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Is Cryoballoon the Preferred Approach to Ablation of Paroxysmal AF?

Peter GuerraInstitut de Cardiologie de Montréal

California Heart RhythmSymposium

September 9-10, 2016

Historical Perspective (1)

• 1992 and 1993:• Dr Peter Freidman, Brigham and Women’s

Hospital –patent for steerable, flexible catheter to deliver cryotherapy

• Abstract presented at NASPE

• 1993-1997:• Research and development with Montreal

Heart Institute• CryoCath incorporates

• 1998:• First patient treated at Montreal Heart Institute

by Dr Marc Dubuc – AVN ablation

Historical Perspective (2)• 2005:

• Arctic Front receives CE mark• 12-month data from German trial

• 2006:• North American Trial (STOP-AF) begins (Oct 2006-July 2011)

• 2007:• First Canadian patient to undergo cryoballoon ablation in the STOP-AF trial at Montreal Heart

Institute

• December 2010• FDA approval of Arctic Front – commercially available in United States

• March 2011• Arctic Front becomes commercially available in Canada

According to Google Maps:Distance from MHI to Medtronic-CryoCath32 km; estimated time 32 minutes!!!

Lower Incidence of Thrombus Formation with Cryoenergy Versus Radiofrequency Catheter Ablation

5.3 mm 5.0 mm

5.7 mm 4.3 mm

Area 25 mm²

Vol 95 mm³

Area 14 mm²

Vol 49 mm³

RFRF CRYOCRYO

Incidence Of Thrombus

13%76%

Khairy et al. Circulation. 2003; 107:2045-50

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Radiofrequency CRYO

Khairy et al. Circulation. 2003; 107:2045-50

Disrupted endocardium

Thrombus

Persistent hemorrhage

+70°C • 50 W • 60 seconds

more homogeneous lesion

well demarcated border

-75°C • 1 x 4 minutes

Intact endocardium

Certain Questions…1. Is cryoenergy effective?

2. Is it safe?

3. How does it compare to RF?• Results• Speed• Flexibility

Certain Questions…1. Is cryoenergy effective?

2. Is it safe?

3. How does it compare to RF?• Results• Speed• Flexibility

• Demographics

• 1387 Patients • 109 persistent AF

• Predominantly Male (73.6%)

• Age 57.5 ± 1.9y

• Normal LVEF and LA dimension

• HTN predominant comorbidity (37.8%)

• Rare Structural heart disease (10.8%)

• Procedural Characteristics

• Procedure Time : 206.3 ± 72.2 min

• Fluoro Time : 46.0 ± 13.3 min• significantly decreased with

familiarity

• 28 mm cryoballoon in 80.1% (681/842)

• 23mm cryoballoon in 13.9% (117/842)

• Both used in 5.3% (44/842)

• 14 studies (932 patients) -combination cryoballoon and focal ablation (up to 17.1% of patients)

Efficacy and safety of cryoballoon ablation for AFA systematic review of published studies

Andrade et al, HEART RHYTHM, VOL 8, NO 9, SEPTEMBER 2011. 1444-51

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Acute Success

• Patients Isolated (n=924):• 98.81% (95% CI 97.88-99.40%)

• Veins Isolated (n=3803):• 98.47% (95% CI 98.03-98.84%)

Andrade et al, HEART RHYTHM, VOL 8, NO 9, SEPTEMBER 2011. 1444-51

Chronic Success

• 3 month blanking period• No AAD after 3 months• Multiple/Unknown Procedures

72.83% (95% CI 68.79‐76.62%)

Andrade et al, HEART RHYTHM, VOL 8, NO 9, SEPTEMBER 2011. 1444-51

Chronic Success – Persistent AF

• 45.16% (95% CI 32.48‐58.32%)• No AAD After 3 months• Allowed Freezor spot ablation

Cryoballoon PVI + CFE + Lines86.4% AF‐free without AADat a mean of 6 months.

Mansour et al. Heart Rhythm 2010;7:452– 458

12 mo Clinical Outcomes Following PV Isolation using 2nd Gen Cryoballoon:

Results of StopAF PAS• prospective, multi-center, non-randomized, single arm,

unblinded study designed to assess long-term safety & effectiveness of the Arctic Front (Medtronic, Inc.; Minneapolis, MN)

• drug-refractory, recurrent symptomatic paroxysmal AF

• 39 study sites (US and Canada) including recent adopters of cryoballoon ablation.

Inclusion Criteria Abbreviated Exclusion Criteria

• Documented paroxysmal AF: • Any previous left atrial ablation or surgery

Diagnosis of paroxysmal atrial fibrillation AND • Pre‐existing hemidiaphragmatic paralysis ≥ 2 episodes of AF in past 3 months, AND • LA diameter > 5.5cm by TTE

≥ 1 episode of documented AF in past 12 months • Stroke within past 6 months

• Age ≥ 18 years • NYHA class III or IV congestive heart failure

• Failure of at least one membrane active AAD • Presence of pacemaker or defibrillator

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Second Generation Catheter• Iterative evolution • ↑ number of jets (4->8)• ↑ refrigerant flow (28mm)• More distal jet position

• Results in:• More uniform cooling• Wider distal cooling zone

Arctic Front Advance Arctic Front

Evidence for the AF Advance

• 345 patients met all inclusion/exclusion criteria• mean follow-up of 588 ± 241 days• PV isolation was achieved in 99.7% of patients.• 89% were treated with the 28mm CB2 exclusively.

Adverse Events

Major Events Patients(n=345)Procedures

(n=353)

PNI Unresolved at Discharge 11 (3.2%) 11 (3.1%)

Transient Ischemic Attack 1 (0.3%) 1 (0.3%)

Pericardial Effusion 3 (0.9%) 3 (0.8%)

Hemoptysis 3 (0.9 %) 3 (0.8%)

PV Stenosis 2 (0.6%) 2 (0.6%)

Atrial-esophageal fistula 0 (0.0%) 0 (0.0%)

Death 0 (0.0%) 0 (0.0%)

Total 20 (5.8%) 20 (5.7%)

All PNI was resolved by 24 months.

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Certain Questions…1. Is cryoenergy effective?

2. Is it safe?

3. How does it compare to RF?• Results• Speed• Flexibility

Updated Worldwide Survey on the Methods, Efficacy, & Safety of Catheter Ablation for Human Atrial Fibrillation

≈1%

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.

Phrenic Nerve Palsy (PNP)

• Distal ablation

• Closer proximity to the PN• courses near RSPV orifice

• Deeper freezing temperatures• less convective heating of

the balloon by atrial blood flow

• Increased speed of ice growth (inversely related to the tissue thickness and temperature gradient)

• Impingement of PN• i.e. Oversized balloons

(28mm)

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Phrenic Nerve Injury - CMAP

Franceschi et al Heart Rhythm 2011 (In Press)Heart Rhythm. 2011 Jun;8(6):885-91Heart Rhythm. 2011 Jul;8(7):1068-71

CMAP Monitoring

CMAP

CMAP Monitoring

CMAP amplitude Safety Margin (-30%)

Clinical experience with a novel electromyographic approach to preventing phrenic nerve injury during cryoballoon ablation in atrial

fibrillation.Circ Arrhythm Electrophysiol. 2014 Aug;7(4):605-11

Mondésert B et al.

• 200 consecutives cases• CMAP monitoring during right-sided veins ablation

• Cryoapplication aborted if perceived decreased diaphragmatic motion or CMAP amplitude decreased by ≥ 30 %

• CMAP reduction (≥30%) occured in 49 pts (24.5%)• 82% occured during RSVP isolation

• Diapragmatic motion reduction in 30/49 pts preceded by CMAP in all.

• Persistent phrenic nerve palsy in 3/200pts (1.5%) and they all recovered within 6 months

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Certain Questions…1. Is cryoenergy effective?

2. Is it safe?

3. How does it compare to RF?• Results• Speed• Flexibility

AF Ablation: Technique and Energy Sources

Radiofrequency Ablation Multiple focal lesions

Time consuming?

3D mapping needed

Cryoablation Single circumferential lesion

Performed quickly?

No 3D mapping needed

Inner Balloon

Outer Balloon

Guide Wire Lumen Thermocouple

Injection Tube

Marker Band

Deflection Wires

Guide Wire

Technique for Cryoablation

• Different setup: • Need to prepare for contrast injection, manifold

• Single transseptal when using Achieve (Medtronic) catheter for mapping

• No 3D Mapping system

Image from CathLab DigestGinapp, Volume 20 - Issue 9 - September 2012

FIRE AND ICE TRIALObjectives and Hypothesis

• Compare the safety and efficacy of PVI by either:– Cryoablation (Arctic Front™ / Arctic Front Advance™ catheters) guided by fluoroscopy OR– RFC ablation (THERMOCOOL® / THERMOCOOL® SF / THERMOCOOL®

SMARTTOUCH® catheters) guided by CARTO® 3D mapping system

• Primary Efficacy Endpoint: Time to first documented recurrence of AF>30s/AT/AFL, prescription of AAD, or re-ablation

Analysis Methods: Non-inferiority log-rank test– Assumed event-free 1 year survival rates of 70% with 10% non-inferiority margin corresponding to

HR=1.43

• Primary Safety Endpoint: Time to first all-cause death, all-cause stroke/TIA or treatment-related serious AEs (e.g. phrenic nerve injury, atrioesophageal fistula, etc.)

28Kuck K-H, et al. Cryoballoon or Radiofrequency Ablation of Paroxysmal Atrial Fibrillation. The New England Journal of Medicine. Epub ahead of print (NEJM 16-02014).

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Patient Flow Chart

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FIRE ICE

ITT = Intention to treat

Kuck K-H, et al. Cryoballoon or Radiofrequency Ablation of Paroxysmal Atrial Fibrillation. The New England Journal of Medicine. Epub ahead of print (NEJM 16-02014).

Primary Efficacy Endpoint Met

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Modified ITT analysis Non-inferiority hypothesis met HR [95% CI] = 0.96 [0.76-1.22]; p

= 0.0004 Superiority test: p = 0.74

Kuck K-H, et al. Cryoballoon or Radiofrequency Ablation of Paroxysmal Atrial Fibrillation. The New England Journal of Medicine. Epub ahead of print (NEJM 16-02014).

Key Treatment-Related Serious Adverse Events

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Event (N, %) RFC(n=376)Cryoballoon

(n=374)

Groin Site Complication* 16 (4.3%) 7 (1.9%)

Atrial Flutter/Atrial Tachycardia** 10 (2.7%) 3 (0.8%)

Phrenic Nerve Injury unresolved at discharge 0 (0%) 10 (2.7%)***

Unresolved at 3 months 0 (0%) 2 (0.5%)

Unresolved at > 12 months 0 (0%) 1 (0.3%)

Cardiac Tamponade/Pericardial Effusion 5 (1.3%) 1 (0.3%)

Stroke/TIA 2 (0.5%) 2 (0.5%)

Atrial Septal Defect 1 (0.3%) 0 (0%)

Esophageal Ulcer 0 (0%) 1 (0.3%)

Pericarditis 0 (0%) 1 (0.3%)

Atrioesophageal Fistula 0 (0%) 0 (0%)

Pulmonary Vein Stenosis 0 (0%) 0 (0%)

* Includes vascular pseudoaneurysm, AV fistula, device-related infection, hematoma, puncture site hemorrhage, groin pain ** Serious (e.g. hospitalization) and causally related to the therapeutic intervention (e.g. ablation-induced or drug-induced)*** 8 resolved by 3 month visit, 1 resolved by 6 months visit, 1 unresolved after 12 month visit

Kuck K-H, et al. Cryoballoon or Radiofrequency Ablation of Paroxysmal Atrial Fibrillation. The New England Journal of Medicine. Epub ahead of print (NEJM 16-02014).

Procedural Characteristics

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Time Measurement (minutes)

RFC (n=376)

Cryoballoon (n=374) P-value

**

Procedure Time*** 140.9 ± 54.9 124.4 ± 39.0

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First vs. Second Generation Balloon

0

20

40

60

80

100

120

140

Time to isolation Procedure Fluoroscopy

CB1GCB2G

P

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Conclusions• Advantages of cryoablation for AF:

• Proven non-thrombogenicity• Catheter adhesion and stability• Connective tissue matrix left intact – no burning, charring or steam pops

• Potentially reducing risk of PV stenosis or esophageal damage• ? Potentially faster (shorter application times) and ”cleaner” for simple PVI

• Balloon catheter design well-adapted for ablating PVs

• Limitations of cryoablation for AF:• increased incidence of phrenic nerve palsy but seems to recover in most

cases• Larger balloon size and following diaphragmatic AP reduces this risk• ? Utility in more persistent AF

• Large world-wide experience, more than 10 years of utilization!