title: Optimizing clinical use of biomarkers in high-risk acute heart failure patients.
abstract: OBJECTIVE
  The clinical value of single biomarkers at single time-points to predict outcomes in patients with acute heart failure (AHF) is limited. We performed a multimarker, multi-time-point analysis of biomarkers for the prediction of post-discharge clinical outcomes in high-risk AHF patients.
  
  
  RESULTS
  A set of 48 circulating biomarkers were measured in the PROTECT trial which enrolled 2033 patients with AHF. Associations between baseline levels of biomarkers and outcomes (30-day all-cause mortality, 30-day death or rehospitalization for renal/cardiovascular causes and 180-day all-cause mortality) were evaluated. Prognostic accuracies of baseline, days 2 or 3, 7, and 14 biomarker measurements were estimated and compared utilizing a time-dependent area under the curve (AUC) analysis. Forty-four biomarkers were significantly associated with outcomes, but 42 had limited prognostic value (C-index < 0.70). However, multimarker models combining best-performing biomarkers from different clusters had a much stronger prognostic value. Combining blood urea nitrogen (BUN), chloride, interleukin (IL)-6, cTnI, sST-2 and VEGFR-1 into a clinical model yielded a 11% increase in C-index to 0.84 and 0.78 for 30-day and 180-day all-cause mortality, respectively, and cNRI of 0.86 95% CI [0.55-1.11] and 0.76 95% CI [0.57-0.87]. Prognostic gain was modest for the 30-day death/rehospitalization for cardiovascular or renal causes endpoint. Comparative time-dependent AUC analysis indicated that late measurements provided superior accuracy for the prediction of all-cause mortality over 180 days, with few exceptions including BUN and galectin-3. However, the predictive value of most biomarkers showed a diminishing pattern over time irrespective of moment of measurement.
  
  
  CONCLUSIONS
  Multimarker models significantly improve risk prediction. Subsequent measurements, beyond admission, are needed for majority of biomarkers to maximize prognostic value over time, particularly in the long term.
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.|Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Biniyam G
authors.initials: BG
authors.lastname: Demissei
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Mattia A E
authors.initials: MA
authors.lastname: Valente
authors.affiliation: Imperial College, London, UK.
authors.forename: John G
authors.initials: JG
authors.lastname: Cleland
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: O'Connor
authors.affiliation: University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.affiliation: Medical University, Clinical Military Hospital, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
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: Beth
authors.initials: B
authors.lastname: Davison
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Givertz
authors.affiliation: Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Bloomfield
authors.affiliation: Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Dittrich
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Meer
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.|Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Hillege
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000401:mortality*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D018570:Risk Assessment
chemical_list: D015415:Biomarkers
keywords: Acute heart failure; Multimarker strategy; Prognosis; Risk stratification; Time-dependent AUC analysis