1. 11 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

2. 22 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 failure 4 Increases US healthcare system costs: $12 billion estimated cost to treat AF 5 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.

3. Thoracic vein and atrial pathogenesis of AF Extension of muscular fibers into pulmonary vein (PV) Ganglia noted in yellow Large and small reentrant wavelets that play a role in initiating and sustaining AF Common locations of PV (purple) and common sites of origin of non-PV triggers (black) Composite of anatomic and arrhythmic mechanisms of AF Calkins et al. Heart Rhythm. 2007;4:1-46. LSPV LIPV RSPV IVC RIPV SVC LSPV LIPV RSPV IVC SVC LSPV LIPV RSPV IVC RIPV SVC LSPV LIPV RSPV IVC RIPV SVC RIPV

4. 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

5. Patient Selection for Ablation More Optimal PatientLess Optimal Patient Variable SymptomsHighly symptomaticMinimally symptomatic Class I and III drugs failed 11 0 AF typeParoxysmalLong-standing persistant AgeYounger (<70 years) Older (  70 years) LA sizeSmaller (<5.0 cm) Larger (  5.0 cm) Ejection fractionNormalReduced Congestive heart failureNoYes Other cardiac diseaseNoYes Pulmonary diseaseNoYes Sleep apneaNoYes ObesityNoYes Prior stroke/TIANoYes Courtesy of Hugh Calkins, MD.

6. 66 Pulmonary Vein Isolation (PVI) is the Cornerstone of AF Ablation “Ablation strategies which target the PVs and/or PV antrum are the cornerstone for most AF ablation procedures.” Cappato et al., Circ Arrhythm Electrophysiol 2010;3;32-38 http://www.HRSonline.org/Policy/ClinicalGuidelines Isolate each PV independently 2007 HRS Consensus Statement Complete electrical isolation should be the goal for targeted PVs and entrance and/or exit block should be demonstrated Left Superior Pulmonary Vein Left Inferior Pulmonary Vein Right Inferior Pulmonary Vein Right Superior Pulmonary Vein Superior Vena Cava Inferior Vena Cava

7. Controlled Trials of AF Ablation Patients Free of AF (% at 1 Year) Courtesy of Jeremy N. Ruskin, MD, Massachusetts General Hospital. Percent

8. 88 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

9. 99 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 Clinical Issues with Conventional RF Focal Ablation Catheter Cappato R, et al. Circulation. 2005;111:1100-1105.

10. 10 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.

11. Arctic Front ® Catheter Design Pressurized N 2 O delivered through ultrafine injection tube Straightforward positioning: over-the-wire, steerable, good visibility Several safety mechanisms: double balloon, pressure and flow monitoring, blood detection Arctic Front Catheter Balloon Segment Inner Balloon Outer Balloon Guide Wire Lumen Thermocouple Injection Tube Marker Band Deflection Wires Guide Wire

12. 12 Hypothermia Ice formation and thawing Apoptosis Necrosis Cryoablation Effects Include Multiple Mechanisms Baust, Institute of Biomedical Technology, SUNY 2002

13. 13 Histological Effect on the Connective Tissue Matrix Cryoadhesion improves contact and stability, minimizing the amount of fluoro used Preserves the extracellular matrix and endothelial integrity 1 Decreases risk of thrombus formation 1 Demonstrates well demarcated lesions 1 1 Sarabanda AV, et al. J Am Coll Cardiol. 2005;46:1902-1912.

14. 14 Properties of Cryoablation Removes heat from the tissue Leads with a wave of hypothermia Ablates at the point of balloon contact Hypothermic Zone Ablation Zone (sub-zero)

15. 15 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

16. 16 How Arctic Front ® Balloon Catheter and Achieve TM Work 1. Access targeted vein 2. Inflate and position 3. Occlude and ablate 4. Assess PVI 16

17. 17 Standardized Procedure Does Not Require Complex 3D Mapping Arctic Front ® Cryoballoon Fluoroscopy image during contrast dye injection shows full occlusion of the left superior pulmonary vein. Arctic Front 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 Arctic Front guide wire lumen, minimizing catheter exchanges Allows the procedure to be performed using a single transseptal puncture Achieve™ Mapping Catheter 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 Entire procedure can be done using fluoroscopy or intracardiac echocardiography

18. 18 Assessment of Real-Time PV Isolation Achieve™ mapping catheter allows for real-time assessment of PV isolation during cryoablation with Arctic Front ® Images: Courtesy of Dr. Schwagten, ZNA Middelheim, Belgium (above) and Dr. Vogt, Herz- und Diabeteszentrum NRW, Germany (right) DelayIncreased Delay Isolation Arctic Front is positioned against the LIPV ostium, with Achieve positioned to assess PV isolation 18

19. 19

20. 20 European Clinical Study Results Symptomatic Drug Refractory PAF Efficacy Results EfficacyNeumannVan BelleKojodjojo PVI 97% Arctic Front ® 98.5% Arctic Front83% 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 59% freedom from AF off AAD at one year with Arctic Front 77% off AAD in most patients at 13 months with Arctic Front 72% off AAD in most patients at 13 months with RF ablation 7-day Holter ECG at 3m intervals 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

21. 21 European Clinical Study Results Arctic Front ® Safety Results NeumannVan BelleKojodjojo 7.5% Phrenic nerve palsy (PNP)*; all recovered at < 1 year (26/346) No PV stenosis No atrioesphageal fistula, stroke, death, or other peri-procedural complications * Primarily in 23 mm balloon 2.8% asymptomatic PNP*; all resolved within 6 months (4/141) 1.4% arteriovenous fistula (2/141) 0.7% left atrial flutter successfully ablated (1/141) No PV stenosis 0.8% pericardial effusion (1/124) 1.6% transient PNP (2/124)

22. 22 Shorter Procedures Demonstrated with Experienced European Users Data from 9 German Centers: Arctic Front ® is 33% faster than point-by- point catheter systems with a 24% reduction in fluoro time. Medtronic data on file. 300 250 200 150 100 50 0 Minutes Lab Occupancy Time Primary Physician Time Fluoroscopy Time -33% -24% Point-by-Point with 3D Mapping Arctic Front

23. 23 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

24. 24 Complications – Meta Analysis Outcomen/N% Phrenic Nerve Palsy (PNP) Any reported PNP PNP persisting post-procedure PNP persisting > 1 year 86/1,349 67/1,349 5/1,349 6.38% 4.73% 0.37% Pulmonary Vein Stenosis (PVS) Any PVS (per patient) PVS requiring intervention 7/773 2/1,163 0.90%* 0.17% Periprocedure events Stroke or TIA Myocardial infarction LA ‐ esophageal fistula Esophageal ulceration Pericardial effusion or tamponade Cardiac tamponade Pulmonary artery rupture 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 24 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.

25. 25 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 long- term 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

26. 26 Blanking period (90 day) 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%) * CRYO: Arctic Front ® System 26 centers in US and Canada AAD optimization DRUG Crossover n = 65 (79%) Cryoballoon ablation (CRYO) n = 163 AAD Rx (DRUG) n = 82 Follow-up at 1, 3, 6, 9 & 12 Months N = 245 Randomized 2:1 to CRYO* or DRUG

27. 27 Treatment Success Effectiveness Results Freedom from AF after 90 Days Blanked for Detectable AF CRYO 69.9% (114 / 163) DRUG 7.3% (6 / 82) OR = 29.5 (12.0 – 72.2) p < 0.001 Blanked for Detectable AF

28. 28 CRYO Procedure Experience Impacts Treatment Success 25 centers n=43 P < 0.001 by quartile (Wald) OR = 1.14 for each procedure 14 centers n=38 10 centers n=42 4 centers n=40 1 st and 2 nd procedures 3 rd – 5 th procedures 6 th – 11 th procedures 12 th – 23 rd procedures 100% 80% 60% 40% 20% 0% Treatment Success 56% 66% 69% 90%

29. 29 Device Related and Procedure Related Serious Adverse Events with Increasing Experience *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) Kowal, et al. in preparation. DR/PR SAE [n (%)] Procedure Sequence by Quartile 1 st and 2 nd 25 centers, n=43 3 rd – 5 th 14 centers, n=38 6 th – 11 th 10 centers, n=42 12 th – 23 rd 4 centers, n=40 Serious Adverse Events* (Initial and Repeat Abls.) 3 (7.0%)3 (7.9%) 4 (9.5%) 0 (0.0%) Serious Adverse Events** (Initial Procedure Only) 3 (7.0%)2 (5.3%)3 (7.1%)0 (0.0%) Serious Adverse Events within 30 days of procedure*** (Initial Procedure Only) 2 (4.7%)1 (2.6%)2 (4.8%)0 (0.0%)

30. 30 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

31. 31 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

32. 32 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

33. 33 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.