Asthma is a condition that affects the airways – the small tubes that carry air in and out of the lungs. When a person with asthma comes into contact with an asthma trigger, their 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-agonists: formoterol or salmeterol. A long-acting beta-agonist is an inhaled drug which opens the airways (bronchodilator) making it easier to breath.
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 either of regular formoterol and regular salmeterol are compared with placebo treatment in patients who are not also taking inhaled steroids. 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 the safest.
We found 10 trials on 6769 adults and adolescents, but we did not find any trials on children. We found no significant difference between the treatments, but serious adverse events were too rare to be confident that the risks are the same for both treatments. There are no trials in children; we therefore could not draw any conclusions for children and so more trials are needed.
The seven identified studies in adults did not show any significant difference in safety between formoterol and budesonide in comparison with salmeterol and fluticasone. Asthma-related serious adverse events were rare, and there were no reported asthma-related deaths. There was a single, small study comparing formoterol and beclomethasone to salmeterol and fluticasone in adults, a single study comparing formoterol and mometasone with salmeterol and fluticasone in adults, and a single study comparing formoterol and fluticasone with salmeterol and fluticasone in adults.
No studies were found in children, so no conclusion can be drawn for this age group.
Overall there is insufficient evidence to decide whether regular formoterol in combination with budesonide, beclometasone, fluticasone or mometasone have equivalent or different safety profiles from salmeterol in combination with fluticasone.
An increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta2-agonists) in chronic asthma has been demonstrated in comparison with placebo in previous Cochrane reviews. This increase was significant in trials that did not randomise participants to an inhaled corticosteroid. However, systematic reviews of trials in which each drug was randomised with an inhaled corticosteroid did not demonstrate significant increases in serious adverse events. The confidence intervals were found to be too wide to be sure that the addition of an inhaled corticosteroid renders regular long-acting beta2-agonists completely safe; there were fewer participants and insufficient serious adverse events in these trials to come to a definitive decision about the safety of combination treatments.
We set out to compare the risks of mortality and non-fatal serious adverse events in trials which have randomised patients with chronic asthma to regular formoterol versus regular salmeterol, when each are used with an inhaled corticosteroid as part of the randomised treatment.
We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked manufacturers' websites of clinical trial registers for unpublished trial data and also checked Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was August 2011.
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 and extracted outcome data. We sought unpublished data on mortality and serious adverse events from the sponsors and authors.
Ten studies on 6769 adults and adolescents met the eligibility criteria of the review. Seven studies (involving 5935 adults and adolescents) compared formoterol and budesonide to salmeterol and fluticasone. All but one study administered the products as a combined inhaler, and most used formoterol 12 µg and budesonide 400 µg twice daily versus salmeterol 50 µg and fluticasone 250 µg twice daily. There were two deaths overall (one on each combination) and neither were thought to be related to asthma.
There was no significant difference between treatment groups (formoterol/budesonide versus salmeterol/fluticasone) for non-fatal serious adverse events, either all-cause (Peto odds ratio (OR) 1.14; 95% confidence interval (CI) 0.82 to 1.59, I2 = 26%) or asthma-related (Peto OR 0.69; 95% CI 0.37 to 1.26, I2 = 33%). Over 23 weeks the rates for all-cause serious adverse events were 2.6% on formoterol and budesonide and 2.3% on salmeterol and fluticasone, and for asthma-related serious adverse events, 0.6% and 0.8% respectively.
There was one study (228 adults) comparing formoterol and beclomethasone to salmeterol and fluticasone, but there were no deaths or hospital admissions. One study (404 adults) compared formoterol and mometasone to salmeterol and fluticasone for 52 weeks, but the small number of events leaves considerable uncertainty about the comparative safety of the two products. Similarly one study (202 adults) compared formoterol and fluticasone with salmeterol and fluticasone, but there was only one serious adverse event in each group.
No studies were found in children.