EAST-AFNET 4 findings suggest optimum treatment window is measured in months

In medicine, results often hinge on timing, and in the case of atrial fibrillation, the ideal timing for rhythm control therapy is early—the sooner, the better.

Paulus Kirchhof, MD, of the University Heart and Vascular Center UKE in Hamburg, who reported findings from the EAST-AFNET 4 trial in a Hot Line session at the European Society of Cardiology (ESC 2020), noted that most adverse events associated with Afib occur within the first year of onset and — perhaps even more importantly—even within a few months of Afib onset, “the atrium may suffer severe damage, some of which may be irreversible.”

In the trial, which was also published online by the New England Journal of Medicine, at an average of 5.1 years of follow-up, early rhythm control was associated with a 21% relative reduction in risk of cardiovascular death, stroke, worsening heart failure, and acute coronary syndrome, which was significant (P =0.005); however, absolute risk reduction worked out to 1.1% per year.

There was no between-group difference in the secondary endpoint of number of nights spent hospitalized.

During an ESC press conference, Kirchhof explained the rational for the study, noting that “most people believe that maintaining sinus rhythm would be helpful for these patients — I believed this—but we didn’t have the data to prove it.”

Kirchhof and colleagues recruited 2,789 patients and assigned 1,395 to early rhythm control and 1,394 to usual care. The median age in each group was 70 and roughly 46% were women.

“Early rhythm control included treatment with antiarrhythmic drugs or atrial fibrillation ablation after randomization. Usual care limited rhythm control to the management of atrial fibrillation–related symptoms,” they explained. Patients in both groups received guideline-recommended treatment for cardiovascular conditions, anticoagulation, and rate control. But the “use of digitalis glycosides and beta-blockers was slightly more common (probably because of the group assignment), and statin use slightly less common, among the patients assigned to usual care,” they noted.

Editorialists from the University of Utah, T. Jared Bunch, MD, and Benjamin A. Steinberg, MD, MHS, wrote that a “defining aspect of the trial is that these patients had atrial fibrillation that had recently been diagnosed (<1 year earlier), with one third of the patients having their first episode of atrial fibrillation… Rhythm-control–related adverse events were infrequent, occurring in 4.9% of patients in the group assigned to early rhythm control, with drug-related bradycardia the most common event.

“A limitation of EAST-AFNET 4, with its low event rates, was that 9.0% and 6.6% of follow-up years in the early-rhythm-control group and usual-care group, respectively, were lost because patients withdrew from the trial or were lost to follow-up (characteristics of the patients not presented),” Bunch and Steinberg wrote. “The burden of atrial fibrillation was not reported, and its role as a contributor to outcomes remains unknown. The reported percentages of patients with sinus rhythm were probably overestimated, since they were assessed by electrocardiography rather than continuous monitoring. The results of this trial support the use of rhythm control to reduce atrial fibrillation–related adverse clinical outcomes when applied early in the treatment of patients with atrial fibrillation. The use of other cardiovascular therapies (including anticoagulants, renin–angiotensin–aldosterone system inhibitors, beta-blockers, and statins) in the trial probably contributed to the low rates of stroke, heart failure, acute coronary syndrome, and death and highlight the need to treat atrial fibrillation with comprehensive management.”

Kirchhof said a key factor contributing to the benefit seen in the trial was that the 135 participating centers were organized in clusters, so that “we had ablation sites available to centers that were not performing ablations themselves. This network structure helps us to deliver rhythm control therapy safely to our patients.”

Asked about specific patient characteristics that could identify patients who might benefit from ablation over antiarrhythmic medications, he said, “initially, the majority of patients were treated with antiarrhythmic drugs, which is, I guess, replicating clinical practice… We saw that 19.4% of patients approximately in the trial (about one third of those in the rhythm control group) have received ablation, and there was still about 45% on drugs. So, this is a strategy trial. We do not yet have data, we are currently analyzing it to see whether there is any difference in the different components. But what I can tell you is that we have very solid data that the safety of rhythm control therapy was going good over the five-year follow-up. We only had 68 patients who experienced serious adverse events related to rhythm control therapy, so that’s a rate of 4.9%, an annual rate of 1%. To put that in perspective, the annualized rate of severe bleeds, on average, [for patients treated with anticoagulants] is about 2%. So, rhythm control therapy as delivered in our trial was very safe, both with ablation and with antiarrhythmics.”

  1. Note that findings from EAST-AFNET 4 suggest that rhythm control therapy reduces event risk in patients with atrial fibrillation when the intervention takes place early.

  2. Be aware that the absolute rhythm control related adverse event rate was 1.1% per year in the EAST-AFNET 4 trial.

Peggy Peck, Editor-in-Chief, BreakingMED™

Kirchhof reported grants from DZHK / BMBF, Sanofi, Abbott, European Heart Rhythm Association / ESC, German Heart Foundation during the conduct of the study. He also has received research support from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies, outside the submitted work. In addition, Kirchhof is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783) issued.

Bunch reported grants from Boston Scientific, grants from Boehringer Ingelheim, grants from AltaThera, outside the submitted work; In addition, Bunch has a patent US10010258B2 – methodology patent to map complex forms of atrial fibrillation – persistent and longstanding persistent atrial fibrillation – and guide treatment issued, a patent US9044143B2 – a device to measure thermal changes broadly in the esophagus to guide ablation issued, a patent US8641710B2 – invented primarily by Dr. John Doty, a CV surgeon, a device to use during atrial fibrillation surgery that will magnetically couple two ablation tools to provide bi-polar ablation issued, a patent US10004894B2 – a device to allow part separation of defibrillation pads to allow better defibrillation vectors during electrophysiology procedures and pacemaker/defibrillator implantation procedures issued, and a patent US9713695B2 – this is a device that helps guide multiple venous access for electrophysiology studies issued.

Steinberg reported personal fees from Merit Medical, personal fees from Bayer, personal fees from Biosense Webster, personal fees from Janssen Scientific Affairs, non-financial support from Boston Scientific, personal fees from AltaThera, outside the submitted work.

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Topic ID: 74,2,2,204,913,192,925,203