Comparative efficacy, safety, and cost-effectiveness of budesonide–formoterol, fluticasone–salmeterol, budesonide maintenance, and albuterol versus terbutaline in asthma management: a comprehensive network meta-analysis

Abstract

Background: Asthma remains a major global health burden with high morbidity and costs, requiring effective treatment to prevent exacerbations. ICS/LABA combinations are widely used for their bronchodilation and anti-inflammatory effects, yet uncertainties persist about their optimal use, safety, and cost-effectiveness, especially in resource-limited settings. Prior reviews have not fully integrated efficacy, safety, and economic impact or explored patient-related factors through meta-regression. Therefore, this study aims to comprehensively evaluate ICS/LABA regimens compared to alternative treatments using a network meta-analysis and meta-regression, incorporating effectiveness, safety, and cost-effectiveness to guide optimal asthma management strategies. Methods: This systematic review and network meta-analysis, registered on OSF, followed PRISMA guidelines to evaluate ICS/LABA versus alternative asthma treatments in terms of efficacy, safety, and cost-effectiveness. Randomized controlled trials from 2013–2024 were included if they reported relevant outcomes. Databases searched were Scopus, PubMed, ProQuest, ScienceDirect, SagePub, and Cochrane. Data extraction, risk of bias assessment (RoB-2), and evidence certainty (GRADE) were conducted independently by multiple reviewers. Statistical analyses used a random-effects network meta-analysis with meta-regression and cost-effectiveness modeling in RStudio, ensuring robust comparisons and exploring modifiers such as age, gender, and follow-up duration. Results: Eleven randomized trials were analyzed. Budesonide–formoterol was most effective in reducing moderate-to-severe exacerbations (OR 0.33, SUCRA 0.99), followed by budesonide maintenance and fluticasone–salmeterol. No significant differences were observed in FEV1 or ACQ-5, though combination therapies ranked higher. Budesonide–formoterol and olodaterol (20 µg) showed the greatest PEFR gains (MD 68.4 and 42.9, p < 0.001). Cost analysis ranked terbutaline as the least expensive ($40) and ICS/LABA combinations as the most expensive ($150). Incremental analysis showed that albuterol ($43/exacerbation avoided) and budesonide maintenance ($364) were cost-efficient, while budesonide–formoterol offered the greatest benefit at a higher cost ($500), underscoring the need to balance efficacy with affordability. Conclusion: ICS/LABA combinations, particularly budesonide–formoterol, provided the greatest efficacy but with the highest incremental cost ($500 per exacerbation avoided). Albuterol and terbutaline were the most affordable options, with albuterol showing a low incremental cost ($43) suitable for milder cases.