Combined corticosteroid and long‐acting beta<sub>2</sub>‐agonist in one inhaler versus long‐acting beta<sub>2</sub>‐agonists for chronic obstructive pulmonary disease

Luis Javier Nannini; Toby J Lasserson; Phillippa Poole

doi:10.1002/14651858.CD006829.pub2

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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 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.

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Figure 2

Study flow diagram for 2007‐2011 literature searches.

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Figure 3

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

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

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).

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

Figure 5

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

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

Figure 6

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

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Analysis 1.1

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

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Analysis 1.2

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

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Analysis 1.3

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

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Analysis 1.4

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

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Analysis 1.5

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

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Analysis 1.6

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

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Analysis 2.1

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

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Analysis 2.2

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

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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).

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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).

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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).

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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).

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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).

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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).

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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.

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Analysis 2.10

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

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Analysis 2.11

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

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Analysis 2.12

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

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Analysis 2.13

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

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Analysis 2.14

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

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Analysis 2.15

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

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Analysis 2.16

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

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Analysis 2.17

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

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Analysis 2.18

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

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Analysis 2.19

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

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Analysis 2.20

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

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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).

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Analysis 2.22

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

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Analysis 2.23

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

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Analysis 2.24

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

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Analysis 2.25

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

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Analysis 2.26

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

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Analysis 2.27

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

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Analysis 2.28

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

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Analysis 2.29

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

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Analysis 2.30

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

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Analysis 3.1

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

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Analysis 3.2

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

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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).

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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).

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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).

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Analysis 3.6

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

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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..

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Analysis 3.8

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

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Analysis 3.9

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

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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).

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Analysis 3.11

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

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Analysis 3.12

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

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Analysis 3.13

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

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Analysis 3.14

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

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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)	⊕⊕⊝⊝ low^2,3	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 low^2,3,7
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.

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

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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
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

Table 1. Search history

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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)

Table 2. Rates and NNT(H) for pneumonia

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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]

Comparison 1. Combined inhalers versus long‐acting beta‐agonists (primary outcomes)

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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]

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

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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]

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

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