High-Dose Edoxaban as Effective as Warfarin for Stroke Prevention in A-fib

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Treatment with a high daily dose of the novel anticoagulant edoxaban is as effective as warfarin in preventing ischemic stroke and reduces intracranial bleeding in patients with nonvalvular atrial fibrillation (A-fib), according to a substudy of the ENGAGE AF-TIMI 48 trial published online June 19, 2014, ahead of print in Stroke. Additionally, the on-treatment analysis demonstrated lower rates of first stroke with the newer anticoagulant.

For the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, investigators randomized 21,105 patients with nonvalvular A-fib at moderate-high risk of stroke to warfarin (target INR 2.0-3.0) or a high (60-mg) or low (30-mg) dose (both adjusted in about a quarter of patients) of edoxaban between November 2008 and November 2010. The results, published in the New England Journal of Medicine in November 2013, showed that both edoxaban regimens were noninferior in preventing stroke or systemic embolism and were associated with lower rates of bleeding and death from cardiovascular causes.
Robert P. Giugliano, MD, SM, of Brigham and Women’s Hospital (Boston, MA), and colleagues conducted a prespecified substudy to delve further into the severity and subtypes of cerebrovascular events in all trial arms.


Comparable Outcomes with the High-Dose, Warfarin

Overall, ischemic stroke occurred at an annual rate of 1.4% (n = 794) and hemorrhagic stroke at 0.29% (n = 164). Patients with ischemic stroke were more likely to be female, older, of Eastern European descent, and have more stroke risk factors, whereas patients with hemorrhagic stroke were more likely to be naive to vitamin K antagonists, receive concomitant aspirin, be of Asian descent, and have higher blood pressure.

All stroke (ischemic or hemorrhagic) occurred in 219 warfarin-treated patients (1.41% per year) compared with 174 patients receiving high-dose (1.13% per year) and 243 receiving low-dose edoxaban (1.55% per year). High-dose edoxaban was associated with fewer first strokes on-treatment than warfarin (HR 0.80; 95% CI 0.65-0.98; P = .027), while low-dose edoxaban resulted in similar rates (HR 1.10; 95% CI 0.91-1.32; P = .33).

Both doses of edoxaban reduced hemorrhagic stroke compared with warfarin. Rates of ischemic cerebrovascular events (ischemic stroke or TIA) were similar with warfarin (1.73% per year) and high-dose edoxaban (1.76% per year) but higher with low-dose edoxaban (2.48% per year; table 1).

Table 1. Cerebrovascular Events: Edoxaban vs Warfarin ITT



P Value

High Dose
Hemorrhagic Stroke
Ischemic Stroke
All Stroke or TIA


< .001

Low Dose
Hemorrhagic Stroke
Ischemic Stroke
All Stroke or TIA


< .001
< .001

Edoxaban reduced intracranial hemorrhage, showing substantial reductions in fatal bleeding with both high (HR 0.58; P = .031) and low doses (HR 0.28; P < .001) compared with warfarin.

High- and low-dose edoxaban also reduced the composite endpoint of death, nonfatal stroke, or intracranial hemorrhage compared with warfarin (HR 0.88; P = .003 and HR 0.90; P = .021, respectively). Both doses were also associated with fewer adverse events than warfarin with the exception of the composite of death or nonfatal ischemic stroke, which was similar in the warfarin and low-dose edoxaban groups (HR 0.96; P = .35).

Edoxaban Mechanism May Protect Against Bleeding

“The precise reason for the halving of [intracranial hemorrhage] reported with factor-specific anticoagulants as compared with warfarin is unknown and is likely multifactorial,” Dr. Giugliano and colleagues write.

A current hypothesis, they say, is that while vitamin K antagonists suppress factor VIIa and tissue factor-VIIa complexes, impairing the “protective hemostatic milieu in the brain that protects elderly patients against the risk of [intracranial hemorrhage],” newer anticoagulants work differently.

They “inhibit clotting factors more distal in the cascade [and] do not interfere with the formation of tissue factor-VIIa complex,” the authors explain. “However, because the subdural, epidural, and subarachnoid spaces are not as rich in tissue factor as the brain, the reduction in bleeding observed with edoxaban and other factor-specific agents in these extraparenchymal locations raises the possibility of other mechanism(s).”

Comparing the rates of intracranial bleeding with even newer anticoagulants in development “that inhibit more proximal targets in the cascade… will be interesting,” they conclude.


Giugliano RP, Ruff CT, Rost NS, et al. Cerebrovascular events in 21,105 patients with atrial fibrillation randomized to edoxaban versus warfarin: Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48. Stroke. 2014;Epub ahead of print.


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  • ENGAGE AF-TIMI 48 and the substudy were funded by Daiichi Sankyo.
  • Dr. Giugliano reports serving as a consultant to and receiving honoraria from Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Sanofi and receiving institutional grant support from AstraZeneca, Daiichi Sankyo, Johnson &amp; Johnson, Merck, and Sanofi.