Outcomes Of Cryoballoon Ablation Of Atrial Fibrillation:
A Comprehensive Review
Arash Aryana, MS, MD, FHRS, Mark R. Bowers,MS, MD, and Padraig Gearoid O’Neill, MD, FHRS
Mercy General Hospital and Dignity Health Heart and Vascular Institute, Sacramento, California.
Over the last decade, cryoballoon ablation has emerged as an effective alternate strategy to point-by-point radiofrequency ablation for treatment of symptomatic atrial fibrillation. There are several reasons for this. First, the acute and long-term safety and efficacy associated with cryoablation appear comparable to that of radiofrequency ablation in patients with both paroxysmal and also persistent atrial fibrillation. Second, cryoablation offers certain advantages over conventional radiofrequency ablation including a gentler learning curve, shorter ablation and procedure times as well as lack of need for costly electroanatomical mapping technologies commonly utilized with radiofrequency ablation. Lastly, with the recent advent of the second-generation cryoballoon, the effectiveness of cryoablation has further improved dramatically. This comprehensive review examines the gradual evolution of the cryoablation tools as well as the rationale and data in support of the currently-available cryoballoon technologies for catheter ablation of atrial fibrillation.
Key Words : Atrial Fibrillation, Catheter Ablation, Cryoablation, Cryoballoon, Outcome.
Corresponding Address : Arash Aryana, MS, MD, FHRSVice ChairDepartment of Cardiology and Cardiovascular SurgeryMercy General Hospital and Dignity Health Heart and Vascular Institute3941 J Street, Suite #350Sacramento, California 95819
Catheter ablation has emerged as a practical approach for treatment of symptomatic atrial fibrillation (AF) in those who fail membrane-stabilizing antiarrhythmic drug (AAD) therapy.1 AF ablation has been shown to improve patient quality of life2 and reduce hospital readmission.3 Additionally, the observed benefits even persist in patients in whom complete freedom from AF cannot be achieved.2 As the role for catheter ablation in the management of AF has evolved within the last 2 decades, so have the ablative techniques and strategies. To date, a variety of energy modalities have been utilized for catheter ablation of AF including unipolar radiofrequency (RF),4 irrigated5 and non-irrigated bipolar RF,6 laser,7 cryothermy,8 and high-intensity focused ultrasound.9 While the long-term safety and efficacy of RF energy has rendered it the mainstay of arrhythmia ablation therapy, there are certain practical and theoretical advantages to using cryoenergy.
The principles of cryobiology were first established with investigations on the treatment of frostbite and tumor destruction.10 Current data suggests that a temperature of −30°C to −40°C is necessary to induce cell death.10 Ice formation is the cornerstone of cellular injury with cryotherapy which occurs both intracellularly and extracellularly. Hypothermy-induced cellular and tissue destruction occurs through immediate and delayed mechanisms.10 The immediate effects including hypothermic injury and cellular freeze rupture are mediated through tissue freezing/thawing, whereas delayed injury results from vasculature damage and apoptosis or programmed cell death.11
Rationale For Using Cryoenergy For AF Ablation
As a result of technological advances, evolutions in catheter design, and improved energy delivery that have come about in the last two decades, cryoablation is now routinely used in cardiac electrophysiology laboratories. Cryotherapy exploits the Joule–Thomson effect12 to achieve temperatures between −30°C to −90°C at the catheter–tissue interface.13 Furthermore, the use of cryoablation for pulmonary (PV) vein isolation may offer certain advantages. First, tissue-catheter adhesion during cryoablation can result in improved catheter stability. Second, cryoablation is associated with reduced pain and discomfort since the afferent pain fibers are ‘frozen’ as opposed to stimulated thermally.14 Third, cryoablation carries a lower risk of thrombus formation and consequently systemic thromboembolization and stroke, since it is associated with decreased activation of platelets and the coagulation cascade as compared with RF.15 Fourth, cryoablation leaves the connective tissue matrix intact and also avoids the risk of steam pops.14 Fifth, the lack of circulation, vascular disruption, and endothelial injury at the center of the cryolesion results in uniform tissue necrosis.14 As a result, unlike with RF, cryolesions consist of a smooth, sharply-demarcated necrotic core corresponding to the frozen volume within the zone of lethality, and they are thought to be associated with reduced likelihood of ulceration, stenosis, and formation of fistulas and strictures.14 Nonetheless, cryoablation can still pose a significant
threat to collateral structures such as the esophagus, lungs, coronary
arteries, and phrenic and vagus nerves.13 Another disadvantage relates
to the impact of blood flow on lesion size. That is, increased blood
flow surrounding the ablation catheter can significantly attenuate the
size of cryolesions. As such, cryoablation is generally more effective
in ‘low-flow’ areas.12 Meanwhile, thaw time continues to remain
the most important determinant of acute and long-term efficacy
associated with cryoablation.16,17
Table 1. Acute and long-term efficacy and safety of PV isolation using the first-generation cryoballoon in non-randomized studies.
| Study | n | Paroxysmal AF, n | Acute PV isolation | Procedure
time, min | Fluoroscopy time, min | Transient PN palsy | Persistent
PN palsy | Freedom from AF during follow-up |
|---|
| Malmborg, et al.28 | 43 | 34 (79%) | 91% | 239 ± 48 | 57 ± 21 | 4.7% | 2.3% | 52% at 9 months |
| Neumann, et al.29 | 346 | 293 (85%) | 97% | 170 | 40 | 7.5% | 0% | 74% at 12 months (paroxysmal AF)
42% at 12 months (persistent AF) |
| Klein, et al.30 | 21 | 21 (100%) | 95% | 165 ± 35 | 39 ± 9 | 14.3% | 4.8% | 86% at 6 months |
| Van Belle, et al.31 | 141 | 141 (100%) | 99% | 207 ± 79 | 50 ± 28 | 2.8% | 0% | 55% at 15 months |
| Chun, et al.32 | 27 | 27 (100%) | 98% (single application) | 220 | 50 | 11.1% | 0% | 70% at 9 months |
| Defaye, et al.33 | 117 | 92 (79%) | 87%
(single application) | 155 ± 43 | 35 ± 15 | 0.9% | 0% | 69% at 12 months (paroxysmal AF)
45% at 12 months (persistent AF) |
| Vogt, et al.34 | 605 | 579 (96%) | 91% | 156 | 25 | 2% | 0% | 62% at 30 months |
| Ferrero-de Loma-
Osorio, et al.35 | 63 | 40 (63%) | 95% | 180 ± 32 | 31 ± 22 | 4.8% | 0% | 72% at 2 years (paroxysmal AF)
36% at 2 years (persistent AF) |
| Aytemir, et al.36 | 236 | 188 (80%) | 99% | 72 ± 5 | 14 ± 3 | 4.6% | 0% | 81% at 18 months (paroxysmal AF)
50% at 18 months (persistent AF) |
| Rao, et al.37 | 51 | 51 (100%) | 97% | 151 ± 30 | 49 ± 12 | 5.9% | 0% | 57% at 36 months |
The safety and feasibility of focal cryoablation (Figure 1-A) for
PV isolation was initially studied in 52 patients with paroxysmal and
persistent AF who underwent PV isolation using this approach.18
While 97% of the targeted PVs were successfully isolated, freedom
from AF was only 56% at 1 year. Though in this study the longterm
clinical efficacy appeared to be lower than conventional RF
ablation, post-procedural computed tomographic (CT) surveillance
demonstrated no evidence of PV stenosis. Hoyt et al.19 also reported
on the feasibility of focal cryoablation in a cohort of 31 paroxysmal
AF patients. Acute PV isolation was attainable in 94% of patients,
but freedom from AF was only 58% at 6 months. Once again, no
cases of PV stenosis were encountered on serial CT surveillance.
Similarly, Kenigsberg et al.20 found that in fact focal cryoablation up
to 15 mm inside the PV ostium was not associated with increased risk
of PV stenosis. Furthermore, endoscopic studies have reported lack
of esophageal ulcerations following focal cryoablation as compared
with the cryoballoon or RF.21 Nonetheless, the practical application
of focal cryoablation for PV isolation appears limited by prolonged
ablation times and reduced long-term efficacy. Additionally, there are
no data currently on the clinical efficacy of linear focal cryoablation
within the left atrium. While clinical studies in patients with atrial
flutter (AFL) have shown that linear lesions can be effectively created
by point-by-point cryoablation, long-term recovery of cavotricuspid
isthmus conduction is generally higher using the latter approach as
compared to RF.22 Recently, the feasibility of a novel cryoablation
system designed for catheter ablation of AF/AFL using a liquid
refrigerant in place of nitrous oxide (used traditionally in catheterbased
cryoablation systems), was described in vivo.23 The latter is
capable of achieving lower nadir temperatures and seems to hold promise for both PV isolation and linear ablations.
Table 2. Acute and long-term outcomes of PV isolation using the first- versus second-generation cryoballoons in non-randomized studies.
| Study | n | Acute PV
isolation | Cryoballoon temperature at
PV isolation, at 60 sec or, at
nadir temperature, ºC | Time to PV isolation or nadir temperature, sec | Ablation Time, min | Procedure time, min | Fluoroscopy time, min | Transient PN palsy | Freedom from AF at 1 year |
|---|
| Martins, et al.47
First-generation balloon
Second-generation balloon
p-value | 66
81 | 81%
90%
0.003 | –36 ± 10*
–32 ± 10*
0.001 | 52 ± 34**
40 ± 25**
0.001 | 26 ± 14
22 ± 7
<0.001 | 120 ± 24
107 ± 24
0.002 | 29 ± 10
25 ± 9
0.020 | 10.6%
24.4%
0.048 | N/A
N/A
N/A |
| Fürnkranz, et al.48
First-generation balloon
Second-generation balloon
p-value | 30
30 | 100%
100%
1.00 | –49 ± 6†
–52 ± 6†
0.005 | 79 ± 60**
52 ± 36**
0.049 | N/A
N/A
N/A | 128 ± 27
98 ± 30
<0.001 | 19 ± 7
13 ± 5
0.001 | 3.3%
3.3%
1.00 | N/A
N/A
N/A |
| Aryana, et al.49
First-generation balloon
Second-generation balloon
p-value | 140
200 | 92%
98%
0.036 | 26 ± 23‡
–32 ± 16‡
<0.001 | 232 ± 77§
209 ± 68§
<0.001 | 61 ± 17
47 ± 12
<0.001 | 209 ± 58
154 ± 47
<0.001 | 42 ± 17
27 ± 12
<0.001 | 12.1%
16.0%
0.311 | 80%
84%
0.289 |
| Straube, et al.50
First-generation balloon
Second-generation balloon
p-value | 364
120 | 99%
100%
0.43 | 61¶ / −50#
−58¶ / −52#
<0.001¶ / 0.074# | 48†† / 76‡‡
33†† / 52‡‡
<0.001†† /
<0.001‡‡ | 60 ± 16
58 ± 12
0.007 | 185 ± 49
175 ± 45
0.038 | 34 ± 12
29 ± 11
<0.001 | 20.6%
27.5%
0.121 | 85%
85%
1.00 |
| Fürnkranz, et al.51
First-generation balloon
Second-generation balloon
p-value | 50
55 | 98%
100%
0.48 | N/A
N/A
N/A | N/A
N/A
N/A | 52 ± 10
33 ± 6
<0.001 | 137 ± 33
94 ± 24
<0.001 | 22 ± 10
13 ± 4
<0.001 | 8.0%
12.7%
0.434 | 64%
84%
0.008 |
| Di Giovanni, et al.52
First-generation balloon
Second-generation balloon
p-value | 50
50 | 100%
100%
1.00 | –50 ± 10†
–52 ± 5†
--- | 69 ± 25**
43 ± 17**
<0.05 | N/A
N/A
N/A | 115 ± 39
90 ± 16
<0.01 | 25 ± 6
18 ± 6
<0.01 | 8.0%
16.0%
0.218 | 66%
84%
0.038 |
| Liu, et al.53
First-generation balloon
Second-generation balloon
p-value | 57
68 | 88%
93%
0.352 | –42 ± 6†
–46 ± 6†
0.003 | N/A
N/A
N/A | 37 ± 10
28 ± 9
<0.001 | 117 ± 26
103 ± 23
0.001 | 20 ± 5
18 ± 5
0.011 | 0%
2.9%
0.159 | 60%
90%
<0.001 |
L*Cryoballoon temperature at PV isolation, **Time to PV isolation, †Nadir cryoballoon temperature, ‡Cryoballoon temperature at 60 sec, §Time to nadir temperature, ¶Cryoballoon temperature at PV, isolation using the 23-mm cryoballoon, #Cryoballoon temperature at PV isolation using the 28-mm cryoballoon, ††Time to PV isolation using the 23-mm cryoballoon, ‡‡Time to PV isolation using the 28-mm cryoballoon
Table 3. Acute and long-term efficacy and safety of PV isolation using the second-generation cryoballoon in non-randomized studies.
| Study | n | Paroxysmal
AF, n | Acute PV isolation | Ablation time,
min | Procedure
time, min | Fluoroscopy
time, min | Transient PN
palsy | Persistent PN palsy | Freedom from AF
during follow-up |
|---|
| Kenigsberg, et al.46 | 43 | 34 (79%) | 100% | 22 ± 4 | 126 ± 23 | 16 ± 8 | N/A | N/A | 95% at 6 months |
| Martins, et al.47 | 81 | 81 (100%) | 90% | 22 ± 7 | 107 ± 24 | 25 ± 9 | 3.3% | 0% | N/A |
| Fürnkranz, et al.48 | 30 | 23 (77%) | 100% | 29 ± 12 | 98 ± 30 | 13 ± 5 | 3.3% | 0% | N/A |
| Aryana, et al.49 | 200 | 143 (72 %) | 98% | 47 ± 12 | 154 ± 47 | 27 ± 12 | 16.0% | 0.5% | 84% at 1 year |
| Straube, et al.50 | 120 | 63 (52%) | 100% | 58 ± 12 | 175 ± 45 | 29 ± 11 | 27.5% | 1.7% | 85% at 1 year |
| Fürnkranz, et al.51 | 55 | 55 (100%) | 100% | 33 ± 6 | 94 ± 24 | 13 ± 4 | 12.7% | 5.4% | 84% at 1 year |
| Di Giovanni, et al.52 | 50 | 50 (100%) | 100% | N/A | 90 ± 16 | 18 ± 6 | 16.0% | 2% | 84% at 1 year |
| Liu, et al.53 | 68 | 50 (74%) | 93% | 28 ± 9 | 103 ± 23 | 18 ± 5 | 2.9% | 0% | 90% at 1 year |
| Bordignon et al.54 | 33 | 26 (79%) | 100% | 33 ± 6 | N/A | N/A | 6.1% | 0% | 85% at 6 months |
| Chierchia, et al.55 | 42 | 42 (100%) | 100% | 31 ± 4 | 95 ± 16 | 20 ± 12 | 19.0% | 0% | 83% at 1 year |
| Metzner, et al.56 | 50 | 36 (72%) | 100% | 35 ± 6 | 140 ± 28 | 25 ± 8 | 2.0% | 0% | 80% at 1 year |
| Ciconte, et al.57 | 143 | 113 (79%) | 100% | 13 ± 5 | 95 ± 16 | 13 ± 8 | 6.3% | 3.5% | 80% at 1 year |
| Aryana, et al.58 | 633 | 472 (75%) | 98% | 40 ± 14 | 145 ± 49 | 29 ± 13 | 7.6% | 1.1% | 77% at 1 year |
Table 4. Acute and long-term outcomes of PV isolation using RF versus the cryoballoon in non-randomized studies.
| Study | n | Paroxysmal AF | Acute PV
isolation | Ablation Time, min | Procedure time,
min | Fluoroscopy
time, min | PN
palsy | Other adverse
events | Freedom from AF during
long-term follow-up |
|---|
| Linhart, et al.68
RF
Cryoballoon | 20
20 | 20 (100%)
20 (100%) | 100%
81% | N/A
N/A | 200 ± 67
166 ± 39 | 55 ± 23
41 ± 13 | 0%
15% | 0%
0% | 45% at 6 months
50% at 6 months |
| Kojodjojo, et al.69
RF
Cryoballoon | 53
90 | 53 (100%)
90 (100%) | 99%
83% | N/A
N/A | 208 ± 58
108 ± 28 | 62 ± 36
27 ± 9 | 0%
2.2% | 3.8%
1.1% | 72% at 1 year
77% at 1 year |
| Tayebjee, et al.70
RF
Cryoballoon | 25
25 | 25 (100%)
25 (100%) | 100%
76% | N/A
N/A | 35
45 | 0%
8% | 0%
4% | 4%
4% | 52% at 1 year
56% at 1 year |
| Kühne, et al.71
RF
Cryoballoon | 25
25 | 25 (100%)
25 (100%) | 00%
100% | 47
45 | 197 ± 52
166 ± 32 | 46 ± 22
61 ± 25 | 0%
4% | 4%
4% | 92% at 1 year
88% at 1 year |
| Sorgente, et al.72
RF
Cryoballoon | 29
30 | 20 (69%)
24 (80%) | 100%
100% | N/A
N/A | N/A
N/A | N/A
N/A | 0%
10% | 13.8%
3.3% | 66% at 1 year
66% at 1 year |
| Herrera Siklódy, et al.73
RF
Cryoballoon | 30
30 | 17 (57%)
21 (70%) | 100%
100% | 52 ± 21
44 ±6 | 200 ± 46
177 ± 30 | 37 ± 16
38 ± 12 | 0%
6.7% | 0%
6.7% | 80% at 1 year
63% at 1 year |
| Schmidt, et al.74
RF
Cryoballoon | 2,870
905 | 2,870 (100%)
905 (100%) | 98%
97% | 33
45 | 165
160 | 24
34 | 0%
2.1% | 4.6%
2.7% | N/A
N/A |
| Mugnai, et al.75
RF
Cryoballoon | 260
136 | 260 (100%)
136 (100%) | 100%
100% | 43 ± 6
45 ± 4 | 192 ± 49
112 ± 58 | 36 ± 14
31 ± 17 | 0%
8.1% | 14.2%
11.0% | 57% at 23 months
63% at 23 months |
| Juliá, et al.76
RF†
Cryoballoon* | 186
100 | 186 (100%)
100 (100%) | 98%
100% | N/A
N/A | 190 ± 57
117 ± 59 | 35 ± 19
27 ± 16 | N/A
N/A | N/A
N/A | 80% at 1 year
81% at 1 year |
| Aryana, et al.58
RF
Cryoballoon** | 422
633 | 319 (76%)
472 (75%) | 99%
98% | 66 ± 26
40 ± 14 | 188 ± 42
145 ± 49 | 23 ± 14
29 ± 1 | 0%
7.6% | 2.6%
1.6% | 60% at 1 year
77% at 1 year |
| Jourda, et al.79
RF†
Cryoballoon** | 75
75 | 75 (100%)
75 (100%) | 100%
100% | 2 ± 13
32 ± 3 | 111 ± 32
134 ± 48 | 21 ± 8
25 ± 10 | 0%
17.3% | 2.7%
1.3% | 88% at 1 year
85% at 1 year |
*Combination of first- and second-generation cryoballoons, **Second-generation cryoballoon only, †Force sensing RF
Cryoballoon Ablation Of AF
In order to overcome the challenges associated with focal
cryoablation for PV isolation, a curvilinear catheter was initially
developed in early 2000s. This catheter consisted of a 64-mm freezing
segment with the ability to expand to a diameter from 18 to 30 mm
(Figure 1-B). Skanes et al.24 reported on the use of this circular
cryoablation catheter. Although using this ablation tool, complete PV
isolation proved possible in 91% of patients without any cases of PV
stenosis, only 22% exhibited freedom from AF at 6 months. On the
other hand, in 44% of patients who underwent a repeat procedure,
PV reconnection was evident in 93% of the previously isolated PVs.
The poor efficacy associated with this catheter was attributed largely
to the undesirable effects of PV blood flow on cryoablation using this
technology and its suboptimal catheter design. As a result, the ‘block
the vein’ strategy was proposed (Figure 1-C). Eventually, based on
this scheme, the first cryoballoon ablation catheter was introduced
and subsequently tested in vivo.25,26
First-Generation (Arctic Front) Cryoballoon
The cryoballoon (Arctic Front, Medtronic, Inc, Minneapolis,
MN) is a steerable, over the wire, 12-French double-walled balloon
catheter system (Figure 2-A). Two sizes are available – a 23 and a 28 mm balloon catheter. Early on, a small study comparing the
outcomes between the curvilinear cryoablation catheter and the
cryoballoon pointed to the superior efficacy associated with the use of
the latter in patients with paroxysmal AF.27 Subsequently, acute and
long-term safety and efficacy of PV isolation using the cryoballoon
was evaluated in several non-randomized studies in patients with
paroxysmal AF (Table 1), reporting long-term success rates ranging
between 55 and 86%.28–37 Neumann et al.29 reported on a prospective,
3-center experience of cryoballoon ablation in 346 patients with
symptomatic, drug refractory paroxysmal and persistent AF. Acute
PV isolation could be achieved in 97% of the targeted PVs, and
freedom from AF was 74% in patients with paroxysmal and 42%
in those with persistent AF. No PV stenosis was again encountered
during follow-up. However, transient phrenic nerve (PN) palsy
occurred in 7.5% of patients; though they all resolved within 1 year.
The Sustained Treatment of Paroxysmal Atrial Fibrillation (STOP
AF) trial is the only published multicenter, prospective, randomizedcontrolled
trial that evaluated the safety and efficacy of cryoballoon
ablation for treatment of AF.8 In this study, 245 patients with
paroxysmal (78%) or early persistent AF (22%) were randomized to
cryoballoon ablation or AAD therapy in a 2:1 randomization scheme.
Cryoablation achieved electrical isolation in 98.2% of PVs, in 97.6%
of patients. Following a 3-month blanking period, freedom from
AF was achieved in 69.9% of patients treated with cryoablation as
compared to only 7.3% using AAD therapy (p<0.001). Transient PN
palsy was encountered in 11.2% which ultimately persisted in 1.5% of
patients at 1 year. Stroke occurred in 2.2% and PV stenosis (defined
as a reduction of >75% in cross-sectional area or a 50% reduction
in PV diameter) in 3.1% of patients treated with cryoablation. Two
patients with PV stenosis were symptomatic and one required PV
stenting. Subsequently, a systematic review of 23 studies published
on the outcomes of cryoballoon ablation among 1,308 patients with
paroxysmal and persistent AF showed a 97.5% acute procedural
success (PV isolation) with freedom from AF in 72.8% at 1 year.38
These findings were generally consistent with those reported in
STOP AF. More recently, Yorgun et al.39 reported on the additional
benefits of cryoballoon-based ablation of AF beyond PV isolation.
The authors found that modification of ganglionic plexi as evaluated
by occurrence of vagal reactions during cryoablation may serve as an independent predictor of AF recurrence during long-term follow-up.
Second-Generation (Arctic Front Advance) Cryoballoon
Soon after the early experiences with the first-generation
cryoballoon it became apparent that ablation using this tool was
prone to certain challenges and drawbacks. Due to its number and
location of refrigerant injection ports, the maximal cooling zone on
the first-generation balloon occurs primarily over its equator (Figure
2-A). Therefore, optimal balloon positioning and orientation at PV
antra is often critical when using this catheter, such that balloon
mal-alignment can frequently compromise uniform tissue cooling
and lesion formation.40 This is further supported by more recent data
showing that durable PV isolation is directly impacted by the degree
of PV occlusion and tissue cooling, which in turn is influenced by the
distance from the balloon (cooling zone These concerns subsequently
led to the development of the second-generation cryoballoon (Arctic
Front Advance, Medtronic, Inc). The principal modification in the
design of this catheter has to do with the expansion of the cooling
zone to the entire distal half of its surface (Figure 2-B). Knecht et
al,42 analyzed the magnitude of ice formation using this new design
as compared to the first-generation cryoballoon and found that the
mean covered surface areas were significantly different for the 28-mm
but not the 23-mm balloons. Where as the first-generation catheter
created non-contiguous ice formation, the second-generation
cryoballoon exhibited a rather homogenous ice cap covering the
entire distal segment of the balloon including its distal pole (the
nose of the balloon). The superior efficacy of the second-generation
cryoballoon was subsequently validated in vivo.43,44 That is, it was
shown that cryoablation of canine PVs through a single 4-min
cryoapplication using the second-generation cryoballoon created
transmural and circumferential lesions resulting in electrical isolation
in 100% of PVs, as compared to only 60% using the first-generation
cryoballoon. A more recent clinical study showed that cryoablation
using this balloon was wide and circumferential with the level of
PV isolation more antral, resulting in generous posterior left atrial
debulking which could in part also account for this balloon’s improved
efficacy.45 Furthermore, Reddy et al.46 evaluated the outcomes of PV
isolation using the second-generation cryoballoon in 21 consecutive
patients with paroxysmal AF, all of whom subsequently underwent a
second remapping procedure to assess for durability of PV isolation at 3 months. The authors found that acute electrical isolation could
be achieved in 83% of PVs using a single cryoapplication, with
91% of PVs still durably isolated at 3 months. This provides clinical
evidence that in fact the improved thermodynamic characteristics
of the second-generation cryoballoon seem to be associated with a
higher rate of both single-shot PV isolation and also chronic lesion
durability, which may translate into improved clinical outcomes.
Meanwhile, several studies have compared the acute and long-term
outcomes of PV isolation using the first- and second-generation
cryoballoons in patients with paroxysmal and persistent AF.47–53
These studies collectively point to the superiority of the second- over
the first-generation cryoballoon based upon several major benchmark
parameters including acute PV isolation, biophysical characteristics,
ablation time, procedure time, fluoroscopic utilization, and longterm
freedom from AF (Table 2). As previously shown by our group,
in addition to faster balloon cooling rates at 30 and 60 sec, shorter
time-to-nadir temperature, and longer interval and total thaw times
observed with the use of the second-generation cryoballoon, we also
found a significantly lower PV reconnection rate at repeat procedure
in those with arrhythmia recurrence during long-term followup
(30% versus 13%; p=0.037).49 Furthermore, these results were
independent of operator experience and learning curve. Furthermore,
Bordignon et al.54 evaluated the magnitude of biomarker release in
66 patients following cryoablation using the first- versus the secondgeneration
cryoballoons and found that despite shorter ablations
required using the second-generation cryoballoon, higher levels
of cardiac biomarkers such as troponin T, creatine phosphokinase
and lactate dehydrogenase could be detected within the first 48
h in patients treated with the latter – possibly suggestive of more effective ablation. Interestingly, these findings also correlated with
higher procedural success at 6 months. Table 3, illustrates a summary
of mid- and long-term clinical outcomes of AF ablation using the
second-generation cryoballoon as assessed by non-randomized single
and multi-center studies.46–58 These studies have consistently reported
improved procedural and clinical outcomes associated with the use of
the second-generation cryoballoon.
PV Isolation Using The Cryoballoon And Predictors Of AF Recurrence
A more recent feature of cryoballoon ablation of AF is the ability
to potentially monitor real-time to PV isolation, also known as timeto-
effect via a single transseptal access. That is, the cryoballoon can
be advanced into the left atrium either over a conventional guide wire
or a specific octapolar spiral mapping catheter/guide wire (Achieve,
Medtronic, Inc) designed for monitoring and recording of PV
potentials to guide real-time PV isolation (Figure 2). To date, this
approach has been validated in several studies.59–61 Nonetheless, the
main limitation of this catheter has to do with its smaller diameter size
(either 15-mm or 20-mm), precluding consistent real-time recording
of PV potentials in patients with larger PV antra. Additionally, the
wider spacing among the electrodes on the catheter further amplifies
far-field electrogram sensing. In a recent publication, Boveda et
al61 reported a stepwise approach using this catheter which could
accurately assess real-time PV isolation in ~98% of the PVs. Though
in our experience, we have been unable to duplicate such a high rate
of confirmation of PV isolation during cryoablation using this spiral
recording catheter, undoubtedly this remains a highly effective tool
for measuring time-to-effect providing overall a simpler method for
validation of PV isolation as compared to other single-shot ablation systems such as the nMARQ or the pulmonary vein ablation catheter
(PVAC).
Meanwhile several other studies have closely examined the
predictors of a successful cryoballoon ablation of AF. One report
found an inverse association between the ovality index and the
orientation of PV ostia as determined by cardiac CT angiography
with the degree of cryoballoon occlusion during catheter ablation.62
Similarly, Kubala et al.63 found that in patients undergoing
cryoballoon ablation, presence of normal versus atypical PV anatomy
such as a common left PV, was associated with improved freedom
from AF during long-term follow-up. With respect to biophysical
characteristics of cryoballoon ablation, it seems that balloon thaw
time and perhaps its secondary derivative, freeze area-under-thecurve,
represent significant predictors of PV reconnection during
follow-up and long-term freedom from AF post-catheter ablation.64,65
On the other hand, cryoablation time and cryoballoon temperature
served as poor and unreliable predictors of such endpoints.65 It
should be emphasized that the freeze area-under-the-curve signifies
a comprehensive metric to assess the magnitude of cryoablation.49
As such, the computed value collectively reflects a multitude of
parameters including duration of cryoapplication, rate of cooling,
nadir temperature, and thaw-time. Meanwhile, another study has
suggested that very cold minimum balloon temperatures (<-51°C)
may in fact be predictive of acute PV isolation.66 Conversely, the
same study found that a minimum balloon temperature ≥-36°C (for
superior PVs) and ≥-33°C (for inferior PVs) predicted failed acute
PV isolation with a relatively high specificity (≥95%). But it should
be pointed out that in this study no data on long-term outcomes
were reported to further corroborate the acute procedural findings
with respect to durability of PV isolation or freedom from AF.
Collectively, we believe that these findings underscore the importance
of the ‘quality’ as opposed to the ‘quantity’ of cryoapplications during
catheter of ablation when using the cryoballoon.
In the meantime, there remains a lack of consensus on the
appropriate ablation dosing when performing an AF ablation
using the cryoballoon – that is, with respect to the ideal freezing
duration and the number of freeze-thaw-freeze cycles. The current
recommendations suggest a 4-min cryoapplication along with a ‘double freeze’ approach (freeze-thaw-freeze cycle). Though the
‘double freeze’ method has been shown to result in more extensive tissue
destruction and deeper, larger lesions due to the repeated freeze/thaw
effects on the cell membrane,14 it has been argued that this data may
largely pertain to the less potent cryoablation tools such as the focal
cryoablation catheter. Indeed, there is cumulative evidence in support
of improved acute and long-term efficacy associated with a single PV
cryoapplication using the second-generation cryoballoon. Ciconte et
al.57 recently reported their results of a single 3-min cryoapplication
using the second-generation cryoballoon in 143 consecutive patients.
The authors achieved acute PV isolation in 94% of PVs using a single
application and in 100% after 1.1 ± 0.4 freezes. After a 3-month
blanking period, freedom from atrial arrhythmias was achieved in
80% of patients at 1 year (82% with paroxysmal versus 73% with
persistent AF). Additionally, 10% of patients underwent a repeat
procedure. Though this data is subject to selection bias, among these
patients 43% of PVs exhibited conduction recovery at redo ablation.
Now it should be called to attention that it would be extremely
difficult to meaningfully compare such data against those derived
from other non-matched series. However, as previously reported
by our group,49 the same outcome of PV reconnection in patients
undergoing repeat procedures following an initial second-generation
cryoballoon ablation using ≥2 applications (≥1 freeze-thaw-freeze
cycle) was found to be 13%. In the long run, whether a second ‘bonus’
freeze will in fact prove necessary still needs to be determined.
A recent study has also evaluated the predictive value of early AF
recurrence following catheter ablation using the first-generation
cryoballoon by analyzing data from the STOP AF trial.67 The
authors found that over half of the patients (51%) experienced an
early recurrence post-ablation within the first 3 months. Moreover,
of these recurrences the great majority (85%) had occurred within the
first month. Though nearly half of these individuals (44%) remained
free of long-term atrial arrhythmias, early recurrence did in fact
correlate with late recurrence of AF. Conversely, only 13% of those
with early recurrences were found to have recurrent AF during longterm
follow-up.
Comparison Of Cryoballoon Versus RF
Though there is limited data on prospective head-to-head comparisons between cryoballoon versus RF catheter ablation of
AF, several non-randomized comparative studies58,68–76 have been
published on the use of the first-generation cryoballoon as compared
to open-irrigated, non-force sensing RF (Table 4). The results have
been largely mixed without any apparent, significant differences
between the two modalities. However, two of the larger series by
Kojodjojo et al.69 and Mugnai et al.75 did in fact illustrate subtle
trends towards improved 1-year outcomes with the first-generation
cryoballoon as compared to RF (77% versus 72% and 63% versus
57%, respectively). Xu et al.77 reported the outcomes from a metaanalysis
of 1,104 patients from published studies, who underwent AF
ablation using the cryoballoon (n=469) or RF (n=635). They found
cryoablation to be associated with a significantly shorter procedure
time (by a weighted mean of 30 min) and fluoroscopy exposure
(by a weighted mean of 14 min), whereas ablation time was nonsignificantly
longer with cryoablation (by a weighted mean of 12
min). Moreover, cryoablation was also found to be associated with
a non-significantly higher rate of long-term success as compared
with RF. Recently, our group has reported on the acute and longterm
outcomes from a large, non-randomized, multicenter study
comparing the second-generation cryoballoon to open-irrigated,
non-force sensing RF.58 The study included 1,196 patients with AF
(76% paroxysmal), and it found that cryoablation was associated with
a superior primary endpoint of freedom from atrial arrhythmias at
12 months following a single catheter ablation procedure without
the use of AAD therapy (76.6% versus 60.4%; p<0.001), and overall a reduced need for AADs (16.7% versus 22.0%; p=0.024) and fewer
repeat ablations (14.6% versus 24.1%; p<0.001) , as compared to
non-contact force sensing RF. In addition, at redo procedure, fewer
patients exhibited PV reconnection if previously ablated using the
cryoballoon (44.2%) as versus RF (65.7%); p=0.002. Cryoablation was
also associated with shorter ablation and procedure times, but greater
fluoroscopic utilization. Both transient and persistent PN palsy
occurred exclusively with cryoablation, whereas all other adverse event
rates were similar between the two groups. These findings coupled
with the relative safety associated with the use of cryoablation using
the second-generation cryoballoon, reproducibility of the results
across a number of different centers with variable procedural volume,
and suggestion of a similar magnitude of benefit in patients with
both paroxysmal and persistent AF, evoked the second-generation
cryoballoon a more favorable ablation tool as compared to non-force
sensing RF with an AF ablation score78 notably greater than that
computed for RF. Additional investigations to evaluate the safety
and efficacy related to the use of cryoballoon ablation in comparison
to the recently made available force-sensing RF ablation catheters
seems necessary to identify the most optimal approach to AF
ablation. Along these lines, Jourda et al.79 reported on a prospective
comparison between force sensing RF and the second-generation
cryoballoon. The study found that both procedural and fluoroscopic
times were shorter with force sensing RF but with similar ablation
times, adverse events, and long-term freedom from AF as compared
to cryoablation using the second-generation balloon. At this point, a larger, multicenter comparison of these two diverse types of ablation
techniques with respect to cost, safety, and efficacy seems relevant.
In addition, Juliá and colleagues76 recently reported on the
incidence and mechanism of atrial tachycardias following catheter
ablation of paroxysmal AF in 286 consecutive patients using the
cryoballoon versus RF. The authors found that the incidence of postablation
atrial tachycardias was significantly lower with cryoablation
as compared to RF (3.0% versus 11.3%; p= 0.028). This difference was
driven largely by the larger (28-mm) second-generation cryoballoon.
Though not entirely clear, the mechanism is believed to be related
to the overall reduced atrial ablation and perhaps larger and more
homogeneous lesions created using the latter balloon.
Cryoballoon Ablation Of Persistent AF
Since the STOP AF study which originally evaluated the outcomes
of cryoablation in patients with paroxysmal and ‘early’ persistent
AF, several non-randomized first-/second-generation cryoballoon
studies have evaluated this therapy in those with both paroxysmal
and persistent AF.46,48–50,53,54,56,58 Specifically, a few additional studies
have explicitly examined the efficacy of cryoablation of non-PV
triggers using the second-generation cryoballoon.80–82 In a recent
multicenter study, the second-generation cryoballoon was shown
to be a safe and effective tool for electrical isolation of the superior
vena cava and ablation of the left atrial roof, the left lateral ridge
and the base of the left atrial appendage throughout both atria in
110 patients with persistent and long-standing persistent AF.82
Complications were rare and at 1 year, 78% of patients remained free
of AF recurrence following a 3-months blanking period. Obviously,
additional data is currently needed to further validate the acute and
long-term outcomes using this approach.
Figure 1. Cryoablation tools originally used for catheter ablation of AF. Panel A, shown, are a 6-mm and a 4-mm tip focal cryoablation catheter. Panel B, illustrates a curvilinear cryoablation catheter with a 64- mm freezing segment and the ability to expand to a diameter of 18 to 30 mm. This was the first cryoablation catheter specifically designed for PV isloation. Panel C, illustrates the ‘block the vein’ strategy – through this approach the PV is mechanically occluded using an angioplasty balloon catheter, advanced through the curvilinear cryoablation catheter to diminish PV blood flow and to further enhance the efficacy of cryoablation.
Recently, a ‘hybrid’ approach involving a thoracoscopic surgical
and a concomitant endocardial cryoballoon PV ablation has been
described in patients with persistent AF or in those with paroxysmal
AF and a failed prior catheter ablation.83 While in two small studies
this approach proved safe and feasible, the long-term efficacy of
this strategy has yet to be evaluated.83,84 For now, the precise role,
applicability and specific advantages of the above-mentioned
approach over each of the individual strategies alone, remain unclear.
Figure 2. The designs of the first- and second-generation cryoballoon catheters, both advanced over an octapolar spiral mapping catheter specifically designed for recording PV potentials to guide real-time PV isolation. Panel A, in the first-generation cryoballoon, the maximal cooling zone (arrow) consists of an equatorial band. Accordingly, optimal balloon alignment would be vital to ensure proper circumferential contact between the PV antra and the cooling zone on this balloon. Panel B, due to design modifications made to the second-generation cryoballoon, the maximal cooling zone on this catheter (arrow) now spans the entire distal half of its surface including the distal tip. This in turn offers a greater cooling surface area while minimizing the impact of balloon orientation on optimal tissue contact.
Several studies have established the overall safety of cryoballoon
ablation of AF,8,38,85 While some have suggested fewer major adverse
events associated with the use of cryoballoon versus RF including
fewer cardiac perforations and fatalities,85 these observations have
not been entirely consistent. Aside from PN palsy which remains the
most frequent complication related to the use of cryoballoon,8,85 the
same adverse events that in general complicate RF ablation also occur
with cryoablation of AF.38,58 These consist of groin complications,
bleeding, thromboembolism, pericardial effusion, gastroparesis, and
atrioesophageal fistula.8,38,85 Though thromboembolism remains rare
in the setting of cryoablation,15 most embolic events as a consequence
of cryoablation are believed to represent air embolism related to the
handling of the larger sheath inside the left atrium. Neumann et
al.86 investigated the incidence of micro-embolization immediately
after catheter ablation of AF with the cryoballoon versus RF in 89
patients using cerebral magnetic resonance. The authors discovered
presence of asymptomatic cerebral lesions one day post-ablation
in 8.9% of patients ablated with cryoballoon versus 6.8% with RF. These outcomes did not differ statistically. Meanwhile, PV stenosis
may also complicate cryoablation of AF. Thought this adverse event
has historically been thought to be a rare sequela of cryoablation,14
there is sufficient evidence to suggest that cryoballoon ablation is
not immune to this type of complication.8 Nonetheless, a recent
meta-analysis documented the overall incidence of PV stenosis
resulting in symptoms or requiring intervention at only 0.17% in
patients who underwent cryoballoon ablation of AF.38 Chierchia
et al. investigated the incidence and outcomes of pericardial
effusion following cryoballoon versus RF ablation, and found no
significant difference between the two modalities (11% versus
16%).87 The authors concluded that this complication was generally
asymptomatic and mild with a benign self-limiting course in nearly
all cases. Lastly, persistent iatrogenic atrial septal defect (iASD)
following cryoablation has also been described.88–90 Specific concerns
surrounding this complication have been raised due to the use of the
larger, 15-French transseptal sheath which is required for delivery of
the cryoballoon catheter into the left atrium. The incidence of iASD
in cryoablation studies varies between 16–31% during short-term
follow-up88,89 and has been reported as high as 20% at 1 year.90 Not
surprisingly, this incidence seems to be higher than that which is
reported for RF which generally utilizes a smaller transseptal sheath
for performing the ablation.89 Though most patients with persistent
iASD seem to tolerate this entity rather well and without apparent
adverse events,88–90 additional studies on larger patient populations
with longer follow-up are needed to reach a firm conclusion.
Meanwhile, some of the more important and specific adverse
events complicating cryoballoon ablation of AF are reviewed in the
ensuing sections.
PN palsy is by far the most common complication of cryoballoon
ablation of AF.8,38 Anatomical studies have revealed the close
proximity of the right PN to the superior vena cava and the anteriorinferior
aspect of the right superior PV, and also the left PN to the
left atrial appendage.78 Hence, catheter ablation in the vicinity of
these structures can potentially yield collateral injury to the adjacent
PN. However, PN injury is not unique to cryoablation. In fact, it
can also occur as a consequence of catheter ablation using RF as
well as other energy modalities.91,92 Overall, the prevalence of PN
palsy due to AF ablation is estimated between 0.37% and 1.6%.91 A
recent study suggested that the mechanism of PN injury as a result
of cryoablation seems to be axonal in nature and characterized by
Wallerian degeneration, with great potential for regeneration and
neuronal recovery.93 Consistent with this, the short-term outcome
of patients with post-ablation PN palsy appears to be favorable with
>80% achieving complete resolution by 1 year.91 As such, PN palsy
may be classified as either transient or persistent. While the incidence
of transient right PN palsy as a consequence of cryoballoon ablation
of AF can reach ≈20%, persistent PN palsy remains uncommon with
a reported incidence of only 0–4% in most studies.29,31,34,36,49,50,58,74,75
Moreover, transient but not persistent right PN palsy has been shown
to occur more frequently using the second-generation as compared
to the first-generation cryoballoon.47,49,52,94 This is likely due to the
second-generation catheter’s increased potency. Furthermore, PN
palsy has also been shown to occur more frequently with the use of
the 23-mm cryoballoon.44,94 In most cases, the latter is believed to
be related to the deployment of a relatively undersized cryoballoon
deeper inside the PV.95 In addition to minimizing the physical distance between the cryoballoon and the PN, cryoablation at a
relatively more distal position inside the right PVs may be more
conducive to enhanced ‘cold’ transfer to deeper tissues such as the
PN due to reduced convective heating of the balloon by atrial blood
flow.94–96 Hence, this may result in deeper penetration of cryoenergy,
thereby increasing the risk of collateral injury.
Esophageal thermal injury seems to occur with left atrial ablation
virtually using any type of energy modality,97,98 including also
cryoenergy.99–102 Furthermore, it is believed that in some patients
this may represent a precursor to atrioesophageal fistula.103 Early
experiences using the first-generation cryoballoon suggested
possibly a lack of esophageal thermal injury associated with
cryoablation as assessed on post-procedural endoscopy, despite steep
luminal esophageal temperature drops during catheter ablation.104
Nonetheless, esophageal thermal injury and ulceration were
subsequently demonstrated in other clinical studies,105 particularly
with the use of the second-generation cryoballoon which can be
associated with esophageal ulcerations in as many as ≈20% of
patients.106,107 It should be emphasized that this incidence generally
remains similar and possibly lower than that reported with RF.108
Though as with ablation using other energy modalities no precise
measures have been identified to mitigate esophageal thermal injury,
Fürnkranz et al.107 found that a luminal esophageal temperature ≤12ºC
during cryoballoon ablation predicted esophageal ulceration with
100% sensitivity and 92% specificity. In a subsequent study,111 these
authors reported that by adopting a strategy of luminal esophageal
temperature-guided cryoablation through interruption of ablation
with esophageal temperatures ≤15°C, the esophageal ulceration rate
decreased to 3%. As such, avoidance of ultra-cold luminal esophageal
temperatures during cryoablation seems prudent.
Both cough and hemoptysis have been reported following
cryoablation of AF.112–118 A persistent dry cough can be detected
more commonly in some patients following cryoballoon ablation.
However, hemoptysis remains rather uncommon with an incidence
ranging between 0–2.1%.114–116 Though hemoptysis can also occur
in the setting of PV stenosis, most cases of hemoptysis following
cryoablation do not seem to accompany such a complication.112–118
Furthermore, most overt cases of hemoptysis seem to manifest
within hours to days following cryoablation,112–114,116 rendering the
possibility of PV stenosis once again less likely. Instead, it has been
postulated that transient interruption of vascular integrity, perhaps
within the pulmonary capillary system due to cryoinjury, may serve
as a possible culprit.113,114,116 Accordingly, some investigators have
attributed this to colder balloon temperatures (<55ºC) and deeper
balloon positioning inside the PVs during cryoablation.112–114,116,117
CT imaging of patients with hemoptysis frequently demonstrates
presence of edema surrounding the PV tissue sometimes with
erosion,112 with118 or without113,114,117 luminal narrowing. Mucosal
hyperemia and erosion can also be detected during bronchoscopy.113,114
Some investigators have ascribed these findings to pulmonary
infarction.116 While this remains unclear based on the reports to date,
both the clinical symptoms and findings appear to be self-limiting
with a gradual resolution over time.112–116 Furthermore, none of these
cases have been associated with catastrophic complications such as
formation of a fistula.
Over the past decade, cryoballoon ablation of AF has emerged
as a practical, alternative strategy to point-by-point RF ablation.
There seem to be several reasons for this. First, the acute and longterm
safety and efficacy associated with cryoablation appear to be
similar to RF, in patients with both paroxysmal and also persistent
AF. Second, this technology also offers certain advantages over
conventional RF ablation including a gentler learning curve and
relative ease of use, shorter ablation and procedure times, and lack
of need for costly electroanatomical mapping equipment commonly
used with RF ablation. More recently, with the advent of the secondgeneration
cryoballoon, the effectiveness of cryoablation has further
improved remarkably. Given that results from several cryoablation
studies strongly suggest a greatly improved efficacy associated with
the use of the second-generation cryoballoon, a prospective headto-
head comparison between the latter and force sensing RF seems
appropriate. As such, we eagerly await the results of ongoing studies
that are currently investigating this topic.
Drs. Aryana and O’Neill have received consulting fees, speaker honoraria and a research grant from Medtronic, Inc.
