Rhythm vs rate control in AF: A win finally?

Early initiation of rhythm-control therapy led to a significantly reduced risk of major adverse cardiovascular (CV) outcomes compared with usual care (typically rate control) in patients with newly diagnosed atrial fibrillation (AF) at risk of stroke, reveals the EAST-AFNET 4* trial presented at ESC 2020.

“This trial is a very important trial — addressing what I would call a classical question in AF management, ie, which approach should we take with the patients: should we go for rate control or rhythm control?” highlighted the session chair Dr Silvia Priori from the University of Pavia, Italy.

“This is indeed the question raised by the AFFIRM** study [almost] 20 years ago, and we are still discussing [it now].”   

Previous trials of rate vs rhythm control, including the AFFIRM trial, have failed to demonstrate superiority of rhythm control using antiarrhythmic drugs over rate control in patients with established AF, said principal investigator Professor Paulus Kirchhof from University Heart and Vascular Center, Hamburg, Germany.

“Most people like me always believed that maintaining sinus rhythm would be helpful, but we didn't have the data to show it,” he said during the online press conference.

Conventionally, rate-control strategies are used preferentially in AF management, while rhythm-control therapy is typically deferred unless patients continue to show persistent symptoms on rate-control approaches that are otherwise effective.

“[However,] the risk of severe CV complications and death in patients with AF is highest in the first year after diagnosis, suggesting that early [rhythm-control] therapy could be beneficial,” noted Kirchhof.

“Furthermore, AF causes atrial damage within a few weeks of disease onset. Early rhythm-control therapy could reduce or prevent this damage, making it more effective,” he added.

Finding a rhythm in practice

In the multinational EAST-AFNET 4 trial with a PROBE*** design, 2,789 patients (mean age 70 years, 46 percent female) with newly diagnosed AF (diagnosed within 1 year) and at least two CV conditions were randomized 1:1 to receive early rhythm-control strategy or usual care. [N Engl J Med 2020;doi:10.1056/NEJMoa2019422]

Early rhythm control involved treatment with antiarrhythmic drugs or catheter ablation. On the other hand, patients assigned to usual care were initially managed with rate control — with rhythm control limited only to manage severe AF-related symptoms despite optimal rate control, in accordance with guidelines recommendation.

The composite primary outcome of CV death, stroke, acute coronary syndrome (ACS) or worsening heart failure (HF) leading to hospitalization occurred in significantly fewer patients in the early rhythm-control group than the usual care group (3.9 vs 5.0 per 100 person-years; hazard ratio [HR], 0.79; p=0.005).

This, according to the researchers, translates to an absolute risk reduction of 1.1 percent per year with early rhythm control.

All individual components of the primary outcome were similarly less common with early therapy vs usual care, with the differences in CV death (HR, 0.72) and stroke (HR, 0.65) being statistically significant between the two groups in favour of early rhythm control.  

The benefit of early rhythm control was also consistent across predefined subgroups, including asymptomatic patients and those without HF.

“Rhythm-control therapy initiated soon after diagnosis of AF reduces CV complications without increasing time spent in hospital and without safety concerns,” stated Kirchhof.

The coprimary endpoint of number of nights spent in the hospital were similar between the two groups (mean, 5.8 vs 5.1 days per year; p=0.23).

“The absence of an appreciable difference in hospital nights is reassuring in view of the excess hospitalizations associated with rhythm-control therapy reported in two previous large trials,” explained the researchers.

The trial was terminated early for efficacy after a median follow-up of 5.1 years.

“As expected, the early rhythm-control strategy was associated with more adverse events [AEs] related to rhythm-control therapy, but the incidence of the overall safety outcome events was similar in the two groups,” reported Kirchhof.

Overall, the primary safety outcome events occurred in 16.6 and 16.0 percent of patients in the early rhythm control and usual care groups. The rates of serious AEs related to rhythm-control therapy were 4.9 percent and 1.4 percent, respectively.

“These results have the potential to completely change clinical practice towards rhythm-control therapy early after the diagnosis of AF,” said Kirchhof.

Driver of success?

Noting that CV event rates in EAST-AFNET 4 were substantially lower than those in other AF trials, invited discussant Dr Tatjana Potpara from University of Belgrade, Serbia, asked: “Is early rhythm control really driving that difference?”

“What could have made the difference was the structured intense follow-up in the early rhythm-control arm [which was absent in the usual care group],” she raised. “Recently the role of such structured holistic management with structured follow-up has been confirmed in a randomized clinical trial showing … improved patient outcomes.”

Indeed, such structured holistic management approach, known as Atrial Fibrillation Better Care (ABC), is also recommended in the new ESC/EACTS^# guidelines released in conjunction with ESC 2020.

“Based on this, I would conclude that the EAST-AFNET 4 trial elegantly showed that an early intervention with structured follow-up significantly reduced CV AEs in patients with recently diagnosed AF,” said Potpara. 

Explaining how EAST-AFNET 4 is different from other trials, Kirchhof said the rhythm control strategy in the current trial included AF ablation, in contrast to previous studies which mainly involved only antiarrhythmic drugs. Also, rhythm control therapy was started early — soon after diagnosis of AF (median time from diagnosis, 36 days).