In a COPD patient eligible for triple inhaled therapy, what is the reduction in mortality risk with fluticasone furoate/umeclidinium/vilanterol (VFU) compared to budesonide/glycopyrrolate/formoterol (GFB) triple therapy?

Mortality Reduction with VFU vs GFB Triple Therapy in COPD

Based on the most recent real-world comparative effectiveness data, fluticasone furoate/umeclidinium/vilanterol (VFU/FF/UMEC/VI) demonstrates an 11% reduction in all-cause mortality risk compared to budesonide/glycopyrrolate/formoterol (GFB/BUD/GLY/FORM) at 12 months, with a hazard ratio of 0.89 (95% CI: 0.80-0.98; P = 0.020). 1

Direct Comparative Evidence

The strongest evidence comes from a 2025 real-world comparative effectiveness study of 44,542 Medicare patients that directly compared these two triple therapies:

• VFU users had 11% lower risk of all-cause mortality at 12 months post-initiation compared to GFB users (5.6% vs. 6.4%; HR 0.89,95% CI: 0.80-0.98; P = 0.020) 1
• This mortality benefit was consistent across different insurance populations (Medicare Advantage, Medicaid, and commercial insurance) 1
• The median follow-up was 9 months after propensity score weighting to adjust for baseline confounding 1

Supporting Evidence from Individual Trials

VFU (FF/UMEC/VI) Mortality Data:

• The IMPACT trial demonstrated VFU reduced all-cause mortality by 28% versus dual LAMA/LABA therapy (HR 0.72,95% CI: 0.53-0.99; P = 0.042) with 99.6% vital status data captured 2
• Independent adjudication confirmed lower rates of cardiovascular death, respiratory death, and COPD-related death with VFU 2
• The 2023 Canadian Thoracic Society guidelines cite IMPACT showing a risk ratio of 0.64 (95% CI: 0.42-0.97) for VFU versus LAMA/LABA 3

GFB (BUD/GLY/FORM) Mortality Data:

• The ETHOS trial showed GFB 320 µg budesonide reduced mortality versus LAMA/LABA with a risk ratio of 0.58 (95% CI: 0.34-0.99) and hazard ratio of 0.54 (95% CI: 0.34-0.87) 3
• Critically, the lower 160 µg budesonide dose did NOT demonstrate mortality benefit, highlighting dose-dependency 3

Meta-Analysis Findings

A 2022 meta-analysis of 21,809 COPD patients from major trials (ETHOS, IMPACT, KRONOS, TRILOGY) found:

• No significant differences in all-cause mortality between triple FDCs when compared indirectly (p > 0.05) 4
• However, mortality protection appeared related to ICS dose 4
• FF/UMEC/VI showed the greatest overall efficacy profile (50.54%) in combined IBiS scoring 4

Cost-Effectiveness Modeling

A 2026 UK cost-effectiveness analysis using matching-adjusted indirect comparison demonstrated:

• GFB showed greater mortality reduction versus VFU in modeled scenarios at both 1-year and 5-year horizons 5
• However, this contradicts the direct real-world comparative data from 2025 1
• The modeling was based on indirect comparisons rather than head-to-head data 5

Clinical Algorithm for Interpretation

When prioritizing the evidence:

1. Direct comparative real-world data (2025) supersedes indirect comparisons and modeling - VFU shows 11% mortality reduction versus GFB 1

2. Both therapies reduce mortality versus dual therapy - The choice between them shows modest differences in real-world practice 3, 1

3. ICS dose matters - GFB's mortality benefit was only demonstrated at the 320 µg budesonide dose, not the 160 µg dose 3

Important Caveats

• Pneumonia risk increases with ICS-containing regimens, particularly in severe/very severe COPD, though the number needed to harm (33 patients for 1 year) is substantially higher than the number needed to treat for exacerbation prevention (4 patients for 1 year) 3

• Both trials (IMPACT and ETHOS) enrolled high-risk patients with CAT ≥10, FEV1 <80% predicted, and ≥2 moderate or ≥1 severe exacerbations in the prior year 3

• Neither IMPACT nor ETHOS showed mortality differences when triple therapy was compared to ICS/LABA dual therapy, only versus LAMA/LABA 3

• The real-world comparative study's 9-month median follow-up is shorter than the pivotal trials, though the 12-month mortality analysis provides robust data 1