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EAST-AFNET 4 @ World Stroke Congress– WSC 2022

Session 0880 - Plenary 01: Opening, Presentation of Award and Late Breaking Trials (ID 294)


Early rhythm-control therapy for atrial fibrillation in patients with history of stroke in the EAST-AFNET4 trial
Wednesday, 26th of October 2022 | / 12:10 – 12:20 pm (CEST)/ 18:10 – 18:20 pm (SGT), room "Hall 406"

Speaker: Märit Jensen


More information

 

AFNET terminates NOAH – AFNET 6 trial ahead of time

Press release

The NOAH – AFNET 6 trial which is conducted to evaluate the potential benefit of oral anticoagulation in patients with atrial high rate episodes (AHRE) is going to be terminated prematurely. The reason for early termination is an observed trend towards futility for efficacy combined with expected safety concerns. Following a recommendation of the study scientific committees, on 2 September 2022, AFNET decided to orderly terminate the NOAH – AFNET6 trial in the coming weeks. The study results will be available next year.

The AFNET is conducting NOAH – AFNET 6 (Non-vitamin K antagonist Oral anticoagulants in patients with AHRE) since 2016 as an investigator-initiated trial in 18 European countries, financially supported by Daiichi Sankyo Europe and the German Centre for Cardiovascular Research (DZHK). Recently the target number of 2538 randomised and treated patients was reached. Early termination of the study means for the participants that they are advised to come timely to the study site for a final visit at which the intake of study medication ends.

It is well established that oral anticoagulation provides effective stroke prevention in patients with Atrial Fibrillation (AF). NOAH – AFNET 6 investigates, whether oral anticoagulation is also adequate in the case of atrial high rate episodes (AHRE), but without overt AF. The trial compares treatment with Edoxaban, a non-vitamin K antagonist oral anticoagulant (NOAC), to current therapy (antiplatelet therapy or no antithrombotic therapy) to prevent stroke, cardiovascular death, or systemic embolism in patients with AHRE aged 65 years or more with at least two stroke risk factors. This is outside the approved indication for Edoxaban. Design and rationale of NOAH – AFNET 6 were published in 2017 (1).

The reasons for early termination given by the Data and Safety Monitoring Board (DSMB) are an observed trend towards futility for efficacy combined with safety concerns. Prof. Paulus Kirchhof, principal investigator of NOAH – AFNET 6 and chairman of the AFNET board, explained: “We have to wait for the analysis of the full data. What we know so far suggests that oral anticoagulation is not as effective as we hoped for in patients with AHRE. On the basis of the available information, AFNET decided that orderly termination of the trial according to study protocol is the best way to fulfil the responsibility towards our patients.”

Prof. Andreas Goette, NOAH – AFNET 6 sponsor representative and member of the AFNET board, stated: “NOAH was designed to find out whether NOAC treatment can reduce the stroke rate significantly. We are already sure that this is not the case. However, there are no unexpected safety concerns visible.”

Prof. Kirchhof concluded: “While the early termination of NOAH is an unexpected development, we are confident that the analysis of the trial data will yield important findings on the optimal antithrombotic therapy for patients with AHRE. We will hopefully be able to report the results next year.”

 

References

[1] Kirchhof et al, Probing oral anticoagulation in patients with atrial high rate episodes: Rationale and design of the Non–vitamin K antagonist Oral anticoagulants in patients with Atrial High rate episodes (NOAH – AFNET 6) trial, Am Heart J. 2017 Aug;190:12-18.
doi: 10.1016/j.ahj.2017.04.015.

 

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

Better therapy for patients with heart failure and atrial fibrillation (CABA-HFPEF-DZHK27 trial)

The study "CABA-HFPEF-DZHK27" (CAtheter-Based Ablation of atrial fibrillation vs. conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) is aiming for a better therapy for patients with heart failure and atrial fibrillation. Charité (Berlin, Germany) has the overall responsibility for the study. This trial is supported by German Centre for Cardiovascular Research (DZHK). Further information can be found in the press release (german only). 

Attaining sinus rhythm mediates improved outcomes with early rhythm control therapy of atrial fibrillation

Press release

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 [1], [2].

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 [3], 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 [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], in patients with different AF patterns [7], and in patients with high comorbidity burden [8].

 

References

 

[1] 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

[2] 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

[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. 2022; 80:283-95. DOI: 10.1016/j.jacc.2022.04.058

[8] 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

 

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