Addition of long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children

Abstract

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...

Safety of formoterol in asthma clinical trials: an update

“…However, the data reported in the present paper, together with the many other meta-analyses and systematic reviews of the existing literature that have been undertaken [5][6][7][8][9][10][11][12][13], are consistent with the likelihood that the problem associated with use of LABAs in asthma is not an intrinsic safety issue related to the LABA itself, but to the overall management of the condition and the lack of appropriate treatment with ICS [23,28,32]. A number of Cochrane reviews [33][34][35][36][37] have addressed the safety of LABA/ICS combinations compared to use of ICS alone, and concluded that while combination therapy in general is favourable compared to ICS-alone treatment in adults, the results are less clear in children for whom limited data are yet available. The FDA trials, which appropriately mandate that all patients are treated with an ICS, are markedly underpowered for any outcome related to mortality, but are well powered to examine SAEs related to asthma as well as other SAEs [22].…”

Current recommendations for the treatment of mild asthma

“…In a 2009 Cochrane review, 27 trials including 8050 participants with mild to moderate asthma (12 trials with a mean baseline FEV 1 ≥80% predicted) evaluated the efficacy of a LABA+ICS combination therapy compared to ICS therapy alone in steroid-naïve persistent asthma patients 21. When comparing LABA+ICS versus a similar dose of ICS, combination therapy did not significantly lower the risk of exacerbations requiring oral steroids, or exacerbations requiring hospital admissions compared with ICS therapy alone.…”

A 12-week open-label, randomized, controlled trial and 24-week extension to assess the efficacy and safety of fluticasone propionate/formoterol in children with asthma

“…Treatment with ICS/LABA combinations has been shown to significantly improve lung function, reduce symptoms, and decrease the need for rescue medication with SABAs compared with ICS alone [Ni Chroinin et al 2009]. Furthermore, the use of single-inhaler ICS/LABA combinations has been shown to increase patients' treatment adherence compared with separate inhalers [Murphy and Bender, 2009], which may improve outcomes.…”