First-line Ablation Bests Drugs for AFib in
Two RCTs

Patrice Wendling

November 17, 2020

Two provocative new studies suggest first-line treatment of paroxysmal atrial fibrillation (AF) with invasive catheter ablation is more effective than standard guideline-recommended antiarrhythmic medications.

Results published in the New England Journal of Medicine from the EARLY-AF and STOP-AF First trials show fewer AF recurrences one year after pulmonary vein isolation with a cryoballoon system (Medtronic).

"First-line ablation was also associated with meaningful improvements in quality of life and symptom status and did not seem to be associated with a significant increase in adverse events relative to antiarrhythmic drug therapy," Jason Andrade, MD, University of British Columbia, Vancouver, Canada, said when presenting the EARLY-AF results during the American Heart Association (AHA) virtual Scientific Sessions.

Three previous trials using point-to-point radiofrequency ablation also reported a benefit on AF recurrence but EARLY-AF "adds in big ways," said Christine M. Albert, MD, MPH, who was the study's invited discussant and is professor and chair of cardiology at Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, California.

It is the largest trial to date, enrolling 303 patients, and, very importantly, used implantable loop recorders to determine AF events, adjudicated by a blinded endpoint committee, she said. "So they equally applied the most sensitive assessment of AF to both treatment groups and they still found a 50% reduction in AF recurrence with ablation."

At 1 year, 42.9% of the ablation group and 67.8% of the antiarrhythmic group had a recurrence of any atrial tachyarrhythmia lasting at least 30 seconds (hazard ratio [HR], 0.48; 95% CI, 0.35 - 0.66); an absolute reduction of 24.9% or a number needed to treat of 4.

Continuous monitoring also allowed assessment of AF burden, which declined in both groups but averaged 3.3% lower with ablation (P = .002), Albert noted.

Other distinguishing features of EARLY-AF are that patients in the antiarrhythmic drug group had their medications adjusted according to a standardized protocol to maximize efficacy, and the trial specifically looked at symptomatic arrhythmia recurrence as a secondary endpoint, which offers some insight into the prevalence of asymptomatic arrhythmias with both treatment options, said Jim W. Cheung, MD, professor of medicine and director of clinical electrophysiology research at Weill Cornell Medicine in New York City. Cheung was not involved with either trial.

The differences in this secondary outcome were more modest, with 11% of the ablation group and 26.2% of the antiarrhythmic group having recurrence of symptomatic episodes of arrhythmia at 1 year (HR, 0.39; 95% CI, 0.22 - 0.68). The absolute reduction was 15.2% and number need to treat 6.5.

"This study will add to some of the debate over the clinical relevance of the conventional definition of atrial arrhythmia recurrence as any episodes lasting over 30 seconds," Cheung told theheart.org | Medscape Cardiology.

Ablation therapy was also associated with marked improvements in quality of life and serious adverse events were comparable with ablation and antiarrhythmics (5 events vs 6 events), he noted.

"Overall, this is a well-designed study, which adds to the broad base of evidence supporting the use of catheter ablation as a first-line treatment approach in patients with symptomatic paroxysmal AF," said Cheung, a member of the American College of Cardiology's Electrophysiology Section and Leadership Council. "The evolution in AF treatment guidelines by the ACC and ESC [European Society of Cardiology] has reflected this."

Catheter ablation first appeared in guidelines more than a decade ago and is recommended in the 2017 ACC AF ablation consensus statement for patients with symptomatic paroxysmal AF if they have not had an acceptable response to at least one rhythm-control drug.

Both Cheung and Albert pointed out that EARLY-AF had several limitations, including a relatively young, healthy cohort of patients (mean age, 58 years) with a low burden of comorbidities, a relatively short duration of follow-up, and a lack of power to detect hard clinical outcomes.

It's unknown whether the results are generalizable to older adults and/or those with persistent AF, to lower volume centers, and to other ablation technologies.

And, "we do not know the time frame during which antiarrhythmic drugs were up-titrated in this study. Therefore, it is unclear if patients were at the maximum dose of tolerated drug before or after the end of the 90-day blanking period," Cheung said.

Crossovers, which have plagued previous AF ablation trials, however, were nonexistent in EARLY-AF, whereas 15 of the 99 patients assigned to antiarrhythmic drug therapy in STOP-AF First crossed over to cryoballoon ablation.

That trial included 203 adults from 24 US sites who had treatment-naive symptomatic, paroxysmal AF for a mean of 1.3 years before enrollment. Arrhythmias were assessed with 12-lead electrocardiography at baseline and at 1, 3, 6, and 12 months; weekly telephone monitoring and when symptoms were present during months 3 through 12; and 24-hour ambulatory monitoring at 6 and 12 months.

The primary efficacy endpoint was treatment success, defined as:

  • Freedom from initial failure of the procedure;

  • Any subsequent AF surgery or ablation in the left atrium including those performed during the 90-day blanking period; or

  • Atrial arrhythmia recurrence (for at least 30 seconds during ambulatory monitoring or at least 10 seconds on 12-lead ECG), cardioversion, or use of class I or III antiarrhythmic drugs in the ablation group outside the blanking period.

At 12 months, treatment success was 74.6% (95% CI, 65.0 - 82.0) in the ablation group and 45% (95% CI, 34.6 - 54.7) with drug-therapy (log-rank P < .001).

There were 22 serious adverse events in 15 patients treated with ablation and 16 serious events in 14 patients treated with drug therapy, according to the investigators, led by Oussama Wazni, MD, section head of electrophysiology and pacing at the Cleveland Clinic, Cleveland, Ohio.

Compared to the previous trials using the more technical demanding point-by-point radiofrequency ablation, cryoballoon ablation is less operator dependent and associated with a benign safety profile, Stefano Bordignon, MD, Cardioangiologisches Centrum Bethanien, Frankfurt, Germany, told theheart.org | Medscape Cardiology via email.

"This is the key for a high and reproducible procedural success with an acceptable safety for an invasive preventive strategy," said Bordignon, who was not associated with either trial but has conducted research on cryoballoon ablation. "So it is not about 'first-line ablation' but about 'first-line cryoballoon ablation.'"

Bordignon noted that more than half of the recurrences on drug therapy in EARLY-AF were asymptomatic, suggesting that antiarrhythmic drugs seem to still work for symptom control, but for rhythm control a first-line cryoballoon ablation performs better. Despite that, the AF burden after the intervention was relatively low in both groups.

"How much AF can be tolerated to obtain the benefit highlighted by the recent published EAST-AFNET 4 trial is still unknown," he said. "A trial like the STOP-AF First and EARLY-AF with hard endpoints would be necessary, but probably not feasible." 

Finally, neither trial mentioned the treatment of comorbidities and lifestyle modification, Bordignon noted. "A comprehensive early rhythm control strategy should also include these interventions. I imagine that in the near future the treatment of AF will focus first on these noninvasive measures during a defined (limited) observation period: in case of failure, an early (cryo)ablation treatment should be proposed to the patients without the need of a failed treatment with AAD."

EARLY-AF was funded by a grant from the Cardiac Arrhythmia Network of Canada and by unrestricted grants from Medtronic and Baylis Medical. STOP-AF First was supported by Medtronic, which was responsible for the development of the final protocol and statistical analysis plan and reviewed the manuscript prior to publication. Statistical analyses were conducted by an author who was a Medtronic employee and independently validated by one of the academic authors.

Albert reported grant support from the National Heart, Lung, and Blood Institute; St. Jude Medical/Abbott; and Roche Diagnostics. Cheung has disclosed no relevant financial relationships.

N Engl J Med. Published online November 16, 2020. EARLY-AF, STOP-AF First

American Heart Association (AHA) Scientific Sessions 2020: Presented November 16, 2020.

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