Key learning points
- Overuse of short-acting beta-agonists (SABAs) contributes to poor asthma control
- SABAs provide symptomatic relief in episodes of worsening asthma but increase airway inflammation and hyperresponsiveness
- ICS/formoterol inhalers provide symptomatic relief and also target airway inflammation and hyperresponsiveness
- There is growing evidence in the benefits of ICS/formoterol inhalers as an alternative reliever strategy
The Global Initiative for Asthma (GINA) have recently taken the unprecedented step of recommending as-needed inhaled corticosteroids (ICS)/formoterol as a preferred reliever therapy over short-acting beta-agonists (SABA) in patients with mild (Step 1 or 2) asthma.1 A growing body of evidence of adverse outcomes related to high SABA use and effectiveness of symptom-driven ICS/formoterol therapy in preventing exacerbations has informed this decision and some of the key components of this evidence are reviewed here.1
The problem with SABA inhalers
Asthma is a chronic, respiratory condition that typically causes airway inflammation.1 It is a major cause of morbidity and mortality worldwide and persistently high levels of poor disease control and asthma-related deaths are a cause for concern.2-4 There is an increasing recognition that a key part of this problem is the common and persisting overuse of SABAs.5
Compelling epidemiological evidence suggests that high levels of SABA use are associated with increased risk of exacerbations, healthcare utilisation and increased mortality.6-8 SABAs are rapid and effective bronchodilators and therefore usually provide rapid symptomatic relief in episodes of worsening asthma. Unfortunately, this temporary symptomatic improvement may ‘mask’ the negative physiological effects of frequent unopposed SABA use, including increased levels of airway inflammation and airway hyperresponsiveness, which may lead to further clinical deterioration.9,10
By contrast, inhalers containing ICS and the long-acting beta-agonist (LABA) formoterol provide prompt symptom relief due to the rapid bronchodilator action of formoterol, but also target airway inflammation and hyperresponsiveness in a synergistic fashion.11
A number of studies, summarised in a meta-analysis demonstrated a reduction in exacerbation risk when using ICS/formoterol as reliever therapy in comparison with SABA.12 The applicability of these results in clinical practice was unclear as these studies had selected patients at a higher risk of exacerbation (all had ≥1 exacerbation in the 12 months preceding the studies). However, ‘real world’ evidence, recently provided by the NOVELSTART and PRACTICAL studies has shown that use of a symptom-driven ICS/formoterol strategy reduces severe exacerbation risk in comparison with a fixed ICS/as-needed (PRN) SABA strategy.13,14
Controversy regarding GINA recommendations
The new approach suggested by GINA has not been universally welcomed, with some authors arguing that the level of evidence for ICS/formoterol is still not sufficient to recommend its use as a first-choice reliever therapy in mild asthma.15 Another criticism is based on the valid observation that many patients with mild asthma do not demonstrate eosinophilic inflammation and therefore may not benefit from inhaled ICS at any point.16
A counterpoint to this argument might consider that the longitudinal stability of phenotypes in mild asthma is unclear and that airway inflammation induced during times of deteriorating asthma may differ to that observed during periods of clinical stability.17,18
Also, other considerations relating to the replacement of SABA by ICS/LABA remain; no safety or efficacy data exist regarding the addition of an ICS/formoterol reliever inhaler to a different maintenance ICS/LABA inhaler.5,19 ICS/formoterol is not licensed in the UK and Europe for use as a reliever therapy alone. The only other combined alternative ICS/SABA is not available in the UK.
In conclusion, there is substantial evidence that adverse outcomes are associated with high doses of unopposed SABA in asthma patients and plausible mechanisms by which these adverse effects may occur. Evidence of the relative benefit of an alternative reliever strategy based on the use of ICS/formoterol is growing and has already led to changes in guidance, but solutions to practical barriers for widespread adoption of this new strategy based on further data are required.
Dr Matthew Martin, NIHR Clinical Lecturer, Nottingham NIHR Respiratory BRC, Nottingham
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