Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews
Abstract
Background
Two large surveillance studies in adults with asthma have found an increased risk of asthma‐related mortality in those who took regular salmeterol as monotherapy in comparison to placebo or regular salbutamol. No similar sized surveillance studies have been carried out in children with asthma, and we remain uncertain about the comparative safety of regular combination therapy with either formoterol or salmeterol in children with asthma.
Objectives
We have used the paediatric trial results from Cochrane systematic reviews to assess the safety of regular formoterol or salmeterol, either as monotherapy or as combination therapy, in children with asthma.
Methods
We included Cochrane reviews relating to the safety of regular formoterol and salmeterol from a search of the Cochrane Database of Systematic Reviews conducted in May 2012, and ran updated searches for each of the reviews. These were independently assessed. All the reviews were assessed for quality using the AMSTAR tool. We extracted the data relating to children from each review and from new trials found in the updated searches (including risks of bias, study characteristics, serious adverse event outcomes, and control arm event rates).
The safety of regular formoterol and salmeterol were assessed directly from the paediatric trials in the Cochrane reviews of monotherapy and combination therapy with each product. Then monotherapy was indirectly compared to combination therapy by looking at the differences between the pooled trial results for monotherapy and the pooled results for combination therapy. The comparative safety of formoterol and salmeterol was assessed using direct evidence from trials that randomised children to each treatment; this was combined with the result of an indirect comparison of the combination therapy trials, which represents the difference between the pooled results of each product when randomised against inhaled corticosteroids alone.
Main results
We identified six high quality, up to date Cochrane reviews. Four of these related to the safety of regular formoterol or salmeterol (as monotherapy or combination therapy) and these included 19 studies in children. We added data from two recent studies on salmeterol combination therapy in 689 children which were published after the relevant Cochrane review had been completed, making a total of 21 trials on 7474 children (from four to 17 years of age). The two remaining reviews compared the safety of formoterol with salmeterol from trials randomising participants to one or other treatment, but the reviews only included a single trial in children in which there were 156 participants.
Only one child died across all the trials, so impact on mortality could not be assessed.
We found a statistically significant increase in the odds of suffering a non‐fatal serious adverse event of any cause in children on formoterol monotherapy (Peto odds ratio (OR) 2.48; 95% confidence interval (CI) 1.27 to 4.83, I2 = 0%, 5 trials, N = 1335, high quality) and smaller increases in odds which were not statistically significant for salmeterol monotherapy (Peto OR 1.30; 95% CI 0.82 to 2.05, I2 = 17%, 5 trials, N = 1333, moderate quality), formoterol combination therapy (Peto OR 1.60; 95% CI 0.80 to 3.28, I2 = 32%, 7 trials, N = 2788, moderate quality) and salmeterol combination therapy (Peto OR 1.20; 95% CI 0.37 to 2.91, I2 = 0%, 5 trials, N = 1862, moderate quality).
We compared the pooled results of the monotherapy and combination therapy trials. There was no significant difference between the pooled ORs of children with a serious adverse event (SAE) from long‐acting beta2‐agonist beta agonist (LABA) monotherapy (Peto OR 1.60; 95% CI 1.10 to 2.33, 10 trials, N = 2668) and combination trials (Peto OR 1.50; 95% CI 0.82 to 2.75, 12 trials, N = 4,650). However, there were fewer children with an SAE in the regular inhaled corticosteroid (ICS) control group (0.7%) than in the placebo control group (3.6%). As a result, there was an absolute increase of an additional 21 children (95% CI 4 to 45) suffering such an SAE of any cause for every 1000 children treated over six months with either regular formoterol or salmeterol monotherapy, whilst for combination therapy the increased risk was an additional three children (95% CI 1 fewer to 12 more) per 1000 over three months.
We only found a single trial in 156 children comparing the safety of regular salmeterol to regular formoterol monotherapy, and even with the additional evidence from indirect comparisons between the combination formoterol and salmeterol trials, the CI around the effect on SAEs is too wide to tell whether there is a difference in the comparative safety of formoterol and salmeterol (OR 1.26; 95% CI 0.37 to 4.32).
Authors' conclusions
We do not know if regular combination therapy with formoterol or salmeterol in children alters the risk of dying from asthma.
Regular combination therapy is likely to be less risky than monotherapy in children with asthma, but we cannot say that combination therapy is risk free. There are probably an additional three children per 1000 who suffer a non‐fatal serious adverse event on combination therapy in comparison to ICS over three months. This is currently our best estimate of the risk of using LABA combination therapy in children and has to be balanced against the symptomatic benefit obtained for each child. We await the results of large on‐going surveillance studies to further clarify the risks of combination therapy in children and adolescents with asthma.
The relative safety of formoterol in comparison to salmeterol remains unclear, even when all currently available direct and indirect trial evidence is combined.
PICOs
Plain language summary
Overview of the safety of regular formoterol or salmeterol in children with asthma
Asthma is a common condition that affects the airways, the small tubes that carry air in and out of the lungs. People can have underlying inflammation in their lungs and sticky mucus or phlegm may build up, which can narrow the airways. When a person with asthma comes into contact with an irritant (an asthma trigger), the muscles around the walls of the airways tighten, the airways become narrower, and the lining of the airways becomes inflamed and starts to swell. This leads to the symptoms of asthma, which are wheezing, coughing and difficulty in breathing. There is no cure for asthma; however, there are medications that allow most people to control their asthma so they can get on with daily life. People with asthma are generally advised to take inhaled corticosteroids to combat the underlying inflammation in their lungs. If asthma is still not controlled, current clinical guidelines recommend the introduction of an additional medication to help. 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, taken by inhaler, are known to improve lung function, symptoms, quality of life and to reduce the number of asthma attacks. However, the evidence for the usefulness of long‐acting beta2‐agonists is more limited in children than adults, and there are concerns about the safety of these drugs in both adults and children. We did this overview to take a closer look at the safety of formoterol or salmeterol, either alone or given in combination with corticosteroid therapy, in children with asthma.
We looked at previous Cochrane reviews on long‐acting beta2‐agonists and also searched for additional trials on long‐acting beta2‐agonists in children. We found a total of 21 trials involving 7318 children that provided information on the safety of formoterol or salmeterol given alone or combined with corticosteroids. We also found one trial on 156 children which directly compared formoterol to salmeterol.
There were more non‐fatal serious adverse events in children taking formoterol or salmeterol compared to those on placebo; for every 1000 children treated with formoterol or salmeterol over six months, 21 extra children suffered a non‐fatal event in comparison with placebo. There was a smaller and non‐significant increase in serious adverse events in children on formoterol or salmeterol and corticosteroids compared to corticosteroids alone: for every 1000 children treated with combination therapy over three months, three extra children suffered a non‐fatal event in comparison with corticosteroids alone. This number illustrates the average difference between combination therapy and corticosteroids. Our analyses showed that in fact the true answer could be between 1 fewer and 12 more children who would experience a non‐fatal event.
We did not have enough numbers from the small trial comparing formoterol to salmeterol, or from information in the other trials, to tell whether one long‐acting beta2‐agonist treatment is safer than the other. There was only one death across all the trials, so we did not have enough information to tell whether formoterol or salmeterol increases the risk of death.
