Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h

Abstract

Background and aims: Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients.

Methods: This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and electrocardiogram (ECG)-diagnosed atrial fibrillation.

Results: Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE ≥24 h were present at baseline in 259/2389 patients (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE ≥24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .001).

Conclusions: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

Keywords: Atrial fibrillation; Atrial high-rate episodes; NOAH-AFNET 6; Stroke.

Structured Graphical Abstract

Anticoagulation with edoxaban in patients with long AHRE ≥24 h. AHRE, atrial high-rate episodes; CI, confidence interval; ECG, electrocardiogram; HR, hazard ratio.

Figure 1

Consolidated standards of reporting trails (CONSORT) flow chart of this secondary pre-specified sub-analysis. Shown is the analysis population, the number of patients with a primary efficacy outcome, the number of patients with a safety outcome, and the number of patients who developed electrocardiogram-diagnosed atrial fibrillation in each group

Figure 2

Atrial high-rate episodes (AHREs) characteristics by atrial high-rate episode duration. (A) Number of atrial high-rate episodes prior to at baseline. (B) Time from last adequate atrial high-rate episode to baseline by atrial high-rate episode duration in months. (C) Duration of the maximal atrial high-rate episode at baseline (longest single episode) in minutes and days. The apparent peak at 4 days (99 h) atrial high-rate episode duration is due to the fact that some manufacturers only store precise atrial high-rate episode durations up to 99 h, while other manufacturers and devices precisely capture atrial high-rate episode durations up to 9999 h. All graphs show separate distributions for each randomized group in the 2389 patients with adequate atrial high-rate episode. There were no differences between randomized groups

Figure 3

Cumulative incidence curves of the primary outcome and secondary outcomes incidence curves considering death competing event (Aalen–Johansen curve). (A) Primary outcome, a composite of stroke, systemic embolism, and cardiovascular death. (B) All-cause death and major bleeding. (C) Ischaemic stroke. (D) Ischaemic stroke or systemic embolism

Figure 4

Cumulative incidence curve from baseline to electrocardiogram-diagnosed atrial fibrillation considering death as competing event (Aalen–Johansen curve; P < .001). Survival curves are shown for patients with long atrial high-rate episode ≥24 h and shorter atrial high-rate episode split by randomized group