Abstract: Five studies met the review entry criteria (5537 adults). Study populations entered the studies having previously been treated with inhaled steroids and had moderate or mild airway obstruction (mean FEV1 predicted between 65% and 84% at baseline). Most of the studies assessed treatment over a period of six months. The studies were at a low risk of selection and performance/detection bias, although we could not determine whether missing data had an impact on the results. Availablility of outcome data was satisfactory. Primary outcomes The odds ratio for exacerbations requiring oral steroids was lower with fluticasone/salmeterol but did not reach statistical significance (OR 0.89, 95% confidence interval (CI) 0.74 to 1.07, four studies, N = 4949). With an assumed risk with budesonide/formoterol of 106/1000 participants requiring oral steroids, treatment with fluticasone/salmeterol would lead to between 25 fewer and seven more people per 1000 experiencing a course of oral steroids. Although the odds of hospital admission was higher with fluticasone/salmeterol, this did not reach statistical significance (OR 1.29, 95% CI 0.68 to 2.47, four studies, 4879 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between three fewer and nine more people per 1000 would be hospitalised on fluticasone/salmeterol. The odds of a serious adverse event related to asthma was higher with fluticasone/salmeterol but did not differ significantly between treatments (OR 1.47, 95% CI 0.75 to 2.86, three studies, 4054 participants). With an assumed risk in the budesonide/formoterol of 7/1000, between two fewer and 13 more people per 1000 would experience a serious adverse event on fluticasone/salmeterol. Secondary outcomes Lung function outcomes, symptoms, rescue medication, composite of exacerbations leading to either emergency department visit or hospital admission, withdrawals and adverse events did not differ statistically between treatments. Assessment of quality of life was limited to two studies, both of which gave results that did not reach statistical significance. One study reported one death out of 1000 participants on fluticasone/salmeterol and no deaths in a similar number of participants treated with budesonide/formoterol. No deaths were reported in the other studies. Statistical imprecision in the effect estimates for exacerbations and serious adverse events do not enable us to conclude that either therapy is superior. The uncertainty around the effect estimates justify further trials to provide more definitive conclusions; the overall quality of evidence based on GRADE recommendations for the three primary outcomes and withdrawals due to serious adverse events was moderate. We rated the quality of evidence for mortality to be low. Results for lung function outcomes showed that the drugs were sufficiently similar that further research is unlikely to change the effects. No trials were identified in the under-12s and research in this population is a high priority. Evaluation of quality of life is a priority for future research.

Plain-language summary: This systematic review examined randomised controlled trials comparing two commonly available combinations administered at a fixed dose through a single inhaler, fluticasone/salmeterol and budesonide/formoterol. We included five studies which recruited 5537 people. The trials were generally well designed but only recruited adults and adolescents and not children. Participants were already taking regular inhaled steroids before the studies commenced and had mild or moderate asthma based on tests of their airway. We found that the number of people who required treatment with oral steroids and admission to hospital was similar between the treatments, but due to the statistical uncertainty of this result we could not rule out important differences in favour of either drug combination. Additional trials would enable us to draw more reliable conclusions about how well these drugs work compared with each other. We also looked at serious adverse events. Again, the results did not indicate that one combination was clearly better than the other, but again these results were imprecise so we cannot be certain. However, lung function and rescue medication use were similar between the treatments. We could not assess the relative effects of these drugs on mortality because there were so few deaths which leads to statistical uncertainty; out of the five studies, one person died. Quality of life was measured in different ways in two studies and we could not determine how the treatments compared in this respect. Further studies are needed to strengthen and better explain these findings. In particular studies which assess the effects of these therapies in children and studies which measure quality of life are a priority.