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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 [1], [2].

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 [3], 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 [4]. Other subgroup analyses demonstrated the prognostic benefit of early rhythm control in patients with AF and heart failure [5], in patients with asymptomatic AF [6], and in patients with different AF patterns, including paroxysmal AF, persistent AF, and first diagnosed AF [7].

References

[1] 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

[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. Submitted

[3] 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

[4] 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

[5] 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

[6] 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.

[7] 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.

Press Contact

Angelika Leute, PhD

Phone: +49 202 2623395

a.leute@t-online.de

Follow us on Twitter @afnet_ev and hashtag #EASTtrial.

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).

www.af-net.eu

The design paper was successfully published in "Frontiers in cardiovascular medicine". Get access to the paper here. 

Die latest results of the EAST-AFNET 4 study will be presented at this year's EHRA congress 2022:

Late Breaking Clinical Trials II
Atrial fibrillation - News on ablation and sex differences
Monday, 4th of April 2022 | 6:15 pm - 7:15 pm (CEST), Room 1
Session chaired by Tatjana Potpara
More information

Press release

Early rhythm control is useful in patients with atrial fibrillation regardless of the AF pattern. Patients with first diagnosed atrial fibrillation benefit from early rhythm control therapy comparably to patients with paroxysmal or persistent AF. This is the result of a subgroup analysis of the EAST – AFNET 4 trial that was presented by Professor Andreas Goette, St. Vincenz Hospital Paderborn, at the American Heart Association (AHA) congress on 14.11.2021 in Boston [1].

Cardiovascular events are more common in the first year after diagnosing atrial fibrillation. The current guidelines for the management of AF recommend anticoagulation and therapy of concomitant cardiovascular conditions in all patients with AF, while rhythm control is not considered as a first line therapy so far. In the EAST – AFNET 4 trial a clinical benefit of systematic, early rhythm control therapy was observed in the overall study population. Whether the AF pattern modifies the effects of early rhythm control therapy on cardiovascular outcomes is not known.

The EAST – AFNET 4 trial investigated whether rhythm control therapy – with antiarrhythmic drugs or ablation – delivered within one year after AF diagnosis improves outcomes. The main study result, published last year [2], demonstrated a clinical benefit of early rhythm control therapy for all patients: Early rhythm control therapy with antiarrhythmic drugs and/or AF 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 EAST – AFNET 4 sub-study, Professor Goette and colleagues analyzed the effect of early rhythm control therapy in three groups of patients with different AF patterns: 1048 patients with first diagnosed AF namely enrolled within seven days after their first AF episode, 2042 patients with paroxysmal AF, and 743 patients with persistent AF. They assessed the effect of early rhythm control therapy in each group and compared interactions between AF pattern and key outcomes such as cardiovascular death, stroke, heart failure, acute coronary syndromes, night spent in hospital, serious adverse events of special interest, and all-cause death. Changes in health-related quality of life were compared as well.

Patients with first diagnosed AF (FDAF) were more often enrolled as in-patients (FDAF 24%, persistent AF 14%, paroxysmal AF 11%). The CHA2DS2VASc score (a measure of the stroke risk) was comparable between AF pattern groups. There were no major differences in anticoagulation and treatment of concomitant cardiovascular conditions. Early rhythm control reduced cardiovascular complications in all three AF patterns. Nights spent in hospital and hospitalization due to acute coronary syndrome were increased in FDAF patients randomized to early rhythm control compared to FDAF patients randomized to usual care, while there was no difference between randomized groups in patients with paroxysmal AF or persistent AF.

Professor Goette summarized the results: “The clinical benefit of early rhythm control was consistent in AF patterns in the EAST – AFNET 4 trial. We found a difference in hospitalization rates. Patients with first diagnosed AF spent more nights in hospital and experienced more often hospitalization for acute coronary syndrome when they were randomized to early rhythm control compared to usual care.” He concluded: “In our opinion, the clinical AF pattern should not influence the decision for rhythm control therapy in patients with recently diagnosed atrial fibrillation and concomitant cardiovascular conditions.”

References

[1] Goette A, Borof K, Breithardt G, Camm AJ, Crijns HJGM, Kuck KH, Wegscheider K, Kirchhof P for the EAST – AFNET 4 investigators. Patients with first diagnosed atrial fibrillation are at high risk of cardiovascular events and suitable for early rhythm control: The EAST-AFNET 4 trial. Abstract AHA congress 2021

[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

Follow us on Twitter @afnet_ev and hashtag #EASTtrial.

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).

www.af-net.eu

Press Contact

Angelika Leute, PhD

Phone: +49 202 2623395

a.leute@t-online.de