EAST-AFNET 4: Early Rhythm Control in AF Gains New Life

Bruce Jancin

August 29, 2020

Initiation of rhythm control with antiarrhythmic drugs and/or ablation in patients with early, recently diagnosed atrial fibrillation led to a significantly lower risk for major adverse cardiovascular outcomes, compared with a rate control strategy, during more than 5 years of follow-up.

The results, from the large randomized EAST-AFNET 4 trial, were presented by Paulus Kirchhof, MD, at the virtual European Society of Cardiology (ESC) Congress 2020 and published simultaneously in The New England Journal of Medicine.

Previous trials of rate vs rhythm control in atrial fibrillation (AF), such as the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, failed to show an advantage for rhythm over rate control in terms of clinical outcomes.

Why was EAST-AFNET 4 different? Kirchhof offered two major reasons: The study incorporated AF ablation as an option in the rhythm control strategy, and treatment started soon after diagnosis of the arrhythmia. Indeed, nearly 40% of patients had their first AF episode at the time of randomization, and the median time from diagnosis to randomization was just 36 days.

"Once you are in AFib for a few months, the atrium suffers severe damage, some of it irreversible, so it becomes more difficult to restore and maintain sinus rhythm when you wait longer," explained Kirchhof, director of the Department of Cardiology at the University Heart and Vascular Center in Hamburg, Germany, and professor of cardiovascular medicine at the University of Birmingham, United Kingdom.

In addition, epidemiologic studies show that the risk for cardiovascular complications is heightened in the first year after diagnosis of AF. "So there's a window of opportunity to prevent complications," he added.

The impetus for conducting EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) was straightforward: "The question of whether rhythm control is beneficial or not has been in the field for several decades. Most people, like me, always believed that maintaining sinus rhythm would help, but we didn't have the data to show it."

Early Rhythm Control Shows Sustained Benefits

EAST-AFNET 4 was a prospective, open, blinded-outcome-assessment trial. It included 2789 patients with early AF and an average CHA2DS2-VASc score of 3.4 who were randomly assigned at 135 sites in 11 European countries to early rhythm control or guideline-recommended rate control.

At a median 5.1 years of follow-up, the primary outcome — a composite of cardiovascular death, stroke, acute coronary syndrome, or hospitalization for worsening heart failure — occurred at a pace of 3.9% per year in the rhythm control group and 5% per year with rate control. This translated to a statistically significant and clinically meaningful 21% relative risk reduction favoring early rhythm control.

The 28% reduction in cardiovascular death with rhythm control was statistically significant, as was the 35% reduction in stroke. However, the 19% reduction in heart failure hospitalizations and 17% decrease in hospitalizations for acute coronary syndrome were not. 

The co-primary endpoint — the mean number of nights spent in the hospital per year, which served as a proxy for the cost of treatment to a healthcare system — didn't differ between the two treatment arms, at roughly 5 nights per year.    

The clinical benefit of early rhythm control was consistent across all 19 prespecified patient subgroups, including patients who were asymptomatic and patients with or without heart failure.

Serious adverse events related to rhythm control therapy — most often drug-related bradycardia — occurred in 4.9% of patients over the course of 5.1 years, compared with a 1.4% serious event rate in patients assigned to rate control. Kirchhof called the roughly 1% per year serious event rate in the rhythm control group quite acceptable.

"To put that in perspective, the annualized rate of severe bleeds on oral anticoagulation — a very beneficial therapy used by more than 90% of participants at 2 years — is about 2%," he noted.

Only 8% of patients randomly assigned to rhythm control received AF ablation as initial therapy, consistent with current clinical practice. By 2 years, 19.4% of the rhythm control group had undergone AF ablation. Also at that time, 15% of the rate control group was receiving rhythm control therapy to help manage AF-related symptoms.

One of the big surprises in the study, he said, was that nearly three-quarters of patients in both groups were asymptomatic at 2 years.

"I think that shows how well we control symptoms, even without rhythm control," he observed.

Results "Move the Field Forward"

Kirchhof stressed that this was a trial of two different treatment strategies, and it's not yet possible to single out any specific component of the rhythm control strategy as being responsible for the improved outcomes.

"I cannot tell you whether the outcome difference was due to AFib ablation, or early treatment, or the fact that we're now better at using antiarrhythmic drugs than we were 20 years ago," he said.

Asked whether the EAST-AFNET 4 findings warrant more aggressive screening for AF to detect and intervene early in the arrhythmia, Kirchhof replied with an unequivocal yes.

"My conclusion is that every patient with newly diagnosed AFib and a CHA2DS2-VASc score of 2 or more should not only receive anticoagulation and rate control, but should also be offered rhythm control therapy at the time of diagnosis, which also means that all of these people have to be seen by a cardiologist who has expertise in the domain of AF management. It's a big clinical challenge, but it leads to a 21% improvement in outcomes, and I think we have to do what's best for our patients," he said.

In an interview, Kalyanam Shivkumar, MD, PhD, called EAST-AFNET 4 "a very important study."

"It moves the field forward, for sure. I think it will change clinical practice, and it should," commented Shivkumar, who was not involved in the study.

"Now there are so many wearable technologies out there — the Apple Watch and others — which will enable rhythm abnormalities to be detected early on. This bodes well for the field," said Shivkumar, who is editor-in-chief of JACC: Clinical Electrophysiology. He is also professor of medicine, radiology, and bioengineering at the University of California, Los Angeles, and director of the UCLA Cardiac Arrhythmia Center.

Dr Kirchhof reported receiving research grants to conduct the EAST-AFNET 4 trial from the German Ministry of Education and Research, the German Center for Cardiovascular Research, the Atrial Fibrillation Network, the European Heart Rhythm Association, St. Jude Medical, Abbott, Sanofi, the German Heart Foundation, the European Union, the British Heart Foundation, and the Leducq Foundation.  

European Society of Cardiology (ESC) Congress 2020. Presented August 29, 2020.

N Engl J Med. Published online August 29, 2020. Abstract   

This article will also appear on  MDedge.com , part of the Medscape Professional Network.


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