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Study flow diagram. This represents the results of all literature searches up to June 2011.
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Figure 1

Study flow diagram. This represents the results of all literature searches up to June 2011.

Risk of bias summary: review authors' judgments about each risk of bias item for each included study.
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Figure 2

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

Forest plot of comparison: 1 Combination fluticasone/salmeterol versus budesonide/formoterol, outcome: 1.1 Participants experiencing exacerbations requiring oral steroid treatment.
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Figure 3

Forest plot of comparison: 1 Combination fluticasone/salmeterol versus budesonide/formoterol, outcome: 1.1 Participants experiencing exacerbations requiring oral steroid treatment.

Forest plot of comparison: 1 Combination fluticasone/salmeterol versus budesonide/formoterol, outcome: 1.2 Participants experiencing exacerbations requiring admission to hospital.
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Figure 4

Forest plot of comparison: 1 Combination fluticasone/salmeterol versus budesonide/formoterol, outcome: 1.2 Participants experiencing exacerbations requiring admission to hospital.

Forest plot of comparison: 1 Combination fluticasone/salmeterol versus budesonide/formoterol, outcome: 1.3 Asthma‐related serious adverse event.
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Figure 5

Forest plot of comparison: 1 Combination fluticasone/salmeterol versus budesonide/formoterol, outcome: 1.3 Asthma‐related serious adverse event.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 1 Participants experiencing exacerbations requiring oral steroid treatment.
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Analysis 1.1

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 1 Participants experiencing exacerbations requiring oral steroid treatment.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 2 Participants experiencing exacerbations requiring admission to hospital.
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Analysis 1.2

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 2 Participants experiencing exacerbations requiring admission to hospital.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 3 Asthma‐related serious adverse event.
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Analysis 1.3

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 3 Asthma‐related serious adverse event.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 4 Participants experiencing exacerbations requiring ED visit/hospitalisation.
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Analysis 1.4

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 4 Participants experiencing exacerbations requiring ED visit/hospitalisation.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 5 Mortality.
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Analysis 1.5

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 5 Mortality.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 6 Asthma Quality of Life Questionnaire.
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Analysis 1.6

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 6 Asthma Quality of Life Questionnaire.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 7 N with improvement in Asthma Quality of Life Questionnaire.
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Analysis 1.7

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 7 N with improvement in Asthma Quality of Life Questionnaire.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 8 Change in am PEF.
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Analysis 1.8

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 8 Change in am PEF.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 9 Change in pm PEF.
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Analysis 1.9

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 9 Change in pm PEF.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 10 Change in FEV1.
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Analysis 1.10

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 10 Change in FEV1.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 11 Change in FEV1 predicted (%).
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Analysis 1.11

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 11 Change in FEV1 predicted (%).

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 12 Change in rescue medication use.
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Analysis 1.12

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 12 Change in rescue medication use.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 13 Change in daytime symptoms.
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Analysis 1.13

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 13 Change in daytime symptoms.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 14 Change in symptom‐free days.
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Analysis 1.14

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 14 Change in symptom‐free days.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 15 Change in nocturnal awakenings.
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Analysis 1.15

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 15 Change in nocturnal awakenings.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 16 Adverse events.
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Analysis 1.16

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 16 Adverse events.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 17 Headache.
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Analysis 1.17

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 17 Headache.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 18 Candidiasis.
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Analysis 1.18

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 18 Candidiasis.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 19 Upper respiratory tract infection.
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Analysis 1.19

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 19 Upper respiratory tract infection.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 20 Dysphonia.
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Analysis 1.20

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 20 Dysphonia.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 21 Rhinitis.
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Analysis 1.21

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 21 Rhinitis.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 22 Throat irritation.
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Analysis 1.22

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 22 Throat irritation.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 23 Cough.
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Analysis 1.23

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 23 Cough.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 24 Tremor.
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Analysis 1.24

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 24 Tremor.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 25 Withdrawals.
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Analysis 1.25

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 25 Withdrawals.

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 26 Withdrawals (adverse events).
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Analysis 1.26

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 26 Withdrawals (adverse events).

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 27 Withdrawals (lack of efficacy).
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Analysis 1.27

Comparison 1 Combination fluticasone/salmeterol versus budesonide/formoterol, Outcome 27 Withdrawals (lack of efficacy).

Summary of findings for the main comparison. Combination fluticasone/salmeterol versus budesonide/formoterol for chronic asthma in adults and children

Combination fluticasone/salmeterol versus budesonide/formoterol for chronic asthma in adults and children

Patient or population: Patients with chronic asthma in adults and children
Settings:
Intervention: combination fluticasone/salmeterol versus budesonide/formoterol

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Combination budesonide/formoterol

Combination fluticasone/salmeterol

Participants experiencing exacerbations requiring oral steroid treatment
Follow‐up: mean 6 months

106 per 10001

95 per 1000
(81 to 113)

OR 0.89
(0.74 to 1.07)

4949
(4 studies)

⊕⊕⊕⊝
moderate2

Participants experiencing exacerbations requiring admission to hospital
Follow‐up: mean 6 months

7 per 10001

8 per 1000
(4 to 16)

OR 1.29
(0.68 to 2.47)

4879
(4 studies)

⊕⊕⊕⊝
moderate2

Asthma‐related serious adverse event
Follow‐up: mean 6 months

7 per 10001

10 per 1000
(5 to 20)

OR 1.47
(0.75 to 2.86)

4054
(3 studies)

⊕⊕⊕⊝
moderate2

Mortality
Follow‐up: mean 6 months

See comment

See comment

Not estimable

4819
(5 studies)

⊕⊕⊝⊝
low3

The data did not generate a pooled effect estimate as no deaths occurred in four out of the five studies.

Withdrawals (adverse events)
Follow‐up: mean 6 months

16 per 10001

15 per 1000
(10 to 23)

OR 0.94
(0.6 to 1.46)

5082
(5 studies)

⊕⊕⊕⊝
moderate2

*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.

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.

1 The mean rate of exacerbations across the BUD/F arms of the trials was used to calculate the assumed risk.
2 Imprecision (‐1): the confidence interval is compatible with superiority of either treatment and could change with the addition of new evidence.
3 Imprecision (‐2): The width of the confidence intervals is very wide and reflects the low rate of events in the analysis. One death occurred in 4819 participants.

Figures and Tables -
Summary of findings for the main comparison. Combination fluticasone/salmeterol versus budesonide/formoterol for chronic asthma in adults and children
Comparison 1. Combination fluticasone/salmeterol versus budesonide/formoterol

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Participants experiencing exacerbations requiring oral steroid treatment Show forest plot

4

4949

Odds Ratio (M‐H, Fixed, 95% CI)

0.89 [0.74, 1.07]

2 Participants experiencing exacerbations requiring admission to hospital Show forest plot

4

4879

Odds Ratio (M‐H, Fixed, 95% CI)

1.29 [0.68, 2.47]

3 Asthma‐related serious adverse event Show forest plot

3

4054

Odds Ratio (M‐H, Fixed, 95% CI)

1.47 [0.75, 2.86]

4 Participants experiencing exacerbations requiring ED visit/hospitalisation Show forest plot

4

4861

Odds Ratio (M‐H, Fixed, 95% CI)

1.30 [0.94, 1.80]

5 Mortality Show forest plot

5

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

6 Asthma Quality of Life Questionnaire Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

7 N with improvement in Asthma Quality of Life Questionnaire Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

8 Change in am PEF Show forest plot

5

5101

L/min (Fixed, 95% CI)

2.24 [‐0.24, 4.73]

9 Change in pm PEF Show forest plot

4

4299

L/min (Fixed, 95% CI)

0.25 [‐0.80, 1.30]

10 Change in FEV1 Show forest plot

4

4845

L (Fixed, 95% CI)

0.00 [‐0.02, 0.02]

11 Change in FEV1 predicted (%) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

12 Change in rescue medication use Show forest plot

3

3469

Puffs/d (Fixed, 95% CI)

‐0.06 [‐0.13, 0.02]

13 Change in daytime symptoms Show forest plot

3

3464

Symptoms (Fixed, 95% CI)

‐0.02 [‐0.06, 0.03]

14 Change in symptom‐free days Show forest plot

2

3027

Symptoms (Fixed, 95% CI)

1.25 [‐1.18, 3.67]

15 Change in nocturnal awakenings Show forest plot

1

Symptoms (Fixed, 95% CI)

Totals not selected

16 Adverse events Show forest plot

3

3547

Odds Ratio (M‐H, Fixed, 95% CI)

1.00 [0.88, 1.15]

17 Headache Show forest plot

4

2916

Odds Ratio (M‐H, Fixed, 95% CI)

1.08 [0.82, 1.43]

18 Candidiasis Show forest plot

2

1272

Odds Ratio (M‐H, Fixed, 95% CI)

1.64 [0.68, 4.00]

19 Upper respiratory tract infection Show forest plot

2

1644

Odds Ratio (M‐H, Fixed, 95% CI)

1.09 [0.81, 1.47]

20 Dysphonia Show forest plot

3

2669

Odds Ratio (M‐H, Fixed, 95% CI)

1.45 [0.87, 2.43]

21 Rhinitis Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

22 Throat irritation Show forest plot

2

1644

Odds Ratio (M‐H, Fixed, 95% CI)

1.39 [0.82, 2.35]

23 Cough Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

24 Tremor Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

25 Withdrawals Show forest plot

5

5082

Odds Ratio (M‐H, Fixed, 95% CI)

0.97 [0.78, 1.20]

26 Withdrawals (adverse events) Show forest plot

5

5082

Odds Ratio (M‐H, Fixed, 95% CI)

0.94 [0.60, 1.46]

27 Withdrawals (lack of efficacy) Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 1. Combination fluticasone/salmeterol versus budesonide/formoterol