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NOAH-AFNET 6

Non–Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial High-Rate Episodes

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Year of Publication: 2023

Authors: Kirchhof P, Toennis T, Goette A, et al.

Journal: The New England Journal of Medicine

Citation: Kirchhof P, et al. N Engl J Med. 2023;389(13):1167–1179.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2303062

PDF: https://pdfs.semanticscholar.org/13ce/0a...298ef3228cc.pdf

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?

Bottom Line

Edoxaban did not significantly reduce cardiovascular death, stroke, or systemic embolism but increased major bleeding risk in patients with AHREs.

        Major Points
        Edoxaban showed no statistically significant reduction in primary efficacy outcome (HR 0.81; P=0.15).
Stroke incidence was low in both groups (~1%/year).
Major bleeding was significantly higher in the edoxaban group (HR 2.10; P=0.002).
Trial stopped early due to safety concerns and futility.
Study included older, high-risk patients (mean age 78, median CHA₂DS₂-VASc score 4).

      

Design

Study Type: Randomized, double-blind, placebo-controlled

Randomization: 1

Blinding: Double-blind

Enrollment Period: 2016–2022

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
AHRE ≥6 minutes duration and ≥170 bpm
Device-based rhythm monitoring
At least one stroke risk factor (e.g., HF, HTN, diabetes, prior stroke/TIA, vascular disease, age ≥75)

Exclusion Criteria

Atrial fibrillation documented on ECG
ACS, PCI, or CABG within 30 days
Life expectancy <12 months
Contraindication to anticoagulation
Need for dual antiplatelet therapy
Other anticoagulation indication

Baseline Characteristics

Characteristic	Comorbidities	Qualifying Event
Hypertension	86.9
Diabetes	26.9
Prior Stroke	10

Arms

Field	Edoxaban	Control
Intervention	Edoxaban 60 mg daily or 30 mg if dose reduction criteria met	Placebo (with/without aspirin 100 mg/day as needed)
Duration	Until trial termination	Until trial termination

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of cardiovascular death, stroke, or systemic embolism	Primary	4.0% per patient-year	3.2% per patient-year	0.81	0.15
Stroke or systemic embolism	Secondary	1.5% per patient-year	1.0% per patient-year	0.65
Cardiovascular death	Secondary	2.2% per patient-year	2.0% per patient-year	0.9
Major Bleeding	Adverse	1.0% per patient-year	2.1% per patient-year		0.002
Composite Death or Major Bleed	Adverse	4.5% per patient-year	5.9% per patient-year		0.03

Subgroup Analysis

No significant treatment effect across subgroups; similar results in sensitivity analyses.

Criticisms

Trial stopped early, limiting power to detect modest benefits.
Stroke rate lower than expected, may reflect low AHRE burden.
Unclear generalizability to other NOACs beyond edoxaban.
Predominantly White European population.

Funding

German Center for Cardiovascular Research, Daiichi Sankyo Europe, European Union, British Heart Foundation, and others

Based on: NOAH-AFNET 6 (The New England Journal of Medicine, 2023)