WHEN AND WHY TO CLOSE LAA ? Matteo Montorfano San Raffaele Hospital Milan, Italy Matteo Montorfano San Raffaele Hospital Milan, Italy

Magnitude of the Problem: Stroke 1.The World Health Organization estimates that in 2001 there were over 20.5 million strokes worldwide, 5.5 million of these were fatal. 1 2.Europe averages approximately 650,000 deaths due to stroke each year. 2 3.Stroke is the 3 rd leading cause of death behind diseases of the heart and cancer and the 1 st cause of serious long-term disability. 3 4.Stroke social cost accounts approximately for the 3% of total health care expenditures. 4 1.The World Health Organization estimates that in 2001 there were over 20.5 million strokes worldwide, 5.5 million of these were fatal. 1 2.Europe averages approximately 650,000 deaths due to stroke each year. 2 3.Stroke is the 3 rd leading cause of death behind diseases of the heart and cancer and the 1 st cause of serious long-term disability. 3 4.Stroke social cost accounts approximately for the 3% of total health care expenditures. 4 1.World Health Report International Cardiovascular Disease Statistics Heart and Stroke Statistical Update, American Heart Association 4. Evers SM, et al. International comparison of stroke cost studies. Stroke

MECHANISMS OF STROKE 5% 20% 25% 20% 30% CARDIOEMBOLISM CRYPTOGENIC LACUNES LARGE ARTERY ATHEROSCLEROSIS LARGE ARTERY ATHEROSCLEROSIS OTHERS Albers GW et al. Antithrombotic and Thrombolytic Therapy for Ischemic Stroke; Chest 2001.

50%50% 15%15% 10%10% 5%5% 10% CARDIOEMBOLIC SOURCES Nonvalvular Atrial Fibrillation Nonvalvular Atrial Fibrillation Acute MI LV thrombus Valvular heart disease Valvular heart disease Prosthetic valves Prosthetic valves Other less common sources (PFO, ASA, aortic debris, etc.) Other less common sources (PFO, ASA, aortic debris, etc.)

Atrial Fibrillation Demographics by Age Adapted from Feinberg WM. Arch Intern Med. 1995;155:469-43

The Impact of Stroke in AF Patients is More Severe Prevention is Paramount European Community Stroke Project of 4462 patients (AF present in 18%) evaluated after a first in a lifetime stroke 1 –Mortality at 3 months AF patients 33% vs Non-AF patients 20% –Morbidity: AF increased by almost 50% the probability of remaining disabled or handicapped European Community Stroke Project of 4462 patients (AF present in 18%) evaluated after a first in a lifetime stroke 1 –Mortality at 3 months AF patients 33% vs Non-AF patients 20% –Morbidity: AF increased by almost 50% the probability of remaining disabled or handicapped 1. Lamass M et al. Characteristics, Outcome, and Care of Stroke Associated with AF in Europe; Stroke

10% SEDE DELLE TROMBOSI NELLA FIBRILLAZIONE ATRIALE NON REUMATICA 90% REUMATICA 40% 60% ATRIO AURICOLA ATRIO AURICOLA

Non-Valvular AF Stroke Prevention Medical Rx Warfarin cornerstone of therapy Warfarin cornerstone of therapy Warfarin Warfarin 60-70% risk reduction vs no treatment 60-70% risk reduction vs no treatment 30-40% risk reduction vs aspirin 30-40% risk reduction vs aspirin Direct thrombin inhibitors (Dabigatran, RE-LY Study). 1 Direct thrombin inhibitors (Dabigatran, RE-LY Study). 1 Warfarin cornerstone of therapy Warfarin cornerstone of therapy Warfarin Warfarin 60-70% risk reduction vs no treatment 60-70% risk reduction vs no treatment 30-40% risk reduction vs aspirin 30-40% risk reduction vs aspirin Direct thrombin inhibitors (Dabigatran, RE-LY Study). 1 Direct thrombin inhibitors (Dabigatran, RE-LY Study). 1 1 Connolly SJ et al., Dabigatran versus warfarin in patients with atrial fibrillation. NEngl J Med 2009; 361:1139–51.

Vitamin K Antagonists (VKA) in AF Recommended in high-risk patients » Monitoring required » Drug interactions » Often not used Recommended in high-risk patients » Monitoring required » Drug interactions » Often not used 38% reduction in strokes, compared to aspirin* Increase in hemorrhage, compared to aspirin* 70% increase extra-cranial 128% increase intra-cranial 38% reduction in strokes, compared to aspirin* Increase in hemorrhage, compared to aspirin* 70% increase extra-cranial 128% increase intra-cranial *Hart RC et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non- valvular AF. Ann Intern Med 2007: 146:

warfarin better control better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate Anticoagulation in AF Stroke risk reductions Stroke: RRR 62% All-cause mortality: RRR 26% Severe bleedings: 1.2%/year

Warfarin is the gold standard in patients with AF

Narrow anticoagulant therapeutic window Stroke risk increases at INR 3 Hylek EM et al, N Engl J Med 1996; 335:

INR at Stroke RCT’s & Warfarin INR at Stroke AFASAKSPAF IBAATAFSPINAFCAFA INR Ratio PT Ratio (ISI 2.4) ACCP raccomandazioni: INR: 2.0– Target range per ogni studio

HEMORRHAGIC COMPLICATIONS OF OAC IN PATIENTS WITH AF HEMORRHAGIC COMPLICATIONS OF OAC IN PATIENTS WITH AF % PER 100 PATIENTS-YEARS (n= 360) (n= 175) (n= 185) Wehinger C. et al, Stroke 2001; 32: * * p= ** p= 0.03 **

ORAL ANTICOAGULATION AND RISK OF BLEEDING ISCOAT Study 2,745 pts Palareti et al, Arch Intern Med 2000; 160: N= 461 Age > 75 (79.9) N= 461 Age < 70 (56.5) PT / YEAR % ns

21-month Follow-Up DES DES n = 71 BMS n = 56 p-Value Major Bleeding (%) NS MACCE (%) NS TVR (%) No significant differences were found between DES vs. BMS, except in TVR risk. Dual Antiplatelet Therapy After PCI with Stenting in Pts Taking Chronic OAC Conclusion: Major bleeding occurred in 5.6% of patients on triple therapy. Half of the events were fatal, and most occurred within the first month. 127 patients who underwent stent implantation and were discharged on triple therapy (aspirin, thienopyridines and warfarin) were analyzed. Rogacka R, et al, JACC Interventions 2008;1:56-61

Hypothesis Stroke in patients with AF is largely due to the LAA as a thromboembolic source

During surgery for mitral stenosis “amputation of the left atrial appendage is recommended to reduce the likelihood of postoperative thromboembolic events” ACC/AHA 2006 Guidelines for valvular heart disease Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study LAA SURGICAL OBLITERATION “An incomplete LAA ligation during surgery of mitral valve replacement considered together with the absence of LAA ligation, increased risk of embolism at follow-up (up to 11.9 x)” Garcia-Fernandez MA et al, J Am Coll Cardiol 2003;42:1253-8

When to close LAA? Non valvular AF, high risk of stroke - Contraindication to OAC - High risk of bleeding with OAC - Difficult to maintain INR within the therapeutic range - Poor compliance - Difficulty to manage the patient because of logistic problems Non valvular AF, high risk of stroke - Contraindication to OAC - High risk of bleeding with OAC - Difficult to maintain INR within the therapeutic range - Poor compliance - Difficulty to manage the patient because of logistic problems

High-risk factors - age > 75 years - prior stroke / TIA or systemic embolism - Hx of hypertension - CHF or poor LV function - rheumatic mitral valve disease -prosthetic heart valves Moderate - risk factors - age years - diabetes mellitus - CAD with preserved LV function High-risk factors - age > 75 years - prior stroke / TIA or systemic embolism - Hx of hypertension - CHF or poor LV function - rheumatic mitral valve disease -prosthetic heart valves Moderate - risk factors - age years - diabetes mellitus - CAD with preserved LV function 1 High Risk Factor ≥ 2 Moderate Risk Factor 1 High Risk Factor ≥ 2 Moderate Risk Factor HIGH RISK AHA – ACCP 2004

CHAD 2 Score - Congestive heart failure (1), - Hypertension (1), - Age >75 years (1), - Diabetes (1), - history of stroke or TIA (2) CHAD 2 Score - Congestive heart failure (1), - Hypertension (1), - Age >75 years (1), - Diabetes (1), - history of stroke or TIA (2) HIGH RISK >1 The European Society for Cardiology recently recommended that the CHADS 2 -VASc scoring system be used if the CHADS2 score is 0 to 1 or when a more detailed assessment of stroke risk is indicated.

CHA 2 DS 2 -Vasc Score - Congestive heart failure or LVEF≤40% (1); - Hypertension (1); - Age≥75 years (2); - Diabetes (1); - Stroke/TIA/thromboembolism (2); - Vascular disease (MI, peripheral arterial disease, or aortic plaque) (1); - Age 65 to 74 years (1); - Sex category female (1); CHA 2 DS 2 -Vasc Score - Congestive heart failure or LVEF≤40% (1); - Hypertension (1); - Age≥75 years (2); - Diabetes (1); - Stroke/TIA/thromboembolism (2); - Vascular disease (MI, peripheral arterial disease, or aortic plaque) (1); - Age 65 to 74 years (1); - Sex category female (1); HIGH RISK ≥2 Low Risk: CHA 2 DS 2 -VASc = 0 Intermediate risk: CHA 2 DS 2 -VASc = 1 High risk: CHA 2 DS 2 -VASc ≥ 2 Low Risk: CHA 2 DS 2 -VASc = 0 Intermediate risk: CHA 2 DS 2 -VASc = 1 High risk: CHA 2 DS 2 -VASc ≥ 2

WATCHMAN ® System Atritech User friendly – simple repositioning and recaptureUser friendly – simple repositioning and recapture Unique design – flexibility to work in varied anatomyUnique design – flexibility to work in varied anatomy Small profile - 9F to 13F delivery sheathSmall profile - 9F to 13F delivery sheath Amplatzer Cardiac Plug AGA Medical Current Generation Devices Nitinol with 160 micron PET filter) 21, 24, 27, 30, 33 mm TEE, Angiography 12 F 45 days of Coumadin

Clinical Studies STUDYPtsSITESCOMMENTS Pilot patient years of follow-up 30 patients with 5+ years of follow-up PROTECT AF ,500 patient years of follow-up 27 months average follow-up per patient Continued Access Registry (CAP) 56726Significantly improved safety results ASAP834 Treat patients contra-indicated for warfarin EVOLVE223Evaluate next generation WATCHMAN Total1,538 PREVAIL≤400≤50 Same endpoints as PROTECT AF Revised inclusion/exclusion criteria Initiate enrollment October 2010

PROTECT-AF Clinical Trial Prospective, randomized study of WATCHMAN LAA Device vs Long-Term Warfarin TherapyProspective, randomized study of WATCHMAN LAA Device vs Long-Term Warfarin Therapy 2:1 allocation ratio device to control2:1 allocation ratio device to control Non-inferiority studyNon-inferiority study 704 randomized patients with non-valvular AF 704 randomized patients with non-valvular AF Mean age – 72 years Mean age – 72 years Permanent atrial Fib – 36% Permanent atrial Fib – 36% Paroxysmal atrial fib – 41% Paroxysmal atrial fib – 41% CHADS 2 1 – 31% CHADS 2 1 – 31% CHADS 2 2 – 35% CHADS 2 2 – 35% Prospective, randomized study of WATCHMAN LAA Device vs Long-Term Warfarin TherapyProspective, randomized study of WATCHMAN LAA Device vs Long-Term Warfarin Therapy 2:1 allocation ratio device to control2:1 allocation ratio device to control Non-inferiority studyNon-inferiority study 704 randomized patients with non-valvular AF 704 randomized patients with non-valvular AF Mean age – 72 years Mean age – 72 years Permanent atrial Fib – 36% Permanent atrial Fib – 36% Paroxysmal atrial fib – 41% Paroxysmal atrial fib – 41% CHADS 2 1 – 31% CHADS 2 1 – 31% CHADS 2 2 – 35% CHADS 2 2 – 35% Holmes DR, et al. The Lancet 2009;374:

PROTECT AF TRIAL Randomized, controlled, statistically valid study to evaluate the WATCHMAN device compared to warfarin.Randomized, controlled, statistically valid study to evaluate the WATCHMAN device compared to warfarin. In PROTECT AF:In PROTECT AF: Noninferiority for all strokes – 26% lower in device group Noninferiority for all strokes – 26% lower in device group Superiority for hemorrhagic stroke – 91% lower in device group Superiority for hemorrhagic stroke – 91% lower in device group Noninferiority for mortality rate – 39% lower rate in device group Noninferiority for mortality rate – 39% lower rate in device group In PROTECT AF, there are early safety adverse events, specifically pericardial effusion; these events have decreased over time Holmes DR, et al. The Lancet 2009;374:

Safety Event Rates PROTECT AF vs CAP PROTECT AF CAPp-value*p-value± EarlyLate Procedure/Device Related Safety Adverse Events within 7 Days 42/542 (7.7%) 27/271 (10.0%) 15/271 (5.5%) 17/460 (3.7%) Serious Pericardial Effusions within 7 Days 27/542 (5.0%) 17/271 (6.3%) 10/271 (3.7%) 10/460 ( 2.2%) Procedure Related Stroke 5/542 (0.9%) 3/271 (1.1%) 2/271 (0.7%) 0/460 (0.0%) *From tests comparing the PROTECT AF cohort with CAP ±From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP) Improvements seen over time for acute safety events Fewer total procedure/device related events Kar et al. TCT 2010

Warfarin Discontinuation Reasons for remaining on warfarin therapy after 45 days Observation of flow in the LAA (n=30) Observation of flow in the LAA (n=30) Physician order (n=13) Physician order (n=13) Other (n=9) Other (n=9) Reasons for remaining on warfarin therapy after 45 days Observation of flow in the LAA (n=30) Observation of flow in the LAA (n=30) Physician order (n=13) Physician order (n=13) Other (n=9) Other (n=9) 87% of implanted subjects were able to cease warfarin at 45 days and the rate further increased at later timepoints Visit Watchman No.% 45 day349/ month347/ month261/ month 95/ Holmes DR, et al. The Lancet 2009;374:

Summary Hemorrhagic stroke risk is significantly lower with the device Hemorrhagic stroke risk is significantly lower with the device When hemorrhagic stroke occurred, risk of death was markedly increased When hemorrhagic stroke occurred, risk of death was markedly increased All cause stroke and all cause mortality risk are non- inferior to warfarin All cause stroke and all cause mortality risk are non- inferior to warfarin There were early safety events, specifically pericardial effusion; these events have decreased over time There were early safety events, specifically pericardial effusion; these events have decreased over time Hemorrhagic stroke risk is significantly lower with the device Hemorrhagic stroke risk is significantly lower with the device When hemorrhagic stroke occurred, risk of death was markedly increased When hemorrhagic stroke occurred, risk of death was markedly increased All cause stroke and all cause mortality risk are non- inferior to warfarin All cause stroke and all cause mortality risk are non- inferior to warfarin There were early safety events, specifically pericardial effusion; these events have decreased over time There were early safety events, specifically pericardial effusion; these events have decreased over time Holmes DR, et al. The Lancet 2009;374:

LAA Closure with Amplatzer Cardiac Plug for Stroke Prevention in AF: Initial Asia-Pacific Experience Methods 20 NVAF pts (16 males, age 68±9 years) with high risk for stroke (CHADS 2 score: 2.3±1.3) and contraindications to OAC received ACP implants from June 2009 to May Procedures guided by fluoroscopy and TEE. - Clinical F-UP at 1 month and then every 3-month. - TEE 1 month (completion of dual anti-platelet therapy). - All patients were prescribed aspirin, mg per day indefinitely, and clopidogrel, 75mg per day for 4 weeks after the procedure. Lam YY et al., Catheter Cardiovasc Interv May 3. doi: /ccd

LAA Closure with Amplatzer Cardiac Plug for Stroke Prevention in AF: Initial Asia-Pacific Experience Results - LAA successfully occluded in 19/20 pts (95%; 1 procedure abandoned because of catheter-related thrombus formation). - Complications: coronary artery air embolism (n=1) and TEE- attributed esophageal injury (n=1). - Mean size of implant: 23.6±3.1 mm. - Average hospital stay: 1.8±1.1 days. - F-UP TEE showed all the LAA orifices sealed without device-related thrombus formation. - No stroke or death at a mean follow-up of 12.7±3.1 months. Lam YY et al., Catheter Cardiovasc Interv May 3. doi: /ccd

LAA Closure with Amplatzer Cardiac Plug in AF: Initial European Experience Methods -An investigator-initiated retrospective data collection to evaluate the initial European experience in pts treated with the ACP between December 2008 and November 2009, beginning with the FIM. -Procedures guided by fluoroscopy and TEE. -Clinical F-UP: up to 24 hr after the procedure (the study aimed to assess solely periprocedural technical and safety issues). Jai-Wun Park et al., Catheter Cardiovasc Interv. 77:700–706 (2011).

LAA Closure with Amplatzer Cardiac Plug in AF: Initial European Experience Results -In 137 of 143 pts, LAA occlusion was attempted, and successfully performed in 132 (96%). -Major complications in 10 (7.0%) pts: 3 ischemic stroke; 2 device embolization, both percutaneously recaptured; 5 clinically significant pericardial effusions. -Minor complications: 4 pericardial effusions, 2 transient myocardial ischemia, 1 loss of the device in the venous system. Jai-Wun Park et al., Catheter Cardiovasc Interv. 77:700–706 (2011).

WATCHMAN ® System Atritech User friendly – simple repositioning and recaptureUser friendly – simple repositioning and recapture Unique design – flexibility to work in varied anatomyUnique design – flexibility to work in varied anatomy Small profile - 9F to 13F delivery sheathSmall profile - 9F to 13F delivery sheath Amplatzer Cardiac Plug AGA Medical Current Generation Devices Nitinol with 160 micron PET filter) 21, 24, 27, 30, 33 mm TEE, Angiography 12 F 45 days of Coumadin

Distribution of number of lobes (1 to 4) of LAA Distribution of number of lobes (1 to 4) of LAA Veinont etal. Anatomy of normal LAA Circulation lobes 54% 1 lobe 20% 3 lobes 23% 4 lobes 3%

The Amplatzer Cardiac Plug 1. Consists of a lobe and a disc connected by a central waist. 2. Designed to sit in the ostium of the appendage requiring only 10mm of depth 1. Consists of a lobe and a disc connected by a central waist. 2. Designed to sit in the ostium of the appendage requiring only 10mm of depth Lobe Waist Disk

Catheter Delivery 9 F, 10 F & 13 Delivery Catheter –100 cm length –3 dimensional curve to facilitate access to left atrial appendage. –0.035 guide wire compatible dilator Alignment during device delivery Where to place transseptal puncture 9 F, 10 F & 13 Delivery Catheter –100 cm length –3 dimensional curve to facilitate access to left atrial appendage. –0.035 guide wire compatible dilator Alignment during device delivery Where to place transseptal puncture

Flexible Delivery Cable “ stiff” proximal section for pushability and control 2 inch “Floppy” distal Section to aid in assessing ACP placement and stability Heat shrink cover for Hemostasis

Pre-Implant Echo and Angio Measurement

Pre-procedural TEE measurements of LAA in multiple views 0 0 view &0 0 view & Views are most important views for measurements and deployment135 0 Views are most important views for measurements and deployment Size of device should be >20 % of max LAA diameterSize of device should be >20 % of max LAA diameter 0 0 view &0 0 view & Views are most important views for measurements and deployment135 0 Views are most important views for measurements and deployment Size of device should be >20 % of max LAA diameterSize of device should be >20 % of max LAA diameter

Access into LAA and angiogram RAO caudal (Echo 135°) Pig tail advanced into LAAPig tail advanced into LAA Advance sheath over pig tailAdvance sheath over pig tail LAA angio (Right Cranial view)LAA angio (Right Cranial view) Sizing of DeviceSizing of Device 20% larger than max diameter20% larger than max diameter Pig tail advanced into LAAPig tail advanced into LAA Advance sheath over pig tailAdvance sheath over pig tail LAA angio (Right Cranial view)LAA angio (Right Cranial view) Sizing of DeviceSizing of Device 20% larger than max diameter20% larger than max diameter

Configuration of Proper Device Size “Tire” shaped-- Proper tension on the device by the LAA “Square” shaped – No tension on the device from the LAA wall “Strawberry” shaped – the device is being squeezed

Correct Deployed Configuration of ACP Small amount of tenting on the lobe Separation between the disc and lobe Concave disc

Figure of 8 subcutaneous suture

Acute2 days 1 month 3 months Necropsy Photos * Proprietary & Confidential. For Internal Use Only

1.Important complications of LAA occlusion are: Cardiac tamponade Cardiac tamponade Stroke Stroke Residual leak Residual leak Vascular complications Vascular complications 2.Attention to detail at every step and proper use of imaging (Fluoro/Echo) can help prevent these complications 1.Important complications of LAA occlusion are: Cardiac tamponade Cardiac tamponade Stroke Stroke Residual leak Residual leak Vascular complications Vascular complications 2.Attention to detail at every step and proper use of imaging (Fluoro/Echo) can help prevent these complications Summary Conclusions

Thank you

Conclusions Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses markedly reduced intra-cerebral, life- threatening and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses markedly reduced intra-cerebral, life- threatening and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding

Percutaneous Left Atrial Appendage Transcatheter Occlusion to Prevent Stroke in High-Risk Patients With Atrial Fibrillation Early Clinical Experience Horst Sievert, MD; Michael D. Lesh, MD; Thomas Trepels; Heyder Omran, MD; Antonio Bartorelli, MD; Paolo Della Bella, MD; Toshiko Nakai, MD; Mark Reisman, MD; Carlo DiMario, MD; Peter Block, MD; Paul Kramer, MD; Dirk Fleschenberg; Ulrike Krumsdorf; Detlef Scherer, MD. Circulation 2002; 105:

Procedure-LAA TEE

Results – Estimated Stroke Reduction Observed incidence of stroke to date: –6 strokes/168 patient years of follow-up: 3.6% annual rate Expected risk of stroke based on patients’ baseline adjusted CHADS 2 score distribution: 6.3% annual rate Estimated 43% reduction in stroke risk

WATCHMAN LAA Closure Device in situ