title: Adjustment of the GRACE score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-ST-elevation acute coronary syndrome.
abstract: OBJECTIVE
  The aim of the study was to evaluate whether knowledge of the circulating concentration of growth differentiation factor 15 (GDF-15) adds predictive information to the Global Registry of Acute Coronary Events (GRACE) score, a validated scoring system for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). We also evaluated whether GDF-15 adds predictive information to a model containing the GRACE score and N-terminal pro-B-type natriuretic peptide (NT-proBNP), a prognostic biomarker already in clinical use.
  
  
  RESULTS
  The GRACE score, GDF-15, and NT-proBNP levels were determined on admission in 1122 contemporary patients with NSTE-ACS. Six-month all-cause mortality or non-fatal myocardial infarction (MI) was the primary endpoint of the study. To obtain GDF-15- and NT-proBNP-adjusted 6-month estimated probabilities of death or non-fatal MI, statistical algorithms were developed in a derivation cohort (n = 754; n = 66 reached the primary endpoint) and applied to a validation cohort (n = 368; n = 33). Adjustment of the GRACE risk estimate by GDF-15 increased the area under the receiver-operating characteristic curve (AUC) from 0.79 to 0.85 (P < 0.001) in the validation cohort. Discrimination improvement was confirmed by an integrated discrimination improvement (IDI) of 0.055 (P = 0.005). A net 31% of the patients without events were reclassified into lower risk, and a net 27% of the patients with events were reclassified into higher risk, resulting in a total continuous net reclassification improvement [NRI(>0)] of 0.58 (P = 0.002). Addition of NT-proBNP to the GRACE score led to a similar improvement in discrimination and reclassification. Addition of GDF-15 to a model containing GRACE and NT-proBNP led to a further improvement in model performance [increase in AUC from 0.84 for GRACE plus NT-proBNP to 0.86 for GRACE plus NT-proBNP plus GDF-15, P = 0.010; IDI = 0.024, P = 0.063; NRI(>0) = 0.42, P = 0.022].
  
  
  CONCLUSIONS
  We show that a single measurement of GDF-15 on admission markedly enhances the predictive value of the GRACE score and provides moderate incremental information to a model including the GRACE score and NT-proBNP. Our study is the first to provide simple algorithms that can be used by the practicing clinician to more precisely estimate risk in individual patients based on the GRACE score and a single biomarker measurement on admission. The rigorous statistical approach taken in the present study may serve as a blueprint for future studies exploring the added value of biomarkers beyond clinical risk scores.
authors.affiliation: Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Widera
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pencina
authors.forename: Allison
authors.initials: A
authors.lastname: Meisner
authors.forename: Tibor
authors.initials: T
authors.lastname: Kempf
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bethmann
authors.forename: Ivonne
authors.initials: I
authors.lastname: Marquardt
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Evangelos
authors.initials: E
authors.lastname: Giannitsis
authors.forename: Kai C
authors.initials: KC
authors.lastname: Wollert
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood* / Q000401:mortality; D000368:Aged; D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000401:mortality; D011237:Predictive Value of Tests; D018570:Risk Assessment / Q000379:methods
chemical_list: D015415:Biomarkers; D055436:Growth Differentiation Factor 15