Regular versus As-needed Treatments for Mild Asthma in Children, Adolescents, and Adults: A Systematic Review and Network Meta-analysis

doi:10.21203/rs.3.rs-4813700/v1

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Regular versus As-needed Treatments for Mild Asthma in Children, Adolescents, and Adults: A Systematic Review and Network Meta-analysis

https://doi.org/10.21203/rs.3.rs-4813700/v1

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Background

Inhaled corticosteroids (ICS) are recommended treatment for mild asthma. We aimed to update the evidence on the efficacy and safety of ICS-containing regimens, leukotriene receptor antagonists (LTRA), and tiotropium relative to as-needed (AN) short-acting β2-agonists (SABA) in children (aged 6 − 11 years) and adolescents/adults.

Methods

A systematic review of randomized controlled trials (RCTs) of regular and AN treatment for mild asthma was conducted. PubMed, Scopus, and ClinicalTrials.gov were searched up to 31st March 2024. RCTs in children or adolescents/adults with mild asthma were eligible if they compared any of the following treatments: ICS alone or in combination with fast-acting bronchodilators (FABA, i.e., formoterol or SABA) or long-acting β2-agonists (LABA), LTRA, tiotropium, and SABA alone, for the following outcomes: exacerbations, asthma symptoms, forced expiratory volume in 1 s (FEV₁), asthma-specific quality-of-life (QoL), or severe adverse events (SAEs). Network meta-analysis (NMA) was used to pool risk ratios (RR) or mean differences for treatment outcomes.

Results

Thirteen RCTs in children, and 29 in adolescents/adults were included. Regular ICS ranked best for preventing exacerbations and improving FEV₁ in children. NMA of RCTs suggested regular ICS were better in preventing exacerbations than LTRA (RR [95% confidence intervals], (0.81[0.69,0.96]) and AN-SABA (0.61[0.48,0.78]), similar to AN-ICS (0.83[0.62,1.12]). In adolescents/adults, for preventing severe exacerbations, regular ICS outperformed AN-SABA (0.58[0.46,0.73]), but AN-ICS/FABA (0.73[0.54,0.97]), and regular ICS/LABA (0.68[0.48,0.97]) surpassed regular ICS. Symptom relief and improved FEV₁ were similar among the ICS-containing regimens. Regular ICS ranked best for improved QoL and least likely for SAEs.

Conclusions

Regular ICS use ranked best for exacerbation prevention and increasing FEV₁ in children with mild asthma. In adolescents/adults, ICS-containing regimens outperformed AN-SABA for exacerbation prevention. Severe exacerbation risk was lowered in regular ICS use than AN use in patients with low FEV₁. Furthermore, regular ICS use enhances FEV₁ and QoL more than AN-SABA and LTRA.

As-needed use

Inhaled treatments

Intermittent asthma

Mild asthma

Network meta-analysis

Regular use

Inhaled corticosteroids (ICS) are currently considered the mainstay treatment for asthma. Historically, treatment for mild asthma was recommended as-needed (AN) with inhaled short-acting β2-agonists (SABA) prescribed on symptom presentation [1]. Nevertheless, frequent exacerbations and deaths have still been reported in approximately one-third of patients [2, 3]. Furthermore, overuse of SABA has also been associated with an increased risk of severe exacerbations and mortality [4], which could be reduced by between one-half and two-thirds in patients regularly treated with low-dose ICS [5]. Other treatment options include a combination of ICS and fast-acting β2-agonist (FABA), i.e., formoterol, as well as leukotriene-receptor antagonists (LTRA) [1, 6]. Theoretically, regular use is preferred to AN for better inflammation control, thus reducing exacerbations and mortality [1, 6]; nevertheless, nonadherence remains a barrier for adopting regular use, due to the infrequency of symptoms [7]. Evidence from several large randomized controlled trials (RCTs) have suggested that the AN-use of ICS in combination with FABA (AN-ICS/FABA) for mild asthma treatment could lower exacerbation rates, compared with AN-SABA alone [8–11]. Recent guidelines have classified asthma treatments based on the frequency of symptoms as follows: in children (aged 6 − 11 years) with asthma step 1 (symptoms < 2 times/month), AN-SABA or low-dose ICS taken whenever SABA is taken (AN-ICS); regular low-dose ICS is preferred and LTRA or AN-ICS as an option for step 2 (symptoms > 2 times/month) [1, 6]. In adolescents/adults, AN-ICS/FABA [1] or AN-ICS [6] is recommended for asthma step 1; regular low-dose ICS or AN-ICS/FABA are preferred [1], or LTRA [6] as an option for asthma step 2. Furthermore, a recent RCT comparing ICS and tiotropium in mild asthmatic adults with low sputum eosinophils showed comparable effects in terms of exacerbation prevention [12].

Four systematic reviews and meta-analyses (SRMAs) have compared the efficacy of AN-ICS/β2-agonists, regular ICS, and AN-SABA as mild asthma treatments [13–16]. In addition, two SRMAs compared AN-ICS and regular ICS for exacerbation prevention [17, 18], and five SRMAs have explored the efficacy of LTRA for exacerbation prevention and symptom improvement [19–23]. However, these previous SRMAs were limited by high levels of heterogeneity, primarily due to the mixture of asthma patients of different age groups and severity levels. A recent systematic review and network meta-analysis (SRNMA) compared the efficacy of different inhaler therapies in preventing exacerbations in both mild and moderate adult asthma [24], both subject to different treatments. As such, there is an unmet need for an updated SRNMA focusing on mild asthmatic patients stratified by age group (i.e., children and adolescents/adults). The optimal treatments for mild asthma across the various options require clarification to inform clinical practice. This study sought to identify variation across the treatment options and rank these based on short- to intermediate-term and long-term outcomes.

This SR was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement for NMAs [25]. The protocol was registered in PROSPERO (CRD42022352384).

Search strategy and study selection

Relevant studies were electronically searched in MEDLINE (PubMed) and Scopus from inception to March 31st, 2024, and ClinicalTrials.gov for a protocol (eAppendix 1). Two reviewers independently screened titles and abstracts and assessed full-text articles for eligibility. RCTs in children (aged 6 − 11 years) or adolescents/adults with mild or intermittent asthma were included without language restrictions if they: (1) compared SABA, ICS, LTRA, ICS/FABA, ICS/ LABA, or tiotropium; (2) had at least one of the following outcomes: exacerbations, asthma symptom scores, forced expiratory volume in 1 s (FEV₁), asthma-specific quality of life (QoL), or adverse events (AEs). RCTs were excluded if they only included participants with exercise-induced asthma or viral-induced wheezing, baseline FEV₁ < 80% predicted, compared different dosages or devices of the same treatment, or had insufficient data for pooling after three contact attempts with the authors. The most recent and completed reports were selected if multiple publications of the same studies were identified.

Interventions of interest

The interventions of interest included the following drug classes as follows: SABA, ICS, LTRA, ICS/FABA, ICS/LABA, and tiotropium, with AN or regular usage, any dosage, and any treatment duration. The inhaler type was not restricted.

Outcomes of interest

The primary outcome was exacerbation, which was defined according to each RCT included; generally, this was classified as non-severe if worsening asthma symptoms led to more SABA use, severe if systemic corticosteroids were used for ≥ 3 days or hospitalization, or otherwise if unspecified. The secondary outcomes comprised: (1) asthma symptoms and asthma control status assessed with the Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), or Pediatric-ACT (p-ACT); (2) FEV₁, as a percentage of predicted value; (3) asthma-specific QoL assessed with the Asthma-QoL Questionnaire (AQLQ) or Pediatric Asthma QoL Questionnaire (PAQLQ); and (4) adverse events (AEs). Severe AEs (SAEs) were based on the definitions for each RCT included, otherwise the AEs were classified as non-severe. All outcomes were evaluated at the end of the study.

Data extraction

Two reviewers independently extracted the following data: study settings, patients’ characteristics (age, sex, smoking status, asthma step, history of exacerbation, history of ICS use, and FEV₁), intervention details (name, dose, frequency, and duration of use), details of the outcome measures, and outcome data. Mild asthma was originally defined as per the individual studies, but was generally as follows: step 1 included symptoms or SABA use ≤ 2 times/month without nocturnal symptoms, used SABA alone, and no risk factors for exacerbations and no exacerbations in the previous year (1); step 2, symptoms or SABA use in the previous month > 2 times but less than daily (1), being treated with low-dose ICS (< 400 mcg/day of budesonide or equivalent) (9). Any disagreements were discussed and a final consensus with an experienced advisor (AT) was made.

Risk of bias assessment

Two reviewers independently assessed the risk of bias for the studies included using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2). The risk of bias was classified as “low risk of bias”, “some concerns”, or “high risk of bias” [26]. Any disagreements were discussed and resolved within the author team.

Data analysis and synthesis

The relative treatment effects on dichotomous exacerbations and adverse events were pooled using risk ratios (RR), continuous outcomes with similar scales (i.e., FEV₁ and AQLQ) were pooled using unstandardized mean differences (USMD), and different scales (i.e., symptom score) were pooled using standardized mean differences (SMD). Formulas of conversion from median into mean and interquartile range into standard deviation (SD) as well as post-treatment means are shown in eAppendix 6.

Direct meta-analysis (DMA) was performed when there were at least three studies for the same comparison. The inverse variance fixed-effect model was used unless heterogeneity was detected (p-value of Q test > 0.1 or I² > 25%), in which case the DerSimonian-Laird random-effects model was used [27]. Baseline patient characteristics (i.e., asthma step, prior ICS use, FEV₁) were considered as a potential source of heterogeneity by fitting each as a covariable in a meta-regression model; sources were confirmed if the model resulted in ≥ 50% reduction in an estimate of the between-study variance (τ²⁾ [28]. As such, subgroup analysis was performed if sufficient studies were available, otherwise, sensitivity analysis was conducted by excluding one study. Publication bias was assessed with funnel plots.

In addition, a two-stage NMA was performed as follows: First, binomial and linear regression analyses were performed on dichotomous and continuous outcomes, respectively, to estimate relative treatment effects. Second, multivariate random-effect meta-analysis was applied to pool the relative treatment effects across individual studies. Then, multiple treatment comparisons were made for each pair of interventions [29]. Third, interventions were ranked based on the surface under the cumulative ranking curve (SUCRA) method [30]. The NMA consistency assumption was assessed by a design-by-treatment interaction model [31, 32], and potential publication bias by comparison-adjusted funnel plots and Egger’s test [33]. All analyses were performed using Stata 18, stratified by age group (i.e., children aged 6 − 11 years and adolescents/adults). Two-sided p-values of 0.05 were used as the threshold for statistical significance, except for the heterogeneity assessment where the Cochrane Q test p-values of 0.1 were used. The Certainty of the evidence generated from the NMA was assessed by using the CINeMA framework [34].

Study selection

A total of 3,270 articles were identified; titles and abstracts of 2,572 records were screened after removing duplicates, and 42 were considered eligible for inclusion (Fig. 1). eAppendix 2 shows the characteristics of the eligible 42 studies. Of these, 13 studies were conducted in children, and 29 in adolescents/adults with sample sizes ranging from 27 to 1,974 and 27 to 1,945 patients, respectively. The years of publication ranged from 1991 to 2022. The mean age ranged from 5.5 to 10.7 in children and 26.6 to 71.0 in adolescents/adults. The mean baseline FEV₁ of these groups ranged from 83.5–102.0% and 84.2–101.0%, respectively. A total of five (i.e., AN-SABA, AN-ICS, regular ICS, LTRA, and regular ICS/SABA) and six treatments (i.e., AN-SABA, regular ICS, LTRA, AN-ICS/FABA, regular ICS/LABA, and tiotropium) were studied in children and adolescents/adults, respectively.

Risk of Bias

Of the studies included, 21.4% were classified as low risk of bias, 59.5% as some concerns, and 19% as high risk of bias, mainly regarding issues associated with the randomization process, deviation from intended intervention, or selection of results reported. (eAppendix 3)

1. Findings in children

1.1 Non-severe exacerbation

A DMA suggested that regular ICS significantly reduced non-severe exacerbations compared with LTRA, with a RR (95%CI) of 0.63 (0.49, 0.82), but not relative to AN-ICS, with a RR (95%CI) of 0.83 (0.61, 1.12), (Fig. 4.1 in eAppendix 4).

Six RCTs [35 − 40] involving 2,716 patients were included in a NMA of interventions, including AN-SABA, AN-ICS, regular ICS, and LTRA (Fig. 2A). Compared with AN-SABA, regular ICS, and LTRA were significantly better in preventing non-severe exacerbations, with RRs (95%CI) of 0.61 (0.48, 0.78), and 0.76 (0.58, 0.99), respectively, while AN-ICS was similar, with a RR (95%CI) of 0.74 (0.53, 1.02), but did not reach significance (Table 1). Ranking by SUCRA indicated that regular ICS had the highest probability of lowering the risk of non-severe exacerbations, followed by AN-ICS, LTRA, and AN-SABA (Table 4.1 in eAppendix 4). There was no evidence of inconsistency in the network (chi-square = 0.5, p-value = 0.919). The comparison-adjusted funnel plot showed no asymmetry (Egger’s test p-value = 0.272).

1.2% predicted FEV₁

A DMA showed that regular ICS increased FEV₁ to a greater extent than AN-SABA, but similar to AN-ICS, with USMDs (95%CI) of 4.30 (0.35, 8.25), and 1.51 (-0.34, 3.37), respectively (Fig. 4.2 in Appendix 4).

Eight RCTs [36 − 38, 41 − 44] involving 3,937 patients were included in a NMA of interventions that included AN-SABA, AN-ICS, regular ICS, LTRA, and regular ICS/SABA (Fig. 2B). Regular ICS resulted in higher FEV₁ compared to AN-SABA, with an USMD (95%CI) of 4.12 (0.74, 7.50), but did not differ significantly from AN-ICS, LTRA, or regular ICS/SABA (Table 2). Ranking by SUCRA indicated that regular ICS had the highest probability of increasing FEV₁, followed by regular ICS/SABA, AN-ICS, LTRA, and AN-SABA (Table 4.2 in eAppendix 4). There was no evidence of inconsistency in the network (chi-square = 0.35, p-value = 0.839).

The comparison-adjusted funnel plot showed asymmetry (Fig. 4.3 in eAppendix 4), based on the comparisons between regular ICS vs. AN-SABA [42], and regular ICS vs. AN-ICS [36] for the patients that had a mean baseline FEV₁ < 90%predicted in the former, and a higher proportion of asthma step 1 and 2 patients with prior ICS use in the latter. A contour-enhanced funnel plot suggested that the asymmetry was attributable to heterogeneity in the baseline FEV₁ and asthma step in patients included. Sensitivity analysis that included the exclusion of one of the two RCTs at a time produced rank orders similar to the main analysis.

1.3 Non-severe adverse events

Five RCTs [35, 37, 39, 40, 45] involving 1,649 patients were included in a NMA of the following interventions: AN-SABA, AN-ICS, regular ICS, and LTRA (Fig. 2C). No differences between ICS, LTRA, and AN-SABA were noted (Table 1). The probability of the lowest risk of AE was with AN-ICS, followed by regular ICS, AN-SABA, and LTRA (Table 4.3 in eAppendix 4). There was no evidence of inconsistency in the network (chi-square = 1.83, p-value = 0.401). The comparison-adjusted funnel plot showed no asymmetry (Egger’s test p-value = 0.127).

2. Findings in adolescents/adults

2.1 Non-severe exacerbation

A DMA found that regular ICS significantly reduced non-severe exacerbations, with a RR (95%CI) of 0.44 (0.32, 0.61) relative to AN-SABA, but not relative to LTRA or regular ICS/LABA, with RRs (95%CI) of 1.18 (0.82, 1.70), and 0.81 (0.40, 1.62), respectively (Fig. 5.1 in eAppendix 5).

Eight RCTs [9, 12, 46 − 51] and one unpublished RCT (NCT1316380) involving 6,421 patients were included in a NMA of the following interventions: AN-SABA, regular ICS, LTRA, AN-ICS/FABA, regular ICS/LAB, and tiotropium (Fig. 3A). The ICS-containing regimens, including ICS alone, AN-ICS/FABA, and regular ICS/LABA, were superior to AN-SABA, with RRs (95%CI) of 0.50 (0.33, 0.76), 0.46 (0.28, 0.75), and 0.41 (0.24, 0.71), respectively (Table 1). Tiotropium outperformed AN-SABA in terms of non-severe exacerbations, with a RR (95%CI) of 0.44 (0.21, 0.94) (Table 1). The ICS-containing regimens and tiotropium showed no significant differences. Ranking by SUCRA indicated that regular ICS/LABA had the highest probability of lowering the risk of non-severe exacerbations, followed by tiotropium, AN-ICS/FABA, regular ICS, LTRA, and AN-SABA (Table 5.1 in eAppendix 5). There was no evidence of inconsistency in the network (chi-square = 9.82, p-value = 0.199). The comparison-adjusted funnel plot showed no asymmetry (Egger’s test p-value = 0.690).

2.2 Severe exacerbation

A DMA suggested that regular ICS significantly reduced severe exacerbations when compared with AN-SABA, with a RR (95%CI) of 0.61 (0.47, 0.80); AN-ICS/FABA and regular ICS/LABA were superior to ICS alone, with RRs (95%CI) of 0.74 (0.56, 0.98), and 0.65 (0.50, 0.84), respectively (Fig. 5.2 in e Appendix 5). Subgroup analyses based on baseline FEV₁ and ACQ-5 are presented in Fig. 5.3 and Fig. 5.4 in eAppendix 5.

Thirteen RCTs [8 − 11, 49, 50, 52 − 58], and two unpublished RCTs (NCT1316380 and NCT455923) involving 27,828 patients were included in a NMA for the following interventions: AN-SABA, regular ICS, AN-ICS/FABA, regular ICS/LABA, and tiotropium. (Fig. 3B) The ICS-containing regimens, including ICS alone, AN-ICS/FABA, and regular ICS/LABA, were less likely to lead to severe exacerbations compared to AN-SABA, with RRs (95%CI) of 0.58 (0.46, 0.73), 0.42 (0.30, 0.58), and 0.39 (0.27, 0.56), respectively. Notably, tiotropium was not superior to AN-SABA in terms of reducing severe exacerbation risk, with a RR (95%CI) of 0.51 (0.13, 1.91) (Table 1). Compared with regular ICS, AN-ICS/FABA and regular ICS/LABA were superior, while AN-ICS/FABA and regular ICS/LABA were similar to each other. According to the SUCRA, regular ICS/LABA had the highest probability of reducing severe exacerbation risk, followed by AN-ICS/FABA, tiotropium, regular ICS, and AN-SABA (Table 5.2 in eAppendix 5). There was no evidence of inconsistency in the network (chi-square = 3.89, p-value = 0.793).

The comparison-adjusted funnel plot showed asymmetry associated with two treatment comparisons, AN-ICS/SABA vs. AN-SABA and AN-ICS/SABA vs. regular ICS, from one RCT [49], (Fig. 5.5 in eAppendix 5). A contour-enhanced funnel plot suggested the asymmetry was attributable to heterogeneity within the RCT which enrolled patients who had achieved asthma control following low-dose ICS prescription during the run-in period. Sensitivity analysis that excluded this RCT produced in a similar rank order to the main analysis.

2.2.3 Asthma symptoms

A DMA indicated that significant symptom reduction was associated with regular ICS compared to AN-SABA, with a SMD (95%CI) of -0.44 (-0.68, -0.21), but not relative to LTRA, with a SMD (95%CI) of -0.83 (-2.17, 0.51). Treatment with AN-ICS/FABA and regular ICS resulted in a similar change in ACQ-5 score, with an USMD (95%CI) of 0.08 (0, 0.17), (Fig. 5.6 in eAppendix 5).

Eleven RCTs [47, 49, 51, 52, 56, 58 − 63] involving 8,392 patients were included in a NMA of the following interventions: AN-SABA, regular ICS, LTRA, AN-ICS/FABA, and regular ICS/LABA (Fig. 3C). All interventions were similar in terms of post-treatment asthma symptoms (Table 2). According to the SUCRA, the highest probability for symptom reduction was associated with LTRA, followed by AN-ICS/FABA, regular ICS/LABA, regular ICS, and AN-SABA (Table 5.3 in eAppendix 5). There was no evidence of inconsistency in the network (chi-square = 3.17, p-value = 0.869).

The comparison-adjusted funnel plot showed asymmetry associated with the comparison of regular ICS vs. LTRA in a single RCT [63], (Fig. 5.7 in eAppendix 5). A contour-enhanced funnel plot suggested that the asymmetry was attributable to the heterogeneity within the RCT that included patients with a very high mean baseline sputum eosinophil of 13%. A sensitivity analysis that excluded this RCT resulted in a different rank order from the main analysis with AN-ICS/FABA becoming top-ranked, followed by regular ICS/LABA, regular ICS, LTRA, and AN-SABA (Table 5.4 in eAppendix 5).

2.2.4%predicted FEV₁

A DMA suggested that regular ICS significantly increased %predicted FEV₁ relative to AN-SABA and LTRA, with USMDs (95%CI) of 3.62 (2.10, 5.14), and 3.96 (0.30, 7.61), respectively (Fig. 5.8 in eAppendix 5). AN-ICS/FABA significantly increased %predicted FEV₁ more than AN-SABA, with an USMD (95%CI) of 3.70 (2.96, 4.44), albeit this did not differ significantly from regular ICS (Fig. 5.9 in eAppendix 5). Results from the subgroup analyses according to the heterogeneity in asthma step and ICS use at baseline are shown in Fig. 5.10 and Fig. 5.11 in eAppendix 5.

Thirteen RCTs [9, 47 − 49, 51, 53, 54, 57, 59 − 61, 64, 65] involving 11,676 patients were included in a NMA of interventions that included AN-SABA, regular ICS, LTRA, AN-ICS/FABA, and regular ICS/LABA (Fig. 3D). ICS-containing regimens were superior to AN-SABA for increasing FEV₁ (Table 2). Compared with LTRA, regular ICS and AN-ICS/FABA were better in terms of FEV₁. Ranking by SUCRA suggested that AN-ICS/FABA had the highest probability of increasing FEV_1, followed by regular ICS, regular ICS/LABA, LTRA, and AN-SABA (Table 5.5 in eAppendix 5). There was no evidence of inconsistency in the network (chi-square = 4.35, p-value = 0.887).

The comparison-adjusted funnel plot showed asymmetry, due to the comparisons between regular ICS vs. AN-SABA [57], and regular ICS vs. regular ICS/LABA [65], (Fig. 5.12 in eAppendix 5). Contour-enhanced funnel plots suggested that the asymmetry was attributable to heterogeneity in the differences in asthma step and ICS use at baseline, respectively. After excluding each RCT one at a time in a sensitivity analysis, the rank orders remained similar to the main analysis.

2.2.5 Asthma-specific quality-of-life

A DMA suggested that LTRA was associated with a significantly worse AQLQ score compared to regular ICS, with an USMD (95%CI) of -0.22 (-0.34, -0.11), (Fig. 5.13 in eAppendix 5). Although regular ICS and AN-SABA were similar, with an USMD (95%CI) of -0.13 (-0.30, 0.03), variation in baseline age and %predicted FEV₁ was present. Use of regular ICS in patients aged < 35 years or who had baseline FEV₁ ≥ 90% predicted did not lead to improved QoL compared to AN-SABA in a subgroup analysis (Fig. 5.14 and Fig. 5.15 in eAppendix 5).

Five RCTs [47, 48, 51, 56, 64] involving 2,630 patients were included in a NMA of the following interventions: AN-SABA, regular ICS, LTRA, and regular ICS/LABA (Fig. 3E). Treatment with regular ICS was associated with significantly better QoL than AN-SABA and LTRA. Regular ICS ranked best for QoL, followed by regular ICS/LABA, AN-SABA, and LTRA (Appendix 5: Table 5.6). There was no evidence of inconsistency in the network (chi-square = 3.92, p-value = 0.270).

The comparison-adjusted funnel plot showed asymmetry, due to the comparison of regular ICS vs. AN-SABA from a single RCT [64] that included only asthma step 1 patients (Fig. 5.16 in eAppendix 5). A contour-enhanced funnel plot suggested missing studies in the non-significant area contributing to potential publication bias. Significant Egger’s test suggested there was a small study effect (p-value = 0.023). Excluding this study in a sensitivity analysis produced a similar rank order to the main analysis.

2.2.6 Severe adverse events

Eight RCTs [8 − 11, 49, 52, 54, 61] involving 27,219 patients were included in a NMA of the following interventions: AN-SABA, regular ICS, AN-ICS/FABA, and regular ICS/LABA (Fig. 3F). Regular ICS was associated with a significantly lower risk of SAE than AN-SABA, with a RR (95% CI) of 0.65 (0.45, 0.94). The lowest risk of SAE was with regular ICS/LABA, followed by regular ICS, AN-ICS/FABA, and AN-SABA (Table 5.6 in eAppendix 5). There was no evidence of inconsistency in the network (chi-square = 3.06, p-value = 0.801). The comparison-adjusted funnel plot showed no asymmetry (Egger’s test p-value = 0.209). A DMA result is presented in Fig. 5.17 in eAppendix 5.

The ratings of confidences in NMA between each treatment comparison are presented in eAppendix 7.

This SRNMA showed that treating mild pediatric asthma with regular ICS was superior to AN-SABA in preventing exacerbations and improving FEV₁ while treating with AN-ICS and LTRA were marginally better than AN-SABA despite no significant difference in FEV₁ between them. Likewise, in adolescents/adults, regular ICS were better than AN-SABA in preventing exacerbations of all severities, but worse than AN-ICS/FABA and regular ICS/LABA in preventing severe exacerbations. Moreover, ICS-containing regimens resulted in marginally better FEV₁ than AN-SABA and LTRA in adults.

In children, we confirmed the superiority of ICS over LTRA in lowering the risk of exacerbations and increasing FEV₁; this was consistent with a previous SRMA on ICS vs. LTRA [21], but contrary to another previous SRMA, where LTRA were reported to be non-inferior to ICS in terms of FEV₁ and asthma symptoms [66]. Nevertheless, the latter SRMA recommended ICS over LTRA in patients with low FEV₁ at baseline, in line with our SRNMA findings. In our SRNMA focusing on mild asthma, AN-ICS were marginally, albeit non-significantly, better than AN-SABA in preventing non-severe exacerbations, but were still ranked lower than regular ICS as a preferred treatment.

In adolescents/adults, the highest- to lowest-ranked interventions for preventing non-severe exacerbations were regular ICS/LABA, tiotropium, AN-ICS/FABA, regular ICS, and LTRA. Although regular ICS/LABA were ranked highest, the upper limits of the RR 95% CI for the three ICS-containing regimens were similar. Therefore, regular ICS monotherapy could be considered non-inferior to ICS/FABA or ICS/LABA in preventing non-severe exacerbations with all providing at least a 25% lowered risk relative to AN-SABA. Regarding our findings related to severe exacerbations, AN-ICS/FABA ranked higher than regular ICS, and lowered severe exacerbation risk by 27% (RR 0.73 [0.54, 0.97]), consistent with previous SRMAs [14, 15]. However, from our subgroup DMA, the superiority of AN-ICS/FABA over regular ICS in preventing severe exacerbation was greater in patients with FEV₁ > 88%predicted (RR 0.39 [0.23, 0.67]) and lower ACQ-5 scores (RR 0.56 [0.37, 0.85]). Therefore, AN-ICS/FABA may be more suitable for patients without impairment of FEV₁ or poor asthma control.

Regarding our findings related to asthma symptoms, we speculate that symptom-driven use of AN-ICS/FABA underlays the highest probability for symptom reduction. However, similar to previous SRMA [67], asthma treatments did not show clear differences, suggesting any may be adopted for symptom relief.

The greater effects of the combination of ICS and FABA or LABA on increasing FEV₁ may be attributed to the long-acting bronchodilator effects exerted by the regimens. Although AN-ICS/FABA ranked best in terms of improved FEV₁, followed by regular ICS/LABA, the overlapping 95% CI upper limits for the USMDs of the ICS-containing regimens, suggested comparable FEV₁ improvements for ICS-containing regimens. LTRA consistently ranked lowest and was similar to AN-SABA, and may not be a good option for mild asthma patients with low FEV₁.

Given exacerbations are less likely in mild asthma patients, QoL indicators may represent an alternative measure as a greater number and severity of exacerbations were previously reported to be associated with impaired QoL in a large cohort study [68]. In our SRNMA, regular ICS was top-ranked for optimizing QoL. However, due to a lack of QoL assessment as an outcome measure particularly in studies of mild pediatric asthma and for some interventions, such as ICS/FABA and ICS/LABA combination therapies, an updated review focused on QoL outcomes is warranted, when more data become available.

Our findings were not always consistent with previous SRNMAs [69, 70]. Overall, we included patients with less severe disease, therefore the treatment effects reported are specific to those with “mild asthma.” The subgroup analyses using DMA approaches to resolve issues around the use of AN-ICS/FABA or regular ICS in mild asthma is a particular strength of our SRNMA given its lack of sufficient consideration in the current asthma treatment guidelines.

Nevertheless, potential limitations exist within our study. First, the classification of asthma steps was not consistent between older and more recent studies where terms such as “intermittent” and “mild persistent” asthma used in the older studies do not directly to asthma “step 1” and “step 2” from more recent studies. To overcome this issue, the definition of asthma step from the recent studies was strictly dispensed to the older. Second, there is a lack of RCTs in children with asthma step 1 and treatments with ICS/FABA or ICS/LABA, undermining treatment recommendations with AN-SABA or AN-ICS or regular ICS in mild pediatric asthma (step 1), or for treatment with ICS/FABA in mild pediatric asthma (step 1 and 2). Furthermore, given the lack of RCTs for AN-ICS treatment in adolescents/adults, further evaluation of this treatment option is warranted. Lastly, treatment adherence was not considered in our SRNMA given the scarcity of reported data. Therefore, an updated review is warranted when additional data becomes available.

The evidence from this systematic review in mild asthma suggests that in children (aged 6 − 11 years), regular ICS represent the optimal treatment for exacerbation prevention and increasing FEV₁. In adolescents/adults, ICS-containing regimens are superior to AN-SABA for lowering exacerbations of all severities, with a greater extent in regular use than AN use for attenuating severe exacerbation, particularly in patients with low FEV₁. Furthermore, regular use of ICS enhances FEV₁ and QoL to a greater extent than AN-SABA and LTRA.

Table 1

Treatment effects of ICS-containing regimens, LTRA, and tiotropium relative to AN-SABA on exacerbation and adverse events
Treatment	Non-severe exacerbation			Severe exacerbation			Non-severe adverse events			Severe adverse events
	Children	Certainty	Adults	Certainty	Adults	Certainty	Children	Certainty	Adults	Certainty	Adults	Certainty
AN-ICS	0.74 (0.53,1.02)	Moderate	NA	NA	NA	NA	0.59 (0.14,2.57)	NA	NA	NA	NA	NA
Regular ICS	0.61 (0.48,0.78)*	High	0.50 (0.33,0.76)*	Moderate	0.58 (0.46,0.73)*	Low	0.88 (0.45,1.72)	High	1.01 (0.86,1.18)	High	0.65 (0.45,0.94)*	High
LTRA	0.76 (0.58,0.99)*	Moderate	0.64 (0.31,1.35)	Low	NA	NA	1.08 (0.56,2.08)	Low	NA	NA	NA	NA
AN-ICS/FABA	NA	NA	0.46 (0.28,0.75)*	Moderate	0.42 (0.30,0.58)*	High	NA	NA	0.97 (0.82,1.15)	High	0.79 (0.52,1.21)	Moderate
Regular ICS/LABA	NA	NA	0.41 (0.24,0.71)*	Moderate	0.39 (0.27,0.56)	Moderate	NA	NA	1.01 (0.81,1.27)	Moderate	0.57 (0.31,1.02)	Low
Tiotropium	NA	NA	0.44 (0.21,0.94)*	Low	0.51 (0.13,1.91)	Very low	NA	NA	NA	Very low	NA	NA

Treatment effects relative to AN-SABA are represented by a RR (95% CI). * indicates statistical significance. Abbreviation: NA: no data for analysis.

Table 2

Treatment effects of ICS-containing regimens, LTRA, and tiotropium relative to AN-SABA on symptom, asthma-specific quality-of-life, and FEV₁
Treatment	Symptom score		AQLQ score^b		% FEV₁ of predicted value^b
	Adults	Certainty	Adults	Certainty	Children	Certainty	Adults	Certainty
AN-ICS	NA	NA	NA	NA	1.91 (-2.23,6.05)	Low	NA	NA
Regular ICS	-0.33 (-0.90,0.24)	Very low	0.21 (0.07,0.35)*	Moderate	4.12 (0.74,7.50)*	Very low	3.53 (1.68,5.38)*	Low
LTRA	-0.94 (-1.93,0.04)	Low	-0.03 (-0.19,0.13)	Moderate	0.92 (-5.65,7.49)	Very low	-0.20 (-3.64,3.25)	Very low
AN-ICS/FABA	-0.48 (-1.49,0.54)	Low	NA	NA	NA	NA	4.45 (1.76,7.15)*	Low
Regular ICS/LABA	-0.41 (-1.17,0.35)	Very low	0.12 (-0.04,0.28)	Moderate	3.10 (-8.32,14.52)**	Very low	3.45 (0.40,6.49)*	Low
Tiotropium	NA	NA	NA	NA	NA	NA	NA	NA

Treatment effects relative to AN-SABA are represented by ^aSMD (95% CI) and ^bUSMD (95% CI). * indicates statistical significance. ** based on one RCT on AN-SABA vs. regular ICS/terbutaline. Abbreviation: NA: no data for analysis.

Ethics approval and consent to participants

Not applicable. This study is a network meta-analysis of secondary data, thus additional ethical approval was not required.

Competing interests

The authors declare that they have no competing interests.

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Regular versus As-needed Treatments for Mild Asthma in Children, Adolescents, and Adults: A Systematic Review and Network Meta-analysis

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Background

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Outcomes of interest

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Risk of bias assessment

Data analysis and synthesis

Results

Study selection

Risk of Bias

1. Findings in children

2. Findings in adolescents/adults

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