Abstract: The review includes 26 trials comparing salmeterol to placebo and eight trials comparing with salbutamol. These included 62,815 participants with asthma (including 2,599 children). In six trials (2,766 patients), no serious adverse event data could be obtained. All-cause mortality was higher with regular salmeterol than placebo but the increase was not significant (Peto odds ratio (OR) 1.33 (95% CI 0.85 to 2.08)). Non-fatal serious adverse events were significantly increased when regular salmeterol was compared with placebo (OR 1.15 95% CI 1.02 to 1.29). One extra serious adverse event occurred over 28 weeks for every 188 people treated with regular salmeterol (95% CI 95 to 2606). There is insufficient evidence to assess whether the risk in children is higher or lower than in adults. We found no significant increase in fatal or non-fatal serious adverse events when regular salmeterol was compared with regular salbutamol. We combined individual patient data from the two largest studies (SNS: n=25,180 and SMART: n=26,355), as all the asthma-related deaths in adults occurred in these studies. In patients who were not taking inhaled corticosteroids, compared to regular salbutamol or placebo, there was a significant increase in risk of asthma-related death with regular salmeterol (Peto OR 6.15 95% CI 1.73 to 21.84). The confidence interval for patients who were taking inhaled corticosteroids is wide and cannot rule in or out an increase in asthma mortality in the presence of an inhaled corticosteroid (Peto OR 2.03 95% CI 0.82 to 5.00). In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol. There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies. Although the increase in asthma-related mortality was smaller in patients taking inhaled corticosteroids at baseline, the confidence interval is wide, so we cannot conclude that the inhaled corticosteroids abolish the risks of regular salmeterol. The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied.

Plain-language summary: There was no statistically significant difference in the number of people who died during treatment with salmeterol compared with placebo or salbutamol. Because so few people die of asthma, huge trials or observational studies are normally required to detect a difference in death rates from asthma. There were more non-fatal serious adverse events in people taking salmeterol compared to those on placebo; for every 188 people treated with salmeterol for 28 weeks, one extra non-fatal event occurred in comparison with placebo. There was no significant differences in serious adverse events in people on salmeterol compared to regular salbutamol. In order to obtain individual patient data on asthma deaths, we looked separately at mortality in two large trials on over 51,000 patients who were not taking inhaled corticosteroids, and found that there was an increase in the number of asthma-related deaths among people on salmeterol. We conclude that, for patients whose asthma is not well-controlled on moderate doses of inhaled corticosteroids, additional salmeterol can improve symptoms but this may be at the expense of an increased risk of serious adverse events and asthma related mortality. Salmeterol should not be used as a substitute for inhaled corticosteroids, and adherence with inhaled steroids should be kept under review if separate inhalers are used. Salmeterol should not be taken by people who are not taking regular inhaled steroids due to the increased risk of asthma-related death.