Catheter ablation of atrial fibrillation in Korea: results from the Korean Heart Rhythm Society Ablation Registry for Atrial Fibrillation (KARA)

This study aims to investigate the current status of AF (atrial fibrillation) catheter ablation in Korea. The patients who underwent AF catheter ablation from September 2017 to December 2019 were prospectively enrolled from 37 arrhythmia centers. Demographic data, procedural characteristics, the extent of catheter ablation, acute success of the ablation lesion set, rate and independent risk factor for recurrence of AF were analyzed. A total of 2402 AF patients [paroxysmal AF (PAF) 45.7%, persistent AF (PeAF) 43.1% and redo AF 11.2%] were included. Pulmonary vein isolation (PVI) was performed in 2378 patients (99%) and acute success rate was 97.9%. Additional non-PV ablation (NPVA) were performed in 1648 patients (68.6%). Post-procedural complication rate was 2.2%. One-year AF-free survival rate was 78.6% and the PeAF patients showed poorer survival rate than the ones with other types (PeAF 72.4%, PAF 84.2%, redo AF 80.0%). Additional NPVA did not influence the recurrence of AF in the PAF patients (PVI 17.0% vs. NPVA 14.6%, P value 0.302). However, it showed lower AF recurrence rate in the PeAF patients (PVI 34.9% vs. NPVA 24.4%, P value 0.001). Valvular heart disease, left atrial diameter, PeAF, PVI alone, need of NPVA for terminating AF, and failed ablation were independent predictors of AF recurrence. Additional NPVA was associated better rhythm outcome in the patients with PeAF, not in the ones with PAF. The independent risk factors for AF recurrence in Korean population were similar to previous studies. Further research is needed to discover optimal AF ablation strategy.

healthcare expenditure also continuously increased [2]. The main stems of AF treatment involve avoiding stroke, improving AF-related symptoms, controlling the heart rate or rhythm, and managing cardiovascular risk factors and concomitant diseases [3]. Catheter ablation of AF was effective in suppressing AF symptoms refractory to antiarrhythmic drug treatment, and recurrence of AF was smaller than medical therapy [4]. It has also been shown to improve quality of life and mortality and cardiovascular outcomes such as stroke, bleeding, and heart failure [5][6][7]. In Korea, AF catheter ablation has increased gradually and safely performed [8,9]. However, there are little data on the current status of AF ablation in Korea. This study aims to establish a prospective AF ablation registry to investigate the current status of AF catheter ablation in Korea.

Study population
The Korean Heart Rhythm Society Ablation Registry for AF (KARA) is an investigator-initiated, multicenter, prospective registry of catheter ablation for AF. This study was approved by the Institutional Review Board of Seoul National University Hospital and each participating arrhythmia center. Written informed consent was obtained from study subjects. The study subjects were the patients who underwent AF catheter ablation for antiarrhythmic drug (AAD)-refractory symptoms from September 2017 to May 2020 in Korea. Young patients under the age of 19, the patients with cognitive impairments that could not understand informed consent, and the patients who did not consent to participate in the study were excluded from the registration.

Data collection
All data were collected in each practicing center and sent to the core laboratory, Seoul National University Hospital. Baseline data included the patients' demographics (e.g., age, height, body weight, and sex), procedure date, type of AF, an indication of catheter ablation, cardiovascular comorbidities such as heart failure, hypertension, diabetes mellitus, cerebrovascular accident or arterial thromboembolic event, ischemic heart disease, valvular heart disease, peripheral arterial disease, presence of any cardiomyopathy, chronic kidney disease, obstructive sleep apnea, and history of any cardiac surgery, prescription of oral anticoagulants or antiplatelet agents, left ventricular (LV) ejection fraction (EF), and left atrial (LA) anteroposterior diameter. Procedural data included the number of previous AF ablation(s), an electrocardiographic (ECG) rhythm at the beginning of the procedure, mode of ablation energy, vendor name of three-dimensional mapping system, procedural time, ablation time, fluoroscopic time, ablation lesion and acute result of each ablation lesion. Acute success of each ablation lesion was assessed by each operator and was defined as entrance and/or exit block for pulmonary vein (PV) or superior vena cava (SVC) isolation, bidirectional block by differential pacing for linear ablation, and disappearance of trigger beat from specific anatomical site for focal trigger ablation. If there was no record of confirmation, the lesion set was considered incomplete. Information for acute complications before discharge and their management were also collected.

Follow-up
Mandatory follow-up visits were performed at 3, 6, and 12 months after the procedure. Twelve-lead ECG was performed at each visit. Long-term ECG test, such as Holter or event recorder was not mandatory, and its use was at the operator's discretion. Additional clinic visits and ECG tests were allowed when the patient became symptomatic or the operator suspected recurrence. At each follow-up visit, cardiovascular outcomes (e.g., ischemic stroke/transient ischemic attack, systemic embolism, aggravation of heart failure, myocardial infarction, and all-cause death), ECG rhythm, and use of AAD were collected. Recurrence of AF was defined as the occurrence of any atrial tachyarrhythmia in 12-lead ECG or lasting more than 30 s in long-term ECG monitoring. The first 90 days from the procedure was regarded as a blanking period, and the recurrence of AF was ignored during this period.

Statistical analysis
Categorical variables were expressed as frequency and percentage. Normally distributed continuous variables were expressed as mean ± standard deviation. The variables that were not normally distributed were expressed as the median [lowest quartile, highest quartile]. The recurrence of AF was compared by the Kruskal-Wallis test and Mann-Whitney test with Bonferroni correction according to the type of AF (paroxysmal, persistent and redoAF). It was also evaluated by Kaplan-Meier survival analysis with the Log-rank test. Cox-proportional hazard model was used to elucidate independent predictors for recurrence of AF. A P value less than 0.05 was considered statistically significant in Kaplan-Meier survival analysis, Cox-proportional regression analysis, and Kruskal-Wallis test for recurrence of AF. In case of intergroup analysis by Mann-Whitney test, P value less than 0.017 was considered significant. All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) & R software version 4.0.2 (R foundation for Statistical Computing, Vienna, Austria).

Subject enrollment and baseline characteristics
Between September 2017 and May 2020, 3239 patients with AF who underwent catheter ablation from 37 centers were enrolled in this registry. Among them, 486 patients enrolled in 2020 were excluded in the present analysis because the follow-up duration was < 1 year. Three hundred and fifty-one patients with incomplete follow-up data were also excluded from the analysis. Finally, 2402 patients were included in this analysis (Fig. 1). The mean age was 60.2 ± 9.6 years old, and the male was 73.6% (n = 1767). The proportion of paroxysmal AF was 45.7% (n = 1097) and that of persistent AF and redo ablation were 43.1% (n = 1035) and 11.2% (n = 270), respectively. Hypertension was the most common comorbidities (n = 1218, 50.7%), was followed by diabetes mellitus (n = 434, 18.1%), heart failure (n = 259, 10.8%), and cerebrovascular accident (n = 219, 9.1%). Proportion of the patients with structural heart diseases such as ischemic heart disease, cardiomyopathy, valvular heart disease, and history of cardiac operation were 7.4% (n = 178), 3.9% (n = 93), 3.8% (n = 92), and 2.1% (n = 51), respectively. A number of 2267 patients (94.4%) received oral anticoagulant before the procedure and direct oral anticoagulants were used in most patients (n = 1996, 83.1%). The mean LV EF was 59%, and LA diameter was 43 mm (Table 1). About 90% of the cases were the firsttime AF ablation (n = 2132, 88.8%). The proportion of cryoablation was 7.9% (n = 190). Mean procedure time, ablation time, and fluoroscopic time were 197.6 ± 90.2, 57.4 ± 42.0, and 33.8 ± 27.0 min ( Table 2).

Acute procedural success rates
A number of 2378 patients received PVI (99.0%) and complete isolation was achieved in 97.9% of the patients.  patients (16.9%). SVC isolation (n = 266, 11.1%), focal ablation on LA appendage (n = 127, 5.3%), and coronary sinus (n = 111, 4.6%) were performed. CTI ablation and SVC isolation showed high acute success rates (97.1% and 91.7%, respectively). Other linear ablations or focal ablations showed modest or low success rates (Table 3). Focal ablation based on complex fractionated atrial electrogram (CFAE) was performed in 254 patients (10.6%). About a half of the patients (n = 1265, 52.7%) were sinus rhythm before the beginning of the procedure. Direct current (DC) cardioversion was performed in 439 patients (18.3%), and 193 patients (8.0%) showed sustained AF at the end of the procedure. After ablation, AF induction test was performed in about 70% of the patients.

Rhythm control outcome and independent predictors for recurrence of atrial fibrillation
Sixty percent of the patients received any AAD after the blanking period (n = 1442, 60.2%). The patients with persistent AF were prescribed the AADs more frequently compared to the patients with paroxysmal AF and redo AF (68.0%, 54.1%, and 53.7%, respectively; P value < 0.001) ( Fig. 2A). Among 2397 patients, freedom from AF at one year was achieved in 1888 patients (78.6%). Those of the patients with paroxysmal, persistent and redo AF were 84.6%, 72.4%, and 80%, respectively (P value < 0.001). In intergroup analysis, the patients with persistent AF showed statistically higher recurrence rate compared to the patients with paroxysmal and redo AF [P value (persistent AF vs. paroxysmal AF) < 0.001; (persistent AF vs. redo AF) 0.012]. The recurrence rates of the patients with paroxysmal AF and redo AF were not statistically different (P value 0.066) (Fig. 2B).  Kaplan-Meier survival analysis showed that the patients with persistent AF showed worse rhythm outcome compared to other types of AF [Log-rank P value (persistent AF vs. paroxysmal AF) < 0.001; (persistent AF vs. redo AF) 0.010]. There was no statistical difference between the patients with paroxysmal AF and redo AF (P value 0.070) (Fig. 3). There was no statistical difference in recurrence of AF according to ablation strategy (PVI alone vs. PVI and additional NPVA) in the patients with paroxysmal AF (17.0% vs. 14.6%, Log rank P value 0.284). However, the patients with persistent AF who received PVI and additional NPVA showed lower recurrence rate than ones received PVI alone (34.9% vs. 24.4%, Log rank P value 0.001) (Fig. 4).

Demographic profiles
This study is a multicenter, prospective registry that enrolled 37 arrhythmia centers in Korea. The demographic profiles of the study population, such as age, Table 3 Acute procedural acute success rate in various types of ablation Data are expressed in frequency (percentage) 1 The percentage was calculated as the number of each type of ablation as denominator and the number of success as numerator 2 It included any focal atrial ablation not mentioned in this  gender distribution, and type of AF were comparable to other Korean or foreign studies [8,10,11]. Of note, the proportion of heart failure patients is relatively low compared to other studies using the Korean claim database [1,8]. However, the rate was similar compared to other cohort studies in Korea [12,13]. NHIS claim data might be over-claimed the heart failure diagnosis related to some drug use and did not have echocardiographic parameters in it. On the other hand, our study had echocardiographic data that could identify the LV dysfunction more correctly. Sleep apnea is known as a risk factor for AF [3]. The prevalence of sleep apnea in patients with AF was variable in previous studies, ranging from 18 to 49% [14,15]. However, an awareness of sleep apnea is not widespread in clinical practice, and a diagnostic test is cumbersome. Therefore, the prevalence of sleep apnea might be underestimated in this study.
The proportion of cryoablation was small because the cryoablation system has been available since late 2018 in Korea, which was very late compared to other countries.

Procedure patterns
Pulmonary vein isolation is a standard procedure in AF ablation. All patients who underwent de novo AF ablation and the patients with AF recurrence were received PVI in this study. Some patients who did not receive PVI were the redo AF patients without PV reconnection. More than 60% of the procedure did not confirm the presence of the dormant conduction in the present registry. It is thought that controversial results for the effectiveness of elimination of the dormant conduction could affect the current practice pattern [16,17]. Interestingly, the incidence of dormant conduction was 11% (n = 96/876) that was lower than in other studies [18,19]. Further evaluations would be needed to clarify it. Additional NPVA were widely performed in this study. The most common lesion set was a CTI linear ablation (n = 1366, 56.9%). Typical atrial flutter often accompanied with AF and the CTI ablation is easy to achieve  bidirectional block [20]. The success rate of the CTI ablation was 97.1% that was consistent with other studies [20,21]. Other LA linear ablations were performed in about 20% of the patients and it was similar to other studies [10,22]. However, the success rates of LA linear ablations were lower than in a previous paper [23]. We considered the linear ablation was not successful when there was no confirmation of the linear lesion set. Probably, it could make underestimation of the success rate of linear lesion sets in this study. Additional NPVA are often performed in patients with persistent AF and macro-reentrant atrial tachycardia. Still, there is no consensus for the effective ablation strategy for persistent or long-standing persistent AF because previous studies showed controversial results [24,25]. It is thought that they influenced the utilization of LA linear ablations although the rate of the patients with persistent AF was 43.1% in this study. Non-PV trigger is an important source of AF development but non-PV trigger ablation was not wildly performed in this study. In addition, it was 30% that did not perform AF induction test. In STAR-AF II trial, the authors reported that additional linear ablation or ablation for complex fractionated electrogram (CFAE) did not show the benefit for AF recurrence in the patients with persistent AF [25]. This result is thought to influence the PVI as the initial ablation strategy for persistent AF. Another possible explanation is that it is often difficult to localize the focal trigger source despite support by a 3D mapping system. Also, there is no clear endpoint for focal trigger ablation.
The SVC isolation was more frequently performed than other non-PV trigger source ablation, and the success rate was high (91.7%). It is thought that there was a definite anatomical structure and a clear endpoint such as an entrance or exit block. Substrate modifications for CFAE, ganglionated plexus, and focal impulse and rotor mapping were performed in limited numbers. The complexity of the procedures, unclear endpoints, and little evidence for better prognosis could hinder the wide adoption of these technologies.

Rhythm outcome
The rate of AF-free survival at one year was 78.6% that was higher than other studies, although about half of the patients were persistent AF [11,26]. Long-term ECG monitoring was not mandatory during the follow-up period and it could make less detection of atrial tachyarrhythmias. In addition, the use of AAD after blanking period was at the physician's discretion in this study. It was different from other clinical trials that strongly discourage the use of AAD after blanking period. Previous studies also reported that the patients with persistent AF showed worse AF-free survival after catheter ablation than the ones with paroxysmal AF and it is consistent with our results [27,28]. In present study, AF-free survival rate of the patients with redo AF was similar to that of the patients with paroxysmal AF. The rate of maintaining sinus rhythm after multiple procedures was higher than that of de novo ablation [29,30]. It is thought that recurrence of AF was reduced by performing PV re-isolation, atrial substrate modification or non-PV trigger elimination during redo-ablation. However, it could not be concluded that the aggressive approach to the patients with redo AF is warranted and further randomized trials should be needed to investigate this issue. Valvular heart disease, LA diameter, persistent AF, PVI alone, and AF termination by non-PV ablation or failed ablation were independent predictors of AF recurrence in this study. Moderate or severe valvular heart diseases and persistent AF are well-known risk factors for AF recurrence after catheter ablation [11]. They cause long-term hemodynamic deterioration, which leads to structural remodeling, and fibrosis of the atrium. Consequently, LA enlargement was developed and it is also a risk factor for AF recurrence after catheter ablation [31]. Our results were consistent with the previous evidence. Interestingly, PVI alone (vs. PVI and additional NPVA) is associated with the increased risk of AF recurrence. There were possible explanations. Impact of additional NPVA on maintaining sinus rhythm after catheter ablation is controversial [25,32]. However, macro-reentrant AT or non-PV trigger related AF were found in 20-30% of the procedure [33,34]. In this situation, additional NPVA is needed to restore sinus rhythm. Our result could be thought as a necessity to find and resolve atrial tachyarrhythmias that were not related to PVs. Second, use of the AADs during the follow-up period was more than 60% and that probably affected to the result. Third, the success rate of the linear ablation might be underestimated  1 Valvular heart disease is defined as stenosis or regurgitation of any valve which severity was moderate or severe 2 NPV ablation is defined as any ablation other than pulmonary vein isolation 3 It is defined as the rhythm state before the first energy delivery of the procedure 4 It is categorized when cardioversion was performed after the first energy delivery of the procedure 5 Induction of AF was usually performed by atrial burst pacing with isoproterenol infusion. Pacing protocol and isoproterenol dose were left to the operator's discretion AF, atrial fibrillation; AT, atrial tachycardia; CI, confidence interval; DCC, direct current cardioversion; EF, ejection fraction; HR, hazard ratio; LAD, left atrial diameter; LV, left ventricle; NPV, non-pulmonary vein; PVI, pulmonary vein isolation; SR, sinus rhythm because we considered the lesion set was incomplete when there was no confirmation of the linear lesion set. Mode of termination was also showed an interesting finding. Termination of AF by PVI had similar prognostic effect compared to sinus rhythm before the first ablation. It could be considered that the PVs were significant AF substrate and other atrial substrates were insufficient to perpetuating AF in both conditions. On the other hand, the fact that AF was terminated by NPVA or failed by any ablation implies that there might be an AF trigger or significant atrial substrates. Meanwhile, there was no difference between the initial sinus rhythm and the termination by cardioversion. It is thought that the timing of DC cardioversion was different for each operator or case.

Limitation
There are several limitations in this study. There was no mandatory recommendation of ablation and follow-up strategy. The definition of acute success may be different depending on the operators. Nonuniform follow-up methodology also influenced collecting recurrence data as asymptomatic or short, intermittent atrial tachyarrhythmia episodes may have been ignored. Second, there was limited data on AF cryoablation. It has been available in Korea since 2018, and it was not widely adopted when the study enrollment was active.

Conclusions
Catheter ablation for AF is an effective and safe treatment modality in Korean real-world practice. Additional NPVA was associated with better rhythm outcome in the patients with persistent AF, not in the ones with paroxysmal AF. Valvular heart disease, persistent AF, PVI alone, need of NPVA for terminating AF, and failed ablation are independent risk factors for AF recurrence after catheter ablation. Those were consistent in the previous studies. Further investigations are needed to discover optimal strategy of catheter ablation for AF.