A Cryo Anatomical Procedure to Everyone? Saverio Iacopino, FACC, FESC

A Cryo Anatomical Procedure to Everyone? Saverio Iacopino, FACC, FESC

AF Clinical/Referral Challenge Asymptomatic 40% 3 Rx Effective 30% Failed Rx Ablation Atrial fibrillation (AF) is the most common Candidate arrhythmia with prevalence > 33 million 30% 1 2 Catheter ablation is a Class I Level A recommendation for treatment of symptomatic paroxysmal AF (PAF) refractory or intolerant to 1 Class I or III antiarrhythmic drug (AAD) 4 1. Rahman, et al. Nat. Rev. Cardiol. 2014; 11: 639 654 2. Wyse, et al. Circ. 1996; 93:1262-1277 3. Savelieva, et al. Pace. 2000; 23: 145-148 4. Calkins, H., et al. Heart Rhythm. 2012; 9(4): p. 632-696.e20 5. Raviele et al. J Cardiovasc Electrophysiol, 2012;23:890-923 Pulmonary vein isolation (PVI) is the cornerstone of AF ablation strategy 5

VP: predominant seat of the " triggers" (AF TRIGGER) VP: arrhythmogenic substrate (MAINTENANCE of AF) Role of the VP Paroxistical Persistent Permanent Role of atrial muscle Type of ABLATION Electrical isolation VP Ablation of the substrate

Different Technology for CA of AF Segmental Ostial CA PVAC CRYOABLATION Circunferential Ostial CA MESH Cardiofocus

Ablation Sites and Ablation Endpoints of the Different Techniques for CA of AF HRS/EHRA/ECAS expert consensus statement 2012

Afib Ablation: Results Clinical Variability (Afib type; cardiomiopathy; atrial remodeling; LV dysfunction) Ablation Strategy Acute and Long-term evaluation of results (antiarrhythmic drugs; diagnostics) Different EP Lab Experience

Cryoballoon Has Experienced Rapid Growth in Worldwide Adoption and Clinical Experience Arctic Front Cryoballoon Medtronic Acquires CryoCath US approval for Artic Front Arctic Front Advance Cryoballoon 7

Cryoablation Ballon Procedure TJ Cohen et al. J Invasive Cardiol 2013;25(6):288-292

Example of Achieve Signals During Ablation Delay / Isolation pv pv pv pv A V A V 9

Cryoablation vs RF Catheter Ablation 28 mm CRYOBALLON LA electroanatomic map CARTO 3D LA electroanatomic map (area of electrical isolation, mean of 40+/- 3.9% of the map s surface)

Year Efficacy Rates Published with Arctic Front Advance Cryoballoon 1-Year Freedom from AF Di Giovanni G, Wauters K, Chierchia GB, et al. One-Year Follow-Up after Single Procedure Cryoballoon Ablation: A Comparison between the First and Second Generation Balloon. J Cardiovasc Electrophysiol. Published online March 18, 2014. Metzner A, Reissmann B, Rausch P, et al. One-Year Clinical Outcome after Pulmonary Vein Isolation using the Second-Generation 28 mm Cryoballoon. Circ Arrhythm Electrophysiol. Published online March 8, 2014. Fürnkranz A, Bordignon S, Dugo D, et al. Improved One-Year Clinical Success Rate of Pulmonary Vein Isolation with the Second- Generation Cryoballoon in Patients with Paroxysmal Atrial Fibrillation. J Cardiovasc Electrophysiol. Published online March 21, 2014.

PV Lesion Durability with RF and Cryo PV re-conduction Using Repeat Electrophysiology and Mapping RF RF: Contact Sensing Arctic Front Arctic Front Advance 1 2 3 4 (n=117) (n=40) (n=75) (n=75) Follow-up** 3 Months 3 Months 12 months 3 months 3 months 3 months (n=12) 5 6 (n=21) 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 Ahmed, et al. J Cardiovasc Electrophysiol, 2010;21(7):731-7, 6 Petru, et al. International Symposium on Progress in Clinical Pacing 2014

NEJM 2016; April 4, 2016

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. SHORTER, MORE CONSISTENT* PROCEDURE TIMES IN CRYOBALLOON GROUP Measurement (minutes) RFC (n=376) Cryoballoon (n=374) P- value ** Procedure Time *** 140.9 ± 54.9 124.4 ± 39.0 <0.0001 LA Dwell Time *** 108.6 ± 44.9 92.3 ± 31.4 <0.0001 Fluoroscopy Time 16.6 ± 17.8 21.7 ± 13.9 <0.0001 * Standard deviations were smaller in the cryoballoon group for all three procedure time measures, indicating more consistent times with less variation from the mean. ** t-test *** Protocol required 30 min. waiting period after last application to assess PV isolation. Kuck KH, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016; 374(23): 2235-45 14

FIRE AND ICE Trial Primary Endpoints Cryoballoon Met Non-inferiority Safety Endpoint Primary Safety Endpoint Results RFC group 51 vs. Cryoballoon group 40 (HR=0.78:95% CI=0.52-1.18; p=0.24) One-year Kaplan-Meier event rate estimates: 10.2% Cryoballoon and 12.8% RFC Kuck KH, et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016; 374(23): 2235-45 15

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 patient s perception regarding the procedural success of an AF ablation procedure." Relative to Radiofrequency Cryoballoon Demonstrated: Kuck, K-H et al. Eur Heart J. 2016; [epub ahead of print] 16

Total Cost Differences Trial-Period Payer Cost Total Trial-Period Cost Difference by Country Country RFC Total Cryo Total P- value DEU 1,020K 775K 245K 0.012 UK 686K 547K 140K 0.013 US $1,729K $1,374K $355K 0.016 Mean follow-up: 1.5 years Total Cost Difference per Patient: Germany 640 UK 364 US $925 DEU ( 1,000) UK ( 1,000) US ($1,000) Kuck KH, et al. The Fire and Ice: Late-breaking Clinical Trial Presentation at APHRS 2016 October 13; Seoul, Korea

Rhythm Control in HF Patients With AFib Approaches to Catheter Ablation in AF and HF J Am Coll Cardiol. 2014;64(7):710-721

Strategies of Ablation for Persistent AFib Sanders P. et al., NEJM, May 7, 2015

Use of the 28-mm Larger Cryoballon Results in the Formation of Wide, Circumferential and Antrally Located Lesions

Freedom ATa recurrences Off Drugs after 1-year follow-up Following Ablation 60% Ciconte, G. et al. Heart Rhythm 2014

CryoAblation - 1STOP Project Patients: 2463 FU: 28 months 1795 Men Mean Age: 61 years 1756 Paroxistical AF 637 Persistent AF 70 Long Lasting Persistent Acute success rate: 98.2%

CryoAblation - 1STOP

CryoAblation - 1STOP Maria Cecilia Hospital Experience

85% A temperature-guided approach based on achieving -40 C within 60 seconds is effective in producing PV isolation and affords freedom from AF at 12-month follow-up in 85% of patients affected by paroxysmal AF after a 3-month blanking period Iacopino S. et al. Heart Rhythm 2016 Nov 18

Second Generation Cryoballoon Ablation for Atrial Fibrillation in Young Adults: Midterm Outcome in Patients Under 40 years of Age Moran D, Iacopino S, and Chierchia GB. Europace. 2017 Jan 25

Second Generation Cryoballoon Ablation for Atrial Fibrillation in Young Adults: Midterm Outcome in Patients Under 40 years of Age 88% Moran D, Iacopino S, and Chierchia GB. Europace. 2017 Jan 25

Conclusion PVI remains the cornerstone of PAF ablation Novel tools might render the procedures safer and faster Early ablation therapy of PAF seems to yield excellent results on a short-mid term F-Up The complication rate might be lower in younger patients Patient selection and EP Lab Experience are the best predictors of success!