Comparative efficacy of long-acting muscarinic antagonist monotherapies in COPD: a systematic review and network meta-analysis

Figures & data

Figure 1 Flow chart of study selection process.

Abbreviations: CDSR, Cochrane Database of Systematic Review; CENTRAL, Cochrane Central Register of Controlled Trials; CSR, clinical study report; DARE, Database of Abstracts of Reviews of Effects; EU-CTR, EU Clinical Trials Register; HTA, Health Technology Assessment; NMA, network meta-analysis; PROSPERO, International Prospective Register of Systematic Reviews; SLR, systematic literature review; WHO ICTRP, World Health Organization International Clinical Trials Registry Platform.

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

Study	Treatment	Trial duration	Inclusion criteria	Background treatment
Chan et al,^Citation4 SAFE,^Citation49,Citation50 SAFE-Portugal^Citation51	Tiotropium 18 µg OD Placebo	48 weeks	≥40 years old; ≥10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%; included if ≥1 exacerbation previous year but not in 6 weeks prior (later amended to include one exacerbation in past 2 years)	Allowed: stable dose oral corticosteroids, ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs
TIPHON^Citation35	Tiotropium 18 µg OD Placebo	36 weeks	≥40 years old; ≥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^Citation3,Citation52	Tiotropium 18 µg OD Placebo	4 years	≥40 years old; ≥10 pack-years; FEV1 ≤70%; FEV1/FVC ≤70%; excluded if exacerbation 4 weeks prior	Allowed: all respiratory medications, except other inhaled anticholinergic drugs
Niewoehner et al^Citation24	Tiotropium 18 µg OD Placebo	6 months	≥40 years old; ≥10 pack-years; FEV1 ≤60%; FEV1/FVC ≤70%; excluded if not recovered from exacerbation ≥30 days prior	Allowed: all other respiratory medications (including ICS and LABAs) Not allowed: open-label anticholinergic bronchodilator
Brusasco et al^Citation27	Tiotropium 18 µg OD Placebo	24 weeks	.40 years old; >10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%	NR
Donohue et al^Citation5	Tiotropium 18 µg OD Placebo	24 weeks	≥40 years old; >10 pack-years; FEV1 ≤60%; FEV1/FVC ≤70%	Allowed: usual ICS and oral steroids Not allowed: inhaled anticholinergic LABAs
Casaburi et al^Citation26	Tiotropium 18 µg OD Placebo	56 weeks	≥40 years old; ≥10 pack-years; FEV1 ≤65%; FEV1/FVC ≤70%	Allowed: stable doses of theophylline, ICS, oral prednisone
Donohue et al^Citation23	Tiotropium 18 µg OD Placebo	26 weeks	Patients aged 40 years or older with a smoking history of 20 pack-years or more and a diagnosis of moderate-to-severe COPD (GOLD criteria) were enrolled. Post-bronchodilator (within 30 minutes of inhaling albuterol 360 µg) FEV1 <80% and ≥30% predicted and FEV1/FVC <70%	Patients could continue ICS monotherapy if stable for 1 month before screening; dose and regimen were to remain 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 β2-agonist/ICS were switched to ICS monotherapy at an equivalent dose. All patients were supplied with albuterol for use as needed
SHINE^Citation29	Glycopyrronium 50 µg OD Tiotropium 18 µg OD Placebo	26 weeks	≥40 years old; diagnosis of 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: LABA, LAMA, LABA/ICS
GLOW1^Citation7	Glycopyrronium 50 µg OD Placebo	26 weeks	≥40 years old; post-bronchodilator FEV1≥30% and <80% of predicted; post-bronchodilator FEV1/FVC <0.7; ≥10 pack-years	Allowed: ICS, intranasal corticosteroids or H1antagonists Not allowed: LABA
GLOW2^Citation8	Glycopyrronium 50 µg OD Tiotropium 18 µg OD Placebo	52 weeks	Males and females ≥40 years, with a smoking history of ≥10 pack-years, a diagnosis of moderate-to-severe stable COPD, post-bronchodilator FEV1≥30% and <80% of the predicted normal, and post-bronchodilator FEV1/FVC <0.70 were enrolled	Allowed: inhaled or intranasal corticosteroids and H1 antagonists; salbutamol/albuterol as rescue medication Not allowed: LAMAs (min 7 days before run-in); LABAs or LABA/ICS combinations (min 48 hours before run-in)
Verkindre et al^Citation22	Tiotropium 18 µg OD Placebo	12 weeks	FEV1≤50%; FEV1/FVC ≤70%; residual volume ≥125%; excluded if unstable doses oral corticosteroid 6 weeks prior	Allowed: stable doses oral corticosteroids, ICS, theophylline preparations, mucolytic agents Not allowed: use of SABAs, oral β2-agonists, or LABAs
Casaburi et al^Citation53	Tiotropium 18 µg OD Placebo	13 weeks	FEV1 ≤65%; FEV1/FVC ≤70%; ≥40 years of age; diagnosis of COPD defined by ATS; smoking history of ≥10 pack-years	Allowed: stable doses of theophylline, ICS, oral prednisone Not allowed: other inhaled or oral bronchodilators
Covelli et al^Citation25	Tiotropium 18 µg OD Placebo	12 weeks	FEV1 ≤60%; FEV1/FVC ≤70%; excluded if exacerbation in prior 6 weeks	Allowed: ICS, LABAs, theophyllines Not allowed: chromones, leukotriene antagonists, inhaled anticholinergics
Garcia et al^Citation28	Tiotropium 18 µg OD Placebo	12 weeks	Ambulatory patients of either sex; >40 years old, diagnosed with COPD (FEV1 <60% of the predicted value and FEV1/FVC <70%); smokers or ex-smokers with a history of having smoked at least 10 pack-years	NR
Moita et al^Citation54	Tiotropium 18 µg OD Placebo	12 weeks	FEV1 ≤70%; FEV1/FVC ≤70%; excluded if ≥3 exacerbations previous year or exacerbation in 6 weeks prior	Allowed: LABAs, theophylline, mucolytics, ICS, stable doses oral corticosteroids. Temporary increases in theophylline or oral steroids for exacerbations Not allowed: theophylline 24-hour preparation
Vogelmeier et al^Citation55	Tiotropium 18 µg OD Placebo	24 weeks	FEV1 <70%, FEV1/FVC <70%; stable COPD; aged 40 years at COPD onset; smoking history of 10 pack-years	Allowed: salbutamol, ICS monotherapy
ACCORD COPD I^Citation56	Aclidinium 400 µg BD Placebo	12 weeks	≥40 years old; current or ex-smokers with ≥10 pack-years; diagnosed with moderate-to-severe COPD (post-bronchodilator FEV1/FVC <70% and FEV1 ≥30% and <80% of predicted)	Allowed: albuterol (rescue medication); ICS; systemic corticosteroids equivalent to ≤10 mg/day of prednisolone or 20 mg every other day, and theophylline if treatment was stable for ≥4 weeks prior to screening Not allowed: inhaled anticholinergics, LABAs
ACCORD COPD II^Citation30	Aclidinium 400 µg BD Placebo	12 weeks	≥40 years old; current or ex-smokers with ≥10 pack-years; diagnosed with moderate-to-severe COPD (post-bronchodilator FEV1/FVC <70% and FEV1 ≥30% and <80% of predicted)	Allowed: albuterol (rescue medication); theophylline; ICS; oral or parenteral corticosteroids equivalent to ≤10 mg/day of prednisolone or 20 mg every other day, if treatment was stable for ≥4 weeks prior to screening Not allowed: anticholinergics, LABAs
ATTAIN^Citation59	Aclidinium 400 µg BD Placebo	24 weeks	≥40 years old; post-bronchodilator FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC <0.7; ≥10 pack-years	Allowed: ICS monotherapy or oral sustained-release theophyllines; systemic corticosteroids at doses equivalent to 10 mg/day of prednisone or 20 mg every other day; and oxygen therapy(<15 hours/day). Inhaled salbutamol was used as a rescue medication
Donohue et al^Citation57	Umeclidinium 62.5 µg OD Placebo	24 weeks	Outpatient; ≥40 years old; diagnosed with COPD; post-salbutamol FEV1/FVC ratio <0.70 and a 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 Not allowed: LABAs, LABA/ICS combination products, short-acting β2-agonists, short-acting anticholinergics, SABA/ICS combination products
AC4115408^Citation34	Umeclidinium 62.5 µg OD Placebo	12 weeks	Outpatient; ≥40 years old; diagnosed with COPD; post-salbutamol FEV1/FVC ratio <0.70 and a post-salbutamol FEV1 ≤70%; smoking history ≥10 pack-years; ≥2 on mMRC	Allowed: salbutamol, ICS, mucolytics Not allowed: LABA, tiotropium, theophyllines, inhaled SABA, inhaled SAMA
SPARK^Citation58	Glycopyrronium 50 µg OD Tiotropium 18 µg OD	24 weeks	≥40 years old; post-bronchodilator FEV1 <50% of predicted normal and FEV1/FVC ratio <0.70; history of ≥ exacerbation in the previous 12 months. Smoking history ≥10 pack-years	Allowed: ICS Not allowed: LABAs
GLOW5^Citation45	Glycopyrronium 50 µg OD Tiotropium 18 µg OD	12 weeks	≥40 years old; post-bronchodilator FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC <0.7; ≥10 pack-years	Allowed: ICS and SABA for rescue medication Not allowed: LABA

Abbreviations: ATS, American Thoracic Society; BD, twice-daily; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting bronchodilator; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; NR, not reported; OD, once-daily; SABA, short-acting β₂ agonist.

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

Study	Treatment	ITT, n	Male, %	Mean age, years (SD)	Current smokers, %	Severe/very severe COPD, %	ICS use, %	Mean COPD duration, years (SD)	Mean pack-years (SD)	FEV1 % predicted (SD)
Chan et al,^Citation4 SAFE,^Citation49,Citation50 SAFE-Portugal^Citation51	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^Citation35	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^Citation3,Citation52	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^Citation24	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^Citation27	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^Citation5	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^Citation26	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^Citation23	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)
SHINE^Citation29	Glycopyrronium 50 µg OD	473	77	64.3 (9.0)	40	37	58	6.5 (5.8)	NR	55 (14)
	Tiotropium 18 µg	480	75	63.5 (8.7)	39	38	59	6.1 (5.5)	NR	55 (14)
	Placebo	232	73	64.4 (8.6)	40	32	58	6.4 (5.7)	NR	55 (13)
GLOW1^Citation7	Glycopyrronium 50 µg OD	552	83	63.8 (9.5)	33	40	55	5.9 (6.0)	44.9 (28.1)	55 (13)
	Placebo	270	81	64.0 (9.0)	34	38	51	6.5 (6.8)	44.6 (24.8)	54 (13)
GLOW2^Citation8	Glycopyrronium 50 µg OD	525	65	63.5 (9.1)	45	37	56	7.2 (6.6)	49.0 (25.4)	56 (13)
	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^Citation22	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^Citation53	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^Citation25	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^Citation28	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^Citation54	Tiotropium 18 µg OD	147	NR	NR	28	NR	NR	NR	NR	NR
	Placebo	164	NR	NR	25	NR	NR	NR	NR	NR
Vogelmeier et al^Citation55	Tiotropium 18 µg OD	221	79	63.4 (9.5)	NR	NR	NR	6.9 (6.3)	38.6 (19.3)	52 (11)
	Placebo	209	78	62.5 (8.6)	NR	NR	NR	6.7 (6.1)	40.1 (22.8)	51 (11)
ACCORD COPD I^Citation56	Aclidinium 400 µg; BD	190	53	64.9 (9.5)	42	NR	47	NR	57.2 (28.5)	54 (13)
	Placebo	186	52	65.1 (9.2)	47	NR	45	NR	52.7 (28.1)	55 (13)
ACCORD COPD II^Citation30	Aclidinium 400 µg BD	177	50	63.2 (9.0)	50	54	42	NR	54.2 (27.7)	50 (13)
	Placebo	182	55	61.7 (9.3)	56	37	39	NR	52.6 (28.4)	55 (13)
ATTAIN^Citation59	Aclidinium 400 µg BD	269	68	62.9 (8.4)	55	31	51	NR	41.7 (21.1)	56 (12)
	Placebo	273	69	62.0 (8.0)	53	34	58	NR	38.9 (18.3)	57 (13)
DB2113373^Citation32; Donohue et al^Citation57	Umeclidinium 62.5 µg OD	418	71	64.0 (9.2)	50	54	52	NR	46.8 (27.0)	47 (13)
	Placebo	280	70	62.2 (9.0)	54	58	49	NR	47.2 (27.2)	47 (13)
AC4115408^Citation34	Umeclidinium 62.5 µg OD	69	64	62.3 (9.5)	54	63	22	NR	45.2 (21.2)	45 (14)
	Placebo	68	62	62.5 (8.7)	53	51	26	NR	52.3 (30.2)	47 (13)
SPARK^Citation58	Glycopyrronium 50 µg OD	740	73	63.1 (8.0)	38	100	75	7.1 (5.3)	44.0 (23.0)	37 (8)
	Tiotropium 18 µg OD	737	75	63.6 (7.8)	37	100	76	7.2 (5.5)	47.0 (28.0)	37 (8)
GLOW5^Citation45	Glycopyrronium 50 µg OD	327	73	63.2 (7.9)	45	42	50	6.5 (5.1)	39.6 (20.4)	53 (13)
	Tiotropium 18 µg OD	330	75	63.7 (8.0)	44	41	53	6.2 (5.1)	40.2 (21.5)	54 (13)

Abbreviations: SD, standard deviation; ITT, intention to treat population; ICS, inhaled corticosteroid; FEV₁, forced expiratory volume in 1 second; NR, not reported; OD, once-daily; BD, twice-daily.

Figure 2 Overall network of studies in the network meta-analysis of umeclidinium versus other LAMAs or placebo for (A) trough FEV₁ at 12 weeks, (B) trough FEV₁ at 24 weeks, (C) SGRQ total score at 24 weeks, (D) TDI focal score at 24 weeks, and (E) rescue medication use at 24 weeks.

Note: Gray italic text indicates studies that did not report measures of uncertainty.
Abbreviations: BD, twice-daily; FEV₁, forced expiratory volume in 1 second; LAMA, long-acting muscarinic antagonist; OD, once-daily; PBO, placebo; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Table 3 Individual study results for trough FEV₁, SGRQ total scores, TDI focal scores, and rescue medication use

Treatment	References	Trough FEV1 at 12 weeks (mean difference in change from baseline), mL (SE)	Trough FEV1 at 24 weeks (mean difference in change from baseline), mL (SE)	SGRQ total score at 24 weeks, mean difference in change from baseline (SE)	TDI focal score at 24 weeks, mean difference (SE)	Rescue medication puffs per day at 24 weeks, mean difference in change from baseline (SE)
Tiotropium versus placebo	Chan et al^Citation4	100 (14.9)	–	–	–	–
	Niewoehner et al^Citation24	100 (10.2)	100 (12.8)	–	–	–
	Donohue et al^Citation23	140 (20.4)	140 (20.4)	−1.00 (0.92)	0.90 (0.23)	−0.60 (0.19)
	SHINE^Citation29	130 (17.9)	130 (17.9)	−0.88 (1.04)	0.58 (0.24)	−0.41 (0.17)
	GLOW2^Citation8	83 (19.3)	84 (21.6)	−2.52 (1.11)	0.94 (0.30)	–
	Verkindre et al^Citation22	110 (40.0)	–	–	–	–
	Casaburi et al^Citation53	150 (14.1)	–	–	–	–
	Covelli et al^Citation25	184 (37.0)	–	–	–	–
	Moita et al^Citation54	102 (31.4)	–	–	–	–
	UPLIFT^Citation3,Citation52	–	100 (7.1)	−2.50 (0.36)		–
	Brusasco et al^Citation27	–	120 (100)	−2.70 (0.99)	1.10 (0.30)	–
	Donohue et al^Citation5	–	137 (20.0)	−2.71 (1.31)a	1.00 (0.33)a	−1.45 (0.25)a
	TIPHON^Citation35	–	–	−3.51 (0.65)	–	–
	Vogelmeier et al^Citation55	–	–	−2.05 (1.27)	–	–
	Casaburi et al^Citation26	–	–	−3.08 (0.89)a	0.80 (0.19)	–
Aclidinium versus placebo	ATTAIN^Citation59	105 (21.1)	128 (22.0)	−4.60 (1.10)	1.00 (0.30)	−0.95 (0.22)a
	ACCORD COPD I^Citation56	124 (20.7)	–	–	–	–
	ACCORD COPD II^Citation30	72 (21.9)	–	–	–	–
Glycopyrronium versus placebo	SHINE^Citation29	120 (15.3)	120 (17.9)	−1.83 (1.04)	0.89 (0.24)	−0.30 (0.17)
	GLOW2^Citation8	97 (16.7)	134 (18.9)	−3.38 (0.97)	0.81 (0.26)	–
	GLOW1^Citation7	108 (14.8)	113 (16.5)	−2.81 (0.96)	1.00 (0.24)	−0.46 (0.16)
Glycopyrronium versus tiotropium	SPARK^Citation58	10 (14.1)	−10 (13.1)	0.10 (0.88)	–	–
	GLOW5^Citation45	4 (15.1)	–	–	–	–
Umeclidinium versus placebo	DB2113373^Citation32	139 (18.1)	115 (20.2)	−4.69 (1.21)	1.00 (0.26)	−0.30 (0.26)
	AC4115408^Citation34	127 (38.3)	–	–	–	–

Note:

a Imputed value.

Abbreviations: –, data not available; FEV₁, forced expiratory volume in 1 second; SD, standard deviation; SE, standard error; SGRQ, St George’s Respiratory Questionnaire total score; TDI, transitional dyspnea index focal score.

Figure 3 Differences in intervention versus the comparator for change from baseline in (A) trough FEV₁ (mL) at 12 weeks, (B) trough FEV₁ (mL) at 24 weeks, (C) SGRQ total scores at 24 weeks, (D) TDI focal scores at 24 weeks, and (E) rescue medication use at 24 weeks (95% CrI and probability of the intervention being better than the comparator).

Abbreviations: CrI, credible interval; FEV₁, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Table S1 Search strategy for the systematic review

Database	MEDLINE^® In-Process and Other Non-Indexed Citations and MEDLINE^®
Platform	Ovid
Date of search	April 16, 2014
Time limits	1946–2014 Week 15
Filters	Lines 6–13 are from the search filter: BMJ Clinical Evidence Strategy (MEDLINE randomised controlled trials strategy using Ovid). Available from: http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665076.html (accessed on April 14, 2014)
#	Searches	Results, n
1	(formoterol or eformoterol or foradil or oxis or atimos modulite or atock or perforomist or salmeterol or serevent or tiotropium or spiriva or Ba 679 BR or indacaterol or onbrez or arcapta or NVA-237 or NVA237 or (NVA adj “237”) or glycopyrronium bromide or glycopyrrolate or seebri or enurev breezhaler or aclidinium bromide or tudorza pressair or eklira genuair or symbicort or advair or seretide or olodaterol or striverdi or umeclidinium or GSK573719 or vilanterol or GW642444 or QVA149 or relvar/breo or zephyr or anoro ellipta).ti,ab,nm.	5,491
2	exp Pulmonary Disease, Chronic Obstructive/or exp Chronic obstructive lung disease/	35,415
3	(COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema).ti,ab.	60,286
4	2 or 3	69,295
5	1 and 4	1,647
6	“Randomised controlled trial”.pt.	370,219
7	(random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.	782,910
8	(retraction of publication or retracted publication).pt.	6,430
9	6 or 7 or 8	867,607
10	(animals not humans).sh.	3,829,658
11	((comment or editorial or meta-analysis or practice-guideline or review or letter or journal correspondence) not “randomised controlled trial”).pt.	3,187,191
12	(random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not “randomised controlled trial”.pt.	47,025
13	9 not (10 or 11 or 12)	649,371
14	5 and 13	637
15	Limit 14 to (English or German)	610
ab, nm, pt, sh, ti: searches performed in abstract, name of substance, publication type, subject heading, and title fields, respectively
Database	EMBASE
Platform	Ovid
Date of search	April 16, 2014
Time limits	1988–2014 Week 15
Filters	Lines 6–12 are from the search filter: BMJ Clinical Evidence Strategy (EMBASE randomized controlled trials strategy using Ovid). Available from: http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665076.html (accessed on April 14, 2014)
#	Searches	Results, n
1	(formoterol or eformoterol or foradil or oxis or atimos modulite or atock or perforomist or salmeterol or serevent or tiotropium or spiriva or Ba 679 BR or indacaterol or onbrez or arcapta or NVA-237 or NVA237 or (NVA adj “237”) or glycopyrronium bromide or glycopyrrolate or seebri or enurev breezhaler or aclidinium bromide or tudorza pressair or eklira genuair or symbicort or advair or seretide or olodaterol or striverdi or umeclidinium or GSK573719 or vilanterol or GW642444 or QVA149 or relovair or zephyr or anoro ellipta).ti,ab.	6,554
2	exp Pulmonary Disease, Chronic Obstructive/or exp Chronic obstructive lung disease/	62,723
3	(COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema).ti,ab.	65,503
4	2 or 3	87,605
5	1 and 4	2,349
6	(random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.	893,801
7	RETRACTED ARTICLE/	6,430
8	6 or 7	900,087
9	(animal$ not human$).sh,hw.	2,500,858
10	(book or conference paper or editorial or letter or review).pt. not exp randomised controlled trial/	3,608,293
11	(random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not exp randomised controlled trial/	51,550
12	8 not (9 or 10 or 11)	681,639
13	5 and 12	914
14	Limit 13 to (English or German)	881
Database	CENTRAL and CDSR
Platform	Cochrane
Date of search	April 16, 2014
Time limits	1988–2014
Filters	n.a.
#	Searches	Results, n
1	(formoterol or eformoterol or foradil or oxis or atimos modulite or atock or perforomist or salmeterol or serevent or tiotropium or spiriva or Ba 679 BR or indacaterol or onbrez or arcapta or NVA-237 or NVA237 or (NVA near/3 237) or glycopyrronium bromide or glycopyrrolate or seebri or enurev breezhaler or aclidinium bromide or tudorza pressair or eklira genuair or symbicort or advair or seretide or olodaterol or striverdi or umeclidinium or GSK573719 or vilanterol or GW642444 or QVA149 or relovair or zephyr or anoro ellipta): ti,ab,kw	4,609
2	MeSH descriptor: [Pulmonary Disease, Chronic Obstructive] explode all trees	2,533
3	(COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema): ti,ab,kw	10,689
4	≤1 and (≤2 or ≤3) in Trials	1,415
5	≤1 and (≤2 or ≤3) (in Cochrane Reviews [Reviews and Protocols])	21
ab, kw, ti: searches performed in abstract, keyword, and title fields, respectively; n.a: not applicable Line 4 corresponds to the CENTRAL database, line 5 to the CDSR database. Both results were exported.
Database	DARE
Platform	CRD (http://www.crd.york.ac.uk/crdweb/)
Date of search	April 16, 2014
Time limits	No time limits
Filters	n.a.
#	Searches	Results, n
1	(formoterol or eformoterol or foradil or oxis or atimos modulite or atock or perforomist or salmeterol or serevent or tiotropium or spiriva or Ba 679 BR or indacaterol or onbrez or arcapta or NVA-237 or NVA237 or (NVA and “237”) or glycopyrronium bromide or glycopyrrolate or seebri or enurev breezhaler or aclidinium bromide or tudorza pressair or eklira genuair or symbicort or advair or seretide or olodaterol or striverdi or umeclidinium or GSK573719 or vilanterol or GW642444 or QVA149 or relovair or zephyr or anoro ellipta) [ANY FIELD]	226
2	(COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema) [ANY FIELD]	828
3	1 and 2 in DARE	62
n.a.: not applicable
Database	HTA
Platform	CRD (http://www.crd.york.ac.uk/crdweb/)
Date of search	April 16, 2014
Time limits	No time limits
Filters	n.a.
#	Searches	Results, n
1	(formoterol or eformoterol or foradil or oxis or atimos modulite or atock or perforomist or salmeterol or serevent or tiotropium or spiriva or Ba 679 BR or indacaterol or onbrez or arcapta or NVA-237 or NVA237 or (NVA and “237”) or glycopyrronium bromide or glycopyrrolate or seebri or enurev breezhaler or aclidinium bromide or tudorza pressair or eklira genuair or symbicort or advair or seretide or olodaterol or striverdi or umeclidinium or GSK573719 or vilanterol or GW642444 or QVA149 or relovair or zephyr or anoro ellipta) [ANY FIELD]	226
2	(COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema) [ANY FIELD]	828
3	1 and 2 in HTA	116
4	HTA: HTA in progress and HTA published	17
Trial registry	clinicaltrials.gov
URL	http://www.clinicaltrials.gov/
Date of search	April 14, 2014
Search strategy	COPD OR COAD OR “Chronic obstructive pulmonary disease” OR “Chronic obstructive lung disease” OR “chronic obstructive airway disease” OR “chronic bronchitis” OR “emphysema” | Phase 2, 3, 4
Results	949
Trial registry	WHO International Clinical Trials Registry Platform (ICTRP)
URL	http://apps.who.int/trialsearch/AdvSearch.aspx
Date of search	April 14, 2014
Search strategy	COPD OR chronic obstructive pulmonary disease OR COAD OR chronic obstructive airway disease OR chronic obstructive lung disease OR chronic bronchitis OR emphysema
Results	3,852 records for 2,922 trials found*
*The WHO ICTRP imports records from several registries. Trials are sometimes recorded in more than one registry. These records can refer to each other using a secondary identification number. The search portal uses this secondary identification number to group records about the same trial together in the search results. All results were reported in an excel database. However, WHO ICTRP also collects data from Asian registries. As non-Caucasian population is an exclusion criterion, trials listed on national non-Caucasian registries were excluded for population not of interest. (ie, Chinese Clinical Trial Registry; Clinical Trials Registry – India; Iranian Registry of Clinical Trials; Japan Primary Registries Network).
Trial registry	Current controlled trials
URL	http://www.controlled-trials.com/
Date of search	April 15, 2014
Search strategy	(COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema) in Databases: ISRCTN Register (International) – copy of ISRCTN Register; Action Medical Research (UK) – subset from ISRCTN Register; The Wellcome Trust (UK) – subset from ISRCTN Register; UK trials (UK) – subset from ISRCTN Register, UK trials only
Results	87
ClinicalTrials.gov was removed from the list of resources searched in this aggregated database, as clinicaltrials.gov was searched directly in a separate search.
Trial registry	EU Clinical Trials Register (EU-CTR)
URL	www.clinicaltrialsregister.eu
Date of search	April 15, 2014
Search strategy	(COPD OR chronic obstructive pulmonary disease OR COAD OR chronic obstructive airway disease OR chronic obstructive lung disease OR chronic bronchitis OR emphysema) AND (Phase II OR Phase III or Phase IV [Select trial phase])
Results	307
Trial registry	Klinische Prüfungen PharmNet.Bund
URL	http://www.pharmnet-bund.de/dynamic/de/klinische-pruefungen/index.htm
Date of search	April 15, 2014
Search strategy	COPD in Textfelder AND Limit to Phase II or Phase III or Phase IV [Trial phase] AND Limit to therapy or safety or efficacy [Trial scope] AND Limit to patients [Trial population]
Results	320
Trial registry	International Prospective Register of Systematic Reviews (PROSPERO)
URL	http://www.crd.york.ac.uk/NIHR_PROSPERO/
Date of search	April 18, 2014
Search strategy	Separate searches for: COPD [ALL FIELDS] or chronic obstructive pulmonary disease [ALL FIELDS] or COAD [ALL FIELDS] or chronic obstructive airway disease [ALL FIELDS] or chronic obstructive lung disease [ALL FIELDS] or chronic bronchitis [ALL FIELDS] or Emphysema [ALL FIELDS] Review status: Any review status
Results	122
*Please note that search terms have to be searched for manually each and every one of them and then de-duplicated at the end.
Trial registry	National Institute for Health Research – Health Technology Assessment (NIHR HTA)
URL	http://www.nets.nihr.ac.uk/projects
Date of search	April 18, 2014
Search strategy	COPD [Keywords] and HTA [programme] in the advanced search
Results	13

Abbreviations: CDSR, Cochrane Database of Systematic Review; CENTRAL, Cochrane Central Register of Controlled Trials; CSR, clinical study report; DARE, Database of Abstracts of Reviews of Effects; EU-CTR, EU Clinical Trials Register; HTA, Health Technology Assessment; ITC, indirect treatment comparison; PROSPERO, International Prospective Register of Systematic Reviews; SLR, systematic literature review; WHO ICTRP, World Health Organization International Clinical Trials Registry Platform.

Table S2 Participants, interventions, comparisons, outcomes, and study design (PICOS) criteria

Criteria		Inclusion	Exclusion
Study design	Abstract selection	Randomized controlled trials	Cross-over studies; post hoc or retrospective analyses; cost-effectiveness analyses; observational studies; reviews or meta-analyses; methodology studies or protocols; N of 1 trials (sample size of one patient); studies lasting less than 2 weeks
	Full-text selection		Studies where patients were required to spend time in a sleep laboratory
Treatment/intervention	Abstract selection	Umeclidinium; tiotropium; aclidinium; glycopyrronium; indacaterol; salmeterol; olodaterol; formoterol	Studies comparing only double or triple therapies (ie, LABA, LAMA, ICS as fixed or open combinations) to each other or to placebo; β-agonists (bambuterol; fenoterol; tulobuterol); short-acting anticholinergics (Ipratropium; Oxitropium); Methylxanthines (theophylline); Inhaled glucocorticosteroids (beclomethasone; budesonide; fluticasone); Leukotriene receptor antagonists (montelukast); combinations of long-acting anticholinergics or LABAs with an ICS; formoterol plus budesonide or fluticasone plus salmeterol that are administered separately; COPD drugs in development or targeting other pathways (roflumilast; polyvalent mechanical bacterial lysate; lipopolysaccharide); all other pharmaceutical interventions not treating COPD (enoxaparin sodium); non-pharmaceutical interventions such as pulmonary rehabilitation
	Full-text selection	Umeclidinium; tiotropium; aclidinium; glycopyrronium; indacaterol; salmeterol; olodaterol; formoterol; administered using any inhalation device	Studies of arformoterol (the (R,R) isomer of formoterol)
Comparator	Abstract and full-text selection	Studies that compare treatments of interest (above) with placebo or to each other	Studies that only compare treatments of interest to treatment not of interest (above) (ie, excluding placebo comparison); studies that only include the treatments of interest in combination with treatments not of interest (ie, prednisolone + formoterol); studies that only include the partial combinations of treatments of interest (ie, Tiotropium + ICS)
Population	Abstract and full-text selection	Patients with COPD as defined by GOLD guidelines (ie, airflow limitation that is not fully reversible); studies that include asthma patients and COPD patients and report data for COPD patients separately; adults; studies that include adults and children and report data for adults separately	Studies with only healthy patients without COPD; studies with patients who have reversible airway or obstructive lung disease; studies with only patients with asthma; studies that include asthma patients and COPD patients but do not report data for COPD patients separately; studies with only patients who have alpha-1-antitrypsin-deficiency-related COPD; studies that include only children; studies that include adults and children but do not report data for adults separately
Outcomes	Abstract and full-text selection	Report results for one of the following outcomes (for all treatments) at any time point ≥10 weeks: trough FEV1 ; post-bronchodilator FEV1; SGRQ total score; proportion of patients with an improvement of at least 4 units in SGRQ total score; TDI focal score; proportion of patients with an improvement of at least 1 unit in TDI score; rate of exacerbations per patient-year over the trial period across definitions; proportion of patients experiencing at least one exacerbation (across definitions) at the end of the study; rescue medication (eg, short-acting β2-agonists, inhaled corticosteroids) allowed; adverse event rates at the end of the study; serious adverse event rates at the end of the study; withdrawals due to adverse event rates at the end of the study; hospitalization due to adverse event rates at the end of the study; mortality rates at the end of the study	Only report the following outcomes (without any outcomes of interest): bioactivity outcomes or biomarkers of inflammation; lung mucociliary clearance; arterial blood gases or degree of pulmonary hyper-inflation; plethysmography and oscillometry; nocturnal hypoxemia; quality of life in EuroQoL; reporting outcomes at time points <10 weeks

Abbreviations: FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β-2 agonist; LAMA, long-acting muscarinic antagonist; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Table S3 Data extraction

Parameters extracted from studies
Study characteristics	Author
	Publication year
	Compared interventions including drug name, dose, and administration frequency
	Number of randomized patients
	Trial design
	Centers and countries
	Inclusion criteria
	Background treatments
	Trial duration
	ICS allowed (as background)
	LABAs allowed (as background)
Baseline patient characteristics	Proportion of males
	Age (SD)
	Proportion of current smokers
	Proportion of patients with severe or very severe COPD
	Proportion of patients using ICS
	Duration of COPD (SD)
	Smoking history pack-years (SD)
	FEV1 % predicted (SD)
	FEV1/FVC percentage (SD)
	FVC mean (SD)
	BDI mean
	Number of exacerbations in previous year
	Percentage reversibility
	Ethnicity
Outcomes at 12 (8–16 weeks) and 24 weeks (20–28 weeks)	Trough FEV1
	TDI focal score
	SGRQ total score
	Rescue medication use (number of puffs per day)

Abbreviations: BDI, Baseline Dyspnea Index; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroids; LABA, long-acting β-2 agonist; SD, standard deviation; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Table S4 Risk of bias assessment for the included studies

Study	Adequate generation of randomization sequence	Adequate allocation concealment	Blinding		Result independent reporting	No other aspects that increase the risk of bias	Risk of bias
			Patients	Caregivers
Chan et al,^Citation1 SAFE,^Citation2,Citation3 SAFE-Portugal^Citation4	Unclear	Yes	Yes	Yes	Yes	Yes	Low
TIPHON^Citation5	Yes	Yes	Yes	Yes	Yes	Yes	Low
UPLIFT^Citation6,Citation7	Yes	Yes	Yes	Yes	Yes	Yes	Low
Niewoehner et al^Citation8	Yes	Yes	Yes	Yes	Yes	Yes	Low
Brusasco et al^Citation9	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Donohue et al^Citation10	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Casaburi et al^Citation11	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Donohue et al^Citation12	Unclear	No	No	No	Yes	Yes	High
SHINE^Citation13	Yes	No	No	No	Yes	Yes	High
GLOW1^Citation14	Unclear	Yes	Yes	Yes	Yes	Yes	Low
GLOW2^Citation15	Unclear	Unclear	Yes	Yes	Yes	Yes	Low
Verkindre et al^Citation16	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Casaburi et al^Citation17	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Covelli et al^Citation18	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Garcia et al^Citation19	Unclear	Yes	Yes	Yes	Yes	Unclear	Low
Moita et al^Citation20	Unclear	Yes	Yes	Yes	Yes	Yes	Low
Vogelmeier et al^Citation21	Unclear	No	No	No	Yes	Yes	High
ACCORD COPD I^Citation22	Unclear	Yes	Yes	Yes	Yes	Yes	Low
ACCORD COPD II^Citation23	No	Yes	Yes	Yes	Yes	Yes	High
ATTAIN^Citation24	Unclear	Yes	Yes	Yes	Yes	Yes	Low
DB2113373,^Citation25 Donohue et al^Citation26	Yes	Yes	Yes	Yes	Yes	Yes	Low
AC4115408^Citation27	Yes	Yes	Yes	Yes	Yes	Yes	Low
SPARK^Citation28	Yes	No	No	No	No	Yes	High
GLOW5^Citation29	Unclear	Yes	Yes	Yes	Yes	Yes	Low

Notes: Unclear randomization means that it was mentioned that the study was randomized (and in most cases even with which ratio, eg, 1:1); however, it was not specified how the randomization was generated (eg, by computer). SPARK,²⁸ SHINE,¹³ Vogelmeier et al,²¹ and Donohue et al¹² included tiotropium 18 µg as an open-label arm and were categorized as having a high risk of bias. ACCORD COPD II²³ had imbalances in baseline characteristics despite randomization (for FEV₁ and the percentage of patients with GOLD stage II and III); due to these issues in randomization ACCORD COPD II was categorized as having a high risk of bias.

Abbreviation: FEV₁, forced expiratory volume in 1 second.

Table S5 Individual study results for trough SGRQ total scores, TDI focal scores, and rescue medication use

Treatment	References	SGRQ total score at 12 weeks, mean difference in change from baseline (SE)	TDI focal score at 12 weeks, mean difference (SE)	Rescue medication puffs per day at 12 weeks, mean difference in change from baseline (SE)
Tiotropium	Donohue et al^Citation12	−1.10 (0.87)	0.80 (0.22)	–
versus placebo	SHINE^Citation13	–	0.59 (0.27)	–
	Verkindre et al^Citation16	−6.50 (2.90)	1.30 (0.89)	−0.13 (0.25)
	GLOW2^Citation15	−2.84 (0.97)	0.26 (0.30)	–
	TIPHON^Citation5	−3.59 (1.22)	–	–
	Casaburi et al^Citation11	–	0.95 (0.18)	–
Aclidinium	ATTAIN^Citation24	−4.09 (1.02)	0.90 (0.28)	–
versus placebo	ACCORD COPD I^Citation22	−2.50 (0.89)	1.00 (0.25)	−0.9 (0.21a)
	ACCORD COPD II^Citation23	−1.10 (1.18)	1.00 (0.28)	−0.31 (0.22a)
Glycopyrronium	SHINE^Citation13	–	0.82 (0.27)	–
versus placebo	GLOW2^Citation15	−3.17 (0.84)	0.60 (0.27)	–
Glycopyrronium	SPARK^Citation28	−0.50 (0.88)	–	–
versus	GLOW5^Citation29	0.65 (0.94)	−0.188 (0.22)	0 (0.15)
tiotropium
Umeclidinium	DB2113373^Citation25	−3.59 (1.06)	0.90 (0.23)	−0.34 (0.25)
versus placebo	AC4115408^Citation27	−7.90 (2.19)	1.00 (0.51)	−0.70 (0.31)

Notes:

a Imputed value; –, no data available.

Abbreviations: SE, standard error; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

Table S6 Differences in intervention versus the comparator for change for SGRQ total scores, TDI focal scores, and rescue medication use at 12 weeks (95% CrI and probability of the intervention being better than the comparator)

Intervention	Comparator
		Placebo	Tiotropium	Aclidinium	Glycopyrronium
SGRQ total score (difference in change from baseline, units) at 12 weeks
Tiotropium	Estimate	−2.49
	95% CrI	−3.56 to −1.41
	P (better)	>99%
Aclidinium	Estimate	−2.68	−0.19
	95% CrI	−3.82 to −1.54	−1.76 to 1.36
	P (better)	>99%	60%
Glycopyrronium	Estimate	−2.74	−0.25	−0.06
	95% CrI	−3.91 to −1.56	−1.07 to 0.56	−1.70 to 1.58
	P (better)	>99%	73%	53%
Umeclidinium	Estimate	−4.41	−1.92	−1.73	−1.67
	95% CrI	−6.27 to −2.53	−4.08 to 0.24	−3.92 to 0.47	−3.88 to 0.54
	P (better)	>99%	96%	94%	93%
TDI focal score (difference versus comparator) at 12 weeks
Tiotropium	Estimate	0.75
	95% CrI	0.53–0.97
	P (better)	>99%
Aclidinium	Estimate	0.97	0.21
	95% CrI	0.66–1.27	−0.16 to 0.59
	P (better)	>99%	87%
Glycopyrronium	Estimate	0.94	0.18	−0.03
	95% CrI	0.69–1.18	0.04 to 0.33	−0.42 to 0.36
	P (better)	>99%	>99%	44%
Umeclidinium	Estimate	0.92	0.16	−0.05	−0.02
	95% CrI	0.51–1.33	−0.30 to 0.63	−0.56 to 0.46	−0.50 to 0.46
	P (better)	>99%	75%	43%	47%
Rescue medication use (difference versus comparator) at 12 weeks
Tiotropium	Estimate	−0.13
	95% CrI	−0.62 to 0.36
	P (better)	0.70
Glycopyrronium	Estimate	−0.13	0.00
	95% CrI	−0.70 to 0.44	−0.29 to 0.29
	P (better)	0.68	50%
Umeclidinium	Estimate	−0.48	−0.35		−0.35
	95% CrI	−0.86 to −0.10	−0.97 to 0.27		−1.03 to 0.34
	P (better)	>99%	86%		84%

Abbreviations: CrI, credible interval; FEV₁, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire; TDI, transitional dyspnea index.

ChanCKNMaltaisFSigouinCHaddonJMFordGTA randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary diseaseCan Respir J20071446547218060091

 PubMed Web of Science ®Google Scholar

Spiriva Assessment of FEV1 (SAFE)The effect of inhaled tiotropium bromide (18 mcg once daily) on the change in FEV1 during long-term treatment in patients with COPD. A one-year parallel group, double-blind, randomised, placebo-controlled studyBoehringer Ingelheim Clinical Trial Register. NLM: NCT02772642005 Available from: http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clini-caltrial/com_EN/results/205/205.259_U05-3345.pdfAccessed October 19, 2015

 Google Scholar

Spiriva® Assessment of FEV1 (SAFE)Boehringer Ingelheim2013 NLM identifier: NCT0277264. Available from: http://trials.boeh-ringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.259_U05-3345.pdfAccessed October 19, 2015

 Google Scholar

Spiriva (Tiotropium Bromide) Assessment of FEV1 – (SAFE-Portugal)Boehringer Ingelheim2013 NLM identifier: NCT0239408. Available from: http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.282_U06-2124.pdfAccessed: October 19, 2015

 Google Scholar

TonnelABPerezTGrosboisJMVerkindreCBravoMLBrunMEffect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPDInt J Chron Obstruct Pulmon Dis2008330131018686739

 PubMedGoogle Scholar

TashkinDPCelliBSennSA 4-year trial of tiotropium in chronic obstructive pulmonary diseaseN Engl J Med20083591543155418836213

 PubMed Web of Science ®Google Scholar

Evaluation of the long-term effects of Spiriva on lung function in COPD patientsBoehringer Ingelheim2005 NLM identifier: NCT0144339. Available from: https://clinicaltrials.gov/ct2/show/results/NCT0144339Accessed October 19, 2015

 Google Scholar

NiewoehnerDERiceKCoteCPrevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trialAnn Intern Med200514331732616144890

 PubMed Web of Science ®Google Scholar

BrusascoVHodderRMiravitllesMKorduckiLTowseLKestenSHealth outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPDThorax20035839940412728159

 PubMed Web of Science ®Google Scholar

DonohueJFvan NoordJABatemanEDA 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterolChest2002122475512114338

 PubMed Web of Science ®Google Scholar

CasaburiRMahlerDAJonesPWA long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary diseaseEur Respir J20021921722411866001

 PubMed Web of Science ®Google Scholar

DonohueJFFogartyCLotvallJOnce-daily bronchodilators for chronic obstructive pulmonary disease indacaterol versus tiotropiumAm J Respir Crit Care Med201018215516220463178

 PubMed Web of Science ®Google Scholar

BatemanEDFergusonGTBarnesNDual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE studyEur Respir J2013421484149423722616

 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

KerwinEHebertJGallagherNEfficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 studyEur Respir J2012401106111423060624

 PubMed Web of Science ®Google Scholar

VerkindreCBartFAguilaniuBThe effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary diseaseRespiration20067342042716484769

 PubMed Web of Science ®Google Scholar

CasaburiRBriggsDDDonohueJFSerbyCWMenjogeSSWitekTJThe spirometric efficacy of once-daily dosing with tiotropium in stable COPD – a 13-week multicenter trialChest20001181294130211083677

 PubMed Web of Science ®Google Scholar

CovelliHBhattacharyaSCassinoCConoscentiCKestenSAbsence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary diseasePharmacotherapy2005251708171816305289

 PubMed Web of Science ®Google Scholar

GarciaRFA randomised, double-blind, placebo-controlled, 12 weeks trial to evaluate the effect of Tiotropium Inhalation Capsules on the magnitude of exercise, measured using an accelerometer, in patients with Chronic Obstructive Pulmonary Disease (COPD)Boehringer Ingelheim Trial Results NLM Identifier: NCT01443262007 Available from: http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.269.pdfAccessed October 19, 2015

 Google Scholar

MoitaJBarbaraCCardosoJTiotropium improves FEV1 in patients with COPD irrespective of smoking statusPulm Pharmacol Ther20082114615117693107

 PubMed Web of Science ®Google Scholar

VogelmeierCKardosPHarariSGansSJMStengleinSThirlwellJFormoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month studyRespir Med20081021511152018804362

 PubMed Web of Science ®Google Scholar

KerwinEMD’UrzoADGelbAFLakkisHGarciaGECaractaCFEfficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I)COPD201299010122320148

 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 Invest201333893904

 PubMed Web of Science ®Google Scholar

JonesPWSinghDBatemanEDEfficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN studyEur Respir J20124083083622441743

 PubMed Web of Science ®Google Scholar

DonohueJFMaleki-YazdiMRKilbrideSMehtaRKalbergCChurchAEfficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPDRespir Med20131071538154623830094

 PubMed Web of Science ®Google Scholar

GlaxoSmithKlineA 12-week, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of GSK573719 delivered once-daily via a novel dry powder inhaler in subjects with chronic obstructive pulmonary diseaseClinical Study Report – AC4115408. NLM identifier: NCT13872302013 Available from: https://gsk.sylogent.com/files/sam-2802-gsk-115408-clinical-study-report-redact.pdfAccessed October 19, 2015

 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 Med2013119920924429126

 PubMed Web of Science ®Google Scholar

ChapmanKRBeehKMBeierJA blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 studyBMC Pulm Med201414424438744

 PubMed Web of Science ®Google Scholar

GlaxoSmithKlineA 24-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of GSK573719/GW642444 inhalation powder and the individual components delivered once-daily via a novel dry powder inhaler in subjects with chronic obstructive pulmonary diseaseClinical Study Report – DB2113373. NLM identifier: NCT13136502013 Available from: https://gsk.sylogent.com/files/sam-3623-gsk-113373-clinical-study-report-redact-v03.pdfAccessed October 19, 2015

 Google Scholar

ChanCKNMaltaisFSigouinCHaddonJMFordGTA randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary diseaseCan Respir J20071446547218060091

 PubMed Web of Science ®Google Scholar

Spiriva Assessment of FEV1 (SAFE)The effect of inhaled tiotropium bromide (18 mcg once daily) on the change in FEV1 during long-term treatment in patients with COPD. A one-year parallel group, double-blind, randomised, placebo-controlled studyBoehringer Ingelheim Clinical Trial Register. NLM: NCT02772642005 Available from: http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.259_U05-3345.pdfAccessed October 19, 2015

 Google Scholar

Spiriva® Assessment of FEV1 (SAFE)Boehringer Ingelheim2013 NLM identifier: NCT0277264. Available from: http://trials.boeh-ringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.259_U05-3345.pdfAccessed October 19, 2015

 Google Scholar

Spiriva (Tiotropium Bromide) Assessment of FEV1 – (SAFE-Portugal)Boehringer Ingelheim2013 NLM identifier: NCT0239408. Available from: http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.282_U06-2124.pdfAccessed October 19, 2015

 Google Scholar

TonnelABPerezTGrosboisJMVerkindreCBravoMLBrunMEffect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPDInt J Chron Obstruct Pulmon Dis2008330131018686739

 PubMedGoogle Scholar

TashkinDPCelliBSennSA 4-year trial of tiotropium in chronic obstructive pulmonary diseaseN Engl J Med20083591543155418836213

 PubMed Web of Science ®Google Scholar

Evaluation of the long-term effects of spiriva on lung function in COPD patientsBoehringer Ingelheim2005 NLM identifier: NCT0144339

 Google Scholar

NiewoehnerDERiceKCoteCPrevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trialAnn Intern Med200514331732616144890

 PubMed Web of Science ®Google Scholar

BrusascoVHodderRMiravitllesMKorduckiLTowseLKestenSHealth outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPDThorax20035839940412728159

 PubMed Web of Science ®Google Scholar

DonohueJFvan NoordJABatemanEDA 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterolChest2002122475512114338

 PubMed Web of Science ®Google Scholar

CasaburiRMahlerDAJonesPWA long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary diseaseEur Respir J20021921722411866001

 PubMed Web of Science ®Google Scholar

DonohueJFFogartyCLotvallJOnce-daily bronchodilators for chronic obstructive pulmonary disease indacaterol versus tiotropiumAm J Respir Crit Care Med201018215516220463178

 PubMed Web of Science ®Google Scholar

BatemanEDFergusonGTBarnesNDual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE studyEur Respir J2013421484149423722616

 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

KerwinEHebertJGallagherNEfficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 studyEur Respir J2012401106111423060624

 PubMed Web of Science ®Google Scholar

VerkindreCBartFAguilaniuBThe effect of tiotropium on hyperinflation and exercise capacity in chronic obstructive pulmonary diseaseRespiration20067342042716484769

 PubMed Web of Science ®Google Scholar

CasaburiRBriggsDDDonohueJFSerbyCWMenjogeSSWitekTJThe spirometric efficacy of once-daily dosing with tiotropium in stable COPD – a 13-week multicenter trialChest20001181294130211083677

 PubMed Web of Science ®Google Scholar

CovelliHBhattacharyaSCassinoCConoscentiCKestenSAbsence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary diseasePharmacotherapy2005251708171816305289

 PubMed Web of Science ®Google Scholar

GarciaRFA randomised, double-blind, placebo-controlled, 12 weeks trial to evaluate the effect of Tiotropium Inhalation Capsules on the magnitude of exercise, measured using an accelerometer, in patients with Chronic Obstructive Pulmonary Disease (COPD)Boehringer Ingelheim Trial Results2007 NLM Identifier: NCT0144326. Available from: http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/205/205.269.pdfAccessed October 19, 2015

 Google Scholar

MoitaJBarbaraCCardosoJTiotropium improves FEV1 in patients with COPD irrespective of smoking statusPulm Pharmacol Ther20082114615117693107

 PubMed Web of Science ®Google Scholar

VogelmeierCKardosPHarariSGansSJMStengleinSThirlwellJFormoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month studyRespir Med20081021511152018804362

 PubMed Web of Science ®Google Scholar

KerwinEMD’UrzoADGelbAFLakkisHGarciaGECaractaCFEffi-cacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I)COPD201299010122320148

 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 Invest201333893904

 PubMed Web of Science ®Google Scholar

JonesPWSinghDBatemanEDEfficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN studyEur Respir J20124083083622441743

 PubMed Web of Science ®Google Scholar

GlaxoSmithKlineClinical Study Report – DB21133732013

 Google Scholar

DonohueJFMaleki-YazdiMRKilbrideSMehtaRKalbergCChurchAEfficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPDRespir Med20131071538154623830094

 PubMed Web of Science ®Google Scholar

GlaxoSmithKlineClinical Study Report – AC41154082013

 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 Med2013119920924429126

 PubMed Web of Science ®Google Scholar

ChapmanKRBeehKMBeierJA blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 studyBMC Pulm Med201414424438744

 PubMed Web of Science ®Google Scholar