Background: In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single -inhaler fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced severe exacerbation rates and all -cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit -risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. Methods: The 52 -week, double-blind IMPACT trial randomized patients with symptomatic COPD and & GE;1 exacerbation in the prior year 2:2:1 to once -daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1-90 and 91-365 days post moderate or severe exacerbation and time -to -first cardiopulmonary composite event. Results: Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49-64.15]; p < 0.001) but not significantly different at 1-90 days post -severe exacerbation (HR: 2.13 [95% CI: 0.86-5.29]; p=0.102). Moderate exacerbations did not significantly increase the risk of ACM during or after an exacerbation. Cardiopulmonary composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively; FF/UMEC/VI significantly reduced cardiopulmonary composite event risk versus UMEC/VI by 16.5% (95% CI: 5.0-26.7; p=0.006). Conclusion: Results confirm a substantial mortality risk during severe exacerbations, and an underlying CV risk. FF/UMEC/VI significantly reduced the risk of a composite cardiopulmonary AE versus UMEC/VI.