title: Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study.
abstract: Growth differentiation factor-15 (GDF-15) predicts death and composite cardiovascular (CV) events in patients with acute coronary syndrome (ACS). We investigated the independent associations between GDF-15 levels and major bleeding, the extent of coronary lesions and individual CV events in patients with ACS.
  
  
  
  Growth differentiation factor-15 was analysed at baseline ( ITALIC! n = 16 876) in patients with ACS randomized to ticagrelor or clopidogrel in the PLATO (PLATelet inhibition and patient Outcomes) trial. Growth differentiation factor-15 levels were related to extent of coronary artery disease (CAD) and to all types of non-coronary artery bypass grafting (CABG)-related major bleeding, spontaneous myocardial infarction (MI), stroke, and death during 12-month follow-up. In Cox proportional hazards models adjusting for established risk factors for CV disease and prognostic biomarkers (N-terminal pro B-type natriuretic peptide, cystatin C, high-sensitive C-reactive protein, and high-sensitive troponin T), 1 SD increase in ln GDF-15 was associated with increased risk of major bleeding with a hazard ratio (HR) 1.37 (95% confidence interval: 1.25-1.51) and with a similar increase in risk across different bleeding locations. For the same increase in ln GDF-15, the HR for the composite of CV death, spontaneous MI, and stroke was 1.29 (1.21-1.37), CV death 1.41 (1.30-1.53), all-cause death 1.41 (1.31-1.53), spontaneous MI 1.15 (1.05-1.26), and stroke 1.19 (1.01-1.42). The ITALIC! C-statistic improved for the prediction of CV death and non-CABG-related major bleeding when adding GDF-15 to established risk factors.
  
  
  
  In patients with ACS, higher levels of GDF-15 are associated with raised risks of all types of major non-CABG-related bleeding, spontaneous MI, and stroke as well as CV and total mortality and seem to improve risk stratification for CV-mortality and major bleeding beyond established risk factors.
  
  
  
  www.clinicaltrials.gov; NCT00391872.
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center, Uppsala, Sweden emil.hagstrom@ucr.uu.se.
authors.forename: Emil
authors.initials: E
authors.lastname: Hagström
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: James
authors.affiliation: Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Bertilsson
authors.affiliation: Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, OH, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Becker
authors.affiliation: AstraZeneca Research and Development, Mölndal, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Himmelmann
authors.affiliation: Medical Department, Hospital Unit West, Herning/Holstebro, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Husted
authors.affiliation: Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: INSERM-Unité 1148, Paris, France Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK.
authors.forename: Philippe Gabriel
authors.initials: PG
authors.lastname: Steg
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.affiliation: Uppsala Clinical Research Center, Uppsala, Sweden Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D054058:Acute Coronary Syndrome; D002097:C-Reactive Protein; D055436:Growth Differentiation Factor 15; D006470:Hemorrhage; D006801:Humans; D020097:Natriuretic Peptide, Brain; D010975:Platelet Aggregation Inhibitors; D013988:Ticlopidine; D016896:Treatment Outcome; D020107:Troponin T
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D010975:Platelet Aggregation Inhibitors; D020107:Troponin T; D020097:Natriuretic Peptide, Brain; D002097:C-Reactive Protein; D013988:Ticlopidine
keywords: Cardiovascular risk factors; GDF-15; Major bleeding; Mortality; Myocardial infarction