Patients with atrial fibrillation (AF) and a history of stroke are at high risk of recurrent stroke and cardiovascular complications. Early rhythm control therapy is safe and appears particularly effective in this vulnerable patient group. This was shown by a subgroup analysis of the EAST – AFNET 4 trial. The results were published in The Lancet Neurology .
The EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial investigated whether rhythm control therapy – using antiarrhythmic drugs or atrial fibrillation ablation – delivered within one year after AF diagnosis improves outcomes. The main study result, published in 2020 , demonstrated that early rhythm control therapy reduced cardiovascular events by 21% in patients with AF and comorbidities: Early rhythm control (ERC) with antiarrhythmic drugs and/or AF ablation reduced the primary outcome, a composite of cardiovascular death, stroke, and hospitalization for worsening heart failure or acute coronary syndrome, in 2789 patients with early AF and cardiovascular risk factors compared to usual care (UC) over a 5-year follow-up time.
Dr. Märit Jensen from University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany, who presented the results at the World Stroke Congress, explained the background of this subgroup analysis of the EAST – AFNET 4 trial: “Ten to fifteen percent of patients with AF have a history of stroke. They are at very high risk of recurrent stroke and cardiovascular events. Because of their age, comorbidities, and often due to long-term disabilities after a stroke, these patients rarely receive rhythm control therapy at present. A strategy of systematic, early rhythm control leads to a significant reduction of stroke and cardiovascular events in patients with recently diagnosed AF. However, patients with AF and prior stroke are often frail and multimorbid and may be at particular risk of side effects of rhythm control therapy. Thus, we analysed whether early rhythm control therapy is safe and can prevent adverse cardiovascular outcome in these patients.”
217 participants (8%) of the EAST – AFNET 4 trial had a history of stroke. Their median age was 72 years. 44% of them were women and mean CHA2DS2-VASc score was 5. Of those 217 patients, 110 (51%) were assigned to early rhythm control and 107 (49%) to usual care.
A first primary outcome event – a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome – occurred in 18 of the patients assigned to early rhythm control (3.7 per 100 person years) and in 33 patients assigned to usual care (7.4 per 100 person years) translating into a hazard ratio of 0.52 (95% confidence interval 0.29 to 0.93).
A primary safety outcome – a composite of death, stroke, or serious adverse events related to rhythm-control therapy – occurred in 17 (16%) patients assigned to early rhythm control and in 30 (28%) patients assigned to usual care. Mortality was lower in patients assigned to early rhythm control (10% vs. 20%).
Dr. Jensen commented on the findings: “Among patients with AF and history of stroke, early rhythm control therapy was associated with a lower risk of adverse cardiovascular outcomes than usual care. The rate of serious adverse events related to antiarrhythmic drugs or AF ablation in the early rhythm control group (3%) did not exceed the rate observed in patients without history of stroke (5%).”
Götz Thomalla, Professor for Clinical Stroke and Imaging research at the UKE and co-author of the study commented: “In this subgroup analysis, the effects of early rhythm control in patients with a history of stroke were consistent with the findings of the primary analysis. Early rhythm control therapy is effective in preventing adverse cardiovascular outcomes in patients with AF who had a stroke. This highlights the importance of good collaboration between neurologists and cardiologists in secondary prevention of stroke patients with atrial fibrillation.”
The principal investigator of EAST – AFNET 4, Professor Paulus Kirchhof, UKE, concluded: “The results of this subgroup analysis point towards a particular effectiveness of early rhythm control treatment in patients with AF and a history of stroke, a subgroup of patients with a well-known high risk of recurrent stroke or other cardiovascular morbidity and mortality. Importantly, early rhythm control appeared equally safe as in patients without prior stroke. Our findings support the use of early rhythm control in patients with AF and history of stroke in addition to anticoagulation and therapy of concomitant cardiovascular conditions.”
Since the publication of the main study result in 2020, different subgroup analyses of the EAST – AFNET 4 study data have been performed. One described the different, variable treatment patterns of antiarrhythmic drugs and AF ablation used in the trial, applied within guideline recommendations . Other subgroup analyses demonstrated the prognostic benefit of early rhythm control in patients with AF and heart failure , in patients with asymptomatic AF , in patients with different AF patterns , and in patients with high comorbidity burden . A mediator analysis identified sinus rhythm as key factor for the effectiveness of early rhythm control .
 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
 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
 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
 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
 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
 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
 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. 15 Aug 2022. DOI: 10.1161/CIRCULATIONAHA.122.060274
 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. DOI: 10.1093/eurheartj/ehac471
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Funding: AFNET, BMBF, DZHK, EHRA, Deutsche Herzstiftung, Abbott, Sanof
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. 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
Angelika Leute, PhD
Phone: +49 202 2623395