TAVR: How We continue to Refine the Technology and Improve the Results CRT 2015 Washington DC, February 22nd, 2015 TAVR: How We continue to Refine the Technology and Improve the Results Eberhard Grube MD, FACC, FSCAI University Hospital, Dept of Medicine II, Bonn, Germany Stanford University, Palo Alto, California, USA

Eberhard Grube, MD Physician Name Company/Relationship Eberhard Grube, MD Medtronic, CoreValve: C, SB, AB, OF Direct Flow: C, SB, AB Mitralign: AB, SB, E Boston Scientific: C, SB, AB Biosensors: E, SB, C, AB Kona: AB, E Abbott Vascular: AB InSeal Medical: AB, E, Valtech: E, SB, Claret: SB Keystone: AB Shockwave: E, AB Key G – Grant and or Research Support E – Equity Interests S – Salary, AB – Advisory Board C – Consulting fees, Honoraria R – Royalty Income I – Intellectual Property Rights SB – Speaker’s Bureau O – Ownership OF – Other Financial Benefits‘ 2

Technology & Core Competencies Unmet Clinical Needs Reduce Complications Deployment Accuracy & Ease of Use Durability PVL Pacemaker Rates Stroke Frame Anatomic Characterization Delivery Systems FEA Modeling Valve Biomaterials Valve Biomaterials Predictive Design & Modeling Procedural Tools Ex-Vivo Testing Animal Testing Capabilities Technology & Core Competencies

Future TAVI Tools/Enablers to further simplify the procedure & advance outcomes Frame & Valve delivery Tissue engineering Advanced steering Advanced sealing Torqueability Adaptive sizing Depth control Frame advancements Low Profile Materials

Imaging Innovation Potential Solutions Imaging Advancement Imaging Needs CT SIZING Support: Assist in valve size decision to minimize PVL potential Pre-case FUSION of Echo & Fluoro: Provide more information to implanter during critical placements Case planning & patient selection Peri-procedure Guidance and confirmation TEE Profile Reduction: Requiring less general anesthesia Post-procedure Follow-up and complication prediction PVL Quantification: Repeatable PVL severity ranking using multiple imaging modalities

What is the current status of TAVI? How are today’s outcomes?

TAVI Results: PARTNER A and B Transcatheter aortic valve replacement (TAVR) is a viable treatment strategy for AS patients at high or extreme surgical risk TAVR has demonstrated significant survival improvements compared to medical management in inoperable patients in the PARTNER B trial1 High risk patients receiving TAVR had similar survival rates to SAVR in the PARTNER A trial2 PARTNER B PARTNER A 1Kapadia , et al., presented at TCT 2012 2Kodali S, et al., presented at ACC 2012

TAVI Results: US CoreValve Pivotal ER and HR TAVR demonstrated significant survival improvements compared to medical management in extreme risk patients in the CoreValve US Pivotal Extreme Risk Study High risk patients receiving TAVR had superior rates to SAVR in the CoreValve US Pivotal High Risk Study CoreValve Extreme Risk Study CoreValve High Risk Study

Major Procedural Complications are Rare CoreValve ADVANCE | Procedural Results

TAVI – 2015 Access Alternatives carotid subclavian/ axillary direct aortic transapical Iliac-aortic conduits transfemoral This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) 11 11

TAVI in Failed Surgical Bioprosthetic Valve

Remaining TAVI Challenges Procedure/Technique Technology Balloon strategies Anti-coagulation mgmt Embolic Protection Stroke Sizing Post-implant intervention (dilation, snare) Depth of Implant Frame design Advanced Sealing Positioning, Recapture AR and PVL Alternative Access Lower profile Access specific delivery Coatings Vascular Complications Depth of Implant Balloon strategies Frame design Stable deployment with recapture Conduction Disturbances

Competitive Landscape CoreValve Sapien XT Direct Flow Lotus Portico Symetis Sapien 3 Centera Study, Sample Size US Pivotal Extreme Risk N=489 PARTNER IIB N=284 DISCOVER CE N=100 (evaluable cohort N=75) Reprise II N=120 Portico CE N=103 Acurate CE N=89 TF CE Pivotal N=150 FIM N=19 30 Day Survival 91.6% 96.5% 98.7% 95.8% 96.4% 96.6% 94.7% Maj. Vasc Comp 8.2% 9.6% 2.7% 2.5% 5.8% 3.4% 6% 0% PPM Rate 21.6% 6.4% 16% 28.6% 9.7% 9% 13.3% 15.8% PVL 41.5% mild, 11.4% mod/severe 75.9% trace/mild, 24.2% mod/severe 28.4% mild, 1.4% mod 20.7% trace/mild, 1.0% moderate 69.3% mild, 4% mod. 4.9% mod 24.1% mild, 3.4% mod 31.6% mild Stroke 2.3% major 3.2% disabling 2.7% major 1.7% disab. 2.9% major 2.2% major 5.3% stroke/TIA Coronary Occlusions NR 0.8% Annulus Rupture 0.1% MI 1.2% 1.8% 1.3% 3.3% 1.9% Performance acceptable but not optimal yet Performance acceptable but not optimal, competitive disadvantage

What devices are here today and what devices are coming?

Clinical Evidence Comparison Reported Implants of CE-Mark Approved Valves (Mainly in Europe) Medtronic CoreValve Edwards Sapien / XT Symetis ACURATE TA JenaValve Portico Engager Direct Flow Lotus Edwards Sapien 3 FIM 17 50 12 21 10 31 11 15 CE Pivotal 126 353 40 73 103 125 100 250 150 Medtronic ADVANCE 1,015 NA FRANCE 2 Registry 1,298 2,635 GARY 3,622 4,758 237 161 92 UK Registry 1,932 2,051 3 35 1 Italian Registry 1,334 Belgian Registry 408 473 Spanish Registry 108 Milan Registry 89 132 Ibero-American 1,220 Swiss Registry 336 317 23 Swedish Registry 311 255 SOURCE Registry 2,307 SOURCE XT Registry 2,706 Other Post-Market Registries 300 180 153 Total Patients 12,116 15,987 594 452 160 227 285 266 165 TOTAL: 30,252 IMPLANTS

CoreValve and EDW continue as the TAVR Workhorses … and both have released their Next Generation Devices Edwards Lifesciences Sapien 3 Medtronic CoreValve Evolut R

Several new TF and TA valves received CE Mark in 12-18 months

Edwards CENTERA Transcatheter Heart Valve Self-expanding Nitinol frame Treated bovine pericardium Contoured frame designed for optimal seating and sealing in the annulus Low frame height designed to minimize conduction disturbances Repositionable 23 mm, 26 mm, 29 mm sizes

Valve Medical TAVI An Ultra-low Profile System True 12Fr (catheter O.D.) profile (3.8 mm diameter) for all valve sizes (1st generation)

Device Components Assembled Device Frame Module Valve Module Nitinol self-expanding frame module inserted in optimal annular location Valve module is reconstituted in ascending Ao Valve module is docked to frame

What technology then is still needed?

Vascular Complications Reduce Complications PVL Pacemaker Rates Stroke Embolic Protection Frame advancements Advanced sealing Vascular Complications Optimal Positioning through Repositionability Adaptive sizing Frame advancements Reduce Profile

Improve Deployment Accuracy, Ease of Use New Repositionable Systems Continued Advancements Depth control Torqueability Advanced steering Low Profile Materials

Continued Trial Follow-up Engineering and Bench Testing Ensure Durability Continued Trial Follow-up Engineering and Bench Testing FEA Modeling Tissue engineering Animal Testing

Imaging Innovation Still Needed Post-procedure Peri-procedure Pre-case Follow-up and complication prediction Case planning & patient selection Guidance and confirmation CT SIZING Support: Assist in valve size decision to minimize PVL potential FUSION of Echo & Fluoro: Provide more information to implanter during critical placements TEE Profile Reduction: Requiring less general anesthesia PVL Quantification: Repeatable PVL severity ranking using multiple imaging modalities

Final thoughts… TAVR in 2015 has been integrated as an important component of the optimal management of complex AS patients. Although clinical outcomes are favorable, there are still many areas to refine, including procedural complications (esp. strokes, vascular events, and PVL), durability and deployment accuracy Future device development and clinical research are still needed to resolve these issues 30

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