Comparative efficacy of indacaterol 150 μg and 300 μg versus fixed-dose combinations of formoterol + budesonide or salmeterol + fluticasone for the treatment of chronic obstructive pulmonary disease – a network meta-analysis

Figures & data

Figure 1 Flow diagram of study selection.

Abbreviations: CSR, complete study reports; FDC, fixed-dose combinations; PICOS, patients, interventions, comparators, outcomes, and study design.

Figure 2 Network of studies.

Note: ^aStudies included predominantly Asian patients.
Abbreviations: BID, twice daily; FDC, fixed-dose combinations; FOR/BUD, FDC formoterol and budesonide; ICS, inhaled corticosteroids; OD, once daily; SAL/FP, FDC salmeterol and fluticasone proprionate.

Table 1 Study characteristics for each study included in the network meta-analysis

Source	Trial type	Location	Duration	Active treatments	Examples of key comorbidity exclusions	Ethnicity^d
Hanania et al^Citation18	RCT, DB, MC	76 centers; US	24 weeks	SAL/FP; 50/250 μg; BID	Patients with asthma and significant medical disorders	White: 91%–96% Black: 3%–5% Asian/other: 2%–3%
Barnes et al^Citation14	RCT, DB, MC	NR	13 weeks	SAL/FP; 50/500 μg; BID	NR	White: 99%–100% Asian: 0%–1%
Calverley et al^Citation15	RCT, DB, MC	196 centers; 25 countries in Europe including Russia, Australia, New Zealand, Canada, South Africa	52 weeks	SAL/FP; 50/500 μg; BID	Patients with other respiratory disorders	NR
Calverley et al^Citation16	RCT, DB, MC	444 centers; 42 countries	3 years	SAL/FP; 50/500 μg; BID	Patients with asthma, other respiratory disorders, or other diagnosis that may interfere with treatment	United States: 23% Europe: 50%; Asia: 12%–13% Other: 15%
Mahler et al^Citation19	RCT, DB, MC	65 centers; US	24 weeks	SAL/FP; 50/500 μg; BID	Patients with asthma and/or significant medical disorders (emphysema: 74%–78%)	White: 92%–95%; Black: 4%–6%; Asian/other: 1%–2%
Zheng et al^Citation22,Table Footnotea	RCT,DB, MC	12 centers: China	24 weeks	SAL/FP; 50/500 μg; BID	Patients with other respiratory disorders and/or significant medical disorders	100% Chinese
Calverley et al^Citation17	RCT, DB, MC	109 centers; 15 countries in Europe, Brazil, South Africa and Asia (China, Malaysia, Taiwan, and Thailand)	52 weeks	FOR/BUD; 9/320 μg; BID;	Patients with history of asthma, seasonal allergic rhinitis prior the age of 40 years, relevant cardiovascular disorders or significant disorder	NR
Rennard et al^Citation20	RCT, DB, DD, MC	237 centers: US and Mexico	52 weeks	FOR/BUD; 9/160 μg; BID; FOR/BUD; 9/320 μg; BID	Patients with history of asthma, seasonal allergic rhinitis prior the age of 40 years, relevant cardiovascular disorders or other respiratory tract disorders	White: 92.5%; Black: 2.6%; Asian: 0.2% Other: 4.7%
Tashkin et al^Citation21	RCT, DB, DD, MC	194 centers; US, Czech Republic, The Netherlands, Poland and South Africa	26 weeks	FOR/BUD; 9/160 μg; BID; FOR/BUD; 9/3200 μg; BID	Patients with history of asthma, seasonal allergic rhinitis before the age of 40 years, any relevant cardiovascular disorders or other respiratory tract disorder	White: 92%–93% Black: 2%–3% Asian: 0%–1% Other: 4%–6%
Dahl et al^Citation4 (B2334)^Table Footnoteb,Citation27 Non-ICS	RCT, DB, DD, MC	240 centers: Europe and Russia, Argentina, Chile, Colombia, Ecuador, Egypt, Israel, Peru, South Korea	52 weeks	IND; 300 μg; OD	Patients with concomitant pulmonary disease, type 1 diabetes, a history of asthma, or significant condition^c	Caucasian: 92%–94% Black: 0% Asian: 2% Other: 5%–6%
Donohu et al^Citation5 (B2335S)^Citation23 Non-ICS	RCT, PC, DB, DD, MC, 2 stage adaptive seamless	334 centers: Argentina, Canada, Germany, India, Italy, Korea, Spain, Sweden, Turkey, Taiwan, US	26 weeks	IND; 150 μg; OD; IND; 300 μg; OD	Patients with concomitant pulmonary disease, type 1 diabetes, a history of asthma, or significant condition^c	Caucasian: 79%–82% Black: 2%–3% Asian: 13%–19% Other: 0%–1%
Kornmann et al^Citation7 (B2336)^Citation24 Non-ICS	RCT, DB, DD, MC	142 centers	26 weeks	IND; 150 μg; OD	Patients with concomitant pulmonary disease, type 1 diabetes, a history of asthma, or significant condition^c	Caucasian: 75%–78% Black: 0% Asian: 16%–17% Other: 7%–8%
Feldman et al^Citation6 (B2346)^Citation28 Non-ICS	RCT, DB, DD, MC	103 centers: US, Australia/New Zealand, Belgium	12 weeks	IND; 150 μg; OD	Patients with a history of asthma or any significant pulmonary disease or cardiovascular abnormality	Caucasian: 92%–93% Black: 5%–6%; Asian: 0.5%; Other 2%:
B2333^Citation26,Table Footnotea Non-ICS	RCT, DB, DD, MC	Multiple centers; China and India	26 weeks	IND; 150 μg; OD; IND; 300 μg; OD	Patients with concomitant pulmonary disease, a history or asthma, type 1 diabetes, or clinically significant condition^c	Caucasian: 4%–5%; Asian: 95% (Chinese 89%–90%)
B1302^Citation25,Table Footnotea Non-ICS	RCT, DB, MC	73 centers; Japan, Taiwan, Korea, India, Hong Kong, and Singapore	12 weeks	IND; 150 μg; OD; IND; 300 μg; OD	Patients with concomitant pulmonary disease, a history or asthma, type 1 diabetes, or clinically significant condition^c	Asian: 100% (Japanese: 43%–45%; Chinese: 15–17%; Korean: 28%–30%)

Notes:

a These studies included predominantly Asian patients;

b This study evaluated indacaterol 600 μg which was not included in the analyses;

c The studies genearlly excluded patients that had a ‘clinically signficiant condition’ or ‘significant medical disorder’ that may have interfered with the study results. For example the protocol for study B2334 indicated the following exclusion: patients who, in the judgment of the investigator or the responsible Novartis personnel, had a clinically relevant laboratory abnormality or a clinically significant condition or any condition which in the investigator’s opinion might have compromised patient safety or compliance, interfered with evaluation, or precluded completion of the study;

d Ethnicity was reported for all patients in the indacaterol studies regardless of ICS use.

Abbreviations: BID, twice daily; DB, double blind; DD, double dummy; FOR/BUD, fixed-dose formoterol and budesonide; ICS, inhaled corticosteroids; IND, indacaterol; MC, multicenter; NR, not reported; OD, once daily; PC, placebo-controlled; RCT, randomized controlled trial; SAL/FP, fixed-dose salmeterol and fluticasone proprionate.

Table 2 Key baseline patient characteristics for each study included in network meta-analysis

Source	Treatment	Randomized no.	% male	Mean age	% current smokers	% severe or very severe	FEV1	FVC	BDI	SGRQ
Hanania et al^Citation18	Placebo	185	68%	65	47%	75%	1.29 (0.43)	NR	5.7 (NR)	CRDQ = 84.8
	SAL/FP 50/250	178	61%	63	43%	79%	1.25 (0.40)	NR	6.1 (NR)	CRDQ = 84.1
Barnes et al^Citation14	Placebo	73	74%	64	59%	19%	1.68 (0.47)	NR	NR	NR
	SAL/FP 50/500	67	82%	65	63%	33%	1.67 (0.44)	NR	NR	NR
Calverley et al^Citation15	Placebo	361	75%	63	47%	66%	1.27 (0.47)	2.50 (0.80)	NR	47.1 (16.5)
	SAL/FP 50/500	358	75%	63	52%	64%	1.31 (0.53)	2.54 (0.84)	NR	47.1 (15.7)
Calverley et al^Citation16	Placebo	1545	76%	65	43%	68%	1.12 (0.40)	NR	NR	49.0 (17.4)
	SAL/FP 50/500	1546	75%	65	43%	68%	1.12 (0.40)	NR	NR	48.9 (17.4)
Mahler et al^Citation19	Placebo	181	75%	64	54%	77%	1.32 (NR)	NR	5.6 (NR)	CRDQ = 86.2
	SAL/FP 50/500	165	62%	62	46%	77%	1.27 (NR)	NR	6.2 (NR)	CRDQ = 87.1
Zheng et al^Table Footnotea,Citation22	Placebo	148	86%	67	23%	60%	1.03 (NR)	NR	NR	44.5 (NR)
	SAL/FP 50/500	297	91%	66	21%	60%	1.06 (NR)	NR	NR	44.8 (NR)
Calverley et al^Citation17	Placebo	256	75%	65	30%	92%	0.98 (0.33)	NR	NR	48.0 (18.0)
	FOR/BUD 9/320	254	78%	64	33%	92%	0.98 (0.33)	NR	NR	48.0 (19.0)
Rennard et al^Citation20	Placebo	481	65%	63	44%	81%	1.10 (0.40)	NR	BCSS: 2.1	54.7 (16.1)
	FOR/BUD 9/160	494	63%	64	42%	83%	1.00 (0.40)	NR	BCSS: 2.2	55.7 (16.7)
	FOR/BUD 9/320	494	62%	63	39%	83%	1.00 (0.40)	NR	BCSS: 2.2	54.6 (17.4)
Tashkin et al^Citation21	Placebo	300	69%	63	40%	76%	1.08 (0.38)	NR	BCSS: 2.0	55.6 (17.0)
	FOR/BUD 9/160	281	64%	64	45%	82%	1.04 (0.40)	NR	BCSS: 2.0	55.5 (16.3)
	FOR/BUD 9/320	277	68%	63	44%	82%	1.04 (0.42)	NR	BCSS: 2.1	56.5 (15.8)
B2334;^b non-ICS^Citation27	Placebo	180	83%	64	46%	38%	1.40 (0.50)	2.77 (0.81)	6.7 (2.3)	43.4 (17.5)
	IND 300	165	82%	64	46%	44%	1.32 (0.42)	2.72 (0.75)	6.5 (2.0)	46.3 (17.5)
B2335S; non-ICS^Citation23	Placebo	226	60%	63	47%	32%	1.39 (0.51)	2.60 (0.79)	6.5 (2.4)	46.7 (17. 5)
	IND 150	240	65%	62	52%	33%	1.43 (0.53)	2.65 (0.78)	6.9 (2.4)	43.2 (19.1)
	IND 300	241	66%	63	50%	34%	1.41 (0.54)	2.72 (0.84)	6.7 (2.3)	44.0 (18.7)
B2336; non-ICS^Citation24	Placebo	187	81%	65	44%	39%	1.37 (0.50)	2.60 (0.78)	6.7 (2.0)	42.5 (18.3)
	IND 150	173	74%	63	51%	38%	1.36 (0.52)	2.56 (0.88)	6.9 (2.0)	42.1 (19.3)
B2346; non-ICS^Citation28	Placebo	125	55%	64	55%	34%	1.37 (0.58)	NR	NR	48.0 (17.3)
	IND 150	144	51%	62	58%	40%	1.35 (0.60)	NR	NR	49.2 (20.2)
B2333^a; non-ICS^Citation26	Placebo	113	94%	64	27%	53%	1.15 (0.39)	2.68 (0.67)	6.5 (2.2)	41.9 (19.6)
	IND 150	116	94%	65	27%	50%	1.11 (0.37)	2.64 (0.60)	6.4 (2.3)	41.8 (18.1)
	IND 300	112	97%	65	25%	46%	1.16 (0.37)	2.70 (0.64)	6.7 (2.1)	42.2 (16.9)
B1302;^a non-ICS^Citation25	Placebo	76	94%	67	27%	35%	1.20 (0.41)	2.67 (0.71)	7.4 (2.5)	38.6 (17.7)
	IND 150	85	96%	67	34%	31%	1.31 (0.45)	2.70 (0.66)	7.5 (2.1)	37.8 (18.3)
	IND 300	87	97%	67	36%	33%	1.22 (0.41)	2.61 (0.68)	7.8 (2.4)	35.5 (16.2)

Notes:

a These studies included predominantly Asian patients;

b this study evaluated indacaterol 600 μg which was not included in the analyses. Data are presented as mean (SD) where available and otherwise indicated by not reported (NR).

Abbreviations: BCSS, Breathless Cough and Sputum Scale Dyspnea Baseline Scores; BDI, Baseline Dyspnea Score; CRDQ, Chronic Respiratory Disease Questionnaire; FEV₁, forced expiratory volume in 1 second; FOR/BUD, fixed-dose formoterol and budesonide; FVC, forced vital capacity; IND, indacaterol; SAL/FP, fixed-dose salmeterol and fluticasone proprionate; SGRQ, St. George’s Respiratory Questionnaire total score.

Table 3 Reported data in individual studies included in the network meta-analysis

		FOR/BUD 9/160 μg			FOR/BUD 9/320 μg			SAL/FP 50/500 μg				SAL/FP 50/250 μg			IND 300 μg				IND 150 μg
		FEV112 wk	FEV16 m	SGRQ	FEV112 wk	FEV16 m	SGRQ	FEV112 wk	FEV16 m	SGRQ	TDI	FEV112 wk	FEV16 m	TDI	FEV112 wk	FEV16 m	SGRQ	TDI	FEV112 wk	FEV16 m	SGRQ	TDI
Hanania et al^Citation18	diff											0.16	0.16	0.80
	SE											0.03	0.03	0.35
Barnes^Citation14	diff							0.17	0.15
	SE							0.04	NR
Calverley et al^Citation15	diff							0.13	0.16	−1.00
	SE							NR	NR	NR
Calverley et al^Citation16	diff									−1.71
	SE									NR
Mahler et al^Citation19	diff							0.20	0.18		1.70
	SE							0.03	0.04		NR
Zheng^Table Footnotea, et al^Citation22	diff							0.15	0.15	−5.74
	SE							NR	NR	1.51
Calverley et al^Citation17	diff						−4.99
	SE						NR
Rennard et al^Citation20	diff	0.07	0.07		0.09	0.08
	SE	NR	NR		NR	NR
Tashkin et al^Citation21	diff	0.06	0.05	−2.95	0.08	0.08	−3.12
	SE	NR	0.02	1.06	NR	0.02	1.06
Non-ICS: B2334^Citation27	diff														0.18	0.18	−5.38	1.44
	SE														0.02	0.03	1.42	0.33
Non-ICS: B2335S^Citation23	diff														0.17	0.16	−1.55	1.11	0.20	0.18	−3.88	1.26
	SE														0.02	0.02	1.16	0.29	0.02	0.02	1.18	0.30
Non-ICS: B2336^Citation24	diff																		0.18	0.17	−6.15	0.90
	SE																		0.02	0.03	1.43	0.32
Non-ICS: B2346^Citation28	diff																		0.16
	SE																		0.03
Non-ICS: B1302^Table Footnotea,Citation26	diff														0.20				0.17
	SE														0.02				0.02
Non-ICS: B2333^Table Footnotea,Citation25	diff														0.14	0.14	−2.29	1.04	0.15	0.13	−2.88	0.81
	SE														0.03	0.03	1.95	0.34	0.03	0.03	1.94	0.34

Notes:

a Mainly Asian population.

Abbreviations: Diff, difference in change from baseline versus placebo; FEV₁, forced expiratory volume in 1 second; FOR/BUD, fixed-dose formoterol and budesonide; ICS, inhaled corticosteroids; IND, indacaterol; m, month; NR, not reported; SAL/FP, fixed-dose salmeterol and fluticasone proprionate; SE, standard error of the difference in change from baseline; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; wk, week.

Table 4 Results of network meta-analysis: all treatments versus placebo without covariates

	Trough FEV1L difference in CFB (95% CrI) at 12 weeks	Trough FEV1L difference in CFB (95% CrI) at 6 months	SGRQ total score difference in CFB (95% CrI) at 6 months	TDI total score difference (95% CrI) at 6 months
All studies
IND 150 μg	0.17 (0.15, 0.20)	0.16 (0.13, 0.19)	−4.43 (−6.67, −2.17)	1.01 (0.65, 1.37)
IND 300 μg	0.17 (0.15, 0.20)	0.16 (0.13, 0.19)	−3.01 (−5.26, −0.81)	1.19 (0.83, 1.55)
SAL/FP 50/500 μg	0.14 (0.13, 0.16)	0.16 (0.13, 0.19)	−2.27 (−4.33, −0.50)	1.70 (1.11, 2.29)
SAL/FP 50/250 μg	0.16 (0.10, 0.21)	0.16 (0.10, 0.22)	NR	0.80 (0.11, 1.49)
FOR/BUD 9/320 μg	0.09 (0.07, 0.11)	0.08 (0.06, 0.10)	−4.03 (−6.46, −1.60)	NR
FOR/BUD 9/160 μg	0.07 (0.05, 0.09)	0.06 (0.04, 0.09)	−2.95 (−6.33, 0.40)	NR
All studies excluding 3 Asian studies
IND 150 μg	0.18 (0.16, 0.21)	0.18 (0.14, 0.21)	−4.89 (−7.35, −2.47)	1.10 (0.67, 1.53)
IND 300 μg	0.17 (0.14, 0.21)	0.17 (0.14, 0.21)	−3.20 (−5.67, −0.84)	1.26 (0.83, 1.69)
SAL/FP 50/500 μg	0.14 (0.12, 0.16)	0.15 (0.12, 0.18)	−1.44 (−3.39, 0.58)	1.70 (1.10, 2.29)
SAL/FP 50/250 μg	0.16 (0.10, 0.21)	0.16 (0.10, 0.22)	NR	0.80 (0.11, 1.49)
FOR/BUD 9/320 μg	0.09 (0.07, 0.11)	0.08 (0.06, 0.10)	−4.02 (−6.25, −1.80)	NR
FOR/BUD 9/160 μg	0.07 (0.05, 0.09)	0.06 (0.04, 0.09)	−2.96 (−6.05, 0.13)	NR

Abbreviations: CFB, change from baseline; CrI, 95% credibility interval; FEV₁, forced expiratory volume in 1 second; FOR/BUD, fixed-dose formoterol and budesonide; IND, indacaterol; NR, not reported; SAL/FP, fixed-dose salmeterol and fluticasone proprionate; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 5 Results of network meta-analysis; Indacaterol 150 μg versus alternatives without covariates

	Trough FEV1L at 12 weeks		Trough FEV1L at 6 months		SGRQ total score at 6 months		TDI total score at 6 months
	Difference in CFB (95% CrI)	Prob of IND 150 being better	Difference in CFB (95% CrI)	Prob of IND 150 being better	Difference in CFB (95% CrI)	Prob of IND 150 being better	Difference (95% CrI)	Prob of IND 150 being better
All studies
SAL/FP 50/500μg	0.03 (0.00, 0.06)	99%	0.01 (−0.04, 0.05)	61%	−2.16 (−4.96, 0.95)	92%	−0.69 (−1.38, 0.01)	3%
SAL/FP 50/250 μg	0.02 (−0.04, 0.08)	72%	0.00 (−0.07, 0.07)	51%	NR	NR	0.21 (−0.57, 0.99)	70%
FOR/BUD 9/320 μg	0.09 (0.06, 0.11)	>99%	0.08 (0.05, 0.12)	>99%	−0.39 (−3.69, 2.92)	60%	NR	NR
FOR/BUD 9/160 μg	0.11 (0.08, 0.13)	>99%	0.10 (0.06, 0.14)	>99%	−1.48 (−5.51, 2.61)	78%	NR	NR
All studies excluding 3 Asian studies
SAL/FP 50/500 μg	0.04 (0.01, 0.08)	99%	0.02 (−0.02, 0.07)	82%	−3.45 (−6.64, −0.39)	98%	−0.60 (−1.34, 0.14)	6%
SAL/FP 50/250 μg	0.03 (−0.04, 0.09)	80%	0.01 (−0.06, 0.08)	66%	NR	NR	0.30 (−0.51, 1.11)	76%
FOR/BUD 9/320 μg	0.10 (0.06, 0.13)	>99%	0.10 (0.05, 0.14)	>99%	−0.86 (−4.20, 2.41)	71%	NR	NR
FOR/BUD 9/160 μg	0.12 (0.08, 0.15)	>99%	0.11 (0.07, 0.16)	>99%	−1.92 (−5.88, 2.00)	85%	NR	NR

Abbreviations: CFB, change from baseline; CrI, 95% credibility interval; FEV₁, forced expiratory volume in 1 second; FOR/BUD, fixed-dose formoterol and budesonide; IND, indacaterol; NR, not reported; Prob, probability; SAL/FP, fixed-dose salmeterol and fluticasone proprionate; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Table 6 Results of network meta-analysis: indacaterol 300 μg versus alternatives without covariates

	Trough FEV1L at 12 weeks		Trough FEV1L at 6 months		SGRQ total score at 6 months		TDI total score at 6 months
	Difference in CFB (95% CrI)	Prob of IND 300 being better	Difference in CFB (95% CrI)	Prob of IND 300 being better	Difference in CFB (95% CrI)	Prob of IND 300 being better	Difference (95% CrI)	Prob of IND 300 being better
All studies
SAL/FP 50/500μg	0.03 (0.00, 0.06)	97%	0.01 (−0.04, 0.05)	62%	−0.74 (−3.56, 2.28)	70%	−0.51 (−1.21, 0.19)	8%
SAL/FP 50/250 μg	0.02 (−0.05, 0.08)	70%	0.00 (−0.07, 0.07)	52%	NR	NR	0.39 (−0.39, 1.17)	84%
FOR/BUD 9/320 μg	0.08 (0.06, 0.11)	>99%	0.08 (0.05, 0.12)	>99%	1.02 (−2.30, 4.28)	26%	NR	NR
FOR/BUD 9/160 μg	0.10 (0.08, 0.13)	>99%	0.10 (0.06, 0.14)	>99%	−0.06 (−4.12, 3.96)	51%	NR	NR
All studies excluding 3 Asian studies
SAL/FP 50/500 μg	0.03 (−0.01, 0.07)	95%	0.02 (−0.03, 0.06)	76%	−1.76 (−4.99, 1.26)	89%	−0.45 (−1.18, 0.29)	12%
SAL/FP 50/250 μg	0.02 (−0.05, 0.08)	70%	0.01 (−0.06, 0.08)	61%	NR	NR	0.46 (−0.35, 1.27)	86%
FOR/BUD 9/320 μg	0.09 (0.05, 0.12)	>99%	0.09 (0.05, 0.13)	>99%	0.81 (−2.50, 4.05)	30%	NR	NR
FOR/BUD 9/160 μg	0.11 (0.07, 0.14)	>99%	0.11 (0.06, 0.15)	>99%	−0.23 (−4.21, 3.60)	55%	NR	NR

Abbreviations: CFB, change from baseline; CrI, 95% credibility interval; FEV₁, forced expiratory volume in 1 second; FOR/BUD, fixed-dose formoterol and budesonide; ICS, inhaled corticosteroids; IND, indacaterol; NR, not reported; Prob, probability; SAL/FP, fixed-dose salmeterol and fluticasone proprionate; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index.

Figure 3 Impact of adjustment for differences in effect-modifiers across studies: difference in indacaterol 150 μg versus alternatives for CFB in FEV₁ at 12 weeks and 95% credible Intervals.

Abbreviations: CFB, change from baseline; FEV₁, forced expiratory volume in 1 second; FOR/BUD 9/160, fixed-dose formoterol and budesonide 9/160 μg; FOR/BUD 9/320, fixed-dose formoterol and budesonide 9/320 μg; IND 150, indacaterol 150 μg; PLBO, placebo; SAL/FP 50/250, fixed-dose salmeterol and fluticasone proprionate 50/250 μg; SAL/FP 50/500, fixed-dose salmeterol and fluticasone proprionate 50/500 μg.

The search strategy was applied for the time period from 1989 to 2009 and 2009 to 2010

No.	Database	Search term
1	MEDLINE	(COPD OR chronic ADJ obstructive ADJ pulmonary ADJ disease OR COAD OR chronic ADJ obstructive ADJ airway ADJ disease OR chronic ADJ obstructive ADJ lung ADJ disease OR chronic ADJ bronchitis OR emphysema).TI,AB. OR Pulmonary-Disease-Chronic-Obstructive#.DE.
2	MEDLINE	(Formoterol OR eformoterol OR foradil OR oxis OR atimos ADJ modulite OR atock OR perforomist OR salmeterol OR serevent OR tiotropium OR spiriva OR Ba ADJ ‘679’ ADJ BR OR Indacaterol OR onbrez OR arcapta).TI,AB.
3	MEDLINE	PT = CONTROLLED-CLINICAL-TRIAL OR PT = RANDOMIZED-CONTROLLED-TRIAL OR Clinical-Trials-As-Topic.DE. OR Controlled-Clinical-Trials-As-Topic.DE. OR Randomized-Controlled-Trials-As-Topic.DE. OR Randomized-Controlled-Trials-As-Topic.DE. OR (randomized OR randomized OR randomly OR placebo).TI,AB. OR trial.TI,AB.
4	MEDLINE	3 AND HUMAN = YES AND ANIMAL = YES
5	MEDLINE	3 AND ANIMAL = YES
6	MEDLINE	3 NOT (4 OR 5)
7	MEDLINE	1 AND 2 AND 3 AND 6 AND LG = EN AND HUMAN = YES AND ADULT#
8	EMBASE	(COPD OR chronic ADJ obstructive ADJ pulmonary ADJ disease OR COAD OR chronic ADJ obstructive ADJ airway ADJ disease OR chronic ADJ obstructive ADJ lung ADJ disease OR chronic ADJ bronchitis OR emphysema).TI,AB.
9	EMBASE	Chronic-Obstructive-Lung-Disease#.DE.
10	EMBASE	(Formoterol OR eformoterol OR foradil OR oxis OR atimos ADJ modulite OR atock OR perforomist OR salmeterol OR serevent OR tiotropium OR spiriva OR Ba ADJ ‘679’ ADJ BR OR Indacaterol OR onbrez OR arcapta).TI,AB.
11	EMBASE	Controlled-Clinical-Trial.DE. OR Double-Blind-Procedure.DE. OR Controlled-Clinical-Trial.DE. OR Randomized-Controlled-Trial.DE. OR Randomized-Controlled-Trial.DE.
12	EMBASE	(randomized OR randomized OR placebo OR randomly).TI,AB. OR trial.TI.
13	EMBASE	(11 OR 12) AND HUMAN = YES AND ANIMAL = YES
14	EMBASE	(11 OR 12) AND ANIMAL = YES
15	EMBASE	(11 OR 12) NOT (13 OR 14)
16	EMBASE	8 OR 9
17	EMBASE	16 AND 15 AND 10 AND LG = EN AND HUMAN = YES AND ADULT = YES
18	MEDLINE and EMBASE [all]	combined sets 7, 17
19	MEDLINE and EMBASE [all]	dropped duplicates from 18
20	MEDLINE and EMBASE [all]	unique records from 18
21	Medline	split set 20
22	EMBASE	split set 20

Notes: .ab. indicates a search for a term in abstract; .pt. indicates a search for a publication type.

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