Risk of exacerbation and pneumonia with single-inhaler triple versus dual therapy in IMPACT

Mark T. Dransfield, Courtney Crim, Gerard J. Criner, Nicola C. Day, David M.G. Halpin, Mei Lan K. Han, C. Elaine Jones, Sally Kilbride, David LaFon, David A. Lipson, David A. Lomas, Neil Martin, Fernando J. Martinez, Dave Singh, Robert A. Wise, Peter Lange

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Rationale: In the IMPACT (Informing the Pathway of COPD Treatment) trial, single-inhaler fluticasone furoate/umeclidinium/ vilanterol (FF/UMEC/VI) triple therapy reduced exacerbation risk versus FF/VI and UMEC/VI and mortality risk versus UMEC/VI. However, pneumonia incidence was higher in the inhaled corticosteroid (FF)–containing arms, raising questions about the relative benefit of exacerbation reduction compared with the increased risk of pneumonia. Objectives: Determine benefit–risk of the three treatments by evaluating time-to-first and rates of composite exacerbation or pneumonia outcomes. Methods: We evaluated time-to-first (prespecified) and rates (post hoc) of investigator-reported pneumonia, serious pneumonia leading to hospitalization or death, and the composite endpoints of 1) moderate (required antibiotics/corticosteroids)/ severe (hospitalized) exacerbation or pneumonia and 2) severe exacerbation or serious (hospitalized) pneumonia. Analyses were repeated for radiographically confirmed pneumonia (post hoc). Results: Moderate/severe exacerbations occurred in 47%, 49%, and 50% of patients randomized to FF/UMEC/VI, FF/VI and UMEC/VI, and pneumonias in 8%, 7%, and 5%, respectively. FF/UMEC/VI reduced the risk of combined moderate/severe exacerbation or pneumonia (time-to-first) versus FF/VI (hazard ratio, 0.87 [95% confidence interval (CI), 0.82–0.92]) and UMEC/VI (0.87 [0.81–0.94]), as well as the risk of combined severe exacerbation or serious pneumonia versus UMEC/VI (0.83 [0.72–0.96]). FF/UMEC/VI reduced the rate of combined moderate/severe exacerbation or pneumonia (rate ratio, 0.78 [0.72–0.84]) and combined severe exacerbation or serious pneumonia (rate ratio, 0.76 [0.65–0.89]) versus UMEC/VI. Results were similar for radiographically confirmed pneumonia endpoints. Conclusions: Despite higher incidence of pneumonia in FF-containing arms, these composite exacerbation/pneumonia outcomes support a favorable benefit–risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.

Original languageEnglish (US)
Pages (from-to)788-798
Number of pages11
JournalAnnals of the American Thoracic Society
Issue number5
StatePublished - May 2021


  • Benefit–risk assessment
  • Chronic obstructive pulmonary disease
  • Corticosteroids
  • Exacerbations
  • Pneumonia

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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