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Left Atrial Appendage Closure

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Presentation on theme: "Left Atrial Appendage Closure"— Presentation transcript:

1 Left Atrial Appendage Closure

2 Disclosure IMPORTANT INFORMATION: These materials are intended to describe common clinical considerations and procedural steps for the on-label use of referenced technologies as well as current standards of care for certain conditions. Of course, patients and their medical circumstances vary, so the clinical considerations and procedural steps described may not be appropriate for every patient or case. As always, decisions surrounding patient care depend on the physician’s professional judgment in light of all available information for the case at hand. Boston Scientific (BSC) does not promote or encourage the use of its devices outside their approved labeling. Boston Scientific does not have an FDA-approved ablation catheter for the treatment of atrial fibrillation. The presenter’s experience with BSC products may not be interpreted or relied upon to support clinical claims about BSC devices or product comparison claims regarding BSC and competitive devices. The experiences of other users may vary. All case studies presented are not necessarily representative of clinical outcomes in all cases as individual results may vary. All material, graphs, data and charts sourcing is on file with the presenter and are the property of their respective copyright owner.

3 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 Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit None

4 Stroke in AF patients People with AF have 5 times the risk of stroke compared to people without AF1 Stroke is more severe for patients with AF, as they have a 70% chance of death or permanent disability1 AF-associated ischemic strokes generally occlude large intracranial arteries depriving a more extensive region of the brain of blood flow2 Thirty-day mortality was greater in AF strokes than in non-AF strokes3 Compared with non-AF patients, AF patients had poorer survival and more recurrences of stroke during the first year of follow-up3 The economic burden of stroke will continue to rise globally as the incidence of stroke increases4 1 Holmes DR. Seminars in Neurology. 2010;30:528–536 2 Tu HT et al, Cerebrovascular Disease. 2010;30(4):389-95 3 Lin HJ. et al, Stroke. 1996;27: 4 Klein A et al, Datamonitor. July 2011

5 Fibrillation causes blood to stagnate in the LAA
91% of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA)1 Fibrillation causes blood to stagnate in the LAA The stagnant blood becomes an ideal environment for a thrombus or blood clot to form The blood clot, or portion of it, dislodges from the LAA and travels through arterial system Thrombus in the LAA The embolism lodges itself in the blood vessels of the brain, restricting blood flow and causing a stroke Images on file at Boston Scientific Corporation 1 Blackshear JL. Odell JA., Annals of Thoracic Surgery. 1996;61:

6 The left atrial appendage is a gestational remnant
Forms during the third week of gestation and serves as the left atrium in the fetus LAA is the about the size of a thumb The opening may be a range of sizes – 10mm - 40mm LAA also varies in structure: may be thin or thick-walled may have “turns” or curves may contain multiple “horns” Images on file at Boston Scientific Corporation Left Atrial Appendage

7 The management of AF is aimed at reducing symptoms and minimizing complications
American Heart Association and European Society of Cardiology guidelines recommend anticoagulation for AF patients1 ESC 2012 Guidelines state that there is no indication for oral anticoagulation or aspirin if the CHA2DS2VASc score is 0 or in women less than 65 years of age without additional risk factors2 Treatment options for AF are based on a complex algorithm based on stroke risk What are the goals of therapy? To minimize symptoms Control thromboembolic risk Ultimately, to prolong life Patients need to be well informed to actively and successfully participate in their treatment decisions 1 Camm AJ et al, Eur Heart J. 2010;31:2369–2429 2 Camm et al. Eur Heart J. 2012;33:1-29; doi /eurheartj/ehs253

8 Control Better (placebo) Reduction of all-cause mortality RRR 26%
Anticoagulation in AF meta-analysis stroke risk reductions with warfarin Warfarin Better Control Better (placebo) AFASAK SPAF BAATAF CAFA SPINAF EAFT 50% -50% Aggregate Reduction of stroke RRR 62% Reduction of all-cause mortality RRR 26% 100% -100% Warfarin is a long standing and, when taken appropriately, effective means of stroke reduction in patients with atrial fibrillation Careful monitoring is required to help ensure that patients remain within the therapeutic range Hart et al. Ann Intern Med. 1999;131:

9 CHADS2 scores establish risk of stroke
CHADS2, developed and validated by Gage et al, is a system for establishing the risk of stroke in patients with non-rheumatic atrial fibrillation1 Patients are awarded points based on comorbidities Condition Points C Congestive heart failure 1 H Hypertension A Age ≥75 years D Diabetes mellitus S2 Previous stroke or TIA 2 European Society of Cardiology Guidelines2 CHADS2 Score Treatment Aspirin 1 Aspirin or warfarin* ≥2 Warfarin * Use of aspirin or warfarin is based on additional patient characteristics such as age, number of risk factors, etc. 1 Gage BF et al, JAMA 2001;285:2864–2870 2 Camm AJ et al, Eur Heart J 2010;31:2369–2429

10 CHA2DS2VASc is a newer scoring system
CHA2DS2VASc, developed by Lip et al, is a refinement of the older CHADS2 Score which includes additional stroke risk factors and puts greater emphasis on age as a risk factor1 Condition/Risk Factor Points C Congestive heart failure 1 H Hypertension A Age ≥75 years 2 D Diabetes mellitus S2 Previous stroke or TIA V Vascular disease Age years Sc Sex (female gender) European Society of Cardiology Guidelines2 CHA2DS2-VASc Score Treatment No treatment 1 Aspirin or warfarin or dabigatran ≥2 Warfarin or dabigatran 1 Lip GY et al, Chest. 2010;137(2):263-72 2 Camm AJ et al, Eur Heart J. 2010;31:2369–2429

11 How do the two CHADS scores compare?
Generally, they result in similar treatment recommendations Where they are the same: Both CHADS systems assign 1 “point” each for presence of congestive heart failure (any), hypertension and diabetes Both CHADS systems assign 2 points for prior TIA or stroke Where they differ: CHA2DS2VASc puts greater emphasis on age, assigning 1 point for age between years, and 2 points for age >75 years. CHADS2 only assigns one point for age >75 years CHA2DS2VASc adds 1 point each for presence of any vascular disease and female gender, which are not included in the CHADS2 score

12 Warfarin effective in preventing coagulation but has significant therapeutic limitations
Warfarin is a long standing and, when taken appropriately, effective means of stroke reduction in patients with AF Careful monitoring is required to help ensure that patients remain within the therapeutic range Many foods and medicines interact with warfarin and these interactions can make it challenging to keep the INR within the therapeutic range Despite efficacy in stroke prevention, warfarin exposes patients to a number of risks (e.g. intracranial hemorrhage and hemorrhagic stroke) Warfarin use represents a challenge to surgeries as patients must discontinue warfarin prior to surgery Warfarin has high rates of discontinuation and non-adherence to therapy Warfarin tops the list for emergency hospitalizations for adverse drug events in older Americans1 A need exists for an anti-thrombotic regimen that does not increase rates of major bleeding, does not interact with other medicines or complicate surgeries and does not require extensive monitoring to maintain efficacy 1 Budnitz DS, et al. NEJM 2011, 365:

13 44% of bleeding events occur in patients above therapeutic range1
Warfarin requires regular monitoring to ensure patients stay within its narrow efficacy range Warfarin has a narrow range of effectiveness, regular monitoring is required to ensure that patients are within the therapeutic range as determined by the international normalized ratio (INR) INR Effectiveness is influenced by interactions with some foods and medications INR must be checked frequently until the correct dose is determined Once optimal dosing is determined and anticoagulation is stabilized, patients generally return for regular INR monitoring monthly Because it is difficult to maintain patients within the narrow therapeutic range, many patients spend a significant amount of time either under- or over- anticoagulated -5 - -4 -3 -2 -1 44% of bleeding events occur in patients above therapeutic range1 Over-anticoagulated Therapeutic Range 48% of thromboembolic events occur in patients below therapeutic range1 Under-anticoagulated 1 Oake N, et al. Can Med Assoc J. 2007:176(11);1589−1594

14 HAS-BLED risk of bleeding
HAS-BLED, developed by Pisters et al, allows clinicians to assess an individual’s risk of bleeding based on comorbidities1 In determining when oral anticoagulation is appropriate, clinicians must balance the CHADS2 or CHA2DS2VASc score against HAS-BLED Unfortunately, a high CHADS score often correlates with a high HAS-BLED score and these patients do not receive anticoagulation due to the high bleeding risk HASBLED Risk of major bleeding in patients with AF in the Euro Heart Survey Condition Points H Hypertension 1 A Abnormal liver and renal function (1 point each) 1 or 2 S Stroke B Bleeding L Labile INR E Elderly (age >65) D Drugs or alcohol (1 point each) Score Bleeds Per 100 Patient Years 1.13 1 1.02 2 1.88 3 3.74 4 8.7 Hypertension, stroke and age are also variables in the CHADS scores 1 Pisters R et al. Chest 2010;138(5):

15 Percent of patients taking warfarin following a stroke1
Warfarin has a high rate of discontinuation and non-adherence to therapy 17.4% of patients discontinue warfarin within 3 months following a stroke Percent of patients taking warfarin following a stroke1 A study of 2,598 stroke patients discovered that 17.4% had ceased taking warfarin altogether 3 months after being discharged following a stroke1 A second study which explored the effect of missed or extra pill bottle openings in warfarin users found that 92% of warfarin users had at least 1 missed or extra pill bottle opening during a 3.5 month period, which overall translated to a 40% rate of non-adherence with warfarin therapy2 Percent of Patients Patients who do not adhere to their warfarin regimen are at increased risk of ischemic and hemorrhagic stroke 1 Bushnell CD et al. Archives of Neurology, 2010;67(12): 2 Kimmel SE et al. Archives of Internal Medicine 2007;167:

16 Three new oral anticoagulants have recently completed clinical trials
RE-LY1 ROCKET-AF2 ARISTOTLE3 Dabigatran Rivaroxaban Apixaban Comparator Warfarin Total Enrolled Subjects 18,113 14,264 18,201 Trial Design Randomized, controlled, non-inferiority (doses of dabigatran were blinded) Randomized, controlled, double-blind, non-inferiority Median Duration of Follow up 2 years 1.94 years 1.8 years Average CHADS2 Score 2.1 3.5 Results (primary outcome = stroke or systemic embolism) Reduction in primary outcome compared to warfarin This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study. 1 Connelly SJ et al, NEJM 2009;361: 2 Patel MR et al, NEJM 2011;365:883-91 3 Granger J. et al, NEJM 2011;365:981-92

17 Major bleeding rates Study Treatment Major Bleeding Hemorrhagic Stroke
RE-LY1 Dabigatran (110 mg) 2.71% 0.12% Dabigatran (150 mg) 3.11% 0.10% Warfarin 3.36% 0.38% ROCKET-AF2 Rivaroxaban 3.6% 0.5% 3.4% 0.7% ARISTOTLE3 Apixaban 2.13% 0.24% 3.09% 0.47% This chart is not based on a head-to-head trial and is not intended to suggest head-to-head comparisons of the separate trials or the therapies under study. 1 Connelly SJ et al, NEJM 2009;361: 2 Patel MR et al, NEJM 2011;365:883-91 3 Granger J. et al, NEJM 2011;365:981-92

18 Dabigatran demonstrated non-inferiority to warfarin in the RE-LY trial
A phase III non-inferiority clinical trial compared dabigatran twice daily at either 110 mg or 150 mg to dose-adjusted warfarin Dabigatran etexilate (Pradaxa®) is an oral pro-drug that is rapidly converted to dabigatran, a direct inhibitor of thrombin Dabigatran at 110 mg demonstrated non-inferiority to warfarin for prevention of stroke and systemic embolism while reducing the rate of major bleeding 150 mg of dabigatran twice daily demonstrated superiority to warfarin at reducing stroke and systemic embolism, though it had a higher bleeding rate than 110 mg (P=0.052) 75 mg dose approved in the US, although no data in patients are available 0.76 relative risk compared to warfarin Percent per year Connelly SJ et al, NEJM. 2009;361:

19 Percent of patients discontinuing therapy1
Like warfarin, dabigatran has demonstrated high rates of non-adherence to therapy During the RE-LY trial, dabigatran demonstrated higher rates of discontinuation than warfarin Dyspepsia, a frequent side effect, contributed to the high rates of discontinuation 21% of patients taking dabigatran at its recommended dose opted to discontinue therapy within 2 years Percent of patients discontinuing therapy1 1 Connelly SJ et al, NEJM. 2009;361:

20 Efficacy of rivaroxaban versus warfarin
ROCKET AF, the recently completed Phase III clinical trial, demonstrated non-inferiority of rivaroxaban to warfarin The ROCKET AF study was a randomized controlled trial of 14,264 patients Rivaroxaban (Xarelto®) is the first oral direct factor Xa inhibitor to the market; once daily dosing Rivaroxaban demonstrated non-inferiority to warfarin in prevention of stroke and systemic embolism In the primary safety analysis, there was no significant difference between rivaroxaban and warfarin with respect to rates of major or nonmajor clinically relevant bleeding Efficacy of rivaroxaban versus warfarin Events/100 pt years Rivaroxaban was found to have similar rates of bleeding and adverse events to warfarin Patel MR et al. NEJM. 2011;365:883-91

21 ARISTOTLE A comparison of apixaban to warfarin
The ARISTOTLE study was a randomized double blind trial of 18,201 patients with a mean CHADS2 score of 2.1, and mean duration for follow-up of 1.8 years Apixaban (Eliquis®) is an oral direct factor Xa inhibitor, taken twice daily Apixaban demonstrated superiority to warfarin in “preventing stroke or systemic embolism”, as well as in reducing bleeding and cardiac death Apixaban did not demonstrate superiority to warfarin in the prevention of ischemic or uncertain type strokes or systemic embolization Efficacy of apixiban versus warfarin 49% lower risk of hemorrhagic stroke Events ( % / yr) Granger J et al, NEJM. 2011;365:981-92

22 AVERROES A comparison of apixaban to aspirin
Trial Design: Patients with AF and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n=2,808) vs aspirin mg daily (n=2,791). Results Stroke or systemic embolism: 1.6%/year with apixaban vs. 3.7%/year with aspirin (P<0.001) Stroke: 1.6%/year vs. 3.4%/year (P<0.001) Clinically relevant nonmajor bleeding: 3.1%/year vs. 2.7%/year (P=0.35) Fatal bleeding: 0.1%/year vs. 0.2%/year (P=0.53) 3.7 P<0.001 % per year 1.6 Conclusions Among patients with AF and elevated risk for stroke who were not suitable for warfarin therapy, apixaban was beneficial Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin, without increasing the risk for major bleeding Stroke or systemic embolism apixaban aspirin Connolly SJ, et al. NEJM .2011;364:806-17

23 Warfarin alternatives exist, but…
Dabigatran, rivaroxaban and apixaban have demonstrated safety and efficacy in clinical trials However, real-world and long-term efficacy and safety and drug interactions have yet to be investigated While new oral anticoagulants may avoid the burden of regular INR monitoring, bleeding risks and high rates of non-adherence are still a problem A need exists for an effective means of stroke reduction that does not expose patients to bleeding events or require long-term patient adherence

24 Drugs for Rhythm/Rate Control (dabigatran, rivaroxaban, apixaban)
AF Treatment Options AF Ablation* Pacing Drugs for Rhythm/Rate Control Embolic Management AND/OR Interventions Drugs (warfarin) Drugs (dabigatran, rivaroxaban, apixaban) Surgical Ligation LAA Clips Endovascular LAA *BSC currently has no ablation catheters FDA-approved for the treatment of AF

25 Mechanical Approaches for Stroke Prophylaxis

26 Left atrial appendage clot on echo: 91% of stroke in AF is caused by blood clots formed in the LAA1
Images on file at Boston Scientific Corporation 1 Blackshear JL, Odell JA, Annals of Thoracic Surgery, 1996;61:

27 Invasive procedures can successfully close the LAA
Surgical approaches to thromboembolic prophylaxis have been explored since the 1940s LAA closure or obliteration has most often been considered as an adjunct to other cardiac procedures such as mitral valvotomy or cardiac bypass surgery Studies on patients undergoing LAA closure have shown a trend toward reduction in embolic events A review of the literature on LAA closure prior to the introduction of the WATCHMAN device found closure rates of 10%-73%1 Method of Successful LAA Closure2 Excision Ligation w/ Sutures Ligation w/ Staples A need exists for a less invasive approach that can consistently close the LAA 1 Dawson AG et al. Interact Cardiovasc Thorac Surg. 2010;10:306-11 2 Kanderian et al. JACC. 2008;52:924–9

28 Guidelines on interventional approaches for stroke prevention in non-valvular AF
In its August 2012 update of guidelines, the European Society of Cardiology stated that LAA closure may be considered in patients at high stroke risk that are contraindicated for long-term oral anticoagulation1 European Society of Cardiology guidelines have given this a class IIb indication with level of evidence B1 AHA/ACC/ESC guidelines recommend the removal of the LAA during cardiac procedures such as coronary bypass or valve repair surgery for patients at risk of developing post-operative AF2 1 Camm et al. Eur Heart J. 2012;33:1-29; doi /eurheartj/ehs253 2 Fuster V et al. Circulation. 2006;114:e257-e35

29 The Amplatzer Cardiac Plug (ACP) is an alternative LAA closure device
Based on the Amplatzer septal occluder, the ACP received CE mark for use in LAA closure in 2008 Cohort studies in Europe1 (143 patients) and Asia2 (20 patients) have demonstrated the feasibility of LAA closure with the ACP The ACP data presented is based on inexperienced implanters1 A small (45 patients) randomized trial (AMPLATZER Cardiac Plug Clinical Trial) is currently exploring the 45-day impact of the ACP3 Results of a large randomized trial are expected by December 20154 Rates of procedure-related adverse events1 % Procedural Complications 2/143 2/143 5/143 1 Park JW et al. Catheter Cardiovasc Interv 2011; 77: 2 Lam YY et al. Catheter Cardiovasc Interv 2012; 79: 3 4 NCT as of 4/15/13 ACP is an investigational device and not FDA approved

30 The WATCHMAN® product is a device for percutaneous closure of the left atrial appendage
WATCHMAN is a self-expanding nitinol frame with fixation anchors and a permeable fabric cover It is designed to be permanently implanted at or slightly distal to the opening of the LAA to trap potential emboli before they exit the LAA Five sizes of device (21, 24, 27, 30 and 33 mm) allow for precise fit within ostium It is implanted via a transseptal approach by use of a catheter- based delivery system The delivery catheter is capable of recapturing the device if necessary Received CE mark in 2005 WATCHMAN ® LAA Closure Device Images on file at Boston Scientific Corporation Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

31 WATCHMAN®: Device Implant Procedure
Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance Access to the left atrium is gained via the femoral vein and transseptal puncture The procedure takes minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure Transseptal puncture Placement of WATCHMAN ® in LAA Images on file at Boston Scientific Corporation Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

32 WATCHMAN®: Device endothelialization
Canine Model – 30 Day Human Pathology - 9 Months Post-implant (Non-device related death) Canine Model – 45 Day Images on file at Boston Scientific Corporation. Results in animal models may not necessarily be indicative of clinical outcomes. Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

33 WATCHMAN Clinical Evidence Portfolio
Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

34 WATCHMAN Evidence-Based Medicine
2002 – Pilot Endpoints: Feasibility and Safety Comparison: nonrandomzed Incl/Excl: CHADS2≥1, able to tolerate warfarin 2008 – CAP Registry Endpoints: Collect additional safety and efficacy data to be pooled with PROTECT AF Incl/Excl: same as PROTECT AF 2010 – PREVAIL Endpoint: Safety and Efficacy Comparison: warfarin Incl/Excl: CHADS2≥2, some exceptions for CHADS2=1 no clopidegrel 7 days prior to procedure 2012: ESC Guidelines & Expanded Indication 2013 EMEA Registry* Endpoint: Additional information in a real-world setting Incl/Excl: All comers 2009 – ASAP Endpoint: Efficacy Comparison: CHADS2 score expected stroke rate Incl/Excl: intolerant or contra-indicated for warfarin 2005 – PROTECT AF Endpoints: Safety and Efficacy Comparison: warfarin Incl/Excl: CHADS2 ≥ 1, able to tolerate warfarin *In planning phase Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

35 WATCHMAN Clinical Portfolio ~2000 patients and 4000 patient-years of data
WATCHMAN is the only device with over 2,000 patients studied in multiple randomized trials and registries and 4,000 patient-years of follow-up Study Patients Sites Comments Pilot 66 8 402 patient years of follow-up >6 years of follow-up PROTECT AF 800 59 1500 patient years of follow-up 2.3 years average follow-up per patient3 CAP (Continued Access Registry ) 460 26 Significantly improved safety results1, 2 ASAP 150 4 Treat patients contra-indicated for warfarin EVOLVE 69 3 Evaluate design changes of a non-commercialized WATCHMAN device PREVAIL 453 41 Same endpoints as PROTECT AF Revised inclusion/exclusion criteria Results presented in March 2013 CAP2 57 16 Prospective, multicenter, single-arm registry 300 patients from 60 sites (PROTECT AF or PREVAIL)4 Total Patients: 2055 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 1Holmes DR et al. Lancet 2009; 374: 534–42 2Reddy VY et al. Circulation. 2011;123: 3Reddy VY et al. Circulation. 2013; 127: 4 As of 2/19/13

36 Demographics Device Patients
Characteristic PROTECT AF N=463 CAP N=566 PREVAIL N=269 P value Age, years 71.7 ± 8.8 (463) (46.0, 95.0) 74.0 ± 8.3 (566) (44.0, 94.0) 74.0 ± 7.4 (269) (50.0, 94.0) <0.001 Gender (Male) 326/463 (70.4%) 371/566 (65.5%) 182/269 (67.7%) 0.252 CHADS2 Score (Continuous) 2.2 ± (1.0, 6.0) 2.5 ± 1.2 (1.0, 6.0) 2.6 ± (1.0, 6.0) CHADS2 Risk Factors CHF 124/463 (26.8%) 108/566 (19.1%) 63/269 (23.4%) Hypertension 415/463 (89.6%) 503/566 (88.9%) 238/269 (88.5%) Age ≥ 75 190/463 (41.0%) 293/566 (51.8%) 140/269 (52.0%) Diabetes 113/463 (24.4%) 141/566 (24.9%) 91/269 (33.8%) Stroke/TIA 82/463 (17.7%) 172/566 (30.4%) 74/269 (27.5%) Most notable differences: Age, Diabetes, and Prior Stroke/TIA Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013 PROTECT AF and CAP data from Reddy, VY et al. Circulation. 2011;123:

37 Average age for WATCHMAN®
The PROTECT AF trial demonstrated non-inferiority of the WATCHMAN® Device to warfarin in 707 randomized patients PROTECT AF was a prospective, randomized, multi-center trial which compared the WATCHMAN Device to warfarin for thromboembolic prophylaxis 707 patients were randomized to either the WATCHMAN Device or warfarin in a 2:1 device to therapy ratio; 93 roll-in patients Patients who received the WATCHMAN Device had 45 days of post operative warfarin therapy to ensure endothelialization Transesophogeal echocardiography was performed at 45 days, 6 months and 1 year to check for device placement, presence of thrombus and flow Patients received up to 5 years of biannual follow-up Baseline Risk Factors CHADS2 WATCHMAN® Warfarin 1 33.9% 27% 2 34.1% 36.1% 3 19% 20.9% 4 8% 9.8% 5 4.1% 6 0.9% 2% Average age for WATCHMAN® was 71.7 years ± 8.8 years Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Holmes DR et al. Lancet .2009;374:534–42

38 PROTECT AF Primary Safety Results
Device Control Observed rate (events per 100 pt-yrs) (95% CrI) Observed rate (events per 100 pt-yrs Rate Ratio Intervention/Control Primary Safety 5.5 ( 4.2, 7.1) 3.6 (2.2, 5.3) 1.53 (0.95, 2.70) Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy, VY et al. Circulation. 2013;127:

39 PROTECT AF Ischemic and hemorrhagic stroke rates
Watchman warfarin Percent of patients Percent of patients Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Holmes DR et al. Lancet. 2009;374:534–42

40 WATCHMAN Safety Data Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

41 Proc/Device Rel. Safety AE w/in 7 days
WATCHMAN® Procedure outcomes in WATCHMAN patients P=0.006* P=0.018* P=0.039* Both the WATCHMAN Device and warfarin patients experienced adverse events The WATCHMAN Device events were concentrated around the time of the procedure Warfarin events occurred at any time (not shown) Proc/Device Rel. Safety AE w/in 7 days *From tests for differences across three groups (early PROTECT AF, late PROTECT AF, and CAP) Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 AE=adverse event; PE=pericardial effusion Reddy VY et al. Circulation. 2011;123:

42 Pericardial Effusion Rates
Rates of pericardial effusion within 7 days of the procedure 32% reduction in rates of pericardial effusion as experience increased Pericardial effusion was the most common adverse event in the WATCHMAN® Device group Of patients experiencing pericardial effusion, 68% were treated with pericardiocentesis and 32% required surgical intervention Rates of pericardial effusion declined at each center as experience with the procedure increased % Patients PROTECT AF PROTECT AF CAP-Continued Access Protocol Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy VY et al. Circulation. 2011;123:

43 PREVAIL Study Goals and Design
Prospective, randomized, multicenter confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device Similar design to PROTECT AF: prospective randomized 2:1 (device: control) trial 407 randomized patients from 41 US centers Inclusion of new centers and new operators to show enhancements to the training program are effective Roll-in phase allowed new centers to implant 2 patients prior to randomization phase Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013

44 Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators p = 0.01 p = 0.282 N= 26 N= 24 Increasing implant success with each trial. Protocol required a minimum of 20% of subjects enrolled at new centers and 25% of subjects enrolled by new operators 18 out of 41 centers did not have prior WATCHMAN experience 40% of patients enrolled at new sites by new operators Implant success defined as deployment and release of the device into the left atrial appendage Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013 PROTECT-AF and CAP data from Reddy VY et al. Circulation. 2011;123:

45 PREVAIL First Primary Endpoint Acute (7-day) Procedural Safety
2.67% One-sided 95% upper CI bound for success 2.0% 2.5% 3.0% Percent of patients experiencing an event 2.2% 2.618% Acute (7-day) occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention 6 events in device group = 2.2% (6/269) Pre-specified criterion met for first primary endpoint (95% Upper confidence bound < 2.67%) Results are preliminary; final validation not yet complete Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013

46 Additional Safety Analysis 7 Day Serious Procedure/Device Related
Composite of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications1 n=39 n=23 n=12 p = 0.005 No procedure-related deaths reported in any of the trials Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 1Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding PREVAIL results from Holmes, DR Jr et al., CIT 2013 PROTECT-AF and CAP data from Reddy, VY et al. Circulation. 2011;123:

47 Pericardial Effusions Requiring Intervention
Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013 PROTECT-AF and CAP data from Reddy VY et al. Circulation. 2011;123:

48 Stroke and Device Embolization
p = 0.007 n=2* n=1 n=2 p = 0.364 Procedure related strokes were reduced Device embolizations remained low Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 *1 additional device embolization was reported at 45 days PREVAIL results from Holmes, DR Jr et al., CIT 2013 PROTECT-AF and CAP data from Reddy VY et al. Circulation. 2011;123:

49 WATCHMAN Efficacy Data
Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

50 Second Primary Endpoint Composite 18-month Efficacy
1.75 95% upper CI bound for non-inferiority 1.07 0.57 1.88 0.5 1.0 1.5 2.0 18-month Rate Ratio Comparison of composite of stroke, systemic embolism, and cardiovascular/unexplained death 18-month event rates in both control and device groups = 0.064 Upper 95% CI bound slightly higher than allowed to meet success criterion (<1.75) Limited number of patients with follow-up through 18 months thus far (Control = 30 pts, Device = 58 pts) ¹CI is one-sided Results are preliminary; final validation not yet complete Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013

51 PREVAIL Control (Warfarin) Group Performance
In spite of the high average CHADS2 score of 2.6 in the control group, the observed rate of stroke in the PREVAIL Control group was lower than in other published warfarin studies PREVAIL control group rate = 0.7 (95% CI 0.1, 5.1) Wide confidence bounds due to small number of patients with 18-months of follow-up Trial Control (Warfarin) Group Stroke, Systemic Embolism Rate (Per 100 PY) PROTECT AF1 1.6 RE-LY (Dabigatran)2 1.7 ARISTOTLE (Apixaban)3 ROCKET AF (Rivaroxaban)4 2.2 PREVAIL 0.7 Results are preliminary; final validation not yet complete PREVAIL results from Holmes, DR Jr et al., CIT 2013 1 Ischemic stroke rate from Holmes et al. Lancet 2009; 374:534-42 2 Connolly et al. N Engl J Med 2009; 361: 3 Granger et al. NEJM 2011; 365:981-92; 4 Patel et al. NEJM 2011; 365:883-91 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

52 Third Primary Endpoint 18-month Thrombolic Events
0.0275 95% upper CI bound for non-inferiority 0.0051 0.0268 0.03 -0.02 -0.01 0.01 0.02 0.03 18-month Rate Difference Comparison of ischemic stroke or systemic embolism occurring >7 days post randomization Endpoint success in the presence of an over performing control group Pre-specified non-inferiority criterion met for third primary endpoint (95% CI Upper Bound < %) Results are preliminary; final validation not yet complete Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PREVAIL results from Holmes, DR Jr et al., CIT 2013

53 PROTECT AF Primary Efficacy Results
Device Control Posterior Probabilities Observed rate (events per 100 pt-yrs) (95% CrI) Rate Ratio Intervention/Control Non-inferiority Superiority Primary Efficacy 3.0 (2.1, 4.3) 4.3 (2.6, 5.9) 0.71 (0.44, 1.30) >0.99 0.88 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy, VY et al. Circulation. 2013;127:

54 PROTECT AF Clinical event rates at 1,065 patient years
38% reduction with WATCHMAN for the composite endpoint for efficacy (including strokes, CV or unexplained death, and systemic embolism) when compared to warfarin Following the periprocedural period, the rate of ischemic stroke with the WATCHMAN® Device was 1.3 per 100 patient years vs 1.6 with warfarin Events in PROTECT AF trial at 1,065 patient years Rate per 100 patient years 38% lower 29% lower 38% lower WATCHMAN Group N=463 Warfarin Group N=244 PNI > 99.9% PNI > 99% PNI > 99.9% Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PNI = Posterior Probabilities for non-inferiority Holmes DR et al. Lancet. 2009;374:534–42

55 PROTECT AF Clinical event rates at 1,500 patient years
WATCHMAN therapy results in a 29% reduction in efficacy events (strokes, CV death and systemic embolism) when compared to warfarin therapy In 1,500 patient years of follow-up, WATCHMAN continues to provide significant reductions in events when compared to warfarin Events in PROTECT AF trial at 1,500 patient years Rate per 100 patient years 29% lower 23% lower 62% lower WATCHMAN Group N=463 Warfarin Group N=244 PNI > 99% PNI > 99% PNI > 99.9% Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 PNI = Posterior Probabilities for non-inferiority Reddy, V et al. Circ. 2013;127:

56 WATCHMAN™ Pilot Study Study Objective: To evaluate the long term embolic stroke rate of patients implanted with the WATCHMANTM left atrial appendage closure Study Design: Prospective, multicenter Primary Endpoint: Embolic stroke Patient Population: n=66; Mean age= years; Mean CHADS₂ score= Mean Follow Up: months Number of Sites: 8 (US and Germany) Presented by: Peter B. Sick, MD,; ESC 2012 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Sick , et al., WATCHMAN Pilot data; ESC 2012

57 WATCHMAN™ Pilot Study Long Term Follow-up
Ischemic Stroke 2 embolic strokes over 6 years of follow up* A 90% reduction when compared to CHADS₂ expected stroke rate Ischemic Stroke Rate (%/pt-yr) 90% Reduction *One stroke at 2 months and one at 39 months in the setting of severe carotid disease Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Sick , et al., WATCHMAN Pilot data; ESC 2012

58 WATCHMAN® PROTECT AF and CAP Warfarin discontinuation
12 months Warfarin Discontinuation 6 months 93.2% Warfarin Discontinuation 45 days 92.2% 86.8% Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy VY et al. Circulation. 2011;123:

59 Patient Populations Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005

60 WATCHMAN® PROTECT AF Outcomes in patients with previous stroke
Primary efficacy in patients with previous stroke2 51% reduction in stroke, cardiovascular death and systemic embolism when used as secondary prevention Primary efficacy is a composite of stroke, cardiovascular death and systemic embolism Patients with a history of stroke or transient ischemic attack (TIA) are at an increased risk of stroke 47% of AF patients experiencing a stroke will suffer a second stroke within 6 months1 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 1 Wolf PA, et al. Stroke 1983;14: 2 Unpublished data on file

61 ASAP Registry Aspirin and Plavix® Registry
Annual risk of stroke with secondary prevention of aspirin or warfarin The ASAP registry, a non-randomized feasibility study, was designed to determine if the WATCHMAN® Device is a safe and effective treatment for people unable to take warfarin AF patients who are contraindicated or intolerant of warfarin have few options for thromboembolic prophylaxis Patients may be treated with aspirin and/or clopidogrel; this treatment paradigm has a higher stroke risk than warfarin % Stroke risk Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Hart RG et al. Stroke. 2004;35:

62 ASAP Registry 150 AF patients contraindicated for long-term warfarin therapy
Patients had a history of hemorrhagic & bleeding tendencies or a hypersensitivity to warfarin 150 patients enrolled at 4 European centers Average CHADS2 = 2.8 Post procedure anti-platelet regimen Clopidogrel through 6 months Aspirin indefinitely Patients were followed for up to 1 year 3, 6, 12, 18 & 24 months TEE at 3 and 12 months Rate of Success with implantation in warfarin contraindicated patients 94.7% successfully implanted Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy, et al. JACC. 2013; In Press.

63 ASAP Registry Expected Stroke Rate
Mean CHADS2 Score in ASAP = 2.8 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy, et al. JACC. 2013; In Press.

64 ASAP Registry Efficacy outcome versus expected
Ischemic Stroke Ischemic Stroke Rate (%/pt-yr) Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy, et al. JACC. 2013; In Press.

65 ASAP Registry Efficacy outcome versus expected
Ischemic Stroke 77% Reduction Ischemic Stroke Rate (%/pt-yr) 64% Reduction Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Reddy, et al. JACC. 2013; In Press.

66 ASAP Registry Efficacy outcomes with devices
PLAATO2 77% Reduction Ischemic Stroke Rate (%/pt-yr) Stroke/TIA Rate (%/pt-yr) Expected Rate (per CHADS₂) Rate in Device Arm PLAATO is an investigational device and not FDA approved Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 1 Reddy, et al. JACC. 2013; In Press. 2 Block PC, et.al. JACC Intervent 2009;2:

67 PROTECT AF: Analysis of Older Patients Methods
In this analysis, PROTECT AF trial subjects ≥75 years old were compared via proportional hazards models for: composite primary efficacy endpoint (stroke, systemic embolism, and cardiovascular/unknown death) stroke all-cause mortality Outcomes are expressed as a % of subjects experiencing the event per year The randomized intent-to-treat group and the post-procedure group were compared to evaluate outcomes after risk associated with the implant procedure Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Kar, S. et al. PROTECT-AF: Watchman LAAC in AF Patients ≥ 75 Years; TCT 2012

68 PROTECT AF: Analysis of Older Patients Results
Average length of follow-up was 27 months 190 patients randomized to the device group; implantation was attempted in 183 subjects 164/183 (88%) were successfully implanted Mean CHADS2 Score was 2.8 (compared to 2.2 in the Overall patient population) Warfarin Discontinuation OVERALL ≥75 YEARS Visit N/ Total Implanted % Total Implanted 45 day 348/401 86.7 139/175 79.4 6 month 355/385 92.2 133/154 86.4 12 month 345/370 93.2 128/142 90.1 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Kar, S. et al. PROTECT-AF: Watchman LAAC in AF Patients ≥ 75 Years; TCT 2012

69 PROTECT AF: Analysis of Older Patients Outcomes ITT Patients ≥75 Years
16/ 391.6 16/ 256.1 12/ 391.6 11/ 256.1 21/ 404.5 15/ 262.1 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 95% of stroke were ischemic, non-inferiority P-values Kar, S. et al. PROTECT-AF: Watchman LAAC in AF Patients ≥ 75 Years; TCT 2012

70 (events/patient-years)
PROTECT AF: Analysis of Older Patients Major Bleeding in ITT Patients ≥75 Years EVENT Device (n=190) Rate (events/patient-years) Control (n=115) Major bleeding 6.1 (23/374.8) 5.1 (13/252.8) Procedure related major bleeding 2.9 (11/385.9) Or 11 events/190 pts (5.8% pts) N/A Non procedure-related major bleeding 3.3 (13/393.3) Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Kar, S. et al. PROTECT-AF: Watchman LAAC in AF Patients ≥ 75 Years; TCT 2012

71 WATCHMAN CHA2DS2VASc PROTECT AF Analysis
Study Objective: Evaluate the PROTECT AF trial results using CHA2DS2VASc scores to better determine stroke risk Study Design: PROTECT AF design used CHADS2 scores. This analysis uses the same data replacing the CHADS2 score with the CHA2DS2VASc score. Primary Endpoint: Embolic stroke Patient Population: n=463; Mean age=72; Mean CHADS₂ score=2.2, Mean CHA2DS₂VASc = 3.5 Total Follow Up: 1500 patient years Number of Sites: 59 in the United States and Europe Presented by: Sven Mobius-Winkler,; ESC 2012 Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Mobius-Winkler, et al., WATCHMAN Pilot data; ESC 2012

72 WATCHMAN CHA2DS2VASc PROTECT AF Analysis
All stroke 37.5 % reduction compared to expected 37.5% Reduction 93% had CHA2DS2VASc score >2 Average CHA2DS2Vasc score: 3.5 Expected risk of stroke: 3% Observed stroke rate: 2% A higher chads 2 score equals a higher stroke risk Expected rate based on CHA2DS2VASc score Observed Rate Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Mobius-Winkler, et al., WATCHMAN Pilot data; ESC 2012

73 PROTECT AF: Health Economics Analysis Objective
To evaluate the long-term differences in quality-adjusted life years gained between LAAC with 5 anticoagulation strategies To estimate the lifetime direct costs & cost-effectiveness of LAAC compared with 5 anticoagulation strategies for stroke reduction in patients with NVAF Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Yan, B et al. Cost Effectiveness of LAAO.; TCT 2012

74 PROTECT AF: Health Economics Analysis Methods
Analytic Perspective US healthcare provider perspective 2009 US dollars Approach Markov decision analytic model Cohort of 65-year-old patients with NVAF 6 stroke preventive strategies 8 different health status in each 1 year Markov cycle Time horizon = lifetime (85 years old) Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Yan, B et al. Cost Effectiveness of LAAO.; TCT 2012

75 PROTECT AF: Health Economics Analysis Results - Cost
Therapy Total Costs (USD) Total QALY gained Cost per QALY gained (USD) Aspirin 12,877 6.12 2,104 Warfarin 23,848 8.27 2,883 Clopidogrel & aspirin 26,287 6.29 4,182 Dabigatran 110mg 42,540 8.77 4,850 Dabigatran 150mg 43,794 9.00 4,864 LAA closure 47,789 14.95 3,197 Cost per QALY = Lifetime incremental costs(USD) per quality-adjusted life year (QALY) gained for each strategy Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Yan, B et al. Cost Effectiveness of LAAO.; TCT 2012

76 PROTECT AF: Health Economics Analysis Monte Carlo Simulation
LAAC was cost-effective >99% simulations using a cost-effectiveness threshold of US$50,000 per QALY gained Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Yan, B et al. Cost Effectiveness of LAAO.; TCT 2012

77 PROTECT AF: Health Economics Analysis Stroke Risk by CHADS Score
LAA Closure CHADS Score 1 CHADS Score 2 3 ≥4 Total Cost 47,259 47,312 47,398 47,551 47,638 Total QALY Gained 14.95 Cost per QALY 3,161 3,165 3,171 3,181 3,187 ICER/QALY gained compared to next best alternative 4,323 4,022 3,587 2,952 2,659 compared to warfarin 3,474 4,038 2,283 1,206 780 Analysis: Cost per QALY = Lifetime incremental costs (USD) per quality-adjusted life year (QALY) gained ICER/QALY = Lifetime incremental cost-effective ratio (ICER) per QALY gained between LAAC & other strategies Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Yan, B et al. Cost Effectiveness of LAAO.; TCT 2012

78 PROTECT AF: Health Economics Analysis Conclusions
Study showed that transcatheter LAAC with the Watchman system was considered a cost-effective strategy compared with aspirin alone, aspirin and clopidogrel, warfarin, dabigatran 150mg or 110mg for stroke reduction in patients with non-valvular atrial fibrillation. Cost-effectiveness of LAAC with the Watchman system improved with increasing risk of stroke & younger age of implantation Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 Yan, B et al. Cost Effectiveness of LAAO.; TCT 2012

79 WATCHMAN® Clinical Program
PROTECT AF1 CAP2 ASAP3,4 PREVAIL5 Trial Design Prospective RCT with patients able to take warfarin Prospective registry with patients able to take warfarin Prospective registry with patients contraindicated for warfarin Outcome WATCHMAN was non-inferior to warfarin in patients at high-risk of thromboembolism Significantly improved safety results from early PROTECT AF experience Ischemic stroke rate significantly reduced in warfarin contra-indicated patients WATCHMAN device was safely implanted by new operators Mean age /CHADS2 72/2.2 74/2.4 72.4/2.8 74/2.6 Total Enrolled Subjects 707 randomized1 93 pts rolled in2 460 150 407 Total Patients Implanted 5422 437 142 269 Implantation Success 89.5%2 95.0% 94.7% 95.1% Primary Efficacy (all-stroke, CV/unexplained death, and systemic embolism) 38% reduction vs warfarin 29% reduction vs. warfarin N/A 0.064 Identical 18-month rates for WATCHMAN and warfarin All-Stroke 29% reduction vs warfarin 23% reduction vs warfarin 77% reduction vs. expected rate per CHADS₂ score Data not yet available Safety (7 day procedure-related*) 8.7%5 4.1%5 53% reduction vs PROTECT AF Pericardial effusion with tamponade=1.3% Major bleeding=2.7% 4.4% 49% reduction vs. PROTECT AF *Composite of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 1 Holmes DR et al. Lancet 2009;374:534–42 2 Reddy VY et al. Circulation. 2013; 127: 3 Sievert H. TCT 2011; 4 Reddy, et al. JACC. 2013; In Press. 5 PREVAIL results from Holmes, DR Jr et al., CIT 2013

80 Conclusions Thromboembolism in AF is a major cause of morbidity and mortality Oral anticoagulation is effective, but many cannot tolerate due to bleeding risk Robust clinical program in place to study WATCHMAN® LAA Closure Device PROTECT AF WATCHMAN non-inferior to warfarin in patients at high-risk of thromboembolism with a trend toward improved outcomes Long-term data showed continued significant reductions in events when compared to warfarin1 CAP Comparison of the early PROTECT-AF, late PROTECT-AF and CAP results indicated the importance of education for this procedure ASAP Ischemic stroke rate in Warfarin contra-indicated patients was dramatically less than the expected rate per the patient population’s CHADS₂ Score PREVAIL trial 2 Despite implantation in higher risk patients, the WATCHMAN device was safely implanted by new operators WATCHMAN was deemed to be a viable and novel option for the reduction of stroke in high risk non-valvular AF patients Caution: In the United States, WATCHMAN is an investigational device limited by Federal law and investigational use only. Not for sale in the US. Prior to use please review device indications, contraindications, warnings, precautions, adverse events, and operational instructions. Only available according to applicable local law. CE Mark received in 2005 1 Reddy, et al., Circulation 2013; 127:720-72 2 PREVAIL results from Holmes, DR Jr et al., CIT 2013


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