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In patients with device-detected atrial fibrillation the risk of stroke appears low (1% per year) compared to patients with ECG-detected atrial fibrillation, even in patients with long episodes. Anticoagulation can slightly reduce stroke risk, but also increase major bleeding. This is the main finding of a sub-analysis of the NOAH – AFNET 6 trial presented by Dr Nina Becher, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany, in the late-breaking clinical trials session at the annual congress of the American Heart Association (AHA) in Philadelphia, USA, and published on 12th November, 2023, in the European Heart Journal (1).

Device-detected atrial fibrillation, also called sub-clinical atrial fibrillation (SCAF) or atrial high-rate episodes (AHRE), are short and rare atrial arrhythmias detected by implanted pacemakers, defibrillators, and loop recorders that enable long-term monitoring of heart rhythm. The episodes resemble atrial fibrillation. Device-detected atrial fibrillation is found in every fifth patient with a pacemaker or another cardiac implanted electronic device (2). Device-detected atrial fibrillation can lead to stroke, but the stroke risk in patients with device-detected atrial fibrillation appears lower than the stroke risk in patients with ECG-documented atrial fibrillation. Observational data suggested that patients with very long episodes of device-detected atrial fibrillation may have a higher stroke risk.

Recently, the NOAH – AFNET 6 (Non vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes) trial found that anticoagulation increases bleeding events in patients with device-detected atrial fibrillation while the effect on stroke was smaller than expected (3).

Dr Becher and the NOAH – AFNET 6 team evaluated the efficacy and safety of anticoagulation with edoxaban in patients with long episodes of device-detected atrial fibrillation lasting 24 hours or more in the NOAH – AFNET 6 trial (1). The findings are consistent with the main trial: Anticoagulation had only has a minor effect on stroke and systemic embolism. An additional analysis including AHRE duration as a continuous variable confirmed that episode duration did not interact with the effect of anticoagulation. The low stroke rate without anticoagulation came as a surprise compared to older analyses. The results will need confirmation in larger and independent data sets.

Dr Becher states: “The effects of anticoagulation in patients with device-detected atrial fibrillation appear consistent across episode durations, including in patients with very long episodes. This highlights the need to involve all patients with device-detected AF in a balanced decision-making process on anticoagulation that considers the effects on stroke and bleeding.”

NOAH – AFNET 6 compared the anticoagulant edoxaban to placebo. A similar trial called ARTESiA (Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Sub-Clinical Atrial Fibrillation) trial tested the efficacy and safety of another anticoagulant, apixaban, in patients with device-detected atrial fibrillation. A trial-level meta-analysis of these two first-in-kind randomized trials of anticoagulation in patients with device-detected atrial fibrillation shows consistent results in both trials (4): Anticoagulation prevents on average three strokes and induces seven major bleeding events per 1000 patient-years of treatment.

Professor Andreas Goette, St. Vincenz Hospital, Paderborn, Germany, who was involved in the NOAH – AFNET 6 trial and in the meta-analysis observes: “On average, anticoagulation reduces stroke by a small absolute amount. This desirable effect comes at the price of an increase in major bleeding events. Clinicians need to consider these effects when taking individual decisions on anticoagulation in patients with device-detected atrial fibrillation.”

Professor Paulus Kirchhof, UKE, lead investigator of the NOAH – AFNET 6 trial, states: “We now have much better estimates of the efficacy and safety of oral anticoagulation in patients with device-detected atrial fibrillation. We clearly need additional methods to identify patients with device-detected atrial fibrillation at high risk of stroke.”

References

(1) Becher N, Toennis T, Bertaglia E, et al. Anticoagulation with edoxaban in patients with long Atrial High-Rate Episodes ≥24 hours. Eur H J 2023; in press. DOI: 10.1093/eurheartj/ehad771

(2) Toennis T, Bertaglia E, Brandes A, et al. The influence of Atrial High Rate Episodes on Stroke and Cardiovascular Death - An update. Europace 2023. DOI: 10.1093/europace/euad166.

(3) Kirchhof P, Toennis T, Goette A, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes. N Engl J Med 2023;389(13):1167-1179. DOI: 10.1056/NEJMoa2303062.

(4) McIntyre WF, Benz A, Becher N, et al. Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: A study-level meta-analysis of NOAH-AFNET 6 and ARTESiA. Circulation 2023; in press. 

About the Atrial Fibrillation NETwork (AFNET)

The Atrial Fibrillation NETwork is an interdisciplinary research network comprising scientists and physicians from hospitals and practices dedicated to improving the management of atrial fibrillation through coordinated research in Germany, Europe, and worldwide. Its main objective is to conduct high quality investigator-initiated clinical trials and registries on a national and international level as well as translational research projects. The AFNET continues the long-term activities of the network which has been funded by the German Federal Ministry of Research and Education over a decade. Since January 2015, specific projects and infrastructures of the AFNET are funded by the German Centre for Cardiovascular Research (DZHK), and some projects by EU research grants. AFNET has long expertise in the management of atrial fibrillation, but also provides support for work in other fields informing cardiovascular care. The results of 20 years of clinical and translational research improved the lives of patients with cardiovascular diseases and influenced treatment guidelines.

www.af-net.eu

Funding of the NOAH trial: AFNET, DZHK, Daiichi Sankyo

NOAH registration: NCT 02618577, ISRCTN 17309850

Press Contact

Angelika Leute, PhD
Phone: +49 202 2623395
a.leute@t-online.de

Press release

On 12 and 13 September international experts in atrial fibrillation come together in Münster, Germany, to take part in the 9^th AFNET/EHRA consensus conference. “Longer and better lives for patients with atrial fibrillation” is the pronounced intention of the two-day expert meeting which is jointly organized by the German Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA) every two years.

Atrial fibrillation (AF) is the most common heart arrhythmia and a growing health problem in an aging society. It affects several million people in Europe and worldwide.

Prof. Paulus Kirchhof, Hamburg, Germany, one of the four chairpersons of the conference and board member of AFNET, explains the background of the expert meeting: “Despite improved treatment options AF patients still suffer strokes, heart failure, and premature death. There are various approaches to optimize care for AF patients. We set out to bring these approaches together. The AFNET/EHRA consensus conference provides a high-level expert forum to discuss recent advances in AF diagnosis and therapy.”  

The participating scientists will discuss new results in AF screening, the therapeutic impact of rare atrial arrhythmias picked up by implanted devices and consumer electronics, the role of early rhythm control, new data on the interaction of comorbidities with AF and AF management, new technologies for AF detection and management, the role of pacing and devices in the management of AF and heart failure, as well as new trial results from the main 2023 congresses.

Participants of the 9^th AFNET/EHRA Consensus Conference come from Europe, USA, Canada, and Australia. The meeting is chaired by four cardiologists: Prof. Andreas Goette, Paderborn, Germany, and Prof. Paulus Kirchhof, Hamburg, Germany, both from AFNET, and Prof. Helmut Pürerfellner, Linz, Austria, and Prof. Isabell van Gelder, Groningen, Netherlands, both from EHRA.

This is already the 9^th meeting of its kind. Since 2007, AFNET and EHRA organize biennial joint conferences in which international AF experts pool their knowledge. After detailed discussions, the scientists publish their results in a consensus report.

Prof. Goette summarizes the experts` aim: “During the conference, we will jointly develop recommendations for better AF management, and we will summarize them afterwards in a position paper. We hope our results will be integrated into the upcoming treatment guidelines of the European Society of Cardiology (ESC) next year.”

The conference is organized and co-financed by AFNET – celebrating 20 years anniversary in 2023 – and EHRA with additional financial support from MAESTRIA which is funded under European Union's (EU) Horizon 2020 research and innovation program (grant number 965286).

About AFNET

The Atrial Fibrillation NETwork is an interdisciplinary research network comprising scientists and physicians from hospitals and practices dedicated to improving the management of atrial fibrillation through coordinated research in Germany, Europe, and worldwide. Its main objective is to conduct high quality investigator-initiated clinical trials and registries on a national and international level as well as translational research projects. The AFNET continues the long-term activities of the network which has been funded by the German Federal Ministry of Research and Education over a decade. Since January 2015, specific projects and infrastructures of the AFNET are funded by the German Centre for Cardiovascular Research (DZHK), and some projects by EU research grants. AFNET has long expertise in the management of atrial fibrillation, but also provides support for work in other fields informing cardiovascular care. The results of 20 years of clinical and translational research improved the lives of patients with cardiovascular diseases and influenced treatment guidelines.

www.af-net.eu

Press Contact

Angelika Leute, PhD

Phone: +49 202 2623395

a.leute@t-online.de

Press release

The clinical trial NOAH – AFNET 6 conducted by the German Atrial Fibrillation Network (AFNET), Münster, Germany, revealed: In patients with atrial high rate episodes (AHRE), but without ECG-documented atrial fibrillation (AF), oral anticoagulation increases bleeding without reducing strokes. Stroke rate was low in patients with AHRE with and without oral anticoagulation. The results were presented today at the annual congress of the European Society of Cardiology (ESC) in Amsterdam and published in the New England Journal of Medicine (1).

Atrial high-rate episodes are short and rare atrial arrhythmias that resemble atrial fibrillation detected by implanted pacemakers, defibrillators, and loop recorders that enable long-term monitoring of heart rhythm. AHRE are found in 10-30% of patients with implanted devices (2). AHRE episodes resemble atrial fibrillation. Therefore, patients with AHRE are often offered treatment with blood thinners (oral anticoagulation) without ECG-documented atrial fibrillation. So far, the efficacy and safety of oral anticoagulation has never been tested in patients with AHRE (2,3).

The Non vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes trial (NOAH-AFNET 6) compared the anticoagulant edoxaban to placebo in an international investigator-initiated, randomized, double-blind, double-dummy outcomes trial. NOAH-AFNET 6 randomized patients with AHRE episodes lasting 6 minutes or longer detected by implantable devices, and aged 65 years or more with at least one additional stroke risk factor of heart failure, hypertension, diabetes, prior stroke or transient ischaemic attack, vascular disease, or age from 75 years. This patient population was outside of the approved indication of edoxaban.

Prof. Paulus Kirchhof, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany, principal investigator of NOAH – AFNET 6 explained the background of the trial: “Whether anticoagulants can prevent strokes in patients with device-detected AHRE, was not known. Although AHRE resemble atrial fibrillation, NOAH – AFNET 6 demonstrates that patients with AHRE are better managed without anticoagulation.”

Between 2016 and 2022, NOAH – AFNET 6 enrolled 2536 patients in 206 sites across 18 European countries. Patients were randomly allocated in a 1:1 fashion to anticoagulation or no anticoagulation. Anticoagulation consisted of edoxaban in the dose approved for stroke prevention in atrial fibrillation (60 mg once daily, reduced to 30 mg once daily according to approved dose reduction criteria for stroke prevention in atrial fibrillation). No anticoagulation consisted of placebo containing no active compound or aspirin 100 mg once daily in patients with an indication for antiplatelet therapy (3).

The analysis included the data of 2536 patients aged 78 on average. 37% were women. The patients had additional stroke risk factors (median CHA2DS2-VASc score 4.0±1.3) and a median AHRE duration of 2.8 hours. All patients were followed until the end of the trial.

In September 2022 it was decided to orderly terminate the trial after enrolment of all patients due to the observed trend towards futility for efficacy combined with expected safety concerns. The analysis of the full data confirms this:

Stroke, systemic embolism, or cardiovascular death occurred in 83 patients in the anticoagulation group and 101 patients in the no anticoagulation group (stroke: 0.9% versus 1.1% per year, systemic embolism: 0.5% versus 1.1% per year, cardiovascular death: 2.0% versus 2.2% per year). This means no significant difference between treatment groups (HR 0.81 [0.6;1.08], p=0.15).

A major bleeding event or death occurred in 149 patients in the anticoagulation group (5.9% per year) and in 114 patients in the no anticoagulation group (4.5% per year), thus more often in patients randomized to anticoagulation (HR 1.3 [1.02;1.67], p=0.03). This was mainly driven by a doubled rate of major bleeding (2.1% versus 1.0% per year), a known side effect of all anticoagulants.

Prof. Kirchhof commented: “As expected, anticoagulation increased bleeding. The low stroke rate with and without anticoagulation was unexpected. The results of NOAH – AFNET 6 clearly suggest to demand ECG documentation of atrial fibrillation prior to initiation of oral anticoagulation. The results also call for randomized trials evaluating anticoagulation in people in whom smartwatches detect arrhythmias that resemble atrial fibrillation.”

Prof. Andreas Goette, St. Vincenz Hospital, Paderborn, Germany, NOAH – AFNET 6 sponsor representative, concluded: “Our results underpin evidence from other trials which indicated that in patients with AHRE anticoagulants may not be as effective in preventing strokes as previously thought. Further research is needed to identify patients with AHRE at high stroke risk and to find the optimal treatment for these persons.”

NOAH – AFNET 6 was financially supported by Daiichi Sankyo Europe and the German Centre for Cardiovascular Research (DZHK). The sponsor of the investigator-initiated trial is AFNET.

References

(1) Kirchhof P et al. Anticoagulation with Edoxaban in Patients with Atrial High Rate Episodes. NEJM 25 August 2023. doi: 10.1056/NEJMoa2303062

(2) Toennis T et al. The influence of atrial high rate episodes on stroke and cardiovascular death – an update. Europace 22 June 2023. doi: 10.1093/europace/euad166

(3) Kirchhof P 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

About the Atrial Fibrillation NETwork (AFNET)

The Atrial Fibrillation NETwork is an interdisciplinary research network comprising scientists and physicians from hospitals and practices dedicated to improving the management of atrial fibrillation through coordinated research in Germany, Europe, and worldwide. Its main objective is to conduct high quality investigator-initiated clinical trials and registries on a national and international level as well as translational reseach projects. The AFNET continues the long-term activities of the network which has been funded by the German Federal Ministry of Research and Education over a decade. Since January 2015, specific projects and infrastructures of the AFNET are funded by the German Centre for Cardiovascular Research (DZHK), and some projects by EU research grants. AFNET has long expertise in the management of atrial fibrillation, but also provides support for work in other fields informing cardiovascular care. The results of 20 years of clinical and translational research improved the lives of patients with cardiovascular diseases and influenced treatment guidelines.
www.af-net.eu

Funding: AFNET, DZHK, Daiichi Sankyo

Registration: NCT 02618577, ISRCTN 17309850

Press Contact

Angelika Leute, PhD

Phone: +49 202 2623395

a.leute@t-online.de

ANET associated events: 

25 August 2023, 8:30, "Stockholm", Stroke and bleeding risk in atrial fibrillation: walking the tight rope (Paulus Kirchhof)

More information.

25 August 2023, 11:15, "Amsterdam", Hot Line Session:  NOAH-AFNET 6: Oral anticoagulation in patients with atrial high rate episodes (Paulus Kirchhof)

More information.

25. August 2023, 16:30, "Hub Rembrandt", Ask the Trialist from Hot Line 1:  NOAH-AFNET 6 (Paulus Kirchhof)

More information.

26 August 2023, 8:30, "Stockholm", Great Debate: controversies in atrial fibrillation - early rhythm control and atrial fibrillation burden (Andreas Götte)

More information.

28 August 2023, 08:30, "Stockholm", Novel approaches: how to provide patient-centred atrial fibrillation care (Stephan Willems)

More information.

28 August 2023, 10:15, "Hub Mondrian", Screening for atrial fibrillation: lessons learned (Renate Schnabel)

More information.

A review article written by the NOAH – AFNET 6 investigators led by Tobias Tönnis from UKE Hamburg summarizes recent evidence on the impact of atrial high rate episodes on stroke and cardiovascular death (1). The new evidence suggests that blood thinners may not be as effective in preventing strokes as previously thought.

Implantable devices and wearables like smart-watches enable continuous or near-continuous monitoring of cardiac rhythm. This leads to detection of short arrhythmias in many people, especially elderly persons with cardiovascular conditions. These arrhythmias, called atrial high rate episodes (AHRE), look like atrial fibrillation (AF). It is well established that blood thinners (anticoagulants) provide effective stroke prevention in patients with AF. Therefore, patients with AHRE are often treated with blood thinners as well.

Dr. Tobias Toennis, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany, explained: “Implanted pacemakers, defibrillators, or cardiac monitors can continuously capture and quantify atrial arrhythmias. Patients with such devices are a suitable population to study the role of infrequent atrial arrhythmias for outcomes in elderly people. AHRE occur in 10-30 % of elderly patients without atrial fibrillation. We reviewed a number of previous AHRE studies and summarized the current knowledge on stroke risk.”

It remains unclear whether anticoagulants can prevent strokes in patients with AHRE. This lack of knowledge is reflected in the current guidelines worldwide. Oral anticoagulants are not routinely recommended in patients with AHRE, but decisions on anticoagulation can be individualized based on clinical risk assessment. 

The reviewed trials indicate: AHRE are associated with an increased thromboembolic risk, even though it is lower than that of clinical AF. The thromboembolic risk appears to be influenced by the duration and frequency of AHRE episodes and by the number and severity of comorbidities. Recently published trials suggest that blood thinners prevent fewer strokes in patients with AHRE than previously thought.

NOAH – AFNET 6 (2), a controlled clinical trial conducted by the German Atrial Fibrillation Network (AFNET), evaluates the efficacy and safety of blood thinners in patients with AHRE. NOAH – AFNET 6 compares treatment with Edoxaban, a non-vitamin K antagonist oral anticoagulant (NOAC), to current therapy (antiplatelet therapy or no antithrombotic therapy) in patients with AHRE aged 65 years or more with at least two stroke risk factors. The trial can be expected to report soon.

The principal investigator of NOAH – AFNET 6, Prof. Kirchhof, UKE, summarized: “NOAH – AFNET 6 will provide much-needed information on the efficacy and safety of oral anticoagulation in patients with AHRE. We hope that these new data will shed some more light on the subject and that further studies will follow.” 

References

(1)    Toennis T et al. The influence of atrial high rate episodes on stroke and cardiovascular death – an update. Europace 22 June 2023. doi: 10.1093/europace/euad166

(2)    Kirchhof 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

About the Atrial Fibrillation NETwork (AFNET)

The Atrial Fibrillation NETwork is an interdisciplinary research network comprising scientists and physicians from hospitals and practices dedicated to improving the management of atrial fibrillation through coordinated research in Germany, Europe, and worldwide. Its main objective is to conduct high quality investigator-initiated clinical trials and registries on a national and international level. The AFNET continues the long-term activities of the network which has been funded by the German Federal Ministry of Research and Education over a decade. Since January 2015, specific projects and infrastructures of the AFNET are funded by the German Centre for Cardiovascular Research (DZHK).

www.af-net.eu

Press Contact

Angelika Leute, PhD
Phone: +49 202 2623395
a.leute@t-online.de