Physicians' Academy for Cardiovascular Education

Lower risk of dementia with direct oral anticoagulants in atrial fibrillation patients

Jacobs V, et al. Am J Cardiol. 2016

Long-Term Population-Based Cerebral Ischemic Event and Cognitive Outcomes of Direct Oral Anticoagulants Compared With Warfarin Among Long-term Anticoagulated Patients for Atrial Fibrillation

Jacobs V, May HT, Bair TL, et al.
Am J Cardiol. 2016; published online ahead of print


Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) indicated for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), and recommended by current guidelines for the prevention of thromboembolism in these patients [1,2]. The advantages of using these agents instead of Vitamin K antagonist (VKAs) include the absence of dietary interactions, fewer drug interactions, no need for routine monitoring, equivalent efficacy, and a decreased risk for bleeding, especially intracranial hemorrhage [3-5].
There is evidence supporting that multiple forms of dementia are associated with AF, and that patients on poorly managed VKA therapy, as measured by suboptimal time in therapeutic range (TTR), are subject to an increased risk for micro-bleeds and micro-thromboemboli, a possible mechanism that causes dementia in AF patients [6-8].
In this study it is hypothesised that the consistent lowering of cerebral ischemic events achieved with DOACs, as well as their relation with a significant reduction in intracranial bleeding, might be associated with a lower rate of dementia compared with warfarin. To test this hypothesis, a retrospective population-based analysis was performed to report on major outcomes including death, stroke/transient ischemic attack (TIA), major bleeding, and dementia, in 5,254 patients on DOACs (median follow-up time: 185 days) or warfarin (median follow-up time: 309 days).
Main results
Mortality and major bleeding:
  • major bleeding was observed more frequently in the warfarin group compared with the DOAC group (5.6% vs 4.3%; p = 0.03)
  • mortality was higher in the warfarin group (10.1% warfarin vs 7.1% DOAC; p <0.0001)
In the adjusted risk analysis in patients taking DOACs compared with those taking warfarin:
  • stroke/TIA occurred less frequently (HR: 0.47; 95% CI: 0.32-0.68; p <0.0001)
  • the risk of major bleeding was 0.70 (HR); 95% CI: 0.57-0.85; p <0.0001
  • dementia occurred more frequently in patients taking warfarin compared with patients taking DOAC: 0.7% vs 0.3% respectively (p = 0.03)
  • after multivariable adjustment, patients taking DOACs had a 51% decreased risk of dementia incidence or subsequent stroke or TIA compared with those taking warfarin (HR: 0.49; 95% CI: 0.35-0.69; p <0.0001)
The allocation of DOACs was as follows:
  • rivaroxaban: 55.3% (n = 1,454)
  • apixaban: 22.5% (n = 590)
  • dabigatran: 22.2% (n = 583)
Comparisons between DOACs:
  • no difference in the rates of major bleeding or death was observed comparing one DOAC with another
  • no difference in the rate of dementia was observed comparing one DOAC with another (apixaban: 0.2%; rivaroxaban: 0.4%; dabigatran: 0%; p = 0.36)
Compared to the DOAC group, the composite outcome of stroke/TIA/dementia was higher in the warfarin group at:  
  • 1 year (2.0% vs 4.1%; P = 0.002)
  • 3 years (3.8% vs 5.6%; P = 0.49)
  • long term (1.8% vs 4.7%; P <0.0001)
Patients taking warfarin with a lower TTR were more likely to develop dementia compared with those patients who were able to achieve a higher TTR.


In a retrospective analysis of 5,254 AF patients, the long-term efficacy and safety was better with DOACs compared with warfarin. DOAC treatment was associated with a lower risk of cerebral ischemic events and new-onset dementia. In patients on warfarin, a lower TTR was associated with a higher dementia risk, supporting the hypothesis that warfarin use may be associated with predisposition to repetitive small cerebral ischemic and hemorrhagic events, leading to dementia.
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