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

Background

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:

• 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.

Conclusion

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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References

1. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094e2106.
2. Kristiansen A, Brandt L, Agoritsas T, et al. Applying new strategies for the national adaptation, updating, and dissemination of trustworthy guidelines: results from the Norwegian Adaptation of the
Antithrombotic Therapy and the Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice guidelines. Chest 2014;146:735e761.
3. Hijazi Z, Hohnloser SH, Oldgren J, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014;129:961e970.
4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883e891.
5. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11:503e511.
6. Bunch TJ, Weiss JP, Crandall BG, et al. Atrial fibrillation is independently associated with senile, vascular, and Alzheimer’s dementia. Heart Rhythm 2010;7:433e437.
7. Kwok CS, Loke YK, Hale R, et al. Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis. Neurology 2011;76:914e922.
8. Jacobs V, Woller SC, Stevens S, et al. Time outside of therapeutic range in atrial fibrillation patients is associated with long-term risk of dementia. Heart Rhythm 2014;11:2206e2213.