Efficacy and Safety of Salmeterol/Fluticasone Compared with Montelukast Alone (or Add-On Therapy to Fluticasone) in the Treatment of Bronchial Asthma in Children and Adolescents: A Systematic Review and Meta-Analysis
Asthma is the most common chronic airway disease in childhood, affecting approximately 3.0% of children in China aged 0 to 14 years. Despite a decrease in the percentage of children experiencing acute asthma attacks and hospitalizations over the past decade, uncontrolled asthma remains a significant challenge in China, posing a substantial economic burden and adversely affecting the quality of life of patients and their caregivers. Inhaled corticosteroids (ICS) are a cornerstone of asthma management, and their use is recommended as soon as possible after diagnosis. However, the stepwise approach to asthma management varies by age, with ICS combined with long-acting beta-agonists (LABA) recommended for children aged 6 years and older, while leukotriene receptor antagonists (LTRA), such as montelukast (MON), are recommended as alternative therapies.
This systematic review and meta-analysis aimed to compare the efficacy and safety of salmeterol/fluticasone (SFC) with montelukast alone or in combination with fluticasone (MFC) in children and adolescents aged 4 to 18 years with bronchial asthma. The study sought to address the lack of published systematic reviews directly comparing these therapies in this age group.
Methods
The study followed a rigorous methodology, including a systematic search of multiple databases, including MEDLINE, EMBASE, the Cochrane Library, and several Chinese databases, from inception to May 24, 2021. Randomized controlled trials (RCTs) comparing SFC with MON or MFC in children and adolescents aged 4 to 18 years with asthma were included. The primary outcome was the risk of asthma exacerbation, while secondary outcomes included the risk of hospitalization, pulmonary function, asthma control level, quality of life, and adverse events (AEs). Data were analyzed using RevMan version 5.3, with pooled effect estimates calculated using random-effects or fixed-effects models depending on heterogeneity.
Results
Of the 1006 articles identified, 21 studies met the inclusion criteria, involving 2643 participants. Two studies were classified as having a low risk of bias. Due to the variability in treatment durations and outcomes across studies, a meta-analysis of the primary outcome was not feasible. However, more studies favored SFC over MON, as SFC was associated with a lower risk of asthma exacerbation. Specifically, one study reported a significant reduction in the risk of asthma exacerbation with SFC after 12 weeks of treatment (10.3% vs. 23.2%), while another study showed a significant reduction in emergency visits with SFC after one year of treatment (7.5% vs. 17.5%).
For secondary outcomes, SFC demonstrated significant improvements in pulmonary function compared to MFC. After four weeks of treatment, SFC showed a significant improvement in peak expiratory flow (PEF)%pred (mean difference [MD]: 5.45; 95% confidence interval [CI]: 1.57–9.34). Additionally, SFC was associated with a higher full-controlled asthma level (risk ratio [RR]: 1.51; 95% CI: 1.24–1.85) and a higher Childhood Asthma Control Test (C-ACT) score (MD: 2.30; 95% CI: 1.39–3.21) compared to MFC.
Regarding the risk of hospitalization, one study favored SFC over MON after one year of treatment, with a significant reduction in hospitalization risk (5% vs. 12.5%). However, no significant differences were observed in other studies comparing SFC with MFC.
In terms of asthma control level, SFC was associated with a higher clinical effective rate and a greater proportion of asthma symptom-free days compared to MON. For example, one study reported a higher clinical effective rate with SFC after eight weeks of treatment, while another study found a higher proportion of asthma symptom-free days with SFC after 12 weeks of treatment.
Adverse events were reported in several studies, with no significant differences observed between SFC and MON or MFC. Two studies comparing SFC with MON reported no significant differences in AEs, while six studies comparing SFC with MFC also found no significant differences.
Discussion
The findings of this systematic review suggest that SFC may be more effective than MFC in improving asthma control and pulmonary function in children and adolescents aged 4 to 18 years. However, the evidence is insufficient to make definitive conclusions about the superiority of SFC over MON, particularly in reducing the risk of asthma exacerbation. The variability in study designs, asthma severity, and treatment durations across the included studies limits the generalizability of the findings.
One of the key strengths of this review is its focus on a specific age group (4 to 18 years) and its inclusion of studies conducted in China, which enhances the applicability of the results to the Chinese population. However, the review also has several limitations, including the variability in asthma diagnoses and the lack of high-quality evidence in many of the included studies. Additionally, the inability to perform a meta-analysis for some outcomes due to insufficient data further limits the robustness of the conclusions.
Conclusion
In conclusion, SFC appears to be more effective than MFC in improving asthma control and pulmonary function in children and adolescents with asthma. However, the evidence is insufficient to conclusively determine the optimal choice between SFC and MON. Further research, including high-quality, long-term RCTs, is needed to clarify the efficacy and safety of these therapies in different populations, particularly in children and adolescents with varying asthma severity and age groups.
doi.org/10.1097/CM9.0000000000001853
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