Occlusion: Patient Selection Are the Data Supportive? Left Atrial Appendage Occlusion: Patient Selection Are the Data Supportive? Keith Dawkins MD FRCP FACC FSCAI Chief Medical Officer Senior Vice President Boston Scientific Corporation

Keith D. Dawkins, MD Salary: Boston Scientific Corporation Ownership Interest (Stocks, Stock Options, or other Ownership Interest):

Treatment Options for Atrial Fibrillation Ablation Pacing Drugs for Rate Control Embolic Management Intervention Warfarin Newer OACs Surgical Ligation LAA Clips Endovascular LAA Closure

Atrial Fibrillation Atrial Fibrillation is the most common sustained cardiac arrhythmia Fivefold increase in stroke when AF is present INR levels outside the therapeutic range (2.0-3.0) occurs in ~50% of patients According to HAS-BLED, 61% of pts currently on Warfarin for AF are at moderate risk of bleeding and an additional 19% are at high risk Risk of Thromboembolism in AF vs. Risk of Bleeding with Anticoagulants Camm AJ: Euro Heart J 2010;31:2369-2429 Pisters R: Chest 2010;138:1093-1100

Atrial Fibrillation in the UK The NHS Information Centre estimated 630,000 cases of AF in the UK, and the number is expected to increase over time 46,000 new cases are diagnosed each year 3-6% of people admitted to the hospital with an acute medical condition also had AF Year 2010 Year 2025 Population with AF (≥ 65 years) 270,172 501,253 Iqbal MB: British Medical Journal 2005; 330:238 Go AS: JAMA 2001;285:2370-2375 http://www.census.gov/population/international/data/idb/informationGateway.php Atrial Fibrillation: the management of atrial fibrillation Costing Report, NICE Clinical Guideline No. 36, July 2006

Warfarin Use in General Practice Initiation of Warfarin 41,000 chronic AF treated by GPs in the UK Administrative database Study Diagnosed after Jan 2000 20 40 60 80 100 Age 40 – 64 Age 85 + Age 80 – 84 Age 75 – 79 Age 70 – 74 Age 65 – 69 Percent (%) 2 4 6 Years after diagnosis Gallagher AM: J Thromb Haemost. 2008;6:1500-1506

Bleeding still occurs with Newer Anticoagulants Dabigatran vs. Warfarin in Patients with Atrial Fibrillation (RE-LY Study) P=0.31 P=0.003 Major Bleeding Risk per year (%) Warfarin Dabigatran 150mgs Dabigatran 110mgs Connolly SJ: N Engl J Med. 2009;361:1139-1151

We understand Warfarin; we are still learning about the newer agents… Hohnloser SH: Circulation 2012; DOI: 10.1161/CIRCULATIONAHA.111.055970 Uchino K: Arch Intern Med 2012; DOI: 10.1001/archinternmed.2011.1666 FDA. Pradaxa (dabigatran etexilate mesylate): Safety review of post-market reports of serious bleeding events. December 7, 2011 Institute of Safe Medication Practices. ISMP Medication Safety Alert, January 12, 2012

No Effective Antidote for Direct Thrombin Inhibitors Eerenberg ES: Circulation 2011:124:1573-1579

Atritech Founded in 2000. Early commercial company Headquarters Minneapolis MN Acquired by BSC (January 19, 2011) Watchman® LAA Closure Device (CE-Mark 2005)

Holmes DR. Lancet 2009;374:534-542

PROTECT AF Trial Prospective, randomized study of WATCHMAN® LAA Closure Device vs. Long-term warfarin therapy 2:1 allocation ratio device to control 800 patients enrolled from February 2005 to June 2008 (93 roll-in; 707 randomized) 59 enrolling centers (U.S. & Europe) Follow-up requirements: TEE follow-up at 45 days, 6 months and 1 year Clinical follow-up biannually up to 5 years INR monitoring every 2 weeks for 6 months and monthly thereafter

PROTECT AF Trial Results At 1065 patient-years, the WATCHMAN® Device was non-inferior to warfarin Rate per 100 patient-years Ischemic Stroke Hemorrhagic Stroke Systemic Embolism CV or Unexplained Death Holmes DR: Lancet 2009;374:534–42

PROTECT AF Trial: Primary Efficacy Results (ITT) Primary Composite Efficacy Endpoint Stroke (Ischemic or Hemorrhagic) Death (Cardiovascular or Unexplained) Systemic Embolism Cohort WATCHMAN® Control Relative Risk (95% CI) Posterior Probabilities Rate (95% CI) Non-inferiority Superiority 600 pt-yrs 4.4 (2.6, 6.7) 5.8 (3.0, 9.1) 0.76 (0.39, 1.67) 0.992 0.734 900 pt-yrs 3.4 (2.1, 5.2) 5.0 (2.8, 7.6) 0.68 (0.37, 1.41) 0.998 0.837 1065 pt-yrs 3.0 (1.9, 4.5) 4.9 (2.8, 7.1) 0.62 (0.35, 1.25) >0.999 0.900 1350 pt-yrs 2.9 (2.0, 4.3) 4.2 (2.5, 6.0) 0.69 (0.42, 1.37) 0.830 1500 pt-yrs (2.1,4.3) 4.3 (2.6, 5.9) 0.71 (0.44, 1.30) 0.846 Results are consistent over time, demonstrating a 30% reduction in primary efficacy, stroke and mortality risk Holmes DR: Lancet 2009;374:534–42

Watchman® Studies STUDY PATIENTS SITES COMMENTS Pilot PROTECT AF 66 8 402 patient years of follow-up 57 patients with 5+ years of follow-up PROTECT AF 800 59 2362 patient years of follow-up 3.3 years average follow-up per patient CAP (Continued Access Registry ) 566 26 Significantly improved safety results ASAP 150 4 Treat patients contra-indicated for warfarin EVOLVE 69 3 Evaluate next generation WATCHMAN® PREVAIL 317 ≤50 Same endpoints as PROTECT AF Revised inclusion/exclusion criteria Initiated enrollment October 2010 Total Patients: 1968 Enrollment as of: 23.01.2012

Improved Watchman® Procedural Outcomes with Increasing Experience P (Implant Success) = 0.001 P (procedure Time) < 0.001 Implant Success (%) Procedure Time (mins) Early (n=271) Late (n=271) CAP (n=460) PROTECT AF Reddy VY: Circulation 2011;123:417-424.

Improved Watchman® Safety with Increasing Experience PROTECT AF Early (n=271) PROTECT AF Late (n=271) CAP (n=460) P=0.006 P=0.018 Adverse Events (%) P=0.039 Procedure/Device AE within 7 days Serious PE within 7 days Procedure Related Stroke Reddy VY: Circulation 2011;123:417-424.

Training is Key to Safe Adoption Core Curriculum e-Learning Simulation Animal Models Proctorship Solo Operator

Potential Indications LAAC Patients unsuitable, intolerant or contraindicated for anticoagulant therapy with warfarin or newer anticoagulants (e.g. bleeding risk, poor control) Patient choice as an alternative to anticoagulant therapy Watchman® implant at the time of AF ablation Watchman® implant at the time of balloon mitral valvuloplasty