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, vs. 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 (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).
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].
Other combinations: In two 24-week RCTs, glycopyrrolate/formoterol improved FEV1 compared to glycopyrrolate, formoterol, tiotropium or placebo (Martinez 2017). A LAMA/LABA fixed dose combination (containing glycopyrrolate 18 mcg and formoterol fumarate 9.6 mcg administered twice daily) delivered by Co-Suspension™ Delivery Technology MDI had similar safety and efficacy to that of its individual monocomponent MDIs in patients with moderate-to-very severe COPD (Hanania 2017). LAMA/LABA FDC MDI could be an option for patients with significant lung function impairment who are unable to generate adequate inspiratory flow through higher resistance devices.
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 of LAMA/LABA combinations compared with monotherapies (Oba 2016) found that the fixed dose combinations provided benefits in lung function compared with their monocomponents, as well as in quality of life, with no increase in adverse outcomes. Combination therapy reduced moderate to severe exacerbations compared with LABA alone (HR 0.92, 95% CrI 0.73-0.93) but not compared with LAMA (HR 0.92, CrI 0.84-1.00). Effects on severe exacerbations were similar with both combination and monotherapies. Other network meta-analyses have also found benefits for LAMA/LABA fixed dose combinations, compared with their monocomponents (Calzetta 2017).
Comparisons of LAMA/LABA vs 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 vs. 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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