Current Trends in the Management of Atrial Fibrillation: Left Atrial Appendage Occlusion Benjamin A. D Souza, MD, FACC, FHRS Assistant Professor of Clinical Medicine Penn Presbyterian Medical Center Cardiac Electrophysiology Perelman School of Medicine at the University of Pennsylvania Atrial fibrillation: Scope of the problem Higher stroke risk for older patients and those with prior stroke or TIA 15-20% of all strokes are Atrial fibrillation (AF)-related AF results in greater disability compared to non-af-related stroke High mortality and stroke recurrence rate AF = most common cardiac arrhythmia, and growing AF increases risk of stroke 5M 12M < 15 20 30 40 50 ~5 M people with AF in U.S., expected to more than double by 2050 1 5x greater risk of stroke with AF 2 1. Go AS. et al, Heart Disease and Stroke Statistics 2013 Update: A Report From the American Heart Association. Circulation. 2013; 127: e6-e245. 2. Holmes DR, Atrial Fibrillation and Stroke Management: Present and Future, Seminars in Neurology 2010;30:528 536. 2 Atrial fibrillation: Scope of the problem AF related hospitalizations almost tripled in 2000 compared with two decades ago In 2001 the total annual costs for treatment of AF were estimated at $6.65 billion in the US As a result of increasing age and improved survival rates in those with coronary artery disease, heart failure, and hypertension, an increase in the prevalence of atrial fibrillation is likely to be exponential and sustained in the foreseeable future. 3 Page 1 1
Sub-types of AF Paroxysmal Recurrent, 2 episodes Terminates spontaneously within 7 days Persistent Episodes lasting > 7 days OR Episodes that require intervention to terminate (medication or electrical cardioversion) Long-Standing Persistent Continuous AF of > 1 year Permanent Mutual decision between patient and physician has been made to cease further attempts to restore/ maintain normal sinus rhythm by any means, including catheter ablation and surgery January 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary, Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2014.03.021. 4 Progression of AF Typical Progression of patients progress from Paroxysmal to Persistent AF 20 % within 1 year of diagnosis 5 Risk Factors of AF Over 60 Yrs of Age Diabetes Hypertension Prior Myocardial Infarctions Coronary Artery Disease Untreated Atrial Flutter Chronic Lung Disease Sleep Apnea Thyroid Disease Serious Illness Or Infection Excessive Alcohol Use Congestive Heart Failure Structural Heart Disease Prior Open Heart Surgery http://www.hrsonline.org/patient-resources/heart-diseases-disorders/atrial-fibrillation-afib/risk- Factors-for-AFib#sthash.vIHHAtio.dpuf 6 Page 2 2
Mechanisms of AF Triggers Rotors 7 AF ablation 8 AF ablation versus medications 9 Page 3 3
Evolution of AF ablation technology 10 Success rates with newer AF technology 11 ABLATION Page 4 4
Stroke prevention in AF CHA2DS2VASc STROKE RISK CRITERIA SCORE C Congestive Heart Failure 1 H Hypertension 1 A Age 75 2 D Diabetes mellitus 1 S Stroke/TIA/Embolism 2 V Vascular Disease 1 A Age 65-74 Years 1 S Sex (female) 1 13 Oral anticoagulation in AF 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 AF Patients Using Anticoagulation Anticoagulation Use Declines with Increased Stroke Risk 1 p < 0.001 (n=27,164) CHADS 2 Score 14 2014 ACC/AHA/HRS Treatment Guidelines to Prevent Thromboembolism in Patients with AF Score 1: Annual stroke risk 1%, oral anticoagulants or aspirin may be considered Score 2: Annual stroke risk 2%-15%, oral anticoagulants are recommended 15 Page 5 5
AF and bleeding risk 16 Use of NOAC at 2 years Source: Martinez C, et al. Therapy Persistence in Newly Diagnosed Non-Valvular Atrial Fibrillation Treated with Warfarin or NOAC. A Cohort Study. Thromb Haemost. 2015 Dec 22;115(1):31-9. doi: 10.1160/TH15-04-0350. 17 AF and Stroke risk AF is the most common cardiac arrhythmia AF increases risk of stroke Blood clots form in the left atrial appendage Many patients are unprotected < Non-LAA 10% 90% Thrombus Originate LAA 15% 10% Non-LAA 70% Intolerant Treated 15% with Contraindicated Warfarin 90% Thrombus Originate LAA > 33M people with AF Worldwide 1 5x greater risk of stroke with of stroke-causing clots that come from the left atrium in non-valvular AF are formed in the LAA 3 AF 2 >90% ~45% of patients eligible for warfarin are untreated (tolerance/adherence) 4 18 Page 6 6
AF and Stroke Stasis-related LA thrombus is a predictor of TIA and ischemic stroke In non-valvular AF, >90% of stroke-causing clots that come from the left atrium are formed in the LAA 1. Stoddard et al. Am Heart J. (2003) 2. Goldman et al. J Am Soc Echocardiogr (1999) 3 Blackshear JL. Odell JA., Annals of Thoracic Surg (1996) 19 Left atrial appendage closure For atrial fibrillation patients not undergoing cardiac surgery who should be treated with long-term oral anticoagulation to prevent embolization but for whom such therapy poses an unacceptably high risk of bleeding Thrombocytopenia or known coagulation defect associated with bleeding Recurrent gastrointestinal bleeding Prior severe bleeding, including intracranial hemorrhage 20 LAA anatomy Wind Sock: An anatomy in which one dominant lobe of sufficient length is the primary structure Chicken Wing: An anatomy whose main feature is a sharp bend in the dominant lobe of the LAA at some distance from the perceived LAA ostium Broccoli: An anatomy whose main feature is an LAA that has limited overall length with more complex internal characteristics 21 Page 7 7
Transseptal puncture Bicaval view: Poster Short axis: Inferior 22 Delivery system Marker bands 23 TEE and anatomy of LAA Device should be at or just distal to the LAA ostium 24 Page 8 8
Endothelization of device Canine Model 30 Day Canine Model 45 Day Human Pathology - 9 Months Post-implant (Non-device related death) 25 LAA closure video 26 Time line for LAA closure 2002 Pilot nonrandomized Feasibility and Safety Mar 2015 FDA Approval 2008 CAP Registry Oct 2014 non-randomized FDA Panel #3 Add l patients and follow-up 2017 ASAP TOO 2010 PREVAIL Randomized Dec 2013 Randomized FDA Panel #2 US Indication Expansion Comparison: warfarin Worldwide study Apr 2009 2012 CAP2 Registry FDA Panel #1 non-randomized Add l patients and follow-up 2005 PROTECT AF Randomized Comparison: warfarin 2013 EWOLUTION, WASP Registries non-randomized 2009 ASAP Real-world, All comers non-randomized Patients Contra-indicated to warfarin* 2016 NESTed SAP Post-approval statistical analysis from NCDR LAAO Registry data 27 Page 9 9
Clinical trials for LAA closure Key Trials N Highlights PROTECT AF 1 (2005-2008) CAP 2 (2008-2010) 707 566 PREVAIL 3 407 (2010-2012) CAP2 579 (2012-2014) EWOLUTION (2013-2015) 4* 1025 Total patients Prospective, randomized 2:1, non-inferiority trial of LAA closure vs. warfarin. Prospective registry allowing continued access to the WATCHMAN Device and gain further information prior to PMA approval. Prospective, randomized 2:1, non-inferiority trial to collect additional information on the WATCHMAN Device. Prospective registry allowing continued access to the WATCHMAN Device prior to PMA approval. Prospective registry allowing all patients receiving a WATCHMAN Device at participating centers in Europe, Middle East and Russia >3,000 ~9,000 Patient-Years of Follow-up 28 Clinical Trial data PROTECT AF CAP Registry PREVAIL CAP2 Registry Enrollment 2005-2008 2008-2010 2010-2012 2012-2014 Purpose Study Design Primary Endpoints Demonstrate safety and effectiveness of the WATCHMAN implant compared to long-term warfarin 2:1 Randomized, non-inferiority Continued Access Registry Non-randomized 1. Effectiveness: Stroke, systemic embolism and cardiovascular/unexplained death 2. Safety: Life-threatening events, which include device embolization requiring retrieval and bleeding events Demonstrate safety and effectiveness of the WATCHMAN implant compared to long-term warfarin 2:1 Randomized, non-inferiority Continued Access Registry Non-randomized 1. Effectiveness: Stroke, systemic embolism and cardiovascular/unexplained death 2. Effectiveness: Ischemic stroke or systemic embolism, occurring after 7 days postrandomization or WATCHMAN implant procedure 3. Safety: Death, ischemic stroke, systemic embolism and procedure/device-related complications within 7 days of implantation procedure 29 CHADS scores in trials Anticoagulation Eligible CHA 2 DS 2 -VASc High Risk Score 2 PROTECT AF 93% CAP 96% PREVAIL 100% CAP2 100% Patients (%) CHA 2 DS 2 -VASc Score 30 Page 10 10
HAS BLED scores in the trials 31 Implant success rates 32 Complication rates 33 Page 11 11
Registry data for LAA closure devices JAAC patient-level meta-analysis of 5 year data from two randomized clinical trials: PROTECT AF and PREVAIL, 5-Year Outcomes After Left Atrial Appendage Closure: From the PREVAIL and PROTECT AF Trials 55% reduction in disabling and fatal stroke 80% reduction in hemorrhagic stroke 52% reduction in non-procedure related major bleeding 27% reduction in all-cause mortality 41% reduction in cardiovascular/unexplained death 34 New ACC/AHA guidelines 35 36 Page 12 12
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