Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children

Evidence Summaries

Level of Evidence = C
In school-aged children insufficiently controlled on inhaled corticosteroids (ICS), addition of long-acting beta2-agonist (LABA) to ICS may not prevent exacerbations requiring systemic steroids compared to using the same or an increased dose of ICS but may improve lung function endpoints. Compared to a double dose ICS, the combination of LABA and ICS appears to increase short-term growth. The quality of evidence is downgraded by study quality (unclear allocation concealment and unclear intention-to-treat adherence), and by imprecise results (wide confidence intervals).

A Cochrane review 1 included 33 studies representing 39 control-intervention comparisons with a total of 6,381 subjects. Most of the participants were inadequately controlled on current inhaled corticosteroid (ICS) dose. The addition of long-acting β2- agonists (LABA) to the same dose of ICS (28 studies) and to an increased dose of ICS (11 studies) was assessed. Salmeterol was used in 12 comparisons and formoterol in 16 comparisons.

Long-acting beta β2 agonist + inhaled corticosteroid versus same dose of inhaled corticosteroid: There was no statistically significant difference in the risk of exacerbations requiring oral steroids between treatments (RR 0.95, 95% CI 0.70 to 1.28; 12 studies, n=1,669). There was no statistically significant group difference in hospital admissions (RR 1.74, 95% CI 0.90 to 3.36, 7 studies, n=1,292) nor in serious adverse events (RR 1.17, 95% CI 0.75 to 1.85, 17 studies, n=4,021). There was a significantly greater improvement in FEV1 with the addition of LABA (inverse variance (IV) 0.08 L, 95% CI 0.06 to 0.10; 9 studies, n=1,942; MD 2.99%, 95% CI 0.86 to 5.11; 7studies, n=534), morning peak expiratory flow (PEF) (IV 10.20 L/min, 95% CI 8.14 to 12.26; 16 studies, n=39 34), reduction in use of daytime rescue inhalations (MD -0.07 puffs/d, 95% CI -0.11 to -0.02; 7 studies, n=1,798) and reduction in use of nighttime rescue inhalations (MD -0.08 puffs/d, 95% CI -0.13 to -0.03; 3 studies, 672). No significant group difference was noted in exercise-induced % fall in FEV1, symptom-free days, asthma symptom score, quality of life, use of reliever medication and adverse events. Withdrawals occurred significantly less frequently with the addition of LABA (RR 0.80, 95% CI 0.67 to 0.94; 23 studies, n=4,374).

Long-acting β2 agonist and inhaled corticosteroid versus increased dose of inhaled corticosteroids: There was no significant difference in the risk of an exacerbation requiring oral steroids between LABA+ICS and a double dose of ICS (RR 1.69, 95% CI 0.85 to 3.32; 3 studies, n=581) nor in risk of hospital admission (RR 1.90, 95% CI 0.65 to 5.54; 4 studies, n=1,008). Use of LABA was associated with greater improvement in morning PEF (MD 8.73 L/min, 95% CI 5.15 to 12.31; 5 studies, n=1,283), but data were insufficient to aggregate on other markers of asthma symptoms, rescue medication use and nighttime awakening. There was no statistically significant difference in the overall risk of all cause withdrawals (RR 0.96, 95% CI 0.67 to 1.37; 8 studies, n=1,491) nor in the risk of overall adverse effects. A significant group difference was observed in linear growth over 12 months, clearly indicating lower growth velocity in the higher ICS dose group (MD 1.21 cm/year, 95% CI 0.72 to 1.70; 2 studies). No statistical significant group difference was noted in serious adverse events (RR 1.54, 95% CI 0.81 to 2.94; 7 studies, n=1,343)

Note: The trend towards increased hospital admission with LABA and toward serious adverse health events compared with an increased dose of ICS is a matter of some concern and calls for larger, longer-term trials to clarify this issue.

References

1. Chauhan BF, Chartrand C, Ni Chroinin M et al. Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev 2015;(11):CD007949.  [PMID:26594816].


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