new frontiers on management of Atrial fibrillation

new frontiers on management of Atrial fibrillation

1. New Frontiers for Management for AF: The cool way to treat it KUSH KUMAR BHAGAT MD, DM CARDIOLOGY

2. Why do we need to treat AF?? (More importantly at an earlier stage)

3. 1 Proietti R, et al. JACC Clin Electrophysiol . 2015;1:105-115. 2 Kirchhof P, et al. N Engl J Med . 2020;383:1305-1316. 3 Almeida ED, et al. Arq Bras Cardiol . 2015; 105:3-10. 4 Link MS, et al. Circ Arrhythm Electrophysiol . 2017;10:e004267. 5 Steinberg BA, et al. Eur Heart J . 2015;36:288-296. 6 Al-Khatib SM, et al. Eur Heart J . 2013;34:2464-2471. 7 de Vos CB, et al. J Am Coll Cardiol . 2010; 55:725-731. AF is a progressive disease 1 and earlier treatment is important. 2 After 12 years, 50⎼77% of patients receiving medical management will develop persistent or permanent atrial fibrillation (AF). 1 Progression of AF is associated with adverse clinical outcomes including a higher risk of heart failure, stroke, mortality, and cardiovascular hospitalization. 4-7 As such, early intervention to decrease AF progression is an important clinical priority. Af progression consequences 3 Early Treatment for Atrial Fibrillation with Catheter Ablation

4. 4 Need for af treatment Large, growing, and underserved patient population 33m Estimated global prevalence 1 2x AF patients will double by 2035 1 Chugh SS, et al. Circulation . 2014;129:837- 8 47. 2 Naccarelli GV, et al . Am J Cardiol . 2009;104:1534-1539. 3 Siontis KC, et al. Heart Rhythm . 2016;13(7):1418–1424. 4 Boriani G, et al. Am J Med . 2015 May;128(5):509-18.e2. 5 Steinberg BA, et al. Am Heart J . 2014;167:735-42.e2. > 60 % Of AF patients experience arrhythmia-related symptoms 3,4 31 % Of patients with AF have ≥ 1 hospitalization per year 5 Early Treatment for Atrial Fibrillation with Catheter Ablation

5. Af is progressive af contributes to cardiac remodeling and further promotes af Increased time in AF drives AF-related cardiac remodeling that promotes longer-standing forms of AF. More time spent in AF makes it more challenging to treat because of remodeled cardiac tissue. Source: Chang ET, et al. PLoS One . 2016;11:e0152349. 5 Early Treatment for Atrial Fibrillation with Catheter Ablation AF-related remodeling  Age/disease-related remodeling  Genetic predisposition 

6. ~1/3 of patients progress from paroxysmal to more advanced stages of AF 6 Proietti R, et al. JACC Clin Electrophysiol . 2015;1:105-115 . Systematic review evaluating the progression of paroxysmal AF to persistent/permanent AF in general population studies (predominantly receiving medical therapy) Patients with AF progression at 1 year ranged from 10⎼20% Rate of progression increased with the duration of follow-up Forest Plot for Percentage of Progression of AF in General Population Studies: Percentage of patients with AF progression ranged from 7.8 ⎼ 77.2%, averaging 31% across 21 studies Prevalence of atrial fibrillation progression 6 Early Treatment for Atrial Fibrillation with Catheter Ablation

7. 28% h igher risk of death in patients with persistent/permanent vs. paroxysmal AF treated with oral anticoagulation 2 Consequences of atrial fibrillation progression earlier treatment is important DECREASED HEALTH-RELATED QUALITY OF LIFE (EuroQoL-5D) due to worsening AF symptoms and adverse events (progression vs. no progression) 1 20% higher risk of stroke or systemic embolism in patients with persistent/permanent vs. paroxysmal AF treated with oral anticoagulation 2 ~1.5 x increased hospitalizations for cardiovascular problems and 2 x for electrical cardioversions (progression vs. no progression) 4 2 x prevalence of heart failure (persistent vs. paroxysmal AF) 3 1 Dudink EAMP, et al. Europace . 2018;20:929-934. 2 Zhang W, et al. Am J Cardiol . 2019;123:922-928. 3 Almeida ED, et al. Arq Bras Cardiol . 2015;105:3-10. 4 de Vos CB, et al. J Am Coll Cardiol . 2010;55:725-731. 7 Early Treatment for Atrial Fibrillation with Catheter Ablation 6.5 x prevalence of stroke (persistent vs. paroxysmal AF) 3

8. The Guidelines today have been influenced by three randomized first-line studies: MANTRA-PAF (2012), RAAFT 1 (2005), and RAAFT-2 (2014). All three studies compared point-by-point radiofrequency ablation and antiarrhythmic drugs as first-line PAF treatment. However, new evidence has been published in three randomized first-line studies: Cryo-FIRST (2021), STOP AF First (2020), and EARLY AF (2020). All three studies evaluated the safety and efficacy of the cryoballoon as a first-line treatment vs. antiarrhythmic drugs (AADs). Catheter ablation as a rhythm control strategy Radiofrequency Ablation Cryoablation 8 Early Treatment for Atrial Fibrillation with Catheter Ablation

9. RFA with 3D mapping

10. 3D MAPPING: NEW DIMENSION IN EP

11. RFA point to point ablation isolating PVS

12. Medtronic CAS | 12 CRYO ABLATION

13. Medtronic CAS | 13 cryoballoon ablation first-line studies

14. Primary publications Early-AF 3 Primary results published in The New England Journal of Medicine, January 2021 Cryo-FIRST 1 Primary results published in Europace , March 17, 2021 STOP AF First 2 Primary results published in The New England Journal of Medicine , January 2021 First-line Trial Comparison 14 1 Kuniss M, et al. Europace . Published online March 17, 2021 . 2 Wazni OM, et al. N Engl J Med. 2021;384(4):316-324. 3 Andrade JG, et al. N Engl J Med. 2021;384(4):305-315.

15. 15 Presentation Title (Edit on Slide Master) | June 1, 2015 | Confidential, for Internal Use Only Approved for persistent af – by us fda Arcticfront advance – stop persistent af trial Results confirm PVI with the Medtronic cryoballoon is safe, effective, and efficient for treating drug-refractory, symptomatic, persistent AF (episode duration < 6 months) and significantly improves patient quality of life, reduces AF-related symptoms, and provides a high rate of freedom from repeat ablation.

16. conclusions THREE INDEPENDENT STUDIES HAVE DEMONSTRATED THAT: As a first-line therapy, cryoballoon ablation is superior to AAD for prevention of atrial arrhythmia recurrence First-line cryoablation is associated with larger improvements in AF-specific quality of life compared to AAD therapy More patients were asymptomatic at 12 months following first-line cryoablation versus AAD therapy Cryoballoon ablation as a first-line rhythm control strategy has an acceptable safety profile First-line Trial Comparison 16

17. 17 FIRE AND ICE Trial FIRE AND ICE Trial: Primary Endpoints 1 Trial Design and Methods:  Prospective, 1:1 randomized, non inferiority study, 16 sites in 8 countries Primary Efficacy Endpoint: Time to first documented recurrence of AF > 30s/AT/AFL, prescription of AAD, or repeat ablation Primary Safety Endpoint: Time to first all-cause death, all-cause stroke/TIA, or treatment-related serious AEs  Cryo Ablation System Customer Presentation

18. 18 K u c k KH , et al. E u r H e a r t J . 2016 ; 37 : 285 8 - 2865. Cryo: 139 events in 89 subjects (89/374; 23.8% ) RFC : 203 events in 135 subjects (135/376; 35.9% ) Cryo: 49 events in 44 subjects (44/374; 11.8% ) RFC : 70 events in 66 subjects (66/376; 17.6% ) 33 % Fewer Repeat Ablations 34% Fewer Cardiovascular Hospitalization 50% Fewer Cardioversions 21% Reduction in All Cause Re -Hospitalization European Heart Journal " T he ex t ent o f reduc t i o n i n re i n t ervent i o n s and re h o s p i t al i za t i o n s i s not o n ly statistically significant but also c li n i c ally relevant. O ur pre s e n t ed da t a ar e t he m a i n events t hat define the p a t i ents ’ percep t i o n reg a rding t he pr o c edur a l s u c c e s s o f a n AF ab la t i o n pr o c edure . " Kowalski M. et al. J Invasive Cardiol . 2016 May;28(5): 176- 1 82. Lieberman Inc., Blinded Market Research Survey, Medtronic data on file . February 2018. CRYOBALLOON VS POINT TO POINT RF ABLATION SECONDARY ANALYSIS OF FIRE AND ICE TRIAL Cryo: 13 DC cardioversions in 12 patients ( 12 /374; 3. 2 % ) RFC : 2 8 cardioversions events ( 24 /376; 6 . 4 % ) Cryo: 210 events in 122 subjects ( 122 /374; 3 2 . 6 % ) RFC : 2 67 events in 156 subjects ( 156 /376; 41 . 5 % ) Cryo Ablation System Customer Presentation

19. With over 14 years of clinical experience, and close to one million procedures performed in over 8 countries, momentum is b uil d i n g f o r t he A r c t i c F r o n t ™ family o f cryoballoons — the safe 1 and consistent 2 way to treat AF. 1 Packer DL, et al. J Am Coll Cardiol . 2013;61: 1713-1723. 2 Kuck KH, et al. N Engl J Med . 2016;374:2235-2245. 19 Early Treatment for Atrial Fibrillation with Catheter Ablation

20. 13 M E DTR ONIC CRYO ABLATI O N S Y STEM COM P O N ENTS CryoConsole A rct i c Fr o nt Advance™ Cardi ac Cryoablation Catheters FlexCath Ad v a nc e ™ Steerable Sheath Achieve Advance ™ Mappi ng Catheters Freezor ™ Family of Cardiac Cryoablation Catheters 23mm a nd 28mm 12Fr Unidirectional 135⁰ 15mm, 20mm or 25mm Images Courtesy of Medtronic. For Illustrative Purpose Only. Tip Length: 4mm, 6 mm, 8 mm Dia: 7Fr, 9 Fr Cryo Ablation System Customer Presentation

21. TH E CRYOABLATION METHOD How Cryoballoon Works: Arctic Front Advance ™ was designed with PVI in mind. The targeted vein is accessed. 21 Early Treatment for Atrial Fibrillation with Catheter Ablation

22. How Cryoballoon Works: Arctic Front Advance ™ was designed with PVI in mind. Cryoballoon is an anatomical approach for PVI; creating contiguous homogenous lesions surrounding the pulmonary vein. 1 The balloon is moved into position and inflated. 1 Sarabanda AV, et al. J Am Coll Cardiol . 2005;46:1902-1912. TH E CRYOABLATION METHOD 22 Early Treatment for Atrial Fibrillation with Catheter Ablation

23. After full occlusion, cryoablation takes place. How Cryoballoon Works: Arctic Front Advance ™ was designed with PVI in mind. Cryoballoon is an anatomical approach for PVI; creating contiguous homogenous lesions surrounding the pulmonary vein. 1 Using safe cryo energy, cryoballoon removes heat from tissue for a more durable method of PVI. 2 1 Sarabanda AV, et al. J Am Coll Cardiol . 2005;46:1902-1912. 2 Ahmed H, et al. J Cardiovasc Electrophysiol . 2010;21:731-737. TH E CRYOABLATION METHOD 23 Early Treatment for Atrial Fibrillation with Catheter Ablation

24. Immediate feedback is received determining PVI success. How Cryoballoon Works: Arctic Front Advance ™ was designed with PVI in mind. Cryoballoon is an anatomical approach for PVI; creating contiguous homogenous lesions surrounding the pulmonary vein. 1 Using safe cryo energy, cryoballoon removes heat from tissue for a more durable method of PVI. 2 Cryoballoon preserves the extracellular matrix. 3 1 Sarabanda AV, et al. J Am Coll Cardiol . 2005;46:1902-1912. 2 Ahmed H, et al. J Cardiovasc Electrophysiol . 2010;21:731-737. 3 Khairy P, et al. Circulation . 2003;107:2045-2050. TH E CRYOABLATION METHOD 24 Early Treatment for Atrial Fibrillation with Catheter Ablation

25. Pressurized liquid N 2 O is delivered from the Cryo Console through an ultrafine, robust injection tube, to the tip of the inner balloon 1. The CryoConsole controls safe delivery of N 2 O to the catheter and return of the warmed vapor. 3. 4. The warmed vapor is scavenged out of the system with help of a scavenging hose 2. Inside the balloon, the liquid N 2 O vaporizes and absorbs heat from the surrounding tissue Cryoablation system components how the system works 25 Images Courtesy of Medtronic. For Illustrative Purpose Only. Cryo Ablation System Customer Presentation

26. COMPARATIVE SUMMARY – CRYO VS radio frequency ABLATION

27. Freezing tissue with a 23 or 28 mm cryoballoon Burning tissue with point-by-point radiofrequency Cryoballoon and radiofrequency ablation are two standard ablation systems used today. 1 1 January CT, et al. J Am Coll Cardiol . 2014;64:e71-e76. Effective pvi requires transmural lesions 28 Early Treatment for Atrial Fibrillation with Catheter Ablation

28. 29 PVI THROUGH Cryoablation scores over RF ABLATION Point by Point Catheter Ablation PVI with Cryoablation T e chn i c a l l y ch a l l e n g ing due to n a v i g a t i o n a nd m a pp ing syst e m s requirements Comparatively simpler with shorter learning curve Challenging to achieve consistent catheter stability and therefore time consuming Easy to reach target area within short time Procedure times, methods and results are operator dependent and varies Predictable and very consistent results : Reduced risk of complications Fewer repeat ablations Enables time for additional EP lab procedures Higher staff satisfaction • • • • • • Cryo Ablation System Customer Presentation

29. Cryo energy offers several unique features: Cryoadhesion improves contact and stability 1 Preserves the extracellular matrix and endothelial integrity 2 Decreases risk of thrombus formation 2,3 Demonstrates well-demarcated lesions 2-4 1 Aryana A, et al. J Atr Fibrillation . 2015;8:1231. 2 Sarabanda AV, et al. J Am Coll Cardiol . 2005;46:1902- 19 12. 3 Khairy P, et al. Circulation . 2003;107:2045-2050. 4 Friedman PL. Curr Opin Cardiol . 2005;20:48-54. Radiofrequency lesion at one week. 3 Arrow indicating thrombus and disrupted endocardium. Cryolesion at one week. 3 Well-demarcated with minimal thrombus and endocardium intact. Cryoablation preserves the extracellular matrix 30 Early Treatment for Atrial Fibrillation with Catheter Ablation

30. features & benefits summarised 01 02 Ablation creates ideal lesions that are wide, extended and circumferential compared to RF 03 Strong clinical evidence and consistent results 04 05 06 Shorter learning curve & easy to adopt Fewer CV Hospitalization and Repeat ablations Simple, Safe, Fast & Effective catheter ablation ACCURACY, SAFETY & EFFICACY Cryo Ablation System Customer Presentation Predictable and short procedure duration – Anatomical design – AFA Pro

31. 1 Packer DL, et al. J Am Coll Cardiol . 2013;61:1713-1723. 2 Giovanni GD, et al. J Cardiovasc Electrophysiol . 2014;25:834-839. 3 Fürnkranz A, et al. J Cardiovasc Electrophysiol . 2014;25:840-844. 4 Aryana A, et al. J Interv Card Electrophysiol . 2014;41:177-186. 5 Aytemir K, et al. Europace . 2015;17:379-387. 6 Greiss H, et al. Pacing Clin Electrophysiol . 2015;38:815-824. 7 Metzner A, et al. Circ Arrhythm Electrophysiol . 2014;7:288-292. 15 Kuck KH, et al. N Engl J Med . 2016;374:2235-2245. 16 Knight B, 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 (Abstract). 17 Su WW, Reddy VY, Bhasin K, et al. Cryoballoon Ablation of Pulmonary Veins for Persistent Atrial Fibrillation: Results From the Multicenter STOP Persistent AF Trial. Heart Rhythm . 2020;17:1841-1847 . 8 Chierchia GB, et al. Europace . 2014;16:639-644. 9 Chierchia GB, et al. J Cardiovasc Electrophysiol . 2015;26:950-955. 10 Kumar N, et al. J Interv Card Electrophysiol . 2014;41:91-97. 11 Jourda F, et al. Europace . 2015;17:225-231. 12 Ciconte G, et al. Heart Rhythm . 2015;12:673-680. 13 Tebbenjohanns J, et al. EP Europace . 2016;18:206-210. 14 Wissner E, et al. Europace . 2015;17:1236-1240. 18 January CT, et al. J Am Coll Cardiol . 2014;64:e1-e76. 19 Zipes DP, et al. Heart Rhythm . 2016;13:e3-e37. 20 Kirchhof P, et al. Eur Heart J . 2016;37:2893-2962. 21 Calkins H, et al. Heart Rhythm . 2017;14:e275-e444. 22 WazniOM , et al. N Engl J Med . 2021;384(4):316-324 . STOP AF First Trial Published 2020 22 12-month Outcome Data Arctic Front Advance Cryoballoon STOP PERSISTENT AF Trial Published 2020 17 12-month Outcome Data Arctic Front Advance Cryoballoon STOP AF PAS Trial Published 2017 16 Two-year Outcome Data Arctic Front Advance Cryoballoon FIRE AND ICE Trial Published 2016 15 Arctic Front and Arctic Front Advance Cryoballoon > 12 Single Center Studies Published 2-14 Arctic Front Advance ™ Cryoballoon STOP AF Pivotal Trial Published 2013 1 Arctic Front Cryoballoon HRS/EHRA/ECAS/ APHRS/SOLAECE MAY 2017 21 Consensus Statement for the Management of Atrial Fibrillation ESC August 2016 20 Guideline for the Management of Atrial Fibrillation ACC/AHA/HRS October 2015 19 Advanced Training Statement BCBS June 2015 Association Coverage ACC/AHA/HRS February 2014 18 Guideline for the Management of Patients with Atrial Fibrillation THE CRYOBALLOON STORY Building the evidence Furthering the cryoballoon story 32 Early Treatment for Atrial Fibrillation with Catheter Ablation

32. Earlier treatment with catheter ablation has been shown to reduce atrial arrhythmia recurrence. Patients can now be referred for a cryoablation without the need for drug therapy failure. Summary of patient benefits 33 Early Treatment for Atrial Fibrillation with Catheter Ablation