title: A multimarker multi-time point-based risk stratification strategy in acute heart failure: results from the RELAX-AHF trial.
abstract: We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF).
  
  
  
  Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91].
  
  
  
  In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy.
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Biniyam G
authors.initials: BG
authors.lastname: Demissei
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Cotter
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Prescott
authors.affiliation: Duke Clinical Research Institute, Durham, NC, USA.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.affiliation: Athens University Hospital, Attikon, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.affiliation: University of California at San Diego, San Diego, CA, USA.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Greenberg
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Pang
authors.affiliation: Medical University, Clinical Military Hospital, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Severin
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Columbia University, New York, NY, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Qian
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: University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.affiliation: Momentum Research, Durham, NC, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Davison
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
mesh_terms: D000208:Acute Disease; D015415:Biomarkers / Q000097:blood*; D001798:Blood Proteins; D002097:C-Reactive Protein / Q000378:metabolism; D055316:Cystatin C / Q000097:blood; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D037502:Galectin 3 / Q000097:blood; D037161:Galectins; D055436:Growth Differentiation Factor 15 / Q000097:blood; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000097:blood; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011379:Prognosis; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D012065:Relaxin / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D020107:Troponin T / Q000097:blood; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D055316:Cystatin C; C526140:GDF15 protein, human; D037502:Galectin 3; D037161:Galectins; D055436:Growth Differentiation Factor 15; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; C428445:LGALS3 protein, human; D010446:Peptide Fragments; D011994:Recombinant Proteins; D020107:Troponin T; C109794:pro-brain natriuretic peptide (1-76); C577649:serelaxin protein, human; D020097:Natriuretic Peptide, Brain; D012065:Relaxin; D002097:C-Reactive Protein
keywords: Acute heart failure; Biomarkers; Multimarker strategy; Prognosis; Risk stratification; Serial measurement