title: Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials.
abstract: BACKGROUND
  Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality.
  
  
  METHODS
  We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242.
  
  
  RESULTS
  Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio [HR] for admission 4·05, 95% CI 1·36-12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83-11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81-19·74).
  
  
  CONCLUSIONS
  Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials.
  
  
  BACKGROUND
  US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust.
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Durheim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Rhonda S
authors.initials: RS
authors.lastname: Roberts
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO, USA; Department of Medicine, University of Colorado, Denver, CO, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Flaherty
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Talmadge E
authors.initials: TE
authors.lastname: King
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Palmer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Raghu
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA.
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Snyder
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA; Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Anstrom
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan, Ann Arbor, MI, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Electronic address: fjm2003@med.cornell.edu.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
mesh_terms: D000368:Aged; D015331:Cohort Studies; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000401:mortality* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012306:Risk; D016019:Survival Analysis; D014481:United States / Q000453:epidemiology; D014797:Vital Capacity / Q000502:physiology*