1. ©2012 MFMER | slide-1 Watchman II: PROTECT AF/PREVAIL Meta-Analysis and Implications David R. Holmes, Jr., M.D. Mayo Clinic, Rochester TCT 2014 Washington, D.C. September 2014

2. ©2012 MFMER | slide-2 Presenter Disclosure Information David R. Holmes, Jr., M.D. “Watchman II: PROTECT AF/PREVAIL Meta-Analysis and Implications” The following relationships exist related to this presentation: Both Mayo Clinic and I have a financial interest in technology related to this research. That technology has been licensed to Boston Scientific.

3. ©2012 MFMER | slide-3 Choose your ruts carefully; You’ll be in them for the next 40 miles

4. ©2012 MFMER | slide-4Background PREVAIL results demonstrated improved safety of LAAC implants with both new and experienced operatorsPREVAIL results demonstrated improved safety of LAAC implants with both new and experienced operators PROTECT AF 4 year data demonstrated superior efficacy of Watchman ImplantationPROTECT AF 4 year data demonstrated superior efficacy of Watchman Implantation 5 year results confirm superiority5 year results confirm superiority However, PREVAIL missed a statistical endpoint goal making the efficacy data difficult to interpretHowever, PREVAIL missed a statistical endpoint goal making the efficacy data difficult to interpret

5. ©2012 MFMER | slide-5 All Serious Complications 7 Day Serious Procedure/Device Related Composite of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications 1 n=39n=23n=12 p = 0.004 No procedure-related deaths in randomized patients in any trials 1 Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press

6. ©2012 MFMER | slide-6 PROTECT-AF: Primary Efficacy Endpoint (2013 vs. 2014) Rate Ratio Posterior Probability Non-inferioritySuperiority December 2013 Panel (2621 Patient-years) Efficacy0.61>99%95% Stroke (all) 0.68>99%83% Systemic embolism N/AN/AN/A Death (CV/unexplained) 0.44>99%99% October 2014 Panel (2717 Patient-years) Efficacy0.60>99%95% Stroke (all) 0.68>99%83% Systemic embolism N/AN/AN/A Death (CV/unexplained) 0.40>99%>99%

7. ©2012 MFMER | slide-7 PREVAIL Trial Primary Endpoints One-sided 95% upper CI bound for success 2.0%2.5% 3.0% Percent of patients experiencing an event 2.2% 2.618% 2.67% Early Safety 95% upper CI bound for non-inferiority 0.5 1.0 1.5 18-month Rate Ratio 2.0 1.07 0.57 1.89 1.75 Primary Efficacy 95% upper CI bound for non-inferiority -0.010 0.01 18-month Rate Difference 0.02 0.0053 -0.020.03-0.03 -0.0190 0.0273 0.0275 Late Ischemic Efficacy Acute (7-day) occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular interventionAcute (7-day) occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention Endpoint Success: 6 events in device group = 2.2% (6/269)Endpoint Success: 6 events in device group = 2.2% (6/269) Comparison of composite of stroke, systemic embolism, and cardiovascular/unexplained deathComparison of composite of stroke, systemic embolism, and cardiovascular/unexplained death Similar 18-month event rates in both device and control groups = 0.064 vs. 0.063Similar 18-month event rates in both device and control groups = 0.064 vs. 0.063 Comparison of ischemic stroke or systemic embolism occurring >7 days post randomizationComparison of ischemic stroke or systemic embolism occurring >7 days post randomization Endpoint success in the presence of an over performing control groupEndpoint success in the presence of an over performing control group

8. ©2012 MFMER | slide-8 PREVAIL Trial Primary Endpoints (Updated Final Analysis) Holmes, DR et al. JACC 2014; In Press Comparison of composite of stroke, systemic embolism, and cardiovascular/unexplained deathComparison of composite of stroke, systemic embolism, and cardiovascular/unexplained death Wide credible intervalsWide credible intervals Posterior Probability for Non- inferiority = 93%Posterior Probability for Non- inferiority = 93% 1.75 18-month Rate Ratio 95% upper CI bound for non-inferiority Dec 2013 Jun 2014 Primary Efficacy Comparison of ischemic stroke or systemic embolism occurring >7 days post randomizationComparison of ischemic stroke or systemic embolism occurring >7 days post randomization Wide credible intervalsWide credible intervals Posterior Probability for Non- inferiority = 89.2%Posterior Probability for Non- inferiority = 89.2% 18-month Rate Difference 95% upper CI bound for non-inferiority 0.0275 Late Ischemic Efficacy Dec 2013 Jun 2014

9. ©2012 MFMER | slide-9 PREVAIL Control (Warfarin) Group Performance  In spite of the high average CHADS 2 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 = 1.0 (95% CI 0.3, 3.1) Wide confidence bounds due to small number of patients with 18-months of follow-upWide 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 AF 1 1.6 RE-LY (Dabigatran) 2 1.7 ARISTOTLE (Apixaban) 3 1.6 ROCKET AF (Rivaroxaban) 4 2.2 PREVAIL 5 1.0 1 Ischemic stroke rate from Holmes et al. Lancet 2009; 374:534-42 2 Connolly et al. N Engl J Med 2009; 361:1139-51 3 Granger et al. N Engl J Med 2011; 365:981-92 4 Patel et al. N Engl J Med 2011; 365:883-91 5 Holmes, DR et al. JACC 2014; In Press

10. ©2012 MFMER | slide-10Purpose To evaluate the totality of randomized data of WATCHMAN versus warfarin forTo evaluate the totality of randomized data of WATCHMAN versus warfarin for Composite efficacyComposite efficacy StrokeStroke DeathDeath BleedingBleeding

11. ©2012 MFMER | slide-11Methods Patient level data was pooled across the 2 randomized trials: PROTECT AF and PREVAIL. Baseline demographics and risk factors compared across trials using: Student's t-test (for continuous variables) Fisher's exact test (for categorical variables) Endpoints were compared across treatment groups using a Cox proportional hazards model stratified by trial.

12. ©2012 MFMER | slide-12 Efficacy0.220.79 Patient-Level Meta-Analysis Efficacy Hazard Ratio (95% CI) P-value Favors WATCHMAN   Favors warfarin HR

13. ©2012 MFMER | slide-13 All stroke or SE 0.941.02 Ischemic stroke or SE 0.051.95 Hemorrhagic stroke 0.0040.22 Patient-Level Meta-Analysis Stroke Hazard Ratio (95% CI) P-value Favors WATCHMAN   Favors warfarin HR

14. ©2012 MFMER | slide-14 Major bleed 0.981.00 Major bleed beyond 7 days 0.0020.51 Patient-Level Meta-Analysis Major Bleeding Hazard Ratio (95% CI) P-value Favors WATCHMAN   Favors warfarin HR

15. ©2012 MFMER | slide-15Characteristic PROTECT AF N=463 PREVAIL N=269 P value Age, years 71.7 ± 8.8 (463) (46.0, 95.0) 74.0 ± 7.4 (269) (50.0, 94.0) <0.001 Gender (Male) 326/463 (70.4%) 182/269 (67.7%) 0.252 CHADS 2 Score (Continuous) 2.2 ± 1.2 (1.0, 6.0) 2.6 ± 1.0 (1.0, 6.0) <0.001 CHADS 2 Risk Factors CHF 124/463 (26.8%) 63/269 (23.4%) Hypertension 415/463 (89.6%) 238/269 (88.5%) Age ≥ 75 190/463 (41.0%) 140/269 (52.0%) Diabetes 113/463 (24.4%) 91/269 (33.8%) Stroke/TIA 82/463 (17.7%) 74/269 (27.5%) Demographics Device Patients PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press Most notable differences: Age, Diabetes, and Prior Stroke/TIA Most notable differences: Age, Diabetes, and Prior Stroke/TIA

16. ©2012 MFMER | slide-16 PROTECT AF “PREVAIL like” Patients vs PREVAIL PROTECT AF “PREVAIL like” Patients vs PREVAIL First Primary Endpoint WATCHMAN GroupsWarfarin Groups

17. ©2012 MFMER | slide-17 PROTECT AF “PREVAIL like” Patients vs PREVAIL PROTECT AF “PREVAIL like” Patients vs PREVAIL Second Primary Endpoint WATCHMAN GroupsWarfarin Groups

18. ©2012 MFMER | slide-18 All-cause death 0.070.73 Cardiovascular / unexplained death 0.0060.48 Patient-Level Meta-Analysis Mortality Hazard Ratio (95% CI) P-value Favors WATCHMAN   Favors warfarin HR

19. ©2012 MFMER | slide-19Summary Outcomes with WATCHMAN were comparable to warfarin for primary efficacy (HR=0.79) Although there were more ischemic strokes in the warfarin arm (HR=1.95), WATCHMAN had significant reduction in hemorrhagic stroke (HR=0.22) There was a significant reduction in CV mortality for WATCHMAN versus warfarin (HR=0.48)

20. ©2012 MFMER | slide-20Conclusions The WATCHMAN device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non valvular atrial fibrillationThe WATCHMAN device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non valvular atrial fibrillation

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22. ©2012 MFMER | slide-22 What is Democracy of Numbers?

23. ©2012 MFMER | slide-23 Choose your ruts carefully; You’ll be in them for the next 40 miles

24. ©2012 MFMER | slide-24Conclusions Additional analyses would be helpful to compare Device performance against historical warfarin performanceAdditional analyses would be helpful to compare Device performance against historical warfarin performance Imputed placeboImputed placebo The WATCHMAN device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non valvular atrial fibrillationThe WATCHMAN device is an alternative to oral anticoagulation therapy for thromboembolic prevention in patients with non valvular atrial fibrillation

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26. ©2012 MFMER | slide-26 Stroke and Atrial Fibrillation Alternative to Warfarin or NOACS Patients who could be treated with warfarin/NOACS Patients who choose not to be treated with warfarin/NOACS Contraindications to warfarin/NOACS

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28. ©2012 MFMER | slide-28 New medicines and new methods of cure always work miracles for awhile William Heberden 1710-1801

29. ©2012 MFMER | slide-29Background PREVAIL results demonstrated improved safety of LAAC implants with both new and experienced operatorsPREVAIL results demonstrated improved safety of LAAC implants with both new and experienced operators PROTECT AF 4 year data demonstrated superior efficacyPROTECT AF 4 year data demonstrated superior efficacy 5 year results confirm5 year results confirm PREVAIL missed endpoint makes the efficacy data difficult to interpretPREVAIL missed endpoint makes the efficacy data difficult to interpret

30. ©2012 MFMER | slide-30 PREVAIL: Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy David Holmes 1, Saibal Kar 2, Matthew Price 3, Brian Whisenant 4, Horst Sievert 5, Shephal K Doshi 6, Kenneth Huber 7, Vivek Y. Reddy 8 1 Mayo Clinic, MN; 2 Cedars Sinai Medical Center, CA; 3 Scripps Clinic, La Jolla, CA; 4 Intermountain Medical Center, UT; 5 Sankt Katharinen, Frankfurt; 6 Pacific Heart Institute, CA; 7 St Luke’s Hospital, MO; 8 Mount Sinai School of Medicine, NY

31. ©2012 MFMER | slide-31 DeviceControl Posterior Probabilities Observed rate (events per 100 pt-yrs) (95% CrI) Observed rate (events per 100 pt-yrs) (95% CrI) (95% CrI) Rate Ratio Intervention/Control (95% CrI) Non-inferioritySuperiority Primary Efficacy 3.0 (2.1, 4.3) 4.3 (2.6, 5.9) 0.71 (0.44, 1.30) >0.990.88 Primary Safety 5.5 ( 4.2, 7.1) 3.6 (2.2, 5.3) 1.53 (0.95, 2.70) N/A PROTECT AF: Primary Efficacy and Safety Results at 1,500 Patient Years Primary EfficacySafety Reddy, VY et al. Circulation. 2013;127:720-729.

32. ©2012 MFMER | slide-32 Study Objective Confirmatory study conducted to provide additional information on the implant procedure and complication rates associated with the device Design Prospective, randomized (2:1) WATCHMAN™ LAA Closure Technology to warfarin Inclusion of new centers and new operators to show enhancements to the training program are effective to confirm late PROTECT-AF and CAP safety Primary Endpoints 1)Early Safety: Acute (7-day) occurrence of death, ischemic stroke, systemic embolism and procedure or device related complications requiring major cardiovascular or endovascular intervention 2)Primary Efficacy: Comparison of composite of stroke, systemic embolism, and cardiovascular/unexplained death 3)Late Ischemic Efficacy: Comparison of ischemic stroke or systemic embolism occurring >7 days post randomization Patient Population n = 407 randomized patients Mean Age = 74.3 ± 7.3 Mean CHADS 2 =2.6 ± 1.0 Number of Sites 41 in the United States (18 new sites) 50 implanters (24 new operators) Enrollment Nov 2010 - Jun 2012 PREVAIL Trial Background Holmes, DR et al. JACC 2014; In Press

33. ©2012 MFMER | slide-33 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. PREVAIL Enrollment Total Enrolled 461 Total Enrolled 461 Roll-In Patients 54 Roll-In Patients 54 Implant Attempt 54 Implant Attempt 54 Device Implanted 51 Device Implanted 51 Unable to Implant 3 Unable to Implant 3 Randomized Patients 407 Randomized Patients 407 WATCHMAN (Device) 269 WATCHMAN (Device) 269 Warfarin (Control) 138 Warfarin (Control) 138 Implant Attempt 265 Implant Attempt 265 No Implant Attempt 4 No Implant Attempt 4 Device Implanted 252 Device Implanted 252 Unable to Implant 13 Unable to Implant 13

34. ©2012 MFMER | slide-34Characteristic 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 CHADS 2 Score (Continuous) 2.2 ± 1.2 (1.0, 6.0) 2.5 ± 1.2 (1.0, 6.0) 2.6 ± 1.0 (1.0, 6.0) <0.001 CHADS 2 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%) Demographics Device Patients PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press Most notable differences: Age, Diabetes, and Prior Stroke/TIA Most notable differences: Age, Diabetes, and Prior Stroke/TIA

35. ©2012 MFMER | slide-35 Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators p = 0.01 Study45-day12-month PROTECT AF 86.6%93.2% PREVAIL92.2%99.3% Implant success defined as deployment and release of the device into the left atrial appendage Warfarin Cessation PREVAIL Implant Success No difference between new and experienced operators Experienced Operators n=26, 96.2% New Operators n=24, 93.2% PREVAIL Implant Success No difference between new and experienced operators Experienced Operators n=26, 96.2% New Operators n=24, 93.2% p = 0.282 PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press

36. ©2012 MFMER | slide-36 All Serious Complications 7 Day Serious Procedure/Device Related Composite of vascular complications includes cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications 1 n=39n=23n=12 p = 0.004 No procedure-related deaths reported in any of the trials 1 Includes observed PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press

37. ©2012 MFMER | slide-37 PREVAIL Pericardial Effusions n=7 n=1 n=1 n=11n=7 n=4 p = 0.027 P = 0.36 PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press

38. ©2012 MFMER | slide-38 PREVAIL Peri-procedural Stroke n=5 n=0 n=1 PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; In Press p = 0.007 Procedure/Device Related Strokes

39. ©2012 MFMER | slide-39 PREVAIL Conclusions Based On Final Pre-specified Analysis From January 2013 Despite implantation in higher risk patients the WATCHMAN device was safely implanted by new operatorsDespite implantation in higher risk patients the WATCHMAN device was safely implanted by new operators 2 of 3 primary endpoints were met even in the presence of an over performing control group2 of 3 primary endpoints were met even in the presence of an over performing control group Results of the PREVAIL trial add to the wealth of previously published data on WATCHMANResults of the PREVAIL trial add to the wealth of previously published data on WATCHMAN

40. ©2014 MFMER | 3365707-40 Transcatheter Heart Valve Review 20 mm 23 mm 26 mm 29 mm Bovine pericardium, ThermaFix tissue treatment Cobalt-chromium alloy 16-1918-2221-2524-28 273-345338-430430-546540-680 18.6-21.020.7-23.423.4-26.426.2-29.4 21.024.527.031.0 15.518.020.022.5 5.5 5.5 6.5 6.5 7.0 7.0 8.5 8.5 7.9 7.9 9.3 9.310.211.6 5.2 5.2 6.6 6.6 7.0 7.0 8.1 8.1 SAPIEN 3 THV Tissue Frame 2D TEE diameter sealing zone (mm) 3D area sealing zone (mm 2 ) 3D area-derived diameter (mm) Crimped height (mm) Expanded height (mm) Foreshortening (mm) Inner skirt height (mm) Outer skirt height (mm) SAPIEN XT THV 23 mm 26 mm 29 mm Bovine pericardium, ThermaFix tissue treatment Cobalt-chromium alloy 18-2221-2524-27 ––– ––– 17.020.022.0 14.017.019.0 3.0 3.0 6.7 6.7 8.7 8.711.6

41. ©2014 MFMER | 3365707-41 Transcatheter Heart Valve Review SAPIEN XT THV 23 mm 26 mm 29 mm Tissue Bovine pericardium, ThermaFix tissue treatment Frame Cobalt-chromium alloy 2D TEE diameter sealing zone (mm) 18-2221-2524-27 3D area sealing zone ––– 3D area-derived diameter ––– Crimped height (mm) 17.020.022.0 Expanded height (mm) 14.017.019.0 Foreshortening (mm) 3.0 3.0 Inner skirt height (mm) 6.7 6.7 8.7 8.711.6

42. ©2014 MFMER | 3365707-42 Transcatheter Heart Valve Review SAPIEN 3 THV 20 mm 23 mm 26 mm 29 mm Tissue Bovine pericardium, ThermaFix tissue treatment Frame Cobalt-chromium alloy 2D TEE diameter sealing zone (mm) 16-1918-2221-2524-28 3D area sealing zone (mm 2 ) 273-345338-430430-546540-680 3D area-derived diameter (mm) 18.6-21.020.7-23.423.4-26.426.2-29.4 Crimped height (mm) 21.024.527.031.0 Expanded height (mm) 15.518.020.022.5 Foreshortening (mm) 5.5 5.5 6.5 6.5 7.0 7.0 8.5 8.5 Inner skirt height (mm) 7.9 7.9 9.3 9.310.211.6 Outer skirt height (mm) 5.2 5.2 6.6 6.6 7.0 7.0 8.1 8.1

43. ©2014 MFMER | 3365707-43 Questions & Discussion

44. ©2014 MFMER | 3365707-44 Holmes, David Valve Review – 3365707 This is the side title color Type first bulleted point hereType first bulleted point here Type first subpoint hereType first subpoint here This is the highlight colorThis is the highlight color ma 8/8/2014 Color Theme %ABCDEF X-Y Axis Highlight Footnote/subdue Notes Bold & Shadow all TextBold & Shadow all Text Black borders on bar graphsBlack borders on bar graphs Line graphs: No shadow on linesLine graphs: No shadow on linesRowColorNo.%1Red 12.3 12.347 2Yellow459.226 3Green 56.7 56.798