The Promise of ABSORB Bioabsorbable Vascular Scaffolds Gregg W. Stone MD Columbia University Medical Center The Cardiovascular Research Foundation

Consulting: Boston Scientific, Reva Gregg W. Stone, MD Consulting: Boston Scientific, Reva

Stone GW et al. JACC 2011 (abstract) SPIRIT III: Target Lesion Failure @5 years TAXUS Express (n=332) XIENCE V (n=669) 30% 5-year HR 0.64 [0.46, 0.89] 25% p=0.008 1-year HR 20% 19.0% 0.56 [0.34, 0.90] p=0.01 TLF (%) Δ6.3% 15% 9.2% 12.7% 10% Δ3.8% ~1.8%/yr event rate after year 1 5% 5.4% 0% 6 12 18 24 30 36 42 48 54 60 Months Number at risk XIENCE V 669 646 616 601 582 571 565 548 537 529 521 TAXUS 332 310 288 274 269 262 255 248 243 231 223 TLF = cardiac death, target vessel MI, or ischemic-driven TLR Stone GW et al. JACC 2011 (abstract)

Target lesion failure (%) Stone GW et al. JACC 2011 (abstract) SPIRIT IV: Target Lesion Failure @3 years 25 XIENCE V (n=2458) TAXUS Express (n=1229) 20 HR [95%CI] = 0.78 [0.63, 0.97] p=0.004 HR [95%CI] = 0.71 [0.56, 0.90] p=0.001 HR [95%CI] = 0.61 [0.46, 0.81] p=0.02 15 11.7% Target lesion failure (%) Δ 2.5% 10 6.7% 9.2% Δ 2.7% 5 ~2.6%/yr event rate after year 1 4.0% 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk XIENCE V 2458 2390 2364 2323 2281 2238 2212 2187 2162 2132 2116 2095 2074 TAXUS 1229 1166 1138 1119 1095 1069 1060 1049 1029 1019 1008 994 979 TLF = cardiac death, target vessel MI, or ischemic-driven TLR Stone GW et al. JACC 2011 (abstract)

Etiology of DES events beyond 1 year Very late thrombosis and restenosis Possible causes Uncovered stent struts (thrombosis) Persistent stimulation of SMCs, from adherent fibrin and/or loss of normal vessel curvature Abnormal shear stress from protruding struts and/or loss of cyclic strain relief (compliance mismatch) Chronic inflammation due to late foreign body reactions and polymer hypersensitivity Positive remodeling with strut malapposition Strut fracture Neoatherosclerosis

Metallic Stent – A caged lumen doomed to get reduced, or a cage doomed to get malapposed Compensatory Expansive Remodeling of EEM BL 1Y PIT 5Y + IT FA Metallic stent is the cage Late acquired malapposition Struts Lumen Reduction - Lumen Reduction Metallic Struts Lumen Reduction by Intrastent Growth of tissue - c/o Patrick Serruys -

Possible Advantages of BVS Restoration of normal vasomotion, with NO production Restoration of normal shear stress and cyclic strain Restoration of normal vessel curvature Reduced risk of very late polymer reactions Avoidance/resolution of positive remodeling and stent malapposition Avoidance/resolution of late strut fractures Less neoatherosclerosis Un-jailing of side-branches Plaque regression MRI/CT imaging follow-up The emotional appeal of normal vessel architecture

Bioresorbable Scaffold – A new treatment Paradigm for Atherosclerotic Plaque Compensatory Expansive Remodeling of EEM 2Y 6M BL PIT + IT FA Lumen Enlargement by Plaque Regression Struts - Lumen Reduction Scaffolding Lumen Enlargement By Bioresorbable Scaffolding - c/o Patrick Serruys -

Late Loss with Xience V vs. Absorb BVS Cumulative frequency distribution (mm) 6 month (SPIRIT II): 0.17 ± 0.32 mm (N=97) 24 month (SPIRIT II): 0.33 ± 0.37 mm (N=97) Late loss (mm) Claessen BE et al. Circ CV Int. 2009;2:339-47

Late Loss with Xience V vs. Absorb BVS Cumulative frequency distribution (mm) 6 month (SPIRIT II): 0.17 ± 0.32 mm (N=97) 24 month (SPIRIT II): 0.33 ± 0.37 mm (N=97) 6 month (Cohort B): 0.19 ± 0.18 mm (N=42) 24 month (Cohort B): 0.27 ± 0.20 mm (N=38) Late loss (mm) Claessen BE et al. Circ CV Int. 2009;2:339-47 Serruys PW. ESC 2012

BVS: Evidence of substantial lumen enlargement due to plaque regression (cohort A pt) Pre-PCI Post-PCI 6 months 2 years 5 years deze biodegradeerbare stent kan stabiliseren een inflammatoire plaque. Op de animatie zien we een plaque groeien met het optreden van een dunne cap – met tenslotte het scheuren van de cap met een stolsel. Een biodegredeerbare stent zou dit kunnen voorkomen. Op de Virtuele histologie van de plaque, zien we de necrotic core, de kern van het vernietigd weefsel van de plaque in contact iis met het lumen van het bloedvat. Post-stenting zien we de appositie van de stent. Na zes maanden zijn de stent struts nog zichtbaar. Na 2 jaar is er een laag van fibrotisch weefsel dat de nectrotic core afdekt. Vessel area (mm2) 15.72 15.34 14.09 13.76 Mean lumen area (mm2) 6.95 6.17 6.56 8.09 Plaque area (mm2) 8.78 9.17 7.54 7.07 11

Long term anatomical and functional assessment of the scaffold by MSCT 116891-002 c/o Patrick Serruys

CFD curves of vessel area, plaque area and lumen area on MSCT at 18 and 60 months % Mean Vessel area at 18 months Mean Vessel area at 60 months Mean Plaque area at 18 months Mean Plaque area at 60 months Mean Lumen area at 18 months Mean Lumen area at 60 months mm2 c/o Patrick Serruys

Sealing and shielding of plaques after scaffold implantation BL BL 6M 24M Example of capping a calcified plaque Brugaletta S et al. Atherosclerosis 2012

Igaki-Tamai Stent (2000) Hideo Tamai, MD Died 14 Feb, 2009

I-T stent @10 Years! C D E A B C E D B A Onuma Y et al. EuroInt 2009 16

ABSORB III + IV A clinical program consisting of 2 integrated randomized trials designed to: Achieve approval of ABSORB in the US and Demonstrate superiority of ABSORB compared to best in class DES

ABSORB III + IV Clinical Trial Program 2,250 pts with up to 2 de novo lesions in different epicardial vessels enrolled, with follow-up for at least 5 years, at up to 122 US and non-US sites 2,000 pts randomized 2:1 ABSORB v XIENCE (+50 lead-in pts and 200 pt non-randomized angio/IVUS/OCT/VM FU cohort) RVD: 2.50 - 3.75 mm; Lesion length: ≤24 mm Scaffold diameters: 2.5, 3.0 and 3.5 mm Scaffold lengths: 12, 18, and 28 mm Primary endpoint (n=2,000): TLF at 1 year (powered for noninferiority) – US approval Key question – will it support pricing and reimbursement in our markets of interest? PIs: SG Ellis, DJ Kereiakes Study chairman: GW Stone

ABSORB III + IV Clinical Trial Program Co-PIs: SG Ellis, DJ Kereiakes ABSORB IV 2,500 - 4,000 additional pts rand 1:1 ABSORB v XIENCE Up to 6,000 total pts with up to 2 de novo lesions in different epicardial vessels randomized, with follow-up for at least 5 years, at up to 160 US and non-US sites RVD: 2.50 - 3.75 mm; Lesion length: ≤24 mm Scaffold diameters: 2.5, 3.0 and 3.5 mm Scaffold lengths: 12, 18, and 28 mm Primary endpoint (n = 4,500 – 6,000): TLF between 1 and 5 years (landmark analysis, powered for superiority) Key question – will it support pricing and reimbursement in our markets of interest? PI: GW Stone Co-PIs: SG Ellis, DJ Kereiakes