Clinician Article

Efficacy and safety of long-acting beta-agonist/long-acting muscarinic antagonist combinations in COPD: a network meta-analysis.

  • Oba Y
  • Sarva ST
  • Dias S
Thorax. 2016 Jan;71(1):15-25. doi: 10.1136/thoraxjnl-2014-206732. Epub 2015 Oct 21. (Review)
PMID: 26490732
Read abstract Read evidence summary
  • Internal Medicine
    Relevance - 7/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 5/7
  • Respirology/Pulmonology
    Relevance - 6/7
    Newsworthiness - 5/7
  • Physical Medicine and Rehabilitation
    Relevance - 4/7
    Newsworthiness - 4/7


BACKGROUND: The place of long-acting ß agonist/long-acting muscarinic antagonist (LABA/LAMA) combinations in stable patients with COPD is not well defined. The purpose of this study was to systematically review the efficacy and safety of LABA/LAMA combinations.

METHODS: Several databases and manufacturers' websites were searched for relevant clinical trials. Randomised control trials, at least 12 weeks duration, comparing a LABA/LAMA combination with placebo and/or monotherapy were included. The data were pooled using a network as well as a traditional direct comparison meta-analysis.

RESULTS: Twenty-three trials with a total of 27 172 patients were included in the analysis. LABA/LAMA combinations were associated with a greater improvement in lung function, St. George's Respiratory Questionnaire (SGRQ) score, and Transitional Dyspnoea Index (TDI) than monotherapies. LABA/LAMA combinations were associated with a significantly greater proportion of SGRQ and TDI responders than monotherapies (OR 1.23 (95% credible interval (CrI) 1.06-1.39), OR 1.34 (95% CrI 1.19-1.50) versus LABAs and OR 1.24 (95% CrI 1.11-1.36), OR 1.31 (95% CrI 1.18-1.46) versus LAMAs, respectively) and fewer moderate-to-severe exacerbations compared with LABAs (HR 0.82 (95% CrI 0.73-0.93)), but not when compared with LAMAs (HR 0.92 (95% CrI 0.84-1.00)). There were no statistically significant differences associated with LABA/LAMA combinations compared with monotherapies in safety outcomes as well as in severe exacerbations.

CONCLUSIONS: The combination therapy was the most effective strategy in improving lung function, quality of life, symptom scores and moderate-to-severe exacerbation rates, and had similar effects on safety outcomes and severe exacerbations as compared with monotherapies.

Clinical Comments

Family Medicine (FM)/General Practice (GP)

Network meta-analysis. Combination therapy looks good but there are still many unanswered questions about type of patients who may benefit from the combination, duration of therapy, longer-term adverse effects, etc.

Family Medicine (FM)/General Practice (GP)

Combining a long-acting muscarinic agent (LAMA) with a long-acting bronchodilator agent (LABA) provides an incremental benefit over use of a LAMA alone or a LABA alone for COPD. The differences are not huge, so it seems to me that one should probably choose single-agent LAMA as first-line inhaled pharmacotherapy for COPD. If a patient is still significantly symptomatic, consider a LAMA/LABA combination instead of changing to a LABA, or start with a LABA, then try a LAMA/LABA if that does not work adequately. But exacerbations still occur and the change in St George`s Respiratory Questionnaire scores are small and not significantly different when LAMA/LABA is compared with LAMA alone or even LABA alone, so don`t expect miracles.

General Internal Medicine-Primary Care(US)

I'm not sure that this is "news" to COPD providers.

General Internal Medicine-Primary Care(US)

This is useful information to primary care providers who see patients with COPD. It is good to know that the combination meds have similar safety profiles to each of their component meds and do have a bit higher efficacy.


Meta-analysis including 23 studies and more then 25,000 patients found that LABA/LAMA combination was superior to LABA or LAMA alone in bettering FEV1, dyspnea, and QOL. LABA/LAMA also decreased exacerbation rate compared to LABA alone. Just as significant was the lack of an increase in adverse events. These new inhalers will likely become key in treating moderate to severe COPD. Where inhaled corticosteroids fit with this new combination remains to be determined.


Network meta-analysis finding that dual LABA/LAMA bronchodilator therapy was better than monotherapy for improving lung function, symptoms and quality of life, but not for reducing severe exacerbations in patients with moderate to severe exacerbations. Differences between dual therapy and monotherapy were of limited magnitude, however, and not always clinically meaningful. Shows that the most potent treatment has the greatest effect, but it doesn't mean that all COPD patients need it. Nevertheless, it provides stronger validation for guideline recommendations to use dual bronchodilator therapy in patient who are more dyspneic or have lower lung function.

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