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Review
, 2013 (8), CD006826

Combined Corticosteroid and Long-Acting beta(2)-agonist in One Inhaler Versus Inhaled Corticosteroids Alone for Chronic Obstructive Pulmonary Disease

Affiliations
Review

Combined Corticosteroid and Long-Acting beta(2)-agonist in One Inhaler Versus Inhaled Corticosteroids Alone for Chronic Obstructive Pulmonary Disease

Luis Javier Nannini et al. Cochrane Database Syst Rev.

Abstract

Background: Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F).

Objectives: To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD).

Search methods: We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers.

Selection criteria: Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component.

Data collection and analysis: Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs.

Main results: A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials.

Authors' conclusions: Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.

Conflict of interest statement

The review authors who have been involved in this review have done so with no known conflicts of interest. None of the authors is considered a paid consultant by any pharmaceutical company that produces agents discussed in this review.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figure 3
Figure 3
Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.1 Exacerbation rates (exacerbations requiring oral corticosteroids).
Figure 4
Figure 4
Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.2 Number of participants with one or more exacerbation.
Figure 5
Figure 5
Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.3 Hospitalisations due to COPD exacerbations.
Figure 6
Figure 6
Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.4 Mortality.
Figure 7
Figure 7
Forest plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.5 Pneumonia.
Figure 8
Figure 8
Funnel plot of comparison: 1 All Combined Inhalers-Primary Outcomes, outcome: 1.4 Mortality.
Analysis 1.1
Analysis 1.1
Comparison 1 All Combined Inhalers ‐ Primary Outcomes, Outcome 1 Exacerbation rates (exacerbations requiring oral corticosteroids).
Analysis 1.2
Analysis 1.2
Comparison 1 All Combined Inhalers ‐ Primary Outcomes, Outcome 2 Number of participants with one or more exacerbation.
Analysis 1.3
Analysis 1.3
Comparison 1 All Combined Inhalers ‐ Primary Outcomes, Outcome 3 Hospitalisations due to COPD exacerbations.
Analysis 1.4
Analysis 1.4
Comparison 1 All Combined Inhalers ‐ Primary Outcomes, Outcome 4 Mortality.
Analysis 1.5
Analysis 1.5
Comparison 1 All Combined Inhalers ‐ Primary Outcomes, Outcome 5 Pneumonia.
Analysis 2.1
Analysis 2.1
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 1 Exacerbation rates.
Analysis 2.2
Analysis 2.2
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 2 Number of participants with one or more exacerbation.
Analysis 2.3
Analysis 2.3
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 3 End of treatment mean number of exacerbations per participant.
Analysis 2.4
Analysis 2.4
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 4 Number of participants with one or more exacerbations by type.
Analysis 2.5
Analysis 2.5
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 5 Exacerbations by type.
Analysis 2.6
Analysis 2.6
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 6 Mortality.
Analysis 2.7
Analysis 2.7
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 7 Mortality-cause specific.
Analysis 2.8
Analysis 2.8
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 8 Change from baseline in St George's Respiratory Questionnaire (total score).
Analysis 2.9
Analysis 2.9
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 9 Change from baseline in Transitional Dyspnoea Index (TDI).
Analysis 2.10
Analysis 2.10
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 10 Change from baseline in Chronic Respiratory Disease Questionnaire scores.
Analysis 2.11
Analysis 2.11
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 11 Change from baseline in predose FEV1.
Analysis 2.12
Analysis 2.12
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 12 Change from baseline in post‐dose FEV1.
Analysis 2.13
Analysis 2.13
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 13 End of treatment am PEF (L/min).
Analysis 2.14
Analysis 2.14
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 14 Absolute shuttle walk test.
Analysis 2.15
Analysis 2.15
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 15 Change from baseline in rescue medication usage (puffs/d).
Analysis 2.16
Analysis 2.16
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 16 Withdrawals.
Analysis 2.17
Analysis 2.17
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 17 Withdrawal due to lack of efficacy/exacerbation.
Analysis 2.18
Analysis 2.18
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 18 Withdrawals due to adverse events.
Analysis 2.19
Analysis 2.19
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 19 Adverse events-any event.
Analysis 2.20
Analysis 2.20
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 20 Adverse events-serious.
Analysis 2.21
Analysis 2.21
Comparison 2 Fluticasone/salmeterol (FPS) versus fluticasone (FP), Outcome 21 Adverse events (specific adverse events).
Analysis 3.1
Analysis 3.1
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 1 Exacerbations.
Analysis 3.2
Analysis 3.2
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 2 Mean exacerbation rates per participant per year.
Analysis 3.3
Analysis 3.3
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 3 Mortality.
Analysis 3.4
Analysis 3.4
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 4 Quality of life-SGRQ total (change scores).
Analysis 3.5
Analysis 3.5
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 5 Symptoms (change scores).
Analysis 3.6
Analysis 3.6
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 6 Breathlessness, cough and sputum score (BCSS) change from baseline-average over treatment period.
Analysis 3.7
Analysis 3.7
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 7 Awakening‐free nights, percentage change from baseline.
Analysis 3.8
Analysis 3.8
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 8 Mean FEV1 (% increase from baseline).
Analysis 3.9
Analysis 3.9
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 9 Pre‐dose FEV1 [L] change from baseline to the average over the randomised treatment period.
Analysis 3.10
Analysis 3.10
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 10 1‐Hour post‐dose FEV1 [L] change from baseline to the average over the randomised treatment period.
Analysis 3.11
Analysis 3.11
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 11 Morning PEFR change from baseline, average over treatment period (L/min).
Analysis 3.12
Analysis 3.12
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 12 Evening PEFR mean change from baseline, average over treatment period (L/min).
Analysis 3.13
Analysis 3.13
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 13 Rescue medication use.
Analysis 3.14
Analysis 3.14
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 14 Sleep score (0 to 4)-change from baseline.
Analysis 3.15
Analysis 3.15
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 15 Dyspnoea score (0 to 4)-change from baseline.
Analysis 3.16
Analysis 3.16
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 16 Cough score (0 to 4)-change from baseline.
Analysis 3.17
Analysis 3.17
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 17 Sputum score (0 to 4)-change from baseline.
Analysis 3.18
Analysis 3.18
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 18 Withdrawals due to worsening COPD symptoms.
Analysis 3.19
Analysis 3.19
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 19 Withdrawals due to adverse events.
Analysis 3.20
Analysis 3.20
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 20 Adverse event-any (one or more).
Analysis 3.21
Analysis 3.21
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 21 Adverse events-serious events.
Analysis 3.22
Analysis 3.22
Comparison 3 Budesonide/formoterol (BDF) versus budesonide (BD), Outcome 22 Adverse events (specific adverse events).
Analysis 4.1
Analysis 4.1
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 1 Patients with one or more exacerbation.
Analysis 4.2
Analysis 4.2
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 2 Mortality.
Analysis 4.3
Analysis 4.3
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 3 Change from baseline in SGRQ (total score).
Analysis 4.4
Analysis 4.4
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 4 Change from baseline in FEV1 AUC0‐12 h (mL) week 26.
Analysis 4.5
Analysis 4.5
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 5 Change from baseline in FEV1 AUC0‐12 h (mL) week 13.
Analysis 4.6
Analysis 4.6
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 6 Mean change from baseline AM pre‐dose FEV1 at 13 weeks (mL).
Analysis 4.7
Analysis 4.7
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 7 Withdrawals-total.
Analysis 4.8
Analysis 4.8
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 8 Withdrawals due to adverse event.
Analysis 4.9
Analysis 4.9
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 9 Withdrawal due to treatment failure.
Analysis 4.10
Analysis 4.10
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 10 Adverse event-any.
Analysis 4.11
Analysis 4.11
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 11 Adverse event-serious.
Analysis 4.12
Analysis 4.12
Comparison 4 Mometasone/formoterol (MF/F) versus Mometasone (MF), Outcome 12 Adverse events (specific adverse events).

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