Abstract: 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. 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. Furthermore, we note there has been some debate about the appropriateness of the analysis conducted in the TORCH trial (see Feeback). 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. Importantly, we cannot comment on the relative contribution of the individual components of combined therapy to the effects identified, as this review presents only the pair-wise comparison between combined therapy and placebo. 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.

Plain-language summary: Nineteen studies involving 10,400 people were included in this review. The studies lasted between 4 and 156 weeks. All of the people included in the studies had COPD of different severity. Both men and women were included, and most of the studies included only adults aged 45 or older. All studies compared a combined inhaler with a placebo that was identical in appearance to the combined inhaler, so the people in the trials did not know whether they were taking the drug or the dummy inhaler. Some of the studies included two groups treated with the combined inhaler; one group was getting a higher dose and one group was getting a lower dose. The evidence presented here is current to June 2013. Most of the studies were sponsored by the pharmaceutical industry. We found that people receiving a combined inhaler were less likely to have a flare-up (‘exacerbation’) of their COPD. The chance of having an exacerbation was reduced by about one quarter. A small reduction in the risk of death was seen over three years, although most of the evidence about death comes from one large, long trial called TORCH. According to TORCH, approximately 42 people would need to be treated with a combined inhaler for three years to prevent one death. We also found that people receiving combined inhalers had small improvements in quality of life, symptoms related to COPD and their breathing tests. However, these improvements may not have been very noticeable to them. People treated with combined inhalers were more likely to have a lung infection called pneumonia. Again, most of the evidence about pneumonia comes from the TORCH trial. According to TORCH, when compared with placebo, for approximately every 17 people treated with combined inhaler, one extra person would get pneumonia. People treated with combined inhalers were no more or less likely to experience serious unwanted events, including side effects, during treatment. No consistent differences were found between the three different types of inhalers included in this review. However, it is important to note that we cannot tell from this review whether it is the combination that is important or whether one of the two drugs in the combined inhaler may have had the real impact. The evidence presented in this review is generally considered to be of moderate quality. Most of the studies did not clearly explain how they decided which people would receive the combined inhaler and which would receive placebo, and this is an important part of a well-conducted study. Also, more people receiving placebo dropped out of the trials than those receiving a combined inhaler. This often happened because of exacerbations of COPD. This means that by the end of the trial, the groups might have been unbalanced, and this could affect the accuracy of the results.