1. October 14-16, 2010 Doral Golf Resort & Spa. Miami, FL October 14-16, 2010 Doral Golf Resort & Spa. Miami, FL Novel DES Designs : Lessons Learned from New Evidence Based Medicine Alfredo E. Rodriguez MD, PhD, FACC, FSCAI Alfredo E. Rodriguez MD, PhD, FACC, FSCAI Centro de Estudios en Cardiologia Intervencionista (CECI) Sanatorio Otamendi / Las Lomas/Clinica IMA Buenos Aires, ARG

2. Why Drug Eluting Stents ???????

3. A B Freedom From Death Freedom From Death,MI,Stroke Five Years Meta Analysis From ARTS,ERACI II,MASS-II and SoS Death, Myocardial Infarction,Stroke Serruys PW,Rodriguez AE,Sigwart U,Hueb W et al Circulation,2008

4. Bare Metal Stent BMS vs. DES Healing In-Stent Restenosis Sirolimus DES

5. # events prevented per Sirolimus Control P-value 1,000 patients Overall 8.9 36.3 0.0001 274 M M ale 9.1 34.3 0.0001 251 Female 8.1 42.9 0.0001 347 Diabetes 17.6 50.5 0.0001 328 No Diabetes 6.1 31.2 0.0001 251 LAD 10.1 41.6 0.0001 315 Non-LAD 8.0 32.7 0.0001 247 Small Vessel (<2.75) 14.9 39.9 0.0001 250 Large Vessel 2.9 33.2 0.0001 303 Short Lesion 8.0 36.1 0.0001 282 Long Lesion (>13.5) 9.9 36.8 0.0001 269 Overlap 8.8 43.5 0.0001 347 No Overlap 8.9 33.6 0.0001 247 Hazards Ratio 95% CI 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 0.7 0.8 0.9 SIRIUS - In-Segment Restenosis Sirolimus better

6. Why New Drug Eluting Stents Designs ???????

7. All Definitions of stent thrombosis was reached in 9%

8. Comparative Effectiveness at Five years of Drug-Eluting Stents, Bare Metal Stents, and Coronary Bypass Surgery: The ERACI III Study. A, Rodriguez, D Boothroyd, L, Grinfeld, J, Mieres, D, Berrocal, C, Fernandez-Pereira, A, O Maree, V, Curotto, M, Russo-Felssen, I F, Palacios, W, O’Neill, M A, Hlatky on behalf of the ERACI III investigators From Otamendi Hospital, Buenos Aires, Argentina; Stanford University School of Medicine, Stanford, CA; Hospital Italiano, Buenos Aires, Argentina; Harvard Medical School, Boston, MA; and University of Miami, Miami, FL ESC Congress 2010 Stockholm, Sweden

9. Rodriguez A, Hlatky M; submitted All Definitions of stent thrombosis was reached in 6.2%

10. TAXUS n=903 PCI n=198 CABG n=1077 CABG n=897 no f/u n=428 5yr f/u n=649 PCI all captured w/ follow up CABG 2500 750 w/ f/u vs Total enrollment N=3075 Stratification: LM and Diabetes Two Registry Arms Randomized Arms n=1800 Two Registry Arms Randomized Arms n=1800 Heart Team (surgeon & interventionalist) PCI N=198 CABG N=1077 Amenable for only one treatment approach TAXUS * N=903 CABG N=897 vs Amenable for both treatment options Stratification: LM and Diabetes LM 33.7% 3VD 66.3% LM 34.6% 3VD 65.4% 23 US Sites62 EU Sites + SYNTAX Trial Design * TAXUS ® Express ® Stent

12. Cumulative Event Rate Three Vessels CAD(%) CABG (502) Taxus (536) p All-cause death5.7%9.5 %0.02 Cardiac death2.9%6.2%0.01 MI3.3%7.1%0.005 Death, stroke, MI10.6%14.8%0.04 Stroke2.9%2.6%Ns Repeat revascularization10.0%19.4%<.001 MACCE18.8%28.8<.001

13. In-Stent Restenosis vs. Stent Thrombosis Acute, Late or Very Late After DES Implantation: Safety/Efficay Ratio Rodriguez AE Expert Opin Emerging Drugs;2009

14. 1.Inflammation ( Drug, Durable Polymer) 2.Delayed Healing (Drug, Durable Polymer) 3.Late Adquired Stent Mal apposition (Drug). 4.Activated Tissue Factor (Drug). 5.Impaired Collateral Circulation (Drug). 6.Endothelial Dysfunction ( Durable Polymer, Drug) etc Potential Adverse Side Effects with First DES Designs

15.  DES with Durable Bio-Compatible Polymers  DES with Bio-Degradable Polymers  Complete Absorbable DES Goals For Next Generation of DES: Combining Safety/ Efficacy

16.  XIENCE V Program  ENDEAVOR Program  ENDEAVOR/ Resolute Program Goals For Next Generation of DES: DES with Bio-Compatible Polymers

17. 6 Months (6M) and 2 Year (2Y) Clinical Results 1 SPIRIT II: Serruys PW, ACCC LBCT Session 2008

18. SPIRIT III, Stone G et al Circulation;2009

19. SPIRIT III: Stone G et al Circulation;2009

29. 29 Endeavor Program Overview 9m 2yr 3yr 4yr 9m 2yr 3yr 4yr ENDEAVOR I ENDEAVOR II ENDEAVOR II CA ENDEAVOR III ENDEAVOR IV ENDEAVOR PK Registry First-in-Man (n=100) 4yr 1:1 RCT vs. BMS (E=598,D=599) PK (n=106) 3yr Continued Access Registry (n=296) 2yr 3:1 RCT vs. Cypher® (E=323,C=113) 2yr 1:1 RCT vs.Taxus® (E=773,T=775) 9mo Pharmacokinetic Study (n=43) 9mo Registry (n=99) 9mo ENDEAVOR Japan E-FIVE Open Label Single Arm (n=8000) US Post Approval PROTECT 1:1 RCT vs. Cypher (E=4400,C=4400) Open Label Single Arm Study Comparing to Pre-Market Data Proposed Ongoing Premarket Safety and Efficacy Package

30. 30 ENDEAVOR III Patient Flowchart Angio F/U (8 mo) 94/11383.2% (12 mo) 112/11399.1% (9 mo) 113/113100% Patients Enrolled N = 436 Randomized3:1 Endeavor n = 323 Cypher n = 113 Angio F/U (8 mo) 277/32385.8% Clinical F/U (12 mo) 320/32399.1% (9 mo) 321/32399.4% Clinical F/U (24 mo) 112/11399.1% 313/32396.9%

31. 31 Endeavor n = 277 Cypher n = 94 Difference [95% CI] QCA In-stent DS - % DS - %24.911.0 13.89 [9.88,17.90] LL - mm LL - mm0.620.15 0.47 [0.36,0.58] ABR - % ABR - %9.72.1 7.6% [3.1%,12.2%] In-segment DS - % DS - %30.423.9 6.56 [3.01,10.12] LL - mm LL - mm0.360.13 0.24 [0.13,0.34] ABR - % ABR - %12.34.3 8.0% [2.4%,13.6%] IVUS Neointimal Volume -mm 3 (n) 24.09 (209) 3.74 (67) 20.36 [15.21,25.50] Vol Obstruction - % (n) 15.9 (187) 2.7 (61) 13.27 [10.48,16.07] Late Incomplete Apposition - % (#/n) 0.5 (1/189) 5.9 (4/68) -5.4% [-11.0%,0.3%] Angiographic and IVUS Results at 8 Months ENDEAVOR III

32. 32 Clinical Events to 24 months ENDEAVOR III Endeavorn=313Cyphern=112Difference [95% CI] Death (all) - % (#) 1.6 (5) 4.5 (5) -2.9%[-6.9%,1.2%] Cardiac Cardiac0 0.9 (1) -0.9%[-2.6%,0.8%] MI (all) - % (#) 0.6 (2) 3.6 (4) -2.9%[-6.5%,0.6%] Q Wave Q Wave00-- Non Q wave Non Q wave 0.6 (2) 3.6 (4) -2.9%[-6.5%,0.6%] Death (cardiac) + MI (all) - % (#) 0.6 (2) 3.6 (4) -2.9%[-6.5%,0.6%] Stent Thrombosis (all) - % (#) 00-- 0-30 days 0-30 days00-- 31-720 days 31-720 days00-- TLR - % (#) 7.0 (22) 4.5 (5) 2.6%[-2.2%,7.3%] TVR (non-TL) - % (#) 8.3 (26) 6.3 (7) 2.1%[-3.4%,7.5%] TVR - % (#) 13.7 (43) 9.8 (11) 3.9%[-2.8%,10.6%] MACE - % (#) 9.3 (29) 11.6 (13) -2.3%[-9.1%,4.4%] TVF - % (#) 14.4 (45) 13.4 (15) 1.0%[-6.4%,8.4%]

33. 33 ENDEAVOR IV 1:1 randomization N = 1,548 patients 80 sites US Primary Endpoint: TVF at 9 months Secondary Endpoints: In-segment % DS at 8 months; TLR and TVR at 9 months Drug Therapy: ASA and Clopidogrel/Ticlid  6 months Zotarolimus Dose: 10  g per mm stent length QCA & IVUS Subset (328 total=21.2%) 30d 6mo 4yr 3yr 2yr 9mo 12mo 8mo 5yr Clinical/MACE Angio/IVUS Single De Novo Native Coronary Lesion Vessel Diameter: 2.5-3.5 mm Lesion Length:  27 mm Pre-dilatation required Taxus Stent n = 774 Endeavor Stent n = 774 1:1 RCT vs Taxus PI: Martin B. Leon

34. 34 ENDEAVOR IV Angiographic and IVUS Results at 8 months Endeavor n = 144 Taxus n = 135 Difference [95% CI] RVD – mm 2.652.68 -0.03 [-0.14, 0.08] In-stent DS - % DS - %26.4116.09 10.32 [5.85, 14.79] LL - mm LL - mm0.670.42 0.25 [0.13, 0.37] ABR - % ABR - %13.36.7 6.6% [-0.4%, 13.6%] In-segment DS - % DS - %32.2826.61 5.68 [1.83, 9.52] LL - mm LL - mm0.360.23 0.13 [0.02, 0.23] ABR - % ABR - %15.310.4 4.9% [-2.9%, 12.7%] IVUS Neointimal Volume - mm 3 (n) 24.14 (74) 14.88 (77) 9.26 [3.46, 15.06] Vol Obstruction - % (n) 15.72 (74) 9.88 (77) 5.84 [2.68, 9.00] Late Incomplete Apposition - % (#/n) 0.9 (1/106) 3.2 (3/95) -2.2% [-6.2%, 1.8%]

39. EuroIntervention. 2007 Feb;2(4):512-7. Late stent thrombosis: the Damocle's sword of drug eluting stents? Rodriguez AE, Rodriguez-Granillo GA, Palacios IF. Otamendi Hospital, Interventional Cardiology Department, Buenos Aires, Argentina. Rodriguez AERodriguez-Granillo GAPalacios IF Abstract As a result of the introduction of drug eluting stents (DES) to clinical practice, angiographic and clinical parameters of restenosis have been significantly improved. However, several recent publications have raised concerns about long-term safety of this technology. They include a potential risk of inducing chronic inflammation within the coronary artery, delayed healing and late stent thrombosis.Recently, late stent thrombosis, a rare but often life threatening event, has been reported to occur more frequently following DES placement. The mechanism of this phenomenon has not been fully elucidated.What is the true incidence of stent thrombosis after DES therapy? Is it similar or higher than with bare metal stents? Are randomised trials with DES therapy overestimating the benefits of this therapy? Which are the potential limitations of these studies? Are DES increasing rates of death and myocardial infarction from randomised trials and registries a true fact? In the following pages we review recently reported data about DES suggesting potential safety concerns associated with the current widespread use of DES. PMID: 19755294 [PubMed - in process]

40.  LEADERS Program  NOBORI Program  ISAR TEST Program  EUCATAX / Camouflage Program Goals For Next Generation of DES: DES with Bio-Degradable Polymers

41. PLA biodegradation and BA9™ elution Abluminal biodegradable coating absorbed after 6-9 months * * Data on file - molecular weight<10kDa Biolimus A9™ Eluting Stent − The abluminal biodegradable polymer DES The product is not available for sale in the USA

43. BESSES 857 Patients 850 Patients Age in years 65  11 65  11 Male gender 75%75% Arterial hypertension74%73% Diabetes mellitus 26%23% - insulin-dependent10%9% Hypercholesterolemia65%68% Family history40%44% Smoking24%25% Previous MI 32%33% Previous PCI 36%37% - with drug-eluting stent12%14% Previous CABG 11%13% Chronic stable angina45%44% Patient Demographics

44. BESSES 857 Patients 850 Patients Acute coronary syndrome 55%56% - Unstable angina22%21% - Non-ST-elevation MI 17%18% - ST-elevation MI 16%17% Left ventricular ejection fraction56  11%55  12% Number of lesions per patient1.5  0.7 1.4  0.7 Lesions per patient - 1 lesion63%69% - 2 lesions29%22% - 3 lesions7%8% - > 4 lesions1%2% De novo lesions92%91% Long lesions (>20 mm)31%27% Small vessels (RVD <2.75 mm)68%69% Off label use 81%78% Patient Characteristics

45. MACE 4 MACE = Cardiac Death, MI, or Clinically-Indicated TVR *P values for superiority 4 Klauss V., TCT 2009 Number at risk BES857804795777760742731725716 SES850791786771747727712707694 Months -12% -16%

46. P=0.58* % P=0.25* P=0.17* P=0.37*P=0.54* 2-Year Efficacy Endpoints 4 $ $ $ Clinically Indicated *P values for superiority 4 Klauss V., TCT 2009

47. P=0.71* % P=0.35*P=0.24*P=0.59*P=0.57*P=0.42* 2-Year Safety Endpoints 4 *P values for superiority 4 Klauss V., TCT 2009

48. Primary and Secondary Definite ST BES N=857 SES $ N=850 Definite Stent Thrombosis % According to ARC Definition $ Includes one secondary, definite ST occurring at 60 days in a patient who had early ST at 3 days *P values for superiority 4 Klauss V., TCT 2009

49.  LEADERS Program  NOBORI Program  ISAR TEST Program  EUCATAX / Camouflage Program Goals For Next Generation of DES: DES with Bio-Degradable Polymers

50. Byrne R and Kastrati A; Interv. Cardiol. (2010) 2(3)

52.  LEADERS Program  NOBORI Program  ISAR TEST Program  EUCATAX / Camouflage Program Goals For Next Generation of DES: DES with Bio-Degradable Polymers

53. Main Idea of the proactive coating: To copy the arterial glycocalyx Eucatech Dual coating technology Effective reduction of neointimal hyperplasia due to Paclitaxel anti-proliferative drug and an effective drug release within 8 to 10 weeks. The Paclitaxel is incorporated in a full short term degradable biological PLGA matrix with a low dose drug content and a no inflammatory reaction.PLGA (Poly lactide-co glycolide) decompensades to carbon dioxide and water. Base layer Camouflage® a full biological, athrombogenic coating provides long term protection and promotes re- endothelization of the stent. Camouflage® is a mimicry of the natural arterial glycocalix. This results in a short term antiplatelet treatment. Drug content 0,25µg/mm² Drug release: within 8-10 weeks 100% PLGA matrix degradiation: 100%

54. Steering and Executive Committee Alfredo Rodriguez, MD, PhD (Argentina) Igor F. Palacios, MD (U.S.A.) David Antoniucci, MD (Italy) Michael Giesse, PhD (Germany) Safery and Ethics Committee Jorge Trongé, MD (Argentina) Arnoldo Dubin, MD, PhD (Argentina) Cristina Sivori, PhD (Buenos Aires) Clinical Events Committee Pablo Boskis, MD, FACC (Argentina) Omar Santaera, MD (Argentina) Miguel Russo Felsen, MD (Argentina) Valeria Curotto, MD (Argentina) Coordinating Center Centro de Estudios en Cardiología Intervencionista Matías Rodríguez Granillo Agustina Rodriguez-Granillo, PhD Quantitative Coronary Analysis Lab and Intravascular Analysis Gastón Rodríguez Granillo, MD, PhD Claudio Llauradó, BS Alejandro Incarbone,,BS Miguel Rosales, MD Chair Alfredo Rodriguez, MD, PhD Participating Centers SANATORIO OTAMENDI y MIROLI (Buenos Aires, Argentina) A. Rodríguez, MD, PhD; J. Mieres, MD, G. Risau, MD; B. Rubilar, MD SANATORIO LAS LOMAS (San Isidro, Argentina) J. Mieres, MD ; G. Pérez, MD CLINCA IMA (Adrogué, Argentina) C. Fernández-Pereira, MD, C. Mauvecín, MD, G. Allende, MD. SANATORIO del SALVADOR (Córdoba, Argentina) CF. Vigo, MD; M. Fernández, MD SANATORIO BELGRANO (Mar del Plata, Argentina) A. Delacasa, MD CLINICA del SOL (Buenos Aires, Argentina) V. Bernardi, MD, M Rodríguez-Alemparte, MD. SANATORIO GUEMES (Buenos Aires, Argentina) M. Bettinotti, MD; A Goldsmit, MD.

55. 4624 Coronary angiographies 2386 PCI with stent deployment 211 pts PES group 211 pts PES group 422 patients enrolled and randomized in the Trial 422 patients enrolled and randomized in the Trial 211 pts BMS group 211 pts BMS group 7 Participating Centers 1158 with Exclusion Criteria Eucatax Trial 1228 pts suitable for EUCATAX trial Eucatax Registry 806 pts randomizable not randomized 150 pts scheduled for angiographic follow up STUDY DESIGN Rodriguez A,Antoniucci D et al Cath Cardiovasc Interv; (2010) 2(3)

56. Baseline Clinical and demographic characteristics Patient characteristics PES (n=211) BMS (n=211) P values Age, years 63.8 ±10.264.7 ± 12.2 0.50 Male, n (%)176 (83.4)167 (79.1)0.26 Hypertension135 (64.0)140 (66.4)0.60 Hypercholesterolemia120 (56.9)108 (51.2)0.24 Chronic renal failure11 (5.2)8 (3.8)0.48 Cardiac heart failure8 (3.8)7 (3.3)0.79 Body mass index>2733 (15.6) 1.00 Current smoking45 (21.3)50 (23.7)0.56 Diabetes Mellitus49 (23.2)34 (16.1)0.07 Family history16 (7.6)13 (6.2)0.56 Peripheral vascular disease14 (6.6)17 (8.1)0.57 Previous stroke7 (3.3)11 (5.2)0.33 Previous MI43 (20.4)36 (17.1)0.38 Previous revascularization75 (35.5)51 (24.2)0.11 Multiple Vessel Disease116 (55.0)127 (60.2)0.27

57. Clinical presentation PES (n=211) BMS (n=211) P values Silent ischemia, n (%)27 (12.8)22 (10.4)0.44 Stable angina (CCS)58 (27.5)48 (22.7)0.26 Unstable angina (BC)126 (59.7)141 (66.8)0.13 CLINICAL PRESENTATION AT CATH LAB

58. Procedural characteristics PES (n=211) BMS (n=211) P values Treated vessels RCA, n (%)43 (17.6)59 (25.1)0.11 LAD153 (62.7)114 (48.5)0.08 LCX45 (18.5)56 (23.8)0.23 LM3 (1.2)6 (2.5)0.30 N Vessels2442350.83 N Lesions2772640.71 Plaque Type B2/C*50.256.90.46 N implanted stents per pt 1.36 ± 0.551.29 ± 0.54 0.21 Stent length, mm 21.7±5.620.0±4.8 0.16 Stent size, mm 2.96±0.42.93±0.5 0.78 Small vessels (RVD <2.75 mm)60.346.40.22 Angiographic baseline characteristics

59. %PESBMSChi 2 MACCE23/21142/2110.01 Freedom from MACCE at 18 months of follow up PESBMS Freedom from TVF at 18 months of follow up %PESBMSChi 2 TVF22/21138/2110.02

60. %PESBMSChi 2 TLR19/27735/2620.012 Freedom from TLR at 18 months of follow up Freedom from TVR at 18 months of follow up PESBMS %PESBMSChi 2 TVR22/24437/2320.02

61. P=1.00 Incidence of Stent Thrombosis. Overall results Incidence of Stent Thrombosis. A.R.C. definition Cumulative results at 18 months of follow up. PESBMS

62. PES (n=98)BMS (n=88)P value Reference Diameter (mm)2.75 +/- 0.482.75+/- 0.360.99 Minimal Luminal Diameter (mm)2.16 +/- 0.911.81 +/-0.750.007 Stenosis Diameter (%)2.74 +/- 29.839.6+/- 23.90.005 Acute Gain1,82+/-0,471.87+/-0.620.45 Net Gain1.3 +/- 0.490.93 +/- 0.630.002 Late Loss (In-stent)0.52+/-0.590.94 +/- 0.700.002 Late Loss (In-segment)0.50 +/-0.560.91 +/-0.690.001 Angiographic Restenosis13.2%34%<0.001 Cumulative results at One year of follow up. Follow Up Q.C.A. analysis

63.  DES with Bio-Compatible Polymers  DES with Bio-Degradable Polymers  Complete Absorbable DES Goals For Next Generation of DES: Combining Safety/ Efficacy

67. All Lesions Meet the Criteria of BeneStent II Definition

68. DES designs with Durable and Bio-compatible Polymer eluted with EES (Xience V) demonstrated a significant improvement in terms of safety and efficacy outcome at 2 years of FU compared to PES with durable polymer. Clinically driven TVR, TLR, MI, cardiac death +MI and VLST were significantly reduced at 2 years of FU(SPIRIT III,IV and Compare) in all cormers excluding Diabetics patients. DES designs with durable and Bio-compatible polymer eluted with ZES (ENDEAVOR) demonstrated a significant reduction of MI compared to first DES designs (ENDEAVOR III and IV), however, long term efficacy of this stent in complex lesion subsets is difficult to determine by the higher amount of LL observed in the FU angiography. New DES Designs: New Technology and New Evidence for Old Problems.

69. DES designs with Bio-degradable polymers demonstrated similar safety and efficacy to first DES designs with durable polymers without any advantage in the safety profile at this time of FU (LEADERS and ISAR Test studies). Dual coating technology using antithrombotic layer behind the PLGA coating is promising in terms of safety, as suggested by the EUCATAX results, although its value in terms of long term efficacy is questionable (LL) and needs further assessment. Finally, complete absorbable stents is the most promising eluted stent technology, although their place in “real world”clinical practice is far to be determined. New DES Designs: New Technology and New Evidence for Old Problems.