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New Advances in Atrial Fibrillation Ablation:
Cryoballoon-Based Pulmonary Vein
Isolation
Ahmed F. Osman, MD, FACC
FESC, FHRS, FASE
Florida Heart Rhythm Specialists, PLLC
Director, Cardiac EP lab, Broward General
Medical Center
NOVA Southeastern University
1
Atrial Fibrillation
Health Risks and Costs
• Negative impact on quality of life
1,2
• Leading cause of stroke: 5x increased risk
3
• Increases risk of heart failure4
• Increases US healthcare system costs:
$12 billion estimated cost to treat AF5
1. Singh SN, et al. J Am Coll Cardiol. 2006;48:721-730.
2. Kang Y. Heart Lung. 2006;35:170-177.
3. Wolf PA, et al. Stroke. 1991;22:983-988.
4. White PD: Heart disease. New York, NY, The McMillan Co, 1937.
5. Kim M, et al. Adv.Ther. 2009;26:847-857.
2
Thoracic vein and atrial pathogenesis of AF
SVC
SVC
Extension of
muscular fibers
into pulmonary
vein (PV)
Ganglia noted
in yellow
LSPV
LIPV
Common
locations of PV
(purple) and
common sites
of origin of
non-PV
triggers (black)
LSPV
LIPV
RSPV
RIPV
LSPV
LIPV
RSPV
RIPV
IVC
IVC
SVC
SVC
RSPV
RIPV
IVC
LSPV
LIPV
Large and small
reentrant
wavelets that
play a role in
initiating and
sustaining AF
RSPV
RIPV
IVC
Calkins et al. Heart Rhythm. 2007;4:1-46.
Composite of
anatomic and
arrhythmic
mechanisms
of AF
Indications for Catheter AF
Ablation
• Symptomatic AF refractory or intolerant to at least
one Class I or III antiarrhythmic medication
• In rare clinical situations, it may be appropriate as
first-line therapy
• Selected symptomatic patients with heart failure
and/or reduced ejection fraction
• Presence of a left atrial thrombus is contraindication
to catheter ablation of AF
“It's far more important to know what person the disease has
than what disease the person has.”
Hippocrates
Patient Selection for Ablation
More Optimal Patient
Less Optimal Patient
Highly symptomatic
Minimally symptomatic
1
0
Paroxysmal
Long-standing persistant
Younger (<70 years)
Older (70 years)
Smaller (<5.0 cm)
Larger (5.0 cm)
Normal
Reduced
Congestive heart failure
No
Yes
Other cardiac disease
No
Yes
Pulmonary disease
No
Yes
Sleep apnea
No
Yes
Obesity
No
Yes
Prior stroke/TIA
No
Yes
Variable
Symptoms
Class I and III drugs failed
AF type
Age
LA size
Ejection fraction
Courtesy of Hugh Calkins, MD.
Pulmonary Vein Isolation (PVI) is the
Cornerstone of AF Ablation
2007 HRS Consensus Statement
“Ablation strategies which target the PVs and/or PV
antrum are the cornerstone for most AF ablation
procedures.”
Superior
Vena
Cava
Left
Superior
Pulmonary
Vein
Left
Inferior
Pulmonary
Vein
Right Superior
Pulmonary Vein
Complete electrical isolation
should be the goal for targeted
PVs and entrance and/or exit
block should be demonstrated
Isolate each PV
independently
Right Inferior
Pulmonary Vein
Inferior Vena Cava
Cappato et al., Circ Arrhythm Electrophysiol 2010;3;32-38 http://www.HRSonline.org/Policy/ClinicalGuidelines
6
Controlled Trials of AF Ablation Patients Free of AF (% at 1 Year)
Ablation
100
90
Control
87
86
79
75
80
86
70
56
Percent
60
50
40
30
20
10
0
RAAFT
CACAF
A4
APAF
Courtesy of Jeremy N. Ruskin, MD, Massachusetts General Hospital.
Milan/NR
PABA CHF
Challenges Using RF Focal Ablation Catheter to
Isolate PV and Ablate Atrial Tissue
• Patient anatomy and atrial tissue depth is variable
• Cardiac contractions make maintaining position
difficult
• Catheter force varies with position in heart
• Technically challenging
• Good lesions require transmurality
• Successful procedure requires contiguous lesions
8
Clinical Issues with Conventional RF
Focal Ablation Catheter
•
•
•
•
•
•
Risk of perforation
Uncontrolled energy delivery
Esophageal damage
Char/coagulum formation
Inconsistent results
Time consuming point-by-point
ablation
• 6% complication rate
• 3- to 6-hour procedure times
• Success rates:
– 14.5% - 76.5% w/o AAD
– 8.8% - 50.3% w/AAD
Cappato R, et al. Circulation. 2005;111:1100-1105.
9
Clinical Issues with Conventional RF
Focal Ablation Catheter
• 6% complication rate
• 3- to 6-hour procedure times
• Success rates:
– 14.5% - 76.5% w/o AAD
– 8.8% - 50.3% w/AAD
Cappato R, et al. Circulation. 2005;111:1100-1105.
10
®
Arctic Front Catheter Design
Arctic Front Catheter Balloon Segment
Outer Balloon
Deflection
Wires
• Straightforward positioning:
over-the-wire, steerable,
good visibility
Inner Balloon
Guide Wire
Lumen
Thermocouple
Injection
Tube
Marker Band
Guide Wire
• Pressurized N2O delivered
through ultrafine injection
tube
• Several safety
mechanisms: double
balloon, pressure and flow
monitoring, blood detection
Cryoablation Effects Include
Multiple Mechanisms
• Ice formation and
thawing
• Apoptosis
• Necrosis
Hypothermia
12
Baust, Institute of Biomedical Technology, SUNY 2002
Histological Effect on the
Connective Tissue Matrix
• Cryoadhesion improves contact and stability, minimizing the
amount of fluoro used
• Preserves the extracellular matrix and endothelial integrity1
• Decreases risk of thrombus formation1
• Demonstrates well demarcated lesions1
1
Sarabanda AV, et al. J Am Coll Cardiol.
2005;46:1902-1912.
13
Properties of Cryoablation
Hypothermic
Zone
Ablation Zone
(sub-zero)
• Removes heat from the tissue
• Leads with a wave of hypothermia
• Ablates at the point of balloon contact
14
Achieve™ Mapping Catheter
• Achieve is an intracardiac
electrophysiology diagnostic
catheter which can be
deployed through the Arctic
Front® guide wire lumen
• Available in 15 mm and
20 mm loop diameters
• Either diameter compatible
with 23 mm and 28 mm
Arctic Front
15
15
How Arctic Front® Balloon Catheter
and AchieveTM Work
1. Access
targeted vein
2. Inflate and
position
3. Occlude and
ablate
4. Assess PVI
16
Standardized Procedure
Does Not Require Complex 3D Mapping
Arctic Front®
Cryoballoon
• Arctic Front creates circumferential
lesions,1 using 2-3 applications per
vein to achieve PVI2
• Does not require 3D mapping
Achieve™
Mapping
Catheter
• Achieve Mapping Catheter can be
deployed through the Arctic Front
guide wire lumen, minimizing
catheter exchanges
• Allows the procedure to be performed
using a single transseptal puncture
Fluoroscopy image during contrast dye injection shows
full occlusion of the left superior pulmonary vein.
Entire procedure can be done using fluoroscopy or intracardiac echocardiography
Image: Courtesy of Dr. Vogt, Herz- und Diabeteszentrum NRW, Germany
1
Sarabanda AV, et al. EffJ Am Coll Cardiol. 2005;46:1902-1912.
2
Medtronic, Inc. Arctic Front Cardiac CryoAblation Catheter clinical reports, in support of FDA premarket approval.
17
1
7
Assessment of Real-Time PV Isolation
• Achieve™ mapping catheter allows
for real-time assessment of PV
isolation during cryoablation with
Arctic Front®
Delay
Increased
Delay
Isolation
Images: Courtesy of Dr. Schwagten, ZNA Middelheim, Belgium (above)
and Dr. Vogt, Herz- und Diabeteszentrum NRW, Germany (right)
Arctic Front is positioned against the
LIPV ostium, with Achieve positioned
to assess PV isolation
18
1
8
19
European Clinical Study Results
Symptomatic Drug Refractory PAF Efficacy Results
Efficacy
Neumann
Van Belle
Kojodjojo
PVI
97% Arctic Front®
98.5% Arctic Front
83% Arctic Front
99% RF ablation
Freedom from
AF
74% off AAD at 1 year
with Arctic Front
73% off AAD at 1 year with
first 3-month blanking
period with Arctic Front
77% off AAD in most
patients at 13 months
with Arctic Front
59% freedom from AF off
AAD at one year with Arctic
Front
72% off AAD in most
patients at 13 months
with RF ablation
EvR 1m pre
3 Month post
24h Holter, 12 lead ECG at
3m intervals
24h Holter monitoring at
1, 3, 6, 12 months
Event recorders
20
7-day Holter ECG at
3m intervals
European Clinical Study Results
Arctic Front® Safety Results
Neumann
• 7.5% Phrenic nerve
palsy (PNP)*; all
recovered at < 1 year
(26/346)
Van Belle
Kojodjojo
• 2.8% asymptomatic PNP*; all
resolved within 6 months (4/141)
• 0.8% pericardial effusion
(1/124)
• 1.4% arteriovenous fistula
(2/141)
• 1.6% transient PNP
(2/124)
• No PV stenosis
• No atrioesphageal
fistula, stroke, death, or
other peri-procedural
complications
• 0.7% left atrial flutter
successfully ablated (1/141)
• No PV stenosis
* Primarily in 23 mm balloon
21
Shorter Procedures Demonstrated with
Experienced European Users
-33%
250
Minutes
Data from 9 German
Centers:
Arctic Front® is 33%
faster than point-bypoint catheter systems
with a 24% reduction
in fluoro time.
300
-33%
200
Point-by-Point
with 3D Mapping
150
Arctic Front
100
-24%
50
0
Lab Occupancy
Time
Medtronic data on file.
Primary Physician
Time
Fluoroscopy
Time
22
Meta Analysis of Clinical Experience
• 539 articles screened, 23 were retained for the
final analysis
• Efficacy results strong:
– Acute success over 98%
– 12-month freedom from AF: 72.83% with 3-month
blanking
– No difference in 6-month and 12-month freedom from
recurrent AF between those who underwent
Cryoballoon ablation for paroxysmal AF and who
underwent RF ablation
Andrade JG, Khairy P, Guerra PG, et al. Efficacy and Safety of Cryoballoon Ablation for Atrial Fibrillation –
A Systematic Review of Published Studies. Heart Rhythm. 2011.
23
Complications – Meta Analysis
Outcome
Phrenic Nerve Palsy (PNP)
Any reported PNP
PNP persisting post-procedure
PNP persisting > 1 year
Pulmonary Vein Stenosis (PVS)
Any PVS (per patient)
PVS requiring intervention
Periprocedure events
Stroke or TIA
Myocardial infarction
LA‐esophageal fistula
Esophageal ulceration
Pericardial effusion or tamponade
Cardiac tamponade
Pulmonary artery rupture
n/N
%
86/1,349
67/1,349
5/1,349
6.38%
4.73%
0.37%
7/773
2/1,163
0.90%*
0.17%
4/1,241
3/1,231
0/1,298
6/116
18/1,231
7/1,231
1/1,231
0.32%
0.24%†
0.00%
5.17%‡
1.46%
0.57%
0.08%
* Studies reporting systematic screening for PVS with non‐invasive imaging
† Two were transient due to air embolism and resolved without sequelae
‡ Outcome reported in three studies of systematic endoscopy post Cryoballoon ablation
Andrade JG, Khairy P, Guerra PG, et al. Efficacy and Safety of Cryoballoon Ablation for Atrial Fibrillation –
A Systematic Review of Published Studies. Heart Rhythm. 2011.
24
European Arctic Front® Study Conclusions for
Symptomatic Drug Resistant PAF Patients
1. Arctic Front System had a very high rate of acute PVI success
2. Arctic Front System had high rate of success in reducing longterm AF events
3. Arctic Front System had a low rate of complications; most
resolved by 1 year
4. Arctic Front System significantly reduced procedure time for
complete PVI compared to other PVI approaches
5. There was no occurrence of atrioesophageal fistula
25
STOP AF Trial
Key Inclusion Criteria:
• ≥ 2 documented AF Episodes
in the prior 2 months
• Efficacy failure of ≥ 1 AAD
(flecainide, propafenone, sotalol)
Redo ablation
n = 31 (19%)
Cryoballoon
ablation (CRYO)
n = 163
Blanking
period (90 day)
AAD Rx (DRUG)
n = 82
AAD
optimization
N = 245
Randomized
2:1 to CRYO*
or DRUG
26 centers in US
and Canada
Follow-up
at 1, 3, 6,
9 & 12
Months
* CRYO: Arctic Front® System
DRUG Crossover
n = 65 (79%)
26
Effectiveness Results
Freedom from AF after 90 Days Blanked for Detectable AF
TreatmentSuccess
Success
Treatment
100%
CRYO 69.9% (114 / 163)
80%
60%
OR = 29.5 (12.0 – 72.2) p < 0.001
40%
20%
Blanked
for
Detectable
AF
DRUG 7.3% (6 / 82)
0%
0
100
200
300
Days
400
500
27
CRYO Procedure Experience
Impacts Treatment Success
Treatment Success
100%
P < 0.001 by quartile (Wald)
OR = 1.14 for each procedure
66%
80%
90%
69%
56%
60%
40%
20%
0%
25
centers
n=43
1st and 2nd
procedures
14
centers
n=38
3rd – 5th
procedures
10
centers
n=42
6th – 11th
procedures
4
centers
n=40
12th – 23rd
procedures
28
Device Related and Procedure Related
Serious Adverse Events with Increasing
Experience
DR/PR SAE
[n (%)]
Serious Adverse
Events*
Procedure Sequence by Quartile
1st and 2nd
3rd – 5th
6th – 11th
12th – 23rd
25 centers, n=43
14 centers, n=38
10 centers, n=42
4 centers, n=40
3 (7.0%)
3 (7.9%)
4 (9.5%)
0 (0.0%)
3 (7.0%)
2 (5.3%)
3 (7.1%)
0 (0.0%)
2 (4.7%)
1 (2.6%)
2 (4.8%)
0 (0.0%)
(Initial and Repeat Abls.)
Serious Adverse
Events**
(Initial Procedure Only)
Serious Adverse Events
within 30 days of
procedure***
(Initial Procedure Only)
*p = 0.27 for SAE by first procedure sequence (initial procedure and reablation)
**p = 0.13 for SAE by first procedure sequence (initial procedure only)
***p = 0.30 for SAE within 30 days by first procedure sequence (initial procedure only)
29
Kowal, et al. in preparation.
Additional STOP AF Results
CRYO Results:
• 98.2% acute procedural success
• 62.2% of patients were treatment successes without any AF
drugs at 12 months
• 60.1% single procedure success rate
• 19% of patients had redo procedures within the first 90-day
follow-up period
DRUG Results:
• 79% of DRUG group demonstrated chronic treatment failure and
crossed over to the cryoablation procedure
30
Phrenic Nerve Palsy (PNP)
• 29/259 (11.2%) procedures:*
– 15 subjects - asymptomatic
– 13 subjects - symptomatic with DOE, SOB, and/or cough
– 25/29 (86.2%) resolved by 1 year
• Median time for CXR resolution 102 days
• 4/259 subjects (1.5%) had an abnormal CXR at
1 year, 1 (0.4%) remained symptomatic
* 29 PNP events out of 259 procedures in 28 subjects
31
STOP AF Trial Conclusions
STOP AF met pre-specified primary effectiveness end point:
• 98.2% of CRYO group had acute procedure success
• 69.9% of CRYO group compared to 7.3% of DRUG group
were considered a treatment success at 12 months
STOP AF met the pre-specified primary safety end points:
• Cryoablation procedure events were observed in 3.1%
(6.3%, UCB) of CRYO group; below the pre-specified 95%
upper confidence bound of 14.8%
• The major AF event rate in the CRYO group was non-inferior
to the DRUG group at 12 months, at 3.1% and 8.5%
respectively
32
Conclusions
Cryoablation for early Atrial Fibrillation:
1. Is effective in isolation of Pulmonary veins.
2. Is a safe procedure.
3. Has shorter procedure times, compared to
conventional RF ablation procedures.
4. Ideal procedure for PV / antral based atrial
fibrillation.
33