A Unique Approach to Creating a Polymer Free Stent The Medtronic Drug Filled Stent Program Josiah N. Wilcox, Ph.D. Chief Scientific Officer Coronary and Renal Denervation Medtronic CardioVascular CRT 2013 February 25, 2013

Major Stock Shareholder/Equity Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Major Stock Shareholder/Equity Full Time Employee Medtronic, Inc. Medtronic CardioVascular

Integrity™ and Resolute Integrity™ A New Standard in Stent Design and Manufacturing Conventional Stent Design Medtronic Modular Design Vs. Slotted Tube Modular Design Medtronic’s Continuous Sinusoid Technology Sinusoidal Formed Wire Helical Wrap Laser Fused 3

Sinusoidal Formed Wire Integrity Platform Continuous Flexibility Due to Unique Sinusoidal Design Flex DES: Stiff Stiff “Box Car” or Coupler Promus Element Flex Stiff Stiff Xience Prime Continuous Sinusoid Flex Integrity 115° Bend Sinusoidal Formed Wire Helical Wrap Laser Fused 4

Resolute Integrity Improves Deliverability Average Push Force (gf) Promus Element DES 2.50 mm x 20 mm Xience Prime DES 2.50 mm x 18 mm Resolute Integrity DES DES 10 20 30 40 50 60 70 80 90 100 86 Superior Deliverability* 69 Lower is Better * Based on 3D tracking bench test data on file at Medtronic, Inc.

Continuous Sinusoid Technology The Next Revolution in Stent Technology Bare Metal Stents Integrity Drug-Filled Stent Enabling designs that could not be attempted in the past Drug-Eluting Stents Resolute Integrity S10 DES It would not be possible to create a thinner strut cobalt alloy stent (< 0.003”) without compromising radiopacity. That’s where Core Wire and New alloys allow stent designs that would not otherwise be possible without major compromise. S10/Core Wire New Alloys Platforms for next gen DES coatings BioLinx (Resolute) PC Technology (Endeavor) Bioabsorbable polymer Nanoporous CAUTION: Design concepts not approved for sale or clinical use

Core wire design featuring thinner struts than Resolute Integrity S10 DES Core wire stent with enhanced deliverability, radiopacity, and size matrix Attribute Description Deliverability Targeted 10-15% Improvement over Resolute Integrity Radiopacity Increased due to core wire technology Expanded Size Matrix New 2.0, 4.5-5.0mm diameters and long length (34 and 38 mm) sizes at 2.25-2.75 diameters Integrity S10 Omega (Element) ML-8 (Xience) Improved Deliverability and Radiopacity Is midpoint between Integrity radiopacity and element good enough? Core wire design featuring thinner struts than Resolute Integrity CAUTION: Design concepts not approved for sale or clinical use

Deliverability – Animal Model 3.0 x 18mm blinded, pairwise testing Bench testing also showed a 27% improvement in trackability

Drug Filled Stent (DFS) Technology Polymer Free Drug Delivery Innovative DES design Essentially a BMS surface Designed to address drug carrier issues such as: Polymer biocompatibility Inflammation upon polymer degradation Surface coating durability Enables use of new drugs without extensive development efforts With CST, Medtronic is working to bring a new concept in DES – a polymer-free Drug Filled Stent Drug is contained in a small diameter hollow core running the length of the stent and elutes in a controlled fashion via tiny holes This design is not possible with laser cut technology From the start, it has a bare metal surface with no durability, biocompatibility, or inflammation issues associated with durable or bioabsorble polymers Elution rates can be controlled by mechanical means – the size (diameter) and number of the holes Elution Holes CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology Core Wire Construction is sacrificial Core Material Co Alloy Shell CAUTION: Design concepts not approved for sale or clinical use

Laser Hole Drilling Facilitate drug filling and elution 500 – 5000 holes per stent (18 mm) Variable hole diameter and shape Automation Throughput Reliability CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology Elution Hole Drilling – The Present and Future CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology De-Coring Process Etching Gas + Sacrificial Core Vapor Phase Etched Core (sublimates) CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology Radial Strength Structural Analysis CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology Radial Strength Structural Analysis CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology Stress Distribution Structural Analysis Driver Drug Filled Stent CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) CAUTION: Design concepts not approved for sale or clinical use

DFS Deliverability Performance Summary- 3.0x18mm Size Track gain over Resolute Integrity Push gain over Resolute Integrity Sub 1mm Crossing Profile CAUTION: Design concepts not approved for sale or clinical use

Radiopacity DFS, no drug BMS CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent (DFS) Technology Possible Elution Mechanism CAUTION: Design concepts not approved for sale or clinical use

DFS Prototype Elution Comparison Drug Filled Stent (DFS) Technology Controllable Elution – In Vitro Standard non-polymeric elution DFS Prototype Elution Comparison 70% 60% 50% 40% 30% 20% 10% 0% % Eluted Time Design 1 Design 2 Design 3 Design 4 Design 5 Design 6 Resolute In vitro testing suggests a variety of elution profiles possible CAUTION: Design concepts not approved for sale or clinical use

Multiple Elution Profiles Possible Pre-Clinical Elution % Drug Remaining In Stent Resolute Xience CAUTION: Design concepts not approved for sale or clinical use

Multiple Elution Profiles Possible Pre-Clinical Elution % Drug Remaining In Stent CAUTION: Design concepts not approved for sale or clinical use

Distribution of drug in the artery wall DFS vs Resolute in porcine coronary arteries CAUTION: Design concepts not approved for sale or clinical use

Drug Filled Stent 28 day histology porcine coronary arteries DFS (No Drug) DFS-1 CAUTION: Design concepts not approved for sale or clinical use

Drug-Filled Stent – Morphometric Data 28-Day Porcine Coronary Arteries 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) CAUTION: Design concepts not approved for sale or clinical use 26

Conclusions Extended drug elution can be achieved in a polymer free stent Variable elution kinetics possible in vivo Clinically relevant drug in tissue levels remain constant for 60 - 180 days after implantation depending on protypes chosen DFS implants result in a significant inhibition of neointimal development compared to BMS controls DFS show excellent healing by 28 days Low inflammation (equivalent to BMS) Residual fibrin was found associated with DFS with drug only (marker for drug action) 100% endothelialization Growth of SMC into the DFS drug lumen The lack of inflammation and complete healing suggests DFS may be appropriate for a wide variety of patients with potential for enhanced safety and outcomes CAUTION: Design concepts not approved for sale or clinical use