Trends over the recent 6 years in ablation modalities and strategies, post‐ablation medication, and clinical outcomes of atrial fibrillation ablation

Abstract Background Ablation strategies and modalities for atrial fibrillation (AF) have transitioned over the past decade, but their impact on post‐ablation medication and clinical outcomes remains to be fully investigated. Methods We divided 682 patients who had undergone AF ablation in 2014–2019 (420 paroxysmal AFs [PAF], 262 persistent AFs [PerAF]) into three groups according to the period, that is, the 2014–2015 (n = 139), 2016–2017 (n = 244), and 2018–2019 groups (n = 299), respectively. Results Persistent AF became more prevalent and the left atrial (LA) diameter larger over the 6 years. Extra‐pulmonary vein (PV)‐LA ablation was more frequently performed in the 2014–2015 group than in the 2016–2017 and 2018–2019 groups (41.1% vs. 9.1% and 8.1%; p < .001). The 2‐year freedom rate from AF/atrial tachycardias for PAF was similar among the three groups (84.0% vs. 83.1% vs. 86.7%; p = .98) but lowest in the 2014–2015 group for PerAF (63.9% vs. 82.7% and 86.3%; p = .025) despite the highest post‐ablation antiarrhythmic drug use. Cardiac tamponade was significantly decreased in the 2018–2019 group (3.6% vs. 2.0% vs. 0.33%; p = 0.021). There was no difference in the 2‐year clinically relevant events among the three groups. Conclusion Although ablation was performed in a more diseased LA and extra‐PV‐LA ablation was less frequent in recent years, the complication rate decreased, and AF recurrences for PAF remained unchanged, but that for PerAF decreased. Clinically relevant events remained unchanged over the recent 6 years, suggesting that the impact of the recent ablation modalities and strategies on remote clinically relevant events may be small during this study period.


| INTRODUC TI ON
Recently, catheter ablation of atrial fibrillation (AF) has become a widely accepted therapy because it has rigid evidence of maintaining sinus rhythm over antiarrhythmic therapy. 1,2 Pulmonary vein isolation (PVI) has been the standard ablation strategy for paroxysmal AF (PAF), and atrial substrate modification such as complex fractionated atrial electrogram (CFAE) ablation, linear ablation, and/or ablation of non-PV triggers had been one of the relevant clinical interests for improving AF ablation in patients with a remodeled atrium including persistent AF (PerAF) and longlasting PerAF over the past decade. [3][4][5] Nonetheless, the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II (STAR-AF2) demonstrated that substrate modification did not reduce the recurrence rate of AF. 5 Three-dimensional mapping and ablation technology for AF ablation has been developed, that is, contact force and the forcetime integral (FTI), 6,7 and has been followed by the ablation index (AI) and lesion size index (LSI), which have been incorporated into both the CARTO3 and Ensite NavX mapping systems to create an appropriate lesion formation. [8][9][10][11][12][13] The balloon-based technologies such as cryoballoon ablation (CBA) and hot balloon ablation (HBA) also have been launched, and the efficacy and safety of those balloon-based ablation systems have been reported in previous studies. [14][15][16][17] Recently, the CABANA and CASTLE-AF trials demonstrated that ablation reduces long-term rehospitalizations because of heart failure (HF) and all-cause mortality mainly driven by the maintenance of sinus rhythm by ablation, 18,19 which may promote more physicians to perform AF ablation throughout the world.
This trend may also motivate physicians to confidently terminate antiarrhythmic drugs (AADs) and oral anticoagulants (OACs) after ablation.
Despite these transitions in the strategies and modalities, their effects on the post-ablation AADs and OACs and subsequent long-term outcomes in real-world practice, remain not fully investigated. Therefore, this study aimed to examine the characteristics of the patients who underwent AF ablation, the transition of the strategies and modalities for AF ablation, and the 2-year success rate and clinical adverse outcomes after AF ablation in the recent 6 years from 2014 to 2019.

| Data collection
The data collection has been described elsewhere. 20,21 In brief, the patient characteristics and pre-ablation (baseline) and follow-up data were obtained through a review of their hospital charts. The pseudonymized patient data were collected in an Excel format by physicians, and it included the patient characteristics such as the

| AF ablation protocol
Before the electrophysiologic study, all AADs were discontinued for at least five half-lives. The analysis was performed with patients under conscious sedation with dexmedetomidine and fentanyl. After a single transseptal puncture was performed, two long sheaths (Agilis steerable sheath and SL0 sheath [Abbott, Inc.]) were inserted into the LA via a transseptal puncture. An activated clotting time > 300 s was maintained by heparin during the procedure.
The 3D geometry of the LA and PVs was created using a CARTO3 (Biosense Webster, Diamond Bar, CA) or Ensite NavX mapping system (Abbott). The transition of the modalities and strategy of the catheter ablation of AF are shown in Figure 1. As for RF ablation, an extensive encircling PVI was performed with an irrigated-tip contact force RF ablation catheter (3.5-mm tip, Navistar ThermoCool Regarding the balloon-based ablation, the Ensite NavX mapping system was used to guide the LA-PV mapping. Since 2014, CBA was performed, as reported previously. 15-17 A 28 mm cryoballoon (ARC-Adv-CB, Arctic Front Advance; Medtronic, Inc) was used and geothermal energy was applied to each PV for 180 s and then for 120 s.
Since 2017, HBA started to be performed as reported previously. 15,16 In brief, a hot balloon (SATAKE HotBalloon; Toray Industries, Inc) using radiofrequency-generated thermal energy was applied to the

| Follow-up
AADs were resumed after the ablation procedure at the operator's decision. All patients underwent routine follow-up at our institution at 3 weeks and 3, 6, 12, and 24 months after ablation or whenever they had any symptoms. Twelve-lead electrograms were recorded at each visit, and 24-h Holter recordings were obtained at 3, 6, 12, and 24 months after the ablation procedure. The patients were generally introduced to other private clinics after 3 months post-ablation and were followed up every 1-3 months thereafter. Recurrence was defined as any document of AF or AT of more than 30 s during 3-24 months after the ablation.

| Study end points
The primary efficacy end point was the freedom from AF or AT recurrence, and the primary safety end point was ablation-related complications during the post-procedural period (within 1 month after ablation). Secondary end points were clinically relevant events including a stroke/TIA, hospitalization because of HF, major bleeding, and cardiovascular events, and all-cause mortality.  Table S1. The overall trend in the patient characteristics was similar regardless of PAF or PerAF.

| Complications and clinical outcomes
The complications associated with AF ablation are shown in Table 3.    Table 4).
The Kaplan-Meier curves for clinically relevant events in the PAF and PerAF patients are shown in Figure 3. There were no differences in the clinically relevant events among the three time period groups.
The details of each adverse event are summarized in

| Main findings
This study had three major findings: (1) the patients were older, more frequently had persistent AF, developed a lower EF, and had a larger

| The time-course changes in the patient characteristics, complications, and recurrence rate of AF/AT after ablation over the recent 6 years
These single-center results showed that patients who had undergone AF ablation gradually became older, and had a larger LAd, lower EF, and more often PerAF and HF over the past 6 years. A higher efficacy in terms of sinus rhythm maintenance by ablation over AADs in symptomatic PAF has been widely established. 1,2,24 Catheter ablation appears to be superior to medical therapy even in PerAF, 8   Note: The number (%) of patients is shown.
Abbreviation: AF, atrial fibrillation. In PAF patients, the 2-year AF/AT freedom rate was similarly high among the three time period groups. PAF patients became older and the LAd larger over those 6 years, suggesting PAF patients with more remodeled substrates were included in the recent years. The postablation use of AADs might be a confounder; however, those were not statistically associated with AF/AT recurrence. Several meta-analysis reports have shown a contact force-guided PVI and balloon-based ablation significantly improved the AF freedom rate. 35,36 The PAF patients in this study underwent a contact force-guided PVI or balloon ablation. Therefore, our results might support a high success rate with PVI methods achieving a durable PVI in PAF patients even when extending the ablation indication to a remodeled LA.
In contrast, we found an important finding that the 2-year AF/ AT freedom rate in PerAF patients was less frequent, however, PerAF

| Long-term clinically relevant outcomes during the recent 6 years
We found a new finding that in both PAF and PerAF, there were only a few incidences of hospitalizations because of HF, major bleeding, and cardiovascular events, strokes/TIAs, and all-cause mortality without any significant difference among the three time period groups.
Numerous studies have demonstrated the potential beneficial effects of sinus rhythm maintenance by catheter ablation on major adverse cardiac and cerebrovascular events. 30 Abbreviations: AT, atrial tachycardia; HR, hazard ratio. Other abbreviations as in Table 1. in Japan. 21,41 The largest multicenter registries in Japan also showed that over half of the patients had continued OACs at 1 year. 21,41 In this study, only a few clinically relevant events occurred during the 2-year follow-up after AF ablation as reported previously, 20,21,41 and those incidences were unchanged over the 6 years. Our results suggested that careful post-ablation management based on the physicians' discretion may be more important for reducing the ultimate clinical outcomes in the remote period after ablation than the recent development of the ablation modalities and strategies in this study cohort during the limited follow-up duration. Nonetheless, more intensive treatment will be needed in patients at high-risk for a stroke, because we found a strong association between clinically relevant events and high-risk patients with a CHADS 2 score ≥2 or CHA 2 DS 2 -VASc score ≥3 as previously reported. 21,40,42

| Study limitations
There were several limitations that should be considered. Our study was a retrospective observational single-center study. Our results may not be generalized to other hospitals, however, our results that suggested that the recent development of the ablation modality and strategy provided a favorable impact on sinus rhythm maintenance, especially in PerAF, but their impact on the post-ablation remote clinical outcomes may have been small in these study patients.

AUTH O R CO NTR I B UTI O N S
Moyuru Hirata and Yasuo Okumura wrote the first draft of the protocol article and carries the overall responsibility for the full study and the study protocol. Yasuo Okumura and Koichi Nagashima were substantial contributors to the study concept and design, article drafting, and critical review of the article and will contribute to the acquisition, analysis, and interpretation of the data. Moyuru

ACK N OWLED G M ENTS
We express our gratitude to all study participants and the supporting staff. We also thank Mr. John Martin for the English language editing.

FU N D I N G I N FO R M ATI O N
This work is own-funded.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The

DATA AVA I L A B I L I T Y S TAT E M E N T
No data are available.

D ECL A R ATI O N S
Approval of research protocol: The study was approved by the Institutional Review Board of Nihon University Itabashi Hospital, and an opt-out system was used to obtain the patients' content for the use of their clinical data for research purposes.