Early treatment of atrial fibrillation for stroke prevention trial (EAST - AFNET 4)
EAST – AFNET 4 is an investigator initiated trial (IIT) that compares two different treatment strategies in atrial fibrillation. The EAST – AFNET 4 trial will test whether an early, comprehensive, rhythm control therapy can prevent adverse cardiovascular outcomes in patients with atrial fibrillation (AF) compared to usual care. Thus, EAST – AFNET 4 aims to further reduce the residual cardiovascular risk in anticoagulated, rate controlled AF patients. The pan-European trial is conducted by the German Atrial Fibrillation NETwork (AFNET) in cooperation with the European Heart Rhythm Association (EHRA).
EAST – AFNET 4 is a prospective, parallel-group, randomized, open, blinded, end-point assessment trial. EAST – AFNET 4 tests the hypothesis that an earlier initiation of rhythm control therapy, when added to a comprehensive AF management strategy, has the potential to disrupt the vicious circles that maintain AF, maintain sinus rhythm more effectively than the current pattern of delayed rhythm control therapy, and to reduce cardiovascular complications.
Patients were eligible for EAST – AFNET 4, if they meet the following criteria:
- Recent onset AF, i.e. AF with a known history of ≤ 1 year prior to randomization and
- Risk for stroke as evidenced by
a) one of the following: age > 75 years, prior stroke or transient ischemic attack (TIA)
b) two of the following: hypertension, diabetes mellitus, left ventricular hypertrophy, age > 65 years, female sex, peripheral artery disease, kidney disease (MDRD stage III or IV), stable heart failure (NYHA II or LVEF <50%), severe coronary artery disease (previous myocardial infarction, CABG or PCI)
Participants were randomized into one of two groups receiving either early rhythm control therapy or usual care.
In the early therapy group, patients received either catheter ablation (usually by pulmonary vein isolation) or adequate antiarrhythmic drug therapy directly after randomization. The initial therapy was selected by the investigator. Upon AF recurrence, both modalities were combined.
Usual care was conducted following the current ESC guidelines for AF treatment. In addition to antithrombotic therapy and therapy of underlying heart disease, usual care usually consisted of an initial attempt to control symptoms by rate control therapy.
The primary outcome parameter of EAST – AFNET 4 is a composite of cardiovascular death, stroke and hospitalization due to heart failure or acute coronary syndrome. All patients are followed up by 6-monthly central follow-up contacts via questionnaires and by outpatient follow-up visits at 12, 24 and 36 months.
The investigators enrolled 2.745 patients from 200 centers in 11 European countries. The first patient was enrolled on July 28, 2011, in Hamburg, Germany. Patient enrolment was completed in 2016, end of study was in June 2020.
Early rhythm control therapy improves outcomes in patients with atrial fibrillation
Patients with newly diagnosed atrial fibrillation (AF) benefit from early rhythm control therapy, according to results of EAST – AFNET 4, an AFNET/EHRA trial presented in a Hot Line session at ESC Congress 2020.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.
Principal investigator Professor Paulus Kirchhof of the University Heart and Vascular Centre UKE Hamburg, Germany and the University of Birmingham, UK, states: “Rhythm control therapy initiated soon after diagnosis of atrial fibrillation reduced cardiovascular outcomes in patients with early AF and cardiovascular conditions without increasing time spent in hospital and without safety concerns. These results have the potential to completely change clinical practice towards rhythm control therapy early after the diagnosis of atrial fibrillation.”
According to guideline recommendations, rhythm control therapy is typically delayed unless patients have persistent symptoms on otherwise effective rate control. The EAST – AFNET 4 trial investigated whether rhythm control therapy – with antiarrhythmic drugs or ablation – delivered soon after AF diagnosis improves outcomes.
“Even on oral anticoagulation and optimal rate control, cardiovascular death, stroke, and heart failure are common in patients with atrial fibrillation, especially in those with concomitant cardiovascular conditions” said Professor John Camm, St. George’s University of London, UK, and EAST executive Steering Committee member.
“The risk of severe cardiovascular outcomes and death in patients with atrial fibrillation is highest in the first year after diagnosis, suggesting that early rhythm control therapy could be most beneficial,” Professor Kirchhof said. “Furthermore, atrial fibrillation causes atrial damage within a few weeks of disease onset. Early rhythm control therapy could reduce or prevent this damage, making it more effective.”
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 randomised 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 atrial fibrillation 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.
The first primary outcome was a composite of cardiovascular death, stroke, or hospitalization with worsening heart failure, and acute coronary syndrome. The second primary outcome was nights spent in hospital per year. The primary safety outcome was a composite of stroke, all-cause death, and serious adverse events caused by rhythm control therapy.
Randomization occurred a median of 36 days after the first diagnosis of AF (‘early AF’). Almost all patients randomized to early rhythm control received the allocated therapy (95%), consisting of either one of the major antiarrhythmic drugs or AF ablation. At two years, 65% of patients randomized to early rhythm control were still on rhythm control therapy, and 19.4% of patients received AF ablation. Of patients randomized to usual care, 85% were managed without rhythm control therapy at 2 years. More patients randomized to early rhythm control (82% at 2 years) were in sinus rhythm than those randomized to usual care (61%).
Approximately every 5th event was prevented by early rhythm control therapy: During a median follow-up of 5.1 years, a first primary outcome event occurred in 249 patients on early therapy and in 316 patients receiving usual care. Adjusting for the group-sequential design of the trial, the first primary outcome occurred less often in patients on early rhythm control (hazard ratio [HR] 0.79; confidence interval [CI] 0.67–0.94; p=0.005). The absolute risk reduction with early rhythm control was 1.1% per year.
Professor Hein Heidbuchel, Antwerp University, Belgium, and President of the European Heart Rhythm Association (EHRA): “The clinical benefit of early rhythm control therapy is remarkably consistent across subgroups, including asymptomatic patients, patients in sinus rhythm at randomization, and those with and without heart failure.” All components of the primary outcome occurred numerically less often in patients randomised to early therapy, and cardiovascular death and stroke were significantly reduced compared to usual care.
Regarding the second primary outcome, there was no difference in nights spent in hospital between groups (early therapy 5.8±21.9 days/year; usual care 5.1±15.5 days/year; p=0.226).
The primary safety outcome did not differ between groups (early therapy 231 events; usual care 223 events). Complications of rhythm control therapy were more common in patients on early therapy, but occurred infrequently, in line with other recent rhythm control trials, while stroke and death were less frequent in patients randomized to early rhythm control, leading to a neutral safety outcome.
Professor Andreas Goette, St. Vincenz-Hospital Paderborn, Germany, and EAST sponsor representative concludes: “AFNET and EHRA conducted EAST – AFNET 4 throughout Europe as a large investigator-initiated trial on a European level. The success of this trial confirms that such trials are a powerful tool to change clinical practice.”
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.
Patients with atrial fibrillation and heart failure benefit from early rhythm control
A subgroup analysis of the EAST – AFNET 4 study population revealed: Early initiation of rhythm control therapy is associated with clinical benefit in patients with heart failure and recently diagnosed atrial fibrillation. The new findings were presented by Dr. Andreas Rillig, UKE Hamburg, at the HRS congress on 30.07.2021 , .
Now the EAST – AFNET 4 investigators studied whether the beneficial effects of early rhythm control can be transferred to the subgroup of HF patients. Principal investigator Professor Paulus Kirchhof of the University Heart and Vascular Centre UKE Hamburg, Germany, explains: “Rhythm control is an important component of AF management in HF patients. However, it is not clear, whether rhythm control therapy conveys clinical benefit in patients with moderately reduced or preserved left ventricular ejection fraction (LVEF). To answer this question, we analyzed the effect of early rhythm control in patients with HF enrolled into the EAST – AFNET 4 trial.”
The analysis includes 798 patients with HF (785 with known LVEF at baseline). The majority, 442 patients, had HF with preserved LVEF (LVEF≥50%), 211 HF with mid-range LVEF (LVEF40-49%), and 132 HF with reduced LVEF (LVEF<40%). 396 patients were randomized to early rhythm control, 402 to usual care.
Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke or hospitalization for worsening of HF or for acute coronary syndrome occurred less frequently in HF patients randomized to early rhythm control (94/396; 5.7 per 100 patient-years) compared to HF patients randomized to usual care (130/402; 7.9 per 100 patient-years).
Early rhythm control therapy was safe in patients with HF. The primary safety outcome – defined as a composite of death, stroke, or serious adverse events of rhythm control therapy – occurred in 71/396 (17.9%) HF patients on early rhythm control and in 87/402 (21.6%) on usual care. Left ventricular function improved in both groups.
Dr. Rillig concludes: “The results of this analysis demonstrate a clinical benefit of early rhythm control therapy for all HF patients of the EAST – AFNET 4 trial. Early rhythm control based on either antiarrhythmic drug therapy or catheter ablation should be offered to all patients with AF and symptoms of HF or reduced LVEF.”
 Rillig A, Ozga A, Magnussen C, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, Eckardt L, Elvan 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 atrial fibrillation and heart failure. Abstract HRS congress 2021
 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; (published ahead of print). DOI: 10.1161/CIRCULATIONAHA.121.05632