Catheter ablation as first-line in atrial fibrillation: is rhythm control finally better than rate control?

KEYWORDS:

• Atrial fibrillation
• catheter ablation
• rhythm control
• anti-arrhythmic drugs
• rate control

1. Introduction

Atrial fibrillation (AF) is estimated to affect 3 million Americans and over 33 million individuals globally [1]. The individual and societal consequences of AF are severalfold, and include a higher risk of stroke, heart failure, dementia, hospitalizations, mortality, and impaired quality of life. The management of AF seeks to prevent thromboembolic events, improve survival, and minimize symptomatic burden through ventricular rate control or maintenance of sinus rhythm.

2. Rate versus rhythm control

In 2002, the landmark AFFIRM and RACE studies showed no difference in overall survival between rate control and an anti-arrhythmic drug (AAD) rhythm control strategy in patients with paroxysmal or persistent AF [2,3]. Notwithstanding the lack of evidence-based survival benefit, a subset of AF patients undoubtedly benefits from efforts to maintain sinus rhythm. This is particularly the case for patients who remain highly symptomatic despite adequate rate control or because of failure to achieve control of the ventricular rate. Patient preference and certain comorbidities, such as tachycardia-induced cardiomyopathy, may also lead to a shared decision to proceed with rhythm control. Further, it is important to note that AFFIRM and RACE enrolled patients with an age average of 69 and 68 years, respectively [2,3]. Whether younger, healthier patients with frequent, symptomatic paroxysmal AF would systematically benefit from rhythm control still remains unknown.

3. Lifestyle modifications

Unlike AAD therapy or catheter ablation, interventions focused on risk factor modifications for patients with AF have the unique potential to target the underlying processes that cause atrial fibrosis and adverse remodeling. Adequate treatment of hypertension, diabetes, obstructive sleep apnea, and obesity are critical for sustaining a rhythm control strategy. Recently, the LEGACY study showed that a ≥ 10% weight loss is associated with a sixfold increase in the probability of AF-free survival in obese patients with AF [4].

4. Anti-arrhythmic drugs

AADs have traditionally been used as first-line therapy to maintain sinus rhythm in patients with AF. However, AADs have important safety limitations. The risk of QT prolongation and torsades de pointes is of particular concern with drugs that prolong repolarization, such as sotalol and dofetilide. Initiation of these agents requires hospitalization for acute monitoring of QT prolongation. Flecainide and propafenone are contraindicated in patients with known coronary artery disease due to increased mortality. Amiodarone is typically used only as second-line agent because of significant systemic toxicities. Dronedarone is associated with less toxicity than amiodarone, albeit at the cost of a reduction in efficacy. Dronedarone increases major adverse cardiovascular events in patients with a history of decompensated heart failure and in those with permanent AF. Thus, it should be discontinued when sinus rhythm is not achieved [1].

The efficacy of AAD is also limited. In AFFIRM, only 62.6% of patients in the rhythm control arm were in sinus rhythm at 5 years, as compared to 34.6% of those randomized to rate control [3]. Interestingly, after multivariate analysis, the use of AADs was associated with an increased hazards ratio (HR) for mortality (HR = 1.49), whereas maintenance of sinus rhythm, regardless of treatment allocation, was associated with a significant reduction in mortality (HR = 0.53) [5]. Altogether, this data indicate that maintenance of sinus rhythm may improve outcomes in AF should there be a more effective and safer therapy than AAD to control the rhythm.

5. Catheter ablation

Catheter ablation with electrical pulmonary vein isolation (PVI) has been established as an effective alternative for rhythm control in patients who previously failed AAD therapy [1,6]. As compared to AAD therapy escalation, catheter ablation can reduce the absolute risk of recurrent symptomatic AF at 1 year by as much as 50% and 26% in patients with paroxysmal and persistent medically refractory AF, respectively [7]. In a recent meta-analysis including over 8000 patients with both paroxysmal and persistent AF, the overall freedom from atrial tachyarrhythmias at ≥12 months after radio-frequency ablation was 63%. This rate was not significantly different when compared to cryoballoon energy source (69.1%) [8]. In studies with long-term follow-up, AF recurrences have been reported in 50–70% of patients after a single ablation of paroxysmal and persistent AF, respectively [9,10]. However, long-term arrhythmia-free survival can be significantly improved with repeat interventions, and may reach nearly two-thirds of patients in 5-year follow-up of redo ablations [10,11].

Operator experience and the use of second-generation technology are important determinants of a higher ablation success rate. Freedom from recurrent AF in follow-up greater than 1 year has been reported at 78% from pooled studies utilizing second-generation cryoballoon and contact-force sensing radio-frequency catheters [8]. On the other hand, targeting non-pulmonary vein triggers or substrate modification, including complex fractionated atrial electrograms and AF-sustaining rotors, have not consistently shown better outcomes as compared to PVI-alone, and thus are not recommended as routine AF ablation strategies.

5.1. Catheter ablation as first-line treatment

Several arguments favor the use of catheter ablation as first-line treatment when rhythm control is warranted. First, secondary analyses from AFFIRM indicate that maintenance of sinus rhythm is associated with improved outcomes in patients with AF [5]. Second, catheter ablation has superior efficacy to AAD and avoids the systemic toxicities and pro-arrhythmia of AAD. Third, propensity-matched observational studies have reported a significant reduction in major cardiovascular events in patients who undergo ablation as compared to medically treated patients. In fact, some data indicate that the rates of stroke and death after AF catheter ablation are similar to those of patients without AF [12,13]. Finally, cumulative evidence has shown that a prolonged AF burden leads to structural and electrical atrial adverse remodeling (i.e. ‘AF begets AF’). These changes further increase the burden of AF and hinder AF therapies, including catheter ablation. In contrast, ablation is associated with reverse remodeling and improved outcomes when performed in younger patients with minimal structural heart disease [14].

The RAAFT, MANTRA-PAF, and RAAFT-2 trials were multicenter, randomized studies which directly compared catheter ablation to AAD as first-line rhythm control strategies for patients with mostly paroxysmal AF. Table 1 summarizes the findings of those studies. The three trials consistently showed a higher freedom from any AF and symptomatic AF with catheter ablation as compared to drug-therapy. The 5-year follow-up of MANTRA-PAF showed persistent higher freedom from any AF (86% vs. 71%) and symptomatic AF (94% vs. 85%) in the ablation group [15–17].

Table 1. Randomized controlled trials comparing catheter ablation to anti-arrhythmic drug therapy as first-line rhythm control strategies for AF.

	RAAFT 2005 [17]	MANTRA-PAF 2012 [15]	RAAFT-2 2014 [16]
Year	2002	2005–2009	2006–2010
Centers	Multicenter; Italy and Germany	Multicenter; Europe	Multicenter; Europe and North America
Number of patients, CA/AAD	33/37	146/148	66/61
Paroxysmal AF (%), CA/AAD	97/95	100	100
Age, mean (years), CA/AAD	53/54	56/54	56/54
Men (%), CA/AAD	NA	68/72	77/74
Mean EF (%), CA/AAD	53/54	NA	61/61
Hypertension (%), CA/AAD	25/28	29/36	42/41
Follow-up	1 year	2 years	2 years
Blanking period	NA	3 months	3 months
Enrollment criteria	Monthly symptomatic episodes, ≥3months	Symptomatic, ≥2 episodes in prior 6 months	Symptomatic, ≤4 episodes in prior 6 months
Freedom from symptomatic AF during follow-up, CA/AAD	87% vs. 37%	93% vs. 84%	59% vs. 43%
Any AF recurrence, CA/AAD	85% vs. 21%	85% vs. 71%	47% vs. 30%

AAD: anti-arrhythmic drug; AF: atrial fibrillation; CA: catheter ablation; EF: ejection fraction; NA: not available.

5.2. Complications and follow-up

The risk of major complications with AF catheter ablation is approximately 5% [6]. Important determinants of the complication rates include operator/center experience, energy source, older age, female gender, and a higher CHADS₂ score. A recent meta-analysis showed that pericardial effusions (2.1% vs. 0.8%) and cardiac tamponade (1.4% vs. 0.3%) were significantly more common with radiofrequency as compared to cryoballoon ablations. In contrast, phrenic nerve palsy is primarily observed with cryoballoon technology, with a pooled incidence of 1.7% at discharge, but only 0.2% in ≥12-month follow-up. Procedural mortality, atrial-esophageal fistula, and symptomatic pulmonary vein stenosis are exceedingly rare, well below 0.5%. Stroke or transient ischaemic attack can occur in up to 1% of patients [8].

Importantly, recurrences of AF after catheter ablation typically are shorter in duration and less symptomatic than pre-ablation arrhythmias. In fact, approximately one in eight AF patients has completely asymptomatic recurrences [18]. Therefore, anticoagulation management post-ablation should follow standard risk stratification recommendations (e.g. CHADS2VASc score), regardless of the rhythm outcome. For that reason, catheter ablation should not be pursued with the purpose of eliminating oral anticoagulation [1,6].

6. Guidelines and future directions

Both the 2014 ACC/AHA/HRS and the 2016 ESC Guidelines for the Management of Patients with Atrial Fibrillation assign a class IIa recommendation to catheter ablation for an initial rhythm control strategy in patients with recurrent symptomatic paroxysmal AF who are naïve to AAD, considering the benefits, risks, and patient preferences.

It remains to be determined in a large, definitive randomized study whether an initial rhythm control strategy with catheter ablation leads to improved mortality and cerebrovascular outcomes as compared to rate control alone. As reported, the better outcomes of AF patients who remain in sinus rhythm, the unfavorable safety profile and limited efficacy of AAD, and the improved outcomes of ablation as compared to AAD are encouraging. The ongoing Catheter Ablation vs. Anti-Arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial will address this question. This study randomized 2204 patients with paroxysmal or persistent AF to catheter ablation or drug therapy (rate or rhythm control). The Early Treatment of Atrial Fibrillation for Stroke Prevention (EAST) trial is another ongoing study to compare a strategy of early standardized rhythm control including catheter ablation to current guideline-directed management of AF. The highly anticipated results of these studies may definitively answer whether early ablation can systematically decrease mortality and stroke in the AF population.

7. Conclusions

In summary, due to the emergence of catheter ablation as a safer and more effective alternative to AAD therapy, there is now continued debate on whether a routine, early catheter ablation rhythm control strategy would prove superior to current standard of care. Although indirect evidence from previous trials suggests this will be the case, we must wait for the results of randomized studies evaluating important clinical outcomes, such as mortality and strokes. In the meantime, it seems appropriate to offer early catheter ablation to patients with recurrent, symptomatic, paroxysmal AF. The ideal strategy for each individual should be chosen through shared decision-making with an informed discussion of the risks, benefits, and uncertainties of each approach.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.