Background
Asthma is a condition that affects the airways – the small tubes that carry air into and out of the lungs. When a person with asthma comes into contact with an asthma trigger, the airways become irritated and the muscles around the walls of the airways tighten, so that the airways become narrower (bronchoconstriction) and the lining of the airways becomes inflamed and starts to swell. Sometimes, sticky mucus or phlegm builds up, which can further narrow the airways. These reactions cause the airways to become narrower and irritated - making it difficult to breathe, and leading to coughing, wheezing, shortness of breath, and tightness in the chest. People with asthma are generally advised to take inhaled steroids to combat the underlying inflammation, but if asthma is still not controlled, current clinical guidelines for people with asthma recommend the introduction of an additional medication to help. A common strategy in these situations is to use a long-acting beta-agonist: formoterol or salmeterol. A long-acting beta-agonist is an inhaled drug that opens the airways (bronchodilator), making it easier to breathe. Inhaled steroids can be added to these bronchodilators in the same inhaler. A variety of inhaled steroids are used in combined inhalers with either formoterol or salmeterol.
We know from previous Cochrane Reviews that there is a small increase in serious adverse events (such as very severe asthma attacks, as well as other life-threatening events) when regular formoterol or regular salmeterol is taken without inhaled steroids, but this increase was not seen when these drugs were used with an inhaled steroid in a single combined inhaler. This review sought information from trials that compared the two treatments (i.e. when people taking salmeterol with an inhaled corticosteroid were compared directly with people taking formoterol and an inhaled corticosteroid) to see if we could determine which drug was safer.
Study characteristics
We carried out a search for studies in February 2021. In total, we included in this review 23 randomised controlled trials comparing formoterol and inhaled corticosteroids with salmeterol and inhaled corticosteroids. Twenty-one studies with 11,572 participants included adults and adolescents. The lower age in these 21 studies varied from 12 to 16 or 18. Eight of these studies (7730 adults) compared formoterol/budesonide combination inhalers with salmeterol/fluticasone, with smaller numbers (1472, 1126, and 1075 adults) comparing the other formoterol combinations with salmeterol/fluticasone. Only 229 adults were available in studies comparing formoterol/budesonide with salmeterol/budesonide. Two studies of 723 participants included children; the age ranges in these studies were 4 to 12 and 5 to 12; both compared formoterol/fluticasone with salmeterol/fluticasone inhalers.
Key results
No certain differences could be detected between combination formoterol/inhaled corticosteroids and salmeterol/inhaled corticosteroids for all-cause mortality nor for all-cause or asthma-related non-fatal adverse events. No deaths from asthma were reported. The included studies had enough participants to assess the benefits of treatment, but they did not include enough people to determine the comparative safety of these treatments.
Quality of the evidence
In general, the included studies had low levels of bias, but there was a low incidence of mortality and serious adverse events, which reduced the certainty of the evidence for different outcomes. The quality of evidence for all-cause mortality and all-cause non-fatal serious adverse events was graded as low and moderate, respectively. The quality of evidence for asthma-related serious adverse events varied from low to very low due to small numbers of asthma-related events and lack of independent assessment of the causation of events.
Conclusions
We found no safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy in adults and children with asthma.
Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome.
We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.
Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta₂-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta₂-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments.
To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid.
We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was 24 February 2021.
We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration.
Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect.
Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229).
In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol.
In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence).
Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation.
The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence).