Overview of Reviews
Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews
Editorial Group: Cochrane Airways Group
Published Online: 6 FEB 2014
Assessed as up-to-date: 3 SEP 2013
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD010314. DOI: 10.1002/14651858.CD010314.pub2.
- Publication Status: New
- Published Online: 6 FEB 2014
For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta
To assess the risk of serious adverse events in adults with asthma treated with regular maintenance formoterol or salmeterol compared with placebo, or when randomly assigned in combination with regular ICS, compared with the same dose of ICS.
We included Cochrane reviews on the safety of regular formoterol and salmeterol from a June 2013 search of the Cochrane Database of Systematic Reviews. We carried out a search for additional trials in September 2013 and incorporated the new data. All reviews were independently assessed for inclusion and for quality (using the AMSTAR tool). We extracted from each review data from trials recruiting adults (participants older than 12 or 18 years of age).
We combined the results from reviews on formoterol and salmeterol to assess the safety of twice-daily regular LABA as a class effect, both as monotherapy versus placebo and as combination therapy versus the same dose of ICS.
We did not combine the results of direct and indirect comparisons of formoterol and salmeterol, or carry out a network meta-analysis, because of concerns over transitivity assumptions that posed a threat to the validity of indirect comparisons.
We identified six high-quality, up-to-date Cochrane reviews. Of these, four reviews (89 trials with 61,366 adults) related to the safety of regular formoterol or salmeterol as monotherapy or combination therapy. Two reviews assessed safety from trials in which adults were randomly assigned to formoterol versus salmeterol. These included three trials with 1116 participants given monotherapy (all prescribed background ICS) and 10 trials with 8498 adults receiving combination therapy. An additional search for trials in September 2013 identified five new included studies contributing data from 693 adults with asthma treated with combination formoterol/fluticasone in comparison with the same dose of inhaled fluticasone, as well as from 447 adults for whom formoterol monotherapy was compared with placebo.
No trials reported separate results in adolescents. Overall, risks of bias for the primary outcomes were assessed as low.
Death of any cause
None of the reviews found a significant increase in death of any cause from direct comparisons; however, none of the reviews could exclude the possibility of a two-fold increase in mortality on regular formoterol or salmeterol (as monotherapy vs placebo or as combination therapy versus ICS) in adults with asthma. Pooled mortality results from direct comparisons were as follows: formoterol monotherapy (odds ratio (OR) 4.49, 95% confidence interval (CI) 0.24 to 84.80, 13 trials, N = 4824), salmeterol monotherapy (OR 1.33, 95% CI 0.85 to 2.08, 10 trials, N = 29,128), formoterol combination (OR 3.56, 95% CI 0.79 to 16.03, 25 trials, N = 11,271) and salmeterol combination (OR 0.90, 95% CI 0.31 to 2.6, 35 trials, N = 13,447). In each case, we did not detect heterogeneity, and the quality of evidence was rated as moderate. Absolute differences in mortality were very small, translating into an increase of 7 per 10,000 over 26 weeks on any monotherapy (95% CI 2 less to 23 more) and 3 per 10,000 over 32 weeks on any combination therapy (95% CI 3 less to 17 more).
Very few deaths were reported in the combination therapy trials, and combination therapy trial designs were different from those of monotherapy trials. Therefore we could not use indirect evidence to assess whether regular combination therapy was safer than regular monotherapy.
Only one death occurred in the monotherapy trials comparing formoterol versus salmeterol, so evidence was insufficient to compare mortality.
Non-fatal serious adverse events of any cause
Direct evidence showed that non-fatal serious adverse events were increased in adults receiving salmeterol monotherapy (OR 1.14, 95% 1.01 to 1.28, I
Direct comparisons of formoterol and salmeterol detected no significant differences between risks of all non-fatal events in adults (as monotherapy or as combination therapy).
Available evidence from the reviews of randomised trials cannot definitively rule out an increased risk of fatal serious adverse events when regular formoterol or salmeterol was added to an inhaled corticosteroid (as background or as randomly assigned treatment) in adults or adolescents with asthma.
An increase in non-fatal serious adverse events of any cause was found with salmeterol monotherapy, and the same increase cannot be ruled out when formoterol or salmeterol was used in combination with an inhaled corticosteroid, although possible increases are small in absolute terms.
However, if the addition of formoterol or salmeterol to an inhaled corticosteroid is found to improve symptomatic control, it is safer to give formoterol or salmeterol in the form of a combination inhaler (as recommended by the US Food and Drug Administration (FDA)). This prevents the substitution of LABA for an inhaled corticosteroid if symptom control is improved on LABA.
The results of three large ongoing trials in adults and adolescents are awaited; these will provide more information on the safety of combination therapy under less supervised conditions and will report separate results for the adolescents included.
Plain language summary
Overview of the safety of regular formoterol or salmeterol in adults with asthma
Asthma is a common condition that affects the airways. When a person with asthma comes into contact with an irritant, the muscles around the walls of the airways tighten and the lining of the airways becomes inflamed and starts to swell. This leads to the symptoms of asthma—wheezing, coughing and difficulty in breathing. No cure for asthma is known; however, there are medications that allow most people to control their asthma so they can get on with daily life.
People with asthma can have underlying inflammation in their lungs, and they are generally advised to take inhaled corticosteroids to combat this inflammation. If asthma still is not controlled, additional medications may be used. One type of additional medication is the long-acting beta
How the overview was done
We looked at previous Cochrane reviews on long-acting beta
We compared formoterol or salmeterol monotherapy versus placebo, and formoterol or salmeterol combination therapy versus corticosteroids alone. We then used the results of these comparisons to look for differences between monotherapy and combination therapy. We also looked at formoterol and salmeterol separately to see whether one was safer than the other, either as monotherapy or as combination therapy. For each comparison, we looked first at risks of death and non-fatal serious adverse events from any cause, and second at risks of death and non-fatal serious adverse events related to asthma.
What was found
The risk of fatal or non-fatal serious adverse events was lower overall in trials with adults taking randomly assigned inhaled corticosteroids, but we found no significant difference between monotherapy and combination therapy in the impact of treatment on risk of death or serious adverse events.
We saw no differences between formoterol and salmeterol monotherapy in risk of death or serious adverse events from any cause or in risk of death or serious adverse events related to asthma. We saw no differences between formoterol and salmeterol combination therapy in the number of deaths or serious adverse events from any cause or in the risk of death related to asthma.
We found no clear differences between the safety of monotherapy and that of combination therapy with long-acting beta