Comparative efficacy of inhaled medications (ICS/LABA, LAMA, LAMA/LABA and SAMA) for COPD: a systematic review and network meta-analysis

Figures & data

Table 1 Study characteristics of the included trials in NMA

Author, year, study name	Study design	Treatments				Trial duration	Inclusion criteria	No of participants	Outcome measured
									FEV1 (weeks)	TDI (weeks)	TDI resp (weeks)	SGRQ (weeks)	SGRQ resp (weeks)	AE (weeks)
Kerwin et al, 2012,^Citation13 ACCORD COPD I	MC, DB, PC	Acl	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	376	√ 12	√ 12	√ 12	√ 12	√ 12
Rennard et al, 2013,^Citation14 ACCORD COPD II	MC, DB, PC	Acl	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	360	√ 12	√ 12	√ 12	√ 12	√ 12	√ 12
Jones et al, 2012,^Citation15 ATTAIN	MC, DB, PC	Acl	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	548	√ 12 24	√ 12 24	√ 24	√ 12 24	√ 24
Lee et al, 2015^Citation16	MC, DB, PC	Acl	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	263	√ 12	√ 12	√ 12	√ 12	√ 12	√ 12
D’Urzo et al, 2011,^Citation17 GLOW1	MC, DB, PC	Glyco	Placebo	–	–	26 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	822	√ 12 24	√ 24	√ 24	√ 24	√ 24	√ 24
Wang et al, 2015,^Citation18 GLOW7	MC, DB, PC	Glyco	Placebo	–	–	26 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years, symptomatic on at least 4 days of the last 7 days	460	√ 12 24	√ 12 24	√ 12 24	√ 12 24	√ 12 24	√ 24
Chapman et al, 2014,^Citation19 GLOW5	MC, DB, AC	Glyco	Tio18	–	–	12 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	657	√ 12	√ 12		√ 12	√ 12	√ 12
Kerwin et al, 2012,^Citation20 GLOW2	MC, DB with open-label Tio18 arm, AC	Glyco	Placebo	Tio18 (open label)	–	52 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	1,066	√ 12 24	√ 12 24	√ 24	√ 12 24	√ 24
Ambrosino et al, 2008^Citation21	MC, DB, PC	Tio18	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	234		√ 12 24		√ 12 24
Brusasco et al, 2003^Citation22	MC, DB, PC	Tio18	Placebo	–	–	26 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥10 pack years	802	√ 24	√ 24	√ 24	√ 24	√ 24
Casaburi et al, 2000^Citation23	MC, DB, PC	Tio18	Placebo	–	–	13 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥10 pack years	470	√ 12					√ 12
Casaburi et al, 2002^Citation24	MC, DB, PC	Tio18	Placebo	–	–	52 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥10 pack years	921	√ 12 24	√ 12 24		√ 24
Chan et al, 2007^Citation25	MC, DB, PC	Tio18	Placebo	–	–	48 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥10 pack years, had one or more exacerbations (requiring antibiotics/steroids) in past 2 years	913	√ 12
Covelli et al, 2005^Citation26	MC, DB, PC	Tio18	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	196	√ 12
Donohue et al, 2010^Citation27	MC, DB with open-label Tio arm, AC	Tio18 (open label)	Placebo	–	–	26 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥20 pack years	833	√ 12 24	√ 12 24	√ 12 24	√ 12 24
Johansson et al, 2008^Citation28	MC, DB, PC	Tio18	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≥60% (mild/moderate COPD), smoking ≥10 pack years, MRC dyspnea ≥2	224	√ 12					√ 12
Moita et al, 2008^Citation29	MC, DB, PC	Tio18	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years. Patients excluded if they had more than one exacerbation in the last year	304	√ 12					√ 12
Niewoehner et al, 2005^Citation30	MC, DB, PC	Tio18	Placebo	–	–	6 months	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	1,829	√ 12 24
Freeman et al, 2007,^Citation31 SPRUCE	MC, DB, PC	Tio18	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred 30%–65%, smoking ≥10 pack years	395	√ 12					√ 12
Trooster et al, 2014^Citation32	MC, DB, PC	Tio18	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred 50%–80%, smoking ≥10 pack years. Patients excluded if on maintenance COPD treatment in the last 6 months	457	√ 12 24
Tashkin et al, 2008,^Citation33 Celli et al, 2009,^Citation34 UPLIFT	MC, DB, PC	Tio18	Placebo	–	–	4 years	≥40 years old, FEV1 pred ≤80%, smoking ≥10 pack years	5,993	√ 12 24			√ 24
Verkindre et al, 2006^Citation35	MC, DB, PC	Tio18	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≤50%, smoking ≥10 pack years, with lung hyperinflation	100	√ 12	√ 12		√ 12	√ 12
Zhou et al, 2017,^Citation36 Tie-COPD	MC, DB, PC	Tio18	Placebo	–	–	1 year	≥40 years old, FEV1 pred ≥50%	841	√ 24
Vincken et al 2002,^Citation37 van Noord et al 2000^Citation38	MC, DB, AC	Tio18	Ipra	–	–	52 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥10 pack years	535	√ 12 24	√ 12 24	√ 12 24	√ 12 24	√ 12 24	√ 12
Bateman et al, 2010^Citation39	MC, DB, PC	Tio5	Placebo	–	–	48 weeks	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	1,323	√ 24
Bateman et al, 2010^Citation40	MC, DB, PC	Tio5	Placebo	–	–	48 weeks	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	3,991	√ 24			√ 24	√ 24
Voshaar et al, 2008^Citation41	MC, DB, AC	Tio5	Ipra	Placebo	–	12 weeks	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	539	√ 12					√ 12
Wise et al, 2013,^Citation42 Wise et al, 2013,^Citation43 Anzueto et al, 2015,^Citation44 TIOSPIR	MC, DB, AC	Tio5	Tio18	–	–	Event- driven trial. Median follow-up 2.3 years	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years	11,405	√ 24
Trivedi et al, 2014^Citation45	MC, DB, PC	Umec	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2	137	√ 12	√ 12	√ 12	√ 12		√ 12
Feldman et al, 2016^Citation46	MC, DB, PC	Umec	Tio18	–	–	12 weeks	≥40 years old, FEV1 pred 30%–70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2	1,017	√ 12	√ 12	√ 12	√ 12	√ 12	√ 12
Rheault et al, 2015^Citation47	MC, open label, AC	Umec	Glyco	–	–	12 weeks	≥40 years old, FEV1 pred 30%–70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2	1,034	√ 12	√ 12	√ 12	√ 12	√ 12	√ 12
D’Urzo et al, 2014,^Citation48 AUGMENT	MC, DB, AC	AclForm	Acl	Placebo	–	24 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	1,015	√ 12 24	√ 24	√ 12 24	√ 24	√ 12 24
Singh et al, 2014,^Citation49 ACLIFORM	MC, DB, AC	AclForm	Acl	Placebo	–	24 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	964	√ 12 24	√ 24	√ 24	√ 24
Vogelmeier et al, 2016,^Citation50 AFFIRM	MC, DB, AC	AclForm	SFC500	–	–	24 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years, CAT score ≥10	933		√ 24	√ 24		√ 24	√ 24
Bateman et al, 2013,^Citation51 SHINE	MC, DB with open-label Tio18 arm, AC	IndaGlyco	Glyco	Placebo	Tio18 (open label)	26 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years, symptomatic on at least 4 days of the last 7 days	1,659	√ 12 24	√ 12 24	√ 24	√ 24	√ 24	√ 24
Dahl et al, 2013,^Citation52 ENLIGHTEN	MC, DB, PC	IndaGlyco	Placebo	–	–	52 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years, symptomatic on at least 4 days of the last 7 days	339	√ 12 24
Vogelmeier et al, 2013,^Citation53 ILLUMINATE	MC, DB, AC	IndaGlyco	SFC500	–	–	26 weeks	≥40 years old, FEV1 pred 40%–80%, smoking ≥10 pack years. Patients excluded if they had more than one exacerbation in the last year	523	√ 12 24	√ 12 24	√ 12 24	√ 12 24	√ 12 24	√ 24
Wedzicha et al, 2016,^Citation54 FLAME	MC, DB, AC	IndaGlyco	SFC500	–	–	52 weeks	≥40 years old, FEV1 pred 25%–60%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2, had one or more exacerbations (requiring antibiotics/steroids) in the last year	3,362	√ 12 24			√ 12 24
Zhong et al, 2015,^Citation55 LANTERN	MC, DB, AC	IndaGlyco	SFC500	–	–	26 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2. Patients excluded if they had more than one exacerbation (requiring antibiotics/steroids) in the last year	744	√ 12 24	√ 12 24		√ 12 24		√ 24
Wedzicha et al, 2013,^Citation56 SPARK	MC, DB with open-label Tio arm, AC	IndaGlyco	Glyco	Tio18 (open label)	–	64 weeks	≥40 years old, FEV1 pred ≤50%, smoking ≥10 pack years, had one or more exacerbations (requiring antibiotics/steroids) in the past year	2,224	√ 12 24			√ 12 24	√ 12 24
Singh et al, 2015,^Citation57 OTEMTO 1	MC, DB, AC	TioOlo	Tio5	Placebo	–	12 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	612	√ 12	√ 12		√ 12	√ 12	√ 12
Singh et al, 2015,^Citation57 OTEMTO 2	MC, DB, AC	TioOlo	Tio5	Placebo	–	12 weeks	≥40 years old, FEV1 pred 30%–80%, smoking ≥10 pack years	607	√ 12	√ 12		√ 12	√ 12	√ 12
Buhl et al, 2015,^Citation58 Buhl et al, 2017,^Citation59 TONADO1	MC, DB, AC	TioOlo	Tio5	–	–	52 weeks	≥40 years old, FEV1 pred ≤80%, smoking ≥10 pack years	1,049	√ 12 24			√ 24	√ 24
Buhl et al, 2015,^Citation58 Buhl et al, 2017,^Citation59 TONADO2	MC, DB, AC	TioOlo	Tio5	–	–	52 weeks	≥40 years old, FEV1 pred ≤80%, smoking ≥10 pack years	1,013	√ 12 24			√ 24	√ 24
Kerwin et al, 2017^Citation60	MC, DB, AC	UmecVil	Umec	–	–	12 weeks	≥40 years old, FEV1 pred 50%–70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 1, and were prescribed with Tio for at least 3 months. Patients were excluded if they had more than two exacerbations in the last year	494	√ 12	√ 12	√ 12	√ 12	√ 12	√ 12
Donohue et al, 2015,^Citation66 study 2	MC, DB, AC	UmecVil	SFC250	–	–	12 weeks	≥40 years old, FEV1 pred 30%–70%, mMRC symptoms scale ≥grade 2	700	√ 12	√ 12		√ 12		√ 12
Singh et al, 2015^Citation67	MC, DB, AC	UmecVil	SFC500	–	–	12 weeks	≥40 years old, FEV1 pred 30%–70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2. Patients were excluded if they had any exacerbation in the last year	716	√ 12	√ 12	√ 12	√ 12	√ 12	√ 12
Tashkin et al, 2008^Citation68	MC, DB, PC	BudeForm	Placebo	–	–	6 months	≥40 years old, FEV1 pred ≤50%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2, had one or more exacerbations (requiring antibiotics/steroids) within 1–12 months before screening	577	√ 24			√ 24	√ 24	√ 24
Rennard et al, 2009^Citation69	MC, DB, PC	BudeForm	Placebo	–	–	12 months	≥40 years old, FEV1 pred ≤50%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2, had one or more exacerbations (requiring antibiotics/steroids) within 1–12 months before screening	975	√ 24
Bhatt et al, 2017^Citation70	MC, DB, PC	FFVI	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years	276	√ 12 24			√ 12 24
Kerwin et al, 2013^Citation71	MC, DB, PC	FFVI	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2	413	√ 24
Martinez et al, 2013^Citation72	MC, DB, PC	FFVI	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years, mMRC symptoms scale ≥grade 2	409	√ 12 24
Covelli et al, 2016^Citation73	MC, DB, AC	FFVI	Tio18	–	–	12 weeks	≥40 years old, FEV1 pred 30%–70%, smoking ≥10 pack years, at least one cardiovascular risk factor	623	√ 12			√ 12	√ 12	√ 12
Pepin et al, 2014^Citation74	MC, DB, AC	FFVI	Tio18	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years, measured aPWV ≥11.0 m/s	257	√ 12			√ 12		√ 12
Dransfield et al, 2014,^Citation75 study 1	MC, DB, AC	FFVI	SFC250	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years	519	√ 12
Dransfield et al, 2014,^Citation75 study 2	MC, DB, AC	FFVI	SFC250	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years	511	√ 12
Dransfield et al, 2014,^Citation75 study 3	MC, DB, AC	FFVI	SFC250	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years	828	√ 12
Agustí et al, 2014^Citation76	MC, DB, AC	FFVI	SFC500	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, smoking ≥10 pack years, ≥1 moderate/severe exacerbation in the past 3 years	528	√ 12			√ 12		√ 12
Asai et al, 2015^Citation77	MC, DB, PC	SFC250	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred 40%–80%	56	√ 12					√ 12
Hanania et al, 2003^Citation78	MC, DB, PC	SFC250	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥20 pack years, moderate dyspnea	363	√ 12 24
Mahler et al, 2002^Citation79	MC, DB, PC	SFC500	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥20 pack years, chronic sputum production for 3 months of a year for 2 years	354	√ 12 24					√ 24
Calverley et al, 2007,^Citation80 Jenkins et al, 2009,^Citation82 Jones et al, 2011,^Citation81 TORCH	MC, DB, PC	SFC500	Placebo	–	–	3 years	≥40 years old, FEV1 pred ≤60%, smoking ≥10 pack years	6,112	√ 24			√ 24
Zheng et al, 2007^Citation83	MC, DB, PC	SFC500	Placebo	–	–	24 weeks	≥40 years old, FEV1 pred 25%–69%	445	√ 24			√ 24		√ 24
Cazzola et al, 2007^Citation84	MC, DB, AC	SFC500	Tio18	–	–	12 weeks	≥50 years old, FEV1 pred ≤80%, smoking ≥20 pack years	60	√ 12					√ 12
Perng et al, 2009^Citation85	Single-center, open label, AC	SFC500	Tio18	–	–	12 weeks	≥40 years old, FEV1 pred ≤80%, smoking ≥20 pack years, newly diagnosed or not on medication for 3 months	67	√ 12			√ 12
Dahl et al, 2001^Citation86	MC, DB, PC	Ipra	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≤70%, symptomatic on at least 4 days of the last 7 days	394				√ 12		√ 12
Taylor et al, 2001^Citation87	MC, DB, PC	Ipra	Placebo	–	–	12 weeks	≥40 years old, FEV1 pred ≤65%, smoking ≥10 pack years	187						√ 12

Abbreviations: AC, active-controlled trials; Acl, aclidinium; AclForm, aclidinium/formoterol; AE, adverse event; aPWV, arterial pulse wave velocity; DB, double-blind; FEV1 pred, FEV1 percentage predicted; FFVI, fluticasone/vilanterol; Glyco, glycopyrronium; IndaGlyco, indacaterol/glycopyrronium; Ipra, ipratropium; MC, multicenter; NMA, network meta-analysis; PC, placebo-controlled trials; resp, responder; SFC250, fluticasone/salmeterol 250/50 mcg; SFC500, fluticasone/salmeterol 500/50 mcg; TDI, transition dyspnea index; SGRQ, St George’s respiratory questionnaire; Tio5, tiotropium 5 mcg; Tio18, tiotropium 18 mcg; TioOlo, tiotropium/olodaterol; Umec, umeclidinium; UmecVil, umeclidinium/vilanterol.

Figure 1 Evidence network of available trials showing direct comparisons of agents with respect to lung function (trough FEV₁) at weeks 12 and 24.

Note: The size of each treatment node is weighted by the number of studies.
Abbreviations: Acl, aclidinium; AclForm, aclidinium/formoterol; BudeForm, budesonide/formoterol; FFVI, fluticasone/vilanterol; Glyco, glycopyrronium; IndaGlyco, indacaterol/glycopyrronium; Ipra, ipratropium; SFC250, fluticasone/salmeterol 250/50 mcg; SFC500, fluticasone/salmeterol 500/50 mcg; Tio5, tiotropium 5 mcg; Tio18, tiotropium 18 mcg; TioOlo, tiotropium/olodaterol; Umec, umeclidinium; UmecVil, umeclidinium/vilanterol.

Table 2 Baseline characteristics and risk of bias of the included trials in NMA

Study, year	Proportion of males (%)	Mean age (years)	Proportion of smokers (%)	Mean COPD duration (years)	FEV1 predicted (%)	Proportion with exacerbation history (%)	Selection bias		Performance bias	Detection bias	Attrition bias	Reporting bias
							Random sequence generation	Allocation concealment?	Blinding of participants and personnel	Blinding of outcome assessments	Incomplete outcome data	Selective reporting
Kerwin et al, 2012,^Citation13 ACCORD COPD I	52	65	44	NR	54	NR
Rennard et al, 2013,^Citation14 ACCORD COPD II	53	62	53	NR	53	NR
Jones et al, 2012,^Citation15 ATTAIN	68	62	54	NR	56	34	Unclear	Unclear	Unclear	Low	Low	Low
Lee et al, 2015^Citation16	98	68	NR	NR	53	NR	Low	Low	Low	Unclear	Low	Low
D’Urzo et al, 2011,^Citation17 GLOW1	82	64	34	6.2	55	21.20	Unclear	Unclear	Unclear	High	Low	Low
Wang et al, 2015,^Citation18 GLOW7	96	65	22	4.4	51	23.70	Unclear	Unclear	Unclear	Unclear	Low	Low
Chapman et al, 2014,^Citation19 GLOW5	74	63	45	6.3	54	23.60	Low	Low	Low	Low	Low	Low
Kerwin et al, 2012,^Citation20 GLOW2	64	64	45	6.6	56	26.50	Low	Low	High	High	Low	Low
Ambrosino et al, 2008^Citation21	84	67	NR	11.1	41	NR	Unclear	Unclear	Low	Low	Low	Low
Brusasco et al, 2003^Citation22	77	64	NR	9.4	39	NR	Unclear	Unclear	Low	Unclear	High	Low
Casaburi et al, 2000^Citation23	65	65	NR	9.0	39	NR	High	Unclear	Low	Unclear	Low	Low
Casaburi et al, 2002^Citation24	65	65	NR	8.4	39	NR	Unclear	Unclear	Low	Unclear	High	Low
Chan et al, 2007^Citation25	60	67	30	9.9	39	100	Unclear	Unclear	Low	Unclear	High	Low
Covelli et al, 2005^Citation26	58	65	39	10.2	39	NR	Unclear	Unclear	Unclear	Unclear	High	Low
Donohue et al, 2010^Citation27	63	64	NR	NR	55	NR	Low	Low	High	High	High	Low
Johansson et al, 2008^Citation28	48	61	60	4.8	73	NR	Unclear	Unclear	Low	Unclear	Unclear	Low
Moita et al, 2008^Citation29	NR	NR	27	NR	41	NR	Unclear	Unclear	Low	Unclear	Low	Low
Niewoehner et al, 2005^Citation30	99	68	30	12.0	36	NR	Low	Unclear	Low	Low	High	Low
Freeman et al, 2007,^Citation31 SPRUCE	54	65	NR	NR	49	NR	Low	Unclear	Low	Unclear	High	Low
Trooster et al, 2014^Citation32	68	62	60	NR	66	NR	Unclear	Unclear	Low	Unclear	Low	Low
Tashkin et al, 2008,^Citation33 Celli et al, 2009,^Citation34 UPLIFT	75	65	30	9.9	48	NR	Low	Low	Low	Low	Low	Low
Verkindre et al, 2006^Citation35	94	61	29	9.4	35	NR	Unclear	Unclear	Low	Unclear	Unclear	Low
Zhou et al, 2017,^Citation36 Tie-COPD	85	64	41	0.6	78	NR	Low	Low	Low	Low	Low	Low
Vincken et al 2002,^Citation37 van Noord et al 2000^Citation38	85	64	NR	11.3	41	NR	Unclear	Unclear	Low	Unclear	High	Low
Bateman et al, 2010^Citation39	74	65	37	8.9	46	NR	Unclear	Unclear	Low	Unclear	High	Low
Bateman et al, 2010^Citation40	78	65	36	8.2	45	NR	Low	Low	Low	Low	High	Low
Voshaar et al, 2008^Citation41	68	64	40	10	41	NR	Unclear	Unclear	Low	Low	High	Low
Wise et al, 2013,^Citation42 Wise et al, 2013,^Citation43 Anzueto et al, 2015,^Citation44 TIOSPIR	61	66	37	NR	48	NR	Low	Low	Low	Low	Low	Low
Trivedi et al, 2014^Citation45	62	63	54	NR	46	NR	Low	Low	Low	Unclear	Low	Low
Feldman et al, 2016^Citation46	72	64	51	NR	51	NR	Low	Low	Low	Unclear	Low	Low
Rheault et al, 2015^Citation47	69	64	48	NR	51	32.5	Low	Low	High	High	Low	Low
D’Urzo et al, 2014,^Citation48 AUGMENT	53	64	52	NR	54	NR	Unclear	Unclear	Low	Low	High	Low
Singh et al, 2014,^Citation49 ACLIFORM	68	63	47	NR	54	NR	Low	Low	Low	Low	High	Low
Vogelmeier et al, 2016,^Citation50 AFFIRM	65	63	NR	NR	53	32	Unclear	Unclear	Unclear	Unclear	Low	Low
Bateman et al, 2013,^Citation51 SHINE	75	64	40	6.2	55	24.90	Low	Low	High	High	Low	Low
Dahl et al, 2013,^Citation52 ENLIGHTEN	77	63	45	5.64	57	34	Low	Unclear	Low	Unclear	High	Low
Vogelmeier et al, 2013,^Citation53 ILLUMINATE	71	63	48	7.0	60	0	Low	Low	Low	Low	Low	Low
Wedzicha et al, 2016,^Citation54 FLAME	76	65	40	7.3	44	100	Low	Low	Low	Low	Low	Low
Zhong et al, 2015,^Citation55 LANTERN	95	65	25	5.2	52	20.8	Low	Low	Low	Low	Low	Low
Wedzicha et al, 2013,^Citation56 SPARK	74	63	38	7.2	37	100	Low	Low	High	High	Low	Low
Singh et al, 2015,^Citation57 OTEMTO 1	60	65	49	NR	55	NR	Unclear	Unclear	Low	Unclear	Low	Low
Singh et al, 2015,^Citation57 OTEMTO 2	63	65	46	NR	55	NR	Unclear	Unclear	Low	Unclear	Low	Low
Buhl et al, 2015,^Citation58 Buhl et al, 2017,^Citation59 TONADO1	72	64	37	NR	50	NR	Low	Unclear	Low	Unclear	High	Low
Buhl et al, 2015,^Citation58 Buhl et al, 2017,^Citation59 TONADO2	72	64	37	NR	50	NR	Low	Unclear	Low	Unclear	High	Low
Kerwin et al, 2017^Citation60	66	64	50	NR	60	34	Low	Low	Low	Low	Low	Low
Siler et al, 2016^Citation61	59	63	54	NR	47	NR	Low	Low	Low	Unclear	Low	Low
Zheng et al, 2015^Citation62	93	64	29	NR	47	NR	Low	Low	Low	Unclear	Low	Low
Donohue et al, 2013^Citation63	71	63	51	NR	47	NR	Low	Low	Low	Unclear	Low	Low
Decramer et al, 2014,^Citation64 study 1	68	64	47	NR	48	48.6	Low	Low	Low	Unclear	Low	Low
Decramer et al, 2014,^Citation64 study 2	68	64	45	NR	48	34.5	Low	Low	Low	Unclear	Low	Low
Maleki-Yazdi et al, 2014^Citation65	68	62	57	NR	46	NR	Low	Low	Low	Unclear	Low	Low
Donohue et al, 2015,^Citation66 study 1	70	63	43	NR	49	NR	Low	Low	Low	Low	Low	Low
Donohue et al, 2015,^Citation66 study 2	76	64	52	NR	50	NR	Low	Low	Low	Low	High	Low
Singh et al, 2015^Citation67	72	62	59	NR	51	0	Low	Low	Low	Unclear	Low	Low
Tashkin et al, 2008^Citation68	68	63	42	NR	40	100	Low	Unclear	Low	Unclear	Low	Low
Rennard et al, 2009^Citation69	64	63	41	10.5	40	100	Unclear	Unclear	Low	Unclear	Low	Low
Bhatt et al, 2017^Citation70	81	68	37	NR	NR	NR	Low	Low	Low	Unclear	Low	Low
Kerwin et al, 2013^Citation71	67	62	54	NR	48	22	Low	Low	Low	Unclear	Low	Low
Martinez et al, 2013^Citation72	72	62	53	NR	48	22	Low	Low	Unclear	Unclear	Low	Low
Covelli et al, 2016^Citation73	65	63	52	NR	50	55	Low	Low	Low	Low	Low	Low
Pepin et al, 2014^Citation74	86	67	46	NR	46	NR	Unclear	Low	Low	Low	Low	Unclear
Dransfield et al, 2014,^Citation75 study 1	69	61	55	NR	48	NR	Low	Low	Low	Unclear	Low	Low
Dransfield et al, 2014,^Citation75 study 2	69	61	55	NR	49	NR	Low	Low	Low	Unclear	Low	Low
Dransfield et al, 2014,^Citation75 study 3	69	61	55	NR	48	NR	Low	Low	Low	Unclear	Low	Low
Agustí et al, 2014^Citation76	82	63	NR	NR	48	89	Low	Unclear	Low	Unclear	Low	Unclear
Asai et al, 2015^Citation77	98	63	50	NR	NR	NR	Low	Unclear	Low	Low	Low	Low
Hanania et al, 2003^Citation78	64	64	45	NR	42	NR	Unclear	Unclear	Low	Low	Low	Low
Mahler et al, 2002^Citation79	69	63	50	NR	41	NR	Unclear	Unclear	Low	Unclear	Low	Low
Calverley et al, 2007,^Citation80 Jenkins et al, 2009,^Citation82 Jones et al, 2011,^Citation81 TORCH	76	65	43	NR	44	NR	Unclear	Unclear	Low	Unclear	Low	Low
Zheng et al, 2007^Citation83	89	66	22	NR	47	NR	Unclear	Unclear	Low	Unclear	Low	Low
Cazzola et al, 2007^Citation84	90	65	88	NR	38	NR	Unclear	Unclear	Low	Unclear	Low	Low
Perng et al, 2009^Citation85	94	73	61	NR	58	NR	Low	Unclear	High	High	Low	Low
Dahl et al, 2001^Citation86	74	63	46	8.0	45	NR	Unclear	Unclear	Low	Low	High	Low
Taylor et al, 2001^Citation87	63	66	NR	9.7	42	NR	Low	Unclear	Low	Unclear	Low	Low

Abbreviations: NMA, network meta-analysis; NR; not reported.

Table 3 Treatment effects on FEV₁ at week 12 – NMA results: combining direct and indirect evidence (lower triangle) and direct evidence (upper triangle)

NMA results (combining direct and indirect estimates)	Direct evidence
	Placebo	−54 (−99.08, −8.92)	−134 86 (−163.11, −106.62)	−92.31 (−220.57, 35.95)	−199.00 (−253.88, −144.12)	−161.86 (−201.19, −122.53)	−164.00 (−190.33, −137.67)	−199.93 (−265.25, −134.62)	−136.51 (−160.74, −112.29)	−137.62 (−169.5, 105.73)	−117.16 (−135.37, −98.95)	−113.02 (−127.61, −98.43)	−127.32 (−150.06, −104.58)	−114.47 (−130.59, −98.36)
	−8.76 (−44.27, 26.74)	Ipra	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	−64.00 (−109.08, −18.92)	−139.20 (−176.44, −101.96)
	−130.18 (−151.46, −108.90)	−121.42 (−162.09, −80.74)	FFVI	40.91 (13.87, 67.95)	23.00 (−20.12, 66.12)	NA	NA	NA	NA	NA	NA	NA	NA	12.40 (−16.82, 41.61)
	−90.44 (−115.14, −65.74)	−81.68 (−124.33, −39.03)	39.74 (15.51, 63.96)	SFC250	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
	−118.55 (−140.12, −96.98)	−109.78 (−150.35, −69.21)	11.64 (−14.81, 38.08)	−28.10 (−57.80, 1.60)	SFC500	−90.00 (−125.28, −54.72)	NA	NA	NA	NA	NA	NA	NA	41.48 (16.46, 66.49)
	−183.67 (−201.93, −165.41)	−174.91 (−213.90, −135.91)	−53.49 (−78.10, −28.88)	−93.23 (−118.04, −68.41)	−65.12 (−88.95, −41.30)	UmecVil	NA	NA	NA	56.00 (24.64, 87.36)	NA	NA	NA	96.66 (76.84, 116.49)
	−164.17 (−194.44, −133.90)	−155.41 (−199.04, −111.77)	−33.99 (−70.72, 2.74)	−73.73 (−112.45, −35.01)	−45.63 (−82.38, −8.88)	19.50 (−15.43, 54.42)	TioOlo	NA	NA	NA	NA	NA	49.13 (22.85, 75.42)	NA
	−192.99 (−213.93, −172.06)	−184.23 (−224.48, −143.98)	−62.81 (−89.97, −35.66)	−102.55 (−132.61, −72.49)	−74.45 (−93.95, −54.95)	−9.32 (−33.70, 15.05)	−28.82 (−65.22, 7.57)	IndaGlyco	NA	NA	89.35 (50.17, 128.53)	NA	NA	84.13 (54.78, 113.48)
	−134.00 (−164.06, −103.94)	−125.24 (−171.76, −78.71)	−3.82 (−40.63, 32.99)	−43.56 (−82.43, −4.68)	−15.46 (−52.42, 21.51)	49.67 (14.53, 84.81)	30.17 (−12.47, 72.82)	58.99 (22.39, 95.60)	AclForm	NA	NA	19.93 (−2.91, 42.76)	NA	NA
	−142.27 (−166.87, −117.67)	−133.50 (−175.84, −91.16)	−12.09 (−42.99, 18.81)	−51.82 (−84.71, −18.94)	−23.72 (−53.95, 6.51)	41.40 (14.57, 68.24)	21.91 (−16.77, 60.58)	50.73 (21.03, 80.43)	−8.27 (−47.09, 30.55)	Umec	33 (5.56, 60.44)	NA	NA	53 (25.56, 80.44)
	−110.92 (−127.58, −94.27)	−102.16 (−140.51, −63.81)	19.26 (−6.18, 44.69)	−20.48 (−48.81, 7.85)	7.62 (−16.37, 31.62)	72.75 (50.48, 95.01)	53.25 (18.98, 87.52)	82.07 (59.86, 104.29)	23.08 (−11.27, 57.43)	31.34 (5.82, 56.87)	Glyco	NA	NA	0.95 (−13.22, 15.12)
	−111.95 (−131.74, −92.17)	−103.19 (−143.84, −62.54)	18.23 (−10.76, 47.21)	−21.51 (−53.05, 10.04)	6.59 (−22.56, 35.75)	71.72 (44.92, 98.52)	52.22 (16.11, 88.33)	81.04 (52.35, 109.74)	22.05 (−7.64, 51.73)	30.31 (−1.17, 61.80)	−1.03 (−26.82, 24.76)	Acl	NA	NA
	−112.16 (−139.57, −84.76)	−103.40 (−143.61, −63.19)	18.02 (−16.52, 52.55)	−21.72 (−58.46, 15.02)	6.38 (−28.27, 41.03)	71.51 (38.80, 104.21)	52.01 (26.94, 77.08)	80.83 (46.57, 115.09)	21.84 (−18.84, 62.51)	30.10 (−6.53, 66.74)	−1.24 (−33.12, 30.64)	−0.21 (−34.00, 33.58)	Tio5	NA
	−104.92 (−116.81, −93.02)	−96.15 (−131.73, −60.58)	25.26 (3.71, 46.81)	−14.48 (−39.53, 10.58)	13.63 (−7.02, 34.27)	78.75 (61.21, 96.29)	59.25 (27.14, 91.37)	88.08 (68.02, 108.13)	29.08 (−3.23, 61.39)	37.35 (13.17, 61.53)	6.00 (−10.53, 22.54)	7.03 (−15.98, 30.04)	7.24 (−22.24, 36.73)	Tio18

Notes: Comparisons between treatments should be read from left to right. The MD in milliliters with 95% CI are shown in the cell. MD >0 favors the column-defining treatment (lower triangle) and the row-defining treatment (upper triangle). Statistically significant results in bold. The lower triangle refers to the area below the colored boxes, correspondingly the upper triangle is the area above the colored boxes.

Abbreviations: Acl, aclidinium; AclForm, aclidinium/formoterol; FFVI, fluticasone/vilanterol; Glyco, glycopyrronium; IndaGlyco, indacaterol/glycopyrronium; Ipra, ipratropium; MD, mean difference; NA, results not available; NMA, network meta-analysis; SFC250, fluticasone/salmeterol 250/50 mcg; SFC500, fluticasone/salmeterol 500/50 mcg; Tio5, tiotropium 5 mcg; Tio18, tiotropium 18 mcg; TioOlo, tiotropium/olodaterol; Umec, umeclidinium; UmecVil, umeclidinium/vilanterol.

Table 4 Treatment effects on FEV₁ at week 24 – NMA results: combining direct and indirect evidence (lower triangle) and direct evidence (upper triangle)

NMA results (combining direct and indirect estimates)	Direct evidence
	Placebo	NA	−137.07 (−169.35, −104.78)	−79.41 (−101.99, −56.83)	−161.00 (−223.72, −98.28)	−128.66 (−207.25, −50.07)	−159.39 (−187.78, −131.00)	NA	−185.39 (−228.68, −142.09)	−138.87 (−156.97, −120.77)	−115.00 (−154.20, −75.80)	−125.22 (−142.65, −107.79)	−115.24 (−131.16, −99.32)	−114.43 (−134.93, −93.93)	−120.41 (−133.99, −106.83)
	48.56 (−3.08, 100.19)	Ipra	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	−161.20 (−200.40, −122.00)
	−137.27 (−174.32, −100.21)	−185.82 (−249.39, −122.26)	FFVI	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
	−79.45 (−111.25, −47.66)	−128.01 (−188.65, −67.37)	57.81 (8.98, 106.64)	BudeForm	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
	−161.00 (−231.13, −90.87)	−209.56 (−296.65, −122.46)	−23.73 (−103.06, 55.59)	−81.55 (−158.55, −4.54)	SFC250	NA	NA	NA	NA	NA	NA	NA	NA	NA	NA
	−95.54 (−117.97, −73.11)	−144.09 (−199.91, −88.28)	41.73 (−1.58, 85.03)	−16.08 (−54.99, 22.83)	65.46 (−8.17, 139.10)	SFC500	NA	NA	−86.15 (−98.06, −74.24)	NA	NA	NA	NA	NA	NA
	−185.89 (−210.29, −161.49)	−234.45 (−289.94, −178.95)	−48.62 (−93.00, −4.24)	−106.44 (−146.52, −66.36)	−24.89 (−99.15, 49.37)	−90.35 (−123.15, −57.56)	UmecVil	NA	NA	NA	52.00 (16.72, 87.28)	NA	NA	NA	92.02 (61.25, 122.78)
	−166.97 (−208.69, −125.25)	−215.53 (−281.26, −149.80)	−29.71 (−85.52, 26.11)	−87.52 (−139.98, −35.06)	−5.97 (−87.58, 75.64)	−71.44 (−118.97, −23.90)	18.92 (−28.77, 66.61)	TioOlo	NA	NA	NA	NA	NA	60.00 (42.36, 77.64)	NA
	−182.82 (−203.61, −162.03)	−231.37 (−285.98, −176.77)	−45.55 (−88.05, −3.06)	−103.37 (−141.36, −65.37)	−21.82 (−94.97, 51.33)	−87.28 (−107.78, −66.78)	3.07 (−27.91, 34.05)	−15.85 (−62.17, 30.48)	IndaGlyco	NA	NA	86.15 (68.77, 103.54)	NA	NA	76.09 (57.73, 94.46)
	−139.37 (−167.96, −110.78)	−187.92 (−246.93, −128.91)	−2.10 (−48.91, 44.70)	−59.91 (−102.67, −17.15)	21.63 (−54.11, 97.37)	−43.83 (−80.21, −7.45)	46.52 (8.96, 84.08)	27.60 (−22.94, 78.15)	43.45 (8.10, 78.80)	AclForm	NA	NA	26.94 (2.72, 51.17)	NA	NA
	−125.54 (−169.40, −81.68)	−174.10 (−241.08, −107.11)	11.73 (−45.70, 69.15)	−46.09 (−100.26, 8.09)	35.46 (−47.26, 118.18)	−30.00 (−79.17, 19.16)	60.35 (17.31, 103.39)	41.43 (−18.78, 101.65)	57.28 (9.13, 105.42)	13.83 (−38.51, 66.17)	Umec	NA	NA	NA	NA
	−119.24 (−138.18, −100.30)	−167.79 (−221.71, −113.88)	18.03 (−23.58, 59.64)	−39.78 (−76.79, −2.78)	41.76 (−30.88, 114.41)	−23.70 (−50.33, 2.93)	66.65 (36.86, 96.44)	47.73 (2.13, 93.34)	63.58 (40.20, 86.96)	20.13 (−14.18, 54.44)	6.30 (−41.09, 53.69)	Glyco	NA	NA	8.18 (−26.31, 42.67)
	−115.15 (−140.60, −89.70)	−163.71 (−221.26, −106.15)	22.12 (−22.84, 67.07)	−35.70 (−76.42, 5.03)	45.85 (−28.76, 120.46)	−19.61 (−53.56, 14.33)	70.74 (35.50, 105.98)	51.82 (2.97, 100.67)	67.67 (34.81, 100.53)	24.22 (−7.41, 55.85)	10.39 (−40.31, 61.09)	4.09 (−27.64, 35.82)	Acl	NA	NA
	−108.33 (−129.58, −87.07)	−156.88 (−211.98, −101.78)	28.94 (−13.79, 71.67)	−28.87 (−67.12, 9.37)	52.67 (−20.61, 125.96)	−12.79 (−43.78, 18.20)	77.57 (46.08, 109.05)	58.65 (22.70, 94.59)	74.49 (45.23, 103.76)	31.04 (−4.55, 66.63)	17.21 (−31.17, 65.60)	10.91 (−17.15, 38.98)	6.82 (−26.30, 39.95)	Tio5	NA
	−114.07 (−126.34, −101.80)	−162.63 (−212.80, −112.45)	23.20 (−15.84, 62.23)	−34.62 (−68.70, −0.54)	46.93 (−24.27, 118.13)	−18.53 (−42.79, 5.72)	71.82 (47.97, 95.68)	52.90 (10.29, 95.52)	68.75 (47.19, 90.30)	25.30 (−5.80, 56.40)	11.47 (−32.97, 55.91)	5.17 (−14.50, 24.84)	1.08 (−27.16, 29.32)	−5.74 (−28.72, 17.23)	Tio18

Notes: Comparisons between treatments should be read from left to right. The MD in milliliters with 95% CI are shown in the cell. MD >0 favors the column-defining treatment (lower triangle) and the row-defining treatment (upper triangle). Statistically significant results in bold.

Abbreviations: Acl, aclidinium; AclForm, aclidinium/formoterol; BudeForm, budesonide/formoterol; FFVI, fluticasone/vilanterol; Glyco, glycopyrronium; IndaGlyco, indacaterol/glycopyrronium; Ipra, ipratropium; MD, mean difference; NA, results not available; NMA, network meta-analysis; SFC250, fluticasone/salmeterol 250/50 mcg; SFC500, fluticasone/salmeterol 500/50 mcg; Tio5, tiotropium 5 mcg; Tio18, tiotropium 18 mcg; TioOlo, tiotropium/olodaterol; Umec, umeclidinium; UmecVil, umeclidinium/vilanterol.

Table 5 SUCRA values for all interventions for each outcome

	FEV1		TDI score		TDI responder		SGRQ score		SGRQ responder		Adverse events
	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks
Placebo	2.6	6.9	2.4	9.6	1.8	10.8	0.7	6.8	1.0	2.0	25.2	62.1
Tio18	29.5	42.6	29.7	40.1	39.1	38.5	32.9	42.1	33.4	30.2	58.9	62.6
Tio5	40.8	36.1	59.5	NA	NA	NA	27.4	44.6	NA	35.2	75.4	NA
Acl	39.6	43.6	56	47.6	36.6	55.4	23.9	51.7	20.1	72.7	63.3	NA
Glyco	39.2	49.2	36.1	54.5	58.3	61.3	50.5	61.3	48.0	32.7	49.9	72.3
Umec	72.6	53.9	42.2	43.8	58.6	34.2	68.1	68.1	38.5	38.1	31.5	29.4
AclForm	64.5	66.8	NA	88.4	72.8	88.7	NA	61.6	68.2	76.9	NA	74.8
IndaGlyco	97.6	91.7	91.6	94.2	49.1	93.5	93.1	60.6	81.7	76.1	NA	83.9
TioOlo	84.2	82.8	97.8	NA	NA	NA	77.0	66.1	93.4	85.0	75.8	NA
UmecVil	93.0	93.3	71.9	53.5	85.1	54.8	65.6	69.5	62.6	60.7	56.6	33.7
SFC500	48.9	24.5	69.9	66.8	85.6	62.2	71.1	19.2	64.6	72.6	49.3	33.3
SFC250	19.4	76.9	35.7	NA	NA	NA	53.0	NA	NA	NA	40.0	26.2
BudeForm	NA	17.5	NA	NA	NA	NA	NA	60.5	NA	48.4	NA	23.4
FFVI	63.0	64.0	NA	NA	NA	NA	75.6	71.9	70.7	NA	28.8	48.5
Ipra	5.1	0.2	7.2	1.5	13.0	0.4	11.2	15.8	17.8	19.6	45.3	NA

Note: The probabilities of each treatment being ranked best are represented by their SUCRA values.

Abbreviations: Acl, aclidinium; AclForm, aclidinium/formoterol; BudeForm, budesonide/formoterol; FFVI, fluticasone/vilanterol; Glyco, glycopyrronium; IndaGlyco, indacaterol/glycopyrronium; Ipra, ipratropium; NA, results not available; SFC250, fluticasone/salmeterol 250/50 mcg; SFC500, fluticasone/salmeterol 500/50 mcg; SGRQ, St George’s Respiratory Questionnaire; SUCRA, Surface Under the Cumulative Ranking; TDI, transitional dyspnea index; Tio5, tiotropium 5 mcg; Tio18, tiotropium 18 mcg; TioOlo, tiotropium/olodaterol; Umec, umeclidinium; UmecVil, umeclidinium/vilanterol.

KerwinEMD’UrzoADGelbAFLakkisHGarciaGil ECaractaCFACCORD I study investigatorsEfficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I)COPD2012929010122320148

 PubMedGoogle Scholar

RennardSIScanlonPDFergusonGTACCORD COPD II: a randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patientsClin Drug Investig20133312893904

 PubMed Web of Science ®Google Scholar

JonesPWSinghDBatemanEDEfficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN studyEur Respir J201240483083622441743

 PubMed Web of Science ®Google Scholar

LeeSHLeeJYooKHEfficacy and safety of aclidinium bromide in patients with COPD: a Phase 3 randomized clinical trial in a Korean populationRespirology20152081222122826370136

 PubMed Web of Science ®Google Scholar

D’UrzoAFergusonGTvan NoordJAEfficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trialRespir Res20111215622151296

 PubMed Web of Science ®Google Scholar

WangCSunTHuangYEfficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 studyInt J Chron Obstruct Pulmon Dis201510576825609940

 PubMed Web of Science ®Google Scholar

ChapmanKRBeehKMBeierJA blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting musca-rinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 studyBMC Pulm Med2014144424438744

 PubMed Web of Science ®Google Scholar

KerwinEHébertJGallagherNEfficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 studyEur Respir J20124051106111423060624

 PubMed Web of Science ®Google Scholar

AmbrosinoNFoglioKBalzanoGPaggiaroPLLessiPKestenSTiotropium and exercise training in COPD patients: effects on dyspnea and exercise toleranceInt J Chron Obstruct Pulmon Dis20083477178019281092

 PubMedGoogle Scholar

BrusascoVHodderRMiravitllesMKorduckiLTowseLKestenSHealth outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPDThorax200358539940412728159

 PubMed Web of Science ®Google Scholar

CasaburiRBriggsDDDonohueJFSerbyCWMenjogeSSWitekTJThe spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study GroupChest200011851294130211083677

 PubMed Web of Science ®Google Scholar

CasaburiRMahlerDAJonesPWA long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary diseaseEur Respir J200219221722411866001

 PubMed Web of Science ®Google Scholar

ChanCKMaltaisFSigouinCHaddonJMFord GTSAFE Study GroupA randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary diseaseCan Respir J200714846547218060091

 PubMed Web of Science ®Google Scholar

CovelliHBhattacharyaSCassinoCConoscentiCKestenSAbsence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary diseasePharmacotherapy200525121708171816305289

 PubMed Web of Science ®Google Scholar

DonohueJFFogartyCLotvallJOnce-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropiumAm J Respir Crit Care Med2010182215516220463178

 PubMed Web of Science ®Google Scholar

JohanssonGLindbergARombergKNordströmLGerkenFRoquetABronchodilator efficacy of tiotropium in patients with mild to moderate COPDPrim Care Respir J200817316917518536860

 PubMedGoogle Scholar

MoitaJBárbaraCCardosoJTiotropium improves FEV1 in patients with COPD irrespective of smoking statusPulm Pharmacol Ther200821114615117693107

 PubMed Web of Science ®Google Scholar

NiewoehnerDERiceKCoteCPrevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trialAnn Intern Med2005143531732616144890

 PubMed Web of Science ®Google Scholar

FreemanDLeeAPriceDEfficacy and safety of tiotropium in COPD patients in primary care – the SPiRiva Usual CarE (SPRUCE) studyRespir Res200784517605774

 PubMed Web of Science ®Google Scholar

TroostersTSciurbaFCDecramerMTiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trialNPJ Prim Care Respir Med2014241400324841833

 PubMed Web of Science ®Google Scholar

TashkinDPCelliBSennSBurkhartDKestenSMenjogeSA 4-year trial of tiotropium in chronic obstructive pulmonary diseaseN Engl J Med2008359151543155418836213

 PubMed Web of Science ®Google Scholar

CelliBDecramerMKestenSLiuDMehraSTashkinDPMortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med20091801094895519729663

 PubMed Web of Science ®Google Scholar

VerkindreCBartFAguilaniuBThe effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary diseaseRespiration200673442042716484769

 PubMed Web of Science ®Google Scholar

ZhouYZhongNSLiXTiotropium in early-stage chronic obstructive pulmonary diseaseN Engl J Med20173771092393528877027

 PubMed Web of Science ®Google Scholar

VinckenWvan NoordJAGreefhorstAPBantjeTAKestenSKorduckiLImproved health outcomes in patients with COPD during 1 yr’s treatment with tiotropiumEur Respir J200219220921611871363

 PubMed Web of Science ®Google Scholar

van NoordJABantjeTAElandMEKorduckiLCornelissenPJA randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study GroupThorax200055428929410722768

 PubMed Web of Science ®Google Scholar

BatemanESinghDSmithDEfficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studiesInt J Chron Obstruct Pulmon Dis2010519720820714373

 PubMedGoogle Scholar

BatemanEDTashkinDSiafakasNA one-year trial of tiotropium Respimat plus usual therapy in COPD patientsRespir Med2010104101460147220620037

 PubMed Web of Science ®Google Scholar

VoshaarTLapidusRMaleki-YazdiRA randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPDRespir Med20081021324117996436

 PubMed Web of Science ®Google Scholar

WiseRAAnzuetoACalverleyPThe Tiotropium Safety and Performance in Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-design and rationaleRespir Res2013144023547660

 PubMed Web of Science ®Google Scholar

WiseRAAnzuetoACottonDDahlRDevinsTDisseBTiotropium Respimat inhaler and the risk of death in COPDN Engl J Med2013369161491150123992515

 PubMed Web of Science ®Google Scholar

AnzuetoAWiseRCalverleyPThe Tiotropium Safety and Performance in Respimat® (TIOSPIR®) Trial: spirometry outcomesRespir Res20151610726369563

 PubMed Web of Science ®Google Scholar

TrivediRRichardNMehtaRChurchAUmeclidinium in patients with COPD: a randomised, placebo-controlled studyEur Respir J2014431728123949963

 PubMed Web of Science ®Google Scholar

FeldmanGMaltaisFKhindriSA randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPDInt J Chron Obstruct Pulmon Dis20161171973027103795

 PubMed Web of Science ®Google Scholar

RheaultTKhindriSVahdati-BolouriMChurchAFahyWAA randomised, open-label study of umeclidinium versus glycopyrronium in patients with COPDERJ Open Res201622

 Google Scholar

D’UrzoADRennardSIKerwinEMMergelVLeselbaumARCaractaCFAUGMENT COPD study investigatorsEfficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD studyRespir Res20141512325756831

 PubMed Web of Science ®Google Scholar

SinghDJonesPWBatemanEDEfficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised studyBMC Pulm Med20141417825404569

 PubMed Web of Science ®Google Scholar

VogelmeierCPaggiaroPLDorcaJEfficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a Phase 3 COPD studyEur Respir J20164841030103927492833

 PubMed Web of Science ®Google Scholar

BatemanEDFergusonGTBarnesNDual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE studyEur Respir J20134261484149423722616

 PubMed Web of Science ®Google Scholar

DahlRChapmanKRRudolfMSafety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN studyRespir Med2013107101558156723867808

 PubMed Web of Science ®Google Scholar

VogelmeierCFBatemanEDPallanteJEfficacy and safety of once-daily QVA149 compared with twice-daily salmeterol–fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group studyLancet Respir Med201311516024321804

 PubMed Web of Science ®Google Scholar

WedzichaJABanerjiDChapmanKRVestboJRocheNAyersRTIndacaterol–glycopyrronium versus salmeterol–fluticasone for COPDN Engl J Med2016374232222223427181606

 PubMed Web of Science ®Google Scholar

ZhongNWangCZhouXZhangNHumphriesMWangLLANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPDInt J Chron Obstruct Pulmon Dis2015101015102626082625

 PubMed Web of Science ®Google Scholar

WedzichaJADecramerMFickerJHAnalysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group studyLancet Respir Med20131319920924429126

 PubMed Web of Science ®Google Scholar

SinghDFergusonGTBolitschekJTiotropium + olodaterol shows clinically meaningful improvements in quality of lifeRespir Med2015109101312131926320402

 PubMed Web of Science ®Google Scholar

BuhlRMaltaisFAbrahamsRTiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4)Eur Respir J201545496997925573406

 PubMed Web of Science ®Google Scholar

BuhlRMagderSBothnerULong-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary diseaseRespir Med2017122586627993292

 PubMed Web of Science ®Google Scholar

KerwinEMKalbergCJGalkinDVUmeclidinium/vilanterol as step-up therapy from tiotropium in patients with moderate COPD: a randomized, parallel-group, 12-week studyInt J Chron Obstruct Pulmon Dis20171274575528280319

 PubMed Web of Science ®Google Scholar

DonohueJFWorsleySZhuCQHardakerLChurchAImprovements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbationsRespir Med2015109787088126006754

 PubMed Web of Science ®Google Scholar

SinghDWorsleySZhuCQHardakerLChurchAUmeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trialBMC Pulm Med2015159126286141

 PubMed Web of Science ®Google Scholar

TashkinDPRennardSIMartinPEfficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trialDrugs200868141975200018778120

 PubMed Web of Science ®Google Scholar

RennardSITashkinDPMcelhattanJEfficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trialDrugs200969554956519368417

 PubMed Web of Science ®Google Scholar

BhattSPDransfieldMTCockcroftJRA randomized trial of once-daily fluticasone furoate/vilanterol or vilanterol versus placebo to determine effects on arterial stiffness in COPDInt J Chron Obstruct Pulmon Dis20171235136528176907

 PubMed Web of Science ®Google Scholar

KerwinEMScott-WilsonCSanfordLA randomised trial of fluticasone furoate/vilanterol (50/25 μg; 100/25 μg) on lung function in COPDRespir Med2013107456056923352226

 PubMed Web of Science ®Google Scholar

MartinezFJBosciaJFeldmanGFluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trialRespir Med2013107455055923332861

 PubMed Web of Science ®Google Scholar

CovelliHPekBSchenkenbergerIScott-WilsonCEmmettACrimCEfficacy and safety of fluticasone furoate/vilanterol or tiotropium in subjects with COPD at cardiovascular riskInt J Chron Obstruct Pulmon Dis201611112

 PubMed Web of Science ®Google Scholar

PepinJLCockcroftJRMidwinterDSharmaSRubinDBAndreasSLong-acting bronchodilators and arterial stiffness in patients with COPD: a comparison of fluticasone furoate/vilanterol with tiotropiumChest201414661521153025058845

 PubMed Web of Science ®Google Scholar

DransfieldMTFeldmanGKorenblatPEfficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patientsRespir Med201410881171117924998880

 PubMed Web of Science ®Google Scholar

AgustíAde TeresaLde BackerWA comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPDEur Respir J201443376377224114969

 PubMed Web of Science ®Google Scholar

AsaiKKobayashiAMakiharaYJohnsonMAnti-inflammatory effects of salmeterol/fluticasone propionate 50/250 mcg combination therapy in Japanese patients with chronic obstructive pulmonary diseaseInt J Chron Obstruct Pulmon Dis20151080381125945045

 PubMed Web of Science ®Google Scholar

HananiaNADarkenPHorstmanDThe efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPDChest2003124383484312970006

 PubMed Web of Science ®Google Scholar

MahlerDAWirePHorstmanDEffectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary diseaseAm J Respir Crit Care Med200216681084109112379552

 PubMed Web of Science ®Google Scholar

CalverleyPMAndersonJACelliBSalmeterol and fluticasone propionate and survival in chronic obstructive pulmonary diseaseN Engl J Med2007356877578917314337

 PubMed Web of Science ®Google Scholar

JenkinsCRJonesPWCalverleyPMEfficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH studyRespir Res2009105919566934

 PubMed Web of Science ®Google Scholar

JonesPWAndersonJACalverleyPMHealth status in the TORCH study of COPD: treatment efficacy and other determinants of changeRespir Res2011127121627828

 PubMed Web of Science ®Google Scholar

ZhengJPYangLWuYMThe efficacy and safety of combination salmeterol (50 microg)/fluticasone propionate (500 microg) inhalation twice daily via accuhaler in Chinese patients with COPDChest200713261756176317951625

 PubMed Web of Science ®Google Scholar

CazzolaMAndòFSantusPA pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPDPulm Pharmacol Ther200720555656116914336

 PubMed Web of Science ®Google Scholar

PerngDWTaoCWSuKCTsaiCCLiuLYLeeYCAnti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPDEur Respir J200933477878419129278

 PubMed Web of Science ®Google Scholar

DahlRGreefhorstLANowakDInhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2001164577878411549532

 PubMed Web of Science ®Google Scholar

TaylorJKotchARiceKIpratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPDChest200112041253126111591569

 PubMed Web of Science ®Google Scholar

SilerTMDonaldACO’DellDChurchAFahyWAA randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol62.5/25 μg on health-related quality of life in patients with COPDInt J Chron Obstruct Pulmon Dis20161197197927274218

 PubMed Web of Science ®Google Scholar

ZhengJZhongNNewlandsAChurchAGohAHEfficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled studyInt J Chron Obstruct Pulmon Dis2015101753176726366068

 PubMed Web of Science ®Google Scholar

DonohueJFMaleki-YazdiMRKilbrideSMehtaRKalbergCChurchAEfficacy and safety of once-daily umeclidinium/vilanterol62.5/25 mcg in COPDRespir Med2013107101538154623830094

 PubMed Web of Science ®Google Scholar

DecramerMAnzuetoAKerwinEEfficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trialsLancet Respir Med20142647248624835833

 PubMed Web of Science ®Google Scholar

Maleki-YazdiMRKaelinTRichardNZvarichMChurchAEfficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trialRespir Med2014108121752176025458157

 PubMed Web of Science ®Google Scholar