TRIPLE VS DUAL INHALED THERAPY IN COPD AND ACUTE EXACERBATIONS: THE EFFECT OF ICS/LABA/LAMA COMBINATIONS ON REDUCING MODERATE–SEVERE EXACERBATIONS COMPARED WITH LABA/LAMA

Abstract Background: Whether inhaled triple therapy (ICS/LABA/LAMA) reduces moderate–severe COPD exacerbations versus dual bronchodilation (LABA/LAMA) remains central to treatment selection. Methods: Following PRISMA principles, we included randomized controlled trials (RCTs), post-hoc analyses, and comparative real-world studies comparing single- or multi-inhaler triple therapy with LABA/LAMA or other standard regimens. Primary outcome was rate of moderate–severe exacerbations; secondary outcomes included hospitalization for COPD, pneumonia, lung function, quality of life, and effect modification by blood eosinophils. Data were extracted verbatim and synthesized narratively with structured tables. Results: Ten included studies (IMPACT, ETHOS, TRIBUTE, KRONOS, SUNSET, ICS-withdrawal cohort, post-hoc eosinophil analyses, and two real-world comparative studies) consistently showed fewer moderate–severe exacerbations with triple therapy versus LABA/LAMA (rate ratio 0.75 vs umeclidinium/vilanterol in IMPACT; 0.76 vs glycopyrrolate/formoterol in ETHOS), with larger benefits at higher blood eosinophil counts. Pneumonia risk was higher with ICS-containing regimens in several trials, though absolute risks were low and varied by program. De-escalation from triple therapy did not increase exacerbations in non-frequent exacerbators overall, but outcomes were worse with eosinophils ≥300 cells/µL. Real-world studies supported trial findings. Conclusions: Triple therapy reduces moderate–severe exacerbations versus LABA/LAMA, particularly in patients with higher eosinophils or prior exacerbations, at the trade-off of increased pneumonia risk. Patient selection using exacerbation history and eosinophil count is essential.