Direct Comparison Between Second-Generation Cryoballoon Ablation Versus Contact Force-Sensing Radiofrequency Ablation in Paroxysmal Atrial Fibrillation Patients: A Systematic Review and Meta-Analysis Study

Pulmonary vein isolation (PVI) is the main ablation approach for paroxysmal atrial brillation (AF). The superiority of the second-generation cryoballoon (2G-CB) ablation over contact force-sensing radiofrequency (CF-RF) ablation is unclear. Therefore, we sought to investigate the superiority of 2G-CB ablation over CF-RF ablation in paroxysmal AF patients. A systematic review and meta-analysis study was conducted. We included 12 studies involving 1419 patients. The overall effects were quantied using pooled odds ratio (OR) or mean difference (MD) for categorical or continuous variables. not superior to CF-RF ablation of paroxysmal AF in terms of acute PVI, freedom from ATAs, and freedom from AF. The 2G-CB ablation procedure can be performed faster than CF-RF ablation, although the uoroscopy time between both groups was not signicantly different. The 2G-CB ablation was also associated with a higher rate of phrenic nerve paralysis than CF-RF.


Abstract Background
Pulmonary vein isolation (PVI) is the main ablation approach for paroxysmal atrial brillation (AF). The superiority of the second-generation cryoballoon (2G-CB) ablation over contact force-sensing radiofrequency (CF-RF) ablation is unclear. Therefore, we sought to investigate the superiority of 2G-CB ablation over CF-RF ablation in paroxysmal AF patients.

Methods
A systematic review and meta-analysis study was conducted. We included 12 studies involving 1419 patients. The overall effects were quanti ed using pooled odds ratio (OR) or mean difference (MD) for categorical or continuous variables.

Conclusion
The 2G-CB ablation was not superior to CF-RF ablation in paroxysmal AF in terms of acute PVI, freedom from ATAs, and freedom from AF. The 2G-CB ablation procedure can be performed faster than CF-RF ablation, although correlated with a higher phrenic nerve paralysis.

Background
In daily clinical practice, the most common arrhythmia encountered by the physician is atrial brillation (AF) [1,2]. AF is strongly correlated with signi cant morbidity, mortality, and decreased quality of life [3][4][5][6]. The ectopic beats of the pulmonary veins (PVs) origin are responsible for the initiation of paroxysmal AF [7,8]. Based on the latest guideline from the European Society of Cardiology (ESC), pulmonary vein isolation (PVI) using catheter ablation is recommended for rhythm control strategy [9]. The complete PVI can be achieved by the radiofrequency or cryoballoon ablation approach. However, several randomized control trials (RCTs) demonstrated con icting data [10][11][12][13]. A meta-analysis of RCTs revealed equal e cacy between them [14].
Until now, either "freezing" or "burning" approaches are still being debated, and innovations are always being made to improve the e ciency and effectiveness of the PVI procedure. The second-generation cryoballoon (2G-CB) catheter was introduced in 2012 to gain more uniform freezing over the whole distal hemisphere of the balloon [15,16]. Compared to the rst-generation cryoballoon (1G-CB) catheter, ablation using 2G-CB catheter demonstrated a similar procedure-related complications rate, reduced uoroscopy time, shorter procedure time, and higher procedural success rate [17,18]. On the other hand, the contact force-sensing radiofrequency (CF-RF) catheter was released in 2014. It was equipped with the speci c ability to measure the real-time catheter-tissue contact force to guide ablation more precisely [19,20]. Compared with non-contact force-sensing radiofrequency (non-CF-RF) ablation, CF-RF ablation revealed lower acute PV reconnection [21], and one-year AF recurrence [22]. Through this systematic review and meta-analysis, we needed to know the superiority of 2G-CB ablation over CF-RF ablation for PVI in paroxysmal AF patients.

Literature search
The present systematic review and meta-analysis study was performed under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [23]. Up to January 2021, relevant articles comparing 2G-CB ablation and RF-CF ablation for paroxysmal AF recorded in the scienti c electronic database such as ClinicalTrials.gov, Cochrane, ProQuest, PubMed, and ScienceDirect, were collected and identi ed according to the eligibility criteria. These keywords: "ablation" or "catheter ablation," AND "pulmonary vein isolation" or "PVI," AND "second-generation cryoballoon" or "2nd generation cryoballoon," AND "contact force radiofrequency," or "contact force-sensing radiofrequency," AND "paroxysmal atrial brillation" or "paroxysmal AF" were used to collect the relevant articles. The potentially relevant articles from the reference list of the assessed articles were also collected and identi ed.

Eligibility criteria
The inclusion criteria included: (1) articles comparing 2G-CB ablation and CF-RF ablation for PVI in paroxysmal AF patients; (2) articles written in English; (3) catheter ablation aimed for rhythm control strategy; (4) sample size had to be at least 20 patients in each study arm; (5) follow-up duration had to be more than three months; (6) clear information about arrhythmia detection method; and (7) articles provided the detailed relevant data on the outcomes of each study arm. Articles were excluded if they: (1) were duplicates; (2) were sub-study of the involved studies; (3) included non-paroxysmal AF patients; (4) had incomparable treatment group and control group; (5) did not report the outcomes of interest.

Exposure and outcomes
In this systematic review and meta-analysis study, the intervention was the ablation strategy. Based on the ablation strategy, patients were divided into two groups, the "2G-CB group" and the "CF-RF group." Freedom from atrial tachyarrhythmias (ATAs) after a single catheter ablation procedure was the primary outcome of this study. The secondary outcome involved: (1) freedom of AF after a single catheter ablation procedure; (2) all procedural complications; (3) pericardial effusion; (4) phrenic nerve palsy; (5) vascular complications; (6) procedure time; and (7) uoroscopy time.
Quality assessment and data extraction Our study included RCTs and cohort studies comparing 2G-CB ablation and CF-RF ablation. The quality assessment of RCTs was performed using the modi ed Jadad scale, which has eight variables [24]. The total modi ed Jadad scale ranged from 0 to 8. RCTs with a modi ed Jadad score of 4 to 8 were considered high-quality [25]. Quality assessment was done using the Methodological Index for Non-randomized Studies (MINORS) for cohort studies. MINORS has 12 variables [26]. The comparative cohort studies with MINORS score of 19 to 24 were considered high-quality [27]. We involved high-quality studies only to minimizing the risk of bias. All essential information about: (1) the rst author name; (2) publication date; (3) study design; (4) 3D mapping system; (5) cryoballoon ablation (CBA) strategy; (6) radiofrequency ablation (RFA) strategy; (7) blanking period; (8) follow up period; (9) antiarrhythmic drugs (AADs) treatment during follow-up period; (10) arrhythmia detection method; (11) treatment arms; (12) number of patients; (13) age; (14) sex; (15) comorbid diseases such as hypertension, coronary artery disease (CAD), heart failure, sleep apnea, diabetes mellitus (DM), stroke, or transient ischemic attack (TIA); and (16) echocardiographic variables such as left ventricular ejection fraction (LVEF), left atrial volume index (LAVI), and left atrial diameter (LAD), were extracted from each article. The categorical and continuous data are presented as mean ± standard deviation (SD) and number (percentage), respectively. For continuous data, we also calculated mean ± SD from the median and interquartile range (IQR) [28][29][30].

Statistical analysis
We followed the standard guideline to conduct the statistical analysis [31]. Heterogeneity among the involved studies was assessed using Cochran's Q test [32]. The p-value of Cochrane's Q test <0.1 was considered as the presence of heterogeneity [33,34]. The xed or random-effect analysis models were applied in the absence or presence of heterogeneity, respectively [35,36]. The pooled effects were presented as odds ratio (0R) or mean difference (MD) for dichotomous or continuous outcomes, respectively. We also estimated their 95% con dence interval (CI). Statistically signi cant was considered if the pvalue <0.05. We used the combination of Egger's test and Begg's test to identify the publication bias. A p-value of <0.05 of Egger's and Begg's test indicated publication bias [37,38]. The statistical analysis was performed by two investigators using a combination of Review Manager (RevMan) version 5.3 (Cochrane, Copenhagen, Denmark) and Comprehensive Meta-Analysis (CMA) version 3.0 (Biostat, New Jersey, United States).
A total 1419 of patients, including 734 patients in the 2G-CB group and 685 patients in the CF-RF group, were involved in this study. Around 65.3% of the study population were male. The mean age of the patients was 60.8 ± 1.1 years old. The prevalence of comorbid conditions such as hypertension, CAD, heart failure, sleep apnea, DM, and stroke or TIA were 45.6%, 9.9%, 4.0%, 7.4%, 9.1%, and 6.6%, respectively. The mean LVEF was 62 ± 1.3 % and the mean LAD was 40.0 ± 1.1 mm. The data about LAVI were available in the study from Jourda et al [43]. The mean LAVI was 40.7 ± 2.1 mL/m2. Table 2 presents the summary of baseline characteristics of patients from the involved studies.

Heterogeneity and publication bias
The heterogeneity was found in procedure time and uoroscopy time (p-value of heterogeneity was <0.1). Therefore, the pooled effect was estimated using random-effect analysis models. For the other outcomes, we did not nd any heterogeneity. We did not nd any publication bias as the p-value for the Begg's test and Egger's test were ≥ 0.05 for all outcomes (Table 3 and Table 4).

Discussions
There are several main ndings from our study. First, our study revealed that 2G-CB ablation had similar e cacy with CF-RF ablation for paroxysmal AF in terms of acute PVI, freedom from ATAs, and freedom from AF. Second, the 2G-CB ablation procedure can be performed faster than CF-RF ablation, even though the uoroscopy time between both groups was similar. Third, 2G-CB ablation was correlated with a higher phrenic nerve paralysis rate. Moreover, all phrenic nerve paralysis complications happened in the 2G-CB group.
Today's paradigm is that electrical isolation of the pulmonary veins from the left atrium is the fundamental of most catheter-based ablation strategies in paroxysmal AF. However, there are no speci c recommendations from the recent guidelines regarding the choice of CBA or RFA [9,51,52]. Until now, the largest RCT comparing CBA and RFA in paroxysmal AF is the FIRE AND ICE trial. The study revealed that CBA was not inferior to RFA regarding the e cacy. The overall safety of both procedures was not signi cantly different. In the FIRE AND ICE trial, the CBA procedures were conducted using 1G-CB or 2G-CB catheters. Moreover, the data of CF-RF catheter were not reported in that trial [13]. The FreezeAF study also revealed the noninferiority of CBA than RFA for rhythm control in paroxysmal AF patients [12]. A meta-analysis of RCTs from Murray et al. comparing CBA using 1G-CB or 2G-CB catheters and RFA demonstrated that CBA and RFA shared equal e cacy. However, that meta-analysis did not provide information about the use of CF-RF catheters [14]. A meta-analysis from Jiang et al. revealed that 2G-CB ablation effectively decreased the recurrence rate of ATAs compared to RFA in paroxysmal AF patients speci cally [53].
Buist et al. conducted RCT to compare 2G-CB ablation and CF-RF ablation in AF patients. However, that study included both paroxysmal AF and persistent AF. That study demonstrated that 2G-CB ablation provided better ATAs-free survival and lower repeat ablation than CF-RF ablation [54]. The CIRCA-DOSE study revealed that 2G-CB ablation and CF-RF ablation resulted in similar e cacy for paroxysmal AF during a one-year follow-up duration [55]. However, the study was compared longer and shorter application time of cryoballoon (CB) ablation to CF-RF ablation, which causes the CG group to be nonuniform. A meta-analysis from Ravi et al., including RCT and cohort studies comparing 2G-CB ablation and CF-RF ablation, revealed that the e cacy Our study demonstrated that 2G-CB ablation in paroxysmal AF could be completed faster than CF-RF ablation. Our result was consistent and supported the previous meta-analysis study from Ravi et al. [56] and Wang et al [57]. The 2G-CB ablation can be conducted faster because of its "single-shot" characteristic used throughout the PVI. On the other hand, CF-RF ablation needs a longer procedure time because of its "point-by-point" approach [11]. Previous meta-analysis demonstrated that uoroscopy time was longer in 2G-CB ablation than CF-RF ablation [56]. However, in our study, both groups revealed no signi cantly different uoroscopy time. We found signi cant heterogeneity while conducting data analysis of procedure time and uoroscopy time. That was because of the diverse habit and experience of uoroscopy utilization among different heart rhythm centers. The increased experience of the operator to perform AF ablation could reduce the uoroscopy time [45]. The high power and short-duration (HPSD) radiofrequency ablation is now being conducted to reduce the overall procedure time in CF-RF ablation. A study from Baher et al. revealed that compared to the conventional method (35 W power for 10 to 30 seconds), the HPSD approach (50 W for 5 seconds) took a shorter procedure time (149 ± 65 minutes vs. 251 ± 101 minutes; p < 0.001) [58]. Until now, no study speci cally compared the 2G-CB ablation and HPSD CF-RF ablation in paroxysmal AF patients. Moreover, almost all CF-RF ablation procedures in this meta-analysis were conducted using the conventional method (25 to 35 W power for at least 20 seconds) [40][41][42][43][44][46][47][48][49][50].
From the safety aspect, our study revealed that 2G-CB ablation and CF-RF ablation had not signi cantly different rates of all-procedural complication, pericardial effusion, and vascular complications. Our results supported the ndings of prior studies. However, those meta-analyses did not provide the data about pericardial effusion and vascular complications [56-57]. Our result revealed that the incidence of pericardial effusion was not signi cantly different in both groups. However, in a prior meta-analysis from Jiang et al., CF-RF ablation had a higher rate of pericardial tamponade than RFA [53]. The possible explanation was: (1). The meta-analysis from Jiang et al. included RFA using the non-CF-RF catheter and CF-RF catheter [53]; (2) Our metaanalysis only included CF-RF ablation; (3) In our meta-analysis, almost all studies used the low-power and/or long-duration radiofrequency strategy in the CF-RF group [41,44,46,50] and (4) CF-RF catheter provides e cient transfer of heat energy to the ablation target [19]. The risk of phrenic nerve paralysis in our meta-analysis was higher in the 2G-CB group than in the CF-RF group. Our result was similar and supported the ndings of the prior meta-analysis studies [53,56].
To the best of our knowledge, our study is the rst systematic review and meta-analysis study comparing 2G-CB ablation and RF-CF ablation for paroxysmal AF patients speci cally. We also did not nd any publication bias in this study. The studies involved in this systematic review and metaanalysis were mainly cohort studies [41-47, 49, 50]. However, we only involved the high-quality study in this meta-analysis.

Conclusions
In conclusion, the 2G-CB ablation was not superior to CF-RF ablation of paroxysmal AF in terms of acute PVI, freedom from ATAs, and freedom from AF.
The 2G-CB ablation procedure can be performed faster than CF-RF ablation, although the uoroscopy time between both groups was not signi cantly different. The 2G-CB ablation was also associated with a higher rate of phrenic nerve paralysis than CF-RF.

Declarations
Ethics approval and consent to participate Ethical approval was not applicable for this systematic review and meta-analysis.

Consent for publication
Not applicable.

Availability of data and materials
All data generated or analysed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests.

Funding
No funding was obtained for this study.
Authors' contributions YW contributed to the study idea, study design, literature search, study quality assessment, data extraction, data analysis, data interpretation, and manuscript preparation. AR contributed to the study design, literature search, study quality assessment, data extraction, data analysis, data interpretation, and manuscript preparation. YY contributed to the study conceive, supervision, data interpretation, and manuscript revision. All authors read and approved the nal manuscript.  Tables  Table 1 Baseline characteristics of the involved studies.     2G-CB = second generation cryoballoon ablation; CI = con dence interval; CF-RF = contact force sensing radiofrequency ablation; MD = mean difference. Figure 1 Flowchart of the study selection process. AF = atrial brillation.