Background
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 beta2-agonists, such as formoterol and salmeterol, which work by reversing the narrowing of the airways that occurs during an asthma attack. These drugs improve lung function, symptoms and quality of life, and reduce the number of asthma attacks. However, there are concerns about the safety of long-acting beta2-agonists, particularly in people who are not also taking corticosteroids. We prepared this overview to take a closer look at the safety of long-acting beta2-agonists, given alone (monotherapy) or in combination with corticosteroids (combination therapy), to adults with asthma.
How the overview was done
We looked at previous Cochrane reviews on long-acting beta2-agonists and found a total of six high-quality reviews on the safety of formoterol or salmeterol. These reviews included a total of 102 studies involving 70,980 adults or teenagers. The most recent search for new studies across all reviews was conducted in September 2013, and we added results from three further studies (1040 participants); these data have been incorporated into the overview.
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 beta2-agonists, or between the safety of formoterol and that of salmeterol. The lower estimates of risk on combination therapy support current guidelines, which advise that long-acting beta2-agonists should be used only in combination with inhaled steroids for adults with asthma. This review suggests that combination therapy is probably safer than use of long-acting beta2-agonists alone, but we do not know exactly how much safer. It is important to continue to collect information on the safety of long-acting beta2-agonists. Three large ongoing trials may provide more information.
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.
For adults with asthma that is poorly controlled on inhaled corticosteroids (ICS), guidelines suggest adding a long-acting beta2-agonist (LABA). The LABA can be taken together with ICS in a single (combination) inhaler. Improved symptom control can be assessed in the individual; however, the long-term risk of hospital admission or death requires evidence from randomised controlled trials. Clinical trials record these safety outcomes as non-fatal and fatal serious adverse events (SAEs), respectively.
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 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, I2 = 0%,13 trials, N = 30,196) but were not significantly increased in any of the other reviews: formoterol monotherapy (OR 1.26, 95% CI 0.78 to 2.04, I2 = 15%, 17 trials, N = 5758), formoterol combination (OR 0.99, 95% CI 0.77 to 1.27, I2 = 0%, 25 trials, N = 11,271) and salmeterol combination (OR 1.15, 95% CI 0.91 to 1.44, I2 = 0%, 35 trials, N = 13,447). This represents an absolute increase on any monotherapy of 43 per 10,000 over 26 weeks (95% CI 6 more to 85 more) and 16 per 10,000 over 32 weeks (95% CI 22 less to 60 more) on any combination therapy.
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).