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A sub-study analysis of the EAST – AFNET 4 trial revealed how genetic risk for atrial fibrillation (AF) and stroke interacts with early rhythm control therapy: Early rhythm control reduces cardiovascular events in patients with AF across the spectrum of genetic AF and stroke risks. Today the findings were published in the journal Cardiovascular Research [1].
The EAST – AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial demonstrated that rhythm control therapy – with antiarrhythmic drugs or atrial fibrillation ablation – delivered within one year after AF diagnosis improves outcomes in patients with AF and comorbidities [2]. 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.
The causes for atrial fibrillation and stroke are manifold and also comprise a heritable component. The genetic risk can be quantified by polygenic risk scores (PRS) using data from large genome-wide association studies. In a collaboration with the Broad Institute of MIT and Harvard in Cambridge, USA, these PRS were tested in the EAST – AFNET 4 study.
Dr. Shinwan Kany, University Medical Center Hamburg Eppendorf, Hamburg, Germany, explained: “Prior studies suggest that patients with a genetic predisposition to AF may suffer more recurrent AF on rhythm control therapy. Additionally, studies using PRS for stroke identified AF patients with an increase in stroke risk when otherwise classified as low risk by CHA2DS2-VASc. This information suggests that early rhythm control therapy could be less effective or less safe in patients with an elevated genomic risk for AF. To assess this, we analyzed the association between genetic AF and stroke risk and cardiovascular events in the EAST – AFNET 4 bio-sample study.”
In the EAST – AFNET 4 bio-sample sub-study, patients were asked to donate a blood sample for later analyses. For the present analysis, blood samples from 1567 of the 2789 trial patients were analyzed. Of these patients, 793 were randomized to early rhythm control, 774 to usual care. They had a median age of 71 years and comprised 44% women. Baseline characteristics were similar between randomized groups.
Consistent with the EAST – AFNET 4 main trial, early rhythm control reduced the primary outcome compared with usual care in the bio-sample sub-population (HR 0.67, p<0.001). The randomized intervention, early rhythm control, did not interact with genetic risk for AF (PRS-AF: interaction p=0.806) or stroke (PRS-Stroke: interaction p=0.765).
As expected, genetic AF risk was associated with recurrent AF, but the attributable risk was modest (HR 1.08), illustrating the effectiveness of modern rhythm control therapy across the spectrum of genetic AF risk. Unexpectedly, genetic stroke risk was associated with a higher risk for heart failure events (HR 1.23, p=0.010) without differences in stroke (HR 1.0, p=0.973) in this well-anticoagulated cohort. The association of genetic stroke risk with heart failure hospitalization was validated in the UK Biobank, a prospective cohort study of over 500,000 participants from the United Kingdom. In the replication analysis, PRS-Stroke was associated with incident AF (HR 1.16, p<0.001) and with incident heart failure (HR 1.08, p<0.001). The association with heart failure was weakened when excluding AF patients (HR 1.03, p=0.001).
EAST – AFNET 4 principal investigator, Professor Paulus Kirchhof, University Medical Center Hamburg Eppendorf, Hamburg, Germany, concluded: “Our bio-sample study shows: Early rhythm control is effective and safe across the spectrum of genetic AF and stroke risks. Our findings support the use of early rhythm control therapy irrespectively of genetic risks for AF and stroke. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risks, cardiovascular diseases, and treatment.”
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 [3]. Other subgroup analyses demonstrated the prognostic benefit of early rhythm control in patients with AF and heart failure [4], in patients with asymptomatic AF [5], in patients with different AF patterns [6], in patients with high comorbidity burden [7] and in patients with prior stroke [8]. A mediator analysis identified sinus rhythm as key factor for the effectiveness of early rhythm control [9].
References
[1] Kany S, Al-Taie C, Roselli C, Pirruccello JP, Borof K, Reinbold C, Suling A, Krause L, Reissmann B, Schnabel R, Zeller T, Zapf A, Wegscheider K, Fabritz L, Ellinor PT, Kirchhof P. 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. DOI: 10.1093/cvr/cvad027
[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
[3] 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
[4] 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
[5] 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.
[6] 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
[7] 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
[8] 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
[9] 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
[10] Gottschalk S, Kany S, König H-H, Crijns HJGM, Vardas P, Camm AJ, Wegscheider K, Metzner A, Rillig A, Kirchhof P, Dams J. 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. EP Europace 2023. DOI: 10.1093/europace/euad051
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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).
www.af-net.eu