Atrial high-rate episode duration does not influence treatment effect of DOAC
In a secondary prespecified analysis of the NOAH-AFNET 6 trial, there was no interaction between atrial high-rate episode (AHRE) duration and the efficacy and safety of edoxaban versus placebo in patients with AHREs and stroke risk factors.
This summary is based on the publication of Becher N et al. - Anticoagulation with edoxaban in patients with long Atrial High-Rate Episodes ≥24 hours. Eur Heart J. 2023 Nov 12:ehad771. doi: 10.1093/eurheartj/ehad771.
Introduction and methods
Background
Atrial high-rate episodes (AHREs) are typically asymptomatic, short atrial arrhythmias (lasting ≥5–6 min) that are detected in ~20% of patients with an implanted pacemaker, defibrillator, or loop recorder [1]. In clinical practice, patients with long AHREs (lasting ≥24 hours) but with no ECG-documented AF are often treated with oral anticoagulation for stroke prevention [2]. However, evidence from randomized trials evaluating anticoagulation in this population is lacking.
Aim of the study
The authors assessed the interactions between AHRE duration at baseline and the efficacy and safety of anticoagulation with edoxaban compared with placebo in patients with AHREs and stroke risk factors, especially when episodes lasted ≥24 hours.
Methods
This was a secondary prespecified analysis of the recent NOAH-AFNET 6 (Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes) trial, which showed that anticoagulation with edoxaban did not reduce the incidence of stroke, systemic embolism, or CV death compared with no anticoagulation in elderly AHRE patients with stroke risk factors [3]. In this European, multicenter, event-driven, double-blind, doubly-dummy, phase 3b RCT, 2536 patients aged ≥65 years with AHREs (duration ≥6 min) and ≥1 additional stroke risk factor but with no ECG-documented AF were randomized to edoxaban or placebo. If AF was detected by ECG, the patient was switched from the study medication to open-label anticoagulation.
In the current analysis, data of 2389 study participants were included, of whom 259 (11%) had a baseline AHRE duration ≥24 hours. Median follow-up duration was 1.8 years.
Outcomes
The primary efficacy endpoint was a composite outcome of stroke, systemic embolism, or CV death. The primary safety endpoint was a composite outcome of major bleeding according to the International Society of Thrombosis and Hemostasis criteria or all-cause mortality. Key secondary efficacy outcomes included the individual components of the primary efficacy endpoint and ECG-diagnosed AF.
Main results
Primary endpoints
- In patients with AHRE duration ≥24 hours, the primary efficacy endpoint (stroke, systemic embolism, or CV death) occurred in 9 of 132 participants treated with edoxaban (4.3% per patient-year) and 14 of 127 placebo-treated participants (6.9% per patient-year) (adjusted HR: 0.66; 95%CI: 0.28–1.53).
- In patients with AHRE duration <24 hours, the incidence of the primary efficacy endpoint was 70 of 1062 in the edoxaban group (3.2% per patient-year) and 80 of 1068 in the placebo group (3.7% per patient-year) (adjusted HR: 0.86; 95%CI: 0.62–1.19). There was no significant interaction between the treatment effect and AHRE duration (P=0.65).
- For the primary safety endpoint (major bleeding or all-cause mortality), the point estimates were almost identical in patients with AHRE duration ≥24 hours (adjusted HR: 1.30; 95%CI: 0.62–2.71) and those with AHRE duration <24 hours (adjusted HR: 1.32; 95%CI: 1.01–1.73; P for interaction=0.96).
- Similar results were observed when AHRE duration was evaluated as a continuous variable.
Secondary endpoints
- Among patients with AHRE duration ≥24 hours, the incidence rates of ischemic stroke were 0.95% per patient-year in the edoxaban group and 0.97% per patient-year in the placebo group (adjusted HR: 1.03; 95%CI: 0.14–7.32). The rates were 0.90% and 0.96% per patient-year, respectively, among patients with AHRE duration <24 hours (adjusted HR: 0.92; 95%CI: 0.50–1.70; P for interaction=0.89).
- Similarly, there were no differences in the incidence rates of any of the other secondary endpoints, nor were there significant interactions by AHRE duration.
- During follow-up, more patients with AHRE duration ≥24 hours at baseline developed ECG-diagnosed AF than patients with shorter AHRE durations (17.0% vs. 8.2% per patient-year; HR: 2.20; 95%CI: 1.71–2.84; P<0.001).
Conclusion
In this secondary prespecified analysis of the NOAH-AFNET 6 trial, there was no interaction between AHRE duration and the efficacy and safety of edoxaban versus placebo in patients with AHREs and stroke risk factors. As patients with AHRE duration ≥24 hours at baseline were more likely to develop ECG-diagnosed AF over time than patients with shorter AHRE durations, the authors believe regular ECG follow-up is indicated in this population.
Notably, the stroke rate was low across AHRE durations, even in the placebo group (~1% per patient-year). The timely detection of ECG-documented AF and initiation of open-label anticoagulation are likely contributors to this observation, according to the authors.
References
1. Toennis T, Bertaglia E, Brandes A, Dichtl W, Fluschnik N, de Groot JR, et al. The influence of atrial high-rate episodes on stroke and cardiovascular death: an update. Europace 2023;25(7):euad166.
2. Perino AC, Fan J, Askari M, Heidenreich PA, Keung E, Raitt MH, et al. Practice Variation in Anticoagulation Prescription and Outcomes After Device-Detected Atrial Fibrillation. Circulation 2019;139(22):2502-2512.
3. Kirchhof P, Toennis T, Goette A, Camm AJ, Diener HC, Becher N, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. N Engl J Med 2023;389(13):1167-1179.