The document discusses newer trends in interventional cardiology, focusing on developments in stent technology, including bare metal stents, drug-eluting stents, and bioabsorbable stents. It describes how stents have evolved from balloon angioplasty to using drugs and biodegradable materials to prevent restenosis. Bioabsorbable stents potentially offer reduced need for long-term blood thinners and restoration of normal vascular function once absorbed. Clinical trials so far show bioabsorbable stents perform similarly to drug-eluting stents with no reported stent thromboses.

1. Dr. Prashant Jagtap Sr. Interventional Cardiologist Wockhardt Hospitals , NAGPUR Newer Trends in Interventional Cardiology

2. Cardiovascular Disease 1.2 Million Heart Attacks

3. Outline

4. Outline

5. Coronary Artery Disease Result of accumulation of atherosclerotic plaque Arteries supplying the heart muscle are occluded Oxygen-rich blood does not reach the heart Symptoms are angina and myocardial infarction http://www.nhlbi.nih.gov/health/dci/Diseases/Cad/CAD_WhatIs.html

6. Coronary Atherosclerosis

7. Angiogram Visualize blockages Catheter is inserted into the leg or arm Contrast dye for visualization X-ray is taken of the arteries Health Care Guideline: Stable Coronary Artery Disease. Institute for Clinical Systems Improvement . !3th ed., 2009 Other Tests EKG Stress test Echocardiograph Blood work

8. Treatment Algorithm

9. Treatments for CAD Health Care Guideline: Stable Coronary Artery Disease. Institute for Clinical Systems Improvement . !3th ed., 2009

10. History of Angioplasty First stainless steel Stent inserted in human artery 1986 2006 30 patients enrolled in the first ever human clinical trial testing a fully Bioabsorbable Drug-eluting Stent (ABSORB trial, Abbott) Drug eluting stents introduced to EU and USA markets 2001-2003 1999 First bioabsorbable PLLA stent in human coronary arteries (Igaki-Tamai) 1977 First Coronary Angioplasty Dr. Andreas Gruentzig

11. Evolution of Angioplasty Lobodzinski, S. S. (2008). Bioabsorbable Coronary Stents. Cardiology Journal , 15(6), 569-571. Pros Cons Balloon Angioplasty Enlarges narrow artery Relieves chest pain Elastic recoil of artery High early restenosis Bare Metal Stents Permanently prop open vessel  less elastic recoil Lower early restenosis Metal scars endothelial tissue Leads to neointimal growth response Contributes to late restenosis Drug Eluting Stent Antiproliferative drug mitigates adverse response to metal  reduce restenosis Incomplete healing  induce chronic inflammatory response Increased risk of thrombosis

13. Video: Stenting Procedure http://www.youtube.com/watch?v=gvRtP3wl_AY

14. Outline

15. Three Generations of Stents Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

16. Restenosis http://www.evgn.org/home/imagesnew/stentv2web.jpg Restenosis and Neo-Intimal Hyperplasia Tissue re-growth into the stent area

17. Drug Eluting Stents: The Problem Curfman GD, Morrissey S, Jarcho JA, Drazen JM. Drug-eluting coronary stents—promise and uncertainty. NEJM . 2007;256:1059-1060

18. Stent Thrombosis Cola, C. Brugaletta, S., Yuste, V. M., Campos, B., Angiolillo, D. J. & Sabete, M. (2009). Diabetes mellitus: a prothrombotic state implications for outcomes after coronary revascularization. Vascular Health and Risk Management , 5, 101-119.

19. Thrombosis: Early vs. Late Events Cola, C. Brugaletta, S., Yuste, V. M., Campos, B., Angiolillo, D. J. & Sabete, M. (2009). Diabetes mellitus: a prothrombotic state implications for outcomes after coronary revascularization. Vascular Health and Risk Management , 5, 101-119.

20. DES: The Market Leader Xience outperforms Taxus Express in SPIRIT IV, Dave Fornell, Diagnostic and Invasive Cardiology. Retrieved on Nov 26th, 2009 from http://www.dicardiology.net/node/34463/3 Sipkoff, M. (2009, Jul 1). Drug-eluting stents make a comeback. ModernMedicine. Retrieved online http://www.modernmedicine.com/modernmedicine/Modern+Medicine+Feature+Articles/Drug-eluting-stents-make-a-comeback/ArticleStandard/Article/detail/607928

21. Stents: Product Label – On or Off? FDA approved lesion parameters Lesion length < 30 mm Vessel diameter: 2.5 mm to 3.75mm Off label examples Lesion in by pass graft Bifurcation lesion Source: FDA Guidance Document on Drug Eluting Stents

22. Outline

23. Kirk. N. Garratt. (2009). Update on DES and Biodegradable Stents 2009

24. BVS Functionality Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

25. The BVS Stent: Polymers PLLA (Poly-L-Lactic Acid) backbone PDLLA (Poly-D,L-lactic acid) coating Both degrade to lactic acid Entire stent absorbs in 2 years Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

26. BVS vs. DES: The Thrombosis Issue Curfman GD, Morrissey S, Jarcho JA, Drazen JM. Drug-eluting coronary stents—promise and uncertainty. NEJM . 2007;256:1059-1060 Drug – Eluting Stent Bioabsorbable stent Polymer not biocompatible Polymers are biocompatible All the drug is not eluted 100% drug is eluted in 4 months Incomplete healing of endothelium Complete healing of endothelium Problems with late and very late ST No reports of ST from phase I study

27. Advantages of the BVS Stent

28. ABSORB: First In-man Study 30 patients, single de novo lesions Composite endpoint: Cardiac death, Myocardial Infarction, Target lesion revascularization (TLR) Secondary end points: In-stent late loss, late ST Results: 0% thrombosis, 0% TLR, MACE (3.3%) Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

29. Bare-Metal vs. Drug-Eluting vs. Bioabsorbable Stents Results taken from the 2006 Spirit IV trial (3, 690 patients), 2002 Sirius trial (1,058 patients) and the Absorb trial (30 patients). All trials were done in patients with similar lesions. The results reported are after 1-year follow-up.

30. Second Generation BVS Stent More even support of arterial wall Lower late stent area loss Higher radial strength Ormiston et al. (2007). Catheterization and Cardiovascular Intervention, 69: 129-131

31. Regulatory Pathway for BVS Based on Drug-Eluting Stents Drug Eluting Stent Stent Platform and Delivery System Drug Carrier “Polymer” PMA – Class III Device Source: Food and Drug Administration, U.S.A Center for Devices and Regulatory Health Center for Drug Evaluation and Research

32. Bioabsorable Vascular Solution

33. Bioresorbable Device Components Bioresorbable Coating PDLLA coating Fully biodegradable Similar dose and release rate to XIENCE V Everolimus Poly (Lactic Acid) (PLLA) Naturally absorbed, fully metabolized Bioresorbable Device Platform MULTI-LINK VISION Stent Delivery System Seven generations of MULTI-LINK success World-class deliverability All illustrations are artists’ renditions

34. Bioabsorbable Vascular Solutions Program Goals Naturally absorbed, fully metabolized Acutely perform like a metallic DES: deliverability, conformability, radial strength Long-term: restore vasomotion, improved clinical outcomes, lower restenosis Compatible with CT imaging

35. Bioresorbable Polymer Everolimus/PDLLA Matrix Coating Thin coating layer Amorphous (non-crystalline) 1:1 ratio of Everolimus/PLA matrix Conformal Coating, 2-4  m thick Controlled drug release PLLA Backbone Highly crystalline Provides device integrity Processed for increased radial strength Polymer backbone Drug/polymer matrix

36. Performance Criteria for a Fully Bioresorbable Device 1 3 6 2 Yrs Mos Forrester JS, et al., J. Am. Coll. Cardiol. 1991; 17: 758. Full Mass Loss & Bioresorption Platelet Deposition Leukocyte Recruitment SMC Proliferation and Migration Matrix Deposition Re-endothelialization Vascular Function Everolimus Elution Support Mass Loss

37. ABSORB Cohort A Excellent 3-Year Clinical Data ABSORB Cohort A 3-Year Data: One MACE* (NQMI); No additional MACE between 6 months and 3 years No stent thrombosis through 3 years Lumen enlargement from 6 months to 2 years by IVUS and OCT Restoration of vasomotion – including the treated segment Bioabsorption of device

38. Key Players in the Bioabsorbable Stent Market

39. Outline

40. Quantitative Analysis Assumptions Costs remain the same in: Cost differential occurs in: Procedure Initial hospitalization Routine follow-ups Acquisition of stent Serious adverse events Anti-platelet therapy (DAT) Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514. Cost Total = Cost Stent + Cost Serious Adverse Events + Cost DAT

41. Cost-Benefit Analysis of BVS on Thrombosis and TLR Rates Filion, K. B., Roy, A. M., Baboushkin, T., Rinfret, S. & Eisenberg, M. J. (2009). Cost-Effectiveness of Drug-Eluting Stents Including the Economic Impact of Late Stent Thrombosis. The American Journal of Cardiology, 103(3): 338-44. Price of stents : $2200 DES (Cypher) $3000 BVS (Abbott)

42. Cost Effectiveness(CE) Analysis Incremental Cost Effectiveness Ratio (ICER) The lower the ICER, the better Compare CE of BVS to DES Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514.

43. Equations for ICER Calculation Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514. ICER – Incremental Cost Effectiveness Ratio BVS – Bioabsorbable Stents SAE – Serious Adverse Events BMS – Bare Metal Stents DAT – Dual Anti-platelet Therapy Freq - Frequency

44. Historical Precedence ICER (BMS vs Balloon) $5000/SAD Avoided ICER (DES vs BMS) $5098/SAD Avoided Cohen, D.J. et al. Cost Effectiveness of Sirolimus-Eluting Stents for Treatment of Complex coronary Stenoses. Circulation 2004; 110: 508-514.

45. ICER of BVS with Three Estimates of Study Outcome

46. Stent Feature Matrix Bare-Metal Stents Drug-eluting Stent Bioabsorbable drug- eluting Stent Reduced Dual-Antiplatelet Therapy No neointimal hyperplasia Restoration of Vasomotion Material (Biocompatible) Lobodzinski, S. S. (2008). Bioabsorbable Coronary Stents. Cardiology Journal , 15(6), 569-571.

47. Conclusion Large coronary stent market BVS improves on thrombosis BVS has the potential to be economically feasible for device manufacturer and healthcare insurers

48. Acknowledgements Dr. Jayson Parker, M.Biotech Dr. Michael Kutryk, St. Michael’s Hospital Dr. Geoff Puley, Trillium Health Center Jennie Kim, Abbott Vascular, U.S.A Dr. Robert Cottone, Orbis Neich Dr. Janarthan Nikhil, Credit Valley Dr. Sidney Kremer, Credit Valley Dr. Kirandeep Nagi, Credit Valley Joanne Barrette, Abbott Vascular Margaret Chong, Abbott Vascular Dr. Jeffrey Pang, Sunnybrook Health Sciences Center Dr. Linda Mackeigan, Leslie Dan School of Pharmacy Dr. Peter Seidelin, Toronto General Hospital

49. Breakthrough Technology for Mitral Regurgitation MITRACLIP video

50. Thank you for listening. Questions?