Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis

Figures & data

Table 1 Key study characteristics for all studies included in the NMA (only arms of interest)

Study	Study design	Treatment	Trial duration	Inclusion criteria	Background treatment
Decramer et al^Citation9 (DB2113360)	Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study	Tiotropium 18 μg OD Vilanterol 22 μg/umeclidinium 55 μg OD	24 weeks	Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV1 ≤70% and post-salbutamol FEV1/FVC ratio <0.7; smoking history a ≥10 pack-years	Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication Not allowed: LABAs, SABAs, short-acting anticholinergics, and SABA/ICS combination products
Decramer et al^Citation9 (DB2113374)	Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study	Tiotropium 18 μg OD Vilanterol 22 μg/umeclidinium 55 μg OD	24 weeks	Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV1/FVC ratio <0.70 and post-salbutamol FEV1 ≤70%; smoking history ≥ 10 pack-years	Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication Not allowed: LABAs, oral SABAs and LABAs, inhaled SABAs, inhaled short-acting anticholinergics, and SABA/ICS combination products
Donohue et al^Citation6 (DB2113373)	Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group study	Placebo Vilanterol 22 μg/umeclidinium 55 μg OD	24 weeks	Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV1/FVC ratio <0.70 and post-salbutamol FEV1 ≤70%; smoking history ≥ 10 pack-years	Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication Not allowed: LABAs, LABA/ICS combination products, SABAs, short-acting anticholinergics, and SABA/ICS combination products
Maleki-Yazdi et al^Citation28 (ZEP117115)	Phase III multicenter, randomized, double-blind, double-dummy, parallel-group study	Tiotropium 18 μg OD Vilanterol 22 μg/umeclidinium 55 μg OD	24 weeks	Outpatient; age ≥40 years; diagnosed with COPD; post-salbutamol FEV1/FVC ratio <0.70 and post-salbutamol FEV1 ≤70%; smoking history ≥ 10 pack-years	Allowed: ICS at a dose of up to 1,000 μg/day of FP or equivalent, salbutamol/albuterol as rescue medication Not allowed: LABAs, LABA/ICS combination products, oral SABAs and LABAs, inhaled SABAs, inhaled short-acting anticholinergics, and SABA/ICS combination products
INTRUST 1 (Mahler et al^Citation17)	Randomized, double-blind, controlled, parallel-group study	Tiotropium 18 μg OD Indacaterol 150 μg + tiotropium 18 μg OD	12 weeks	Age ≥40 years; post-bronchodilator FEV1 ≤65% and ≥30%; post-bronchodilator FEV1/FVC <70%; smoking history ≥ 10 pack-years	Allowed: ICS monotherapy, salbutamol/albuterol as rescue medication Not allowed: LABAs, SABAs (except those prescribed in the study), theophylline, and anticholinergics
INTRUST 2 (Mahler et al^Citation17)	Randomized, double-blind, controlled, parallel-group study	Tiotropium 18 μg OD Indacaterol 150 μg + tiotropium 18 μg OD	12 weeks	Age ≥40 years; post-bronchodilator FEV1 ≤65% and ≥30%; post-bronchodilator FEV1/FVC <70%; smoking history ≥ 10 pack-years	Allowed: ICS monotherapy, salbutamol/albuterol as rescue medication Not allowed: LABAs, SABA (except those prescribed in the study), theophylline, and anticholinergics
Aaron et al^Citation20	Randomized, double-blind, placebo-controlled study	Tiotropium 18 μg OD + salmeterol 25 μg 2 puffs bid Tiotropium l8 μg OD + placebo 2 puffs bid Tiotropium 18 ug OD + fluticasone 250 ug/salmeterol 25 ug 2 puffs bid	52 weeks	Age ≥35 years; diagnosed with moderate or severe COPD; ≥ 1 exacerbation of COPD requiring systemic steroids or antibiotics in previous 12 months; smoking history ≥ 10 pack-years; post-bronchodilator FEV1 ≤65%; FEV1/FVC <70%.	Allowed: albuterol for relief of symptoms Not allowed: ICS, LABAs, and anticholinergics
ENLIGHTEN (Dahl et al^Citation13)	Multicenter, randomized, double-blind, parallel-group, placebo-controlled study	Placebo QVA149 (indacaterol 110 ug/glycopyrronium 50 ug) OD	52 weeks	Age ≥40 years; diagnosed with moderate or severe COPD (stage II or III according to GOLD 2008 criteria); post-bronchodilator FEV1 <80% and ≥30%; post-bronchodilator FEV1/FVC <0.70; smoking history ≥ 10 pack-years	Allowed: albuterol as rescue medication, ICS monotherapy Not allowed: long-acting bronchodilators (LABAs, LAMAs, theophylline) and short-acting muscarinic antagonists
SPARK (Wedzicha et al^Citation16)	Multicenter, randomized, double-blind, parallel-group, active-controlled study	Tiotropium 18 μg OD QVA149 (indacaterol 110 ug/glycopyrronium 50 ug) OD	64 weeks	Age ≥40 years; diagnosed with severe or very severe COPD (stage III or IV according to GOLD 2008 criteria); post-bronchodilator FEV1 <50%; FEV1/FVC <0.70; ≥1 exacerbation in the previous 12 months requiring systemic corticosteroids or antibiotics; smoking history ≥ 10 pack-years	Allowed: salbutamol, stable dose of ICS Not allowed: long-acting bronchodilators
SHINE (Bateman et al^Citation11)	Multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled (open-label) study	Placebo Tiotropium 18 μg OD QVA149 (indacaterol 110 ug/glycopyrronium 50 ug) OD	26 weeks	Age ≥40 years; diagnosed with moderate or severe COPD (stage II or III according to GOLD 2008 criteria); post-bronchodilator FEV1 <80% and ≥30%; post-bronchodilator FEV1/FVC <0.70; smoking history ≥ 10 pack-years	Allowed: salbutamol/albuterol as rescue medication, inhaled or intranasal corticosteroids in constant doses Not allowed: LABAs, LAMAs, and LABA/ICS
Vogelmeier et al^Citation19	Randomized, partially blinded, placebo-controlled study	Formoterol 10 μg bid + tiotropium 18 μg OD Tiotropium 18 μg OD Placebo	24 weeks	Diagnosed with stable COPD; age ≥40 years at COPD onset; smoking history ≥ 10 pack-years; FEV1 <70% of patient’s predicted normal value (and ≥ 1.00 L); FEV1/FVC <70%	Allowed: salbutamol, ICS monotherapy
Tashkin et al^Citation18	Active-control led, double-blind, multicenter study	Tiotropium l8 μg OD + formoterol 12 μg bid Tiotropium l8 μg OD + placebo bid	12 weeks	Age ≥40 years; post-bronchodilator FEV1 <70% and >30% of the predicted normal value or >0.75 L, whichever was lesser at run-in; FEV1/FVC <0.70	Continued use of prior stable ICS regimens and systemic corticosteroids for the treatment of exacerbations was permitted throughout the study. All patients were provided with albuterol inhalers for use as rescue medication.
Chan et al^Citation36 Bl trial: 205.259	Randomized, double-blind, parallel-group study	Tiotropium 18 μg OD Placebo	48 weeks	Age ≥40 years; smoking history ≥ 10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%; included if ≥ 1 exacerbation noted during the previous year, but not within 6 weeks prior to treatment (later amended to include 1 exacerbation in past 2 years)	Allowed: stable dose of oral corticosteroids, ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs
TIPHON (Tonnel et al^Citation37)	Randomized, double-blind, multicenter study	Tiotropium 18 μg OD Placebo	36 weeks	Age ≥40 years; smoking history > 10 pack-years; FEV1, 20%–70%; FEV1/FVC ≤70%;	Allowed: stable doses of theophylline preparations (excluding 24-hour preparations), mucolytics, ICS, and oral steroids
UPLIFT (Tashkin et al^Citation38 and Celli et al^Citation35)	Placebo-controlled study and randomized, double-blind study	Tiotropium 18 μg OD Placebo	4 years	Age ≥40 years; smoking history > 10 pack-years; FEV1, ≤70%; FEV1/FVC ≤70%; excluded if exacerbation observed 4 weeks prior	Allowed: all respiratory medications, except other inhaled anticholinergic drugs
Niewoehner et al^Citation40	Randomized, double-blind study	Tiotropium 18 μg OD Placebo	6 months	Age ≥40 years; smoking history ≥ 10 pack-years; FEV1 ≤60%; FEV1/FVC ≤70%; excluded if no recovery from exacerbation ≥30 days prior	Allowed: all other respiratory medications (including ICS and LABAs) Not allowed: open-label anticholinergic bronchodilators
Brusasco et al^Citation41	Randomized, placebo-controlled, double-blind, double-dummy study	Tiotropium 18 μg OD Placebo	24 weeks	Age >40 years; smoking history > 10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%	NR
Donohue et al^Citation25	Randomized, placebo-controlled, double-blind, double-dummy, parallel-group study	Tiotropium 18 μg OD Placebo	24 weeks	Age ≥40 years; smoking history > 10 pack-years; FEV1 ≤60%; FEV1/FVC ≤70%	Allowed: regular ICS and oral steroids Not allowed: inhaled anticholinergic LABAs
Casaburi et al^Citation42	Randomized, double-blind placebo-controlled study	Tiotropium 18 μg OD Placebo	56 weeks	Age ≥40 years; smoking history ≥ 10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%	Allowed: stable doses of theophylline, ICS, and oral prednisone
Donohue et al^Citation43	Randomized, double-blind study	Tiotropium 18 μg OD Placebo	26 weeks	Patients aged ≥40 years; smoking history ≥20 pack-years; diagnosed with moderate-to-severe COPD (GOLD criteria) were enrolled. Post-bronchodilator (within 30 minutes of inhaling albuterol 360 ug) FEV1 <80% and ≥30% of the predicted normal value; FEV1/FVC <70%	Patients could continue ICS monotherapy if stable for 1 month before screening; dose and regimen were kept stable throughout the study. Before the start of the run-in period, treatment with anticholinergic bronchodilators or with β2-agonists was discontinued with appropriate washout, and patients receiving fixed-combination P2-agonists/ICS were switched to ICS monotherapy at an equivalent dose. All patients were provided albuterol for use as needed
GLOW 2 (Kerwin et al^Citation44)	Randomized, placebo-controlled study	Tiotropium 18 μg OD Placebo	52 weeks	Patients aged ≥40 years; any sex; smoking history ≥ 10 pack-years; diagnosed with moderate-to-severe stable COPD; post-bronchodilator FEV1 ≥30% and <80% of the predicted normal value; post-bronchodilator FEV1/FVC <0.70 were enrolled	Allowed: inhaled or intranasal corticosteroids and HI antagonists, salbutamol/albuterol as rescue medication Not allowed: LAMAs (at least 7 days before run-in), LABAs or LABA/ICS combinations (at least 48 hours before run-in)
Verkindre et al^Citation45	Randomized, placebo-controlled study	Tiotropium 18 μg OD Placebo	12 weeks	FEV1 ≤50%; FEV1/FVC ≤70%; residual volume ≥ 125%; excluded if unstable doses of oral corticosteroids received 6 weeks prior	Allowed: stable-dose oral corticosteroids, ICS, theophylline preparations, mucolytic agents Not allowed: SABAs, oral β2-agonists, or LABAs
Casaburi et al^Citation46	Randomized, double-blind, placebo-controlled, multicenter study	Tiotropium 18 μg OD Placebo	13 weeks	Age ≥40 years; diagnosed with COPD defined by ATS; smoking history > 10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%	Allowed: stable doses of theophylline, ICS, oral prednisone Not allowed: other inhaled or oral bronchodilators
Covelli et al^Citation47	Randomized, double-blind, placebo-controlled, parallel-group study	Tiotropium 18 μg OD Placebo	12 weeks	FEV1 ≤60%; FEV1/FVC ≤70%; excluded if exacerbation during 6 weeks prior	Allowed: ICS, LABAs, and theophyllines Not allowed: cromones, leukotriene antagonists, and inhaled anticholinergics
Garcia et al^Citation48	Randomized, double-blind, placebo-controlled study	Tiotropium 18 μg OD Placebo	12 weeks	Ambulatory patients of either sex; age >40 years; diagnosed with COPD (FEV1 <60% of the predicted value and FEV1/FVC <70%); smokers or	NR
Moita et al^Citation49	Randomized, double-blind, placebo-controlled study	Tiotropium 18 μg OD Placebo	12 weeks	ex-smokers with smoking history ≥ 10 pack-years FEV1 ≤70%; FEV1/FVC ≤70%; excluded if ≥3 exacerbations during the previous year or an exacerbation 6 weeks prior	Allowed: LABAs, theophylline, mucolytics, ICS, stable-dose oral corticosteroids; temporary increases in theophylline or oral steroids for exacerbations Not allowed: 24-hour preparations of theophylline

Abbreviations: ATS, American Thoracic Society; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced expiratory vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; NMA, network meta-analysis; OD, once daily; QVA149, indacaterol/glycopyrronium; NR, not reported; SABA, short-acting β2-agonist.

Figure 1 Summary of study-flow (A) registries (B) study selection.

Abbreviations: CDSR, Cochrane Database of Systematic Review; CSR, clinical study report; DARE, Database of Abstracts of Reviews of Effects; EMBASE, Excerpta Medica dataBASE; EU-CTR, European Union Clinical Trials Register; HTA, Health Technology Assessment Database; GSK, GlaxoSmithKline; MEDLINE, Medical Literature Analysis and Retrieval System Online; NMA, network meta-analysis; PROSPERO, international prospective register of systematic review; WHO ICTRP, World Health Organization International Clinical Trials Registry Platform.

Table 2 Key patient characteristics at baseline for all studies included in the NMA (only arms of interest)

Studies included in the NMA	Treatment	ITT (n)	Male (%)	Age (SD) in years	Current smokers (%)	Severe or very severe (%)	ICS usage (%)	COPD duration mean (SD) in years	Pack-years (SD)	FEV1% predicted (SD)
Decramer et al^Citation9 (DB2113360)	Tiotropium 18 μg OD	208	67	62.6 (9.39)	48	53	45	NR	41.9 (24.44)	47.8 (13.36)
	Vilanterol 22 μg/umeclidinium 55 μg OD	212	70	63 (8.67)	46	50	44	NR	44.8 (27.65)	48.0 (12.94)
Decramer et al^Citation9 (DB2113374)	Tiotropium 18 μg OD	215	71	65.2 (8.3)	47	52	53	NR	54.0 (31.59)	47.4 (13.10)
	Vilanterol 22 μg/umeclidinium 55 μg OD	217	65	65 (8.62)	42	51	47	NR	47.8 (26.13)	47.7 (13.55)
Donohue et al^Citation6 (DB2113373)	Placebo	280	70	62.2 (9.04)	54	58	49	NR	47.2 (27.21)	46.7 (12.71)
	Vilanterol 22 μg/umeclidinium 55 μg OD	413	74	63.1 (8.71)	49	51	51	NR	46.5 (25.80)	47.8 (13.19)
Maleki-Yazdi et al^Citation28 (ZEP117115)	Tiotropium 18 μg OD	451	67	62.7 (8.50)	54	58	53	NR	44.4 (25.03)	46.5 (12.76)
	Vilanterol 22 μg/umeclidinium 55 μg OD	454	68	61.9 (8.41)	59	60	54	NR	44.1 (24.44)	46.2 (13.02)
INTRUST 1 (Mahler et al^Citation17)	Tiotropium 18 μg OD	564	67	63.4 (9.22)	36	53	52	6.6 (6.45)	47.2 (26.58)	48.9 (11.46)
	Indacaterol 150 μg OD + tiotropium 18 μg OD	570	70	64.0 (9.07)	40	53	52	7.1 (6.12)	47.2 (25.86)	48.3 (9.70)
INTRUST 2 (Mahler et al^Citation17)	Tiotropium 18 μg OD	570	68	62.8 (8.98)	43	54	51	7.1 (6.26)	46.3 (24.64)	48.6 (9.76)
	Indacaterol 150 μg OD + tiotropium 18 μg OD	572	63	63.1 (8.83)	38	54	57	7.3 (6.48)	46.2 (25.52)	48.6 (9.74)
Aaron et al^Citation20	Tiotropium 18 μg OD	156	53.8	68.1 (8.9)	27	NR	25	11.3 (8.8)a	51.8 (28.0)	42.1 (13.5)
	Tiotropium 18 μg OD + salmeterol 25 μg 2 puffs bid	148	57.4	67.6 (8.2)	24.3	NR	34.9	NR	48.7 (27.1)	41.2 (13.0)
ENLIGHTEN (Dahl et al^Citation13)	Placebo	113b	76.1	62.9 (8.14)	45	19	39	5.46 (5.1)	38.1 (15.93)	59.43 (12.5)
	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD	226b	77.3	62.5 (8.81)	45	31	46	5.82 (5.74)	36.3 (16.01)	56.39 (13.27)
SPARK (Wedzicha et al^Citation16)	Tiotropium 18 μg OD	742b	75	63.6 (7.8)	37	100	76	7.2 (5.5)	47 (28)	37.4 (8.1)
	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD	741b	76	63.1 (8.1)	38	100	75	7.2 (5.8)	45 (23)	37.0 (8.1)
SHINE (Bateman et al^Citation11)	Placebo	234b	72.8	64.4 (8.6)	40	32	58	6.4 (5.7)	NR	55.2 (12.7)
	Tiotropium 18 μg OD	483b	75.0	63.5 (8.7)	39	38	59	6.1 (5.5)	NR	55.1 (13.5)
	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD	475b	76.4	64.0 (8.9)	40	34	56	6.0 (5.5)	NR	55.7 (13.2)
Vogelmeier et al^Citation19	Tiotropium 18 μg OD	221	79.2	63.4 (9.5)	NR	NR	NR	6.9 (6.3)	38.6 (19.3)	51.6 (11.2)
	Formoterol 10 μg bid + tiotropium 18 μg OD	207	79.2	62.6 (8.8)	NR	NR	NR	7.2 (7.0)	37.9 (18.2)	50.4 (10.5)
	Placebo	209	77.5	62.5 (8.6)	NR	NR	NR	6.7 (6.1)	40.1 (22.8)	51.1 (11)
Tashkin et al^Citation18	Tiotropium 18 μg OD + formoterol 12 μg bid	124	65	63.8 (8.7)	49	NR	27	NR	NR	NR
	Tiotropium 18 μg OD + placebo bid	131	68	63.9 (8.5)	46	NR	27	NR	NR	NR
Chan et al^Citation36 BI trial: 205.259	Tiotropium 18 μg OD	608	59	67.0 (8.7)	32	NR	66	9.9 (8.1)	50.2 (22.6)	39 (13)
	Placebo	305	61	67.0 (9.1)	30	NR	71	9.9 (7.9)	51.0 (26.3)	39 (14)
TIPHON (Tonnel et al^Citation37)	Tiotropium 18 μg OD	266	87	65.0 (9.7)	24	57	38	7.9 (7.6)	44.4 (21.3)	47 (13)
	Placebo	288	85	64.0 (10.1)	30	62	36	8.0 (7.9)	43.0 (22.5)	46 (12)
UPLIFT (Tashkin et al^Citation38 and Celli et al^Citation39)	Tiotropium 18 μg OD	2,987	75	65.0 (8.4)	29	52	62	9.9 (7.6)	49.0 (28.0)	40 (12)
	Placebo	3,006	74	65.0 (8.5)	30	53	62	9.7 (7.4)	48.4 (27.9)	39 (12)
Niewoehner et al^Citation40	Tiotropium 18 μg OD	914	98	67.6 (8.7)	29	NR	61	12.2 (10.4)	67.4 (35.4)	36 (13)
	Placebo	915	99	68.1 (8.5)	30	NR	58	11.9 (10.5)	69.4 (36.6)	36 (13)
Brusasco et al^Citation41	Tiotropium 18 μg OD	402	77	63.8 (8.0)	NR	NR	NR	9.0 (7.3)	44.1 (22.9)	39 (12)
	Placebo	400	76	64.6 (8.6)	NR	NR	NR	9.8 (7.4)	42.4 (22.7)	39 (12)
Donohue et al^Citation29	Tiotropium 18 μg OD	209	74	64.5 (7.9)	NR	NR	66	9.2 (7.8)	47.0 (25.0)	41 (NR)
	Placebo	201	75	65.6 (7.8)	NR	NR	66	9.7 (7.9)	46.0 (24.0)	41 (NR)
Casaburi et al^Citation42	Tiotropium 18 μg OD	550	67	65.0 (9.0)	NR	NR	44	8.6 (7.4)	63.0 (31.0)	39 (14)
	Placebo	371	63	65.0 (9.0)	NR	NR	40	8.1 (6.8)	59.0 (30.0)	38 (14)
Donohue et al^Citation43	Tiotropium 18 μg OD	420	65	64 (8.8)	NR	NR	35	NR	50.0 (25.1)	54 (16)
	Placebo	425	61	63.6 (8.9)	NR	NR	40	NR	49.7 (23.9)	56 (14)
GLOW 2 (Kerwin et al^Citation44)	Tiotropium 18 μg OD	267	63	63.9 (8.2)	44	NR	52	7.5 (6.6)	50.2 (28.0)	56 (13)
	Placebo	268	65	63.6 (9.1)	46	NR	51	7.4 (6.6)	48.0 (24.0)	56 (14)
Verkindre et al^Citation45	Tiotropium 18 μg OD	46	94	61.0 (9.5)	24	NR	NR	9.7 (6.9)	45.6 (23.1)	35 (9)
	Placebo	54	94	60.0 (10.2)	33	NR	NR	8.8 (6.6)	41.8 (18.0)	36 (9)
Casaburi et al^Citation46	Tiotropium 18 μg OD	276	67	65.0 (8.6)	NR	NR	NR	9.3 (8.0)	64.5 (33.1)	39 (14)
	Placebo	188	63	65.0 (9.0)	NR	NR	NR	8.6 (6.9)	60.5 (30.2)	38 (14)
Covelli et al^Citation47	Tiotropium 18 μg OD	94	66	66.0 (8.9)	40	NR	54	10.1 (8.1)	66 (35.6)	40 (13)
	Placebo	84	49	63.0 (9.2)	37	NR	58	10.4 (7.7)	65 (31.2)	39 (14)
Garcia et al^Citation48	Tiotropium 18 μg OD	123	NR	NR	NR	NR	NR	NR	NR	NR
	Placebo	125	NR	NR	NR	NR	NR	NR	NR	NR
Moita et al^Citation49	Tiotropium 18 μg OD	147	NR	NR	28	NR	NR	NR	NR	NR
	Placebo	164	NR	NR	25	NR	NR	NR	NR	NR

Notes:

a Duration of reported dyspnea.

b Randomized population.

Abbreviations: bid, twice daily; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FP, fluticasone propionate; ICS, inhaled corticosteroid; ITT, intent-to-treat; NMA, network meta-analysis; NR, not reported; OD, once daily; QVA149, indacaterol/glycopyrronium; SD, standard deviation.

Figure 2 Overall network of studies in the NMA analysis of UMEC/VI versus LABA/LAMA combination therapies evaluated at 24 weeks for (A) trough FEV₁, (B) SGRQ total score, (C) TDI focal score, and (D) rescue medication use.

Notes: Studies in bold represent those that report only mean values without reporting SE, SD, and 95% CI. Studies DB2113360 and DB2113374 from Decramer et al.⁹ Study DB2113373 from Donohue et al.⁶ Study ZEP117115 from Maleki-Yazdi et al.²⁸
Abbreviations: CI, confidence interval; FEV₁, forced expiratory volume in 1 second; FOR, formoterol; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; NMA, network meta-analysis; PBO, placebo; QVA149, indacaterol/glycopyrronium; SAL, salmeterol; SD, standard deviation; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnoea index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

Table 3 Individual study results at 12 weeks and 24 weeks for trough FEV₁, SGRQ total scores, TDI focal scores, and rescue medication use (puffs/day)

Study	Treatment	Weeks	Trough FEV1 in mL (difference in CFB), mean (SE)	SGRQ total score (difference in CFB), mean (SE)	TDI focal score (difference in TDI), mean (SE)	Rescue medication use (difference in puffs/day vs placebo), mean (SE)
Donohue et al^Citation6 (DB2113373)	Vilanterol 22 μg/umeclidinium 55 μg OD vs placebo	12	195.00 (17.86)	−4.72 (1.06)	1.30 (0.23)	−1.00 (0.24)
		24	167.00 (20.15)	−5.51 (1.21)	1.20 (0.26)	−0.80 (0.26)
Decramer et al^Citation9 (DB2113360)	Vilanterol 22 μg/umeclidinium 55 μg OD vs tiotropium 18 μg OD	12	95.00 (21.94)	−2.01 (1.26)	0.70 (0.31)	−0.51 (0.32)
		24	60.00 (25.26)	−0.17 (1.37)	0.20 (0.36)	−0.60 (0.31)
Decramer et al^Citation9 (DB2113374)	Vilanterol 22 μg/umeclidinium 55 μg OD vs tiotropium 18 μg OD	12	80.00 (24.49)	−0.23 (1.29)	0.20 (0.26)	−0.78 (0.30)
		24	90.00 (26.02)	0.75 (1.47)	−0.10 (0.31)	−0.70 (0.28)
Maleki-Yazdi et al^Citation28 (ZEP117115)	Vilanterol 22 μg/umeclidinium 55 μg OD vs tiotropium 18 μg OD	12	109.00 (15.82)	−2.08 (0.70)		−0.50 (0.10)
		24	112.00(16.07)	−2.10(0.77)		−0.50 (0.13)
SHINE^Citation11	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD vs placebo	12	230.00 (17.86)	−3.99 (0.87*)	1.22(0.26)
		24	200.00 (17.86)	−3.01 (1.04)	1.09(0.24)	−0.96 (0.17)
SHINE^Citation11	Tiotropium 18 μg OD vs placebo	12	130.00 (17.86)	−2.37 (0.87*)	0.59 (0.27)
		24	130.00 (17.86)	−0.88 (1.04)	0.58 (0.24)	−0.41 (0.17)
SPARK^Citation16	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD vs tiotropium 18 μg OD	12	70.00 (13.79)	−3.00 (0.88)
		24	70.00 (13.79)	−1.60 (0.92)
ENLIGHTEN^Citation13	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg) OD vs placebo	12	163.00 (32.02)
		24	152.00 (35.36)
Niewoehner et al^Citation40	Tiotropium 18 μg OD vs placebo	12	100.00 (10.00)
		24	100.00 (13.00)
Donohue et al^Citation43	Tiotropium 18 μg OD vs placebo	12	140.00 (20.41)	−1.10 (0.87)	0.75 (0.22)
		24	140.00 (20.41)	−1.00 (0.92)	0.87 (0.23)	−0.60 (0.19)
GLOW 2^Citation44	Tiotropium 18 μg OD vs placebo	12	83.00 (19.00)	−2.84 (0.97)	0.26 (0.30)
		24	84.00 (21.60)	−2.52 (1.11)	0.94 (0.30)
TIPHON^Citation37	Tiotropium 18 μg OD vs placebo	12		−3.59 (1.22)
		24		−3.51 (0.65)
Casaburi et al^Citation42	Tiotropium 18 μg OD vs placebo	12			0.95 (0.18)
		24			0.85 (0.19)
INTRUST 1^Citation17	Indacaterol 150 μg OD + tiotropium 18 μg OD vs tiotropium 18 μg OD	12	80.00 (12.76)			−1.10 (0.18)
INTRUST 2^Citation17	Indacaterol 150 μg OD + tiotropium 18 μg OD vs tiotropium 18 μg OD	12	70.00 (10.20)			−0.70(0.15)
Tashkin et al^Citation18	Tiotropium 18 μg OD + formoterol 12 μg bid vs tiotropium 18 μg OD	12	90.00 (28.06)	−1.01 (1.68*)	0.07 (0.39)	−0.25 (0.35*)
Chan et al^Citation36	Tiotropium 18 μg OD vs placebo	12	100.00 (15.00)
Niewoehner et al^Citation40	Tiotropium 18 μg OD vs placebo	12	100.00 (10.00)
Verkindre et al^Citation45	Tiotropium 18 μg OD vs placebo	12	110.00 (40.00)	−6.50 (2.90)	1.28 (0.89)	−0.13 (0.25)
Casaburi et al^Citation46	Tiotropium 18 μg OD vs placebo	12	150.00 (14.00)
Covelli et al^Citation47	Tiotropium 18 μg OD vs placebo	12	184.00 (37.00)
Moita et al^Citation45	Tiotropium 18 μg OD vs placebo	12	102.00 (31.38)
Aaron et al^Citation20	Tiotropium 18 μg OD + salmeterol 50 μg vs tiotropium 18 μg OD	24	18.49 (45.46)	−1.47 (0.69)	−0.42 (0.43)
UPLIFT^Citation38,Citation35	Tiotropium 18 μg OD vs placebo	24	100.00 (7.00)	−2.5 (0.36)
Brusasco et al^Citation41	Tiotropium 18 μg OD vs placebo	24	120.00 (100.00)	−2.7 (0.99)	1.10 (0.30)
Donohue et al^Citation29	Tiotropium 18 μg OD vs placebo	24	137.00 (20.00)	−2.71 (0.99*)	1.02 (0.25*)	−1.45 (0.26*)
Vogelmeier et al^Citation19	Tiotropium 18 μg OD + formoterol 10 μg bid vs placebo	24		−2.93 (1.33)
Vogelmeier et al^Citation19	Tiotropium 18 μg OD + formoterol 10 μg bid vs tiotropium 18 μg OD	24		−0.88(1.84)
Vogelmeier et al^Citation19	Tiotropium 18 μg OD vs placebo	24		−2.05(1.27)

Notes:

* Imputed value. Blank spaces in the table indicate not applicable.

Abbreviations: bid, twice daily; CFB, change from baseline; FEV₁, forced expiratory volume in 1 second; OD, once daily; QVA149, indacaterol/glycopyrronium; SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Table 4 Results of the NMA

Intervention	Weeks		Comparator
			Placebo	Tiotropium 18 μg	QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)	Tiotropium 18 μg + salmeterol 50 μg	Tiotropium 18 μg + formoterol 10 μg	Tiotropium 18 μg + formoterol 12 μg	Tiotropium 18 μg + indacaterol 150 μg
CFB in trough FEV1
Tiotropium 18 μg	12	Estimate	114.50
		95% Crl	103.60, 125.30
		P (better)	>99%
	24	Estimate	105.40
		95% Crl	95.10, 115.90
		P (better)	>99%
QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)	12	Estimate	198.70	84.20
		95% Crl	178.50, 218.70	65.58, 102.90
		P (better)	>99%	>99%
	24	Estimate	177.50	72.01
		95% Crl	157.30, 197.80	53.74, 90.75
		P (better)	>99%	>99%
Vilanterol 22 μg/umeclidinium 55 μg	12	Estimate	208.10	93.65	9.41			3.86	19.80
		95% Crl	187.90, 228.40	74.53, 112.60	−16.96, 35.77			−54.14,62.18	−4.90, 44.40
		P (better)	>99%	>99%	76%			55%	94%
	24	Estimate	191.50	86.16	14.14	67.40
		95%Crl	169.70, 213.40	65.74, 106.50	−14.18, 42.25	−25.25, 159.40
		P (better)	>99%	>99%	84%	92%
Formoterol 12 μg + tiotropium 18 μg	12	Estimate	204.30	89.78	5.56
		95%Crl	148.30, 260.00	34.82, 144.50	−52.53, 63.42
		P (better)	>99%	>99%	57%
Indacaterol 150 μg + tiotropium 18 μg	12	Estimate	188.30	73.85	−10.32			−15.94
		95%Crl	169.30, 207.40	58.21, 89.46	−34.82, 13.93			−72.84, 41.26
		P (better)	>99%	>99%	20%			29%
Tiotropium 18 μg + salmeterol 50 μg	24	Estimate	124.50	19.18	−53.00
		95%Crl	33.98, 214.20	−71.35, 108.70	−146.80, 38.38
		P (better)	>99%	65%	13%
SGRQ total score
Tiotropium 18 μg	12	Estimate	−2.52
		95%Crl	−3.51, −1.53
		P (better)	>99%
	24	Estimate	−2.50
		95%Crl	−3.01, −2.01
		P (better)	>99%
QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)	12	Estimate	−5.52	−3.00
		95%Crl	−7.50, −3.52	−4.72, −1.28
		P (better)	>99%	>99%
	24	Estimate	−A.27	−1.77
		95%Crl	−5.34, −3.20	−2.75, −0.78
		P (better)	>99%	>99%
Vilanterol 22 μg/umeclidinium 55 μg	12	Estimate	−4.35	−1.83	1.17
		95%Crl	−5.58, −3.11	−2.81, −0.84	−0.81, 3.15
		P (better)	>99%	>99%	12%
	24	Estimate	−4.09	−1.58	0.18	−0.11	−0.68
		95%Crl	−5.23, −2.95	−2.66, −0.52	−1.28, 1.63	−1.84, 1.61	−1.77, 0.39
		P (better)	>99%	>99%	41%	55%	89%
Tiotropium 18 μg + formoterol 10 μg	24	Estimate	−3.41	−0.90	0.86
		95%Crl	−3.95, −2.86	−1.06, −0.74	−0.13, 1.86
		P (better)	>99%	>99%	4%
Tiotropium 18 μg + salmeterol 50 μg	24	Estimate	−3.98	−1.47	0.29		−0.57
		95%Crl	−5.42, −2.53	−2.83, −0.12	−1.38, 1.96		−1.93, 0.79
		P (better)	>99%	98%	37%		80%
TDI focal score
Tiotropium 18 μg	12	Estimate	0.76
		95% Crl	0.55, 0.97
		P (better)	>99%
	24	Estimate	0.87
		95% Crl	0.67, 1.07
		P (better)	>99%
QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)	12	Estimate	1.33	0.57
		95% Crl	0.92, 1.73	0.18, 0.96
		P (better)	>99%	>99%
	24	Estimate	1.34	0.46
		95% Crl	1.03, 1.64	0.21,0.72
		P (better)	>99%	>99%
Vilanterol 22 μg/umeclidinium 55 μg	12	Estimate	1.22	0.46	−0.10			0.39
		95% Crl	0.90, 1.54	0.16, 0.77	−0.59, 0.38			−0.43, 1.22
		P (better)	>99%	>99%	34%			83%
	24	Estimate	1.04	0.16	−0.30	0.58
		95% Crl	0.68, 1.39	−0.19, 0.52	−0.73, 0.13	−0.33, 1.50
		P (better)	>99%	82%	9%	90%
Tiotropium 18 μg + formoterol 12 μg	12	Estimate	0.83	0.07	−0.50
		95%Crl	0.03, 1.62	−0.70, 0.83	−1.36, 0.36
		P (better)	0.98	57%	13%
Tiotropium 18 μg + salmeterol 50 μg	24	Estimate	0.45	−0.42	−0.89
		95% Crl	−0.42, 1.31	−1.26, 0.42	−1.77, −0.01
		P (better)	0.85	16%	2%
Rescue medication use
Tiotropium 18 μg	12	Estimate	−0.21
		95% Crl	−0.60, 0.18
		P (better)	0.86
	24	Estimate	−0.46
		95% Crl	−0.68, −0.23
		P (better)	>99%
Vilanterol 22 μg/umeclidinium 55 μg	12	Estimate	−0.93	−0.71					0.15
		95% Crl	−1.31, −0.55	−1.08, −0.35					−0.28, 0.58
		P (better)	>99%	>99%					25%
	24	Estimate	−0.97	−0.51	0.02
		95% Crl	−1.25, −0.69	−0.71, −0.31	−0.27, 0.32
		P (better)	>99%	>99%	43%
Indacaterol 150 μg + tiotropium 18 μg	12	Estimate	−1.08	−0.86
		95% Crl	−1.53, −0.63	−1.09, −0.64
		P (better)	>99%	>99%
QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)	24	Estimate	−0.99	−0.54
		95% Crl	−1.27, −0.72	−0.77, −0.31
		P (better)	>99%	>99%

Notes: Differences in intervention versus the comparator for CFB in trough FEV₁ (mL), SGRQ total scores, TDI focal scores, and rescue medication use at 12 weeks and 24 weeks, 95% CrI, and probability (P) that the intervention is better than the comparator. Blank spaces in the table indicate not applicable.

Abbreviations: CFB, change from baseline; CrI, credible interval; FEV₁, forced expiratory volume in 1 second; NMA, network meta-analysis; OD, once daily; QVA149, indacaterol/glycopyrronium; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Figure 3 Forest plot for (A) mean trough FEV₁, (B) mean SGRQ total scores, (C) mean TDI focal scores, and (D) mean rescue medication use of UMEC 55 μg/VI 22 μg versus comparators at 24 weeks.

Notes: Dotted lines included in panels (A–C) indicate the MCIDs versus placebo if these have been defined: these have been included in the graph for reference purpose only. The values shown on the right of each figure represent mean (95% CI).
Abbreviations: CFB, change from baseline; FEV₁, forced expiratory volume in 1 second; FOR, formoterol; MCID, minimal clinically important difference; PBO, placebo; QVA149, indacaterol/glycopyrronium; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol.

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