Comparative efficacy of inhaled corticosteroid and long-acting beta agonist combinations in preventing COPD exacerbations: a Bayesian network meta-analysis

Figures & data

Table 1 Study characteristics of included trials that provide data on the total number of exacerbations and/or the mean annual rate of exacerbations

Study, year	Number of patients	Duration of treatment (weeks)	Treatment comparisons	Baseline characteristics				Reported severity of exacerbations		Quality assessment
				Mean age	Male %	Baseline FEV1 predicted %	LTOT excluded	Moderate to severe	Severe only	Concealed allocation	ITT analysis	Blinding
Mahler et al, 2002^Citation15	674	24	FP/SAL (500/50 μg bid) SAL (50 μg bid) FP (500 μg bid) PLB bid	63	66	41	Yes	Yes	NR	Unclear	Unclear	Yes
Calverley et al, 2003^Citation16	1,465	52	FP/SAL (500/50 μg bid) SAL (50 μg bid) FP (500 μg bid) PLB bid	63	73	45	Yes	Yes	NR	Yes	Yes	Yes
Calverley et al, 2003^Citation17	1,022	52	BUD/FM (320/9 μg bid) FM (9 μg bid) BUD (400 μg bid) PLB bid	64	76	36	Yes	Yes	Yes	Unclear	Unclear	Yes
Hanania et al, 2003^Citation18	723	24	FP/SAL (250/50 μg bid) SAL (50 μg bid) FP (250 μg bid) PLB bid	64	63	42	Yes	Yes	NR	Unclear	Unclear	Yes
Szafranski et al, 2003^Citation19	812	52	BUD/FM (320/9 μg bid) FM (9 μg bid) BUD (400 μg bid) PLB bid	64	79	36	Yes	Yes	NR	Yes	Yes	Yes
SFCT0I study, 2005^Citation12	387	52	FP/SAL (250/50 μg bid) SAL (50 μg bid) FP (250 μg bid) PLB bid	64	80	NR	Yes	Yes	Yes	Unclear	Unclear	Yes
Calverley et al, 2007^Citation5	6,112	156	FP/SAL (500/50 μg bid) SAL (50 μg bid) FP (500 μg bid) PLB bid	65	76	44	Yes	Yes	Yes	Yes	Yes	Yes
Kardos et al, 2007^Citation20	994	44	FP/SAL (500/50 μg bid) SAL (50 μg bid)	64	76	40	Yes	Yes	Yes	Yes	Yes	Yes
Zheng et al, 2007^Citation21	445	24	FP/SAL (500/50 μg bid) PLB bid	66	89	47	Yes†	Yes	Yes	Unclear	Unclear	Yes
Ferguson et al, 2008^Citation22	776	52	FP/SAL (250/50 μg bid) SAL (50 μg bid)	65	55	33	No	Yes	NR	Yes	Unclear	Yes
Tashkin et al, 2008^Citation23	1,417	24	BUD/FM (160–320/9 μg bid) FM (9 μg bid) BUD (320 μg bid) PLB bid	63	69	40	No	Yes	Yes	Unclear	Yes	Yes
Anzueto et al, 2009^Citation24	778	52	FP/SAL (250/50 μg bid) SAL (50 μg bid)	65	54	34	No	Yes	NR	Unclear	Unclear	Yes
Rennard et al, 2009^Citation25	1,964	52	BUD/FM (160–320/9 μg bid) FM (9 μg bid) PLB bid	63	64	40	No	Yes	NR	Unclear	Yes	Yes
Calverley et al, 2010^Citation26	718	48	BDP/FM (400–800/24 μg bid) FM 24 bid	64	81	42	Yes	Yes	Yes	Yes	Yes	Yes
SUMIRE study, 2011^Citation13	1,293	12	BUD/FM (320/9 μg bid) FM (9 μg bid)	65	89	36	No	Yes	Yes	Unclear	Unclear	Yes
Sharafkhaneh et al, 2012^Citation27	851	52	BUD/FM (160–320/9 μg bid) FM (9 μg bid)	63	62	38¶	No	Yes	Yes	Yes	Unclear	Yes
Tashkin et al, 2012^Citation28	2,251	26	MF/FM (200–400/10 μg bid) MF (400 μg bid) FM (10 μg bid) PLB bid	60	76	39	Yes	Yes	Yes	Yes	Unclear	Yes
Zhong et al, 2012^Citation29	308	24	BUD/FM (160/4.5 μg bid) BUD (200 μg bid)	65	95	33	No	Yes	NR	Unclear	Yes	Yes
Dransfield et al, 2013^Citation14	1,624	52	FF/VI (100/25 μg qd) VI (25 μg qd)	64	58	45	Yes†	Yes	Yes	Yes	Yes	Yes
Kerwin et al, 2013^Citation31	1,030	24	FF/VI (100–200/25 μg qd) FF (100) VI (25 μg qd) PLB qd	63	67	43	Yes	Yes	Yes	Yes	Yes	Yes
Martinez et al, 2013^Citation30	1,224	24	FF/VI (100–200/25 μg qd) FF (100–200 μg qd) VI (25 μg qd) PLB qd	62	72	44	Yes	Yes	Yes	Yes	Yes	Yes

¶ Notes: Postbronchodilator;

† less than 12 hours LTOT was allowed.

Abbreviations: BDP, beclomethasone dipropionate; bid, twice a day; BUD, budesonide; FEV₁, forced expiratory volume in I second; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; ITT, intention to treat; LTOT, long-term oxygen therapy; MF, mometasone furoate; NR, not reported; PLB, placebo; qd, once a day; SAL, salmeterol; VI, vilanterol.

Figure 1 Flow of study selection.

Figure 2 Diagram displaying the network of eight arms involved in the Bayesian analyses.

Notes: The links between nodes are used to indicate a direct comparison between pairs of treatments. The numbers shown along the link lines indicate the number of trials comparing pairs of treatments head-to-head.
Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; ICS, inhaled corticosteroids; LABA, long-acting beta agonists; MF, mometasone furoate; PLB, placebo; SAL, salmeterol; VI, vilanterol.

Figure 3 Pooled effect estimate on moderate-to-severe exacerbations for all combined inhalers versus placebo.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; MF, mometasone furoate; SAL, salmeterol; VI, vilanterol.

Figure 4 Pooled effect estimate on moderate-to-severe exacerbations for all combined inhalers versus long acting beta-agonist.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; MF, mometasone furoate; SAL, salmeterol; VI, vilanterol.

Figure 5 Pooled effect estimate on severe exacerbations for all combined inhalers versus placebo.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; MF, mometasone furoate; SAL, salmeterol; VI, vilanterol.

Figure 6 Pooled effect estimate on severe exacerbations for all combined inhalers versus long acting beta-agonist.

Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; FF, fluticasone furoate; FM, formoterol; FP, fluticasone propionate; MF, mometasone furoate; SAL, salmeterol; VI, vilanterol.

Table S1 Definitions of COPD exacerbations in the included trials

Study, year	Moderate	Severe
Mahler et al, 2002^Citation15	Requiring either oral antibiotics and/or corticosteroids	Requiring in-hospital admission for a COPD exacerbation
Calverley et al, 2003^Citation16	Worsening of COPD symptoms that required treatment with antibiotics, oral corticosteroids, or both	Requiring hospitalization
Calverley et al, 2003^Citation17	Requiring medical intervention (oral antibiotics and/or corticosteroids)	Requiring hospitalization
Hanania et al, 2003^Citation18	Requiring treatment with antibiotics and/or corticosteroids	Requiring hospitalization
Szafranski et al, 2003^Citation19	Requiring antibiotics and/or oral corticosteroids	Requiring hospitalization
SFCT01 study, 2005^Citation12	Requiring treatment with antibiotics and/or oral corticosteroids	Requiring emergency hospital treatment and hospitalization
Calverley et al, 2007^Citation5	Requiring treatment with antibiotic agents and/or systemic corticosteroids	Requiring hospitalization
Kardos et al, 2007^Citation20	Requiring both a change of respiratory medication (increased dose of prescribed or addition of new drugs, ie, antibiotics, mucolytics, systemic steroids, theophylline), and medical assistance	Deterioration in COPD resulting in hospitalization or emergency room treatment
Zheng et al, 2007^Citation21	Worsening of symptoms that required treatment with antibiotics or oral corticosteroids	Worsening of symptoms that required hospitalization
Ferguson et al, 2008^Citation22	Requiring treatment with oral corticosteroids or antibiotics	Requiring hospitalization
Tashkin et al, 2008^Citation23	Requiring treatment with oral corticosteroids	Requiring hospitalization
Anzueto et al, 2009^Citation24	Requiring antibiotics and/or oral corticosteroids	Requiring hospitalization
Rennard et al, 2009^Citation25	Requiring an oral corticosteroid	Requiring hospitalization
Calverley et al, 2010^Citation26	Need for treatment with oral corticosteroids and/or antibiotics	Need to visit or be admitted to a hospital
SUMIRE study, 2011^Citation13	Requiring treatment with a course of systemic steroid	Requiring hospitalization
Sharafkhaneh et al, 2012^Citation27	Requiring antibiotics and/or oral corticosteroids	Requiring hospitalization
Tashkin et al, 2012^Citation28	Requiring antibiotic and/or oral steroid treatment	Requiring emergency treatment or hospitalization
Zhong et al, 2012^Citation29	Requiring oral/intravenous corticosteroids and/or antibiotics	Requiring emergency room treatment or hospitalization
Dransfield et al, 2013^Citation14	Necessitating treatment with oral corticosteroids or antibiotics or both	Necessitating hospital admission
Kerwin et al, 2013^Citation31	Requiring systemic corticosteroids and/or antibiotics	Requiring hospitalization
Martinez et al, 2013^Citation30	Requiring systemic corticosteroids and/or antibiotics	Requiring hospitalization

Abbreviation: COPD, chronic obstructive pulmonary disease.

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