Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation Ramon Quesada, MD, FACP,FACC, FSCAI, Medical Director, Interventional Cardiology Baptist Cardiac & Vascular Institute Miami, Florida

Ramon Quesada, MD DISCLOSURES I have no real or apparent conflicts of interest to report.

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Grant/Research Support None Consulting Fees/Honoraria Abbott, Cordis, St. Jude, W.L. Gore, NMT Medical, Terumo & Boston Scientific Corporation Major Stock Shareholder/Equity None Royalty Income None Ownership/Founder None Intellectual Property Rights None Other Financial Benefit None

A major source of cardiogenic embolism-related stroke Atrial Fibrillation A major source of cardiogenic embolism-related stroke 500,000 strokes per year AHA estimates that 15 – 20% of strokes/year are related to AF 90% of thrombus originate in LAA Source: Neurology, 1978; Stroke, 1985; European Heart Journal, 1987; Lancet, 1987

Challenges in Treating AF However warfarin is not always well-tolerated Narrow therapeutic range (INR between 2.0 – 3.0) Effectiveness is impacted by interactions with some foods and medications Requires frequent monitoring and dose adjustments Published reports indicate that less than 50% of patients eligible are being treated with warfarin due to tolerance or non-compliance issues SPORTIF trials suggest only 60% of patients treated are within a therapeutic INR range, while 29% have INR levels below 2.0 and 15% have levels above 3.0

CHADS Score Is Anticoagulation Warranted? Medical Condition # points Prior Stroke 2 Congestive Heart Failure 1 High Blood Pressure Diabetes Age 75 or Older Washington University St. Louis

CHADS Score Estimate of Yearly Stroke Risk Yearly Risk of Stroke 1.9% 1 2.8% 2 4.0% 3 5.9% 4 8.5% 5 12.5% 6 18.2% Washington University St. Louis

Surgical Closure of Left Atrial Appendage as a Source of Emboli An Alternative to Medical Therapy: Surgical Closure of Left Atrial Appendage as a Source of Emboli

Mechanical Closure of Left Atrial Appendage as a Source of Emboli An Alternative to Medical Therapy: Mechanical Closure of Left Atrial Appendage as a Source of Emboli

2D TEE for measures/thrombus assessment of LAA

3D TEE for LAA assessment

PLAATO Implant

WATCHMAN® LAA Device Fully Deployed 8-20% Compressed 160 µ PET Fabric Nitinol Frame Barbs

WATCHMAN® LAA System Access Catheters 14F Double Curve 14F Single Curve

WATCHMAN® LAA System Delivery Catheter WATCHMAN® 12F Device

Release Criteria Details All criteria must be met prior to device release Stability - fixation barbs engaged / device is stable Position – device is distal to or at the ostium of the LAA Size – device is compressed 10-20% of original size Seal - device spans ostium, all lobes of LAA are covered If necessary, device can be recaptured (partially or full) If full recapture – new device must be used Implant face distal to ostium Radial force at shoulders Fixation barbs engage LAA wall

WATCHMAN® LAA Delivery Catheter Device Deployment Pre-deployment angio to define the LAA (20% of patients have multiple lobes). 1.5 laa mora

WATCHMAN® LAA Delivery Catheter Device Deployment Pre-deployment positioning to ensure adequate coverage of the LAA “neck” 2/5 laa mora

WATCHMAN® LAA Delivery Catheter Device Deployment Pre-deployment testing of fixation of the device to the walls of the LAA to prevent migration of the device. 3/5 laa mora

WATCHMAN® LAA Delivery Catheter Device Deployment Release of the device once all “pre-testing” of placement and fixation is complete. 4/5 laa mora

WATCHMAN® LAA Delivery Catheter Device Deployment Post deployment angio 5/5 laa mora

WATCHMAN® LAA Device: Final Placement

Human pathology: 9 months post-implant (non-device related) WATCHMAN® LAA Device Healing Response Canine model – 30 day Human pathology: 9 months post-implant (non-device related) Canine model – 45 day

WATCHMAN® LAA Device: 45 Day Follow-up

Sick, J Am Coll Cardiol 2007;49: 1490–5 66 pts. underwent device implantation. Mean follow-up was 740 ±341 days. ACC 2009: Duration of f/u now out to 5 years (mean >1300 days) At 45 days, 93% (54 of 58) devices showed successful sealing of LAA No strokes occurred during follow-up despite 90% of patients with discontinuation of anticoagulation. The expected annual risk of stroke based on the CHADS2 score in this study cohort was calculated to be 1.9/year. In long term follow up 63/66 (95%) patients were off warfarin. Two patients experienced a TIA and one patient had an embolic stroke with severe carotid disease at 39 months. This reflects an actual stroke rate of 1 in 251 patient years (0.4%), whereas the expected stroke rate according to the CHADS2 Score would have been 5.75%. Although the number of patients does not provide sufficient power to demonstrate equivalence or superiority to anticoagulation, the results appear generally comparable to those reported for the PLAATO System (ev3 Inc.,Plymouth, Minnesota), which has also been demonstrated in 205 of 210 implanted patients to have a lower event rate of stroke (5 strokes at a mean follow-up of 14.7 months) compared with the expected stroke rate predicted by the CHADS2 score Sick, J Am Coll Cardiol 2007;49: 1490–5

What We’ve Learned From This Pilot Series Appreciation of the variability of the anatomy of the LAA Use of additional imaging tools Variability and the fragility of the LAA required modifications to the device

LAA Comes In All Shapes And Sizes

LAA Comes In All Shapes And Sizes. Imaging The Left Atrium MRA and computed tomographic (CT) imaging allow for precise 3D reconstruction of structures such as the LAA, which may prove complementary to intraprocedural transesophageal echocardiographic data in selecting and sizing occlusion devices. Pre-procedural MRA and CT imaging of the LA and pulmonary veins now is used in conjunction with other imaging modalities to direct catheter ablation of AF in many centers.

CT LAA Reconstruction Compared To TEE

Improvements in Device Technology Shorter length device Modification in the delivery sheath with markers and a softer tip

Improvements in Device Technology Shorter length device Modification in the delivery sheath with markers and a softer tip

WATCHMAN Device, Access Sheath And Adjunctive Procedure Tools A shorter WATCHMAN device has become the preferred implant of choice in the study as it may allow additional patients with limited LAA depth to be further considered for device implantation

Bilobar LAA

Short Device Sealing One Lobe

Post Deployment - Complete Sealing of LAA

Improvements in Device Technology Shorter length device Modification in the delivery sheath with markers and a softer tip

WATCHMAN® LAA Access Sheath 14F Double Curve 14F Single Curve

Delacruz 19 20 The use of the radiopaque marker bands permits more accurate positioning prior to device deployment

Pre-deployment 21 mm device Dela cruz 15

Device deployed in “perfect” position Dela Cruz 5

PROTECT AF Clinical Trial Design Prospective, randomized study of WATCHMAN LAA Device vs. Long-term Warfarin Therapy 2:1 allocation ratio device to control 800 Patients enrolled from Feb 2005 to Jun 2008 Device Group (463) Control Group (244) Roll-in Group (93) 59 Enrolling Centers (U.S. & Europe) Follow-up Requirements TEE follow-up at 45 days, 6 months and 1 year Clinical follow-up biannually up to 5 years Regular INR monitoring while taking warfarin Enrollment continues in Continued Access Registry

Patient Study Timeline Day 45 postimplant Day 0 Day 2-14 Ongoing to 5 years Device subject takes warfarin Device subject has ceased warfarin Preimplant interval Device Device subject gets implant Randomize Control Control subject takes warfarin Day 0 Ongoing to 5 years 3000838-60

Warfarin Discontinuation 87% of implanted subjects were able to cease warfarin at 45 days and the rate further increased at later time points Visit Watchman N/Total (%) 45 day 349/401 (87.0) 6 month 347/375 (92.5) 12 month 261/280 (93.2) 24 month 95/101 (94.1) Reasons for remaining on warfarin therapy after 45-days: Observation of flow in the LAA (n = 30) Physician Order (n = 13) Other (n = 9)

PROTECT AF Trial Endpoints Primary Efficacy Endpoint All stroke: ischemic or hemorrhagic deficit with symptoms persisting more than 24 hours or symptoms less than 24 hours confirmed by CT or MRI Cardiovascular and unexplained death: includes sudden death, MI, CVA, cardiac arrhythmia and heart failure Systemic embolization Primary Safety Endpoint Device embolization requiring retrieval Pericardial effusion requiring intervention Cranial bleeds and gastrointestinal bleeds Any bleed that requires ≥ 2uPRBC NB: Primary effectiveness endpoint contains safety events

Key Participation Criteria Key Inclusion Criteria Age 18 years or older Documented non-valvular AF Eligible for long-term warfarin therapy, and no other conditions that would require long-term warfarin therapy Calculated CHADS2 score > 1 Key Exclusion Criteria NYHA Class IV Congestive Heart Failure ASD and/or atrial septal repair or closure device Planned ablation procedure within 30 days of potential WATCHMAN Device implant Symptomatic carotid disease LVEF < 30% TEE Criteria: Suspected or known intracardiac thrombus (dense spontaneous echo contract)

Patient Demographics Baseline Demographics Characteristic WATCHMAN Control N= 244 P-value Age (years) 71.7 ± 8.8 463 (46.0, 95.0) 72.7 ± 9.2 244 (41.0, 95.0) 0.1800 Height (inches) 68.2 ± 4.2 462 (54.0, 82.0) 68.4 ± 4.2 244 (59.0, 78.0) 0.6067 Weight (lbs) 195.3 ± 44.4 463 (85.0, 376.0) 194.6 ± 43.1 244 (105.0, 312.0) 0.8339 Gender Female Male 137/463 (29.6) 326/463 (70.4) 73/244 (29.9) 171/244 (70.1) 0.9276

Patient Demographics Baseline Risk Factors WATCHMAN N= 463 Control P-value CHADS2 Score 1 2 3 4 5 6 158/463 (34.1) 157/463 (33.9) 88/463 (19.0) 37/463 (8.0) 19/463 (4.1) 4/463 (0.9) 66/244 (27.0) 88/244 (36.1) 51/244 (20.9) 24/244 (9.8) 10/244 (4.1) 5/244 (2.0) 0.3662 AF Pattern Paroxysmal Persistent Permanent Unknown 200/463 (43.2) 97/463 (21.0) 160/463 (34.6) 6/463 (1.3) 99/244 (40.6) 50/244 (20.5) 93/244 (38.1) 2/244 (0.8) 0.7623 LVEF % 57.3 ± 9.7 460 (30.0, 82.0) 56.7 ± 10.1 239 (30.0, 86.0) 0.4246

Potential Safety Endpoints Device Procedural complications Pericardial effusion Stroke – ischemic Bleeding during 45 days of Warfarin

Protect AF: Lancet: August 15, 2009

Safety Events Stroke Safety stroke events Also counted as efficacy events in efficacy analyses 5 events in device group classified as “ischemic stroke” All periprocedural: extended hospitalization by 7 days 3 were related to air embolism 1 hemorrhagic stroke in device group vs 6 in control group Device event occurred 15 days post implant while patient was on warfarin 4/6 stroke events in control group patients resulted in death 3000838-65

Protect AF: Lancet: August 15, 2009

Protect AF: Lancet: August 15, 2009

Protect AF: Lancet: August 15, 2009

Primary efficacy results by patient subgroup Protect AF: Lancet: August 15, 2009

Risk/Benefit Analysis Intent-to-treat analysis Primary endpoint (intent to treat) achieved Other statistically significant endpoint findings Noninferiority for the primary efficacy event rate – 32% lower in device group Noninferiority for all strokes – 26% lower in device group Superiority for hemorrhagic stroke – 91% lower in device group Noninferiority for mortality rate – 39% lower rate in device group Increased rate of primary safety events for the device group relative to the control group Most events in the device group were procedural effusions that decreased over the course of the study 87% of patients were able to discontinue warfarin at 45 days 3000838-120

Conclusion The WATCHMAN LAA Technology offers a safe and effective alternative to warfarin in patients with non-valvular atrial fibrillation at risk for stroke and who are eligible for warfarin therapy 3000838-124

International Symposium on Endovascular Therapy I S E T Save the Date January, 2011 Thank You