ICS-formoterol reliever versus ICS and short-acting β₂-agonist reliever in asthma: a systematic review and meta-analysis

Abstract

BackgroundThe Global Initiative for Asthma recommends as-needed inhaled corticosteroid (ICS)-formoterol as an alternative to maintenance ICS plus short-acting beta2-agonist (SABA) reliever at Step 2 of their stepwise treatment algorithm. Our aim was to assess the efficacy and safety of these two treatment regimens, with a focus on severe exacerbation prevention.MethodsWe performed a systematic review and meta-analysis of all randomised controlled trials (RCTs) comparing as-needed ICS-formoterol with maintenance ICS plus SABA. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to 12 December 2019. The primary outcome was time to first severe exacerbation. RCTs were excluded if they used as-needed budesonide-formoterol as part of a maintenance and reliever regimen, or did not report on severe exacerbations. The review is registered with PROSPERO (CRD42020154680).ResultsFour RCTs (n=8065 participants) were included in the analysis. As-needed ICS-formoterol was associated with a prolonged time to first severe exacerbation (hazard ratio 0.85, 95%CI 0.73 to 1.00; p=0.048) and reduced daily ICS dose (mean difference −177.3 mcg, 95%CI −182.2 to −172.4). Asthma symptom control was worse in the as-needed group (ACQ-5 mean difference 0.12, 95%CI 0.09 to 0.14), though did not meet the minimal clinically important difference of 0.50 units. There was no significant difference in serious adverse events (odds ratio 1.07 95%CI 0.84 to 1.36).ConclusionAs-needed ICS-formoterol offers a therapeutic alternative to maintenance low-dose ICS plus SABA in asthma and may be the preferred option if severe exacerbation prevention is the primary aim of treatment.

The cost-effectiveness of as-needed budesonide-formoterol versus low-dose inhaled corticosteroid maintenance therapy in patients with mild asthma in Canada

“…This therapeutic approach is supported by the results of two pivotal 52-week, double-blind, randomized controlled trials, SYGMA 1 [18] and SYGMA 2 [19], in patients with mild asthma, and two open-label, 52-week studies in patients with mild-to-moderate asthma (PRACTICAL) [20] or mild asthma (Novel START) [21], as well as a complementary systematic review and meta-analysis [22]. SYGMA 1, SYGMA 2 and Novel START demonstrated a comparable annual rate of severe exacerbations between as-needed budesonideformoterol and twice daily budesonide maintenance (low-dose ICS) plus as-needed terbutaline (SABA), whereas the rate was significantly lower with as-needed budesonide-formoterol in the PRACTICAL study [20].…”

Updated Australian guidelines for mild asthma: what's changed and why?

“…A recent meta-analysis of all four studies found that as-needed budesonide–formoterol reduced the risk of emergency department visits for asthma by 35% compared with regular ICS plus as-needed SABA. 16 …”

Stepping down for mild asthma and disadvantages of the ‘as‐needed’ strategy—Perspectives from a developing country

“…• Second, although there is strong evidence to support the efficacy of the as-needed strategy, assessment of the underlying airway inflammation in asthma using fractional exhaled nitric oxide (NO) measurement showed higher levels of NO in mild asthma patients with asneeded treatment compared with patients under maintenance treatment. 2 In the PRACTICAL study, NO levels were also greater after 1 year of follow-up in patients switched from ICS treatment at baseline to as-needed ICS-FOR treatment. 4 This suggests that loss of control of airway inflammation can occur with long-term as-needed treatment and contribute to worsening of asthma symptoms.…”

“…1 This strategy resulted in reducing the risk of severe exacerbation but with limited evidence of improvement in both symptom control and lung function compared with daily low-dose ICS treatment. 2 Despite the unquestionable strength of evidence provided by randomized controlled trials on the efficiency of the as-needed strategy, we are not absolutely certain about the effectiveness of this strategy when applied to real-world clinical practice in low-and middle-income countries, for these reasons:…”