1. 1. Marc Unterman, M.D. Interventional Cardiologist at Gwinnet Medical Specialists American Board of Internal Medicine American Board of Internal Medicine Cardiovascular Interventional Cardiology Subspecialty Special interests Include: Interventional Cardiology, Coronary Angioplasty, Coronary Atherectomy, Intracoronary Stents, and Peripheral Vascular Angioplasty. Medical School: Emory University School Of Medicine Residency: Grady Health System Fellowship: University of Cincinnati Hospital
2. 2. WATCHMAN Clinical Summary
3. 3. WATCHMAN LAAC Device Background People with AF have 5 times the risk of stroke compared to people without AF1 Stroke more severe with AF 70% chance of death or permanent disability1 The economic burden of stroke will rise globally as the incidence increases2 1. Holmes DR. Seminars in Neurology. 2010;30:528536 2. Klein A et al, Datamonitor. July 2011. 3. Blackshear JL. Odell JA., Annals of Thoracic Surgery. 1996;61:755-759 In non-valvular AF, >90% of stroke-causing clots that come from the left atrium are formed in the LAA3 The WATCHMAN LAAC device is intended to reduce the risk of stroke by closing off the left atrial appendage.
4. 4. WATCHMAN Evidence-Based Medicine 2012: ESC Guidelines & Expanded Indication 2002 Pilot Endpoints: Feasibility and Safety Comparison: nonrandomzed Incl/Excl: CHADS21, able to tolerate warfarin 2005 PROTECT AF Endpoints: Safety and Efficacy Comparison: warfarin Incl/Excl: CHADS2 1, able to tolerate warfarin 2008 CAP Registry Endpoints: Collect safety & efficacy data to be pooled with PROTECT AF Incl/Excl: same as PROTECT AF 2009 ASAP Endpoint: Efficacy Comparison: CHADS2 score expected stroke rate Incl/Excl: intolerant or contra-indicated for warfarin 2010 PREVAIL Endpoint: Safety and Efficacy Comparison: warfarin Incl/Excl: CHADS22, some exceptions for CHADS2=1 no clopidogrel within 7 days of procedure 2013 EU & Asia Registries Endpoint: Additional information in a real-world setting Incl/Excl: All comers 2014 PREVENT (Post Approval Study) Endpoint: Additional information in a real-world setting Incl/Excl: US Indication
5. 5. All Studies: Favorable Procedural Safety Profile for 7-day Safety Events 9.9% 4.8% 4.1% 4.1% 3.8% 0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% CAP PREVAIL CAP2 Patients with Safety Event (%) PROTECT AF 1st Half 2nd Half N=232 N=231 N=566 N=269 N=579 All Device and/or procedure-related serious adverse events within 7 Days including composite of vascular complications such as cardiac perforation, pericardial effusion with tamponade, ischemic stroke, device embolization, and other vascular complications such as PE not necessitating intervention, AV fistula, major bleeding requiring transfusion, pseudoaneurysm, hematoma and groin bleeding 1 FDA Panel October 2014.
6. 6. PROTECT AF 4 Year: Primary Efficacy Endpoint a Events per 100 patient-years (95% credible interval); b Composite of stroke, systemic embolization, or cardiovascular/unexplained death For Bayesian analysis, a posterior probability of 97.5% represents non-inferiority; 95% represents superiority. Reddy, VY et al. JAMA. 2014; 312(19):1988-1998.
7. 7. 2.3 1.5 1.0 0.5 3.8 2.2 2.4 1.2 0 1 2 3 4 5 6 Primary Efficacy All Stroke CV or Unexplained Death Disabling Stroke PROTECT AF 4 Year: Results Rateper100patientyears PS = 96% 40% lower WATCHMAN N=463 Warfarin N=244PN = Posterior Probability for Non-Inferiority Ps = Posterior Probability for Superiority Disabling or fatal strokes were those with an MRS of 3-6 post stroke. Non-disabling were those with an MRS of 0-2 post stroke. For Bayesian analysis, a posterior probability of 97.5% represents non-inferiority; 95% represents superiority. PN > 99% 32% lower PS = 99% 60% lower PS = 98% 63% lower Reddy, VY et al. JAMA. 2014; 312(19):1988-1998.
8. 8. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 ` CAP & PROTECT: Consistent Efficacy, No Signal of Increased Late Events Primary Efficacy Event-free Probability Time (years) PROTECT AF PROTECT AF CAP CAP 463 382 360 337 321 235 566 503 468 435 293 59 3.5 1.6 3.9 1.5 CHA2DS2-VASc Score FDA Panel October 2014. PAF=2717 Pt yrs, CAP=2022 Pt yrs
9. 9. PREVAIL Trial Primary Endpoints At the protocol pre-specified endpoint evaluation (all patients completed minimum of 6 months follow-up)1: Safety: Acute (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) 1st Primary Efficacy: Comparison of composite of stroke, systemic embolism, and cardiovascular/unexplained death Similar 18-month event rates in both device and control groups = 0.064 vs. 0.063 Upper credible interval crossed pre-specified bound for non-inferiority 2nd Primary Efficacy: Comparison of ischemic stroke or systemic embolism occurring >7 days post randomization Endpoint met in the presence of an over performing control group Upper credible interval crossed pre-specified bound for non-inferiority with additional follow-up2 1Holmes, DR et al. JACC. 2014; 64(1):1-12 2 FDA Panel October 2014. PREVAIL=860 Pt yrs The PREVAIL trial results published in JACC are based on the final pre-specified analysis from January 2013.
10. 10. 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5 PROTECT AF, CAP, and PREVAIL Consistent WATCHMAN Efficacy Free from Efficacy Primary Endpoint (%) Time (years) 463 382 360 337 321 235 566 503 468 435 293 59 269 234 182 37 0PREVAIL PROTECT AF CAP PREVAIL PROTECT AF CAP EC-15 FDA Panel October 2014. PAF=2717 Pt yrs; CAP=2022 Pt yrs; PREVAIL=860 Pt yrs
11. 11. PREVAIL: Warfarin Ischemic Stroke Rate Differs from Other Trials Trial (Warfarin Arm) Ischemic Stroke Rate per 100 pt-yrs Mean CHADS2 PREVAIL2 2.6 PROTECT AF1 2.2 RE-LY3 2.1 ROCKET AF3 3.5 ARISTOTLE3 2.1 ENGAGE4 2.8 Rate per Patient-years 0.3 1.1 1.2 1.42 1.05 1.25 0.1 1 10 1Reddy, VY et al. JAMA. 2014; 312(19):1988-1998. 2Holmes, DR et al. JACC. 2014; 64(1):1-12 3Miller. AJC (2012). 4Giugliano. NEJM (2013)
12. 12. Rate of Success with implantation in warfarin contraindicated patients 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 Follow-up @ 3, 6, 12, 18 & 24 months TEE at 3 and 12 months ASAP 150 AF patients contraindicated for long term warfarin therapy 94.7% successfully implanted Reddy, et al. JACC 2013; 61(25):25516
13. 13. 7.3% 5.0% 1.7% 0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% 7.0% 8.0% Expected, based on CHADS Score Expected, if Clopidogrel was used throughout follow-up Observed rate in ASAP ASAP Reduction in ischemic stroke versus expected rate IschemicStrokeRate(%/pt-yr) 77% Reduction 64% Reduction Reddy, et al. JACC 2013; 61(25):25516
14. 14. WATCHMAN Pilot Study 6-year Follow-up 4.8% 0.5% 0.0% 1.0% 2.0% 3.0% 4.0% 5.0% 6.0% IschemicStrokeRate(%/pt-yr)* Expected, based on CHADS Score of 1.8 Observed rate in 6 year follow up *One stroke at 2 months and one at 39 months in the setting of severe carotid disease 90% Reduction 2 embolic strokes over 6 years of follow up* 90% reduction when compared to a CHADS expected stroke rate Sick , et al., WATCHMAN Pilot data; ESC 2012
15. 15. WATCHMAN Robust Clinical Portfolio >2,500 patients with >6,000 patient years follow-up Significantly improved safety results2 and efficacy consistent with PROTECT AF1,5 Pilot Early feasibility with >6 years of follow-up Consistent procedural safety results5 CAP Registry CAP2 WATCHMAN primary efficacy, CV death, and less disabling strokes superior to warfarin at 4 years1 Expected rate of stroke reduced by 77% in patients contraindicated to warfarin3 Improved implant success procedure safety confirmed with new and experienced operators4 PROTECT-AF ASAP PREVAIL 1 Reddy, VY et al. JAMA. 2014; 312(19):1988-1998. 2 Reddy, VY et al. Circ. 2011;123:417-424; 3 Reddy, et al. JACC 2013; 61(25):25516. 4 Holmes, DR et al. JACC. 2014; 64(1):1-12. 5 FDA Panel October 2014.
16. 16. ABBREVIATED STATEMENT (US) WATCHMANTM Left Atrial Appendage Closure Device with Delivery System and WATCHMAN Access System INDICATIONS FOR USE The WATCHMAN Device is indicated to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular atrial fibrillation who: Are at increased risk for stroke and systemic embolism based on CHADS2 or CHA2DS2-VASc scores and are recommended for anticoagulation therapy; Are deemed by their physicians to be suitable for warfarin; and Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin. The WATCHMAN Access System is intended to provide vascular and transseptal access for all WATCHMAN Left Atrial Appendage Closure Devices with Delivery Systems. CONTRAINDICATIONS Do not use the WATCHMAN Device if: Intracardiac thrombus is visualized by echocardiographic imaging. An atrial septal defect repair or closure device or a patent foramen ovale repair or closure device is present. The LAA anatomy will not accommodate a device. See Table 46 in the DFU. Any of the customary contraindications for other percutaneous catheterization procedures (e.g., patient size too small to accommodate TEE probe or required catheters) or conditions (e.g., active infection, bleeding disorder) are present. There are contraindications to the use of warfarin, aspirin, or clopidogrel. The patient has a known hypersensitivity to any portion of the device material or the individual components (see Device Description section) such that the use of the WATCHMAN Device is contraindicated. WARNINGS Device selection should be based on accurate LAA measurements obtained using fluoro and ultrasound guidance (TEE recommended) in multiple angles (e.g., 0, 45, 90, 135). Do not release the WATCHMAN Device from the core wire if the device does not meet all release criteria. If thrombus is observed on the device, warfarin therapy is recommended until resolution of thrombus is demonstrated by TEE. The potential for device embolization exists with cardioversion 90% of stroke-causing clots that come from the left atrium are formed in the LAA3.
17. 22. SH 286002 AB MAR 2015 2014 AHA/ACC/HRS Treatment Guidelines to Prevent Thromboembolism in Patients with AF Assess stroke risk with CHA2DS2-VASc score Score 1: Annual stroke risk 1%, oral anticoagulants or aspirin may be considered Score 2: Annual stroke risk 2%-15%, oral anticoagulants are recommended Balance benefit vs. bleeding risk 2014 AHA/ACC/HRS Guideline for the Management of Patients with AF January, CT. et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. JACC. 2014; doi: 10.1016/j.jacc.2014.03.022
18. 23. SH 286002 AB MAR 2015 Oral Anticoagulation is Standard of Care, but Not Ideal for All Warfarin Bleeding risk Daily regimen High non-adherence rates Regular INR monitoring Food and drug interaction issues Complicates surgical procedures Novel Oral Anticoagulants Bleeding risk Daily regimen High non-adherence rates Complicates surgical procedures Lack of reversal agents High cost 1. Piccini, et al.. Pharmacotherapy in Medicare beneficiaries with atrial fibrillation. Heart Rhythm. 2012;9:1403-1408 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1 2 3 4 5 6 CHADS2 Score p < 0.001 (n=27,164) AFPatientsUsing Anticoagulation Anticoagulation Use Declines with Increased Stroke Risk1
19. 24. SH 286002 AB MAR 2015 Anticoagulant Therapy Carries Risk of Intracerebral Hemorrhage or Death Spontaneous intra- parenchymal bleed Hemorrhagic transformation
20. 25. SH 286002 AB MAR 2015 Despite Increasing NOAC Adoption, Overall Rate of Anticoagulation in High Risk NVAF Patients has Not Improved 1. Jani, et al. Uptake of Novel Oral Anticoagulants in Patients with Non-Valvular and Valvular Atrial Fibrillation: Results from the NCDR-Pinnacle Registry. ACC 2014 Results from the NCDR PINNACLE Registry1 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 2011 Q1 2011 Q2 2011 Q3 2011 Q4 2012 Q1 2012 Q2 2012 Q3 2012 Q4 Total on Oral Anticoagulation Warfarin NOACs Anticoagulant Use in Patients with NVAF and CHADS2 2 n=25719 n=29194 n=31582 n=36490 n=67102 n=70667 n=70320 n=71396
21. 26. SH 286002 AB MAR 2015 Discontinuation and Major Bleeding Rates with NOACs Treatment Study Drug Discontinuation Rate Major Bleeding (rate/year) Rivaroxaban1 24% 3.6% Apixaban2 25% 2.1% Dabigatran3 (150 mg) 21% 3.3% Edoxaban4 (60 mg / 30 mg) 33 % / 34% 2.8% / 1.6% Warfarin1-4 17 28% 3.1 3.6% There is an unmet need of stroke risk reduction for patients with AF who are seeking an alternative to long-term OACs 1Connolly, S. NEJM 2009; 361:1139-1151 2 yrs follow-up (Corrected) 2Patel, M. NEJM 2011; 365:883-891 1.9 yrs follow-up, ITT 3Granger, C NEJM 2011; 365:981-992 1.8 yrs follow-up, 4Giugliano, R. NEJM 2013; 369(22): 2093-2104 2.8 yrs follow-up.
22. 27. SH 286002 AB MAR 2015 WATCHMANTM Left Atrial Appendage Closure Device First-of-its-Kind, Proven Alternative to Long-Term Warfarin Therapy for Stroke Risk Reduction in Patients with Non-Valvular Atrial Fibrillation The most studied LAAC device, and the only one proven with long-term data from randomized trials or multi-center registries Commercially available internationally since 2009, with over 10,000 implants worldwide Registered in over 70 countries SH 286002 AB MAR 2015
23. 28. SH 286002 AB MAR 2015 Favorable Procedural Safety Profile: 7-Day Safety Events 9.9% 4.8% 4.1% 4.1% 3.8% 0.0% 2.0% 4.0% 6.0% 8.0% 10.0% 12.0% CAP PREVAIL CAP2 Patients with Safety Event (%) PROTECT AF 1st Half 2nd Half n=232 n=231 n=566 n=269 n=579 All Device and/or procedure-related serious adverse events within 7 Days Learning Curve ~50% New Operators in PREVAIL Source: FDA Oct 2014 Panel Sponsor Presentation.
24. 29. SH 286002 AB MAR 2015 Implant Success & Warfarin Cessation p = 0.04 Study 45-day 12-month PROTECT AF 87% >93% CAP 96% >96% PREVAIL 92% >99% 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% New Operators n=24 93% p = 0.28 PROTECT AF and CAP: Reddy, VY et al. Circulation. 2011;123:417-424. PREVAIL: Holmes, DR et al. JACC 2014; 64(1):1-12.
25. 30. SH 286002 AB MAR 2015 Most Studied LAAC Device. Only One with Long-Term Clinical Data PROTECT AF CAP Registry PREVAIL CAP2 Registry Totals Enrollment 2005-2008 2008-2010 2010-2012 2012-2014 Enrolled 800 566 461 579 2406 Randomized 707 --- 407 --- 1114 WATCHMAN: warfarin (2:1) 463 : 244 566 269 :138 579 1877: 382 Mean Follow-up (years) 4.0 3.7 2.2 0.58 N/A Patient-years 2717 2022 860 332 5931 Source: FDA Oct 2014 Panel Sponsor Presentation.
26. 31. SH 286002 AB MAR 2015 Patient Risk Factors Across Trials Characteristic PROTECT AF N=707 CAP N=566 PREVAIL N=407 CAP2 N=579 p-value CHADS2 Score 2.2 1.2 2.5 1.2 2.6 1.0 2.7 1.1