Data concerning all patients undergoing the first PVI using CBA technology, between August 2014 and November 2020, who accomplished more than 12 months of follow-up, referred to four centers (Arrythmology Unit, Cardiology Department, Santa Marta Hospital, in Lisbon; Cardiology Department, Gaia/Espinho Hospital Center, Gaia; CUF Tejo Hospital, Heart & Vessels Center, Lisbon; CUF Porto Hospital, Heart Center, Porto) were retrospectively analyzed. The objectives of this analysis were to assess the procedural characteristics, efficacy, safety, and long-term outcomes when using a CBA catheter to treat patients with AF.

In this evaluation window, data were collected on procedures performed by seven unique operators at the mentioned centers (two centers were tertiary public hospitals, and the other two centers were private hospitals). The selection of patients to undergo the cryoablation technique was left at the discretion of the different participating centers.

Subject data were excluded from current analysis if patients were diagnosed with long-standing persistent AF (continuous AF >12 months), had a prior cardiac ablation for the treatment of atrial arrhythmia(s), had incomplete baseline data reported, or had not completed 12 months of follow-up at the time of the analysis.

All patients had symptomatic and drug-resistant (who had failed at least one antiarrhythmic drug) AF (paroxysmal or persistent for <12 months). Subjects were classified as having PAF if they had an episode(s) of AF that terminated spontaneously or with intervention within seven days of onset. Patients were classified as having persistent AF if they had a sustained episode(s) of AF that lasted longer than seven days but less than 12 months, including episodes ≥7 days that were terminated by cardioversion.1

All participants provided written informed consent for both the ablation procedure and data collection. Data were collected for each patient from clinical records and included demographic, clinical information, pharmacological therapy, date of hospitalization and discharge, presence of comorbidities, ablation characteristics, and cardiovascular events during hospitalization and long-term outcomes.

All the procedures were performed using the Arctic Front™ Advance Pro Cryoballoon (Medtronic Inc, Minneapolis, MN), and the 28-mm cryoballoon catheter. Research in this study was conducted according to the Helsinki Declaration guidelines on human research. All patients provided written informed consent.

Patients underwent preprocedural transthoracic echocardiography to assess left ventricular ejection fraction, left atrial dimensions, and exclusion of structural heart disease. A preprocedural computed tomography or magnetic resonance imaging (with the segmentation of the left atrium) was performed to assess left atrial anatomy and to exclude the presence of intracardiac thrombi. Additionally, if the mentioned imaging study was performed >48 hours before ablation, transesophageal echocardiography was done on the day of the procedure (for exclusion of thrombi). All antiarrhythmic medications except amiodarone were usually discontinued >5 half-lives before the ablation. Regarding oral anticoagulation, patients underwent ablation either with continued oral anticoagulation (for at least three weeks before ablation) using warfarin with a therapeutic INR (2.0–3.0) or using low-molecular-weight heparin bridging. If the patient was under direct oral anticoagulants (DOAC) the dosage was omitted in the evening before the ablation. Throughout the procedure, there was rigorous monitoring of oxygen saturation and ECG. All the procedures were carried out in conscious sedation, using propofol infusion, or under general anesthesia.

Through the right femoral vein, a deflectable decapolar catheter was inserted and positioned into the coronary sinus to guide the transseptal puncture and to pace the left atrium for electrophysiological study.

A single transseptal puncture was performed using a needle system (BRK, St. Jude Medical, St. Paul, MN, USA) and a standard transseptal sheath (SL1 8F or 8.5F, St. Jude Medical, St. Paul, MN, USA), that was later exchanged with the steerable 15F sheath (FlexCath™, 15F, Medtronic, Inc., Minneapolis, MN, USA) for the advancement of the cryoballoon.

Immediately before transseptal puncture, heparin was administered intravenously as a bolus (100 U/kg of standard heparin), followed by additional bolus to achieve an activated clotting time between 300 and 350 s during the procedure. Throughout the procedure, the FlexCath was continuously irrigated with heparinized saline. The 28-mm balloon was used for all procedures. The balloon was advanced to the antrum of each PV and different cryoballoon positions were assessed by injecting contrast into the vein distal to the balloon to ensure optimal occlusion.

Regarding energy applications, after successful PVI (240 s, aiming for a minimum temperature of less than −40°C), an additional freeze-cycle of the same duration was applied at the discretion of the operator. The application was aborted if the minimum temperature went below −60°C.

Phrenic nerve function was checked during energy application in the right PV by pacing with a diagnostic catheter at the level of the right subclavian vein and adjunctive monitoring for diaphragmatic function by observing diaphragmatic movement under fluoroscopy, by manual abdominal palpation, and concomitantly by using diaphragmatic compound motor action potential (CMAP) recording.10 The ablation was immediately stopped if phrenic nerve function was affected (either by observing a reduction in the CMAP potential amplitude or by visual or manual inspection).

The goal of CBA was to obtain electrical isolation of the four major PV. Combined common left PV was likewise ablated to achieve similar blockage. Electrical isolation was established after evaluating bidirectional block, confirmed with high-output pacing (10 V, 2.9 ms) using the Achieve™ mapping catheter (Medtronic, Inc., Minneapolis, MN, USA). If there were any residual conduction, further cryotherapy applications were delivered until isolation was established. Before withdrawing the catheter from the left atrium, operators confirmed that all PV potentials were abolished or dissociated.

After ablation, all patients remained under continuous monitoring at the cardiology ward or intensive care unit for at least 24 hours.

After the ablation procedure, patients were discharged on antiarrhythmic drugs at the discretion of the operator, together with either warfarin or a direct oral anticoagulant. Patients were observed for routine follow-up in the outpatient clinic one to three months after the procedure, and every three to six months (or earlier, if symptoms) during the first year post-ablation. After one year, clinical appointments were scheduled every six months. At each visit, a standard 12-lead ECG was obtained. All patients were followed up with a 24 hour Holter or external event recorder at each outpatient visit. A recurrence was considered if there were any documented episodes of AF or atrial arrhythmias lasting >30 s or sustained symptomatic episodes of rapid palpitations after a 90-day blanking period post-PVI. Antiarrhythmic drugs were continued for between three to six months after the ablation procedure and were thereafter withdrawn – except for beta-blockers – if the patients were free from arrhythmia-related symptoms. Oral anticoagulation was re-evaluated in the third month, and the decision for continued use was based on the CHA2DS2-VASc score. Clinical events occurring during the follow-up were evaluated. Success was defined as freedom from symptomatic arrhythmia and the absence of AF or any atrial tachyarrhythmia (AT) during the above-mentioned ECG monitoring.

Descriptive statistics were used to summarize patient characteristics, procedural characteristics, safety, and follow-up. Continuous variables were expressed as mean±SD, and categorical data were summarized as frequencies and percentages. The baseline characteristics of the patients and outcomes were compared between the subgroups with the use of the Kruskal–Wallis test for continuous variables and the chi-square test or Fisher's exact test for dichotomous variables, when appropriate. Pearson's correlation coefficient was used to test associations between continuous variables. The Kaplan–Meier method was used to determine cumulative estimates of AF recurrence from the time of enrollment through posterior follow-up, according to the treatment group, with between-group comparisons of cumulative event rates calculated using the log-rank test. Univariate and multivariate Cox regression models were used to determine what variables were significant by themselves in predicting arrhythmia recurrence. All statistical tests were two-sided, and a p-value of <0.05 was considered to indicate statistical significance. The p-values for interaction are reported. Data were analyzed using IBM SPSS for Windows, version 28.0 (IBM SPSS Inc., Chicago, IL).

This non-randomized cohort consisted of 406 consecutive patients (270 men; 66.5%), which corresponded to about 25% of the total AF ablations in each center. The mean age of the cohort was 57.7±12.4 years (range 14–82 years) and the mean follow-up duration was 22.0±15.0 months. Of these, 326 (80.2%) patients had PAF, and 82 (20.1%) had PersAF. Concomitant cardiovascular diseases included essential hypertension in 165 (40.6%) patients, coronary heart disease in 16 (3.94%), and sick sinus syndrome with a permanent pacemaker in 4 (0.98%). The left ventricular ejection fraction was normal in all but 17 patients (4.18%). The left atrial diameter was 44±6 mm (range 35–62 mm). The procedure was the first ablation performed in all patients. Regarding the distribution of the patients included in the registry by centers, 147 patients were included in Gaia/Espinho Hospital Center, 182 patients in Santa Marta Hospital, 66 patients in CUF Tejo Hospital, and 11 patients in CUF Porto Hospital. Detailed baseline clinical and demographic characteristics of the study population are reported in Table 1.

Regarding anatomic variations of the PV ostia, we found that they were present in 66 (16.2%) patients. Of these anatomic variations, 47 (11.5%) patients had a left common ostium, 18 (4.4%) had a third right PV with a separate ostium (accessory right middle or upper PV draining independently into the left atrium), and 1 patient had three left PV separated ostia.

As stated previously, cryothermal energy applications were delivered to each PV (maximum duration 240 s per application), aiming for a minimum temperature of less than −40°C. The mean procedure time (from the first insertion to the withdrawal of all catheters) was 107.7±50.9min and the fluoroscopy time was 19.5±9.7 min. Isolation of all pulmonary veins was achieved in 99.2% (n=403) of patients. Radiofrequency touch up was required in three patients (0.7%), all of them undergoing cryoablation in the initial phase of the center's experience. In our study cohort, there was no documentation of atrial tachycardia or left atrial flutter, but there were two right atrial flutters during the procedure that required cavotricuspid isthmus ablation with a radiofrequency catheter.

Procedural and periprocedural complications occurred in 30 patients (7.3%), the most frequent being phrenic nerve palsy (Table 2). The paralysis was observed in 20 patients (4.9%) and led to acutely stopping the application and repositioning the cryoballoon. There was an immediate recovery in all but one patient, in whom phrenic nerve palsy persisted beyond the end of the procedure, with the need for respiratory rehabilitation exercises and full recovery eight months after ablation. Other complications included four (0.98%) cases of pericardial effusion requiring draining, four (0.98%) cases of minor hemorrhage in the access site or a false aneurysm formation, one (0.25%) case of acute hemoptysis, and one (0.25%) case of transient high-degree atrioventricular block. Transfusion of blood products was not necessary in any of the cases described.

After a mean follow-up of 22.0±15.0 months, 310 (76.3%) patients remained in stable sinus rhythm, without evidence of AF recurrence, with no antiarrhythmic drugs (Figure 1). Symptomatic and clinically typical sustained episodes (without available documentation), AF, or a sustained AT (atrial tachycardia or atrial flutter – including typical and atypical atrial flutter) were documented in 98 (24.1%) patients.

Figure 1.

Procedural success is given as freedom from atrial fibrulation as a function of time.

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Detailing the population with AF/AT recurrence: 67 (16.5%) were from the PAF group and 31 (7.6%) from the persistent AF group (Figure 2). Regarding the specific recurrence rate inside each group, there was a 20.5% in the PAF group and a 38.7% recurrence rate in the persistent AF group (p<0.01). Twenty-seven patients (27.5% of all recurrences) received a second procedure (all cases performed with RF).

Figure 2.

Kaplan–Meier analysis showing atrial arrhythmia-free survival by type of atrial fibrillation (paroxysmal vs. non-paroxysmal), after a single cryoballoon procedure.

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In the univariate Cox regression analysis, the left atrial indexed volume (LAIV, ml/m2) was identified as a predictor of arrhythmia recurrence (p=0.03), left atrial diameter (mm), and the type of AF (paroxysmal vs. non-paroxysmal) were also independent predictors of AF/AT recurrence (p=0.039 and p=0.045; respectively). The remaining clinical and analytical covariates (including gender, age, body mass index, obstructive sleep apnea, heart failure, valvular, and coronary heart disease) were not considered predictors of recurrence.

Patients with a normal left atrial volume index (LAVI) (<30 ml/m2) achieved 85% arrhythmia-free survival during the long-term follow-up period (Figure 3). Patients with mildly (<35 ml/m2) and moderately (<40 ml/m2) enlarged atria achieved 79% and 75% arrhythmia-free survival, respectively. Patients with a severely dilated LA (>40 ml/m2) achieved only 64% arrhythmia-free survival.

Figure 3.

Arrhythmia-free survival during the long-term follow-up period, according to left atrial index volume.

Left atrial index volume (LAIV): normal – <30 ml/m2; mildly dilated – <35 ml/m2; moderately dilated – <40 ml/m2; severely dilated – >40 ml/m2).12

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Our study is a multi-center real-life assessment, with a single-arm observational design, not a randomized controlled trial. Also, this was not a prospective study with a predefined protocol for all centers. However, all the operators used the current standard technique for PVI with the 28-mm Arctic Front Advance Pro Cryoballoon.

No continuous or long-duration monitoring for detecting arrhythmia recurrence was systematically used. Therefore, AF recurrence rate and asymptomatic episodes might have been underestimated. On the other hand, symptomatic sustained episodes, even without documentation, were considered recurrences.