Comparative efficacy of aclidinium versus glycopyrronium and tiotropium, as maintenance treatment of moderate to severe COPD patients: a systematic review and network meta-analysis

Figures & data

Figure 1 Flow diagram of study selection process.

Note: Both a publication and CSR were available for the ATTAIN and ACCORD I study.
Abbreviations: PICOS, population, intervention, comparators, outcomes, and study design; CSRs, clinical study reports; ACCORD, AClidinium in Chronic Obstructive Respiratory Disease COPD; ATTAIN, Aclidinium To Treat Airway obstruction IN COPD patients.

Table 1 Characteristics of included studies

Source	Trial design	Treatment	Number of patients	Location	Inclusion/exclusion criteria	Background treatment	Study duration	Jadad score
Bateman^Citation27	RCT, PC, DB, MC	Tiotropium, 5 μg, OD; Tiotropium, 10 μg, OD; Placebo	670 667 653	South Africa, Europe, Canada	≥ 40 years age; FEV1 ≤ 60%; FEV1 ≤ 70% of FVC; ≥ 10 pack-years; diagnosis of COPD and stable, moderate-to-severe airway obstruction	Allowed: oral and inhaled corticosteroids, theophylline, mucolytic agents and antileukotrienes, salbutamol. Patients on long-acting β-adrenergics and inhaled corticosteroids were switched to a monoproduct inhaled corticosteroid prior to run-in	48 weeks	3
Bateman^Citation28	RCT, PC, DB, PG, MC	Tiotropium, 5 μg, OD; Placebo	1 952 1 965	336 centers; 31 countries	FEV1 ≤ 60% prebronchodilator; FEV1/FVC ≤ 70% prebronchodilator; ≥40 years age; ≥ 10 pack-years	Allowed: salbutamol pMDI; all respiratory medications were permitted Not allowed: inhaled anticholinergics	48 weeks + 1 week run-in	5
Voshaar^Citation42	RCT, PC, DB, MC	Tiotropium, 5 μg, OD; Tiotropium, 10 μg, OD; Ipratropium, 36 μg, OD; Placebo	180 180 178 181	64 centers; Europe, South Africa, USA, Canada	FEV1 ≤ 60% prebronchodilator; FEV1/FVC ≤ 70%; ≥ 10 pack-years	Allowed: salbutamol, oral corticosteroids, orally inhaled corticosteroids, theophyllines, and mucolytics Not allowed: anticholinergics, inhaled β-adrenergics other than salbutamol, fixed combination inhalers	12 weeks	3
Brusasco^Citation25	RCT, PC, DB, MC, DD	Tiotropium, 18 μg, OD; Salmeterol, 50 μg, BID; Placebo	402 405 400	18 countries	FEV1 ≤ 65%; FEV1/FVC ≤ 70%; > 40 years of age; > 10 pack-years	NR	24 weeks	4
Casaburi^Citation30	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	279 191	25 centers; USA	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	13 weeks	3
Casaburi^Citation31	2 RCTs, PC, DB, MC	Tiotropium; 18 μg; OD; Placebo	550 371	50 centers	FEV1 ≤ 65%; FEV1/FVC ≤ 70%	Allowed: stable doses of theophylline, ICS, oral prednisone	56 weeks	3
Chan^Citation32	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	608 305	101 centers; Canada	FEV1 ≤ 65%; FEV1/FVC ≤ 70%; ≥ 1 exacerbation previous year but not 6 weeks prior to randomization	Allowed: stable dose oral corticosteroids, ICS, theophylline preparations, mucolytic preparations (not containing bronchodilators), LABAs	48 weeks	4
Covelli^Citation33	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	100 96	12 centers; USA	FEV1 ≤ 60%; FEV1/FVC ≤ 70% excluded if exacerbation in prior 6 weeks	Allowed: ICS, LABAs and theophyllines Not allowed: cromones, leukotriene antagonists, and inhaled anticholinergics	12 weeks	4
Donohue^Citation34	RCT, PC, DB, MC, DD	Tiotropium, 18 μg, OD; Salmeterol, 50 μg, BID; Placebo	209 213 201	39 countries; 12 countries	FEV1 ≤ 60%; FEV1/FVC ≤ 70%; ≥40 years of age; smoking history of > 10 pack-years	Allowed: usual ICS and oral steroids Not allowed: Inhaled anticholinergic LABAs	24 weeks	4
Donohue^Citation35	RCT, PC, DB,** MC, DD	Indacaterol, 150 μg, OD; Indacaterol, 300 μg, OD; Tiotropium, 18 μg, OD; Placebo	420 418 420 425	USA, Europe	FEV1 30%–80% postbronchodilator; FEV1/FVC < 70%; ≥40 years age; ≥20 pack-years; diagnosis of moderate-to-severe COPD (GOLD criteria)	ICS monotherapy, albuterol, treatment with anticholinergic bronchodilators or [β2-agonists was discontinued with appropriate washout; patients receiving fixed-combination [β2-agonist/ICS were switched to ICS monotherapy at an equivalent dose	26 weeks	4
Moita^Citation36	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	147 164	31 centers; Portugal	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 preparations	12 weeks	4
Niewoehner^Citation37	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	914 915	26 centers; USA	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	24 weeks	4
Tashkin (UPLIFT)^Citation38	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	2 987 3 006	490 centers; 37 countries	FEV1 ≤ 70%; FEV1/FVC ≤ 70%; excluded if exacerbation 4 weeks prior	Allowed: all respiratory medications, except other inhaled anticholinergic drugs	4 years	5
Tonnel (TIPHON)^Citation35	RCT, PC, DB, MC	Tiotropium, 18 μg, OD; Placebo	266 288	123 centers; France	FEV1 20%–70%; FEV1/SVC ≤ 70%	Allowed: stable doses of theophylline preparations (excluding 24-hour preparations), mucolytics, ICS, and oral steroids	36 weeks	5
Verkindre^Citation40	RCT, PC, DB, MC	Tiotropium; 18 μg, OD; Placebo	46 54	10 centers; France	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 ß2-agonists, or LABAs	12 weeks	3
Vogelmeier^Citation41	RCT, PC, DB,* MC	Formoterol, 12 meg BID + Tiotropium, 18 meg, OD; Formoterol, 12 μg, BID; Tiotropium, 18 μg, OD; Placebo	207 210 221 209	86 centers; 8 countries Europe	FEV1 < 70%; FEV1/FVC < 70%; stable COPD; aged 40 years at COPD onset; ≥ 10 pack-years	Allowed: salbutamol, ICS monotherapy	24 weeks	3
CSR ACCORD I^Citation22	RCT, MC, PC, DB	Aclidinium, 200 μg, BID; Aclidinium, 400 μg, BID; Placebo	185 190 187	106 centers; USA, Canada	≥40 years of age, ≥ 10 pack-years; stable, moderate-to-severe COPD as defined by criteria of GOLD; FEV1 30%–80% postsalbutamol; FEV1/FVC < 70% Excluded: patients with asthma; respiratory tract infection or COPD exacerbation in the 6 weeks before visit 1	ICS allowed; LABA discontinued	12 weeks	4
CSR ACCORD II^Citation24	RCT, MC, PC, DB	Aclidinium, 200 μg, BID; Aclidinium, 400 μg, BID; Placebo	184 178 182	103 centers; USA Canada	≥40 years of age, ≥ 10 pack-years; stable, moderate-to-severe COPD as defined by criteria of GOLD; FEV1 30%–80% postsalbutamol; FEV1/FVC < 70% Excluded: patients with asthma; respiratory tract infection or COPD exacerbation in the 6 weeks before visit 1	ICS allowed; LABA discontinued	12 weeks	4
CSR ATTAIN^Citation25	RCT, MC, PC, DB	Aclidinium, 200 μg, BID; Aclidinium, 400 μg, BID; Placebo	277 269 273	103; Europe, South America, Russia, South Africa	≥ 10 pack-years; FEV1 30%–80% postsalbutamol; FEV1/FVC < 70%	NR	24 weeks	4
GLOW 1^Citation43	RCT, DB, PC, MC	Glycopyrronium, 50 meg, OD; Placebo	552 270	128; US, Europe, Australia, SE Asia, South America	postbronchodilator FEV1 ≥ 30% and < 80%; postbronchodilator FEV1/FVC < 0.7; ≥ 10 pack-years	Allowed: ICS monotherapy, short acting β2-agonists as required Not allowed: LABAs, LAMAs, theophylline	26 weeks	3
GLOW 2^Citation44	RCT, MC, PC, DB**	Glycopyrronium, 50 μg, OD; Tiotropium, 18 μg, OD; Placebo	529 268 269	NR	Men and woman aged ≥40 years, smoking history ≥10 pack-years, moderate-to-severe stable COPD (2008 GOLD guidelines), postbronchodilator FEV1 ≥ 30% and < 80% of the predicted normal, and postbronchodilator FEV1/FVC < 0.70 were enrolled	Allowed: concomitant medications (inhaled or intranasal corticosteroids and H1 antagonists) and salbutamol/albuterol inhaler to be used as rescue medication during the study Not allowed: LABA LAMA	52 weeks	3

Notes:

* Tiotropium versus placebo is not DB;

** open label for tiotropium arm. + indicates that the first two lines of this cell (Formoterol and Tiotropium) were administered simultaneously.

Abbreviations: BID, twice daily; COPD, chronic obstructive pulmonary disease; CSR, clinical study report; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium; TIPHON, Tiotropium: Influence sur la Perception de l’amelioration des activites Habituelles Objectivee par une echelle Numerique; ACCORD, ACIidinium in Chronic Obstructive Respiratory Disease COPD; ATTAIN, Aclidinium To Treat Airway obstruction IN COPD patients; GLOW, GLycopyrroniurn bromide in COPD airways clinical study 1; DB, double blind; DD, double dummy; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, Global initiative for chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; LABA, long acting β-agonist; LAMA, long-acting muscarinic antagonist; MC, multicenter; NR, not reported; OD, once daily; OL, open label; PC, placebo controlled; RCT, randomized controlled trial; S, south; SE, southeast; USA, United States of America; pMDI, pressurized metered-dose inhaler; ATS, American Thoracic Society.

Table 2 Patient characteristics at baseline for the included studies (only arms of interest)

Author	Treatment	Male (%)	Mean age (years)	Current smokers (%)	Patients in severe or very severe COPD states (%)	Patients with concomitant ICS use (%)	Mean pack-years	Mean FEV1% pred
Bateman^Citation27	Tiotropium, 5 μg, OD;	73	65	38	NR	49	NR	38
	Placebo	75	65	36	NR	55	NR	38
Bateman^Citation28	Tiotropium, 5 μg, OD;	78	65	36	NR	56	46	40
	Placebo	77	65	36	NR	56	45	40
Voshaar^Citation42	Tiotropium, 5 μg, OD;	69	64	37	59	48	52	40
	Placebo	69	63	43	47	52	51	42
Brusasco^Citation29	Tiotropium, 18 μg, OD;	77	64	NR	82	NR	44	39
	Placebo	76	65	NR	82	NR	42	39
Casaburi^Citation30	Tiotropium, 18 μg, OD;	67	65	NR	NR	NR	65	39
	Placebo	63	65	NR	NR	NR	61	38
Casaburi^Citation31	Tiotropium, 18 μg, OD;	67	65	NR	NR	43	63	39
	Placebo	63	65	NR	NR	40	59	38
Chan^Citation32	Tiotropium, 18 μg, OD;	59	67	32	NR	66	50	39
	Placebo	61	67	30	NR	71	51	39
Covelli^Citation33	Tiotropium, 18 μg, OD;	66	66	40	NR	54	66	40
	Placebo	49	63	37	NR	58	65	39
Donohue^Citation34	Tiotropium, 18 μg, OD;	74	65	42	59	66	47	41
	Placebo	75	66	42	60	66	46	41
Donohue^Citation35	Tiotropium, 18 μg, OD;	65	64	NR	NR	35	50	54
	Placebo	61	63	NR	NR	40	50	56
Moita^Citation36	Tiotropium, 18 μg, OD;	NR	NR	28	NR	NR	Per	Per
	Placebo	NR	NR	25	NR	NR	subgroup	subgroup
Niewoehner^Citation37	Tiotropium, 18 μg, OD;	98	68	29	NR	61	67	36
	Placebo	99	68	30	NR	58	69	36
Tashkin	Tiotropium, 18 μg, OD;	75	65	29	52	62	49	40
(UPLIFT)^Citation38	Placebo	74	65	30	53	62	48	39
Tonnel	Tiotropium, 18 μg, OD;	87	65	24	57	38	44	47
(TIPHON)^Citation39	Placebo	85	64	30	62	36	43	46
Verkindre^Citation40	Tiotropium, 18 μg, OD;	94	61	24	NR	NR	46	35
	Placebo	94	60	33	NR	NR	42	36
Vogelmeier^Citation41	Tiotropium, 18 μg, OD;	79	63	NR	44	NR	39	52
	Placebo	78	62	NR	46	NR	40	51
CSR	Aclidinium, 400 μg, BID;	53	65	42	36	47	57	48
ACCORD I^Citation22	Placebo	52	65	47	37	45	53	48
CSR	Aclidinium, 400 μg, BID;	50	63	50	54	39	54	44
ACCORD II^Citation24	Placebo	55	62	56	37	42	53	49
CSR	Aclidinium, 400 μg, BID;	68	63	55	31	51	42	51
ATTAIN^Citation25	Placebo	69	62	53	34	58	39	52
GLOW 1^Citation43	Glycopyrronium, 50 μg, OD;	83	64	33	40	55	45	NR
	Placebo	81	64	34	38	51	45	NR
GLOW 2^Citation44	Glycopyrronium, 50 μg, OD;	65	64	45	37	56	49	NR
	Tiotropium, 18 μg, OD;	63	64	44	35	52	50	NR
	Placebo	65	64	46	35	51	48	NR

Abbreviations: BID, twice daily; COPD, chronic obstructive pulmonary disease; CSR, clinical study report; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium; TIPHON, Tiotropium: Influence sur la Perception de l’amelioration des activites Habituelles Objectivee par une echelle Numerique; ACCORD, AClidinium in Chronic Obstructive Respiratory Disease COPD; ATTAIN, Aclidinium To Treat Airway obstruction IN COPD patients; GLOW, GLycopyrronium bromide in COPD airways clinical study; FEV₁% pred, forced expiratory volume in 1 second percentage predicted at baseline; ICS, inhaled corticosteroids; OD, once daily; NR, not reported.

Table 3 Individual studies results included in the network meta-analysis

Figure 2 Network formed by interventions and their direct comparisons included in the analyses.

Note: The GLOW2 trial compares glycopyrronium to tiotropium 18 μg and placebo and is therefore included three times in this figure.
Abbreviations: GLOW, GLycopyrronium bromide in COPD airways clinical study; OD, once daily; BID, twice a day.

Table 4 Base case: results of the NMA for all treatments versus placebo

	Trough FEV1		SGRQ total score		SGRQ % responders		TDI focal score		TDI % responders
	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks	12 weeks	24 weeks
	Diff CFB (95% Crl)	Diff CFB (95% Crl)	Diff CFB (95% Crl)	Diff CFB (95% Crl)	Odds ratio	Odds ratio	Diff CFB (95% Crl)	Diff CFB (95% Crl)	Odds ratio	Odds ratio
TIO 5	0.12 (0.07,0.16)	0.1 1 (0.08,0.15)		−2.20 (−3.10,−1.30)		1.44 (1.27, 1.63)
TIO 18	0.11 (0.10,0.12)	0.1 1 (0.09,0.13)	−2.37 (−3.48,−1.25)	−2.45 (−3.18,−1.71)	1.82 (1.32,2.53)	1.50 (1.24, 1.83)	0.77 (0.53, 1.02)	0.92 (0.71, 1.13)	1.69 (1.29, 2.23)	1.67 (1.42, 1.97)
GLYCO	0.11 (0.08,0.13)	0.13 (0.09,0.17)	−2.99 (−4.53,−1.45)	−3.11 (−4.38,−1.84)		1.56 (1.16,2.09)	0.80 (0.32, 1.27)	0.92 (0.59, 1.25)		1.69 (1.38, 2.07)
AB400	0.11 (0.08,0.14)	0.13 (0.07,0.19)	−3.38 (−4.82,−1.95)	−4.63 (−6.85, −2.42)	1.75 (1.34,2.27)	1.94 (1.38,2.73)	0.93 (0.53, 1.33)	1.00 (0.43, 1.57)	1.99 (1.53, 2.60)	1.58 (1.13, 2.33)

Abbreviations: AB 400, aclidinium 400 μg bromide twice daily; CFB, change from baseline; Crl, credible interval; FEV₁, forced expiratory volume in 1 second; GLYCO, glycopyrronium 50 μg bromide once daily; NMA, network meta-analysis; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO 5, tiotropium 5 μg bromide once daily; TIO 18, tiotropium 18 μg bromide once daily.

Table 5 Results of the network meta-analysis for AB400 versus all other treatments

	Trough FEV1				SGRQ				TDI
	12 weeks		24 weeks		12 weeks		24 weeks		12 weeks		24 weeks
	Diff CFB (95% Crl)	Probability AB400 better	Diff CFB (95% Crl)	Probability AB400 better	Diff CFB (95% Crl)	Probability AB400 better	Diff CFB (95% Crl)	Probability AB400 better	Diff CFB (95% Crl)	Probability AB400 better	Diff CFB (95% Crl)	Probability AB400 better
Scenario 1: excluding LABA allowing studies
TIO 5	−0.01 (−0.06, 0.05)	41%	0.00 (−0.05, 0.06)	57%
TIO 18	−0.01 (−0.04, 0.02)	32%	0.00 (−0.04, 0.05)	58%			−2.29 (−4.66, 0.07)	97%
GLYCO	0.00 (−0.03, 0.04)	55%	0.00 (−0.05, 0.05)	46%			−1.55 (−4.12, 1.00)	88%
Scenario II: including ACCORD II
TIO 5	−0.02 (−0.09, 0.05)	28%
TIO 18	−0.02 (−0.05, 0.02)	19%			−0.50 (−2.20, 1.18)	72%			0.17 (−0.26, 0.60)	78%
GLYCO	−0.01 (−0.06, 0.04)	33%			0.12 (−1.89, 2.11)	45%			0.15 (−0.45, 0.74)	69%
Base case: adjusted for ICS
TIO 5	−0.01 (−0.06, 0.05)	40%	0.02 (−0.03, 0.06)	75%			−2.53 (−4.94, −0.12)	98%
TIO 18	0.00 (−0.04, 0.03)	38%	0.02 (−0.03, 0.06)	78%	−0.47 (−2.45, 1.51)	68%	−2.15 (−4.49, 0.17)	97%	0.34 (−0.20, 0.89)	89%	0.02 (−0.60, 0.65)	53%
GLYCO	0.00 (−0.04, 0.04)	49%	0.00 (−0.05, 0.05)	47%	−0.44 (−2.55, 1.68)	66%	−1.54 (−4.10, 1.01)	88%	0.14 (−0.48, 0.76)	67%	0.08 (−0.58, 0.74)	59%
Base case: adjusted for FEV1% predicted
TIO 5	0.00 (−0.08, 0.08)	45%	0.00 (−0.08, 0.07)	44%			−3.47 (−6.21, −0.74)	>99%
TIO 18	0.00 (−0.05, 0.05)	46%	0.01 (−0.07, 0.07)	51%	−1.12 (−3.95, 0.70)	89%	−2.83 (−5.30, −0.37)	99%	0.20 (−0.29, 0.69)	79%	0.10 (−0.56, 0.76)	62%
GLYCO	0.00 (−0.06, 0.06)	53%	0.00 (–0.09, 0.06)	30%	−1.05 (−3.30, 1.20)	82%	−2.30 (−5.03, 0.43)	95%	0.19 (−0.46, 0.84)	71%	0.11 (−0.61,0.82)	61%

Abbreviations: AB400, aclidinium 400 μg bromide twice daily; CFB, change from baseline; Crl, credible interval; FEV₁ forced expiratory volume in 1 second; FEV₁ pred, FEV₁ percentage predicted at baseline; GLYCO, glycopyrronium 50 μg bromide once daily; ICS, inhaled corticosteroids; LABA, long-acting β-agonist; ACCORD, ACIidinium in Chronic Obstructive Respiratory Disease COPD; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO 5, tiotropium 5 μg bromide once daily; TIO 18, tiotropium 18 μg bromide once daily.

Figure 3 Forest plot of base case network meta-analysis results for aclidinium.

Note: Difference in change from baseline (CFB), 95% credible intervals (95% Crl) and probability that aclidinium is better than the comparator at 12 weeks and 24 weeks.
Abbreviations: AB400, aclidinium 400 μg twice daily; TI05, tiotropium 5 μg bromide once daily; TI018, tiotropium 18 μg bromide once daily; GLYC050, glycopyrronium 50 μg once daily; FEV, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table S1 Search strategy

Databases: Embase, MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations

Search engine: Ovid

Time period: 1989 to October 2012

Search date: October 26th, 2012

1. Tiotropium bromide/or aclidinium bromide/or glycopyrronium bromide/(6235)

2. (Tiotropium or spiriva or aclidinium bromide or Eklira or Glycopyrronium or NVA-237 or NVA237 or (NVA adj “237”) or glycopyrronium bromide or glycopyrrolate).ti,ab. (3378)

3. (COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema).ab. or (COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema).ti. (112741)

4. Exp Pulmonary Disease, Chronic Obstructive/or exp Chronic obstructive lung disease/(74383)

5. (Randomised or randomized or randomly or placebo or trial).ab. or (randomised or randomized or randomly or placebo or trial).ti. (1503026)

6. Exp RANDOMIZED CONTROLLED TRIAL/(654235)

7. Exp controlled clinical trial/(530101)

8. (1 or 2) and (3 or 4) and (5 or 6 or 7) (1004)

9. (Animals not humans).sh. (3705463)

10. 8 not 9 (1004)

11. 10 (1004)

12. Limit 11 to English language (944)

13. Limit 12 to yr = “1989-Current” (944)

14. Remove duplicates from 13 (632)

Database: Cochrane

Search date: October 26th, 2012

1. MeSH descriptor Pulmonary Disease, Chronic Obstructive explode all trees (1834)

2. (COPD or chronic obstructive pulmonary disease or COAD or chronic obstructive airway disease or chronic obstructive lung disease or chronic bronchitis or emphysema) (9973)

3. Tiotropium or spiriva or aclidinium bromide or Eklira or Glycopyrronium or NVA-237 or NVA237 or (NVA adj “237”) or glycopyrronium bromide or glycopyrrolate (953)

4. ((#1 OR #2) AND #3) (520)

5. (#4), from 1989 to 2012 limit to trials (446)

Database: clinicaltrials.gov

Search date: October 26th, 2012

NVA-237 or NVA237 or (NVA adj “237”) or glycopyrronium bromide or glycopyrrolate [INTERVENTION]

AND copd [CONDITION]

AND (“Phase II” OR “Phase III” OR “Phase IV”) [PHASE]

Database: Pubmed

Search date: October 26th, 2012

1. Search tiotropium OR spiriva OR aclidinium bromide OR Eklira OR Glycopyrronium OR NVA-237 OR NVA237 OR glycopyrronium bromide OR glycopyrrolate [Title/Abstract] (1782)

2. Search COPD OR chronic obstructive pulmonary disease OR COAD OR chronic obstructive airway disease OR chronic obstructive lung disease OR chronic bronchitis OR emphysema [Title/Abstract] (65084)

3. Search randomised OR randomized OR randomly OR placebo OR trial [Title/Abstract] (846800)

4. Search ((#3) AND #2) AND #1 (366)

5. Search ((“Glycopyrrolate” [Mesh]) OR “tiotropium” [Supplementary Concept]) OR “(3R)-3-((hydroxy(di-2-thienyl)acetyl)oxy)-1-(3-phenoxypropyl)-1-azoniabicyclo(2.2.2)octane bromide” [Supplementary Concept] Filters: Publication date from 2012/01/01 to 2013/12/31 (55)

6. Search (#4) NOT #5 Filters: Publication date from 2012/01/01 to 2013/12/31 (32)

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