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Low concentrations of three selected biomarkers in the blood of patients with atrial fibrillation identify patients with a high chance of attaining sinus rhythm. This is the main result of this analysis of the EAST – AFNET 4 biomolecule study. Today the findings have been presented by AFNET Steering Committee member Prof. Larissa Fabritz, University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany, at the annual congress of the European Society of Cardiology (ESC) in London and published in the European Heart Journal (1).
Atrial Fibrillation (AF) is the most common arrhythmia in senior people. AF often occurs in patients with cardiovascular comorbidities. Recurrent AF is determined by interactions between cardiovascular disease processes and rhythm-control therapy. Predictors of attaining sinus rhythm at follow-up are not well known.
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). A biomolecule study embedded into the EAST – AFNET 4 trial found that biomolecule concentrations in the blood of AF patients can be used to identify patients at high and low cardiovascular risk (13).
Prof. Paulus Kirchhof, UKE, principal investigator of EAST – AFNET 4 and AFNET board chair, explained: “Predicting the chance of attaining sinus rhythm could help to identify patients requiring intensive rhythm control. The cardiovascular complication-reducing effect of early rhythm control therapy shown in the EAST – AFNET 4 study is mainly mediated by sinus rhythm at 12-month follow-up. In this new analysis, we wanted to assess which biomarkers can be used to predict sinus rhythm at 12 months in patients with atrial fibrillation with and without early rhythm control therapy.”
14 biomarkers reflecting AF-related cardiovascular disease processes were quantified in the blood of 1586 participants of the EAST – AFNET 4 biomolecule study. Three of these biomarkers – ANGPT2, BMP10, and NT-proBNP – proved to be linked to future sinus rhythm. Higher baseline concentrations of these biomarkers were independently associated with a lower chance of sinus rhythm at 12-months, and low concentrations of ANGPT2, BMP10 and NT-proBNP predicted sinus rhythm during follow-up. The predictive effect of NT-proBNP was reduced in patients receiving early rhythm control therapy (Pinteraction=0.033). Analysis of heart rhythm at 24 months and external validation confirmed the results.
Prof. Fabritz concluded: “Our findings suggest that the three biomarkers NT-proBNP, ANGPT2 and BMP10 identify patients with AF at high risk of not attaining sinus rhythm in the future. The disease processes related to the novel biomarkers ANGPT2 and BMP10 likely also contribute to future sinus rhythm with and without rhythm control therapy. NT-proBNP elevations interact with early rhythm control, potentially suggesting repeat assessment of NT-proBNP to monitor the effectiveness of rhythm control.”
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, Al-Taie C, Borof K, Breithardt G, Camm J, Crijns HJGM, Cardoso VR, Chua W, van Elferen S, Eckardt L, Gkoutos G, Goette A, Guasch E, Hatem S, Metzner A, Mont L, Murukutla AV, Obergassel J, Rillig A, Sinner MF, Schnabel RB, Schotten U, Sommerfeld LC, Wienhues-Thelen U-H, Zapf A, Zeller T, Kirchhof P. Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET4 biomolecule study. Eur Heart J. accepted. DOI: 10.1093/eurheartj/ehae611
(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
(13) 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
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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.
Fabritz L et al. Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET4 biomolecule study. Eur Heart J. accepted.
DOI: 10.1093/eurheartj/ehae611
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