Comparison of procedural efficacy, balloon nadir temperature, and incidence of phrenic nerve palsy between two cryoballoon technologies for pulmonary vein isolation: A systematic review and meta‐analysis

Abstract Introduction In May 2020, a novel cryoballoon system (POLARx; Boston Scientific) became available for catheter ablation of atrial fibrillation (AF). The design of the cryoballoon is comparable to the Arctic Front Advance Pro (AFA‐Pro; Medtronic), but it is more compliant during freezing. We compared the procedural efficacy, biophysical parameters, and risk of phrenic nerve palsy (PNP) between the two cryoballoons. Methods Embase, MEDLINE, Web of Science, Cochrane, and Google Scholar databases were searched until June 1, 2021 for relevant studies comparing POLARx versus AFA‐Pro in patients undergoing pulmonary vein isolation (PVI) for AF. Results A total of four studies, involving 310 patients were included. There was no difference between the two groups for outcomes regarding procedural efficacy: acute PVI (odds ratio [OR]: 0.43; 95% confidence interval [CI]: 0.06 to 3.03; p = .40), procedure time (mean difference [MD]: 8.15 min; 95% CI: −8.09 to 24.39; p = .33), fluoroscopy time (MD: 1.32 min; 95% CI: −1.61 to 4.25; p = .38) and ablation time (MD: 1.00 min; 95% CI: −0.20 to 2.20; p = .10). The balloon nadir temperature was lower for all individual pulmonary veins (PV) in POLARx compared with AFA‐Pro (MD: −9.74°C, −9.98°C, −6.72°C, −7.76°C, for left superior PV, left inferior PV, right superior PV, and right inferior PV, respectively; all p < .001). The incidence of PNP was similar between groups (OR: 0.79; 95% CI: 0.22 to 2.85; p = .72). Conclusion In AF patients undergoing PVI, POLARx and AFA‐Pro had a similar procedural efficacy. Balloon nadir temperatures were lower with POLARx, however, the incidence of PNP was similar.


| INTRODUCTION
Pulmonary vein isolation (PVI) remains the cornerstone of catheter ablation of atrial fibrillation (AF). 1 Among the different available single-shot devices, cryoballoon has demonstrated to be as effective and safe as radiofrequency ablation for achieving PVI. [2][3][4][5][6][7][8] Advantages of the cryoballoon in comparison to radiofrequency ablation is the shorter procedure duration and lower interoperator variability in outcomes. [2][3][4][5][6][7][8] In May 2020, a novel cryoballoon was introduced, the POLARx cryoablation system (Boston Scientific). One of the unique features of this cryoballoon is that it maintains a uniform pressure and size during inflation and cryoablation. Several centers have published their initial clinical experience with this POLARx cryoablation system and have compared it with the fourth-generation Arctic Front Advance Pro (AFA-Pro) cryoballoon (Medtronic). [9][10][11][12] Most of these studies are limited by their small sample size, observational design, and single-center design. A meta-analysis may overcome part of these limitations and may provide more robust data. These data are relevant for operators interested in the performance of the novel POLARx cryoballoon in clinical practice.

| Aim of the study
The aim of this comprehensive meta-analysis was to compare the differences in procedural efficacy, balloon nadir temperature, and incidence of phrenic nerve palsy (PNP) between POLARx and AFA-Pro in patients with AF undergoing PVI.

| Search strategy and study selection
This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis literature search extension (PRISMA-S) and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklists (Appendix SA). 13,14 The librarian-mediated systematic search strategy of our center was previously described. 15 The following electronic databases were searched on June 1, 2021: EMBASE (Ovid), MEDLINE (Ovid), Web of Science Core Collection (Web of Knowledge), Cochrane Central Register of Controlled Trials (Wiley), and Google Scholar. The search involved the following keywords: ("polarx" OR ("cryoablation" or "cryoballoon") OR ("fourthgeneration" or "4 th -generation" or "4 th -CB" or "CB4" or "CBG4" or "arctic front" or "AFA-Pro")) AND ("pulmonary vein isolation" or "PVAI" or "PVI"). The complete search strategy per database is reported as Supporting Information (Appendix SB). We also searched ClinicalTrials.gov to identify ongoing trials. The search was limited to the English language and adult (18 years or older) human participants. All searches were limited to publications from 2019 to 2021 given that the POLARx cryoballoon was only commercially available in May 2020. Reference lists of included studies were manually screened to identify additional studies.

| Eligibility criteria
The studies included fulfilled the following criteria: (1) patients with paroxysmal and/or persistent AF undergoing PVI with a cryoballoon; (2) comparison of POLARx cryoballoon with AFA-Pro cryoballoon; and (3) reported outcome data including but not limited to acute PVI success, procedure time, fluoroscopy time, ablation time, balloon nadir temperature for each pulmonary vein (PV), and PNP. The following exclusion criteria were used: conference abstracts, case reports, review articles, editorials, and letters to the editor. Two reviewers screened articles using EndNote for inclusion independently, retrieved potentially relevant articles, and determined their eligibility. 16 Disagreements were resolved through consensus, and consultation of a third reviewer if necessary.

| Data abstraction, data extraction, and quality assessment
The following baseline patient characteristics were extracted from each

| Statistical analysis
For continuous outcome variables, the pooled mean difference (MD) and the corresponding 95% confidence intervals (CI) were estimated using the inverse-variance method. If a study provided medians and interquartile ranges or ranges, we estimated the means and SDs using Wan et al.'s 17 method for the purpose of this meta-analysis. For categorical outcome variables, the pooled odds ratio (OR) and corresponding 95% CI were estimated using Mantel-Haenszel random-effects model. 18

| Search results and baseline characteristics
Among 917 unique citations, 14 citations were retrieved for full-text review. Following the review, a total of four studies met inclusion criteria ( Figure 1). [9][10][11][12] All four included studies were observational in design and found to be of good quality based on the Newcastle Ottawa scale (Table S1).
In total, 310 patients were included in the analysis of whom 142 and 168 patients underwent ablation with the POLARx and AFA-Pro system, respectively. The characteristics of the included studies are summarized in Table 1. Baseline patient characteristics among the included studies are shown in Table 2. The mean or median age of the patients ranged from 61 to 69 years and the proportion of males ranged from 52% to 84%. The proportion of patients with paroxysmal AF ranged from 36% to 95%.

| Pooled analysis
There was no difference in achieving successful acute PVI between the two groups (OR: 0.43; 95% CI: 0.06 to 3.03; p = .40). There was also no statistically significant difference between the two groups in the out-

| Sensitivity analysis
There was significant statistical heterogeneity (I 2 ≥ 50%) for the outcomes

| STUDY LIMITATIONS
All studies included in this meta-analysis were observational studies, but they were of good quality based on the Newcastle Ottawa scale. Ideally, the results of our meta-analysis should be confirmed in randomized controlled trials. Currently, there are two ongoing randomized controlled trials comparing POLARx and AFA-Pro for the treatment of paroxysmal AF (NCT04704986, ACTRN12621000003875); however, both trials are not recruiting patients according to the latest update (June 1, 2021). For some outcome parameters, there was significant heterogeneity between studies, but to account for this we used a random-effects model a priori.
We report only on the acute outcome; thus, we do not have data on longterm outcome such as persistent PNP and freedom from atrial arrhythmia. This limitation is inherent to the recent introduction of the POLARx cryoballoon. Furthermore, it was not possible to provide a forest plot for time-to-isolation as most studies did not provide data on how often time-to-isolation could be recorded. Finally, considering the selection of centers for limited market release of the POLARx cryoballoon who published their initial experience, the results of this meta-analysis should be viewed with caution as it may not be generalizable to other centers.

| CONCLUSION
The novel POLARx cryoballoon is comparable to AFA-Pro with regard to procedural efficacy in terms of acute PVI, procedural time, fluoroscopy time, and ablation time. Although the balloon nadir temperatures were significantly lower with POLARx, the risk of PNP was comparable to AFA-Pro.

ACKNOWLEDGMENTS
The authors wish to thank Maarten F. M. Engel, PhD, from the Erasmus MC Medical Library for developing and updating the search strategies.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.