Combination therapy of inhaled steroids and long-acting beta-agonists versus long-acting beta-agonists alone for chronic obstructive pulmonary disease

Nannini LJ, Cates CJ, Lasserson TJ, Poole P

Published Online:

May 12, 2010

Combinations of two classes of medication in one inhaler have been developed to treat people with COPD as this may make it easier to take the medication than using separate inhalers. Two types of combined inhaler exist currently: budesonide/formoterol (BDF - 'Symbicort'), and fluticasone/salmeterol (FPS - 'Advair', 'Viani' or 'Seretide'). The results of the studies showed that combined inhalers were effective and reduced the frequency of exacerbations compared with their long-acting beta-agonist component, but there was an overall increased risk of pneumonia with combined inhalers. Future research is required to show whether the drugs reduce hospitalisations, and to better estimate the increased risk of pneumonia. More trials with budesonide/formoterol are required, and comparing different doses of inhaled corticosteroids.

Abstract (click to read)

Background:

The co-administration of inhaled corticosteroids and long-acting beta-agonists in a combined inhaler is intended to facilitate adherence to medication regimens, and to improve efficacy in COPD. In this review they are compared with mono component long-acting beta-agonists.

Objectives:

To assess the efficacy of combined inhaled corticosteroids and long-acting beta-agonists preparations with mono component long-acting beta-agonists in adults with chronic obstructive pulmonary disease.

Search strategy:

We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007.

Selection criteria:

Studies were included if they were randomised and double-blind. Studies could compare a combined inhaled corticosteroids and long-acting beta-agonist preparation with component long-acting beta-agonist preparation.

Data collection and analysis:

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

Main results:

Ten studies of good methodological quality met the inclusion criteria, randomising 7598 participants with severe chronic obstructive pulmonary disease. Eight studies assessed fluticasone/salmeterol, and two studies budesonide/formoterol. The exacerbation rates with combined inhalers were reduced in comparison to long-acting beta-agonists alone (Rate Ratio 0.82, 95% CI 0.78 to 0.88). There was no significant difference in mortality between combined inhalers and long-acting beta-agonists alone. Pneumonia occurred more commonly with combined inhalers (OR 1.58; (95% CI 1.32 to 1.88). There was no significant difference in terms of hospitalisations, although the two studies contributing data to this outcome may have been drawn from differing populations. Combination was more effective than long-acting beta-agonists in improving quality of life measured by the St George Respiratory Questionnaire, and the Chronic Respiratory Questionnaire, and predose and post dose FEV1.

Authors' conclusions:

Combination therapy was more effective than long-acting beta-agonists in reducing exacerbation rates, although the evidence for the effects on hospitalisations was mixed, and requires further exploration. No significant impact on mortality was found even with additional information from the TORCH trial. The superiority of combination inhalers should be viewed against the increased risk of side-effects, particularly pneumonia. Additional studies on budesonide/formoterol are required and more information would be useful of the relative benefits and adverse event rates with different doses of inhaled corticosteroids.

This record should be cited as:

Nannini LJ, Cates CJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD006829. DOI: 10.1002/14651858.CD006829

Assessed as up to date:

August 22, 2007

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Primary Review Group:

Airways Group

PEARLS - Practical Evidence About Real Life Situations (click to read)

Clinical question:

Is the combination of a corticosteroid and long-acting beta-agonist in one inhaler more effective than long-acting beta-agonists alone for chronic obstructive pulmonary disease (COPD)?

Bottom line:

In people with COPD, compared to long-acting beta-agonists alone, use of a combination corticosteroid and long-acting beta-agonist in one inhaler can reduce exacerbations by 18 per cent, and improve quality of life and pre-dose and post-dose FEV1.The evidence for the effect on hospitalisations was mixed, and could be explained by differing risk of hospitalisation across study populations. No significant impact on mortality was found.The NNT* to prevent one exacerbation in one year was 4 (combination versus placebo).The NNT to prevent one death (combination versus placebo) in the largest study was 38.¹ The benefits of this treatment need to be balanced with the increased risk of pneumonia which is due to the added cortisone. *NNT = number needed to treat to benefit one individual. 1. Calverley P et al,TORCH investigators. N Engl J Med 2007;356:775–89.

Caveat:

Inhaled steroids for COPD carry an increased risk of pneumonia (a relative increase of around 50 per cent). In the TORCH study with rates of pneumonia of 20 per cent over 3 years in this population, the NNH** was 12. In another study with rates of 2 per cent over one year the NNH was 84.This needs further study to determine the clinical relevance as the Cochrane review does not show an increase in exacerbations or deaths despite the increase in pneumonia. **NNH = number needed to treat to cause harm in one individual.

Context:

Combinations of 2 classes of medication in one inhaler have been developed to treat people with COPD as this may make it easier to take the medications than using 2 separate inhalers. Two types of combined inhaler exist currently: budesonide/formoterol (BDF – “Symbicort”) and fluticasone/salmeterol (FPS – “Advair” “Viani” or “Seretide”).

Cochrane Systematic Review:

Nannini LJ et al. Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease. Cochrane Reviews 2007, Issue 4. Article No. CD006829. DOI: 10.1002/14651858.CD006829. This review contains 10 trials involving 7598 participants.

Authored by:

Brian R McAvoy

Cochrane Primary Health Care Field

Health topics:

Lungs & airways > Chronic obstructive pulmonary disease (stable) > Combination/additive drug treatment

Lungs & airways > Chronic obstructive pulmonary disease (stable) > Corticosteroids (inhaled, oral or intranasal)

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Independent high-quality evidence for health care decision making

Combination therapy of inhaled steroids and long-acting beta-agonists versus long-acting beta-agonists alone for chronic obstructive pulmonary disease

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