Combined corticosteroid and long-acting beta₂-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease

Luis Javier Nannini, Phillippa Poole, Stephen J Milan, Rebecca Holmes, Rebecca Normansell
Cochrane Database of Systematic Reviews 2013, (11): CD003794

BACKGROUND: Both long-acting beta2-agonists (LABA) and inhaled corticosteroids (ICS) have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their coadministration in a combination inhaler may facilitate adherence to medication regimens and improve efficacy.

OBJECTIVES: To determine the efficacy and safety of combined ICS and LABA for stable COPD in comparison with placebo.

SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, reference lists of included studies and manufacturers' trial registries. The date of the most recent search was June 2013.

SELECTION CRITERIA: We included randomised and double-blind studies of at least four weeks' duration. Eligible studies compared combined ICS and LABA preparations with placebo.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study risk of bias and extracted data. Dichotomous data were analysed as fixed-effect odds ratios (OR) or rate ratios (RR) with 95% confidence intervals (95% CI), and continuous data as mean differences with 95% confidence intervals.

MAIN RESULTS: Nineteen studies met the inclusion criteria (with 10,400 participants randomly assigned, lasting between 4 and 156 weeks, mean 42 weeks). Studies used three different combined preparations (fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol). The studies were generally at low risk of bias for blinding but at unclear or high risk for attrition bias because of participant dropouts. 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 the combined therapies indicated that exacerbations were less frequent when compared with placebo (Rate Ratio 0.73; 95% CI 0.69 to 0.78, 7 studies, 7495 participants); the quality of this evidence when GRADE criteria were applied was rated as moderate. Participants included in these trials had on average one or two exacerbations per year, which means that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years in these individuals. An overall reduction in mortality was seen, but this outcome was dominated by the results of one study (TORCH) of fluticasone/salmeterol. Generally, deaths in the smaller, shorter studies were too few to contribute to the overall estimate. Further longer studies on budesonide/formoterol and mometasone/formoterol are required to clarify whether this is seen more widely. When a baseline risk of death of 15.2% from the placebo arm of TORCH was used, the three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was 42 (95% CI 24 to 775). All three combined treatments led to statistically significant improvement in health status measurements, although the mean differences observed are relatively small in relation to the minimum clinically important difference. Furthermore, symptoms and lung function assessments favoured combined treatments. An increase in the risk of pneumonia was noted with combined inhalers compared with placebo treatment (OR 1.62, 95% CI 1.36 to 1.94), and the quality of this evidence was rated as moderate, but no dose effect was seen. The three-year NNTH for one extra case of pneumonia was 17, based on a 12.3% risk of pneumonia in the placebo arm of TORCH. Fewer participants withdrew from the combined treatment arms for adverse events or lack of efficacy.

AUTHORS' CONCLUSIONS: Combined inhaler therapy led to around a quarter fewer COPD exacerbations than were seen with placebo. A significant reduction in all-cause mortality was noted, but this outcome was dominated by one trial (TORCH), emphasising the need for further trials of longer duration. Increased risk of pneumonia is a concern; however, this did not translate into increased exacerbations, hospitalisations or deaths. Current evidence does not suggest any major differences between inhalers in terms of effects, but nor is the evidence strong enough to demonstrate that all are equivalent. To permit firmer conclusions about the effects of combined therapy, more data are needed, particularly in relation to the profile of adverse events and benefits in relation to different formulations and doses of inhaled ICS. Head-to-head comparisons are necessary to determine whether one combined inhaler is better than the others.

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