A mediator analysis of the EAST – AFNET 4 trial dataset revealed the key factor for the effectiveness of early rhythm control (ERC) in patients with atrial fibrillation (AF): The presence of sinus rhythm at 12 months after randomization explains 81% of the outcome-reducing effect of ERC. Other factors, e. g. blood pressure or recurrent AF, only explain small portions of the effect. The results were presented by Professor Lars Eckardt, University Hospital Münster, Germany, at the annual congress of the European Society of Cardiology (ESC) in Barcelona, Spain, on 29.08.2022 , .
The EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial investigated whether rhythm control therapy – with antiarrhythmic drugs or atrial fibrillation ablation – delivered within one year after AF diagnosis improves outcomes. The main study result, published in 2020 , demonstrated a clinical benefit of early rhythm control therapy for patients with AF and comorbidities: 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.
Professor Eckardt explains: “The EAST – AFNET 4 trial demonstrated that systematic early rhythm control reduced cardiovascular outcomes by 21% compared to usual care. But it was not yet known which components of early rhythm control therapy contributed to the outcome reduction. To identify possible mediators of the observed treatment effect, we scrutinized the EAST – AFNET 4 trial dataset for factors of early rhythm control that were associated with reduced cardiovascular outcomes.”
All participants of the EAST – AFNET 4 trial were examined in a study visit at 12 months after randomization. At that time, 90% of study patients (1257/1395 randomized to early rhythm control and 1260/1394 randomized to usual care) had not reached the first primary outcome. The data of these patients were incorporated into the mediator analysis.
Fourteen potential mediators of early rhythm control were identified at the 12-month visit. Of these, sinus rhythm at 12 months explained 81% of the treatment effect compared to usual care during the remainder of follow-up (4.1 years). In patients not in sinus rhythm at 12 months, early rhythm control did not reduce future cardiovascular outcomes (HR 0.94, 95% CI [0.65-1.67]). Inclusion of AF recurrence in the model only explained 31% of the treatment effect, and inclusion of systolic blood pressure at 12 months only 10%, respectively. Within the EAST – AFNET 4 trial, a total of 340/1395 (24%) patients randomized to early rhythm control therapy underwent AF ablation. There was no difference in outcomes in patients who underwent AF ablation compared to those who did not undergo AF ablation.
Professor Eckardt summarizes the findings: “Successful rhythm control therapy, estimated by the presence of sinus rhythm at 12 months after randomization, mediates most of the reduction in cardiovascular outcomes achieved by early rhythm control in the EAST – AFNET 4 trial. Based on these results, clinicians implementing early rhythm control should aim for early and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities. Further population-based investigations and clinical trials of AF management strategies may help to clarify the role of AF ablation and antiarrhythmic drug therapy for outcome reduction in patients with recently diagnosed AF and comorbidities.”
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 .
 Eckardt L, Sehner S, Suling A, Borof K, Breithardt G, Crijns HJGM, Goette A, Wegscheider K, Zapf A, Camm AJ, Metzner A, Kirchhof P. Predictors and mediators of improved outcomes on early rhythm control - an analysis of the EAST – AFNET 4 data set. Latest Science in Atrial Fibrillation, Abstract, ESC Congress 2022
 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
 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.
 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. Effect of atrial fibrillation presentation on 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
Angelika Leute, PhD
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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. 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).