NOAH-AFNET 6
Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes
Clinical Question
Does edoxaban reduce cardiovascular events in patients with device-detected atrial high-rate episodes (AHREs) who do not have ECG-confirmed atrial fibrillation?
Study Overview
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.
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).
Design
Study Type: Randomized, double-blind, double-dummy, placebo-controlled, event-driven
Randomization: 1
Blinding: Double-blind
Enrollment Period: June 2016 – September 2022
Follow-up Duration: 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
Sample Size: 2536
Analysis: Modified intention-to-treat
Inclusion Criteria
- Age ≥65 years
- AHREs detected by implanted devices (pacemaker, defibrillator, CRT, or implantable loop recorder) with no history of AF on ECG
- AHREs occurring at least 2 months after implantation of the device
- Qualifying AHRE with atrial rate ≥170 bpm and duration ≥6 minutes (no upper duration limit)
- At least one stroke risk factor: heart failure, hypertension, diabetes, previous stroke/TIA, vascular disease (prior MI, aortic plaque, peripheral/carotid/cerebral arterial disease), or age ≥75 years
Exclusion Criteria
- Atrial fibrillation documented on ECG
- ACS, PCI, or CABG within 30 days before enrollment
- Life expectancy <12 months
- Contraindication to oral anticoagulation or to edoxaban
- Indication for dual antiplatelet therapy
- Other indication for oral anticoagulation
Arms
| Field | Edoxaban | Control |
|---|---|---|
| Intervention | Edoxaban 60 mg once daily (30 mg once daily if body weight ≤60 kg, CrCl 15–50 mL/min, or concomitant strong P-glycoprotein inhibitor) | Placebo (double-dummy, with or without aspirin 100 mg/day per indication) |
| Duration | Until trial termination (median 21 months) | Until trial termination (median 21 months) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Composite of cardiovascular death, stroke, or systemic embolism (time-to-event) | Primary | 4.0% per patient-year (101/1266) | 3.2% per patient-year (83/1270) | 0.81 | 0.15 |
| Stroke or systemic embolism | Secondary | 1.5% per patient-year (38/2509) | 1.0% per patient-year (25/2566) | 0.65 | |
| Ischemic stroke | Secondary | 1.1% per patient-year (27/2519) | 0.9% per patient-year (22/2573) | 0.79 | |
| Systemic embolism | Secondary | 1.1% per patient-year (28/2515) | 0.5% per patient-year (14/2579) | 0.51 | |
| Cardiovascular death | Secondary | 2.2% per patient-year (57/2540) | 2.0% per patient-year (52/2595) | 0.9 | |
| Major Bleeding | Adverse | 1.0% per patient-year (25/2508) | 2.1% per patient-year (53/2534) | 2.1 | 0.002 |
| Composite Death or Major Bleed | Adverse | 4.5% per patient-year (114/2508) | 5.9% per patient-year (149/2534) | 1.31 | 0.03 |
| Death from Any Cause | Adverse | 3.7% per patient-year (94/2540) | 4.3% per patient-year (111/2595) | 1.16 | 0.28 |
Subgroup Analysis
Results were consistent across prespecified subgroups and in per-protocol and safety-population sensitivity analyses.
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.
Funding
German Center for Cardiovascular Research (DZHK) and Daiichi Sankyo Europe, with additional support from the European Union, British Heart Foundation, German Research Foundation, and Leducq Foundation
Based on: NOAH-AFNET 6 (The New England Journal of Medicine, 2023)
Authors: Kirchhof P, Toennis T, Goette A, et al.
Citation: Kirchhof P, et al. N Engl J Med. 2023;389(13):1167–1179.
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