left atrial appendage closure with watchman device

describes the procedure for LAA closure with watchman device. the pre-op preparations, procedural techniques, and outcomes

1. LAA closure Indication and Technique Bernard Abi-Saleh , MD, FACP, FACC, FHRS Section of Cardiac Electrophysiology and Pacing Division of Cardiovascular Diseases American University of Beirut Medical Center

2. SH-153304-AA Apr 2013 More than 90% of thrombus in non- valvular AF patients originates in the left atrial appendage (LAA) 6 1 Blackshear JL . Odell JA ., Annals of Thoracic Surgery. 1996;61:755-759 Fibrillation causes blood to stagnate in the LAA The stagnant blood becomes an ideal environment for a thrombus or blood clot to form The blood clot, or portion of it, dislodges from the LAA and travels through arterial system The embolism lodges itself in the blood vessels of the brain, restricting blood flow and causing a stroke Images on file at Boston Scientific Corporation Thrombus in the LAA Refer to glossary for reference of supporting data

3. SH-153304-AA Apr 2013 ESC guidelines for the management of AF All patients with AF and one risk factor should be on anticoagulation therapy (CHA 2 DS 2 -VASc ≥ 1*) Bleeding risk should be assessed before starting anticoagulation (HAS-BLED ≥ 3 is considered high risk of bleeding) * Except if the only risk factor is “female” Refer to glossary for reference of supporting data

4. SH-153304-AA Apr 2013 Risk factors Bleeding Risk Camm, et al., ESC 2010 Guidelines for the management of Atrial Fibrillation European Heart Journal; doi:10.1093/eurheartj/ehq278 HAS-BLED H Hypertension 1 A Renal / liver dysfunction 1 or 2 S Stroke 1 B Bleeding 1 L Labile INRs 1 E Elderly (age > 65 yrs ) 1 D Drugs or alcohol abuse 1 or 2 Maximum score 9 “Decision-making for thromboprophylaxis needs to balance the risk of stroke against the risk of major bleeding , especially ICH, which is the most feared complication of anticoagulation therapy and confers a high risk of death and disability” (ESC guidelines 2012) Score Bleeds per 100 patient-years 1.13 1 1.02 2 1.88 3 3.74 4 8.70 Refer to glossary for reference of supporting data

5. SH-153304-AA Apr 2013 The new oral anticoagulants reduce the risk of stroke This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study. Study Treatment Major Bleeding Hemorrhagic Stroke Discontinuation in the study RE-LY 7 Dabigatran (110 mg) 2.71% 0.12% 20,7% Dabigatran (150 mg) 3.11% 0.10% 21,2% Warfarin 3.36% 0.38% 16,6% ROCKET-AF 8 Rivaroxaban 3.6% 0.5% 23.7% Warfarin 3.4% 0.7% 22,2% ARISTOTLE 9 Apixaban 2.13% 0.24% 25.3% Warfarin 3.09% 0.47% nc But they have continued bleeding and discontinuation over time Refer to glossary for reference of supporting data

6. Thromboembolism versus Haemorrhage 1-2% pa 3-4% pa Bleeding risk Thromboembolic risk ? Left Atrial Occlusion Device

7. Occluding/Sealing the LAA Endovascular Watchman ACP/Amulet Epicardial Lariat

8. Endovascular Devices

9. Percutaneous closure of the left atrial appendage with the WATCHMAN ™ device The WATCHMAN device is designed to reduce the risk of stroke by closing off the left atrial appendage, which is known to be the main source of blood clots in patients with atrial fibrillation An alternative treatment to OAC SH-153304-AA Apr 2013 Indications , contraindications, warnings and instructions for use can be found in the product labeling supplied with each device. Information for the use only in countries with applicable health authority product registrations . Refer to glossary for reference of supporting data

10. Discussion on patient profiles 1 - Non- valvular AF: excluding rheumatic valvular disease or prosthetic heart valves 2 – For contraindications, refer to Instructions for use of the anticoagulants drugs NOACs (dabigatran, rivaroxaban, and apixaban) are not recommended in patients with severe renal impairment ( CrCl <30 mL/min) - 2012 focus update of the ESC Guidelines for the management of atrial fibrillation 3 - Transient Ischemic Attack 4 – Examples: difficulties to stabilize INR (International Normalized Ratio) in the therapeutic range, compliance issues, discontinuation… SH-153304-AA Apr 2013 Refer to glossary for reference of supporting data

11. Procedural Step Trans- septal Device Sizing: Angiogram and TEE Device Delivery

12. Not All Trans- S eptal Are Equal LAA is an Anterior and Cranial structure Trans- septal Should be a posterior and low cross

13. Posterior and Low Cross Bicaval View Short Axis

14. Posterior vs. Anterior Cross Mobius-Winker S, World Journal of cardiology 2015

15. The Most Anterior Lobe Should be Targeted Anterior Posterior

16. Device Sizing-Assessment of LAA Dimensions Measure LAA ostium in at least 4 TEE views At 0 deg (from left coronary artery to a point 2 cm from tip of the LUPV limbus ) At 45, 90, 135 deg (from the top of the MV annulus to a point 2 cm from tip of the LUPV limbus ) Measure the approximate LAA usuable length from the ostium line to the apex of the LAA

17. The Watchman Device Percutaneous LAA Occlusion The device is a self-expanding nitinol frame with fixation barbs and a permeable polyester fabric cover, loaded inside a catheter and delivered trans- septally into the LAA.

18. Maximum LAA Ostium (mm) Device Size (mm) (uncompressed diameter) 17-19 21 20-22 24 23-25 27 26-28 30 29-31 33 Device Sizing-Assessment of LAA Dimensions Device sizing is based on maximum LAA diameter Maximum LAA ostium size should be >17mm or <31mm to accommodate available device sizes Available/useable LAA length should be equal to or greater than the ostium

19. Delivery System

20. OPTIMAL POSITION

21. The Watchman Device All criteria must be met prior to device release ( PASS) P osition – device is distal to or at the ostium of the LAA A nchor – fixation anchors engaged / device is stable S ize – device is compressed 8-20% of original size S eal – device spans ostium , all lobes of LAA are covered Percutaneous LAA Occlusion

22. The Watchman Device Percutaneous LAA Occlusion Position: Device should be at or just distal to the LAA ostium

23. The Watchman Device Percutaneous LAA Occlusion To test stability, gently retract deployment knob and let go, observe device returns to original position If the device moves to where position is no longer acceptable or the compression is no longer sufficient, the device should be recaptured Test stability more than once if device stability is questionable Hemostasis Valve Core Wire Deployment Knob Anchor: Pass or Fail Test

24. The Watchman Device Percutaneous LAA Occlusion Device Size (uncompressed diameter) Maximum (20%) Compression Measured Diameter* Minimum (8%) Compression Measured Diameter* 21 16.8 mm 19.3 mm 24 19.2 mm 22.1 mm 27 21.6 mm 24.8 mm 30 24.0 mm 27.6 mm 33 26.4 mm 30.4 mm *Measure in-situ device diameter at approximate TEE angles of 0, 45, 90 and 135 degrees to accurately assess device compression 20.8 Device Compression Table 8 – 20% of original device size selected Size

25. The Watchman Device Percutaneous LAA Occlusion S eal Residual flow around the device of ≤ 5mm acceptable If all 4 device release criteria are met (PASS), device can be released Counter clockwise on proximal handle 3-5 turns

26. The Watchman Device Percutaneous LAA Occlusion Human Pathology - 9 Months Post-implant ( Non-device r elated death)

27. Case 2 76 year old man with CAD s/p CABG, atrial fibrillation on anticoagulation and CHF s/p BiV -ICD implantation admitted to the hospital for subarachnoid hemorrhage. Anticoagulation was held for 2 months with complete disappearance of the bleed.

28. Percutaneous LAA Occlusion The Watchman Device In March 2015, the US Food and Drug Administration(FDA ) approved the Watchman device (Boston Scientific Corp) for minimally invasive LAA closure after completion of two pivotal randomized clinical trials designed to demonstrate safety and efficacy of the device in comparison to warfarin therapy.

29. The Watchman Device M ost studied LAAC device The only one proven with long-term data from randomized trials or multi-center registries Percutaneous LAA Occlusion

30. Watchman Story First implant in Human: 2002 CE Mark Approval in Europe 2005 PROTECT-AF 2009 PROTECT-AF (Longer Follow-up) 2013 and 2014 PREVAIL 2014 FDA approval 2015 EWOLUTION 2016 Real World data 2017

31. PROTECT AF C- Percutaneous LAA Occlusion Study Design & Objective Prospective, randomized (2:1), non-inferiority trial of LAA closure vs. warfarin in non-valvular AF patients for prevention of stroke Primary Endpoint Efficacy : Composite end point of stroke, cardiovascular death or systemic embolization Safety : Major bleeding, device embolization or pericardial effusion Statistical Plan All analyses by intention-to-treat Bayesian (stratified for CHADS 2 score) : Primary Efficacy and Safety endpoints Cox Proportional: All Secondary Analyses Patient Population n = 707 Mean CHADS 2 = 2.2, CHA 2 DS 2 - VASc = 3.5 Key Inclusion Criteria Paroxysmal / Persistent / Permanent AF CHADS ≥ 1 (93% had a CHA 2 DS 2 - VASc Score ≥2) Eligible for long-term warfarin therapy Mean Follow-Up 2,717 patient-years, 48 months Number of Sites 59 in the United States and Europe Enrollment Feb 2005 – June 2008

32. C- Percutaneous LAA Occlusion PROTECT AF: Primary safety results Event-free probability Safety of the procedure ???? Primary Safety Endpoint 1- Device embolization requiring retrieval 2- Pericardial effusion requiring intervention 3- Cranial bleeds and gastrointestinal bleeds 4- Any bleed that requires ≥ 2uPRBC

33. C- Percutaneous LAA Occlusion PROTECT AF: Primary efficacy results Event-free probability Intent-To-Treat Cohort: Non-inferiority criteria met Primary Efficacy Endpoint deficit with symptoms persisting >24 hours 1- All stroke: ischemic or hemorrhagic symptoms <24 hours confirmed by CT or MRI 2- Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure 3- Systemic embolization

34. C- Percutaneous LAA Occlusion PROTECT AF: Stroke 5 events in device group classified as “ischemic stroke” All periprocedural : extended hospitalization by 7 days 3 were related to air embolism 1 hemorrhagic stroke in device group vs 6 in control group Device event occurred 15 days post implant while patient was on warfarin 4/6 stroke events in control group patients resulted in death

35. C- Percutaneous LAA Occlusion PROTECT AF: All Stroke Event-free probability ITT cohort: Non-inferiority criteria met

36. C- Percutaneous LAA Occlusion PROTECT AF: Hemorrhagic Stroke ITT cohort: Superiority criteria met Event-free probability

37. PROTECT AF 4-Year Results in JAMA WATCHMAN TM Met Criteria for both Noninferiority and Superiority for the Primary Composite Endpoint Compared to Warfarin Reddy , VY et al. JAMA. 2014;312(19):1988-1998. SH-230506-AB MAR15

38. C- Percutaneous LAA Occlusion PROTECT AF: Risk/Benefit analysis Statistically significant endpoint findings Noninferiority for the primary efficacy event rate – 32% lower in device group Noninferiority for all strokes – 26% lower in device group Superiority for hemorrhagic stroke – 91% lower in device group Noninferiority for mortality rate – 39% lower rate in device group Increased rate of primary safety events for the device group relative to the control group Most events in the device group were procedural effusions that decreased over the course of the study 87% of patients were able to discontinue warfarin at 45 days

39. 2 Randomized Trials and 2 Registries PROTECT AF CAP Registry PREVAIL CAP2 Registry Totals Enrollment 2005-2008 2008-2010 2010-2012 2012-2014 Enrolled 800 566 461 579 2406 Randomized 707 --- 407 --- 1114 WATCHMAN: warfarin (2:1) 463 : 244 566 269 :138 579 1877: 382 Mean Follow-up (years) 4.0 3.7 2.2 0.58 N/A Patient-years 2717 2022 860 332 5931 Source: FDA Oct 2014 Panel Sponsor Presentation.

40. Improvement in Procedural Safety Profile: 7-Day Safety Events Patients with Safety Event (%) PROTECT AF 1 st Half 2 nd Half n =232 n =231 n =566 n =269 n =579 Learning Curve ~50% New Operators in PREVAIL

41. Implant Success & Warfarin Cessation p = 0.04 Study 45-day 12-month PROTECT AF 87% >93% CAP 96% >96% PREVAIL 92% >99% Implant success defined as deployment and release of the device into the left atrial appendage Warfarin Cessation p = 0.28 PROTECT AF and CAP: Reddy , VY et al. Circulation. 2011;123:417-424 . PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.

42. EWOLUTION registry Boersma L.V.A. et al. European Heart Journal (2016) 37, 2465–2474

43. EWOLUTION registry Boersma L.V.A. et al. European Heart Journal (2016) 37, 2465–2474

44. Post-Approval U.S. Experience With Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation

45. Device thrombus

46. Device thrombus Boersma L et al. Heart Rhythm 2017

47. Device thrombus Boersma L et al. Heart Rhythm 2017

48. EU approval for DAPT for 3 m