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AIM: This study aims to systematically evaluate which single-inhaler triple therapy (inhaled corticosteroids [ICS], long-acting β2-agonists [LABA], and long-acting muscarinic antagonists [LAMA]) is safer and more effective for treating chronic obstructive pulmonary disease (COPD). METHODS: A comprehensive search was performed in PubMed, Embase, Ovid, Cochrane library and Google Scholar from database establishment to November 2025. Searches were limited to English articles. The RCTs that compared single-inhaler triple therapy (ICS/LABA/LAMA) with triple therapy (ICS/LABA+LAMA) or dual therapy (ICS/LABA or LABA/LAMA) for COPD were included. Minimum duration ≥ 12 weeks and minimum participant numbers ≥ 300 patients. Outcomes included forced expiratory volume in 1 s (FEV1), moderate and severe exacerbations, St George’s Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index (TDI) focal score and safety. RESULTS: 12 RCTs (n = 28930 patients) were included in this network meta-analysis. Fluticasone furoate/vilanterol/umeclidinium (FF/VIL/UMEC) was statistically significantly more effective at increasing trough FEV1 (based on change from baseline) than dual therapies (ICS/LABA or LABA/LAMA), free triple therapy (ICS/LABA+LAMA), budesonide/formoterol fumarate/glycopyrronium bromide (BUD/FOR/GLY) and beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FOR/GLY). In addition, FF/VIL/UMEC, BUD/FOR/GLY, and free triple therapy (ICS/LABA+LAMA) showed significant improvement in the total SGRQ score to dual therapies (ICS/LABA or LABA/LAMA). FF/VIL/UMEC and free triple therapy (ICS/LABA+LAMA) showed borderline significant improvement in the total SGRQ score to BDP/FOR/GLY. CONCLUSION: The four available single-inhaler triple therapies and free triple therapy appear to have similar effectiveness and safety. Given the absence of direct comparison studies differences cannot be found with a sufficient level of certainty. Further analysis is needed, as additional evidence becomes available.

Abstract licence: CC BY-NC-ND

BackgroundOnly few randomized controlled trials (RCTs) for head-to-head comparison have been conducted between various combinations of long-acting muscarinic antagonists (LAMAs) and long-acting beta-agonists (LABAs). Our study was conducted to compare acute exacerbation and all-cause mortality among different LAMA/LABA regimens using Bayesian network meta-analysis (NMA).MethodsWe searched Medline, EMBASE, and the Cochrane library (search date: July 1, 2019). We included parallel-group RCTs comparing LAMA/LABA combinations with other inhaled drugs in the stable COPD for ≥ 48 weeks. Two different network geometries were used. The geometry of network (A) had nodes of individual drugs or their combination, while that of network (B) combined all other treatments except LAMA/LABA into each drug class. This study was prospectively registered in PROSPERO; CRD42019126753.ResultsWe included 16 RCTs involving a total of 39,065 patients with stable COPD. Six combinations of LAMA/LABA were identified: tiotropium/salmeterol, glycopyrrolate/indacaterol, umeclidinium/vilanterol, tiotropium/olodaterol, aclidinium/formoterol, and glycopyrrolate/formoterol. We found that umeclidinium/vilanterol was associated with a lower risk of total exacerbations than other LAMA/LABAs in the NMA using network (A) (level of evidence: low or moderate). However, the significant differences were not present in the NMA of network (B). There were no significant differences among the LAMA/LABA combinations in terms of the number of moderate to severe exacerbations, all-cause mortality, major adverse cardiovascular events, or pneumonia.ConclusionsThe present NMA including all available RCTs provided that there is no strong evidence suggesting different benefits among LAMA/LABAs in patients with stable COPD who have been followed up for 48 weeks or more.Trial registrationThis study was prospectively registered in PROSPERO; CRD42019126753.

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BackgroundCombined ICS and long-acting bronchodilators (LABD) more effectively reduce COPD exacerbations than LABD therapy alone. Corticosteroid-related adverse effects, including pneumonia, limit ICS use. Previous data suggest this risk is lower for extrafine beclometasone (ef-BDP). We compared pneumonia risk among new users of fixed dose ICS/LABD formulations containing ef-BDP, versus patients initiating LABD without any ICS.MethodsA propensity-matched historical cohort study design used data from OPCRD. COPD patients with ≥1 year of continuous data who initiated LABD or ICS/LABD formulations containing ef-BDP were matched. Primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions, with non-inferiority boundary of 15%.Results23,898 COPD patients were matched, who were 68±11 years, 54.3% male and 56% current-smokers, while 43% were former-smokers. Initiation of ef-BDP/LABD was not associated with an increased risk of pneumonia versus LABD, for either a sensitive 0.89 (0.78-1.02), P = 0.08 or a specific 0.91 (0.78-1.05), P = 0.18 definition of pneumonia. The probability of remaining pneumonia free 1-year after ef-BDP/LABD was 98.4%, which was comparable to LABD at 97.7%, and was sustained up to 6 years of observation; non-inferiority criterion was met for both definitions. Initiation of ef-BDP/LABD was also associated with a reduced risk of developing LRTIs in the propensity matched cohort.ConclusionRisk of pneumonia when using ICS for the management of COPD reported in several randomised controlled trials may not be relevant with ef-BDP in a diverse real-world clinical population.

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BackgroundThe comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD.Methods207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 μg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 μg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) 1 1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively.ResultsThe modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [- 13, 43]; Study 207609: 11 mL [- 20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 (ConclusionsFF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0-24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen.Trial registrationGSK (207608/207609; NCT03478683/NCT03478696).

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