Modern aspects in multidisciplinary thromboembolic prophylaxis. AMPLATZER Left Atrial Appendage data update

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1 Modern aspects in multidisciplinary thromboembolic prophylaxis AMPLATZER Left Atrial Appendage data update Igal Moarof, MD Interventional Cardiology Kantonsspital Aarau

2 Potential conflicts of interest Speaker s name: Igal Moarof I have the following potential conflicts of interest to report: Consultant for SJM / Abbott

3 AMPLATZER left atrial appendage occlusion Clinical Data ACP Initial EU Registry¹ N = 37 ACP EU Prospective Observational Study² N = 4 Amulet Global Observational Study4 N = 88 ACP Multicenter experience³ N = 47 AMPLATZER Amulet IDE LAA Occluder RCT N = >6 (ongoing) Physician-Driven Published Real-World Data N = > published papers (Pubmed search). Park, J. W., et al. (). LAA closure with AMPLATZER Cardiac Plug in atrial fibrillation - initial European experience. Catheterization and Cardiovascular Interventions, 77(5), Walsh, K. (, May). LAA closure with the AMPLATZER cardiac plug: results of the European post-market observational study. Presented at EuroPCR, Paris. 3. Tzikas, A., et al. (6). LAA occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention, (), Landmesser, U. et al.. 7. LAA occlusion with the AMPLATZER Amulet device: periprocedural and early clinical/echocardiographic data from a global prospective observational study. EuroIntervention 7;3-online publish-ahead-of-print June 7

4 Multicenter Study Experience With the AMPLATZER Cardiac plug Single-arm multicenter clinical evaluation of ACP for stroke prevention in AF pts. Total patients,47 Number of centers Patient years follow-up,349 CHA DS -VASc (Mean) 4.5 HAS-BLED (Mean) 3. Age (Mean) 74.9 Prior stroke / TIA 37% Previous major bleeding 47% Taking OAC at time of implant 9.5% Concomitant procedures to LAAO.6% Tzikas, A. et al. (6). Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention, (), 7-79.

5 Multicenter Study Experience with the AMPLATZER Cardiac Plug Indication for LAAO in more than, patients: Previous major bleeding High bleed risk CAD and stenting Drug Interaction Stroke on Warfarin Previous minor bleeding Renal or hepatic disease Labile INR Risk of falls 9% 8% 7% 6% 5% 4% % 35% 47% % 5% % 5% % 5% 3% 35% 4% 45% 5% Tzikas, A. et al. (6). Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention, (), 7-79.

6 Multicenter Study Experience With the AMPLATZER Cardiac Plug 6% 4% Effectiveness in Stroke Reduction vs. Estimated 5,6% 6% Effectiveness in Bleeding Reduction vs. Estimated 4% 5,34% -59% - 6% % %,3% Estimated based on CHA DS -VASc score Observed rate in study % %,8% Estimated based on HAS-BLED score Observed rate in study Total Patients Total Patient Years CHA DS -VASc Score Total Patients Total Patient Years HAS-BLED Score Estimated Stroke Rate per CHA DS -VASc Actual Annual Stroke Rate (N strokes + TIA) Estimated Bleeding Rate per HAS-BLED Actual Annual Bleeding Rate (N major bleeds) 5.6%.3% (3) 5.34%.8% (8) Tzikas, A. et al. (6). Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention, (), 7-79.

7 TE rate [events/year] Expected and observed stroke rates in AMPLATZER LAA Occluders 9,6 8 8,6 7,7 7, ,8 58% 5% 58% 6,7 5,9 5,6 5,8 5,3 5% 75% 6% 68% 59% 6% 7% 66% 58% Expected* Observed,98,4,4,3,5 3,,3,3,, Walsh Kefer Lopez- Minguez Urena Chun Santoro Kebernik Tzikas Korsholm Berti Berti - Patients Patient years NR Strokes/TIAs TEreduction [%] 5% 58% 75% 6% N/A 68% 5% 59% 6% 7% 66% * Expected stroke rates are based on the patients CHADS or CHADSVASc scores.. Walsh et al. Presented at EuroPCR, Paris.. Kefer, J. et al. Acta Cardiolog. 368(6); López-Mínguez et al. Heart. 5;: Urena et al. JACC Cardiovascular Interventions, 3. 6, Chun et al. Heart Rhythm, 3, Santoro et al. EuroIntervention, 6. (), Kebernik et al. Cardiology and Therapy, 5. 4(), Tzikas et al. EuroIntervention, 6. (), Korsholm et al. EuroIntervention. 7;:75-8. Berti et al. Heart. 6;: Berti et al., Int J Cardiol. 7 Jul 6. pii: S67-573(7).

8 Reported by Procedural success and safety with AMPLATZER Cardiac Plug > patients* Nietlispach¹ Park² (Multi) Berti³ (Italian) Walsh 4 (Multiple) Santoro 5 (Spain) Tzikas 6 (Multiple) Lopez- Minguez 7 (Spain) Meerkin 8 (Israel) Betts 9 (UK) Berti () (Italian) Nielsen- Kudsk (Nordic) Enrollment period 8 /8 /9 /9 4/3 8/9 9/ /9 / /8 /3 3/9 3 NR 7/9 /4 /8-4/5 9 /5 CHADS NR NR NR.6 NR.8 3 (median) ±.4 - NR CHA DS -VASc (median) (median) - 4. ± ± Patients enrolled Successful device implantation Major peri-procedural complications Stroke/TIA MI / air embolism Device embolization Major tamponade/effusion Major bleeding Other 7 (97.5%) 7 (5.8%) 3 3 (96.4%) (7.3%) (96.7%) 4 (3.3%) 3 97 (96.6%) 6 (.9%) (95.5%) 4 (3.%) 3 9 (97.3%) 5 (4.97%) (94.6%) 9 (5.4%) 4 (%) (.%) 9 (95.%) 6 (4.8%) All studies include learning curve increased success rates and reduced complication rates with increasing operator experience. Procedures carried out according to IFU with Echocardiography and fluoroscopy. 585 (95.4%) 38 (6.%) 4 7 (97.%) 7 (4.%) 3.Nietlispach et al. Cath and Card Int., 3. 8, Park et al. Cath.and Card.Int.,. 77(5), Berti et al. J.American College of Cardiology: Card. Int. 4. 7, Walsh et al. Presented at EuroPCR, Paris. 5. Santoro et al. EuroIntervention, 6. (), Tzikas et al. EuroIntervention, 6. (), López-Minguez et al. Heart, 5., Meerkin et al. International Journal of Cardiology, 3. 68, Betts et al. Catheter Cardiovasc Interv. 6 Sep. [Epub ahead of print]. Berti et al. Int J Cardiol. 7 Jul 6. [Epub ahead of print]. Nielsen-Kudsk et al. EuroIntervention. 7 Jun ;3(3): doi:.444/eij-d-7-.

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10 AMPLATZER Amulet Device Multicentre prospective real-world observational study Procedural and up to 3 month follow up Study and patient characteristics Enrollment,88 (6 centers, enrolled between June 5 and September 6) Age 75±8.5 years CHA DS -VASc 4.±.6 (64.9% CHA DS -VASc score 4) HASBLED 3.3±. (77.% HAS-BLED score 3) Follow up.4±.8 months. Indication General Anaesthesia 8.8% absolute or relative contraindication to LT OAC 7.4% previous major bleeding 56.5% Landmesser, U.,et al. EuroIntervention 7;3-online publish-ahead-of-print June 7

11 AMPLATZER Amulet Device Multicentre prospective real-world observational study Procedural and up to 3 month follow up Results Successful implantation 99% Closure < 3mm (follow up) 98.% First device choice 93.9% % 5% LAA Closure Rates 99,6% 98,% LAA closure defined by an independent echo core lab as absence of peri-device flow or- flow of < 3 mm jet into the LAA Implanting centers reported: 99.7% at implant and 99.4% at 3 months of patients had no leak or < 5mm. % LAA Closure (Implant) LAA Closure (-3 Month Visit) Landmesser, U.,et al. EuroIntervention 7;3-online publish-ahead-of-print June 7

12 AMPLATZER Amulet Device Multicentre prospective real-world observational study During Procedure and Index Hospitalization (CEC Adjudicated) Results Major AE 3.% Major bleeding: Pericardial effusion/tamponade Pericardiocentesis Surgery.4% (.%) (.9%) (.3%) Vascular complications.9% Death.% cardiac perforation cardiorespiratory arrest/shock Device embolization.% Landmesser, U.,et al. EuroIntervention 7;3-online publish-ahead-of-print June 7

13 AMPLATZER Amulet Device Multicentre prospective real-world observational study Procedural and up to 3 month follow up Post procedural medication (discharge) Single antiplatelet 3% Dual antiplatelet 54.3% Oral anticoagulation 8.9% No antithrombotic therapy % Device Associated Thrombus: Ten () cases of device on thrombus were reported through 9 days of implant. Represents.9% device on thrombus rate within 9 days of implants in all implanted patients in the study. ( out of 77 implant attempts) Represent.5% ( out of 673 echoes adjudicated by core lab) One patient had an ischemic stroke 8 days after detection of device thrombus. Landmesser, U.,et al. EuroIntervention 7;3-online publish-ahead-of-print June 7

14 Procedural success and safety of AMPLATZER Amulet LAA occluder > patients* Study Freixa Cruz² Abualsaud³ Bartoletti 4 Karczewski 5 Kleinecke 6 Landmesser 7 Aguirre 8 Enrollment period 7/ - 6/3 Mean stroke risk CHADS CHA DS -VASc NA 4.3 ±.7 4 NA 4.9 ±.3 /9 6/ /4 /5 NA 4(median) NA /4 8/5 3 5 NA 5. ±.8 6/5 9/6 NA 4.±.6 LAA occlusion attempted Successful device implantation Major peri-procedural complications Stroke TIA MI / coronary air embolism Device embolization Major tamponade//effusion Major bleeding Other Minor peri-procedural complications LAA closure success (% < 3mm leak) 4 (96%) (%) 3 (%) 39 (%) 34 (%) 49 (98%) 4 (retropharyngea l hematoma) 77 (99%) deaths (perforation and cardiac arrest) 3 (vascular) 5 ( vascular) (vascular) -3 mths: % Procedures performed with recommended echocardiographic and fluoroscopic Guidance 6 days: % Mean.4 mths: 96% Mean 89 ± 9 days 9.6% pts<5mm leak) 6 mths: % 6 weeks: % Mean.4±.8 mths: 98.%. Freixa X, et al. Int J Cardiol. 4 Jul ;74(3): Cruz-González, I. et al. Revista Española de Cardiología, 5. 68, Abualsaud, A. et al. J.Inv. Card., 6. 8, Bartoletti,S. et al. Heart 6;:A45-A Karczewski M. et al. Kardiochir Torakochirurgia Pol. 6 Jun;3(): Kleinecke C, et al. Cardiol J. 7 Feb 5. [Epub ahead of print] 7. Landmesser, U.,et al. EuroIntervention 7;3-online publish-ahead-of-print June 7 8. Aguirre et al. Catheter Cardiovasc Interv. 7 Aug 4. [Epub ahead of print] 6-9/6 3.8 ±. NA (%) 3 days: % <5mm

15 Aspirin alone for post-implant antithrombotic therapy Study and patient characteristics Results Enrollment CHADS-VASc 4.4±.6 HASBLED 4.±. Follow up Indication 7 patients March -March 5 Median.3 years 8% Bleeding indication Success % Complication rate Stroke risk Bleeding risk Device related thrombus 4.6% Annual risk of stroke reduced by 6% to predicted rate Annual risk of bleeding reduced by 57% /7 (.9%) had clopidogrel due to aspirin intolerance month post implant at 6 weeks managed with heparin At month follow up 6% patients were without any ASA or antithrombotic medication Conclusion Aspirin monotherapy is safe post LAAO with AMPLATZER LAAO Devices Korsholm K, et al. EuroIntervention. 6 Dec 5. [Epub ahead of print]

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17 AMPLATZER Amulet Device Randomized control trial - ongoing Study Overview Objective Prospective, randomized, multi-center active control trial designed to evaluate the safety and effectiveness of the AMPLATZER Amulet Left Atrial Appendage Occluder (LAAO). The AMPLATZER Amulet is intended to reduce the risk of thromboembolism from the left atrial appendage (LAA) in patients with non-valvular atrial fibrillation (AF). To evaluate the safety and effectiveness of the AMPLATZER Amulet device by demonstrating that the device is non-inferior to the commercially available WATCHMAN left atrial appendage closure device (Control) in subjects with non-valvular AF. Endpoints Primary safety endpoint: o Composite of procedure-related complications, all cause death, major bleeding through months Primary effectiveness endpoint: o A composite of ischemic stroke or systemic embolism through 8 months Primary mechanism of action endpoint: o Device closure (defined as residual jet around the device <5mm) at the 45d visit Design Study Population Data Collection Status Ongoing Prospective, global, multi-center active control trial with : randomization to Amulet (Treatment) or WATCHMAN (Control), evaluating approximately >6 patients Patients aged 8 and older, with non-valvular atrial fibrillation (AF) who: Are at increased risk for stroke and systemic embolism based on CHADS and CHADS-VASc scores Are recommended for anticoagulation therapy Are deemed by their physician to be suitable for warfarin; and Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin Baseline, Procedure, Discharge, Follow-up (45d, 6mo, mo, 8mo, 4mo and annually for 5 years) Testing/Assessments: TEE (baseline, 45d, mo), TTE (at discharge), medication assessment (all visits), MRI/CT (after suspected stroke/tia)

18 Summary AMPLATZER Left Atrial Appendage Occluders demonstrate experienced operators are able to achieve an implant success rate between 95% and %. AMPLATZER Left Atrial Appendage Occluders show there is an overall procedural complication rate of 4% or lower. The most common procedure-related safety event is pericardial effusion, occurring less frequently with increasing operator experience. Closure (<3mm jet at follow up) in more than 9% of patients. Longer-term follow-up results show stable and effective LAA occlusion over time and a reduction in stroke rate between approximately 6% and 75%, compared to the stroke incidence predicted by the CHADS or CHA DS -VASc score.

19 Conclusion Randomized control trials still lacking The majority of patients implanted according to European guidelines (Unable to tolerate OAC) results demonstrate: Percutaneous LAA occlusion is a feasible option for stroke reduction in AF patients at high risk for stroke who are contraindicated to long term oral anticoagulation Percutaneous LAA occlusion is a feasible option for stroke reduction in AF patients at high risk for stroke who have suffered a stroke despite OAC. LAA occlusion is also associated with markedly less major bleeding than OAC.