Combined corticosteroid and long‐acting beta‐agonist in one inhaler versus placebo for chronic obstructive pulmonary disease

Luis Javier Nannini; Christopher J Cates; Toby J Lasserson; Phillippa Poole

doi:10.1002/14651858.CD003794.pub3

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Figure 1

Flow chart to illustrate separation of review between three comparisons. Six RCTs met the original entry criteria of the review. All of these had a placebo and long‐acting beta‐agonist arm, and five assessed combination against steroids. Seven new studies with one or more control comparisons were identified: five had a placebo arm, three had a long‐acting beta‐agonist arm, and two had an inhaled steroid treatment arm.

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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

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Figure 3

Summary of findings table for exacerbations, mortality, quality of life, pneumonia and adverse events

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Figure 4

Forest plot of pooled rate ratios for combination fluticasone and salmeterol and placebo, with the summary estimate for TRISTAN included (primary analysis) and removed (sensitivity analysis)

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Figure 5

Pooled effect estimate on mortality for all combined inhalers versus placebo

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Analysis 1.1

Comparison 1 Combined inhalers versus Placebo (Primary Outcomes), Outcome 1 Exacerbation Rates with combined inhalers v. placebo.

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Analysis 1.2

Comparison 1 Combined inhalers versus Placebo (Primary Outcomes), Outcome 2 Mortality.

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Analysis 1.3

Comparison 1 Combined inhalers versus Placebo (Primary Outcomes), Outcome 3 Pneumonia.

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Analysis 2.1

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 1 Number of participants with one or more exacerbation.

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Analysis 2.2

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 2 End of treatment mean number of exacerbations per participant.

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Analysis 2.3

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 3 Exacerbations.

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Analysis 2.4

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 4 Number of exacerbations by type.

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Analysis 2.5

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 5 Exacerbations by type.

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Analysis 2.6

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 6 Mortality.

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Analysis 2.7

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 7 Change from baseline in St George's Respiratory Questionnaire (total score).

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Analysis 2.8

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 8 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

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Analysis 2.9

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 9 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

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Analysis 2.10

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 10 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

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Analysis 2.11

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 11 End of treatment St George's Respiratory Questionnaire scores (total score).

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Analysis 2.12

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 12 End of treatment St George's Respiratory Questionnaire scores (domain ‐ breathlessness).

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Analysis 2.13

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 13 Change from baseline in Canadian Respiratory Disease Questionnaire scores.

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Analysis 2.14

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 14 Change from baseline in Transitional Dyspnoea Index (TDI) scores.

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Analysis 2.15

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 15 End of treatment symptom scores.

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Analysis 2.16

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 16 Change from baseline in predose FEV1.

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Analysis 2.17

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 17 Change from baseline in postdose FEV1.

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Analysis 2.18

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 18 End of treatment FEV1 (% predicted).

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Analysis 2.19

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 19 End of treatment FEV1 (Litres).

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Analysis 2.20

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 20 End of treatment am PEF (L/min).

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Analysis 2.21

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 21 End of treatment shuttle walk test.

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Analysis 2.22

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 22 End of treatment rescue medication usage (puffs/day).

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Analysis 2.23

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 23 Change from baseline in rescue medication usage (puffs/day).

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Analysis 2.24

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 24 Adverse events ‐ any event.

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Analysis 2.25

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 25 Adverse events ‐ candidiasis.

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Analysis 2.26

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 26 Withdrawals due to adverse events.

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Analysis 2.27

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 27 Withdrawals due to lack of efficacy/exacerbations.

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Analysis 2.28

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 28 Withdrawals.

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Analysis 2.29

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 29 Adverse events ‐ pneumonia.

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Analysis 2.30

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 30 Adverse events ‐ nasopharyngitis.

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Analysis 2.31

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 31 Adverse events ‐ pharyngolaryngeal pain.

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Analysis 2.32

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 32 Adverse events ‐ upper respiratory tract infection.

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Analysis 2.33

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 33 Adverse events ‐ headache.

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Analysis 2.34

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 34 Adverse events ‐ hoarseness.

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Analysis 2.35

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 35 Adverse events ‐ pyrexia.

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Analysis 2.36

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 36 Adverse events ‐ cough.

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Analysis 2.37

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 37 Adverse events ‐ palpitations.

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Analysis 2.38

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 38 Adverse events ‐ mouth ulceration.

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Analysis 2.39

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 39 Adverse events ‐ toothache.

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Analysis 2.40

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 40 Adverse events ‐ urinary tract infection.

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Analysis 2.41

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 41 Adverse events ‐ dyspnoea.

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Analysis 2.42

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 42 Adverse events ‐ blood glucose increased.

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Analysis 2.43

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 43 Adverse events ‐ insomnia.

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Analysis 2.44

Comparison 2 Fluticasone/salmeterol (FPS) versus placebo (PLA), Outcome 44 Adverse events ‐ bronchitis.

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Analysis 3.1

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 1 Severe Exacerbations.

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Analysis 3.2

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 2 Mean severe exacerbation rates per patient per year.

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Analysis 3.3

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 3 Quality of life ‐ SGRQ (change scores).

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Analysis 3.4

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 4 Quality of life ‐ change scores.

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Analysis 3.5

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 5 Rescue medication usage.

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Analysis 3.6

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 6 Symptoms (change scores).

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Analysis 3.7

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 7 Mean FEV1 (% change from baseline).

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Analysis 3.8

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 8 Adverse events ‐ 'serious events'.

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Analysis 3.10

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 10 Adverse events ‐ pneumonia.

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Analysis 3.11

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 11 Withdrawals due to worsening COPD symptoms.

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Analysis 3.12

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 12 Withdrawals due to adverse events.

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Analysis 3.13

Comparison 3 Budesonide/formoterol (BDF) versus placebo (PLA), Outcome 13 Mortality.

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Table 1. Search history

Version	Detail
1st published version ‐ Issue 4, 2003 (All years to April 2002)	References identified: 34 References retrieved: 7 Studies excluded 3 (Cazzola 2000; Chapman 2002; Soriano 2002) Studies identified from supplementary searching: 4 (Dal Negro 2003; Hanania 2003 ‐ both included; Cazzola 2002a; Cazzola 2004 ‐ both excluded). Studies included: 4
2nd published version ‐ Issue 3, 2004 (April 2003‐April 2004)	References identified: 12 References retrieved: 3 (2 papers full publication of a previously included or cited studies study (Dal Negro 2003; Hanania 2003). Hand searching identified two further references to the COSMIC 2003 study. Studies identified from supplementary searching: 1 (TRISTAN 2003) New studies included: 2 Total studies included: 6
3rd published version ‐ Issue 3, 2005 (April 2004‐April 2005)	References identified: 52 References retrieved: 46 (references to studies already included/excluded/ongoing: 24) New unique studies identified: 10 (ongoing studies: 2) New studies included: 0 Total studies included: 6
4th published version ‐ April 2005 ‐ April 2007	References identified: 66 References retrieved: 27 (references to studies already included/excluded/ongoing: ) New unique studies identified: 8 (ongoing studies: 0) New studies included: 7 Total studies included: 13

Table 1. Search history

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Table 2. Rates and NNT of mortality

Study ID	Study duration	Placebo rate (%)	NNT
TORCH	156 weeks	15.2	42 (24 to 387)
SCO100540	24 weeks	0	NA
SFCT01	52 weeks	0	NA
TRISTAN	52 weeks	1.94	292 (169 to 2628)
Mahler 2002	24 weeks	1.66	293 (176 to 1540)
Calverley 2003	52 weeks	1.95	249 (149 to 1307)
Szafranski 2003	52 weeks	4.5	110 (66 to 581)

Table 2. Rates and NNT of mortality

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Table 3. Rates and NNT of pneumonia

Study ID	Study duration	Placebo rate (%)	NNT(h)
Hanania 2003	24 weeks	0	NA
Mahler 2002	24 weeks	0	NA
Barnes 2006	13 weeks	0	NA
SCO100540	24 weeks	0	NA
O'Donnell 2006	8 weeks	1.56	83
TORCH	156 weeks	12.3	13
TRISTAN	52 weeks	0.83	153
Calverley 2003	52 weeks	3.6	36

Table 3. Rates and NNT of pneumonia

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Comparison 1. Combined inhalers versus Placebo (Primary Outcomes)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Exacerbation Rates with combined inhalers v. placebo Show forest plot	5		Rate Ratio (Fixed, 95% CI)	0.74 [0.69, 0.79]

1.1 Fluticasone/salmeterol	3		Rate Ratio (Fixed, 95% CI)	0.74 [0.69, 0.80]
1.2 Budesonide/formoterol	2		Rate Ratio (Fixed, 95% CI)	0.74 [0.62, 0.88]
2 Mortality Show forest plot	7	5752	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.65, 0.96]

2.1 Fluticasone/salmeterol	5	4829	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.65, 0.97]
2.2 Budesonide/formoterol	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.73]
3 Pneumonia Show forest plot	8	5739	Odds Ratio (M‐H, Fixed, 95% CI)	1.83 [1.51, 2.21]

3.1 FPS	7	5229	Odds Ratio (M‐H, Fixed, 95% CI)	1.80 [1.48, 2.18]
3.2 BDF	1	510	Odds Ratio (M‐H, Fixed, 95% CI)	4.13 [0.87, 19.64]

Comparison 1. Combined inhalers versus Placebo (Primary Outcomes)

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Comparison 2. Fluticasone/salmeterol (FPS) versus placebo (PLA)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants with one or more exacerbation Show forest plot	5	1235	Odds Ratio (M‐H, Fixed, 95% CI)	0.88 [0.67, 1.15]

1.1 Reversible population	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	0.32 [0.06, 1.66]
1.2 Partially reversible population (mixed population)	2	713	Odds Ratio (M‐H, Fixed, 95% CI)	1.00 [0.69, 1.44]
1.3 Poorly reversible population	2	396	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.53, 1.21]
2 End of treatment mean number of exacerbations per participant Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Poorly reversible population	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Exacerbations Show forest plot	3		Rate ratio (Fixed, 95% CI)	0.74 [0.69, 0.80]

3.1 Partially reversible population (mixed population)	0		Rate ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Poorly reversible population	3		Rate ratio (Fixed, 95% CI)	0.74 [0.69, 0.80]
4 Number of exacerbations by type Show forest plot	2		Odds Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Requirement for oral steroids	2	417	Odds Ratio (M‐H, Fixed, 95% CI)	1.01 [0.61, 1.68]
4.2 Requirement for antibiotic treatment	1	140	Odds Ratio (M‐H, Fixed, 95% CI)	0.80 [0.26, 2.44]
4.3 Requirement for oral steroid or antibiotic treatment	1	140	Odds Ratio (M‐H, Fixed, 95% CI)	3.32 [0.13, 82.80]
4.4 Hospitalisation	1	140	Odds Ratio (M‐H, Fixed, 95% CI)	3.32 [0.13, 82.80]
5 Exacerbations by type Show forest plot	3		Rate ratio (Fixed, 95% CI)	Subtotals only

5.1 Requirement for oral steroids	3		Rate ratio (Fixed, 95% CI)	0.57 [0.52, 0.63]
5.2 Requirement for antibiotic treatment	1		Rate ratio (Fixed, 95% CI)	0.60 [0.43, 0.84]
5.3 Requirement for oral steroid or antibiotic treatment	0		Rate ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
5.4 Hospitalisation	2		Rate ratio (Fixed, 95% CI)	0.83 [0.70, 0.97]
6 Mortality Show forest plot	5	4829	Odds Ratio (M‐H, Fixed, 95% CI)	0.79 [0.65, 0.97]

6.1 Mortality: three year data	1	3057	Odds Ratio (M‐H, Fixed, 95% CI)	0.81 [0.66, 0.99]
6.2 Mortality: >one and <three year data	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Mortality: one year data	3	1426	Odds Ratio (M‐H, Fixed, 95% CI)	0.63 [0.21, 1.90]
6.4 Mortality: 6 month data	1	346	Odds Ratio (M‐H, Fixed, 95% CI)	0.15 [0.01, 3.01]
7 Change from baseline in St George's Respiratory Questionnaire (total score) Show forest plot	4		SGRQ units (Fixed, 95% CI)	‐2.90 [‐3.61, ‐2.18]

7.1 Partially reversible population (mixed population)	0		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Poorly reversible population	4		SGRQ units (Fixed, 95% CI)	‐2.90 [‐3.61, ‐2.18]
8 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot	1		SGRQ units (Fixed, 95% CI)	Totals not selected

8.1 Partially reversible population (mixed population)	0		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Poorly reversible population	1		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot	1		SGRQ units (Fixed, 95% CI)	Totals not selected

9.1 Partially reversible population (mixed population)	0		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Poorly reversible population	1		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot	1		SGRQ units (Fixed, 95% CI)	Totals not selected

10.1 Partially reversible population (mixed population)	0		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Poorly reversible population	1		SGRQ units (Fixed, 95% CI)	0.0 [0.0, 0.0]
11 End of treatment St George's Respiratory Questionnaire scores (total score) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

11.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Poorly reversible population	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 End of treatment St George's Respiratory Questionnaire scores (domain ‐ breathlessness) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

12.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Poorly reversible population	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Change from baseline in Canadian Respiratory Disease Questionnaire scores Show forest plot	2	712	Mean Difference (IV, Fixed, 95% CI)	5.0 [2.48, 7.52]

13.1 Partially reversible population (mixed population)	2	712	Mean Difference (IV, Fixed, 95% CI)	5.0 [2.48, 7.52]
13.2 Poorly reversible population	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Change from baseline in Transitional Dyspnoea Index (TDI) scores Show forest plot	2	707	Mean Difference (IV, Fixed, 95% CI)	1.04 [0.56, 1.53]

14.1 Partially reversible population (mixed population)	2	707	Mean Difference (IV, Fixed, 95% CI)	1.04 [0.56, 1.53]
14.2 Poorly reversible population	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 End of treatment symptom scores Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

15.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 Poorly reversible population	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
16 Change from baseline in predose FEV1 Show forest plot	5		Litres (Fixed, 95% CI)	0.16 [0.14, 0.19]

16.1 Reversible population	3		Litres (Fixed, 95% CI)	0.19 [0.15, 0.24]
16.2 Partially reversible population (mixed population)	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
16.3 Poorly reversible population	4		Litres (Fixed, 95% CI)	0.15 [0.11, 0.18]
16.4 Unclear reversibility	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Change from baseline in postdose FEV1 Show forest plot	1		Litres (Fixed, 95% CI)	Totals not selected

17.1 Reversible population	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 Partially reversible population (mixed population)	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
17.3 Poorly reversible population	1		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
17.4 Unclear reversibility	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
18 End of treatment FEV1 (% predicted) Show forest plot	1		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected

18.1 Partially reversible population (mixed population)	0		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Poorly reversible population	1		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 End of treatment FEV1 (Litres) Show forest plot	2		Litres (Fixed, 95% CI)	0.13 [0.10, 0.16]

19.1 Partially reversible population (mixed population)	0		Litres (Fixed, 95% CI)	0.0 [0.0, 0.0]
19.2 Poorly reversible population	2		Litres (Fixed, 95% CI)	0.13 [0.10, 0.16]
20 End of treatment am PEF (L/min) Show forest plot	1		L/min (Fixed, 95% CI)	Totals not selected

20.1 Partially reversible population (mixed population)	0		L/min (Fixed, 95% CI)	0.0 [0.0, 0.0]
20.2 Poorly reversible population	1		L/min (Fixed, 95% CI)	0.0 [0.0, 0.0]
21 End of treatment shuttle walk test Show forest plot	1		Metres (Fixed, 95% CI)	Totals not selected

21.1 Partially reversible population (mixed population)	0		Metres (Fixed, 95% CI)	0.0 [0.0, 0.0]
21.2 Poorly reversible population	1		Metres (Fixed, 95% CI)	0.0 [0.0, 0.0]
22 End of treatment rescue medication usage (puffs/day) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

22.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
22.2 Poorly reversible population	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
23 Change from baseline in rescue medication usage (puffs/day) Show forest plot	2	703	Mean Difference (IV, Fixed, 95% CI)	‐1.19 [‐1.83, ‐0.55]

23.1 Partially reversible population (mixed population)	2	703	Mean Difference (IV, Fixed, 95% CI)	‐1.19 [‐1.83, ‐0.55]
23.2 Poorly reversible population	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
24 Adverse events ‐ any event Show forest plot	8	5493	Odds Ratio (M‐H, Fixed, 95% CI)	1.10 [0.96, 1.27]

24.1 Reversible population	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	1.20 [0.59, 2.46]
24.2 Partially reversible population (mixed population)	2	717	Odds Ratio (M‐H, Fixed, 95% CI)	1.42 [1.03, 1.96]
24.3 Poorly reversible population	5	4650	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.88, 1.21]
25 Adverse events ‐ candidiasis Show forest plot	6	1958	Odds Ratio (M‐H, Fixed, 95% CI)	5.73 [3.07, 10.67]

25.1 Reversible population	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.06, 16.88]
25.2 Partially reversible population (mixed population)	2	717	Odds Ratio (M‐H, Fixed, 95% CI)	11.13 [3.36, 36.90]
25.3 Poorly reversible population	3	1115	Odds Ratio (M‐H, Fixed, 95% CI)	4.40 [2.01, 9.62]
25.4 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
26 Withdrawals due to adverse events Show forest plot	8	5110	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.65, 0.88]

26.1 Partially reversible population (mixed population)	1	354	Odds Ratio (M‐H, Fixed, 95% CI)	0.69 [0.31, 1.51]
26.2 Poorly reversible population	6	4630	Odds Ratio (M‐H, Fixed, 95% CI)	0.76 [0.65, 0.89]
26.3 Unclear reversibility	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.47]
27 Withdrawals due to lack of efficacy/exacerbations Show forest plot	5	4620	Odds Ratio (M‐H, Fixed, 95% CI)	0.30 [0.21, 0.42]

27.1 Partially reversible population (mixed population)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.2 Poorly reversible population	5	4620	Odds Ratio (M‐H, Fixed, 95% CI)	0.30 [0.21, 0.42]
27.3 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28 Withdrawals Show forest plot	8	5450	Odds Ratio (M‐H, Fixed, 95% CI)	0.70 [0.62, 0.78]

28.1 Reversible population	1	121	Odds Ratio (M‐H, Fixed, 95% CI)	2.95 [0.30, 29.18]
28.2 Partially reversible population (mixed population)	2	709	Odds Ratio (M‐H, Fixed, 95% CI)	0.82 [0.60, 1.13]
28.3 Poorly reversible population	5	4620	Odds Ratio (M‐H, Fixed, 95% CI)	0.68 [0.60, 0.76]
28.4 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29 Adverse events ‐ pneumonia Show forest plot	7	5229	Odds Ratio (M‐H, Fixed, 95% CI)	1.80 [1.48, 2.18]

29.1 Reversible population	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.47]
29.2 Partially reversible population (mixed population)	2	709	Odds Ratio (M‐H, Fixed, 95% CI)	5.55 [0.26, 116.46]
29.3 Poorly reversible population	4	4394	Odds Ratio (M‐H, Fixed, 95% CI)	1.80 [1.48, 2.18]
29.4 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30 Adverse events ‐ nasopharyngitis Show forest plot	2	3535	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [1.05, 1.56]

30.1 Partially reversible population (mixed population)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.2 Poorly reversible population	2	3535	Odds Ratio (M‐H, Fixed, 95% CI)	1.28 [1.05, 1.56]
30.3 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31 Adverse events ‐ pharyngolaryngeal pain Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

31.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Adverse events ‐ upper respiratory tract infection Show forest plot	5	4963	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [1.04, 1.47]

32.1 Partially reversible population (mixed population)	2	709	Odds Ratio (M‐H, Fixed, 95% CI)	1.25 [0.81, 1.92]
32.2 Poorly reversible population	3	4254	Odds Ratio (M‐H, Fixed, 95% CI)	1.23 [1.02, 1.48]
32.3 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
33 Adverse events ‐ headache Show forest plot	5	4367	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.85, 1.32]

33.1 Reversible population	1	123	Odds Ratio (M‐H, Fixed, 95% CI)	0.22 [0.02, 2.01]
33.2 Partially reversible population (mixed population)	2	709	Odds Ratio (M‐H, Fixed, 95% CI)	1.38 [0.91, 2.10]
33.3 Poorly reversible population	2	3535	Odds Ratio (M‐H, Fixed, 95% CI)	0.97 [0.75, 1.27]
33.4 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
34 Adverse events ‐ hoarseness Show forest plot	2	585	Odds Ratio (M‐H, Fixed, 95% CI)	8.79 [1.11, 69.62]

34.1 Partially reversible population (mixed population)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
34.2 Poorly reversible population	2	585	Odds Ratio (M‐H, Fixed, 95% CI)	8.79 [1.11, 69.62]
34.3 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35 Adverse events ‐ pyrexia Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

35.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
36 Adverse events ‐ cough Show forest plot	4	1057	Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.29, 1.29]

36.1 Reversible population	1	126	Odds Ratio (M‐H, Fixed, 95% CI)	3.15 [0.13, 78.72]
36.2 Partially reversible population (mixed population)	1	346	Odds Ratio (M‐H, Fixed, 95% CI)	0.49 [0.18, 1.31]
36.3 Poorly reversible population	2	585	Odds Ratio (M‐H, Fixed, 95% CI)	0.66 [0.18, 2.44]
36.4 Unclear reversibility	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
37 Adverse events ‐ palpitations Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

37.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
37.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
37.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
38 Adverse events ‐ mouth ulceration Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

38.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
38.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
38.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
39 Adverse events ‐ toothache Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

39.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
39.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
39.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
40 Adverse events ‐ urinary tract infection Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

40.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
40.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
40.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
41 Adverse events ‐ dyspnoea Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

41.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
41.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
41.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
42 Adverse events ‐ blood glucose increased Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

42.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
42.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
42.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
43 Adverse events ‐ insomnia Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

43.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
43.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
43.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
44 Adverse events ‐ bronchitis Show forest plot	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected

44.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
44.2 Poorly reversible population	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
44.3 Unclear reversibility	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Fluticasone/salmeterol (FPS) versus placebo (PLA)

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Comparison 3. Budesonide/formoterol (BDF) versus placebo (PLA)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Severe Exacerbations Show forest plot	2		Rate ratio (Fixed, 95% CI)	0.74 [0.62, 0.88]

1.1 Partially reversible	0		Rate ratio (Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Poorly reversible	2		Rate ratio (Fixed, 95% CI)	0.74 [0.62, 0.88]
2 Mean severe exacerbation rates per patient per year Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Poorly reversible population	2		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Quality of life ‐ SGRQ (change scores) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1 Partially reversible population (mixed population)	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Poorly reversible population	2		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Quality of life ‐ change scores Show forest plot	2		SGRQ (Fixed, 95% CI)	‐6.06 [‐7.90, ‐4.22]

4.1 Partially reversible (mixed population)	0		SGRQ (Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Poorly reversible	2		SGRQ (Fixed, 95% CI)	‐6.06 [‐7.90, ‐4.22]
5 Rescue medication usage Show forest plot	2		Puffs per day (Fixed, 95% CI)	‐0.87 [‐1.15, ‐0.58]

5.1 Partially reversible (mixed population)	0		Puffs per day (Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Poorly reversible	2		Puffs per day (Fixed, 95% CI)	‐0.87 [‐1.15, ‐0.58]
6 Symptoms (change scores) Show forest plot	2		Symptom scale (Fixed, 95% CI)	‐0.63 [‐0.90, ‐0.37]

6.1 Partially reversible (mixed population)	0		Symptom scale (Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Poorly reversible	2		Symptom scale (Fixed, 95% CI)	‐0.63 [‐0.90, ‐0.37]
7 Mean FEV1 (% change from baseline) Show forest plot	2		% increase (Fixed, 95% CI)	14.40 [11.91, 16.90]

7.1 Partially reversible (mixed population)	0		% increase (Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Poorly reversible	2		% increase (Fixed, 95% CI)	14.40 [11.91, 16.90]
8 Adverse events ‐ 'serious events' Show forest plot	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.78, 1.45]

8.1 Partially reversible population (mixed population)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Poorly reversible population	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.78, 1.45]
9 Adverse events ‐ candidiasis	0		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9.1 Partially reversible population (mixed population)	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Poorly reversible population	0		Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Adverse events ‐ pneumonia Show forest plot	1	510	Odds Ratio (M‐H, Fixed, 95% CI)	4.13 [0.87, 19.64]

11 Withdrawals due to worsening COPD symptoms Show forest plot	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	0.40 [0.28, 0.58]

11.1 Partially reversible population (mixed population)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Poorly reversible population	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	0.40 [0.28, 0.58]
12 Withdrawals due to adverse events Show forest plot	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	1.30 [0.78, 2.18]

12.1 Partially reversible population (mixed population)	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Poorly reversible population	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	1.30 [0.78, 2.18]
13 Mortality Show forest plot	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.73]

13.1 Mortality as primary outcome	0	0	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Mortality data collected as secondary/unpublished outcome	2	923	Odds Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.73]

Comparison 3. Budesonide/formoterol (BDF) versus placebo (PLA)

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