Outcome: change from baseline in SGRQ score

2.3.1 Outcome: change from baseline in SGRQ score at three months

We included 28 studies of 19 interventions and four treatment groups for this outcome (Appendix 3;Figure 27a and b). Note that interventions formoterol 4.5 µg twice daily, formoterol 9 µg twice daily, glycopyrronium 15.6 µg twice daily, tiotropium 5 µg once daily, indacaterol/glycopyrronium 27.5 µg/15.6 µg twice daily, and olodaterol/tiotropium 5 µg/5 µg once daily are disconnected from the main treatment network (Figure 27a), but we included them in a class/group.

Figure 27. Change from baseline in SGRQ score at 3 months in the low-risk population

a: network diagram of interventions; b: network diagram of treatment groups; c: deviance plot; d: plot of relative effects. Values less than 0 favour the first named treatment group. FM: formoterol; Glyco: glycopyrronium; ICS: inhaled corticosteroid; IND: indacaterol; LABA: long-acting beta2-agonist; LAMA: long-

acting muscarinic antagonist; Olo: olodaterol; Tio: tiotropium

2.3.1.1 Model selection and inconsistency checking

We chose a fixed-treatment-effect model with fixed-class effects, assuming consistency. We also report results based on the random- treatment-effects model with fixed-class effects for comparison (

Appendix 4).

2.3.1.2 NMA results

The NMA included a total of 20,594 participants (LABA: 3933, LAMA: 7849, LABA/ICS: 2396, LABA/LAMA: 6416). Figure 27d andTable 44show the mean difference in change from base- line in SGRQ score at three months for each treatment group com- pared to every other. There is evidence to suggest that both LABA/ LAMA and LABA/ICS improve SGRQ score at three months compared to LAMA (MD −1.64, 95% CrI −2.2 to −1.08; MD −1.68, 95% CrI −2.59 to −0.78), although the MDs do not reach the clinical significance of MCID of 4. There is no evidence of differences across the other comparisons.Table 45shows the rank statistics for the four treatment groups (sorted by mean rank). The highest ranked treatment groups are LABA/ICS and LABA/ LAMA, both with a median rank of 2 (95% CrI 1st to 3rd).

2.3.1.3 Pairwise meta-analyses

There is evidence to suggest that LABA/LAMA improves SGRQ score at three months compared to LAMA (MD −1.60, 95% CI −2.19 to −1.01), and that LAMA improves the score compared to LABA (MD 1.84, 95% CI 0.87 to 2.80), but the mean differences do not reach the clinical significance of MCID of 4. There is no ev- idence of differences across the other comparisons, however, a clin- ically significant difference cannot be excluded favouring LABA/ LAMA over LABA given its 95% CI crossing the line of MCID of 4 (MD −1.29, 95% CI −4.29, 1.71;Appendix 7). The certainty of evidence for LABA/ICS versus LAMA and LAMA versus LABA was moderate due to a suboptimal information size, which could explain discrepancies with the NMA results. Otherwise all other results were consistent with the NMAs. The certainty of evidence was moderate for LABA/LAMA versus LAMA or LABA and high for LABA/LAMA versus LABA/ICS and LABA/ICS versus LABA. There was no difference between random and fixed analyses.

2.3.2 Outcome: change from baseline in SGRQ score at six months

We included 20 studies of 17 interventions and four treatment groups for this outcome (Appendix 3;Figure 28a and b).

Figure 28. Change from baseline in St George’s Respiratory Questionnaire score at 6 months in the low-risk population. a: network diagram of interventions; b: network diagram of treatment groups; c: deviance plot; d: plot of

relative effects. Values less than 0 favour the first named treatment group. FM: formoterol; Glyco: glycopyrronium; ICS: inhaled corticosteroid; IND: indacaterol; LABA: long-acting beta2-agonist; LAMA: long-

acting muscarinic antagonist; Olo: olodaterol; Tio: tiotropium

2.3.2.1 Model selection and inconsistency checking

We chose a fixed-treatment-effect model with fixed-class effects, assuming consistency. We also report results based on the random- treatment-effects model with fixed-class effects for comparison (

Appendix 4).

2.3.2.2 NMA results

The NMA included a total of 16,508 participants (LABA: 4351, LAMA: 4454, LABA/ICS: 2880, LABA/LAMA: 4823). Figure 28d andTable 46show the mean difference in change from base- line in SGRQ score at six months for each treatment group com- pared to every other. There is evidence to suggest that both LABA/ LAMA and LABA/ICS reduce SGRQ score compared to LABA at six months (MD −1.36, 95% CrI −2.12 to −0.60; MD −1.14, 95% CrI −1.90 to −0.37), and that LABA/LAMA reduces SGRQ score compared to LAMA (MD −1.18, 95% CrI −1.80 to -0.56),

although the differences do not reach the clinical significance of MCID of 4.Table 47shows the rank statistics for the four treat- ment groups (sorted by mean rank). The highest ranked treatment group was LABA/LAMA with a median rank of 1 (95% CrI 1st to 2nd).

2.3.2.3 Pairwise meta-analyses

The results from pairwise MAs were consistent with the NMAs and there is no evidence of clinically significant improvement in SGRQ score at six months (MCID of 4 or greater), with any treatment group compared to the others (Appendix 7). There were no data available for LABA/ICS versus LAMA. The certainty of evidence was high for LAMA versus LABA, moderate for LABA/ LAMA versus LAMA or LABA and LABA/ICS versus LABA, and low for LABA/LAMA versus LABA/ICS. There was no difference between random and fixed analyses.

2.3.3 Outcome: change from baseline in SGRQ score at 12 months

We included six studies of 10 interventions and four treatment groups for this outcome (Appendix 3;Figure 29a and b). Note that interventions salmeterol 50 µg twice daily and salmeterol/ fluticasone 50 µg/500 µg twice daily are disconnected from the main treatment network (Figure 29a), but we included them in a class/group model.

Figure 29. Change from baseline in SGRQ score at 12 months in the low-risk population

a: network diagram of interventions; b: network diagram of treatment groups; c: deviance plot; d: plot of relative effects. Values less than 0 favour the first named treatment group. FP: fluticasone propionate; ICS:

inhaled corticosteroid; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; SAL: salmeterol

2.3.3.1 Model selection and inconsistency checking

We chose a fixed-treatment-effect model with fixed-class effects, assuming consistency. We also report results based on the random- treatment-effects model with fixed-class effects for comparison (

Appendix 4).

2.3.3.2 NMA results

The NMA included a total of 6849 participants (LABA: 2021, LAMA: 2163, LABA/ICS: 873, LABA/LAMA: 1792).Figure 29d

andTable 48show the mean difference in change from baseline in SGRQ score at 12 months for each treatment group compared to every other. There is some evidence to suggest that LABA/ICS improves SGRQ score at 12 months compared to LABA using the fixed-effect model (MD −1.69, 95% CrI −2.81 to −0.57). Both LABA/LAMA and LABA/ICS showed a reduction in SGRQ score compared to LAMA when using the fixed effect model (MD −0.89, 95% CrI −1.66 to −0.11) and MD −1.85, 95% CrI −3.28 to −0.43). Increased uncertainty in the random-effects model leads to inconclusive results and the mean differences do not reach the clinical significance of MCID of 4.Table 49shows

the rank statistics for the four treatment groups (sorted by mean rank). The highest ranked treatment group is LABA/ICS with a median rank of 1 (95% CrI 1st to 2nd).

2.3.3.3 Pairwise meta-analyses

The results from pairwise MAs were consistent with the NMAs and there is no evidence that any treatment group is associated with clinically significant improvement in SGRQ score at 12 months compared to the others (Appendix 7). The certainty of evidence was high for LABA/LAMA versus LABA and LAMA versus LABA, moderate for LABA/ICS versus LABA, and very low for LABA/

LAMA versus LAMA. There was no direct comparison for LABA/ LAMA versus LABA/ICS and LABA/ICS versus LAMA. There was no difference between random and fixed analyses.

2.3.4 Rank probabilities for change from baseline in SGRQ score

Figure 30plots the ranks of SGRQ score at 3, 6 and 12 months for each treatment group. The vertical axis shows the probability of being ranked best, second best, third best, or worst treatment group. LABA and LAMA have a high probability of ranking 3rd or 4th at all time points whereas LABA/ICS has a high probability of being the best at 12 months.

Figure 30. Plot of rank probabilities for each treatment group

Change from baseline in St George’s Respiratory Questionnaire score at 3 (solid line), 6 (dashed line), and 12 months (dotted line), in the low-risk population ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist;

2.4 Outcome: transitional dyspnoea index (TDI)