Atrial fibrillation is the most common arrhythmia worldwide, affecting millions of the general population. It is a leading cause of stroke and is associated with many other long-term adverse cardiovascular issues. Long-term management of atrial fibrillation can involve simply controlling the ventricular rate with AV nodal blocking agents (rate control strategy) versus restoring and maintaining sinus rhythm (rhythm control strategy). For many years, pharmacologic rate control or rhythm control were both considered acceptable first-line therapeutic strategies. More recently, however, catheter ablation has emerged as a viable and potentially more effective treatment option than drug therapy, especially in patients with heart failure. Given the increasing efficacy and safety of ablation, practice is evolving toward ablation being considered first-line therapy for more patients. Indeed, both the 2014 AHA/ACC/HRS guidelines and the 2020 ESC guidelines for management of atrial fibrillation state that ablation can be considered as a first-line approach in patients with either symptomatic paroxysmal or persistent atrial fibrillation [1, 2]. In this editorial, we will further discuss evidence supporting catheter ablation as first-line therapy for atrial fibrillation.
Strategies for atrial fibrillation management over the years have varied, with rate control becoming a widely accepted primary approach after the AFFIRM trial in 2002, which showed no mortality benefit with rhythm control compared to rate control [3]. However, most patients were older, and mean follow-up was only 3.5 years which may have been inadequate to compare mortality between the two groups. Additionally, a later analysis of the AFFIRM results led to a strong suspicion that antiarrhythmic drug toxicities counterbalanced any benefits of maintaining sinus rhythm [4]. Enrolled patients in the rhythm control arm were also required to fail two anti-arrhythmic agents prior to being considered for catheter ablation, which was still in its early iterations during that time period. Consequently, the vast majority of patients received only drug therapy for rhythm control; only 14/2033 patients (less than 1%) in the rhythm control arm underwent ablation.
Nonetheless, there are distinct advantages associated with a rhythm control strategy. Notably, patients frequently remain symptomatic from atrial fibrillation in spite of adequate rate control. Early rhythm control furthermore prevents progression of atrial remodeling and fibrosis, increasing the likelihood of maintaining sinus rhythm long term; this is particularly important in younger patients [5]. Additionally, many patients, in particular those with left ventricular systolic dysfunction, may be unable to tolerate the doses of rate slowing medications necessary to achieve adequate rate control.
In spite of the data from AFFIRM, more recent trials have shown there may actually be substantial benefit to a rhythm control approach. The EAST-AFNET 4 study enrolled patients with demographics similar to those studied in the AFFIRM trial, but all with a recent diagnosis of atrial fibrillation within the 12 months before enrollment. Patients were randomized to receive either rate control or early rhythm control (either anti-arrhythmic therapy or ablation). Results demonstrated that early rhythm control was associated with a significant reduction in the primary composite outcome of mortality, stroke, hospitalization for heart failure, or hospitalization for acute coronary syndrome. Additionally, reduced risk of stroke and cardiovascular mortality were also noted in the early rhythm control group [6].
With the potential advantages of early rhythm control more well-established, determining the optimal therapy for maintenance of sinus rhythm becomes more critical. The RAAFT-1 study published in 2005 was one of the earliest randomized studies to evaluate the efficacy of catheter ablation versus anti-arrhythmic therapy, showing significantly lower rates of atrial fibrillation recurrence and hospitalizations in those randomized to therapy with catheter ablation at 1-year follow-up [7]. Furthermore, the ablation arm demonstrated significant improvement in quality-of-life scores. MANTRA-PAF, published in 2012, randomized patients with paroxysmal atrial fibrillation to undergo radiofrequency catheter ablation or therapy with antiarrhythmics, and showed significantly lower arrhythmia burden in the group randomized to ablation at 24-month follow-up [8]. The subsequent RAAFT-2 trial again demonstrated lower rates of atrial arrhythmia recurrence in patients randomized to catheter ablation versus those randomized to therapy with anti-arrhythmic drugs [9].
Since publication of the RAAFT-2 study in 2014, evidence in support of catheter ablation as a more effective and potential first-line therapy for atrial fibrillation has continued to accumulate, especially for patients with atrial fibrillation and systolic heart failure. The AATAC trial published in 2016, enrolling patients with persistent atrial fibrillation and NYHA class II-III heart failure with reduced ejection fraction, evaluated the efficacy of rhythm control with amiodarone versus catheter ablation. Patients randomized to catheter ablation were noted to have lower rates of recurrent atrial fibrillation, fewer hospitalizations, and reduced mortality. In addition, patients undergoing ablation were noted to have more improvement in left ventricular ejection fraction compared to those who received therapy with amiodarone [10]. Published in 2018, CASTLE-AF demonstrated improved rates of the primary composite outcome of mortality and heart failure hospitalizations in patients with at least moderate left ventricular systolic dysfunction who were managed with catheter ablation compared to those managed with pharmacologic therapy for rate or rhythm control. Patients randomized to ablation were also noted to have lower rates of hospitalization, lower rates of death, and lower rates of death from a cardiovascular cause [11].
The large, randomized CABANA trial from 2019 evaluated the efficacy of catheter ablation compared to conventional medical therapy (rate or rhythm control) in patients with symptomatic atrial fibrillation, regardless of ejection fraction. While this study failed to show significant benefit in favor of ablation as it pertained to the primary composite outcome of death, stroke, bleeding, or cardiac arrest, catheter ablation was associated with reduced rates of all-cause mortality or cardiovascular hospitalizations, reduced rates of arrhythmia recurrence and lower arrhythmia burden, improved quality-of-life, as well as improved outcomes in heart failure patients in a post-hoc analysis [12, 13]. Despite the equivocal outcome in terms of the primary endpoint, this trial further supports ablation as an effective therapy for rhythm control in patients with symptomatic atrial fibrillation, and in patients with atrial fibrillation and heart failure. Regarding the primary endpoint, it should also be noted that the study population in CABANA differed from the study population of the aforementioned EAST-AFNET 4 trial in that the average time since onset of atrial fibrillation was >1 year and nearly half of the patients enrolled had persistent or long-standing persistent atrial fibrillation, and therefore these results should not interfere with the notion that early rhythm control may have a beneficial effect as it pertains to reduction of major adverse cardiac events.
A flurry of subsequent data from studies published in 2021 further established the efficacy of early ablation as first-line therapy in patients with symptomatic paroxysmal atrial fibrillation. The STOP AF First, EARLY-AF, and Cryo-FIRST studies were all randomized trials published in 2021 evaluating cryoablation as first-line therapy of symptomatic paroxysmal atrial fibrillation versus antiarrhythmic drug therapy. All three trials demonstrated superior outcomes (significantly lower rates of recurrence) in the cryoablation groups. Furthermore, all three studies showed no significant difference in the rates of adverse events between the two groups, highlighting the relative safety and low-risk nature of ablation [14–16].
The EARLY-AF trial was unique in that all patients enrolled underwent loop recorder implantation for rigorous rhythm monitoring after intervention. Recently 3-year follow-up data were published, again showing significantly lower rates of recurrent atrial tachyarrhythmias as well as improved quality-of-life scores in the ablation group at 3 years, reinforcing the notion that early ablation is superior first-line therapy for rhythm control. The authors further noted that rates of progression to persistent atrial fibrillation were significantly reduced in patients who underwent ablation, suggesting a disease-modifying effect. Perhaps just as striking, there was a significantly lower rate of hospitalizations in the ablation arm, as well as a lower overall incidence (although not statistically significant) of serious adverse events (10.1% in the antiarrhythmic drug group versus 4.5% in the ablation group), again highlighting the safety of an early ablation approach [17].
Overall, there seem to be clear benefits to an early rhythm control strategy, and accumulating evidence suggests that catheter ablation is not only the most effective rhythm control approach, but that it may be disease-modifying, and is at the very least as safe as anti-arrhythmic drugs. We have therefore reached a point where it not only seems reasonable, but potentially evolving toward standard-of-care, to consider and/or offer ablation as first-line therapy for appropriate patients with atrial fibrillation, especially in the subset of patients with heart failure with reduced ejection fraction. This may become even more apparent in the future as advances in catheter ablation continue to improve its efficacy and safety.