Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Arrhythmia/Electrophysiology
Safety and Efficacy of Cryoballoon Ablation for Paroxysmal Atrial Fibrillation in Japan – Results From the Japanese Prospective Post-Market Surveillance Study –
Ken OkumuraKazuo MatsumotoYoshinori KobayashiAkihiko NogamiRobert B HokansonFred Kuefferfor the CRYO-Japan PMS Study Investigators
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2016 年 80 巻 8 号 p. 1744-1749

詳細
Abstract

Background: Outcomes of cryoballoon ablation for paroxysmal atrial fibrillation (PAF) have been reported in the Western countries but not in Japan. The CRYO-Japan PMS study was a single-arm, observational, multicenter, prospective study of the 2nd-generation cryoballoon Arctic Front AdvanceTM. We evaluated device- and procedure-related complications and clinical outcomes at 6 months.

Methods and Results: The 616 patients (male, 72%; mean age, 63±11 years) were enrolled from 33 Japanese hospitals. Of all patients, 610 had PAF, and procedural data were analyzed in 607. A subset of 328 patients was followed for 6 months for the primary efficacy analysis. AF recurrence outside the 3-month blanking period or repeat ablation was considered treatment failure. Pulmonary vein isolation was achieved in 606/607 patients (99.8%); 1 patient (0.3%) had a repeat ablation during the blanking period. Freedom from AF at 6 months was 88.4% (95% CI: 84.1–91.6%). Device- and/or procedure-related adverse events included phrenic nerve injury unresolved at hospital discharge in 9/616 patients (1.5%), which resolved within 6 months in 7, pericardial effusion in 5/616 (0.8%), and tamponade in 4/616 (0.6%). One non-device-related death from pneumonia was reported 6 days post-procedure.

Conclusions: Cryoballoon ablation is safe and effective for Japanese PAF patients, with 88.4% AF freedom at 6 months post-ablation. (Circ J 2016; 80: 1744–1749)

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia worldwide, with increased mortality rates and various morbidities, including clinical symptoms, impaired cardiac function and thromboembolism.13 The overall prevalence of AF in Japan is estimated as 0.56% (3.2% for age ≥80 years), and projected to increase to 1.1% by the year 2050.4

Editorial p 1695

Packer et al first reported the safety and effectiveness of cryoablation for pulmonary vein isolation (PVI) using a cryoballoon system for patients with drug-refractory recurrent symptomatic paroxysmal AF (PAF).5 In Japan, the Japanese Heart Rhythm Society and Japanese Society of Pediatric Cardiology and Cardiac Surgery submitted a request for Accelerated Approval and Reimbursement Process to the Ministry of Health, Labour, and Welfare (MHLW). Approval from the Pharmaceutical and Medical Devices Agency was obtained in February 2014 under the condition that a post-marketing surveillance (PMS) study would be completed.

Accordingly, we conducted the CRYO-Japan PMS study to evaluate: (1) the safety profile of cryoablation in Japanese patients with PAF, (2) freedom from AF recurrence through a 6-month post-ablation period after a 3-month blanking period; and (3) procedural parameters such as procedural and fluoroscopy times.

Methods

Study Design

The CRYO-Japan PMS study was a single-arm, observational, multicenter, prospective study initiated following the market release of the 2nd-generation cryoballoon (CB2), Arctic Front AdvanceTM (Medtronic, Inc), in Japan. A total of 33 study sites participated in the study (Appendix S1). All physicians involved in this PMS study were required to attend the cryoballoon training program provided by Medtronic, Inc before starting the study.

This PMS study was conducted in compliance with the ‘Good Post Marketing Study Practice (GPSP)’ as set out by the MHLW Ordinance No. 38 (March 23rd, 2005). After approval by the ethics committee in each institution, written informed consent was obtained from the patients involved in the study. All patients undergoing ablation procedures for PAF between July 1, 2014 and October 19, 2014 were followed for 6 months. In patients undergoing ablation after October 19, 2014, only baseline and procedural safety data were obtained. Final database lock for this report occurred on July 22, 2015.

Cryoablation Procedure

Cryoablation intervention followed the current clinical practice standards at each center. The goal of cryoablation was electrical PVI of the 4 major PVs and/or their anomalous equivalents (common ostium) as confirmed by entrance and/or exit block.

Transseptal catheterization was performed under fluoroscopic guidance and/or navigation tool via the femoral vein and standard transseptal sheath, which was exchanged for a 15F outer diameter steerable sheath (FlexCathTM Advance; Medtronic, Inc). Thereafter, a 23-mm or 28-mm cryoballoon catheter was advanced over a guidewire or circular mapping catheter (AchieveTM; Medtronic, Inc) to the left antrum and to each PV ostium as reported previously.5

After confirming PV occlusion induced by the balloon inflated with contrast medium, cryoablation was performed with a 180–240 s application as the standard application while assessing entrance and/or exit block using a circular mapping catheter (AchieveTM). The application was started from the left superior PV (LSPV), followed by the left inferior PV (LIPV), right inferior PV (RIPV) and finally right superior PV (RSPV). Extra applications and the application times were left to the discretion of the operator. Additional ablations either as focal cryoablation using a Freezor MAX cryoablation catheter (Medtronic, Inc) or as RF ablation were allowed if PVI was not achieved by ≥1 cryoablations. The selection of the energy level and catheter was at the discretion of the operator. Acute procedural success was defined as the demonstration of electrical isolation of all PVs by the entrance block to the PV and exit block to the left atrium.

In alignment with the Arctic Front Advance Instructions for Use, continuous phrenic nerve pacing was used throughout each cryoablation application in the right PVs. To avoid phrenic nerve injury (PNI), changes in the strength of the diaphragmatic contraction were confirmed by placing a hand on the patient’s abdomen in the location of the diaphragm. Fluoroscopy and/or compound motor action potential were also used to monitor diaphragmatic movement.

Patient Follow-up

Baseline evaluation included physical examination, general medical history, and antiarrhythmic medication usage. Procedural data, including cryoablation details and any complications, were required to be reported for all patients. For the patients who were followed through 6 months, arrhythmic events and AF ablative interventions were reported post-discharge through the 6 months.

Study Objectives and Monitoring

The primary objectives of the study were to report on the safety of the cryoballoon procedure, and freedom from AF recurrence during 6 months. A 3-month interval following the initial cryoablation treatment date was considered as the blanking period, and AF attacks detected within this period were not considered as treatment failure. Late recurrence was denoted when there was a documented episode of AF lasting longer than 30 s or a repeat ablation procedure was reported outside the 3-month blanking period. The assessment of arrhythmic events during the 6-month follow-up was at the discretion of the investigators, based on 24-h Holter ECG, 12-lead ECG and/or clinical symptoms. Use of antiarrhythmic drug therapy was at the discretion of the study physicians.

All device-related adverse events (AEs), defined as those considered to be related to the use of cryoballoon ablation system such as PNI, and procedure-related AEs, defined as those considered to be related to the ablation procedure and not necessarily to the cryoablation system such as puncture site hematoma and pericardial effusion, were reported. An independent Safety Evaluation Committee, consisting of independent practicing arrhythmia specialists, was responsible for review and adjudication of all reported AEs as well as their relationship to the device and procedure. The analyses in this report were based on the adjudication of the independent Safety Evaluation Committee.

Statistical Analysis

Continuous variables were calculated using descriptive statistics including n, mean, standard deviation (SD), minimum, median, interquartile range, and maximum. The number and percentage of patients were calculated for discrete variables. The comparison of the procedure times, including total laboratory time, left atrial dwell time and fluoroscopy time among the groups of procedure number 1–16, number 17–32, and number 33–50 within each center, was made by one-way ANOVA. The Kaplan-Meier method was used to evaluate efficacy (freedom from AF) at 6 months post-ablation. Ablation duration <60 s was classified as an aborted ablation attempt and excluded from the analysis. Major device- and/or procedure-related AEs were included in this analysis. The level of statistical significance was P<0.05.

Results

We enrolled 616 patients from 33 institutions (Appendix S1). Baseline and safety data are reported for all 616 patients, but acute efficacy data are reported for 607 (6 patients were classified as persistent AF and were excluded, and detailed procedural data were not reported for 3 patients). Of the 616 patients, 328 PAF patients were followed for 6 months. Figure 1 summarizes the patient disposition in the study.

Figure 1.

Disposition of all 616 patients enrolled in the CRYO-Japan PMS Study. The procedure and safety cohort includes 607 patients meeting inclusion/exclusion criteria and treated with 2nd-generation cryoballoon. The 6-month efficacy cohort included 328 patients with 6 months’ follow-up post-ablation. AF, atrial fibrillation.

Patient Characterization and Acute Procedural Success Rate

Table 1 summarizes the patients’ demographics and characteristics. The average age of the enrolled patients was 63±11 years, 72% were male, and the average length of AF diagnosis prior to enrollment was 45±61 months, ranging from 1 to 444 months.

Table 1. Demographics and Baseline Characteristics of AF Patients Prior to Treatment
Patient characteristics Safety population (n=616)
Sex
 Male 445 (72.0%)
 Female 171 (28.0%)
Age (years) 63.0±11.1
Height (cm) 165.2±8.9
Weight (kg) 65.4±12.2
BMI 23.9±3.4
Type of AF
 Paroxysmal 610 (99.0%)
 Persistent 4 (0.6%)
 Long-standing persistent 2 (0.3%)
History of AF (months) 45.1±60.6
Frequency of AF
 <Once a month 166 (26.9%)
 <Once a week 162 (26.3%)
 <Once a day 61 (9.9%)
 >Once a day 52 (8.4%)
 Unknown 175 (28.4%)
Echocardiographic data
 LVEF (%) 65.4±7.7
 LA dimension (mm) 38.3±6.1
 LA volume (ml) 57.2±22.5
Antiarrhythmic history (per patient) 1.3±0.6
CHADS2-VASc 1.8±1.5
Hypertension 271 (44.0%)
Diabetes 60 (9.7%)
Stroke or TIA 45 (7.3%)
CAD 22 (3.6%)
AF ablation history
 No prior AF ablation 608 (98.7%)
 Prior AF ablation using RF 7 (1.1%)
 Unknown 1 (0.2%)

Data are mean±standard deviation (SD) or n (%). Reported in only 230/616 (37.3%) of patients. AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; LA, left atrial; LVEF, left ventricular ejection fraction; RF, radiofrequency; TIA, transient ischemic attack.

Acute procedural success, defined as isolation of all major PVs, was achieved during the first cryoablation procedure in 99.8% (606/607) of the patients. In these 607 patients, a total of 2,414 PVs were treated with cryoballoon therapy. Of the 2,414 PVs, 111 (4.6%) required additional catheter-based focal ablation in ≥1 PV: 12 LSPVs, 23 LIPVs, 17 RSPVs and 59 RIPVs; 85 (77%) were treated with focal cryoablation, and the other 26 (23%) with focal RF ablation. For the cryoballoon alone, the acute success rate in each PV was 97.2%, 90.0%, 98.2% and 96.1% in RSPV, RIPV, LSPV and LIPV, respectively. PVI was successfully achieved in the common anatomical variations: 7 right middle PVs, 1 left middle PV and 4 common left PVs.

A 23-mm cryoballoon was used in 23 (3.8%) patients and a 28-mm cryoballoon in 584 (96.2%) patients. Focal ablation was used in 15.9% of procedures. The mean number of cryo-applications per vein was 2.2±0.9. Table 2 summarizes the cryoablation characteristics, including the number of cryoablation attempts, nadir (coldest measured) temperature, and cryoablation duration for each of the 4 main PVs. Table 3 summarizes the cryoablation procedure times.

Table 2. Summary of Cryoablation Procedures in Japanese Patients With PAF
Procedure variable Balloon size
23 mm
(n=23)
28 mm
(n=584)
PVs attempted (n)
 LSPV 23 579
 LIPV 23 573
 RSPV 23 582
 RIPV 23 576
Total no. of applications (n)
 LSPV 50 1,336
 LIPV 48 1,256
 RSPV 52 1,226
 RIPV 47 1,299
Mean no. of applications (n)
 LSPV 2.2±0.7 2.3±1.0
 LIPV 2.1±0.8 2.2±0.8
 RSPV 2.3±0.7 2.1±0.7
 RIP 2.0±0.8 2.3±0.9
Mean nadir balloon temperature (℃)
 LSPV −51.1±8.3 −47.6±7.7
 LIPV −45.2±6.8 −43.0±6.1
 RSPV −52.9±7.3 −50.8±7.8
 RIPV −45.4±8.7 −44.8±8.2
Mean freeze duration (s)
 LSPV 141.1±38.7 156.7±31.9
 LIPV 152.9±38.3 149.3±35.2
 RSPV 132.3±40.0 150.4±33.5
 RIPV 148.3±36.7 154.9±34.3

LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary; PAF, paroxysmal atrial fibrillation; RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein.

Table 3. Procedure Times for Cryoballoon Ablation for PAF in Japanese Patients
Parameter Overall
(n=607)
Procedure no.
1–16 within a
center (n=373)
Procedure no.
17–32 within a
center (n=174)
Procedure no.
33–50 within a
center (n=60)
P value*
Laboratory time (min) 187.8±53.7 197.5±57.4 178.2±45.7 155.2±27.8 <0.001
Procedure time (min) 150.2±48.9 157.5±52.0 144.1±42.1 123.3±32.5 <0.001
LA dwell time (min) 95.6±35.4 101.4±39.0 86.7±28.2 85.4±20.5 <0.001
Total fluoroscopy time (min) 53.2±27.1 56.1±29.5 51.4±22.1 41.4±20.8 <0.001

Data are mean±SD. *ANOVA. Abbreviations as in Tables 1,2.

The number of procedures performed within a center ranged from 1 to 50, with an average of 16±12 procedures per center. The overall mean laboratory time, defined as the time from when the patient entered the procedure room to the time the patient exited the room was 187.8±53.7 min. The overall mean procedure time, defined as the time from puncture to removal of the sheath was 150.2±48.9 min. The overall mean left atrial dwell time and fluoroscopy times were 95.6±35.4 and 53.2±27.1 min, respectively. All these procedure times decrease with learning experience within a center (all P<0.001) (Table 3).

AEs

Major device-related AEs occurred in 23 patients (3.7 %), and procedure-related events in 24 (3.9%) (Table 4). PNI was unresolved at hospital discharge in 9 patients (1.5%). All these patients were asymptomatic; PNI resolved in 7 of them before the 6-month follow-up ended, but remained in 1 patient at 6 months and had an unknown outcome in the remaining patient who was lost to follow-up. There were no reports of atrioesophageal fistula or device-related death.

Table 4. Major Device- and Procedure-Related Adverse Events in Japanese Patients Undergoing Cryoballoon Ablation for PAF
No. of AEs (n, % of patients) Safety population (n=616)
Event description Device-related Procedure-related
Cardiac tamponade 4 (4, 0.6%) 4 (4, 0.6%)
Death: worsening interstitial pneumonia 0 (0, 0.0%) 1 (1, 0.16%)
Hematoma at puncture site 3 (3, 0.5%) 3 (3, 0.5%)
Pericardial effusion 5 (5, 0.8%) 5 (5, 0.8%)
Pleural effusion 1 (1, 0.2%) 1 (1, 0.2%)
PV stenosis 1 (1, 0.2%) 1 (1, 0.2%)
Unresolved PNI at discharge 9 (9, 1.5%) 9 (9, 1.5%)
Atrioesophageal fistula 0 (0, 0.0%) 0 (0, 0.0%)
Total 23 (23, 3.7%) 24 (24, 3.9%)

Death reviewed by study events committee and classified as unrelated to the study ablation catheter. This event was classified as procedure-related, because it was not possible to determine if the inflammatory response after ablation may have led to worsening interstitial pneumonia as the primary cause of death. PNI, phrenic nerve injury; PV, pulmonary vein.

One patient was observed to have PV stenosis, defined as a 30% reduction in diameter compared with baseline for all 4 PVs. The event was non-serious and asymptomatic, and had unresolved at the time of 6-month follow-up.

One non-device-related death (pneumonia) was reported 6 days after the cryoablation. The patient had a history of heart failure and interstitial pneumonia 11 months prior to the ablation procedure. There were no abnormalities on transesophageal echocardiography performed before the ablation. The cryoablation procedure was successful with no AEs. However, 3 days post-ablation the patient presented with a high fever and a chest X-ray revealed reticulated shadowing in both lung fields and recurrence of pneumonia. Steroid pulse therapy was administered 6 days post-ablation but the patient died. An autopsy was not performed. The event was independently adjudicated as unrelated to study devices, but the relationship to the procedure was unknown.

Follow-up Data (6-Month Freedom From AF)

A total of 34/328 of the patients reported a chronic treatment failure. As shown in Figure 2, freedom from AF at 6 months was 88.4% (95% confidence interval: 84.1–91.6%). The primary reason for failure was the presence of detectable AF during the post-blanking period in 33 patients. A repeat ablation procedure was performed in 1 patient during the blanking period.

Figure 2.

Kaplan-Meier curves for freedom from chronic treatment failure for patients treated with Arctic Front AdvanceTM (n=328). The solid line is the Kaplan-Meier estimate, and the dashed lines are the 95% confidence interval. Freedom from atrial fibrillation (AF) at 6 months was 88.4% (95% CI: 84.1–91.6%).

Discussion

The current trial is the first multicenter evaluation of the procedural characteristics and clinical outcomes in Japanese PAF patients undergoing PVI with a CB2 ablation system. Based on the data from the CRYO-Japan PMS, PVI using the CB2 is both safe and effective in preventing recurrent AF in Japanese patients, with acute procedural success of 99.8% and freedom from AF of 88.4% at 6 months post-ablation.

Clinical Outcomes

Several studies have reported on cryoballoon outcomes since Packer et al first reported 69.9% freedom from AF in the STOP-AF study.5 Five recent studies report encouraging clinical outcomes when comparing the 1st- and 2nd-generation cryoballoon systems, with an average increase of 17.4% in the freedom from AF.610 Additionally, 6 publications evaluated the CB2 system exclusively, and reported rates of freedom from AF of 80–90%.1115 The results of the present study, with 88.4% freedom from AF at 6 months, are consistent with the outcomes reported in these global studies on the effectiveness of cryoablation.

However, the CRYO-Japan PMS study is the first evaluation of procedural characteristics, balloon temperatures, acute procedural success, and AEs by operators who had not used the 1st-generation cryoballoon, which was not released in Japan. The CB2 features 8 refrigerant ports as opposed to the 4 refrigerant ports in the 1st-generation system. This modification, combined with the 15% increase in refrigerant flow in the 28-mm 2nd-generation balloon, results in more uniform cooling.

The results of the present study demonstrated similar procedural safety and efficacy using the CB2 with those reported by users with experience of both the 1st- and 2nd-generation devices. The consistent outcomes in the CRYO-Japan PMS study suggest that design enhancements are the most likely contributor to the improved outcomes with the CB2, than increased operator experience. However, it is important to acknowledge the cryoballoon training program and recent publications sharing cryoballoon best practices as references for new cryoballoon users.16

Although one may expect longer procedure times with operators who are new to the cryoballoon procedure, and a higher rate of repeat procedures, this was not the case in the CRYO-Japan PMS study when compared with the pivotal STOP-AF study.5 The total laboratory occupancy time in STOP-AF was 371 min, compared with 188 min in the CRYO-Japan PMS. And fluoroscopy time was 63 min in STOP-AF, compared with 53 min in the CRYO-Japan PMS. Although an average of 53 min of fluoroscopy time is higher than in recent publications reporting on using the CB2,1115 there was a mean decrease from an average of 56 min in the first 16 procedures at one of the sites to 41 min for the 33rd to 50th procedures at the same site as operators became more familiar with the procedure and technology. And 19% of the patients in STOP-AF had a repeat procedure in the blanking period, compared with only 1 patient (0.3%) in CRYO-Japan PMS.

Safety of the Cryoballoon for AF Ablation

The AE rates observed in the CRYO-Japan PMS study, with new cryoballoon users, were also consistent with published safety outcomes for users with experience with the 1st- and 2nd-generation cryoballoon and consistent with event rates observed across the ablation technologies.

Since the pivotal STOP-AF study results were first presented, and reported a PNI rate of 11.2%,5 the incidence of PNI has steadily decreased, driven by greater awareness, operator experience, and improvements in technology and monitoring. The rate of PNI unresolved at discharge was comparatively low in this study (1.5%), but consistent with other recent publications reporting rates of 2–7%.11,12,14,15,17

These results suggest that the improved cooling characteristics of the CB2 do not translate to a higher rate of AEs even for new cryoballoon users.

Study Limitations

This was a non-randomized, single-arm, observational PMS study. The relatively short duration of the follow-up (mean follow-up period: 189 days) may not represent the chronic clinical outcomes of cryoablation. Recurrence monitoring was performed according to standard of care; more rigorous monitoring may have detected additional arrhythmia recurrence. It would be interesting to analyze what among the patients’ characteristics is predictive for AF recurrence, including AF burden, cryoablation characteristics such as the nadir temperature, and others. Future subanalysis may reveal such predictive factors.

Conclusions

PVI using the CB2 system for Japanese patients with PAF was an effective treatment in this study, with a freedom from AF of 88.4% at 6 months. A total of 9 of the 607 patients (1.5%) had PNI reported as unresolved at discharge, with 1 reporting unresolved PNI at 6 months (0.2%). Compared with global studies, the rate of PNI was relatively low in this study. Based on this evaluation of the efficacy and safety of the device in post-marketing clinical settings, the cryoballoon system is considered safe and effective for treating patients with recurrent drug-refractory PAF in routine clinical practice in Japan.

Acknowledgments

We are grateful to the health care professionals, investigational institutions and patients for their cooperation with this cryoballoon system PMS.

Disclosures

K.O., K.M., Y.K., and A.N. have received consulting fees and speaker honoraria from Medtronic Japan Co, Ltd. R.B.H. and F.K. are employees of Medtronic, Inc.

Supplementary Files

Supplementary File 1

Appendix S1. CRYO-Japan PMS Study Investigators

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-16-0285

References
 
© 2016 THE JAPANESE CIRCULATION SOCIETY
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