D-dimer and risk of thromboembolic and bleeding events in patients with atrial fibrillation--observations from the ARISTOTLE trial

J Thromb Haemost. 2014 Sep;12(9):1401-12. doi: 10.1111/jth.12638. Epub 2014 Jul 24.


Background: D-dimer is related to adverse outcomes in arterial and venous thromboembolic diseases.

Objectives: To evaluate the predictive value of D-dimer level for stroke, other cardiovascular events, and bleeds, in patients with atrial fibrillation (AF) treated with oral anticoagulation with apixaban or warfarin; and to evaluate the relationship between the D-dimer levels at baseline and the treatment effect of apixaban vs. warfarin.

Methods: In the ARISTOTLE trial, 18 201 patients with AF were randomized to apixaban or warfarin. D-dimer was analyzed in 14 878 patients at randomization. The cohort was separated into two groups; not receiving vitamin K antagonist (VKA) treatment and receiving VKA treatment at randomization.

Results: Higher D-dimer levels were associated with increased frequencies of stroke or systemic embolism (hazard ratio [HR] [Q4 vs. Q1] 1.72, 95% confidence interval [CI] 1.14-2.59, P = 0.003), death (HR [Q4 vs. Q1] 4.04, 95% CI 3.06-5.33) and major bleeding (HR [Q4 vs. Q1] 2.47, 95% CI 1.77-3.45, P < 0.0001) in the no-VKA group. Similar results were obtained in the on-VKA group. Adding D-dimer level to the CHADS2 score improved the C-index from 0.646 to 0.655 for stroke or systemic embolism, and from 0.598 to 0.662 for death, in the no-VKA group. D-dimer level improved the HAS-BLED score for prediction of major bleeds, with an increase in the C-index from 0.610 to 0.641. There were no significant interactions between efficacy and safety of study treatment and D-dimer level.

Conclusion: In anticoagulated patients with AF, the level of D-dimer is related to the risk of stroke, death, and bleeding, and adds to the predictive value of clinical risk scores. The benefits of apixaban were consistent, regardless of the baseline D-dimer level.

Keywords: D-dimer; apixaban; atrial fibrillation; risk assessment; warfarin.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Aged
  • Anticoagulants / therapeutic use
  • Atrial Fibrillation / blood
  • Atrial Fibrillation / complications*
  • Cohort Studies
  • Embolism / blood
  • Female
  • Fibrin Fibrinogen Degradation Products / metabolism*
  • Fibrinolytic Agents / chemistry
  • Hemorrhage
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • Pyrazoles / administration & dosage
  • Pyridones / administration & dosage
  • Risk Assessment
  • Risk Factors
  • Stroke / blood
  • Thromboembolism / blood*
  • Treatment Outcome
  • Vitamin K / antagonists & inhibitors
  • Warfarin / administration & dosage
  • Warfarin / therapeutic use


  • Anticoagulants
  • Fibrin Fibrinogen Degradation Products
  • Fibrinolytic Agents
  • Pyrazoles
  • Pyridones
  • fibrin fragment D
  • Vitamin K
  • apixaban
  • Warfarin