The incidence of a primary outcome of a composite of cardiovascular death, stroke, or systemic embolism was not reduced by anticoagulation with edoxaban in patients with device-detected atrial high-rate episodes (AHREs) compared with placebo, researchers report. Instead, the incidence of a composite of death or major bleeding was higher with edoxaban, and the incidence of stroke was low in both groups.
Participants in the NOAH-AFNET 6 trial were adults older than 65 years of age with AHREs lasting for at least 6 minutes and 1 or more additional risk factors for stroke. Randomization to edoxaban or placebo had these effects on the primary outcome and a safety outcome of a composite of death from any cause or major bleeding: “The analysis population consisted of 2,536 patients (1,270 in the edoxaban group and 1,266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year).”
Editorial: “Although AHREs are known to be associated with stroke, the risk of stroke remains substantially less than the risk associated with ECG-documented paroxysmal or sustained atrial fibrillation,” editorialists write. “The lack of efficacy of anticoagulation in reducing stroke in the current trial may have resulted in part from the fact that only a subset of the AHREs were thrombogenic (namely, atrial fibrillation episodes of sufficient duration, frequency, or both). Future investigation may benefit from studying the clinical characteristics of populations suitable for rhythm monitoring, the threshold characteristics of AHREs that lead to thrombus formation, and the specific atrial tachyarrhythmias that occur during an AHRE that could justify anticoagulation. However, the device-detected AHREs that occurred in this trial do not adequately infer a definitive diagnosis of paroxysmal atrial fibrillation for all patients or a subsequent risk of stroke.”