Rhythm Control Cuts First CV Events in Early Atrial Fibrillation: EAST-AFNET 4

(UPDATED) Swift initiation of rhythm-control therapy in patients with recently diagnosed atrial fibrillation in the setting of other cardiovascular conditions reduced the risk of CV events as compared with usual care—typically rate control—in the EAST-AFNET 4 trial, presented today. A co-primary endpoint of annual nights spent in the hospital, however, did not differ between groups.

“I think that these results will inform the future use of rhythm-control therapy in patients with AF,” Paulus Kirchhof, MD (University Heart and Vascular Center, Hamburg, Germany and the University of Birmingham, England), told journalists during an online press conference ahead of the virtual European Society of Cardiology Congress 2020. “They suggest that early rhythm-control therapy should be offered to all patients with early AF at risk of cardiovascular complications.”

Past trials, most notably the 2002 AFFIRM trial, failed to establish a role for rhythm control—used to maintain sinus rhythm—against the gold-standard rate control, which slows the ventricular rate, at least in the prevention of hard events. Subsequent meta-analyses have backed up those initial results. But the last two decades have seen the emergency of new antiarrhythmic drugs, like dronedarone (Multaq; Sanofi-Aventis), as well as results from the CABANA trial, showing that ablation cuts the risk of recurrent A-fib over the longer term. It was unknown whether intervening earlier in recently diagnosed A-fib, using drugs and ablation as needed, would lend support to rhythm control.

EAST-AFNET 4 was one of three Hot Line sessions presented on the opening day of the meeting and was published simultaneously in the New England Journal of Medicine.

Getting Into Rhythm

EAST-AFNET 4 randomized 2,789 patients from 135 centers in 11 European countries to either early rhythm control (using an antiarrhythmic drug or ablation) or to usual care (typically rate-control therapy). In the rhythm-control group, the most commonly used drug was flecainide, followed by amiodarone and dronedarone; ablation was used initially in 8% of patients—a rate that rose to 19.4% by 2 years. In the usual-care group, 7% of patients had undergone A-fib ablation by the 2-year mark.

The trial was stopped at a median of 5.1 years of follow-up per patient after a third interim analysis pointed to efficacy. At the cutoff, a first primary endpoint event—CV death, stroke, or hospitalization for either heart failure or ACS—had occurred at a rate of 3.9 per 100 person-years in the rhythm control group and in 5 per 100 person-years in the usual care group (HR 0.79; 95% CI: 0.66-0.94). Of note, Kirchhof stressed to the media, all components of the primary endpoint also numerically favored rhythm control.

For the trial’s other primary endpoint, mean number of nights in hospital—which Kirchhof explained was intended as “rough estimate” of the therapy’s costs—was no different between the rhythm and usual-care groups at 5.8 and 5.1 days per year. In terms of safety, rates of the primary safety outcome (death, stroke, or serious adverse events related to rhythm-control therapy) did not differ between treatment groups, although serious adverse events occurred more commonly in the early rhythm-control group: 4.9% versus 1.4%. These, however, were rare, Kirchhof noted.

Data to Show It

During the online press conference, Kirchhof stressed that the question of whether rhythm control could be effective in the care of A-fib patients at risk of stroke has been dogging the field for decades. “Most people like me always believed that maintaining sinus rhythm would be helpful, but we didn't have the data to show it,” he commented.

Ten years spent on this trial have taught participating investigators a number of things. “First of all we learned how to use antiarrhythmic drugs,” giving these according to a detailed protocol allowing physicians to tailor the therapy to the patient, he said. “Secondly, we started early, and I think that is a key difference of EAST-AFNET 4 as compared to other studies.”

Third, he continued, the decision to use “clusters of sites” allowed investigators to make sure that no matter where patients were enrolled, they would have access to ablation if that was deemed necessary. “This network structure helped us to deliver rhythm-control therapy safely to our patients,” said Kirchhof.

To TCTMD, Kirchhof emphasized that the rationale for intervening early in atrial fibrillation is now well-established. “There are good epidemiological data to show that complications are more common in the first year of the diagnosis of AF, so there is a window of opportunity to prevent complications,” he said. “Secondly—probably more important for our thinking—once you are in AF for a few months the atria suffer severe damage, some of it irreversible, so that it becomes more difficult to restore and maintain sinus rhythm when you wait longer.”

Praise and Caveats

Discussing the findings following Kirchhof’s Hot Line presentation, Tatjana Potpara, MD, PhD (University of Belgrade, Serbia), noted that event rates including stroke and cardiovascular death were markedly lower in EAST-AFNET 4 than those seen in other A-fib trials and registries. “Is early rhythm control really driving that difference?” she asked, noting that the rate of guideline-directed anticoagulation therapy was “almost ideal” in the rhythm-control group, as was risk factor management. “What could have made the difference was the structured intense follow-up in the early rhythm-control arm,” she speculated, particularly since patients in this group were requested to report for twice-weekly ECG monitoring, with the option of extra visits as needed, “and that was not available for the usual-care arm.”

Given the high adherence to the ECG monitoring, it may be that patients in this study group were also more adherent to other beneficial therapies, she said.

In a recent, post-hoc analysis of AFFIRM, she continued, structured holistic management of patients with A-fib “was the strategy that really made a difference,” for hard outcomes. In fact, this approach to management, dubbed the Atrial Fibrillation Better Care (ABC) approach, is also advocated in new joint ESC/European Association of Cardio-Thoracic Surgery guidelines released today. “Recently the role of such structured holistic management with structured follow-up has been confirmed in a randomized clinical trial showing that such ABC-adherent care improves patient outcomes,” Potpara said. “Based on this, I would conclude that the EAST trial elegantly showed that an early intervention with structured follow-up significantly reduced cardiovascular adverse events in patients with recently diagnosed AF. However, the role of early rhythm control itself in the observed difference in event rates is unclear.”

Commenting on the study, Jason Andrade, MD (Vancouver General Hospital, Canada), pointed out that in the 18 years since AFFIRM was published, physicians “have largely considered rate and rhythm control to be largely comparable from the perspective of hard cardiovascular outcomes.” Recent observational data, however, including a population-wide analysis from the province of Quebec, Canada, “suggested that a primary strategy of rhythm control may be associated with reduced mortality, and with lower rates of stroke. The landmark study presented by Kirchof et al provides confirmation of these findings in a large, robust, randomized trial.”

In an editorial accompanying the study, T. Jared Bunch, MD, and Benjamin A. Steinberg, MD (both University of Utah, Salt Lake City), point to a number of trial limitations, including the study’s low event rates and the proportion of patients who either withdrew from the trial or were lost to follow-up (9% and 6.6% of follow-up years in the rate-control and usual-care groups, respectively). Atrial fibrillation burden also was not reported, they note, so “its role as a contributor to outcomes remains unknown.” Moreover, the true rate of patients maintaining sinus rhythm can’t be known for sure, since investigators used electrocardiography during follow-up appointments rather than continuous monitoring. 

All the same, they write, “the results of this trial support the use of rhythm control to reduce atrial fibrillation-relate adverse clinical outcomes when applied early. . . . 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.”

Andrade, too, offered a number of caveats. “The authors postulate that the difference from previous studies may be related to the early use of catheter ablation,” he told TCTMD in an email. “While previous pharmacologic rate versus rhythm control trials have been relatively neutral, I’m not sure we can attribute the mortality advantage entirely to the inclusion of ablation in the current study. Firstly, 53% of patients in CABANA were antiarrhythmic-naïve. Given CABANA’s relatively neutral result it suggests that first-line ablation may not be the entire answer.” 

Moreover, the proportion of patients who received ablation in both trial arms was relatively low. “As such, we will likely need to see the results of first-line ablation studies for newly diagnosed AF, such as EARLY-AF [for which Andrade is the principal investigator] or STOP-AF FIRST, which is also being presented at ESC, before we can draw conclusions regarding the role of ablation.”

More likely, Andrade concluded, the explanation for rhythm control’s success in EAST-AFNET 4 as compared with earlier analyses lies in differences in patient selection and follow-up duration.