The effect of adding a long-acting beta-agonist to inhaled steroids in people not previously treated with inhaled steroids

Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM

Published Online:

February 17, 2010

In patients with asthma who require daily anti-inflammatory therapy, there is insufficient evidence to support initiating therapy with a combination of inhaled corticosteroids (ICS) and long-acting ß2-agonist (LABA) rather than with inhaled corticosteroids alone. Most consensus statements recommend the addition of LABA as second line therapy, only in asthmatic individuals who remain insufficiently controlled on maintenance inhaled corticosteroids. Yet, many physicians initiate combination therapy in patients with asthma, without a prior trial of inhaled corticosteroids alone. The purpose of this review was to compare the benefit and safety profile of initiating treatment with the combination of ICS and LABA as compared to a (1) similar and (2) higher dose of ICS alone in asthmatic patients who had not received ICS previously. This review identified 28 randomised controlled trials. The combination of ICS and LABA did not reduce the risk of patients with exacerbations requiring rescue oral corticosteroids but improved lung function, symptoms and minimally reduced the use of rescue ß2-agonists as compared to a similar dose of ICS alone. Initiating ICS at a higher dose than that used with LABA in the control group significantly reduced the risk of exacerbations and study withdrawals over that observed with the combination of LABA and a lower dose of ICS; there is insufficient evidence to comment on the impact on lung function, symptoms and use of rescue ß2-agonists. The current evidence does not support use of combination therapy with LABA and ICS as first line treatment in adults and children with asthma, without a prior trial of inhaled corticosteroids.

Abstract (click to read)

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 strategy:

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 corticosteroids. There was a high level of statistical heterogeneity for FEV1 and morning peak flow. There was no statistically significant group difference in the risk of serious adverse events. Due to insufficient data we could not aggregate results for hospital admission, symptoms and other outcomes.

Authors' conclusions:

In steroid-naive patients with mild to moderate airway obstruction, the combination of ICS and LABA does not significantly reduce the risk of patients with exacerbations requiring rescue oral corticosteroids over that achieved with a similar dose of ICS alone. However, it significantly improves lung function, reduces symptoms and marginally decreases rescue ß2-agonist use. Initiation of a higher dose of ICS is more effective at reducing the risk of exacerbations requiring rescue systemic corticosteroids, and of withdrawals, than combination therapy. Although children appeared to respond similarly to adults, no firm conclusions can be drawn regarding combination therapy in steroid-naive children, given the small number of children contributing data.

This record should be cited as:

Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM. Addition of long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD005307. DOI: 10.1002/14651858.CD005307.pub2

Assessed as up to date:

June 11, 2008

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Primary Review Group:

Airways Group

Asthma topics:

Treating with Medications > Combination Inhalers

Treating with Medications > Chronic Asthma > Beta-agonists, long-acting

Treating with Medications > Chronic Asthma > Combination and additive therapies

Health topics:

Lungs & airways > Asthma (chronic) > Bronchodilators