Optimizing the Use of Inhaled Corticosteroid/Long-Acting β₂-Agonist Combinations in Patients with Moderate-to-Severe Asthma

Abstract

Current clinical recommendations for asthma management are based on a symptom-driven, stepwise approach; however, the effects of patient characteristics and patient preference should be considered as they can influence adherence and, in turn, treatment effectiveness. In this Practical Approach article, an international group of asthma specialists reviews the current evidence to be considered when prescribing (as initial or secondary therapy) conventional maintenance inhaled corticosteroid (ICS)/long-acting β₂-agonist (LABA), plus as-needed short-acting β₂-agonist (SABA), or maintenance and reliever therapy (MART) with ICS, and the LABA formoterol (FOR), to patients on the 2025 Global Initiative for Asthma (GINA) treatment steps 3 and 4 with moderate-to-severe asthma. Many of the trials evaluating MART performed during the last 2 decades have explored MART, and the results have influenced the current recommendations proposed by 2025 GINA and others; however, the ‘conventional’ strategy relying on maintenance ICS/LABA therapy plus as-needed SABA may be more suitable to some patients and easier to manage for some healthcare professionals (HCPs). The purpose of this article is to provide a practical approach to help HCPs choose the best management regimen for each patient, to facilitate a personalised strategy tailored to the individual patient characteristics rather than a uniform approach. A special focus is placed on circumstances where a conventional ICS (± LABA) + SABA strategy should be followed. The focus of asthma management should not be on asthma control alone, but should also consider the risk of long-term outcomes, particularly future exacerbation risk. In addition to real-world effectiveness, baseline characteristics and behavioural patterns, such as patient preferences and adherence patterns, need to be considered when choosing between conventional dosing with maintenance ICS/LABA plus as-needed SABA or MART.

Key Summary Points

Current recommendations for doctors treating patients with asthma are predominantly based on their symptoms.

Doctors need clear guidance on how to choose the best approach for treating each individual patient; the focus of treatment should aim not only to control immediate asthma symptoms, but also to provide long-term prevention of asthma exacerbations.

In this Practical Approach article, a group of asthma specialists provide guidance to doctors on the use of a combined inhaled corticosteroid/long-acting β2-agonist inhaler with a rescue short-acting β2-agonist inhaler, or a single inhaler, that acts as both preventor and rescue, known as maintenance and reliever therapy.

Based on clinical studies, a treatment's effectiveness is the most important factor when deciding which treatment to select; however, patient characteristics (such as body mass index, smoking history and sex), preferences and the likelihood of taking their inhaler as prescribed must also be considered.

Introduction

Current clinical recommendations for asthma management are based on a symptom-driven, stepwise approach; beyond this general strategy, the effects of individual characteristics of patients with moderate-to-severe asthma need to be considered since they influence outcomes and their modulation by treatments [1]. Features to be considered encompass endotypic and phenotypic traits, behavioural characteristics and values and preferences, which are well-known determinants of adherence, and thus treatment effectiveness [2–5].

In this Practical Approach article, an international group of asthma specialists review the current evidence for initial or secondary treatment with maintenance inhaled corticosteroid (ICS)/long-acting β₂-agonist (LABA) plus as-needed short-acting β₂-agonist (SABA) or maintenance and reliever therapy (MART) with ICS and the LABA formoterol (FOR), in particular, for patients on the 2025 Global Initiative for Asthma (GINA) treatment steps 3 and 4 with moderate-to-severe asthma [6]. This article will provide practical context to help healthcare professionals (HCPs) identify patients who may benefit from GINA track 2 versus track 1 in their daily practice and simplify the process of changing to maintenance ICS/LABA plus as-needed SABA, where appropriate, which ultimately means identifying the best profile for each strategy (Fig. 1).

Fig. 1.

Practical approach for selecting conventional ICS/LABA plus SABA versus MART in patients with moderate-to-severe asthma. ACT Asthma Control Test, ACQ-5 5 item Asthma Control Questionnaire, BMI body mass index, DPI dry powder inhaler, FeNO fractional exhaled nitric oxide, FEV₁ forced expiratory volume in one second, FOR formoterol, FVC forced vital capacity, GINA Global Initiative for Asthma, HCP healthcare professional, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, MART maintenance and reliever therapy, MDI metered-dose inhaler, PEF peak expiratory flow, SABA short-acting β₂-agonist

There are several global and regional clinical guidelines and recommendations for the management of asthma [7–13], and guidance can differ slightly between them. The 2025 GINA recommendations [6] are widely used by HCPs managing patients with asthma and underpin many regional treatment guidelines [7–13]. As advised by the 2025 GINA recommendations, the preferred initial treatment for patients with asthma is treatment track 1, which at treatment steps 3 and 4 consists of a low-to-medium ICS dose in combination with FOR as MART [6]. If track 1 is not possible or if a patient’s asthma control is stable, with good adherence and no exacerbations in the previous year, treatment track 2 is an alternative option, consisting of a low-to-medium dose of maintenance ICS/LABA plus as-needed SABA at steps 3 and 4 [6]. Many of the strategy trials performed during the last 2 decades assessed MART, with promising results leading to the current strategic recommendations proposed by GINA and others [14–17]. However, the interest in this strategy should not ignore the fact that the ‘conventional’ strategy relying on maintenance ICS/LABA therapy plus as-needed SABA could be more suitable for some patients and easier to manage for some HCPs. In addition, the choice of strategy has economic implications, and the replacement of all SABA relievers by ICS/FOR combinations may not be sustainable in some contexts. The purpose of this article is to provide a practical approach to help HCPs choose and manage the best regimen for each individual patient, to facilitate a personalised strategy tailored to an individual patient’s characteristics rather than a uniform approach.

A challenge for managing patients with asthma is defining ‘asthma control’, with a Delphi panel identifying 19 different consensus or guideline definitions of asthma control [18]. Treatment decisions may be influenced by the choice of the definition of asthma control used to drive care; for example, the 2025 GINA recommendations define lack of asthma control as use of SABA more than twice per week over the last 4 weeks [6], while Spanish guidelines define lack of control as SABA use more than twice per month [7]. A universally accepted definition and measure of asthma control that is utilised and understood by patients, HCPs and researchers is required [18]. In clinical practice, several studies found that the primary treatment objective considered by HCPs is to achieve control of asthma symptoms rather than a reduction in exacerbations [2, 5, 19]. However, patients whose asthma is considered well-controlled may still be at risk of poor long-term outcomes, including severe exacerbations and mortality, hence controlling both symptoms and future exacerbation risk is critical [3, 4, 6]. The efficacy of available therapeutic options should encourage HCPs and patients to be ambitious in terms of treatment goals to minimise the risk of poor outcomes from both a short- and long-term perspective. Asthma control can be evaluated by lung function and questionnaires, such as the 5 item Asthma Control Questionnaire (ACQ-5) or the Asthma Control Test (ACT). The ACQ is a validated tool used to measure asthma control and change in control; it has questions which are completed by the patient relating to asthma symptoms and rapid-onset β₂-agonist use, and a question on forced expiratory volume in 1 s (FEV₁), which is answered by the clinician [20]. Similarly, the ACT is a validated tool used to measure asthma control based on five questions regarding shortness of breath, how a patient rates their asthma control, rescue medication use, impact of asthma at work or school and whether symptoms cause the patient to wake up at night [20, 21].

Other challenges for HCPs are patient adherence to their medication and inhaler technique. There is no valid and universally used tool to assess adherence in asthma, with poor adherence to medication a key reason for its suboptimal management [22]. Poor adherence can be attributed to several factors, including patients feeling that their asthma does not impact their daily life, doubting their diagnosis, lack of understanding about the difference between maintenance and reliever inhalers, poor inhaler technique and concerns about side effects [22]. Proper inhaler technique is necessary for good asthma control; however, a meta-analysis by Chrystyn et al. showed that, across all devices tested, 14–92% of patients who use inhalers make at least one critical technique error that hampers effective drug delivery [23]. A study also found that 44.3% (n = 109/246) of patients surveyed agreed that they did not receive guidance from their HCP about how to use their device [24]. Insufficient education may lead to misunderstanding and misuse of the treatment strategy, leading to poor effectiveness; hence, there is a need for adequate patient education to ensure good adherence and technique. For some patients, it may be easier to understand the ‘conventional’ treatment strategy with different inhalers and timing of drug administration (conventional versus on-demand) for the maintenance controller and the reliever. Others may be better candidates for MART, with the same inhaler for both maintenance and reliever therapy. One challenge to consider with this last strategy is that some patients will use the treatment only on demand, which is not appropriate for patients on GINA steps 3 and 4 [6].

Treatment Initiation: How to Decide on the Initial Treatment?

HCPs should first evaluate asthma control by assessing symptoms using ACQ-5 or ACT (Fig. 1), with scores of ≥1.5 and 20 indicating poor symptom control, respectively [25]. An ACT score of ≤19 has been shown to predict exacerbations and urgent healthcare resource utilisation within the next six months [25–27]. Lung function can be measured by FEV1, forced vital capacity (FVC) and peak expiratory flow (PEF) to track a patient’s trajectory over time [28]. A decrease in FEV1 and PEF are indicative of poor asthma control that may require an adjustment of treatment [28, 29]. HCPs can also evaluate the evolution of Type 2 airway inflammation biomarkers (fractional exhaled nitric oxide [FeNO]), as well as rescue medication use, with overuse of SABA defined as ≥3 inhalers per year [30].

For effective asthma management, the patient’s history of exacerbations must also be considered (Fig. 1), although there is a lack of consensus on how many exacerbations over the long term should be considered indicative of ‘uncontrolled’ asthma. Clinical trials and most clinical practice guidelines define ‘uncontrolled asthma’ as two severe exacerbations or one hospitalisation due to asthma in the past year [14–17].

HCP treatment decisions are influenced by clinical guidelines and recommendations, evidence from clinical studies, patient characteristics and real-life clinical practice [14–17, 25–30].

As per 2025 GINA recommendations, a patient presenting with asthma symptoms less than 3–5 days per week with normal or near-normal lung function should be initiated on as-needed-only low-dose ICS-formoterol (track 1), as-needed ICS-SABA (track 2, step 1) or low dose ICS plus as-needed SABA or ICS-SABA, and possibly a leukotriene receptor antagonist, if needed. Patients may be initiated on MART or low-to-medium dose maintenance ICS/LABA plus as-needed SABA if they have asthma symptoms most days (4–5 days per week) or experience waking due to asthma at least once a week [6].

When Should ICS Plus As-Needed SABA Be Stepped Up to Maintenance ICS/LABA?

As per GINA 2025 recommendations (track 2, steps 1 and 2), ICS plus as-needed SABA is prescribed in lieu of SABA alone [6]. Many patients with moderate asthma are initially treated with maintenance ICS/LABA plus as-needed SABA or MART, although some guidelines advocate for the conventional use of ICS in step 2 to optimise the control of inflammation and minimise the risk of exacerbations, not waiting for symptoms to trigger the administration of ICS [7–13]. If patients being managed with ICS-only experience uncontrolled symptoms, then a step up to MART or maintenance ICS/LABA plus as-needed SABA is required [6]. Step-up to maintenance ICS/LABA plus as-needed SABA may also be required if there are persistent day symptoms, nighttime symptoms and poor lung function with the use of rescue medication (SABA use 2–3 times per week) [6] and if the HCP has doubts about proper adherence. If adherence is a concern, a maintenance ICS/LABA plus as-needed SABA should be selected rather than ICS alone; ICS/LABA treatment has been shown to provide a longer protective effect and is superior at preventing exacerbations than ICS alone [31].

How to Decide Which Maintenance ICS/LABA to Initiate?

Table 1 and Figure 1 show key considerations for deciding which maintenance ICS/LABA to initiate.

Table 1.

How to decide which maintenance ICS/LABA to initiate?

Factors to consider	Explanation
Treatment efficacy	•Treatment decisions may be based on achieving control of asthma symptoms [2, 5, 19], reducing exacerbations [2, 5, 19], patient lung function (FEV1, FVC), airway remodelling (biopsy and histological staining) and Type 2 airway inflammation (biomarker) [1]. Another key aim of treatment is to prevent overreliance on SABA and reduce the risk of oral corticosteroid use [6] •HCPs have indicated that trying another treatment regimen is mainly considered as a result of worsening symptoms, poor asthma control and exacerbations [19]
Patient characteristics	•Patient characteristics, such as body mass index, sex and smoking status, account for differences in symptom control, exacerbation risk and use of relievers [3, 4]. As such, ‘treatable traits’ should be considered to ensure personalised management of moderate-to-severe asthma [3, 4] and selection of the most effective maintenance ICS/LABA for an individual patient [4] •Modelling studies have shown that some treatable traits impact exacerbation risk, poor asthma control and SABA use. These treatable traits include obesity, smoking, female sex, high ACQ-5, and low lung function, among others [1] •Body mass index (BMI): higher BMI (overweight: ≥25 to <30 kg/m2; obese: ≥30 kg/m2) is associated with a worse ACQ-5 score, a higher risk of exacerbations, and lower quality of life [4, 32] •Sex: female sex is known to be associated with an increased risk exacerbations [4, 33] •Smoking status and history: current smoking is potentially associated with a higher rate of exacerbations. Patients with asthma who currently smoke use approximately 75% more reliever inhaler than patients who never smoked. Furthermore, reliever use in former smokers was approximately 42% higher than in those who never smoked [4] •Male patients with a BMI <25 kg/m2 who do not smoke and have no exacerbation history (over the last 12 months), have a lower risk of exacerbation than females with a BMI <25 kg/m2 who smoke and have a history of exacerbations [4] •Consider beliefs, treatment goals and expectations •Maintenance ICS/LABA plus as-needed SABA should be considered for patients with airway remodelling [34]
Poor adherence and improper technique	•Poor asthma control and exacerbations may be caused by sub-optimal adherence to ICS-containing therapies [35] •The device, including patient history of devices used and regimens using different inhaler types (such as DPI versus MDI) or multiple devices, can compromise proper inhalation technique and adherence [24] •To improve adherence, consider: •Patient history of devices used •Patient ability to use and preference for device regimen (DPI versus MDI) •Patient preference for single (MART) or multiple devices (ICS/LABA plus as-needed SABA)

ACQ-5 5 item Asthma Control Questionnaire, ACT Asthma Control Test, BMI body mass index, DPI dry powder inhaler, FVC forced vital capacity, FEV₁ forced expiratory volume in one second, HCP healthcare professional, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, MDI metered dose inhaler, SABA short-acting β₂-agonist

When Should Maintenance ICS/LABA Plus As-Needed SABA or MART Be Used?

The Asthma Patients' and Physicians' Perspectives on the Burden and Management of Asthma (APPaRENT) 3 study (N = 1398) showed that 84% of patients believed their asthma to be well controlled; however, the mean ACT score was 15.7, but a score of > 19 is considered well-controlled, suggesting that patients may overestimate their level of asthma control [2]. Therefore, prescribing based on patient symptoms alone may not be sufficient to achieve asthma control. Reliever medication using MART delegates part of the anti-inflammatory (‘controller’) treatment decisions to the patient, allowing patients to appropriately manage symptoms using MART as-needed. However, if this is not effective, or if this strategy leads to poor adherence due to misunderstanding or reluctance, conventional maintenance ICS/LABA plus as-needed SABA may be preferred. GINA track 1 (MART) is the preferred treatment track [6], a recommendation based on findings from MART studies [14–17].

Although not a universal finding [36], one systematic literature review and meta-analysis found no difference in the efficacy of conventional maintenance ICS/LABA plus as-needed SABA versus MART for clinical outcomes, such as FEV₁, rate of exacerbation, use of reliever medication and patient adherence for any of the assessed patient characteristics (smoking history, body mass index, age, lung function and ACQ-5 at baseline). These findings suggest that GINA treatment track 1 should not be systematically considered as superior to track 2 [37]. Aiming for asthma control means aiming at reducing rescue medication use, which in some patients might not be achieved with MART because of patients being inappropriately prescribed SABA while on MART or overusing ICS/FOR as a reliever within MART [19], bringing the use of this strategy in these patients into question [14–17]. Furthermore, some patients and HCPs may be reluctant to wait for symptoms to drive the increase in ICS dosing through rescue use of ICS/FOR as MART, and may prefer a regimen of maintenance ICS/LABA plus as-needed SABA.

The patient’s profile, adherence pattern, beliefs, treatment goals and expectations should be considered in selecting the best treatment strategy. If adherence is a concern for a patient on MART (e.g. not requiring repeat prescriptions when expected), if spirometry shows fixed airflow obstruction, suboptimal lung function or poor fractional exhaled nitric oxide [38] or if the HCP considers it may fail, then a conventional maintenance ICS/LABA regimen plus as-needed SABA should be selected. The risk of exacerbations should be considered by looking at lung function and frequency of exacerbations in patients receiving GINA treatment steps 3 and 4 to avoid increasing asthma severity [1, 3, 4]. Asthma control and asthma clinical remission should be used to help decide between maintenance ICS/LABA plus as-needed SABA or MART.

Changing Treatment

Table 2 and Fig. 1 show key considerations for deciding when and how treatment should be changed from MART to maintenance ICS/LABA plus as-needed SABA.

Table 2.

When and how should treatment be changed from MART to maintenance ICS/LABA plus as-needed SABA?

Factors to consider
Efficacy	•Treatment should only be changed if it is in the patient’s best interest and the decision should be based on scientific evidence [39] •Within the appropriate treatment options, patient abilities and preferences should be considered •Shared decision making between HCPs and patients should be prioritised as this is known to increase adherence and patient engagement [40] •If there is any indication of lack, loss or decrease in efficacy or adherence on any treatment track (e.g., GINA treatment track 1 or 2; exacerbations, poor control, etc.), then an alternative treatment track should be selected [6] •Consider switching to maintenance ICS/LABA plus as-needed SABA if: •A patient on ICS-only maintenance experiences an exacerbation or requires a systemic corticosteroid in the prior year, or if adherence is a concern for a patient on MART •Spirometry shows fixed airflow obstruction, or FeNO remains high •An abrupt switch from a well-used and well-adopted device or management strategy should be discouraged as the change could lead to deterioration in asthma control
Poor adherence and patient preference	•Poor asthma control and exacerbations may be caused by sub-optimal adherence to ICS-containing therapies [35] •Good communication with the patient will assist with understanding and recognising barriers to adherence to MART or if the patient does not implement it correctly (e.g., repeated requests for SABA) [2, 19] •Patients may prefer simplified regimens, such as a once-daily rather than a twice-daily ICS/LABA. However, as MART uses the same device for maintenance and reliever therapy, some patients may prefer this to maintenance ICS/LABA plus SABA [41] •Patients may often request SABA even when on a MART regimen [19], possibly as their asthma may be uncontrolled on MART, they prefer their previous regimen, or they misunderstand the new MART regimen [42] •Patients may need guidance to improve their adherence to the prescribed regimen •If patients frequently use rescue SABA or do not use maintenance treatment (reliever only), discussions should be had with the patient to help improve their understanding of how to use their inhaler(s). It is important to acknowledge the patient’s improvements so that they can understand the treatment is working •Patients may be unlikely to ask for clarification of discussions if they do not understand how their treatment strategy (conventional or MART) works, and may request a separate SABA inhaler as their rescue inhaler while being prescribed MART. HCPs should take sufficient time to clearly explain how to use MART and ensure adequate patient understanding and engagement in this strategy. If challenges with adherence and technique persist, maintenance ICS/LABA plus as-needed SABA therapy may be more appropriate than MART for these patients •Once a conventional regimen has been selected, selection of a specific drug depends on patient preference for device and drug, e.g., dry powder may be easier to inhale and some patients may prefer a dose counter in a DPI to see the remaining doses [43, 44]
Cost and carbon footprint	•Cost may play a role in treatment decisions, particularly as patients with poor asthma control may experience a high economic burden [45]. Cost can be high if a patient uses many doses of rescue in a MART regimen compared with SABA [46] •While the primary objective is proper asthma control, once this has been achieved, the carbon footprint of inhalers is worth considering [8, 47]. The 2025 GINA recommendations encourage the use of DPIs where clinically appropriate, which have a lower carbon footprint than pressurised MDIs [48]. However, abrupt (unaccompanied) switch from a well-used and well-adopted MDI should be discouraged since it could lead to loss of control, which can have a high carbon foot print (especially when hospital care is required) [49]. Importantly, new propellant gases with much lower carbon footprints are currently being developed [50]

DPI dry powder inhaler, FeNO fractional exhaled nitric oxide, GINA Global Initiative for Asthma, HCP healthcare professional, ICS inhaled corticosteroid, LABA long-acting β₂-agonist, MART maintenance and reliever therapy, MDI metered-dose inhalers, SABA short-acting β₂-agonist

Challenges and Future Considerations of Asthma Management

Reductions in severe asthma exacerbations have been demonstrated in MART studies [14–17]. A common concern in asthma clinical trials is the definition of a severe exacerbation, which is typically defined as requiring systemic corticosteroids for at least 3 days, hospitalisation or an emergency department visit resulting in treatment with systemic corticosteroids [14–17]. However, individuals experiencing events defined in these ways have very different levels of exacerbation severity: in MART, as in most recent asthma studies, most exacerbations did not require hospitalisation, which is the ultimate marker of severity [14–17]. This makes it difficult to reach conclusions regarding the respective effects of available strategies on the most severe end of the exacerbation spectrum.

It is important to personalise treatment decisions (beyond biomarkers) based on patient profiles to help anticipate and determine initial treatment decisions. A simple tool is needed to assess adherence in clinical practice. A new tool, the Adherence to Asthma Medication Questionnaire (AAMQ-13), with 13 questions assessing patient adherence and predicting patterns of non-adherence, is in development [51]. Furthermore, the Adelphi Adherence Questionnaire (ADAQ) is a 13-item patient-reported outcome tool that assesses adherence and drivers of non-adherence [52]. This is a generic tool designed for multiple diseases; patients with asthma (8/57, 14%) were included in the development interview process [52]. Another promising tool is the Medication Adherence Report Scale (MARS-5) questionnaire, which is a validated tool used to assess adherence in children with asthma; however, a potential limitation is its self-reporting nature [53].

Final Remarks

The focus of asthma management should not be on asthma control alone; it should also include the risk of long-term outcomes, particularly future exacerbations. Efficacy based on clinical studies and tailored to the individual patient and disease characteristics are the most important factors in deciding which treatment strategy should be implemented. In some circumstances (persisting exacerbations, lung function impairment, poor control despite MART, adherence or preference issues), maintenance ICS/LABA plus as-needed SABA, or more rigorous treatments like single inhaler triple therapy or biologics should be preferred to optimise treatment outcomes.

Author Contributions

Gabriel Garcia, Kittipong Maneechotesuwan, Prabhuram Krishnan, Manish Verma and Nicolas Roche contributed to the conception and/or design of the work, data interpretation, and reviewed and contributed to the content of the manuscript, and had authority in the decision to submit the manuscript.

Funding

This study, including study design, data collection, analysis and interpretation, medical writing, submission support and journal rapid service and open access fees for the manuscript, was funded by GSK.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Declarations

Conflict of interest

Trademarks are the property of their respective owners (QualityMetric incorporated, Asthma Control Test [ACT]; Qoltech, 5 item Asthma Control Questionnaire [ACQ-5]). Gabriel Garcia has participated in advisory boards for GSK, AstraZeneca, Sanofi, Novartis and Boehringer-Ingelheim; he has received honoraria for speaking at sponsored meetings from GSK, Boehringer-Ingelheim, AstraZeneca, Sanofi, Phoenix and Novartis, and is a principal investigator in trials sponsored by GSK, Boehringer-Ingelheim, AstraZeneca, Novartis, Sanofi, PPD, Zambon, Parexel, Covance, IQVIA and Chiesi. Nicolas Roche is in receipt of grants from Chiesi, GSK, Pfizer; personal consulting fees from AstraZeneca, Austral, Biosency, Chiesi, GSK, Pfizer, Roche, Sanofi; personal payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Chiesi, GSK, Menarini, MSD, Sanofi, Zambon; and support for attending meetings and/or travel from AstraZeneca, Chiesi, and GSK. Kittipong Maneechotesuwan has received honoraria for lectures, presentations, speakers’ bureaus or educational events from AstraZeneca, Boehringer Ingelheim, GSK, Novartis and Sanofi. Prabhuram Krishnan and Manish Verma are employees of and hold financial equities in GSK.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.