Abstract: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler. Deaths Eleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths). No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group. Non-fatal serious adverse events A total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27). Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22). Asthma-related serious adverse events Eighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8). Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12). We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS. Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment. However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice.

Plain-language summary: In total, we have included 41 studies in 27,951 adults and eight studies in 8453 children. Almost all studies used a combination inhaler to deliver salmeterol with ICS and compared this with the same dose of ICS for an average of six months. We did not find a difference in the risk of death or serious adverse events in either adults or children. Eleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 adults taking regular ICS at the same dose. For every 1000 adults treated for 25 weeks, researchers reported one death on ICS alone and a corresponding risk on salmeterol and ICS of one death (95% confidence Interval (CI) 0 to 2 deaths). No deaths in any studies were attributed to asthma, and researchers reported no deaths at all among children. A non-fatal serious adverse event of any cause occurred in 332 adults on regular salmeterol with ICS compared to 282 adults on regular ICS alone. For every 1000 adults treated for 25 weeks, 21 serious adverse events occurred on ICS alone, and the corresponding risk on salmeterol and ICS was 23 adults (95% CI 20 to 27). A total of 65 of 4229 children on regular salmeterol with ICS suffered a serious adverse event of any cause compared to 62 of 4224 children on regular ICS alone. For every 1000 children treated for 23 weeks, 15 serious adverse events occurred on ICS alone, and the corresponding risk on salmeterol and ICS was also 15 children (95% CI 11 to 22). Reviewers assessed the overall risk of bias for all-cause events as low. The two new large studies performed independent assessment to identify the cause of asthma-related serious adverse events. This makes current data on asthma events more reliable than previously reported. Trials reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. The risk of dying from asthma while receiving either treatment was therefore very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS. We can now say that the worst-case estimate (safety margin) from this review is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to ICS alone). These possible risks must be weighed against the benefits experienced by people who take combination treatment. People monitored in the new trials took over 90% of their prescribed treatment. This is much more than the average amount of medication that people take outside a trial. Therefore the effects shown in trials may be different from the effects experienced by people at home who are not taking their inhalers as prescribed. Because very few people die of asthma, trials would have to be very large to detect differences in the death rate. Therefore it is probably not feasible to find out if adding salmeterol to ICS causes more deaths among participants in randomised controlled trials - as these trials would be very large, difficult to run, and expensive. It might be better to use case-control studies or to review asthma deaths (e.g. from medical records).