EP Guided Therapy For Atrial Fibrillation

EP Guided Therapy For Atrial Fibrillation Ali Al Mudamgha, MD, FACC, FHRS Cardiac Electrophysiology And Arrhythmia Service St. Joseph s Hospital Syracuse, NY

Disclosures Medtronic Advisory Board Afib Physician Educator, St. Jude Medical Physician Trainer and Proctor Spectranetics Corp. Consultant EP Division BSX Medical

AFIB Misconceptions Classically Felt to Be a Benign Dysrhythmia Increased Mortality Symptoms from Loss of Atrial Kick Many Variables Minimum Will Complain of Palpitations Most Complain of SOB, DOE and Poor Exercise Tolerance

Demographic Profile 26% of Men and 28% of Women After Age 40 HTN Obesity Endurance Exercise Sleep Apnea Thyroid Disease ETOH

Demographics Age Is Most Powerful Risk Factor Rare Prior to Age 50 10% Of All Individuals Older Than 80 40% Increased Risk Of AFIB If Have A First Degree Relative

Demographics 33 Million People Worldwide Have AFIB 3 5 Million In USA AFIB Increases Risk Of Stroke By 5 Fold Average Increased Risk Of SCD Increase Risk Of CHF Increase Risk Of Dementia

Demographics Increased Fatigue Decreased Exercise Tolerance Impairment in Quality Of Life Prognosis Is Similar For Symptomatic vs. Asymptomatic Individuals 26 Billion Dollar Annual Increase in US Health Costs

Treatment Of AFIB Ideal Therapy Should Abolition of Atrial Fibrillation Restoration of SR Reestablish or Maintain AV Synchrony Restore Atrial Transport Reduce or Eliminate Risk of Thromboembolism

Medical Therapy Maintenance of SR with Antiarrhythmic Drugs to Reduce CVA or Death is Unproven No Arrhythmia Can Be 100% Suppressed with an Antiarrhythmic Drug Goal of Therapy is Reduction of Symptoms by Decreasing Recurrence and Prolonging Time Between Episodes Mortality Increases with Drug 0.8% to 2.9%

Medical Therapy High Recurrence Rate HTN Enlarged LA CHF AFIB for 1 Year or Longer 23% Remain in SR After 1 Year 16% Remain in SR After 2 Years Significant Side Effects Worsening CHF Bradycardia ProArrhythmia Aggravation of Atrial Function Leading to Thromboembolism

Non Drug Therapy Ablate and Pace Ablation of AV Node Leading to CHB Need Rate Responsive Pacemaker Patient Must Remain on Coumadin Most Patients Have Improvement in Symptoms, QOL, and Exercise Tolerance Initial Increase in Torsade from Bradycardia (corrected by pacing @ 90 bpm for 2 weeks) We Lose to AFIB

AFFIRM NIH Sponsored Trial 4060 Patients 65 y.o. Randomized Rate Control Dig, Beta Blockers, Calcium Blockers 80 bpm@ Rest and 110 bpm@ 6 minute walk 5% Needed Complete AV Node Ablation Rhythm Control Most Effective Drug After 3.5 years 63% of Patients had tried Amio

AFFIRM Results 80% Had Adequate Rate Control 62% Maintained SR After 5 Years No Difference in Mortality, CVA, or QOL Increased Mortality Trend in Rhythm Arm

AFFIRM Strengths Confirmed That Use of Antiarrhythmic Drugs Was Not Beneficial Limitations Maintenance of SR Difficult Did Not Have Ablate and Pace Arm Did Not Have Surgical/Ablation Arm

EP Guided Therapy Catheter Based Therapy To Treat AFIB Goal Is Restoration Of SR Ablation Means To Destroy Electrical Tissue With A Catheter RF Energy Cryo What Should We Ablate?

Left Atrium Jäis 1997 First to Show Cure of Afib with Focal Ablation 9 Patients High Rate of Recurrence and PV Stenosis Pappone Circumferential Ablation 80 91% Effective No PV Stenosis Difficult Procedure Pulmonary Vein Triggers Up to 94% in Many Series LSPV RSPV LIPV RIPV

Pulmonary Veins Four Distinct Veins 60% Most Common Variant Is Left Common PV Sleeves Of Cardiac Tissue Extend Onto The PV s PV s Have Shorter APD Compared To Atrium PV Fiber Orientation Promote Reentry Autonomic Nerve Bundles At PV LA Junction

Ablation Of Pulmonary Veins Studies Are Clear The PV s Need To Always Be Targeted 70 80% Freedom From AFIB High Recurrence Rate 30% Need Procedure Done Multiple Times Shifting Pendulum Linear Lesions MAZE Non PV Triggers FIRM

Technologies RF Most Common For All Ablations Found In Every EP Lab Easier To Use For PV Variant Different Complications CRYO Newer Technology Not Available In Every Center Isolates Vein As A Whole Different Complications

How the Arctic Front Advance Cardiac CryoAblation System Works 1. Liquid N 2 O is delivered from the CryoConsole through an injection tube to the inner balloon. 4. The CryoConsole controls safe delivery of N 2 O to the catheter and return of the vapor. Numerous safety systems mitigate potential hazards. 2. Inside the balloon the liquid N 2 O vaporizes and absorbs heat from the surrounding tissue. 3. The vapor is returned to the console through a lumen maintained under vacuum.

First Generation Cryoballoon Outcomes: STOP AF Primary Effectiveness 69.9% freedom from AF at 12 months 3.1% rate of cryoablation procedure events and 3.1% major AF events in ablation arm 19.0% (31/163) repeat ablation rate during the 90 day blanking period N=245: Patients Randomized N=163: Patients Randomized to Cryoablation N= 82: Patients Randomized to AADs Packer, et al. Cryoballoon Ablation of Pulmonary Veins for Paroxysmal Atrial Fibrillation: First Results of the North American Arctic Front (STOP AF) Pivotal Trial. J Am Coll Cardiol. April 23, 2013;61(16):1713-1723. 22

Second Generation Arctic Front Advance Cryoballoon: STOP AF Post Approval Study Results 82.2% freedom from AF at 12 months, 75.3% from AF at 24 months (n=344) 5.8% (20/344) adverse event rate 3.2% (11/344) PNI unresolved at hospital discharge, 0.3% (1/344) ongoing 24 months post ablation Knight BP, et al. Second-generation Cryoballoon Ablation in Paroxysmal Atrial Fibrillation Patients: 24-month safety and efficacy from the STOP AF Post-Approval Study. Presented at HRS 2017 (Moderated Poster). 23

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%) N = 245 Randomized 2:1 to CRYO* or DRUG Cryoballoon ablation (CRYO) n = 163 Blanking period (90 day) Follow-up at 1, 3, 6, 9 & 12 Months 26 centers in US and Canada AAD Rx (DRUG) n = 82 AAD optimization * CRYO: Arctic Front System Packer DL, Kowal RC, Wheelan KR, et al. Cryoballoon Ablation of Pulmonary Veins for Paroxysmal Atrial Fibrillation: First Results of the North American Arctic Front (STOP AF) Pivotal Trial. J Am Coll Cardiol. April 23, 2013;61(16):1713-1723. DRUG Crossover n = 65 (79%)

CRYO Safety Information STOP AF met primary safety endpoint No atrio esophageal fistula 1/228 stroke (0.4% CRYO patients) related to procedure/device 7/228 (3.1% CRYO patients) pulmonary vein stenosis 29/259 (11.2% CRYO procedures includes DRUG crossovers) phrenic nerve palsy (PNP)

FIRE AND ICE Trial Primary Endpoints Cryoballoon Met Non inferiority Efficacy Endpoint TRIAL DESIGN & METHODS (NCT01490814) Prospective, 1:1 randomized, non inferiority study (762 patients from 16 sites in 8 countries) compared efficacy and safety of PVI using Cryoballoon vs. Radiofrequency (RFC) ablation with CARTO 3D mapping system in patients with PAF. Primary Efficacy Endpoint: Time to first documented recurrence of AF>30s/AT/AFL, prescription of AAD, or repeat ablation. Kuck KH, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016; 374(23): 2235 45. 26

FIRE AND ICE Trial Secondary Analyses Significant Improvements Favoring Cryoballoon European Heart Journal The authors stated, "The extent of reduction in reinterventions and rehospitalizations is not only statistically significant but also clinically relevant. Our presented data are the main events that define the patients perception regarding the procedural success of an AF ablation procedure." Relative to Radiofrequency Cryoballoon Demonstrated: 21% Fewer all cause hospitalizations 33% Fewer Repeat ablations 34% Fewer Cardiovascular hospitalizations 50% Fewer DC cardioversions

Cryoballoon vs. Radiofrequency Ablation Meta Analysis Demonstrates Reproducibility of Cryoballoon Ablation 40 Studies Including 11,395 Patients Cryoballoon Demonstrated: Lower Risk of AF Recurrence Reduced Procedure Time No difference in major complication rates Arctic Front vs. AFA Both associated with reduced procedure times vs. radiofrequency Lower AF recurrence rate vs. radiofrequency with AFA but not Arctic Front Reduced rate of major complications with AFA vs. Arctic Front Forest plots of AF recurrence for cryoballoon ablation versus radiofrequency ablation: (A) CB 1 versus RFCA; (B) CB 2 versus RFCA; (C) CB 1 versus MTCA. AF = atrial fibrillation; CB = cryoballoon; MTCA = multiparty catheter; Liu, et al. Pacing Clin Electrophysiol. 2016 May 16. doi: 10.1111/pace.12889. Epub RFCA = irrigated tip radiofrequency catheter. 28

Retrospective Multi Center Analysis Demonstrates Cryoballoon Reproducibility Compared to Radiofrequency Cryoballoon ablation resulted in better midterm efficacy vs. RF ablation at a median follow up of 14 months (p < 0.001) Cryoballoon Ablation * Radiofrequency Ablation Major complications with significant differences: Pericardial effusion (1.7% RF vs. 0.3% Cryoballoon; p=0.036) PNI (0.0% RF vs. 1.8% Cryoballoon; p=0.004). Mean procedure time: 136±57min for RF and 120±36min for Cryo (p <0.001) Mean fluoroscopy time: 21±13min for RF and 23±9min for Cryo (p=0.073). AF ablation procedure caseload was heterogeneous: A and B <100 AF ablations/year C and D 100 150 AF ablations/year E >200 AF ablations/year F 500 AF ablations/year *Cryoballoon ablation procedures were performed with the first generation Arctic Front catheter and Flexcath steerable sheath. Radiofrequency group, WACA was performed using either a 3.5 or a 4 mm tip irrigated catheter guided by 3D mapping and navigation. The contact sensing catheters were used on 100/467 (21.4%) patients. Providencia et al. Europace. 2016. pii: euw080. [Epub ahead of print]; French AF (NCT01918670) 29

PV Lesion Durability with Radiofrequency and Cryoballoon Studies Evaluating PV Reconduction after the Index Procedure % of Patients without Gaps During Remapping Procedure 100% 80% 60% RF RF: Contact Sensing Arctic Front Cryoballoon 63% Arctic Front Advance Cryoballoon 67% 78% 40% 20% 30% 23% 8% 35% 0% 1 2 3 4 GAP AF Willems Jiang EFFICAS I EFFICAS II* Ahmed SUPIR 5 6 7 Patients (n) n=117 n=40 n=75 n=75 n=24 n=12 n=21 Follow up** 3 Months 3 Months 12 Months 3 Months 3 Months 3 Months 3 Months * Calculated rate from manuscript data reporting 9/24 patients with gaps. **Time between index procedure and re mapping procedure. All patients were evaluated regardless of clinical symptoms 1 Late Breaking Clinical Trials session I at the EHRA EUROPACE 2013 meeting in Athens, Greece; 2 Williems, et al. J Cardiovasc Electrophysiol. 2010; 21(10):1079 84; 3 Jiang, et al. Heart Rhythm. 2014;11(6):969 76; 4 Neuzil, et al. Circ Arrhythm Electrophysiol. (2):327 33; 5 Kautzner, et al. Europace. 2015; 2015 Aug;17(8):1229 35; 6 Ahmed, et al. J Cardiovasc Electrophysiol. 2010;21(7):731 7; 7 Reddy, et al. J Cardiovasc Electrophysiol. 2015 May;26(5):493 500 30

Redo with Cryoballoon after index RF De Regibus, et al: 47 patients with PAF underwent CBA after AF recurrence with past RF index procedure Mean f/u of 15±8 months after 3 mo blanking period 83% patients free from any atrial tachycardia or AF De Regibus, et al. Repeat procedures using the second generation cryoballoon for recurrence of atrial fibrillation after initial ablation with conventional radiofrequency. J Interv Card Electrophysiol. 2017 Feb. [Epub ahead of print] 31

Arctic Front Advance Success Among Different Age Groups Abugattas, et al.: 53 patients 75+ years old with drug refractory PAF 106 patients <75 years old with drug refractory PAF 12 month follow up Success rate 81.1% (75+) vs 84.9% (<75) (p=0.54) Pott, et al: 40 patients (mean age 78.3) 77.5% PAF 12 month follow up Success rate 86.4% Moran, et al: 57 patients <40 years old Median follow up 18 ±10 months Freedom from AF 88% 1. Abugattas, et al. Europace. 2017 Apr 10. [Epub ahead of print]. 2. Pott, et al. J Cardiol. 2017 Jan;69(1):24 29. 3. Moran, et al. Europace. 2017 Jan 25. [Epub ahead of print]. 32

Single Procedure Freedom from AF, AT and AFL Arctic Front Advance Cryoballoon Single Center Published Studies Arctic Front Cryoballoon Arctic Front Advance Cryoballoon 100% 91% 90% 80% 84% 84% 82% 81% p=0.038 p=0.008 p=ns 66% 64% p=0.012 69% P<0.001 64% 80% 83% 82% 85% 85% 80% 80% 82% 60% 40% 20% 0% Di Giovanni (n=100) Fürnkranz (n=105) Aryana (n=340) Aytemir (n=306) Greiss (n=376) Metzner (n=49) Chierchia (n=42) Chierchia (n=287) Kumar (n=40) Jourda (n=75) Ciconte (n=143) Tebbenjohanns (n=192) Wissner (n=45) Arrhythmia Monitoring Methods and Definition of Procedure Success (Freedom from AF Only or AF/AT/AFL) Varied Between Studies Di Giovanni, et al. J Cardiovasc Electrophysiol. 2014; 25(8):834-9; Fürnkranz, et al. Journal of Cardiovascular Electrophysiology. 2014 ;25(8):840-4; Aryana, et al. J Interv Card Electrophysiol. 2014;41(2):177-186; Aytemir, et al. Europace. 2015;17(3):379-87; Greiss, et al. PACE. 2015 Jul;38(7):815-24; Metzner, et al. Circ Arrhythm Electrophysiol. 2014; 7(2):288-292; Chierchia, et al. Europace. 2014; 16(5):639-644; Chierchia, et al. J Cardiovasc Electrophysiol. 2015; In Press; 16(5):639-644; Kumar et al. J Interv Card Electrophysiol. 2014;41(1):91-7; Jourda, et al. Europace. 2015;17(2):225-31; Ciconte, et al. Heart Rhythm. 2015;12(4):673-80; Tebbenjohanns, et al. Europace. 2015; Wissner, et al. Europace. 2015 Aug;17(8):1236-40; 33

Multicenter Comparison: Arctic Front Advance vs. Conventional RF 1,196 Procedures Retrospectively Analyzed 773 AFA Patients and 423 RF Patients 100% Freedom From AF/AFL/AT Recurrence At 12 Months CB2 (n=773) RF (n=423) P value 80% 76.6% p<0.001 Procedure Time 145±49 188±42 p<0.001 Fluoro Time 29±13 23±14 p<0.001 Adverse Events 1.6% 2.6% p=0.207 AAD Use 16.7% 22% P=0.024 Repeat Procedures 14.6% 24.1% p<0.001 60% 40% 20% 60.4% 0% Arctic Front Advance Conventional Catheter Aryana, et al. J Cardiovasc Electrophysiol. 2015 Aug;26(8):832 9 34

Wide Antral Balloon Ablation with Arctic Front Advance Cryoballoon Post Procedure Voltage Maps Patients 43 Balloon and Application Time Extent of posterior wall ablation 6 month Freedom from AF CB2 28 mm 3 min 73% 95% Kenigsberg, et al. Heart Rhythm. 2014; 12(2):283 90. 35

Designed to ablate a broader range of pulmonary vein anatomies Arctic Front Cryoballoon Arctic Front Advance Cryoballoon In Arctic Front Cryoballoon, the most concentrated cooling zone occurs near the equator of the balloon. Aligning the balloon coaxially with the PV may be an important factor, but may be difficult in some vein anatomies. Arctic Front Advance Cryoballoon with EvenCool Cryo Technology is designed to allow more flexibility in balloon positioning to ablate the PVs. 36

Cryo Ablation Arctic Front Cryoballoon Achieve Mapping Catheter The cryoballoon creates circumferential lesions, 1 using 2-3 applications per vein to achieve PVI 2 Does not require 3D mapping Achieve Mapping Catheter can be deployed through the cryoballoon 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. 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.

Adverse Event Details * 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 KH, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016; 374(23): 2235 45. 38

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

PROTOCOL AT ST. JOSEPH S MRI OR CT TO DEFINE PV S Anticoagulation Coumadin 4 Days Prior With Single Dose Arixtra NOAC The Night Before TEE R/O LAA CLOT On Day Of Procedure GETA Access Via Right Femoral Vein Catheter Advanced Into Right Atrium Transeptal Performed Heparin Given Ablation Performed

PROTOCOL AT ST. JOSEPH S Discharged Same Day Anticoagulation All Started Night Of Procedure. Everyone Needs Regardless Of CHADS2 VaSC Coumadin Doubled With Single Dose Arixtra Continue 3 Months Regardless Of CHADS2 VaSC Pre Procedure Antiarrhythmic Drugs Blanking Period NO IMPROVEMENT IN FIRST 3 MONTHS!!!!!!!!

Post Ablation Protocol Holter At 1 and 3 Months Cardiovert And Start AAD After 4 Weeks If Needed SOB First Few Days: R/O Pericardial Effusion Late: Consider Phrenic Nerve Injury GI Symptoms Very Common Early: Consider PPI etc After 2 Weeks Consider Atrio Esophageal Fistula EGD Or CT

Post Ablation Protocol After 3 Months Anticoagulate Based On CHADS2 VaSC Stop Meds If No AFIB Consider Second Ablation If Symptomatic After 6 9 Months

Conclusions AFIB Is A Hemorrhoid For Electrophysiologists Look For Symptoms Beyond Palpitations No Benefit In Restoring SR Unless Symptoms Ablation Is Superior To Meds Consider Ablation In All Symptomatic Individuals Ablate and PACE Excellent Results Chronic AFIB Low Ablation Success Rate Patients