Edoxaban Dosing Regimens Evaluated for AF-Related Stroke

Brain in stroke. Magnetic resonance imaging (MRI) scan of an axial section through the brain of an 80-year-old male patient following a stroke. A stroke, or cerebrovascular accident (CVA), is the rapid loss of brain function due to a disturbance in the blood supply to the brain. An ischaemic stroke is caused by a reduction in the blood supply to an area of the brain.
The comprehensive net clinical outcomes of low- and high-dose edoxaban was evaluated for stroke in atrial fibrillation.

Atrial fibrillation treated with a low-dose edoxaban regimen was linked to lower rates of the composite endpoint of major bleeding, stroke and systemic embolism and mortality when compared with high-dose regimens, according to findings of a randomized trial published in the Journal of the American College of Cardiology. Secondary and tertiary net clinical outcomes were similar between the low- and high-dose edoxaban regimens.

Patients (N=14,014) with AF who had moderate to high risk for stroke were recruited for the Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, a phase 3, double-blind, double-dummy study. Patients were randomized to receive higher- (60 mg; n=7012) or lower-(30 mg; n=7002) dose edoxaban. Stroke, major adverse cardiovascular events, and mortality were assessed at a median of 2.8 years.

Patients were aged median 72 (interquartile range [IQR], 64-78) years, 38.4% were women, 13.8% were Asian, 93.6% had hypertension, 57.4% had congestive heart failure, 36.3% had diabetes, 33.4% coronary artery disease, and 28.3% a history of stroke or transient ischemic attack.

The primary composite outcome of stroke, systemic embolic events, major bleeding, or death was observed among 7.26% of the low-dose and 8.01% of the high-dose groups (hazard ratio [HR], 0.90; 95% CI, 0.84-0.98; P =.014). No differences were observed for the secondary composite (disabling stroke, life-threatening bleed, or all-cause mortality: HR, 0.94; 95% CI, 0.86-1.04; P =.021) or tertiary composite (stroke, systemic embolism, life-threatening bleed, or all-cause mortality: HR, 1.01; 95% CI, 0.93-1.11; P =.74) endpoints.

However, patients randomized to the low-dose group had higher risk for systemic embolic events (HR, 1.92; 95% CI, 1.03-3.59; P =.040), ischemic stroke (HR, 1.43; 95% CI, 1.21-1.69; P <.0001), nonfatal stroke (HR, 1.43; 95% CI, 1.20-1.71; P <.0001), stroke (HR, 1.30; 95% CI, 1.11-1.52; P =.001), and myocardial infarction (HR, 1.28; 95% CI, 1.02-1.61; P =.034) and lower risk for gastrointestinal major bleeding (HR, 0.57; 95% CI, 0.46-0.70; P <.0001), hemorrhagic stroke (HR, 0.61; 95% CI, 0.39-0.96; P =.034), nonintercranial bleeding (HR, 0.63; 95% CI, 0.54-0.74; P <.0001), major bleeding events (HR, 0.64; 95% CI, 0.55-0.74; P <.001), intercranial hemorrhage (HR, 0.65; 95% CI, 0.44-0.97; P =.035), and all bleeding events (HR, 0.78; 95% CI, 0.73-0.83; P <.0001), compared with high-dose recipients.

The purpose of this prespecified analysis was to generate hypotheses and was not sufficiently powered for subgroup analyses.

These data suggest that lower-dose may be linked to a higher risk for stroke or systemic embolism when compared with the higher-dose edoxaban regimen, but lower rates of

bleeding and the composite endpoint of major bleeding, stroke and systemic embolism, and mortality.

“These results could aid physicians in evidence-based individualization of edoxaban dosing,” the study authors noted.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Steffel J, Ruff CT, Yin O, et al. Randomized, double-blind comparison of half-dose versus full-dose edoxaban in 14,014 patients with atrial fibrillation. J Am Coll Cardiol. 2021;77(9):1197-1207. doi:10.1016/j.jacc.2020.12.053