DOI: 10.1111/pace.13721
E L E C T R O P H Y S I O L O G Y
Long-term outcomes of pulmonary vein isolation using
second-generation cryoballoon during atrial fibrillation
ablation
Ugur Canpolat MD
1Duygu Kocyigit MD
2Muhammed Ulvi Yalcin MD
3Cem Coteli MD
1Yusuf Ziya Sener MD
1Metin Oksul MD
1Kadri Murat Gürses MD
4Banu Evranos MD
1Hikmet Yorgun MD
1,5Kudret Aytemir MD
11Arrhythmia and Electrophysiology Unit,
Department of Cardiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
2Cardiology Clinics, Afyonkarahisar Dinar State
Hospital, Afyonkarahisar, Turkey
3Department of Cardiology, Selcuk University,
Konya, Turkey
4Department of Basic Medical Sciences, Adnan
Menderes University, Aydin, Turkey
5Department of Cardiology, Cardiovascular
Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
Correspondence
Ugur Canpolat, MD, Associate Professor, Arrhythmia and Electrophysiology Unit, Department of Cardiology, Faculty of Medicine, Hacettepe University, Altindag, 06100 Ankara, Turkey.
Email: dru_canpolat@yahoo.com
Ugur Canpolat and Duygu Kocyigit contributed equally to this manuscript.
Abstract
Background: Currently available second-generation cryoballoon (CB2) is accepted as an effective
and safe tool for pulmonary vein isolation (PVI). Although much more data exist about 1-year out-comes of CB2 ablation, data on long-term outout-comes are scarce.
Objective: We aimed to assess the long-term outcomes of PVI using CB2 in a large-scale
symp-tomatic atrial fibrillation (AF) population at our tertiary referral center.
Methods: In this nonrandomized prospective observational study, a total of 486 patients with
paroxysmal (71%) or persistent (29%) AF who underwent index PVI using CB2 at our hospital between January 2013 and June 2017 were enrolled. Atrial tachyarrhythmia (ATa)-free survival was defined as the absence of AF, atrial flutter, or atrial tachycardia recurrence≥30 s following a 3 months blanking period. Predictors of recurrence were evaluated by univariate and multivari-ate Cox proportional hazards regression models.
Results: Acute procedural success rate was 99.8% (1898/1902 PVs). Mean procedural and
flu-oroscopy time were 64.9± 9.2 and 12.1 ± 2.6, respectively. At median 39 (interquartile range: 26-56) months follow-up, ATa-free survival was 78.6% after a single procedure (280/345 [81.2%] for paroxysmal AF vs. 102/141 [72.3%] for persistent AF, P= .019) and 84.4% after a mean 1.48± 0.42 ablations. Cox regression analysis showed that left atrium diameter, duration of AF history, and early ATa recurrence were found as the independent predictors of late recurrence. Phrenic nerve palsy was observed in 17 (3.5%) patients.
Conclusions: CB2-based PVI is effective to maintain sinus rhythm in a significant proportion
of paroxysmal and persistent AF patients with an acceptable complication rate at long-term follow-up.
K E Y W O R D S
atrial fibrillation, complication, cryoballoon, recurrence
1
I N T RO D U C T I O N
As pulmonary vein (PV) isolation (PVI) is accepted as the cornerstone of all atrial fibrillation (AF) ablation procedures, recent expert
consen-sus document recommends to isolate PVs at first either using point-by-point radiofrequency (RF) or cryoballoon (CB) ablation in all patients, including paroxysmal and nonparoxysmal AF.1CB technology has been shown to be as effective as RF technique for AF ablation.2
The second-generation CB (Arctic Front Advance, Medtronic Inc., Minneapolis, MN, USA) (CB2) has several advantages over the first generation in terms of design, enabling better cooling properties, and larger lesion formation.3Although there were several studies about 1-year follow-up results of CB2, few studies have reported its mid-and long-term satisfactory efficacy like RF ablation.4,5 However, all those studies with extended follow-up data included limited numbers of patients. Thus, large-scale data are still needed to delineate the long-term success and safety of CB2.
In this large-scale study, we aimed to report the safety and efficacy of CB2 for PVI in paroxysmal and persistent AF patients at long-term follow-up.
2
M E T H O D S
2.1
Study population
In this prospective observational study, patients who underwent index PVI alone using CB2 for symptomatic paroxysmal or persistent AF at our tertiary referral center in between January 2013 and June 2017 were consecutively included (Figure 1). Paroxysmal and persistent AF were defined in accordance with appropriate guidelines.
Exclusion criteria for catheter ablation were left atrial (LA) diam-eter of>55 mm, severe valvular disease, evidence of LA thrombi, life-expectancy<12 months, reversible causes of AF (such as uncon-trolled thyroid dysfunction), preprocedural significant coronary artery stenosis, myocardial infarction, or cardiac surgery within the previous 3 months, and contraindication to anticoagulation and pregnancy. Additionally, patients who underwent re-do catheter ablation due to previous CB1-based AF ablation (n= 22), non-PV trigger ablation (superior vena cava and/or left atrial appendage [LAA]) (n= 184 patients) using CB2 during index procedure,<12 months follow-up data, and lost to follow-up (n = 8) were also excluded from our observational study cohort (Figure 1).
Informed consent was obtained from all participants. The study was carried out in compliance with the Helsinki Declaration. The study was approved by the local institutional ethical committee.
2.2
Preablation protocol
Transthoracic echocardiography to assess the left ventricular ejection fraction (LVEF), valvular pathology, and intracavitary dimensions was performed before the procedure in all patients. In eligible (serum cre-atinine≤1.5 mg/dL) patients, preprocedural computed tomography (CT) angiography was performed to evaluate the PV anatomy using dual-source 64-slice multidetector CT scanner (Somatom Definition; Siemens, Erlangen, Germany).
All antiarrhythmic drugs were discontinued 5 days prior to the pro-cedure. All procedures were performed with uninterrupted oral anti-coagulation with warfarin if international normalized ratio (INR) was <2.5. Novel oral anticoagulants were ceased 24-48 h before the pro-cedure taking the renal function tests into account. All patients
under-went transesophageal echocardiography the day before the procedure to assess interatrial septum and presence of thrombus in the LA or LAA as well as valvular functions. Pharmacologically facilitated electrical cardioversion was performed if the cardiac rhythm was AF before the procedure. If cardioversion was unsuccessful, catheter ablation proce-dure has been performed under AF rhythm.
2.3
Ablation procedure
The details of the PV isolation were defined previously.6The proce-dure was performed under conscious sedation by the administration of midazolam and fentanyl boluses. Invasive arterial blood pressure, oxy-gen saturation, and electrocardiogram (ECG) were continuously moni-tored during the entire procedure. After femoral vein punctures, a 6-Fr steerable decapolar catheter (PrefaceR Biosense Webster, Diamond
Bar, CA, USA) was placed into the coronary sinus. Single transseptal puncture by modified Brockenbrough technique (BRK-1, St. Jude Med-ical, St. Paul, MN, USA) was performed under fluoroscopy and 8-Fr transseptal sheath (PrefaceR Biosense Webster or SL1, St. Jude
Medi-cal) was placed into the LA. Just after LA access, unfractionated heparin boluses have been repeatedly administered to maintain the activated clotting time of 300-350 s. The transseptal sheath was then exchanged with a 15-Fr FlexCath Advance sheath (Medtronic CryoCath, Min-neapolis, MN, USA) over a stiff guidewire (0.032-inch, 180-cm Super Stiff, St. Jude Medical). Second-generation 28-mm CB catheter (Arctic Front AdvanceTM, Medtronic, Minneapolis, MN, USA) was used for PVI in all patients. The inner balloon 15-mm AchieveTM(Medtronic Cry-oCath) circular mapping catheter was used both to maneuver CB into the PVs and assessment of PV signals. The assessment of CB occlusion is performed through the injection of 50% diluted contrast through the CB catheter’s central lumen and ablation started after optimal vessel occlusion. Baseline potentials of PVs were recorded using Achieve catheter, which was positioned at the PV ostium by prolapsus maneuver. The duration of each freezing cycle was 180-240 s for each targeted PV. Freezing duration shortened over time from 240 s freezes with bonus application per vein to 180 s freezes with or without bonus application per vein. After one application, an additional bonus freeze of 180-240 s duration was applied in the case of disappearance of the PV potentials> 60 s during the first cycle and in the occurrence of early PV reconnection. If PV signal was invisible at baseline, one 180-240-s freeze without bonus has been applied. The right phrenic nerve was constantly paced from the superior vena cava during freezing at the right-sided PVs with a 2000-ms cycle and a 12-mA output in order to detect phrenic nerve palsy (PNP). Intermittent fluoroscopy and direct palpation of the right hemi-diaphragmatic excursion was performed during phrenic nerve stimulation. At the end of the procedure, PV conduction was re-evaluated by the circular mapping catheter.
Successful PVI was defined as the elimination or dissociation of all the visible PV potentials recorded by the circular mapping catheter. Minimum cooling temperature was recorded in all patients, whereas the time to PV signal isolation was recorded in case of visible PV sig-nals during the procedure. If a real-time recording of PV potentials was not achieved because of distal positioning of the mapping catheter,
F I G U R E 1 Flowchart showing the details of patient enrollment and clinical follow-up data. AAD = antiarrhythmic drug; AF = atrial fibrillation;
ATa= atrial tachyarrhythmia; CB = cryoballoon; LA = left atrial; LAA = left atrial appendage; PV = pulmonary vein; PVI = pulmonary vein isolation; SVC= superior vena cava
mapping catheter was immediately retracted after each completed freeze to re-evaluate the PV activity. Electrical PV isolation was con-firmed by entrance and exit block maneuvers by coronary sinus elec-trode and circular mapping catheter stimulation, respectively.
2.4
Postablation protocol
Transthoracic echocardiography was performed to exclude pericar-dial effusion at the end of the procedure. Following sheath removal, a figure-of-eight suture has been applied since 2014.7Postprocedurally,
all patients were monitored for 18 h in a telemetry unit with contin-uous ECG monitoring. They were discharged on the following day, if clinically stable. Before the discharge, access site was evaluated in all patients.
Anticoagulation therapy was initiated 4-6 h after the procedure. Systemic anticoagulation with either warfarin or novel oral anticoag-ulantss was recommended for at least 3 months after the procedure and CHA2DS2-VASc risk score was used to decide on long-term antico-agulation at the 3-month visit. Patients received preprocedural antiar-rhythmic drugs for 3 months after the procedure.
2.5
Study endpoints
Acute procedural success was defined as electrical isolation of all PVs. Any episodes of atrial tachyarrhythmia (ATa) (AF/atrial flutter/atrial tachycardia) that lasted for at least 30 s were accepted as recurrence. Recurrence within the postablation 3 months blanking period was termed as “early recurrence,” whereas recurrence after postablation 12 months was termed as “late recurrence.” Within the blanking period, recurrent arrhythmias were managed with antiarrhythmic drugs or electrical cardioversion.
2.6
Follow-up
Patients were scheduled for outpatient clinic visits at 1st, 3rd, 6th, and 12th months and every 1 year thereafter. Twenty-four-hour Holter monitorization was done at each visit to evaluate the recurrence besides routine cardiologic examination, including electrocardiogra-phy and transthoracic echocardiograelectrocardiogra-phy. When patients experienced symptoms that could be related to AF recurrence or complications of the catheter ablation, they were evaluated earlier at either emergency department or outpatient clinics.
2.7
Statistical analysis
One-sample Kolmogorov-Smirnov test was used to test whether parameters were normally distributed. Normally distributed con-tinuous parameters were presented as mean ± standard deviation (SD). Skewed continuous parameters were expressed as median (interquartile range [IQR], defined as the difference between 25th and 75th percentiles). Categorical data were presented as frequencies (n) and percentages (%) and were compared using chi-square test. Normally distributed and skewed continuous parameters were com-pared between two groups using Student’s t-test and Mann-Whitney U tests, respectively. A multivariable Cox regression model was used to estimate hazard ratios (HRs) for ATa recurrence while controlling for baseline characteristics. Event-free survival was estimated by the Kaplan-Meier method and compared by log-rank test. Receiver operating characteristic curve analysis was used to determine the optimum cutoff levels of LA diameter to predict the late recurrence.
Statistical analyses were performed using SPSS statistical soft-ware (IBM SPSS Statistics for Windows, Version 20.0, IBM Corp., Armonk, NY, USA). A two-tailed P< .05 was considered statistically significant.
3
R E S U LT S
3.1
Baseline characteristics
A total of 486 patients who underwent CB2-based index PVI during AF ablation procedure were included in the final analysis (Figure 1). Base-line demographic, clinical, and laboratory characteristics of the study population are given in Table 1. Among the whole study group, 71% of patients had paroxysmal AF. Median duration of AF history was 24 (5-60) months. AF ablation was performed after anti-arrhythmic drug
TA B L E 1 Baseline characteristics of the study population (n= 486)
Parameters Age (years) 59.8± 10.9 Male gender 235 (48.4%) BMI (kg/m2) 26.1± 6.8 Hypertension 244 (50.2%) Diabetes mellitus 76 (15.6%)
Coronary artery diseasea 210 (43.2%)
Hyperlipidemiab 182 (37.4%)
Stroke/TIA 12 (2.5%)
HFrEF 13 (2.7%)
Alcohol intakec 85 (17.5%)
Current smoker 93 (19.1%)
CHA2DS2-VASc score 1.93± 0.49
AF type
Paroxysmal AF 344 (71%)
Nonparoxysmal AF 142 (29%)
Duration of AF history (months) 24 (5-60)
Failed no. AADs 1.80± 0.45
Indication for ablation
First-line therapy 105 (21.6%)
After antiarrhythmic drug failure 381 (78.4%) Failed antiarrhythmic therapyd
Class I antiarrhythmic 166 (43.6%)
Class III antiarrhythmic 146 (38.3%)
Both 69 (18.1%) Oral anticoagulation None 223 (45.9%) Warfarin 99 (20.4%) NOAC 164 (33.7%) Serum creatinine (mg/dL) 0.86± 0.28 GFR (mL/min/1.73 m2) 59.0± 4.3
Left atrial diameter (anteroposterior) (mm) 38.5± 5.7 Left ventricular ejection fraction (%) 61.7± 6.9 Common trunk pulmonary vein 110 (22.6%)
Right common 10 (2.1%)
Left common 100 (20.5%)
Accessory pulmonary vein 51 (10.5%)
Right accessory 48 (9.9%)
Left accessory 3 (0.6%)
Data are median (interquartile range), means± standard deviation or n (%). AAD= antiarrhythmic drug; AF = atrial fibrillation; BMI = body mass index; BP= blanking period; GFR = glomerular filtration rate; HFrEF = heart fail-ure with reduced ejection fraction; NOAC= novel oral anticoagulant; TIA = transient ischemic attack.
aDefined as previous history for ischemic heart disease.
bDyslipidemia is defined as total cholesterol≥200 mg/dL or treatment with
a lipid-lowering agent.
cAlcohol intake is defined as having up to 1 drink per day for women and
up to 2 drinks per day for men in which heavy drinkers and abusers were excluded.
dPercent of 381 patients who underwent cryoablation for AF due to failed
(AAD) failure in 78.4% of patients and as a first-line therapy in 21.6% of patients due to patient preference. Mean LA anteroposterior diameter was 38.5± 5.7 mm and mean LVEF was 61.7 ± 6.9%. While 22.6% of patients had common PV anatomy, 10.5% had an accessory PV.
The comparison of baseline data between paroxysmal and persis-tent AF patients is shown in Supplementary File S1. Patients with per-sistent AF showed greater LA diameter (41.5± 5.6 vs. 37.3 ± 4.9, P< .001), lower LVEF (59.6 ± 8.2 vs. 62.3 ± 6.6, P < .001), and higher rate of common or accessory PV (P= .02) compared to paroxysmal AF.
3.2
Procedural data, cooling characteristics, and
acute procedural outcomes
Procedural details and cooling characteristics of CB2 for each PV are shown in Supplementary File S2. Acute procedural success was achieved in 1898/1902 (99.8%) PVs. Mean skin-to-skin procedural time and fluoroscopy time were 64.9± 9.2 and 12.1 ± 2.6, respectively. Bonus freezes have been applied in a total of 278 (57.2%) patients. Freezing durations per vein were 180 s in 246 (50.6%) patients and 240 s in 240 (49.4%) patients, respectively.
3.3
Complications
Periprocedura complications of the study group are given in Table 2. No deaths occurred related to the procedure. Twelve patients (2.5%) had access site complications. Among these 12 patients, one of them underwent covered stent implantation due to iatrogenic femoral arterio-venous fistula. Intervention has not been required in other groin complications. Transient ischemic attack has occurred in two patients (0.4%), which did not cause any neurologic disability and resolved in 24 h. Only one patient (0.2%) required percutaneous peri-cardiocentesis just after trans-septal puncture in whom the dure performed after hemodynamic stabilization at the same proce-dure. Postprocedural minimal pericardial effusion was also observed in 10/486 (2%) patients. Twenty-eight patients (5.8%) had asystole or bradyarrhythmia and hypotension during/after cryo-application to left superior pulmonary vein (LSPV), which resolved following the adminis-tration of intravenous atropine and saline infusion.
A total of 17 patients (3.5%) experienced PNP during the procedure. 88.2% (n= 15) occurred during cryo-application at right superior pul-monary vein. Median time to PNP was 28 s. Median temperature at the time of PNP was –46◦C. Also, 82.3% of the cases (n= 14) were tran-sient and resolved prior to discharge. Two of the cases (11.8%) were persistent and resolved at third and ninth months. One case (5.9%) was long-standing persistent and resolved at 14th month by the help of physical rehabilitation.
3.4
Clinical follow-up
Follow-up characteristics of the study population are given in Supple-mentary File S3. Subjects were followed-up for a median of 39 (26, 56) months. Early recurrence occurred in 39 patients (8%). Sinus rhythm was achieved spontaneously in 16 patients. Among the remaining 23
TA B L E 2 Periprocedural complications of cryoablation for atrial
fibrillation (n= 486)
Overall 32 (6.6%)
Death related to the procedure 0 (0.0)
Access site complications 12 (2.5)
Pseudoaneurysm 2 (0.4) Femoral hematoma 9 (1.9) Arteriovenous fistula 1 (0.2) Retroperitoneal hematoma 0 (0.0) Neurologic complications 2 (0.4) TIA 2 (0.4) CVA 0 (0.0)
Atrial esophageal fistula 0 (0.0)
Cardiac tamponade 1 (0.2)
Requiring pericardiocentesis 1 (0.2)
Requiring surgery 0 (0.0)
PV stenosisa 0 (0.0)
Phrenic nerve palsy 17 (3.5)
At right superior PVb 15 (88.2)
At right inferior PVb 2 (11.8)
Time to phrenic nerve palsy (s) 28± 12 Temperature at phrenic nerve palsy (–◦C) 46± 5
Transientb 14 (82.3)
Persistentb(> 24 h) 2 (11.8)
Long-standing persistentb(> 12 months) 1 (5.9)
Data are median (interquartile range), means± standard deviation or n (%).
◦C= Celsius; CVA = cerebrovascular attack; PV = pulmonary vein; s =
sec-onds; TIA= transient ischemic attack.
aClinically symptomatic.
bPercent of patients who experienced phrenic nerve injury.
patients, nine underwent electrical and 14 underwent pharmacologi-cal cardioversion for conversion to sinus rhythm.
ATa-free survival rate after blanking period was found to be 78.6% (382/486). In a subgroup analysis according to the AF subtype, both early and late recurrence rates were higher in persistent AF compared to paroxysmal AF patients (12.1% vs. 6.4%, P= .043; 27.7% vs. 18.8%, P= .038, respectively) (Supplementary File S1). Among 104 patients who experienced any ATa recurrence after blanking period, 64 (61.5%) were followed-up with medical treatment and the remaining 40 (38.5%) patients underwent re-do catheter ablation via CB2 (n= 18) or RF ablation (n= 22). After a mean number of 1.48 ± 0.42 procedures, overall ATa-free survival was 84.4% (410/486). The details of clinical follow-up and re-do catheter ablation procedures are also shown in Figure 1.
Among 104 patients with late recurrence, 32 of them underwent second procedure and further eight of them underwent a third pro-cedure. During the second procedure, PV reconnection was observed in 19 patients, LA substrate was found in five patients, typical atrial flutter was detected in six patients, and the remaining two patients were diagnosed as LA tachycardia (one roof dependent and one
F I G U R E 2 Details of re-do ablation procedures among patients with pulmonary vein reconnection. LIPV = left inferior pulmonary vein;
LSPV= left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein [Color figure can be viewed at wileyonlinelibrary.com]
anterior wall). While re-do CB2 ablation was performed in 18 patients, the remaining cases were performed by RF ablation. LAA isolation was included in all patients with re-do CB2 ablation. Furthermore, during the third procedure, PV reconnection was observed in three patients and LA substrate was detected in the remaining five patients. Patchy substrates were ablated as homogenization; however, LA lines were created in the case of extensive and/or severe substrate. The details of PV reconnection sites are also schematized in Figure 2 appropriately. Most common reconnection sites were LSPV anterior-superior region (20%) and right inferior pulmonary vein posterior-inferior region (40%).
3.5
Predictors of clinical outcome
Demographic, clinical, procedural, and follow-up characteristics regarding the presence of any ATa recurrence after blanking period following index CB2 ablation are shown in Table 3. Subjects with ATa recurrence were found to have a higher prevalence of nonparoxysmal AF (37.5% vs. 26.7%) (P= .038). Duration of AF history was also signif-icantly longer in patients with ATa recurrence (P= .008). Patients with ATa recurrence demonstrated greater anteroposterior LA diameter (P< .001). Among procedural details and cooling characteristics of CB2 ablation, no significant difference was observed for any param-eter between groups (P> .05). Furthermore, there was no difference between patients with and without late recurrence in regard to bonus freeze rates (224 [58.6%] patients vs. 54 [51.9%] patients, P= .219)
and freezing durations per vein (198 [51.8%] patients vs. 48 [46.2%] patients for 180 s vs. 184 [48.2%] patients vs. 56 [53.8%] patients for 240 s, P= .304, respectively). Early recurrence rate after CB2 ablation was also higher among patients with late recurrence (16.3% vs. 5.8%, P= .002).
Results of Cox regression model for identifying predictors of any recurrence after blanking period following single cryoablation are shown in Table 4. In the multivariate analysis, LA diameter (HR: 1.95, 95% confidence interval [CI]: 1.34-2.84, P = .001), duration of AF history (HR: 1.003, 95% CI: 1.001-1.006, P= .016), and early recurrence (HR: 2.06, 95% CI: 1.20-3.54, P= .008) were found to be independent predictors of late ATa recurrence. Kaplan-Meier curves for clinical outcome demonstrated the relative proportion of patients in stable sinus rhythm during follow-up following index CB2-based PVI (Figure 3). Receiver operating characteristic analysis explored the rela-tion between LA diameter and AF recurrence (cutoff level of 45 mm, sensitivity 78%, specificity 93%, P< .001). Also, Kaplan-Meier curves comparing ATa-free survival rates in subjects regarding the occurrence of early recurrence and LA diameter cutoff of 45 mm are demonstrated in Figure 4A and B. Median survival rate was significantly lower in subjects with LA diameter≥45 mm (54.9% vs. 81.4%, log rank, P = .001) and early recurrence (56.4% vs. 80.5%, log rank, P<. 001).
Moreover, as shown in Table 5, LA diameter (HR: 1.98, 95% CI: 1.22-3.24, P= .006), duration of AF history (HR: 1.004, 95% CI: 1.001-1.007, P= .048), and early recurrence (HR: 3.52, 95% CI: 1.83-6.79, P < .001) were found to be independent predictors of late ATa recurrence in
TA B L E 3 Demographic, clinical, laboratory, and follow-up characteristics of the study patients due to occurrence of late recurrence following
index cryoablation (n= 486)
Late recurrence (–) (n = 382) Late recurrence (+) (n = 104) P value
Age (years) 59.4± 11.4 60.1± 12.7 .639
Male gender 182 (47.6) 53 (51.0) .581
BMI (kg/m2) 26.3± 6.6 25.5± 7.4 .319
Hypertension 190 (49.9) 54 (52.9) .656
Diabetes mellitus 57 (15.0) 19 (18.6) .361
Coronary artery diseasea 162 (42.5) 48 (47.1) .432
Hyperlipidemiab 137 (36) 45 (44.1) .136 Stroke/TIA 10 (2.6) 2 (1.9) 1.000 HFrEF 8 (2.2) 5 (4.9) .170 Alcohol intakec 66 (17.3) 19 (18.6) .770 Current smoker 74 (19.4) 19 (18.6) 1.000 AF type Paroxysmal AF 280 (73.3) 65 (62.5) .038 Nonparoxysmal AF 102 (26.7) 39 (37.5)
Duration of AF history (months) 21 (12-60) 36 (19-76) .008
Failed no. AADs 1.78± 0.44 1.83± 0.46 .386
CHA2DS2-VASc score 1.93± 0.48 1.95± 0.54 .621
Left atrial diameter (mm) 38.0± 5.2 40.0± 5.8 <.001
LVEF (%) 61.5± 6.7 61.3± 8.7 .740
Pulmonary vein anatomy
Common trunk pulmonary vein 85 (24.9) 25 (26.1) .266
Accessory pulmonary vein 35 (10.3) 16 (16.7)
Early recurrence 22 (5.8) 17 (16.3) .002
Follow-up (months) 39 (26-56) 40 (26-57) .436
Data are median (interquartile range), means± standard deviation, n (%).
AAD= antiarrhythmic drug; AF = atrial fibrillation; BMI = mass index; BP = blanking period; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; TIA= transient ischemic attack.
aDefined as previous history for ischemic heart disease.
bDyslipidemia is defined as total cholesterol≥200 mg/dL or treatment with a lipid-lowering agent.
cAlcohol intake is defined as having up to 1 drink per day for women and up to 2 drinks per day for men in which heavy drinkers and abusers were excluded.
TA B L E 4 Cox regression model for identifying predictors of late recurrence following index cryoablation procedure in all patients
Univariate Multivariate
Parameter HR 95% CI P value HR 95% CI P value
Nonparoxysmal AF 1.60 1.08-2.38 .020 1.09 0.70-1.69 .704
Duration of AF history (months) 1.003 1.001-1.005 .019 1.003 1.001-1.006 .016
Left atrial diameter (mm) 2.18 1.54-3.07 <.001 1.95 1.34-2.84 .001
Early recurrence 2.61 1.55-4.39 <.001 2.06 1.20-3.54 .008
AF= atrial fibrillation; CI = confidence interval; HR = hazard ratio.
patients with paroxysmal AF and only LA diameter (HR: 2.29, 95% CI: 1.28-4.12, P= .005) was found to be an independent predictor of late ATa recurrence in patients with persistent AF.
4
D I S C U S S I O N
To the best of our knowledge, our study as a single-center experience is the first showing both the safety and efficacy of CB2 for PVI at
long-term follow-up in a large-scale AF patient population. Major find-ings of the study included: (a) CB2 was effective in both paroxys-mal and persistent AF patients, with freedom from ATa of 68.1% at median 39 (IQR: 26-56) months. (b) The rate of major complications was 6.6%, with only one patient having permanent PNP that resolved at 14th month follow-up. PNP (3.5%) and groin complications (2.5%) were the most common Periprocedura complications. (c) Early recur-rence of ATa, duration of AF history, and LA diameter were found as
F I G U R E 3 Kaplan-Meier curve showing the ATa-free survival rate of 78.6% at median 39 months follow-up. ATa = atrial tachyarrhythmia
[Color figure can be viewed at wileyonlinelibrary.com]
TA B L E 5 Cox regression model for identifying predictors of late
recurrence following index cryoablation procedure in patients according to the AF subtypes
Paroxysmal AF
Multivariate
Parameter HR 95% CI P value
Duration of AF history (months) 1.004 1.001-1.007 .048 Left atrial diameter (mm) 1.98 1.22-3.24 .006 Early recurrence 3.52 1.83-6.79 <.001
Persistent AF
Multivariate
Parameter HR 95% CI P value
Left atrial diameter (mm) 2.29 1.28-4.12 .005 AF= atrial fibrillation; CI = confidence interval; HR = hazard ratio.
the significant predictors of late recurrence during median 39 months follow-up.
4.1
Procedural characteristics
The CB2 catheter has a larger surface area of coolant distribution compared with first-generation CB catheter, allowing a more extended and simultaneous circumferential ablation with the promise of shorter fluoroscopy and procedure times.6 Since the approval of the CB2, there have been several clinical evidence/protocols from high-volume and experienced centers toward fewer (single freeze vs. bonus) and shorter (180 vs. 240 s) cryo-applications per PV due to similar efficacy and less complication rates.3,8We also implemented such a strategy at our institute where time-to-PVI has become much more important issue. After first cryo-application, an additional bonus freeze of
180-240 s duration was applied in the case of disappearance of the PV potentials>60 s during the first cycle. However, there were several protocols regarding the total freezing time and single freeze strat-egy in which each center often applies its experiences. CB catheter ablation has been performed in our large-volume center since 2009. Due to our experience in this field, despite the bonus freezing cycles in some patients, our skin-to-skin procedure time and fluoroscopy times were shorter as compared to previous studies. All operators performing CB ablation were also experienced in structural and coronary interventions besides electrophysiology (EP) procedures, thus time to LA access (including transseptal puncture) was very short, which was known as one of the main rate-limiting steps of LA procedures. At least two experienced operators have been available rather than fellow or nurse as an assistant/second operator during all procedures, which significantly fastened the steps for CB ablation in our study population. Furthermore, we were familiar with the LA and PV anatomy via preprocedural CT; thus, access to each pulmonary vein and positioning of CB catheter at the PV ostia did not take too much time and fluoroscopy was only used up to confirmation of complete occlusion of each PV via contrast injection.
4.2
Complications of catheter ablation for AF
Among the different techniques for PVI, CB ablation has been reported to result in lowest overall complication rates.9Rate of major com-plications following PVI using CB2 has been reported to be variable up to 18.2%.9Such a variety between complication rates was due to inclusion of different complication variables for the overall calcula-tion. In a recent study, Rottner et al9showed that “time-to-effect”-based strategy (additional 120 s freezing after PVI) using CB2 was more safer than other protocols (240 s bonus freeze and 240 s no
F I G U R E 4 (A) Kaplan-Meier curve showing the comparison of late recurrence rates according to occurrence of early recurrence after CB2
ablation (56.4% in early recurrence group vs. 80.5% in no-early recurrence group, log-rank, P< .001). (B) Kaplan-Meier curve showing the comparison of late recurrence rates according to LA diameter cutoff of 45 mm after CB2 ablation (54.9% in LA diameter≥45 mm group vs. 81.4% in LA<45 mm group, log-rank, P < .001). CB2 = second-generation cryoballoon; LA = left atrial [Color figure can be viewed at
wileyonlinelibrary.com]
bonus freeze) (3.7% vs. 8.1%, P= .026) in terms of overall complication rate. Similar to previous studies, overall complication rate was 6.6% in our study which included all the parameters as mentioned previous studies.
Access site complication rates after CB2 ablation have been reported between 1% and 5%.9Although groin complications are the
second common problem after CB2 ablation in our patient group, it has been significantly reduced after the implementation of “figure-of-eight” suture.7Furthermore, before suturing, heparin reversal using protamine prior to sheath removal might have also minimized vascular complications as had been reported previously by our group without causing any increase in thrombotic events.10
The incidence of thromboembolic complications, including peripro-cedural stroke and transient ischemic attack following cryoablation for AF, has been reported to vary between 0.2% and 0.4% in previ-ous studies.11We had a similar rate (0.4%) of clinically symptomatic cerebral embolic events, which have been resolved in 24 h. Both cerebrovascular events occurred in patients receiving bridging ther-apy before the procedure. After evidence for the safety and protec-tive role of uninterrupted anticoagulation during catheter ablation in COMPARE study,12we also implemented such protocol in our EP lab-oratory and all procedures were performed with uninterrupted oral anticoagulation with warfarin if INR was<2.5.
Phrenic nerve palsy, the most commonly reported complication of CB ablation, frequently occurs during cryo-application to the right superior PV. The overall PNP rate has been shown to vary between 2.7% and 13.5% in different studies with different assessment techniques.2,9,11,13In a very recent STOP AF Post-Approval Study, the rate of PNP was reported as 3.2%.14It was most commonly known as a benign complication due to temporary pattern. In our study, the PNP rate was found to be 3.5% (2.9% transient PNP). Although PNP was frequent while ablating right superior PV, recently Abugattas et al15 reported that the rate of PNP during right inferior PV cryoablation was around 3.5% similar to right superior PV. In our study, there were only two of 17 patients with PNP while ablating right inferior PV. Such a dif-ference between studies in regard to the occurrence of PNP might be due to initiation of cryo-application from right superior or inferior PV at first, longer duration of cryo-application, or bonus cryo-application. Time to recovery from persistent PNP has also been reported to dif-fer between studies up to 10 months. In our study, among 17 patients who experienced PNP, 82.3% (n= 14) had transient PNP, all of which resolved during the procedure or prior to discharge. The remainder of cases resolved at 3rd, 9th, and 14th-month follow-up.
4.3
AF recurrence rates
Early recurrence after RF catheter ablation has been suggested to result from inflammation or incomplete lesion healing. Ablation with CB was expected to result in a lower rate of early recurrence because of the relatively reduced inflammatory reaction due to the creation of well-demarcated lesions using cryo-energy.16Nevertheless, clinical studies have revealed high early recurrence rates up to 50%, compara-ble to RF catheter ablation with no statistically significant difference.17 Early recurrence rate was observed in 8% of patients undergoing CB2-based AF ablation in our study. As in our study, early recurrence has been shown to be a significant predictor of late recurrence during follow-up.6,17
In our study, including both paroxysmal and persistent AF patients, the ATa-free survival rate was found to be 78.6% at a median of 39 (IQR: 26-56) months follow-up (81.2% for paroxysmal and 72.3% for nonparoxysmal AF groups, respectively). Recently, STOP AF Post-Approval Study revealed that freedom from AF was 81.6% at 12 months, 73.8% at 24 months, and 68.1% at 36 months in 244 paroxys-mal AF patients undergoing CB2-based PVI. Takarada et al18reported an AF-free survival without AADs after a single procedure was 71.5%
in paroxysmal AF patients at a mean 38.0± 7.4 months follow-up. Furthermore, in the multicenter Italian Clinical Service 1STOP project, Tondo et al19 reported that the AF-free survival was 63.9% at 12 months and 51.5% at 18 months in 486 nonparoxysmal AF patients. Furthermore, Akkaya et al20reported a 67.9% ATa-free success rate in 102 persistent AF patients with a 5-year follow-up. The difference in regard to success rates in such patient groups between center-based studies most commonly depends on the study population, patient char-acteristics, and operator experience rather than center experience for CB ablation, and follow-up methodology. In our study, the ATa-free survival rate was somewhat higher in persistent AF group as compared to previous studies that might be due to (a) baseline characteristics of the patients with persistent group and (b) high-level single-center experience for any model of CB. When we looked at the re-do ablation procedural details, it was obvious that PV reconnection was the most commonly encountered issue in paroxysmal AF patients; however, additional ablative strategies besides PV reisolation were required in persistent AF patients. Such issue regarding atrial substrate causing recurrence might be the main reason of difference in terms of success rates during long-term follow-up between paroxysmal and persistent AF patients.
It is of note that the majority of studies evaluating the efficacy of CB ablation for AF have used 24-h ECG Holter monitorization during follow-up visits. A recent study investigating the use of internal loop recorder for more precise determination of the success of PVI by CB ablation, in which 98.3% of the patients had undergone ablation using CB2, has reported that early recurrence occurred in 28.3% of patients (n= 17), out of whom 14 (82.3%) had also late recurrences.21In this study, late recurrence rate was 55%.21These data suggest that subclin-ical recurrence rates are actually higher than clinsubclin-ically reported rates when compared to several single-center-based studies.
4.4
Predictors of AF recurrence
Several predictors of AF recurrence following AF ablation using CB2 have been described in previous studies. These include AF type,6,8 duration of AF history,6,8 LA diameter,5 time to PVI,8 and early recurrence.8,17,21Type and duration of AF as markers of atrial remodel-ing are well-known predictors of AF recurrence, since longer exposure to arrhythmia results in more significant atrial structural and electrical remodeling,22which may also explain the predictive role of LA ter for AF recurrence. In accordance with previous findings, LA diame-ter, duration of AF history, and early recurrence were found to be inde-pendent predictors of late recurrence in our current study. While early recurrence, LA diameter, and duration of AF history were found as the predictors of late ATa recurrence in paroxysmal AF patients, only LA diameter was found to be associated with late recurrence in persistent AF patients of our study population, which were also consistent in very recent study findings.20,23
4.5
Study limitations
Our study should be interpreted with some limitations. This is a nonrandomized single-center prospective study; however, there was
no selection bias for study inclusion since all consecutive patients undergoing CB2-based PVI at our institution were included for anal-ysis. Asymptomatic cerebrovascular events or esophageal injury may have gone undetected. Similarly, none of the patients were system-atically evaluated for PV stenosis using chest CT unless they pre-sented with possible symptoms. Although the vast majority of patients presented with sustained forms of ATa, some asymptomatic nonsus-tained episodes may have been missed due to utilization of 24-h Holter monitorization during follow-up. Finally, because of their low inci-dence, no predictors of complications could be identified.
5
C O N C L U S I O N
Our study is one of the largest single-center studies to report the safety and efficacy of PVI using CB2 at median 39 months follow-up in symptomatic patients with paroxysmal and persistent AF. Freedom from ATa was 78.6% after single CB2-based procedure and 84.4% after repeat ablation procedures during long-term follow-up.
AC K N O W L E D G M E N T
None declared.
C O N F L I C T O F I N T E R E S T
U.C.: Proctoring for Abbott, Lecturer for Medtronic; H.Y.: Proctor-ing and Lecturer for Abbott, ProctorProctor-ing and Lecturer for Medtronic; K.A.: Proctoring and Lecturer for Abbott, Proctoring and Lecturer for Medtronic, Proctoring for Biosense Webster; D.K., M.U.Y., C.C., Y.Z.S., M.O., K.M.G., and B.E.: None declared.
O RC I D
Ugur Canpolat MD https://orcid.org/0000-0002-4250-1706 Banu Evranos MD https://orcid.org/0000-0003-1425-7432
R E F E R E N C E S
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S U P P O RT I N G I N F O R M AT I O N
Additional supporting information may be found online in the Support-ing Information section at the end of the article.
How to cite this article: Canpolat U, Kocyigit D, Yalcin MU, et al. Long-term outcomes of pulmonary vein isola-tion using second-generaisola-tion cryoballoon during atrial fibril-lation abfibril-lation. Pacing Clin Electrophysiol. 2019;42:910–921.
