To our best knowledge, this is the first proof-of-concept systematic review and meta-analysis to systematically explore the efficacy and safety of the ICS/FABA regimen in single inhaler as reliever therapy in intermittent and mild asthma. Our study included the six trials with 1300 patients and suggests that the as-needed use of ICS/FABA regimen significantly reduces exacerbations, including severe exacerbations, nocturnal awakening, prolongs time to first exacerbation and improves FEV 1 % predicted as compared to the as-needed FABA regimen, but it is inferior to the regular ICS regimen except for time to first exacerbation. The safety analysis indicated that the regular ICS regimen especially in a long-term treatment would lead to a small reduction in growth compared to either as-needed ICS/FABA or FABA regimens in the children and adolescent population. Our study shows that the ICS/FABA regimen in a single inhaler as a symptom-driven therapy would be a promising alternative regimen in management of intermittent or mild persistent asthma.

There are two important characteristics about the included RCTs for this meta-analysis. The first is the limited number of subjects involved in this meta-analysis, which resulted in under-powering with less than 0.80 to find statistical difference in some outcomes, especially in the sub-group meta-analysis, although most of the included studies calculated adequate power for their specific primary outcomes rather than ours in this study. The second is all included studies were completed in an ideal setting but not in real-world conditions [33], because all included subjects were requested to have an adherence of more than 75% before recruitment. In the real-world setting, the adherence of daily ICS was only 37.6% (95% CI = [33.1, 42.2]) in our additional meta-analysis. Therefore, the regular ICS regimen would not be more effective than the as-needed ICS/FABA strategy as poor adherence to ICS is correlated with asthma-related outcomes [34].

Despite effective pharmacological options for treating asthma, most patients fail to achieve good control in the real world. Non-adherence is common, with over-reliance on SABA and under-use of ICS frequently being observed. Therefore, there is a real need to consider new approaches to improve outcomes. One regimen that has attracted attention and controversy is single inhaler for maintenance and relief therapy (SMART). The SMART or single inhaler therapy (SiT) means that a single inhaler contains two drugs. One of these drugs acts quickly and termed the ‘reliever’, and the other one works much more slowly and is called the ‘preventer’. patients on SMART have one inhaler for use every day to control their underlying inflammation and also for symptom relief. The timely ICS use at the time of increased symptoms can improve asthma outcomes by reducing exacerbation risk [35]. In recent decades, evidence has demonstrated that using combined ICS and FABA as reliever medication can reduce the exacerbation rate [36,37,38] and have a lower total ICS exposure, without compromising outcomes against current best practice strategies using a fixed-dose ICS/LABA combination inhaler. But most of this evidence comes from moderate to severe asthma patients, who have a greater risk of exacerbations. Thus, GINA [1] recommended ICS/formoterol, a ICS/FABA inhaler, as reliever medication for moderate to severe asthma patients except for patients with intermittent and mild asthma. In our study, we extended this efficacy to the population with intermittent and mild asthma in significant improvements of nocturnal awakening times, FEV 1 % predicted, exacerbations and the time to first exacerbation compared the as-needed use of ICS/FABA regimen with the as-needed FABA regimen.

A possible concern with as-needed ICS/FABA is that inadequate anti-inflammatory treatment may be given to some patients, who would be at higher risk of exacerbations. Treatment with daily ICS at low doses decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma [39, 40]. Good adherence is needed for the efficiency of daily ICS therapy, but patients trend to use ICS intermittently and occasionally [15, 16]. Previous research has shown that nonadherence of ICS results in poor clinical control and increases school and work absenteeism, unscheduled health-care utilization, morbidity, and mortality [34, 41, 42]. We performed an additional meta-analysis in the adherence of the daily ICS therapy in a real-world setting in this study, and found the real-life adherence of daily use of ICS was 37.6% (95% CI = [33.1, 42.2]) with obvious heterogeneity between real-world RCTs and observational studies (Additional file 1: Table S9), while, it was more than 75% in our included studies significantly related to the reduced asthma exacerbations [43]. With regard to potential corticosteroid side effects, treatment with the as-needed ICS/FABA regimen was characterized by a lower average ICS dose and in children or adolescent population, by a higher linear growth than treatment with regular daily ICS regimen.

Based on the results of our study, the current recommendation from guidelines that regular ICS should be initiated only when patients use their SABA more than twice per week needs to be revisited, because the evidence that this approach works in real-life clinical practice is limited. The potential benefits of this approach were compromised by both low rates of ICS prescription in patients, even in the setting of poor control, and poor adherence by patients who were prescribed ICS regimen. Accordingly, the as-needed ICS/FABA regimen would be a promising alternative therapy, which might represent an effective, safe, and novel therapy for the treatment of intermittent and mild asthma. It may be particularly useful for selected patients who adhere poorly to their regular daily ICS regimen.

From a clinical point of view, the as-needed use of ICS/FABA regimen is a promising choice for the long-term management of intermittent and mild asthma. Exacerbations are major determinants of the direct cost of asthma, and preventing exacerbations is one of the key goals in asthma management [44]. In our study, compared with the as-needed use of FABA regimen, the as-needed use of ICS/FABA as monotherapy statistically reduced moderate to severe exacerbations and severe exacerbations. In addition, the number of patients that need to be treated for one of them to benefit from decreased moderate to severe exacerbations compared with the as-needed use of FABA regimen was 10 (the number of moderate to severe exacerbations that to be decreased from treating 1000 patients compared with the as-needed use of FABA regimen was 101 ((95%-CI = [51, 138])) and the number of patients that need to be treated for one of them to benefit from decreased severe exacerbations compared with the as-needed use of FABA regimen was 16 (the number of severe exacerbations that to be decreased from treating 1000 patients compared with the as-needed use of FABA regimen was 62 (95%-CI = [9, 96])). On the other hand, as we had mentioned above, good adherence is needed for the efficiency of daily ICS therapy, and there are some interventions to improve adherence to ICS may take many forms, including audiovisual reminders [45, 46], electronic monitoring [46], interactive voice response system via mobile phone [47], text message reminders [48] and parent education [49]. However, the magnitude of the improvements in adherence was generally not large (range from 4% to 20%) [50]. This improvement does not ensure the good adherence of ICS regimen (75%). Besides, the successful interventions to promote adherence were complex and multi-faceted and included combinations of counselling, education, more convenient care, self-monitoring, reinforcement, reminders, and other forms of additional attention or supervision [51, 52].

There are several limitations to this study that needs to be addressed. First, this study aimed to demonstrate the proof-of-concept whether the ICS/FABA in a single inhaler as reliever therapy in intermittent and mild persistent asthma was feasible in clinical practice, therefore two of included studies [29, 30] involved the use of the ICS and the FABA in separate inhalers but not in a single inhaler. Second, we included the limited number of studies that had inadequate power to find some difference in the subgroup analysis. Third, we used GetData Graph Digitizer to mine data and the Cochrane handbook recommended principals to deal with missing data, which would result in some potential impact on outcomes. Fourth, there was obvious heterogeneity in some outcomes such as the moderate to severe exacerbations, but it could be partly explained by different age groups. Fifth, all included RCTs were completed in an ideal condition with more than 75% of adherence rather than a real-world setting. To provide additional information in real-life adherence of regular ICS regimen, we pooled the rates of adherence across real-world RCTs and observational studies.