NOAH-AFNET 6
(2023)Objective
Edoxaban versus placebo in patients with device-detected atrial high-rate episodes (AHREs) without ECG-documented atrial fibrillation.
Study Summary
• Edoxaban did not significantly reduce the incidence of cardiovascular death, stroke, or systemic embolism compared to placebo. • However, it was associated with a higher incidence of major bleeding and all-cause mortality. • The overall incidence of stroke was low in both groups. • The trial was stopped early due to futility and safety concerns.
Intervention
Edoxaban 60 mg daily (or 30 mg if dose reduction criteria met) vs. placebo; patients were ≥65 years with AHRE ≥6 minutes and at least one stroke risk factor; median follow-up was 21 months.
Study Design
Arms: Edoxaban vs Placebo
Outcome
• Major bleeding occurred in 2.1% with edoxaban vs. 1.0% with placebo (HR 2.10; 95% CI 1.30–3.38; p=0.002). • Composite safety outcome (death or major bleeding): HR 1.31; p=0.03. • The trial did not demonstrate a benefit in stroke prevention with edoxaban in this population.
Bottom Line
In older patients with device-detected AHREs and stroke risk factors, edoxaban did not significantly reduce cardiovascular death, stroke, or systemic embolism but increased major bleeding and the composite of death or major bleeding.
Major Points
- Edoxaban did not significantly reduce the primary composite of CV death, stroke, or systemic embolism (HR 0.81; 95% CI 0.60–1.08; P=0.15).
- Stroke incidence was low in both groups (~1% per patient-year).
- Major bleeding was significantly higher with edoxaban (2.1 vs 1.0% per patient-year; HR 2.10; 95% CI 1.30–3.38; P=0.002).
- Composite safety outcome of death or major bleeding was higher with edoxaban (HR 1.31; 95% CI 1.02–1.67; P=0.03).
- Death from any cause was not significantly different (4.3% vs 3.7% per patient-year; HR 1.16; 95% CI 0.88–1.53; P=0.28).
- Trial stopped early on the basis of safety concerns and an informal futility assessment for efficacy.
- Population was older and high-risk (mean age 78, median CHA₂DS₂-VASc 4).
Study Design
- Study Type
- Randomized, double-blind, double-dummy, placebo-controlled, event-driven
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 2536
- Follow-up
- Median 21 months
- Centers
- 206
- Countries
- Austria, Belgium, Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, Portugal, Romania, Spain, Sweden, Ukraine, United Kingdom
Primary Outcome
Definition: Composite of cardiovascular death, stroke, or systemic embolism (time-to-event)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 4.0% per patient-year (101/1266) | 3.2% per patient-year (83/1270) | 0.81 (0.60–1.08) | 0.15 |
Limitations & Criticisms
- Trial stopped early (184 of 220 planned primary events), limiting power to detect a modest benefit.
- Observed stroke rate was lower than expected, likely reflecting low AHRE burden.
- Generalizability to other NOACs beyond edoxaban is unknown.
- Study population was predominantly White European; race/ethnicity not systematically recorded.
Citation
Kirchhof P, et al. N Engl J Med. 2023;389(13):1167–1179.