Radiofrequency or cryoballoon ablation for index pulmonary vein isolation: What is the impact on long‐term clinical outcomes after repeat ablation?

The current study sought to assess the impact of the utilized energy source during index ablation on long‐term clinical outcomes after repeat ablation of atrial fibrillation (AF). Index ablation procedures were either performed using radiofrequency current (RFC) (RFC group) or cryoballoon (CB) ablation (CB group). Repeat ablation was performed by the use of RFC.


| INTRODUCTION
Catheter ablation (CA) is an effective treatment for patients suffering from atrial fibrillation (AF). 1 The target of ablation is the antral aspect of the pulmonary veins (PVs) and complete isolation of the PV is the key procedural endpoint for all patterns of AF. 1 The two most commonly used approaches for pulmonary vein isolation (PVI) are radiofrequency current (RFC) ablation in conjunction with three-dimensional (3D) electroanatomic mapping and cryoballoon (CB) ablation. RFC ablation allows for individual point-by-point ablation guided by the patient's anatomy, but it demands a long learning curve. CB ablation is a "singleshot" device with a fixed diameter of either 23 or 28 mm and a relatively simple, time-saving application with a short learning curve.
Despite these differences, both methods have been shown to be equally effective and safe for the treatment of paroxysmal AF. 2 However, taking account of both energy sources, CA for AF is still limited by a considerably high rate of atrial arrhythmia recurrences (AAR). [2][3][4] Consequently, there is a large number of patients undergoing repeat ablation procedures aiming at stable sinus rhythm (SR) maintenance. The main reason for AAR following CA is the electrical reconnection of the PV. 5,6 In contrast to index ablation procedures, in which extensive CA is performed to achieve electrical isolation of the PV from the atrial myocardium, repeat ablation aiming at reisolation of the PVs mostly demands only a limited number of energy applications along the areas of electrical reconnection; therefore, the treatment of choice in repeat ablation procedures is point-by-point RF ablation. Of note, gap localizations of initially isolated PVs differ considerably in patients who underwent CB ablation from patients being treated with RFC. 7,8 The impact of these different characteristics of both energy sources on clinical success rates is under continuous investigation.
The current study was designed to assess the effects of a hybrid ablation approach (CB ablation as index procedure followed by repeat ablation using RFC) as compared with the exclusive use of RFC ablation on clinical outcomes of patients with repeat ablation for the treatment of AF.

| Inclusion and exclusion criteria
Patients with symptomatic paroxysmal AF (as defined by 2016 ESC guidelines), 1 who underwent an index ablation procedure applying either cryothermal energy or RFC and repeat ablation for the treatment of AAR using exclusively RFC, were included into the current study. Exclusion criteria were an LA diameter of more than 60 mm, severe valvular heart disease and contraindications to postinterventional oral anticoagulation.
The current study constitutes a retrospective analysis based on institutional databases. The study was approved by the local ethical boards and performed in accordance with the Declaration of Helsinki of 2013.

| Periprocedural management
Transesophageal echocardiography was performed before CA in all patients to rule out intracardiac thrombi and to assess the LA diameter. No further preprocedural imaging was performed.

| Intraprocedural management
The intraprocedural management has been described in detail before. [9][10][11] In brief, in patients on vitamin K antagonists, the procedure was performed under therapeutic INR values of 2 to 3. Novel oral anticoagulants were stopped the day before the procedure and continued 6 hours postablation. All procedures were performed under deep sedation using midazolam, sufentanil, and propofol. One or two diagnostic catheters were introduced via the femoral vein and/or the left subclavian vein and positioned within the coronary sinus and/or along with the His bundle. Transseptal puncture was per-

| Ablation protocol: CB-based PVI
The 28-mm second-generation CB was utilized exclusively. The transseptal sheath was exchanged over a guidewire for a 12F steerable sheath (FlexCath Advance; Medtronic Inc), through which the CB was advanced into the LA. Guiding of the CB to the target PV was performed over a 20-mm spiral mapping catheter (Achieve;

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Medtronic Inc) and complete occlusion of the PV ostium was verified by contrast injection through the central lumen of the inflated CB.
Patients were treated based on a "time-to-isolation" (TTI) guided ablation protocol. This means, after live verification of PVI, freezing was continued for an additional 120 seconds; if the TTI could not be recorded, the freeze-cycle duration was set at 180 seconds; no additional bonus-freeze cycle was applied after successful PVI. 9 An esophageal temperature probe (Sensitherm; St Jude Medical Inc and Circa; Circa Scientific Inc) was inserted and positioned according to the individual CB position to provide esophageal temperature monitoring during energy delivery. The intraluminal esophageal temperature cut-off was set at 15°C. 12 During CB ablation along the septal PVs, continuous phrenic nerve

| Ablation protocol: RFC ablation
In patients undergoing irrigated RFC as index ablation procedure, circumferential PVI was performed in conjunction with 3D electroanatomic mapping, as previously described. 15 The procedural endpoint was the absence of any PV potential recorded by a spiral mapping catheter (Lasso; Biosense Webster, Diamond Bar, CA) placed along the ostium of the respective PV.

| Ablation protocol: repeat procedures
Repeat ablation procedures were performed in patients with AAR.
Electrical reconduction gaps of reconnected PVs were identified and closed with RFC ablation aiming at PV reisolation. Additional ablation strategies beyond PVI were only performed in patients with (a) AT that was not related to PV reconduction gaps; (b) recurrence of AF despite durable isolation of the PVs; or (c) AF that could not be converted to SR by reisolation of the PVs or direct current cardioversion. Additional ablation strategies included bidirectional conduction block of the anterior line, complex fractionated atrial electrogram ablation, bidirectional conduction block of the mitral valve isthmus line, and/or bidirectional conduction block of the LA roofline. In the case of focal AT or non-PV triggers for AF, RFC ablation was performed aiming at substrate/trigger elimination.

| Postprocedural care
Transthoracic echocardiography was performed in all patients to rule out pericardial effusion. All patients were treated with proton-pump inhibitors for 6 weeks. Low-molecular-weight heparin was administered in patients on vitamin K antagonists and an international normalized ratio (INR) less than 2.0 until a therapeutic INR of 2 to 3 was reached. Novel oral anticoagulants were reinitiated 6-hour postablation. Anticoagulation was continued for at least 3 months and thereafter based on the individual CHA 2 DS 2 -VASc score. Previously ineffective antiarrhythmic drugs were continued for 3 months.

| Follow-up
Following a blanking period of 3 months, patients completed outpatient clinical visits at 3, 6, and 12 months and in 6-month intervals thereafter; the clinical visits included ECGs and 24-hour Holter ECGs. In addition, regular telephone interviews were performed and outpatient clinical visits were immediately initiated in case of symptoms suggestive of recurrent arrhythmia.

| Endpoints
The primary endpoint was a recurrence of a symptomatic and/or documented episode of AAR with a duration of more than 30 seconds outside the 3-month blanking period. Secondary endpoints were acute procedural characteristics and major complications (transient ischemic attack, stroke, pericardial tamponade, PN palsy, and severe bleeding requiring blood transfusion).

| Statistics
All data were evaluated retrospectively. Continuous data are described as mean and standard deviation if normally distributed; otherwise, the median and interquartile range (IQR [first quartile; third quartile]) are reported. Categorical data are described with absolute and relative frequencies. Based on a logistic regression model (global test of no-regression) baseline variables were simultaneously compared between the two groups.
Differences in logarithmic-transformed procedural data were analyzed with two-sample t tests. Freedom from AAR was estimated with the Kaplan-Meier method. Differences in recurrence-free survival were analyzed with the logrank test.
All P values were two-sided and a P value of less than .05 was considered significant. All calculations were performed with the statistical analysis software R (R Core Team, 2018).

| Patients
A total of 195 patients with symptomatic paroxysmal AF underwent PVI applying either RFC ablation (n = 138) or 28-mm second-generation CB ablation (n = 57). All 195 patients underwent repeat ablation applying exclusively RFC. There were no statistically significant differences in baseline characteristics or comorbidities between the two cohorts (P = 1.0). The patients' baseline characteristics are given in Table 1  There was a trend towards higher durability of PVI following CB ablation without meeting statistical significance (P = .074). PV reconnection rates are given in Table 3.  Table 4.
differences between the two groups (P = .78). Recurrence-free survival is shown in Figure 1.

| Catheter ablation for paroxysmal AF
CA is the most effective treatment for patients with symptomatic AF. 1 In the FIRE AND ICE trial, CB ablation was noninferior to RFC ablation in terms of efficacy and safety. 2   Calculations on the basis of a mixed logistic regression model revealed a trend toward higher durability of PVI following CB ablation without reaching statistical significance (P = .074).
substrate modification in small PV, 19 but less extended LA ablation in large PV. In contrast, the level of isolation when using RFC is not affected by the size of the PV and the size of the lesion set can be individualized. Recent data indicates that CB ablation results in a higher rate of durable PVI as compared to RFC. 20 Accordingly, we have found a trend towards higher durability of PVI following CB ablation, although our results did not meet statistical significance (P = .074).
The concept of the current study was based on the hypothesis that either the exclusive use of RFC with the same level of isolation during index and repeat ablation (and thereby potentially more effective lesion formation) or the use of two different energy sources (cryothermal and RFC) might be beneficial for patients with repeat ablation of AF.
Interestingly, during the follow-up period of our study, there was no difference between the two groups regarding clinical outcomes (P = .78).
Noteworthy, despite repeat ablation, was performed in all patients, AAR was still considerably high. The main driver for AAR following CA is reconnection of previously isolated PVs; however, Kuck et al 6 reported on a surprisingly high AAR rate of 57% also in patients with proof of durable PVI. 6 Considering these results, efforts are needed not just to increase the rate of durable PVI, but also to identify patients for whom additional ablation strategies are beneficial. In those patients, improved mapping and ablation of extrapulmonary vein triggers for AF might be an additional key aspect to increase clinical outcomes.

| Procedural aspects
During index ablation, procedure times were significantly shorter in patients undergoing CB ablation as compared to RFC ablation; in contrast, fluoroscopy times, DAP and the amount of contrast dye used during the index procedure were significantly higher for CB ablation.
These findings are in accordance with previous reports and explained by the fact that RFC is guided by 3D mapping, whereas CB ablation is only guided by fluoroscopy and sufficient occlusion during freeze applications of the PV is verified by injection of contrast dye. 2,[21][22][23] The lower demand of contrast dye in RFC ablation can be a useful consideration when treating patients with chronic kidney disease.
In our study, repeat ablation procedures were significantly shorter in patients undergoing originally RFC ablation. In CB ablation, conduction gaps of initially isolated PV are mainly the result of a poor tissue balloon contact. Since the CB is a "single-shot" device, the area of electrical reconnection can involve a larger aspect of the PV. In contrast, PV conduction gaps following RFC ablation are oftentimes strictly circumscribed and might thereby be easier (and time-saving) identified.

| Limitations
The current study is an observational, single-center, nonrandomized analysis. Repeat ablation was exclusively performed by the use of RFC ablation; no information can be given regarding clinical outcomes of patients undergoing repeat ablation with the use of CB ablation. At our center, RFC ablation is more frequently used for index PVI as compared with CB ablation. This aspect resulted in different numbers of patients being included in the two groups and might have biased the findings.

| Conclusions
In patients with repeat ablation of AF, the exclusive use of RFC ablation and the use of CB with subsequent RFC ablation are equally effective in terms of freedom from AAR. Although CB ablation results in shorter index ablation procedures times, durations of repeat ablation are significantly longer as compared to patients being initially treated with RFC. CB ablation appears to ensure a higher rate of durable PVI.