Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease

Kayleigh M Kew; Alieksei Seniukovich

doi:10.1002/14651858.CD010115.pub2

Cochrane Database of Systematic Reviews

Esteroides inhalados y riesgo de neumonía para la enfermedad pulmonar obstructiva crónica

Information

DOI:

https://doi.org/10.1002/14651858.CD010115.pub2 Copy DOI

Database:

Cochrane Database of Systematic Reviews

Version published:

10 March 2014see what's new

Type:

Intervention

Stage:

Review

Cochrane Editorial Group:

Cochrane Airways Group

Copyright:

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

Article metrics

Altmetric:

Cited by:

Cited 0 times via Crossref Cited-by Linking

Collapse

Authors

Kayleigh M Kew

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

[email protected]
Alieksei Seniukovich

Grodno Clinic Hospital #2, Grodno, Belarus

Contributions of authors

Alieksei Seniukowich and Kayleigh Kew extracted data. Kayleigh conducted the analysis, interpreted the data and wrote up the results, with clinical input from Alieksei.

Charlotta Karner, authored the protocol, sifted the search and contributed to data extraction.

Sources of support

Internal sources

NIHR, UK.

This review is supported by a programme grant from NIHR.

External sources

No sources of support supplied

Declarations of interest

None known.

Acknowledgements

We are grateful to Elizabeth Stovold for her help in designing the search strategy and to Charlotta Karner for her role in study selection and data extraction.

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 review authors and do not necessarily reflect those of NIHR, NHS or the Department of Health.

Julia Walters was the Editor for this review and commented critically on the review.

Version history

Published

Title

Stage

Authors

Version

2014 Mar 10

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease

Review

Kayleigh M Kew, Alieksei Seniukovich

https://doi.org/10.1002/14651858.CD010115.pub2

2012 Sep 12

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease

Protocol

Charlotta Karner, Aliaksei Seniukovich

https://doi.org/10.1002/14651858.CD010115

Differences between protocol and review

The subgroup analysis stated in the protocol based on diagnostic criteria for pneumonia could not be conducted, as most trials did not state the definition. We included studies using fluticasone furoate, alone or in combination with the LABA vilanterol; these new formulations were not anticipated during the writing of the protocol. For reasons explained in the review, we chose not to calculate an indirect comparison of fluticasone/LABA versus budesonide LABA.

We added the following additional comparisons: fluticasone furoate/vilanterol versus vilanterol; fluticasone/vilanterol versus budesonide/formoterol.

We added to the methods a section on assessing transitivity.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans; Male; Middle Aged;

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Figure 1

Direct and indirect comparisons of fluticasone and budesonide covered in the review.

Navigate to figure in ReviewOpen in new tab

Figure 2

Study flow diagram.

Navigate to figure in ReviewOpen in new tab

Figure 3

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

Navigate to figure in ReviewOpen in new tab

Figure 4

Summary of pooled effects of trials comparing ICS versus placebo and combination versus LABA.
Non‐fatal serious adverse pneumonia events were those requiring hospital admission. Data for all pneumonia events were not pooled because of heterogeneity.

Navigate to figure in ReviewOpen in new tab

Figure 5

Indirect comparisons of fluticasone and budesonide monotherapy.

Non‐fatal serious adverse pneumonia events were defined as those requiring hospital admission.

Navigate to figure in ReviewOpen in new tab

Figure 6

Indirect comparisons of fluticasone and budesonide monotherapy—Sensitivity analysis removing (Calverley 2007 TORCH).

Navigate to figure in ReviewOpen in new tab

Analysis 1.1

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 1 Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 1.2

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 2 Mortality, all‐cause.

Navigate to figure in ReviewOpen in new tab

Analysis 1.3

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 3 Mortality, due to pneumonia.

Navigate to figure in ReviewOpen in new tab

Analysis 1.4

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 4 Non‐fatal, serious adverse events (all).

Navigate to figure in ReviewOpen in new tab

Analysis 1.5

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 5 All pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 1.6

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 6 Withdrawals.

Navigate to figure in ReviewOpen in new tab

Analysis 2.1

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 1 Dose—Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 2.2

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 2 Duration—Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 3 % FEV1 predicted normal—Non‐fatal, serious adverse pneumonia events.

Analysis 2.3

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 3 % FEV₁ predicted normal—Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 3.1

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 1 Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 3.2

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 2 Mortality, all‐cause.

Navigate to figure in ReviewOpen in new tab

Analysis 3.3

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 3 Mortality, due to pneumonia.

Navigate to figure in ReviewOpen in new tab

Analysis 3.4

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 4 Non‐fatal, serious adverse events (all).

Navigate to figure in ReviewOpen in new tab

Analysis 3.5

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 5 All pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 3.6

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 6 Withdrawals.

Navigate to figure in ReviewOpen in new tab

Analysis 4.1

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 1 Dose ‐ Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 4.2

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 2 Duration ‐ Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 3 % FEV1 predicted normal ‐ Non‐fatal, serious adverse pneumonia events.

Analysis 4.3

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 3 % FEV₁ predicted normal ‐ Non‐fatal, serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Analysis 5.1

Comparison 5 Sensitivity analysis—risk of bias, Outcome 1 Non‐fatal serious adverse pneumonia events.

Navigate to figure in ReviewOpen in new tab

Summary of findings for the main comparison. Fluticasone for chronic obstructive pulmonary disease

Fluticasone for chronic obstructive pulmonary disease
Patient or population: patients with chronic obstructive pulmonary disease Intervention: fluticasone (alone or with LABA co‐intervention) Comparison: placebo or LABA monotherapy (dependent upon whether fluticasone was given with LABA in the intervention group) Setting: community
Outcomes Follow‐ups presented as weighted means	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Fluticasone
Non‐fatal, serious adverse pneumonia events (requiring hospital admission) Follow‐up: 18 months	25 per 1000	43 per 1000 (37 to 51)	OR 1.78 (1.50 to 2.12)	19,504 (17 studies)	⊕⊕⊕⊕ high
Mortality, all‐cause Follow‐up: 19 months	58 per 1000	58 per 1000 (51 to 65)	OR 0.99 (0.87 to 1.13)	20,861 (22 studies)	⊕⊕⊕⊕ high
Mortality, due to pneumonia Follow‐up: 18 months	2 per 1000	3 per 1000 (2 to 5)	OR 1.23 (0.70 to 2.15)	19,532 (18 studies)	⊕⊕⊕⊝ moderate¹
Non‐fatal, serious adverse events (all) Follow‐up: 19 months	227 per 1000	237 per 1000 (225 to 251)	OR 1.06 (0.99 to 1.14)	20,381 (19 studies)	⊕⊕⊕⊕ high
All pneumonia events Follow‐up: 22 months	72 per 1000	116 per 1000 (104 to 129)	OR 1.68 (1.49 to 1.90)	15,377 (11 studies)	⊕⊕⊕⊝ moderate²
Withdrawals Follow‐up: 18 months	343 per 1000	297 per 1000 (286 to 310)	OR 0.81 (0.77 to 0.86)	21,243 (26 studies)	⊕⊕⊕⊕ high
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio. Unless otherwise stated, subgroup differences between monotherapy studies (fluticasone versus placebo) and combination therapy studies (fluticasone/LABA versus LABA) were not significant.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Wide confidence intervals include significant benefit and harm, based on very few events (‐1 for imprecision). ²More than half the studies did not report the outcome (‐1 for publication bias).

Summary of findings for the main comparison. Fluticasone for chronic obstructive pulmonary disease

Navigate to table in Review

Summary of findings 2. Budesonide for chronic obstructive pulmonary disease

Budesonide for chronic obstructive pulmonary disease
Patient or population: patients with chronic obstructive pulmonary disease Intervention: budesonide (alone or with LABA co‐intervention) Comparison: placebo or LABA monotherapy (dependent upon whether fluticasone was given with LABA in the intervention group) Setting: community
Outcomes Follow‐ups presented as weighted means	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Budesonide
Non‐fatal, serious adverse pneumonia events (requiring hospital admission) Follow‐up: 9 months	9 per 1000	15 per 1000 (9 to 24)	OR 1.62 (1.00 to 2.62)	6472 (7 studies)	⊕⊕⊕⊝ moderate^1,2
Mortality, all‐cause Follow‐up: 14 months	17 per 1000	16 per 1000 (11 to 21)	OR 0.90 (0.65 to 1.24)	10,009 (12 studies)	⊕⊕⊕⊝ moderate³
Mortality, due to pneumonia Follow‐up: 12 months	0 per 1000	0 per 1000 (0 to 0)	OR 4.46 (0.07 to 286.99)	1511 (3 studies)	⊕⊝⊝⊝ very low^2, ⁴
Non‐fatal, serious adverse events (all) Follow‐up: 14 months	145 per 1000	146 per 1000 (124 to 172)	OR 1.01 (0.83 to 1.22)	10,009 (12 studies)	⊕⊕⊕⊝ moderate⁵
All pneumonia events Follow‐up: 10 months	28 per 1000	31 per 1000 (23 to 41)	OR 1.12 (0.83 to 1.51)	7011 (6 studies)	⊕⊕⊕⊝ moderate^1,2
Withdrawals Follow‐up: 14 months	280 per 1000	232 per 1000 (216 to 248)	OR 0.78 (0.71 to 0.85)	10150 (15 studies)	⊕⊕⊕⊕ high
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; OR: Odds ratio. Unless otherwise stated, subgroup differences between monotherapy studies (budesonide versus placebo) and combination therapy studies (budesonide/LABA versus LABA) were not significant.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹Confidence intervals are quite wide but are not considered serious enough to downgrade. ²More than half the studies did not report the outcome (‐1 for publication bias). ³Confidence interval includes significant benefit and potential harm. ⁴Very wide confidence intervals. Only one death observed over the three studies (‐2 for imprecision). ⁵I² = 59%, P value 0.002 (‐1 for inconsistency).

Summary of findings 2. Budesonide for chronic obstructive pulmonary disease

Navigate to table in Review

Table 1. Fluticasone—summary of studies and baseline characteristics

Study ID	Duration (m)	N Rand	Funder	ICS dose (mcg)	% Male	Mean age	Pack‐years	% pred FEV₁
Fluticasone versus placebo (n = 18)
Bourbeau 2007	3	41	GSK	1000	78	65	53	57
Burge 2000	36	740	GSK	1000	75	64	44	50
Calverley 2003 TRISTAN^a	12	763	GSK	1000	73	63	43	45
Calverley 2007 TORCH^a	36	3097	GSK	1000	76	65	49	44
Choudhury 2005	12	260	Indep.	1000	52	67	39	54
GSK FLTA3025 2005	6	640	GSK	500, 1000	69	64	‐	‐
GSK SCO104925 2008^a	3	84	GSK	1000	77	64	‐	‐
GSK SCO30002 2005	12	256	GSK	1000	82	65	‐	‐
Hanania 2003^a	6	368	GSK	500	63	64	57	42
Hattotuwa 2002	3	36	GSK	1000	87	65	63	46
Kerwin 2013^a,b	6	413	GSK	100	66	62	46	42
Lapperre 2009	30	55	GSK	1000	86	60	43	55
Mahler 2002^a	6	349	GSK	1000	66	65	55	41
Martinez 2013^a,b	6	612	GSK	100, 200	72	62	43	48
Paggiaro 1998	6	281	‐	1000	74	63	‐	57
Schermer 2009	36	190	Indep.	1000	71	59	28	64
van Grunsven 2003	24	48	GSK	500	52	47	9	97
Verhoeven 2002	6	23	GSK	1000	82	55	26	63
	WM 22 m	459	‐	‐	72	62	43	54
Fluticasone/LABA combination versus LABA monotherapy (n = 15)
Anzueto 2009	12	797	GSK	500	54	65	57	34
Calverley 2003 TRISTAN^a	12	731	GSK	1000	73	63	43	45
Calverley 2007 TORCH^a	36	3088	GSK	1000	76	65	49	44
Dal Negro 2003	12	12	‐	500	92	‐	42	50
Dransfield 2013^b	12	3255	GSK	50, 100, 200	57	64	‐	45
Ferguson 2008	12	782	GSK	500	55	65	56	33
GSK FCO30002 2005	3	140	GSK	1000	66	62	‐	‐
GSK SCO100470 2006	6	1050	GSK	500	78	64	‐	‐
GSK SCO104925 2008^a	3	77	GSK	1000	77	64	‐	‐
GSK SCO40041 2008	36	186	GSK	500	61	66	‐	‐
Hanania 2003^a	6	355	GSK	500	63	64	57	42
Kardos 2007	10	994	GSK	1000	76	64	37	40
Kerwin 2013^a,b	6	617	GSK	100	67	63	46	43
Mahler 2002^a	6	325	GSK	1000	66	65	55	41
Martinez 2013^a,b	6	610	GSK	100, 200	72	62	43	48
	WM 16 m	867	‐	‐	69	64	53	42
^aMulti‐arm studies making both comparisons of interest (ICS vs placebo and ICS/LABA vs LABA). ^bStudies using vilanterol as the LABA combination and monotherapy comparator, with fluticasone furoate. Dose is given as the total received per day (i.e. 500 signifies 250 morning and evening). WM = weighted mean.

Table 1. Fluticasone—summary of studies and baseline characteristics

Navigate to table in Review

Table 2. Budesonide—summary of studies and baseline characteristics

Study ID	Duration (m)	N Rand	Funder	ICS dose (mcg)	% Male	Mean age	Pack‐years	% pred FEV₁
Budesonide versus placebo (n = 13)
Bourbeau 1998	6	79	AZ	640	79	66	51	37
Calverley 2003b^a	12	513	GSK	640	76	64	35	36
Laptseva 2002	6	49	NR	640	NR	NR	NR	NR
Mirici 2001	3	50	NR	640	75	53	27	62
Ozol 2005	6	26	NR	640	69	65	45	59
Pauwels 1999	36	1277	AZ	640	73	52	39	77
Renkema 1996	24	39	AZ	1280	100	55	NR	64
Senderovitz 1999	6	26	NR	640	54	61	NR	NR
Shaker 2009	36	254	AZ	640	58	64	56	52
Szafranski 2003^a	12	403	AZ	640	79	64	45	36
Tashkin 2008 SHINE^a	6	575	AZ	640	68	63	41	40
Vestbo 1999	36	290	AZ	640	88	59	NR	87
Yildiz 2004	3	38	?	1280	100	67	51	46
	WM 23 m	278	‐	‐	77	61	43	54
Budesonide/LABA combination versus LABA monotherapy (n = 7)
Calverley 2003b^a	12	509	GSK	640	76	64	35	36
Calverley 2010	11	481	Chiesi	640	81	64	39	42
Fukuchi 2013	3	1293	AZ	640	89	65	44	41
Rennard 2009	12	1483	AZ	320, 640	63	63	NR	39
Sharafkhaneh 2012	12	1219	AZ	320, 640	62	63	44	38
Szafranski 2003^a	12	409	AZ	640	79	64	45	36
Tashkin 2008 SHINE^a	6	1129	AZ	320, 640	68	63	41	40
	WM 9 m	932	‐	‐	75	64	41	39
^aMulti‐arm studies making both comparisons of interest (ICS vs placebo and ICS/LABA vs LABA). Dose is given as the total received per day (i.e. 640 signifies 320 morning and evening). WM = weighted mean.

Table 2. Budesonide—summary of studies and baseline characteristics

Navigate to table in Review

Table 3. BDP equivalent doses

Drug	Daily dose (mcg)	BDP equivalent (mcg)
Budesonide	320	320
	640	640
	1280	1280
Fluticasone	500 (propionate)	1000
	1000 (propionate)	2000
	50 (furoate)	500
	100 (furoate)	1000
	200 (furoate)	2000

Table 3. BDP equivalent doses

Navigate to table in Review

Table 4. Control group event rates

	Monotherapy comparison—Placebo control events		Combination comparison—LABA control events
	Fluticasone	Budesonide	Fluticasone	Budesonide
Pneumonia‐related serious adverse events	2.5%, 77/310	0.9%, 4/445	2.5%, 134/5420	0.9%, 19/2079
	0.5% without TORCH		0.7% without TORCH
All‐cause mortality	7.6%, 282/3713	2.1%, 37/1763	5.1%, 254/5489	1.5%, 37/2534
	2.4% without TORCH		1.2% without TORCH
All‐cause serious adverse events	25%, 882/3471	15%, 268/1763	21%, 1152/5489	14%, 356/2534
	14% without TORCH		14% without TORCH
For the fluticasone control groups with and without the large 3‐year TORCH study.

Table 4. Control group event rates

Navigate to table in Review

Comparison 1. Fluticasone versus controls (all outcomes by treatment)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐fatal, serious adverse pneumonia events Show forest plot	17	19504	Odds Ratio (M‐H, Fixed, 95% CI)	1.78 [1.50, 2.12]

1.1 Fluticasone versus placebo	11	6635	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [1.39, 2.44]
1.2 Fluticasone/LABA versus LABA	13	12869	Odds Ratio (M‐H, Fixed, 95% CI)	1.75 [1.41, 2.17]
2 Mortality, all‐cause Show forest plot	22	20861	Odds Ratio (M‐H, Fixed, 95% CI)	0.99 [0.87, 1.13]

2.1 Fluticasone versus placebo	15	7857	Odds Ratio (M‐H, Fixed, 95% CI)	1.05 [0.88, 1.25]
2.2 Fluticasone/LABA versus LABA	14	13004	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.78, 1.12]
3 Mortality, due to pneumonia Show forest plot	18	19532	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.23 [0.70, 2.15]

3.1 Fluticasone versus placebo	12	6665	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.20 [0.52, 2.77]
3.2 Fluticasone/LABA versus LABA	13	12867	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.25 [0.59, 2.65]
4 Non‐fatal, serious adverse events (all) Show forest plot	19	20381	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.99, 1.14]

4.1 Fluticasone versus placebo	12	7377	Odds Ratio (M‐H, Fixed, 95% CI)	1.07 [0.95, 1.20]
4.2 Fluticasone/LABA versus LABA	14	13004	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.96, 1.16]
5 All pneumonia events Show forest plot	11	15377	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [1.49, 1.90]

5.1 Fluticasone versus placebo	6	4971	Odds Ratio (M‐H, Fixed, 95% CI)	1.62 [1.33, 1.97]
5.2 Fluticasone/LABA versus LABA	9	10406	Odds Ratio (M‐H, Fixed, 95% CI)	1.72 [1.47, 2.01]
6 Withdrawals Show forest plot	26	21243	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.77, 0.86]

6.1 Fluticasone versus placebo	18	8227	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.70, 0.84]
6.2 Fluticasone/LABA versus LABA	15	13016	Odds Ratio (M‐H, Fixed, 95% CI)	0.85 [0.79, 0.92]

Comparison 1. Fluticasone versus controls (all outcomes by treatment)

Navigate to table in Review

Comparison 2. Subgroup analyses—fluticasone versus controls

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dose—Non‐fatal, serious adverse pneumonia events Show forest plot	17	19504	Odds Ratio (M‐H, Fixed, 95% CI)	1.76 [1.48, 2.08]

1.1 Fluticasone propionate 500 mcg (250 mcg bid)	6	3857	Odds Ratio (M‐H, Fixed, 95% CI)	1.46 [0.91, 2.36]
1.2 Fluticasone propionate 1000 mcg (500 mcg bid)	9	10138	Odds Ratio (M‐H, Fixed, 95% CI)	1.78 [1.47, 2.16]
1.3 Fluticasone furoate 50 mcg	2	1366	Odds Ratio (M‐H, Fixed, 95% CI)	2.10 [0.73, 6.06]
1.4 Fluticasone furoate 100 mcg	3	2447	Odds Ratio (M‐H, Fixed, 95% CI)	1.61 [0.70, 3.70]
1.5 Fluticasone furoate 200 mcg	2	1696	Odds Ratio (M‐H, Fixed, 95% CI)	2.38 [0.87, 6.51]
2 Duration—Non‐fatal, serious adverse pneumonia events Show forest plot	17	19504	Odds Ratio (M‐H, Fixed, 95% CI)	1.79 [1.51, 2.12]

2.1 Duration ≤ one year	14	13078	Odds Ratio (M‐H, Fixed, 95% CI)	1.91 [1.39, 2.63]
2.2 Duration > one year	3	6426	Odds Ratio (M‐H, Fixed, 95% CI)	1.74 [1.42, 2.13]
3 % FEV₁ predicted normal—Non‐fatal, serious adverse pneumonia events Show forest plot	12	17211	Odds Ratio (M‐H, Fixed, 95% CI)	1.82 [1.53, 2.17]

3.1 FEV1 < 50% predicted	10	17133	Odds Ratio (M‐H, Fixed, 95% CI)	1.84 [1.55, 2.20]
3.2 FEV1 ≥ 50% predicted	2	78	Odds Ratio (M‐H, Fixed, 95% CI)	0.21 [0.01, 4.53]

Comparison 2. Subgroup analyses—fluticasone versus controls

Navigate to table in Review

Comparison 3. Budesonide versus controls (all outcomes by treatment)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐fatal, serious adverse pneumonia events Show forest plot	7	6472	Odds Ratio (M‐H, Fixed, 95% CI)	1.62 [1.00, 2.62]

1.1 Budesonide versus placebo	3	867	Odds Ratio (M‐H, Fixed, 95% CI)	3.47 [1.11, 10.83]
1.2 Budesonide/formoterol versus formoterol	5	5605	Odds Ratio (M‐H, Fixed, 95% CI)	1.33 [0.78, 2.28]
2 Mortality, all‐cause Show forest plot	12	10009	Odds Ratio (M‐H, Fixed, 95% CI)	0.90 [0.65, 1.24]

2.1 Budesonide versus placebo	8	3487	Odds Ratio (M‐H, Fixed, 95% CI)	0.85 [0.52, 1.37]
2.2 Budesonide/formoterol versus formoterol	7	6522	Odds Ratio (M‐H, Fixed, 95% CI)	0.94 [0.61, 1.46]
3 Mortality, due to pneumonia Show forest plot	3	1511	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.46 [0.07, 286.99]

3.1 Budesonide versus placebo	2	292	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Budesonide/formoterol versus formoterol	1	1219	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.46 [0.07, 286.99]
4 Non‐fatal, serious adverse events (all) Show forest plot	12	10009	Odds Ratio (M‐H, Random, 95% CI)	1.01 [0.83, 1.22]

4.1 Budesonide versus placebo	8	3487	Odds Ratio (M‐H, Random, 95% CI)	1.02 [0.69, 1.50]
4.2 Budesonide/formoterol versus formoterol	7	6522	Odds Ratio (M‐H, Random, 95% CI)	0.93 [0.78, 1.11]
5 All pneumonia events Show forest plot	6	7011	Odds Ratio (M‐H, Fixed, 95% CI)	1.12 [0.83, 1.51]

5.1 Budesonide versus placebo	3	1378	Odds Ratio (M‐H, Fixed, 95% CI)	0.87 [0.50, 1.50]
5.2 Budesonide/formoterol versus formoterol	5	5633	Odds Ratio (M‐H, Fixed, 95% CI)	1.24 [0.87, 1.77]
6 Withdrawals Show forest plot	15	10150	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.71, 0.85]

6.1 Budesonide versus placebo	11	3627	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.69, 0.93]
6.2 Budesonide/formoterol versus formoterol	7	6523	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.67, 0.86]

Comparison 3. Budesonide versus controls (all outcomes by treatment)

Navigate to table in Review

Comparison 4. Subgroup analyses—budesonide versus controls

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dose ‐ Non‐fatal, serious adverse pneumonia events Show forest plot	7	6472	Odds Ratio (M‐H, Fixed, 95% CI)	1.54 [0.96, 2.48]

1.1 Budesonide 320 mcg (160 mcg bid)	3	1775	Odds Ratio (M‐H, Fixed, 95% CI)	0.68 [0.27, 1.71]
1.2 Budesonide 640 mcg (320 mcg bid)	6	4659	Odds Ratio (M‐H, Fixed, 95% CI)	2.02 [1.15, 3.57]
1.3 Budesonide 1280 mcg (640 mcg bid)	1	38	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Duration ‐ Non‐fatal, serious adverse pneumonia events Show forest plot	7	6471	Odds Ratio (M‐H, Fixed, 95% CI)	1.62 [1.00, 2.62]

2.1 Duration ≤ one year	6	6217	Odds Ratio (M‐H, Fixed, 95% CI)	1.41 [0.83, 2.37]
2.2 Duration > one year	1	254	Odds Ratio (M‐H, Fixed, 95% CI)	3.53 [0.95, 13.15]
3 % FEV₁ predicted normal ‐ Non‐fatal, serious adverse pneumonia events Show forest plot	7	6471	Odds Ratio (M‐H, Fixed, 95% CI)	1.60 [0.99, 2.59]

3.1 FEV1 < 50% predicted	6	6217	Odds Ratio (M‐H, Fixed, 95% CI)	1.39 [0.82, 2.34]
3.2 FEV1 ≥ 50% predicted	1	254	Odds Ratio (M‐H, Fixed, 95% CI)	3.53 [0.95, 13.15]

Comparison 4. Subgroup analyses—budesonide versus controls

Navigate to table in Review

Comparison 5. Sensitivity analysis—risk of bias

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐fatal serious adverse pneumonia events Show forest plot	16		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Fluticasone versus control	12	16338	Odds Ratio (M‐H, Fixed, 95% CI)	1.82 [1.52, 2.19]
1.2 Budesonide versus control	4	3515	Odds Ratio (M‐H, Fixed, 95% CI)	3.28 [1.22, 8.81]

Comparison 5. Sensitivity analysis—risk of bias

Navigate to table in Review

The Cochrane Library

Scolaris Language Selector Scolaris Language Selector

Cochrane Review language

Website language

Scolaris Content Language Banner Portlet Scolaris Content Language Banner Portlet

Scolaris Content Display Scolaris Content Display

Esteroides inhalados y riesgo de neumonía para la enfermedad pulmonar obstructiva crónica

Information

Article metrics

Altmetric:

Cited by:

Authors

Contributions of authors

Sources of support

Internal sources

External sources

Declarations of interest

Acknowledgements

Version history

Differences between protocol and review

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

PICOs

PICOs

Population

Intervention

Comparison

Outcome

Scolaris Language Selector Scolaris Language Selector

Scolaris Content Display Scolaris Content Display

Previously accessed institutions

Scolaris Content Display Scolaris Content Display

Institutional users

Previously accessed institutions

Other access options

Cochrane Review language

Website language

Information

Article metrics

Altmetric:

Cited by:

Authors

Contributions of authors

Sources of support

Internal sources

External sources

Declarations of interest

Acknowledgements

Version history

Differences between protocol and review

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

PICOs

PICOs

Population

Intervention

Comparison

Outcome

Copy or download citation

Cochrane Review language

Website language

Previously accessed institutions

Institutional users

Previously accessed institutions

Other access options