Thromboembolic Prevention in Atrial High-Rate Episodes: Is There Benefit? (NOAH-AFNET 6 Study)

Prolonged atrial arrhythmias expose patients to increased risks of thromboembolism. The results of a meta-analyses revealed a fourfold increased risk of stroke and systemic embolism in patients with atrial high-rate episodes (AHRE) lasting ≥30 sec.1 Nevertheless, these episodes are often subclinical and detected only on long-term implantable monitors. Whether initiating anticoagulation therapy in this patient population can improve clinical outcomes is unknown. Two randomized controlled trials—the LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals) study and STROKESTOP (Systematic ECG Screening for Atrial Fibrillation Among 75 Year Old Subjects in the Region of Stockholm and Halland, Sweden) study—examined a similar question in patients with subclinical atrial fibrillation (AF) in recent years and yielded contradictory conclusions,2,3 further complicating the plot.

The NOAH-AFNET 6 (Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes) study was a double-blind, double-dummy trial in which 2,536 patients >65 years of age with AHRE lasting for ≥6 min identified on implanted cardiac devices and who had at least one additional risk factor for stroke were randomized in a 1:1 fashion to edoxaban therapy or placebo.4 At median follow-up of 21 months, the trial was terminated early because of a lack of significant difference in the primary efficacy outcome (cardiovascular death, stroke, or systemic embolism) between the two groups (3.2% vs. 4% per patient-year; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.6-1.08) and a higher rate of adverse safety events (death, major bleeding) in patients randomized to edoxaban therapy (5.9% vs. 4.5% per patient-year; HR, 1.31; 95% CI, 1.02-1.67).4 Although 18.2% of patients with AHRE were eventually diagnosed with AF on electrocardiogram,4 it is important to emphasize that current evidence does not support systemic anticoagulation in patients with only AHRE but not a diagnosis of AF. There is an increased risk of major bleeding or death when systemic anticoagulation is initiated in these patients.


  1. Sagris D, Georgiopoulos G, Pateras K, et al. Atrial high-rate episode duration thresholds and thromboembolic risk: a systematic review and meta-analysis. J Am Heart Assoc 2021;10:[ePub ahead of print].
  2. Svendsen JH, Diederichsen SZ, Højberg S, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (the LOOP study): a randomised controlled trial. Lancet 2021;398:1507-16.
  3. Svennberg E, Friberg L, Frykman V, Al-Khalili F, Engdahl J, Rosenqvist M. Clinical outcomes in systematic screening for atrial fibrillation (STROKESTOP): a multicentre, parallel group, unmasked, randomised controlled trial. Lancet 2021;398:1498-506.
  4. Kirchhof P, Toennis T, Goette A, et al.; NOAH-AFNET 6 Investigators. Anticoagulation with edoxaban in patients with atrial high-rate episodes. N Engl J Med 2023;389:1167-79.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP

Keywords: AHA Annual Scientific Sessions, AHA23, Anticoagulation Management, Anticoagulants, Stroke, Thromboembolism

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