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Press release

An analysis of the biomolecule substudy of the EAST – AFNET 4 trial revealed: biomolecule concentrations in the blood of patients with atrial fibrillation can be used to identify patients at high and low cardiovascular risk. Today the findings were presented by Prof. Larissa Fabritz, University Medical Center Hamburg Eppendorf, Hamburg, Germany, at the Frontiers in CardioVascular Biomedicine Congress in Amsterdam and published in Cardiovascular Research (1).

Atrial Fibrillation (AF) is the most common arrhythmia in elderly people. AF often occurs in patients with cardiovascular comorbidities with shared disease mechanisms. Little is known about the disease processes leading to AF-related complications and their interactions in patients with AF.

The EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial demonstrated that early rhythm control – with antiarrhythmic drugs or atrial fibrillation ablation – delivered within one year after AF diagnosis improves outcomes in 2789 patients with early AF and cardiovascular risk factors compared to usual care (UC) over a 5-year follow-up time (2). A series of sub-analyses of the EAST – AFNET 4 data set verified the results for different sub-groups. (3-12).

This substudy tested whether circulating biomolecules can be used to measure AF related disease processes and their interactions in patients and how they relate to stroke, heart failure, acute coronary syndrome, and cardiovcascular death. Paulus Kirchhof, principal investigator of EAST – AFNET 4 and author on the paper, explained: “We were fortunate that we precisely could quantify thirteen biomolecules related to different disease processes in the EAST – AFNET 4 biomolecule study, Clustering methods capturing interactions between biomolecules were applied to identify patients at risk of cardiovascular events based on biomolecule concentrations. Thereby, four AF subphenotypes with distinct biomolecule profiles and risk of complications were identified. The results provide insights into the drivers of AF-related complications in patients.”

The prespecified analysis of the EAST – AFNET4 biomolecule study assigned 1586 patients (71 years old, 46% women) into four clusters based on blood concentrations of thirteen precisely-quantified biomolecules. These biomarkers potentially reflect ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each patient cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow up 2.9 years).

The highest-risk patient cluster mainly showed cardiometabolic disturbances, with elevated concentrations of the biomolecules BMP10, IGFBP7, NT-proBNP, ANGPT2 and GDF15. Patients in the lowest-risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of hsCRP, IL-6, and D-dimer. Patients in the highest-risk cluster had a 5-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control therapy was effective across clusters.

Prof. Fabritz concluded: “The EAST – AFNET 4 biomolecule study showed: Biomolecule concentrations identify cardiometabolic subtypes in patients with atrial fibrillation at high and low cardiovascular risk. Biomolecule-based patient clusters can be used to advance management of atrial fibrillation. Our findings call for future research into the effects of biomolecules on cardiovascular function. These patient clusters open new treatment options in each cluster, enabling research testing the effectiveness in patients with specific subphenotypes.”

The EAST – AFNET 4 biomolecule substudy was performed on an international level in cooperation with the European research consortia CATCH ME and MAESTRIA.

References

(1) Fabritz L, Chua W, Cardoso VR, Al-Taie C, Borof K, Suling A, Krause L, Kany S, Magnussen C, Wegscheider K, Breithardt G, Crijns HJGM, Camm AJ, Gkoutos G, Ellinor PT, Goette A, Schotten U, Wienhues-Thelen U-H, Zeller T, Schnabel RB, Zapf A, Kirchhof P. Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study. Cardiovasc Res 2024. DOI: 10.1093/cvr/cvae067

(2) Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, Fetsch T, van Gelder IC, Haase D, Haegeli LM, Hamann F, Heidbüchel H, Hindricks G, Kautzner J, Kuck K-H, Mont L, Ng GA, Rekosz J, Schön N, Schotten U, Suling A, Taggeselle J, Themistoclakis S, Vettorazzi E, Vardas P, Wegscheider K, Willems S, Crijns HJGM, Breithardt G, for the EAST–AFNET 4 trial investigators. Early rhythm control therapy in patients with atrial fibrillation. N Engl J Med 2020; 383:1305-1316. DOI: 10.1056/NEJMoa2019422

(3) Metzner A, Suling A, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Elvan A, Goette A, Haegeli LM, Heidbuchel H, Kautzner J, Kuck KH, Mont L, Ng GA, Szumowski L, Themistoclakis S, van Gelder IC, Vardas P, Wegscheider K, Willems S, Kirchhof P. Anticoagulation, therapy of concomitant conditions, and early rhythm control therapy: a detailed analysis of treatment patterns in the EAST - AFNET 4 trial. EP Europace 2022; 24:552–564. DOI: 10.1093/europace/euab200

(4) Rillig A, Magnussen C, Ozga, Suling A, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Elvan A, Goette A, Gulizia M, Haegeli LM, Heidbuchel H, Kuck KH, Ng GA, Szumowski L, van Gelder IC, Wegscheider K, Kirchhof P. Early rhythm control therapy in patients with heart failure. Circulation 2021;144(11):845-858. DOI: 10.1161/CIRCULATIONAHA.121.056323

(5) Willems S, Borof K, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Gessler N, Goette A, Haegeli LM, Heidbuchel H, Kautzner J, Ng GA, Schnabel R, Suling A, Szumowski L, Themistoclakis S, Vardas P, van Gelder IC, Wegscheider K, Kirchhof P. Systematic, early rhythm control therapy equally improves outcomes in asymptomatic and symptomatic patients with atrial fibrillation: the EAST-AFNET 4 Trial. Eur Heart J. 2022; 43:1219-1230. DOI: 10.1093/eurheartj/ehab593.

(6) Goette a, Borof K, Breithardt G, Camm AJ, Crijns H, Kuck KH, Wegscheider K, Kirchhof P, MD. Presenting Pattern of Atrial Fibrillation and Outcomes of Early Rhythm Control Therapy. J Am Coll Cardiol. 2022; 80:283-95. DOI: 10.1016/j.jacc.2022.04.058

(7) Rillig A, Borof K, Breithardt G, Camm AJ, Crijns HJGM, Goette A, Kuck KH, Metzner A, Vardas P, Vettorazzi E, Wegscheider K, Zapf A, Kirchhof P. Early rhythm control in patients with atrial fibrillation and high comorbidity burden. Circulation. 2022 Sep 13;146(11):836-847. DOI: 10.1161/CIRCULATIONAHA.122.060274

(8) Jensen M, Suling A, Metzner A, Schnabel R, Borof K, Goette A, Haeusler KG, Zapf A, Wegscheider K, Fabritz L, Diener H-C, Thomalla G, Kirchhof P. Early rhythm-control therapy for atrial fibrillation in patients with a history of stroke: a subgroup analysis of the EAST- AFNET 4 trial. Lancet Neurol 2023; 22: 45–54. DOI: 10.1016/PIIS1474-4422(22)00436-7 

(9) Eckardt L, Sehner S, Suling A, Borof K, Breithardt G, Crijns HJGM, Goette A, Wegscheider K, Zapf A, Camm AJ, Metzner A, Kirchhof P. Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST – AFNET 4 trial. Eur Heart J, 2022 Oct 21;43(40):4127-4144. DOI: 10.1093/eurheartj/ehac471

(10) Van Gelder IC, Ekrami NK, Borof K, Fetsch T, Magnussen C, Mulder BA, Schnabel R, Wegscheider K, Rienstra M, Kirchhof P; EAST-AFNET 4 Trial Investigators. Sex Differences in Early Rhythm Control of Atrial Fibrillation in the EAST-AFNET 4 Trial. J Am Coll Cardiol. 2023 Feb 28;81(8):845-847. DOI: 10.1016/j.jacc.2022.12.011.

(11) Gottschalk S, Kany S, König H-H, Crijns HJGM, Vardas P, Camm AJ, Wegscheider K, Metzner A, Rillig A, Kirchhof P, Dams J. Cost- effectiveness of early rhythm-control versus usual care in atrial fibrillation care: an analysis based on the German subsample of the EAST-AFNET 4 trial. EP Europace 2023 May 19;25(5). DOI: 10.1093/europace/euad051

(12) Kany S, Al-Taie C, Roselli C, Pirruccello JP, Borof K, Reinbold C, Suling A, Krause L, Reissmann B, Schnabel R, Zeller T, Zapf A, Wegscheider K, Fabritz L, Ellinor PT, Kirchhof P. Association of genetic risk and outcomes in patients with early rhythm control therapy in atrial fibrillation: results from the EAST-AFNET4 study. Cardiovasc Res 2023 Aug 7;119(9):1799-1810. DOI: 10.1093/cvr/cvad027

Press Contact

Angelika Leute, PhD

Phone: +49 202 2623395

a.leute@t-online.de

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Funding: AFNET, BMBF, DZHK, EHRA, Deutsche Herzstiftung, Abbott, Sanofi

About the EAST – AFNET 4 trial

EAST – AFNET 4 is an investigator-initiated trial (IIT) that compared two different treatment strategies in atrial fibrillation. The EAST – AFNET 4 trial tested whether an early, comprehensive rhythm control therapy can prevent adverse cardiovascular outcomes in patients with atrial fibrillation (AF) compared to usual care.

A total of 2789 patients with early AF (diagnosed less than a year ago) and at least two cardiovascular conditions (approximating a CHA₂DS₂-VASc score >=2) were enrolled by 135 sites in 11 countries during 2011 to 2016. Patients were randomized 1:1 to early rhythm control therapy or usual care, stratified by sites. Patients in both groups received guideline-recommended treatment for underlying cardiovascular conditions, anticoagulation, and rate control.

All patients in the early rhythm control group received antiarrhythmic drugs or catheter ablation after randomization (chosen by the local study teams). Rhythm control therapy was escalated with AF ablation and/or antiarrhythmic drugs when recurrent AF was documented clinically or by ECG, including monitoring with patient-operated ECG devices.

Patients in the usual care group were initially managed with rate control. Rhythm control therapy was only used to improve atrial fibrillation-related symptoms despite optimal rate control, following current guidelines.

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

Press release

In patients with device-detected atrial fibrillation and a high comorbidity burden, oral anticoagulation increases bleeding without a clear reduction in stroke. This is the main finding of a sub-analysis of the NOAH – AFNET 6 trial presented by Dr Julius Nikorowitsch, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany, in a late-breaking science session at the annual congress of the European Heart Rhythm Association (EHRA) in Berlin, Germany, today and simultaneously published in the European Heart Journal (1).

Device-detected atrial fibrillation (DDAF) are short and typically rare episodes of atrial fibrillation (AF) detected by pacemakers, defibrillators, and implanted loop recorders capable of continuous rhythm monitoring. Device-detected atrial fibrillation is found in every fifth patient with a 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.

Recently, the NOAH – AFNET 6 (Non vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes) trial found that anticoagulation expectedly increases bleeding events in patients with device-detected atrial fibrillation while the stroke preventing effect was smaller than expected (3). This even applies to patients with long episodes of device-detected AF (4). A meta-analysis of NOAH – AFNET 6 confirmed an increase in bleeding and detected a small reduction in ischemic strokes with anticoagulation (5).

Dr Nikorowitsch explained: ”Older age, female sex, kidney disease, diabetes, heart failure, and other comorbidities increase the risk of adverse cardiovascular outcomes. We were interested if oral anticoagulation might reduce cardiovascular event rates in patients with a high burden of these factors and device-detected AF. To address this, we performed a prespecified secondary analysis of the NOAH – AFNET 6 data set.”

NOAH – AFNET 6 randomized 741 elderly patients (mean age 79 years, 52% women) with device-detected AF and multiple comorbidities (CHA2DS2-VASc >4) into two cohorts: one receiving anticoagulation with edoxaban, the other without anticoagulation. This patient population was outside of the approved indication of edoxaban. The stroke rate was low without anticoagulation (1.3%/year). Anticoagulation did not considerably reduce thrombo-embolic events, but increased bleeding and death in this patient group. Older age, diabetes, and kidney disease independently predicted the primary outcome defined as a composite of stroke, systemic embolism, or cardiovascular death. Anticoagulation, age, heart failure, diabetes, prior stroke, and kidney disease predicted safety outcome defined as major bleeding event or death.

Prof. Paulus Kirchhof, UKE, principal investigator of the NOAH – AFNET 6 trial, concluded: “The findings are consistent with the main trial: The stroke rate in patients with device-detected AF is low, even with multiple comorbidities. Anticoagulation had only a minor effect on stroke and systemic embolism. Our results, together with other data and considering the limitations of all subgroup analyses, can help to adapt the safe and effective use of oral anticoagulants in patients with device-detected AF and multiple stroke risk factors in clinical practice, and in future guidelines. They also call for new methods to identify patients with device-detected AF at high risk of stroke which might benefit from anticoagulation.”

References

(1) Lip YH, Nikorowitsch J, Sehner S et al. Oral anticoagulation in device-detected atrial fibrillation: effects of age, sex, cardiovascular comorbidities, and kidney function on outcomes in the NOAH-AFNET 6 trial. Eur Heart J. 2024 April 9. DOI: 10.1093/eurheartj/ehae225

(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 Jul 4;25(7). 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) Becher N, Toennis T, Bertaglia E, et al. Anticoagulation with edoxaban in patients with long Atrial High-Rate Episodes ≥24 hours. Eur Heart J. 2024 Mar 7;45(10):837-849. DOI: 10.1093/eurheartj/ehad771

(5) McIntyre WF, Benz AP, Becher N, et al. Direct Oral Anticoagulants for Stroke Prevention in Patients with Device-Detected Atrial Fibrillation: A Study-Level Meta-Analysis of the NOAH-AFNET 6 and ARTESiA Trials. Circulation. 2023. DOI: 10.1161/CIRCULATIONAHA.123.067512

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.kompetenznetz-vorhofflimmern.de

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

An international panel of experts published recommendations to improve management of atrial fibrillation (AF). The position paper summarizes the results of the 9th AFNET/EHRA consensus conference – a two-day expert meeting which was jointly organized by the German Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA) in Münster, Germany, in September 2023. Today the consensus report was presented at the EHRA congress in Berlin by Prof. Dominik Linz, Maastricht, The Netherlands, and simultaneously published in Europace (1).

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

During the 9th AFNET/EHRA consensus conference 83 international interdisciplinary scientists pooled their knowledge on AF management and research and discussed new insights and treatment options. Prof. Linz, first author of the paper, explained: “After two days of fruitful discussion, we merged our findings. The essence of the meeting was summarized in five recommendations.”

1. Active rhythm management should be part of the default initial treatment for all suitable patients with AF.

2. Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes but also increases major but non-lethal bleeding.

3. More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics and imaging can support this.

4. The presence of AF should trigger systematic work-up and comprehensive treatment of concomitant cardiovascular conditions.

5. Machine learning algorithms have been used to improve detection of AF and can help to prevent development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF.

Prof. Paulus Kirchhof, Hamburg, Germany, one of the four chairpersons of the conference and board member of AFNET, concluded: “Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF. A low AF burden is associated with low rates of stroke and heart failure. Reducing AF burden is developing into a therapeutic goal in patients with AF.”

Prof. Andreas Goette, Paderborn, Germany, also chairman of the conference and AFNET board member, stated: “We are curious to see whether our recommendations will be incorporated into the upcoming AF guidelines and change clinical practice.”

Participants of the 9th AFNET/EHRA Consensus Conference came from Europe, USA, Canada, and Australia. The meeting was 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.

The conference was organized and co-financed by AFNET 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). Industry participants paid an attendance fee.

References

1. Linz D et al. Longer and better lives for patients with atrial fibrillation: The 9th AFNET/EHRA Consensus Conference. Europace 2024 April 9. DOI: 10.1093/europace/euae070

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

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