title: Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation.
abstract: BACKGROUND
  Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study.
  
  
  METHODS
  Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics.
  
  
  RESULTS
  Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P = .0041), major bleedings (P = .0001), vascular death (P < .0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P < .0001). CRP was independently related to myocardial infarction (P = .0047), vascular death (P = .0004), and the composite thromboembolic outcome (P = .0001). When further adjusted for cardiac (troponin and N-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P < .0001), major bleeding (P < .0170) and the composite thromboembolic outcome (P < .0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P = .0017) when adding IL-6 to the clinically used CHA2DS2-VASc risk score with net reclassification improvement of 28%.
  
  
  CONCLUSIONS
  In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Aulin
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Clinical Chemistry, Uppsala University, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Sweden.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hijazi
authors.affiliation: Lankenau Institute for Medical Research and the Heart Center, Wynnewood, PA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Ezekowitz
authors.affiliation: Uppsala Clinical Research Center, Uppsala University, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Andersson
authors.affiliation: Population Health Research Institute, Hamilton, Canada.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Connolly
authors.affiliation: 3rd Department of Internal Medicine Cardiology and Emergency Medicine, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.affiliation: Boehringer-Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Uppsala Clinical Research Center and Department of Medical Sciences, Cardiology, Uppsala University, Sweden. Electronic address: Jonas.oldgren@ucr.uu.se.
authors.forename: Jonas
authors.initials: J
authors.lastname: Oldgren
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*; D000069604:Dabigatran / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D020521:Stroke / Q000097:blood / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; 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; C508600:IL6 protein, human; D015850:Interleukin-6; D014859:Warfarin; D002097:C-Reactive Protein; D000069604:Dabigatran