Cryoballoon Ablation of PulmonaryVeins for Paroxysmal Atrial FibrillationFirst 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 AblationCryoballoon AblationSTOP-AF TrialSTOP-AF Trial

Trial Design - Multicenter Randomized ClinicalTrial Design - Multicenter Randomized ClinicalPatientsPatientsEnrollmentEnrollmentEnrolling centers Enrolling centers Follow-upFollow-up

OrganizationOrganizationPrincipal InvestigatorPrincipal InvestigatorSteering Committee ChairSteering Committee ChairClinical Events CommitteeClinical Events Committee

Image Core LaboratoryImage Core LaboratoryECG Core LaboratoryECG Core LaboratoryCROCROStudy SponsorStudy Sponsor

245 (82 DRUG, 163 CRYO)245 (82 DRUG, 163 CRYO)Oct 10, 2006-June 30, 2008Oct 10, 2006-June 30, 200826 (U.S. and Canada)26 (U.S. and Canada)12 months12 months

Douglas Packer, MDDouglas Packer, MDJeremy Ruskin, MDJeremy Ruskin, MDDenis Roy, MD, Andrew Epstein, MD, Denis Roy, MD, Andrew Epstein, MD, and Alfred Buxton, MDand Alfred Buxton, MDeImageeImageAgility ResearchAgility ResearchCato ResearchCato ResearchMedtronic Cryocath LPMedtronic Cryocath LP

STOP-AF Study Hypotheses

Primary Effectiveness Hypothesis:Primary Effectiveness Hypothesis: Cryoballoon ablation would have significantly Cryoballoon ablation would have significantly

greater Treatment Success at 12 months than greater Treatment Success at 12 months than Drug therapyDrug therapy

Co-Primary Safety HypothesesCo-Primary Safety HypothesesCryoablation Major AF Event (MAFE) rate would be Cryoablation Major AF Event (MAFE) rate would be

non-inferior to DRUG, andnon-inferior to DRUG, andCryoablation Procedure Event (CPE) rate would be Cryoablation Procedure Event (CPE) rate would be

< 14.8%< 14.8%

BlankingBlankingperiod (90 day)period (90 day)Redo ablationRedo ablation

n=31n=31

Drug Drug optimizationoptimization

90 days90 days

Study Design of the STOP-AF Trial

AA RxAA Rxfailurefailuren=304n=304

RandomizedRandomized2:1 to ablation vs.2:1 to ablation vs.

Drug RxDrug Rx

ScreeningScreeningExclusionExclusion

n=46n=46

Consent withdrawal Consent withdrawal n=7n=7

Screening failureScreening failuren=6n=6

CryoballoonCryoballoonablationablationn=163n=163

Drug RxDrug Rxn=82n=82

Cross-overCross-overn=65n=65

Follow-Follow-upup

1,3,6,9, 1,3,6,9, &12 mo&12 mo

HoltersHoltersWeeklyWeeklyTTMsTTMs

Inclusions:Patients >2 AF episodes in 2 months w ECG doc. of 1Rx Failure of > 1 AA Rx

1º Study Outcome Measures• Effectiveness: freedom from CTF =Effectiveness: freedom from CTF =

No detectable AF (non-blanked period)No detectable AF (non-blanked period)No use of nonstudy drugsNo use of nonstudy drugsNo AF interventionsNo AF interventions

• SafetySafetyMAFE:MAFE: composite of disease / treatment composite of disease / treatment

SAEsSAEsCPE (Cryo) only:CPE (Cryo) only:

composite of device/procedure-composite of device/procedure-related SAEsrelated SAEs

Arctic Front CryocatheterArctic Front Cryocatheterand Ablation Methodsand Ablation Methods

Cryoballoon designCryoballoon designCryoballoon sizesCryoballoon sizes 23 and 28 mm23 and 28 mmStructureStructure Double balloonDouble balloonCooling (in balloon)Cooling (in balloon) Liquid Liquid gas gas

transitiontransitionBalloon deliveryBalloon delivery

CatheterCatheter SteerableSteerableSheathSheath 14 French14 French

deflectabledeflectableAblation Ablation PVI w / no linesPVI w / no lines

Focal CatheterFocal Catheter 99 Fr, 8mm tipFr, 8mm tip

Baseline Characteristics

* p value for comparison between DRUG and CRYO subjects* p value for comparison between DRUG and CRYO subjects

Baseline/demographicBaseline/demographic ALLALL DRUGDRUG CRYOCRYO p value*p value*Age (years)Age (years) 56.656.6 56.456.4 56.756.7 0.800.80Male (%)Male (%) 77%77% 78%78% 76%76% 0.870.87Left atrial AP diameter (mm)Left atrial AP diameter (mm) 40.540.5 40.940.9 40.340.3 0.350.35LV ejection fraction (%)LV ejection fraction (%) 60%60% 61%61% 60%60% 0.410.41

NYHANYHANone / Class I (%)None / Class I (%) 94%94% 94%94% 93%93% 1.001.00Class II (%)Class II (%) 6.5%6.5% 6.1% 6.1% 6.7% 6.7% 1.001.00

AF episodes within 2 mo (no.)AF episodes within 2 mo (no.) 23.223.2 21.221.2 24.324.3 0.540.54Previous cardioversion (%)Previous cardioversion (%) 22%22% 21%21% 23%23% 0.870.87History of atrial flutter (%)History of atrial flutter (%) 45%45% 44%44% 46%46% 0.790.79

Efficacy-failed AF drugsEfficacy-failed AF drugsFlecainide (%)Flecainide (%) 36%36% 35%35% 37%37% 0.870.87Propafenone (%)Propafenone (%) 47%47% 44%44% 49%49% 0.500.50Sotalol (%)Sotalol (%) 29%29% 31%31% 29%29% 0.880.88

CHADS2CHADS2 0.6 0.6 0.6 0.6 0.6 0.6 0.920.92Overall SF-36 (v2) scoreOverall SF-36 (v2) score 70.670.6 70.470.4 70.870.8 0.870.87

Baseline Subject-Reported ArrhythmiaBaseline Subject-Reported ArrhythmiaSymptom Prevalence in STOP-AFSymptom Prevalence in STOP-AF

0

20

40

60

80

100

Prior AFPrior AFhosphosp

DizzinessDizziness

%%

PalpitationsPalpitations RapidRapidheart beatheart beat

DyspneaDyspnea FatigueFatigue SyncopeSyncope

SubjectsSubjects All (n = 245) All (n = 245) DRUG (n = 82) DRUG (n = 82) CRYO (n = 163) CRYO (n = 163)

3636

1121123434

14142222

7878

213213 7373140140

164164 5656 108108

1411415353

8888

1891896666

123123

1212 6666

P=0.451P=0.451

P=0.415P=0.415

P=0.552P=0.552

P=0.775P=0.775P=0.132P=0.132

P=0.423P=0.423

P=0.224P=0.224

Subject-reported arrhythmia symptomsSubject-reported arrhythmia symptoms

Cryoballoon Procedural DataCryoballoon Procedural Data• Acute Procedural Success (APS) ≥ 3 PVs isolated at end of first Acute Procedural Success (APS) ≥ 3 PVs isolated at end of first

procedure procedure 98.2% 98.2% • Balloon-only per-vein APS of all attempted PVs 90.8% Balloon-only per-vein APS of all attempted PVs 90.8% • Mean durations:Mean durations:

• Procedure = Procedure = 371.0 min (200 – 650) 371.0 min (200 – 650)• Cryoablation = Cryoablation = 65.7 min (17 – 180) 65.7 min (17 – 180)• Fluoro = Fluoro = 62.8 min (8 – 229) 62.8 min (8 – 229)

• Deliveries / PV Deliveries / PV 2.9 – 3.4 2.9 – 3.4 • Cryoballoon temperatures Cryoballoon temperatures - 49ºC to - 54ºC - 49ºC to - 54ºC • Mean duration / delivery Mean duration / delivery 196 – 230 secs196 – 230 secs• Repeat cryoablation in 31 Ablation patients Repeat cryoablation in 31 Ablation patients

all with ERAF within the 90 day follow-up 19%all with ERAF within the 90 day follow-up 19%

0

20

40

60

80

100

0 100 200 300 400 500

Primary Effectiveness Analysis Treatment Success

Trea

tmen

t suc

cess

Tr

eatm

ent s

ucce

ss

(%)

(%)

DaysDays

P<0.001P<0.001

vs 7.3% (SE 2.9%)vs 7.3% (SE 2.9%)

CRYO 69.9% 114/163 CRYO 69.9% 114/163

BlankedBlanked DRUG Rx 7.3% 6/82DRUG Rx 7.3% 6/82

30 days

KM estimate 68.6% (SE 3.9%)KM estimate 68.6% (SE 3.9%)

Treatment Success By Analysis Method

0

20

40

60

80

100

On Rx

DRUGn = 82

%

CRYOn = 163

(19% redo)

p < 0.001AbsoluteAbsolute 62.6% 62.6%

n = 67.3%

n = 11469.9%

n = 94(57.7%)

NoDrug

n = 2012.3% n = 98

60.1 %

AbsoluteAbsolute 56.8% 56.8%

p < 0.001

9%

65.8%

On-TreatmentAnalysis

CRYOon / offdrug

n = 163

CRYOsingleproc

n = 163

DRUGn = 67

CRYOn = 114

Intention to TreatOn / Off

DrugSingle

Ablation

Ongoing Drug Rx in CRYO SubjectsTreatment in STOP-AF at 12 Months

Baseline 12 months

PtPt(%)(%)

Anti-arrhythmic DrugsAnti-arrhythmic Drugs WarfarinWarfarin

100100

8080

6060

4040

2020

00

100%100%

26%26%

Baseline 12 months

95%95%

24%24%

Symptom Reduction (CRYO)Symptom Reduction (CRYO)

CRYO SUBJECTS 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%

Complication Rate in STOP-AF Trial

PtPt(%)(%)

CryoablationCryoablationProcedureProcedure

EventsEvents2020

1515

1010

55

00

8.5%8.5%n=7n=7

Major AFMajor AFEventsEvents

CombinedCombinedCPE andCPE and

MAFEMAFE

AblationAblation

3.1 (6.3)%3.1 (6.3)%n=5n=5

14.8%14.8%

P<0.001P<0.001

AblationAblationn=163n=163

DrugDrugn=82n=82

3.1%3.1%n=5n=5

AblationAblationn=163n=163

DrugDrugn=82n=82

8.5%8.5%n=7n=7

6.1%6.1%n=10n=10

P<0.001P<0.001 P=0.595P=0.595

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 EventCRYO

(n = 163)DRUG(n = 82)

Stroke 4 2.5% 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%Phrenic nerve palsy 22 13.5% 6 7.3% Persistent phrenic nerve palsy 4 2.5% 0 0.0%PV stenosis 5 3.1% 2 2.4%

Pulmonary Vein Area ChangePu

lmon

ary

vein

s (n

o.)

Pulm

onar

y ve

ins

(no.

)

Cryoablated pulmonary veins, change inCryoablated pulmonary veins, change incross sectional area from baselinecross sectional area from baseline

-100%-100% -75%-75% -50%-50% -25%-25% -0%-0% +25%+25% >+100%>+100%

10, 1.1%10, 1.1% 23, 2.5%23, 2.5%

180, 19.4%180, 19.4%

433, 46.7%433, 46.7%

219, 23.6%219, 23.6%

35, 3.8%35, 3.8%

n = 927 cryoablated PVsn = 927 cryoablated PVs10 stenotic PVs in 7 pts10 stenotic PVs in 7 pts >75% area change>75% area change1 cryo abl only in 4 pts1 cryo abl only in 4 pts2 cryo abls in 2 pts2 cryo abls in 2 pts1 RF redo in 1 pt1 RF redo in 1 pt

Phrenic Nerve Paralysis in theSTOP-AF Trial in 228 Patients

0

20

40

60

80

100

ImmediateImmediatepost-procedurepost-procedure

ResolvedResolvedat 12 moat 12 mo

PersistingPersistingat 12 moat 12 mo

11.2%11.2%n=29n=29

86.2%86.2%n=25n=25

13.8%13.8%n=4n=4

28 patients1 with Sx

Limitations of theSTOP-AF Trial

• Early Cross-over to cryoballoon ablation Early Cross-over to cryoballoon ablation from Drug Rx after 14-28 daysfrom Drug Rx after 14-28 days

• Shorter concurrent drug treatment periodShorter concurrent drug treatment period

• Permitted redo ablations during blankingPermitted redo ablations during blanking

• Use of PV area vs diameter for PV Use of PV area vs diameter for PV stenosis Dxstenosis Dx

• Limited choice of antiarrhythmic drugsLimited choice of antiarrhythmic drugs

Conclusions

• Cryoballoon ablation is effective for treating Cryoballoon ablation is effective for treating recurrent drug-refractory paroxysmal AF in recurrent drug-refractory paroxysmal AF in symptomatic patientssymptomatic patients

• Balloon-only ablation is feasible in the majority of Balloon-only ablation is feasible in the majority of patientspatients

• Pulmonary vein stenosis may occur with Pulmonary vein stenosis may occur with cryoablationcryoablation

• Phrenic nerve injury occurring with cryoablation is Phrenic nerve injury occurring with cryoablation is largely reversiblelargely reversible

• The STOP-AF Trial endpoints were all reachedThe STOP-AF Trial endpoints were all reached