Early initiation of rhythm control therapy was found to reduce cardiovascular outcomes in patients with newly diagnosed atrial fibrillation (AF) and cardiovascular conditions, according to the primary results of a clinical trial presented at the European Society of Cardiology Congress 2020, held virtually August 29 to September 1 and published in the New England Journal of Medicine.1,2

The results of the multi-center, prospective, randomized, open, blinded-outcome assessment Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST – AFNET 4; ClinicalTrials.gov Identifier: NCT01288352) were presented by Paulus Kirchhof, MD, professor of cardiovascular medicine at the University Heart and Vascular Center at UKE Hamburg and first author on this study.

An estimated 5% of patients with AF — even when adequately managed — are thought to experience serious cardiovascular events that include stroke, heart failure, acute coronary syndrome, and cardiovascular death. Antiarrhythmic drugs — which, along with AF ablation are safe approaches for patients with AF and concomitant cardiovascular conditions — were not found to be superior to rate control strategies in achieving rhythm control in patients with established AF in previous clinical trials.

Investigators postulated that initiating rhythm control therapy earlier and treating patients with established AF with a combination of AF ablation and antiarrhythmic drugs, would more effectively maintain sinus rhythm than rhythm control that is undertaken later.

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With this trial, researchers sought to test whether early initiation of rhythm control therapy would be superior to usual care for the treatment of patients with early and recently diagnosed AF who are at risk for stroke.

A total of 2789 patients recruited from 135 sites across 11 countries considered to be at risk for cardiovascular events (ie, with a CHA2DAS2VASc score ≥2) who had recent-onset AF (“early AF”; ie, ≤1 year) were randomly assigned to receive early rhythm control therapy (n=1395; average age, 70.2±8.4 years; 46.2% women; average CHA2DAS2VASc score, 3.4±1.3; stable heart failure, 28.4%) or usual care (n=1394; average age, 70.4±8.2 years; 46.5% women; average CHA2DAS2VASc score, 3.3±1.3; stable heart failure, 28.8%). Early rhythm control consisted of anticoagulation treatment and AF ablation or antiarrhythmic drug therapy; in cases of recurrent AF, patients underwent reablation or had their antiarrhythmic drug regimen adapted. Usual care consisted of anticoagulation treatment and rate control, supplemented with rhythm control for patients who were symptomatic and on optimal rate control therapy.

Concomitant cardiovascular disease was treated in both groups. In-person follow-ups occurred at 1 and 2 years after randomization, and events were recorded until the end of the study (median follow-up, 5.1 years). The study’s primary outcomes were a composite of cardiovascular death, stroke, acute coronary syndrome, or worsening heart failure, and the number of nights spent in hospital per year, with a 20% reduction in the composite outcome deemed to be clinically relevant.

At randomization, 95% of patients in the early rhythm control group received active rhythm control therapy (flecainide, 35.9%; amiodarone, 19.6%; dronedarone, 16.7%; propafenon, 7.0%; other antiarrhythmic drug, 7.6%), and 8.0% received AF ablation. At 2 years, 65.1% of patients in this group were still on active rhythm control therapy, and 19.4% had received AF ablation. In usual care, 95.8% and 85.4% of patients were managed without rhythm control therapy at randomization and at the 2-year follow-up, respectively.

The composite primary outcome occurred in 249 and 316 patients treated with early rhythm control and usual care, respectively (event rate: 3.9 per 100 person-years and 5.0 per 100 person-years, respectively; hazard ratio [HR], 0.79; 95% CI, 0.66-0.94; hazard reduction, 21%; P =.005). Each component of the composite primary outcome was less frequent in participants receiving early rhythm control vs usual care (uncorrected HRs: cardiovascular death, 0.72; 95% CI, 0.52-0.98; stroke, 0.65; 95% CI, 0.44-0.97; worsening heart failure, 0.81; 95% CI, 0.65-1.02; hospitalization with acute coronary syndrome, 0.83; 95% CI, 0.58-1.19).

The other primary outcome — nights spent in hospital per year — was comparable between the 2 groups (mean: early rhythm control, 5.8±21.9; usual care, 5.1±15.5; incidence rate ratio, 1.08; 99% CI, 0.92-1.28). At the 2-year follow-up, a greater percentage of patients receiving early rhythm control vs usual care was in sinus rhythm (82.1% vs 60.5%, respectively; odds ratio, 3.13; 95% CI, 2.55-3.84), and the majority of participants were asymptomatic (74.3% and 72.6%, respectively; 95% CI, 0.93-1.40).

Quality of life, cognitive function, physical scores, and left ventricular function were unchanged at 2 years in both groups and comparable between treatment groups.

The occurrence of the primary safety outcome was comparable in the early rhythm control and usual care groups (16.6% and 16.0%, respectively), however, the occurrence of stroke (2.9% vs 4.4%, respectively) and death (9.9% vs 11.8%, respectively; not significant) was greater in patients treated with usual care. A greater number of serious adverse events occurred in participants treated with the early rhythm control therapy vs usual care (4.9% vs 1.4%, respectively).

“These results have the potential to inform the future use of rhythm control therapy, further improving the care of patients with early AF,” concluded Dr Kirchhof.

We reached out to Dr Kirchhof to find out more about the impact on clinical care and outcomes of these results for patients with early AF.

The type of antiarrhythmic drugs administered to study participants who received early rhythm control therapy both at baseline and at the 2-year follow-up suggest that these patients did not have significant structural heart diseases or recent unstable heart failure. In addition, the median left atrial diameter of 43 mm in this cohort indicates little remodeling. These parameters indicate that participants in this cohort were at moderate risk for recurrent atrial fibrillation. Would you foresee that high-risk patients would also benefit from early rhythm control therapy?

Dr Kirchhof: EAST – AFNET 4 was designed to include an “all comer” population of patients with newly diagnosed AF with concomitant conditions. The trial was conducted throughout Europe, from Poland to the United Kingdom (see map on www.easttrial.org), and three-quarters of the study sites were small hospitals or outpatient cardiology practices that do not offer ablation.

Among the participants, 29% had heart failure, approximately 12% had a prior stroke, mean age was 70 years at enrollment, and the mean CHA2DAS2VASc score was 3.4. These parameters are very comparable to other recent large trials in AF. So these patients were already quite diverse, with many patients with severe heart disease at enrollment. The relatively small left atrial size is probably a feature of the recent onset AF in many patients at baseline. It is also worthwhile to keep in mind that rhythm control therapy was applied throughout the trial duration, so that mean age approached 75 years towards the end of the study.

Follow-up was more thorough in the early rhythm control group, in which participants were requested to record electrocardiograms (ECGs) twice a week, which were relayed to investigators. Based on those recordings, participants had the option of coming for additional visits. This follow-up was not available to patients getting usual care. In addition, the nearly 300,000 ECGs recorded in the early rhythm control group indicate high adherence in this group. Do you think these factors may have had an impact on the observed difference in cardiovascular event rates?

Dr Kirchhof: We are analyzing this in detail and will report more on this topic in the future. The first thing to observe is that EAST – AFNET 4 had a simple follow-up scheme: The trial only had 2 in-person follow-up visits per patient (at 1 and 2 years), and the follow-up was organized by questionnaires sent to patients. We are currently analyzing the therapy and visit patterns in more detail and will report more on this later.

But we can already say that the telemetric ECG monitoring did not increase care by much: There were just over 200 ‘triggered visits’ in the early therapy group, so approximately 2% to 4% of patients had a triggered visit per year of follow-up. There were almost 100 triggered visits in patients randomly assigned to usual care, or approximately 1% to 2% of patients. I really doubt that seeing 1% to 2% of patients once per year can explain the 20% reduction in cardiovascular death, stroke, worsening of heart failure, and ACS observed throughout the follow-up of the trial.

How will the results of this trial affect clinical care?

Dr Kirchhof: All patients with recently diagnosed AF and concomitant conditions (in simple terms: those with recently diagnosed AF who are eligible for oral anticoagulation) should receive rhythm control therapy in addition to anticoagulation, rate control, and therapy of concomitant conditions.


Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


  1. Kirchhof P. EAST–AFNET 4*: Effects of early rhythm control therapy in patients with atrial fibrillation. Paper presented at: Hot Line Session 3. European Society of Cardiology Congress; August 29-September 1, 2020.
  2. Kirchhof P, Camm AJ, Goette A, et al; for the EAST-AFNET 4 Trial Investigators. Early rhythm-control therapy in patients with atrial fibrillation. Published online August 29, 2020. N Engl J Med. doi: 10.1056/NEJMoa2019422