The Endeavor Zotarolimus-Eluting Stent: Device Description and Comprehensive Update of the Clinical Trial Program

Endeavor DES Device Technology Overview Clinical Trial Perspectives

Endeavor DES Device Technology Overview

ENDEAVOR Safety Considerations Design Features Histopathology Rapid drug elution Stent design = reduced injury (rounded thin struts) % Drug Eluted Time (Days) PC Basecoat (≈ 1μm) Drug Layer 90% Zotarolimus 10% PC (≈ 2-4μm) Stent Strut Biocompatible PC Safeformulation

% Endotheliazation Endothelial Coverage Histopathology Porcine days Days Endeavor eNOS Staining BaselineAch (10 -5M ) mm 90days Vaso-reactivity ENDEAVOR Safety Considerations Animal Studies (rabbits and pigs)

OCT Angioscopy Endothelial Function Proximal Distal ENDEAVOR Safety Considerations Human Results IVUS ZES (n=14) vs. SES 8 mos FU ZES improved neointimal coverage (P=0.0004) and fewer thrombi Awata et al; J Am Coll Cardiol 2008;52; overlapped ZES in 17 6 mos FU (24,076 struts analyzed) ZES no malapposed or uncovered struts; no intraluminal thrombus Guagliumi et al; ESC ZES 8 mos FU 0.4% late incomplete apposition; no positive remodeling; homogeneous neointimal distribution Fitzgerald et al; Stanford IVUS core lab ZES (n=20) vs. SES (n=20) vs. BMS (n=10); Ach 6 mos; ZES improved endothelial function cw SES (P<0.001) and similar to BMS Kim et al; ACC 2008

Endeavor DES Clinical Trial Perspectives

Endeavor Clinical Program Overview 1yr 2yr 3yr 4yr 5yr Continued Access Single Arm (n = 296) 4yr ENDEAVOR II CA ENDEAVOR I Single Arm First-in-Man (n = 100) 5yr ENDEAVOR II 1:1 RCT vs. BMS (E = 598,D = 599) PK (n = 106) 4yr ENDEAVOR III 3:1 RCT vs. Cypher ® (E = 323,C = 113) 3yr ENDEAVOR IV 1:1 RCT vs.Taxus ® (E = 773,T = 775) 2yr ENDEAVOR PK Pharmacokinetic Study (n = 43) 2yr Single Arm (n = 99) 1yr ENDEAVOR Japan E-FIVE Open Label Single Arm (n = 8000) 1yr PROTECT 1:1 RCT vs. Cypher (E = 4400,C = 4400) Post Approval Premarket Safety and Efficacy Package

1yr 2yr 3yr 4yr 5yr Continued Access Single Arm (n = 296) 4yr ENDEAVOR II CA ENDEAVOR I Single Arm First-in-Man (n = 100) 5yr ENDEAVOR II 1:1 RCT vs. BMS (E = 598,D = 599) PK (n = 106) 4yr ENDEAVOR III 3:1 RCT vs. Cypher ® (E = 323,C = 113) 3yr ENDEAVOR IV 1:1 RCT vs.Taxus ® (E = 773,T = 775) 2yr ENDEAVOR PK Pharmacokinetic Study (n = 43) 2yr Single Arm (n = 99) 1yr ENDEAVOR Japan E-FIVE Open Label Single Arm (n = 8000) 1yr PROTECT 1:1 RCT vs. Cypher (E = 4400,C = 4400) Ongoing Premarket Safety and Efficacy Package 20,519 Patients Endeavor Clinical Program Overview

D eliverabilit y E fficacy S afety Endeavor DES

D eliverabilit y Endeavor DES

(%) (%) p = (%) (%) ENDEAVOR III 99.4% 95.6% Procedural Success Endeavor (n = 323) Cypher (n = 113) ENDEAVOR IV p = % 96.8% Procedural Success Endeavor (n = 774) Taxus (n = 775) ENDEAVOR Deliverability Procedural Success vs. Cypher and Taxus

TCTMD Physician Survey on DES Use Patterns % Physicians US (n=143) OUS (n=347) Deliverability EndeavorCypherXience/PromusTaxus TCTMD

D eliverabilit y more user-friendly (esp. Rx platform) very deliverable in complex lesions and challenging anatomy excellent sidebranch access Endeavor is… Endeavor DES

E fficacy Endeavor DES

SIRIUS (n=501/525) TAXUS IV (n=618/650) Pivotal Trials TLR - DES Arms ENDEAVOR II, SIRIUS, and TAXUS IV NA EII (n=581/598) Years of Follow-up TLR (%) Years of Follow-up TLR (%) Years of Follow-up TLR (%)

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 Endeavor IV Single Blind RCT vs. Taxus DES PI: Martin B. Leon Single De Novo Native Coronary Lesion Vessel Diameter: 2.5–3.5 mm Lesion Length: ≤ 27 mm Pre-dilatation required 1:1 randomization N = 1,548 patients 80 sites US Endeavor Stent n=774 Taxus Stent n=774 30d 6mo 4yr 3yr 2yr 9mo 12mo 8mo 5yr Clinical/MACE Angiography/IVUS QCA and IVUS Subset (328 total = 21.2%)

Endeavor IV TLR and TVR at 12 months Endeavor (34/749) Taxus (24/741) Endeavor (47/749) Taxus (50/741) P = TLRTVR Rate P = % 3.2% 6.3% 6.7%

Endeavor IV TLR by Angio FU at 12 mos TLR Rate 12/141 4/133 22/60820/608 EndeavorTaxusEndeavorTaxus Angiographic Follow-up Clinical Follow-up P =0.070 P = % of pts 82% of pts

Endeavor In-Stent Late Loss Endeavor II, II CA, III and IV % of Patients TLR Probability In-Stent LL (mm) 800 pts with angio FU at 8 mos

Primary Endpoint: MACE at 12 months Secondary Endpoints: MACE at 30 days and 6 mo, Stent thrombosis, procedure success rate; device success rate; lesion success rate Drug Therapy: ASA and Clopidogrel ≥ 3 months Zotarolimus Dose: 10  g per mm stent length Primary Endpoint: MACE at 12 months Secondary Endpoints: MACE at 30 days and 6 mo, Stent thrombosis, procedure success rate; device success rate; lesion success rate Drug Therapy: ASA and Clopidogrel ≥ 3 months Zotarolimus Dose: 10  g per mm stent length Single and Multiple Coronary Artery Lesions Stent Diameters: mm Stent Length: 8/9-30 mm Single and Multiple Coronary Artery Lesions Stent Diameters: mm Stent Length: 8/9-30 mm N = 8,000 patients followed for 1 yr N = 2,000 patients followed for 2 yrs N = 2,000 patients followed for 2 yrs 200 sites Europe, Asia Pacific, Israel, New Zealand, South America Clinical/MACE 30d 6mo 2yr 12mo E-Five Registry Prospective Multicenter Registry PIs: Chaim Lotan, Ian Meredith, and Martin Rothman

Cardiac Death MI e-Five (n = 7832) TVRMACETLRTVFDeathARC ST Def ARC ST Def/Prob E-Five Registry Clinical Events to 12 mos

E-Five Registry High Risk Patients and Lesions High Risk included patients with: AMI (<72 hrs) 13.9% AMI (<72 hrs) 13.9% Multivessel stenting 10.9% Multivessel stenting 10.9% Long lesion (>27 mm) 16.6% Long lesion (>27 mm) 16.6% Ostial lesion 5.8% Ostial lesion 5.8% Bifurcated lesion 18.9% Bifurcated lesion 18.9% In-stent restenosis 4.8% In-stent restenosis 4.8% Graft stenting 1.8% Graft stenting 1.8% Severe tortuosity 3.3% Severe tortuosity 3.3% Small vessel (RVD<2.5 mm)OR Small vessel (RVD<2.5 mm)OR Large vessel (RVD>3.5 mm) 18.3% Large vessel (RVD>3.5 mm) 18.3% Left main stenting 2.4% Left main stenting 2.4% Moderate/severe Calcification 31.6% Moderate/severe Calcification 31.6% Moderate/severe renal impairment 5.3% Moderate/severe renal impairment 5.3%8314Patients6189 High Risk 2125SimpleSimple

0% 3% 6% 9% 12% 15% Time after Initial Procedure (days) Cumulative Incidence of TLR 2.8% 5.0% 4.5% Simple (n = 2,125 pts) High Risk (n = 6,189 pts) Overall (n = 8,314 pts) TLR Standard Overall High Risk E-Five Registry – “High Risk” Cumulative TLR to 12 mos

Endeavor 在 “ 真实世界 ” 研究中一致的 TLR ESTROFA-2 TLR rates not available. 1 E-Five 12-month data: Rothman et al., EuroPCR Lassen F et al., TCT months 12 months E-Five 1 n = 7832 SORT-OUT III 2 n = 1162

E fficacy Endeavor DES associated with higher angio late loss but, similar TLR/TVR, even in some high restenosis subgroups angio FU magnifies the visual “oculostenotic reflex” when late loss is relatively higher Endeavor is…

S afety Endeavor DES

Time after Initial Procedure (days) Cumulative Incidence of Def/Prob ST (ARC) % 0.5% 1.0% 1.5% 2.0% 2.5% 0.9% 0.1% Endeavor Taxus 1-2year HR 0.17 [0.20, 1.39]P=0.059 Endeavor Taxus ENDEAVOR IV – 2yr FU ARC Def/Prob ST mos (VLST)

0.0% 0.5% 1.0% 1.5% 2.0% 2.5% 3.0% ARC (Def/Prob) Endeavor No. at Risk Cypher Taxus Year2 Years3 Years Pooled Data Xience V /Promus NA NA 4 Years Days Endeavor Stent: 确保长期安全性 ARC 定义 ( 肯定 / 可能 ) 累积 4 年支架血栓 Results come from separate clinical trials. Data may differ in a head-to-head comparison. 1. Leon et al. TCT Mauri L et al. N Engl J Med. 2007;356: Serruys PW et al. ACC Stone GW et al. PCR 2008.

Endeavor 在 “ 真实世界 ” 的 研究一致的血栓发生率 n=1162 ARC 定义 1 E-Five 12-month data: Rothman et al., EuroPCR Hernandez et al., TCT Lassen F et al., TCT months 12 months E-Five 1 n = 7832 ESTROFA-2 2 n = 967 SORT-OUT III 3 n = 1162

% Physicians US (n=143) OUS (n=347) EndeavorCypherXience/PromusTaxus TCTMD Physician Survey on DES Use Patterns Safety (esp. stent thrombosis)

S afety Endeavor DES associated with improved pre-clinical safety evaluations AND very low clinical safety endpoints (death and MI) AND very low stent thrombosis (esp. very late) – “BMS-like” IVUS without late incomplete apposition or aneurysms Endeavor is…

All Comers Dual APT >3 to <12 months N = 8800 >200 International Sites Randomization 1:1 Endeavor N=4400 Clinical Follow-up 30d6mo 4 yr 3yr 30mo24mo5 yr Primary Endpoint: ARC Definite or Probable Stent Thrombosis at 3 years Principle Secondary Endpoints: Death/Non-Fatal MI, Cardiac death/Non-Fatal MI Additional Endpoints: MACCE, TLR, TVR, Procedural Success Clinical Follow up and Dual Antiplatelet Monitoring: At 30 days, and every 6 months until 3 years, than each year until 5 years Cypher N= mo18mo PROTECT Worldwide RCT (Endeavor vs. Cypher) >8500 pts enrolled

Endeavor Experience 1 case from Fu Wai 1 case from Fu Wai