Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children

Background

Most consensus statements recommend use of long-acting beta2-agonists (LABA) as adjunct therapy to inhaled corticosteroids (ICS) for poorly controlled asthma, despite the use of low-dose ICS.

Review question

What are the benefits and safety of the combination of LABA and ICS in children with persistent asthma when compared with the same dose or a higher dose of ICS alone?

What evidence did we find?

From available evidence until January 2015, we found 39 eligible studies evaluating the combination of LABA and ICS in children with persistent asthma. Of these, 28 studies compared LABA with the same dose of ICS, and the remaining studies compared LABA with a larger dose of ICS.

The number of people who had an exacerbation (worsening of symptoms) that required treatment with oral steroids was not significantly different. However, lung function improved in people taking LABA and steroids compared with the same dose of steroids only or larger doses of steroids. No evidence suggested increased serious adverse events or adverse events (also known as side effects) with the addition of LABA.

Compared with the same dose of ICS, people used less of their rescue/relief bronchodilator treatment. There was no benefit for control of asthma symptoms when LABA added to ICS was compared with higher doses of ICS. The higher dose of ICS was associated with 1.2 cm per year lower growth than was observed with the combination of LABA and a lower dose of ICS.

Conclusion

In children with persistent asthma, the combination of LABA and ICS did not reduce the risk of exacerbations requiring steroid treatment but did improve lung function when compared with the same, or a higher, dose of ICS. No differences in adverse effects were apparent, with the exception of better growth with use of ICS and LABA compared with a higher ICS dose. The trend towards increasing chances of hospital admission indicates the need for continuous monitoring and additional trials in children.

Quality of the evidence

Overall, we judged the quality of evidence to be moderate. Most outcomes showed wide confidence intervals, which led to downgrading of the quality of evidence to moderate. In a few outcomes for which open-label studies contributed data, we further downgraded evidence quality to low.

Authors' conclusions: 

In children with persistent asthma, the addition of LABA to ICS was not associated with a significant reduction in the rate of exacerbations requiring systemic steroids, but it was superior for improving lung function compared with the same or higher doses of ICS. No differences in adverse effects were apparent, with the exception of greater growth with the use of ICS and LABA compared with a higher ICS dose. The trend towards increased risk of hospital admission with LABA, irrespective of the dose of ICS, is a matter of concern and requires further monitoring.

Read the full abstract...
Background: 

Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed for children with asthma.

Objectives: 

To assess the safety and efficacy of adding a LABA to an ICS in children and adolescents with asthma. To determine whether the benefit of LABA was influenced by baseline severity of airway obstruction, the dose of ICS to which it was added or with which it was compared, the type of LABA used, the number of devices used to deliver combination therapy and trial duration.

Search strategy: 

We searched the Cochrane Airways Group Asthma Trials Register until January 2015.

Selection criteria: 

We included randomised controlled trials testing the combination of LABA and ICS versus the same, or an increased, dose of ICS for at least four weeks in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included markers of exacerbation, pulmonary function, symptoms, quality of life, adverse events and withdrawals.

Data collection and analysis: 

Two review authors assessed studies independently for methodological quality and extracted data. We obtained confirmation from trialists when possible.

Main results: 

We included in this review a total of 33 trials representing 39 control-intervention comparisons and randomly assigning 6381 children. Most participants were inadequately controlled on their current ICS dose. We assessed the addition of LABA to ICS (1) versus the same dose of ICS, and (2) versus an increased dose of ICS.

LABA added to ICS was compared with the same dose of ICS in 28 studies. Mean age of participants was 11 years, and males accounted for 59% of the study population. Mean forced expiratory volume in one second (FEV1) at baseline was ≥ 80% of predicted in 18 studies, 61% to 79% of predicted in six studies and unreported in the remaining studies. Participants were inadequately controlled before randomisation in all but four studies.

There was no significant group difference in exacerbations requiring oral steroids (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.28, 12 studies, 1669 children; moderate-quality evidence) with addition of LABA to ICS compared with ICS alone. There was no statistically significant group difference in hospital admissions (RR 1.74, 95% CI 0.90 to 3.36, seven studies, 1292 children; moderate-quality evidence)nor in serious adverse events (RR 1.17, 95% CI 0.75 to 1.85, 17 studies, N = 4021; moderate-quality evidence). Withdrawals occurred significantly less frequently with the addition of LABA (23 studies, 471 children, RR 0.80, 95% CI 0.67 to 0.94; low-quality evidence). Compared with ICS alone, addition of LABA led to significantly greater improvement in FEV1 (nine studies, 1942 children, inverse variance (IV) 0.08 L, 95% CI 0.06 to 0.10; mean difference (MD) 2.99%, 95% CI 0.86 to 5.11, seven studies, 534 children; low-quality evidence), morning peak expiratory flow (PEF) (16 studies, 3934 children, IV 10.20 L/min, 95% CI 8.14 to 12.26), reduction in use of daytime rescue inhalations (MD -0.07 puffs/d, 95% CI -0.11 to -0.02, seven studies; 1798 children) and reduction in use of nighttime rescue inhalations (MD -0.08 puffs/d, 95% CI -0.13 to -0.03, three studies, 672 children). 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.

A total of 11 studies assessed the addition of LABA to ICS therapy versus an increased dose of ICS with random assignment of 1628 children. Mean age of participants was 10 years, and 64% were male. Baseline mean FEV1 was ≥ 80% of predicted. All trials enrolled participants who were inadequately controlled on a baseline inhaled steroid dose equivalent to 400 µg/d of beclomethasone equivalent or less.

There was no significant group differences in risk of exacerbation requiring oral steroids with the combination of LABA and ICS versus a double dose of ICS (RR 1.69, 95% CI 0.85 to 3.32, three studies, 581 children; moderate-quality evidence) nor in risk of hospital admission (RR 1.90, 95% CI 0.65 to 5.54, four studies, 1008 children; moderate-quality evidence).

No statistical significant group difference was noted in serious adverse events (RR 1.54, 95% CI 0.81 to 2.94, seven studies, N = 1343; moderate-quality evidence) and no statistically significant differences in overall risk of all-cause withdrawals (RR 0.96, 95% CI 0.67 to 1.37, eight studies, 1491 children; moderate-quality evidence). Compared with double the dose of ICS, use of LABA was associated with significantly greater improvement in morning PEF (MD 8.73 L/min, 95% CI 5.15 to 12.31, five studies, 1283 children; moderate-quality evidence), but data were insufficient to aggregate on other markers of asthma symptoms, rescue medication use and nighttime awakening. There was no group difference in 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 (two studies: MD 1.21 cm/y, 95% CI 0.72 to 1.70).

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