Long‐acting inhaled therapy (beta‐agonists, anticholinergics and steroids) for COPD: a network meta‐analysis

Kayleigh M Kew; Sofia Dias; Christopher J Cates

doi:10.1002/14651858.CD010844.pub2

Cochrane Database of Systematic Reviews

Tratamiento por inhalación de acción prolongada (agonistas beta, anticolinérgicos y esteroides) para la EPOC: un metanálisis de redes

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DOI:

https://doi.org/10.1002/14651858.CD010844.pub2 Copiar DOI

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Cochrane Database of Systematic Reviews

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26 marzo 2014see what's new

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Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Vías respiratorias

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Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Kayleigh M Kew

Correspondencia a: Population Health Research Institute, St George's, University of London, London, UK

[email protected]
Sofia Dias

School of Social and Community Medicine, University of Bristol, Bristol, UK
Christopher J Cates

Population Health Research Institute, St George's, University of London, London, UK

Contributions of authors

Kayleigh Kew extracted data, assessed trials for methodological quality and otherwise constructed the review. Sofia Dias conducted the network meta‐analyses and constructed figures. Chris Cates assisted with statistical issues and clinical interpretation of the results. All authors contributed to the writing of the review.

Sources of support

Internal sources

No sources of support supplied

External sources

Kayleigh Kew, UK.

NIHR, Programme grant funding
Christopher Cates, UK.

NIHR, Programme grant funding

Declarations of interest

None known.

Acknowledgements

We are grateful to Elizabeth Stovold for her help in designing the search strategy.

Milo Puhan was the Editor for this review and commented critically on the review.

CRG Funding Acknowledgement: The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Airways Group.

Disclaimer: The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Version history

Published

Title

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Authors

Version

2014 Mar 26

Long‐acting inhaled therapy (beta‐agonists, anticholinergics and steroids) for COPD: a network meta‐analysis

Review

Kayleigh M Kew, Sofia Dias, Christopher J Cates

https://doi.org/10.1002/14651858.CD010844.pub2

2013 Dec 02

Long‐acting inhaled therapy (beta‐agonists, anticholinergics and steroids) for COPD: a network meta‐analysis

Protocol

Kayleigh M Kew, Tianjing Li

https://doi.org/10.1002/14651858.CD010844

Differences between protocol and review

We did not perform a formal cost‐effectiveness analysis and instead presented a summary in the discussion. We did not systematically contact trial authors to ask for additional data or risk of bias, and two review authors did not independently extract data. So as not to delay publication, data and risk of bias were cross‐checked in studies with extraction in previous reviews by one review author (KMK), and discrepancies were resolved by a second review author (CJC). The objective "How does combining different pharmacological treatments affect the long‐term efficacy?" was not addressed and so was removed.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Male; Middle Aged;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.
^aAll 58 studies identified in the review search were also identified in the electronic database search.
Abbreviations: CDSR = Cochrane Database of Systematic Reviews.

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Figure 2

Network structures for both outcomes at six months.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

St George's Respiratory Questionnaire (SGRQ) change from baseline—six‐month and 12‐month class results.

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Trough forced expiratory volume in one second (FEV1) change from baseline—six‐month and 12‐month class results.

Figure 5

Trough forced expiratory volume in one second (FEV₁) change from baseline—six‐month and 12‐month class results.

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Figure 6

St George's Respiratory Questionnaire (SGRQ) probability ranking diagrams—six months and 12 months.

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Forced expiratory volume in one second (FEV1) probability ranking diagrams—six months and 12 months.

Figure 7

Forced expiratory volume in one second (FEV₁) probability ranking diagrams—six months and 12 months.

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Table 1. All included studies—summary characteristics

Study ID	Weeks	Arms included^a	N	Age^b	% male	% pred FEV_1b	Pack‐years^b
Abrahams 2013	24	tiotropium, placebo	856	64.2	64.9	43.3	46.9
ACCLAIM 2009	52	aclidinium, placebo	843	62.4	78.6	53.9	39.9
ACCLAIM II 2009	52	aclidinium, placebo	804	65.1	63.0	50.3	57.9
Anzueto 2009	52	salmeterol, salmeterol/fluticasone	797	65.4	54	34.0	57.2
ATTAIN 2011	24	aclidinium (2), placebo	828	62.4	67.4	52.5	40.2
Bateman 2010a	48	tiotropium, placebo	3991	64.8	77.6	39.9	46
Bateman 2010b	48	tiotropium (2), placebo	1990	65.0	74.2	37.7	nr
Bateman 2013 [SHINE]	26	indacaterol, tiotropium, glycopyrronium, placebo	1667	64.0	74.9	55.0	nr
Bourbeau 1998	26	budesonide, placebo	79	66	78.6	36.5	51
Brusasco 2003	26	salmeterol, tiotropium, placebo	1207	64.2	76.3	38.5	43.8
Burge 2000 [ISOLDE]	156	fluticasone, placebo	751	63.8	74.6	50.2	44
Calverley 2003a	52	formoterol, budesonide, formoterol/budesonide, placebo	1122	64	76	36	39
Calverley 2003 [TRISTAN]	52	salmeterol, fluticasone, salmeterol/fluticasone, placebo	1466	63.2	72.5	44.7	42.3
Calverley 2003b	52	mometasone, placebo	631	nr	nr	47	nr
Calverley 2007 [TORCH]	156	salmeterol, fluticasone, salmeterol/fluticasone, placebo	6185	65.0	75.8	44.0	48.5
Calverley 2008	52	mometasone (2), placebo	911	65.1	68.3	42.3	nr
Calverley 2010	48	formoterol, formoterol/budesonide	718	63.9	81.3	42.4	38.8
Campbell 2005	26	formoterol, placebo	432	55	67	53.6	37
Casaburi 2002	52	tiotropium, placebo	921	65	65.0	38.7	61.4
Chan 2007	48	tiotropium, placebo	913	66.8	59.7	39.4	50.6
Cooper 2010	104	tiotropium, placebo	519	64.6	77.3	38.2	51.7
Dahl 2010	52	formoterol, placebo	867	63.5	31.9	51.7	40.8
Dal Negro 2003	52	salmeterol, salmeterol/fluticasone, placebo	18	nr	83.3	50.0	41.4
Doherty 2012	26	formoterol, mometasone, formoterol/mometasone (2), placebo	1196	59.7	75.2	38.6	45.1
Donohue 2010 [INHANCE]	26	indacaterol (2), tiotropium, placebo	1683	63.6	62.8	55.6	49.7
Dusser 2006	48	tiotropium, placebo	1010	64.7	88	47.9	nr
Fang 2008	52	tiotropium, salmeterol/fluticasone	126	62.5	73.8	nr	nr
Ferguson 2008	52	salmeterol, salmeterol/fluticasone	782	64.9	55	32.8	56.5
FLTA3025	26	fluticasone (2), placebo	640	64.4	68.8	nr	nr
Gelb 2012	52	aclidinium (2)	605	nr	nr	46.5	nr
GLOW1 2011	26	glycopyrronium, placebo	822	63.9	81.8	54.6	44.8
GLOW2 2012	52	glycopyrronium, tiotropium, placebo	1066	63.6	64.2	56.0	49.1
Hanania 2003	26	salmeterol, fluticasone, salmeterol/fluticasone, placebo	723	63.9	63.1	42	56.5
Kardos 2007	43	salmeterol, salmeterol/fluticasone	994	63.9	75.8	40.4	36.9
Kornmann 2011	26	salmeterol, placebo	339	63.3	74.7	53.3	40.3
Lapperre 2009	130	fluticasone (2), salmeterol/fluticasone, placebo	114	61	86.6	55.3	44.3
Laptseva 2002	26	budesonide, placebo	49	nr	nr	nr	nr
Mahler 2002	26	salmeterol, fluticasone, salmeterol/fluticasone, placebo	674	63.5	65.8	41	40.8
Mahmud 2007	26	salmeterol, tiotropium	90	nr	91	nr	nr
Niewoehner 2005	26	tiotropium, placebo	1829	67.9	98.5	35.6	68.4
Ohar 2013	26	salmeterol, salmeterol/fluticasone	639	nr	nr	nr	nr
Ozol 2005	26	budesonide, placebo	26	65.4	69.2	59.2	45.0
Paggiaro 1998	26	fluticasone, placebo	281	63	74	57	nr
Pauwels 1999	156	budesonide, placebo	1277	52.5	72.9	76.9	39.3
Powrie 2007	52	tiotropium, placebo	142	66.4	62.9	50.0	55.2
Renkema 1996	104	budesonide, placebo	39	55	100	63.5	nr
Rennard 2009	52	formoterol, budesonide, formoterol/budesonide, placebo	1964	63.2	63.9	39.6	40 (med)
Rossi 2002	52	formoterol (2), placebo	645	62.7	83.3	nr	nr
Schermer 2009	156	fluticasone, placebo	190	59.0	70.5	64.5	28.3
SCO100470	26	salmeterol, salmeterol/fluticasone	1050	63.6	77.8	nr	nr
SCO30002	52	salmeterol/fluticasone, fluticasone, placebo	387	64.8	82	nr	nr
SCO40041	156	salmeterol, salmeterol/fluticasone	186	65.7	61.3	nr	nr
Senderovitz 1999	26	budesonide, placebo	26	60.5	53.5	nr	nr
Shaker 2009	104+	budesonide, placebo	254	63.6	58.3	52	56
Sharafkhaneh 2012	52	formoterol, budesonide/formoterol (2)	1219	63.0	62.0	37.7	44.3
SLMF4010	26	salmeterol, placebo	34	63.8	88.3	nr	nr
SPARK 2013	64	tiotropium (OL), glycopyrronium	1483	63.4	74.1	nr	nr
Szafranski 2003	52	formoterol, budesonide, formoterol/budesonide, placebo	812	64	78.8	36.2	44.5
Tashkin 2008 [SHINE]	26	formoterol, budesonide, formoterol/budesonide (3), placebo	1704	63.4	66.9	39.9	40 (med)
Tashkin 2008a [UPLIFT]	208	tiotropium, placebo	5993	64.5	74.7	39.4	48.7
Tashkin 2012	26	formoterol, mometasone, formoterol/mometasone (2), placebo	1055	59.8	77.5	nr	40.4
To 2011	52	salmeterol, indacaterol	186	69.1	nr	53	nr
Tonnel 2008 [TIPHON]	39	tiotropium, placebo	554	64.2	86.1	46.9	43.7
Trooster 2011	24	tiotropium, placebo	457	61.8	68.4	nr	nr
Verhoeven 2002	26	fluticasone, placebo	23	55	82.3	63.5	25.5
Vestbo 1999	156	budesonide, placebo	290	59.1	87.5	86.6	nr
Vogelmeier 2008	26	formoterol, tiotropium, placebo	640	62.6	77.5	51.4	38.0
Vogelmeier 2011 [POET]	52	salmeterol, tiotropium	7384	62.9	74.7	49.3	38.3
Wedzicha 2008 [INSPIRE]	104	tiotropium, salmeterol/fluticasone	1323	64.5	82.5	39.3	40.4
Zheng 2006	24	salmeterol/fluticasone, placebo	448	66.3	88.6	nr	nr
Zhong 2012	24	budesonide, formoterol/budesonide	308	65.2	95.1	32.7	nr
^aNumbers in parentheses indicate multiple doses of the same treatment. ^bAge, % predicted FEV₁ and pack‐years smoked are reported as means unless otherwise stated. bid = twice daily. FEV₁ = forced expiratory volume in one second. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid combination therapy. LAMA = long‐acting muscarinic antagonist. nr = not reported. PBO = placebo inhaler. qd = once daily.

Table 1. All included studies—summary characteristics

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Table 2. SGRQ network composition and transitivity assessmenta

Comparison	Comparisons	N	Age^b	% male	% FEV_1c	Packs^d
LABA vs placebo	16	13,808	62.9	74.7	46.2	42.5
LAMA vs placebo	15	22,406	64.2	71.3	47.1	47.5
ICS vs placebo	10	8153	63.4	74.9	41.7	42.7
LABA/ICS vs placebo	10	9097	63.1	75.3	39.7	42.4
LABA vs LAMA	2	2680	63.7	69.5	55.2	49.7
LABA vs ICS	7	6226	62.7	73.8	40.0	42.7
LABA vs LABA/ICS	13	12,505	63.1	71.0	38.8	43.9
LAMA vs ICS	0	‐	‐	‐	‐	‐
LAMA vs LABA/ICS	1	1323	64.5	82.5	39.3	40.4
ICS vs LABA/ICS	10	8721	62.9	75.3	38.8	42.9
^aSummary population data are for all study comparisons excluding those made in the 29 studies that could not be included in either the six‐month or the 12‐month SGRQ network. ^bAge = mean years. ^c% FEV₁ = mean percentage predicted FEV₁. ^dPacks = mean pack‐years. FEV₁ = forced expiratory volume in one second. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid combination therapy. LAMA = long‐acting muscarinic antagonist. SGRQ = St George's Respiratory Questionnaire.

Table 2. SGRQ network composition and transitivity assessmenta

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Table 3. FEV1 network composition and transitivity assessmenta

Comparison	Comparisons	N	Age^b	% male	%FEV_1c	Packs^d
LABA vs Placebo	13	8680	63.3	73.2	47.7	43.9
LAMA vs Placebo	16	23,111	64.3	72.2	47.6	48.9
ICS vs Placebo	12	4574	63.6	71.9	46.2	45.2
LABA/ICS vs Placebo	9	4978	63.9	73.5	41.6	44.4
LABA vs LAMA	2	2680	63.7	69.5	55.2	49.7
LABA vs ICS	5	2506	63.6	67.1	40.6	46.7
LABA vs LABA/ICS	12	8005	63.7	68.8	39.9	45.8
LAMA vs ICS	0	‐	‐	‐	‐	‐
LAMA vs LABA/ICS	0	‐	‐	‐	‐	‐
ICS vs LABA/ICS	8	4560	63.6	71.7	39.0	45.5
^aSummary population data are for all study comparisons excluding those made in the 23 studies that could not be included in either the six‐month or the 12‐month FEV₁ network; all doses are given in micrograms. ^bAge = mean years. ^c% FEV₁ = mean percentage predicted FEV₁. ^dPacks = mean pack‐years. FEV1 = forced expiratory volume in one second. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid combination therapy. LAMA = long‐acting muscarinic antagonist.

Table 3. FEV1 network composition and transitivity assessmenta

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Table 4. Distribution of studies by individual treatment node

Class	Treatment node mcg	Studies
LABA	Formoterol 12 bid	Calverley 2003a; Calverley 2003 [TRISTAN]; Calverley 2010; Campbell 2005; Dahl 2010; Doherty 2012; Rennard 2009; Rossi 2002; Sharafkhaneh 2012; Szafranski 2003; Tashkin 2008 [SHINE]; Tashkin 2012; Vogelmeier 2008^a
	Formoterol 24 bid	Rossi 2002
	Indacaterol 300 qd	Dahl 2010; Donohue 2010 [INHANCE]
	Indacaterol 600 qd	Dahl 2010
	Indacaterol 150 qd	Bateman 2013 [SHINE]; Donohue 2010 [INHANCE]
	Salmeterol 50 bid	Anzueto 2009; Brusasco 2003; Dal Negro 2003^a; Calverley 2007 [TORCH]; Ferguson 2008; Hanania 2003^a; Kardos 2007; Kornmann 2011; Mahler 2002^a; Mahmud 2007^a; Ohar 2013^a; SCO100470; SCO40041^a; SLMF4010; Vogelmeier 2011 [POET]^a
LAMA	Tiotropium 5 qd	Abrahams 2013; Bateman 2010a; Bateman 2010b
	Tiotropium 10 qd	Bateman 2010b
	Tiotropium 18 qd	Bateman 2013 [SHINE]; Brusasco 2003; Casaburi 2002; Chan 2007; Cooper 2010^a; Donohue 2010 [INHANCE]; Dusser 2006^a; Fang 2008^a; GLOW2 2012; Mahmud 2007^a; Niewoehner 2005^a; Powrie 2007^a; SPARK 2013; Tashkin 2008a [UPLIFT]; Tonnel 2008 [TIPHON]; Trooster 2011^a; Vogelmeier 2008^a; Vogelmeier 2011 [POET]^a; Wedzicha 2008 [INSPIRE]
	Aclidinium bromide 200 qd	ACCLAIM 2009; ACCLAIM II 2009
	Aclidinium bromide 200 bid	ATTAIN 2011; GLOW1 2011
	Aclidinium bromide 400 bid	ATTAIN 2011; Gelb 2012
	Glycopyrronium bromide 50 qd	Bateman 2013 [SHINE]; GLOW1 2011; GLOW2 2012; SPARK 2013
ICS	Budesonide 320‐400 bid	Calverley 2003a; Laptseva 2002^a; Ozol 2005^a; Pauwels 1999^a; Senderovitz 1999^a; Shaker 2009^a; Szafranski 2003; Tashkin 2008 [SHINE]; Zhong 2012
	Budesonide 750‐1000 bid	Bourbeau 1998; Renkema 1996^a; Vestbo 1999
	Fluticasone 250 bid	FLTA3025; Hanania 2003
	Fluticasone 500 bid	Burge 2000 [ISOLDE]; Calverley 2003 [TRISTAN]; Calverley 2007 [TORCH]; FLTA3025; Lapperre 2009^a; Mahler 2002; Paggiaro 1998; Schermer 2009; SCO30002^a; Verhoeven 2002^a
	Mometasone 400 bid or 800 qd	Calverley 2003b; Calverley 2008; Doherty 2012; Tashkin 2012
LABA/ICS	Formoterol/bud 12/160 bid	Rennard 2009; Sharafkhaneh 2012; Tashkin 2008 [SHINE]; Zhong 2012
	Formoterol/bud 12/320 bid	Calverley 2003a; Calverley 2010; Rennard 2009; Sharafkhaneh 2012; Szafranski 2003; Tashkin 2008 [SHINE]
	Formoterol/mom 12/200 bid	Doherty 2012; Tashkin 2012
	Formoterol/mom 12/400 bid	Doherty 2012; Tashkin 2012
	Salmeterol/flut 50/250 bid	Anzueto 2009; Dal Negro 2003; Fang 2008^a; Hanania 2003; Ohar 2013
	Salmeterol/flut 50/500 bid	Calverley 2003 [TRISTAN]; Calverley 2007 [TORCH]; Ferguson 2008; Lapperre 2009^a; Mahler 2002; SCO100470; SCO30002^a; SCO40041^a; Wedzicha 2008 [INSPIRE]; Zheng 2006
PBO	Placebo inhaler	Abrahams 2013; ACCLAIM 2009; ACCLAIM II 2009; ATTAIN 2011; Bateman 2010a; Bateman 2010b; Bateman 2013 [SHINE]; Bourbeau 1998; Brusasco 2003; Burge 2000 [ISOLDE]; Calverley 2003a; Calverley 2003 [TRISTAN]; Calverley 2003b; Calverley 2007 [TORCH]; Calverley 2008; Calverley 2010; Campbell 2005; Casaburi 2002; Chan 2007; Cooper 2010^a; Dahl 2010; Dal Negro 2003; Doherty 2012; Donohue 2010 [INHANCE]; Dusser 2006^a; FLTA3025; GLOW1 2011; GLOW2 2012; Hanania 2003; Kornmann 2011; Lapperre 2009^a; Laptseva 2002^a; Mahler 2002; Niewoehner 2005^a; Ozol 2005; Paggiaro 1998; Pauwels 1999^a; Powrie 2007; Renkema 1996^a; Rennard 2009; Rossi 2002; Schermer 2009; SCO30002; Senderovitz 1999; Shaker 2009; Sharafkhaneh 2012; SLMF4010; SPARK 2013; Szafranski 2003; Tashkin 2008 [SHINE]; Tashkin 2008a [UPLIFT]; Tashkin 2012; To 2011^a; Tonnel 2008 [TIPHON]; Trooster 2011; Verhoeven 2002^a; Vestbo 1999; Vogelmeier 2008^a; Zheng 2006
^aStudies not contributing data to either outcome. bid = twice daily. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid combination therapy. LAMA = long‐acting muscarinic antagonist. PBO = placebo inhaler. qd = once daily.

Table 4. Distribution of studies by individual treatment node

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Table 5. Sensitivity analysis—blinding

Study ID	Arm removed	Analyses affected
Bateman 2013 [SHINE]	Tiotropium 18 mcg	SGRQ6m, FEV6m
Donohue 2010 [INHANCE]	Tiotropium 18 mcg	SGRQ6m, FEV6m
GLOW2 2012	Tiotropium 18 mcg	SGRQ6m, FEV6m, SGRQ12m, FEV12m
SPARK 2013	Whole study (2 arms)	SGRQ6m, FEV6m, SGRQ12m, FEV12m
Vogelmeier 2008	Tiotropium 18 mcg	Did not appear in analyses
FEV = forced expiratory volume in one second SGRQ = St George's Respiratory Questionnaire 6m = six month analysis 12m = 12 month analysis

Table 5. Sensitivity analysis—blinding

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Table 6. SGRQ class effects versus placebo (six months)a

	Effect vs placebo Class NWMA		Effect vs placebo Sensitivity analysis		Rank
Class	Median	95% CrI	Median	95% CrI	Mean	Median	95% CrI	Pr (best)
LABA/ICS	‐3.89	(‐4.70 to ‐2.97)	‐3.89	(‐4.66 to ‐3.05)	1.0	1	(1 to 2)	0.96
LAMA	‐2.63	(‐3.53 to ‐1.97)	‐2.78	(‐3.58 to ‐2.13)	2.4	2	(1 to 4)	0.03
LABA	‐2.29	(‐3.18 to ‐1.53)	‐2.09	(‐2.93 to ‐1.36)	3.1	3	(2 to 4)	0.01
ICS	‐2.00	(‐3.06 to ‐0.87)	‐1.96	(‐2.99 to ‐0.91)	3.5	4	(2 to 4)	0.00
^aFor effects versus placebo, smaller values indicate larger benefits of the active treatment; all doses are given in micrograms. Crl = credible interval. SGRQ = St George's Respiratory Questionnaire. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid. LAMA = long‐acting antimuscarinic antagonist. NWMA = network meta‐analysis. Pr = probability.

Table 6. SGRQ class effects versus placebo (six months)a

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Table 7. SGRQ individual treatment effects versus placebo (six months)a

Rank (from class NWMA)		Effect vs placebo Class NWMA		Effect vs placebo NWMA no class		Rank (from class NWMA)
Class	Treatment (number daily doses)	Median	95% CrI	Median	95% CrI	Mean	Median	95% CrI	Pr (best)
LABA	Form 12 (2)	‐1.84	(‐2.60 to ‐0.94)	‐1.20	(‐2.10 to ‐0.30)	14.9	15	(10 to 17)	0.00
	Ind 300 (1)	‐2.38	(‐3.63 to ‐1.44)	‐3.10	(‐4.86 to ‐1.36)	11.3	12	(5 to 17)	0.00
	Ind 150 (1)	‐2.75	(‐3.95 to ‐1.85)	‐3.67	(‐4.76 to ‐2.58)	8.7	8	(3 to 16)	0.01
	Salm 50 (2)	‐2.20	(‐2.98 to ‐1.43)	‐2.27	(‐3.27 to ‐1.27)	12.9	13	(7 to 17)	0.00
LAMA	Tio 5 (1)	‐2.50	(‐3.16 to ‐1.86)	‐2.42	(‐3.20 to ‐1.63)	10.5	10	(6 to 16)	0.00
	Tio 18 (1)	‐2.53	(‐3.12 to ‐1.97)	‐2.66	(‐3.33 to ‐1.99)	10.3	10	(6 to 15)	0.00
	Acl 200 (2)	‐2.66	(‐4.04 to ‐1.70)	‐3.79	(‐6.14 to ‐1.45)	9.1	9	(2 to 16)	0.01
	Acl 400 (2)	‐2.81	(‐4.40 to ‐1.90)	‐4.59	(‐6.94 to ‐2.23)	7.9	7	(1 to 15)	0.03
	Gly 50 (1)	‐2.63	(‐3.42 to ‐1.94)	‐2.83	(‐3.74 to ‐1.91)	9.5	9	(5 to 15)	0.00
ICS	Bud 400 (2)	‐1.76	(‐2.82 to ‐0.55)	‐0.97	(‐2.32 to 0.38)	14.9	16	(7 to 17)	0.00
	Flut 500 (2)	‐1.95	(‐3.07 to ‐0.74)	‐1.71	(‐3.40 to ‐0.01)	13.9	15	(6 to 17)	0.00
	Mom 400 (2)	‐2.28	(‐3.51 to ‐1.19)	‐2.77	(‐4.47 to ‐1.09)	11.9	13	(5 to 17)	0.00
LABA/ICS	Form‐bud 12/160 (2)	‐4.04	(‐4.91 to ‐3.15)	‐3.85	(‐4.99 to ‐2.70)	2.6	2	(1 to 6)	0.29
	Form‐bud 12/320 (2)	‐3.80	(‐4.63 to ‐2.84)	‐3.31	(‐4.39 to ‐2.22)	3.9	4	(1 to 9)	0.10
	Form‐mom 12/200 (2)	‐3.85	(‐4.82 to ‐2.66)	‐3.45	(‐5.17 to ‐1.74)	3.7	4	(1 to 10)	0.15
	Form‐mom 12/400 (2)	‐3.75	(‐4.72 to ‐2.48)	‐3.09	(‐4.81 to ‐1.37)	4.3	4	(1 to 11)	0.10
	Salm‐flut 50/500 (2)	‐4.05	(‐4.97 to ‐3.18)	‐4.36	(‐5.60 to ‐3.12)	2.6	2	(1 to 6)	0.31
^aFor effects versus placebo, smaller values indicate larger benefits of the active treatment; all doses are given in micrograms. Crl = credible interval. SGRQ = St George's Respiratory Questionnaire. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid. LAMA = long‐acting antimuscarinic antagonist. NWMA = network meta‐analysis. Pr = probability.

Table 7. SGRQ individual treatment effects versus placebo (six months)a

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Table 8. FEV1 class effects versus placebo (six months)a

	Effect vs placebo Class NWMA		Effect vs placebo Sensitivity analysis		Rank
Class	Median	95% CrI	Median	95% CrI	Mean	Median	95% CrI	Pr (best)
LABA/ICS	133.30	(100.60 to 164.00)	132.80	(98.93 to 165.60)	1.1	1	(1 to 2)	0.9
LAMA	103.50	(81.78,124.90)	103.60	(79.01 to 126.60)	2.4	2	(1 to 3)	0.1
LABA	99.44	(71.98,127.80)	99.86	(70.41 to 130.50)	2.6	3	(1 to 4)	0.0
ICS	65.36	(33.06,96.91)	65.52	(31.23 to 97.16)	3.9	4	(3 to 4)	0.0
^aFor effects versus placebo, smaller values indicate larger benefits of the active treatment; all doses are given in micrograms. Crl = credible interval. FEV₁ = forced expiratory volume in one second. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid. LAMA = long‐acting antimuscarinic antagonist. NWMA = network meta‐analysis. Pr = probability.

Table 8. FEV1 class effects versus placebo (six months)a

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Table 9. FEV1 individual treatment effects versus placebo (six months)a

		Effect vs placebo Class NWMA		Effect vs placebo NWMA no class		Rank (from class NWMA)
Class	Treatment (number daily doses)	Median	95% CrI	Median	95% CrI	Mean	Median	95% CrI	Pr (best)
LABA	Form 12 (2)	94.88	(60.70 to 122.80)	53.92	(13.00 to 94.07)	12.0	13	(5 to 18)	0.00
	Ind 300 (1)	103.30	(71.95 to 150.10)	137.90	(63.69 to 209.90)	9.5	10	(2 to 16)	0.02
	Ind 150 (1)	99.53	(72.32 to 127.20)	100.70	(65.74 to 133.80)	10.8	12	(4 to 16)	0.00
	Salm 50 (2)	101.00	(73.39 to 130.70)	114.70	(75.96 to 149.30)	10.3	11	(4 to 16)	0.00
LAMA	Tio 5 (1)	105.40	(81.87 to 131.80)	110.50	(73.82 to 145.40)	8.9	9	(3 to 15)	0.01
	Tio 10 (1)	106.40	(79.80 to 142.00)	121.00	(62.88 to 175.20)	8.6	8	(2 to 15)	0.02
	Tio 18 (1)	105.20	(85.54 to 125.50)	107.00	(82.93 to 129.50)	9.0	9	(4 to 15)	0.00
	Acl 200 (1)	98.83	(59.06 to 123.20)	59.31	(9.47 to 107.90)	11.3	11	(5 to 18)	0.00
	Acl 200 (2)	100.60	(65.20 to 127.10)	74.82	(11.81 to 134.20)	10.7	11	(4 to 17)	0.00
	Acl 400 (2)	107.30	(80.93 to 143.50)	108.80	(45.06 to 168.30)	8.2	8	(2 to 15)	0.02
	Gly 50 (1)	103.60	(79.83 to 127.50)	101.50	(67.86 to 133.40)	9.5	10	(3 to 15)	0.00
ICS	Bud 400 (2)	61.89	(23.86 to 94.06)	14.59	(‐29.22 to 58.25)	17.6	18	(14 to 19)	0.00
	Bud 750+ (2)	63.10	(14.75 to 99.65)	‐2.26	(‐95.77 to 91.34)	17.3	18	(12 to 19)	0.00
	Flut 250 (2)	66.78	(34.19 to 101.10)	76.18	(29.36 to 122.30)	16.9	17	(11 to 19)	0.00
	Flut 500 (2)	72.16	(40.20 to 109.80)	97.04	(54.90 to 138.40)	15.9	16	(8 to 19)	0.00
LABA/ICS	Form‐bud 12/160 (2)	131.10	(91.65 to 164.00)	80.84	(26.99 to 132.70)	3.9	3	(1 to 13)	0.16
	Form‐bud 12/320 (2)	127.30	(85.14 to 159.50)	72.77	(28.75 to 116.70)	4.7	4	(1 to 14)	0.11
	Salm‐flut 50/250 (2)	139.70	(106.20 to 182.90)	173.00	(116.20 to 226.40)	2.4	2	(1 to 8)	0.39
	Salm‐flut 50/500 (2)	137.10	(104.40 to 172.10)	152.40	(104.10 to 197.80)	2.8	2	(1 to 9)	0.26
^aFor effects versus placebo, bigger values indicate larger benefits of the active treatment; all doses are given in micrograms. Crl = credible interval. FEV₁ = forced expiratory volume in one second. ICS = inhaled corticosteroid. LABA = long‐acting beta₂‐agonist. LABA/ICS = long‐acting beta₂‐agonist/inhaled corticosteroid. LAMA = long‐acting antimuscarinic antagonist. NWMA = network meta‐analysis. Pr = probability.

Table 9. FEV1 individual treatment effects versus placebo (six months)a

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