Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes - NOAH-AFNET 6

Contribution To Literature:

Highlighted text has been updated as of November 12, 2023.

In patients with implanted cardiac device-detected AHREs, edoxaban was not associated with decreased incidence of CV death, stroke, or systemic embolism but were associated with increased bleeding compared with placebo.


The goal of this trial was to determine the effect and safety of systemic anticoagulation with edoxaban in patients who are at increased risk of stroke, without known atrial fibrillation (AF), and found to have atrial high-rate episodes (AHREs) detected by an implanted cardiac device.

Study Design

  • Randomized
  • European multinational, multicenter
  • Double-blind, double-dummy

Patients without known AF, at increased stroke risk, and with AHREs detected on an implanted cardiac device were randomized to receive edoxaban (n = 1,270), a non-vitamin K antagonist oral anticoagulant (NOAC), or placebo (n = 1,266). The standard edoxaban dose of 60 mg/day for AF could be reduced based on clinical indication according to European regulations. The double-dummy placebo contained either no active compound or aspirin 100 mg based on clinical indication. Follow-up visits were conducted at 6-month intervals.

  • Total number of enrollees: 2,536
  • Median duration of follow-up: 21 months
  • Mean patient age: 78 years
  • Percentage female: 37.4%

Inclusion criteria:

  • Age ≥65 years
  • Presence of implanted pacemaker, defibrillator, or loop recorder >2 months prior
  • 1 AHRE at ≥180 atrial bpm for ≥6 minutes
  • At least one of the following: age ≥75 years, clinical heart failure, left ventricular ejection fraction (LVEF) <45%, hypertension, diabetes, prior stroke or transient ischemic attack, vascular disease

Exclusion criteria:

  • Previously diagnosed AF or atrial flutter
  • Other indication for anticoagulation
  • Contraindication to oral anticoagulation or edoxaban specifically
  • Indication for long-term antiplatelet therapy, excluding aspirin
  • Acute coronary syndrome, coronary revascularization, or stroke ≤30 days prior
  • Creatinine clearance <15 mL/min

Other salient features/characteristics:

  • Median number of AHREs: 2.8
  • Median AHRE duration: 2.8 hours
  • Median CHA2DS2-VASc score: 4
  • Percentage diagnosed with AF during study period: 18.2%
  • Percentage of placebo receiving aspirin: 53.9%

Principal Findings:

The trial was stopped early due to concerns regarding both safety and futility.

Primary efficacy outcome, composite of cardiovascular (CV) death, stroke, or systemic embolism, for edoxaban vs. placebo per patient-year: 3.2% vs. 4.0% (p = 0.15)

The primary safety outcome, composite of all-cause mortality or major bleeding, for edoxaban vs. placebo per patient-year: 5.9% vs. 4.0% (p = 0.03)

Secondary efficacy outcomes for edoxaban vs. placebo per patient-year:

  • Ischemic stroke: 0.9% vs. 1.1%
  • Systemic embolism: 0.5% vs. 1.1%
  • CV death: 2.0% vs. 2.2%

Secondary safety outcomes for edoxaban vs. placebo per patient-year:

  • All-cause mortality: 4.3% vs. 3.7% (p = 0.28)
  • Major bleeding: 2.1% vs. 1.0% (p = 0.002)

AHRE duration: ≥24 hours (10.8%), median maximum duration 55 hours; <24 hours (89.2%), median maximum duration 2.2 hours. No difference for edoxaban vs. placebo for primary efficacy outcome (p for interaction = 0.65), ischemic stroke (p for interaction = 0.89), CV death (p for interaction = 0.58). Incidence of ECG-diagnosed AF for ≥24 vs. <24 hours: 17.0%/patient-year vs. 8.2%/patient-year (p < 0.001).


The NOAH-AFNET 6 trial demonstrates no reduction in CV death, stroke, or systemic embolism with edoxaban compared with placebo in a population at increased risk of stroke and with incidentally detected AHRE but without known AF, independent of AHRE duration. Edoxaban was associated with an increase in the primary safety outcome, which was driven predominantly by more frequent major bleeding events. Patients with AHRE ≥24 hours had a higher risk of developing ECG-diagnosed AF over the duration of follow-up. These data provide novel insight into an important population in whom the role of systemic anticoagulation has historically been unclear.

Interestingly, despite selecting for patients with a higher stroke risk, as evidenced by the median CHA2DS2-VASc score of 4, the incidence of the primary outcome in the placebo group was lower than expected based on prior data from comparable populations with AF. This may suggest that the diagnosis of AF itself carries an increased stroke risk, perhaps reflecting higher cumulative arrhythmia burden and consequent risk of intracardiac thrombus in such patients compared to those exhibiting only AHRE. Despite these findings, AHRE may still be of clinical relevance, as nearly 1 in 5 patients was ultimately diagnosed with AF at study completion. The lower-than-expected primary event rate, coupled with early study termination before reaching prespecified enrollment, may have increased the risk of type II error. Further, edoxaban’s observed lack of efficacy may not be representative of other NOACs or vitamin K antagonists, which may be the focus of future investigation.


Becher N, Toennis T, Bertaglia E, et al., on behalf of the NOAH-AFNET 6 Investigators. Anticoagulation With Edoxaban in Patients With Long Atrial High-Rate Episodes ≥24 Hours. Eur Heart J 2023;Nov 12:[Epub ahead of print].

Presented by Dr. Nina Becher at the American Heart Association Scientific Sessions, Philadelphia, PA, November 12, 2023.

Kirchhof P, Toennis T, Goette A, et al., on behalf of the NOAH-AFNET 6 Investigators. Anticoagulation With Edoxaban in Patients With Atrial High-Rate Episodes. N Engl J Med 2023;389:1167-79.

Editorial: Stone PH, Sauer WH. Harnessing the Deluge of Rhythm-Monitoring Data for the Prevention of Stroke. N Engl J Med 2023;389:1232-4.

Presented by Dr. Paulus Kirchhof at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 25, 2023.

Clinical Topics: Arrhythmias and Clinical EP, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: AHA23, Anticoagulation Management, Arrhythmias, Cardiac

< Back to Listings