Comparison of procedural efficacy and biophysical parameters between two competing cryoballoon technologies for pulmonary vein isolation: Insights from an initial multicenter experience

Abstract Introduction Recently a novel cryoballoon system (POLARx, Boston Scientific) became available for the treatment of atrial fibrillation. This cryoballoon is comparable with Arctic Front Advance Pro (AFA‐Pro, Medtronic), however, it maintains a constant balloon pressure. We compared the procedural efficacy and biophysical characteristics of both systems. Methods One hundred and ten consecutive patients who underwent first‐time cryoballoon ablation (POLARx: n = 57; AFA‐Pro: n = 53) were included in this prospective cohort study. Results Acute isolation was achieved in 99.8% of all pulmonary veins (POLARx: 99.5% vs. AFA‐Pro: 100%, p = 1.00). Total procedure time (81 vs. 67 min, p < .001) and balloon in body time (51 vs. 35 min, p < .001) were longer with POLARx. After a learning curve, these times were similar. Cryoablation with POLARx was associated with shorter time to balloon temperature −30°C (27 vs. 31 s, p < .001) and −40°C (32 vs. 54 s, p < .001), lower balloon nadir temperature (−55°C vs. −47°C, p < .001), and longer thawing time till 0°C (16 vs. 9 s, p < .001). There were no differences in time‐to‐isolation (TTI; POLARx: 45 s vs. AFA‐Pro 43 s, p = .441), however, POLARx was associated with a lower balloon temperature at TTI (−46°C vs. −37°C, p < .001). Factors associated with acute isolation differed between groups. The incidence of phrenic nerve palsy was comparable (POLARx: 3.5% vs. AFA‐Pro: 3.7%). Conclusion The novel cryoballoon is comparable to AFA‐Pro and requires only a short learning curve to get used to the slightly different handling. It was associated with faster cooling rates and lower balloon temperatures but TTI was similar to AFA‐Pro.


| INTRODUCTION
The cornerstone of atrial fibrillation (AF) ablation is complete isolation of the pulmonary veins (PVs). 1 Among the different available single-shot devices, the cryoballoon has demonstrated to be as effective and safe as radiofrequency ablation for achieving pulmonary vein isolation (PVI), while being associated with shorter procedure duration and longer fluoroscopy time. [2][3][4][5][6][7] Furthermore, cryoballoon ablation seems to be less operator-dependent than radiofrequency ablation. 8 Recently, a novel cryoballoon was introduced, the POLARx cryoablation system (Boston Scientific). The unique feature of this cryoballoon is that it maintains a uniform pressure and size during inflation and cryoablation. Theoretically, a more compliant balloon can improve PV occlusion resulting in a more effective cryoenergy delivery. Currently, limited data exists on the biophysical characteristics of this novel cryoballoon. 9 Knowledge of biophysical parameters, such as nadir balloon temperature and balloon thawing time, is important as they have been shown to be associated with durability of PVI after cryoballoon ablation. 10-12

| Aim of the study
The aim of this study was to compare the procedural efficacy and biophysical parameters of the novel POLARx system (Boston Scientific) with the currently established fourth-generation Arctic Front Advance Pro system (AFA-Pro, Medtronic).

| Study population
In this prospective cohort study, we included consecutive patients who underwent a first-time cryoballoon ablation for the treatment of symptomatic paroxysmal or persistent AF between May and October 2020. Starting in May 2020, there was a limited market release of the POLARx cryoablation system in Europe. Patients were included from three highly experienced cryoballoon ablation centers. The study was approved by the institutional review board of each center.

| Periprocedural management
All patients received oral anticoagulation for at least 4 weeks before ablation. Periprocedural anticoagulation regime was carried out according to the local standards. To exclude left atrial thrombi, all patients underwent transesophageal echocardiogram within 24 h of the procedure or by intracardiac echocardiography before transseptal puncture.

| Ablation procedure
All procedures were performed with local anesthesia and analgosedation. After vascular access was obtained, a single transseptal puncture was performed. Intravenous heparin was administered to achieve a target activated clotting time of more than or equal to 300 s. All patients underwent PVI using a 28-mm cryoballoon After optimal PV occlusion was achieved, assessed by contrast injection, cryoablation was started. A time-to-isolation (TTI) guided ablation protocol was used. The freeze duration was 180 s if TTI was less than 60 s, otherwise a 240-s freeze cycle was employed. No bonus freeze was employed routinely. PVI was confirmed by entrance/exit block at the end of the procedure.
During cryoablation of the right-sided PVs, either breathing maneuvers or high-output right phrenic nerve stimulation was performed using a diagnostic catheter in the right subclavian vein or superior vena cava. Diaphragmatic excursion was assessed by palpation or, in case of the POLARx system, by using the Diaphragmatic Movement Sensor (DMS). The DMS uses an accelerometer and provides a relative measure of the diaphragmatic excursion.
Whenever the diaphragmatic excursions decreased or the DMS percentage drops below a cutoff (65%), cryoablation was immediately terminated. During cryoablation of the left-sided PVs, a diagnostic catheter was placed in the right ventricle to provide ventricular pacing in case of a vagal response after cryoablation.  chosen because a previous study demonstrated that a thawing time till 0°C more than or equal to 10 s predicts durable PVI after cryoballoon ablation with the second-generation cryoballoon (Arctic Front Advance, Medtronic). 10 TTI was defined as the time duration required to achieve PVI after start of CBA. All time variables were expressed in seconds.

| Data collection
With the AFA-Pro cryoballoon system, TTI was manually recorded after achieving PVI. The cryoablation binary data files stored in the CryoConsole (Medtronic) were used to analyze various biophysical parameters (i.e., balloon temperature at TTI, time to balloon temperature −30°C, time to balloon temperature −40°C, nadir balloon temperature, and thawing time till 0°C).
With the POLARx cryoballoon system, TTI could be annotated by the operator during the CBA by pressing the foot pedal for 3 s.
Most biophysical data can be exported from the SMARTFREEZE console (Boston Scientific) onto a pdf-file (i.e., TTI, time to balloon temperature −30°C, time to balloon temperature −40°C, nadir balloon temperature, and thawing time till 0°C). Only balloon temperature at TTI had to be collected from the cryoablation binary data files from the SMARTFREEZE console (Boston Scientific).

| Follow-up
All patients were followed up for at least 1 month after the procedure to collect data on acute procedural complications and mainly to rule out atrioesophageal fistula. Patients with phrenic nerve palsy underwent a chest x-ray during follow-up. Patients who developed pulmonary symptoms underwent a cardiac computed tomography to rule out complications. Antiarrhythmic drugs were stopped at the discretion of the operator.

| Statistical method
Continuous data are presented as median with 25th and 75th percentile as the data were not normally distributed. Categorical variables are presented by frequencies and percentages. Differences of continuous variables between the two groups were analyzed with the nonparametric Mann-Whitney U-test. Differences between categorical variables were evaluated using the χ 2 test or Fisher′s exact test. Statistical analyses were performed using MATLAB R2020a. All statistical tests were two-sided. p values less than .05 were considered statistically significant.

| Study population
In the study period, 110 consecutive patients underwent a first cryoballoon ablation for the treatment of AF. The POLARx and AFA-Pro system was used in 57 and 53 patients, respectively. The short-tip POLARX balloon was used in the majority (93.0%) of the cases in the POLARx group. Baseline patient characteristics are presented in Table 1 Table 2.
Procedure time and balloon in body time were longer, and the amount of contrast agent used was higher in the POLARx group in comparison with the AFA-Pro group. Other procedure-related variables, including the median number of CBA per patient, fluoroscopy time, radiation dose, and additional CTI ablation were similar between groups (

| Comparison of procedural and biophysical parameters between groups
There was no difference in the magnitude of PV occlusion between groups (Table 3). In the majority of cases a Grade 4 occlusion could be achieved. Cryoablation with POLARx was associated with a shorter time to balloon temperature −30°C and −40°C, a lower balloon nadir temperature, and a longer thawing time till 0°C. PV potentials could be recorded more often during CBA with POLARx than with AFA-Pro (96.3% vs. 88.6%, p < .001). TTI could be recorded in 93.1% of PVs using POLARx versus 79.6% using AFA-Pro (p < .001). There were no differences in TTI between systems, however, POLARx was associated with a lower balloon temperature at TTI in comparison with AFA-Pro. Detailed information with regard to balloon nadir temperature and thawing time till 0°C for each PV is presented in Figure 2. POLARx was associated with a lower balloon nadir temperature and longer thawing time till 0°C for each PV in comparison with AFA-Pro.

| Procedural and biophysical parameters associated with acute PVI
A comparison of procedural and biophysical parameters of CBAs resulting in acute PVI or no acute PVI per system is provided in

| Complications
Overall, the incidence of complications was low in both groups. One groin hematoma occurred in the POLARx group which was treated conservatively. Two phrenic nerve palsies were recognized in each group, which did not recover at hospital discharge (

| DISCUSSION
Cryoballoon ablation has established itself as an alternative technique to radiofrequency ablation for the treatment of patients with symptomatic AF. 14 Several randomized trials have shown noninferiority with respect to efficacy and safety of the first-and second-generation cryoballoon systems in comparison with radiofrequency ablation. [2][3][4][5] The fourth-generation cryoballoon (AFA-Pro,  Balloon-tissue contact is important to achieve an optimal effect of cryoballoon ablation. The magnitude of PV occlusion as visualized by PV angiography is a practical marker of optimal balloon-tissue contact and is a predictor of a durable PVI. 10 In clinical practice, the aim is to achieve a Grade 4 PV occlusion before starting cryoabla- Several studies have shown that TTI is the most powerful predictor of durable PV isolation. 10,[18][19][20][21] In clinical practice, a TTI less than or equal to 60 s is the target for CBA. In our study, there was no difference in the median TTI between both systems and the median TTI was less than or equal to 60 s. This suggests that the speed of cryoenergy transfer to the atrial tissue is similar between both systems. Interestingly, TTI could be recorded in a higher percentage of PVs with POLARx than with AFA-Pro (93.1% vs. 79.6%). This difference may be explained by the shorter distal tip of POLARx (5 mm) in comparison to AFA-Pro (8 mm), which brings the circular mapping catheter closer to the PV ostium. Furthermore, there is an additional insulation of the core wire in POLARMAP (circular mapping catheter) which allows an increase in recording gain without jeopardizing the quality of the signal (higher signal-to-noise ratio).
Several biophysical parameters have been evaluated as possible predictors of durable PV isolation, such as balloon cooling rates, balloon nadir temperature, and balloon thawing times. [10][11][12] Previous studies have shown that the most reliable biophysical marker of durable PVI is the balloon thawing time with the first-and secondgeneration cryoballoon (Arctic Front and Arctic Front Advance, Medtronic). 10,12 Longer thawing times may not only represent colder CBA but also more effective CBA. A longer thawing time is believed to promote additional cellular injury. 10,22 The present study showed that the POLARx system has a longer thawing time till 0°C than AFA-Pro. Whether this translates into a higher prevalence of durable PV isolation with POLARx is unknown and requires further investigation.
In our study,

| Study limitations
First, the data acquired from the POLARx system was based on our initial experience with this novel cryoballoon system. Although the general workflow of the procedure is similar to the AFA-Pro system, there are small differences with regard to the approach to achieve optimal PV occlusion. This is reflected by the longer procedure and

| CONCLUSION
The novel POLARx cryoballoon is comparable with AFA-Pro with regard to efficacy and safety. Accordingly, a short learning curve is required to get used to the slightly different handling due to the compliant nature of the balloon. POLARx was associated with faster cooling rates and lower balloon temperatures but TTI was similar in both groups.

ACKNOWLEDGMENTS
This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Abbreviations: AFA-Pro, Arctic Front Advance Pro; CBA, cryoballoon application; PVI, pulmonary vein isolation. a Only CBA>100 s was incorporated in the data.