title: Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation.
abstract: OBJECTIVE
  Atrial fibrillation (AF) is a risk factor for stroke and mortality and the prothrombotic state has been linked to inflammation. In this study we evaluated the relationship between inflammatory biomarkers at baseline and future risk of cardiovascular events in the Apixaban for Reduction In Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.
  
  
  METHODS
  The ARISTOTLE trial randomised 18,201 patients with AF to apixaban or warfarin. Interleukin 6 (IL-6) and C reactive protein (CRP) were analysed in plasma obtained at randomisation from 14,954 participants, and median follow-up was 1.9 years. Association between quartile groups of IL-6 and CRP and outcomes were analysed by Cox regression adjusted for clinical risk factors and other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).
  
  
  RESULTS
  The IL-6 median level was 2.3 ng/L (IQR 1.5-3.9), median CRP level was 2.2 mg/L (1.0-4.8). IL-6 and CRP were significantly associated with all-cause mortality independent of clinical risk factors and other biomarkers (HR (95% CI) 1.93 (1.57 to 2.37) and 1.49 (1.24 to 1.79), respectively, Q4 vs Q1). IL-6 was associated with myocardial infarction, cardiovascular mortality, and major bleeding beyond clinical risk factors but not in the presence of cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C). Neither inflammatory biomarker was associated with stroke/systemic embolism. Risk prediction for stroke, death and major bleeding was not improved by IL-6 or CRP when added to clinical risk factors and the other cardiovascular biomarkers (NT-proBNP, troponin, GDF-15, cystatin C).
  
  
  CONCLUSIONS
  In patients with AF on anticoagulation, after accounting for clinical risk factors and other biomarkers, biomarkers of inflammation were significantly associated with an increased risk of mortality. However, there were no associations with the risk of stroke or major bleeding.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00412984 post-results.
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hijazi
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Aulin
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Andersson
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Alexander
authors.affiliation: Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gersh
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
authors.affiliation: Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Hanna
authors.affiliation: Cardiology Department, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Horowitz
authors.affiliation: Boston University Medical Center, Boston, Massachusetts, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hylek
authors.affiliation: Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Department of Medical Sciences, Clinical Chemistry, University Hospital, Uppsala, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D001281:Atrial Fibrillation / Q000097:blood / Q000150:complications / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D006801:Humans; D007249:Inflammation / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects; D018570:Risk Assessment / Q000379:methods; D013923:Thromboembolism / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000925:Anticoagulants; D015415:Biomarkers; D015850:Interleukin-6; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D014859:Warfarin; D002097:C-Reactive Protein