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Review
. 2012 Sep 12;2012(9):CD006829.
doi: 10.1002/14651858.CD006829.pub2.

Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease

Luis Javier Nannini  1 , Toby J Lasserson, Phillippa Poole
Affiliations
Review

Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease

Luis Javier Nannini et al. Cochrane Database Syst Rev. .

Abstract

Background: Both inhaled steroids (ICS) and long-acting beta(2)-agonists (LABA) are used in the management of chronic obstructive pulmonary disease (COPD). This updated review compared compound LABA plus ICS therapy (LABA/ICS) with the LABA component drug given alone.

Objectives: To assess the efficacy of ICS and LABA in a single inhaler with mono-component LABA alone in adults with COPD.

Search methods: We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search was November 2011.

Selection criteria: We included randomised, double-blind controlled trials. We included trials comparing compound ICS and LABA preparations with their component LABA preparations in people with COPD.

Data collection and analysis: Two authors independently assessed study risk of bias and extracted data. The primary outcomes were exacerbations, mortality and pneumonia, while secondary outcomes were health-related quality of life (measured by validated scales), lung function, withdrawals due to lack of efficacy, withdrawals due to adverse events and side-effects. Dichotomous data were analysed as random-effects model odds ratios or rate ratios with 95% confidence intervals (CIs), and continuous data as mean differences and 95% CIs. We rated the quality of evidence for exacerbations, mortality and pneumonia according to recommendations made by the GRADE working group.

Main results: Fourteen studies met the inclusion criteria, randomising 11,794 people with severe COPD. We looked at any LABA plus ICS inhaler (LABA/ICS) versus the same LABA component alone, and then we looked at the 10 studies which assessed fluticasone plus salmeterol (FPS) and the four studies assessing budesonide plus formoterol (BDF) separately. The studies were well-designed with low risk of bias for randomisation and blinding but they had high rates of attrition, which reduced our confidence in the results for outcomes other than mortality.Primary outcomes There was low quality evidence that exacerbation rates in people using LABA/ICS inhalers were lower in comparison to those with LABA alone, from nine studies which randomised 9921 participants (rate ratio 0.76; 95% CI 0.68 to 0.84). This corresponds to one exacerbation per person per year on LABA and 0.76 exacerbations per person per year on ICS/LABA. Our confidence in this effect was limited by statistical heterogeneity between the results of the studies (I(2) = 68%) and a risk of bias from the high withdrawal rates across the studies. When analysed as the number of people experiencing one or more exacerbations over the course of the study, FPS lowered the odds of an exacerbation with an odds ratio (OR) of 0.83 (95% CI 0.70 to 0.98, 6 studies, 3357 participants). With a risk of an exacerbation of 47% in the LABA group over one year, 42% of people treated with LABA/ICS would be expected to experience an exacerbation. Concerns over the effect of reporting biases led us to downgrade the quality of evidence for this effect from high to moderate.There was no significant difference in the rate of hospitalisations (rate ratio 0.79; 95% CI 0.55 to 1.13, very low quality evidence due to risk of bias, statistical imprecision and inconsistency). There was no significant difference in mortality between people on combined inhalers and those on LABA, from 10 studies on 10,680 participants (OR 0.92; 95% CI 0.76 to 1.11, downgraded to moderate quality evidence due to statistical imprecision). Pneumonia occurred more commonly in people randomised to combined inhalers, from 12 studies with 11,076 participants (OR 1.55; 95% CI 1.20 to 2.01, moderate quality evidence due to risk of bias in relation to attrition) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There were no significant differences between the results for either exacerbations or pneumonia from trials adding different doses or types of inhaled corticosteroid.Secondary outcomes ICS/LABA was more effective than LABA alone in improving health-related quality of life measured by the St George's Respiratory Questionnaire (1.58 units lower with FPS; 2.69 units lower with BDF), dyspnoea (0.09 units lower with FPS), symptoms (0.07 units lower with BDF), rescue medication (0.38 puffs per day fewer with FPS, 0.33 puffs per day fewer with BDF), and forced expiratory volume in one second (FEV(1)) (70 mL higher with FPS, 50 mL higher with BDF). Candidiasis (OR 3.75) and upper respiratory infection (OR 1.32) occurred more frequently with FPS than SAL. We did not combine adverse event data relating to candidiasis for BDF studies as the results were very inconsistent.

Authors' conclusions: Concerns over the analysis and availability of data from the studies bring into question the superiority of ICS/LABA over LABA alone in preventing exacerbations. The effects on hospitalisations were inconsistent and require further exploration. There was moderate quality evidence of an increased risk of pneumonia with ICS/LABA. There was moderate quality evidence that treatments had similar effects on mortality. Quality of life, symptoms score, rescue medication use and FEV(1) improved more on ICS/LABA than on LABA, but the average differences were probably not clinically significant for these outcomes. To an individual patient the increased risk of pneumonia needs to be balanced against the possible reduction in exacerbations.More information would be useful on the relative benefits and adverse event rates with combination inhalers using different doses of inhaled corticosteroids. Evidence from head-to-head comparisons is needed to assess the comparative risks and benefits of the different combination inhalers.

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Conflict of interest statement

The authors who have been involved in this review have done so without any known conflicts of interest. None of the authors are considered a paid consultant by any pharmaceutical company which produces agents discussed in this review.

Figures

1
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.
2
2
Study flow diagram for 2007‐2011 literature searches.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
4
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).
5
5
Forest plot of comparison: 1 Combined inhalers versus Long‐acting beta2‐agonists (Primary Outcomes), outcome: 1.2 Mortality.
6
6
Forest plot of comparison: 1 Combined inhalers versus long‐acting beta2‐agonists (primary outcomes), outcome: 1.3 Pneumonia.
1.1
1.1. Analysis
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 1 Exacerbation rates (combined inhaler versus LABA alone).
1.2
1.2. Analysis
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 2 Number of participants with one or more exacerbation.
1.3
1.3. Analysis
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 3 Hospitalisations.
1.4
1.4. Analysis
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 4 Mortality.
1.5
1.5. Analysis
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 5 Pneumonia.
1.6
1.6. Analysis
Comparison 1 Combined inhalers versus long‐acting beta‐agonists (primary outcomes), Outcome 6 Pneumonia subgrouped by dose.
2.1
2.1. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 1 Exacerbations by type.
2.2
2.2. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 2 Mortality by duration.
2.3
2.3. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (total score).
2.4
2.4. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).
2.5
2.5. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).
2.6
2.6. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 6 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).
2.7
2.7. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 7 End of treatment St George's Respiratory Questionnaire scores (total score).
2.8
2.8. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 8 End of treatment St George's Respiratory Questionnaire scores (domain ‐ symptoms).
2.9
2.9. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 9 Change from baseline in Chronic Respiratory Disease Questionnaire scores.
2.10
2.10. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 10 End of treatment Transitional dyspnea index (TDI).
2.11
2.11. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 11 End of treatment symptom scores.
2.12
2.12. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 12 Change from baseline in Transitional Dyspnoea Index (TDI).
2.13
2.13. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 13 Change in MRC rated dyspnoea.
2.14
2.14. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 14 Change from baseline in dyspnoea score.
2.15
2.15. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 15 Mean Change nighttime awakenings.
2.16
2.16. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 16 Change from baseline in predose FEV1.
2.17
2.17. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 17 Change from baseline in postdose FEV1.
2.18
2.18. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 18 End of treatment FEV1 (Litres).
2.19
2.19. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 19 FEV1 (% predicted ‐ absolute scores).
2.20
2.20. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 20 Change from baseline in am PEF (L/min).
2.21
2.21. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 21 Change from baseline in rescue medication usage (puffs/day).
2.22
2.22. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 22 End of treatment rescue medication usage (puffs/day).
2.23
2.23. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 23 Adverse events ‐ any event.
2.24
2.24. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 24 Adverse events ‐ candidiasis.
2.25
2.25. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 25 Adverse events ‐ pneumonia.
2.26
2.26. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 26 Adverse events ‐ headache.
2.27
2.27. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 27 Adverse events ‐ upper respiratory tract infection.
2.28
2.28. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 28 Withdrawals.
2.29
2.29. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 29 Withdrawals due to lack of efficacy.
2.30
2.30. Analysis
Comparison 2 Fluticasone and salmeterol (FPS) versus salmeterol (SAL), secondary outcomes, Outcome 30 Withdrawals due to adverse events.
3.1
3.1. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 1 Quality of life ‐ SGRQ (change scores).
3.2
3.2. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 2 Quality of life ‐ SGRQ (change scores).
3.3
3.3. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 3 Change from baseline in St George's Respiratory Questionnaire (domain ‐ symptoms).
3.4
3.4. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 4 Change from baseline in St George's Respiratory Questionnaire (domain ‐ activity).
3.5
3.5. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 5 Change from baseline in St George's Respiratory Questionnaire (domain ‐ impact).
3.6
3.6. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 6 Mean FEV1 (% increase from baseline).
3.7
3.7. Analysis
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..
3.8
3.8. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 8 Symptoms ‐ breathlessness (change scores).
3.9
3.9. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 9 Change from baseline in cough score.
3.10
3.10. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 10 Change from baseline in rescue medication usage (puffs/day).
3.11
3.11. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 11 Adverse events ‐ 'serious' events.
3.12
3.12. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 12 Adverse events ‐ candidiasis.
3.13
3.13. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 13 Withdrawals due to adverse events.
3.14
3.14. Analysis
Comparison 3 Budesonide and formoterol (BDF) versus formoterol (F), secondary outcomes, Outcome 14 Withdrawals due to worsening COPD symptoms.
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References

References to studies included in this review

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Mahler 2002 {published and unpublished data}
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Rennard 2009 {published data only}
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SCO100470 {unpublished data only}
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TORCH {published and unpublished data}
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TRISTAN {published and unpublished data}
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    1. Calverley PMA, Pauwels RA, Vestbo J, Jones PW, Pride NB, Gulsvik A, et al. Salmeterol/fluticasone propionate combination for one year provides greater clinical benefit than its individual components. Proceedings of the 98th International American Thoracic Society Conference http://www.abstracts‐on‐line.com/abstracts/ATS. 2002:A98 [Poster 306].
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References to studies excluded from this review

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Lindberg 2007 {published data only}
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Schermer 2007 {published data only}
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References to other published versions of this review

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