Combined Corticosteroid and Long-Acting Beta-Agonist in One Inhaler for Chronic Obstructive Pulmonary Disease

A Cochrane review [Abstract] 1 included 15 studies comparing the efficacy of combined inhaled corticosteroids (ICS) and long-acting beta-agonists to mono-component inhaled corticosteroids in adults with chronic obstructive pulmonary disease (COPD), with a total of 7 814 subjects with predominantly poorly reversible, severe COPD. Three different combination preparations (fluticasone/salmeterol [FPS], budesonide/formoterol [BDF], and mometasone furoate/formoterol [MF/F]) were used. Exacerbation rates requiring oral corticosteroids were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, n=5 601) compared with ICS alone. No significant difference in the rate of hospitalisations due to COPD exacerbations was observed (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, n=7 060). Mortality was lower with combined treatment (OR 0.78, 95% CI 0.64 to 0.94; 12 studies, n=7 518) 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. Lung function data favoured combination treatment, 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. The odds of pneumonia were not significantly different after combination treatment than after mono-component steroid (OR 1.08, 95% CI 0.91 to 1.28; 12 studies, n=7 315).

Another Cochrane review 2 (abstract , review [Abstract]) included 14 studies comparing the efficacy of combined inhaled corticosteroids and long-acting beta-agonists to mono-component long-acting beta-agonists (LABA), with a total of 11 794 adult subjects with severe COPD. Ten studies assessed fluticasone/salmeterol, and 4 studies budesonide/formoterol. The exacerbation rates with combined inhalers were reduced in comparison to long-acting beta-agonists alone (rate ratio 0.76, 95% CI 0.68 to 0.84). There was no significant difference in mortality between combined inhalers and long-acting beta-agonists alone. Pneumonia occurred more commonly with combined inhalers (OR 1.55, 95% CI 1.20 to 2.01) with an annual risk of around 3% on LABA alone compared to 4% on combination treatment. There was no significant difference in terms of hospitalisations. Combination was more effective than LABA in improving quality of life and FEV₁. Candidiasis (OR 3.75, 95% CI 2.33 to 6.04) and upper respiratory infection (OR 1.32, 95% CI 1.12 to 1.55) occurred more frequently with FPS than salmeterol only. Adverse event data relating to candidiasis for BDF studies were not combined as the results were very inconsistent.

Another Cochrane review 3 (abstract , review [Abstract]) included 19 studies comparing the efficacy of combined inhaled corticosteroids and long-acting beta-agonists to placebo in adults with COPD, with a total of 10 400 patients. Three different combination preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol) were used. Compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations. Mometasone/formoterol reduced the number of participants experiencing one or more exacerbation. Pooled analysis of combination therapies indicated that exacerbations were less frequent when compared with placebo (rate ratio 0.73, 95% CI 0.69 to 0.78; 7 studies, n=7 495). There was an overall reduction in mortality (OR 0.82, 95% CI 0.68 to 0.99; 16 studies,n=10 129), but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. The three year NNT to prevent one extra death was 42 (95% CI 24 to 775; baseline risk 15.2%). All three combined treatments led to statistically significant improvement in health status measurements, although the clinical importance of the differences observed is open to interpretation. Symptoms and lung function assessments favoured combination treatments. There was an increase in the risk of pneumonia with combined inhalers (OR 1.62, 95% CI 1.36 to 1.94). The three year NNTH for one extra case of pneumonia was 17 (95% CI 27 to 12; baseline risk 12.3%). Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy.

The following decision support rules contain links to this evidence summary:

• Combined corticosteroid and long-acting beta-agonist for COPDhttp://www.ebmeds.org/ebmeds/ebmeds_home.asp?mode=scripts&submode=view&id=scr00421&country=UK

References

• Nannini LJ, Poole P, Milan SJ et al. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;(8):CD006826. [PubMed].
• Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012;(9):CD006829. [PubMed].
• Nannini LJ, Poole P, Milan SJ et al. Combined corticosteroid and long-acting beta2-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013;(11):CD003794. [PubMed].