August 11, 2026American Heart Journal
Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: Design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF–TIMI 48)
Key result
ENGAGE AF-TIMI 48 evaluates whether edoxaban is noninferior to warfarin for stroke prevention in AF.
- n=20,500
Why the study?
Vitamin K antagonists have significant limitations, including food and drug interactions and frequent monitoring, prompting evaluation of the direct factor Xa inhibitor edoxaban as a more convenient alternative.
Does edoxaban prevent stroke and systemic embolism in patients with atrial fibrillation and a CHADS(2) score ≥2 compared to warfarin?
Population
Approximately 20,500 AF patients with CHADS(2) score ≥2
Comparison
Two edoxaban exposure strategies (60 mg or 30 mg daily) vs warfarin
Design
Phase 3, randomized, double-blind, double-dummy, multinational noninferiority trial
Follow-up
Expected median 24 months
Authors
Discussion
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Implication
ENGAGE AF-TIMI 48 is a phase 3 trial designed to evaluate the noninferiority of two exposure strategies of edoxaban compared to warfarin for stroke prevention in atrial fibrillation.
Key Points
- This trial aims to determine the noninferiority of edoxaban compared to warfarin for preventing stroke and systemic embolism in atrial fibrillation patients.
- Phase 3 randomized, double-blind, double-dummy design involving approximately 20,500 subjects.
- Participants randomized to high exposure edoxaban (60 mg), low exposure edoxaban (30 mg), or warfarin titrated to INR 2.0-3.0.
- Median follow-up of 24 months with eligibility criteria including documented atrial fibrillation ≤12 months and CHADS(2) score ≥2.
- The primary objective is to confirm edoxaban's noninferiority to warfarin for stroke prevention.
- Safety endpoints include assessing modified International Society on Thrombosis and Haemostasis major bleeding rates, though specific rates are not provided.
Study Design
Type
RCT (n=20,500)
Blinding
Double-blind, double-dummy
Randomization
Stratified by CHADS(2) score and anticipated drug exposure
Multicenter
Yes
Structured PICO
Does edoxaban prevent stroke and systemic embolism in patients with atrial fibrillation and a CHADS(2) score ≥2 compared to warfarin?
P
Population
Approximately 20,500 patients with atrial fibrillation and a CHADS(2) score ≥2, with an expected median follow-up of 24 months.
I
Intervention
Edoxaban high exposure (60 mg daily, adjusted for drug clearance) or edoxaban low exposure (30 mg daily, adjusted for drug clearance)
C
Comparator
Warfarin titrated to an international normalized ratio of 2.0 to 3.0 (with sham INRs for edoxaban patients to maintain blinding)
O
Outcome
Prevention of stroke and systemic embolismcomposite
ENGAGE AF-TIMI 48 is a phase 3 trial designed to evaluate the noninferiority of two exposure strategies of edoxaban compared to warfarin for stroke prevention in atrial fibrillation.
Cite This Study
Ruff et al. (2010) conducted an RCT in Atrial fibrillation (n=20,500). Edoxaban vs. Warfarin was evaluated on Stroke and systemic embolism. The ENGAGE AF-TIMI 48 trial will randomize approximately 20,500 patients to evaluate whether edoxaban is noninferior to warfarin for preventing stroke and systemic embolism in atrial fibrillation.