Adv Ther (2023) 40:1301–1316 https://doi.org/10.1007/s12325-022-02410-z COMMENTARY The Changing Asthma Management Landscape and Need for Appropriate SABA Prescription Christian Domingo . Dave Singh Received: October 26, 2022 / Accepted: December 14, 2022 / Published online: January 30, 2023 Ó The Author(s) 2023 ABSTRACT lack of consensus between treatment guidelines on how SABA should be used, and as-needed Short-acting b2 agonists (SABAs) have been a ICS-formoterol is suggested by some as an mainstay of asthma treatment since the 1950s, alternative reliever therapy. Here, we examine and have been mainly recommended as-needed the pharmacology and current use of inhaled for symptom relief alongside daily inhaled cor- SABAs, identify that regular dosing of ICS can ticosteroid (ICS)-based maintenance treatment encourage appropriate SABA use, and appraise for the past 30 years. However, patient adher- the evidence used to support the changing ence to regular ICS-based anti-inflammatory reliever treatment recommendations. We con- maintenance therapy is frequently poor, lead- clude that SABA continues to play an important ing to SABA overuse for symptom relief and role in the asthma management landscape, and associated poor outcomes. At present, there is a give our views on how it should be used in patients with mild–moderate asthma, to com- plement regular ICS-based maintenance treatment. Keywords: Asthma; GINA; Guidelines; Recommendations; SABA; Salbutamol; Treatment C. Domingo (&) Autonomous University of Barcelona (UAB), Sabadell, Barcelona, Spain e-mail: cdomingo@tauli.cat D. Singh University of Manchester, Manchester University National Health Service Foundation Trust, Manchester, UK e-mail: DSingh@meu.org.uk C. Domingo S. Pneumologia, Planta Primera, Edifici Tauli Nou, Corporació Sanitària Parc Tauli, Parc Tauli 1, 08208 Sabadell, Barcelona, Spain 1302 Adv Ther (2023) 40:1301–1316 superior efficacy and safety of inhaled versus Key Summary Points oral SABAs were also demonstrated in the 1990s [4], leading asthma guidelines to favor inhaled Inhaled short-acting b2 agonist (SABA) administration [5–9]. A regimen that combines reliever therapy, as a complement to inhaled SABA reliever for use as required with regular inhaled corticosteroid (ICS)-based ICS-based regular maintenance therapy was maintenance treatment, plays a well- proposed for patients with frequent symptoms established role in asthma management to improve asthma control, reduce lung func- tion deterioration, and prevent exacerbations An appraisal of current evidence found [1, 2]. that regular ICS with as-needed SABA In 1994, the addition of a long-acting b2 gives better asthma control and agonist (LABA) to ICS treatment for poorly bronchoprotection compared with as- controlled asthma was shown to give better needed ICS-formoterol, even at clinical outcomes compared to increasing the suboptimal adherence ICS dose [1, 10]. Inhaled fluticasone propionate Regular ICS dosing encourages appropriate (FP) and salmeterol was the first combination SABA use by managing airway ICS and LABA maintenance therapy licensed for inflammation, improving asthma control, use [11]. The early 2000s saw development of and subsequently reducing the need for regimens with ICS and the fast-onset LABA symptom relief formoterol (FOR) [2, 12]. Despite treatment advances, current asthma SABA reliever use is a valuable tool for management is often suboptimal [13, 14]. To assessing asthma control, and thereby address this, treatment recommendations are informing treatment modification shifting to reflect concerns regarding poor decisions patient adherence to maintenance therapy, It is our view that treatment over-reliance on SABA, and newly available data recommendations should encourage on ICS dosing approaches [9, 15, 16]. As some regular ICS dosing, supported by as- recommendations now propose use of ICS-FOR needed SABA use and patient education in place of SABA [9, 15], it is relevant to re- on the importance of adherence evaluate current evidence for SABA treatment, and to discuss the concerns around its overuse, in order to understand how SABAs should be used appropriately in practice. In this commentary, we summarize the pharmacology, recommendations for use, and INTRODUCTION prescription of inhaled SABAs, then present an appraisal of the available evidence around SABA Asthma has been treated with b agonists for use for asthma symptom relief. We recognize thousands of years, since the first medicines that as-needed ICS-FOR is now being proposed were derived from plants (Fig. 1) [1, 2]. Inhaled as a reliever therapy, but note that, at present, short-acting b2 agonists (SABAs), including while as-needed use of ICS-FOR is accepted in salbutamol, were developed in the 1950s and some recommendations, including those of the became the primary therapies for all asthma Global Initiative for Asthma (GINA) and the severities [1, 2]. After it was established in the National Asthma Council in Australia [9, 17], it 1990s that asthma is a chronic inflammatory has not been approved by the US Food and Drug disease, inhaled corticosteroids (ICSs) were Administration, European Medicines Agency, or identified as the most effective anti-inflamma- the majority of scientific societies [5–8, 18–24]. tory treatment [3], and recommendations for Based on the evidence, we give our views on SABA use were changed from ‘regular’ to ‘as- appropriate SABA use in mild–moderate needed’ therapy for symptom relief [1, 2]. The asthma. This article is based on a review of Adv Ther (2023) 40:1301–1316 1303 Fig. 1 History of SABA use. *The US Food and Drug propionate, GINA Global Initiative for Asthma, ICS Administration, European Medicines Agency and the inhaled corticosteroid, LABA long-acting b2 agonist, majority of scientific societies have not approved this MART maintenance and reliever therapy, SABA short- indication [5–8, 18–24]. FOR formoterol, FP fluticasone acting b2 agonist, SAL salmeterol previously conducted studies and does not with higher affinity than salbutamol, leading to contain any new studies with human partici- more prolonged signal transduction [27]. Both pants or animals performed by any of the inhaled salbutamol and FOR have fast onset of authors. action, with some studies showing that salbu- tamol has a comparable or slightly faster onset of action than FOR [27–30]. SABA PHARMACOLOGY A double-blind randomized controlled trial (RCT) has shown no difference between the B2 agonists exert their ability to relax airway bronchodilator effect of salbutamol and ICS- smooth muscle (ASM) by binding b2 adrenore- FOR in average forced expiratory volume in 1 s ceptors, which are present in high numbers (FEV1) achieved from first dose to a 90-min within ASM [25, 26]. Following binding, the assessment point [mean ratio 98.4%; 95% con- canonical signaling pathway generates intra- fidence interval (CI) 91.6, 105.7; p = 0.66] [30]. cellular cyclic adenosine monophosphate In a different RCT, focusing on an earlier time- (cAMP), which activates the effectors cAMP-de- point clinically relevant in terms of acute pendent protein kinase A and exchange protein bronchodilation (2 min), the non-inferiority activated by cAMP. These effectors induce the FEV1 boundary of - 0.06 L for budesonide relaxation of the ASM through phosphorylation (BUD)-FOR compared with salbutamol was not of key regulatory proteins, down-regulation of met [31]; mean FEV1 change from baseline Ras homolog family member A (RhoA), and 2 min after treatment administration was 0.08 L sequestration of intracellular calcium ions for BUD-FOR [standard deviation (SD) 0.14, [25, 26]. n = 49] and 0.17 L for salbutamol (SD 0.18, Although the LABA FOR and the SABA n = 48) [31]. Over the 30 min post-dose, FEV1 salbutamol are both b2 receptor agonists, dif- was higher with salbutamol than BUD-FOR ferences in the electrochemical shapes of their (mean difference 0.10 L, p\0.001); however, head groups mean that FOR binds the receptor this was less than the suggested threshold for 1304 Adv Ther (2023) 40:1301–1316 the minimum patient perceivable improvement canisters per year (corresponding to[1 inhala- of 0.23 L [32], and the study did not show any tion per day) without adequate regular ICS differences in perceived breathlessness between maintenance therapy is associated with the treatments [31]. Another RCT examining increased hospitalization and mortality risk, effects 1 min after administration showed that irrespective of asthma severity [9, 14, 42, 43]. salbutamol was significantly more effective at High SABA reliever use associated with under- reversing methacholine-induced dyspnea than use of ICS treatment remains common: in a BUD-FOR (mean change in Borg score – 0.41 for study of UK treatment patterns published in salbutamol vs. BUD-FOR; p = 0.024); however, 2021, 19.1–24.2% of patients used C 4 SABA after 3 min, while there was still a numerical inhalers per year, attributable to underuse of difference in favor of salbutamol, while the maintenance treatment [44]. Excessive SABA difference between the treatments was no use, insufficient uptake of ICS prescriptions, and longer statistically significant [33]. Taken toge- failures to issue personal asthma action plans ther, the results from these RCTs suggest that identified in an audit of 50 UK practices high- patients are not likely to experience better relief light that more proactive asthma care is needed with BUD-FOR than salbutamol [30, 31, 33]. [45]. The Swedish SABINA II registry study (n = 365,324) has reported that higher SABA use SABA SAFETY is associated with increased exacerbation and mortality risk in the real world, but this does Historically, high doses of agents with weaker not mean that a causal effect was shown; b2-selectivity, isoprenaline and fenoterol, have notably, inappropriate use of SABA was com- been associated with mortality epidemics in the mon, as SABA overuse (C 3 canisters per year) 1960s and 1970s [1, 2, 34]. However, since reg- was reported in 30% of patients, and 28% of the ulatory warnings were issued for these mole- study population took no ICS maintenance cules, fewer deaths have been associated with therapy [43]. Approximately 85% of patients SABA use [35, 36]. In addition, it has been who overused SABA at baseline had continuous reported that there is no direct association overuse during the observation period, and the between mortality risk and treatment with the proportion of patients not using ICS was more stronger b2-selectivity molecule, salbutamol, than doubled by the end of the study [43]. used appropriately (defined as supporting suit- It is probable that the poor asthma outcomes able regular ICS-based maintenance therapy) seen with increased SABA reliever use result [35]. from underlying uncontrolled asthma, often While use of SABAs alone does not treat air- associated with inadequate ICS use, rather than way inflammation and may cause tachyphylaxis SABA use itself [46]. Conversely, less require- [2, 37–39], ICS treatment reverses desensitiza- ment for SABA appears to correspond with bet- tion of b2 receptors caused by b2 agonist expo- ter asthma control: in an Australian pharmacy- sure [37–39], and evidence from cell culture based survey of 412 patients, a greater propor- studies suggests that therapeutic doses of topi- tion of SABA non-overusers had well-controlled cal corticosteroids increase b2 receptor density asthma than SABA overusers (48.1% vs. 5.9%, in human nasal mucosa cells [40]. Therefore, respectively; p\0.001) [47]. In a study demon- patients with good adherence to regular ICS strating daily SABA use as a strong predictor of treatment may be less prone to b2 agonist poor future asthma control and severe exacer- tachyphylaxis and more likely to experience bations, it was noted that only 21.7% of maximal benefit from their SABA reliever patients had well-controlled asthma at baseline therapy. [48]. These findings suggest that, in many cases, Suboptimal ICS use results in inadequate poor asthma control likely precedes and drives anti-inflammatory treatment, often coupled SABA overuse and future adverse outcomes. with increasing use of reliever treatment Overall, it is clear that frequent use of as- [16, 40, 41]. Receiving C 3 SABA 200-dose needed SABA, without regular ICS-based Adv Ther (2023) 40:1301–1316 1305 Table 1 Advantages and disadvantages of ICS-FOR versus overuse, when it occurs. In patients regularly SABA reliever use in mild asthma taking ICS, high levels of SABA use should be viewed as an indicator of poor asthma control As-needed Advantages Disadvantages reliever and prompt physicians to review their asthma therapy management [9, 42, 48, 50–52]. ICS-FOR Guaranteed As-needed ICS use administration may lead to ICS REGULAR DOSING: BENEFITS of ICS to treat undertreatment AND CHALLENGES underlying of inflammation inflammation in and airway A major pathophysiology underlying asthma is airway inflammation [53, 54]. Continuous reg- patients with remodeling [62] ular use of ICS therapy reduces inflammation, poor adherence Less symptom exacerbation risk, and asthma-related mortality to maintenance control than with across all severities [53–58]. The long-term ICS [9, 64] SABA [65] benefit of daily low-dose ICS has even been shown in patients with mild asthma and inter- SABA (to Underlying Potential for mittent symptoms present B 2 days per week complement inflammation overreliance on [53]. regular ICS treated SABA and Unfortunately, many patients do not adhere therapy) effectively by underuse of ICS well to long-term daily ICS-based maintenance regular ICS in patients with therapy [16, 41]. Patients perceive that ICSs do [53–58] poor adherence not provide immediate symptom relief and may [59–61, 80] have concerns about side effects with regular Better symptom corticosteroid use [41, 57]. Such patients fre- control than with Potential for less quently rely on SABA alone for symptom relief, ICS-FOR [65] exacerbation which can lead to increased SABA use and ICS control than with underuse leading to poor asthma outcomes ICS-FOR [66] [9, 59–61]. Under-treatment of inflammation causes FOR formoterol, ICS inhaled corticosteroid, SABA short- decline in lung function, worsening of asthma acting b2 agonist control, increased risk of exacerbation, and air- way remodeling [62]. In addition, a population- based cohort study of the Canadian Saskatch- maintenance therapy, is not appropriate, and ewan Health databases showed that the mor- leads to suboptimal asthma management [9]. tality rate ratio for asthma-related death Poor adherence to ICS treatment likely con- increased from * 0.2 with 12 canisters per year tributes to worsening of unstable asthma and to * 0.6 with 6 canisters per year and to[2.25 increases the risk of severe exacerbations [49]. with no ICS use [56]. Additionally, secondary analyses of an RCT Modeling studies suggest that poor (B 50%) comparing BUD-FOR maintenance and reliever adherence to regular ICS therapy gives a sub- therapy (MART) versus fixed dose BUD-FOR plus optimal asthma control benefit-risk profile for as-needed SABA showed that, for C 90% of the BUD and FP, while there is less loss of bron- days on which reliever therapy was overused, choprotection with the longer-acting corticos- patients did not obtain medical review within teroid fluticasone furoate [57, 58]. This 48 h of overuse, regardless of the ICS-LABA highlights that the clinical outcomes of poor regimen they were prescribed [49]. This indi- adherence may vary with the ICS molecule cates that, unfortunately, there is often a lack of prescribed [57, 58]. Overall, poor adherence to action by healthcare providers to address SABA ICS, and thus under-treatment of inflammation, can explain why studies have noted adverse 1306 Adv Ther (2023) 40:1301–1316 outcomes with SABA use in the absence of reg- needed ICS-FOR recommendations was an ular ICS therapy [9, 14, 42, 43, 45, 48, 58]. acceptance that patients with asthma fre- Implementation of adequate, regularly- quently have poor adherence to ICS-based dosed ICS therapy can encourage appropriate maintenance therapy and, subsequently, an SABA reliever use [61]. A retrospective cohort over-reliance on SABA for symptom relief study of British Columbian administrative [9, 69]. health data showed that regular ICS use (ratio of SYGMA 1 showed that fewer exacerbations ICS to total asthma medications[0.5) was and superior asthma control were achieved with strongly associated with lower risk of SABA as-needed BUD-FOR versus as-needed SABA in overuse in the following year, versus irregular GINA Step 2 patients, for whom maintenance ICS use (OR 0.10; 95% CI 0.10, 0.11) [61]. ICS is recommended. However, when regular BUD was used with as-needed SABA, as-needed BUD-FOR gave inferior asthma control by REVIEW OF LITERATURE comparison, measured by well-controlled COMPARING ICS-FOR VERSUS SABA asthma weeks and the Asthma Control Ques- AS RELIEVER MEDICATION, tionnaire-5 (ACQ-5), while exacerbation rates ACCORDING TO ASTHMA SEVERITY were similar [65]. As-needed BUD-FOR gave well-controlled asthma for 34.4% of the elec- Over the last two decades, low-dose ICS-FOR has tronically recorded weeks, in comparison to been introduced as MART for moderate–severe 44.4% with regular BUD plus as-needed SABA asthma [2, 9, 12, 63]. More recently, attempts (OR 0.64; 95% CI 0.57, 0.73) [65]. The SYGMA 2 have been made to present ICS-FOR as a useful study, comparing as-needed BUD-FOR versus reliever treatment for mild asthma [2, 9, 12, 63]. regular BUD with as-needed SABA, provided a The rationale for this approach is to guarantee similar pattern of results: there was no differ- administration of ICS, or a higher dose of ICS, at ence in exacerbation rates (the primary out- the time of an exacerbation, with the LABA FOR come), while ACQ-5 and lung function favored being used for symptom relief [9, 64]. There are regular BUD with as-needed SABA [65, 70]. potential advantages and disadvantages to RCTs ensure high levels of treatment adher- reliever treatment with as-needed ICS-FOR and ence. The open-label PRACTICAL trial was SABA (Table 1); however, the evidence for these designed to allow real-life adherence patterns in therapies must be carefully interpreted with patients with mild–moderate asthma; 60% regard to the clinical characteristics of the adherence was observed in the regular BUD populations studied, and whether regular treatment arm, which is lower than in the maintenance treatment was used. SYGMA RCTs [65, 70, 71]. The rate of severe In 2019, GINA recommendations underwent exacerbations was lower with as-needed BUD- major updates to incorporate emerging data, FOR than regular BUD plus as-needed SABA in particularly from the SYGMA studies, on as- PRACTICAL (relative rate 0.69; 95% CI 0.48, needed ICS-FOR use, and shifted to encourage 1.00; p = 0.049) [71]. Severe exacerbations were ‘‘as-needed low-dose ICS-FOR’’ in place of SABA defined as use of systemic corticosteroids reliever in mild and moderate asthma for C 3 days because of asthma, or admission to [15, 42, 43, 56, 63, 65–68]. Among the cited hospital or an emergency department because studies is a 24-week trial of 303 patients that of asthma requiring systemic corticosteroids showed fewer severe asthma exacerbations were [71]. Subgroup analysis indicated that the experienced with ICS-FOR maintenance therapy treatment difference was greater in individuals plus as-needed ICS-FOR, versus ICS-FOR main- with lower adherence [71]. Overall, for GINA tenance therapy plus as-needed SABA (relative Step 2 patients, SYGMA and PRACTICAL high- rate 0.54; 95% CI 0.36, 0.82; p = 0.004), poten- light the benefits of regular ICS treatment tially due to increased ICS exposure [63]. combined with SABA on asthma control when Another key reason for the introduction of as- levels of adherence are high, but that the ben- efits of regular ICS treatment are compromised Adv Ther (2023) 40:1301–1316 1307 Fig. 2 Graphical overview of asthma control and severe for C 3 days, hospitalization, or an emergency department exacerbation data from the SYGMA 1, SYMGA 2, Novel visit leading to systemic corticosteroid treatment. ACQ-5 START, and PRACTICAL studies. *SYGMA 2 used an Asthma Control Questionnaire-5, BUD budesonide, CI upper one-sided 95% CI for severe exacerbation rate ratio. confidence interval, FOR formoterol, ICS inhaled corti- *, , à In all studies, severe exacerbations were defined as costeroid, SABA short-acting b2 agonist worsening asthma leading to systemic corticosteroid use by poor adherence which could then favor the there was no significant difference between as- use of as-needed BUD-FOR instead. It is impor- needed BUD-FOR and regular BUD therapy plus tant to note that these studies do not provide as-needed SABA (relative rate 1.12; 95% CI 0.70, evidence that as-needed ICS-FOR has greater 1.79; p = 0.65) [66]. An exacerbation was efficacy than as-needed SABA for GINA Step 1, defined as worsening asthma that resulted as the SYGMA studies were conducted in GINA in C 1 of the following: an urgent medical step 2 patients, and most of the participants in consultation; prescription of systemic gluco- the PRACTICAL study were using ICS before corticosteroids; or an episode of high b2 agonist study entry and/or had partly controlled or use, defined as[16 actuations of albuterol uncontrolled asthma. or[8 actuations of BUD-FOR within 24 h [66]. The open-label Novel START study was con- As-needed BUD-FOR only outperformed regular ducted in patients with mild asthma, using BUD plus as-needed SABA on the secondary SABA without ICS prior to study enrollment endpoint of reducing the risk of severe exacer- [66]. At baseline, the mean ACQ-5 score was 1.1, bations (relative risk, 0.44; 95% CI 0.20–0.96) and 45.5% of the population were using SABA [66]. On the other hand, regular ICS plus SABA more than twice per week [66]. These charac- provided better symptom control than as-nee- teristics indicate that many patients had sub- ded ICS-FOR, with lower ACQ-5 scores observed optimal asthma control on SABA treatment (mean difference 0.14, 95% CI 0.05, 0.23) [66]. alone, and therefore it would be incorrect to When airway inflammation was measured, the classify them as needing GINA Step 1 treatment. mean fraction of exhaled nitric oxide across all The patients were randomized to receive as- timepoints was significantly higher with as- needed BUD-FOR, SABA alone, or regular BUD needed ICS-FOR versus ICS maintenance ther- therapy (which was taken at 56% adherence) apy plus as-needed SABA (ratio of geometric plus as-needed SABA. The primary endpoint was means 1.13; 95% CI 1.02, 1.25; p\0.001) annualized exacerbation rate; this was lower [66, 71]. This is consistent with other evidence with as-needed BUD-FOR versus SABA (relative suggesting that as-needed use of ICS may result rate 0.49; 95% CI 0.33, 0.72; p\0.001), but in reduced bronchoprotection, undertreatment 1308 Adv Ther (2023) 40:1301–1316 of asthma, and worsening control compared recommendations now favor reliever treatment with regular ICS [57, 62]. with as-needed low-dose ICS-FOR for mild Overall, the SYGMA RCTs and the open-label asthma (Steps 1 and 2) and ICS-FOR mainte- PRACTICAL and Novel START studies have nance therapy is accepted as the Track 1 treat- focused on study populations comprising either ment for moderate–severe asthma (GINA Step 3 entirely, or at least partly, GINA Step 2 patients and beyond) [9]. Many other asthma guidelines [65, 66, 70, 71]. With this in mind, the results advocate for regular ICS-based maintenance showing that as-needed ICS-FOR is superior to treatment complemented with as-needed SABA SABA alone are expected, as any ICS-based ther- [5–9, 20–24]. These disparities may lead to apy would result in better outcomes compared confusion on best practice among healthcare with SABA monotherapy in this context. The professionals. outcomes for as-needed ICS-FOR versus regular The APPaRENT 1 study showed that the ICS- ICS with as-needed SABA require careful inter- based treatment approaches used by most pretation. The results indicate that good adher- physicians for asthma Steps 1 and 2 involve ence to regular ICS with as-needed SABA gives regularly-dosed ICS and as-needed SABA reliever better outcomes compared with as-needed ICS- (21.2%; 156/736), while 13.0% (96/736) were FOR [65, 66, 70, 71]. While suboptimal adher- prescribed as-needed ICS-FOR [72]. This could ence to regular ICS still gives better asthma con- be explained by the finding that more physi- trol than as-needed ICS-FOR, as-needed ICS-FOR cians prioritize symptom control than exacer- may prevent more severe exacerbations in these bation risk in patients with mild asthma [287/ patients (summarized in Fig. 2) [65, 66, 70, 71]. 736 (9.0%) vs. 85/736 (11.5%), respectively] [72], since the SYGMA 1 study showed inferior symptom control with as-needed ICS-FOR ver- VALUE OF RELIEVER USE sus regularly dosed ICS [65, 72], and a retro- FOR ASSESSMENT OF ASTHMA spective matched cohort study demonstrated CONTROL STATUS better symptom control with once-daily fluti- casone furoate-vilanterol versus twice-daily An advantage of SABA reliever therapy is that BUD-FOR [73]. Importantly, patients receiving the frequency of uptake is a helpful and com- ICS-FOR MART remain susceptible to SABA monly employed measure of asthma control overuse; the APPaRENT studies reported that [42, 48, 50–52]. Indeed, the GINA assessment of 85.4% (479/561) of physicians prescribed SABA asthma control considers frequency of SABA in addition to MART (APPaRENT 1) [72], with reliever use, alongside daytime symptoms, the same incorrect use of MART reported by nighttime awakening, and activity limitation 85% (521/616) of patients (APPaRENT 2) [74]. due to asthma [9]. It might be possible to use as- needed ICS-FOR uptake as an indicator of asthma control for ICS-FOR regimens, but the AUTHORS VIEWPOINT relationship between frequency of ICS-FOR use Appropriate Regular ICS-Based and patient outcomes is not yet well established Maintenance Therapy is Key to Optimize [9]. Asthma Management DIFFERENCES BETWEEN Since 2019, the GINA strategy has proposed two TREATMENT GUIDELINES treatment tracks for adults and adolescents AND PHYSICIAN ATTITUDES (Table 3) [9]. However, based on the strong evidence that regular ICS can manage the TO RELIEVER TREATMENT inflammation underlying asthma, improve asthma control, and subsequently reduce the Global and national guidelines for SABA use need for SABA to relieve symptoms, we feel that vary (Table 2) [5–9, 20–24]. Notably, GINA treatment recommendations should not Table 2 Summary of adult asthma treatment recommendations by various guidelines Canada [20] France [21] GINA [9] Japan [7] Korea [8] Year updated 2021 2021 2022 2020 2016 STEP PREF M: None M: None M: None M: Low-dose ICS/LTRA M: None 1 R: As-needed SABA/ R: As-needed SABA/ICS ? FOR R: As-needed low-dose theophylline R: As-needed SABA BUD ? FOR ICS ? FOR R: SABA ALT M: Low-dose ICS M: Low-dose ICS whenever M: Low-dose ICS SABA taken R: As-needed SABA R: As-needed SABA Adv Ther (2023) 40:1301–1316 R: As-needed SABA STEP PREF M: ICS M: Low-dose ICS/as-needed M: None M: Low/medium-dose ICS/ M: Low-dose ICS 2 ICS ? FOR ICS ? LABA/LAMA/ R: As-needed SABA/ R: As-needed low-dose R: As-needed SABA BUD ? FOR R: As-needed SABA/ICS ? FOR ICS ? FOR LTRA/theophylline ALT M: LTRA M: LTRA M: Low-dose ICS/low-dose ICS R: SABA M: LTRA / R: As-needed SABA/ R: As-needed SABA whenever SABA taken/LTRA low-dose theophylline BUD ? FOR R: As-needed SABA R: As-needed SABA STEP PREF M: ICS ? LABA M: Low-dose ICS ? LABA M: Low-dose M: Medium/high-dose ICS/ M: Low-dose ICS ? LABA 3 R: As-needed SABA/ R: As-needed SABA/ICS ? FOR ICS ? FOR ICS ? LABA/LAMA/ R: As-needed SABA/low-dose BUD ? FOR LTRA/theophylline/anti-IL- ICS ? FOR R: As-needed low-dose 4Ra Ab ICS ? FOR R: SABA ALT M: ICS ? LTRA M: Medium-dose ICS/low-dose M: Low-dose ICS ? LABA M: Medium/high-dose ICS/low-dose R: As-needed SABA/ ICS ? LTRA/low-dose R: As-needed SABA ICS ? LTRA (or ? theophylline) BUD ? FOR ICS ? theophylline R: As-needed SABA/low-dose R: As-needed SABA ICS ? FOR STEP PREF M: ICS ? LTRA and/or M: Medium-dose ICS ? LABA M: Medium-dose ICS ? FOR M: High-dose ICS/ M: Medium/high-dose ICS ? LABA 4 tiotropium ICS ? LABA/LAMA/ R: As-needed SABA/ICS ? FOR R: As-needed low-dose R: As-needed SABA/low-dose R: As-needed SABA/ ICS ? FOR LTRA/theophylline/anti-IL- ICS ? FOR BUD ? FOR 4Ra Ab/anti-IgG Ab/anti-IgE ALT M: High-dose ICS/high-dose M: Medium/high-dose Ab/ anti-IL-5Ra/oral M: High-dose ICS ? LTRA ICS ? LTRA/high-dose ICS ? LABA corticosteroid/bronchial (or ? theophylline) ICS ? theophylline R: As-needed SABA thermoplasty R: As-needed SABA/low-dose R: As-needed SABA R: SABA ICS ? FOR 1309 Table 2 continued 1310 NAEPP [5] Singapore [6] Spain [22] Thailand [23] United Kingdom [24] Year updated 2020 2020 2021 2021 2019 STEP PREF M: None M: Low-dose ICS/LTRA with as- M: None M: Daily low-dose ICS M: Low-dose ICS 1 ALT R: As-needed SABA needed low-dose ICS ? FOR/ R: As-needed SABA/ICS ? FOR/ R: As-needed low-dose R: As-needed SABA low-dose ICS whenever SABA ICS ? SAL ICS ? FOR/as-needed SABA taken R: As-needed SABA/as-needed ICS ? FOR STEP PREF M: Low-dose ICS M: Low-dose ICS/LTRA with as- M: Low-dose ICS M: Daily low-dose ICS ? LABA M: Low-dose ICS 2 R: As-needed SABA needed low-dose ICS ? FOR/ R: As-needed SABA/ICS ? FOR/ R: As-needed low-dose R: As-needed SABA low-dose ICS whenever SABA ICS ? SAL ICS ? FOR/as-needed SABA taken ALT M: Daily LTRA/cromolyn, M: LTRA nedocromil, zileuton or R: As-needed SABA/as-needed ICS ? FOR R: As-needed SABA/ICS ? FOR/ theophylline ICS ? SAL R: As-needed SABA STEP PREF M: Daily combination low-dose M: Low-dose ICS ? LABA/low- M: Low-dose ICS ? LABA M: Medium-dose ICS ? LABA M: Add inhaled LABA to low- 3 ICS ? FOR dose ICS ? LTRA/medium- R: As-needed SABA/ICS ? FOR R: As-needed low-dose dose ICS (fixed-dose or R: As-needed ICS-FOR dose ICS/MART with low-dose ICS ? FOR/as-needed SABA MART) ICS ? FOR ALT M: Daily medium-dose ICS/low- M: Medium-dose ICS R: As-needed SABA (unless R: As-needed SABA/as-needed using MART) dose ICS ? LABA/low-dose R: As-needed SABA/ICS ? FOR ICS ? LAMA/low-dose ICS ? FOR ICS ? LTRA/ ICS ? theophylline or zileuton R: As-needed SABA STEP PREF M: Daily medium-dose M: Medium-dose ICS ? LABA/ M: Medium-dose ICS ? LABA M: Medium/high-dose M: Increase ICS to medium- 4 ICS ? FOR medium-dose ICS ? LTRA/ R: As-needed SABA/ICS ? FOR ICS ? LABA ? xanthines/ dose or add LTRA high-dose ICS (tiotropium can LTRA/LAMA/biologics/low- R: Medium-dose ICS ? FOR R: As-needed SABA be added)/MART with dose OCS ALT M: Daily medium-dose medium-dose ICS ? FOR M: Medium-dose ICS ? LTRA/ ICS ? LABA or daily medium- medium-dose R: As-needed low-dose dose ICS ? LAMA R: As-needed SABA/as-needed ICS ? LABA ? LAMA ICS ? FOR/as-needed SABA ICS ? FOR R: As-needed SABA R: As-needed SABA/ICS ? FOR Where ? is shown, combination therapy can be used if available Ab antibody, ALT alternative treatment track, BUD budesonide, FOR formoterol, GINA Global Initiative for Asthma, ICS inhaled corticosteroid, IL interleukin, IgE/G immunoglobulin E/G, LABA long- acting b2 agonist, LAMA long-acting muscarinic antagonist, LTRA leukotriene receptor antagonist, M maintenance, MART maintenance and reliever therapy, NAEPP National Asthma Education and Prevention Program, OCS oral corticosteroid, PREF preferred treatment track, R reliever, SABA short-acting b2 agonist, SAL salmeterol Adv Ther (2023) 40:1301–1316 Adv Ther (2023) 40:1301–1316 1311 Table 3 Changes in treatment options recommended by GINA in 2018 and post-2019 GINA 2018 [81] GINA 2019 [15] and 2020 [82] GINA 2021 [80] and 2022 [9] STEP PREF Maintenance: None Maintenance: None Track Maintenance: None 1 Reliever: As-needed Reliever: As-needed low-dose 1 Reliever: As-needed low-dose SABA ICS 1 FOR ICS ? FOR ALT Maintenance: Low- Maintenance: Daily low-dose Track Maintenance: Low-dose ICS dose ICS ICS whenever SABA taken 2 whenever SABA taken Reliever: As-needed Reliever: As-needed SABA Reliever: As-needed SABA SABA STEP PREF Maintenance: Low- Maintenance: Daily low-dose Track Maintenance: None 2 dose ICS ICS 1 Reliever: As-needed low-dose Reliever: As-needed Reliever: As-needed low-dose ICS ? FOR SABA ICS 1 FOR ALT Maintenance: Low- Maintenance: Daily LTRA/low- Track Maintenance: Low-dose ICS/low- dose ICS ? LABA/ dose ICS whenever SABA 2 dose ICS whenever SABA taken/ LTRA taken LTRA Reliever: As-needed Reliever: As-needed SABA Reliever: As-needed SABA SABA Where ? is shown, combination therapy can be used if available. The recommendations changed in 2019 are highlighted in bold ALT alternative treatment track, FOR formoterol, GINA Global Initiative for Asthma, ICS inhaled corticosteroids, LABA long-acting b2 agonist, LTRA leukotriene receptor antagonist, PREF preferred treatment track, SABA short-acting b2 agonist concede to the challenges of adherence superiority of as-needed ICS-FOR over regular [47, 54, 57, 75]. We also believe, along with ICS plus as-needed SABA for exacerbation end- others, that recommendations favoring ICS- points, when adherence is suboptimal FOR reliever regimens over as-needed SABA are [65, 66, 70, 71]. With this complexity, it is rea- not based on clear-cut evidence [76–79], as the sonable to state that the scientific case for SYGMA RCTs and supporting open-label studies favoring ICS-FOR over regular ICS plus as-nee- give rise to complex data that need careful ded SABA is far from clear-cut. Indeed, for GINA interpretation and understanding Step 2, it appears that the best outcomes are [65, 66, 70, 71]. The main contentious points to achieved by striving to improve regular ICS consider are: (1) these studies mainly focus on treatment adherence [65, 66, 70, 71]. It can be GINA Step 2 patients, and have not provided an argued that, when a patient requires adminis- evidence base to differentiate ICS-FOR and tration of as-needed ICS-FOR, it is because they SABA in GINA Step 1 patients; and (2), in GINA are symptomatic, and therefore their asthma is Step 2 patients, the SYGMA RCT evidence does uncontrolled; as such, leaving the decision of not show any superiority of as-needed ICS-FOR when to take ICS to the patient may lead to over regular ICS treatment plus as-needed SABA, undertreatment [57]. In our view, for appropri- while the latter regimen achieves better asthma ate patients, the benefits of regular ICS dosing control. In support of as-needed ICS-FOR, the are sufficient to warrant proactive efforts to open-label studies do show evidence of improve patient adherence. This might be 1312 Adv Ther (2023) 40:1301–1316 achieved through better education of patients needed ICS-FOR has greater efficacy than as- about the function of their medications and the needed SABA for mild asthma (GINA Step 1), or need for regular ICS-based treatment to opti- that ICS-FOR has greater efficacy overall than mize clinical outcomes [9]. regular ICS plus as-needed SABA for GINA Step 2, because the SYGMA RCTs and the open-label SABA Overuse is a Result and Indicator PRACTICAL and Novel START studies showed a of Poor Asthma Control pattern of better asthma control with regular ICS plus as-needed SABA, while the benefit of We believe SABA overuse is likely the result of as-needed ICS-FOR on exacerbations was only chronic poor asthma control rather than its evident in patients with poor adherence cause. Unfortunately, based on the misinter- [65, 66, 70, 71]. Furthermore, the inclusion of pretation of some study results, conclusions mixed populations of patients with different have instead been drawn that SABA overuse asthma severities makes the results of these itself might drive loss of asthma control and studies difficult to disentangle [65, 66, 70, 71]. increase mortality risk [43]. Additionally, sev- More data are needed to align expert opin- eral studies currently cited to support the GINA ions on asthma treatment and to support the Step 2 recommendations include data from development of globally aligned recommenda- patients who did not receive SABA appropri- tions [76, 78]. Based on the evidence, we believe ately (to complement regular ICS-based main- that patients with asthma who have regular tenance treatment), meaning conclusions about symptoms need regular treatment, which the efficacy and safety of SABA monotherapy means regular use of ICS-based maintenance have been extended to recommendations for therapy to treat the underlying pathophysiol- patients who should not receive SABA alone ogy of asthma [53, 54]. The benefits of regular [9, 43, 65, 66]. ICS dosing are clear, so our view is that treat- SABAs represent an important tool for mea- ment recommendations should not risk subop- suring the success of asthma management [9]. timal treatment (which leads to reduced asthma In our opinion, results from the key studies control) by conceding to the challenges of poor cited by GINA to support a shift away from adherence [47, 54, 57, 75]. Instead, better SABA use only further highlight the need to adherence might be achieved through proactive monitor frequency of SABA uptake and to use efforts to improve patient education [9]. this assessment as a measure for asthma control Appropriate SABA use is to complement regular [42, 43, 56, 67, 68]. Increases in SABA use ICS (as an infrequent reliever), and, in should prompt investigations into the clinical exchange, regular ICS supports appropriate measures of control, asthma management plan, SABA use by managing underlying inflamma- adherence, and inhaler technique of the patient tion to minimize symptoms [3, 53–58, 60, 61]. [9]. Conclusions ACKNOWLEDGEMENTS Inhaled SABA reliever use to complement ICS- Funding. This study, along with the Rapid based maintenance treatment is well-estab- Service and Open Access Fees for publication lished in asthma management, and we believe it were funded by GSK. remains a useful tool to assess asthma control, inform treatment modification decisions, and Medical Writing and Editorial Assis- individualize management of acute symptoms tance. Bhumika Aggarwal and Sourabh Fulmali, [1, 2]. We are not alone in our opinion that the of GSK, assisted development of the manuscript evidence base does not yet fully endorse use of through facilitation of author meetings and ICS-FOR regimens, and, at present, there is no provision of requested references. Editorial robust or clear-cut evidence showing that as- support (in the form of writing assistance, Adv Ther (2023) 40:1301–1316 1313 including preparation of the draft manuscript Commons licence, and indicate if changes were under the direction and guidance of the made. The images or other third party material authors, incorporating authors’ comments for in this article are included in the article’s each draft, assembling tables and figures, Creative Commons licence, unless indicated grammatical editing and referencing) was pro- otherwise in a credit line to the material. If vided by Phoebe Hobbs of Fishawack Commu- material is not included in the article’s Creative nications Ltd, UK, and was funded by GSK. Commons licence and your intended use is not permitted by statutory regulation or exceeds the Author Contributions. All named authors permitted use, you will need to obtain permis- meet the International Committee of Medical sion directly from the copyright holder. To view Journal Editors (ICMJE) criteria for authorship a copy of this licence, visit http:// for this article, take responsibility for the creativecommons.org/licenses/by-nc/4.0/. integrity of the work as a whole, and have given their approval for this version to be published. 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