Comparative Efficacy and Safety of Inhaled Maintenance Therapy Strategies for Quality of Life in COPD: A Systematic Review and Bayesian Network Meta-Analysis.

Background: Inhaled maintenance therapies are central to the long-term management of chronic obstructive pulmonary disease (COPD), but their comparative effects on health-related quality of life across the treatment-escalation pathway remain unclear. This systematic review and Bayesian network meta-analysis compared major inhaled treatment strategies using change in St. George's Respiratory Questionnaire (SGRQ) total score as the primary outcome, with exploratory assessment of safety. Methods: PubMed, Embase, Cochrane Library, Web of Science, and Scopus were searched from inception to May 21, 2025, with supplementary citation tracking and ClinicalTrials.gov screening. Randomized controlled trials in stable COPD comparing placebo, long-acting muscarinic antagonists (LAMA), long-acting beta-2 agonists (LABA), inhaled corticosteroid plus LABA (ICS+LABA), LABA plus LAMA (LABA+LAMA), or triple therapy were included. Bayesian random-effects network meta-analysis was performed. Transcriptomic analyses were conducted only as exploratory mechanistic contextualization and were not treated as primary clinical endpoints. Results: Fourteen randomized trials were included. Triple therapy showed the greatest improvement in SGRQ total score versus placebo (mean difference [MD] -3.99; 95% credible interval [CrI] -5.86 to -2.16) and ranked highest by surface under the cumulative ranking curve. Compared with LABA+LAMA, triple therapy was associated with greater improvement in SGRQ total score (MD -1.42; 95% CrI -2.62 to -0.16), whereas differences among other active regimens were generally small. In connected safety networks, no clear differences versus placebo were observed for adverse events, serious adverse events, discontinuation due to adverse events, or death. Direct meta-analysis of four trials showed increased pneumonia risk with triple therapy versus LABA+LAMA (odds ratio 1.50; 95% confidence interval 1.16-1.93). Conclusion: Triple therapy was associated with the greatest average improvement in SGRQ total score in stable COPD, but its incremental benefit over dual bronchodilation was modest and below the conventional SGRQ minimal clinically important difference. Treatment escalation should therefore be individualized, balancing potential quality-of-life gains against pneumonia risk with ICS-containing regimens. Registration: PROSPERO CRD420261407792.