Cryoballoon Ablation of Pulmonary
Veins for Paroxysmal Atrial Fibrillation
First Results of the North American Arctic
Front STOP-AF Pivotal Trial
Douglas L. Packer, James M. Irwin,
Jean Champagne, Peter G. Guerra, Marc Dubuc, Kevin R.
Wheelan, Robert C. Kowal, Vivek Reddy, John W. Lehmann,
Richard G. Holcomb, Jeremy N. Ruskin for the STOP-AF
Cryoablation Investigators
ACC Atlanta
March 15, 2010
Disclosure Information
Dr. D. Packer in the past 12 months has provided consulting services for
Biosense Webster, Inc., Biotronik, Inc., Boston Scientific, CyberHeart,
InnerPulse, Medtronic, Inc., nContact, Sanofi-Aventis, St. Jude Medical,
and Toray Industries. Dr. Packer received no personal compensation for
these consulting activities;
Dr. Packer receives research funding from the NIH, Medtronic, Inc.,
Siemens AG, EP Limited, Minnesota Partnership for
Biotechnology and Medical Genomics/ University of Minnesota, Biosense
Webster, Inc. and Boston Scientific.
Additional information available from Mayo Communications
Cryoballoon Ablation
STOP-AF Trial
Trial Design - Multicenter Randomized Clinical
Patients
245 (82 DRUG, 163 CRYO)
Enrollment
Oct 10, 2006-June 30, 2008
Enrolling centers
26 (U.S. and Canada)
Follow-up
12 months
Organization
Principal Investigator
Douglas Packer, MD
Steering Committee Chair Jeremy Ruskin, MD
Clinical Events Committee Denis Roy, MD, Andrew Epstein, MD,
and Alfred Buxton, MD
eImage
Image Core Laboratory
Agility Research
ECG Core Laboratory
Cato Research
CRO
Medtronic Cryocath LP
Study Sponsor
STOP-AF Study Hypotheses
Primary Effectiveness Hypothesis:
 Cryoballoon ablation would have significantly
greater Treatment Success at 12 months than
Drug therapy
Co-Primary Safety Hypotheses
Cryoablation Major AF Event (MAFE) rate would be
non-inferior to DRUG, and
Cryoablation Procedure Event (CPE) rate would be
< 14.8%
Study Design of the STOP-AF Trial
Inclusions:
Patients >2 AF episodes in
2 months w ECG doc. of 1
Rx Failure of > 1 AA Rx
AA Rx
failure
n=304
Cryoballoon
ablation
n=163
Blanking
period (90 day)
Redo ablation
n=31
Followup
1,3,6,9,
&12 mo
Randomized
2:1 to ablation vs.
Drug Rx
Holters
Drug Rx
n=82
Screening
Exclusion
n=46
Drug
optimization
90 days
Weekly
TTMs
Consent withdrawal
n=7
Screening failure
n=6
Cross-over
n=65
1º Study Outcome Measures
• Effectiveness: freedom from CTF =
No detectable AF (non-blanked period)
No use of nonstudy drugs
No AF interventions
• Safety
MAFE: composite of disease / treatment
SAEs
CPE (Cryo) only:
composite of device/procedurerelated SAEs
Arctic Front Cryocatheter
and Ablation Methods
Cryoballoon design
Cryoballoon sizes
23 and 28 mm
Structure
Double balloon
Cooling (in balloon)
Liquid  gas
transition
Balloon delivery
Catheter
Steerable
Sheath
14 French
deflectable
Ablation
PVI w / no lines
Focal Catheter
9 Fr, 8mm tip
Baseline Characteristics
Baseline/demographic
Age (years)
Male (%)
Left atrial AP diameter (mm)
LV ejection fraction (%)
ALL
56.6
77%
40.5
60%
DRUG
56.4
78%
40.9
61%
CRYO
56.7
76%
40.3
60%
p value*
0.80
0.87
0.35
0.41
NYHA
None / Class I (%)
Class II (%)
AF episodes within 2 mo (no.)
Previous cardioversion (%)
History of atrial flutter (%)
94%
6.5%
23.2
22%
45%
94%
6.1%
21.2
21%
44%
93%
6.7%
24.3
23%
46%
1.00
1.00
0.54
0.87
0.79
Efficacy-failed AF drugs
Flecainide (%)
Propafenone (%)
Sotalol (%)
CHADS2
Overall SF-36 (v2) score
36%
47%
29%
0.6
70.6
35%
44%
31%
0.6
70.4
37%
49%
29%
0.6
70.8
0.87
0.50
0.88
0.92
0.87
* p value for comparison between DRUG and CRYO subjects
Baseline Subject-Reported Arrhythmia
Symptom Prevalence in STOP-AF
Subjects
All (n = 245)
100
DRUG (n = 82)
CRYO (n = 163)
P=0.552
213
73
P=0.423
140
66
P=0.775
80
P=0.132
164 56 108
60
%
123
53
141
P=0.415
189
88
78
112
34
40
P=0.451
20
36
14
P=0.224
22
12
0
Prior AF
hosp
Dizziness Palpitations
Rapid
heart beat
Dyspnea
Fatigue
Subject-reported arrhythmia symptoms
6
6
Syncope
Cryoballoon Procedural Data
• Acute Procedural Success (APS) ≥ 3 PVs isolated at end
•
•
•
•
•
•
of first procedure
98.2%
Balloon-only per-vein APS of all attempted PVs 90.8%
Mean durations:
• Procedure =
371.0 min (200 – 650)
• Cryoablation =
65.7 min (17 – 180)
• Fluoro =
62.8 min
(8 – 229)
Deliveries / PV
2.9 – 3.4
Cryoballoon temperatures
- 49ºC to - 54ºC
Mean duration / delivery
196 – 230 secs
Repeat cryoablation in 31 Ablation patients
all with ERAF within the 90 day follow-up
19%
Primary Effectiveness Analysis
Treatment Success
Treatment success
(%)
30 days
100
CRYO 69.9% 114/163
80
60
P<0.001
40
20
DRUG Rx 7.3%
Blanked
6/82
0
0
100
200
300
400
Days
KM estimate
68.6% (SE 3.9%)
vs 7.3% (SE 2.9%)
500
Treatment Success By Analysis Method
100
Intention to Treat
n = 114
69.9%
80
60
%
40
20
0
On / Off
Drug
n = 20
12.3%
On Rx
Single
Ablation
On-Treatment
Analysis
n = 98
60.1 %
65.8%
p < 0.001
Absolute
 62.6%
n=6
7.3%
DRUG
n = 82
n = 94
(57.7%)
p < 0.001
No
Drug
Absolute
 56.8%
9%
CRYO
n = 163
(19% redo)
CRYO
on / off
drug
n = 163
CRYO
single
proc
n = 163
DRUG
n = 67
CRYO
n = 114
Ongoing Drug Rx in CRYO Subjects
Treatment in STOP-AF at 12 Months
Warfarin
Anti-arrhythmic Drugs
100
100%
95%
80
Pt 60
(%)
40
26%
24%
20
0
Baseline
12 months
Baseline
12 months
Symptom Reduction (CRYO)
Baseline
% (n / 163)
Month 12
% (n / 163)
Symptomatic AF episodes
100.0%
19.6%
Dizziness
47.9%
8.6%
Palpitations
85.9%
25.2%
Rapid heart beat
66.3%
16.0%
Dyspnea
54.0%
8.6%
Fatigue
75.5%
12.9%
Syncope
3.7%
0.6%
CRYO SUBJECTS
Complication Rate in STOP-AF Trial
Cryoablation
Procedure
Events
Major AF
Events
Combined
CPE and
MAFE
P<0.001
P=0.595
20
P<0.001
15
14.8%
8.5%
n=7
10
Pt
(%)
5
3.1 (6.3)%
n=5
8.5%
n=7
6.1%
n=10
3.1%
n=5
0
Ablation
Ablation
n=163
Drug
n=82
Ablation
n=163
Drug
n=82
All Serious Adverse Events: Cryoablation 12.3%; Drug Rx 14.6% p=0.69
Summary of All Adverse Events
(Intention-to-Treat)
Type of Adverse Event
Stroke
CRYO
(n = 163)
4
2.5%
DRUG
(n = 82)
1
1.2%
TIA
3
1.8%
1
1.2%
Tamponade
1
0.6%
1
1.2%
Myocardial infarction
2
1.2%
0
0.0%
Hemorrhage requiring transfusion
3
1.8%
1
1.2%
New atrial flutter
6
3.7%
13
15.9%
Atrial esophageal fistula
0
0.0%
0
0.0%
Death
1
0.6%
0
0.0%
New or worsened AV fistula
2
1.2%
0
0.0%
Pseudoaneurysm
1
0.6%
1
1.2%
22
13.5%
6
7.3%
4
2.5%
0
0.0%
5
3.1%
2
2.4%
Phrenic nerve palsy
Persistent phrenic nerve palsy
PV stenosis
Pulmonary Vein Area Change
Pulmonary veins (no.)
500
400
300
n = 927 cryoablated PVs
10 stenotic PVs in 7 pts
>75% area change
1 cryo abl only in 4 pts
2 cryo abls in 2 pts
1 RF redo in 1 pt
433, 46.7%
219, 23.6%
200
180, 19.4%
100
35, 3.8%
10, 1.1% 23, 2.5%
0
-100% -75%
-50%
-25%
-0%
+25% >+100%
Cryoablated pulmonary veins, change in
cross sectional area from baseline
Phrenic Nerve Paralysis in the
STOP-AF Trial in 228 Patients
100
11.2%
n=29
80
60
40
86.2%
n=25
20
28 patients
0
Immediate
post-procedure
13.8%
n=4
Resolved
at 12 mo
Persisting
at 12 mo
1 with Sx
Limitations of the
STOP-AF Trial
• Early Cross-over to cryoballoon ablation
from Drug Rx after 14-28 days
• Shorter concurrent drug treatment period
• Permitted redo ablations during blanking
• Use of PV area vs diameter for PV
stenosis Dx
• Limited choice of antiarrhythmic drugs
Conclusions
• Cryoballoon ablation is effective for treating
recurrent drug-refractory paroxysmal AF in
symptomatic patients
• Balloon-only ablation is feasible in the majority of
patients
• Pulmonary vein stenosis may occur with
cryoablation
• Phrenic nerve injury occurring with cryoablation is
largely reversible
• The STOP-AF Trial endpoints were all reached