Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: Serious adverse events

Abstract

Background: 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. Objectives: 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. Search methods: 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 We checked manufacturers' websites of clinical trial registers for unpublished trial data and also checked Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol.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. Selection criteria: 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. Data collection and analysis: 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 We sought unpublished data on mortality and serious adverse events from the sponsors and authors. Main results: 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. Authors' conclusions: 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.