Managing the Left Atrial Appendage: Concepts & Controversies

Managing the Left Atrial Appendage: Concepts & Controversies SH-102103-AD- APR 2013 Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC Professor Department of Cardiac Sciences Section Chief Cardiology Division, Libin Cardiovascular Institute, University of Calgary Zone Head Cardiology, South Eastern Alberta Alberta Health Services Adjunct Professor of Medicine/Cardiology McMaster University Associate Scientist Arrhythmia & Global Health Population Health Research Institute

Conflicts of Interest I implant LAAC Devices. Research Grants: Bayer, Biosense Webster, Biotronik, Boston Scientific, Medtronic, Pfizer, St. Jude Medical, Transoma, CIHR, WHO-TDR, COLCIENCIAS, Juan Valdez Café de Colombia, Other Undisclosed Colombian Pharmaceutical Companies! Honorarium: Biosense Webster, Boston Scientific, BMS, Biotronik, Daiichi-Sankyo, Medtronic, Pfizer, St. Jude Medical, Sorin, Transoma, Astra Zeneca, Boeringher Ingelheim, Procaps, Sanofi-Aventis, Merck, Servier. Advisory Boards: Medtronic, Biosense Webster, Boston Scientific, Biotronik, Transoma, Schering Plough, Boeringher Ingelheim, Sanofi Aventis, Procaps, Biocaps, Servier Steering Committees: Medtronic, BSCI, Daiichi Sankyo, Biosense Webster, STOP-HARM, ASAP-TOO

Overview SH-102103-AD- APR 2013 LAA & Stroke NOAC Evidence LAAC Evidence Future Trials Current Guidelines

Left atrial appendage: cul-de-sac predisposed to stasis-precipitated thrombi

The immobility of the auricular walls makes them defenceless against thrombotic deposits, as a horse should be against flies without his cutaneous muscles. Acta Medica Scanda 1948

Serial sections of the left atrial appendage were prepared [in AF-patients with embolic stroke] in every case mural thrombus, not obvious to the naked eye, was found in the interstices of the trabeculae carneae. C.M. Fisher. Can Med Assoc J 1953; 69: 257. 1913-2012 (b. Waterloo, Ontario) SH-102103-AD- APR 2013

Atrial Fibrillation 16% of brain infarcts Aortic Arch Plaque Carotid Atherosclerosis Other Heart Disease Cerebral Small Artery Disease Left Atrial Thrombi 12% of brain infarcts (3/4ths of AF-associated stroke)

91% of stroke in AF is caused by blood clots that form in the left atrial appendage (LAA) 1 SH-102103-AD- APR 2013 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 The embolism lodges itself in the blood vessels of the brain, restricting blood flow and causing a stroke Thrombus in the LAA Images on file at Boston Scientific Corporation 1 Blackshear JL. Odell JA., Annals of Thoracic Surgery. 1996;61:755-759

Cactus Chicken wing Di Biasi L et al JACC2012;60;531-38.

LAA Anatomy Di Biasi L et al JACC2012;60;531-38.

Windsock Cauliflower Di Biasi L et al JACC2012;60;531-38.

Stroke or systemic emboli (primary outcome events) in 4 large randomized trials comparing DOACs with highquality warfarin anticoagulation SH-102103-AD- APR 2013 Data shown are for higher dosages of dabigatran (150mg twice daily) and edoxaban (60mg daily). Ruff CT et al. Lancet 2013 (on-line Dec 4 th )

DOACs vs. warfarin phase III RCTs in atrial fib: Intracerebral hemorrhage P Value Dabigatran 110 mg BID P <.001 Dabigatran 150 mg BID P <.001 Rivaroxaban 20 mg QD P =.024 Apixaban 5 mg BID P <.001 Edoxaban 60 mg QD P < 0.001 Edoxaban 30 mg QD P < 0.001 0.00 Connolly SJ, et al. N Engl J Med. 2009;361:1139 1151. Patel MR, et al. N Engl J Med. 2011;365:883 891. Granger C, et al. N Eng J Med. 2011;365:981 992. Giugliano RP, et al. N Engl J Med 2013; online Nov 19 0.25 0.50 0.75 1.00 1.25 DOAC better HR (95% CI) Warfarin better

Stroke Treatment Option: Direct Oral Anticoagulants (DOACs) SH-102103-AD- APR 2013 Treatment Study Drug Discontinuation Rate Major Bleeding (rate/year) Rivaroxaban 1 24% 3.6% Apixaban 2 25% 2.1% Dabigatran 3 (150 mg) Edoxaban 4 (60 mg / 30 mg) 21% 3.3% 33 % / 34% 2.8% / 1.6% Warfarin 1-4 17 28% 3.1 3.6% 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. SH-230506-AD June15 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.

Stroke Treatment Option: Direct Oral Anticoagulants (DOACs) SH-102103-AD- APR 2013 ~30% of NOAC patients stop taking any drug at 2 years Treatment 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. Study Drug Discontinuation Rate Major Bleeding (rate/year) Rivaroxaban 1 24% 3.6% Apixaban 2 25% 2.1% Dabigatran 3 (150 mg) Edoxaban 4 (60 mg / 30 mg) 21% 3.3% 33 % / 34% 2.8% / 1.6% Warfarin 1-4 17 28% 3.1 3.6% SH-230506-AD June15 There is an unmet need of stroke risk reduction for patients with AF who are seeking an alternative to long-term OACs SH-230609-AG NOV2016 ource: Martinez C, et al. Therapy Persistence in Newly Diagnosed Non-Valvular Atrial Fibrillation Treated with Warfarin or NOAC. A Cohort Study. Thromb aemost. 2015 Dec 22;115(1):31-9. doi: 10.1160/TH15-04-0350. 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.

AF Treatment Options SH-102103-AD- APR 2013 AF Ablation* Pacing Drugs for Rhythm/Rate Control AND/OR Embolic Management 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

Left Atrial Occluding Devices LA LAA PLAATO (terminated) Watchman Amplatzer LARIAT

Left atrial appendage clot on echo: 91% of stroke in AF is caused by blood clots formed in the LAA 1 1 Blackshear JL, Odell JA, Annals of Thoracic Surgery, 1996;61:755-759 SH-102103-AD- APR 2013 Clot Images on file at Boston Scientific Corporation

Invasive procedures can successfully close the LAA Method of Successful SH-102103-AD- APR 2013 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 LAA Closure 2 80% 60% 40% 20% 0% 73% 23% Excision Ligation w/ Sutures 0% Ligation w/ Staples Surgical LAA closure prior to the closure rates of 10%-73% 1 1 Dawson AG et al. Interact Cardiovasc Thorac Surg. 2010;10:306-11 2 Kanderian et al. JACC. 2008;52:924 9

Currently Reported RCTs SH-102103-AD- APR 2013 Study Trial Size (N) Trial Type and Comparator Length of Follow up LAAOS I 77 Pilot RCT; Surgical LAA 13 months Healey, 2005 occlusion vs. No LAA occlusion (control group). Nagpal, 2009 43 Pilot RCT; Surgical LAA 9 days occlusion vs. No LAA occlusion (control group). PROTECT-AF 707 Percutaneous LAA 2.3 years Reddy, 2013 occlusion vs. No LAA occlusion (control group). LAAOS II 51 Pilot RCT; Surgical LAA 1 year Whitlock, 2013 occlusion vs. No LAA occlusion (control group). PREVAIL trial Holmes, 2014 407 RCT; 2:1 fashion; Percutaneous LAA occlusion vs. No LAA occlusion (control group). 18 months

ATCHMAN LAA Closure Device in situ Holmes et al, 2009

WATCHMAN : Device Implant Procedure SH-102103-AD- APR 2013 Procedure is performed under either general anesthesia or conscious sedation with fluoroscopic and transesophageal echocardiography (TEE) guidance Transseptal puncture Access to the left atrium is gained via the femoral vein and transseptal puncture Placement of WATCHMAN in LAA The procedure takes 35-60 minutes on average and patients are monitored in the hospital for at least 24 hours following the procedure 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

WATCHMAN : Device endothelialization SH-102103-AD- APR 2013 Canine Model 30 Day Canine Model 45 Day Human Pathology - 9 Months Post-implant (Non-device related death) 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

WATCHMAN Device Clinical Program Pilot Early feasibility with >6 years of follow-up PROTECT- AF CAP Registry WATCHMAN primary efficacy, CV death, and allcause mortality superior to warfarin at 4 years 1 Significantly improved safety results 2 ASAP Expected rate of stroke reduced by 77% in patients contraindicated to warfarin 3 PREVAIL Improved implant success; procedure safety confirmed with new and experienced operators 4 CAP2 Enrolled up to 1500 patients at ~ 60 sites SH-230506-AD June15 1 Reddy, VY et al. HRS 2013.. 2 Reddy, VY et al. Circulation. 2011;123:417-424; 3 Reddy, et al. JACC. 2013; In Press. 4 Holmes, DR Jr et al., CIT 2013

Demographics Device Patients SH-102103-AD- APR 2013 Characteristic Age, years PROTECT AF N=463 71.7 ± 8.8 (463) (46.0, 95.0) CAP N=566 74.0 ± 8.3 (566) (44.0, 94.0) PREVAIL N=269 74.0 ± 7.4 (269) (50.0, 94.0) P value <0.001 Gender (Male) 326/463 (70.4%) 371/566 (65.5%) 182/269 (67.7%) 0.252 CHADS 2 Score (Continuous) CHADS 2 Risk Factors 2.2 ± 1.2 (1.0, 6.0) 2.5 ± 1.2 (1.0, 6.0) 2.6 ± 1.0 (1.0, 6.0) 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%) <0.001 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;123:417-424.

HR p-value Efficacy 0.79 0.22 Meta-Analysis Shows Comparable Primary Efficacy Results to Warfarin All stroke or SE 1.02 0.94 Ischemic stroke or SE 1.95 0.05 Hemorrhagic stroke 0.22 0.004 Ischemic stroke or SE >7 days 1.56 0.21 CV/unexplained death 0.48 0.006 Source: Holmes DR, et al. Holmes, DR et al. JACC 2015; In Press. Combined data set of all PROTECT AF and PREVAIL WATCHMAN patients versus chronic warfarin patients SH-230506-AD June15 HR p-value Efficacy 0.79 0.22 All stroke or SE 1.02 0.94 Ischemic stroke or SE 1.95 0.05 Hemorrhagic stroke 0.22 0.004 Ischemic stroke or SE >7 days 1.56 0.21 CV/unexplained death 0.48 0.006 All-cause death 0.73 0.07 Major bleed, all 1.00 0.98 Major bleeding, non procedure-related 0.51 0.002 Favors WATCHMAN All-cause death 0.73 0.07 Major bleed, all 1.00 0.98 Major bleeding, non procedure-related 0.51 0.002 Favors warfarin 0.01 0.1 1 10 Hazard Ratio (95% CI) Favors WATCHMAN Favors warfarin 0.01 0.1 1 10 Hazard Ratio (95% CI)

Ischemic Stroke Risk (Events/100 Patient-Years) Device Reduced Ischemic Stroke Over No Therapy 8 7 6 5 4 3 2 79% Relative Reduction 67% Relative Reduction 83% Relative Reduction Imputed Ischemic Stroke Rate* 1 0 PROTECT AF PREVAIL CAP Only Baseline CHA 2 DS 2 -VASc = 3.4 Baseline CHA 2 DS 2 -VASc = 3.8 Baseline CHA 2 DS 2 -VASc = 3.9 * Imputation based on published rate with adjustment for CHA 2 DS 2 -VASc score (3.0); Olesen JB. Thromb Haemost (2011) FDA Oct 2014 Panel Sponsor Presentation. Hanzel G, et al. TCT 2014 (abstract) SH-230506-AD June15

Long-term PROTECT AF Primary Efficacy (2621 Patient-years) 100 HR: 0.61, 95% CI: 0.38 to 0.97; p=0.0348 Freedom from Primary Efficacy Event (%) 90 80 0 WATCHMAN Control 0 1 2 3 4 5 Time (Years) WATCHMAN Control 463 382 360 337 317 196 244 218 200 173 147 87

Post Procedure Therapy Destination Therapy Warfarin + ASA (81mg) daily Clopidogrel (75mg) + ASA (325 mg) daily ASA (325mg) daily Implant 45 days* 6 months *if leak >5mm, patients remained on warfarin + ASA until seal documented, skipping the clopidogrel + ASA pharmacotherapy Bleeding Rate (n events / N at risk) LAAC (n=732) Event Rate per 100 pt-yrs (n events / N at risk) Long-term warfarin (n=382) Rate Bleeding Rate (n events/n at risk) Event Rate per 100 pt-yrs (n events / N at risk) Ratio P value Overall 10.8 (79/732) 3.5 (79/2268) 11.3 (43/382) 3.6 (43/1187) 0.96 0.84 Post Procedure 5.9 (40/682) 1.8 (40/2255) 11.3 (43/381) 3.6 (43/1180) 0.49 0.001 Destination 3.2 (19/601) 1.0 (19/1958 9.7 (35/360) 3.5 (35/1004) 0.28 <0.001 Overall period defined as after randomization to the end of follow-up; post-procedural period as >7 days after randomization to the end of follow-up; destination therapy period as beyond 180 days post-randomization, when patients assigned to LAA closure were eligible to receive aspirin alone. Price, M. J., V. Y. Reddy, et al. JACC: CV Interv 2015; 8(15): 1925-1932 SH-230609-AG NOV2016

Briceno D, et al. Circ EP 2015 SH-102103-AD- APR 2013

Network meta-analysis for stroke SH-102103-AD- APR 2013 According to the random effects model, LAAC device was found to reduce the risk of stroke by 15% when compared with NOACS Treatment 1 vs. Treatment 2 O.R. (95% Cr.I.) LAAC device versus WARFARIN 0.71 (0.42 1.23) 0.75 (0.38 1.44) LAAC device versus NOACS 0.81 (0.48 1.41) 0.85 (0.63 1.05) NOACS versus WARFARIN 0.88 (0.81 0.95) 0.88 (0.44 1.87) 0.1 1 10 Heterogeneity (Vague) = 0.1456 95% CrI (0.02675 0.6404) Favours Treatment 1 Favours Treatment 2 Fixed Effects Random Effects (Vague Prior) www.hqontario.ca

League table for the outcome of Stroke OR <1 Means the Treatment in Top Left is Better LAAC device 0.85 (0.63 1.05) NOACS 0.75 (0.38 1.44) 0.88 (0.44 1.87) WARFARIN www.hqontario.ca

Probability of Being Ranked Rankogram for the outcome of Stroke Random Effects (Vague) Rankogram 1 0.9 0.8 LAAC device NOACS WARFARIN 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Best 1 2 3 Rank Worse www.hqontario.ca

All cause mortality Treatment 1 vs. Treatment 2 O.R. (95% Cr.I.) LAAC device versus WARFARIN 0.68 (0.46 1.02) 0.63 (0.44 1.08) LAAC device versus NOACS 0.77 (0.52 1.17) 0.71 (0.49 1.22) NOACS versus WARFARIN 0.89 (0.84 0.94) 0.88 (0.80 0.97) 0.1 1 10 Heterogeneity (Vague) = 0.03566 95% CrI (0.0006505 0.2938) Favours Treatment 1 Favours Treatment 2 Fixed Effects Random Effects (Vague Prior) www.hqontario.ca

Hemorrhagic stroke Treatment 1 vs. Treatment 2 O.R. (95% Cr.I.) LAAC device versus WARFARIN 0.19 (0.05 0.60) 0.22 (0.05 0.94) LAAC device versus NOACS 0.42 (0.11 1.35) 0.45 (0.29 0.79) NOACS versus WARFARIN 0.45 (0.37 0.55) 0.48 (0.10 2.30) 0.01 0.1 1 10 Heterogeneity (Vague) = 0.2726 95% CrI (0.01987 1.246) Favours Treatment 1 Favours Treatment 2 Fixed Effects Random Effects (Vague Prior) www.hqontario.ca

Ischemic stroke www.hqontario.ca

www.hqontario.ca SH-102103-AD- APR 2013 GRADE Evidence Profile Comparison Direct evidence Indirect evidence Network meta-analysis LAAO closure device vs NOACS OR [95% Cr.I] Quality of evidence OR [95% Cr.I] Quality of evidence OR [95% Cr.I] Quality of evidence Not availabl e Not applicable 0.83 [0.43, 1.84] ǂ Low Same as indirect evidence Same as indirect evidence Downgraded for indirectness, precision

Case Presentation SH-102103-AD- APR 2013 76 yr old male Chronic AF since 2000 Hypertension, Type II DM, Dyslipidemia, Stroke/TIA 2006 Left hemisphere (CT documented) July 2013 Right Hemispheric TIA (MRI) CKD Creatinine 520 egrf =14.6, Dialysis 3/week Gastric Antral Vascular Ectasia Recurrent severe bleeding with transfusions every 2 weeks. Chronic rheumatoid arthritis, Gout Polyclonal gamopathy M Spikes Factor XII Deficiency Referred to determine best Stroke Prevention Therapy!

Stroke rate No OAC CKD SH-102103-AD- APR 2013 egrf 30-59 ml/min/1.73m 2 =7.5%/yr egrf < 30 ml/min/1.73m 2 = 8.1% ESRD hemodialysis 2 10 greater incidence of stroke RR 6.1, 95% CI 5.1-7.1 10 33/1000 patient-yrs Hemorraghic stroke HR 6.83, 95% CI 5.87-7.92 Banerjee A, et al. Chest 2014;145:1370-82.

Saw J, et al. J Cardiovasc Electrophysiol. 2017 Jan 27. doi: 10.1111/jce.13168. [Epub ahead of print] SH-102103-AD- APR 2013

SS:888 SH-102103-AD- APR 2013

ESS: 400 SH-102103-AD- APR 2013

LAAOS III Project Office Project Office: LAAOSIII@phri.ca Co-Principal Investigators: Richard Whitlock and Stuart Connolly 2947 recruited to date Research Coordinator: Kate Brady Richard.whitlock@phri.ca

J Am Coll Cardiol 2016;68:1929 40. SH-102103-AD- APR 2013