Introduction

Pulmonary vein (PV) isolation is a well-established, safe, and effective treatment for symptomatic atrial fibrillation (AF) [1, 2]. Radiofrequency catheter ablation (RFCA) and cryoballoon (CB) ablation (CBA) have shown similar results in randomized trials [3, 4]. Nevertheless, between 15% and 43% of patients may require a repeat AF ablation procedure due to symptomatic recurrence [5–7]. It is, however, not established which is the most suitable ablation technique for patients undergoing a repeat AF ablation and the possible influence of the technique used in the index procedure. The use of CBA for repeat ablation has been studied in small works with conflicting results [8–12]. The aim of this study is to evaluate the efficacy of CBA as a redo procedure for patients with prior AF ablation, by either CBA or RFCA.

Methods

Study design

The Spanish Registry of Cryoballoon Ablation (RECABA) [13] (NCT02785991) was an observational, prospective, nation-wide, multicenter study of cryoballoon AF ablation in Spanish centers. Patients were enrolled between September 2016 and January 2019. Inclusion criteria were: 1) person older than 18 years, 2) eligible for CBA according to local practice, 3) life expectancy longer than 1 year, and 4) signed informed consent.

Presented herein, is a post-hoc retrospective analysis of patients who were included for a repeat AF ablation and the previous procedure could be either CBA or RFCA. AF classification as paroxysmal (PAF) or persistent (PerAF) followed the current European Society of Cardiology guidelines at the inclusion period [14]. Data were gathered during a baseline visit at the procedure and at an established 12-month follow-up visit. For this analysis, the selected patients were those who completed a 12-month follow-up. Ethics Committee approval was obtained following local regulations, and the study was conducted in compliance with the Declaration of Helsinki and Spanish laws and regulations (Royal Decree 1090/2015, Royal Decree 1616/2009, Order SAS/3470/2009 of 16 December). The study was approved by the IRB, Comité Ético de Investigación Clínica de Euskadi (CEIC-E) on May 9, 2016. All patients signed informed consent upon inclusion.

Objective and endpoints

The main purpose of RECABA was to assess the standard clinical practice of CBA in Spanish centers. Considering the aim of this analysis, two groups were defined within the population, including: 1) Prior-CB: Patients referred for CBA who had undergone a previous CBA, and 2) Prior-RF: Patients referred for CBA who had undergone previous RFCA. The primary endpoint of the study was freedom from AF at 12 months after a 3-month blanking period. Secondary endpoints were clinical characteristics of the patients, dose and biophysical variables of CBA applications, vein reconnection pattern, and efficacy and safety of the procedure in the defined groups.

Cryoballoon ablation

The description of CBA has been widely reported elsewhere [15–17]. In the RECABA study, each center followed their local standards practices. In general, the procedure took place under sedation or general anesthesia. Left atrial access was performed using a dedicated needle followed by a heparin bolus. Anticoagulation status was monitored using activated clotting time with a target of 300–350 s. A 23- or 28-mm second-generation cryoballoon catheter (ArticFront ADV; Medtronic, Inc.) was deployed in the left atrium through a dedicated delivery sheath (Flexcath of Flexcath ADV; Medtronic, Inc.). Operators used a dedicated inner-lumen diagnostic catheter (Achieve of Achieve ADV; Medtronic, Inc.) to monitor local vein electrograms status during freeze applications. The initial presence of electrograms in PVs were considered reconnections. Number and length of CB applications were at the discretion of local operator, including applications on PVs isolated in previous procedures or the use of bonus freeze-applications. The use of adenosine challenge and the length of the post isolation waiting period were at the discretion of the operator. The procedure endpoint was the persistent isolation of all PVs.

Post-ablation management and follow-up

Patient’s anticoagulation and antiarrhythmic drug regime followed local protocols and were at the treating cardiologist discretion. Follow-up visits were in accordance with local practice, with a pre-stablished 12-month follow-up visit. Arrhythmia detection could be based on Holter monitoring, event recording systems, implantable devices, and/or in-clinic electrocardiogram (ECG) recording. AF recurrence was defined as an AF event lasting longer than 30 s registered by the abovementioned methods.

Statistical analysis

Quantitative variables are summarized with means and standard deviations or median and interquartile range when appropriate. Differences between groups were assessed using the t-test, or the Kruskal-Wallis test when a parametric test could not be performed. Categorical variables are summarized with percentages and differences assessed by the Pearson c2 test. The Kaplan-Meier method was used to build event-curves of survival from the primary endpoint and to calculate the 12-month freedom from AF estimates for each group. Log-rank test assessed the difference between groups. Univariate and multivariate Cox proportional-hazards regression models were built to evaluate possible predictors of AF-recurrence. Predictors were included in the multivariate model when a significance level of p-value below 0.10 was achieved. Statistical significance was assumed for two-sided p-values below 0.05. Data were analyzed using STATA v.15 software (StataCorp LLC).

Results

Population baseline characteristic

In total, 1733 patients from 27 Spanish centers were included in RECABA between September 2016 and January 2019. Seventy-seven (4.3%) patients underwent CBA as a redo procedure due to recurrence after an index procedure and 74 completed a 12-month follow-up visit and were included in this analysis. Thirty-three (44.6%) subjects had undergone a previous CBA (Prior-CB group) and 41 (55.4%) a previous RFCA (Prior-RF group) (Central illustration). Twenty-seven (36.5%) patients were female and mean age was 58.8 ± 10.2 years. Additionally, 60 (81.1%) subjects had PAF and 14 (18.9%) had PerAF.

Central illustration. Graphical abstract showing group definition, pulmonary veins reconnection pattern, Kaplan-Meier survival curves and main findings; Adj-HR — adjusted hazard ratio; AF — atrial fibrillation; CBA — cryoballoon ablation; PV — pulmonary veins; RECABA — Registro Español de Crioablación de con Balón — Spanish registry of cryoballoon ablation; RFCA — radiofrequency catheter ablation; Prior-RF — patients subjected to cryoballoon ablation after a failed previous radiofrequency atrial fibrillation ablation; Prior-CB — patients subjected to cryoballoon ablation after a failed previous cryoballoon atrial fibrillation ablation.

Table 1 summarizes patients baseline characteristics. Thirty-one patients from the Prior-CB group (93.9%) underwent a sole index procedure, while 30 from the Prior-RF (73.2%) underwent more than one preceding AF ablation procedures (c2 = 5.4, p = 0.02).

The median CHA2DS2-VASc score was 1 (interquartile range [IQR] 0–2) with no differences between groups (Kruskal-Wallis test p = 0.67). Overall, 84.9% of patients were on anti-arrhythmic drugs (AADs) at the time of the procedure, 1.6% had left ventricular ejection fraction below 35%, and 53.2% of subjects had a dilated left atrium (LA) defined as either LA diameter larger than 40 mm or LA area larger than 20 cm2.

Cryoballoon ablation

Table 2 summarizes procedural data. From 74 procedures, 60 (82.2%) were performed using a single 28-mm CB, without differences between groups (c2 = 2.04, p = 0.361).

Routine bonus freeze-application was more common in the Prior-CB group, with 51.6% of patients vs. 13.9% of the Prior-RF group (p = 0.003). Adenosine challenge was not used in any patient. The average procedure duration was 115.1 ± 44.5 min, with no differences between groups. In total, 49 (66.2%) patients were on AAD at discharge, being flecainide the most common AAD prescribed with 59.6% of patients, followed by amiodarone in 19.1% of them, without existing differences between groups. Patients were discharged on anticoagulation, with 66.2% of them on a direct oral anticoagulant drug, also without differences between groups.

Pulmonary vein reconnections after a previous procedure

Sixty-three out of 156 (40.4%) veins were reconnected in the Prior-RF group as compared with 17 out of 103 (16.5%) in the Prior-CB group (c2 test p = 0.0001). The mean number of reconnected PVs per patient was 0.5 ± 0.7 in the Prior-CB group vs. 1.5 ± 1.4 in the Prior-RF group. T-test = 3.8, p = 0.0003. The most frequently reconnected PV in the Prior-RF group was the left superior pulmonary vein (LSPV) with 54.1%, whereas in the Prior-CB group it was the right inferior PV with 22.2%, without statistically significant differences within groups. The 66.7% of the Prior-RF group and 40% of Prior-CB left common trunks were reconnected, without statistically significant differences between groups (c2 test p = 1). Both superior PVs were more commonly reconnected in the Prior-RF group than in the Prior-CB group, with 41% vs. 9% in right superior pulmonary vein (RSPV) (c2 test p = 0.008) and 54.1% vs 17% in LSPV (c2 test p = 0.005). Table 3 and Figure 1 show the pattern of vein reconnection within Prior-RF and Prior-CB groups.

Figure 1. Distribution of pulmonary vein reconnection in patients who had undergone a previous radiofrequency ablation (Prior-RF) or cryoballoon ablation (Prior-CB). Pearson’s χ2 test performed to show differences in the proportion of reconnection for each vein between groups.

Procedural and peri-procedural adverse events

Only 1 patient in the Prior-RF group had a procedural adverse event which presented as temporary phrenic nerve palsy and none of the Prior-CB patients had any procedural adverse events. More detailed information on adverse events in the RECABA study is described elsewhere [13].

Follow-up and AF recurrences

Patients included in this analysis were followed for a mean of 12.6 ± 1.8 months. AF detection was performed with an ECG at clinic visit in 35.1% of patients, 62.1% received a Holter monitor and 2.7% a loop recorder. There were no differences between groups (χ2 test p = 0.28). Kaplan-Meier survival estimates of 12-month freedom from AF recurrence were 61.0% (95% confidence interval [CI]: 41.4–75.8%) for the Prior-CB group and 89.2% (95% CI: 73.6–95.9%) for the Prior-RF group. Log-rank test for equality of survival function χ2 = 9.24, p = 0.002. Figure 2 depicts the Kaplan-Meier curves.

Figure 2. Kaplan-Meier survival curves for atrial fibrillation recurrence after a 3-month blanking period. Log-rank test is performed to compare the predefined groups, showing significant differences between them; Prior-RF — patients subjected to cryoballoon ablation after a failed previous radiofrequency atrial fibrillation ablation; Prior-CB — patients subjected to cryoballoon ablation after a failed previous cryoballoon atrial fibrillation ablation.

Table 4 shows univariate Cox regression models of possible predictors of AF recurrence. Figure 3 depicts the multivariate model that points to prior CBA as the sole independent predictor of AF recurrence, adjusted by obesity, obstructive sleep apnea, CHA2DS2-VASc score equal or greater than 2 points and finding all PVs already isolated. Prior-CB patients had more than double the likelihood of AF recurrence, with and adjusted hazard ratio of 2.67 (95% CI: 1.05–6.79). There were 6 hospitalizations in 5 patients due to AF-related events not linked to the procedure.

Figure 3. Multivariate Cox regression model of atrial fibrillation recurrence. Being subjected to cryoballoon ablation after a failed previous cryoballoon atrial fibrillation ablation vs. a previous radiofrequency catheter ablation was the only independent predictor of atrial fibrillation recurrence; CI — confidence interval; CHA2DS2-VASc — Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes mellitus, Stroke or transient ischemic attack, Vascular disease, Age 65–74 years, Sex category.

Discussion

The study results demonstrated that repeat CBA shows higher rates of AF recurrences compared to after a previous RFCA. Multivariate Cox regression pointed Prior-CB as the only independent predictor of AF recurrence in the present series. These data suggest that patients with AF recurrence after CBA may benefit from another ablation technique after a recurrence. In summary, RFCA may be more suitable for repeat procedures for the ability of performing non-PV related ablations.

Pulmonary vein reconnection after a previous procedure

In the present study, a larger number of reconnected PVs are described in patients after a previous RFCA procedure (40.4%, 1.5 ± 1.4 per patient) than after a previous CBA (16.5%, 0.5 ± 0.7 per patient) and an overall low number of reconnected PVs in the latter group.

Ciconte et al. [18] described a 20.4% of reconnected PVs after an index CBA (1.2 PV per patient) vs. 36.1% after contact-force RFCA (1.8 PV per patient), with a similar pattern as in the current study. In their series, LSPV were less frequently reconnected after CBA than after RFCA (8% vs. 38%). Pointing in this direction is also noted in Kuck et al. [19] analyzing the repeat procedures after the FIRE and ICE trial. They report an average of 2.1 reconnected PV per patient after RFCA vs. 1.4 after CBA. Moreover, there were less reconnected LSPV in the CBA group (28% vs. 60%) and a trend in RSPV (29% vs. 52%).

However, other published works did not find differences. Zeljkovic et al. [20] presented a series of patients with an index CBA or RFCA that underwent a repeat procedure using RFCA. The average reconnected PVs per patient were 2.1 for CBA and 2.2 for RFCA. In addition, Cheung et al. [21] analyze the repeat procedures from the CIRCA-DOSE trial, where patients were randomized to contact-force RFCA, 2-min CBA, or 4-min CBA. There were no differences in the reconnection pattern in those patients submitted to a repeat procedure, with a median and IQR of 2 (1–2), 2 (1–3), and 1 (1–4) of reconnected PVs per patient, respectively. Glowniak et al. [8] presented a similar series of patients with an index CBA or RFCA that underwent CBA as a repeat procedure. In their series, there was a larger proportion of reconnected PVs with 66.9% after an index RFCA and 51.5% after CBA.

In general, the present results are driven by a high burden of isolated veins after an index CBA, while reconnection pattern after RFCA is more like the abovementioned studies. These can be explained by the difficulties in keeping the catheter stable while ablating the LSPV ridge and LA roof at RSPV antrum. On the other hand, the CBA technique has improved in recent years, with standardized dosing protocols and lessons learnt from repeat procedures that may have led to more durable PV isolations in current procedures [16, 17, 22–28].

Cryoballoon ablation after an index procedure

Despite the abovementioned differences in PV reconnections between the Prior-CB and Prior-RF groups, no differences could be found in the number of CB freeze-applications, nadir temperature, thawing time, or fluoroscopy time. This means that it was common to perform CB applications on previously isolated veins, maybe aiming to perform wider, more antral lesions.

In the present series, up to 60.6% of Prior-CB patients had no reconnected PVs in the redo procedure, compared to 24.4% in the Prior-RF group. Being CBA, a technique designed to perform only PV isolation, it is intuitive to think that another round of freeze applications on already-isolated PVs will not be of much effect.

There were also slightly more patients in the Prior-CB group that used a 23-mm CB. This could be in the setting of changing the balloon size from the previous procedure as has been proposed, aiming to change the effect of CBA on an already ablated atrium [12].

Atrial fibrillation recurrence

According to available research, this is the largest series of patients that used CBA as a redo technique, with 33 patients. Data regarding a second CBA as a repeat ablation procedure are scarce. Schade et al. [11] published a series in 2013 of 47 patients that underwent a second CBA after AF recurrence. They used the first-generation CB (Artic Front, Medtronic) for both procedures and the rates of subjects with 1, 2, 3, or 4 reconnected PVs were 19.1%, 47.6%, 30.9%, and 2.4%, respectively. The pattern of reconduction was evenly distributed, which was between 63% of LSPV and 43% of right inferior pulmonary vein (RIPV). Sixty percent of patients remained AF-free after 12 months. Westra et al. [12] tried a different approach. They performed repeat ablations in 40 patients with recurrent AF after an index CBA, a repeat CBA using a different sized CB (i.e., changing from 23-mm to 28-mm in the second procedure and vice versa). The first procedures were performed with either the first- or second-generation CB and the repeat CBA only with the second-generation CB. Vein reconnection rates were 36% after first-generation CB (1.4 PVs per patient) and 18% for second-generation one (0.7 PVs per patient). The 1-year AF recurrence-free survival rate was 70%, with no differences regarding the index procedure balloon generation. The use of a 23-mm CB failed to be a predictor of recurrence in the current series, which could be driven by a small number of patients. However, the use of different sized CB remains an interesting concept.

The clinical outcomes of Glowniak’s study differ from the present results. In his series, both groups (CBA after and index CBA or RFCA) reach a 70.3% AF-free survival rate at 15 months. This divergence may be driven by the differences in PV reconnections. Their patients present more reconnected veins in the repeat CBA group (51.5% vs. 16.5% in the current series) which may be the reason for the AF recurrence and therefore solved with a new CBA. However, the current Prior-CB group has lower reconnection rates and relapse could be driven by non-PV triggers, which would not benefit from another PV isolation-only procedure [29]. Nevertheless, regression analysis showed that a Prior-CB was the strongest predictor of recurrence, overcoming the rate of already isolated veins (Fig. 3). This could mean that this effect is not only driven by the rate of reconnected PVs, but by the previous CBA procedure itself and thus selecting a population with worse arrhythmic prognosis.

On the other hand, the Prior-RF group had better outcome with a survival estimate of almost 90% at 12 months, which is consistent to other published works. De Regibus et al. [30] used a second-generation CB in 47 patients with recurrent AF after RFCA. Fifty-three percent of patients presented with one reconnected PV, 23.4% with 2, 17% with 3, and 6.4% with all-four PVs reconnected. After a follow-up of 15 months, 83% remained AF-free after a 3-month blanking period. Verlato et al. [9] share a work, where they alternate the ablation technique for the repeat procedure (i.e., index CBA followed by RFCA and vice versa). They included 349 patients in the RF-then-CB group and 125 in the CB-then-RF group. Ablation of non-PV triggers, left atrial flutter or cavo-tricuspid isthmus in the redo RFCA procedure was at the operators’ discretion. They showed a reconnection rate of 3.7 PVs per patient in the RF-then-CB group and 1.4 PVs the CB-then-RF, and an outcome of freedom from AF at 12 months after a 3-month blanking period of 76.6% vs. 89.1%, respectively. Forty-seven percent of patients in the CB-then-RF group underwent additional non-PV ablation. The RF-then-CB population is represented in the current study and presents a similar outcome, while the CB-then-RF shows the best results. These findings are consistent with those herein, and points in the direction that RFCA may be more suitable for repeat procedures for the ability of performing non-PV ablations.

Limitations of the study

This is a non-predefined analysis of a prospective cohort study, with a limited number of patients compared to the whole population included. However, it is the largest cohort of patients with CBA as a redo procedure with 74 patients. The main limitation of the present study is the lack of procedural data from previous ablations, like the size or generation of the CB used, the CB application protocol or if RFCA consisted of more than PVI. Another limitation would be the method for AF detection, as only 2.7% of patients would receive an insertable loop recorder.

Nevertheless, this does not invalidate the present work since results are consistent with previously published data and the groups were mostly homogeneous. Moreover, RECABA was a multicentric study focused on describing everyday practice, and having present results despite heterogenous protocols weighed more on validating them.

Conclusions

Pulmonary vein reconnections are more frequently found in patients submitted to repeat AF ablation after an index RFCA than after an index CBA. Patients submitted to a repeat CBA have more AF recurrences than those that undergo CBA as a redo after an index RFCA. These data suggest that patients with AF recurrence after CBA may benefit from other ablation techniques after a recurrence.

Acknowledgments

We would like to thank I. Molina, S. Bello, and P. Pascual from Medtronic scientific department, who were responsible for the study’s national coordination and database.

Conflict of interest: Jorge Enrique Toquero Ramos is a member of the Medtronic European Advisory Board and received fees for active participation in training courses. Óscar Cano Pérez received consultant honoraria from Medtronic, Biotronik and Boston Scientific. The rest of the authors do not disclose any conflict of interest.