Scolaris Content Display Scolaris Content Display

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 beta2‐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 beta2agonist arm, and two had an inhaled steroid treatment arm.
Figures and Tables -
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 beta2‐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 beta2agonist arm, and two had an inhaled steroid treatment arm.

Study flow diagram for 2007‐2011 literature searches.
Figures and Tables -
Figure 2

Study flow diagram for 2007‐2011 literature searches.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figures and Tables -
Figure 3

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

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.1 Exacerbation rates (combined treatment versus beta2‐agonist).
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.1 Exacerbation rates (combined treatment versus beta2‐agonist).

Forest plot of comparison: 1 Combined inhalers versus Long‐acting beta2‐agonists (Primary Outcomes), outcome: 1.2 Mortality.
Figures and Tables -
Figure 5

Forest plot of comparison: 1 Combined inhalers versus Long‐acting beta2‐agonists (Primary Outcomes), outcome: 1.2 Mortality.

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.3 Pneumonia.
Figures and Tables -
Figure 6

Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.3 Pneumonia.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).
Figures and Tables -
Analysis 1.1

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.
Figures and Tables -
Analysis 1.2

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.
Figures and Tables -
Analysis 1.3

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.
Figures and Tables -
Analysis 1.4

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.
Figures and Tables -
Analysis 1.5

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.
Figures and Tables -
Analysis 1.6

Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.
Figures and Tables -
Analysis 2.1

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.
Figures and Tables -
Analysis 2.2

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).
Figures and Tables -
Analysis 2.3

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).
Figures and Tables -
Analysis 2.4

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).
Figures and Tables -
Analysis 2.5

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).
Figures and Tables -
Analysis 2.6

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).
Figures and Tables -
Analysis 2.7

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).
Figures and Tables -
Analysis 2.8

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.
Figures and Tables -
Analysis 2.9

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).
Figures and Tables -
Analysis 2.10

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.
Figures and Tables -
Analysis 2.11

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).
Figures and Tables -
Analysis 2.12

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.
Figures and Tables -
Analysis 2.13

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.
Figures and Tables -
Analysis 2.14

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.
Figures and Tables -
Analysis 2.15

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.
Figures and Tables -
Analysis 2.16

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.
Figures and Tables -
Analysis 2.17

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).
Figures and Tables -
Analysis 2.18

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).
Figures and Tables -
Analysis 2.19

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).
Figures and Tables -
Analysis 2.20

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).
Figures and Tables -
Analysis 2.21

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).
Figures and Tables -
Analysis 2.22

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.
Figures and Tables -
Analysis 2.23

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.
Figures and Tables -
Analysis 2.24

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.
Figures and Tables -
Analysis 2.25

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.
Figures and Tables -
Analysis 2.26

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.
Figures and Tables -
Analysis 2.27

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.
Figures and Tables -
Analysis 2.28

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.
Figures and Tables -
Analysis 2.29

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.
Figures and Tables -
Analysis 2.30

Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).
Figures and Tables -
Analysis 3.1

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).
Figures and Tables -
Analysis 3.2

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).
Figures and Tables -
Analysis 3.3

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).
Figures and Tables -
Analysis 3.4

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).
Figures and Tables -
Analysis 3.5

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).
Figures and Tables -
Analysis 3.6

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period..
Figures and Tables -
Analysis 3.7

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period..

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).
Figures and Tables -
Analysis 3.8

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.
Figures and Tables -
Analysis 3.9

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).
Figures and Tables -
Analysis 3.10

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.
Figures and Tables -
Analysis 3.11

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.
Figures and Tables -
Analysis 3.12

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.
Figures and Tables -
Analysis 3.13

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.
Figures and Tables -
Analysis 3.14

Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.

Summary of findings for the main comparison. Combined inhalers compared to LABAs for COPD

Combined inhalers compared to LABAs for COPD

Patient or population: COPD
Intervention: Combined inhalers
Comparison: LABA inhalers

Setting: community

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

LABA inhalers

Combined inhalers

Annual Exacerbation Rates
Follow‐up: median 1 year

1 per person per year

0.76 per person per year

(0.32 exacerbations fewer to 0.16 exacerbations fewer)

Rate ratio 0.76

(0.68 to 0.84)

99211
(9 studies)

⊕⊕⊝⊝
low2,3

The control arm exacerbation rates ranged from 0.9 to 1.5 per year in the studies of at least one year duration that included participants with severe COPD who had at least one exacerbation in the previous year.4

Number of people experiencing one or more exacerbations

Follow up: median 1 year

47 per 100

42 per 100

(38 to 46)

OR 0.83 (0.70 to 0.98)

3357

(6 studies)

⊕⊕⊕⊝
moderate5

The evidence summarised for this outcome comes only from studies evaluating fluticasone/salmeterol. As such evidence for this outcome does not apply to budesonide/formoterol.

Annual hospitalisation rates

Follow‐up: 1 to 3 years

0.16 per person per year6

0.15 per person per year

(0.1 to 0.21)

Rate ratio 0.79

(0.55 to 1.13)

48791

(3 studies)

⊕⊕⊝⊝

very low2,3,7

Mortality
Follow‐up: median 1 year

8 per 1000

7 per 1000
(5 to 9)

OR 0.92
(0.76 to 1.11)

10681
(10 studies)

⊕⊕⊕⊝
moderate7

The majority of data on mortality was derived from TORCH (vital status was ascertained in the patients who withdrew from treatment in this study). Control arm event rates varied from 0.4% to 5% in the one year studies.

Pneumonia
Follow‐up: median 1 year

27 per 1000

41 per 1000
(32 to 54)8

OR 1.55
(1.2 to 2.01)

11076
(12 studies)

⊕⊕⊕⊝
moderate2

See Table 2 for control arm event rates in all studies

*The basis for the assumed risk (was the median control group risk across studies of one year duration). 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 This is the number of participants randomised in the studies. The analysis took account of the amount of time the participants were enrolled for prior to withdrawal.

2 Risk of bias (‐1): High withdrawal rates in all the longer trials.
3 Inconsistency (‐1): Significant heterogeneity between trial results.
4 Exacerbations were moderate or severe requiring oral corticosteroids, antibiotics or leading to hospital admission.

5 Publication bias (‐1): Data from a key study of fluticasone and salmeterol (TORCH) and from studies evaluating budesonide/formoterol were not available as binary data and did not contribute to this measurement of exacerbations. Whilst the analysis of the data as rates in these studies is likely to reflect the individual trial protocols, we cannot be sure that their absence from this outcome measure has little or no impact on the pooled odds ratio.

6 Annualised rates of hospitalisation have been estimated from the three year study TORCH.

7 Imprecision (‐1): Confidence interval includes possible harm and benefit.

8 See Table 2 for a range of NNT(H) results for risk of pneumonia across the trials of different durations.

Figures and Tables -
Summary of findings for the main comparison. Combined inhalers compared to LABAs for COPD
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

Update: 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

Update: 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

Update: 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: 4
Total studies included: 10

Update: April 2007‐ November 2011

References identified: 207
References retrieved: 4 (references to studies already included/excluded/ongoing: )
New unique studies identified: 4 (ongoing studies: 0)
New studies included: 4
Total studies included: 14

Figures and Tables -
Table 1. Search history
Table 2. Rates and NNT(H) for pneumonia

Study ID

Study duration

Rate on LABA alone %

NNT (calculated from pooled OR using Visual Rx)

O'Donnell 2006

8 weeks

0

NA

Hanania 2003

24 weeks

0.6

291 (192 to 525)

Mahler 2002

24 weeks

0

NA

SCO100470

24 weeks

0.8

219 (145 to 395)

Tashkin 2008

26 weeks

1.76

107 (59 to 291)

Kardos 2007

48 weeks

1.4

126 (84 to 228)

TRISTAN

52 weeks

2.4

75 (50 to 135)

Calverley 2003

52 weeks

2.7

67 (45 to 120)

Anzueto 2009

52 weeks

2.5

76 (42 to 207)

Rennard 2009

52 weeks

3.43

56 (31 to 152)

Ferguson 2008

52 weeks

3.9

50 (28 to 135)

TORCH

156 weeks

13.3

17 (12 to 29)

Figures and Tables -
Table 2. Rates and NNT(H) for pneumonia
Comparison 1. Combined inhalers versus long‐acting beta‐agonists (primary outcomes)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbation rates (combined inhaler versus LABA alone) Show forest plot

9

Rate ratio (Random, 95% CI)

0.76 [0.68, 0.84]

1.1 Fluticasone/salmeterol

5

Rate ratio (Random, 95% CI)

0.77 [0.66, 0.89]

1.2 Budesonide/formoterol

4

Rate ratio (Random, 95% CI)

0.73 [0.64, 0.83]

2 Number of participants with one or more exacerbation Show forest plot

6

3357

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]

2.1 Fluticasone/salmeterol

6

3357

Odds Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]

2.2 Budesonide/formoterol

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Hospitalisations Show forest plot

3

Rate ratio (Random, 95% CI)

Subtotals only

3.1 Fluticasone/salmeterol

3

Rate ratio (Random, 95% CI)

0.79 [0.55, 1.13]

4 Mortality Show forest plot

10

10681

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.76, 1.11]

4.1 Fluticasone/salmeterol

6

7408

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]

4.2 Budesonide/formoterol

4

3273

Odds Ratio (M‐H, Random, 95% CI)

1.03 [0.40, 2.67]

5 Pneumonia Show forest plot

12

11076

Odds Ratio (M‐H, Random, 95% CI)

1.55 [1.20, 2.01]

5.1 Fluticasone/salmeterol

9

8242

Odds Ratio (M‐H, Random, 95% CI)

1.75 [1.25, 2.45]

5.2 Budesonide/formoterol

3

2834

Odds Ratio (M‐H, Random, 95% CI)

1.09 [0.69, 1.73]

6 Pneumonia subgrouped by dose Show forest plot

12

11076

Odds Ratio (M‐H, Random, 95% CI)

1.56 [1.26, 1.93]

6.1 Lower dose FPS (250/50 bid)

3

1934

Odds Ratio (M‐H, Random, 95% CI)

2.19 [1.35, 3.53]

6.2 Higher dose FPS (500/50 bid)

6

6308

Odds Ratio (M‐H, Random, 95% CI)

1.55 [0.92, 2.61]

6.3 Lower dose BDF (160/9 bid)

2

1164

Odds Ratio (M‐H, Random, 95% CI)

1.10 [0.53, 2.26]

6.4 Higher dose BDF (320/9 bid)

3

1670

Odds Ratio (M‐H, Random, 95% CI)

1.08 [0.60, 1.97]

Figures and Tables -
Comparison 1. Combined inhalers versus long‐acting beta‐agonists (primary outcomes)
Comparison 2. Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Exacerbations by type Show forest plot

5

Rate ratio (Random, 95% CI)

Subtotals only

1.1 Requirement for oral steroids

4

Rate ratio (Random, 95% CI)

0.71 [0.62, 0.81]

1.2 Hospitalisation

3

Rate ratio (Random, 95% CI)

0.79 [0.55, 1.13]

2 Mortality by duration Show forest plot

6

7408

Odds Ratio (M‐H, Random, 95% CI)

0.93 [0.76, 1.13]

2.1 Mortality: three year data

1

3054

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.75, 1.14]

2.2 Mortality: >one and <three year data

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Mortality: one year data

5

4354

Odds Ratio (M‐H, Random, 95% CI)

0.94 [0.51, 1.70]

2.4 Mortality: 6 month data

0

0

Odds Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Change from baseline in St George's Respiratory Questionnaire (total score) Show forest plot

6

SGRQ units (Random, 95% CI)

‐1.58 [‐2.15, ‐1.01]

4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot

4

St George's RQ score (Random, 95% CI)

‐2.78 [‐3.88, ‐1.68]

5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot

4

SGRQ units (Random, 95% CI)

‐1.31 [‐2.38, ‐0.24]

6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot

4

SGRQ units (Random, 95% CI)

‐1.41 [‐2.33, ‐0.50]

7 End of treatment St George's Respiratory Questionnaire scores (total score) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

9 Change from baseline in Chronic Respiratory Disease Questionnaire scores Show forest plot

2

680

Mean Difference (IV, Random, 95% CI)

2.83 [0.25, 5.41]

10 End of treatment Transitional dyspnea index (TDI) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

11 End of treatment symptom scores Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

12 Change from baseline in Transitional Dyspnoea Index (TDI) Show forest plot

2

677

Mean Difference (IV, Random, 95% CI)

0.61 [‐0.47, 1.68]

13 Change in MRC rated dyspnoea Show forest plot

1

symptoms (Random, 95% CI)

Totals not selected

14 Change from baseline in dyspnoea score Show forest plot

2

Mean Difference (Random, 95% CI)

‐0.09 [‐0.13, ‐0.05]

15 Mean Change nighttime awakenings Show forest plot

2

1554

Mean Difference (IV, Random, 95% CI)

‐1.34 [‐2.07, ‐0.61]

16 Change from baseline in predose FEV1 Show forest plot

5

Litres (Random, 95% CI)

0.07 [0.05, 0.10]

16.1 Reversible population

3

Litres (Random, 95% CI)

0.07 [0.02, 0.12]

16.2 Partially reversible population (mixed population)

2

Litres (Random, 95% CI)

0.08 [0.04, 0.12]

16.3 Poorly reversible population

2

Litres (Random, 95% CI)

0.06 [0.01, 0.12]

17 Change from baseline in postdose FEV1 Show forest plot

3

Litres (Random, 95% CI)

0.05 [0.03, 0.06]

18 End of treatment FEV1 (Litres) Show forest plot

2

1780

Mean Difference (IV, Random, 95% CI)

0.01 [‐0.02, 0.03]

19 FEV1 (% predicted ‐ absolute scores) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

20 Change from baseline in am PEF (L/min) Show forest plot

2

L/min (Random, 95% CI)

11.61 [7.91, 15.30]

21 Change from baseline in rescue medication usage (puffs/day) Show forest plot

4

2435

Mean Difference (IV, Random, 95% CI)

‐0.38 [‐0.61, ‐0.16]

22 End of treatment rescue medication usage (puffs/day) Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

23 Adverse events ‐ any event Show forest plot

9

8250

Odds Ratio (M‐H, Random, 95% CI)

1.05 [0.93, 1.19]

24 Adverse events ‐ candidiasis Show forest plot

6

3118

Odds Ratio (M‐H, Random, 95% CI)

3.75 [2.33, 6.04]

25 Adverse events ‐ pneumonia Show forest plot

9

8242

Odds Ratio (M‐H, Random, 95% CI)

1.75 [1.25, 2.45]

26 Adverse events ‐ headache Show forest plot

8

7237

Odds Ratio (M‐H, Random, 95% CI)

1.06 [0.90, 1.26]

27 Adverse events ‐ upper respiratory tract infection Show forest plot

7

6198

Odds Ratio (M‐H, Random, 95% CI)

1.32 [1.12, 1.55]

28 Withdrawals Show forest plot

9

8226

Odds Ratio (M‐H, Random, 95% CI)

0.85 [0.77, 0.94]

29 Withdrawals due to lack of efficacy Show forest plot

6

6739

Odds Ratio (M‐H, Random, 95% CI)

0.53 [0.39, 0.72]

30 Withdrawals due to adverse events Show forest plot

8

7895

Odds Ratio (M‐H, Random, 95% CI)

0.90 [0.79, 1.02]

Figures and Tables -
Comparison 2. Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes
Comparison 3. Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Quality of life ‐ SGRQ (change scores) Show forest plot

4

3442

SGRQ (Random, 95% CI)

‐2.69 [‐3.82, ‐1.55]

2 Quality of life ‐ SGRQ (change scores) Show forest plot

4

Mean Difference (IV, Random, 95% CI)

Totals not selected

3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms) Show forest plot

2

2233

Mean Difference (IV, Random, 95% CI)

‐3.43 [‐5.13, ‐1.72]

4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity) Show forest plot

2

2215

Mean Difference (IV, Random, 95% CI)

‐1.57 [‐2.87, ‐0.27]

5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact) Show forest plot

2

2222

Mean Difference (IV, Random, 95% CI)

‐2.28 [‐3.60, ‐0.95]

6 Mean FEV1 (% increase from baseline) Show forest plot

1

Std. Mean Difference (IV, Random, 95% CI)

Totals not selected

7 Mean change from baseline in pre dose FEV1 to the average over the randomised treatment period. Show forest plot

2

1203

Mean Difference (IV, Random, 95% CI)

0.05 [0.00, 0.09]

8 Symptoms ‐ breathlessness (change scores) Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.07 [‐0.12, ‐0.01]

9 Change from baseline in cough score Show forest plot

2

2308

Mean Difference (IV, Random, 95% CI)

‐0.06 [‐0.11, ‐0.00]

10 Change from baseline in rescue medication usage (puffs/day) Show forest plot

2

2310

Mean Difference (IV, Random, 95% CI)

‐0.33 [‐0.57, ‐0.09]

11 Adverse events ‐ 'serious' events Show forest plot

4

3243

Odds Ratio (M‐H, Random, 95% CI)

0.92 [0.69, 1.25]

12 Adverse events ‐ candidiasis Show forest plot

2

Odds Ratio (M‐H, Random, 95% CI)

Subtotals only

13 Withdrawals due to adverse events Show forest plot

4

3243

Odds Ratio (M‐H, Random, 95% CI)

0.88 [0.65, 1.19]

14 Withdrawals due to worsening COPD symptoms Show forest plot

2

918

Odds Ratio (M‐H, Random, 95% CI)

0.49 [0.32, 0.74]

Figures and Tables -
Comparison 3. Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes