O1.2.3 Long-acting bronchodilator combinations (LAMA/LABA)

A Cochrane systematic review of ten studies found that the combination of tiotropium and a long-acting beta2-agonist provided small improvements in health-related quality of life (mean difference in total SGRQ of -1.34, 95% CI -1.87 to -0.80 over 3 to 12 months) and bronchodilation (mean difference in pre-bronchodilator FEV1 0.06 L; 95% CI 0.05 to 0.07), compared to tiotropium alone (Farne 2015) [evidence level I]. Similar results were found for LABA plus tiotropium vs. LABA alone. It should be noted that the majority of participants in these studies had severe COPD. The clinical importance of these small benefits was uncertain. No statistically significant differences in mortality or hospital admissions were found.

Tiotropium and olodaterol fixed dose combinations (FDC) 2.5/5 μg and 5/5 μg administered via the Respimat Soft Mist Inhaler in patients with moderate to very severe COPD significantly improved lung function compared to mono-components after 24 weeks (Beeh 2015, Buhl 2015b). Statistically significant improvements in SGRQ total score compared to the mono-components were only seen for tiotropium and olodaterol FDC 5/5 μg. Adverse events were comparable between the FDCs and the mono-components. Adverse events were mainly COPD exacerbations and infections and were comparable between the FDCs and the monocomponents. Changes in breathlessness at 24 weeks assessed by transition dyspnoea index (TDI) did not show clinically significant differences between FDC and monocomponents (Ferguson 2017).

Dual bronchodilation with a combination of indacaterol and glycopyrronium, given once daily, was found to increase FEV1 (pre-dose) compared to the monocomponents, tiotropium (Bateman 2013) (with a comparable safety profile (Dahl 2013) or placebo (Bateman 2013, Dahl 2013, Wedzicha 2013) [evidence level II]. Moderate to severe exacerbations were reduced by 12% with the combination compared to glycopyrronium (Wedzicha 2013). The combination of indacaterol and glycopyrronium showed favourable improvements in lung function over salmeterol-fluticasone in a study of moderate to severe COPD patients without exacerbations in the previous year (Vogelmeier 2013) [evidence level II]. Overall, these benefits of indacaterol/ glycopyrronium were supported by systematic reviews (Ulrik 2014 , Rodrigo 2014) [evidence level 1].

Indacaterol 110μg and glycopyrronium 50μg once daily delivered via the Breezhaler device is non-inferior to formoterol (bd) plus once-daily tiotropium for health-related quality of life, with consistent improvement in lung function and dyspnoea (Buhl 2015a).

A meta-analysis comparing LABA/ICS with LAMA/LABA has shown significantly greater improvements of trough FEV1 by 71 (95% CI: 48–95) mL, TDI by 0.38 points (95% CI: 0.17–0.58), less exacerbations with an OR of 0.77 (95% CI: 0.62–0.96) and less pneumonia with an OR of 0.28 (95% CI: 0.12–0.68) in the LAMA/LABA group (Horita 2015). Frequencies of any adverse event, all-cause death and change of total score of SGRQ were not different in the two groups. However, these results have to be interpreted with caution due to the high heterogeneity among studies.

Wedzicha et al (Wedzicha 2016) performed a double-blind, randomised controlled trial comparing indacaterol 110 μg/glycopyrronium 50 μg once daily to fluticasone 500 μg/salmeterol 50 μg twice daily in over 3,000 patients with moderate to severe COPD with a history of at least one exacerbation in the previous year. Patients receiving indacaterol/glycopyrronium had an 11% lower annual rate of exacerbations (3.59 vs. 4.03; rate ratio, 0.89; 95% confidence interval 0.83 to 0.96; P=0.003). The rate of moderate to severe exacerbations was also lower. The reduction of exacerbations was independent of baseline eosinophil count and use of inhaled corticosteroids at time of recruitment. Trough FEV1 was 62mls higher at 52 weeks in the indacaterol + glycopyrronium group (P<0.001) and SGRQ was 1.8 points lower in this group (P<0.01). Whilst statistically significant, these two measures are of unclear clinical significance.  Based on this trial, in COPD patients with frequent exacerbations, this LAMA/LABA combination is superior to this ICS/LABA combination. It is not known if this is a class effect. This trial does not address the role of ‘triple therapy’ (ICS, LABA, LAMA) in this patient group.

Once-daily umeslidinium/ vilanterol 62.5/25 mcg was well tolerated and provided clinically-significant improvements in lung function and symptoms compared with placebo in patients with COPD (Donohue 2013, Donohue 2014) [evidence level II]. Combination treatment with once-daily umeclidinium plus vilanterol improved lung function compared with tiotropium monotherapy in patients with moderate to very severe COPD (Decramer 2014, Maleki-Yazdi 2014). All treatments had a similar safety profile. There were no significant differences between treatment groups with respect to risk of COPD exacerbation, transition dyspnoea index (TDI) focal score; Shortness of Breath with Daily Activity (SOBDA) diary score or SGRQ scores (Decramer 2014) [evidence level II].

A systematic review of the efficacy and safety of umeclidinium/vilanterol for the treatment of COPD (n=9609) in patients with moderate to severe COPD found benefits in terms of mean trough FEV1 of the dual bronchodilator compared with its monocomponents or tiotropium (via HandiHaler) or fluticasone propionate/salmeterol (via Accuhaler). Umeclidinium/vilanterol also reduced the likelihood of exacerbations compared with monocomponents. There were no differences in dyspnoea, QoL, or exacerbation risk between umeclidinium/vilanterol and tiotropium (Rodrigo 2015) [evidence level I]. Results were similar in another systematic review of umeclidinium/vilanterol (Wang 2016b).

Two phase III randomized, double blind, and placebo controlled trials – PINNACLE-1 and PINNACLE-2 – investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6-mg (GFF) metered dose inhaler (MDI) formulated using the Co-Suspension Delivery Technology in patients with moderate-to-very severe COPD. 2,103 and 1,615 patients (40-80 years of age), respectively, were randomised to GFF MDI, GP MDI 18 mg, FF MDI 9.6 mg, or placebo MDI (all twice daily), or tiotropium 18 mg dry powder inhaler (once daily in PINNACLE-1 only [open-label active comparator]). Efficacy and safety were assessed over 24 weeks.  At 24 weeks, compared to placebo, the GFF MDI showed greater change from baseline in morning predose trough FEV1 of 150 mL and 103 mL in PINNACLE-1 and PINNACLE-2, respectively (all P < .0001). In PINNACLE-1, GFF MDI showed significant differences of 59 mL and 64 mL vs. GP MDI and FF MDI, respectively (all P < .0001). In PINNACLE-2, GFF MDI showed significant differences of 54 mL (P = .0003) and 56 mL (P = .0002) vs. GP MDI and FF MDI, respectively. In PINNACLE-1 only, GFF MDI showed significant differences in SGRQ total score at week 24 vs. placebo (–2.52) and GP MDIs (–2.33). In PINNACLE-1 and PINNACLE-2, GFF MDI showed a significant reduction in rescue albuterol use over 24 weeks vs. placebo MDI (–1.08 and –1.04 puffs/d, respectively). In PINNACLE-2, a significant reduction vs. GP MDI (–0.57) was seen, with nominal significance vs. FF MDI (–0.29). GFF MDI had a safety and tolerability profile similar to that of placebo MDI, monocomponent MDIs, and open-label tiotropium (Martinez 2017).

Similarly, in patients with moderate-to-severe COPD and infrequent exacerbations, two recent multi-centre studies found that once daily umeclidinium/vilanterol improved lung function compared with combination twice daily fluticasone proprionate/salmeterol, although there were no differences in dyspnoea or quality of life between the treatment groups (Donohue 2015).

Twice daily aclidinium/formoterol had greater bronchodilation over placebo (mean morning pre-dose 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) alone in patients with COPD (Bateman 2015, D’Urzo 2014, Singh 2014b) [evidence level II]. This dual bronchodilator resulted in some improvements in dyspnoea and health-related quality of life (SGRQ scores), and was well-tolerated. Aclidinium/formoterol reduced the rate of moderate to severe exacerbations requiring a change in treatment by 29%, compared to placebo, but not compared to aclidinium or formoterol alone (Bateman 2015).

Fixed dose LAMA/LABA combinations are now becoming available. 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 (so-called 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 (mean improvement in FEV1 over placebo 201 ml (95% Credible interval (Cr I) 172-230) to 243 ml (95% CrI 139-351) 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 the monocomponents (Calzetta 2017).