FormalPara Key Summary Points

Appropriate use of ICS-based maintenance treatment with SABA as an as-needed reliever is an effective and safe treatment for patients with asthma.

There is no scientific evidence from randomised controlled trials of a causal link between SABA use as a reliever and mortality or serious adverse events (including exacerbations).

Increased SABA use warns of a deterioration in asthma control, and patients at risk of this should be rapidly identified to ensure they are receiving adequate ICS-based controller therapy. Issues of inhaler technique and treatment adherence should be regularly checked and addressed.

Any patient concerns and/or knowledge gaps should be addressed by encouragement and educational activities to ensure the appropriate use of their inhaled controller and reliever medications.

Introduction

The role of as-needed inhaled short-acting β2-agonists (SABAs) in the management of asthma has become the subject of a debate as a result of disparities between asthma management guidelines [1,2,3,4,5,6,7,8,9] and differing opinions among the respiratory professional community [10,11,12,13], while there is universal agreement that inhaled corticosteroids (ICS) are the most effective anti-inflammatory treatment for asthma [1,2,3,4,5,6,7,8,9, 12,13,14]. The Global Initiative for Asthma (GINA) now recommends as-needed low-dose ICS-formoterol for symptom relief (symptom driven approach) for mild asthma and ICS-formoterol maintenance and reliever therapy (MART) for moderate to severe asthma (track 1) in preference to as-needed SABA plus ICS (step 1) and regular dosing with an ICS-containing maintenance therapy plus SABA as-needed with all severities of asthma over steps 2 to 4 (track 2) [1]. Whereas other guidelines still recommend a strategy of maintenance ICS-based therapy complemented with as-needed SABA used as reliever medication (proactive regular dosing approach) [2,3,4,5,6, 8, 9]. It is recognised that adherence to controller therapy is often suboptimal in asthma [1], particularly in patients with mild asthma; for these patients, proactive efforts are required to address issues of poor adherence [13, 15]. The Asthma Patients’ and Physicians’ Perspectives on the Burden and Management of Asthma 2 (APPaRENT 2) online survey showed that physicians most often prescribed a proactive regular dosing regimen of ICS/long-acting β2-agonist (LABA) with or without as-needed SABA for patients with moderate-to-severe asthma, suggesting physicians were more aligned to GINA 2021 track 2 recommendations than track 1 (MART) [16].

Several previous publications have equated the use of as-needed SABA with the use of SABAs as monotherapy and this inconsistent message can be confusing to the medical community [17]. Today, the use of SABA as monotherapy is discouraged [1]. As the discussions over the role of as-needed SABA continue in the professional community, it has been highlighted on both sides of the debate that any fundamental changes to recommendations require further clinical research to make any changes more widely acceptable [12, 13, 18, 19]. In this article, we examine the evidence for the appropriate use of SABA as a reliever medication in the management of asthma, together with a critique of data that has led to the condemnation of SABA used as a reliever. Our aim is not to compare the two reliever strategies of ICS-formoterol and as-needed SABA, as this has been addressed in a previous review article by Domingo and Singh [13]; here we focus on the role of as-needed SABA as a complementary reliever to regular ICS-based maintenance treatment. This article is based on a review of previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Current Positioning of SABAs as Reliever Medications

SABA Responsiveness (Reversibility) to Confirm Asthma Diagnosis

Positive responsiveness (‘reversibility’) to SABA, defined as an increase from baseline in forced expiratory volume in 1 s (FEV1) of greater than 200 mL or more than 12% after inhaled SABA, is a diagnostic criterion for asthma in adults and children aged 6–11 years [1].

SABA Used as Reliever as Part of a Regular ICS-Based Treatment Strategy

Proactive regular dosing with an ICS-containing maintenance therapy plus SABA as-needed is an effective treatment option for patients with asthma who are adherent to treatment [2, 20, 21]. Regular use of low-dose ICS is associated with a reduction in asthma-related hospitalisations and a decreased risk of death from asthma [22,23,24], and discontinuation of ICS can be detrimental [22]. Specific scenarios where as-needed SABA would be the only reliever available for use with ICS-based therapy would be (i) maintenance treatment with ICS alone, ICS/LABA (track 2), or ICS/LABA/long-acting muscarinic antagonist (LAMA), (ii) for asthma exacerbations treated in emergency situations where a patient’s peak inspiratory flow may preclude the use of a dry powder inhaler, (iii) for paediatric indication in mild asthma (this is the only option available in children up to 12 years).

The complementary use of SABA as-needed as a reliever is for the treatment of acute bronchospasm and should be required infrequently when asthma is well controlled. The anti-inflammatory effects of this treatment strategy are associated with regular ICS-based therapy.

In children with asthma, as-needed SABA is the sole reliever medication recommended in children under 5 years (all GINA steps) and in children aged 6–11 years (GINA steps 1 and 2) [1]. As-needed SABA is also a preferred reliever medication for children aged 6–11 years at GINA steps 3 and 4, to complement regular daily ICS or ICS/LABA treatment.

Prevention of Exercise-Induced Bronchoconstriction

SABA is one of the most effective treatments for preventing intermittent exercise-induced bronchoconstriction in both patients without asthma and those with asthma who otherwise have well-controlled disease [25, 26].

Treatment of Acute Asthma Exacerbations

In primary care and emergency care settings (emergency department, during hospitalization, or in intensive care unit), immediate and repeated administrations of inhaled SABA via pressurised metered dose inhaler (pMDI), pMDI plus spacer, or nebulization are recommended as the initial treatment for exacerbations [1, 27]. A shortage of SABA inhalers during the COVID-19 pandemic reinforced the importance of the role of inhaled SABA in managing asthma [10].

Challenges to Appropriate SABA Use as a Reliever Medication

Overuse of SABA When ICS is Underused

Patient adherence to ICS-based maintenance treatment is often poor in the real world [1], despite the need for regular ICS treatment as evidenced by high healthcare resource use and high SABA usage patterns [28,29,30]. A fear of corticosteroids or a lack of understanding of the requirement for regular treatment [31, 32] may incline patients to underuse their regular ICS maintenance treatment and to use their SABA inhalers more frequently. Patients who use their regular ICS treatment correctly and have well-controlled asthma should have little need for reliever medication [2]. In a retrospective cohort database study of adults and adolescents with asthma (n = 343,520), patients who received appropriate amounts of ICS in the previous 12 months (defined as 50% or more of their total inhaler prescriptions in the preceding year being ICS or ICS/LABA) were significantly less likely to use SABAs inappropriately in the following year (odds ratio 0.10; 95% CI 0.10–0.11) [33].

Discussion and Debate of SABA Use IN Asthma (SABINA) Programme

The SABINA programme investigated the global burden of SABA use and associations with asthma-related outcomes, and comprised three main pillars: SABINA I, SABINA II and SABINA III [34] (Table 1). Data from the SABINA studies have been published in several peer-reviewed articles [35,36,37,38], and some of these have been cited in articles challenging the role of SABA in asthma management [11, 39] as well as in recent revisions to the GINA strategy document [1].

Table 1 Overview of published SABINA trials
Full size table

Whilst a strength of the SABINA programme is in the magnitude of the programme and its ambitious aim to assess the burden of SABA globally, there are several limitations to the study designs and hence interpretation of these data (Table 1). All of the SABINA studies were observational, retrospective studies which traditionally represent an opportunity to raise questions regarding a specific topic but provide a lower level of evidence than randomised controlled trials (RCTs) and meta-analyses. In all studies, SABA prescriptions were used as a proxy for SABA use [35,36,37,38]; additionally in SABINA III, data for SABA over-the-counter purchases were based on patient recall at the study visit. Across the SABINA studies, SABA use of three or more canisters per year was varyingly referred to as ‘high use’, ‘overuse’, ‘excessive use’ and ‘overprescription’. There is currently no universally accepted or validated definition of SABA overuse [40]. The origination of the threshold of three canisters came from a study based on a medication claims database that evaluated asthma exacerbations (not mortality) and which did not provide baseline data for asthma treatment or severity of asthma [41].

In the reporting of results in the SABINA studies, clear claims were made of the associations between SABA overuse and poor asthma-related outcomes including the increased risk of exacerbations [35, 36], and mortality [35], but less scrutiny was given to the characteristics of the patients included in the studies. Baseline data in SABINA I showed among all patients with asthma only 18% had at least 75% of days covered with ICS prescriptions, 35% had received no ICS prescriptions and 13% had had at least one exacerbation in the previous year [36]. In the Swedish cohort of SABINA II, of patients who collected three or more canisters of SABA in the baseline year (34%), on average 26.5% were not being treated with any ICS and 22% were prescribed oral corticosteroids (OCS) [35] (Table 2). Baseline patient characteristics differed widely across groups with medication and resource use data indicating that patients who collected more canisters had more severe symptoms compared to those collecting fewer canisters. Of note, the pattern of SABA overuse continued with approximately 85% of patients with asthma who overused SABA at baseline continuing to overuse them during the 3-year observation period, and the proportion of all patients not being treated with ICS almost doubled during this time [35]. These data indicate that a substantial proportion of patients were being insufficiently treated for their asthma, may have had poor asthma control (no asthma control assessments were done/reported), and continued to be insufficiently treated, despite the warning signals of high SABA use and OCS prescriptions. Other points worthy of mention are that, for patients in SABINA I categorised as British Thoracic Society (BTS) steps 3–5, only 9% experienced at least two exacerbations in the baseline year [36]; and during a 9-year follow-up of 365,324 patients in the Swedish cohort, of those who had collected more than three SABA canisters in the baseline year, 21 had died from asthma, representing just 1.72% of all deaths during this period [35].

Table 2 Select baseline characteristics by SABA canisters collected in the previous year (SABINA II Swedish cohort)
Full size table

While the statistical findings in the SABINA studies suggest an association between more SABA use and worse outcomes (e.g. exacerbations and mortality), there is no proof of a causal link, and no plausible mechanism discussed. From a statistical point of view, to show an independent association between increased SABA use and worse asthma outcomes would require adjustment for all confounding factors, particularly those relating to asthma control. Several of the SABINA studies conducted multivariable analyses that adjusted for various patient characteristics, but the only variable indicative of ‘asthma control’ was history of exacerbations in the prior year [35, 36, 38]. After adjustment for these factors the association between SABA use and worse outcomes was attenuated but remained significant; however, with a variable as strongly correlated with poor asthma control as SABA use is, there is a high likelihood that confounding variables remain. To demonstrate that SABA use is causally related to poor outcomes, the adjustments made would require completely removing the confounding factor of poor asthma control and the factors which lead to it, and unfortunately, the SABINA database is not rich enough to allow for such adjustments. The use of some language suggestive of a causal link is problematic—for example, by referring to dose-dependent or dose–response effects [35, 36], or claims that such data support the need for “limiting access” to [42] or “phasing out” of SABAs [11]. What the SABINA studies do show is that patients who use their SABA inhalers frequently do not use regular ICS appropriately, and it is this underuse of ICS that may put patients at risk of poor outcomes [1, 30].

The differences in recommendations across asthma treatment guidelines and in the opinions of respiratory specialists on the role of as-needed SABA may partly be due to a lack of clear evidence from the key studies that evaluated the efficacy of ICS/formoterol regimens in mild asthma, resulting in the call for more data to align expert opinions and global guidelines on asthma treatment [13].

Evidence for Appropriate SABA Use as a Reliever

SABA Onset of Action

Inhaled salbutamol has a fast onset of action resulting in bronchodilator effects within a few minutes of inhalation [43, 44]. Compared with ICS/formoterol, salbutamol has been shown to have a similar [45] or slightly faster onset of action [44]. In a randomised, crossover, single-dose study in adults with stable, mild to moderate asthma comparing budesonide/formoterol Turbuhaler with salbutamol pMDI, over a 30-min time course, there was strong evidence of a higher FEV1 with salbutamol, but no difference in perceived breathlessness [44].

No Evidence of Causal Link Between SABA Use as a Reliever and Mortality or Adverse Events

No studies have demonstrated a causal link between SABA use as a reliever and mortality. A systematic literature review and meta-analysis of 24 RCTs conducted over the past 25 years demonstrated no evidence of excess mortality with SABA when used as a reliever monotherapy (fixed dose or as-needed) with average SABA use across studies of 4–7 canisters per year [17]. This study also showed no causal link between SABA use as a reliever and increased serious adverse events (including exacerbations), supporting the well-tolerated profile of SABAs, especially salbutamol, when used appropriately as prescribed by the physician. In a prospective, study of 203 patients diagnosed with new-onset adult asthma in Finland, patients were followed up for 12 years to determine the prevalence of high SABA use as a reliever, defined as at least 36 SABA canisters dispensed in 12 years (average of three or more SABA canisters per year) [46]. During the 12 years of follow-up, patients were dispensed an average of six canisters of SABA and 48 canisters of ICS, corresponding to a median use two SABA puffs and 11 ICS puffs per week. Only 10% of the patients were classified as high SABA users during this period. High SABA users were more likely to be obese and have more comorbidities than patients who were not high SABA users, consistent with the SABINA II cohort in which the use of antidepressants, hypnotics and sedatives was greater in patients with SABA overuse [35]. In addition, a greater proportion of high SABA users had uncontrolled asthma and severe asthma (despite high ICS adherence), indicating these patients should be recognised and treated appropriately in clinical practice [46].

Studies that have been cited as showing a link between SABA use as a reliever and poorer outcomes in fact demonstrated that regular use of low-dose ICS (measured as number of ICS canisters in the previous year) was associated with a decreased risk of death from asthma [22] and the prevention of a large proportion of asthma-related hospital admissions [23], supporting the premise that poorly controlled and asthma undertreated with ICS is the reason for poor asthma-related outcomes, rather than SABA overuse per se. This is further supported by studies that have demonstrated significant associations between poorly controlled asthma and increased numbers of asthma-related hospitalisations and emergency room visits [47, 48]. Similar findings are seen in the SABINA II study (Fig. 3, [35]), when exacerbation-free survival was evaluated in SABA over users with and without ICS treatment; the number of subjects in the group of SABA overuse (more than 11 canister/year) free of exacerbations at 36 months was double in the group treated with ICS versus those not treated with ICS.

Monitoring of SABA Use as an Indicator of Asthma Control and Impending Exacerbations

The frequency of SABA use as a reliever is an integral component of the most commonly used and validated asthma control tools (Asthma Control Test, Childhood Asthma Control Test, Asthma Control Questionnaire, Asthma Therapy Assessment Questionnaire [49]), as well as the non-validated GINA assessment of asthma control which stipulates a cutoff of at most two puffs per week, together with no daytime symptoms, no night-time awakening and no activity limitations, to indicate well-controlled asthma [1]. The GINA assessment does not include the frequency of as-needed ICS-formoterol, and therefore cannot be used in patients on ICS-formoterol treatment regimens. A benefit of the asthma control tools is that they can give a weekly measure of the frequency of reliever use, highlighting if a patient is overusing their reliever inhaler so that a healthcare professional can understand the reasons for overuse (e.g. low adherence, poor inhaler technique, step-up in controller therapy required) and initiate any action.

An analysis of individual measures of asthma control using data from the Gaining Optimal Asthma controL (GOAL) study showed that adjusting the dose of ICS or ICS/LABA to achieve well-controlled asthma reduced SABA use as a reliever [50]. In accordance with this, a 3-year real-life study of regular ICS-based maintenance treatment and as-needed SABA aimed at achieving sustained asthma control showed that this strategy resulted in improvements in airway hyperresponsiveness together with lung function improvements, symptom control and decreased reliever use (Fig. 1) [51]. In an Australian pharmacy-based survey of 412 patients, those using SABA appropriately were significantly more likely to have well-controlled asthma than SABA over users [52].

Fig. 1
figure 1

Time course for changes in lung function, symptoms, rescue use and airway hyperresponsiveness. (i) Mean morning and evening PEF (L/min). (ii) > 75% Rescue and symptom-free days and nights (proportion of patients). (iii) Geometric mean PC20 (mg/mL). PEF, peak expiratory flow; PC20, provocation concentration of methacholine causing 20% fall in forced expiratory volume in 1 s. Reprinted from Respiratory Medicine, 103:348–355, 2009, Lundbäck B et al., Asthma control over 3 years in a real-life study, Copyright (2008) with permission from Elsevier

Full size image

Monitoring of daily SABA has also been shown to be a useful indicator of an impending asthma exacerbation [53]. A post hoc analysis of the AUSTRI study demonstrated that, in patients with a history of severe asthma exacerbations, reliever medication use was higher pre exacerbation and post exacerbation than the average for non-exacerbating patients [53]. Close attention to such patterns could prevent exacerbations of asthma by prompting patients to implement their asthma action plan or reminding them to take their regular controller therapy. Appropriate SABA use as an infrequent reliever is to complement regular ICS, and in exchange, regular ICS supports appropriate SABA use by managing underlying inflammation to minimize symptoms [13].

Practical Solutions to Ensure Appropriate SABA Use as a Reliever in Clinical Practice

Several practical solutions can be employed by healthcare professionals to help ensure the appropriate use of SABAs as a reliever medication (Fig. 2). Patients at risk of overusing their SABA relievers should be identified, including patients having more asthma-related primary care visits in the past year [33], patients with a history of frequent exacerbations (two or more courses of OCS in the past year) [54], patients with severe asthma, smokers and those with increased comorbidities such as COPD, diabetes and obesity [46, 54]. Once identified, physicians should ensure that these patients are receiving adequate ICS-based controller medication. In our view, starting effective treatment early to improve asthma outcomes will build patient confidence. Patients should also be encouraged to use their medications appropriately through educational initiatives—patients involved in the management of their asthma have better asthma outcomes [55,56,57]. Good quality education programmes to ensure that patients understand that asthma is a chronic inflammatory condition that requires regular ongoing treatment even when they do not perceive their symptoms also result in improved adherence to therapy, and fewer hospitalisations and other healthcare visits [55,56,57]. In clinical practice, a written asthma action plan is an effective tool to help patients self-manage their asthma and is recommended for all patients [1, 58, 59]. The criteria for increase in dose of ICS controller medications will vary across patients, and ICS dose may be increased when there is a clinically important change in patient’s asthma control and specific instructions for changes to reliever and controller medications should be part of the asthma action plan [1].

Fig. 2
figure 2

Practical solutions to ensure appropriate SABA use as a reliever in clinical practice. ICS, Inhaled corticosteroid; SABA, short-acting β2-agonist

Full size image

Ongoing and regular clinical reviews are essential to check a patient’s inhaler technique and adherence to therapy. Primary care teams should work collaboratively to monitor levels of asthma prescriptions and patient adherence—this may involve electronic surveillance to alert physicians and or asthma nurses to inappropriate ICS controller (too few) and SABA reliever (too many) prescribing [30, 60, 61], the use of an asthma inhaler adherence tool (e.g. Test of Adherence to Inhalers questionnaire [62]) and the involvement of pharmacists to help in patient education, to ensure patients have an action plan to follow and to encourage patient adherence [52, 63].

Authors’ Opinion: How Should Increased SABA Use be Regarded in Clinical Practice?

Increased SABA use warns of deterioration of asthma control signalled by a marked increase in patients’ symptoms. In our view, the issue is not simply in the excessive use of SABA but rather in the response of the patients to their increased symptoms for which they perceive an increase in SABA to be required. In a recent targeted review aimed at understanding patient perspectives on medication adherence, Amin et al. identified underuse of ICS and overuse of SABA as the manifestation of poor adherence, related to patients’ doubts about asthma diagnosis and low perceived need for asthma medications, inadequate communication between patients and physicians, perceived medication concerns, and suboptimal patient knowledge, including incorrect inhaler technique [64]. SABAs represent an important tool for measuring the success of asthma management and an increased SABA use should act as a warning signal that initiates a rapid response from the healthcare system to address any patient concerns and/or knowledge gaps to ensure the appropriate use of their inhaled controller and reliever medications.

Conclusions

There is no evidence to suggest a causal link between SABA use as a reliever and mortality or serious adverse events (including exacerbations) in patients with asthma. Scientific evidence supports the appropriate use of ICS-based maintenance treatment with SABA as-needed as a reliever  to be an effective and safe treatment for patients with asthma who are adherent to treatment. SABA use also has an important role in assessing asthma control and in the management of exercise-induced bronchoconstriction and acute exacerbations, and should be part of the asthma control assessment.

Patients at risk of inappropriate ICS and as-needed SABA use should be rapidly identified to ensure they are receiving adequate ICS-based controller therapy. In discussing asthma management with patients, the management goal should be the suppression of the underlying inflammation. As-needed ICS-based therapies (step 1, mild asthma) or regular ICS-based maintenance therapy (steps 2 to 5) should be complemented with the appropriate use of as-needed SABA. This is key to optimizing asthma management and should be encouraged and promoted with educational activities.