NOAH-AFNET 6 trial: Oral anticoagulation not recommended for patients with atrial high rate episodes

Blood thinners (anticoagulants) cause bleeding without preventing stroke in patients with atrial high rate episodes (AHRE), but without electrocardiogram (ECG)-diagnosed atrial fibrillation, according to late breaking research presented in a Hot Line session today at ESC Congress 2023 and simultaneously published in the New England Journal of Medicine.

Anticoagulants prevent strokes in patients with atrial fibrillation but are not effective in those without atrial fibrillation, for example in patients with heart failure. Atrial high-rate episodes (AHRE) are short and rare atrial arrhythmias that resemble atrial fibrillation detected by implanted pacemakers, defibrillators, and loop recorders. AHRE are found in 10-30% of patients with implanted devices. While AHRE are associated with an increased risk of stroke, the risk is lower than for those with atrial fibrillation. ESC guidelines recommend oral anticoagulation to prevent stroke in patients with atrial fibrillation and increased stroke risk and propose individualized decisions in patients with AHRE, but without ECG-documented atrial fibrillation.

NOAH-AFNET 6 was the first trial to investigate the efficacy and safety of oral anticoagulation in patients with AHRE, but without ECG-documented atrial fibrillation. The randomized, double-blind, double-dummy trial compared the anticoagulant edoxaban to placebo in patients ≥65 years with AHRE episodes ≥6 minutes detected by implantable devices, and with at least one additional stroke risk factor (heart failure, hypertension, diabetes, prior stroke or transient ischaemic attack, vascular disease, or age ≥75 years). This patient population was outside the approved indication of edoxaban.

In 206 sites across 18 European countries, patients were randomly allocated in a 1:1 fashion to anticoagulation or no anticoagulation. Anticoagulation consisted of edoxaban in the dose approved for stroke prevention in atrial fibrillation (60 mg once daily, reduced to 30 mg once daily according to approved dose reduction criteria for stroke prevention in atrial fibrillation). No anticoagulation consisted of placebo containing no active compound or aspirin 100 mg once daily in patients with an indication for antiplatelet therapy. The primary outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and all-cause death. All patients were followed until the end of the trial.

The primary, modified intention-to-treat analysis population consisted of 2,536 patients who received at least one dose of study drug. Patients were elderly with multiple stroke risk factors: the mean age was 78 years, 37% were women and the median CHA₂DS₂-VASc score was 4. The median AHRE duration at baseline was 2.8 hours without an upper limit, and 97% of AHRE showed atrial rates >200 beats per minute, clearly resembling atrial fibrillation.

The trial was stopped early due to safety signals and a trend towards futility for efficacy after enrolment of all planned patients. The primary efficacy outcome occurred in 83 patients in the anticoagulation group (3.2%/year) and in 101 patients in the no anticoagulation group (4.0%/year), for a hazard ratio (HR) of 0.81 (95% confidence interval [CI] 0.6-1.1]; p=0.15). The stroke rate was low in both randomized groups (without anticoagulation 1.1%/year, with anticoagulation 0.9%/year). The primary safety outcome occurred in 149 patients in the anticoagulation group (5.9%/year) and in 114 patients in the no anticoagulation group (4.5%/year), for a HR of 1.3 (95% CI 1.0-1.7; p=0.03). The difference in safety outcomes was driven by an expected increase in major bleeding in patients receiving anticoagulation (HR 2.10; 95% CI 1.30-3.38; p=0.002). ECG-diagnosed atrial fibrillation developed in 462/2536 patients (18%; 8.7%/year).

The NOAH-AFNET 6 trial found that oral anticoagulation in patients with AHRE increases bleeding without reducing a composite outcome of stroke, systemic embolism, or cardiovascular death. The increased bleeding on anticoagulation therapy was expected. The low stroke rate with and without anticoagulation was unexpected. The results of NOAH-AFNET 6 clearly suggest to demand ECG documentation of atrial fibrillation prior to initiation of oral anticoagulation. Further research is needed to better understand the stroke risk in patients with very rare and short atrial arrhythmias."

Paulus Kirchhof , Principal Investigator, University Heart & Vascular Center Hamburg, Germany