Comparing between second-generation cryoballoon vs open-irrigated radiofrequency ablation in elderly patients: Acute and long-term outcomes.

Abstract Background Limited comparative data are available regarding catheter ablation (CA) of atrial fibrillation (AF) using second‐generation cryoballoon (CB‐2) vs radiofrequency (RF) ablation in elderly patients (>75‐year‐old). Hypothesis CB‐2 ablation may demonstrate different outcomes compared with that using RF ablation for elderly patients with AF. Method Elderly patients with symptomatic drug‐refractory AF were included in the study. Pulmonary vein isolation was performed in all patients. Results A total of 324 elderly patients were included (RF: 176, CB‐2:148) from September 2016 to April 2019. The CB‐2 was associated with shorter procedure time and left atrial dwell time (112.9 ± 11.1 vs 135.1 ± 9.9 minutes, P < .001; 53.7 ± 8.9 vs 65.1.9 ± 9.0 minutes, P < .001), but marked fluoroscopy utilization (22.1 ± 3.3 vs 18.5 ± 3.6 minutes, P < .001). Complications occurred in 3.3% (CB‐2) and 6.2% (RF) of patients with no significant different (P = .307). The length of stay after ablation was shorter, but the costs were higher in the CB‐2 group (1.94 vs 2.53 days, P < .001 and 91 132.6 ± 3723.5 vs 81 149.4 ± 6824.1 CNY, P < .001) compared to the RF group. Additionally, the rate of early recurrence of atrial arrhythmia was lower in the CB‐2 group (14.2 vs 23.3%, P = .047), but the long‐term success rate was similar between two groups. Conclusions CB‐2 is associated with shorter procedure time, left atrial dwell time, and length of stay after ablation, but its costs and fluoroscopy time are greater than the RF group. Moreover, the rate of complications and long‐term success are similar between the two groups.


| INTRODUCTION
Atrial fibrillation (AF) is the most common cardiac arrhythmia and affects approximately 10 million individuals in China. 1 The incidence and prevalence of AF increase with age, and it has a striking impact on the morbidity and mortality in older age groups (>75-year-old). 2,3 Catheter ablation (CA) is an effective treatment for AF in younger patients; also, some recent studies showed that CA is safe and effective in elderly patients. 2,[4][5][6] A large number of studies and meta-analyses showed comparable clinical benefits between secondgeneration cryoballoon (CB-2) and radiofrequency (RF) ablation, but most of them exclude elderly patients. [7][8][9] Therefore, head-to-head statistics comparing RF and CB-2 in elderly patients with AF are scarce. In order to identify the approach with maximal benefits to the elderly patients, the costs and clinical outcomes were compared between CB-2 and RF for elderly patients in China in this study.

| Periprocedural management
The ablation procedures were performed under conscious sedation and analgesia with appropriate doses of midazolam and alfentanil or fentanyl. Two diagnostic catheters were introduced via a femoral vein and/or the right internal jugular vein and positioned within the coronary sinus and right ventricular apex or right ventricle. Next, the transseptal puncture was performed using fluoroscopic guidance by modified Brockenbrough technique, and an 8.5-French (Fr) transseptal sheath (SL1, St. Jude Medical Inc., St. Paul, Minnesota) was placed into the LA. Transseptal puncture was followed by administration of an intravenous bolus of heparin (100 IU/kg) to maintain an activated clotting time of 300 to 350 seconds. Subsequently, selective PV angiographies were performed to identify the individual PV ostia. The esophagus was not monitored during the procedure. Uninterrupted oral anticoagulants (OAC) were applied for all patients periprocedure.
Administration of anti-arrhythmic drugs was stopped 3 months after ablation.

| Irrigated RF ablation
The three-dimensional reconstruction of the LA and PV ostia was performed using an electroanatomic mapping system (Carto 3, Biosense Webster Inc. to the operator throughout the procedure, to achieve at least 10 g (mean) with a vector perpendicular to the tissue and an upper limit of 50 g. No ablation-index-guided ablation was applied in those patients.
The ablation strategy was performed around the PV ostia (creating contiguous focal lesions at a distance of >5 mm from the ostia of the PVs resulting in circumferential lines) without additional adjunctive left atrial ablation. The endpoint of PVI was to obtain complete electrical isolation of PVs and confirmation of bidirectional block with a waiting time of 20 minutes after the final application. After isolation, if the AF did not convert to sinus rhythm (SR), external electrical cardioversion (ECv) was performed.

| Cryoballoon ablation
A 15-Fr steerable sheath (FlexCath, Medtronic, Minneapolis, Minnesota) was advanced through the transseptal puncture. Then, a CB-2 (Arctic Front Advance, Medtronic) was introduced into the sheath, inflated, and advanced to the ostium of each PV. The PV occlusion was assessed by venous angiography. Optimal vessel occlusion was achieved when selective contrast injection showed total contrast retention without backflow to the atrium. After the occlusion was documented, ablation was performed with at least two applications per vein, each for 150 to 180 seconds. The PV activity was recorded using Circular Achieve Catheter (Achieve, Medtronic) at a proximal site in the ostium prior to ablation in each vein. During the ablation of right PVs, a quadripolar catheter was inserted in the superior vena cava to monitor phrenic nerve palsy (PNP) by pacing the right phrenic nerve with a 1500-ms cycle and a 20-mA output. The freezing cycle was terminated immediately after a loss of capture, or the strength of right hemidiaphragmatic contractions was attenuated. No any additional RF ablations were applied during or after cryoablation were included. The Achieve Catheter was reintroduced and the bidirectional block was checked with a waiting time of 20 minutes after the last application. After isolation, if the AF did not convert to SR, external ECv was performed.

| Clinical follow-up
After discharge, the patients were scheduled for follow-up visits with baseline ECG and 24 hours Holter monitoring at 3, 6, 12, 18, and 24 months. Additional telephonic interviews were conducted regularly. In the case of symptoms suggestive of recurrent arrhythmia, additional visits were recommended. If atrial arrhythmias occurred during blanking period, patients would be called bake for cardioversion by drug or electric methods, recurrence occurred post blanking period, redo-ablation would be suggested.

| Definitions
The primary endpoints were freedom from AF or atrial tachycardia at 12 and 24 months after the procedure. Atrial arrhythmias recrudescence was defined as any symptomatic or asymptomatic atrial arrhythmia lasting >30 seconds after completing the blanking period

| Statistical analysis
Continuous measures are expressed as the mean ± SD and compared using Student's t test. Categorical variables were compared using a chi-squared or Fisher's exact test. A value of P < .05 was considered statistically significant. For Kaplan-Meier plot and patients at risk, a log-rank test was used to compare the AF recurrence-free survival between the groups. Statistical analysis was done using SPSS (version 22.0, SPSS Inc., Chicago, Illinois) and GraphPad Prism 6 (GraphPad Software, Inc.).

| Procedural results
Procedural data are summarized in Table 2. Accordingly, the success of PVI was similar between CB-2 and RF (97.8% vs 98.4%, P = .416).
Statistically, compared to the RF group, the total procedure time and the left atrial dwell time was shorter in the CB-2 group (112.9 ± 11.1 vs 135.1 ± 9.9 minutes, P < .001; 53.7.4 ± 9.0 vs 65.0 ± 9.0 minutes, P < .001). However, the fluoroscopy time was longer in the CB group than in the RF group (22.1 ± 3.3 vs 18.5 ± 3.6 minutes, P < .001).

| Complications
Complications were presented in 16 patients with no significant differences between the two groups (CB-2 group: 5 [3.38%] and RF group: 11 [6.25%], P = .307). None of the patients died due to a procedure-related event during follow-up. Groin hematoma occurred in five patients in the RF group and two patients in the CB-2 group, no further intervention required. One patient in the RF group developed inguinal pseudoaneurysms that required thrombin injection.
Stroke occurred in one patient in the CB-2 group. In this case, emergency cerebrovascular revascularization was successfully performed.
Transient PNP was presented in one case only in the CB-2 group with complete resolution after 3 days. Pericardial tamponade occurred in one patient in the CB-2 group and two in the RF group. Furthermore, surgical treatment was essential only in the patient from the CB-2 group; the other patients of tamponades were successfully treated by pericardiocentesis. Two patients in the RF group showed mild pericardial effusions, but no invasive treatment was necessary. One patient in the RF group experienced cardiogenic shock after the procedure. In both groups, neither atrio-esophageal fistula nor PV stenosis (PVS) was reported. A summary of the complications is provided in Table 3.

| Clinical outcomes
Until discharge, ERAA was less frequently observed in the CB-2 group than in the RF group (14.2% vs 23.3%, P = .047). A total of 13 patients were lost to follow-up (CB-2 group: five patients, RF group: seven patients). After an overall mean follow-up of 14.33 ± 9.07 (range:  months, the rate of recurrence of AF after a single procedure for CB-2 and RF was 24.3% (35/148 patients) and 27.8% (50/176 patients), respectively, and this difference did not reach statistical significance (P = .375). At the 12-month follow-up, 83.8% of the patients in the CB-2 group and 80.1% of the patients in the RF group (P = .47), and at 24 months, 79.1% of the patients in the CB-2 group and 75.6% of the patients in the RF group (P = .507) remained free from any atrial arrhythmia recurrence as assessed by Kaplan-Meier method (Figure 1).

| Costs and hospital stay
The hospitalization costs were significantly higher in the CB-2 group than in the RF group (91 132. 6 Table 3. The mean length of hospital stay after ablation was significantly longer for the RF group (2.53 days) than the CB-2 group (1.94 days) (P < .001). There were six patients in the RF group whose length of stay after ablation exceeded 5 days, four due to pericardial tamponade/effusion, one due to cardiogenic shock, and one due to inguinal pseudoaneurysms. There were three patients whose length of stay after ablation exceeded 5 days in CB group: one due to PNP, one due to stroke, and one due to pericardial tamponade (Table 3).

| DISCUSSION
Several clinical trials demonstrated that CA is safe and effective in elderly patients with AF. However, a comparing about costs and clinical outcomes between different ablation energy in these patents are limited. To the best of our knowledge, this might be the largest study presenting costs and long-term outcome of elderly patients with AF in the CB-2 and RF groups. The major findings of the current study are as follows: 1. The CB-2 group was associated with short procedure time, left atrial dwell time, and prolonged fluoroscopy time. Moreover, the rate of PVI was similar between the two groups.
2. ERAA was less frequent in the CB-2 group than the RF group.
However, no differences were detected in terms of long-term success rates between RF and CB-2 groups.
3. The complication rates were similar between the CB-2 and RF groups.
4. The CB-2 group was associated with higher hospitalization costs but the shorter length of stay after ablation as compared to the RF group.

| Procedural characteristics
In the current study, procedure time and left atrial dwell time were shorter in the CB group than in the RF group, whereas fluoroscopy time was longer, which was consistent with the previous studies. 7,[9][10][11] Single transseptal puncture and single-step circumferential ablations with large cooling surface area might be the key factors to the short duration of the CB-2 group. 9 The prolonged fluoroscopy time in the CB-2 group might be attributed to the necessity of high-resolution fluoroscopy images to prove the balloon's occlusion. However, in the RF group, catheter guidance could be achieved with the use of an electroanatomical mapping system, which leads to a short fluoroscopy time. 7

| Efficacy
Several trials of PVI concluded that the efficacy profile for older patients was comparable to that of the younger patients with a high rate of PVI. The results in the current study are in line with the previously published data, without significant difference in terms of PVI between the RF and CB groups. 2,4,6,7 ERAA following ablation of AF is relatively common. Several studies reported that the variable rate of overall ERAA was 37.8%, (range: 16-67%), irrespective of the ablation energy applied, [12][13][14][15][16] with the incidence of ERAA being highest in the immediate post-ablation period (first 2 weeks) and decreasing progressively thereafter. 14,15 Although ERAA might not imply long-term failure, the rates of late recurrences remain higher in patients with ERAA than in those without (54% vs 7%). 16 Miyazaki et al found that there was no significant difference in ERAA between the RF and CB groups. 17  well-demarcated homogeneous lesions through a directed freezing process. [19][20][21] Thus, the relatively reduced inflammatory reaction explains a low rate of ERAA in the CB-2 group. [22][23][24] F I G U R E 1 Kaplan-Meier survival curves of patients free from AF after the 3-month blanking period following the initial procedure As individuals age, myocardium becomes increasingly infiltrated with fatty deposits and fibrosis. The elderly patients would be less likely to respond to AF ablation due to an altered electroanatomical atrial substrate. 25 However, Corrado et al reported that 127 (73%) octogenarians with AF maintained SR with a single procedure at 20 ± 14 months of follow-up. 25  was similar to that of RF 28 ; however, the long-term clinical data are yet scarce. In the current study, the success rate was 83.8% in the CB group and 80.1% in the RF group without significant difference at 12 months post-procedure. At 24 months follow-up, 79.1% in the CB-2 group and 75.6% in the RF group were free from atrial arrhythmia (P = .507). Kaplan-Meier estimation did not reveal any significant difference in clinical outcomes after a single procedure between CB-2 and RF at the mean follow-up of 14.33 ± 9.07 months (log rank = 0.508), which was in line with the previously published data. 28 Therefore, elderly patients with AF could achieve acute and long-term success from CA by both CB-2 and RF.

| Safety
The main reason for withholding ablation in elderly patients might be increasing the risk of periprocedural complications. However, data on the complications of elderly patients undergoing ablation of AF are yet limited and inconsistent. Guiot et al demonstrated that age >75 years is an independent predictor of late cerebrovascular events. 29  Reportedly, PNP is a most common complication of CB ablation (13-19%); however, in this study, PNP was presented in only one case in the CB-2 group, while applying the right superior pulmonary vein (RSPV) ablation with complete resolution after 3 days. So, the incidence of PNP was significantly lower than that reported previously.
The significantly lower rate of PNP might be due to the efficiency of close phrenic nerve monitoring.
Furthermore, data on CA of AF stated that 0.3 to 1.3% patients of the CB ablation and 1.3 to 1.9% patients of the RF ablation suffered cardiac tamponade. 9,28,34,35 In the current study, three patients The sheath of CB-2 procedure is larger than that of the RF procedure (15 vs 8.5 Fr); however, in the present study, the rate of hematoma in the RF group (five patients, 2.84%) was higher than that in the CB-2 group (two patients, 1.33%). This phenomenon may be due to more attention would be taken to larger sheath in CB-2 procedure subjectively, and the other reason may be due to double puncture and two long sheaths were applied in the one vein in the RF procedure.

| Costs and hospital stay
Presently, data comparing the costs and the length of stay between RF and CB ablation for AF are sparse, especially for elderly patients.
Yokokawa et al analyzed 146 patients who had received ablation and demonstrated that CB has a higher cost than RF. The study found that the high cost in the CB group was mainly due to equipment cost. In addition, procedure duration significantly enhanced the cost as it is time-dependent cost based on the elements such as anesthesia services, use of the electrophysiology laboratory, and post-anesthesia recovery units. 37 In the current study, hospitalization costs are composed of five parts: diagnostic costs, procedure equipment and disposable supplies costs, procedure costs, medication costs, and comprehensive medical costs. The hospitalization costs were significantly higher in the CB-2 group than the RF group, which was primarily due to the high costs of procedure equipment and disposable supplies in CB-2 group (75 734.79 vs 63 660.52, P < .001). However, double transseptal procedure and prolonged hospital stay after ablation led to the higher procedure and comprehensive medical costs in the RF group as compared to the CB group. Intriguingly, no significant different was observed in the diagnostic and medication costs between two groups.
In the case of elderly patients, CB-2 seemed to shorten the length of hospital stay after ablation due to the low rate of complications; combining complications would affect the length of stay after ablation severely.
The other reason might be that the large subset of patients in the RF group received warfarin for anticoagulation post-ablation. Such patients would need additional hospital stay to monitor the oscillation of international normalized ratio (INR) and adjust the dose of the warfarin.

| Study limitations
The present study has some limitations. First, this is a single-center retrospective study, the choice of ablation technique was discrete by operating electrophysiologist, and the number of patients in the analysis was limited, which could introduce selection bias. Future randomized studies with a larger population are essential. Second, there were no criteria to select the irrigated catheter and no AI technology guiding the ablation in the RF group, which might affect the procedural results and long-term outcomes. Third, we performed "Costs" instead of "cost-effectiveness." Fourth, asymptomatic episodes of atrial tachyarrhythmia might have been missed, and hence, the success rates might be overestimated. Persistent monitoring (such as CIED) is useful for long-term follow-up. Lastly, we did not systematically monitor the putative, mild, or asymptomatic complications (such as PV stenosis); therefore, the complication rate might have been underestimated.

| CONCLUSION
The results of the current study showed that both CB-2 and RF ablation are safe and effective with high success rates and low complication with respect to AF in elderly patients. CB-2 exhibited short procedure time, left atrial dwell time, and length of stay after ablation, as well as a low rate of ERAA. However, the costs and fluoroscopy time of CB-2 group are greater than that of the RF group.