CLINICAL RESEARCH
Europace (2016) 18, 206–210
doi:10.1093/europace/euv189
Ablation for atrial fibrillation
Shortening of freezing cycles provides equal
outcome to standard ablation procedure using
second-generation 28 mm cryoballoon after
15-month follow-up
Jürgen Tebbenjohanns*, Claudia Höfer, Lars Bergmann, Michael Dedroogh,
Daniela Gaudin, Axel von Werder, and Klaus Rühmkorf
Department of Cardiology, Medical Clinic I, Helios Klinikum Hildesheim, Senator-Braun-Allee 33, 31135 Hildesheim, Germany
Received 4 March 2015; accepted after revision 27 April 2015; online publish-ahead-of-print 11 June 2015
Aims
Complications such as thermal oesophageal lesions, phrenic nerve injury, and pulmonary haemorrhage were found in
cryoballoon (CB) ablation. Whether shortening of freezing times translates into equal efficacy rate and outcome is unknown. The aim of this study was to test the hypothesis that a single freeze cycle per pulmonary vein (PV) without
dormant conduction during adenosine infusion is equally effective to standard CB procedure with a bonus freeze after
documented PV isolation (PVI).
.....................................................................................................................................................................................
Methods
In 53 patients with drug-refractory atrial fibrillation (AF) demonstrating PVI after a single 240 s freeze cycle without PV
activity during adenosine no additional bonus freeze was applied (study group). In 139 patients, PVI was performed using
and results
a bonus freeze (240 s) after documented PVI (control group). Primary endpoint was recurrence of AF. Secondary endpoint was the assessment of quality of life (QoL-score from 1 to 6, being 1 the best and 6 the worst). Follow-up (FU) was
performed at 3, 6, and 12 months. Freedom from symptomatic AF during a mean FU of 458 + 107 days was achieved in
43 (81%) patients in the study group and in 110 (79%) control patients (P ¼ ns). The QoL-score improved equally in
both groups (4.8 + 0.9 to 2.1 + 0.7, P , 0.05 and 4.7 + 0.6 to 2.2 + 0.6, P , 0.05). Procedure duration (79 + 14 vs.
98 + 16 min, P , 0.01) was shorter in the study group. Complication rate was similar in both groups.
.....................................................................................................................................................................................
Conclusion
Shortening of freezing times to 4 min per PV without residual dormant PV conduction after adenosine provocation is
equally effective to the standard CB ablation protocol using a bonus freeze.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Catheter ablation † Cryoballoon ablation † Atrial fibrillation † Phrenic nerve palsy † Adenosine
Introduction
Second generation cryoballoon (CB) catheter ablation for pulmonary vein isolation (PVI) shows freedom from atrial fibrillation (AF) in
80% of patients after 1-year follow-up1 – 3 and is more efficient, with
a 90% isolation rate after a single 240 s freeze and shorter procedure duration compared with the first generation CB.4,5 However, a
higher incidence of transient phrenic nerve palsy (PNP), up to 24%,
and persistent PNP (2 – 4%) have been reported.1 – 8 Thermal
oesophageal lesions have been described in up to 12 – 19% of
patients.9,10 In addition, three cases of lethal atrio-oesophageal
fistula,11,12 as well as pulmonary haemorrhage,13 have been reported. Since the purpose of CB ablation is to create transmural lesions, subsequent collateral damage of tissues adjacent to the left
atrium must be taken into consideration. Nadir CB return gas temperatures and duration of freezing cycles were considered to be related to thermal injury of the oesophagus and the phrenic nerve.
Also, a modified protocol was proposed to avoid damage, including
stopping the freezing cycle if nadir temperature exceeded 2608C
and shortening of the freezing time to 180 s if real-time PVI is
achieved in ,80 s. However, there is no study to show that an additional bonus freezing cycle after confirmed PVI is required.
* Corresponding author. Tel: +49 5121 8943102; fax: +49 5121 8943105, E-mail address: [email protected], [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
207
Reduced freezing times in cryoballoon ablation
What’s new?
† Cryoballoon ablation with a single 4 min freeze is highly
effective with 80% in sinus rhythm after 15 months.
† A single freeze provides a low prevalence of adenosineinduced dormant conduction.
† The procedure duration in a single freeze group is significantly shorter compared with the bonus freeze group.
Therefore, we compared two CB ablation strategies of a prospective registry with and without an additional bonus freeze after
documented PVI.
discontinued in case of loss of diaphragmatic contraction. A maximum
of two freezing cycles were applied to each PV. Following CB ablation,
both sheaths were removed and transthoracic echocardiography was
undertaken to rule out pericardial effusion.
Oral anticoagulation was started the day after the procedure for at
least 2 months according to the CHA2DS2VASc score.
Follow-up
After discharge from the hospital, all patients were scheduled for outpatient clinic visits at 3, 6, 12, and 18 months, including 24-h Holter monitoring and external event recording for 4 weeks in case of suspicious
symptoms. After a blanking period of 3 months, all documented episodes of AF . 30 s were considered as a recurrence. Quality of life
(QoL) was assessed using a simplified score with a range from ‘1’
(best) to ‘6’ (worst). It measures patient-perceived symptom severity
and impairment comparable to the CCS-SAF scale.14
Methods
Endpoints
We included 53 consecutive patients (study group) with drug-refractory
paroxysmal AF or short-standing persistent AF (≤3 months) and compared these to a retrospective control group of 139 patients. Patients
were excluded if they had a prior PV ablation procedure, a prosthetic
heart valve, left atrial (LA) enlargement (.55 mm), LA thrombus, or
contraindication to oral anticoagulation. All patients gave written informed consent. The study was approved by the institutional ethics
committee. Transoesophageal echocardiography was performed prior
to the ablation procedure to exclude LA thrombus and to measure
LA dimensions and left ventricular ejection fraction. No additional CT
or MRI was performed.
The primary endpoint of this consecutive study was first
electrocardiogram-documented recurrence of AF after a blanking period of 3 months. Secondary endpoint was the assessment of QoL.
Ablation procedure
Patient characteristics
All procedures were performed under conscious sedation using propofol and fentanyl. A 6 F decapolar catheter was positioned into the coronary sinus via the right femoral vein. A single transseptal puncture
under fluoroscopic guidance was performed using a 8.5 F long sheath
(SL1, St. Jude Medical, Inc., St. Paul, MN, USA). A guidewire was used
to introduce a 12 F steerable sheath (Flexcath Advance, Medtronic,
Inc., MN, USA) continuously flushed with heparinized saline. Heparin
was administered to maintain an activated clotting time between 250
and 350 s. Pulmonary venograms were then acquired to identify the
PV ostia with a 5 F multipurpose catheter. The 28 mm CB was introduced into the LA via the sheath and PV recordings of the left superior
PV close to the LA were acquired during baseline and coronary sinus
(CS) stimulation using a spiral mapping catheter (20 mm Achieve, Medtronic) advanced through the central lumen of the CB catheter. Then,
the CB was inflated and advanced to the ostium of the PV. The quality
of PV occlusion was documented by injection of contrast medium
through the central lumen. Once the best occlusion was obtained, a
freeze cycle of 240 s was applied. After successful PVI was achieved, a
bolus of adenosine was given during CS stimulation with an observed
short duration of a third degree AV block to unmask dormant PV conduction (n ¼ 53, study group). Once dormant PV activity was observed,
a bonus cryoapplication was applied. In the remaining 139 patients (control group), no adenosine was given and an additional bonus freeze of
240 s was applied for each PV. After PVI of the left superior pulmonary
vein (LSPV), the same procedure was undertaken for the left inferior
pulmonary vein (LIPV), the right superior pulmonary vein (RSPV), and
finally the right inferior pulmonary vein (RIPV). Before ablation of the
RSPV, the decapolar catheter in the CS was placed into the superior
vena cava to continuously pace the right phrenic nerve at 2000 ms cycle
length with high output and pulse width. Freezing was immediately
We enrolled 192 patients, 53 (28%) in the study group and 139
(72%) in the control group. Patients in the study group were older
(66 + 10 vs. 61 + 11 years, P , 0.05) and had a slightly longer history of AF (6 + 4 vs. 5 + 3 years, P , 0.05). No differences were
found in gender distribution, CHA2DS2VASc score, LA diameter,
type of AF, and number of prior external cardioversions (Table 1).
Statistical analysis
Normally distributed variables were expressed as mean + SD and compared by using the Student’s t-test. A P-value of ,0.05 was considered
statistically significant.
Results
Ablation procedure
Mean procedure duration was shorter in the study group (78 + 12
vs. 93 + 12 min, P , 0.01). Also, the freezing cycle times were significantly shorter in the study group (1059 + 174 vs. 1725 + 334 s,
Table 1 Baseline characteristics
Variable
Study
group
(n 5 53)
Control
group
(n 5 139)
P
................................................................................
Age, years
66 + 10
61 + 11
,0.05
Female, n (%)
26 (49)
64 (46)
ns
Years with AF
CHA2DS2VASc score
6+4
1.8 + 1.2
5+3
1.9 + 1.3
,0.05
ns
LA diameter (mm)
40 + 6
41 + 7
ns
Paroxysmal AF, n (%)
Persistent AF, n (%)
38 (72%)
15 (28)
87 (63%)
51 (37)
ns
ns
Prior external cardioversion, n
2+4
2+8
ns
208
J. Tebbenjohanns et al.
P , 0.01). No difference was found in mean fluoroscopy time
(14 + 3 vs. 14 + 4 min, P ¼ ns) and the use of external cardioversion during the procedure (25 vs. 36%, P ¼ ns) (Table 2).
In the study group, a total of 211 PV were identified, including one
left common PV (1.9%). During the first CB application, electrical
PVI was achieved in 188/211 (89%) PVs, in 47/52 (90%) LSPVs, in
49/52 (94%) LIPVs, in 46/53 (87%) RSPVs, in 46/53 (87%) RIPVs,
and in 0/1 left common pulmonary vein. Adenosine was used in
188 PVs and unmasked dormant PV activity in 4/188 (2%) in 4/53
(8%) patients (Figure 1). A bonus freeze CB application was applied
to these four PVs.
Complications
TIA/stroke occurred in 1/53 (1.9%) patient in the study group and in
2/139 (1.4%) patients in the control group. The patient in the study
group was an 80-year-old male with persistent AF and a high CHA2DS2VASc score of 7 who developed a stroke with subsequent haemiplegia after removal of the sheaths. After exclusion of intracranial
haemorrhage, intravenous thrombolysis was applied and full recovery occurred within 12 h. The two patients in the control group had
TIA with some minor transient disorders and no persistent deficit
24 h after the procedure. Phrenic nerve palsy occurred in 3/53
(6%) patients in the study group and in 7/139 (5%) patients in the
control group (P ¼ ns). In all patients PNP occurred during RSPV
isolation. Phrenic nerve palsies were transient in 9/10 (90%) patients
and resolved spontaneously within 30 s to 20 min. In 1/139 (0.7%)
patient in the control group PNP persisted after discharge. Total recovery of diaphragmatic function was observed after a follow-up of
3 months. Pericardial effusion was noted in one patient at the end of
the ablation procedure.
Follow-up
During a mean follow-up of 458 + 107 days including a 3-month
blanking period, 43/53 (81%) patients of the study group and 110/
139 (79%) patients of the control group were in stable sinus rhythm
without symptomatic and/or observed episode of AF (Figure 2). The
QoL-score improved equally in both groups (4.8 + 0.9 to 2.1 + 0.7,
P , 0.05 and 4.7 + 0.6 to 2.2 + 0.6, P , 0.05). No differences were
found between both groups during baseline and follow-up (P ¼ ns).
Procedure duration (min)
78 + 12
93 + 12
,0.01
Fluoroscopy (min)
14 + 3
14 + 4
ns
1
1.5
2
2.5
3
3.5
4
4.5
5
Freeze duration (s)
Phrenic nerve palsy, n (%)
1059 + 174
3 (6)
1725 + 334
7 (5)
,0.01
ns
5.5
6
Pericardial effusion
0 (0)
1 (0.7)
ns
TIA/Stroke
External cardioversion, n (%)
1 (1.9%)
13 (25)
2 (1.4%)
49 (36)
ns
ns
A
Table 2 Ablation procedure
Variable
Study
group
(n 5 53)
Control
group
(n 5 139)
P
................................................................................
B
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
Figure 2 The QoL-score improved equally and significantly in
both groups. Best result ¼ ‘1’; worst result ¼ ‘6’; study group in
white bars; control group in black bar.
I
III
PV1/2
PV2/3
PV3/4
PV4/5
PV5/6
PV6/7
PV7/8
CS 1,2
CS 3,4
Figure 1 Adenosine test during CS stimulation: dormant PV activity occurred followed by AV block.
209
Reduced freezing times in cryoballoon ablation
Discussion
Clinical outcome
The most important finding of this study is that a single 240 s freeze
per PV was as equally effective as conventional second generation
CB ablation using a bonus freeze after proven PVI. Freedom from
symptomatic AF and improvement of QoL were similar in both
groups with 80% of the patients in sinus rhythm after a mean followup period of 15 months.
Duration of freezing cycles
Our results are consistent with a recent study that showed similar efficacy of a single freeze cycle of 3 min with an isolation rate of 91%
after the first CB application and an arrhythmia-free survival of 80%
after 12 months.15,16 Our data support the hypothesis that, with
the technical improvements of the second generation CB, the need
for a standard bonus CB application after observed PVI is questionable. A bonus freeze failed to demonstrate further benefit and was
associated with a higher complication rate, at least using the first generation CB. The second generation CB has been redesigned. The
number of injection ports was doubled from four to eight and
were positioned more distally, with a consequent more uniform
zone of freezing on the balloon surface. The second generation CB
provides lower temperature of the refrigerant and faster isolation
time in comparison with the first generation CB. Animal studies
have shown durable PV isolation even with shorter freeze cycle duration.17 In this canine model, no difference was found histologically in
lesion depth and in circumferential transmural lesions between 2 and
4 min application duration. In fact, stricture of the PV due to neointimal proliferation was observed after 4 min freezes but not with 2 min
freeze duration. In addition, at least focal cryolesions have shown a
constant lesion size with a 3 min freeze cycle. These observations
from animal studies raise the question of optimal freezing cycles in second generation CB ablation.18 The proposed 4 min freeze time was
determined many years ago using the focal cryo technique with a different refrigerant.17 The data from Ciconte et al. 16 using a single 3 min
CB freeze are very promising and show comparable outcome results
to our findings with 80% in sinus rhythm after 1-year follow-up.
Whilst the optimal ablation duration has to be defined it becomes
more and more evident that a bonus freeze after proven isolation
of the PV is not necessary with the second generation CB. Since
complications, such as thermal oesophageal lesions9,10 with atriooesophageal fistula,11,12 phrenic nerve injury,1 – 8 PV stenosis, and pulmonary haemorrhage,13 were found in CB ablation, a reduction of the
freeze cycles times with additional shortening of the procedure duration should contribute to a safe procedure in terms of reduction or
even avoidance of serious adverse events.
Adenosine effect
Our study showed reconnection after proven PVI with adenosine in
only 2% of the PVs and 8% of the patients. Ciconte et al.19 showed
similar results with a trend to higher rates of PV activity after adenosine (4% of the PVs and 12% of the patients tested). In another study
with the second generation CB adenosine showed dormant reconduction in four patients (10%), in four PVs (5%).20 The difference
might be explained by a longer waiting period after initial PVI and
isoproterenol administration before adenosine testing. These results and ours are in contrast to an earlier study that demonstrated
PV activity in 9/132 (8%) PVs in 7/38 (21%) patients.21 Patients with
dormant PV conduction underwent further CB application and
showed significantly fewer AF recurrences during long-term followup (34 vs. 54% in the control group). However, in that study the first
generation CB was used and one can consider that in our study with
the second generation CB, the amount of tissue with only mild and
reversible damage was smaller. This finding may also contribute to
the well accepted observation that the second generation CB is
more efficient and provides a better outcome.22 – 24 Reversible injury of the surrounding tissue is a common effect in radiofrequency
ablation of the PVs and explains the even higher rates of dormant PV
activity up to 35% of the PVs.25
Limitations
The present study was not randomized and the single freeze group
(study cohort) was compared with a retrospective analysed bonus
freeze group (control group). There is, thus, a difference between
the baseline characteristics of the two groups (study group patients
were older and had a longer history of AF). Also, we did not specifically addressed the potential complication of thermal injury of the
oesophagus by routine gastroscopy. However, collateral damage
such as oesophageal thermal injury is related to minimal balloon temperature, minimal oesophageal temperature, and duration of freeze
cycles.6,7 Finally, the QoL-score is not yet validated but, likewise,
showed an expected result that correlated to procedure success.
Conclusions
Shortening of freezing times to 240 s without a bonus freeze with
adenosine provocation is equally as effective as the standard CB ablation protocol using a bonus freeze in 15-month follow-up. This
shortened CB ablation protocol significantly cuts down procedure
duration.
Conflict of interest: Tebbenjohanns has received honoraria from
Medtronic for lectures.
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