Question:In people with chronic obstructive pulmonary disease (COPD), what are the effects of combined corticosteroid and long-acting beta-agonist (LABA) in one inhaler versus LABA alone?

Clinical Answer:

In people over age 45 with stable COPD, there is low quality evidence that a combination corticosteroid plus long-acting beta-agonist (LABA) inhaler (salmeterol/fluticasone or formoterol/budesonide) can reduce the annual rate of COPD exacerbations per patient by about one fifth compared with LABA (salmeterol or formoterol) alone, but there is moderate quality evidence that neither combination reduces mortality. Adding fluticasone to salmeterol may also improve measures of health status and measures of lung function, but there are insufficient data to determine the impact of budesonide/formoterol combination on these outcomes. The benefits of combined salmeterol/fluticasone must be weighed against the increase in adverse effects: the combination can approximately double the risk of pneumonia, and increase the risk of oral candidiasis and upper respiratory tract infections. While the available evidence does not demonstrate these same risks with adding budesonide to formoterol, this evidence is less robust than that for salmeterol/fluticasone due to the larger number of participants in the salmeterol/fluticasone trials.

Full outcome data is detailed below:

1.Any combined inhalers versus long-acting beta-agonist monotherapy

  • Population, Intervention, Comparator

    Population:

    People with moderate to severe chronic obstructive pulmonary disease

    Intervention:

    Fluticasone/salmeterol 250 mcg-500mcg/50 mcg twice daily (10 trials) or budesonide/formoterol (BDF) 320 mcg/9 mcg twice daily (2 trials)

    Comparator:

    Salmeterol 50mcg twice daily or formoterol 9 mcg twice daily

  • OUTCOME 1.1: Mortality, median 1 year

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

    Narrative result:

    Ten RCTs with 10681 participants found no statistically significant difference between groups. Click below for separate subgroup analyses of each corticosteroid combination. Most of the data on mortality come from a single large trial (3000 participants).

    Relative effect or mean difference:

    There was no statistically significant difference between groups (OR 0.92, 95% CI 0.76 to 1.11).

    Forest plot from Cochrane Review

    Absolute effect:

    7 per 1000 people (95% CI 5 to 9) with combination corticosteroid plus LABA compared with 8 per 1000 people with LABA alone.

    Reference:
    Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    • Subgroup analysis 1.1.1: Mortality - Fluticasone/salmeterol
      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases.

      Narrative result:

      Six RCTs with 7408 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (OR 0.93, 95% CI 0.76 to 1.13).

      Forest plot from Cochrane Review

      Absolute effect:

      There was no statistically significant difference between groups.

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: April 2007]
    • Subgroup analysis 1.1.2: Mortality - Budesonide/formoterol
      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases.

      Narrative result:

      Four RCTs with 3273 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (OR 1.03, 95% CI 0.40 to 2.67).

      Forest plot from Cochrane Review

      Absolute effect:

      There was no statistically significant difference between groups.

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
  • OUTCOME 1.2: Pneumonia, median 1 year

    Risk of bias of studies:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

    Narrative result:

    12 RCTs with 11076 participants found that combination corticosteroid plus LABA increased pneumonia compared with LABA alone.

    Relative effect or mean difference:

    There was a statistically significant difference between groups, in favor of LABA alone (OR 1.55, 95% CI 1.20 to 2.01).

    Forest plot from Cochrane Review

    Absolute effect:

    41 per 1000 people (95% CI 32 to 54) with combination corticosteroid plus LABA compared with 27 per 1000 people with LABA alone.

    Reference:
    Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    • Subgroup analysis 1.2.1: Pneumonia - Fluticasone/salmeterol
      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

      Narrative result:

      Nine RCTs with 8242 participants found that combination fluticasone/salmeterol increased pneumonia compared with salmeterol alone. Click below for separate subgroup analyses of each corticosteroid combination.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of LABA (OR 1.75, 95% CI 1.25 to 2.45).

      Forest plot from Cochrane Review

      Absolute effect:

      40 per 1000 people (95% CI 30 to 50) with combination corticosteroid plus LABA compared with 20 per 1000 people with LABA alone.

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: April 2007]
    • Subgroup analysis 1.2.2: Pneumonia - Budesonide/formoterol
      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

      Narrative result:

      Three RCTs with 2834 participants found no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (OR 1.09, 95% CI 0.69 to 1.73).

      Forest plot from Cochrane Review

      Absolute effect:

      There was no statistically significant difference between groups.

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
  • OUTCOME 1.3: Exacerbations, including those requiring urgent visits or hospitalization, median 1 year

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was low quality. See Summary of findings from Cochrane review

    Narrative result:

    Nine RCTs with 5696 participants found that combination corticosteroid and LABA reduced exacerbations compared with LABA alone. Click below for separate subgroup analyses of each corticosteroid combination.

    Relative effect or mean difference:

    There was a statistically significant difference between groups, in favor of combination (Rate ratio 0.76, 95% CI 0.68 to 0.84).

    Forest plot from Cochrane Review

    Reference:
    Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    Reference:
    Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    • Subgroup analysis 1.3.1: Exacerbations -Fluticasone/salmeterol
      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

      Narrative result:

      Five RCTs with 4778 participants found that combination fluticasone/salmeterol reduced exacerbations compared with salmeterol alone.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of combination (Rate ratio 0.77, 95% CI 0.66 to 0.89).

      Forest plot from Cochrane Review

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    • Subgroup analysis 1.3.2: Exacerbations -Budesonide/formoterol
      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

      Narrative result:

      Four RCTs with 918 participants found that combination budesonide/formoterol reduced exacerbations compared with formoterol alone.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of combination (Rate ratio 0.73, 95% CI 0.64 to 0.83).

      Forest plot from Cochrane Review

  • OUTCOME 1.4: Number of participants with one or more exacerbation

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

    Narrative result:

    Six RCTs with 3357 participants found that combination treatment with fluticasone/salmeterol reduced number of participants with one or more exacerbation compared with LABA. There were no trials of budesonide/formoterol that assessed this outcome.

    Relative effect or mean difference:

    There was a statistically significant difference between groups, in favor of combination (OR 0.83, 95% CI 0.70 to 0.98).

    Forest plot from Cochrane Review

    Absolute effect:

    42 per 100 people (95% CI 38 to 46) with combination compared with 47 per 100 people with LABA.

    Reference:
    Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    • OUTCOME 1.5: Lung function

      Narrative result:

      The trials assessed lung function in different ways so results for all corticosteroids could not be meta-analyzed. Results were inconsistent with different measurements. Click below for full details.

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • Subgroup analysis 1.5.1: Change from baseline in Transitional Dyspnea Index (TDI) - fluticasone/salmeterol
        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Two RCTs with 677 participants found no statistically significant difference between groups.

        Relative effect or mean difference:

        There was no statistically significant difference between groups (mean difference 0.61, 95% CI -0.47 to 1.68).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • Subgroup analysis 1.5.2: End of treatment FEV1 (Liters) - fluticasone/salmeterol
        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Two RCTs with 1780 participants found no statistically significant difference between groups.

        Relative effect or mean difference:

        There was no statistically significant difference between groups (mean difference 0.01, 95% CI -0.02 to 0.03).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • Subgroup analysis 1.5.3: Change from baseline in pre-dose FEV1 - fluticasone/salmeterol
        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Five RCTs with 798 participants found that fluticasone/salmeterol improved pre-dose FEV1 from baseline compared with salmeterol alone.

        Relative effect or mean difference:

        There was a statistically significant difference between groups, in favor of fluticasone/salmeterol (0.07 Liters, 95% CI 0.05 to 0.10).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • Subgroup analysis 1.5.4: Change from baseline in post-dose FEV1 - fluticasone/salmeterol
        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Three RCTs with 4770 participants found that fluticasone/salmeterol improved post-dose FEV1 from baseline compared with salmeterol alone.

        Relative effect or mean difference:

        There was a statistically significant difference between groups, in favor of fluticasone/salmeterol (Liters 0.05, 95% CI 0.03 to 0.06).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • Subgroup analysis 1.5.5: Change from baseline in rescue medication usage (puffs/day) - subgroup: fluticasone/salmeterol
        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Four RCTs with 2435 participants found that fluticasone/salmeterol reduced the need for rescue medication (puffs/day) compared with salmeterol alone.

        Relative effect or mean difference:

        There was a statistically significant difference between groups, in favor of combination (mean difference -0.38 puffs/day fewer than baseline, 95% CI -0.61 to -0.16).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • Subgroup analysis 1.5.6: Rescue medication usage - subgroup: budesonide/formoterol
        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Two RCTs with 2310 participants found that budesonide/formoterol reduced the need for rescue medication (puffs/day) compared with formoterol alone.

        Relative effect or mean difference:

        There was a statistically significant difference between groups, in favor of budesonide/formoterol (mean difference -0.33, 95% CI -0.57 to -0.09).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
    • OUTCOME 1.6: Quality of life measured by St George's Respiratory Questionnaire (total score) - fluticasone/salmeterol

      Risk of bias of studies:

      Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

      Narrative result:

      Six RCTs with 4700 participants found that fluticasone/salmeterol improved St George's Respiratory questionnaire total scores compared with salmeterol alone. The minimal clinically important difference (MCID) for the SGRQ is around four units and lower scores indicate less impairment.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of fluticasone/salmeterol (reduction from baseline in SGRQ units -1.58, 95% CI -2.15 to -1.01).

      Forest plot from Cochrane Review

      Reference:
      Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
      • OUTCOME 1.7: Quality of life measured by St George's Respiratory Questionnaire (total score) - budesonide/formoterol

        Risk of bias of studies:

        Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

        Narrative result:

        Four RCTs with 3442 participants found that budesonide/formoterol improved St George's Respiratory questionnaire total scores compared with formoterol alone. The minimal clinically important difference (MCID) for the SGRQ is around four units and lower scores indicate less impairment.

        Relative effect or mean difference:

        There was a statistically significant difference between groups, in favor of budesonide/formoterol (SGRQ -2.69, 95% CI -3.82 to -1.55).

        Forest plot from Cochrane Review

        Reference:
        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
        • OUTCOME 1.8: Adverse events

          Narrative result:

          The trials assessed adverse events in different ways so results for all corticosteroids could not be meta-analyzed. Click below for separate subgroup analyses of each corticosteroid combination.

          Reference:
          Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.1: Withdrawals due to adverse events - fluticasone/salmeterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Eight RCTs with 7895 participants found no statistically significant difference between groups.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 0.90, 95% CI 0.79 to 1.02).

            Forest plot from Cochrane Review

            Absolute effect:

            There was no statistically significant difference between groups.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.2: Withdrawals due to adverse events - budesonide/formoterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Four RCTs with 3243 participants found no statistically significant difference between groups.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 0.88, 95% CI 0.65 to 1.19).

            Forest plot from Cochrane Review

            Absolute effect:

            There was no statistically significant difference between groups.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.3: Adverse events - any event - fluticasone/salmeterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Nine RCTs with 8250 participants found no statistically significant difference between groups.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 1.05, 95% CI 0.93 to 1.19).

            Forest plot from Cochrane Review

            Absolute effect:

            There was no statistically significant difference between groups.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.4: Adverse events - candidiasis - fluticasone/salmeterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Six RCTs with 3118 participants found that fluticasone/salmeterol increased candidiasis compared with salmeterol alone.

            Relative effect or mean difference:

            There was a statistically significant difference between groups, in favor of salmeterol (OR 3.75, 95% CI 2.33 to 6.04).

            Forest plot from Cochrane Review

            Absolute effect:

            7 per 100 people (95% CI 5 to 11) with fps compared with 2 per 100 people with salmeterol.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.5: Adverse events - pneumonia - fluticasone/salmeterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Nine RCTs with 8242 participants found that fluticasone/salmeterol increased pneumonia compared with salmeterol alone.

            Relative effect or mean difference:

            There was a statistically significant difference between groups, in favor of salmeterol alone (OR 1.75, 95% CI 1.25 to 2.45).

            Forest plot from Cochrane Review

            Absolute effect:

            4 per 100 people (95% CI 3 to 5) with fluticasone/salmeterol compared with 2 per 100 people with salmeterol alone.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.6: Adverse events - upper respiratory tract infection - fluticasone/salmeterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Seven RCTs with 6198 participants found that fluticasone/salmeterol increased upper respiratory tract infection compared with salmeterol alone.

            Relative effect or mean difference:

            There was a statistically significant difference between groups, in favor of salmeterol (OR 1.32, 95% CI 1.12 to 1.55).

            Forest plot from Cochrane Review

            Absolute effect:

            14 per 100 people (95% CI 12 to 16) with fluticasone/salmeterol compared with 11 per 100 people with salmeterol alone.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]
          • Subgroup analysis 1.8.7: Adverse events - 'serious' events - budesonide/formoterol
            Risk of bias of studies:

            Most of the data analyzed in the review comes from trials of good design with adequate randomization and blinding procedures to minimize the risk of selection and performance or detection biases. However, many of the trials had high risk of attrition bias as they failed to report data on all of the participants randomized.

            Narrative result:

            Four RCTs with 3243 participants found no statistically significant difference between groups. The nature of the ‘serious’ adverse events was not reported.

            Relative effect or mean difference:

            There was no statistically significant difference between groups (OR 0.92, 95% CI 0.69 to 1.25).

            Forest plot from Cochrane Review

            Absolute effect:

            There was no statistically significant difference between groups.

            Reference:
            Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]

        Additional Information:

        DOI

        10.1002/cca.56

        Publication Dates

        1. Published Online: 29 JAN 2013

        CCA derived from

        Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829.pub2. [Review search date: November 2011]

        How to Cite

        In people with chronic obstructive pulmonary disease (COPD), what are the effects of combined corticosteroid and long-acting beta-agonist (LABA) in one inhaler versus LABA alone? William Cayley Jr (MD MDiv) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2012. DOI: 10.1002/cca.56.

        Further Information

        • CCA Associate editor: William Cayley Jr (MD MDiv), Professor, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
        • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.