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Cochrane Database of Systematic Reviews

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease

Information

DOI:
https://doi.org/10.1002/14651858.CD010115.pub2Copy DOI
Database:
  1. Cochrane Database of Systematic Reviews
Version published:
  1. 10 March 2014see what's new
Type:
  1. Intervention
Stage:
  1. Review
Cochrane Editorial Group:
  1. Cochrane Airways Group

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

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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

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.

Direct and indirect comparisons of fluticasone and budesonide covered in the review.
Figures and Tables -
Figure 1

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

Study flow diagram.
Figures and Tables -
Figure 2

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 3

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

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.
Figures and Tables -
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.

Indirect comparisons of fluticasone and budesonide monotherapy.Non‐fatal serious adverse pneumonia events were defined as those requiring hospital admission.
Figures and Tables -
Figure 5

Indirect comparisons of fluticasone and budesonide monotherapy.

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

Indirect comparisons of fluticasone and budesonide monotherapy—Sensitivity analysis removing (Calverley 2007 TORCH).
Figures and Tables -
Figure 6

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

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 1 Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 1.1

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

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 2 Mortality, all‐cause.
Figures and Tables -
Analysis 1.2

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

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 3 Mortality, due to pneumonia.
Figures and Tables -
Analysis 1.3

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

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 4 Non‐fatal, serious adverse events (all).
Figures and Tables -
Analysis 1.4

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

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 5 All pneumonia events.
Figures and Tables -
Analysis 1.5

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

Comparison 1 Fluticasone versus controls (all outcomes by treatment), Outcome 6 Withdrawals.
Figures and Tables -
Analysis 1.6

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

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 1 Dose—Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 2.1

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

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 2 Duration—Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 2.2

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

Comparison 2 Subgroup analyses—fluticasone versus controls, Outcome 3 % FEV1 predicted normal—Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 2.3

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

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 1 Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 3.1

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

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 2 Mortality, all‐cause.
Figures and Tables -
Analysis 3.2

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

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 3 Mortality, due to pneumonia.
Figures and Tables -
Analysis 3.3

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

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 4 Non‐fatal, serious adverse events (all).
Figures and Tables -
Analysis 3.4

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

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 5 All pneumonia events.
Figures and Tables -
Analysis 3.5

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

Comparison 3 Budesonide versus controls (all outcomes by treatment), Outcome 6 Withdrawals.
Figures and Tables -
Analysis 3.6

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

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 1 Dose ‐ Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 4.1

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

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 2 Duration ‐ Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 4.2

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

Comparison 4 Subgroup analyses—budesonide versus controls, Outcome 3 % FEV1 predicted normal ‐ Non‐fatal, serious adverse pneumonia events.
Figures and Tables -
Analysis 4.3

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

Comparison 5 Sensitivity analysis—risk of bias, Outcome 1 Non‐fatal serious adverse pneumonia events.
Figures and Tables -
Analysis 5.1

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

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).

Figures and Tables -
Summary of findings for the main comparison. Fluticasone for chronic obstructive pulmonary disease
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)

⊕⊕⊕⊝
moderate1,2

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 low2, 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)

⊕⊕⊕⊝
moderate1,2

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).

Figures and Tables -
Summary of findings 2. Budesonide for chronic obstructive pulmonary disease
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 TRISTANa

12

763

GSK

1000

73

63

43

45

Calverley 2007 TORCHa

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 2008a

3

84

GSK

1000

77

64

GSK SCO30002 2005

12

256

GSK

1000

82

65

Hanania 2003a

6

368

GSK

500

63

64

57

42

Hattotuwa 2002

3

36

GSK

1000

87

65

63

46

Kerwin 2013a,b

6

413

GSK

100

66

62

46

42

Lapperre 2009

30

55

GSK

1000

86

60

43

55

Mahler 2002a

6

349

GSK

1000

66

65

55

41

Martinez 2013a,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 TRISTANa

12

731

GSK

1000

73

63

43

45

Calverley 2007 TORCHa

36

3088

GSK

1000

76

65

49

44

Dal Negro 2003

12

12

500

92

42

50

Dransfield 2013b

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 2008a

3

77

GSK

1000

77

64

GSK SCO40041 2008

36

186

GSK

500

61

66

Hanania 2003a

6

355

GSK

500

63

64

57

42

Kardos 2007

10

994

GSK

1000

76

64

37

40

Kerwin 2013a,b

6

617

GSK

100

67

63

46

43

Mahler 2002a

6

325

GSK

1000

66

65

55

41

Martinez 2013a,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.

Figures and Tables -
Table 1. Fluticasone—summary of studies and baseline characteristics
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 2003ba

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 2003a

12

403

AZ

640

79

64

45

36

Tashkin 2008 SHINEa

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 2003ba

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 2003a

12

409

AZ

640

79

64

45

36

Tashkin 2008 SHINEa

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.

Figures and Tables -
Table 2. Budesonide—summary of studies and baseline characteristics
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

Figures and Tables -
Table 3. BDP equivalent doses
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.

Figures and Tables -
Table 4. Control group event rates
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]

Figures and Tables -
Comparison 1. Fluticasone versus controls (all outcomes by treatment)
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]

Figures and Tables -
Comparison 2. Subgroup analyses—fluticasone versus controls
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]

Figures and Tables -
Comparison 3. Budesonide versus controls (all outcomes by treatment)
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]

Figures and Tables -
Comparison 4. Subgroup analyses—budesonide versus controls
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]

Figures and Tables -
Comparison 5. Sensitivity analysis—risk of bias