Percutaneous Device Occlusions for Left Atrial Appendage (LAA) Julie Logan, RN Foundation for Cardiovascular Medicine La Jolla, CA Julie Logan, RN Foundation for Cardiovascular Medicine

Julie Logan, RN DISCLOSURES I have no real or apparent conflicts of interest to report.

Conflict of Interest Speaker’s name: Julie Logan, RN  I have the following potential conflicts of interest to report:  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  I do not have any potential conflict of interest Julie Logan, RN Foundation for Cardiovascular Medicine

Facts about Atrial Fibrillation (AF) AF is the most common cardiac arrhythmia Affects more than 3 million individuals in the US Projected to increase to 16 million by 2050 Patients with AF have a 5-fold higher risk of stroke Over 87% of strokes are thromboembolic Greater than 90% of thrombus accumulation originates in the Left Atrial Appendage (LAA) Stroke is the number one cause of long-term disability and the third leading cause of death in patients with AF Julie Logan, RN Foundation for Cardiovascular Medicine

Atrial fibrillation is a major source of cardiogenic embolic related stroke 500,000++strokes per year (U.S only) AHA estimates that 20% of strokes/year are related to AF Julie Logan, RN Foundation for Cardiovascular Medicine Source: Neurology, 1978; Stroke, 1985; European Heart Journal, 1987; Lancet, 1987

Stroke: A Life Threatening and Debilitating Disease Functional impact of AF-related strokes Julie Logan, RN Foundation for Cardiovascular Medicine

Atrial fibrillation patients have a much higher incidence of stroke Cardiovascular patients with atrial fibrillation are six times more likely to have stroke than patients without AF Comparison of stroke risk for patients with and without AF Source: Neurology, 1978; Stroke, 1985; European Heart Journal, 1987; Lancet, 1987 Julie Logan, RN Foundation for Cardiovascular Medicine

Warfarin Use in AF Patients by Age 58.1% 60.7% 57.3% 44.3% 35.4% Only 55% of AF patients with no contraindications to warfarin had evidence of warfarin use in previous 3 months Other studies site warfarin use among AF patients from 17% - 50% Elderly patients with an increased absolute risk of stroke were least likely to be taking warfarin Julie Logan, RN Foundation for Cardiovascular Medicine

AF Strokes: Occur primarily with sub-therapeutic INR . Adequacy of anticoagulation in patients with AF coming to a hospital clinic LOW INR < 1.6 79.3% Therapeutic INR 2 - 3 17.2% HIGH INR > 3.2 3.5% Julie Logan, RN Foundation for Cardiovascular Medicine

Dual and Triple Anticoagulation Therapy Julie Logan, RN Foundation for Cardiovascular Medicine American Journal of Cardiology

Left atrial appendage is a major source of thrombi that cause stroke in AF patients 91% of all thrombus in patients with AF is found in the left atrial appendage (LAA) The four largest TEE studies comprising 1,181 patients showed that 98% of thrombi were found in the LAA Location of thrombi in non-rheumatic atrial-fibrillation 1 Julie Logan, RN Foundation for Cardiovascular Medicine

Thrombi Formation in the LAA Julie Logan, RN Foundation for Cardiovascular Medicine

LAA – What does it do? May mediate thirst in hypovolemia via stretch receptors Modulates relationship between pressure & volume Improve filling of LV Endocrine organ – ANP 40-fold higher in LAA than in the rest of the atrial free wall or ventricle Julie Logan, RN Foundation for Cardiovascular Medicine

Left Atrial Appendage Post Mortem LAA Casts LAA body – variable size and morphology 0.77 to 19.27 cm2 and trabeculated Julie Logan, RN Foundation for Cardiovascular Medicine

Why not make it go away? Left Atrial Appendage Julie Logan, RN Foundation for Cardiovascular Medicine

Surgical LAA Closure Julie Logan, RN Foundation for Cardiovascular Medicine JACC vol.52, No11, Sept, 2008;Kanderian et al

Left Appendage Closure Devices PLATTO™ WATCHMAN® Julie Logan, RN Foundation for Cardiovascular Medicine Amplatzer Cardiac Plug

Non-Warfarin Candidates What can we learn from the PLAATO™ device feasibility trial? LA Side LAA Side Julie Logan, RN Foundation for Cardiovascular Medicine

PLAATO European Registry (90% 2 mos echo proven closure) Stroke: 3 strokes / 129 patient years F/U 8.2% 2.3% 72% Stroke Reduction: (based on 129 documented pt years) Julie Logan, RN Foundation for Cardiovascular Medicine 19

North American PLAATO 5 yr F/U Annualized Stroke Rate . North American PLAATO N=64 Treatment success @ 30 days = 100% by TEE 30 day freedom from major adverse events = 98% N=64 6.6% 3.3% Predicted Actual Julie Logan, RN Foundation for Cardiovascular Medicine

WATCHMAN® Device Frame: Nitinol (shape memory) 160 µ PET fabric Device available in various sizes: 21, 24, 27, 30 and 33 mm (diameter) Device diameter is measured across face of device Device Length = Device Diameter Barbs Frame: Nitinol (shape memory) Contour shape accommodates most LAA anatomy Barbs engage the LAA tissue Fabric Cap: Polyethyl terephthalate (PET) Fabric Prevents harmful emboli from exiting during the healing process Julie Logan, RN Foundation for Cardiovascular Medicine

WATCHMAN® LAA closure system Procedure consists of percutaneous placement via transseptal of a filter device just distal to the ostium of the left atrial appendage to keep harmful sized emboli from exiting. Julie Logan, RN Foundation for Cardiovascular Medicine

WATCHMAN® Procedure Julie Logan, RN Foundation for Cardiovascular Medicine

RAO “Long Axis” View On the left is a 3D surface reconstruction of the LA-PVs derived from a CT Angiogram. Julie Logan, RN Foundation for Cardiovascular Medicine

Positioning the Sheath The pigtail is “twirled” to ensure that the sheath is free in the LAA. Julie Logan, RN Foundation for Cardiovascular Medicine

Sizing / Positioning the Device Top left: Endo luminal view of the left-sided structures: LAA on right and left PVs on the left. Bottom left: TEE…measuring the appendage Right: Positioning the Watchman within the sheath to the ostium of the LAA. TEE Julie Logan, RN Foundation for Cardiovascular Medicine

Deploying the Device TEE Julie Logan, RN Foundation for Cardiovascular Medicine

Deploying the Device Assessing Stability Releasing the Device Julie Logan, RN Foundation for Cardiovascular Medicine

WATCHMAN® LAA System – Internal view of Complete Healing of LA Canine – 45 days Human @ Autopsy – 9 mos Julie Logan, RN Foundation for Cardiovascular Medicine

WATCHMAN® Left Atrial Appendage System for Embolic PROTECTion in Patients with Atrial Fibrillation (PROTECT AF) Julie Logan, RN Foundation for Cardiovascular Medicine

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 Julie Logan, RN Foundation for Cardiovascular Medicine

Enrollment Among Sites Average patients enrolled per site: 14 Interventional cardiologists and electrophysiologists participated Enrollment was 53% / 47% between specialists Top enrolling site = 9.3% of patients Julie Logan, RN Foundation for Cardiovascular Medicine

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 Julie Logan, RN Foundation for Cardiovascular Medicine

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 Julie Logan, RN Foundation for Cardiovascular Medicine

INR Measurements – Control Group INR Values Total Measurements With N/Total (%) Patients Ever Having INR < 2.0 1170/3948 29.6% 189/202 93.6% INR > 2.0 to < 3.0 2170/3948 55.0% 197/202 97.5% INR > 3.0 to < 4.0 446/3948 11.3% 149/202 73.8% INR > 4.0 162/3948 4.1% 86/202 42.6% 55% within therapeutic range - consistent with clinical practice Most patients had an INR outside of the recommended range at least once during the study 34% of Control Patients interrupted Warfarin therapy Julie Logan, RN Foundation for Cardiovascular Medicine

Warfarin Discontinuation- Watchman group 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) Julie Logan, RN Foundation for Cardiovascular Medicine

PROTECT AF Efficacy Endpoint Primary Efficacy Endpoint All stroke: ischemic or hemorrhagic Cardiovascular and unexplained death Systemic thromboembolism Julie Logan, RN Foundation for Cardiovascular Medicine

Intent-to-Treat: Primary Efficacy Results Cohort WATCHMAN Control Rel. Risk (95% CI) Posterior Probabilities Rate (95% CI) Non-inferiority Superiority 600 pt-yrs 4.4 2.6, 6.7 5.8 3.0, 9.1 0.76 0.39, 1.67 0.992 0.734 900 pt-yrs 3.4 2.1, 5.2 5.0 2.8, 7.6 0.68 0.37, 1.41 0.998 0.837 Endpoint criteria met 32% lower relative risk in WATCHMAN Group Julie Logan, RN Foundation for Cardiovascular Medicine

Intent-to-Treat: All Stroke Cohort WATCHMAN Control Rel. Risk (95% CI) Posterior Probabilities* Rate (95% CI) Non-inferiority Superiority 600 pt-yrs 3.4 1.9, 5.5 3.6 1.5, 6.3 0.96 0.43, 2.57 0.927 0.488 900 pt-yrs 2.6 1.5, 4.1 3.5 1.7, 5.7 0.74 0.36, 1.76 0.998 0.731 26% lower relative risk in WATCHMAN Group Julie Logan, RN Foundation for Cardiovascular Medicine

Primary Efficacy Kaplan-Meier Estimates Cohort 1 Year Event Rate (95% CI) 2 Year Event Rate (95% CI) 3 Year WATCHMAN 3.6 (1.8, 5.3) 6.5 (3.1, 10.0) 7.9 (3.6, 12.2) Control 4.3 (1.5, 7.0) 9.7 (4.6, 14.8) 12.3 (5.2, 19.5) Julie Logan, RN Foundation for Cardiovascular Medicine

Pericardial Effusions by Experience Pericardial effusions – most common safety issue Throughout PROTECT AF Trial, procedural modifications and training enhancements were implemented Procedural events would be expected to decrease over time Site implant group Any Serious No. % No. % Early patients (1-3) 13/154 8.4 10/154 6.5 Late patients (4) 27/388 7.0 17/388 4.4 Total 40/542 7.2 27/542 5.0 Continued ACCESS Registry- CAP Any Serious No. % No. % 1/88 1.1 1/88 1.1 3000838-70 Julie Logan, RN Foundation for Cardiovascular Medicine

Intent-to-Treat: All-Cause Mortality Cohort WATCHMAN Control Rel. Risk (95% CI) Posterior Probabilities* Rate (95% CI) Non-inferiority Superiority 600 pt-yrs 3.4 1.8, 5.4 4.9 2.3, 7.8 0.69 0.33, 1.66 0.991 0.779 900 pt-yrs 2.9 1.7, 4.4 4.7 2.5, 7.1 0.61 0.32, 1.32 0.999 0.889 39% lower relative risk in WATCHMAN Group Julie Logan, RN Foundation for Cardiovascular Medicine

Learning Curve Early vs. Late Patients Investigational; no claims can be made from this slide. Julie Logan, RN Foundation for Cardiovascular Medicine 43 April 23, 2009 43

Learning Curve Tertiles by Enrollment Date and CAP Investigational; no claims can be made from this slide. Julie Logan, RN Foundation for Cardiovascular Medicine 44 April 23, 2009 44

Conclusion - Warfarin Long-term Warfarin treatment of patients with AF has been found effective, but presents considerable difficulties and risks Difficult to maintain patients in therapeutic range/compliance Increased risk of hemorrhagic stroke and fatal bleeds over time PROTECT AF trial evaluated the WATCHMAN device compared to Warfarin Only study comparing device to drug for stroke prevention in AF Prospective, randomized, controlled study of 800 patients 86% of WATCHMAN patients successfully implanted and able to discontinue Warfarin therapy Julie Logan, RN Foundation for Cardiovascular Medicine

Conclusion - Safety Any invasive procedure has potential complications Majority of WATCHMAN safety events occurred in the first 7 days (mostly pericardial effusions and procedural ischemic strokes) Pericardial effusions did NOT cause death or long-term disability With experience (procedural / training modifications), positive trends were observed in all procedural categories Procedure safety events: Serious pericardial effusion: All-cause mortality was 39% lower in the WATCHMAN group (2.9 vs. 4.7) 9% 4% 1% 7% 4% 1% Julie Logan, RN Foundation for Cardiovascular Medicine

Conclusion - Efficacy Efficacy Events - 32% fewer in the WATCHMAN group (3.4 vs. 5.0) Composite of ischemic stroke, hemorrhagic stroke, systemic embolism, CV or unexplained death Non-inferiority was achieved Strokes - 26% fewer in the WATCHMAN group (2.6 vs. 3.5) Procedural ischemic strokes occurred in 1.1% of WATCHMAN patients (0% in CAP) After Day 0, WATCHMAN ischemic stroke rate is 1.7% versus 2.0% for Control No hemorrhagic stroke risk in WATCHMAN after warfarin discontinuation versus 2% for Control Risk of death was markedly increased with hemorrhagic stroke Potentially, 26,000 strokes per year are preventable with WATCHMAN Julie Logan, RN Foundation for Cardiovascular Medicine