Use of anticoagulants is not justified to prevent stroke in patients with device-detected atrial high-rate episodes (AHREs), a major trial suggests.

Presented at the ESC 2023 meeting in Amsterdam, the results of the NOAH-AFNET 6 study showed that in patients with AHREs, anticoagulation with edoxaban did not significantly reduce the risk of stroke but led to a higher incidence of a composite of death or major bleeding.

The German-led study was initiated to investigate the uncertainty around stroke risk and use of anticoagulants to address this risk with AHREs that are detected in 10-30% of patients while using implanted pacemakers, defibrillators, and loop recorders.

The authors noted that while AHRE are associated with an increased risk of stroke, the risk was lower than for those with atrial fibrillation, and ESC guidelines propose individualised decisions in patients with AHRE, but without ECG-documented atrial fibrillation.

The multinational, multicentre randomised, double-blind NOAH-AFNET 6 trial compared the anticoagulant edoxaban to placebo in 2,536 patients elderly patients (mean age 78 years) with AHRE episodes ≥6 minutes detected by implantable devices, and with at least one additional stroke risk factor.

Patients in the study had multiple stroke risk factors 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, resembling atrial fibrillation.

Patients were allocated to placebo or edoxaban in the dose approved for stroke prevention in AF (60 mg once daily, reduced to 30 mg once daily according to approved dose reduction criteria for stroke prevention in atrial fibrillation).

However 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 was a composite of stroke, systemic embolism, or cardiovascular death.  This 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 randomised groups (without anticoagulation 1.1%/year, with anticoagulation 0.9%/year).

The safety outcome was a composite of major bleeding and all-cause death. This 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).

Patients were elderly with multiple stroke risk factors: the, 37% were women and the median CHA₂DS₂-VASc score was 4.5 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.

Important message (not only) for #EPeeps from #ESCCongress in Amsterdam:
NOAH-AFNET 6 trial: OAC in Pat. with AHRE

🎯 No significant difference in CV death, stroke or systemic embolism between edoxaban & placebo

🎯 Edoxaban led to significant increase in major bleeding https://t.co/3VO6YP13Rv

— Sebastian Feickert (@sebFeickert) August 26, 2023

The study investigators said the increased bleeding rate on anticoagulation therapy was expected but the low stroke rate in both groups was unexpected and led to an unfavourable balance of risk and benefit.

“The findings of this trial — the low incidence of stroke that was not further reduced by treatment with edoxaban — may make it appropriate to withhold anticoagulant therapy in patients with AHREs,” they wrote in findings published simultaneously in the NEJM (link here).

Principal investigator Professor Paulus Kirchhof of the University Heart & Vascular Centre Hamburg, Germany, said the AHRE patients studied in the NOAH-AFNET 6 trial had a low arrhythmia burden  – characterised by the paucity and brevity of atrial arrhythmias – compared to patients with AF.

“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,” he said.