Respiratory Trials·org

Topic

COPD

Bronchodilators, inhaled steroids, oxygen, and lung volume reduction.

Long-acting bronchodilators are the foundation. Where a LAMA and a LABA have been compared head to head, the LAMA prevented more exacerbations (POET-COPD), and dual bronchodilation outperformed an inhaled steroid combination in patients selected for exacerbations (FLAME).

Inhaled corticosteroids buy exacerbation reduction and pay for it in pneumonia. TORCH established both halves of that bargain and famously missed a mortality benefit at p=0.052. Adding a steroid to dual bronchodilation reduces exacerbations further (IMPACT, ETHOS, TRIBUTE), though IMPACT withdrew inhaled steroids at randomisation in most participants, which flatters the triple arm. ETHOS also found the lower budesonide dose worked as well as the higher. Going the other way, most patients without frequent exacerbations can have the steroid withdrawn without penalty — unless their blood eosinophils are raised (SUNSET).

The eosinophil has become a treatment target rather than merely a steroid-response marker. Dupilumab cut exacerbations by 30% in eosinophilic COPD already on triple therapy (BOREAS), and mepolizumab by 21% (MATINEE) — though neither improved quality of life as much as the exacerbation numbers suggest. Benralizumab given during an acute eosinophilic exacerbation outperformed prednisolone (ABRA).

Oral and inhaled add-ons occupy the space beyond triple therapy. Roflumilast's primary analysis missed significance and its sensitivity analysis met it (REACT); tolerability limits it in practice. Ensifentrine, the first new inhaled class in decades, improved lung function in both replicate trials with placebo-level side effects (ENHANCE). Daily azithromycin for a year reduces exacerbations at the cost of hearing loss and resistance (MACRO).

Oxygen is the oldest evidence here and the most misapplied. Long-term oxygen improves survival in severe resting hypoxaemia (NOTT, MRC oxygen) and does nothing at all for moderate desaturation (LOTT). More hours are not better: 24 a day was no better than 15 (REDOX).

Exacerbations respond to antibiotics when the three Anthonisen criteria are met — increased dyspnoea, sputum volume and purulence (Anthonisen 1987). For volume reduction, surgery offers no overall survival benefit but a real one in upper-lobe emphysema with low exercise capacity, and harm in the wrong phenotype (NETT).

Long-term oxygen therapy

Trial Year Therapy Effect Finding
REDOX 2024 Long-term oxygen therapy 24 hours a day of oxygen was no better than 15 in severe hypoxaemia
LOTT 2016 Supplemental oxygen Oxygen for moderate desaturation did nothing for survival, admissions, or quality of life
MRC oxygen 1981 Domiciliary oxygen Domiciliary oxygen for at least 15 hours a day improved survival in hypoxaemic cor pulmonale
NOTT 1980 Continuous oxygen Continuous oxygen halved mortality compared with nocturnal-only oxygen in hypoxaemic COPD

Triple versus dual therapy

Trial Year Therapy Effect Finding
ETHOS 2020 Budesonide/glycopyrrolate/formoterol Triple therapy beat both dual therapies, and the lower steroid dose worked as well as the higher
IMPACT 2018 Fluticasone furoate/umeclidinium/vilanterol Triple therapy reduced exacerbations versus either dual therapy, at the cost of more pneumonia
TRIBUTE 2018 Beclometasone/formoterol/glycopyrronium Extrafine triple therapy modestly reduced exacerbations versus dual bronchodilation, without excess pneumonia

Biologics for eosinophilic COPD

Trial Year Therapy Effect Finding
MATINEE 2025 Mepolizumab Mepolizumab reduced exacerbations by 21% in eosinophilic COPD on triple therapy, without improving symptoms
BOREAS 2023 Dupilumab Dupilumab cut exacerbations by 30% in eosinophilic COPD already on triple therapy

Phosphodiesterase inhibitors

Trial Year Therapy Effect Finding
ENHANCE 2023 Ensifentrine Ensifentrine improved lung function in both replicate trials and reduced exacerbations, with placebo-level tolerability
REACT 2015 Roflumilast Roflumilast missed its primary endpoint by a whisker and hit it on the sensitivity analysis

Antibiotics for exacerbations

Trial Year Therapy Effect Finding
Anthonisen 1987 1987 Broad-spectrum antibiotics Antibiotics helped exacerbations defined by increased dyspnoea, sputum volume and purulence

Inhaled steroid and LABA versus placebo

Trial Year Therapy Effect Finding
TORCH 2007 Salmeterol/fluticasone Salmeterol/fluticasone narrowly missed a mortality benefit but reduced exacerbations, at the cost of more pneumonia

LABA/LAMA versus LABA/ICS

Trial Year Therapy Effect Finding
FLAME 2016 Indacaterol/glycopyrronium Dual bronchodilation beat LABA/ICS for exacerbation prevention, with less pneumonia

LAMA versus LABA

Trial Year Therapy Effect Finding
POET-COPD 2011 Tiotropium Tiotropium prevented exacerbations better than salmeterol

Long-term macrolides

Trial Year Therapy Effect Finding
MACRO 2011 Azithromycin Daily azithromycin for a year cut exacerbations and improved quality of life, at the cost of hearing loss and resistance concerns

Lung volume reduction

Trial Year Therapy Effect Finding
NETT 2003 Lung volume reduction surgery No overall survival benefit, but a real one for upper-lobe emphysema with low exercise capacity

Withdrawing inhaled steroid

Trial Year Therapy Effect Finding
SUNSET 2018 Indacaterol/glycopyrronium Stopping inhaled steroids cost a little lung function but no extra exacerbations, except in eosinophilic patients

Key references

Guidelines, standards and reviews for this topic.