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Second-generation cryoballoon ablation for treatment of
persistent atrial fibrillation: Three-year outcome and predictors
of recurrence after a single procedure
Short title: Akkaya: Cryoballoon ablation of persistent AF
Ersan Akkaya, MD*; Alexander Berkowitsch, PhD*; Sergej Zaltsberg, MD*; Harald Greiss, MD*;
Christian W. Hamm, MD*†; Johannes Sperzel, MD*; Thomas Neumann, MD* and Malte Kuniss, MD*
*Dept. of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany
†
Med. Clinic I, Justus-Liebig University, Giessen, Germany
Correspondence:
Ersan Akkaya, Department of Cardiology, Kerckhoff Heart Center
Benekestr. 2-8, 61231 Bad Nauheim, Germany
Fax: +49-6032-9963236
Telephone: +49-6032-9960
Email: e.akkaya@kerckhoff-klinik.de
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/jce.13372.
This article is protected by copyright. All rights reserved.
Prof. Thomas Neumann and Dr. Malte Kuniss have received honoraria from Medtronic as invited
speakers and for advisory board meetings. Other authors: No disclosures.
Abstract
Introduction: Data on long-term outcomes of cryoballoon (CB) ablation for treatment of persistent
atrial fibrillation (AF) are sparse. Here, we report the first 3-year follow-up results and predictors of
success for catheter ablation using the second-generation CB in patients with persistent AF.
Methods and Results: For this prospective observational study, we enrolled 101 patients ablated
with the second-generation CB at our institution. The endpoint was the first documented recurrence
(>30 sec) of AF, atrial flutter, or atrial tachycardia after a 3-month blanking period. Follow-up data
were collected during outpatient clinic visits and included Holter-ECG recordings. The impact of
several variables on recurrence was evaluated by means of univariate and multivariate analyses and
Cox proportional hazards regression models.
After a median follow-up of 37 (31/42) months, recurrence was documented in 30 patients (29.7%).
The median procedure and fluoroscopy times were 120 (102/147) and 20 (16/27) min, respectively.
Phrenic nerve palsy occurred in 2.0% of the patients. Among the 30 patients who experienced
recurrence, 16 underwent repeat ablation in radiofrequency technique. Cox regression analysis
showed that left atrial area >21 cm2 and AF history duration >2 years independently predicted
recurrence.
Conclusions: Sinus rhythm was maintained in a substantial proportion of patients even 3 years after
CB ablation. Patients with a non-enlarged left atrium and short AF history had the best outcome.
This article is protected by copyright. All rights reserved.
2
Keywords: cryo-ablation; persistent atrial fibrillation; second-generation cryoballoon; phrenic nerve
palsy; long-term outcome
Introduction
Pulmonary vein isolation (PVI) via cryoballoon (CB) ablation is an effective, safe therapy for
paroxysmal atrial fibrillation (AF),1 offering many advantages over radiofrequency (RF) ablation.2
Compared with the first-generation CB, the second-generation CB (CB-Adv) is more effective in acute
PVI and is associated with better clinical outcomes.3–5 PVI using CB-Adv is increasingly performed on
patients with persistent AF. Recent studies reported 1- to 2-year outcomes after PVI for persistent
AF.6–10 However, the long-term (3-year) success rate of this procedure, as it is defined by the
HRS/EHRA/ECAS
Expert
Consensus
Statement,11
is
not
well-known.
Following
these
recommendations, we report 3-year outcomes and predictors of arrhythmia recurrence after
treatment of persistent AF by CB-Adv ablation.
Methods
Study population
This prospective observational study involved 101 patients with persistent AF who underwent an
initial PVI procedure since May 2012 at our institution. Persistent AF is defined as AF that persists
without interruption for 7 days but not longer than 12 months. Medical history was obtained from
outpatient visit data collected by thoroughly reviewing medical records including electrocardiograms
(ECGs) and Holter-ECG recordings of AF episodes. Additionally, patients were questioned for
intensity and duration of arrhythmia-related symptoms (palpitations, chest discomfort, dyspnea,
fatigue and dizziness). In all patients, AF was documented at least on separate ECGs within the last 3
months before ablation. The risks of ablation were discussed in detail with the patients, all of whom
This article is protected by copyright. All rights reserved.
3
provided written informed consent before the procedure. The study was approved by the
institutional ethics committee and performed according to the Declaration of Helsinki principles.
Exclusion criteria were longstanding persistent AF, severe LA dilatation (LA area>40 cm2),11 acute
reversible causes of AF, moderate-to-severe valvular stenosis or insufficiency, congenital heart
disease, myocardial infarction or coronary artery bypass graft surgery <3 months before ablation,
severe respiratory insufficiency, bleeding diathesis or intolerance to heparin or oral anticoagulation,
left atrial (LA) thrombus at time of ablation, pregnancy, severe comorbidity, and New York Heart
Association class IV heart disease.
Preprocedural management
Transesophageal echocardiography before PVI excluded the presence of intracavitary
thrombi. LA area was measured by transthoracic echocardiography, and left ventricular ejection
fraction was calculated by the modified Simpson’s method from apical 4- and 2-chamber views.11
Oral anticoagulation therapy included interrupted phenprocoumon with heparin bridging or
continuous phenprocoumon, targeting an internationally normalized ratio >2 before PVI. Depending
on the number of daily doses, patients on novel oral anticoagulants received their last dose 12–24 h
before PVI.
Ablation procedure
CB ablation was performed under conscious sedation or general anaesthesia. We used
biplane fluoroscopy with 60° left and 30° right anterior oblique views. After single transseptal access
with an SL-1 sheath (St. Jude Medical, Minneapolis, MN, USA) using the modified Brockenbrough
technique (BRK-1, St. Jude Medical), an exchange wire was placed in the left superior pulmonary
vein (PV). The SL-1 sheath was then replaced with a steerable sheath (FlexCath AdvanceTM,
Medtronic). LA and PV anatomy were visualized by PV angiography. Diagnostic mapping was
This article is protected by copyright. All rights reserved.
4
conducted with a 6-Fr decapolar catheter (IBI, St. Jude Medical). Through the steerable sheath, a 15or 20-mm-diameter inner lumen mapping catheter (Achieve™, Medtronic) was placed proximal to
each PV ostium to record PV signals before ablation. The 28-mm CB-Adv was advanced over the
Achieve catheter, inflated, and positioned at each PV ostium. Selective contrast injections revealed
any vessel occlusion or atrial backflow. If occlusion was acceptable, a ≥180-sec freeze-thaw cycle was
initiated. The Achieve catheter was actively used during cryoablation; time to PV isolation (“time-toeffect”) was recorded “online” when PV potentials completely disappeared or were dissociated from
LA activity. If online signals were unavailable because the mapping catheter was distally positioned,
the Achieve catheter was retracted after freeze-thaw cycle completion and placed more proximally
for recording of pre-ablation PV potentials. After successful PVI one additional bonus-freeze-cycle
was applied in all patients. During septal PV ablation, the decapolar catheter was positioned in the
superior vena cava to stimulate the diaphragm via electrical pacing of the ipsilateral phrenic nerve
(2500-msec cycle). Phrenic nerve function loss was detected using diaphragmatic compound motor
action potentials. Refrigerant delivery was stopped immediately if diaphragmatic movement
weakened or was lost or if the amplitude of the potentials decreased by 30%.
In cases in which AF persisted after the isolation of all PVs, an additional LA roof line (RL) was
created as previously described.12 We applied cryoenergy close to the position used during isolation
of the left superior PV. Several overlapping freezes (180 sec) were applied along the LA roof by slight
clockwise rotation combined with slight sheath and incremental CB retraction until the original
position used to isolate the right superior PV was reached. For AF without conversion to sinus
rhythm (SR), electrical cardioversion was performed, and PVI as well as conduction block at the LA
roof was verified after conversion to SR. The procedural endpoint was a complete PVI and
conduction block across the LA roof and ascending activation across the posterior LA wall,
demonstrated by caudocranial ascending activation and a conduction delay next to the ablation line
This article is protected by copyright. All rights reserved.
5
of > 120 msec during pacing at the right atrial upper septum during SR. Conduction block was
assessed by mapping of activation at the posterior LA wall using established methods and
definitions.13 During baseline pacing, antero-posterior activation of the roof and craniocaudal
activation of the posterior LA wall would exclude conduction block of the roof.
Finally, isolation of all PVs with verified exit and entrance blocks for ≥30 minutes after initial
PVI was documented. Patients with documented typical right atrial flutter prior to procedure or
periprocedural development of typical atrial flutter also underwent cavotricuspid isthmus RF
ablation (4-mm irrigated-tip catheter, Thermocool, Biosense Webster, Diamond Bar, CA, USA).
Pericardial effusion was excluded by echocardiography immediately after ablation.
Postprocedural management
Patients were monitored by telemetry for ≥24 h. In patients with persistent phrenic nerve palsy
(PNP) at the end of the procedure, phrenic nerve function was assessed via chest radiography of
diaphragmatic movement before discharge. Oral anticoagulation was prescribed for 3 months
postprocedurally and according to the CHA2DS2-VASc score thereafter. Periprocedural complications
were defined as described in the consensus statement.13
Follow-up
The study endpoint was the first documented >30-sec recurrence of AFLAT (AF, atrial flutter,
or atrial tachycardia) in the absence of antiarrhythmic drugs (AADs) after a blanking period of 3
months. Patients were monitored for 28 months via resting ECG, 7-day Holter-ECGs, and
echocardiography during follow-up visits at at 3- month or 6-month intervals in the first year and
every 6 months thereafter. Follow-up was additionally monitored by telephone. Patients were asked
to obtain an ECG if they experienced palpitations outside of Holter-ECG monitoring periods. AFLAT
recurrences were also diagnosed via implanted loop recorders, pacemakers, or dual-chamber
implantable cardioverter-defibrillators. AADs were given if arrhythmia recurred during the blanking
This article is protected by copyright. All rights reserved.
6
period and were continued until the end of the 3-month follow-up period. Patients who experienced
highly symptomatic drug-refractory AFLAT recurrence after the blanking period were evaluated for a
repeat ablation with a RF catheter guided by an electroanatomic mapping system.
Statistical analysis
Continuous data are presented as medians with standard deviations and interquartile ranges
(IQRs), and categorical variables are given as numbers and percentages. The effect of discrete
variables was studied using Kaplan-Meier survival analysis with the log-rank test. Univariate
association of continuous variables, including constructed scores with outcome, was analyzed using
receiver operating characteristic (ROC) curves, and parameters were dichotomized at the optimal
cut-off point determined from maximum sum of specificity and sensitivity with Youden’s method.14
The impact of discrete variables on outcome was determined with positive and negative prediction
accuracy and hazard ratio. To avoid model over-fitting, only parameters significantly associated with
outcome in the univariate analyses were included in the multivariate Cox regression model
performed using the step-down procedure. Two-tailed p-values ≤0.05 were considered statistically
significant. Statistical analyses were performed using SPSS software (SPSS Inc, Chicago, IL, USA).
Results
Baseline patient characteristics
A total of 101 patients underwent CB ablation. All patients had undergone at least one
external electrical cardioversion before ablation. Approximately 30% of all patients with
symptomatic AF did not have a history of rhythm control with AADs, owing either to
contraindications or refusal of chronic drug therapy. Our cohort of patients mainly includes patients
without LA enlargement (LA area < 20 cm2: 20 patients) or mild (LA area > 20 cm2 and < 30 cm2: 67
This article is protected by copyright. All rights reserved.
7
patients) to moderate LA dilatation (LA area > 30 cm2: 14 patients). The baseline characteristics are
summarized in Table 1.
Procedural characteristics
All cryoablations were performed with the 28-mm CB-Adv, which allowed isolation of all veins
without the need for additional focal catheter ablations. A freeze-cycle of 240-second duration was
applied in the first 52 patients, while a 180-second freeze-cycle was admitted to the following 49
patients. PVI was performed with a median of 2 freezes/vein in the 398 veins identified. For most of
veins, single-shot PVI was achieved (80.9%). The minimal nadir temperature was achieved in the
right superior PV. RLs were created in 41 patients (40.6%). Acute success in generation of linear roof
lesions was achieved in all patients, applying on average 5 (IQR 4-6) freezes with nadir temperature
of -46°C (-38 / -43) and a total freezing time of 720 (592-1080) sec. Further applications after PVI and
LA roof ablation were necessary in 4 of 41 patients during SR to achieve conduction block across LA
roof. A learning curve was observed in terms of the number of freezes needed for roofline
generation: in the first, patients close to six freezes were necessary on average for success, whereas
in later procedures, rooflines could be generated using an average of four and five freezes.
The median procedure and fluoroscopy times were 120 and 20 minutes, respectively. At the
beginning of the procedure, 40 patients (40.6%) were in SR, and 61 (60.4%) presented with AF.
Conversion to SR occurred during ablation in 25 of these 61 patients (20 patients during PVI and 5
patients during LA roof ablation). AF termination occured in 20 patients during PVI in the left
superior PV (5/20=25%), left inferior PV (8/20=40%), right superior PV (3/20=15%) or right inferior
PV (4/20=20%). Conversion to SR during LA roof ablation predominantly occured close to the left PV
(2/5=40%) or right PV (2/5=40%) and less frequently in the mid roof (1/5=20%). In the remaining 36
patients, SR was restored by external electrical cardioversion. Procedural characteristics are
displayed in Table 2.
This article is protected by copyright. All rights reserved.
8
Complications
Two types of complications were recorded as single events. PNP with recovery by discharge, the
most common complication, was present in 2 (2.0%) patients after ablation; PNP occurred due to a
too distal positioning of the CB in the right superior PV. In both cases, the double stop active balloon
deflation technique was used. Fortunately, phrenic nerve function was totally restored in all patients
at hospital discharge. One patient (1.0%) had a vascular complication (minor groin haematoma) that
was treated conservatively. No other complications or deaths were observed.
Follow-up
After a median follow-up of 37 (IQR 25/75 31/42) months, 71 (70.3%) patients were AFLATfree (Figure 1). Arrhythmia-free survival rates after a single catheter ablation procedure were 89.1%,
76.9%, and 70.3% at 1, 2 and 3 years. Patients with an additional RL had a higher AFLAT-free survival
rate than those with PVI only (78.0% vs. 65.0%), but the difference was not statistically significant
(P=0.22). Furthermore, there was no significant difference between patients presenting in sinus
rhythm and those presenting in AF before ablation procedure with an arrhythmia-free survival of
77.5% vs. 65.6% (P=0.27), respectively.
Of the 30 patients with AFLAT recurrence, 16 underwent a repeat procedure. Among the
remaining 14 patients, asymptomatic AF was documented in 4 patients; for 2 of these patients, a
rate control strategy was used. The other 10 patients with recurrent AF received at least one AAD
beyond the 6-month follow-up and did not undergo a repeat procedure; 3 of these 10 patients had
spontaneous conversion to SR without AF recurrence during further follow-up.
Among the 16 patients who underwent a repeat procedure using three-dimensional mapping
technology, the mean time from index procedure to repeat procedure was 9 (IQR 25/75 5/15)
months. One of the 16 patients had an additional macroreentrant PV tachycardia due to a
conduction gap in the left superior PV. PV reconnections were identified in 14 (87.5%) of the 16
This article is protected by copyright. All rights reserved.
9
patients who underwent a repeat procedure. Three of the 14 patients with PV conduction gaps also
showed fractionated potentials in low-voltage areas while repeat ablation. The conduction gaps
were distributed as follows: right superior PV, 8; right inferior PV, 8; left superior PV, 10; and left
inferior PV, 8. The most frequent locations of PV reconnections were the anterior aspect of the leftsided veins at the ridge with the LA appendage and the inferior and anterior aspects of the right
inferior PV. In the remaining 2 patients without PV reconnections, a low-voltage guided ablation was
performed. No other extrapulmonary potential foci of potential AF triggers were detected in our
patient cohort. The main cause of recurrence changed from the reconduction of initially isolated PVs
to non-PV substrates from the early (≤1 year) to the late phase (> 1 year) after index procedure.
AFLAT recurrences of all patients with low-voltage areas occurred after one year following the
ablation procedure. In the early phase only PV reconductions as possible triggers of recurrence could
be detected.
Predictors of recurrence
Associations between several variables and the clinical outcome of interest were identified by
univariate and multivariate analyses and Cox proportional hazards regression models. Univariate
associations were observed for LA area and AF history duration. Stepwise multivariate analysis
confirmed that these variables independently predicted outcome (Table 3). ROC analysis revealed
that LA area and AF history were associated with outcome (Figure 2), and increased LA area was the
strongest predictor (area under the curve, 0.724).
The optimal cut-off point of LA area with a sensitivity of 80% and specifity of 62% was 21 cm2
(positive predictive value: 47.1%; negative predictive value:88.0%). Of the 50 patients with LA area
≤21 cm2, only 6 (12.0%) experienced AFLAT recurrence, whereas 24 (47.1%) of the 51 patients with
LA area >21 cm2 showed AFLAT recurrence (p<0.01; Figure 3A).
This article is protected by copyright. All rights reserved.
10
The optimal cut-off point for AF history was 2 years after first diagnosis with a sensitivity of 80% and
specifity of 56%. By cut-off located at 2 years of AF history the positive predictive value was 42.6%,
and the negative predictive value was 86.4%. Of the 45 patients with AF history ≤2 years, AFLAT
recurrence was noted in only 7 (15.6%), whereas 23 (41.1%) of the 56 patients with AF history >2
years (p<0.01) experienced AFLAT recurrence (Figure 3B). Among patients undergoing repeat
ablation, all 5 patients with low-voltage areas as non-PV triggers had a LA area > 21 cm2 and history
of AF > 2 years. However, 6 patients with a LA area > 21 cm2 and AF history > 2 years showed PV
reconnections as sole triggers.
Discussion
To our knowledge, this is the first analysis presenting 3-year follow-up outcomes after PVI
with CB-Adv in persistent AF patients. The major results of our study were as follows: (1) After a
single procedure with the CB-Adv, 70.3% of the patients maintained SR during long-term follow-up,
and the complication rate was low. (2) LA area was the strongest predictor of AFLAT recurrence. (3)
LA area ≤21 cm2 and AF history duration ≤2 years were associated with significantly better outcomes.
Complications
Acute procedural complications associated with CB ablation are reported in 3%–5% of
cases.4,6,7 In our study, the most common periprocedural complication was PNP (2.0%); rates of PNP
after PVI with the CB-Adv as high as 5.5% have been reported.7 Finally, access-site complications
occurred in 1.0% of our patients, which is comparable to previously reported rates.15 No late or
unexpected complications were detected during long-term follow-up.
Three-year outcome
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11
The efficacy of CB-Adv in patients with paroxysmal AF has been demonstrated in several
clinical trials with promising success rates. Five observational studies6-10 provided data on the shortto midterm outcome in patients after PVI using CB-Adv for the treatment of persistent AF, being in
line with published data after RF ablation.15 Interest in using CB-Adv for PVI is increasing, because
procedure times are shorter with CB ablation than with RF ablation,15,16 due to reduced freeze cycle
times17 and single-shot applications,18,19 not being associated with smaller lesion surface areas using
nitrous oxide as refrigerant.20
Furthermore, there is some evidence, that PVI alone is not inferior to additional substrate
modification in patients with paroxysmal AF, as well as in patients with persistent AF.21 Interestingly,
the success rate for PVI alone in the STAR-AF trial21 was higher than previously reported. The reason
for this is not clearly understood. For example, during the enrollment of this trial, contact forcesensing catheters became available for commercial use. These catheters have been shown to
improve procedural success, and may account for some of the clinical outcome seen in this study.
However, this evidence has allowed among others for the expansion of the initial indication for PVI
using CB, resulting in its adoption as the first approach even among patients with persistent AF.2,6-10
The short- to midterm success rate of PVI in patients with persistent AF using the firstgeneration CB is reportedly low (45% at 1-year follow-up),22 but the modifications present in CB-Adv
have played an important role in improving outcomes. The lesions created by second-generation
balloons are wider and more homogeneous than those produced by first-generation balloons,23
allowing for wide antral ablation of the PVs which are involved in AF initiation and maintenance.
These changes may lead to substrate modification in regions, such as the PV antrum, that are
involved in AF persistency.24 Certainly, it is also important to consider the hypothesis that
modification of targeting rotors in the atrial substrate or the influence of the intrinsic cardiac
autonomic nervous system could lead to better outcomes following PVI with CB-Adv.
This article is protected by copyright. All rights reserved.
12
Short- to midterm (1-2 year) success rates of up to 69% after CB-Adv ablation for treatment of
persistent AF have recently been reported.6–10 In our study with a longer follow-up, the 3-year singleprocedure clinical success rate after CB PVI maintains at an acceptable high level of 70.3%.
We performed an additional LA roof ablation in order to modify the substrate between the
upper PVs and left atrial appendage in a minority of patients. The creation of linear lesions at the LA
roof in our trial led to a slightly better outcome than PVI only without statistic significance, although
this must be viewed with caution owing to the low number of patients with additional RLs.
Nevertheless, the additional LA roof ablation may justify the higher arrhythmia free survival rate,
compared to previous experiences.6-10 Wide antral PVI and roof ablation may have abolished AF
drivers or sources in those regions. We want to mention, that the population in our trial mainly
consists of patients without LA enlargement or mild to moderate LA dilatation (possibly representing
an “earlier” stage of persistent AF), which in addition may explain the overall success rate.
In patients undergoing repeat ablation (n=16), electrical PV reconduction was the sole cause
(in 56.3% of the patients) of arrhythmia recurrence after the index procedure using CB-Adv,
especially in patients showing recurrences in the early phase after index procedure. Non-PV
substrates as possible triggers occurred in all cases in patients with recurrences in the late phase
after index procedure. However, additional extrapulmonary arrhythmic substrate should be
considered in patients who present with arrhythmia recurrence and persistent PVI during a repeat
procedure.
Finally, it should be noted, that the Kaplan-Meier survival curve after index procedure did
not reach the nadir state after 3 years of follow-up. Despite our promising results, longer follow-up
studies are needed for evaluating the nadir of survival slope. However, statements about significant
predictors could be made with a high statistic power.
Predictors of recurrence
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13
Despite efforts to specify reliable, easily obtained predictors of clinical outcomes after PVI
with CB-Adv, the complexity of AF presents difficulties. Some predictors of poorer outcomes after
PVI with CB in patients with persistent AF have been proposed. Specifically, long AF history,7 AF
recurrence during the blanking period,7–9 and high BMI10 have been reported as independent
predictors of arrhythmia recurrence.
However, preprocedural independent predictors of long-term outcome after PVI for
persistent AF have not been described for CB-Adv.
We found that LA size >21 cm2 was a significant predictor of recurrence. Interestingly, this LA
area cut-off confirms with normal reference LA areas reported in published echocardiography data
obtained from a standard population.11 Patients with a dilated left atrium have a stronger tendency
to develop AFLAT recurrences. An LA area >21 cm2 may be accompanied by LA remodelling and
respective interstitial fibrosis, which could explain the increased incidence of AFLAT recurrence. The
importance of LA size as an independent predictor of success partially supports the critical mass
hypothesis. Although PVI with CB-Adv is effective and leads to both PVI and LA substrate
modification, the use of CB-Adv might be insufficient in patients with an enlarged left atrium due to
larger residual substrate areas.
Our result stresses the importance of the LA substrate, which should be considered in
concert with a longer AF history, as this factor affects substrate remodelling. AF tends to become
more persistent over time owing to the progression of electrical and structural remodelling of the
atria. This process promotes both reentry and ectopic activity, which may serve as substrates for and
triggers of AF.25 In our trial, non-PV substrates could be detected more frequent in patients
undergoing repeat ablations with an enlarged left atrium and longer AF history. On the basis of the
above-described evidence, it is therefore not surprising that these patients had worse outcomes
This article is protected by copyright. All rights reserved.
14
after PVI as index procedure. This result suggests that early intervention to interrupt continuous
remodelling and prevent further AF development should be considered.
Nevertheless, we want to mention that there are no randomized data comparing PVI in
patients with persistent AF using CB technique or point-by point lesions using RF. Randomized trials
are needed, before CB ablation of persistent AF will be taken as possible technique on board by
current guidelines.
Study limitations
This non-randomized study suffers from the inherent limitations of the study design.
Another limitation is that our follow-up results based on intermittent rhythm monitoring are
presented without consideration of recurrence during the blanking period, which could lead to
overestimation of the true success rate. In addition, the procedures were performed by experienced
operators in a high-volume center. Physicians unfamiliar with CB technologies would need to master
the RL technique in addition to PVI. We observed a learning curve for this additional procedure, with
fewer freezes necessary with increasing experience, but it is not clear how far this can be generalized
to widespread use in common practice.
An additional LA roof ablation was performed only in a minority of patients presenting with
AF at the beginning of the procedure. Nevertheless, the success rate might be explained by
additional roof ablation in a cohort of patients with relatively small left atria. However, the impact of
additional substrate modification at the LA roof on the outcome should be evaluated in a
randomized trial with a larger cohort of patients, including those with larger left atria. In addition,
the modest number of patients with repeat ablations prevents free extrapolation to the full range of
patients with arrhythmia recurrences. Finally, we analyzed only the most well-known non-invasive
clinical predictors of AFLAT recurrence. However, although other clinical variables may predict
This article is protected by copyright. All rights reserved.
15
outcomes after PVI, our results suggest that success probability can be stratified by 2 simple
variables: LA area >21 cm2 and AF history duration >2 years.
Clinical implications
Our data might help clinicians to estimate success probability and the need for potential
repeat ablation through the simple evaluation of non-invasive clinical parameters before PVI of
persistent AF patients. In addition, our data might facilitate identification of the best therapeutic
strategy; that is, stratification of AF patients by risk of recurrence might help the physician and the
patient make a therapeutic decision. Persistent AF patients with a non-enlarged LA and a short AF
history at the initiation of treatment are the best candidates for the CB ablation as index procedure.
Conclusions
SR was maintained in a substantial proportion of patients, even 3 years after CB ablation. CBAdv ablation was found to be effective, especially in persistent AF patients with a normal LA area
(<21 cm2) and a short AF history (<2 years). Our data suggest that the performance of earlier
ablation on persistent AF patients with a shorter AF history and a non-enlarged LA may improve the
long-term success rates associated with this procedure.
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Tables
Table 1. Baseline clinical and demographic characteristics of all patients (n=101).
Baseline characteristics
Patients, n
101
Demographic variables
Age (years), IQR 25/75
64 (55/70)
Female gender, n (%)
34 (33.7)
Medical history
Structural heart disease, n (%)
10 (9.9)
History of AF (years), IQR 25/75
2.7 (0.5/5.7)
Right atrial flutter, n (%)
12 (11.9)
Hypertension, n (%)
78 (77.2)
Diabetes, n (%)
14 (13.9)
BMI (kg/m²), IQR 25/75
28.4 (25.5/31.8)
History of stroke/TIA, n (%)
4 (4.0)
This article is protected by copyright. All rights reserved.
21
Vitamin K antagonists
46 (45.5)
Novel oral anticoagulants
55 (54.5)
CHA2DS2-Vasc score, mean±SD
1.9±1.4
Echocardiography
LVEF (%), IQR 25/75
62 (57/62)
LA area (cm²), IQR 25/75
22.1 (19.7/25.6)
Abnormal anatomy, n (%)
14 (13.9)
Common ostium, n (%)
10 (9.9)
Accessory PV, n (%)
4 (4.0)
Medical treatment before PVI, n (%)
70 (69.3)
Failed class I drugs, n (%)
38 (37.6)
Failed sotalol therapy, n (%)
1 (1.0)
Failed dronedarone therapy, n (%)
17 (16.8)
Failed amiodarone therapy, n (%)
14 (13.9)
Laboratory data
GFR (ml/min/1.7 m²), IQR 25/75
73.4 (59.7/83.6)
Abbreviations: AF, atrial fibrillation; BMI, body mass index; IQR, interquartile range; GFR, glomerular filtration
rate; LA, left atrial; PV, pulmonary vein; LVEF, left ventricular ejection fraction; PVI, pulmonary vein isolation;
SD, standard deviation; TIA, transient ischaemic attack.
This article is protected by copyright. All rights reserved.
22
Table 2. Procedural characteristics of all patients (n = 101).
Procedural characteristics
Number of all PVs, n (%)
398
Basic data
Procedure time (min), IQR 25/75
120 (102/147)
Fluoroscopy time (min), IQR 25/75
20 (16/27)
Nadir temperature reached during CB applications (-°C), IQR 25/75
Left superior PV
52 (48/54)
Left inferior PV
48 (44/53)
Right superior PV
54 (41/55)
Right inferior PV
52 (46/54)
Cumulative time of CB application (min), IQR 25/75
Left superior PV
8 (6/8)
Left inferior PV
8 (6/8)
Right superior PV
6 (6/8)
Right inferior PV
8 (6/10)
Cumulative time of CB application per patient (min), IQR 25/75
Time of CB application per PV (sec), IQR 25/75
31 (26/36)
210 (180/235)
Number of CB applications per patient, IQR 25/75
9 (8/10)
Number of CB applications per PV, IQR 25/75
2 (1/3)
Online signals, number of all PVs (%)
196 (49.3)
Single-shot isolation, number of all PVs (%)
322 (80.9)
Left superior PV
79 (78.2)
Left inferior PV
92 (91.1)
Right superior PV
82 (81.2)
Right inferior PV
69 (68.3)
This article is protected by copyright. All rights reserved.
23
AF at beginning of ablation, n (%)
61 (60.4)
IntraECV, n (%)
36 (35.6)
Roof line, n (%)
41 (40.6)
Cavotricuspid isthmus ablation, n (%)
12 (11.9)
Time of CB application, period including the application of refrigerant during the CB but not including the CB
thaw time. Freeze number, count of cryoablation applications. CB nadir temperature, lowest observed return
gas temperature measured on the CB system. Procedure time, “skin-to-skin,” time from first vascular entrance
to last catheter removal. Fluoroscopy time, time recorded using the laboratory recording system; Single-shot,
number of PVs isolated during first ablation.
Abbreviations: AF, atrial fibrillation; CB, cryoballoon; IntraECV, intraprocedural electrical cardioversion; IQR,
interquartile range; PV, pulmonary vein.
This article is protected by copyright. All rights reserved.
24
Table 3. Predictors of outcome after cryoballoon ablation.
95% CI
AUC
P value
Continuous Variables (ROC analysis)
Lower
Upper
Age
0.536
0.412
0.660
0.58
BMI
0.559
0.443
0.676
0.35
CHA2DS2-VASc score
0.522
0.402
0.642
0.73
GFR
0.505
0.370
0.639
0.94
LA area
0.724
0.617
0.831
< 0.01
Length of AF history
0.707
0.601
0.813
< 0.01
Left ventricular ejection fraction
0.429
0.308
0.550
0.26
Discrete Variables
HR
Abnormal PV anatomy
1.973
0.805
4.836
0.14
Antiarrhythmic drug therapy
1.131
0.518
2.472
0.76
Diabetes
1.156
0.496
2.696
0.74
Female gender
1.668
0.809
3.438
0.17
History of stroke/TIA
1.297
0.176
9.535
0.80
Hypertension
2.877
0.872
9.486
0.08
LA area > 21 cm²
5.159
2.105
12.644
< 0.01
Length of AF history > 2 years
3.878
1.577
9.539
< 0.01
Structural heart disease
1.412
0.493
4.047
0.52
Multivariate Cox regression model
HR
LA area > 21 cm²
6.661
2.584
17.171
< 0.01
Length of AF history > 2 years
6.342
2.360
17.043
< 0.01
This article is protected by copyright. All rights reserved.
25
Abbreviations: AUC, area under the curve; AF, atrial fibrillation; BMI, body mass index; CI, confidence interval;
HR, hazard ratio; GFR, glomerular filtration rate; LA, left atrial; PV, pulmonary vein; TIA, transient ischaemic
attack.
Figure legends
Figure 1. Three-year outcome in patients with persistent AF. AFLAT-free survival curve after single
ablation procedure performed using the Arctic Front Advance cryoballoon.
Abbreviations: AFLAT, atrial fibrillation, atrial flutter, or atrial tachycardia.
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26
Figure 2. Receiver operating characteristic (ROC) curve demonstrating the association between
outcomes and LA area and length of AF history in patients treated with the Arctic Front Advance
cryoballoon.
Abbreviations: AF, atrial fibrillation; AUC, area under the curve; CI, confidence interval; LA, left atrial;
Std, standard.
This article is protected by copyright. All rights reserved.
27
Figure 3 A-B. Three-year outcome after ablation procedure performed using the Arctic Front
Advance cryoballoon regarding (A) LA area and (B) length of AF history.
Abbreviations: AFLAT, atrial fibrillation, atrial flutter, or atrial tachycardia; LA, left
atrial.
This article is protected by copyright. All rights reserved.
28
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