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Many patients with atrial fibrillation (AF) experience stroke, cardiovascular death and other cardiovascular complications. Early rhythm control can prevent some of these events but is often withheld from elderly patients with multiple comorbidities. Catheter ablation is the most effective rhythm-controlling therapy but has mainly been tested in younger patients. The German Atrial Fibrillation Network (AFNET) initiated the EASThigh – AFNET 11 trial to investigate whether early catheter ablation can reduce outcomes in patients with AF and comorbidities. EASThigh – AFNET 11 enrolled the first patient on 14.10.2024.
Atrial fibrillation (AF) epidemic affects the health of a growing number of people worldwide. Patients with AF are at risk of stroke, heart failure, death and dementia. Many patients develop AF in old age, and older people with cardiovascular comorbidities are at highest risk of AF-related complications.
The EAST – AFNET 4 trial, successfully completed in 2020, and subsequent sub-analyses demonstrated that systematic rhythm control therapy, initiated early in all patients using antiarrhythmic drugs or AF ablation, can reduce AF-related complications compared to usual care (1). These findings and subsequent analyses by others shifted the AF treatment paradigm towards earlier and broader use of rhythm control therapy.
Prespecified secondary analyses of the EAST – AFNET 4 data suggest that patients with AF and a high comorbidity burden benefit most from early rhythm control (2). The outcome-reducing effect of early rhythm control is mediated by attaining sinus rhythm (3). AF ablation targeting the pulmonary veins is the most effective rhythm control therapy and is therefore an attractive rhythm control therapy in patients with a high comorbidity burden who need multiple other medications and are at high risk of recurrent AF. Therefore, the Early atrial fibrillation Ablation for STroke prevention in patients with high comorbidity burden (EASThigh – AFNET 11) trial evaluates early AF ablation targeting the pulmonary veins as a first-line rhythm control therapy in elderly patients with multiple comorbidities, defined by a CHA2DS2VASc score of 4 or more. All participants will be randomized 1:1 to either early AF ablation using established single-shot devices or usual care consisting of anticoagulation and guideline-compliant treatment of existing concomitant diseases. EASThigh – AFNET 11 plans to randomize approximately 2350 patients in 200 sites in Europe, Canada and Australia. The primary outcome is a composite of cardiovascular death, stroke and hospitalization due to heart failure. Safety outcomes include ablation-related complications and mortality.
Rhythm control therapy, and especially AF ablation, is still not often used in elderly patients with AF and comorbidities. The trial will determine the safety and effectiveness of early AF ablation in this understudied population. While AF ablation is a mature technology, there are few controlled trials evaluating the safety of AF ablation in elderly patients with AF and comorbidities. The EASThigh – AFNET 11 investigators intend to fill this evidence gap.
Prof. Paulus Kirchhof, University Medical Center Eppendorf (UKE), Hamburg, Germany, international chief investigator of EASThigh – AFNET 11 and chair of the AFNET board, clarifies the role of catheter ablation: “The outcome-reducing effect of early rhythm control in the EAST – AFNET 4 trial mainly relied on the safe use of established antiarrhythmic drugs. EASThigh – AFNET 11 evaluates a more effective rhythm control therapy, AF ablation. This is a logical and important next step to define the role of early AF ablation to help our patients with AF.”
Prof. Andreas Goette, St. Vincenz Hospital Paderborn, Germany, member of the EASThigh – AFNET 11 steering committee and of the AFNET board, expresses the expectations of the study as follows: “The results will inform practice guidelines and routine patient care, helping to define the best treatment for patients with AF and a high comorbidity burden. The results of the EASThigh – AFNET 11 trial have great potential to contribute to healthier ageing in a large population at increased risk of premature death, stroke, and heart failure.”
Dr. Andreas Rillig, University Medical Center Eppendorf (UKE), Hamburg, Germany, and co-chief investigator of the EASThigh – AFNET 11 trial states: “To maximize safety and warrant highly consistent efficacy the steering committee decided that early AF ablation will be delivered using single-shot cryoballoon-based isolation of the pulmonary veins in the trial. EASThigh – AFNET 11 is a team effort thanks to which we can enroll the patient in the trial today.”
EASThigh – AFNET 11, like EAST – AFNET 4, is an investigator-initiated trial comparing two approved treatment strategies in patients with AF. Sponsor of the trial is AFNET. Following an endorsement by the Global Cardiovascular Research Funders Forum, the trial is currently funded by the Else Kröner-Fresenius-Stiftung (EKFS), other public funders, and by Medtronic. Steering committee members include Paulus Kirchhof AFNET and Hamburg, Germany, Andreas Rillig, Hamburg, Germany, Jason Andrade, Vancouver, Canada, Andreas Goette, AFNET and Paderborn, Germany, José Merino, Madrid, Spain, Andreas Metzner, Hamburg, Jens Cosedis Nielsen, Aarhus, Denmark, Andre Ng, Leicester, UK, Sam Riahi, Aalborg, Denmark, Prash Sanders, Adelaide, Australia, Ulrich Schotten, AFNET and Maastricht, Netherlands, Kevin Vernooy, Maastricht, Stephan Willems, AFNET and Hamburg, Germany, Antonia Zapf, AFNET and Hamburg, Germany and a patient representative who contributes the perspective of those affected.
References
(1) 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
(2) 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
(3) Eckardt L et al. 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
Registration: NCT06324188.
About the EAST – AFNET 4 trial
EAST – AFNET 4 was completed in 2020. It was an investigator-initiated trial (IIT) that compared two different treatment strategies in atrial fibrillation (AF). The EAST – AFNET 4 trial tested whether an early, comprehensive rhythm control therapy can prevent adverse cardiovascular outcomes in patients with 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 AF-related symptoms despite optimal rate control, following current guidelines.
Several publications reported the effects of early rhythm control therapy in different subpopulations and the interaction of early rhythm control therapy with genetic data and biomolecule concentrations in the EAST – AFNET 4 biomolecule study.
EAST – AFNET 4 sub-analyses
• Rillig A et al. Early rhythm control therapy in patients with heart failure. Circulation 2021;144(11):845-858. DOI: 10.1161/CIRCULATIONAHA.121.056323
• Metzner A et al. Anticoagulation, therapy of concomitant conditions, and early rhythm control therapy: a detailed analysis of treatment patterns in the EAST - AFNET 4 trial. Europace 2022; 24:552–564. DOI: 10.1093/europace/euab200
• Willems S et al. 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
• Goette A et al. 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
• Rillig A et al. 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
• Eckardt L et al. 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
• Jensen M et al. 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
• Van Gelder IC et al; 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
• Gottschalk S et al. 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. Europace 2023 May 19;25(5). DOI: 10.1093/europace/euad051
• Kany S et al. 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
• Fabritz L et al. Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study. Cardiovasc Res 2024. DOI: 10.1093/cvr/cvae067
• Rillig A et al. Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial. Europace 2024 Jun 3;26(6). DOI: 10.1093/europace/euae121
• Fabritz L et al. Biomarker-based prediction of sinus rhythm in atrial fibrillation patients: the EAST-AFNET 4 biomolecule study. Eur Heart J. 2024, published online 2 Sep 2024, doi: 10.1093/eurheartj/ehae611
About the Atrial Fibrillation NETwork (AFNET)
The Atrial Fibrillation NETwork (AFNET) is an interdisciplinary research network comprising scientists and physicians from hospitals and practices dedicated to improving the management of AF through coordinated research in Germany, Europe, and worldwide. Its main objective is to conduct high quality investigator-initiated clinical trials, registries, and translational research projects in Germany and internationally. AFNET was created over 20 years ago and initially funded by a large grant from the German Federal Ministry of Research and Education. The current structure, AFNET e.V., was founded in 2010 and continues this work with continued funding for projects and infrastructures from the German Centre for Cardiovascular Research (DZHK), from EU research grants, and from industry partners. AFNET has long expertise in the management of AF, but also provides support for work in other fields informing cardiovascular care. AFNET also organizes regular consensus conferences with the European Heart Rhythm Association (EHRA). The results of 20 years of clinical and translational research improved the lives of patients with cardiovascular diseases and influenced treatment guidelines.
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a.leute@t-online.de
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