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 Table of Contents  
Year : 2017  |  Volume : 2  |  Issue : 2  |  Page : 73-80

The real-time assessment of pulmonary vein isolation and safety of cryoballoon 3 versus cryoballoon 2 for atrial fibrillation: A systemic review and meta-analysis

1 Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
2 Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
3 Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China

Date of Web Publication31-Jan-2018

Correspondence Address:
Prof. Tong Liu
Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin
Prof. Yunlong Xia
Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJHR.IJHR_6_17

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Objectives: Cryoballoon ablation (CBA) has become a routine treatment option for paroxysmal atrial fibrillation (PAF). The third-generation CB (CB3) also known as “Arctic Front Advance ST” (CB-ST) was designed with a shorter distal tip. There have been several publications describing the characteristics of the CB3 system. We, therefore, undertook this systemic review and meta-analysis to compare the efficacy and safety of CB3 versus the second-generation CB (CB2) also known as “Arctic Front Advance.” Methods and Results: We performed a search on PubMed, Embase, and Web of Science database for studies published by August 2016 using the keywords “CB3,” “short-tip cryoballoon,” “Arctic Front Advance ST,” “CB3,” “cryoablation,” and “CBA.” Six studies with a total of 1625 patients were identified. There were 351 patients underwent CBA with CB3, and 1274 underwent CBA with CB2. Overall analyses indicated that there was a significant improvement in the real-time pulmonary vein isolation (RT-PVI) recording rate with CB3 compared to CB2 (odds ratio of 3.08, P < 0.00001). The procedure time (PT) was shorter for CB3 (weighted mean difference [WMD], 95% confidence interval CI: −10.27, [ − 19.2, −1.35], P = 0.02), while fluoroscopic time (WMD, 95% CI: 0.71, [ − 1.27, 2.68], P = 0.48) was not statistically different between the two groups. Conclusions: In this meta-analysis involving 1625 patients, the CB3 system decreased PT, enhanced RT-PVI recording rate while maintaining a similar safety profile.

Keywords: Atrial fibrillation, second-generation cryoballoon, third-generation cryoballoon

How to cite this article:
Li D, Ng CY, Waleed KB, Yu H, Guan X, Wang X, Gao L, Yin X, Liu T, Xia Y. The real-time assessment of pulmonary vein isolation and safety of cryoballoon 3 versus cryoballoon 2 for atrial fibrillation: A systemic review and meta-analysis. Int J Heart Rhythm 2017;2:73-80

How to cite this URL:
Li D, Ng CY, Waleed KB, Yu H, Guan X, Wang X, Gao L, Yin X, Liu T, Xia Y. The real-time assessment of pulmonary vein isolation and safety of cryoballoon 3 versus cryoballoon 2 for atrial fibrillation: A systemic review and meta-analysis. Int J Heart Rhythm [serial online] 2017 [cited 2023 Jun 5];2:73-80. Available from: https://www.ijhronline.org/text.asp?2017/2/2/73/224358

  Introduction Top

Atrial fibrillation (AF) is the most common cardiac arrhythmia associated with disabling complications.[1],[2] As major trigger for AF originates in the pulmonary veins (PV), PV isolation (PVI) has become the cornerstone of catheter ablation for AF.[3] Cryoballoon ablation (CBA) was designed to be a more efficient approach to PVI compared to conventional radiofrequency ablation (RFA).

The first generation CB (CB1) also known as “Arctic Front” and the second generation cryoballoon (CB2) known as “Arctic Front Advance” have demonstrated similar efficacy but significantly shorter procedure time (PT) compared to RFA.[4],[5] A recent retrospective analysis suggested improved durability of PVI compared to open irrigated, nonforce sensing RFA.[6]

However, the risk of major complications in two ablation approach appears similar. Phrenic nerve palsy (PNP) is a complication unique to CBA consistently seen in every clinical trial although it rarely persists.[7] Suggestion indicated that the risk of cardiac tamponade is lower with CBA compared to conventional RFA.[4],[5],[8] While animal models demonstrated that cryoablation was associated with lower incidence of thrombus formation and less thrombus volume, the risk of stroke in human trials was similar.[9],[10]

PV potential (PVP) is frequently not seen during occlusion of the PV with cryoballoon as the mapping poles are deep in the PVs.[11] In addition, cryoballoon catheter is not recognized by the Electroanatomical Mapping System used in RFA. As a result, fluoroscopic time (FT) can be longer in CBA.[4],[11] CB2 was designed with a larger cooling surface area compared to CB1, achieved significantly lower temperature, and reduced arrhythmia recurrence rate on the long-term follow-up. However, the increased efficacy occurred in the expense of higher incidence of transient and persistent PNP.[12]

Early studies of the use of mapping catheter during CBA showed that it reduced PT and fluoroscopy use.[13] However, the real-time PVI (RT-PVI) recording rate was only available in half of the PVs with the previous cryoballoon. The long distal tip (13 mm) of the first- and second-generation CB resulted in a long distance between the mapping catheter (Achieve catheter) and the PV ostium (PVO) during cryoapplication. The unsatisfactory RT-PVI recording function, enhanced procedure difficulties, may lead to unnecessary ablation and its associated complications.[14]

The third generation of cryoballoon (CB3) also known as “Arctic Front Advance ST” (CB-ST) was designed to overcome the shortcomings of previous CB in RT-PVI recording function. The distal tip of the CB catheter was made 5 mm – shorter than previous CB to enhance RT-PVI recording by decreasing the distance between the mapping catheter and PVO. Hypothetically, procedure efficacy and postoperation complication may improve by shorter tip above cryoballoon. Several researches had published precisely described details for CB3. In this systemic review and meta-analysis, we examined the characteristics, safety and efficacy of CB3 versus CB2 in patients with paroxysmal AF (PAF).

  Methods Top

The included studies were selected by two researchers (DL and HY) independently. PubMed, Embase, and Web of Science databases were searched for appropriate studies published by August 2016 using the keywords “CB2,” “CB3,” “short-tip CB,” and “Arctic Front Advance ST.” The inclusion criteria were: (1) Studies comparing CB2 with CB3, (2) published in English, and (3) human subjects. We attempted to contact the authors for any missing data. Outcome data were analyzed for RT-PVI recording function, FT, PT, minimum temperature, and transient PNP. The quality of included studies was assessed with the Newcastle-Ottawa Scale.[15] All analyses were performed with RevMan 5.3 software (Review Manager 5.3, The Cochrane Collaboration, Oxford, UK) and Stata 12.0 software (StataCorp LP, College Station, TX, USA).

RT-PVI recording and transient PNP was analyzed as dichotomous data using odds ratio (OR) with 95% confidence intervals (95% CI). Minimum temperature, FT, and PT were described as continuous variable analyzed using weighted mean differences (WMD) with 95% CI. To evaluate the heterogeneity across studies, we used I 2 derived from the Chi-square test, which describes the percentage of the variability in effect estimates resulting from heterogeneity, rather than sampling error (chance).

Pooled analyses were calculated using random- or fixed-effect models based on I 2 (I 2 > 0.25 as random-effect model whereas I 2 ≤ 0.25 as fixed-effect model),[16] then Chi-square and degree of freedom (df) were listed. To detect publication bias, visual examination of the funnel plot was performed for the RT-PVI recording comparison. We also carried out analyses for RT-PVI recording function using random-effect model. All P values were two-tailed, and statistically difference was set at 0.05.

  Results Top

A flow diagram of the data search and study selection is presented in [Figure 1]. The initial search resulted in 241 articles from PubMed, Embase, and Web of science databases. After viewing article characteristics, 46 articles were excluded because: (1) Reviews or meeting abstracts (n = 37), (2) Editorials (n = 4), (3) Animal subjects (n = (5). After review of titles/abstracts, 173 articles were excluded as the inclusion criteria were not met. A total of 22 trials were further investigated and 16 studies were excluded because 13 were a duplicate article and the other 3 did not mention the CB2 concurrently. The remaining six studies involving 1274 patients were included in the final analysis.[16],[17],[18],[19],[20],[21],[22] The quality of included studies assessed with the Newcastle-Ottawa Scale is shown in [Table 1].
Figure 1: Flow diagram of study selection process

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Table 1: Quality of included studies assessed with the Newcastle-Ottawa Scale

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A total of 1625 patients from the six studies were identified, 351 patients underwent CBA with the CB3 and 1274 underwent CBA with the CB2. Characteristics of the six trials were presented in [Table 2]. We summarized the baseline demographics of enrolled studies including patient age, proportion of PAF, left atrial diameter (LAD), coronary artery diseases (CAD), arterial hypertension, type 2 diabetes mellitus, and CHA2 DS2-VASc-score in [Table 3]. There was no significant difference in the baseline demographic data between CB3 group (experimental group) and CB2 group (control group).
Table 2: Baseline patient characteristics of enrolled study

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Table 3: Characteristics of enrolled study

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Real-time pulmonary vein isolation recording

The use of CB3 resulted in significantly improved RT-PVI recording compared to CB2 (OR = 3.08, 95% CI: 2.11–4.50, P < 0.00001). Corresponding Chi-square value was 21.94 and df was 5, observed P = 0.0005 could consider as significantly. As I 2 was 77%, the sensitivity analysis further adopted and after excluded two studies [6],[22] resulted in resolution of heterogeneity (OR = 2.99, 95% CI 2.14–4.19, P < 0.00001), I 2 decreased to 55% and result preserved no evidence of statistically difference. Forest plots of the pooled analyses are shown in [Figure 2] and [Figure 3]. The results were unchanged for each of the PVs. RT-PVI recording rate was 0.85 (95% CI: 0.82–0.89) for CB3 versus 0.64 (95% CI: 0.54–0.74) for CB2. Forest plots are shown in [Figure 4].
Figure 2: The forest plot for RT-PVIRR= Real-time pulmonary vein isolation recording rate comparing third-generation cryoballoon to second-generation cryoballoon

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Figure 3: The sensitivity analysis for third-generation cryoballoon and second-generation cryoballoon comparing third-generation cryoballoon to second-generation cryoballoon

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Figure 4: The forest plot for third-generation cryoballoon and second-generation cryoballoon in real-time pulmonary vein isolation recording rate

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Minimum temperature during cryoapplication

The pooled analysis demonstrated that the lowest temperature reached is higher in CB3 compared to CB2 for all PVs: 1.41 (WMD) for left superior pulmonary veins (LSPVs) (95% CI: 1.06–2.89, P < 0.00001), 3.00 for left inferior pulmonary veins (LIPVs) (95% CI: 1.33–4.67, P = 0.0004), 2.13 for right superior pulmonary veins (RSPVs) (95% CI: 0.81–3.45, P = 0.002), and 1.90 for right inferior pulmonary veins (95% CI: 0.51–3.29, P = 0.007). The forest plots of lowest temperature are shown in [Figure 5].
Figure 5: The forest plot for minimal temperature for left superior pulmonary veins, left inferior pulmonary veins, right superior pulmonary veins, and left inferior pulmonary veins

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Fluoroscopic time and procedure time

The PT observed in CB3 was 10.27 min (WMD) shorter than CB2 (95% CI: 19.2–1.35, P = 0.02) whereas no significant difference was seen in FT (0.71 WMD, 95% CI: 1.27–2.68, P = 0.48). Forest plots are shown in

[Figure 6].
Figure 6: The forest plot for procedure time and fluoroscopic time comparing third-generation cryoballoon with second-generation cryoballoon

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Transient phrenic nerve palsy

Only four trials reported the incidence of transient PNP. No statistical difference was seen between CB3 and CB2 (OR: 0.63, 95% CI: 0.21–1.89, P = 0.41). Forest plot is shown in [Figure 7].
Figure 7: The forest plot for transient phrenic nerve palsy comparing third-generation cryoballoon to second-generation cryoballoon

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Report bias

Distribution of six trials roughly arrayed in a symmetrically funnel form suggested low report bias. Funnel plot is shown in [Figure 8].
Figure 8: The funnel plot for real-time pulmonary vein isolation recording rate

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  Discussion Top

CB2 was designed with a larger cooling surface which has translated to improved efficacy and lower arrhythmia recurrence rate.[12] CB3 inherited the efficacy of CB2 with additional improvements mediated by the 40% – shorter distal tip compared to the previous generations CB. The shorter distal tip allows for an improved RT-PVI recording function which appears to have favorable effects in the number of cryoapplications, minimal temperature during ablation and the total PT. However, the positive findings did not translate into a decrease in procedural complications or arrhythmia recurrence rate although that remains to be seen with the long-term follow-up.[17],[18]

CB3 provided higher RT-PVI recording function generally, while not all PVs benefited from the shorter distal tip of CB3 for RT-PVI recording. The RSPV and uncommon variation of PVs (such as LCPV and RCPV) have lower PVP recording rate. Fürnkranz et al.[19] demonstrated that RT-PVI recording function did not improve for LCPVs and RSPVs using CB3. A similar finding for RSPV was found by Koektuerk et al.[22] The orientation and the size of the PVs likely account for these findings as they both determine contact of mapping catheter contact with the PVO during cryoapplication.

Heeger et al.[21] reported a nearly 4°C higher average minimum temperature with CB3. Our meta-analysis showed a higher minimum temperature as well with varying difference depending on the PV. The largest difference was seen in LIPV with a WMD of 3°C, whereas the smallest difference was seen in LSPV with a WMD of 1.41°C. The risks of esophageal thermal lesions and gastroparesis increases with lower esophageal temperature during cryoapplication.[23] However, the risk of PNP was unchanged with CB3 in our pooled analysis likely because the difference in minimum temperature was small. One possible explanation for the higher minimum temperature in CB3 is the more proximal location of the thermocouple in CB3. The total number of cryoapplications and dosing strategy may also have contributed to the difference in temperature.[17],[18],[22]

Signal noise during cryoapplication with CB3 was described by Fürnkranz et al.[19] The shorter distal tip increases the likelihood of enclosement of ≥1 of the bipoles with the growing iceball. However, signal noise did not interfere with RT-PVI recording as other bipoles are uninterrupted.[19] Koektuerk et al.[22] described a similar finding with signal noise that mainly occurred after PVI.

The stability of CB3 was not evaluated in this meta-analysis due to lack of published data. Furnkranz et al.[19] reported balloon dislodgement rate in 6% of patients during the hockey stick maneuver with CB3 while no dislodgement occurred with CB2. The mapping catheter had to be exchanged with a stiff guidewire for stability in 8% of patients undergoing CB3.

One of the most important advantages of CB3 over CB2 is the PT. The PT for CB3 was 10.27 min (WMD) shorter than CB2. Aryana et al.[17] reported that the left atrial dwell time is shorter with CB3 which likely accounts for most of the difference seen in the total procedural time. Interestingly, studies included in our meta-analysis that were published earlier showed the minimal difference in PT [18],[21] whereas studies published later showed significantly shorter PT.[17],[18],[19] This finding may be explained by operator familiarity with the newer generation CB system. There was no difference in the FT between the two generations of CB systems. Heeger et al.[21] showed more CB cycle until PVI for CB3, and other researches demonstrated no differences in total CB cycle. This result may accounted by the shorter tip could not maintain sustain of CB, added procedure instability.

The data on long-term outcomes are limited. Aryana's multi-center study demonstrated no significant difference in recurrence of atrial arrhythmias after 10-month follow-up.[17] Pott et al.[18] showed a similar finding with an average follow-up time of 6 months. As shorter time-to-PVI (TPVI) especially <60 s were considered as optimistic outcome of long-term PVI, while most observed studies demonstrated negative result for shorter TPVI application CB3. Considering of TPVI was statistically no difference between CB2 and CB3, the negative result was predictable and understandable.[17],[18],[19],[20],[21],[22]

CB3 system offers significant advantages in RT-PVI recording rate and PT over the CB2 system. The higher minimum temperature does not appear to be clinically significant and the safety profile appears to be similar to CB2. Nevertheless, questions on dosing of cryoapplications and the long-term durability of the lesions need to be addressed on future studies.


There were several limitations to our meta-analysis: (1) Studies included were non-randomized. Therefore, selection bias may exist. (2) We did not evaluate long-term outcomes of CB3 because of limited published data. (3) Ablation protocols were different based on the institution. (4) Heterogeneity ratio (I2) was higher than 50% indicating significant statistical heterogeneity. (5) Most studies were single-center trials. (6) Restricted enrolled patients diminished the significance. (7) Preoperation imagine was absent and basic characteristics were not inconsistent.

  Conclusions Top

In this meta-analysis of 1625 patients, the CB3 system decreased overall PT, enhanced RT-PVI recording rate while maintaining a similar safety profile.


We would like to thank Prof. Fürnkranz Alexander for providing additional data and Prof. Xin Chen for assistance in the methodology of this meta-analysis.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3]


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