Is it safe to add regular formoterol to inhaled corticosteroid (ICS) for adults or children with asthma?
Asthma is a disease of the lungs. Symptoms include wheezing, breathlessness, and chest tightness. Two main features of asthma are underlying inflammation and bronchoconstriction (tightening of the muscles around small tubes in the lungs). The inflammation can be treated with daily steroid inhalers. The bronchoconstriction can be treated with a beta2-agonist to relax the muscles. This opens up the airways and makes it easier to breathe. Beta2-agonists can be used two ways: to provide relief from symptoms of chest tightness ('short-acting beta2-agonists') and to help prevent symptoms from occurring ('long-acting beta2-agonists', or LABAs).
When asthma is not controlled by daily low-dose ICS, many asthma guidelines recommend additional daily LABA, such as formoterol. We are confident that LABA improves lung function, symptoms, quality of life, and exacerbations. However, there is long-standing controversy about how safe these drugs are for people with asthma. This is what we wanted to explore in this review by focusing on rare and serious harms. These are defined as events that are life-threatening, require admission to hospital or prolongation of existing hospitalisation, or result in persistent or significant disability/incapacity or a birth defect.
We analysed data from 29 studies in 35,751 adults and 10 studies in 4035 children aged up to 17 years. The participants in the studies had a range of asthma severity, with most having been previously treated with regular ICS (over a wide range of doses). There were too few children in the studies to allow us to be certain about the effects in children.
Thirty deaths were reported in 35,751 adults. Seventeen of these deaths were reported in participants taking formoterol and ICS, and 13 deaths in participants who were taking ICS alone. Three deaths reported in adults taking formoterol and ICS were due to asthma, but there were no deaths due to asthma with ICS alone. No deaths were reported in children up to 17 years age.
The number of people experiencing serious harms of any cause was similar in adults with and without formoterol. Although there was no difference in the risk of serious harms in adults with asthma taking regular formoterol in combination with ICS compared to ICS alone, we could not confidently exclude a reduced or increased risk of events compared to taking ICS alone.
Quality of the evidence
We were moderately certain regarding the data in adults, but less certain about the effects of adding formoterol to ICS in children. Given the low number of deaths that occurred in the studies, we do not yet have enough information to be able to measure accurately the risk of adding formoterol to ICS on number of deaths.
Almost all trials were sponsored by drug manufacturers.
Other concerns were that the cause of serious adverse events (i.e. whether they were judged by the trialists to be asthma-related or not) were not independently assessed, and it may have been possible to guess which treatment group the person experiencing the adverse event was from. Although the people in the trial did not know whether they had been given a dummy drug or the active treatment, formoterol has quite a large effect on symptoms. This meant that they might have been able to guess who was taking formoterol. It was not possible for us to tell whether this occurred or not, which is why we primarily look at the all-cause events, which do not require assessment of cause.
We are not able to state confidently that adding formoterol to ICS carries no risk of increasing the number of deaths in comparison with ICS alone. On the other hand, we found no conclusive evidence of an increase in serious harm. Three asthma-related deaths occurred in a total of 12,777 adults treated with formoterol in combination with ICS. We found no conclusive evidence of risk of non-fatal serious harms attributed to asthma when formoterol was combined with ICS in adults.
This Plain language summary is current as of February 2019.
We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).
We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).
The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.
We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.
Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA).
To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone.
We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019.
We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks.
We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events.
We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.
Seventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).
In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).
Non-fatal serious adverse events
A total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).
Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).
Asthma-related serious adverse events
Ninety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).
Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11).