NOAH-AFNET 6: No benefit of oral anticoagulation among patients with atrial high-rate episodes in the absence of confirmed AF

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By Lucas Marinacci on

Key Points

  • This trial randomized elderly patients without a known diagnosis of atrial fibrillation with device-detected atrial high-rate episodes (AHREs) and a median CHA2DS2VASC of 4 to edoxaban or placebo.
  • The study was stopped early due to safety concerns and trend towards futility for efficacy after enrollment of all planned patients.
  • Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not result in lower incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo. Rather, it was associated with a higher incidence of a composite of death or major bleeding.
  • The results indicate that patients with AHREs on their implanted device should not be prescribed anticoagulation unless atrial fibrillation is diagnosed on surface ECG. However, the stroke rates in the control arm were lower than expected.

Atrial high-rate episodes (AHRE) are short, infrequent runs of atrial tachyarrhythmia detected by pacemakers, defibrillators, and implantable loop recorders that resemble atrial fibrillation (AF).  AHREs are detected in up to 30% of elderly patients with an implanted device and have been associated with the development of electrocardiogram (ECG) documented paroxysmal AF and an increased risk of stroke in prospective cohort studies.1  Whether anticoagulation with a non-vitamin K oral anticoagulants might benefit those with AHREs but without ECG-documented AF is unknown.

On August 25th, 2023 the results of Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes (NOAH–AFNET 6) were presented in a Hot Line Session at ESC Congress 2023 with simultaneous publication in the New England Journal of Medicine2. In this event-driven, double-blind, double-dummy, randomized trial, patients aged 65 and older with a recorded AHRE (atrial rate of at least 170 beats per minute [BPM] for at least 6 minutes) on their implanted device and a modified CHA2DS2VASc score of at least 2 but without any history of overt AF were randomized to edoxaban or placebo.

The primary efficacy outcome was time from randomization to the first occurrence of a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of death from any cause or major bleeding. Patients who developed ECG-documented atrial fibrillation in the control arm were transitioned from placebo to oral anticoagulation and were censored at that time point.

Overall, 2536 patients were randomized, received at least one dose of the study drug and were analyzed in a modified intention to treat analysis, with a median follow-up time of 21 months.  Patients were elderly (mean age 78), majority male (63%), with a median CHA2DS2VASC score of 4 and a median AHRE length of 2.8 hours. The trial was stopped early following a recommendation from the data safety and monitoring board due to safety concerns and a tendency towards futility.

The primary efficacy endpoint 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). There was an increase in major bleeding or cardiovascular death in the intervention arm (HR 1.31, 95% CI 1.07-1.67; p= 0.15) which was driven by an increase in major bleeding (HR 2.10, 95% CI 1.30-3.38; p= 0.002), without any significant difference in the primary outcome.  The stroke rates were similar in both groups (~1% per year).  The stroke rate without anticoagulation was lower than the investigators had expected.  ECG-diagnosed atrial fibrillation developed in 18% of the patients. The results were consistent across multiple sensitivity analyses and pre-specified subgroups.  In particular, there was no effect modification observed based on the duration of AHRE.

According to principal investigator Paulus Kirchhof of the University Heart & Vascular Center Hamburg, Germany: “NOAH-AFNET 6 demonstrates that anticoagulation should not be used in patients with AHRE until atrial fibrillation is documented by ECG…..better methods to estimate stroke risk in patients with rare atrial arrythmias are needed.”

 

References

  1. Bertaglia E, Blank B, Blomström-Lundqvist C, et al. Atrial high-rate episodes: prevalence, stroke risk, implications for management, and clinical gaps in evidence. Europace. 2019;21:1459–1467.
  2. Kirchhof P, Toennis T, Goette A, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. NEJM. 2023.