title: Early vs. late worsening heart failure during acute heart failure hospitalization: insights from the PROTECT trial.
abstract: BACKGROUND
  Worsening heart failure (WHF) symptoms despite initial therapy during admission for acute heart failure (AHF) is associated with worse outcomes. The association between the time of the WHF event and the intensity of WHF therapy with outcomes is unknown.
  
  
  RESULTS
  In the PROTECT trial of 2033 AHF patients, we investigated the association between time of occurrence of WHF and intensity of therapy, with subsequent outcomes. WHF was defined by standardized, physician-determined assessment. Early WHF was defined as occurring on days 2-3 and late on days 4-7. Low intensity included restarting/increasing diuretics or vasodilators and high intensity included initiation of inotropes, vasopressors, inodilators, or mechanical support. Outcomes were death or cardiovascular/renal hospitalization over 60 days and death over 180 days. Of the 1879 patients with complete follow-up after day 7, 12.7% (n = 238) experienced WHF: 47.9% early and 52.1% late. Treatment intensity was low in 72.3% and high in 24.8% (2.9% missing). After adjusting for baseline predictors of outcome, WHF was associated with a trend toward increased 60-day death or cardiovascular/renal hospitalization [hazard ratio (HR) 1.26; 95% confidence interval (CI) 0.99-1.60; P = 0.063] and increased 180-day death (HR 1.77; 95% CI 1.33-2.34; P < 0.001). There was no evidence of a differential association between the time of occurrence of WHF and outcomes. High-intensity therapy was not significantly associated with increased event rates (180-day mortality: HR 1.44; 95% CI 0.80-2.59 vs. low).
  
  
  CONCLUSIONS
  Inhospital WHF was associated with increased 180-day death. The time of occurrence and intensity of WHF therapy may provide less prognostic information than whether or not WHF occurred.
authors.affiliation: Duke University Hospital, Medicine, Division of Cardiology, 2301 Erwin Road, Durham, NC 27713, USA.|Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mentz
authors.affiliation: University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Cotter
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Milo
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: McKendry
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Chiswell
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Davison
authors.affiliation: National Heart and Lung Institute, Imperial College London (Royal Brompton & Harefield Hospitals) and Department of Cardiology, Castle Hill Hospital, University of Hull, Kingston-upon-Hull, UK.
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bloomfield
authors.affiliation: University of Iowa Carver College of Medicine Cardiovascular Research Center, Iowa City, IA, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Dittrich
authors.affiliation: Duke University Hospital, Medicine, Division of Cardiology, 2301 Erwin Road, Durham, NC 27713, USA.|Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Fiuzat
authors.affiliation: Medical University, Military Hospital, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Givertz
authors.affiliation: University of Groningen, Groningen, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: University of California at San Francisco (SF) and SF Veterans Affairs Medical Center, SF, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.affiliation: Duke University Hospital, Medicine, Division of Cardiology, 2301 Erwin Road, Durham, NC 27713, USA.|Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
mesh_terms: D000368:Aged; D018450:Disease Progression; D004232:Diuretics / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology; D006760:Hospitalization; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011897:Random Allocation; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use
chemical_list: D004232:Diuretics; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents
keywords: Acute heart failure; Intensity; Outcomes; Timing; Worsening heart failure