Left Atrial Appendage Closure Device David R. Holmes, Jr., M.D. Mayo Clinic, Rochester CRT 2017 Washington, DC February 2017 test

Presenter Disclosure Information David R. Holmes, Jr., M.D. “Left Atrial Appendage Closure Device” The following relationships exist related to this presentation: Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Boston Scientific.

Left Atrial Appendage Occlusion What Do We Know? Stroke and AF NOACs IFU Post FDA approval What about adjunctive therapy

AFib, Stroke and TIA Systematic Review & Meta-Analysis Background Meta-analysis to estimate the proportion of patients after a stroke or TIA who have newly diagnosed AFib after sequential phases of cardiac monitoring 50 studies and 11,658 patients Sposato et al: Lancet Neurol 14: 377, 2015

AFib, Stroke and TIA Systematic Review & Meta-Analysis Findings Prevalence of AFib either known or newly diagnosed is ~40% Newly detected AFib might be diagnosed in nearly 25% of patients with stroke/TIA Sequential cardiac monitoring increases the yield of detection Sposato et al: Lancet Neurol 14: 377, 2015

Adherence to OAC U.S. commercial insurance data base (administrative claims) 66,661 patients with atrial fibrillation treated between November 2010 and December 2014 CHA2DS2VASc score ≥2 ~90% HAS-BLED ≥3 ~50% Median F/U 1.1 yrs 6.0 15.8 59.1 19.1

Adherence to OAC Proportion of Days Covered Median: 1.1 yrs % Adherence Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

Adherence to OAC ≥6 Months Findings No significant effect between non-adherence and risk of stroke with CHA2DS2VASc score 0/1 In non-adherent patients risk of stroke with CHA2DS2VASc score 2/3; HR 2.73 (95% CI 1.76-4.23) In non-adherent patients risk of stroke with CHA2DS2VASc score ≥4 markedly elevated Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

US Reimbursement Status CMS National Coverage Decision (2/8/16) Criteria for coverage CHADS2 score 2 or CHA2DS2-VASc score 3 A formal shared decision making interaction with an independent noninterventional physician using an evidence-based decision tool on oral anticoagulation in patients with NVAF Suitable for short-term warfarin but deemed unable to take long term oral anticoagulation

Left Atrial Appendage Closure vs Warfarin in AF A Patient-Level Meta-Analysis HR P Efficacy 0.79 0.22 All Stroke or SE 1.02 0.94 Ischemic Stroke or SE 1.95 0.05 Hemorrhagic Stroke 0.22 0.004 CV/Unexplained Death 0.48 0.006 All-Cause Death 0.73 0.07 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Left Atrial Appendage Closure VOL. 65, NO. 24, 2015 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2015.04.025 as an Alternative to Warfarin for Stroke Prevention in Atrial Fibrillation A Patient-Level Meta-Analysis David R. Holmes, JR, MD,* Shephal K. Doshi, MD,y Saibal Kar, MD,z Matthew J. Price, MD,x Jose M. Sanchez, MD,k Horst Sievert, MD,{ Miguel Valderrabano, MD,# Vivek Y. Reddy, MD** This study sought to assess composite data regarding left atrial appendage closure (LAAC) in 2 ran- domized trials compared to warfarin for prevention of stroke, systemic embolism, and cardiovascular death in patients with nonvalvular AF. METHODS Our meta-analysis included 2,406 patients with 5,931 patient-years (PY) of follow-up from the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) and PREVAIL (Prospective Randomized Evaluation of the Watchman LAA Closure Device In Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trials, and their respective registries (Continued Access to PROTECT AF registry and Continued Access to PREVAIL registry). RESULTS With mean follow-up of 2.69 years, patients receiving LAAC with the Watchman device had significantly fewer hemorrhagic strokes (0.15 vs. 0.96 events/100 patient-years [PY]; hazard ratio [HR]: 0.22; p 1⁄4 0.004), cardiovascular/ unexplained death (1.1 vs. 2.3 events/100 PY; HR: 0.48; p 1⁄4 0.006), and nonprocedural bleeding (6.0% vs. 11.3%; HR: 0.51; p 1⁄4 0.006) compared with warfarin. All-cause stroke or systemic embolism was similar between both strategies (1.75 vs. 1.87 events/100 PY; HR: 1.02; 95% CI: 0.62 to 1.7; p 1⁄4 0.94). There were more ischemic strokes in the device group (1.6 vs. 0.9 and 0.2 vs. 1.0 events/100 PY; HR: 1.95 and 0.22, respectively; p 1⁄4 0.05 and 0.004, respectively). Both trials and registries identified similar event rates and consistent device effect in multiple subsets. CONCLUSIONS In patients with NVAF at increased risk for stroke or bleeding who are candidates for chronic antico- agulation, LAAC resulted in improved rates of hemorrhagic stroke, cardiovascular/unexplained death, and nonprocedural bleeding compared to warfarin. Favors Watchman   Favors warfarin 0.01 0.1 1 10 Hazard ratio (95% CI) Combination of PROTECT AF and PREVAIL patients receiving the Watchman device, vs warfarin for overall stroke, ischemic stroke, and all-cause death. J Am Coll Cardiol; 65:2614, 2015

Mortality Reduction (vs warfarin) P=0.0379 Reduction in all-cause mortality (%) P=0.051 P=0.047 P=0.13 (NS) P=0.15 (NS) RE-LY ROCKET-AF ARISTOTLE PROTECT AF Results from different clinical trials: 1Connolly, S. NEJM 2009; 361:1139-1151 – 2 yrs f-up 2Patel, M. NEJM 2011; 365:883-891 – 1.9 yrs f-up, ITT 3Granger, C NEJM 2011; 365:981-992 – 1.8 yrs f-up 4Reddy, V. LBCT HRS 2013 – 4 yrs f-up

EWOLUTION Serious Procedure-/Device-Related Events through 7 days % Boersma et al: Euro Heart J, doi:10.1083/eurheartj/ehv730

Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals Bleeding Outcomes after Left Atrial Appendage Closure Compared with Long-term Warfarin Freedom of Major Bleeding Over 3 Adjunctive Pharmacotherapy Intervals 72% >6 months post-procedure p < 0.001 Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): 1925-1932

Procedural Success ~50% new operators ~50% new operators N=449 N=566 Implant success defined as deployment and release of the device into the LAA; no leak ≥ 5 mm

Outcomes in the Post-FDA Approval Watchman Experience N=3822   Post-FDA Approval Experience Complications Pericardial Tamponade 39 (1.02%) Treated with Pericardiocentesis 24 (0.63%) Treated Surgically 12 (0.31%) Resulted in Death 3 (0.078%) Pericardial Effusion – No Intervention 11 (0.29%) Procedure-Related Stroke Device Embolization 9 (0.24%) Removed Percutaneously 3 Removed Surgically 6 Death Procedure-Related Mortality Additional Mortality within 7 days 1 (0.026%)

Summary Following United States FDA approval, this dataset represents the first patients implanted with this novel therapy Device usage, procedure time, and implant success rates are consistent with clinical trial results Safety complications rates in the initial experience are consistent with clinical trial results  Cardiac tamponade and procedure-related mortality occurred in ~1% and <0.1% of patients, respectively

Watchman Implantation NOACs vs Warfarin Multicenter Registry 214 patients undergoing clinically indicated Watchman implantation treated with NOAC 212 patients undergoing clinically indicated Watchman implantation treated with Warfarin as per IFU Enomoto et al: Heart Rhythm 14:19-24, 2017

Watchman Implantation NOACs vs Warfarin Adverse events NOACs (n=214) Warfarin (n=212) P Stroke, TIA, or systemic embolism Periprocedure 0 (0%) 1.0 Postprocedure 1 (0.5%) Other complications 2 (0.9%) 0.3 LAA thrombosis LAA thrombosis or embolic event (including stroke, TIA, or systemic embolism) 3 (1.4%) Enomoto et al: Heart Rhythm 14:19-24, 2017

Conclusion: NOACs proved to be a feasible peri- and postprocedural alternative regimen to warfarin for preventing device-related thrombosis and thromboembolic complications expected early after appendage closure with the Watchman device, without increasing the risk of bleeding.

ASAP-TOO Up to 888 randomized patients Primary effectiveness endpoint Time to first occurrence of ischemic stroke or systemic embolism Primary safety endpoint MACE during index hospitalization All-cause death Ischemic stroke Systemic embolism Device/procedural events requiring significant intervention

Left Atrial Appendage Occlusion What Do We Know? Stroke and AF NOACs IFU Post FDA approval What about adjunctive therapy

EWOLUTION: 3-months outcome of Left Atrial Appendage Closure with the WATCHMAN device in Europe Thrombus at the device, leakage at follow-up, device embolisation, post-procedural drug regimen and impact of center experience data from the prospective 1,025 patients EWOLUTION Registry M. W. Bergmann1, B. Schmidt2, T. Betts3, E. Teiger4, C. Tamburino5, E. Pokushalov6, S. Kische7, T. Schmitz8, H. Ince9, H. Sievert10, L.V.A. Boersma11 – (1) Cardiologicum Hamburg, Germany (2) Cardiology Centre Bethanien (CCB), Frankfurt, Germany (3) John Radcliffe Hospital, Oxford, United Kingdom (4) University Hospital Henri Mondor, Creteil, France (5) Ferrarotto Hospital, Catania, Italy (6) State Research Institute of Circulation Pathology, Novosibirsk, Russian Federation (7) Vivantes Klinikum Friedrichshain, Berlin, Germany (8) Elisabeth Krankenhaus Essen, Germany (9) Vivantes Klinikum Urban, Berlin, Germany (10) CardioVascular Center Frankfurt, Germany (11) St Antonius Hospital, Nieuwegein, Netherlands. test

Potential Conflicts of Interest Speaker's name: Martin W. Bergmann I have the following potential conflicts of interest to report: Consultant: Biosense Webster, BOSTON SCIENTIFIC Honorarium: BAYER PHARMA AG, BIOTRONIK, Boehringer Ingelheim, DAIICHI SANKYO and ELI-LILLY, Novartis, ST. JUDE MEDICAL

Topics EWOLUTION study design & population EWOLUTION results @ 3 months Open question: impact of center experience? Open question: impact of post-implant drug regimen? Conclusions Prof. M.W. Bergmann 2016

EWOLUTION Study Design & Population Study objective Collect real-world WATCHMAN LAAO experience outside of selected populations in prior RCT Study design Prospective, single-arm, multi-center registry of the Watchman LAA Closure Technology Primary endpoint 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 Patient population >1,000 patients Number of sites 47 throughout Europe, Russia and Middle East Enrollment Started October 2013 – completed May 2015 Follow-up Standard practice at participating centers Normally 1-3 months post-procedure Annually thereafter for a total of 2 years Prof. M.W. Bergmann 2016

EWOLUTION Study Design & Population Top 10 enrolling centers Pt Enrolled (no.) Berlin, Germany (Atmowihardjo/Ince) 86 Berlin, Germany (Kische) 68 Hamburg, Germany (Meincke/Bergmann) 55 Novosibirsk, Russia (Pokushalov) 51 Essen, Germany (Schmitz) 48 Frankfurt, Germany (Schmidt) 40 Dublin, Ireland (Foley) 37 Mainz, Germany (Gori) 33 Krasnoyarsk, Russia (Protopopov) 29 n=1,025 Prof. M.W. Bergmann 2016

EWOLUTION Study Design & Population Informed consent obtained Reassess per physician’s discretion LAA criteria met? NO Withdrawal (Intent) YES n=5 reimplant Implant of WATCHMAN ***subject is enrolled*** Device not implanted Device implanted n=1,005 Follow-up according to center’s practice Withdrawal (attempt) n=15 Boersma LVA et al. Catheter Cardiovasc Interv 2015 EWOLUTION: design of a registry to evaluate real-world clinical outcomes in patients with AF and high stroke risk-treated with the WATCHMAN left atrial appendage closure technology Prof. M.W. Bergmann 2016

EWOLUTION: Patient Flow Up to 3 Months Informed consent obtained: n=1,025 Anatomy considered not suitable at prescreening: n=5 study population Implant of WATCHMAN: n=1,020 Unsuccessful Implant: n=15 Patients with Watchman implant: n=1,005 Death: n=21 Withdrawals: n=5 Patients with Watchman implant @ 3 months: n=979 Prof. M.W. Bergmann 2016

EWOLUTION: Device Sizing Mean Compression (%) 15% 16% 17% 21% 18% (n=124) (n=285) (n=307) (n=154) (n=98) Prof. M.W. Bergmann 2016

EWOLUTION: Procedural Results @ 3 Months % Implant success First device release successful First device size correct Complete Seal or jet size 5 mm at implant Complete seal or jet size 5 mm at first FU Prof. M.W. Bergmann 2016

Effect of Center Experience – Procedural Enrolment Quartile Subjects (Mean ± SD Min – Max) First Device Release Successful (%) First Device Size correct (%) Complete Seal or Jet Size 5 mm at implant (%) Complete Seal or Jet Size 5 mm at First FU (%) 1 11 ± 5 1 – 18 65.2 88.6 100.0 99.1 2 23 ± 2 20 – 27 70.4 92.5 99.0 3 33 ± 5 28 – 40 65.0 92.3 99.6 4 63 ± 18 48 – 86 84.4 98.8 99.2 98.2 P-value <0.0001 0.3545 0.8332 Prof. M.W. Bergmann 2016

EWOLUTION: Safety @ 3 mo. Other SAEs # pts (n=1,020) Pts (%) Heart Failure 19 9.5 18 1.8 Pulmonary 13 6.5 12 1.2 Arrhythmias 10 5.0 9 0.9 Systemic Infection 7 3.5 0.7 Peripheral Vascular Disease 6 3.0 5 0.5 Vascular damage @ puncture site 2.5 4 0.4 Genito-urinary 3 0.3 Cancer 2.0 Prof. M.W. Bergmann 2016

EWOLUTION: SAE Distribution @ 3 Months

Effect of Center Experience – SAEs @ 3 Mo Quartile 1 (1-18 pts enrolled) Quartile 2 (20-27 pts enrolled) Quartile 3 (28-40 pts enrolled) Quartile 4 (48-86 pts enrolled) Prof. M.W. Bergmann 2016

Post-Implant Drug Regimen Patient Baseline Characteristics Nothing (n=67) Single APT (n=72) Dual APT (n=607) Warfarin (n=159) NOAC (n=113) P<0.0001 P<0.0001 Prof. M.W. Bergmann 2016

SAE Stratified for Post-Implant Drug Regimen Nothing (n=67) Single APT (n=72) Dual APT (n=607) Warfarin (n=159) NOAC (n=113) P=0.275 % P=0.792 P=0.768 P=0.498 Prof. M.W. Bergmann 2016

EWOLUTION: Summary LAAC with WATCHMAN has a high success rate and low periprocedural events even in a high risk, mostly oral anticoagulation contraindicated patient population With current training standards, centers with less experience have the same high success rates with low complication rate Within the first three months after LAA closure, bleeding itself is the issue with the highest event rate All drug regimen appear safe, with NOAC presenting with the  lowest bleeding rate without an increase in thrombus at the device or stroke SAE rates Prof. M.W. Bergmann 2016

Proportion with thromboembolic event Effectiveness of LAAO for the Reduction of Thromboembolism in Patients With AFib HR 0.61, CI 0.46-0.82, P=0.009 HR 0.85, CI 0.74-0.97, P=0.015 Proportion with thromboembolic event Proportion dead LAAO No LAAO LAAO No LAAO Days Days

Left Atrial Appendage Obliteration LAA and Obliteration Schwartz et al: JACC Intv 3:870, 2010

Left Atrial Appendage Obliteration Dog Heart 72 Hours After Device Implantation Schwartz et al: JACC Intv 3:870, 2010

Expected Annual Rate of Stroke Based on CHADS2 Score Gage 2004 Gage 2001 Event rate – pt/yr (%) CHADS2 score of the ASAP population CHADS2 score Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

ASAP Registry All cause stroke/SE 2.3% / year Ischemic stroke Hemorrhagic stroke 0.6% / year Expected by CHADS2 7.3% / year Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

ASAP Study Clinical Outcomes Entire Cohort Events/Pt-Yrs* Primary efficacy 8/175.0 (4.6%) Death, all cause 9/180.0 (5.0%) All stroke 4/176.0 (2.3%) Ischemic stroke 3/176.9 (1.7%) Hemorrhagic stroke 1/179.1 (0.6%) Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

ASAP Study Procedure & Device-Related Serious Adverse Events Device embolization 2 (1.3%) Pericardial effusion with tamponade (percutaneous drainage) Pericardial effusion, no tamponade (no intervention required) 3 (2.0%) Device thrombus with ischemic stroke 1 (0.7%) Femoral pseudoaneurysm ( surgically repaired) 1. (0.7%) Femoral hematoma/bleeding Other Total patients with procedure- and device-related SAEs 13 (8.7%) Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

EWOLUTION Multicenter registry of 1,021 patients treated with Watchman LAAC – 2013-2015 47 centers 13 countries Objective: obtain clinical data on Procedural success and 30-day outcomes Long-term outcomes Bleeding Stroke/TIA Boersma et al: Euro Heart J, doi:10.1083/eurheartj/ehv730

EWOLUTION Age (yrs) 73 ± 9 History TIA 10.7% History Stroke 19.7% History hemorrhagic stroke 15.0% Not eligible for OAT 61.8% CHA2DS2-VASc 4.5 ± 1.6 HAS-BLED Score 2.3 ± 1.2 Boersma et al: Euro Heart J, doi:10.1083/eurheartj/ehv730

EWOLUTION 30-Day Outcome 34 SAEs in 32 patients – 3.6% Major bleeding requiring transfusion – 17 Pericardial effusion – 7 Ischemic stroke – 3 Overall mortality – 0.7% Boersma et al: Euro Heart J, doi:10.1083/eurheartj/ehv730

EWOLUTION Implant Success Comparison % Boersma et al: Euro Heart J, doi:10.1083/eurheartj/ehv730

Conclusion: Left atrial appendage closure with the WATCHMAN device has a high success rate in complete LAAC with low peri-procedural risk, even in a population with a higher risk of stroke and bleeding, and multiple co-morbidities. Improvement in implantation techniques has led to a reduction of peri-procedural complications previously limiting the net clinical benefit of the procedure.

Watchman Implantation Patients not taking Warfarin Single center study 59 consecutive patients with relative/absolute contraindications to warfarin treated with Watchman Approach Device size chosen to be 15-30% larger than the LAA diameter in contrast to usual practice (8-20%) Meincke et al: EuroIntervention 9:463-468, 2013

Procedural and Clinical Outcome Pericardial effusion 2 (3.3%) Ischemic stroke 1 (1.7%) Follow-up (6.3 mo) TIA Device thrombus (no events) 3 (5.0%) Meincke et al: EuroIntervention 9:463-468, 2013

Conclusions: Our data suggest that DAPT can be used safely during the first 45 days in patients with contraindications to warfarin. An algorithm employing larger devices in relation to the LAA ostium with consecutively larger compression improved procedural safety compared to the current standard regarding leakage and device repositioning.

ASAP Study Watchman Device Multicenter Registry 150 patients with nonvalvular AF who were ineligible for warfarin Clinical (N=150) % Age, yrs 72.5 ± 7.4 Male 96 (64.0) Stroke risk factors Heart failure or reduced LVEF 43 (28.7) Hypertension 142 (94.7) Age ≥ 75 yrs 64 (42.7) Diabetes mellitus 48 (32.0) Prior stroke or TIA 61 (40.7) Vascular disease 27 (18.0) Age 65 to 74 years Female 54 (36.0) Reddy VY et al: J Am Coll Cardiol 61:2551-6, 2013

ASAP (Aspirin Plavix) Study Patients history of hemorrhagic & bleeding tendencies or a warfarin hypersensitivity 150 patients, 4 European centers Average CHADS2 = 2.8 Post procedure anti-platelet regimen Clopidogrel through 6 months Aspirin indefinitely Patients followed to 2 years Follow-up @ 3, 6, 12, 18 & 24 months TEE at 3 and 12 months Average follow-up was 14.4 months Rate of success with implantation in warfarin contraindicated patients1 94.7% successfully implanted Avg. Procedure Time = 51.5 mins 1 Braut A et al, LAA closure with the WATCHMAN Device in patients with contraindications to warfarin: preliminary results from the ASA Plavix registry (ASAP), ESC Congress 2011, Paris 27-31 August 2011 The WATCHMAN Device is not approved for patients contraindicated to OACs

Results Expected and Observed Stroke Rates (per 100 patient-years) 7.3% 77% Reduction Expected, based on CHADS2 score Expected, if Clopidogrel was used throughout follow-up Observed rate in ASAP 5.0% 1.7% Observed rate of ischemic stroke represents a 77% reduction from the expected event rate

Conclusions: LAA closure with the Watchman device can be safely performed without a warfarin transition, and is a reasonable alternative to consider for patients at high risk for stroke but with contraindications to systemic oral anticoagulation.

EWOLUTION: Patient Baseline Characteristics % Male Gender 60 History of Ischemic Stroke 20 Previous Hemorrhagic Stroke 15 Prior Major or predisposition to bleeding 39 CHA2DS2-VASc score 5 49 HAS-BLED 3 40 Contra-indication for oral anticoagulation 72 Age 80 years 26 Hypertension (uncontrolled or history of hypertension) 86 Congestive heart failure 34 Type II diabetes 29 Vascular disease 42 Abnormal renal function 16 Abnormal liver function 4 Prof. M.W. Bergmann 2016

EWOLUTION: Safety Results @ 3 Months % All SAEs (n pt=146) Device/ procedure related SAEs (n pts=42) Bleeding SAEs (n pts=38) Thrombus on the device (n pts=20) All deaths (n pts=21) PE/ cardiac tamponade (n pts=7) Strokes (n pts=4) Device embolization (n pts=4) Prof. M.W. Bergmann 2016

EWOLUTION: Safety Results @ 3 Months N=1025, AC contraindicated 72% All SAEs (n pt=146) Device/ procedure related SAEs (n pts=42) Bleeding SAEs (n pts=38) Thrombus on the device (n pts=20) All deaths (n pts=21) PE/ cardiac tamponade (n pts=7) Strokes (n pts=4) Device embolization (n pts=4) Prof. M.W. Bergmann 2016

Oral Anticoagulation in NVAF Medical and pharmacy claims data base 45,092 newly diagnosed NVAF patients Nov. 2010 – Nov. 2013 41% treated with an OAC, warfarin and NOAC Average F/U – 2.25 years 72.7% discontinued OAC 17.7% within 3 months 55% within 12 months <2 39.8% 2/3 42.4% >3 40.3% Jain, Circulation 134:A15102, 2016

Adherence to OAC Proportion of Days Covered Median: 1.1 yrs % Adherence Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

Adherence to OAC Incidence of Stroke/100 person years Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

OAC Survival Analysis using Bleeding as Outcome Time not taking OAC All major bleeding Gastrointestinal bleeding Intracranial hemorrhage CHA2DS2VASc score 0 or 1 <1 wk Ref 1 wk to 1 mo 0.93 (0.48-1.79) 1.13 (0.53-2.44) 0.33 (0.04-2.78) 1-3 mo 0.59 (0.29-1.22) 0.48 (0.18-1.28) 0.25 (0.03-2.15) 3-6 mo 0.29 (0.10-0.84) 0.36 (0.11-1.21) 0.23 (0.05-0.96) ≥6 mo 0.46 (0.25-0.86) 0.46 (0.21-1.00) NA Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

OAC Survival Analysis using Bleeding as Outcome Time not taking OAC All major bleeding Gastrointestinal bleeding Intracranial hemorrhage CHA2DS2VASc score 2 or 3 <1 wk Ref 1 wk to 1 mo 1.04 (0.80-1.35) 1.03 (0.74-1.43) 0.99 (0.50-1.96) 1-3 mo 1.07 (0.83-1.38) 1.14 (0.83-1.55) 1.05 (0.55-2.02) 3-6 mo 0.87 (0.64-1.18) 0.79 (0.53-1.17) 1.17 (0.59-2.33) ≥6 mo 0.68 (0.52-0.90) 0.64 (0.45-0.92) 0.90 (0.48-1.69) Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

OAC Survival Analysis using Bleeding as Outcome Time not taking OAC All major bleeding Gastrointestinal bleeding Intracranial hemorrhage CHA2DS2VASc score ≥4 <1 wk Ref 1 wk to 1 mo 1.11 (0.98-1.26) 1.04 (0.89-1.21) 0.31 (0.94-1.82) 1-3 mo 0.90 (0.78-1.04) 0.84 (0.71-1.00) 1.23 (0.87-1.74) 3-6 mo 0.94 (0.80-1.10) 0.91 (0.76-1.11) 1.20 (0.82-1.76) ≥6 mo 0.79 (0.67-0.93) 0.75 (0.61-0.91) 1.06 (0.72-1.56) Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

Adherence to OACs Apixaban (n=3,900) Dabigatran (n=10,235) Rivaroxaban (n=12,336) All NOACs (n=26,471) Warfarin (n=38,190) P ( NOACs vs Warfarin) Adjusted adherence, 955 CI All (%) 52.1 (50.3-53.9) 45.9 (44.8-47.1) 47.6 (46.6-48.7) 47.5 (46.7-48.2) 38.7% (38.1-39.3) <0.001 CHA2DS2VASc score 0 or 1 (%) 40.6 (35.8-45.4) 28.6 (26.3-30.9) 30.8 (28.7-32.9) 30.8 (29.3-32.3) 25.2 (23.4-27.0) CHA2DS2VASc score 2 or 3 (%) 51.9 (48.9-55.0) 46.9 (45.1-48.6) 48.8 (47.2-50.5) 48.3 (47.2-49.5) 37.3 (36.3-38.4) CHA2DS2VASc score ≥4 (%) 54.1 (51.8-56.5) 48.7 (47.1-50.3) 50.1 (48.7-51.5) 50.1 (49.0-51.1) 42.0 (41.3-42.7) Yao et al: J Am Heart Assoc doi:10.1161/JAHA.115.003074, 2006

Conclusions: Adherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA2DS2VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA2DS2VASc score 0 or 1.

FRACTAL Registry Warfarin Use 1005 patients, first documented episode of atrial fibrillation % Study population Ideal candidates Women Age >85 Follow-up (months) Initially, 65% of subjects were prescribed warfarin at baseline, but only 44% were taking it at 30 months. Reynolds et al: Am J Cardiol 97:538, 2006

Atrial Fibrillation in Cryptogenic Stroke Multicenter RCI 572 patients with cryptogenic ischemic stroke/TIA within past 6 months Randomization to Additional non-invasive ambulatory ECG with 30-day event triggered records, or Conventional 24-hr Holter Gladstone et al: N Engl J Med; 370:2467, 2014

AFib in Patients with Cryptogenic Stroke Intervention Group (n=286) Control Group (n=285) Absolute Difference (95% CI) P No. of patients needed to screen Outcome no./total no. (%) Points (%) Primary outcome: detection of AFib with duration 30 sec within 90 days† 45/280 (16.1) 9/277 (3.2) 12.9 (8.0-17.6) <0.001 8 (5.7-12.5) Secondary outcomes Detection of Afib with duration 30 sec 44/284 (15.5) 7/277 (2.5) 13.0 (8.4-17.6) 8 (5.7-11.9) Detection of AFib with duration 2.5 min 28/284 (9.9) 7.4 (3.4-11.3) 14 (8.8-29.4) of any duration 56/284 (19.7) 13/277 (4.7) 15.0 (9.8-20.3) 7 (4.9-10.2) Gladstone et al: N Engl J Med; 370:2467, 2014

AFib in Patients with Cryptogenic Stroke Therapy Intervention Group (n=286) Control Group (n=285) Absolute Difference (95% CI) P After study monitoring no./total no. (%) Points (%) Therapy at 90 days after randomization Anticoagulant therapy 52/280 (18.6) 31/279 (11.1) 7.5 (1.6 to 13.3) 0.01 Antiplatelet therapy only 223/280 (79.6) 246/279 (88.2) -8.6 (-14.6 to -2.5) 0.006 Therapy at randomization changed by 90 days From antiplatelet therapy to anticoagulant therapy 38/280 (13.6) 13/279 (4.7) 8.9 (4.2 to 13.6) <0.001 From anticoagulant therapy to antiplatelet therapy 3/280 (1.1) 2/279 (0.7) 0.4 (-1.2 to 1.9) 0.66 Gladstone et al: N Engl J Med; 370:2467, 2014

AFib in Patients with Cryptogenic Stroke Patients with AFib detected (%) Duration of ECG Monitoring Gladstone et al: N Engl J Med; 370:2467, 2014

Conclusions: Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal AFib was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of AFib by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring. (Funded by the Canadian Stroke Network and others; EMBRACE ClinicalTrials.gov number, NCT00846924.) Gladstone et al: N Engl J Med; 370:2467, 2014

AFib After Stroke and TIA Hazard ratio 5.8 (95% CI 3.3-10.2) Log-rank P<0.0001 Mobile cardiac outpatient telemetry Cumulative probability of diagnosis of PSAF (%) Implantable loop recording Days between start of cardiac monitoring and first diagnosis of PSAF Sposato et al: Lancet Neurol 14: 377, 2015

AFib, Stroke and TIA Systematic Review & Meta-Analysis Background Atrial fibrillation associated with 5x increase in stroke In patients with AFib, those with stroke have a 15% incidence of recurrence within 1 year 20% of patients with stroke have prior diagnosis of AFib Concern A substantial proportion of patients with stroke may have clinically undetected PAF Sposato et al: Lancet Neurol 14: 377, 2015

AFib, Stroke and TIA Systematic Review & Meta-Analysis Diagnostic modalities Admission ECG Serial ECGs Continuous in-patient ECG Holter monitoring Mobile out-patient telemetry External loop recording Implantable loop recording Post-stroke atrial fibrillation AFib or flutter – chronic or paroxysmal irrespective of duration Sposato et al: Lancet Neurol 14: 377, 2015

Interpretation By sequentially combining cardiac monitoring methods, atrial fibrillation might be newly detected in nearly a quarter of patients with stroke or transient ischaemic attack. The overall proportion of patients with stroke who are known to have atrial fibrillation seems to be higher than previously estimated. Accordingly, more patients could be treated with oral anticoagulants and more stroke recurrences prevented. Sposato et al: Lancet Neurol 14: 377, 2015

Post-FDA Approval, Initial US Clinical Experience with Watchman Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation Vivek Y. Reddy MD1*, Douglas N. Gibson MD2, Saibal Kar3, William O’Neill MD4, Shephal K. Doshi MD5, Rodney P. Horton MD6, Maurice Buchbinder MD7, Nicole T. Gordon BSEE8, David R. Holmes MD9* *Both authors contributed equally to the development of this manuscript 1Icahn School of Medicine at Mount Sinai, New York, NY; 2Scripps Clinic, La Jolla, CA; 3Cedars Sinai Medical Center, Los Angeles, CA; 4Center for Structural Heart Disease, Henry Ford Hospital, Detroit, MI; 5St. John’s Health Center, Santa Monica, CA; 6Texas Cardiac Arrhythmia Institute, Austin, TX; 7Foundation for Cardiovascular Medicine, La Jolla, CA; 8Boston Scientific Corporation, St. Paul, MN; 9Department of Cardiology, Mayo Clinic, Rochester, MN test

Presenter Disclosure Information David R. Holmes, Jr., M.D. “Post-FDA Approval, Initial US Clinical Experience with Watchman Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation” The following relationships exist related to this presentation: Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Boston Scientific.

Background March 2015 FDA approval of left atrial appendage occlusion (LAAC) with Watchman™ device to reduce risk of stroke in NVAF Clinical procedures initiated using following criteria Patients met FDA clinical criteria Local site patient consent and IRB Physicians experienced with or trained in patient selection, as well as in procedural performance Procedures performed with trained Watchman clinical specialist in attendance

Background Issue Outcome of patients implanted between March 2015 (FDA approval), and August 2016 (LAAC Registry certified) Remains unknown without formalized data on safety or usage.

Purpose In the absence of a prospective registry from the time of FDA approval of the WATCHMAN LAAC device, we sought to analyze procedural safety data in the initial post-approval launch as reported to the manufacturer

Methods March 2015 – May 2016 3,822 consecutive patients underwent LAAC with Watchman™ implantation by 382 physicians at 169 U.S. centers 50% of procedures performed by newly trained operators Each implant was required to be performed with Watchman clinical specialist in attendance Details of each procedure recorded on standardized forms, and events reported to manufacturer per de- identified patient data

Methods (cont) Major complications Pericardial effusion, need for urgent cardiac surgery, stroke, device embolization, and death Reviewed independently by Sponsors – Medical Safety Group Authors VR – electrophysiologist DRH – interventional cardiologist

Outcomes in the Post-FDA Approval Watchman Experience   Post-FDA Approval Experience Procedural Parameters No. of Procedures 3822 Implantation Success, % 3653 (95.6%) Procedure Duration, min Median 50 min IQR (1st) 36 min IQR (3rd) 66 min Devices Used per Procedure 1.38

Procedural Success ~50% new operators ~70% new operators N=449 N=566 Implant success defined as deployment and release of the device into the LAA; no leak ≥ 5 mm

Average # of Devices/Implant Attempt Devices per Case1-2 Average # of Devices/Implant Attempt 1 WATCHMAN FDA Panel Sponsor Presentation. Oct 2014; 2 Boersma, L.et al. EHJ; published online Jan 2016 in press

Procedure Duration WATCHMAN FDA Panel Sponsor Presentation. Oct 2014

Outcomes in the Post-FDA Approval Watchman Experience N=3822   Post-FDA Approval Experience Complications Pericardial Tamponade 39 (1.02%) Treated with Pericardiocentesis 24 (0.63%) Treated Surgically 12 (0.31%) Resulted in Death 3 (0.078%) Pericardial Effusion – No Intervention 11 (0.29%) Procedure-Related Stroke Device Embolization 9 (0.24%) Removed Percutaneously 3 Removed Surgically 6 Death Procedure-Related Mortality Additional Mortality within 7 days 1 (0.026%)

Comparison of Procedural Complications Across Watchman Studies

Comparison of Procedural Complications Across Watchman Studies PROTECT-AF PREVAIL CAP CAP2 EWOLUTION Post-FDA Approval Aggregate Data Pericardial Tamponade 20 (4.3%) 5 (1.9%) 8 (1.4%) 11 (1.9%) 3 (0.29%) 39 (1.02%) 86 (1.28%) Treated with pericardiocentesis 13 (2.8%) 4 (1.5%) 7 (1.2%) n/a 2 (0.20%) 24 (0.63%) Treated surgically 7 (1.5%) 1 (0.4%) 1 (0.2%) 1 (0.10%) 12 (0.31%) Resulted in death 3 (0.78%) Pericardial effusion – no intervention 4 (0.9%) 5 (0.9%) 3 (0.5%) 4 (0.39%) 11 (0.29%) 27 (0.40%) Procedure-related stroke 5 (1.15%) 1 (0.37%) 2 (0.35%) 3 (0.078%) 12 (0.18%) Device embolization 3 (0.6%) 2 (0.7%) 9 (0.24%) 17 (0.25%) Removed percutaneously 1 3 Removed surgically 2 6 Death Procedure-related mortality 1 (0.1%) 4 (0.06%) Additional mortality within 7 days 1 (0.17%) 1 (0.026%) 5 (0.07%)

Device Embolization Details Device Size Method of Removal 21 mm Percutaneous Snare 33 mm Surgical 30 mm 24 mm 27 mm

Summary Following United States FDA approval, this dataset represents the first patients implanted with this novel therapy Device usage, procedure time, and implant success rates are consistent with clinical trial results Safety complications rates in the initial experience are consistent with clinical trial results  Cardiac tamponade and procedure-related mortality occurred in ~1% and <0.1% of patients, respectively

Conclusion In the real-world post-FDA approval experience of Watchman LAAC, procedural success was high and complication rates low. Complications were low even with ~50% of the operators being new to the procedure. This demonstrates that early procedure learnings can be transferred through rigorous training.