Edoxaban for atrial high-rate episodes: more harm than good?

The Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial High-Rate Episodes (NOAH-AFNET 6) trial is an event-driven, double-blind, double-dummy, randomized trial assessing the efficacy and safety of oral anticoagulant therapy with the non-vitamin K antagonist (NOAC) edoxaban in patients with short-duration atrial high-rate episodes (AHREs) detected on implantable cardiac devices, who had clinical risk factors for stroke. 1 The trial was funded by Daiichi Sankyo Europe and the German Centre for Cardiovascular Research.• The trial enrolled patients 65 years of age or older who had AHREs lasting for at least 6 min and one or more additional risk factors for stroke (heart failure, hypertension, diabetes, prior stroke or transient ischaemic attack, vascular disease, or age ≥75 years).Patients were randomly assigned in a 1:1 ratio to receive edoxaban [60 mg once daily, reduced to 30 mg once daily according to approved dose reduction criteria for stroke prevention in atrial fibrillation (AF)] or placebo (containing no active compound or aspirin 100 mg once daily for patients with an indication for antiplatelet therapy).The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis.The safety outcome was a composite of death from any cause or major bleeding, as defined by the International Society on Thrombosis and Haemostasis.• The modified intention-to-treat population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group; mean age, 78 years; 37% women; median CHA 2 DS 2 -VASc score, 4; median duration of AHREs, 2.8 h; 54% of patients in the placebo group received aspirin).The trial was terminated early, after a median follow-up of 21 months for two reasons: likely futility for efficacy and safety concerns.At the time of termination, the planned enrolment had been completed, and 184 of 220 planned primary outcome events had occurred.• A primary endpoint occurred at a rate of 3.2% per patient-year in the edoxaban group vs. 4.0% in the placebo group [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.60-1.08;P = .15],a non-significant benefit that was lower than the expected HR = 0.68.The incidence of stroke was low and similar in both groups: 0.9% vs. 1% per patient-year in the edoxaban vs. placebo arm, respectively.Safety outcomes occurred at a significantly higher rate in the edoxaban group (5.9% vs. 4.5% per patient-year; HR, 1.31; 95% CI, 1.02-1.67;P = .03).This difference was largely driven by the expected increase in major bleeding in patients receiving anticoagulation (2.1% vs. 1.0% per patient-year; HR 2.10; 95% CI 1.30-3.38;P = .002).The rate of electrocardiogram (ECG)-diagnosed AF in the entire cohort was 18.2% (8.7% per patient-year).Subgroup analyses based on the duration of AHREs, baseline stroke risk, and aspirin use showed no statistically significant interactions.