths were adjudicated, these were most frequently due to cardiovascular causes. 23–26 These findings suggest that the increased risk of worsening of heart failure observed among users of bronchodilators compared with non-users is more likely to be related to the underlying pulmonary disease than to an effect of the medications. This is further supported by the results from the current study where, despite users of LABA having less severe COPD and having the lowest incidence rate of hospitalisations for heart failure than aclidinium users, users of other study medications did not have an increased risk of hospitalisations for heart failure when compared with LABA and after the analysis was adjusted for COPD severity.…”

Section: Discussionmentioning

confidence: 92%

A Cohort Study to Evaluate the Risk of Hospitalisation for Congestive Heart Failure Associated with the Use of Aclidinium and Other Chronic Obstructive Pulmonary Disease Medications in the UK Clinical Practice Research Datalink

Rebordosa¹,

Plana²,

Rubino

et al. 2021

COPD

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Background The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium. Objective To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA. Methods This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates. Results The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69–70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53–1.53) for aclidinium, 1.02 (0.69–1.51) for tiotropium, 0.86 (0.50–1.47) for other LAMAs, 1.09 (0.41–2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS. Conclusion The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA.

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“…In a post-hoc analysis of the IMPACT trial, the ICS add-on effect on the moderate or severe exacerbations was reduced among prior ICS nonusers, but not in that of the ETHOS trial [ 15 , 42 ]. On the other hand, both trials have shown no apparent difference in the mortality in the ICS nonusers with a limited sample size [ 43 , 44 ]. Therefore, the results in the ICS nonusers remain unclear but the impact of ICS withdrawal could have been anticipated to be small because these trials demonstrated that both therapeutic and adverse effects could last after three months when excluding the influence of ICS withdrawal [ 42 – 44 ].…”

Section: Discussionmentioning

confidence: 99%

Triple versus LAMA/LABA combination therapy for patients with COPD: a systematic review and meta-analysis

et al. 2021

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Background Recently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial. Methods We searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest. Results We identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64–0.83) and improved the QOL score and trough FEV1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18–0.48) and mortality (odds ratio 0.66, 95% CI 0.50–0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16–2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV1 than LAMA/LABA. Concerning the trough FEV1, QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference. Conclusion Triple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations. Clinical Trial Registration: PROSPERO; CRD42020191978.

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Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study

Abstract: A. were involved in the acquisition of data and data interpretation. S.B. and P.D. were involved in conception/design and data analysis/interpretation. C.R. and P.D. were involved in conception/design, the acquisition of data, and data interpretation.

Cited by 163 publications

References 22 publications

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids

Functional respiratory imaging assessment of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate metered dose inhalers in patients with COPD: the value of inhaled corticosteroids

A Cohort Study to Evaluate the Risk of Hospitalisation for Congestive Heart Failure Associated with the Use of Aclidinium and Other Chronic Obstructive Pulmonary Disease Medications in the UK Clinical Practice Research Datalink

Triple versus LAMA/LABA combination therapy for patients with COPD: a systematic review and meta-analysis

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