LAAC: What Does the Post Marketing Data Tell Us? Tilak K.R. Pasala, MD, MRCP Fellow, Structural and Congenital Heart Carlos E. Ruiz, MD, PhD, FACC, FESC, MSCAI Professor of Cardiology in Pediatrics and Medicine Director of Structural and Congenital Heart Disease Program Good afternoon, My name is Tilak Pasala, I am a structural heart disease fellow with Dr. Carlos Ruiz. My topic today is LAAC: what does the post marketing data tell us?

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Tilak Pasala, MD  I have no relevant financial relationships Carlos E. Ruiz, MD Grant / Research Support Philips – St Jude Medical - Medtronic Consulting Fees / Honoraria Valtech – St. Jude Medical – LivaNova Royalty / Intellectual Property Rights Gore Major Stock Shareholder / Equity Vascular Therapies – MitrAssist – Entourage – BioInspire – Cardiac Implants – Valtech – Pi-Cardia – HRT - Medivalve These are the disclosures

LAA closure devices in the market WATCHMANTM Device AMPLATZERTM AmuletTM Device CE Mark – January 18th, 2013 Not approved in US AMPLATZER™ Amulet™ LAA Occluder Trial (Amulet IDE): start date Aug 2016 So far – 111/1700 enrolled FDA approval date - March 13th, 2015 CMS coverage decision - February 2016 LAAC registry – August 2016 While several devices for LAAC are approved, they are mostly in Europe. Post-market data is available for two devices, mainly – watchman device and Amlplatzer amulet device. The watchman device was approved by the FDA to reduce the risk of stroke NVAF in March 2015, although CMS coverage and LAAC registry were done much later in Feb 2016 and Aug 2016 respectively. But the company has done a tremendous job by allowing trained watchman clinical specialist in attendance at every implantation in the country – who were able to collect the data. The Amulet device obtained CE mark in January 2013 and most of the experience is in Europe. Although, Amulet IDE trial has started in Aug 2016 in the US. So far over a 100 devices have been implanted.

WatchmanTM device Ewolution Registry* October 2013 – May 2015 1025 pts from 47 sites in Europe, Russia and Middle East Initial US Clinical Experience (Post FDA approval)** March 2015 – May 2016 3,822 consecutive patients underwent LAAC with Watchman™ implantation by 382 physicians at 169 U.S. centers Two main studies are reported with the watchman device. The Ewolution registry reporting the experience the European experience between 2013 to 2015, over a 1000 patients have had wathman devices implanted in Europe, Russia and the middle East. In the US, post FDA approval over 3800 patients under watchman implantation. Post FDA approval US clinical experience was reported from March 2015 to May 2016, over 3800 pts at 169 US centers are performed. *Bergmann MW. Presented at TCT 2016 **Reddy, V. Y. et al. J Am Coll Cardiol. 2017;69(3):253-61

EWOLUTION Registry (Watchman) Registry on WATCHMAN outcomes in Real-Life Utilization In the Ewolution registry, Watchman device was implanted in 1020 pts and the 3 month follow up data from was available in 80% of these patients. M.W. Bergmann, EuroPCR 2016 LBT 5

EWOLUTION: Patient characteristics

Watchman device: Procedural parameters Comparison of procedural parameters No procedures is more than all the randomized controlled trials combined. Implantation success is superior. Procedural duration is similar. Devices per procedure – were similar if not less. More importantly – 50% of procedures were preformed by newly trained operators So, the learning curve is getting better, so much so that new operators can be trained to achieve a high success rate. ~50% of procedures performed by newly trained operators

Watchman device - Major complications While that is the experience with procedural success there is a positive note in the complication rates too. All the major complications are lower in the post-approval era when compared to the randomized controlled trials despite >50% of the operators were newly trained. When we take a deeper look at the type of complications – it is important to note that the stroke and death rates are less than 0.1% Stroke & Death ~ <0.1%

THE AMULET STUDY Prospective, multicenter, international observational study. TEE at 1-3 months Independent echo core lab Clinical events committee 1073 patients enrolled between Jun 2015 and Sept 2016 in 64 clinical sites in Europe, Middle East, Asia, Australia, South America 13 patients Device not implanted* 1060 patients with AMPLATZER Amulet LAA Occluder implanted Not completed 1st F/U @ database lock** (N=349) While the experience with watchman device is very encouraging, a similar experience has been noted with the amulet device post-approval. In the Amulet Study which is a prospective, multicenter international observational study with > 1000 pts with 1-3 Month Follow Up Completed (N = 711) Hildick-Smith D. Presented at TCT 2016

Amulet device: Patient characteristics Mean ± SD or % n=1071* Age (years) 75 ± 8 Gender - Female 35.6% Prior Stroke 27.1% Prior TIA 10.6% Heart Failure 17.4% Diabetes 31.4% Hypertension 84.2% Prior History of Major Bleeding 72.5% CHA2DS2-VASc Score > 4 65% HAS-BLED > 3 58% It is interesting to note that a high CHADS VASc scores were seen in 65% of the patient suggesting that even in the real world high risk patients are getting these procedures.

Amulet device: Procedural parameters ACP Registry1 Watchman EWOLUTION2 Amulet Study Implant Success 97.3% 98.5% 98.8% LAA Closure Rate (1-3 months) < 5 mm 98.1% 99.3% 100.0% The implant success was very high and the LAA closure rate on TEE was 100%. Amulet is superior to ACP and is comparable to watchman device. First device selected implanted – 93% 1 Tzikas et al. EuroIntervention. 2015;10 3 Boersma et al. Eur Heart J. 2016 Aug;37(31):2465-74.

Amulet device: Major adverse events Device/Procedure Related MAE No. % Death Related to Cardiac Perforation Related to Myocardial Infarction Related to Cardiorespiratory Arrest 3 1 0.3% 0.1% Stroke Pericardial Effusion Resulted in Pericardiocentesis Resulted in Surgical Intervention 5 4 0.5% 0.4% Embolization Bleeding 10 0.9% Other 7 0.7% TOTAL 29 2.7%

Amulet device: Outcomes Comparison with other devices ACP Registry1 Watchman EWOLUTION2 Amulet Study Device or Procedure-Related Complications 5.0% 2.7% Early Mortality 0.8% (30-day) 0.7% (30-day) 0.3% (7-day) Amulet is superior to ACP and is comparable to watchman device. 1 Tzikas et al. EuroIntervention. 2015;10 3 Boersma et al. Eur Heart J. 2016 Aug;37(31):2465-74.

Summary Procedural success was high and consistent with clinical trial results Complications were low even with >50% of the operators being newly trained Post-market data is encouraging and LAAO maybe a viable alternative to oral anticoagulants

thank you Tilak.Pasala@hackensackmeridian.org Carlos.Ruiz@hackensackmeridian.org

Ewolution registry: Safety endpoints - 3 months M.W. Bergmann, EuroPCR 2016 LBT 16