Persistent atrial fibrillation over 3 years is associated with higher recurrence after catheter ablation

Abstract Instruction Longer atrial fibrillation (AF) durations have higher recurrence rates after rhythm control. However, there is limited data on the effect of the AF duration on recurrence after atrial fibrillation catheter ablation (AFCA). In the present study, we investigated the rhythm outcome of AFCA according to the AF duration based on the first electrocardiogram (ECG) diagnosis. Methods and Results We included 1005 patients with AF (75% male, 59 ± 11 years old) who underwent AFCA and whose first ECG diagnosis time point was evident. The clinical characteristics and rhythm outcomes were compared based on the AF duration (≤3 years, n = 537; >3 years, n = 468) and AF burden (paroxysmal atrial fibrillation [PAF], n = 387; persistent atrial fibrillation [PeAF], n = 618). Longer AF durations were associated with older age (P = .020), larger left atrial size (P = .009) and a higher number of patients with hypertension (P < .001) or PeAF (P < .001). During 24 ± 22 months of follow‐up, the postablation clinical recurrence rate was higher in patients with a longer AF duration (logrank P = .002). The AF recurrence rate was significantly higher in PeAF patients with an AF duration >3 years (logrank P = 0.009), but not in subjects with PAF (logrank P = .939). In a multivariate Cox regression analysis, a longer AF duration was significantly associated with a higher clinical recurrence rate after AFCA in PeAF patients (adjusted hazard ratio, 1.06; range, 1.03‐0.10; P = 0.001), but not PAF. Conclusion Although longer AF duration was associated with higher clinical recurrence rates after AFCA, the rate was significant in patients with PeAF lasting >3 years, but not in PAF patients.

persistent forms in PeAF than in PAF patients, 5 and in patients with a higher number of cardiovascular risk factors. 6 The aggressive rhythm control slows the AF progression, and the AF progression rate is 3.3-fold lower in the rhythm-control group than the rate control group. 3,6 Catheter ablation of AF is an effective rhythm control strategy that reduces the AF burden, heart failure mortality, 7 risks of a stroke, 8 and risk of cognitive dysfunction. 9 The AF duration has been considered an important prognostic factor for the rhythm outcome after a maze procedure 10 or AF ablation. 11 However, AF is less consistent with symptoms and asymptomatic subclinical AF is common. Reportedly, over 40% of patients did not complain of any significant symptoms under an appropriate rate control. 12 Therefore, determining the exact AF duration based on the symptoms is difficult. However, we measured the time period from the first electrocardiogram (ECG) diagnosis of AF to the de novo atrial fibrillation catheter ablation (AFCA) in our AF ablation study population. In addition, we monitored the postablation AF recurrence by a consistent long-term rhythm monitoring protocol according to the 2012 HRS/EHRA/ECAS Expert consensus statement guidelines. 13,14 In the present study, we tested the hypothesis whether the documented ECG-based AF duration was closely associated with a high recurrence rate after radiofrequency AFCA.

| Study population
The study protocol adhered to the Declaration of Helsinki and was approved by the Institutional Review Board of the Yonsei University Health System. All patients provided written informed consent for inclusion in the Yonsei AF Ablation Registry Database (registered at clinicaltrials.gov as NCT02138695). From March 2009 to September 2017, 1005 patients who underwent AFCA for AF and whose first ECG diagnosis time point was evident were analyzed (75% male, 59 ± 11 years of age, 39% PAF). AF onset was defined as the index ECG showing AF. AF that terminates spontaneously or with intervention within 7 days of onset was classified as PAF. 15 We analyzed the sensitivity and specificity for predicting clinical recurrences of AF after AFCA on the basis of the different cut-off ranges of the AF duration ( Figure 1 and Table S1). As a result of the analysis, the 3-year cut-off value represented the best dichotomy among a number of tested cut-off values. Therefore, we compared the patients with an AF duration of less than 3 years and those with that longer than 3 years based on a preliminary adjusted hazard ratio (HR) analysis. The clinical characteristics and rhythm outcomes were compared based on the AF duration (≤3 years, n = 537; >3 years, n = 468) and AF burden (PAF, n = 387; PeAF, n = 618). Exclusion criteria were as follows: (a) valvular AF, (b) structural heart disease other than left ventricular hypertrophy, (c) left atrial (LA) diameter ≥60 mm, and (d) a history of a previous AF ablation or cardiac surgery. All antiarrhythmic drugs (AADs) were discontinued for a minimum period of five half-lives before the procedure. Anticoagulation therapy was maintained before the catheter ablation. The anatomy of the LA and the pulmonary veins (PVs) in all patients was imaged using three-dimensional (3D) spiral computed tomography (CT) scans (64 Channel, LightSpeed Volume CT, Philips, Brilliance 63, Amsterdam, Netherlands).

| Atrial fibrillation catheter ablation
The details of the AFCA technique and strategy were described in our previous study. 16  The procedure ended when no immediate recurrence of AF was observed within 10 minutes after cardioversion with an isoproterenol infusion (5-10 μg/min). Non-PV foci under an isoproterenol infusion were also ablated.

| Postablation follow-up
The patients without antiarrhythmic medications were discharged after the procedure unless early recurrence of AF/AT or symptomatic frequent atrial premature beats were evident. Patients visited the outpatient clinic regularly at 1, 3, 6, and 12 months and then every 6 months or whenever symptoms occurred after the AFCA. All patients underwent ECG at each visit and 24-hour Holter recordings at 3 and 6 months and every 6 months thereafter following the 2012 HRS/EHRA/ECAS Expert Consensus Statement guidelines. 13 Holter monitoring or event monitor recordings were obtained when patients reported symptoms of palpitation suggestive of arrhythmia recurrence. AF recurrence was defined as any episode of AF or AT of at least 30 seconds in duration. Any ECG documentation of an AF recurrence within a 3-month blanking period was diagnosed as an early recurrence and an AF recurrence more than 3 months after the procedure was diagnosed as a clinical recurrence.

| Statistical analyses
Continuous variables were summarized as the mean ± standard deviation and compared using a Student t test and analysis of

| Baseline characteristics
The baseline clinical characteristics of the study population are shown in Table 1. We compared the patient with AF duration less than 3 years and those with longer than 3 years based on preliminary adjusted HR analysis ( Figure 1). The sex distribution did not statistically significantly differ between the two groups. A longer AF duration was associated with older age (P = .020), a higher number of patients with hypertension (P < .001) and PeAF (P < .001).
The LA diameter on echocardiography also increased as the AF duration increased (P = .009), while the endocardial voltage of the LA decreased as the AF duration increased (P < .001). Other comorbidities including the CHA 2 DS 2 -VASc score and baseline echocardiographic and CT parameters did not significantly differ between the groups.

| Procedural results and clinical outcome after catheter ablation of AF
The procedural results and clinical outcomes are summarized in  Table 2). The Kaplan-Meier analysis also showed a significantly higher clinical recurrence of AF in patients with a longer preprocedural AF duration ( Figure 2, logrank P = .002).
In the subgroup analysis based on the AF type, the clinical recurrence YU ET AL.

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rate did not significantly differ among the patients with PAF ( Figure 3A, logrank P = .939). However, in the PeAF group, the clinical recurrence rate was significantly higher in patients with a longer AF duration ( Figure 3B, logrank P = .009).

| AF duration as a predictor of a clinical recurrence of AF after catheter ablation
Univariate and multivariate Cox regression analyses were performed to identify the predictors of a clinical recurrence of AF after catheter ablation (

| Main findings
In the present study, the time period from the first ECG diagnosis of AF to the AFCA and clinical recurrence was measured using guideline-based rhythm monitoring. The longer duration of AF was associated with a higher clinical recurrence rate after catheter ablation but was only significant in the patients with PeAF lasting more than 3 years. An AF duration-dependent difference in the clinical recurrence rate was not observed in the patients with PAF.

| AF progression and catheter ablation
AF is a chronic degenerative rhythm disorder with continuous progression associated with aging, LA enlargement, and heart failure. 17 AF progression is more significant and accelerated in patients with associated hypertension, valvular disease, chronic lung disease, and a previous ischemic stroke. 18,19 AFCA is an effective rhythm control strategy to reduce the AF burden, however, the evolution of the abnormal atrial substrate progresses despite a successful ablation procedure and likewise the aging process. 20 Furthermore, the development and advances in the catheter ablation technology, as well as the accumulated experience, have not been translated into a significant procedural success. 21 Park et al 14 found that extra-PV ablation and 1-year recurrence rates in the AF ablation study cohort have been decreasing in part due to the improved catheter technology in the past 9 years. However, patients with a first recurrence continue to appear consistently even after 5 years from successful catheter ablation. Obesity, 22 metabolic syndromes, 23 and obstructive sleep apnea 24 are associated with a high probability of an AF recurrence after catheter ablation. Therefore, strategies aiming at a reduction in AF development or progression, such as lifestyle and risk factor management, are necessary to improve the therapeutic outcome of AFCA. [25][26][27][28] 4.3 | Why persistent AF ablation is more likely affected by the AF duration?
In the present study, a longer AF duration, especially longer than 3 years, was associated with a higher clinical recurrence of atrial arrhythmias after catheter ablation in patients with PeAF, but not in

| Clinical implications
The recommended AF rhythm control in the current guidelines is intended for patients with symptomatic AF rather than ECG-based AF. 30,31 However, AF progression to PeAF or permanent AF is accompanied by high cardiovascular risk and long-term mortality. 32,33 In addition, metabolic syndrome, which is associated with AF progression, increases the nonthromboembolic adverse cardiac outcomes in patients with AF. 34

| Limitations
The present study had several limitations. First, although we attempted to define the duration of AF in patients with a clear time point for the first ECG diagnosis, the possibility of a discrepancy between the ECG-based AF duration and actual AF duration remains. Especially in patients with PAF, the duration of AF was more difficult to determine and thus the relationship between an AF recurrence and the AF duration in those patients was less clear. Second, contrary to the continuous rhythm monitoring using an implantable loop recorder, the current guideline-based consistent rhythm monitoring schedule could not detect all the subclinical AF episodes. Third, this was an observational study from a single-center cohort that included a highly selected group of patients referred for AFCA. Despite this limitation, a realistic and consistent rhythm monitoring method was applied for all patients included in the AF ablation study cohort based on real-world practice.

| CONCLUSION
A longer duration of AF was associated with a higher clinical recurrence rate after catheter ablation; however, a significance was only observed in patients with PeAF of more than 3 years. An AF duration-dependent difference in the clinical recurrence rate was not observed in patients with PAF. F I G U R E 4 Kaplan-Meier analysis of the AF recurrence-free survival after catheter ablation in patients with persistent AF after a propensity score-matching between patients with persistent and paroxysmal AF. AF, atrial fibrillation