NOAH = NO Anticoagulation for Atrial High-Rate Events >6 Minutes

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EP LAB DIGEST. 2023;23(10):4.

Dear Readers,

The advent of device diagnostics in pacemakers and defibrillators to accurately detect atrial fibrillation (AF) as atrial high-rate events (AHREs) has given rise to the regular conundrum of whether to prescribe these patients with oral anticoagulation (OAC) for device-detected AF, and how much AF is needed to increase the risk of stroke. Finding AF in device patients is common and it is tempting to start OAC in all patients with a CHA₂DS₂-VASc score >1. However, it is logical that detecting AF in a patient with a pacemaker that is continuously monitoring for AF will identify a patient with a lower burden of AF, compared to a patient who is found to be in AF on a 12-lead electrocardiogram (EKG), for example, and who might not benefit from OAC. Data has suggested that patients with only a few minutes of AF are at an increased risk of stroke. Although subsequent analyses have shown that the risk of stroke is only elevated when these episodes last more than 6 hours,¹ a 2021 meta-analysis found that single AHRE episodes ≥30 seconds and cumulative AHRE duration ≥24 hours are associated with increased risk of stroke or systemic embolism.² Based on available data, the threshold to start OAC by some physicians is very low and the use of OAC in this scenario varies considerably among doctors.³

To help answer the question of whether to start OAC in patients with device-detected AF, large randomized trials were designed. Findings are expected soon in the ARTESiA trial,⁴ which has enrolled 4000 patients. The NOAH study⁵ results were presented by Dr Paulus Kirchhof at the European Society of Cardiology Congress 2023 and published in August 2023.⁶

The NOAH trial was a multicenter European study that enrolled 2536 patients ≥65 years of age with newly diagnosed, device-detected AF lasting at least 6 minutes as well as at least one additional risk factor for stroke. The median CHA₂DS₂-VASc score was 4. Patients were randomly assigned to receive edoxaban or placebo in a 1:1 ratio and followed for an average of 21 months. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, and the safety outcome was a composite of death from any cause or major bleeding. The average number of AF episodes was 2.8 and the average AF episode duration was 2.8 hours. EKG-diagnosed AF developed in 18% of patients. The incidence of stroke was relatively low and the use of OAC was not associated with a decrease in stroke (.9% in the edoxaban group vs 1.1% in the placebo event) or in the primary efficacy endpoint. However, anticoagulation was associated with more bleeding compared with placebo 5.9% vs 4.0% (P=.03).

The NOAH trial has shown that starting OAC in the form of edoxaban in patients who have AF detected by their pacemaker or defibrillator for more than 6 minutes in duration does not reduce their risk of stroke and doubles their risk of major bleeding. It also showed that the absolute risk of stroke and bleeding in this population in the modern era with a CHA₂DS₂-VASc score of 4 was very low. In many ways, these findings are not surprising given that many trials have shown that much longer episodes are needed to increase the risk of stroke. A cutoff of at least more than 6 hours of AF might be more reasonable. The TRENDS study¹ and the Veterans Administration trial by Turakhia et al⁷ showed that multiple hours of AF were needed to increase the risk of stroke. Another consideration is that the effect of an episode of AF might only be transient, and that anticoagulation is needed only in the short term. Short-term, patient-guided OAC for wearable device-detected AF is in fact the basis of the REACT-AF trial, which just began enrolling patients.⁸ The results of the ARTESiA trial using apixaban will be available soon, but like the NOAH trial, ARTESiA used a device-detected AF cutoff of ≥6 minutes in duration.⁴

The results of NOAH should impact practice—physicians should have a strong reason to start OAC in patients with only minutes of device-detected AF. What we still do not know, however, is if patients with much longer episodes (>6 or 24 hours) should be treated with OAC and whether the OAC should be continuous or intermittent. 

Disclosures: Dr Knight has served as a paid consultant to Medtronic and was an investigator in the PULSED AF trial. In addition, he has served as a consultant, speaker, investigator, and/or has received EP fellowship grant support from Abbott, AltaThera, AtriCure, Baylis Medical, Biosense Webster, Biotronik, Boston Scientific, CVRx, Philips, and Sanofi; he has no equity or ownership in any of these companies.

References

1. Glotzer TV, Daoud EG, Wyse DG, et al. The relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol. 2009;2(5):474-480. doi:10.1161/CIRCEP.109.849638

2. Georgiopoulos G, Pateras K, Perlepe K, et al. Atrial high-rate episode duration thresholds and thromboembolic risk: a systematic review and meta-analysis. J Am Heart Assoc. 2021;10(22):e022487. doi:10.1161/JAHA.121.022487

3. Perino AC, Fan J, Askari M, et al. Practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation: insights from the Veterans Health Administration. Circulation. 2019;139(22):2502-2512. doi:10.1161/CIRCULATIONAHA.118.038988

4. Lopes RD, Alings M, Connolly SJ, et al. Rationale and design of the apixaban for the reduction of thrombo-embolism in patients with device-detected sub-clinical atrial fibrillation (ARTESiA) trial. Am Heart J. 2017;189:137-145. doi:10.1016/j.ahj.2017.04.008

5. Kirchhof P, Blank BF, Calvert M, et al. Probing oral anticoagulation in patients with atrial high rate episodes: rationale and design of the non-vitamin k antagonist oral anticoagulants in patients with atrial high rate episodes (NOAH-AFNET 6) trial. Am Heart J. 2017;190:12-18. doi:10.1016/j.ahj.2017.04.015

6. Kirchhof P, Toennis T, Goette A, et al, on behalf of the NOAH-AFNET 6 investigators. Anticoagulation with edoxaban in patients with atrial high-rate episodes. N Engl J Med. 2023 Aug 25. Online ahead of print. doi:10.1056/NEJMoa2303062

7. Turakhia MP, Ziegler PD, Schmitt SK, et al. Atrial fibrillation burden and short-term risk of stroke. case-crossover analysis of continuously recorded heart rhythm from cardiac electronic implanted devices. Circ Arrhythm Electrophysiol. 2015;8(5):1040-1047. doi:10.1161/CIRCEP.114.003057

8. Peigh G, Passman RS. “Pill-in-pocket” anticoagulation for stroke prevention in atrial fibrillation. J Cardiovasc Electrophysiol. 2023 Feb 17. Online ahead of print. doi:10.1111/jce.15866