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Evidence summaries

Long-Acting Beta2-Agonists in Addition to Inhaled Corticosteroids in Chronic Asthma

In adults with asthma who remain symptomatic on inhaled corticosteroids, the addition of a long-acting beta-2 agonist reduces the rate of exacerbations, improves lung function and symptoms and reduces the use of rescue medication, and may not increase serious adverse events compared to remaining on similar doses of inhaled corticosteroids as monotherapy. Level of evidence: "A"

A Cochrane review [Abstract] 1 included 77 studies with a total of 21 248 subjects (4 625 children and 16 623 adults) generally symptomatic with moderate airway obstruction despite their current inhaled corticosteroid (ICS) regimen. The duration of the intervention was between 12 and 16 weeks in 56% of the studies; 21% of the studies lasted between 4 and 8 weeks, and 23% lasted from 24 to 54 weeks. Formoterol (42 studies) or salmeterol (35 studies) were most frequently added to low-dose ICS (200 to 400 µg/day of beclomethasone or equivalent) in 49% of the studies. The addition of a daily long-acting beta-2 agonist (LABA) to ICS reduced the risk of exacerbations requiring oral steroids by 23% from 15% to 11% (RR 0.77, 95% CI 0.68 to 0.87, 28 studies, n=6808). The number needed to treat with the addition of LABA to prevent one use of rescue oral corticosteroids is 41 (29, 72), although the event rates in the ICS groups varied between 0% and 38%. Studies recruiting adults dominated the analysis (6203 adults, 605 children). The subgroup estimate for paediatric studies was not statistically significant (RR 0.89, 95% CI 0.58 to 1.39) and includes the possibility of the superiority of ICS alone in children.

Higher than usual dose of LABA was associated with significantly less benefit. The difference in the relative risk of serious adverse events with LABA was not statistically significant from that of ICS alone (RR 1.06, 95% CI 0.87 to 1.30). The addition of LABA significantly improved FEV1 (0.11 litres, 95% 0.09 to 0.13), and increased the proportion of symptom-free days (11.88%, 95% CI 8.25 to 15.50) compared to ICS monotherapy. It was also associated with a reduction in the use of rescue short-acting ß2-agonists (-0.58 puffs/day, 95% CI -0.80 to -0.35), fewer withdrawals due to poor asthma control (RR 0.50, 95% CI 0.41 to 0.61), and fewer withdrawals due to any reason (RR 0.80, 95% CI 0.75 to 0.87). There was no group difference in risk of overall adverse effects (RR 1.00, 95% CI 0.97 to 1.04), withdrawals due to adverse health events (RR 1.04, 95% CI 0.86 to 1.26) or specific adverse health events.

A systematic review 2 including 66 trials from the same pharmaceutical company, with a total of 20 966 subjects mostly with moderate to severe persistent asthma, was abstracted in DARE. The studies compared inhaled corticosteroids plus salmeterol (50μg twice daily) with inhaled corticosteroids alone. Median trial duration was 12 weeks (1 to 52 weeks). For severe asthma-related exacerbations, the summary risk difference for the combination, in a single or separate device, compared with inhaled corticosteroids alone was -0.025 (95% CI -0.036 to -0.014; 24 trials, n=7 549). There was no statistically significant difference between the two treatment groups in asthma-related hospitalisations (OR 1.07, 95% CI 0.66 to 1.73; 26 trials) nor in the risk of asthma-related death.

A Cochrane review [Abstract] 3, assessing the risk of serious adverse events in patients with chronic asthma using salmeterol with inhaled corticosteroids as compared to inhaled corticosteroids alone, included 41 studies (27 951 participants) in adults and adolescents, and 8 studies (8 453 participants) in children. Eleven deaths occurred in 14 233 adults on regular salmeterol with inhaled corticosteroids, and 13 deaths in 13 718 adults on regular inhaled corticosteroids at the same dose (Peto OR 0.80, 95% CI 0.36 to 1.78; 41 studies, n=27 951). No children died, and no adults or children died of asthma, so it remains uncertain about mortality in children and about asthma mortality in any age group. There was no statistically significant difference in the incidence of non-fatal serious adverse events between the groups: Peto OR 1.14 for adults (95% CI 0.971 to 1.33; 41 studies, n=27 951), Peto OR 1.04 for children (95% CI 0.73 to 1.48; 8 studies, n=8 453). Asthma-related serious adverse events were reported in 80 and 67 adults in each group respectively (Peto OR 1.15, 95% CI 0.83 to 1.59; 41 studies, n=27 951), and in 29 and 23 children in each treatment group (Peto OR 1.25, 95% CI 0.72 to 2.16; 8 studies, n= 8 453).

A Cochrane review [Abstract] 4 included 20 studies on adults and adolescents (10 578 participants) and 7 studies on children and adolescents (2 788 participants). The review assessed the risk of serious adverse events in patients with chronic asthma using formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone. Six deaths occurred in participants taking regular formoterol with inhaled corticosteroids, and one in a participant administered regular inhaled corticosteroids alone. The difference was not statistically significant (Peto OR 3.56, 95% CI 0.79 to 16.03; 22 studies, n=10 578). All deaths were reported in adults, and one was believed to be asthma-related.Non-fatal serious adverse events of any cause were similar for each treatment in adults (Peto OR 0.98, 95% CI 0.76 to 1.27; 22 studies, n=10 578), and an increase in events in children on regular formoterol was not statistically significant (Peto OR 1.62, 95% CI 0.80 to 3.28; 7 studies, n=2 788).Asthma-related serious adverse events on formoterol were lower in adults (Peto OR 0.49, 95% CI 0.28 to 0.88; 21 studies, n=10 208) and although they were higher in children (Peto OR 1.49, 95% CI 0.48 to 4.61; 7 studies, n=2 788), this was not statistically significant.

A Cochrane review [Abstract] 5, assessing the risk of serious adverse events in patients with chronic asthma using regular formoterol as compared to regular salmeterol included 4 studies involving 1116 adults and 156 children. All studies were open label comparing formoterol 12 μg versus salmeterol 50 μg twice daily. All patients were already taking inhaled corticosteroids. There was only one death in an adult (which was unrelated to asthma), and none in children, and there were no significant differences in non-fatal serious adverse events comparing formoterol to salmeterol in adults (Peto OR 0.77; 95% CI 0.46 to 1.28), or children (Peto OR 0.95; 95% CI 0.06 to 15.33). Over a 6 month period in studies involving adults that contributed to this analysis the percentage with serious adverse events were 5.1% for formoterol and 6.4% for salmeterol; and over a 3 month period the percentage of children with serious adverse events were 1.3% for formoterol, and 1.3% for salmeterol.

A Cochrane review [Abstract] 1 included 10 studies with a total of 3275 subjects. Studies that compared reduced dose (mean 60% reduction) combination of inhaled corticosteroid (ICS) and long acting beta agonist (LABA) to a fixed moderate/high dose ICS found no significant difference in severe exacerbations requiring oral corticosteroids (RR 1.0, 95%CI 0.76 to 1.32), withdrawal due to worsening asthma (RR 0.82, 95%CI 0.5 to 1.35) or airway inflammation. There were also significant improvements in FEV1 (change from baseline WMD 0.10, 95%CI 0.07 to 0.12), morning and evening PEF and percent rescue free days with LABA. Two studies provided outcomes for a reduced/tapering ICS dose comparison. More participants receiving the LABA/reduced ICS combination achieved a reduction in ICS dose reaching significance in one study. A significant reduction of 253 mcg beclomethasone was achieved in one study.

A Cochrane review [Abstract] 6 included 10 studies with a total of 3275 subjects. Studies that compared reduced dose (mean 60% reduction) combination of inhaled corticosteroid (ICS) and long acting beta agonist (LABA) to a fixed moderate/high dose ICS found no significant difference in severe exacerbations requiring oral corticosteroids (RR 1.0, 95%CI 0.76 to 1.32), withdrawal due to worsening asthma (RR 0.82, 95%CI 0.5 to 1.35) or airway inflammation. There were also significant improvements in FEV1 (change from baseline WMD 0.10, 95%CI 0.07 to 0.12), morning and evening PEF and percent rescue free days with LABA. Two studies provided outcomes for a reduced/tapering ICS dose comparison. More participants receiving the LABA/reduced ICS combination achieved a reduction in ICS dose reaching significance in one study. A significant reduction of 253 mcg beclomethasone was achieved in one study.

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    References

    • Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev 2010;(5):CD005535. [PubMed].
    • Bateman E, Nelson H, Bousquet J, Kral K, Sutton L, Ortega H, Yancey S. Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events. Ann Intern Med 2008;149(1):33-42. [PubMed][DARE]
    • Cates CJ, Schmidt S, Ferrer M et al. Inhaled steroids with and without regular salmeterol for asthma: serious adverse events. Cochrane Database Syst Rev 2018;(12):CD006922. [PubMed]. [PubMed].
    • Cates CJ, Jaeschke R, Schmidt S et al. Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2013;(6):CD006924. [PubMed].
    • Cates CJ, Lasserson TJ. Regular treatment with formoterol versus regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2012;(3):CD007695. [PubMed].
    • Gibson PG, Powell H, Ducharme F. Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children. Cochrane Database Syst Rev 2005;(4):CD005076. [PubMed]

Primary/Secondary Keywords