Article Text

other Versions

Download PDFPDF
Original article
Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation
  1. Ziad Hijazi1,2,
  2. Julia Aulin1,2,
  3. Ulrika Andersson1,
  4. John H Alexander3,
  5. Bernard Gersh4,
  6. Christopher B Granger3,
  7. Michael Hanna5,
  8. John Horowitz6,
  9. Elaine M Hylek7,
  10. Renato D Lopes3,
  11. Agneta Siegbahn1,8,
  12. Lars Wallentin1,2
  13. on behalf of the ARISTOTLE Investigators
  1. 1Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
  2. 2Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
  3. 3Duke University Medical Center, Durham, North Carolina, USA
  4. 4Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  5. 5Bristol-Myers Squibb, Princeton, New Jersey, USA
  6. 6Cardiology Department, University of Adelaide, Adelaide, South Australia, Australia
  7. 7Boston University Medical Center, Boston, Massachusetts, USA
  8. 8Department of Medical Sciences, Clinical Chemistry, University Hospital, Uppsala, Sweden
  1. Correspondence to Dr Ziad Hijazi, Uppsala Clinical Research Center, Uppsala University, Uppsala Science Park, Uppsala SE-752 37, Sweden; Ziad.Hijazi{at}


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.

Trial registration number identifier: NCT00412984 post-results.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Linked Articles