Bioresorbeerbare “stents” Dokter Luc Janssens Imeldaziekenhuis Bonheiden Elewijt, 21 september 2013

Bioresorbable Vascular Scaffolds: A New Paradigm in the Treatment of Coronary Artery Disease

PCI Historical Perspective 1977 Andreas Gruntzig performs the first PTCA in Zurich, Switzerland 1988 Julio Palmaz and Richard Schatz develop a stainless steel stent for coronary applications 2001 - 2003 Drug eluting stents are introduced to the European and U.S. markets 1977 Balloon Angioplasty (PTCA) 1 Bare Metal Stents (BMS) 2 Coronary Drug Eluting Stents (DES) 3 Researchers develop early concepts of bioresorbable devices aimed at functioning as a temporary scaffold in the coronary vessel 1983 1999 Japanese researchers implant bioresorbable PLLA scaffold in human coronary arteries (Igaki-Tamai device) 2003 Abbott Vascular establishes the BVS development team 2006 Abbott Vascular enrolls 30 patients in ABSORB, the first ever human clinical trial testing a fully bioresorbable drug eluting scaffold The idea for developing a temporary coronary scaffold began in the 1980s

ABSORB EXTEND Clinical Results – MACE at 12 Months ‘ 1977 2000 A.B. ,the 1st PTCA by Andreas Gruentzig on September 29, 1977, attended and spoke at the 30th Anniversary on September 30, 2007 in Zurich, an incredible tribute to the breakthrough made by Andreas 30 years ago1 In patients who did not suffer sub-acute closure due to dissections, or restenosis due to negative remodeling in the first few months, long term results following balloon angioplasty were very encouraging and durable, with loss in MLD not seen until 17 years post procedure2 1. Meier, B., N Engl J Med. 2001; 344: 144-145. 2. Hatrick, R., et al. EuroIntervention. 2009;5:121-126.

Interventional cardiology treatment: a historical unmet need ‘ Success of early PCI treatment (POBA) has been demonstrated for as long as 17 yearsx Long-term POBA Serial Angiography Studies 1977 * 0.5 1 1.5 2 2.5 3 Baseline Post 6-months 4.5 yrs 10 years 17 yrs MLD (mm) Guiteras Val Hatrick 2000 Meier, B., N Engl J Med. 2001; 344: 144-145 POBA is limited by acute recoil, sub-acute closure, and dissections Guiteras-Val, P., et al. Am J Cardiol. 1999;83:868-874. / Hatrick, R., et al. EuroIntervention. 2009;5:121-126.

The Clinical Need for a Bioresorbable Vascular Scaffold’ Rationale Vessel scaffolding is only needed transiently* Vision Improve Long Term Outcomes for Patients by Leaving No Scaffold Behind1 Potential Benefits Restore the vessel to a more natural state, capable of natural vascular function Eliminate chronic sources of vessel irritation and inflammation Vessels remain free for future treatment options Reduce the need for prolonged DAPT2 Allows for use of non-invasive imaging techniques (CCTA) Improve patient quality of life *Serruys PW, et al., Circulation 1988; 77: 361. Serial study suggesting vessels stabilize 3-4 months following PTCA. 1 – Small platinum markers at scaffold edges remain for fluoroscopic landmarking. 2. The Absorb IFU indicates DAPT for a minimum of 6 months.

‘Caged’ (Stented) Vessel’ Delayed Healing  Stent Thrombosis? * uncovered struts1 Benign NIH Neo-Atheroma  Stent Thrombosis? In-Stent Restenosis Late Acquired Malapposition  Stent Thrombosis? 1. Virmani, R. Tissue responses in pre-clinical models; CIT 2010 NIH: NeoIntimal Hyperplasia

Potential of a Fully* Bioresorbable Vascular Scaffold’ Benign NIH Expansive Remodeling1 Late Lumen Gain In-Scaffold Restenosis Plaque Regression2 Since struts disappear, issues related to very late persistent strut malapposition and chronically uncovered struts become irrelevant 1Serruys, PW, ABSORB Cohort B 1-year results; ACC 2011 / 2Serruys, PW, et al. Lancet. 2009; 373: 897-910. *Small platinum markers at scaffold edges remain for fluoroscopic landmarking. NIH: NeoIntimal Hyperplasia

The Clinical Need for a Bioresorbable Vascular Scaffold’ Rationale Vessel scaffolding is only needed transiently* Vision Improve Long Term Outcomes for Patients by Leaving No Scaffold Behind1 Potential Benefits Restore the vessel to a more natural state, capable of natural vascular function Eliminate chronic sources of vessel irritation and inflammation Vessels remain free for future treatment options Reduce the need for prolonged DAPT2 Allows for use of non-invasive imaging techniques (CCTA) Improve patient quality of life *Serruys PW, et al., Circulation 1988; 77: 361. Serial study suggesting vessels stabilize 3-4 months following PTCA. 1 – Small platinum markers at scaffold edges remain for fluoroscopic landmarking. 2. The Absorb IFU indicates DAPT for a minimum of 6 months.

How Absorb Resorbs Water in surrounding vascular cells and blood penetrates polymer matrix Long polymer chains become shorter and shorter    Initially, hydrolysis preferentially cleaves amorphous tie chains, leading to a decrease in molecular weight without altering radial strength Tie chains When enough tie chains are broken, the device begins losing radial strength To understand how the device is able to maintain its strength for a period of several months, even while undergoing degradation, it is worth looking at how the degradation process works. Degradation occurs by hydrolysis. Water in the surrounding vascular cells and blood penetrates into the polymer matrix and starts to cleave ester bonds in the long polymer chains, creating shorter and shorter chains, until ultimately monomer units and small oligomers diffuse out of the polymer matrix and are subsequently metabolized. In the first few months, this degradation process causes a reduction in molecular weight, but the strength of the scaffold is not impacted. This is because water can only penetrate the amorphous phase of the polymer matrix, and the device gets its structural support and strength from the crystalline domains. It is only when enough of the amorphous tie chains that link the crystalline domains are hydrolyzed that the scaffold loses its strength. Analogies: bridge supports, brick wall  Support  Molecular Weight Mass Loss 1 3 6 12 18 24 Months

The Absorb BVS scaffold is replaced by functional cellular Matrix As the polymer matrix becomes more porous, extracellular matrix material in the form of proteoglycan is able to penetrate into the spaces between polymer crystalline structures; eventually, the area becomes filled by cells

Resorption: Vascular Response Absorb BVS Resorption Site Polymer is replaced by an increasingly cellular provisional matrix 1 month 6 months 12 months 24 months 30 months 36 months 42 months XIENCE V Representative photomicrographs of porcine coronary arteries, 2x, Movat’s pentachrome Images on file with Abbott Vascular

Resorption: Vascular Response Resorption Site Absorb BVS Polymer is replaced by an increasingly cellular provisional matrix 1 month 6 months 12 months 24 months 30 months 36 months 42 months XIENCE V Representative photomicrographs of porcine coronary arteries, 20x, Hematoxylin and Eosin Images on file with Abbott Vascular

Absorb Conformability Absorb provides better conformability compared to metallic platforms 88° 91° Absorb BVS Serruys, PW. , Seeing is believing: the clinical evidence so far; PCR 2010; J. Gomez-Lara, JACC Cardiovascular Interventions. 2010; 3: 1190-8.

Restore : Preliminary Evidence of Vasomotion Suggests Improved Long-term Outcomes 1 6 Months1 12 Months2 24 Months3 ABSORB Cohort B1 ABSORB Cohort B2 ABSORB Cohort A (N=15) (N=6) (N=19) (N=13) (N=9) (N=7) 0.5 Vasodilation (pre-drug infusion to post-drug infusion)  in Vessel Diameter (mm) Vasoconstriction -0.5 Acetylcholine Methergine -1 1. Adapted from Serruys, PW. ACC 2011 / 2. Adapted from Serruys, PW. ACC 2011 / 3. Adapted from Serruys, PW, et al. Lancet 2009; 373: 897-910. B

Restore: Late Lumen Gain Offers the Potential for Reduced TLR* Post-PCI 6 Months 2 Years n = 33 n = 33 n = 33 ABSORB Lumen Area  7.2% Scaffold Area Cohort B Lumen Area 6.53 mm2 6.36 mm2 6.85 mm2 Serial Analysis*  1.7% Late Loss = 0.19 mm *Serruys, PW., TCT 2011 B

Current PCI Options for Treating CAD There is still room for improvement Serruys, PW. PCR 2010 Serruys, PW. PCR 2010 B

ABSORB EXTEND Clinical Results MACE at 12 Months Intent to Treat (ITT) Analysis – Interim Snapshot The datasets are from different trials and displayed for descriptive purposed only. MACE: a composite of cardiac death, MI, and ischemia-driven TLR Chevalier, ABSORB EXTEND 12-month outcomes in the first 450 patient enrolled, Rotterdam EuroPCR Focus on BVS 2013

The Absorb BVS System Meeting an unmet clinical need? Rationale Vessel scaffolding is only needed transiently* Vision Improve Long Term Outcomes for Patients by Leaving No Scaffold Behind1 Potential Benefits Restore the vessel to a more natural state, capable of natural vascular function Eliminate chronic sources of vessel irritation and inflammation Vessels remain free for future treatment options Reduce the need for prolonged DAPT2 Allows for use of non-invasive imaging techniques (CCTA) Improve patient quality of life *Serruys PW, et al., Circulation 1988; 77: 361. Serial study suggesting vessels stabilize 3-4 months following PTCA. 1 – Small platinum markers at scaffold edges remain for fluoroscopic landmarking. 2. The Absorb IFU indicates DAPT for a minimum of 6 months.

Absorb May be Especially Beneficial for Certain Patient Types Young patients may need future interventions that can be complicated or compromised by a permanent implant First time, young patients* Patients at risk for future interventions Bioresorbable vascular scaffolds will preserve more treatment options for future interventions Non-invasive imaging for early and late follow- up is feasible with BVS Non-invasive assessment of patients by MSCT Population with nickel allergy is estimated to be 8.6% of the general population1 Allergic reactions to nickel and molybdenum released from stents may be one of the triggering mechanisms for in-stent restenosis2 Patients with metal allergy *Young patient defined as <65 years of age / 1. Thyssen et al. Contact Dermatitis 2007 / 2. Koster, Lancet, Vol 356, 12/2/00

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