No Clear Explanation for Benefits of Early Rhythm Control in EAST-AFNET4

A deeper dive into the EAST-AFNET 4 trial did not reveal any clear explanation for the reduction in major cardiovascular events seen with early rhythm control versus usual care in patients recently diagnosed with atrial fibrillation (AF).

There were no differences in use of anticoagulation, rate control therapy, or treatment of hypertension, heart failure, and diabetes between the two treatment strategies, Andreas Metzner, MD (University Heart & Vascular Center Hamburg, Germany), reported last week during the virtual European Heart Rhythm Association Congress 2021.

Although the average number of in-person follow-up visits was higher in the early rhythm control group, related mostly to the need to adjust therapy shortly after randomization, the difference was small—just 0.19 visits per patient.

“Systematic and early rhythm control results in clinical benefit when added to evidence-based oral anticoagulation, therapy of concomitant cardiovascular conditions, and rate control therapy,” Metzner concluded. He added during a panel discussion, however, that it’s “not easy to explain what finally made a difference.”

Looking for Clues

Reported last year at the virtual European Society of Cardiology Congress 2020 and published in the New England Journal of Medicine, EAST-AFNET 4 showed that starting rhythm control early after an AF diagnosis reduced composite cardiovascular events (CV death, stroke, and hospitalization for heart failure or ACS).

But there were remaining questions around the drivers of the benefit and how early rhythm control was delivered in the trial. Metzner presented a detailed analysis of the trial data to look for answers.

The investigators found that use of oral anticoagulation was high in both arms (over 90%), with direct oral anticoagulants accounting for more than half of medications taken. There were no differences observed between trial arms in treatment of hypertension, heart failure, diabetes, and other concomitant CV conditions. About 70% of patients were taking renin-angiotensin-aldosterone-system inhibitors, and blood pressure was in the normal range throughout the study period in both groups.

Most patients (about 80%) received rate control therapy, with similar use in the two trial arms. Usage declined over time, to a slightly greater extent in patients who had been randomized to early rhythm control.

The vast majority of choices around rhythm control therapy in the trial were consistent with Class I recommendations from the 2020 European AF guidelines. In the usual care arm, use of antiarrhythmic drugs (AADs) was low, whereas about 84% of patients assigned to early rhythm control received AADs as initial therapy. After 2 years, 45% of patients in the latter arm were still taking AADs; about 25% had undergone AF ablation.

Randomization to early rhythm control was strongly related to a lower likelihood of receiving no therapy, and an increased likelihood of receiving AADs and undergoing AF ablation, Metzner reported. Use of ablation also was related to country of enrollment and enrollment at a site that offered ablation, “suggesting that local availability played an important role,” he said.

Living Better or Longer

Serving as a discussant following Metzner’s presentation, Nikolaos Dagres, MD (Heart Center Leipzig, Germany), an author of the latest European AF guidelines, noted that EAST-AFNET 4 is the first trial comparing rhythm control and usual care in the last 20 years, showing a significant reduction in the primary endpoint but no significant changes in total mortality or quality of life. The trial demonstrates that rhythm control therapy can be implemented safely and without major adverse events, he said.

Dagres said it’s important to note that the trial focused on early rhythm control in patients with a short history of AF, many of whom were asymptomatic or in sinus rhythm at enrollment. “So this is not a population representative of the majority of patients that we see in clinical practice, but similar to those that we see for the first time in the course of their AF disease.”

In my opinion, the question about the effect on mortality is still not answered and could have a different answer in a larger population. Nikolaos Dagres

He pointed out that there was regular ECG transmission in the rhythm control arm, but not in patients receiving usual care. “This may hypothetically have resulted in closer monitoring and integrated patient care in the rhythm control arm, and we know from several studies that remote monitoring and active patient involvement may improve outcomes,” Dagres said.

Ultimately, he said, when making decisions about treatment, two questions need to be answered: will patients live better or will they live longer?

“There is no evidence from the [EAST-AFNET 4] trial that patients live better with early rhythm control, but there could be evidence that they may live longer,” Dagres said, noting that there was a nonsignificant 19% relative difference in mortality favoring early rhythm control. “But keep in mind that this was not shown in 20 or 50 events, but in a considerable number of approximately 300 total events. So in my opinion, the question about the effect on mortality is still not answered and could have a different answer in a larger population.”

Dagres acknowledged that the primary indication for rhythm control in the latest guidelines is a reduction in AF symptoms and improvement in quality of life, which were not seen in EAST-AFNET 4. But, he added, the guidance states that several other factors that favor use of rhythm control should be considered, including a short history of AF.

“So the [EAST-AFNET 4] findings are not in contrast with the 2020 guideline recommendations,” Dagres argued. “To decide whether we should implement on a much-broader basis rhythm control in early AF, in my opinion, we would need more data on the treatment changes triggered by the monitoring in the rhythm control arm.”