2 AF is a Growing Problem Associated with Greater Morbidity and Mortality AF = most common cardiac arrhythmia, and growingAF increases risk of strokeHigher stroke risk for older patients and those with prior stroke or TIA15-20% of all strokes are AF-relatedAF results in greater disability compared to non-AF-related strokeHigh mortality and stroke recurrence rate‘15 ‘20 ‘30 ’40 ‘505M12M<~5 Mpeople with AF in U.S., expected to more than double by 205015xgreater risk of stroke with AF2Go 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.
3 Assess stroke risk with CHA2DS2-VASc score 2014 ACC/AHA/HRS Treatment Guidelines to Prevent Thromboembolism in Patients with AFAssess stroke risk with CHA2DS2-VASc scoreScore 1: Annual stroke risk 1%, oral anticoagulants or aspirin may be consideredScore ≥2: Annual stroke risk 2%-15%, oral anticoagulants are recommendedBalance benefit vs. bleeding risk2014 AHA/ACC/HRS Guideline for the Management of Patients with AFJanuary, CT. et al AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. JACC. 2014; doi: /j.jacc
4 Oral Anticoagulation is Standard of Care, but Not Ideal for All WarfarinBleeding riskDaily regimenHigh non-adherence ratesRegular INR monitoringFood and drug interaction issuesComplicates surgical proceduresNovel Oral AnticoagulantsLack of reversal agentsHigh costCHADS2 Scorep < 0.001(n=27,164)AF Patients UsingAnticoagulationAnticoagulation Use Declines with Increased Stroke Risk11. Piccini, et al.. Pharmacotherapy in Medicare beneficiaries with atrial fibrillation. Heart Rhythm. 2012;9:
5 Anticoagulant Use in Patients with NVAF and CHADS2 ≥ 2 Despite Increasing NOAC Adoption, Overall Rate of Anticoagulation in High Risk NVAF Patients has Not ImprovedTotal on Oral AnticoagulationWarfarinNOACsAnticoagulant Use in Patients with NVAF and CHADS2 ≥ 2n=25719n=29194n=31582n=36490n=67102n=70667n=70320n=71396Results from the NCDR PINNACLE Registry11. 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
6 Introducing the WATCHMAN™ LAAC Device A first-of-its-kind, proven alternative to long-term warfarin therapy for stroke risk reduction in patients with non-valvular AFMost studied LAAC therapy, only one proven with long-term data from randomized trials or multi-center registriesComparable stroke risk reduction, and statistically superior reductions in hemorrhagic stroke, disabling stroke and cardiovascular death compared to warfarin over long-term follow-up1,2Reddy, V et al. JAMA 2014; Vol. 312, No. 19.Reddy, V et al. Watchman I: First Report of the 5-Year PROTECT-AF and Extended PREVAIL Results. TCT 2014.
7 WATCHMAN™ LAAC Closure Device Minimally Invasive, Local SolutionAvailable sizes: 21, 24, 27, 30, 33 mm diameterIntra-LAA designAvoids contact with left atrial wall to help prevent complicationsNitinol FrameConforms to unique anatomy of the LAA to reduce embolization risk 10 active fixation anchors - designed to engage tissue for stabilityProximal FaceMinimizes surface area facing the left atrium to reduce post-implant thrombus formation160 micron membrane PET cap designed to block emboli and promote healing Warfarin Cessation92% after 45 days, >99% after 12 months195% implant success rate1160 Micron MembraneAnchors1. Holmes, DR et al. JACC 2014; Vol. 64, No. 1
8 WATCHMAN™ Pre-Loaded Delivery System WATCHMAN™ Access Sheath14F outer diameter (4.7mm), 12F inner diameter (4mm)75 cm working lengthWATCHMAN™ Delivery SheathPreformed access sheath curve shapes guide position in LAA
9 WATCHMAN™ Left Atrial Appendage Closure (LAAC) Device Procedure One-time implant that does not need to be replacedPerformed in a cardiac cath lab/EP suite, does not need hybrid ORPerformed by a Heart TeamIC/EP or IC&EP, TEE, General Anesthesia, Surgical Back- up, WATCHMAN Clinical SpecialistTransfemoral Access: Catheter advanced to the LAA via the femoral vein (Does not require open heart surgery)General anesthesia*1 hour procedure*1-2 day hospital stay** Typical to patient treatment in U.S. clinical trials
11 Device Release Criteria: PASS WATCHMAN™ Device features one-step deploymentRecapturable and RepositionableAll criteria must be met prior to device release (PASS)Position – device is distal to or at the ostium of the LAAAnchor – fixation anchors engaged / device is stableSize – device is compressed 8-20% of original sizeSeal – device spans ostium, all lobes of LAA are coveredCaution: Investigational device limited to investigational use only under US federal law. Not for sale.135803
12 Device Release Criteria – Position Device should be at or just distal to the LAA ostium
13 Device Release Criteria – Anchor To test stability, gently retract deployment knob and let go, observe device returns to original positionIf the device moves to where position is no longer acceptable or the compression is no longer sufficient, the device should be recapturedTest stability more than once if device stability is questionablePass or Fail TestDeployment KnobCore WireHemostasis Valve
14 Device Release Criteria - Size 20.8Device Compression Table8 – 20% of original device size selectedDevice Size(uncompressed diameter)Maximum (20%)Compression Measured Diameter*Minimum (8%) Compression Measured Diameter*2116.8 mm19.3 mm2419.2 mm22.1 mm2721.6 mm24.8 mm3024.0 mm27.6 mm3326.4 mm30.4 mm*Measure in-situ device diameter at approximate TEE angles of 0, 45, 90 and 135 degrees to accurately assess device compressionCaution: Investigational device limited to investigational use only under US federal law. Not for sale.
15 Device Release Criteria – Seal Residual flow around the device of ≤ 5mm acceptableIf all 4 device release criteria are met (PASS), device can be releasedCounter clockwise on proximal handle 3-5 turns
16 WATCHMAN™ Device Endothelialization Canine Model – 30 DayHuman Pathology - 9 Months Post-implant(Non-device related death)Canine Model – 45 DayImages on file at Boston Scientific Corporation.Results in animal models may not necessarily be indicative of clinical outcomes.
17 WATCHMAN™ Clinical Leadership The WATCHMAN™ LAAC Device is the most studied LAAC device and the only one proven with long-term data from randomized trials or multi-center registriesFive studies, >2400 patients, nearly 6000 patient-years of follow-upThe WATCHMAN Device can be implanted safely1, enables patients to discontinue warfarin2 and reduces AF stroke risk comparably to warfarin3.95% implant success rate4>92% warfarin cessation after 45 days, >99% after 1 year4WATCHMAN™ therapy demonstrated comparable stroke risk reduction, and statistically superior reductions in hemorrhagic stroke, disabling stroke and cardiovascular death compared to warfarin over long-term follow-up5,6:32% in all cause stroke685% in hemorrhagic stroke563% in disabling stroke656% in cardiovascular death51. PROTECT AF, CAP, PREVAIL and CAP2; PROTECT AF, CAP, PREVAIL; 3. PROTECT AF; 4. Holmes, DR et al. JACC 2014; Vol. 64, No. 1; 5. Reddy, V et al. TCT 2014; Reddy, V et al. JAMA 2014; Vol. 312, No. 19
18 Most Studied LAAC Device. Only One with Long-Term Clinical Data PROTECT AFCAPRegistryPREVAILCAP2TotalsEnrollmentEnrolled8005664615792406Randomized707---4071114WATCHMAN: warfarin (2:1)463 : 244269 :1381877: 382Mean Follow-up (years)4.03.72.20.58N/APatient-years271720228603325931Source: FDA Oct 2014 Panel Sponsor Presentation.
19 Patient Risk Factors Across Trials CharacteristicPROTECT AF N=707CAPN=566PREVAIL N=407CAP2N=579p-valueCHADS2 Score2.2 ± 1.22.5 ± 1.22.6 ± 1.02.7 ± 1.1<0.0001CHADS2 Risk Factors (% of Patients)CHF26.923.319.127.10.004Hypertension89.891.488.892.50.15Age ≥ 7543.153.651.859.7<0.001Diabetes26.232.424.933.70.001Stroke/TIA18.527.830.429.0CHA2DS2-VASc3.5 ± 1.63.9 ± 1.54.0 ± 1.24.5 ± 1.3Source: FDA Oct 2014 Panel Sponsor Presentation.
20 Implant Success & Warfarin Cessation Implant success defined as deployment and release of the device into the left atrial appendagePREVAIL Implant SuccessNo difference between new and experienced operatorsExperienced Operatorsn=2696%New Operatorsn=2493%Warfarin CessationStudy45-day12-monthPROTECT AF87%>93%CAP96%>96%PREVAIL92%>99%p = 0.28PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.
21 Favorable Procedural Safety Profile: 7-Day Safety Events Patients with Safety Event(%)Learning CurvePROTECT AFn=232n=231n=566n=269n=5791st Half2nd Half~50% New Operators in PREVAILAll Device and/or procedure-related serious adverse events within 7 DaysSource: FDA Oct 2014 Panel Sponsor Presentation.
22 WATCHMAN™ PROTECT AF Study Overview Long-Term, Final 5-Year Results Study Design & ObjectiveProspective, randomized (2:1), non-inferiority trial of LAA closure vs. warfarin in non-valvular AF patients for prevention of strokePrimary EndpointEfficacy: Composite end point of stroke, cardiovascular death or systemic embolizationSafety: Major bleeding, device embolization or pericardial effusionStatistical PlanAll analyses by intention-to-treatBayesian (stratified for CHADS2 score) : Primary Efficacy and Safety endpointsCox Proportional: All Secondary AnalysesPatient Populationn = 707Mean CHADS2= 2.2, CHA2DS2-VASc = 3.5Key Inclusion CriteriaParoxysmal / Persistent / Permanent AFCHADS ≥ 1 (93% had a CHA2DS2-VASc Score ≥2)Eligible for long-term warfarin therapyMean Follow-Up2,717 patient-years, 48 monthsNumber of Sites59 in the United States and EuropeEnrollment Feb 2005 – June 2008
23 Posterior Probability PROTECT AF: Final, 5-Year Primary Efficacy Events Consistent with 4-Year ResultsEvent Rate(per 100 Pt-Yrs)Rate Ratio(95% CrI)Posterior ProbabilityWATCHMANWarfarinNon-inferioritySuperiorityPrimary efficacy220.127.116.11(0.42, 1.07)>99.9%95.4%Stroke (all)1.50.68(0.42, 1.37)99.9%83%Systemic embolism0.20.0N/A--Death (CV/unexplained)1.02.30.44(0.26, 0.90)98.9%Source: FDA Oct 2014 Panel Sponsor Presentation.
24 PROTECT AF 4-Year Results in JAMA WATCHMANTM Met Criteria for both Noninferiority and Superiority for the Primary Composite Endpoint Compared to WarfarinReddy, VY et al. JAMA. 2014;312(19):
25 PROTECT AF/PREVAIL Pooled Analysis: Less Bleeding with WATCHMANTM Device 6 Months Post-Implant WarfarinFree of Major Bleeding Event (%)HR = 0.29p<0.00171%Relative ReductionIn Major Bleeding after cessation of anti-thromboticsAspirinWarfarin +AspirinWarfarin +AspirinWATCHMAN Device Arm Drug ProtocolAspirin+ ClopidogrelTime (days)Time (months)Definition of bleeding: Serious bleeding event that required intervention or hospitalization according to adjudication committeePrice, MJ. Avoidance of Major Bleeding with WATCHMAN Left Atrial Appendage Closure Compared with Long-Term Oral Anticoagulation : Pooled Analysis of the PROTECT-AF and PREVAIL RCTs. TCT 2014 (abstract)
26 WATCHMANTM Device Reduces Ischemic Stroke Over No Therapy (Events/100 Patient-Years)Ischemic Stroke Risk79%Relative Reduction67%83%BaselineCHA2DS2-VASc = 3.4BaselineCHA2DS2-VASc = 3.8BaselineCHA2DS2-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)
27 WATCHMAN Clinical Leadership Continued Investment EWOLUTION RegistryEndpoints: Additional information in real-world settingEst. Enrollment: Up to 1,000 patientsTarget Follow-up Duration: 2 yearsSites: 75 international centersWATCHMAN Asia Pacific (WASP) RegistryEst. Enrollment: 300 patientsSites: 10 sites in Asia Pacific regionWATCHMAN Post Approval StudyCurrently in discussions with the FDA