Oral anticoagulation in patients with atrial high rate episodes (AHRE) increases bleeding without reducing a composite outcome of stroke, systemic embolism or cardiovascular death.
This is the headline finding from the NOAH-AFNET 6 trial, presenting during a hot line trial session at the European Society of Cardiology (ESC) annual congress (25–28 August, Amsterdam, The Netherlands) by Paulus Kirchhof (University Heart and Vascular Centre UKE Hamburg, Hamburg, Germany and University of Birmingham, Birmingham, UK) and published simultaneously in the New England Journal of Medicine (NEJM).
Kirchhof commented that the trial’s results demonstrate that anticoagulation should not be used in patients with AHRE until atrial fibrillation (AF) is documented by electrocardiogram (ECG), describing this as a potentially “practice-changing” finding.
AHREs are short and rare atrial arrhythmias that resemble AF detected by implanted pacemakers, defibrillators, and loop recorders, and are found in 10‒30% of patients with implanted devices. They are associated with an increased risk of stroke, though this is lower than for those with AF. European guidelines recommend oral anticoagulation to prevent stroke in patients with AF and increased stroke risk and propose individualised decisions in patients with AHRE but without ECG documented AF.
NOAH-AFNET 6 investigated the efficacy and safety of oral anticoagulation in patients with AHRE, but without ECG-documented AF. The randomised, double-blind, double-dummy trial compared edoxaban to placebo in patients ≥65 years with AHRE episodes of six minutes or more 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 AF (60mg once daily, reduced to 30mg once daily according to approved dose reduction criteria for stroke prevention in AF).
No anticoagulation consisted of placebo containing no active compound or aspirin 100mg 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 4.5 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.
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%/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 Kirchhof detailed, occurring at a rate of 1.1% per year in those without anticoagulation, and 0.9% in those with anticoagulation, a finding that the investigator described as “unexpected”.
The primary safety outcome occurred in 149 patients in the anticoagulation group (5.9% per year) and in 114 patients in the no anticoagulation group (4.5% per year), for a HR of 1.3 (95% CI 1-1.7; 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 AF developed in 462/2536 patients (18%; 8.7% per 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,” said Kirchhof, the trial’s principal investigator. “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 AF 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.”