New England Journal of Medicine JUNE 24, 2020

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD

Klaus F. Rabe, Fernando J. Martinez, Gary T. Ferguson, et al.

Bottom Line

In patients with moderate-to-very-severe COPD and a history of exacerbations, triple therapy with budesonide, glycopyrrolate, and formoterol significantly reduced the rate of moderate or severe COPD exacerbations compared with dual therapies.

Key Findings

1. Triple therapy with high-dose ICS (budesonide 320 μg) significantly reduced the annual rate of moderate or severe COPD exacerbations by 24% compared to glycopyrrolate/formoterol (rate ratio, 0.76; P<0.001) and by 13% compared to budesonide/formoterol (rate ratio, 0.87; P=0.003).

2. Triple therapy with low-dose ICS (budesonide 160 μg) also showed significant reductions in the annual rate of moderate or severe COPD exacerbations compared to glycopyrrolate/formoterol (rate ratio, 0.75; P<0.001) and budesonide/formoterol (rate ratio, 0.86; P=0.002).

3. A secondary analysis indicated that high-dose triple therapy (budesonide 320 μg) was associated with a 46% lower risk of all-cause mortality compared to glycopyrrolate/formoterol (hazard ratio, 0.54; 95% CI, 0.34-0.87), though this outcome was not part of the primary hierarchical testing sequence.

4. The incidence of pneumonia was higher in groups receiving ICS-containing therapies (3.5-4.5%) compared to those not receiving them (2.3%).

Study Design

Design

RCT

Double-Blind

Sample

8,509

Patients

Duration

52 wk

Median

Setting

Multicenter, 26 countries

Population Symptomatic patients aged 40-80 with moderate-to-very severe COPD and at least one moderate or severe exacerbation in the previous year.

Intervention Twice-daily fixed-dose triple therapy via pMDI (budesonide/glycopyrrolate/formoterol at 320/18/9.6 μg or 160/18/9.6 μg).

Comparator Twice-daily fixed-dose dual therapy (glycopyrrolate/formoterol 18/9.6 μg or budesonide/formoterol 320/9.6 μg).

Outcome Annual rate of moderate or severe COPD exacerbations.

Study Limitations

• The mortality results were based on secondary endpoints and were not part of the prespecified hierarchical testing, meaning these findings should be interpreted as exploratory.

• Missing vital status data for some patients necessitated retrieval efforts to confirm the robustness of the mortality findings.

• The 52-week study duration may not be sufficient to fully capture long-term safety signals or the full clinical impact of mortality reduction.

• The trial specifically enrolled patients with a history of exacerbations, which limits the generalizability of these findings to patients with mild COPD or those without a history of frequent exacerbations.

Clinical Significance

The ETHOS trial provides robust evidence for the use of single-inhaler triple therapy in symptomatic COPD patients with a history of exacerbations. It demonstrates that triple therapy is more effective at reducing exacerbation frequency than either dual LAMA/LABA or ICS/LABA therapy, and provides options for choosing ICS dosage to potentially optimize the benefit-risk profile regarding exacerbation control versus ICS-related side effects like pneumonia.

Historical Context

The management of moderate-to-severe COPD has evolved from monotherapies to dual bronchodilation, and finally to triple therapy (LAMA/LABA/ICS). Previous studies like FLAME and IMPACT established the role of triple therapy, but ETHOS uniquely compared two different doses of an inhaled corticosteroid within a single-inhaler triple regimen to determine the lowest effective dose for exacerbation reduction and to evaluate its impact on all-cause mortality.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How do the distinct pharmacological mechanisms of inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and long-acting beta-2 agonists (LABA) synergistically address the pathophysiology of moderate-to-severe COPD?

Key Response

ICS reduces chronic airway inflammation and suppresses immune response; LAMA prevents bronchoconstriction by blocking M3 receptors in the parasympathetic nervous system; and LABA promotes bronchodilation by stimulating beta-2 receptors in the sympathetic system. Combining them addresses both the mechanical obstruction and the underlying inflammatory drivers of COPD exacerbations.

Resident

In the context of the ETHOS trial, how should a patient's blood eosinophil count influence your decision to initiate triple therapy over dual LAMA-LABA therapy?

Key Response

While triple therapy showed benefits across multiple subgroups, the magnitude of the reduction in exacerbation rates was greater in patients with higher blood eosinophil counts. This aligns with the understanding that eosinophilia is a biomarker for ICS responsiveness in COPD, identifying those most likely to benefit from the budesonide component.

Fellow

The ETHOS trial demonstrated a mortality benefit for triple therapy containing 320-μg of budesonide versus LAMA-LABA, but not for the 160-μg dose. What are the clinical implications regarding the dose-response relationship of ICS for survival in COPD?

Key Response

This suggests a potential dose-dependent effect of ICS on mortality. While both doses reduced exacerbations similarly, only the higher dose reached statistical significance for reducing all-cause mortality compared to LAMA-LABA. This highlights that for high-risk patients, the anti-inflammatory potency might be a critical factor in preventing fatal events.

Attending

How do you reconcile the ETHOS trial's evidence of reduced mortality with the well-documented increased risk of pneumonia associated with triple therapy when counseling a patient with frequent exacerbations?

Key Response

The decision involves weighing a significant reduction in the risk of death (all-cause mortality) and severe exacerbations against a higher incidence of non-fatal pneumonia. Clinicians must practice precision medicine by identifying 'high-benefit' patients (frequent exacerbators, high eosinophils) where the mortality reduction outweighs the risk of localized infectious complications.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ETHOS trial utilized a 'retrieved dropout' strategy to collect survival data for patients who discontinued treatment. How does this approach impact the internal validity and the interpretation of the all-cause mortality endpoint compared to a standard ITT analysis?

Key Response

Collecting data regardless of treatment adherence (retrieved dropouts) minimizes attrition bias and allows for a more robust assessment of the 'true' survival benefit. It moves the analysis closer to a true Intention-to-Treat (ITT) population, reducing the risk that deaths in the dual-therapy arms were missed because patients dropped out due to worsening symptoms.

Journal Editor

A major criticism of COPD trials like ETHOS is the potential for 'ICS withdrawal' bias in the LAMA-LABA arm. How does the study design address or fail to address the possibility that increased exacerbations in the dual-therapy arm were simply due to removing ICS from patients previously controlled on it?

Key Response

Since many patients were on ICS prior to the trial, switching them to the LAMA-LABA arm could trigger a rebound inflammatory effect. A tough reviewer would flag this as a threat to validity, suggesting that the 'benefit' of triple therapy might be partially explained by the 'harm' of withdrawing maintenance therapy in the control group rather than the superiority of the triple combination itself.

Guideline Committee

Given that ETHOS provides high-level evidence for mortality reduction with triple therapy, should GOLD guidelines be updated to recommend triple therapy as initial management for 'Group E' patients with a high exacerbation burden, rather than a step-up approach?

Key Response

Current GOLD guidelines generally suggest starting with dual therapy (LAMA-LABA) and escalating. However, ETHOS (along with the IMPACT trial) provides Level A evidence that triple therapy is superior for survival and exacerbation prevention in patients with a history of exacerbations. This may justify moving triple therapy to an earlier position in the algorithm for patients with ≥2 moderate or ≥1 severe exacerbation in the prior year.

Clinical Landscape

Noteworthy Related Trials

2016

FLAME Trial

n = 3362 · NEJM

Tested

Indacaterol/glycopyrronium

Population

Patients with COPD and a history of exacerbations

Comparator

Salmeterol/fluticasone

Endpoint

Annual rate of all COPD exacerbations

Key result: Dual bronchodilation was superior to inhaled glucocorticoid-long-acting beta-agonist therapy in preventing exacerbations.

2018

KRONOS Trial

n = 1902 · Lancet Respir Med

Tested

Budesonide/glycopyrrolate/formoterol fumarate

Population

Patients with moderate to very severe COPD

Comparator

Budesonide/formoterol and glycopyrrolate/formoterol

Endpoint

Pre-dose FEV1 and rate of moderate or severe exacerbations

Key result: Triple therapy provided greater improvements in lung function and reduced exacerbations compared to dual therapies.

2018

IMPACT Trial

n = 10355 · NEJM

Tested

Fluticasone furoate/umeclidinium/vilanterol

Population

Patients with symptomatic COPD and a history of exacerbations

Comparator

Fluticasone furoate/vilanterol and umeclidinium/vilanterol

Endpoint

Annual rate of moderate or severe COPD exacerbations

Key result: Triple therapy resulted in a lower rate of exacerbations and improved lung function and health-related quality of life compared to dual therapies.

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