title: Growth differentiation factor 15, a marker of oxidative stress and inflammation, for risk assessment in patients with atrial fibrillation: insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.
abstract: BACKGROUND
  Growth differentiation factor 15 (GDF-15), high-sensitivity troponin, and N-terminal pro-brain natriuretic peptide levels are predictive of death and cardiovascular events in healthy elderly subjects, patients with acute coronary syndrome, and patients with heart failure. High-sensitivity troponin I and N-terminal pro-brain natriuretic peptide are also prognostic in patients with atrial fibrillation. We evaluated the prognostic value of GDF-15 alone and in addition to clinical characteristics and other biomarkers in patients with atrial fibrillation.
  
  
  RESULTS
  The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients. Efficacy and safety outcomes during 1.9 years of follow-up were compared across quartiles of GDF-15 by use of Cox analyses adjusted for clinical characteristics, randomized treatment, and other biomarkers. The GDF-15 level showed a median of 1383 ng/L (interquartile range, 977-2052 ng/L). Annual rates of stroke or systemic embolism ranged from 0.9% to 2.03% (P<0.001); of major bleeding, from 1.22% to 4.53% (P<0.001); and of mortality, from 1.34% to 7.19% (P<0.001) in the lowest compared with the highest GDF-15 quartile. The prognostic information provided by GDF-15 was independent of clinical characteristics and clinical risk scores. Adjustment for the other cardiac biomarkers attenuated the prognostic value for stroke, whereas the prognostic value for mortality and major bleeding remained. Apixaban consistently reduced stroke, mortality, and bleeding, regardless of GDF-15 levels.
  
  
  CONCLUSIONS
  GDF-15 is a risk factor for major bleeding, mortality, and stroke in atrial fibrillation. The prognostic value for major bleeding and death remained even in the presence of N-terminal pro-brain natriuretic peptide and high-sensitivity troponin I.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00412984.
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.). Lars.Wallentin@ucr.uu.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hijazi
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Ulrika
authors.initials: U
authors.lastname: Andersson
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hylek
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Signild
authors.initials: S
authors.lastname: Asberg
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: From the Department of Medical Sciences, Cardiology (L.W., Z.H.), Department of Medical Sciences, Cardiovascular Epidemiology (S.A.), and Department of Medical Sciences, Clinical Chemistry (A.S.), and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (L.W., Z.H.); Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden (U.A.); Duke University, Medical Center, Durham, NC (J.H.A., R.D.L., C.B.G.); Gabriele d'Annunzio University, Chieti, and Gabriele Monasterio Foundation, Pisa, Italy (R.D.C.); Bristol-Myers Squibb, Princeton, NJ (M.H.); University of Adelaide, Adelaide, Australia (J.D.H.); and Boston University Medical Center, Boston, MA (E.M.H.).
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D004311:Double-Blind Method; D065427:Factor Xa Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D018570:Risk Assessment; D020521:Stroke / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy; D013923:Thromboembolism / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy
chemical_list: D015415:Biomarkers; D065427:Factor Xa Inhibitors; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban
keywords: atrial fibrillation; biological markers; cardiovascular physiological processes; growth differentiation factor 15; natriuretic peptide, brain; risk assessment; troponin