Subanalysis of the EAST – AFNET 4 trial: Patients with AF and high comorbidity burden benefit from early rhythm control
Early rhythm control therapy reduces cardiovascular complications compared to usual care in patients with atrial fibrillation and a high comorbidity burden (CHA2DS2-VASc score ≥4). These patients should preferentially be treated with early rhythm control to protect them from cardiovascular outcomes. This is the result of a subgroup analysis of the EAST – AFNET 4 trial that was presented by Dr. Andreas Rillig, University Heart and Vascular Center Hamburg-Eppendorf, Germany, at the Heart Rhythm congress in San Francisco, USA, on 29.04.2022 , .
Rhythm control therapy can prevent recurrences of atrial fibrillation (AF). In clinical practice, it is primarily offered to relatively young and healthy patients. The EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial demonstrated that early rhythm control (ERC) therapy decreases cardiovascular outcomes compared to usual care (UC) in patients with recently diagnosed AF and comorbidities. The efficacy and safety of early rhythm control in patients with multiple cardiovascular comorbidities and higher age was analyzed in the present, prespecified subanalysis.
The EAST – AFNET 4 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 all patients: Early rhythm control therapy with antiarrhythmic drugs and/or atrial fibrillation ablation reduced 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 over a 5-year follow-up time.
In the present subgroup analysis, the EAST – AFNET 4 investigators compared the effectiveness of early rhythm control in patients with multiple comorbidities and in those with fewer comorbidities. Professor Paulus Kirchhof of the University Heart and Vascular Centre UKE Hamburg, Germany, and principal investigator of the study, explains: “Traditionally, we tend to offer rhythm control therapy to young and relatively healthy patients with atrial fibrillation. This subanalysis enabled us to compare effectiveness and safety of early rhythm control therapy in patients with fewer comorbidities to those with multiple comorbidities.”
The analysis included 1093 patients with high comorbidity burden (CHA2DS2-VASc ≥4) aged 74.8±6.8 years and 1696 with lower comorbidity burden (CHA2DS2-VASc <4) aged 67.4±8.0 years. 61% of the first group and 37% of the second group were women.
Early rhythm control reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA2DS2-VASc scores ≥4 (ERC: 5.5 events/100 patient-years; UC: 8.4 events/100 patient-years), but not in patients with fewer comorbidities (CHA2DS2-VASc <4, ERC: 3.0/100 patient-years; UC: 3.2/100 patient-years, interaction p = 0.037).
The primary safety outcome – a composite of death, stroke, or serious adverse events of rhythm control therapy – was not different between study groups in patients with high comorbidity burden (CHA2DS2-VASc ≥4, ERC: 112/549 events (20.4%); UC: 132/544 events (24.3%)), but occurred more often in patients with CHA2DS2-VASc <4 randomized to early rhythm control compared to usual care. (ERC: 119/846 (14.1%) patients; UC: 91/850 (10.7%) patients), mainly due to bradycardia-related events. Life-threatening events or total mortality were not different between groups.
Dr. Rillig summarizes the main findings: “Based on this prespecified subanalysis of the EAST – AFNET 4 trial, patients with recently diagnosed AF and multiple cardiovascular comorbidities should have priority access to rhythm control therapy to reduce cardiovascular outcomes. Although there was no difference in life-threatening events between groups or strata, our safety results highlight the need to develop safer technologies for AF ablation and safer ways to deliver antiarrhythmic drug therapy. Specific trials are needed to validate our findings.”
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 , and in patients with different AF patterns, including paroxysmal AF, persistent AF, and first diagnosed AF .
 Rillig A, Breithardt G, Camm AJ, Crijns H, Goette A, Kuck KH, Metzner A, Vardas P, Vettorazzi E, Wegscheider K, Zapf A, Kirchhof P. Early rhythm control in patients with atrial fibrillation according to CHA2DS2-VASc score and age. Late Breaking Clinical Trials Abstract, HRS Congress 2022
 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. Submitted
 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, in press
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).
Rillig A, Breithardt G, Camm AJ, Crijns H, Goette A, Kuck KH, Metzner A, Vardas P, Vettorazzi E, Wegscheider K, Zapf A, Kirchhof P. Early rhythm control in patients with atrial fibrillation according to CHA2DS2-VASc score and age. Late Breaking Clinical Trials Abstract, HRS Congress 2022