WATCHMANTM Left Atrial Appendage Closure Device

WATCHMANTM Left Atrial Appendage Closure Device
Clinical Data Overview SH AD MAY2017

Need for a Device-Based Alternative for Stroke Risk Reduction
Agenda Need for a Device-Based Alternative for Stroke Risk Reduction WATCHMANTM Clinical Data Clinical study overview Efficacy – Stroke risk reduction Efficacy – Bleeding reduction Procedural Success and Safety Future Patient Populations SH AD MAY2017

Need for a Device-Based Alternative for Stroke Risk Reduction

AF is a Growing Problem Associated with Greater Morbidity and Mortality
AF = most common cardiac arrhythmia, and growing AF increases risk of stroke Higher stroke risk for older patients and those with prior stroke or TIA 15-20% of all strokes are AF-related AF results in greater disability compared to non-AF-related stroke High mortality and stroke recurrence rate ‘15 ‘20 ‘30 ’40 ‘50 5M 12M < ~5 M people with AF in U.S., expected to more than double by 20501 5x greater risk of stroke with AF2 Go AS. et al, Heart Disease and Stroke Statistics—2013 Update: A Report From the American Heart Association. Circulation. 2013; 127: e6-e245. Holmes DR, Atrial Fibrillation and Stroke Management: Present and Future, Seminars in Neurology 2010;30:528–536.

AF Creates Environment for Thrombus Formation in Left Atrium
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 TIA1 and ischemic stroke2. In non-valvular AF, >90% of stroke-causing clots that come from the left atrium are formed in the LAA3. 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)

Aspirin (81-325 mg daily) or warfarin (INR 2-3)
2014 ACC/AHA/HRS Treatment Guidelines to Prevent Thromboembolism in Patients with AF Assess stroke risk with CHA2DS2-VASc score Score 1: Annual stroke risk 1%, oral anticoagulants or aspirin may be considered Score ≥2: Annual stroke risk 2%-15%, oral anticoagulants are recommended Balance benefit vs. bleeding risk 2014 AHA/ACC/HRS Guideline for the Management of Patients with AF CHA2DS2 VASc Score Recommendation No anticoagulant 1 Aspirin ( mg daily) or warfarin (INR 2-3) ≥2 Oral anticoagulants are recommended (warfarin (INR 2-3), dabigatran, rivaroxaban or apixaban January, CT. et al AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. JACC. 2014; doi: /j.jacc N

Oral Anticoagulation is Standard of Care, but Not Ideal for All NCDR Pinnacle Registry
Use of OACs in AF Patients peaks at ~50%, use declines with increasing risk Warfarin Bleeding risk Daily regimen High non-adherence rates Regular INR monitoring Food and drug interaction issues Complicates surgical procedures Novel Oral Anticoagulants Daily or 2x/daily regimen Limited reversal agents High cost 1. Hsu, J et al. JAMA Cardiol. Published online March 16, doi: /jamacardio

~30% of NOAC patients stop taking any drug at 2 years
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

Introducing the WATCHMAN™ LAAC Device
Indications for Use The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non- valvular atrial fibrillation who: Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy; Are deemed by their physicians to be suitable for warfarin; and Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin SH AD MAY2017

WATCHMAN Clinical Data
Clinical Study Overview

WATCHMAN Clinical Leadership More than 2,400 patients and nearly 6,000 patient-years of follow-up
Mar 2015 FDA Approval 2002 – Pilot nonrandomized Feasibility and Safety 2008 – CAP Registry non-randomized Add’l patients and follow-up Oct 2014 FDA Panel #3 2017 ASAP TOO Randomized US Indication Expansion Worldwide study 2010 – PREVAIL Randomzied Comparison: warfarin Dec FDA Panel #2 Apr FDA Panel #1 2012 – CAP2 Registry Non-Randomzied Add’l patients and follow-up 2013 EWOLUTION, WASP Registries non-randomized Real-world, All comers 2009 – ASAP non-randomized Patients Contra-indicated to warfarin* 2005 – PROTECT AF Randomized Comparison: warfarin 2016 NCDR LAAO Registry Post-approval statistical analysis * Not US indication N

WATCHMAN™ - Most Studied LAAC Device Only one proven with long-term data from randomized trials and multi-center registries Key Trials N Highlights PROTECT AF1 ( ) 707 Prospective, randomized 2:1, non-inferiority trial of LAA closure vs. warfarin. CAP2 ( ) 566 Prospective registry allowing continued access to the WATCHMAN Device and gain further information prior to PMA approval. PREVAIL3 ( ) 407 Prospective, randomized 2:1, non-inferiority trial to collect additional information on the WATCHMAN Device. ( ) 579 Prospective registry allowing continued access to the WATCHMAN Device prior to PMA approval. EWOLUTION ( )4* 1025 Prospective registry allowing all patients receiving a WATCHMAN Device at participating centers in Europe, Middle East and Russia Total patients >3,000 ~7,000 Patient-Years of Follow-up WATCHMAN is the most studied LAAC device - most patients and only one with long-term clinical data. Protect AF was prospective, randomized, multicenter trial with 707 patients studying the device versus warfarin. Cap was a prospective continued access registry collecting additional data on device patients while awaiting approval Prevail was the 2nd prospective, randomized trial versus warfarin to collect additional device data Cap2 was another prospective continued access registry after Prevail. Portfolio of over 2000 patients studied with over 6000 patient years of follow-up 3 positive votes from FDA sponsored panels [CLICK] * Majority of patients enrolled could not take anticoagulation and therefore contraindicated in the US per current labeling. 1 Reddy, et al. JAMA ;312(19): 2 Reddy VY et al. Circulation. 2011; 123: 3 Holmes et al., JACC 2014,;4(1): 1-11. 4Boersma, L. V. A., et al. CCI (2015); 88(3):

WATCHMAN™ - Most Studied LAAC Device Only one proven with long-term data from randomized trials and multi-center registries PROTECT AF CAP Registry PREVAIL CAP2 Enrollment Purpose 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 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 2. Effectiveness: Ischemic stroke or systemic embolism, occurring after 7 days post-randomization or WATCHMAN implant procedure 3. Safety: Death, ischemic stroke, systemic embolism and procedure/device-related complications within 7 days of implantation procedure Source: FDA Oct 2014 Panel Sponsor Presentation. 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.

Majority of patients were at a high stroke risk, and all were eligible for anti-coagulation
Anticoagulation Eligible CHA2DS2-VASc Score ≥2 93% High Risk PROTECT AF CAP PREVAIL CAP2 96% 100% Patients (%) …93% of patients in PROTECT had a CHADS VASc score of 2 OR MORE. [PAUSE] This OVERWHELMING MAJORITY of PROTECT patients are considered high risk according to the more contemporary and more sensitive indicator of stroke risk. [CLICK] Similarly, 96% of the CAP patients and ALL PREVAIL and CAP2 patients had scores of 2 or more. CHA2DS2-VASc Score AHA/ACC/HRS Guidelines (2014); Holmes, DR et al. J Am Coll Cardiol. 2015;65(24): N

Majority of patients in the trial were at a moderate to high bleeding risk
…93% of patients in PROTECT had a CHADS VASc score of 2 OR MORE. [PAUSE] This OVERWHELMING MAJORITY of PROTECT patients are considered high risk according to the more contemporary and more sensitive indicator of stroke risk. [CLICK] Similarly, 96% of the CAP patients and ALL PREVAIL and CAP2 patients had scores of 2 or more. *Estimated AHA/ACC/HRS Guidelines (2014); Holmes, DR et al. J Am Coll Cardiol. 2015;65(24): N

Efficacy – Stroke Risk Reduction

PROTECT AF/PREVAIL Meta-Analysis: WATCHMAN Comparable to Warfarin
HR p-value Efficacy 0.79 0.22 All stroke or SE 1.02 0.94 Ischemic stroke or SE 1.95 0.05 Hemorrhagic stroke 0.004 Ischemic stroke or SE >7 days 1.56 0.21 CV/unexplained death 0.48 0.006 All-cause death 0.73 0.07 Major bleed, all 1.00 0.98 Major bleeding, non procedure-related 0.51 0.002 Efficacy comparable All stroke comparable, but balanced by more isc strokes in WM, but less hemorrhagic. After accounting for the proc strokes in the early PAF experience, no statistical difference in isch strokes CV death statistically favors WM All cause death and major bleeding are comparable between therapies, but after accounting for procedure-related bleeding events such as PEs, major bleeding rates favor WM Favors WATCHMAN   Favors warfarin Hazard Ratio (95% CI) N Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):

PROTECT AF Ischemic Strokes: Same Rate Once Accounting For Procedure-related Strokes
Patients with Ischemic Stroke(%) 6 Procedure related Strokes (primarily air emboli) Non- Procedure related Five of these ischemic strokes occurred on the day of the implant; one additional event occurred before the procedure. These are represented here in dark green. [CLICK] Comparing the remaining events in the WATCHMAN arm to control, we see that the ischemic stroke rate is NUMERICALLY THE SAME in both arms at around 4%. While clearly the Intention-to-Treat analysis is by far the most important….this analysis DOES provide some insight into the mechanism of action in appendage closure… It is consistent with the underlying hypothesis: that LOCAL THERAPY with appendage closure achieves a similar result as SYSTEMIC THERAPY with oral anticoagulation. N Reddy, V. et al. Circulation 123(4):

PROTECT AF/PREVAIL Meta-Analysis: WATCHMAN Comparable to Warfarin
HR p-value Efficacy 0.79 0.22 All stroke or SE 1.02 0.94 Ischemic stroke or SE 1.95 0.05 Hemorrhagic stroke 0.004 Ischemic stroke or SE >7 days 1.56 0.21 CV/unexplained death 0.48 0.006 All-cause death 0.73 0.07 Major bleed, all 1.00 0.98 Major bleeding, non procedure-related 0.51 0.002 Efficacy comparable All stroke comparable, but balanced by more isc strokes in WM, but less hemorrhagic. After accounting for the proc strokes in the early PAF experience, no statistical difference in isch strokes CV death statistically favors WM All cause death and major bleeding are comparable between therapies, but after accounting for procedure-related bleeding events such as PEs, major bleeding rates favor WM Favors WATCHMAN   Favors warfarin Hazard Ratio (95% CI) N Holmes, DR et al. J Am Coll Cardiol. 2015;65(24):

Warfarin Ischemic Stroke Rate in PREVAIL Differs from Other Trials
Trial (Warfarin Arm) Ischemic Stroke Rate per 100 pt-yrs Mean CHADS2 PREVAIL 2.6 PROTECT AF 2.2 RE-LY1 2.1 ROCKET AF1 3.5 ARISTOTLE1 ENGAGE2 2.8 The missed endpoints can be largely attributed to the low rate of events in the warfarin arm of Prevail. Here we see that the warfarin ischemic stroke rate in Prevail differs from all other contemporary trials in similar patients using warfarin as a control. There was only one stroke in the warfarin arm of Prevail over almost 2 years of follow-up. The observed rate has a point estimate of only 0.3% with extremely wide confidence intervals. [CLICK] Rate per Patient-years 1 Miller. AJC (2012) 2 Giugliano. NEJM (2013) N

- FDA Panel (Oct. 2014) SH AD MAY2017

Baseline CHA2DS2-VASc Score
Ischemic Stroke Rate Aligns with Expected Rate Based on Risk Score PROTECT AF 5 Yrs / PREVAIL 3 Yrs (TCT 2016) Untreated AF Treated with Anticoagulants WATCHMAN Arm Ischemic Stroke Risk (events per 100 pt-yrs) PREVAIL PROTECT AF 2.3 1.8 1.3 1.3 CAP2 CAP Baseline CHA2DS2-VASc Score Friberg. Eur Heart J (2012); NICE UK (2014). WATCHMAN FDA Panel Sponsor Presentation. Oct 2014; Redd et al. TCT 2016.

WATCHMANTM May Reduce Ischemic Stroke by 67-83% Over No Therapy
(Events/100 Patient-Years) Ischemic Stroke 79% Relative Reduction 67% 83% Baseline CHA2DS2-VASc = 3.5 Baseline CHA2DS2-VASc = 3.8 Baseline CHA2DS2-VASc = 3.9 * Imputation based on published rate with adjustment for CHA2DS2-VASc score (3.0); Olesen JB. Thromb Haemost (2011) FDA Oct 2014 Panel Sponsor Presentation. Hanzel G, et al. TCT 2014 (abstract)

WATCHMAN Disabling Stroke Reduction Superior to Warfarin in PROTECT AF
Event Rate (per 100 pt-yrs) Rate Ratio (95% CrI) Posterior Probabilities, % WATCHMAN N=463 Warfarin N=244 Non- Inferiority Superiority Stroke (all) 1.5 2.2 0.68 (0.42, 1.37) >99 83 Disabling 0.5 1.2 0.37 (0.15, 1.00) 98 Non-disabling 1.0 1.05 (0.54, 2.80) 89 34 Disabling stroke defined as Modified Rankin Score 3-6 Notes: Posterior Probability for non-inferiority must be >=97.5% to be considered non-inferior. Credible intervals crossing unity do not indicate that non-inferiority has not been achieved, as Bayesian distributions are not symmetrical. Posterior Probability for superiority must be >95.0% to be considered superiority 63% 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. 2014 N

Efficacy – Bleeding Reduction

Bleeding Risks Compound Over Time
CHA2DS2-VASc* Score Annual % Stroke Risk HAS-BLED** Score Annual % Bleed Risk 10-Year Bleeding Risk (%)*** 0.9 8.6 1 1.3 3.4 29.2 2 2.2 4.1 34.2 3 3.2 5.8 45.0 4 4.0 8.9 60.6 5 6.7 9.1 61.5 * 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

72% Major Bleeding Reduction Long Term Post-Impalnt
Post Procedure Therapy Destination Therapy Warfarin + ASA (81mg) daily Clopidogrel (75mg) + ASA (325 mg) daily ASA (325mg) daily Implant 45 days* 6 months *if leak >5mm, patients remained on warfarin + ASA until seal documented, skipping the clopidogrel + ASA pharmacotherapy LAAC (n=732) Long-term warfarin (n=382) Rate Ratio P value Bleeding Rate (n events / N at risk) Event Rate per 100 pt-yrs (n events/N at risk) Event Rate per 100 pt-yrs Overall 10.8 (79/732) 3.5 (79/2268) 11.3 (43/382) 3.6 (43/1187) 0.96 0.84 Post Procedure 5.9 (40/682) 1.8 (40/2255) (43/381) (43/1180) 0.49 0.001 Destination 3.2 (19/601) 1.0 (19/1958 9.7 (35/360) (35/1004) 0.28 <0.001 Overall period defined as after randomization to the end of follow-up; post-procedural period as >7 days after randomization to the end of follow-up; 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):

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):

Procedural Success and Safety

~70% new operators performed 50% of procedures
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 * The EWOLUTION Registry is a European prospective registry which reflects CE Mark indications for use which differ from the FDA indications for use. 1 Boersma, L.et al. EHJ 2016;37(31): 2465.; 2 Reddy VY, Holmes DR, et al. JACC 2016; 69(3):

~50% New Operators in PREVAIL
Favorable Procedural Safety Profile: All Device and/or Procedure-related Serious Adverse Events within 7 Days ~50% New Operators in PREVAIL The pre-specified safety definitions across the trials differed. So they could be compared, we used a broad definition that included all procedural events in each trial. Beyond the first half of PREVAIL, safety event rates are low and comparable to other procedures performed in the LA like AF ablation Procedure complication rates continued to improve with each trial Especially important, because 50% of the operators in Prevail had no prior experience with LAA closure. N=232 N=231 N=566 N=269 N=579 N=10191 * The EWOLUTION Registry is a European prospective registry which reflects CE Mark indications for use which differ from the FDA indications for use. 1 Boersma, LVA.et al. EHJ 2016; 37(31): 2465.

Clinical Trial Experience Post Approval Experience
Favorable Procedural Safety Profile: Major Procedural Complications Across WATCHMAN Studies Clinical Trial Experience Post Approval Experience CAP (N=566) CAP2 (N=579) PREVAIL (N=269) PROTECT AF (N=463) EWOLUTION (N=1021) Post-FDA Approval (N=3822) * The EWOLUTION Registry is a European prospective registry which reflects CE Mark indications for use which differ from the FDA indications for use. Reddy VY, Holmes DR, et al. JACC 2016; 69(3):

Favorable Procedural Safety Profile: Major 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 29% Removed surgically 2 6 71% Death Procedure-related mortality 1 (0.1%) 4 (0.06%) Additional mortality within 7 days 1 (0.17%) 1 (0.026%) 5 (0.07%) * The EWOLUTION Registry is a European prospective registry which reflects CE Mark indications for use which differ from the FDA indications for use. Reddy VY, Holmes DR, et al. JACC 2016; 69(3):

WATCHMAN Implant Procedure
*The performance and timing of TEE to re-evaluate the LAA seal is left to physician discretion. Typical to patient treatment in U.S. clinical trials

WATCHMAN enables patients to discontinue taking long-term OAC
92% of patients were able to discontinue warfarin after 45 days, with 99% able to discontinue after 1 year3 92% 92% 99% 45 Days 1 Year Warfarin Cessation with WATCHMAN 1. Reddy, VY et al. Circulation. 2011;123: WATCHMAN FDA Panel Sponsor Presentation. Oct Holmes, DR et al. JACC 2014; 64(1):1-12.

Future Patient Populations* * Data presented is in patients primarily contraindicated for LAAC with WATCHMAN in the United States.

ASAP Registry Efficacy outcome versus expected
Ischemic Stroke 77% Reduction Ischemic Stroke Rate (%/pt-yr) 64% Reduction * Data presented is in patients currently contraindicated for LAAC with WATCHMAN in the United States. Reddy et al. JACC 2013; 61(25): 551–6.

Registry on WATCHMAN Outcomes in Real-Life Utilization: EWOLUTION
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: >1000 patients Number of Sites: 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.

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

EWOLUTION - baseline characteristics
Percentage Congestive heart failure 34% Hypertension (uncontrolled or history) 86% Age ≥ 80 years 26% Diabetes 29% Stroke Ischemic/Hemorrhagic 20% / 15% Vascular disease 42% Female Gender 40% Abnormal renal/liver function 16% / 4% Prior Major Bleeding or predisposition to bleeding 39% CHA2DS2-VASc score ≥ 5 49% HAS-BLED ≥ 3 Contra-indication (N)OAC 73% 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.

EWOLUTION – low annual stroke rate in full cohort
RR 84% RR 85% *Effectiveness in stroke reduction vs. estimated in the absence of therapy for comparable CHA2DS2-VASc scores based on Friberg et al. EHJ 2012 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.

EWOLUTION – low annual bleeding rate in full cohort
RR 48% RR 54% *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.

EWOLUTION – low event rates in warfarin Eligible patients
RR 83% RR 65% US-like indication *Estimated rates in absence of therapy based on Friberg et al. EHJ 2012 **Estimated rates under VKA therapy based on Lip et al. JACC 2011 Boersma LVA, et al. HRS2017; Late Breaking Clinical Trials: Chicago IL, USA.

ASAP-TOO (NCT02928497): Overview
Study Objective Evaluate LAA Closure with WATCHMAN in NVAF patients deemed not suitable for oral anti-coagulation therapy Study Design Prospective, multi-center Randomized 2:1 (Watchman vs Control) Considering Group Sequential Design Primary Endpoint Effectiveness Endpoint Time to first occurrence of ischemic stroke or systemic embolism 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 Patient Population 888 Number of Sites 100 global sites Follow-up* 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 46

ASAP-TOO Device Group Medication Therapy
Visit Interval Aspirin Clopidogrel* Discharge through 3-month visit Yes, suggested dose: mg Yes Suggested dose: 75mg 3-month visit through 12-month visit No, unless other indication Following the 12-month visit No, unless other indication *Clopidogrel may be substituted with ticagrelor or prasugrel if the subject requires the medication for other indications (e.g. acute coronary syndromes treated with drug eluting stents) or if the subject has a known resistance to clopidogrel. **Patients are allowed to be on dual antiplatelet therapy (outside of the protocol required 3- months period) if indicated due to a condition other than WATCHMAN implantation. Holmes et al. AHJ 2017; In Press

WATCHMAN is the most studied LAAC Device with Long-term Clinical Data
Results Safety WATCHMAN procedure is safe 95% implant success; ~4% complication rates1 Primary Efficacy WATCHMAN comparable to warfarin 21% reduction in events (p=0.22)3 All-Stroke 63% reduction in disabling strokes (Ps=>99%)2; 78% reduction in hemorrhagic strokes (p=0.004)3 CV / Unexp death WATCHMAN superior to warfarin 52% reduction in events (p=0.006)3 Major Bleeding WATCHMAN comparable to warfarin; superior to warfarin post-procedure 52% reduction post-procedure (p=0.002); 72% reduction after 6-months (p=0.001)4 Warfarin WATCHMAN allows the majority of patients to discontinue warfarin 92% of patients discontinue after 45-days; 99% of patients discontinue after 1 year5 1. WATCHMAN FDA Panel Sponsor Presentation. Oct 2014.; 2 Reddy, et al. JAMA ;312(19): 3 Holmes, DR et al. JACC. 2015;65(24): ; 4 Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): ; 5.Holmes, DR et al. JACC 2014; 64(1): 1-12.

WATCHMAN™ Clinical Leadership
WATCHMAN is a safe alternative to long-term warfarin therapy which offers comparable stroke risk reduction and enables patients to stop taking warfarin1,2 WATCHMAN therapy demonstrated comparable stroke risk reduction and statistically superior reductions in major non-procedure related bleeding and cardiovascular death compared to warfarin2,4: WATCHMAN demonstrated 95% implant success rate in both clinical and commercial setting3,5 >92% warfarin cessation after 45 days, >99% after 1 year1 1Holmes, DR et al. JACC 2014; 64(1). 2Holmes, DR et al. JACC 2015; 65(2). 3Reddy VY, Holmes DR, et al. JACC 2016; Reddy, V. Y., D. N. Gibson, et al. JACC 2017; 69(3).. 4Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15). 5Reddy, V. Y., D. N. Gibson, et al. JACC 2017; 69(3).

ABBREVIATED STATEMENT WATCHMANTM Left Atrial Appendage Closure Device with Delivery System and WATCHMAN Access System Indications for use The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation who: Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy; Are deemed by their physicians to be suitable for warfarin; and Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin. The WATCHMAN Access System is intended to provide vascular and transseptal access for all WATCHMAN Left Atrial Appendage Closure Devices with Delivery Systems. Contraindications Do not use the WATCHMAN Device if: Intracardiac thrombus is visualized by echocardiographic imaging. An atrial septal defect repair or closure device or a patent foramen ovale repair or closure device is present. The LAA anatomy will not accommodate a device. See Table 46 in the DFU. Any of the customary contraindications for other percutaneous catheterization procedures (e.g., patient size too small to accommodate TEE probe or required catheters) or conditions (e.g., active infection, bleeding disorder) are present. There are contraindications to the use of warfarin, aspirin, or clopidogrel. The patient has a known hypersensitivity to any portion of the device material or the individual components (see Device Description section) such that the use of the WATCHMAN Device is contraindicated. Warnings Device selection should be based on accurate LAA measurements obtained using fluoro and ultrasound guidance (TEE recommended) in multiple angles (e.g., 0º, 45º, 90º, 135º). Do not release the WATCHMAN Device from the core wire if the device does not meet all release criteria. If thrombus is observed on the device, warfarin therapy is recommended until resolution of thrombus is demonstrated by TEE. The potential for device embolization exists with cardioversion <30 days following device implantation. Verify device position post-cardioversion during this period. Administer appropriate endocarditis prophylaxis for 6 months following device implantation. The decision to continue endocarditis prophylaxis beyond 6 months is at physician discretion. For single use only. Do not reuse, reprocess, or resterilize. Precautions The safety and effectiveness (and benefit-risk profile) of the WATCHMAN Device has not been established in patients for whom long-term anticoagulation is determined to be contraindicated. The LAA is a thin-walled structure. Use caution when accessing the LAA and deploying the device. Use caution when introducing the WATCHMAN Access System to prevent damage to cardiac structures. Use caution when introducing the Delivery System to prevent damage to cardiac structures. To prevent damage to the Delivery Catheter or device, do not allow the WATCHMAN Device to protrude beyond the distal tip of the Delivery Catheter when inserting the Delivery System into the Access Sheath. If using a power injector, the maximum pressure should not exceed 100 psi. In view of the concerns that were raised by the RE-ALIGN1 study of dabigatran in the presence of prosthetic mechanical heart valves, caution should be used when prescribing oral anticoagulants other than warfarin in patients treated with the WATCHMAN Device. The WATCHMAN Device has only been evaluated with the use of warfarin post-device implantation. ADVERSE EVENTS Potential adverse events (in alphabetical order) which may be associated with the use of a left atrial appendage closure device or implantation procedure include but are not limited to: Air embolism, Airway trauma, Allergic reaction to contrast media/medications or device materials, Altered mental status, Anemia requiring transfusion, Anesthesia risks, Angina, Anoxic encephalopathy, Arrhythmias, Atrial septal defect , AV fistula , Bruising, hematoma or seroma, Cardiac perforation , Chest pain/discomfort, Confusion post procedure, Congestive heart failure, Contrast related nephropathy, Cranial bleed, Decreased hemoglobin, Deep vein thrombosis, Death, Device embolism, Device fracture, Device thrombosis, Edema, Excessive bleeding, Fever, Groin pain, Groin puncture bleed, Hematuria, Hemoptysis, Hypotension, Hypoxia, Improper wound healing, Inability to reposition, recapture, or retrieve the device, Infection / pneumonia, Interatrial septum thrombus, Intratracheal bleeding, Major bleeding requiring transfusion, Misplacement of the device / improper seal of the appendage / movement of device from appendage wall, Myocardia erosion, Nausea, Oral bleeding, Pericardial effusion / tamponade, Pleural effusion, Prolonged bleeding from a laceration, Pseudoaneurysm, Pulmonary edema, Renal failure, Respiratory insufficiency / failure, Surgical removal of the device, Stroke – Ischemic , Stroke – Hemorrhagic, Systemic embolism, TEE complications (throat pain, bleeding, esophageal trauma), Thrombocytopenia, Thrombosis, Transient ischemic attack (TIA), Valvular damage, Vasovagal reactions There may be other potential adverse events that are unforeseen at this time. CAUTION: Federal law (USA) restricts this device to sale by or on the order of a physician. Rx only. Prior to use, please see the complete “Directions for Use” for more information on Indications, Contraindications, Warnings, Precautions, Adverse Events, and Operator’s Instructions. © 2015 Boston Scientific Corporation or its affiliates. All rights reserved. 1Eikelboom JW, Connolly SJ, Brueckmann M, et al. N Engl J Med 2013;369:

WATCHMANTM Left Atrial Appendage Closure Device

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WATCHMANTM Left Atrial Appendage Closure Device

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