William A. Gray MD System Chief of Cardiovascular Services, Main Line Health President, Lankenau Heart Institute Wynnewood, Pennsylvania USA

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1 William A. Gray MD System Chief of Cardiovascular Services, President, Wynnewood, Pennsylvania USA

2 What does Guilty until Effective mean?

3 A fact is a simple statement that everyone believes. It is innocent unless found guilty. A hypothesis is a novel suggestion that no one wants to believe. It is guilty, until found effective. Edward Teller

4 Despite NOAC Adoption and Ability to Switch NOACs, Adherence to Anticoagulation Remains a Challenge ~30% of NOAC patients stop taking any drug at 2 years Source: Martinez C, et al. Therapy Persistence in Newly Diagnosed Non-Valvular Atrial Fibrillation Treated with Warfarin or NOAC. A Cohort Study. Thromb Haemost Dec 22;115(1):31-9. doi: /TH SH AD MAY2017

5 1. Stoddard et al. Am Heart J. (2003) 2. Goldman et al. J Am Soc Echocardiogr (1999) 3 Blackshear JL. Odell JA., Annals of Thoracic Surg (1996) Connection Between Non-Valvular AF-Related Stroke and the Left Atrial Appendage AF Creates Environment for Thrombus Formation in Left Atrium Stasis-related LA thrombus is a predictor of TIA 1 and ischemic stroke 2. In non-valvular AF, >90% of stroke-causing clots that come from the left atrium are formed in the LAA 3.

6 Transcatheter LAA Occlusion Self-expanding nitinol cage, circa 2002 PLAATO Device IC AD APR 2017

WATCHMAN Left Atrial Appendage Closure Device Nitinol frame Anchor s 160 µm PET fabric cap Intra-LAA design 1. Data on file Boston Scientific 2. Schwartz et al.

7: 801-9, 2014 160 µm Polyethylene terephthalate (PET) cap PET cap designed to block emboli from exiting the LAA PET cap intended to promote endothelialisation during healing process 1,2,3 10 active

7 WATCHMAN Left Atrial Appendage Closure Device Nitinol frame Anchor s 160 µm PET fabric cap Intra-LAA design 1. Data on file Boston Scientific 2. Schwartz et al., Healing Stages of Intracardiac Devices. JACC vol Kar et al. Anatomical Impact of LAA Closure Devices. JACC: Cardiovascular Interventions. Vol. 7: 801-9, µm Polyethylene terephthalate (PET) cap PET cap designed to block emboli from exiting the LAA PET cap intended to promote endothelialisation during healing process 1,2,3 10 active fixation anchors around device perimeter engage LAA tissue for stability and retention Nitinol frame radially expands to maintain position in LAA Engineered to conform to the individual anatomy of the LAA Size metrics: 21, 24, 27, 30, 33 mm (diameter) Manufacturer: Boston Scientific IC AD APR 2017

8 IC AD APR 2017 Watchman Implant Final 3D Echo shows flat device surface

9 IC AD APR 2017 Watchman Implant 45 day TEE Canine at 45 days

WATCHMAN Clinical Program More than 2,400 patients and nearly 6,000 patient-years of follow-up 2002 Pilot nonrandomized Feasibility and Safety 2008 CAP Registry non-randomized Add l patients and

10 WATCHMAN Clinical Program More than 2,400 patients and nearly 6,000 patient-years of follow-up 2002 Pilot nonrandomized Feasibility and Safety 2008 CAP Registry non-randomized Add l patients and follow-up Apr 2009 FDA Panel # PREVAIL Randomzied Comparison: warfarin Oct 2014 FDA Panel #3 Dec 2013 FDA Panel # CAP2 Registry Non-Randomzied Add l patients and follow-up Mar 2015 FDA Approval 2017 ASAP TOO Randomized US Indication Expansion Worldwide study 2005 PROTECT AF Randomized Comparison: warfarin 2009 ASAP non-randomized Patients Contra-indicated to warfarin* 2013 EWOLUTION, WASP Registries non-randomized Real-world, All comers 2016 NCDR LAAO Registry Post-approval statistical analysis

11 PROTECT AF CAP Registry PREVAIL CAP2 Registry Enrollment Purpose Demonstrate safety and effectiveness of the WATCHMAN implant compared to long-term warfarin Continued Access Registry Demonstrate safety and effectiveness of the WATCHMAN implant compared to long-term warfarin Continued Access Registry Study Design 2:1 Randomized, non-inferiority Non-randomized 2:1 Randomized, non-inferiority Non-randomized Primary Endpoints 1. Effectiveness: Stroke, systemic embolism and cardiovascular/unexplained death 2. Safety: Life-threatening events, which include device embolization requiring retrieval and bleeding events 1. Effectiveness: Stroke, systemic embolism and cardiovascular/unexplained death 2. Effectiveness: Ischemic stroke or systemic embolism, occurring after 7 days postrandomization or WATCHMAN implant procedure 3. Safety: Death, ischemic stroke, systemic embolism and procedure/device-related complications within 7 days of implantation procedure

Most patient studied were had significant stroke risk and were good candidates for warfarin Patients (%) 50% 40% 30% 20% CHA 2 DS 2 -VASc Score 2 PROTECT AF 93% CAP

12 Most patient studied were had significant stroke risk and were good candidates for warfarin Patients (%) 50% 40% 30% 20% CHA 2 DS 2 -VASc Score 2 PROTECT AF 93% CAP 96% PREVAIL 100% CAP2 100% 10% 0% CHA 2 DS 2 -VASc Score AHA/ACC/HRS Guidelines (2014); Holmes, DR et al. J Am Coll Cardiol. 2015;65(24): N

13 Most patients had at least moderate bleeding risk 80% 70% 60% Patients (%) 50% 40% 30% 20% 10% PROTECT AF CAP PREVAIL CAP2 0% HAS BLED* Score

14 WATCHMAN Clinical Data Stroke reduction efficacy

15 PROTECT AF and PREVAIL: Watchman comparable to warfarin HR p-value Efficacy All stroke or SE Ischemic stroke or SE Hemorrhagic stroke Ischemic stroke or SE >7 days CV/unexplained death All-cause death Major bleed, all Major bleeding, non procedure-related Favors WATCHMAN Favors warfarin Hazard Ratio (95% CI) Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):

16 N.B.-PREVAIL had an atypically low stroke rate on warfarin Trial (Warfarin Arm) Ischemic Stroke Rate per 100 pt-yrs Mean CHADS PREVAIL 2.6 PROTECT AF 2.2 RE-LY ROCKET AF ARISTOTLE ENGAGE Miller. AJC (2012) Giugliano. NEJM (2013) Rate per patient-years N

17 6.0% PROTECT AF: Once procedure related embolism is removed embolic stroke prevention efficacy equivalent Patients with Ischemic Stroke(%) 5.0% 4.0% 3.0% 2.0% 1.0% 6 Procedure related Strokes (primarily air emboli) Non- Procedure related 0.0% WATCHMAN Control

18 Ischemic Stroke (Events/100 Patient-Years) Watchman may reduce ischemic stroke by 67-83% over no therapy % Relative Reduction PROTECT AF Baseline CHA 2 DS 2 -VASc = % Relative Reduction PREVAIL Only Baseline CHA 2 DS 2 -VASc = 3.8 CAP 83% Relative Reduction Baseline CHA 2 DS 2 -VASc = 3.9 * Imputation based on published rate with adjustment for CHA 2 DS 2 -VASc score (3.0); Olesen JB. Thromb Haemost (2011) Imputed Ischemic Stroke Rate* Observed WATCHMAN Ischemic Stroke Rate FDA Oct 2014 Panel Sponsor Presentation. Hanzel G, et al. TCT 2014 (abstract)

19 Watchman disabling stroke reduction superior to warfarin in PROTECT AF Event Rate (per 100 pt-yrs) Posterior Probabilities, % PROTECT AF WATCHMAN N=463 Warfarin N=244 Rate Ratio (95% CrI) Non- Inferiority Superiority Stroke (all) (0.42, 1.37) >99 83 Disabling (0.15, 1.00) >99 98 Non-disabling (0.54, 2.80) Disabling stroke defined as Modified Rankin Score % reduction in disabling/fatal strokes with WATCHMAN Bayesian Posterior prob for NI must be 97.5%; Posterior Prob for Superiority must be >95% Reddy, et al. JAMA N

20 Watchman Efficacy: Bleeding Reduction

21 Bleeding risks compound over patient lifetime CHA 2 DS 2 - VASc* Score Annual % Stroke Risk HAS-BLED** Score Annual % Bleed Risk 10-Year Bleeding Risk (%)*** * 2014 AHA / ACC / HRS Guidelines ** Lip. JACC (2011) *** Assumes constant risk despite increasing age and bleeding risk is independent from bleeding risk in previous years N

22 72% major bleeding reduction long-term post-implant Warfarin + ASA (81mg) daily Post Procedure Therapy Clopidogrel (75mg) + ASA (325 mg) daily Destination Therapy ASA (325mg) daily Implant 45 days* 6 months *if leak >5mm, patients remained on warfarin + ASA until seal documented, skipping the clopidogrel + ASA pharmacotherapy Overall Post Procedure Bleeding Rate (n events / N at risk) 10.8 (79/732) 5.9 (40/682) LAAC (n=732) Event Rate per 100 pt-yrs (n events / N at risk) 3.5 (79/2268) 1.8 (40/2255) Long-term warfarin (n=382) Bleeding Rate (n events/n at risk) 11.3 (43/382) 11.3 (43/381) Event Rate per 100 pt-yrs (n events / N at risk) 3.6 (43/1187) 3.6 (43/1180) Rate Ratio P value Destination 0.28 <0.001 (19/601) (19/1958 (35/360) (35/1004) Overall period defined as after randomization to the end of follow-up; post-procedural period as >7 days after randomization to the end of followup; destination therapy period as beyond 180 days post-randomization, when patients assigned to LAA closure were eligible to receive aspirin alone. Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15):

23 Landmark analysis of bleeding outcomes Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals 72% reduction in major bleed >6 months post-procedure p < Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15):

24 Procedural Success and Safety

25 Procedural success ~70% new operators performed 50% of procedures ~50% new operators Implant success defined as deployment and release of the device into the LAA; no leak 5 mm

26 Improving and favorable procedural safety profile 12% 10% 9.9% 8% Patients With Safety Event w/i 7 days (%) 6% 4% 4.8% 4.1% 4.1% 3.8% 2.8% 2% 0% PROTECT AF PROTECT AF CAP PREVAIL CAP2 EWOLUTION* 1st Half 2nd Half N=232 N=231 N=566 N=269 N=579 N=1019 1

27 Individual components of MAE Complication Rates 5% 4% 3% 2% 1% Clinical Trial Experience Post Approval Experience Pericardial Tamponade Procedure-Related Stroke Device Embolization Procedure-Related Death 0% PROTECT AF (n=463) CAP (n=566) PREVAIL (n=269) CAP2 (n=579) EWOLUTION (n=1021) US Cohort (n=3822)

28 Net clinical benefit assessment

30 Watchman-enabled warfarin discontinuation 92% of patients were able to discontinue warfarin after 45 days, with 99% able to discontinue after 1 year 3 92% 92% 99% 92% 99% 45 Days 1 Year Warfarin Cessation with WATCHMAN

31 Future Patient Populations

32 ASAP registry O:E Ischemic Stroke Rate (%/pt-yr) 8.0% 7.0% 6.0% 5.0% 4.0% 3.0% 2.0% 1.0% Ischemic Stroke 7.3% 5.0% 1.7% 77% Reduction 64% Reduction Expected, based on CHADS₂ Score Expected, if Clopidogrel was used throughout follow-up Observed rate in ASAP 0.0% Reddy et al. JACC 2013; 61(25):

33 Registry on WATCHMAN Outcomes in Real-Life Utilization: EWOLUTION Study Objective: Study Design: Primary Endpoint: Patient Population: Number of Sites: Collect real-world WATCHMAN LAAO experience outside of selected populations in prior RCT Prospective, single-arm, multi-center registry of the Watchman LAA Closure Technology Primary analysis includes procedural success and safety, incidence of stroke, bleeding, and death after 2 yr of FU Investigator and Medical Safety Group for adjudication >1000 patients 47 throughout Europe, Russia and Middle East Enrollment: Started October Completed May 2015 Follow-up: Standard practice at participating centers Normally 1-3 months post-procedure Annually thereafter for a total of 2 years Boersma LVA, et al. HRS2017; Late Breaking Clinical Trials: Chicago IL, USA.

34 EWOLUTION: patient flow up to 1-year Informed consent obtained: N = 1025 Implant of WATCHMAN: N = 1020 Patients with successful Watchman implant: N = 1005 Anatomy considered not suitable at prescreening: N = 5 End of study < 1 year (N = 112) Deceased: N = 91 Withdrawn: N = 8 Lost To FU: N = 13 Active 1 year: N = 893/1005 (89%) Pts with TEE: N = 875/1005 (87%) Active Pts with > 11m of data: 804/893 (91%)

35 EWOLUTION: Single antiplatelet/no therapy subgroup baseline characteristics: Characteristic Single AP/no therapy cohort (n=766) Age (median[iqr]) 74 (67, 79) Congestive heart failure 34% Hypertension (uncontrolled or history) 87% Age 80 years 24% Diabetes (Type I or Type II) 28% Prior Stroke Ischemic / Hemorrhagic 20% / 16% Vascular disease 39% Female gender 40% Abnormal renal / liver function 14% / 4% Prior Major Bleed or predisposition to bleeding 37% CHADS 2 score 2.8 ± 1.3 CHA 2 DS 2 -VASc score 4.4 ± 1.6 HAS-BLED 3 38% Contra-indication OAC 72% M.W. Bergmann et al, TCT 2018

EWOLUTION antiplatelet/oac treatment at follow-up 6% None 58% 14% 8% 7% SAPT study population 71% 60% 26% 7% 27% 8% 8% 2-YR FU IMPLANT DAPT (N)OAC FIRST CHANGE subgroup representative of whole study

36 EWOLUTION antiplatelet/oac treatment at follow-up 6% None 58% 14% 8% 7% SAPT study population 71% 60% 26% 7% 27% 8% 8% 2-YR FU IMPLANT DAPT (N)OAC FIRST CHANGE subgroup representative of whole study population postprocedural drug therapy at the discretion of the individual operator peri-device leakage or devicethrombus not a reason for continued DAPT or OAC (imaging available) several characteristics identified in patients not included in this subgroup (comorbitities like ACS, lost for FU, non-cv mortality) - unrelated to device, procedure or clinical endpoint 766 patients were identified who were on single AP/no therapy for 12 months (or until study completion) or with events while on single AP/no therapy. Median (IQR) time on single/none: 559 (464, 663) days M.W. Bergmann et al, TCT 2018

37 EWOLUTION: low annual stroke rate in full cohort 12% 10% Expected, based on CHA2DS2-VASc* Observed in EWOLUTION 10.1% 8% 6% 4% 7.2% RR 84% RR 85% 2% 0% 1.1% Ischemic Stroke 1.5% Ischemic Stroke/TIA/SE *Effectiveness in stroke reduction vs. estimated in the absence of therapy for comparable CHA 2 DS 2 -VASc scores based on Friberg et al. EHJ 2012

EWOLUTION: low annual bleeding rate in full cohort 6% Expected, based on HAS-BLED* Observed in EWOLUTION 5% 5.0% 5.0% 4% 3% 2.6% RR 48% 2.3% RR 54% 2% 1% 0% Major Bleeding Major Bleeding Excl.

38 EWOLUTION: low annual bleeding rate in full cohort 6% Expected, based on HAS-BLED* Observed in EWOLUTION 5% 5.0% 5.0% 4% 3% 2.6% RR 48% 2.3% RR 54% 2% 1% 0% Major Bleeding Major Bleeding Excl. Procedural *Effectiveness in bleeding reduction vs. estimated under VKA therapy for comparable HAS-BLED scores based on Lip et al. JACC 2011 These data are for the full cohort of patients, 73% of whom may be contraindicated in the US per current labeling Boersma LVA, et al. HRS2017; Late Breaking Clinical Trials: Chicago IL, USA.

39 EWOLUTION: low event rates in warfarin-eligible patients 10% Expected, based on CHA2DS2-VASc* Observed in EWOLUTION 10% Expected, based on HAS-BLED** Observed in EWOLUTION 8% 8% 6% 4% 2% 6.4% 1.1% RR 83% 6% 4% 2% 4.7% 1.7% RR 65% 0% Ischemic Stroke *Estimated rates in absence of therapy based on Friberg et al. EHJ % Major Bleeding **Estimated rates under VKA therapy based on Lip et al. JACC 2011

40 single AP/no therapy : ischemic stroke events ischemic stroke after switch to single AP/no therapy 14 ischemic strokes Rate 1.3 / 100 pt-yrs Disabling strokes: 2/14 Fatal Strokes: None Days M.W. Bergmann et al, TCT 2018

41 Study Objective Study Design ASAP-TOO (NCT ): Overview Evaluate LAA Closure with WATCHMAN in NVAF patients deemed not suitable for oral anti-coagulation therapy Prospective, multi-center Randomized 2:1 (Watchman vs Control) Considering Group Sequential Design Effectiveness Endpoint Time to first occurrence of ischemic stroke or systemic embolism Primary Endpoint Patient Population 888 Number of Sites Follow-up* Safety Endpoint 7-day rate of all-cause death, ischemic stroke, systemic embolism, or device- or procedure- related events requiring open cardiac surgery or major endovascular intervention 100 global sites 45 Day with TEE 6,18 month phone visit 12 month with TEE Bi-annually for years 2-5 Brain imaging required at baseline if prior stroke or TIA Holmes et al. AHJ 2017; in press

42 LAAO: Endocardial vs. Pericardial Ease of delivery No LA foreign body Closure Efficacy Complications

43 Mark Reisman MD

44 IC AD APR 2017 Next generation devices: Watchman FLEX, AMULET, WAVECREST and UltraSeal Watchman FLEX AMULET WaveCrest Cardia UltraSeal

45 Thank you

Left Atrial Appendage Occlusion

Left Atrial Appendage Occlusion A new strategy to prevent stroke in atrial fibrillation Ashok Talreja MD and Arijit Chanda MD VHVI symposium 24th February 2018 Outline of presentation 1. Risk of stroke