ABSTRACT
Background
Atrial fibrillation (AF) prevalence has increased with Japan's aging population. Data on cryoballoon ablation (CBA) for persistent AF (PsAF) in Japan is limited. This study reports CBA clinical outcomes in PsAF patients in Japan from the prospective Cryo Global Registry.
Methods
Data was analyzed from 60 Japanese centers with 1226 PsAF patients that underwent CBA. The primary endpoints were serious adverse events and freedom from atrial arrhythmia (AA) recurrence, at 12 months. The effect of ablation strategy (pulmonary vein isolation [PVI] or PVI with additional ablations [PVI+]) was evaluated. Quality‐of‐life (QoL) was measured by EQ‐5D‐3L questionnaire.
Results
The patient mean age was 68 ± 10 years and 29.0% were female. The overall 12‐months Kaplan–Meier (KM) estimate for freedom from AA recurrence was 84.4% (95% CI: 82.2%–86.3%). Among PVI+ patients, 33.0% received cavotricuspid isthmus (CTI) and 34.6% received non‐CTI ablation (majority being left‐atrial roofline [27.2%]). The 12‐months KM estimate for freedom from AA recurrence was higher for PVI+ subgroup (86.6% [CI: 83.6%–89.1%]) than PVI subgroup (82.0% [CI: 78.6%–84.9%]) (HR adj = 1.40, p = 0.025). Twenty‐two serious adverse events were reported in 1.6% patients. At 12 months, compared to baseline, QoL improved with a mean summary‐index score difference of 0.03 ± 0.16 (p < 0.001) and a mean EQ visual analogue scale score difference of 7.9 ± 18.5 (p < 0.001).
Conclusion
This study showed CBA is safe and effective for PsAF treatment in real‐world use in Japan.
Trial Registration
Cryo Global Registry, ClinicalTrials.gov ID NCT02752737
Keywords: cryoballoon ablation, Japan, persistent atrial fibrillation, pulmonary vein isolation, registry
Cryoballoon ablation is a safe and effective treatment for patients with persistent atrial fibrillation in Japan, leading to improved quality of life. Real‐world data support its use as a beneficial option for these patients.
Abbreviations
- AA
Atrial arrhythmia
- AADs
Antiarrhythmic drugs
- AF
Atrial fibrillation
- AFL
Atrial flutter
- AT
Atrial tachycardia
- CBA
Cryoballoon ablation
- CTI
Cavotricuspid isthmus
- KM
Kaplan–Meier
- LA
Left atrium
- PNI
Phrenic nerve injury
- PsAF
Persistent atrial fibrillation
- PV
Pulmonary vein
- PVI
Pulmonary vein isolation
- PVI+
Pulmonary vein isolation and ablation targets beyond pulmonary vein isolation
- QoL
Quality‐of‐life
1. Introduction
The prevalence of atrial fibrillation (AF) increases as the population ages [1, 2, 3]. In Japan, in 2021, AF ablation was the leading procedure (75.0% of all ablation procedures) and the percentage of patients over 75 years of age was 28.3% [4]. Reports on clinical outcomes of cryoballoon ablation (CBA) treatment of AF patients in Japan are limited [4].
A previous analysis of the Cryo Global Registry demonstrated that CBA was safe and effective for treatment of paroxysmal AF (PAF) in Japan, reporting 88.5% freedom from atrial arrhythmia (AA) at 12 months [5]. Overall, earlier studies on use of CBA for treatment of persistent AF (PsAF) have reported lower efficacy outcomes than what is reported for PAF [6]. For example, the CRYO4PERSISTENT AF trial reported that CBA with a pulmonary vein isolation (PVI) only approach for PsAF treatment resulted in 61% success at 12 months [7]. The STOP Persistent AF trial showed CBA was safe and effective in the treatment of drug‐refractory PsAF patients using a PVI only approach and reported 54.8% freedom from AA at 12 months [8]. Notably, these studies enrolled patients who were refractory or intolerant to at least one antiarrhythmic drug (AAD), evaluated a PVI only approach, and included a minority of Japanese patients. This current study evaluated data from the Cryo Global Registry (NCT02752737) and reported on the real‐world safety and efficacy outcomes in PsAF patients treated with the Arctic Front Cardiac Cryoablation Catheter System (Medtronic Inc., Minneapolis, MN) (referred to as cryoballoon) in Japan.
2. Methods
2.1. Study Design
The Cryo Global Registry (NCT02752737) is a prospective, multicenter, post‐market study. The aim of the registry is to evaluate clinical outcomes in a broad patient population treated with CBA. The objective of this study using the registry data was to evaluate safety and efficacy of CBA to treat PsAF patients in Japan. Data were collected at 60 centers in Japan (Table S1). The study was conducted according to Good Clinical Practices, in compliance with local regulations, and in accordance with the principles outlined in the Declaration of Helsinki. Each center received approval by an independent ethics and institutional review board and obtained written informed patient consent prior to enrollment.
2.2. Patient Population
The inclusion criteria in the registry for Japan were (i) subject must be at least 20 years of age, (ii) subject who intended on the operation of approved and commercially available Arctic Front Cardiac Cryoablation catheter, (iii) subject who has the will to comply with the research requirements and informed consent, and (iv) subject who has symptomatic PAF and PsAF with drug resistance. The exclusion criteria in the registry for Japan were (i) any subject enrolled and/or jointly enrolled in other research, and the treating physician deemed it as inappropriate for the patient to join this research due to the scientific reasons, etc., and (ii) subject applicable for the exclusion criteria required by the local law. This analysis included a subset of patients from the registry that were diagnosed with PsAF, enrolled in the registry, and treated with CBA as index (first) PVI procedure at 60 centers in Japan between January 2021 and June 2022 (Figure 1). Patients with prior PVI, PAF and longstanding PsAF were excluded from this analysis. The procedure and patient follow‐up were performed according to the corresponding Japanese center's standard‐of‐care protocol.
FIGURE 1.
Patient enrollment and follow‐up in the current study. The flow of patient enrollment and the 12‐month follow‐up visit which resulted in the inclusion of 1226 PsAF patients that were treated with an index CBA procedure in Japan for analysis in the current study. CBA, Cryoballoon ablation; PsAF, Persistent atrial fibrillation.
2.3. Ablation Procedure
The CBA procedure was performed as previously described [7, 8, 9, 10] and as briefly mentioned here. Patients were first sedated using general anesthesia or using deep or conscious sedation. An over‐the‐wire steerable sheath was used to introduce a 23‐ or 28‐mm CBA catheter (Arctic Front, Arctic Front Advance, or Arctic Front Advance Pro Cardiac Cryoablation Catheter System; Medtronic Inc.) into the left atrium (LA). CBA catheters were introduced into the LA by a femoral or superior venous approach and transseptal puncture. The CBA catheter was steered in the LA either over a J‐tip guidewire or a dedicated inner‐lumen octopolar/decapolar circular mapping catheter (Achieve or Achieve Advance; Medtronic Inc.) and was directed to the targeted pulmonary vein (PV). The CBA catheter was inflated and positioned at the antral surface of the PV. After PV occlusion, the cryo‐application was initiated. The number and duration of freezes delivered per PV were determined by the physician. It was recommended to pace the right phrenic nerve during all right‐sided cryo‐applications to monitor phrenic nerve function during each freeze. Ablations beyond PVI, including cavotricuspid isthmus (CTI) ablation, were performed depending upon the patient treatment plan and local standard‐of‐care per study site. All procedural tools and techniques to guide/monitor/assess the CBA procedure were applied at the physician's discretion. Physicians determined appropriate periprocedural anticoagulation and initiation/continuation of AADs and followed local standard‐of‐care policies to discharge patients.
2.4. Patient Follow‐Up, Data Collection, and Monitoring
The patient medical history was collected at the baseline visit, and follow‐up was conducted according to local standard‐of‐care protocols. An in‐person or remote telephone visit was required at 12 months after the cryoablation index procedure. An electrocardiogram, Holter monitor, trans‐telephonic monitor, insertable cardiac monitor, pacemaker and/or implantable cardioverter defibrillator could be used to monitor for atrial arrhythmia (AA) recurrence. Cardiovascular medications, adverse events, and quality‐of‐life (QoL) data as assessed by the EQ‐5D‐3L questionnaire were collected at baseline and during the 12‐month follow‐up visit. All adverse events were followed until the event was resolved, or the event was unresolved with no further actions, or the patient exited the registry.
2.5. Endpoints
The primary efficacy endpoint was freedom from a ≥ 30 s recurrence of AA (atrial fibrillation (AF), atrial flutter (AFL), and/or atrial tachycardia (AT)) following a 90‐day blanking period. Patients were managed according to local standard‐of‐care protocols during the 90‐day blanking period without penalty toward the primary efficacy endpoint. Post hoc analysis was performed to evaluate the effect of the ablation strategy (PVI or PVI with additional ablations [PVI+]) on the primary efficacy outcome. The serious device‐ and/or procedure‐related adverse event rates through 12 months were evaluated to assess the safety of the CBA catheter. Adverse event seriousness and relatedness to the CBA catheter system and/or ablation procedure was classified by the investigator (according to ISO 14155:2001). Serious adverse events included all events that led to death, or to a serious deterioration in health that resulted in either (i) a life‐threatening illness or injury, (ii) a permanent impairment in body structure or function, (iii) inpatient or prolonged hospitalization, or (iv) medical intervention to prevent life‐threatening illness or injury. Changes in QoL between baseline and the 12‐month follow‐up were measured by the EQ‐5D‐3L questionnaire.
2.6. Statistical Analysis
Baseline characteristics and procedural characteristics were summarized using appropriate summary statistics. Continuous variables were presented as mean and standard deviation, and median and interquartile range. Categorical variables were presented as counts and percentages. Differences in baseline characteristics between the cohort of subjects with PVI+ strategy versus subjects with PVI only strategy were tested with a two‐sample t‐test for continuous variables and Fisher's exact test for categorical variables. Similarly, differences in procedural characteristics were tested with a two‐sample t‐test for continuous variables and Fisher's exact test for categorical variables. For skewed continuous data, Wilcoxon rank‐sum test was utilized. Kaplan–Meier (KM) methods were used to estimate freedom from AA (AF/AFL/AT) recurrence, repeat ablation, All‐Cause hospitalization and cardiovascular‐related rehospitalization at 12 months. Standard error was approximated using Greenwood's formula. For subjects with an AA recurrence, follow‐up time was set to the date of AA recurrence. For subjects without a reported AA recurrence that completed a 12‐months visit, the subject was censored at the 12‐months visit date. For subjects without a reported AA recurrence that exit prior to completing a 12‐months visit, those subjects were censored at the last study contact date recorded on a case report form which may include the last study visit, death date, study exit date, or last arrhythmia monitoring date. Unadjusted and adjusted hazard ratios (HR) were calculated with Cox regression. Unadjusted models included only group cohort (PVI+ vs. PVI only) as a covariate in the model. Adjusted models accounted for differences in baseline characteristics between PVI+ and PVI only cohorts utilizing propensity score methods. In the adjusted Cox regression model, group cohorts (PVI+ vs. PVI only) and propensity score were included as covariates. Propensity scores were calculated from a logistic regression model with the indicator of PVI+ or PVI only patients as the dependent variable and baseline characteristics (excluding CHAD2DS2‐VASc, prior PVI and AAD at Baseline) included as covariates in the model. CHAD2DS2‐VASc score was excluded as it is a composite of other variables in the model (heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack), prior PVI was excluded due to no data and AAD at Baseline due to its correlation with First‐line. Multiple imputation methods were utilized in the propensity score modeling, imputing baseline data for patients missing data. Multivariate imputation by fully conditional specification methods were utilized with logistic regression method specified for classification variables and regression methods utilized for continuous variables [11]. Changes in quality‐of‐life from baseline to 12 months were assessed with a 2‐sided t‐test, and McNemar's test was used to compare arrhythmia related symptoms from baseline to 12 months. Differences in serious adverse events and safety rates between PVI+ and PVI only cohorts of patients were assessed with Fisher's exact test. Statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, North Carolina).
3. Results
3.1. Baseline Patient Characteristics
The analysis cohort included a total of 1226 patients diagnosed with PsAF and treated with an index CBA procedure using the PVI approach at a total of 60 centers in Japan between January 2021 and June 2022. Baseline patient characteristics are detailed in Table 1. Of the 1226 patients, 29% (356) were female. The patients had a mean age of 68 ± 10 (median of 70; IQR 62–76) years, mean BMI of 25 ± 4 (median of 24; IQR 22–26) kg/m2, and a mean CHA2DS2‐VASc score of 2.5 ± 1.6 (median of 2.0; IQR 1.0–4.0). The time from PsAF diagnosis to enrollment was a mean of 0.4 ± 1.2 (median of 0.2; IQR 0.1–0.4) years. Among all patients, 1.6% (20) patients had prior AFL ablation, 2.7% (33) had a history of AFL and 0.7% (9) had a history of AT. At baseline, the majority of patients [69.1% (847)] were not on Class I/III AADs for rhythm control. Post hoc analysis was performed to evaluate differences in baseline characteristics between the PVI+ and PVI only subgroups. These differences and their statistical analyses are presented in Table 1. A notable finding was that patients in the PVI+ subgroup [3.6% (n = 23)] had a greater history of AFL compared to those in the PVI only subgroup [1.7% (n = 10)] (p = 0.04).
TABLE 1.
Baseline patient characteristics.
| Subject characteristics | Total subjects (N = 1226) | PVI+ (N = 631) | PVI only (N = 595) | p a |
|---|---|---|---|---|
| Female sex (N [%]) | 356 (29.0%) | 183 (29.0%) | 173 (29.1%) | > 0.99 |
| Age in years (mean ± SD) | 68 ± 10 | 68 ± 10 | 68 ± 11 | 0.57 |
| Body mass index in kg/m2 (mean ± SD) b | 25 ± 4 | 25 ± 4 | 24 ± 4 | 0.80 |
| CHA2DS2‐VASc score (mean ± SD) | 2.5 ± 1.6 | 2.6 ± 1.6 | 2.5 ± 1.7 | 0.23 |
| Years diagnosed with PsAF (mean ± SD) c | 0.4 ± 1.2 | 0.5 ± 1.4 | 0.3 ± 0.8 | 0.85 |
| Prior atrial flutter ablation (N [%]) | 20 (1.6%) | 8 (1.3%) | 12 (2.0%) | 0.37 |
| Prior PVI (N [%]) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | NA |
| History of atrial flutter (N [%]) | 33 (2.7%) | 23 (3.6%) | 10 (1.7%) | 0.04 |
| History of atrial tachycardia (N [%]) | 9 (0.7%) | 7 (1.1%) | 2 (0.3%) | 0.18 |
| Left atrial diameter in mm (mean ± SD) d | 42 ± 6 | 42 ± 6 | 42 ± 6 | 0.14 |
| Left ventricular ejection fraction in % (mean ± SD) e | 58 ± 11 | 58 ± 11 | 58 ± 11 | 0.71 |
| Number of failed AADs (mean ± SD) | 0.2 ± 0.5 | 0.3 ± 0.5 | 0.2 ± 0.4 | 0.01 |
| 0 previously failed AADs (N [%]) | 977 (79.7%) | 486 (77.0%) | 491 (82.5%) | |
| On AAD at baseline | 130 (10.6%) | 50 (7.9%) | 80 (13.4%) | |
| Not on AAD at baseline | 847 (69.1%) | 436 (69.1%) | 411 (69.1%) | |
| 1 prior AAD failure | 219 (17.9%) | 129 (20.4%) | 90 (15.1%) | |
| 2 prior AAD failure | 23 (1.9%) | 13 (2.1%) | 10 (1.7%) | |
| 3 or more prior AAD failure | 3 (0.2%) | 2 (0.3%) | 1 (0.2%) | |
| Not reported | 4 (0.3%) | 1 (0.2%) | 3 (0.5%) | |
| Hypertension (N [%]) | 667 (54.4%) | 336 (53.2%) | 331 (55.6%) | 0.42 |
| Prior cardiac device implant f (N [%]) | 13 (1.1%) | 8 (1.3%) | 5 (0.8%) | 0.58 |
| Subject taking class I–IV AADs at baseline | 0.57 | |||
| No | 981 (80.0%) | 509 (80.7%) | 472 (79.3%) | |
| Yes | 245 (20.0%) | 122 (19.3%) | 123 (20.7%) | |
| Class I | 9 (0.7%) | 5 (0.8%) | 4 (0.8%) | |
| Class II | 39 (3.2%) | 21 (3.3%) | 18 (3.0%) | |
| Class III | 13 (1.1%) | 4 (0.6%) | 9 (1.5%) | |
| Class IV | 45 (3.7%) | 14 (2.2%) | 31 (5.2%) | |
| Not reported | 139 (11.3%) | 78 (12.4%) | 61 (10.3%) | |
| NYHA classification | 0.03 g | |||
| Subject does not have heart failure (N [%]) | 476 (38.8%) | 247 (39.1%) | 229 (38.5%) | |
| Class I | 192 (15.7%) | 105 (16.6%) | 87 (14.6%) | |
| Class II | 207 (16.9%) | 121 (19.2%) | 86 (14.5%) | |
| Class III | 36 (2.9%) | 25 (4.0%) | 11 (1.8%) | |
| Class IV | 2 (0.2%) | 2 (0.3%) | 0 (0.0%) | |
| NYHA status not reported (N [%]) | 85 (6.9%) | 33 (5.2%) | 52 (8.7%) | |
| Prior myocardial infarction (N [%]) | 27 (2.2%) | 17 (2.7%) | 10 (1.7%) | 0.25 |
| Prior stroke/transient ischemic attack (N [%]) | 95 (7.7%) | 53 (8.4%) | 42 (7.1%) | 0.39 |
| History of coronary artery disease (N [%]) | 88 (7.2%) | 51 (8.1%) | 37 (6.2%) | 0.22 |
| Diabetes (N [%]) | 166 (13.5%) | 82 (13.0%) | 84 (14.1%) | 0.62 |
| Sleep apnea (N [%]) | 75 (6.1%) | 36 (5.7%) | 39 (6.6%) | 0.55 |
Abbreviations: PsAF, Persistent atrial fibrillation; SD, standard deviation.
Statistical tests comparing PVI+ cohort vs. PVI Only cohort. Continuous variables compared with t‐test, binary variables compared with exact test.
1222 subjects with BMI reported; 627 PVI+, 595 PVI only.
1066 subjects with PsAF diagnosis date reported; 558 PVI+, 508 PVI only.
1141 subjects with left atrial diameter reported; 587 PVI+, 554 PVI only.
1171 subjects with left ventricular ejection fraction reported; 597 PVI+, 574 PVI only.
Prior cardiac devices include implantable pulse generator (IPG), implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy defibrillator (CRT‐D), and insertable cardiac monitor (ICM).
Wilcoxon rank‐sum test comparing distribution of severity of NYHA (from no heart failure through Class IV) between PVI+ and PVI only.
3.2. Procedural Characteristics
The CBA device‐ and procedure‐related data is detailed in Table 2. The total procedure time defined as venous access to last cryocatheter (CBA) removal was a mean of 78 ± 31 (median of 73; IQR 55–95) min. LA dwell time was a mean of 50 ± 22 (median of 45; IQR 35–60) min, total fluoroscopy time was a mean of 48 ± 41 (median of 35; IQR 19–62) min, and fluoroscopy time during cryoablation was a mean of 23 ± 19 (median of 16; IQR 10–31) min. General anesthesia was utilized in 46.9% (575) procedures, deep/moderate sedation in 7.8% (96) procedures, and conscious sedation in 45.3% (555) procedures. Pre‐procedural imaging with computed tomography (CT) or magnetic resonance imaging (MRI) was performed in 46.5% (570) procedures, intra‐procedural 3D electroanatomical mapping was performed in 62.4% (765) procedures, intracardiac echocardiography (ICE) was used in 47.4% (581) procedures, and esophageal monitoring was used in 70.7% (867) procedures. Phrenic nerve function was monitored in 98.9% (1212) of the subjects using pace/palpate/diaphragm stimulation and/or compound motor action potential (CMAP) methods.
TABLE 2.
Procedure characteristics.
| Procedure characteristics | Total subjects (N = 1226) | PVI+ (N = 631) | PVI only (N = 595) | p i |
|---|---|---|---|---|
| Cryoballoon catheter used to ablate pulmonary vein | NA | |||
| Arctic Front 23 mm (N [%]) | 1 (0.08%) | 0 (0.0%) | 1 (0.2%) | |
| Arctic Front 28 mm (N [%]) | 2 (0.16%) | 1 (0.2%) | 1 (0.2%) | |
| Arctic Front Advance 23 mm (N [%]) | 2 (0.16%) | 2 (0.3%) | 0 (0.0%) | |
| Arctic Front Advance 28 mm (N [%]) | 119 (9.71%) | 70 (11.1%) | 49 (8.2%) | |
| Arctic Front Advance 28 mm | Arctic Front Advance Pro 28 mm (N [%]) | 24 (1.96%) | 10 (1.6%) | 14 (2.4%) | |
| Arctic Front Advance 28 mm | Arctic Front Advance Pro 28 mm | RF (N [%]) | 2 (0.16%) | 1 (0.2%) | 1 (0.2%) | |
| Arctic Front Advance 28 mm | RF (N [%]) | 12 (0.98%) | 7 (1.1%) | 5 (0.8%) | |
| Arctic Front Advance Pro 28 mm (N [%]) | 938 (76.51%) | 467 (74.0%) | 471 (79.2%) | |
| Arctic Front Advance Pro 28 mm | Freezor MAX (N [%]) | 10 (0.82%) | 4 (0.6%) | 6 (1.0%) | |
| Arctic Front Advance Pro 28 mm | RF (N [%]) | 48 (3.92%) | 33 (5.2%) | 15 (2.5%) | |
| Not reported (N [%]) | 68 (5.55%) | 36 (5.7%) | 32 (5.4%) | |
| Mapping catheter model used | NA | |||
| Achieve 15 mm (N [%]) | 5 (0.4%) | 5 (0.8%) | 0 (0.0%) | |
| Achieve 20 mm (N [%]) | 798 (65.1%) | 407 (64.5%) | 391 (65.7%) | |
| Achieve 25 mm (N [%]) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Achieve Advance 15 mm (N [%]) | 1 (0.1%) | 0 (0.0%) | 1 (0.2%) | |
| Achieve Advance 20 mm (N [%]) | 418 (34.1%) | 215 (34.1%) | 203 (34.1%) | |
| Achieve Advance 25 mm (N [%]) | 2 (0.2%) | 2 (0.3%) | 0 (0.0%) | |
| Steerable sheath used | NA | |||
| FlexCath (N [%]) | 19 (1.5%) | 6 (1.0%) | 13 (2.2%) | |
| FlexCath Advance (N [%]) | 1173 (95.7%) | 616 (97.6%) | 557 (93.6%) | |
| Total lab occupancy time in minutes a (mean ± SD) | 144 ± 60 | 172 ± 56 | 114 ± 47 | < 0.01 |
| Total procedure time, venous access to venous closure in minutes b (mean ± SD) | 117 ± 53 | 144 ± 50 | 88 ± 38 | < 0.01 |
| Total procedure time, venous access to last cryocatheter removal in minutes c (mean ± SD) | 78 ± 31 | 89 ± 31 | 66 ± 25 | < 0.01 |
| Left atrial dwell time in minutes d (mean ± SD) | 50 ± 22 | 56 ± 23 | 43 ± 18 | < 0.01 |
| Total fluoroscopy time in minutes e (mean ± SD) | 48 ± 58 | 53 ± 65 | 43 ± 48 | < 0.01 |
| Fluoroscopy time during cryoablation in minutes f (mean ± SD) | 23 ± 19 | 23 ± 19 | 23 ± 19 | 0.98 |
| Sedation method (N [%]) | < 0.01 h | |||
| General | 575 (46.9%) | 334 (52.9%) | 241 (40.5%) | |
| Deep/moderate | 96 (7.8%) | 60 (9.5%) | 36 (6.1%) | |
| Conscious | 555 (45.3%) | 237 (37.6%) | 318 (53.4%) | |
| Not reported | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Pre‐procedural mapping (CT and/or MRI) (N [%]) | 570 (46.5%) | 292 (46.3%) | 278 (46.7%) | 0.91 |
| Intra‐procedural 3D electroanatomical mapping (N [%]) | 765 (62.4%) | 394 (62.4%) | 371 (62.4%) | > 0.99 |
| Intracardiac echocardiography (N [%]) | 581 (47.4%) | 323 (51.2%) | 258 (43.4%) | < 0.01 |
| Esophageal monitoring (N [%]) | 867 (70.7%) | 453 (71.8%) | 414 (69.6%) | 0.41 |
| Types of esophageal monitoring | ||||
| Temperature probe | 837 (68.3%) | 431 (68.3%) | 406 (68.2%) | |
| ICE | 33 (2.7%) | 25 (4.0%) | 8 (1.3%) | |
| Other | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Not done | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Phrenic nerve monitoring (N [%]) | 1212 (98.9%) | 627 (99.4%) | 585 (98.3%) | 0.11 |
| Pacing/palpate | 1064 (86.8%) | 558 (88.4%) | 506 (85.0%) | |
| Diaphragm stimulation | 548 (44.7%) | 284 (45.0%) | 264 (44.4%) | |
| Pacing/palpate/diaphragm stimulation | 1138 (92.8%) | 584 (92.6%) | 554 (93.1%) | |
| CMAP | 1068 (87.1%) | 580 (91.9%) | 488 (82.0%) | |
| Other | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| CTI (cavotricuspid isthmus) ablation strategy reported (N [%]) | 405 (33.0%) | 405 (64.2%) | 0 (0.0%) | NA |
| Beyond PVI non‐CTI ablation strategy reported (N [%]) | 424 (34.6%) | 424 (67.2%) | 0 (0.0%) | NA |
| LA AF trigger | 22 (1.8%) | 22 (3.5%) | 0 (0.0%) | |
| RA AF trigger | 9 (0.7%) | 9 (1.4%) | 0 (0.0%) | |
| Superior vena cava vein trigger | 68 (5.5%) | 68 (10.8%) | 0 (0.0%) | |
| Inferior vena cava vein trigger | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Mitral valve isthmus or line | 8 (0.7%) | 8 (1.3%) | 0 (0.0%) | |
| Left sided roofline | 334 (27.2%) | 334 (52.9%) | 0 (0.0%) | |
| CFAE (complex fractionated atrial electrograms) | 6 (0.5%) | 6 (1.0%) | 0 (0.0%) | |
| CardioInsight detection | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Rotor | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | |
| Other | 108 (8.8%) | 108 (17.1%) | 0 (0.0%) | |
| Acute success (for all targeted PVIs) (N [%]) | < 0.01 | |||
| Yes | 1152 (94.0%) | 607 (96.2%) | 545 (91.6%) | |
| No | 22 (1.8%) | 10 (1.6%) | 12 (2.0%) | |
| Not reported | 52 (4.2%) | 14 (2.2%) | 38 (6.4%) | |
| Focal touch‐up with focal RF catheter (N [%]) | 62 (5.1%) | 41 (6.5%) | 21 (3.5%) | 0.02 |
| Focal touch‐up with focal cryo catheter (N [%]) | 10 (0.8%) | 4 (0.6%) | 6 (1.0%) | 0.54 |
| Acute success with no focal touch‐up g | 0.62 | |||
| Yes | 1025 (98.5%) | 529 (83.8%) | 496 (83.4%) | |
| No | 16 (1.5%) | 7 (1.1%) | 9 (1.5%) | |
| Isoproterenol and/or adenosine use (N [%]) | 456 (37.2%) | 198 (31.4%) | 258 (43.4%) | < 0.01 |
| Length of hospital stay in days (mean ± SD) | 2.5 ± 3.0 | 2.4 ± 2.3 | 2.6 ± 3.6 | < 0.01 |
| Same day discharge | 2 (0.2%) | 1 (0.2%) | 1 (0.2%) | |
| 1 day | 191 (15.6%) | 81 (12.8%) | 110 (18.5%) | |
| 2 days | 750 (61.2%) | 424 (67.2%) | 326 (54.8%) | |
| 3+ days | 281 (22.9%) | 125 (19.8%) | 156 (26.2%) | |
| AAD at discharge (N [%]) | 0.27 | |||
| Yes | 321 (26.2%) | 174 (27.6%) | 147 (24.7%) | |
| No | 900 (73.4%) | 455 (72.1%) | 445 (74.8%) | |
| Not reported | 5 (0.4%) | 2 (0.3%) | 3 (0.5%) | |
| AAD at the 12‐months follow‐up (N [%]) | < 0.01 | |||
| Yes | 421 (34.3%) | 239 (37.9%) | 182 (30.6%) | |
| No | 748 (61.0%) | 356 (56.4%) | 392 (65.9%) | |
| Not reported | 57 (4.6%) | 36 (5.7%) | 21 (3.5%) | |
| Anticoagulants at discharge (N [%]) | 0.09 | |||
| Yes | 1152 (94.0%) | 600 (95.1%) | 552 (92.8%) | |
| No | 71 (5.8%) | 30 (4.8%) | 41 (6.9%) | |
| Not reported | 3 (0.2%) | 1 (0.2%) | 2 (0.3%) |
Abbreviations: AAD, Antiarrhythmic drug; AF, Atrial fibrillation; CFAE, Complex fractionated atrial electrograms; CMAP, Compound motor action potential; CT, Computed tomography; LA, Left atrial; MRI, Magnetic resonance imaging; MVI, Mitral valve isthmus; PVI, Pulmonary vein isolation; RA, Right atrial; RF, Radio Frequency; SD, standard deviation.
1212 subjects reported total lab occupancy time; 621 PVI+ and 591 PVI only.
1214 subjects reported total procedure time (venous access to closure); 622 PVI+ and 592 PVI only.
1222 subjects reported total procedure time (venous access to cryocatheter removal); 628 PVI+ and 594 PVI only.
1220 subjects reported total atrial dwell time; 626 PVI+ and 594 PVI only.
1198 subjects reported total fluoroscopy time; 618 PVI+ and 580 PVI only.
1184 subjects reported fluoroscopy time during cryoablation; 606 PVI+ and 578 PVI only.
Acute Success for PVIs without focal touch‐up, N = 1041.
Wilcoxon rank‐sum test comparing the distribution of sedation method (general, deep/moderate, and conscious) between PVI+ and PVI only.
Two‐sample t‐test for continuous variables and exact test for categorical variables.
The PVI only and PVI+ subgroups comprised of 48.5% (595) and 51.5% (631) of patients, respectively. In addition to the use of cryoballoon, the PVI+ strategy involved the use of other catheters such as standard irrigated radiofrequency (RF) or contact force sensing RF depending on the local practice. Among patients receiving PVI+ ablation, 33.0% (405) received CTI ablation and 34.6% (424) received non‐CTI ablation (including, 1.8% (22) LA AF trigger; 0.7% (9) right atrium (RA) AF trigger; 5.5% (68) superior vena cava (SVC) trigger; 0.7% (8) mitral valve isthmus (MVI) targeted or MVI line performed; 27.2% (334) left‐sided or left‐atrial roofline; 0.5% (6) complex fractionated atrial electrogram based locations; and 8.8% (108) other additional ablation locations). Out of the 1226 patients, the overall acute success (defined as successful isolation of all targeted pulmonary veins) was achieved in 94.0% (1152) patients; acute success was not reported in 4.2% (52) patients. Focal RF PVI touch‐up and focal Cryo PVI touch‐up were performed in 5.1% (62) and 0.8% (10) patients, respectively. Post hoc analysis revealed that acute success was achieved in 91.6% (545) patients in the PVI only subgroup and was achieved in 96.2% (607) patients in the PVI+ subgroup. The differences in procedural characteristics for each of the two subgroups and their statistical analyses are presented in Table 2. The length of hospital stay after index procedure was a median of 2 days.
A post hoc analysis revealed that, of 1226 patients, 81.7% (1002) patients received CBA treatment within 6 months of their PsAF diagnosis. After the index CBA procedure, a total of 1169 patients completed the 12‐month follow‐up final study visit for this analysis (Figure 1). At the 12‐month follow‐up visit, 61.0% (748) patients were not on any AADs, and 4.6% (57) patients did not report on AAD usage.
3.3. Safety
Out of 1226 PsAF patients, 22 serious device‐ and/or procedure‐related adverse events in a total of 20 patients were reported (Table 3). The overall serious adverse event rate was 1.6% (20). Cardiac tamponade occurred in 0.2% (3) patients. A complete list of the serious device‐ and/or procedure‐related adverse events is provided in Table 3. Post hoc analysis revealed that the rate of serious adverse events was higher in the PVI+ subgroup (2.2%) than in the PVI only subgroup (1%), although the difference was not statistically significant (p = 0.12).
TABLE 3.
Serious adverse events.
| Serious device‐ and/or procedure‐related adverse events | Number of events (subjects, %) | |||
|---|---|---|---|---|
| Total subjects (N = 1226) | PVI+ (N = 631) | PVI only (N = 595) | p c | |
| Total | 22 (20, 1.6) | 16 (14, 2.2) | 6 (6, 1) | 0.12 |
| Altered state of consciousness (due to sedation drugs) | 1 (1, 0.1) | 0 (0, 0.0) | 1 (1, 0.2) | |
| Atrial septal defect acquired | 1 (1, 0.1) | 1 (1, 0.2) | 0 (0, 0.0) | |
| Cardiac tamponade | 3 (3, 0.2) | 0 (0, 0.0) | 3 (3, 0.5) | |
| Femoral artery aneurysm | 1 (1, 0.1) | 1 (1, 0.2) | 0 (0, 0.0) | |
| Groin site complication a | 7 (7, 0.6) | 5 (5, 0.8) | 2 (2, 0.3) | |
| Pericarditis | 1 (1, 0.1) | 1 (1, 0.2) | 0 (0, 0.0) | |
| Phrenic nerve injury (PNI) | 1 (1, 0.1) | 1 (1, 0.2) | 0 (0, 0.0) | |
| Supraventricular arrhythmias b | 7 (5, 0.4) | 7 (5, 0.8) | 0 (0, 0.0) | |
Hematoma (2), hematoma muscle (1), puncture site hematoma (1), puncture site discharge (1), vascular pseudoaneurysm (2).
Atrial fibrillation (4), atrial flutter (2), atrial tachycardia (1).
Fisher's exact test identified no difference in the serious device and/or procedure related adverse events between PVI+ and PVI only cohorts.
Although 1 phrenic nerve injury (PNI) event was reported to be a serious adverse event, there were a total of 19 (transient and persistent) PNIs that were reported in this study (Table S2). Of these, 2 were resolved before discharge, 11 were resolved after discharge (none led to rehospitalization), and 6 PNIs were unresolved at the time of study exit. Overall, 2 PNIs led to the use of mecobalamin medication (1 resolved after discharge and the other was unresolved at the time of study exit).
3.4. Efficacy
Cardiac monitoring was completed in 96.3% (1180) patients at least once during the 12‐month follow‐up according to standard‐of‐care protocols (Table 4). This monitoring was performed using either electrocardiogram (ECG) in 94.7% (1161) patients or Holter monitoring in 50.7% (622) patients. At the 12‐month follow‐up, the average number of ECG monitoring visits was 4.2 ± 2.5 per patient, and the average number of Holter monitoring visits was 0.9 ± 1.2 per patient. Most Holters used were of 24 h monitoring length (1005), and 50.7% (622) patients were monitored at least once during the 12 months using Holter. The overall CBA efficacy determined as the KM estimate at 12 months for freedom from AA recurrence was 84.4% (95% CI: 82.2%–86.3%) (Figure 2A). The KM estimates for freedom from repeat ablation, all‐cause hospitalization, and cardiovascular‐related rehospitalization at 12 months were 90.2% (95% CI: 88.3%–91.7%), 83.8% (95% CI: 81.6%–85.8%), and 85.9% (95% CI: 83.7%–87.7%), respectively.
TABLE 4.
Overview of follow‐up monitoring visits.
| Arrhythmia monitoring visits | Number of subjects (N = 1226) |
|---|---|
| Monitored at least once during the 12‐months follow‐up | 1180 (96.3%) |
| ECG method | 1161 (94.7%) |
| Holter method | 622 (50.7%) |
| Average number of ECG monitoring visits through 12 months | 4.2 ± 2.5 |
| Average number of Holter monitoring visits through 12 months | 0.9 ± 1.2 |
Abbreviation: ECG, Electrocardiogram.
FIGURE 2.
Freedom from atrial arrhythmia recurrence at 12 months. Panel A: KM estimate at 12 months for freedom from AA (AF/AT/AFL) recurrence in the overall PsAF patient population who underwent CBA in Japan. Panel B: Comparison of efficacy between the PVI only and PVI+ subgroups in terms of KM estimate at 12 months for freedom from AA (AF/AT/AFL) recurrence. The two subgroups in this post hoc analysis were: PVI only subgroup (red line) and PVI+ subgroup (blue line), where the PVI+ ablation strategy is defined as PVI along with ablation of targets beyond PVI at the discretion of the operating physician. AA, Atrial arrhythmia; AF, Atrial fibrillation; AFL, Atrial flutter; AT, Atrial tachycardia; CBA, Cryoballoon ablation; HRadj, Adjusted hazard ratio; HRunadj, Unadjusted hazard ratio; KM, Kaplan–Meier; PsAF, Persistent atrial fibrillation; PVI, Pulmonary vein isolation.
Post hoc analysis was performed to study the effect of PVI only versus PVI+ strategy on freedom from AA recurrence (Figure 2B). PVI+ was performed in 51.5% (631) patients. The KM estimates at 12 months for freedom from AA recurrence were higher in the PVI+ subgroup (86.6% [CI: 83.6%–89.1%]) than in the PVI only subgroup (82.0% [CI: 78.6%–84.9%]) (HR adj = 1.40, p = 0.025) in a propensity score adjusted analysis.
3.5. Quality‐of‐Life
The QoL measures are shown in Table 5. QoL was measured by the general EQ‐5D‐3L questionnaire. Among 1079 patients, the mean summary‐index score improved significantly at 12 months by 0.03 ± 0.16 (p < 0.001) points from baseline. The EQ visual analogue scale (VAS) score also improved significantly at 12 months by 7.9 ± 18.5 (p < 0.001). At baseline, 70.4% (823) patients reported ≥ 1 AF‐related symptoms which significantly decreased to 9.9% (116) patients at the 12‐month follow‐up visit (p < 0.01). Palpitations were the most frequently reported symptom with the incidence decreasing from 41.5% (485) patients at baseline to 4.9% (57) patients at 12 months (Table S3).
TABLE 5.
Changes in quality‐of‐life through EQ‐5D‐3L questionnaire.
| Japan sites | Measures at visit | Difference from baseline | |||
|---|---|---|---|---|---|
| Visit | N a | Mean ± SD | N b | Mean ± SD | p c |
| Summary‐index score d | |||||
| At baseline | 1079 | 0.91 ± 0.14 | |||
| At 12 months | 1079 | 0.94 ± 0.13 | 1079 | 0.03 ± 0.16 | < 0.001 |
| Visual analogue scale score e | |||||
| At baseline | 1073 | 73.5 ± 16.0 | |||
| At 12 months | 1073 | 81.4 ± 14.9 | 1073 | 7.9 ± 18.5 | < 0.001 |
The number of subjects with score available at the study visit.
The number of subjects with score available at both baseline and at the 12‐months visits.
Paired t‐test.
EQ‐5D‐3L score ranging from 0 to 1, with higher scores indicating a better health‐related quality‐of‐life.
Score from a vertical visual analogue scale (VAS) on which patients provide a global assessment of their health, ranging from 0 to 100, with higher scores indicating a better health‐related quality‐of‐life.
4. Discussion
In this sub‐analysis from the Cryo Global Registry, we evaluated real‐world clinical outcomes in patients diagnosed with PsAF and treated with an index CBA procedure at 60 centers in Japan. The serious adverse events observed were consistent with the previous reports discussed below. In our study, post hoc analysis showed there was a significant difference among PVI and PVI+ patients with regard to the primary efficacy endpoint. The PVI+ subgroup showed greater efficacy than PVI only subgroup.
With regard to safety, the serious adverse event rate observed in our study was low (1.6%) and comparable to global real‐world results [6, 12, 13]. The total (transient and persistent) PNI rate (1.5%) was lower than observed in the study from the YETI registry [13] (4.2%) specifically evaluating the PNI incidence and recovery during cryoballoon‐based PVI.
With regard to efficacy, although CBA is superior to AAD treatment for the maintenance of sinus rhythm, ablation success is still limited in patients with PsAF [9, 14, 15, 16]. Real‐world registries (using standard‐of‐care monitoring and ablation strategies) have reported 64%–71% success rates of CBA in PsAF patients [6, 17, 18]. In our study, the overall freedom from AA recurrence for PsAF treatment in Japan was high (84.4%) compared to previous studies. We performed several post hoc analyses to explain these results.
Several strategies and targets beyond PVI have been suggested to improve outcome in PsAF patients (including the left‐atrial posterior wall, low voltage areas, and CTI), but these ablation strategies have not shown increased efficacy in large randomized trials [19, 20, 21, 22, 23]. In our post hoc evaluation, PVI+ ablation (performed at the discretion of the investigators), showed significantly higher (86.6%) efficacy than the PVI only subgroup (82.0%); HR adj = 1.40, p = 0.025, in a propensity score adjusted analysis. The most common PVI+ ablation lesions were CTI ablation (33.0%) and left‐atrial roofline ablation (27.2%). According to the latest expert consensus statement on catheter and surgical ablation of AF; 92.1% of the writing group members perform CTI ablation in patients with prior history or intra‐procedural induction of CTI‐dependent AFL during AF catheter ablation. The low prevalence of prior AFL (2.7% in the overall population; 3.6% in the PVI+ subgroup; 1.7% in the PVI only subgroup) in this Japan PsAF study cohort may not fully explain all the CTI ablations performed in the study. A high rate of CTI ablation was also reported in another real‐world study using cryoballoon in Japan, and may represent local standard‐of‐care [5, 24]. A recent study based on CRALAL randomized clinical trial reported PsAF patients that underwent additional RA linear ablation had improved outcomes compared to patients that underwent PVI alone [25].
Additionally, in our study, arrhythmia monitoring was performed according to the standard‐of‐care methods at each site in Japan, which can lead to underestimation of asymptomatic arrhythmia recurrence [26]. Monitoring was performed using ECG (94.7%) and/or Holter (50.7%); these methods were consistent with standard clinical practice [27]. Therefore, the CBA results reported in our study may better reflect the incidence of clinically relevant AA recurrences. In this study, at 12 months compared to baseline, QoL improved with a mean summary‐index score difference of 0.03 ± 0.16 (p < 0.001), a mean VAS score difference of 7.9 ± 18.5 (p < 0.001), and the percentage of patients with ≥ 1 AF‐related reported symptoms decreased to 9.9% from 70.4% (p < 0.01), which is consistent with previous observations [5, 6]. These aforementioned data support the clinical effectiveness of CBA for treating PsAF patients in Japan.
Overall, compared to previous studies discussed above, the high CBA efficacy observed in our study may be attributed to factors, including application of additional ablations beyond PVI and standard‐of‐care practices in Japan. In summary, the real‐world results presented in our study demonstrated that CBA is safe and effective for the treatment of PsAF patients in Japan. The safety and efficacy of AF ablation has seen remarkable improvements alongside notable advancements in the technologies employed for these procedures, particularly the new pulsed field ablation technology. Despite this progress, numerous crucial questions remain unresolved, particularly concerning the improvement in long‐term outcomes and regarding the optimal ablation approach for the treatment of patients with PsAF [28, 29].
4.1. Limitations
There are several limitations in this study due to its observational design, including potential bias in patient selection for ablation candidacy during real‐world evaluations, as well as bias and variability in the PVI+ strategy depending on the treatment plan and standard‐of‐care at each study site. Comparisons between subgroups (PVI only and PVI+) may be influenced by baseline characteristics. Variability in physician experience level is another factor that may impact the results. Additionally, there was no control group to compare with CBA in this study. CBA was performed within 6 months of diagnosis in most patients, which may have introduced patient selection bias that could significantly impact the efficacy results. Arrhythmia monitoring was performed according to the local standard‐of‐care methods at each site in Japan, and primarily using 12‐lead and/or 24 h‐Holter ECG methods which could lead to underestimation of asymptomatic arrhythmia recurrence [26]. As more intensive or continuous surveillance methods (e.g., implantable loop recorders or daily smartphone‐based ECG) are not routinely utilized, asymptomatic or brief arrhythmia recurrences may have been under‐detected [30, 31]. Consequently, the event rates observed in this Japan‐based study may be lower than those reported in international registries that employ frequent or continuous monitoring, suggesting methodological differences in arrhythmia detection rather than true variations in ablation efficacy. Furthermore, the lack of systematic rhythm monitoring in this study may have resulted in an overestimation of the reported efficacy. These limitations can significantly contribute to the underestimation of AA recurrence during follow‐up.
5. Conclusion
This study extracted real‐world data from the prospective Cryo Global Registry and analyzed clinical outcomes in 1226 PsAF patients that were treated with CBA in Japan. Most patients in this analysis were treated with CBA < 6 months from PsAF diagnosis with either a PVI or PVI+ ablation strategy. Overall, CBA resulted in few reported serious adverse events, a high KM estimate for freedom from AA recurrence at 12 months, a significant improvement in QoL summary‐index score, and a reduction in AF‐related reported symptoms at 12 months compared to baseline. Furthermore, a post hoc analysis showed both, PVI only and PVI+, subgroups demonstrated high effectiveness in terms of freedom from AA recurrence at 12 months; however, PVI+ exhibited significantly higher efficacy compared to PVI only. Thus, CBA was demonstrated to be a safe and effective treatment option for patients suffering from PsAF in Japan. However, it should be acknowledged that this study has several limitations due to its observational design. Notably, this study primarily reported the use of 12‐lead and/or 24‐h Holter ECG methods for arrhythmia recurrence detection.
Funding
This work was sponsored by Medtronic Inc., Minneapolis, MN.
Disclosure
Permission statement: The authors agree to the terms of the publisher regarding permission for reproduction of material, provided the original work is properly cited.
Ethics Statement
The study was conducted according to Good Clinical Practices, in compliance with local regulations, and in accordance with the principles outlined in the Declaration of Helsinki.
Consent
Each center received approval by an independent ethics and institutional review board and obtained written informed patient consent prior to enrollment.
Conflicts of Interest
The Cryo Global Registry was sponsored by Medtronic Inc., Minneapolis, MN. Masato Murakami received speaker honorarium from Medtronic Japan. Fumiharu Miura received speaker honorarium from Medtronic Japan, Johnson & Johnson, Japan Lifeline, and Biotronik Japan. Atsuhiko Yagishita received speaker honorarium from Medtronic Japan, and scholarship fund from Abbott Medical Japan. Yasuyuki Egami received trust research/joint research funds from Abbott Medical Japan, Japan Lifeline, and Boston Scientific. Kenji Ando received speaker honorarium from Abbott Medical Japan, Biotronik Japan, Japan Lifeline, Novartis, and Medtronic Japan. Junichi Nitta received speaker honorarium from Medtronic Japan. Neha Sawhney and Valentine Obidigbo are employees of Medtronic Inc. The remaining authors of the manuscript have no conflicts of interest to declare.
Supporting information
Tables S1–S3: joa370291‐sup‐0001‐TablesS1‐S3.docx.
Acknowledgments
Certain information reported in this article was presented as a poster by Dr. Junichi Nitta at the 2025 European Heart Rhythm Association (EHRA) scientific congress on March 30, 2025, in Vienna. The authors thank the Cryo Global Registry‐Medtronic Inc., team members for their assistance and contributions to this study, data management and statistical support. The authors are particularly grateful to Ryan Radtke from Medtronic for his support in the registry, and to Hae Lim, Kelly Bragt, Daniel Becker and Jada Selma from Medtronic for their support in the generation of the manuscript.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S3: joa370291‐sup‐0001‐TablesS1‐S3.docx.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.