WATCHMAN Phase I Training Introduction / Orientation

WATCHMANTM Left Atrial Appendage Closure DeviceClinical Data Overview SH 286002 AC JUN 2015

AgendaThe Need for a Device-Based Alternative to Long-Term Warfarin TherapyWATCHMANTM LAAC Clinical Data OverviewSafety Event Rates from various WATCHMAN studiesImplant Success and Warfarin CessationEfficacy Event Rates vs WarfarinEfficacy Event Rates vs No TherapyLong-Term Reduction in Major Bleeding from Pooled Data Analysis

SH 286002 AC JUN 2015 SH 286002 AC JUN 2015

WATCHMANTM Indications for UseThe 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; andHave an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin.

WATCHMAN is NOT intended to be a broad replacement for Oral Anticoagulants (OAC) SH 286002 AC JUN 2015 SH 286002 AC JUN 2015 AF is a Growing Problem Associated with Greater Morbidity and Mortality ~5 Mpeople with AF in U.S., expected to more than double by 20501AF = most common cardiac arrhythmia, and growingAF increases risk of stroke5xgreater risk of stroke with AF2

90% of stroke-causing clots that come from the left atrium are formed in the LAA3.SH 286002 AC JUN 2015 2014 AHA/ACC/HRS Treatment Guidelines to Prevent Thromboembolism in Patients with AFAssess stroke risk with CHA2DS2-VASc score

Score 1: Annual stroke risk 1%, oral anticoagulants or aspirin may be consideredScore 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

January, CT. et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. JACC. 2014; doi: 10.1016/j.jacc.2014.03.022SH 286002 AC JUN 2015 Oral Anticoagulation is Standard of Care, but Not Ideal for All WarfarinBleeding riskDaily regimen High non-adherence ratesRegular INR monitoring Food and drug interaction issuesComplicates surgical procedures

Novel Oral AnticoagulantsBleeding riskDaily regimen High non-adherence ratesComplicates surgical proceduresLack of reversal agents High cost

1. Piccini, et al.. Pharmacotherapy in Medicare beneficiaries with atrial fibrillation. Heart Rhythm. 2012;9:1403-1408CHADS2 Scorep < 0.001(n=27,164)AF Patients Using AnticoagulationAnticoagulation Use Declines with Increased Stroke Risk1SH 286002 AC JUN 2015 Anticoagulant Therapy Carries Risk of Intracerebral Hemorrhage or DeathSpontaneous intra-parenchymal bleedHemorrhagic transformation

SH 286002 AC JUN 2015 Despite Increasing NOAC Adoption, Overall Rate of Anticoagulation in High Risk NVAF Patients has Not Improved1. Jani, et al. Uptake of Novel Oral Anticoagulants in Patients with Non-Valvular and Valvular Atrial Fibrillation: Results from the NCDR-Pinnacle Registry. ACC 2014

Results from the NCDR PINNACLE Registry1Total on Oral Anticoagulation

Warfarin

NOACsAnticoagulant Use in Patients with NVAF and CHADS2 2n=25719n=29194n=31582n=36490n=67102n=70667n=70320n=71396SH 286002 AC JUN 2015 Discontinuation and Major Bleeding Rates with NOACsTreatmentStudy Drug Discontinuation RateMajor Bleeding (rate/year)Rivaroxaban124%3.6%Apixaban225%2.1%Dabigatran3 (150 mg)21%3.3%Edoxaban4(60 mg / 30 mg)33 % / 34% 2.8% / 1.6%Warfarin1-417 28%3.1 3.6%There is an unmet need of stroke risk reduction for patients with AF who are seeking an alternative to long-term OACs1Connolly, S. NEJM 2009; 361:1139-1151 2 yrs follow-up (Corrected) 2Patel, M. NEJM 2011; 365:883-891 1.9 yrs follow-up, ITT 3Granger, C NEJM 2011; 365:981-992 1.8 yrs follow-up, 4Giugliano, R. NEJM 2013; 369(22): 2093-2104 2.8 yrs follow-up.SH 286002 AC JUN 2015 Click to add notes

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WATCHMANTM Left Atrial Appendage Closure DeviceFirst-of-its-Kind, Proven Alternative to Long-Term Warfarin Therapy for Stroke Risk Reduction in Patients with Non-Valvular Atrial Fibrillation

The most studied LAAC device, and the only one proven with long-term data from randomized trials or multi-center registries

Commercially available internationally since 2009, with over 10,000 implants worldwide

Registered in over 70 countries

SH 286002 AB MAR 2015 SH 286002 AC JUN 2015 Favorable Procedural Safety Profile: 7-Day Safety Events Patients with Safety Event (%)PROTECT AF1st Half2nd Halfn=232n=231n=566n=269n=579All Device and/or procedure-related serious adverse events within 7 DaysLearning Curve~50% New Operators in PREVAILSource: FDA Oct 2014 Panel Sponsor Presentation. SH 286002 AC JUN 2015 Implant Success & Warfarin Cessationp = 0.04Study45-day12-monthPROTECT AF87%>93%CAP96%>96%PREVAIL92%>99%Implant success defined as deployment and release of the device into the left atrial appendageWarfarin CessationPREVAIL Implant Success

No difference between new and experienced operators

Experienced Operatorsn=2696%New Operatorsn=2493%p = 0.28PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424.PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.

SH 286002 AC JUN 2015 Most Studied LAAC Device. Only One with Long-Term Clinical DataPROTECT AFCAPRegistryPREVAIL

CAP2RegistryTotalsEnrollment2005-20082008-20102010-20122012-2014Enrolled 8005664615792406Randomized707---407---1114WATCHMAN: warfarin (2:1)463 : 244566269 :1385791877: 382Mean Follow-up (years)4.03.72.20.58N/APatient-years271720228603325931Source: FDA Oct 2014 Panel Sponsor Presentation. SH 286002 AC JUN 2015 Majority of Patients at High Stroke Risk, All Eligible for Anti-coagulationPROTECT AFCHA2DS2-VASc Score 2293%High Risk1CAPPREVAILCAP2Patients(%)CHA2DS2-VASc Score96%100%100%Anticoagulation Eligible1Source: Holmes, DR et al. JACC 2015. In Press.1. AHA/ACC/HRS Guidelines (2014). SH 286002 AC JUN 2015 Patient Risk Factors Across TrialsCharacteristicPROTECT AFN=707CAPN=566PREVAILN=407CAP2N=579p-valueCHADS2 Score 2.2 1.2 2.5 1.22.6 1.02.7 1.1