Background In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled ß2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids. Objectives To determine the effect of the combination of long-acting ß2 agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the risk of asthma exacerbations, pulmonary function and on other measures of asthma control, and to look for characteristics associated with greater benefit for either treatment option. Search methods We identified randomised controlled trials (RCTs) through electronic database searches (MEDLINE, EMBASE and CINAHL), bibliographies of RCTs, clinical trial registries and correspondence with manufacturers until May 2008. Selection criteria RCTs that compared the combination of inhaled LABA and ICS to a higher dose of inhaled corticosteroids, in children and adults with asthma. Data collection and analysis Two authors independently assessed methodological quality and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was the number of patients experiencing one or more asthma exacerbations requiring oral corticosteroids. Main results This review included 48 studies (15,155 participants including 1155 children and 14,000 adults). Participants were inadequately controlled on their current ICS regimen, experiencing ongoing symptoms and with generally moderate (FEV1 60% to 79% of predicted) airway obstruction. The studies tested the combination of salmeterol or formoterol with a median dose of 400 mcg/day of beclomethasone or equivalent (BDP-eq) compared to a median of 1000 mcg/day of BDP-eq, usually for 24 weeks or less. There was a statistically significantly lower risk of exacerbations requiring systemic corticosteroids in patients treated with LABA and ICS (RR 0.88, 95% CI 0.78 to 0.98, 27 studies, N = 10,578) from 11.45% to 10%, with a number needed to treat of 73 (median study duration: 12 weeks). The study results were dominated by adult studies; trial data from three paediatric studies showed a trend towards increased risk of rescue oral steroids (RR 1.24, 95% CI 0.58 to 2.66) and hospital admission (RR 2.21, 95% CI 0.74 to 6.64) associated with combination therapy. Overall, there was no statistically significant difference in the risk ratios for either hospital admission (RR 1.02, 95% CI 0.67 to 1.56) or serious adverse events (RR 1.12, 95% CI 0.91 to 1.37). The combination of LABA and ICS resulted in significantly greater but modest improvement from baseline in lung function, symptoms and rescue medication use than with higher ICS dose. Despite no significant group difference in the risk of overall adverse events (RR 0.99, 95% CI 0.95 to 1.03), there was an increase in the risk of tremor (RR 1.84, 95% CI 1.20 to 2.82) and a lower risk of oral thrush (RR 0.58, 95% CI 0.40 to 0.86)) in the LA...

Background Long-acting inhaled ß2-adrenergic agonists (LABAs) are recommended as ’add-on’ medication to inhaled corticosteroids (ICS) in the maintenance therapy of asthmatic adults and children aged two years and above. Objectives To quantify in asthmatic patients the safety and efficacy of the addition of LABAs to ICS in patients insufficiently controlled on ICS alone. Search methods We identified randomised controlled trials (RCTs) through electronic database searches (the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers until May 2008. Selection criteria We included RCTs if they compared the addition of inhaled LABAs versus placebo to the same dose of ICS in children aged two years and above and in adults. Data collection and analysis Two review authors independently assessed studies for methodological quality and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was the relative risk (RR) of asthma exacerbations requiring rescue oral corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), rescue beta2-agonist use, symptoms, withdrawals and adverse events. Main results Seventy-seven studies met the entry criteria and randomised 21,248 participants (4625 children and 16,623 adults). Participants were generally symptomatic at baseline with moderate airway obstruction despite their current ICS regimen. Formoterol or salmeterol were most frequently added to low-dose ICS (200 to 400 μg/day of beclomethasone (BDP) or equivalent) in 49% of the studies. The addition of a daily 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, 6808 participants). 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 adult participants versus 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 led to a significantly greater improvement in FEV1 (0.11 litres, 95% 0.09 to 0.13) and in 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 statistically significant group difference ...

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Background Consensus statements recommend the addition of long-acting inhaled ß2-agonists (LABA) only in asthmatic patients who are inadequately controlled on inhaled corticosteroids (ICS). It is not uncommon for some patients to be commenced on ICS and LABA together as initial therapy. Objectives To compare the efficacy of combining inhaled corticosteroids with long-acting ß2-agonists (ICS+LABA) with inhaled corticosteroids alone (ICS alone) in steroid-naive children and adults with persistent asthma. We assessed two protocols: (1) LABA + ICS versus a similar dose of ICS (comparison 1) and (2) LABA + ICS versus a higher dose of ICS (comparison 2). Search methods We identified randomised controlled trials through electronic database searches (May 2008). Selection criteria Randomised trials comparing ICS + LABA with ICS alone in children and adults with asthma who had no inhaled corticosteroids in the preceding 28 days prior to enrolment. Data collection and analysis Each author assessed studies independently for risk of bias and extracted data. We obtained confirmation from the trialists when possible. The primary endpoint was rate of patients with one or more asthma exacerbations requiring rescue systemic corticosteroids. Results are expressed as relative risks (RR) for dichotomous data and as mean differences (MD) or standardised mean differences (SMD) for continuous data. Main results Twenty-eight study comparisons drawn from 27 trials (22 adult; five paediatric) met the review entry criteria (8050 participants). Baseline data from the studies indicated that trial populations had moderate or mild airway obstruction (FEV1 65% predicted), and that they were symptomatic prior to randomisation. In comparison 1, the combination of ICS and LABA was not associated with a significantly lower risk of patients with exacerbations requiring oral corticosteroids (RR 1.04; 95% confidence interval (CI) 0.73 to 1.47) or requiring hospital admissions (RR 0.38; 95% CI 0.09 to 1.65) compared to a similar dose of ICS alone. The combination of LABA and ICS led to a significantly greater improvement from baseline in FEV1 (0.12 L/sec; 95% CI 0.07 to 0.17), in symptoms (SMD −0.26; 95% CI −0.37 to −0.14) and in rescue ß2-agonist use (−0.41 puffs/day; 95% CI −0.73 to −0.09) compared with a similar dose of ICS alone. There was no significant group difference in the risk of serious adverse events (RR 1.15; 95% CI 0.64 to 2.09), any adverse events (RR 1.02; 95% CI 0.96 to 1.09), study withdrawals (RR 0.95; 95% CI 0.82 to 1.11), or withdrawals due to poor asthma control (RR 0.94; 95% CI 0.63 to 1.41). In comparison 2, the combination of LABA and ICS was associated with a higher risk of patients requiring oral corticosteroids (RR 1.24; 95% CI 1 to 1.53) and study withdrawal (RR 1.31; 95% CI 1.07 to 1.59) than a higher dose of ICS alone. For every 100 patients treated over 43 weeks, nine patients using a higher dose ICS compared to 11 (95% CI 9 to 14) on LABA and ICS suffered one or more exacerbations requiring rescue oral cortico...

BackgroundLong‐acting ß2‐ agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed in asthmatic children.ObjectivesTo compare the safety and benefit of adding LABA to ICS with the same or an increased dose of ICS in children with persistent asthma.Search strategyWe searched the Cochrane Airways Group Asthma Trials Register (May 2008).Selection criteriaWe 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.Data collection and analysisStudies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible.Main resultsA 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 FEV1 at baseline was 80% of predicted or above in 10 studies; FEV1 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 FEV1 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 FEV1, 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).Authors' conclusionsIn 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.Plain Language SummaryAddition of long‐acting beta‐agonists to inhaled corticosteroids for chronic asthma in childrenMost consensus statements recommend the use of long‐acting ß2‐agonists (LABA) as adjunct therapy to inhaled corticosteroids for poorly controlled asthma. The purpose of this review was to identify the benefits and safety profile of adding long‐acting ß2‐agonists to inhaled corticosteroids in asthmatic children. Based on the identified paediatric randomised trials, the addition of long‐acting ß2‐agonists did not significantly reduce the risk of asthma exacerbations requiring rescue systemic steroids, but improved lung function compared to ongoing treatment with a similar dose of inhaled corticosteroids. There was no evidence of increased serious side effects or withdrawals with the addition of long‐acting ß2‐agonists. Compared to doubling the dose of inhaled corticosteroids, the combination of LABA and inhaled steroids did not lead to a significant reduction in the rate of moderate exacerbations or hospital admissions, but it improved lung function and lead to greater growth.