Experience and procedural efficacy of pulmonary vein isolation using the fourth and second generation cryoballoon: The shorter, the better?

The second‐generation cryoballoon (CB2) provides effective and durable pulmonary vein isolation (PVI) associated with encouraging clinical outcome. The novel fourth‐generation cryoballoon (CB4) incorporates a 40% shorter distal tip. This design change may translate into an increased rate of PVI real‐time signal recording, facilitating an individualized ablation strategy using the time to effect (TTE).


| INTRODUCTION
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults. 1 Current AF guidelines recommend the rhythm control strategy for symptoms and quality of life improvement in patients, stating that pulmonary vein isolation (PVI) performed using either radiofrequency (RF), or cryoballoon (CB) catheters should be the standard choice. 1 For the treatment of patients with paroxysmal AF (PAF), the FIRE AND ICE trial demonstrated noninferiority of CBbased PVI versus RF-based PVI in terms of efficacy and safety. 2,3 Different CB ablation strategies may apply a fixed freeze cycle duration of 180-240 s, often followed by a bonus-freeze cycle. [4][5][6][7][8] However, ablation protocols have recently been modified aiming at shorter and fewer CB applications and demonstrated comparable clinical outcomes. 4,5,[8][9][10][11] The latest strategies introduced the time to effect (TTE), defining the time to PVI, as an essential indicator for durable PVI. [12][13][14] By preventing a proximal positioning of the circular mapping catheter, the long distal tip of the second-generation cryoballoon (CB2) limits the optimal recording of PV signals, possibly leading to a limited use of the TTE strategy. To increase the rate of real-time PV recordings, the third-generation cryoballoon (CB3; Arctic Front Advance ST; Medtronic Inc.) was designed with a 40% shorter tip, facilitating a more proximal spiral catheter position. In consequence, several studies demonstrated a significantly higher rate of real-time PV recordings when utilizing the CB3 compared to CB2. 11,[15][16][17] However, acute and 1-year efficacy was similar for both systems. 18 Thus, the CB3 did not pass the limited market release.
The novel fourth-generation CB (CB4; Artic Front Advance Pro; Medtronic Inc.), also with a 40% shortened tip compared to the CB2, aims at better catheter maneuverability and improved recording of PV signals. 19 The purpose of this prospective analysis was to assess the procedural efficacy and ablation characteristics of the CB4 in comparison to the CB2 for PVI in a large data setting.

| Intraprocedural management
Our intraprocedural management has been described in detail before. 20  domen. In addition, the continuous motor action potential (CMAP) was monitored. Refrigerant delivery was stopped immediately if weakening or loss of diaphragmatic movement, or the reduction of CMAP amplitude was noted. 23 If phrenic nerve palsy (PNP) occurred, no additional freeze cycle was applied along the septal PVs.

| Cryoballoon-based PVI
The 28 mm CB2 was advanced into the LA via the 15 French steerable sheath and a spiral mapping catheter (20 mm diameter; Achieve, Medtronic, Inc.) was advanced into the target PV to record electrical activity.
The occlusion of the PV ostium was verified by contrast dye injections.
A pop-out phenomenon was defined by the observation of a balloon dislodgement from the PV ostium after initializing the freezing process.
This was evaluated by a second injection of contrast medium and fluoroscopy 5-10 s after initializing the freezing process. If stable occlusion was verified, the freeze cycle was continued; if the occlusion was not perfect the balloon was slightly repositioned and a third contrast dye injection was utilized to verify occlusion or the freeze cycle was stopped and a further attempt was made. The minimum CB cut-off temperature was set at −60°C.

| Statistical analysis
Continuous variables are presented as means and SDs; they were compared using Student's t test. Categorical variables are presented as absolute and relative frequencies; they were compared using the χ 2 test or Fisher's exact test (in case of small expected cell frequencies). All p values are two-sided and a p-value < .05 was considered statistically significant. All calculations were performed with the statistical analysis software SAS (version 9.3; SAS Institute Inc.).

| Acute ablation results per individual PV
Ablation data per individual PV is summarized in Table 3.  1) The CB4 provides a high rate of acute PVI, similar to the CB2.
2) The rate of TTE recordings was significantly higher when using the CB4.
3) The total freezing time was significantly shorter in the CB4 group, with no difference in the time to PVI, total procedure time and total fluoroscopy time.
4) There was a similarly low incidence of periprocedural complications in both groups.
According to the latest guidelines, PVI is the main procedural end-point in AF ablation, with both RF ablation and CB ablation accepted for this purpose. 1 The FIRE AND ICE trial prospectively ran- was taken from the European market, because of observed differences in minimal CB freeze temperatures most likely due to a changed position of the temperature probe of the CB3 to a more proximal position, which causes a minimally longer distance of the returning gas to the temperature probe and therefore higher returning gas temperatures. 11,15 The new CB4 catheter, which was designed to improve the TTE incidence and the catheter maneuverability, has recently been introduced into clinical practice. It provides a 40% shortened distal tip (8 vs. 13 mm) and similar technical properties, including the cooling specifications, when compared to CB2. 19,26 The present study confirms that the mean number of freeze cycles until PVI is similar for both CB2 and CB4-guided ablations. A high rate of acute PVI can be achieved with both the generations and the acute efficacy was not influenced by the balloon type. There was also no difference between the minimal intraluminal esophageal temperatures. Even so, the mean minimal balloon-temperature was significantly lower when using the CB2.
As discussed above, the high incidence of real-time PV potential recordings is an essential prerequisite for the personalized TTE-based ablation procedures. With its shorter catheter tip, the CB4 allows better proximal positioning of the Achieve catheter and increased maneuverability, which in turn should increase the rate of live TTE-guided PVIs.
Analyzing 100 patients Rottner et al. 31 found a strong trend toward a higher incidence of live recordings of the PVs using the novel catheter as compared to CB2, but without reaching statistical significance. In our analysis, the CB4 group showed a statistically significant increase in the percentage of TTE recordings in comparison to the control group, which translated into a shorter total freezing time when using a TTE based protocol. When analyzing the individual PVs, the significantly shorter total freezing time for the CB4 group was observed for the right PVs and the left inferior PV, while the increased rate of PV potential recordings is present only for the right superior PV. This effect was driven by a higher rate of real time recordings and therefore less necessity of utilizing bonus freeze applications. Even if the CB type did not influence the total procedure time and total fluoroscopy time, the total amount of contrast was significantly lower in the CB4 group.
Characteristic complications of CB-based PVI such as PNP or a significant drop in intraluminal esophageal temperatures potentially resulting in esophageal thermal injury typically occur at later stages of the freeze cycles. 32 In the current study, even though the total freezing time was significantly shorter in the CB4 group, the major and minor complications incidence was similar for both catheters.
Thus, we confirm that the safety profile of CB4 is similar to that of the CB2. Further analyses should be conducted to assess the longterm effectiveness of the novel cryoballoon. In their study they used the latest version of the Achieve catheter (Achieve Advance; Medtronic Inc), which is more flexible in its handling when compared to the previous version (Achieve; Medtronic). Since we only used the Achieve catheter, there was no need to use a stiff wire to improve CB alignment or stability. These findings are in line with other reports on the CB4 procedural characteristics. 33

| LIMITATIONS
The current study represents a single-center experience in a limited number of patients. However, this is the largest analysis focusing on the acute efficacy and safety of the CB4 compared to the CB2. No randomization has been performed. Yet, consecutive patients were prospectively evaluated in this study. Only acute efficacy and safety data are provided, while long-term clinical outcome will need future assessment.

| CONCLUSIONS
To the best of our knowledge this is the largest study reporting on the acute results of CB4-based PVI as compared to CB2. While demonstrating an identical acute efficacy for PVI, the CB4 provides a significantly increased rate of real-time PV-recordings and thus facilitates individual ablation strategies considering the TTE.

ACKNOWLEDGMENT
Open access funding enabled and organized by Projekt DEAL.

AUTHOR CONTRIBUTIONS
Concept/design, data collection, data analysis and interpretation, and

DATA AVAILABILITY STATEMENT
The data will be available on request.