O1.2.3 Long-acting bronchodilator combinations (LAMA/LABA)
A number of LAMA/LABA fixed dose combinations in a single inhaler are available in Australia, which are delivered via a range of devices:
- aclidinium/formoterol (Genuair)
- glycopyrronium/indacaterol (Breezhaler)
- tiotropium/olodaterol (Respimat)
- umeclidinium/vilanterol (Ellipta)
Aclidinium/formoterol: Twice daily aclidinium/formoterol had greater bronchodilation over placebo (mean FEV1 up to 143 ml greater), and to a lesser extent, versus formoterol (mean FEV1 53 ml greater) or aclidinium (small differences at various timepoints) (Bateman 2015, D’Urzo 2014, Singh 2014b) [evidence level II]. There were some improvements in dyspnoea and health-related quality of life (HRQoL), measured by St George’s Respiratory Questionnaire (SGRQ). Aclidinium/formoterol reduced the rate of moderate to severe exacerbations by 29%, when compared to placebo, but not when compared to aclidinium or formoterol alone (Bateman 2015). In a systematic review of seven trials (Ni 2018), the aclidinium/formoterol fixed dose combination (FDC) was found to improve dyspnoea and lung function compared to the monocomponents or placebo. Quality of life (SGRQ) was better with the combination compared to formoterol or placebo. There was no difference between the FDC and monotherapy or placebo for hospital admissions, mortality, and non-fatal adverse events. A lower risk of moderate exacerbations was observed with the FDC compared to formoterol but not with the FDC compared with aclidinium [evidence level I].
Glycopyrronium/indacaterol: Once daily indacaterol/glycopyrronium had greater bronchodilation compared with glycopyrronium, indacaterol, tiotropium (Bateman 2013) or placebo (Bateman 2013, Dahl 2013, Wedzicha 2013) [evidence level II]. Moderate to severe exacerbations were reduced by 12% with indacaterol/glycopyrronium, compared to glycopyrronium (Wedzicha 2013). These benefits were supported by systematic reviews (Ulrik 2014 , Rodrigo 2014) [evidence level I].
Tiotropium/olodaterol: Once daily tiotropium/olodaterol significantly improved lung function, quality of life (SGRQ total score) and breathlessness (transition dyspnoea index), compared to tiotropium or olodaterol (Miravitlles 2017) [evidence level I]. However, patients taking tiotropium/olodaterol 5 μg/5 μg and tiotropium 5 μg (two puffs once daily via the Respimat device) had no significant differences in moderate and severe exacerbation rate (rate ratio [RR] 0·93, 99% CI 0·85–1·02;p=0·0498) and time to first moderate or severe event ([HR] 0·95, 99% CI 0·87–1·03; p=0·12) over a 52-week treatment period compared to tiotropium alone (Calverley 2018b) [evidence level II].
Umeclidinium/vilanterol: Once-daily umeclidinium/vilanterol improved lung function and symptoms, when compared with placebo (Donohue 2013, Donohue 2014) [evidence level II]. Systematic reviews of umeclidinium/vilanterol have shown improved FEV1, reduced dyspnoea and reduced rate of exacerbations, when compared with umeclidinium or vilanterol (Rodrigo 2015, Wang 2016b) [evidence level I].
Systematic reviews of LAMA/LABA combinations: A meta-analysis and systematic review of results of 8,641 participants in 22 double blinded RCTs comparing a once-daily LAMA/LABA combination with placebo demonstrated similar clinically and statistically significant differences with each of the inhalers with respect to SGRQ quality of life (4.1 units), and improvement in FEV1 (200mls). Of the four once-daily LAMA/LABA combinations studied, only the combination of umeclidinium/vilanterol (using the Ellipta inhaler device) was evaluated with respect to the outcome of exacerbation rate, with an overall pooled rate reduction of 47% in three studies (Maqsood 2019) [evidence level I].
A systematic review of 24 studies (n=45,441 participants) found statistically significant reductions in hospital admissions (risk ratio 0.89, 95% CI 0.82 to 0.97) and exacerbations (risk ratio 0.80, 95% CI 0.69 to 0.92) with LAMA/LABA combination therapy, compared with LAMA or LABA monotherapy (Mammen 2020) [evidence level I]. Reductions in dyspnoea and health-related quality of life did not reach MCID.
Network meta-analyses of LAMA/LABA: Because head to head studies of all relevant treatment options may not be available, indirect comparisons of treatments using a technique comparing relative effects against a common comparator (network meta-analysis) offers a way of comparing the relative effects of treatment. A network meta-analysis was undertaken for dual combination inhalers compared with single-agent long-acting bronchodilators (Oba 2018) [evidence level I]. In the network meta-analysis, LAMA/LABA inhalers decreased the rate of moderate to severe exacerbations compared to ICS/LABA (HR 0.86, 95% credible interval (CrI) 0.76 to 0.99), LAMA (HR 0.87, 95% CrI 0.78 to 0.99), and LABA (HR 0.70, 95% CrI 0.61 to 0.80) in frequent exacerbators (moderate certainty of evidence), with LABA being the least beneficial. However, the evidence was not statistically significant in some of the pairwise meta-analyses between treatments.
Comparisons of LAMA/LABA versus ICS/LABA: In the FLAME study, indacaterol /glycopyrronium once daily was compared to fluticasone/salmeterol twice daily in an RCT of 3,362 patients with moderate to severe COPD, who had a history of at least one exacerbation in the previous year (Wedzicha 2016b). Patients receiving indacaterol/glycopyrronium had a lower annual rate of exacerbations (rate ratio 0.89; 95% CI 0.83 to 0.96). Trough FEV1 was 62 ml higher at 52 weeks and SGRQ was 1.8 points lower with indacaterol/glycopyrronium although these changes were of unclear clinical significance. The reduction of exacerbations was independent of baseline eosinophil count and use of inhaled corticosteroids at time of recruitment (Roche 2017) .
A Cochrane systematic review analysed 11 RCTs (9,839 patients) studying LAMA/LABA versus ICS/LABA therapy (Horita 2017). Compared to ICS/LABA, LAMA/LABA resulted in a small reduction in the rate of exacerbations (OR 0.82, 95% CI 0.70 to 0.96), no significant change in mean SGRQ score (although there was a higher proportion achieving the MCID) and a small improvement in FEV1 (mean difference 0.08 L, 95% CI 0.06 to 0.09). Pneumonia rates were lower, and there was no change in mortality. The studies were heterogeneous in study design and of relatively short duration, and the evidence was of low to moderate quality. Even with these limitations, this systematic review supports the use of LAMA/LABA fixed dose combinations over ICS/LABA inhalers, when initiating long-acting inhaled medicines. Further RCTs of ICS/LABA/LAMA in a single inhaler are awaited, to clarify their efficacy compared to LAMA/LABA. See Appendix 5. Table of Minimum Clinically Important Differences.
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