Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children.
BACKGROUND
Long-acting ss(2)- agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed in asthmatic children.


OBJECTIVE
To compare the safety and benefit of adding LABA to ICS with the same or an increased dose of ICS in children with persistent asthma.


METHODS
We searched the Cochrane Airways Group Asthma Trials Register (May 2008).


METHODS
We included randomised controlled trials testing the combination of LABA and ICS versus the same or an increased dose of ICS for minimum of at least 28 days in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included pulmonary function, symptoms, adverse events, and withdrawals.


METHODS
Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible.


RESULTS
A total of 25 trials representing 31 control-intervention comparisons were included in the review randomising 5572 children. Most of the participants were inadequately controlled on current ICS dose. We assessed the addition of LABA to the same dose of ICS and to an increased dose of ICS:(1) The addition of LABA to ICS was compared to same dose ICS, namely 400 mcg/day of beclomethasone or less in 16 of the 24 studies. The mean age of participants was 10 years and males accounted for 64% of the study populations. The mean FEV(1) at baseline was 80% of predicted or above in 10 studies; FEV(1) 61% to 79% of predicted in eight studies; and unreported in the remaining study. Participants were inadequately controlled before randomisation in all but seven studies. Compared to ICS alone, the addition of LABA to ICS was not associated with a significant reduction in exacerbations requiring oral steroids (seven studies, RR 0.92 95% CI 0.60 to 1.40). Compared to ICS alone, there was a significantly greater improvement in FEV1 with the addition of LABA (nine studies; 0.08 Litres, 95% CI 0.06 to 0.11) but no statistically significant group differences in symptom-free days, hospital admission, quality of life, use of reliever medication, and adverse events. Withdrawals occurred significantly less frequently with the addition of LABA.(2) A total of seven studies assessed the addition of LABA to ICS therapy compared with an increased dose of ICS randomising 1021 children. The mean age of participants was 8 years with 67% of males. The baseline mean FEV(1) was 80% of predicted or above in 2 of the 3 studies reporting this characteristic. All trials enrolled participants who were inadequately controlled on a baseline dose equivalent to 400 mcg/day of beclomethasone or less. There was no group significant difference in the risk of an exacerbation requiring oral steroids with the combination of LABA and ICS compared to a double dose of ICS (two studies, RR 1.5 95% CI 0.65 to 3.48). The increased risk of hospital admission with combination therapy was also not statistically significant (RR 2.21 95% CI 0.74 to 6.64). Compared to double dose ICS, use of LABA was associated with a significantly greater improvement in morning PEF (four studies; MD 7.55 L/min 95% CI: 3.57 to 11.53) and evening PEF L/min (three studies, MD 5.5 L/min; 95% CI 1.21 to 9.79), but there were insufficient data to aggregate data on FEV(1), symptoms, rescue reliever use, and quality of life. There was no statistically significant difference in the overall risk of all cause withdrawals (five studies; RR 0.71; 95% CI 0.42 to 1.20. There was no group difference in the risk of overall adverse effects detected. Short term growth was significantly greater in children treated with combination therapy compared to double dose ICS (two studies: MD 1.2 cm/year; 95% CI 0.72 to 1.7).


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 was superior for improving lung function compared to the same dose of ICS. Similarly, compared to a double dose ICS, the combination of LABA and ICS did not significantly increase the risk of exacerbations requiring oral steroids, but was associated with a significantly greater improvement in PEF and growth. The possibility of an increased risk of rescue oral steroids and hospital admission with LABA therapy needs to be further examined.
Ni Chroinin
Muireann
M
Division of Children's Services, Cork University Hospital, Cork, Ireland.
Lasserson
Toby J
TJ
Greenstone
Ilana
I
Ducharme
Francine M
FM
D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000009:adverse effects; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy; D001507:Beclomethasone / Q000008:administration & dosage / Q000009:adverse effects; D002648:Child; D004359:Drug Therapy, Combination; D004983:Ethanolamines / Q000008:administration & dosage; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D000068299:Salmeterol Xinafoate
D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D004983:Ethanolamines; D000068299:Salmeterol Xinafoate; D001507:Beclomethasone; D000420:Albuterol; D000068759:Formoterol Fumarate