Endeavor IV A Randomized Comparison of a Zotarolimus Eluting Stent

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hgilli01, favourited this 4 Years ago.

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Slide 1 :

Endeavor IV: A Randomized Comparison of a Zotarolimus-Eluting Stent and a Paclitaxel-Eluting Stent in Patients with Coronary Artery Disease Martin B. Leon, MD Columbia University Medical Center Cardiovascular Research Foundation New York City Monday, October 22, 2007

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Presenter Disclosure Information for TCT 2007; October 20-25, 2007 Martin B. Leon, M.D. Scientific Advisory Board: Medtronic Vascular, Abbott Vascular, Cordis-JNJ, and Boston Scientific

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Endeavor DES System PC Technology Drug: Zotarolimus Stent Delivery System Driver Cobalt Alloy Stent

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Polymer and Drug Matrix Tissue Blood PC Basecoat (˜ 1µm thick) Drug Layer 90% Zotarolimus (10µg/mm) 10% PC (˜ 2-4µm thick) PC Overspray (˜ 0.1 µm thick) Stent Strut 3.0 mm Stents 500x magnification Illustrative Not to Scale Taxus Cypher Endeavor

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Porcine Drug Elution Kinetics and PK Zotarolimus is hydrophobic and rapidly elutes from the hydrophilic PC polymer matrix within 14 days Blood and Arterial Tissue Zotarolimus Concentration Zotarolimus is highly lipophilic enabling rapid arterial tissue loading and drug retention which is sustained for ~28 days Drug Elution by Recovered Drug from Stent

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Biocompatibility (Inflammation Scores) Porcine inflammation scores show mild response to a 3X overdose (30µg/mm) and 6X overdose (overlapping 30µg/mm) at all chronic time points up to 180 days with single and overlapped stents. *CVPath, Dr Renu Virmani Inflammation Scores Inflammation Scores1 28 to 180 days Inflammation Scores1 28 to 180 days Inflammation Scores Days Days 1 Bare stent controls matched with test groups 2 Not Done *P<0.05 compared to the respective controls 1 Bare stent controls matched with test groups 2 Not Done *P<0.05 compared to the respective controls 4 9 4 5 8 n 7 28 90 180 7 6 4 5 7 n 7 28 90 180 9 7 ND2 * * ND2 * *

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1 Bare stent controls matched with test groups 1 Bare stent controls matched with test groups *P<0.05 compared to respective controls Endothelial Coverage Porcine histology and SEM show rapid endothelial replacement with both single and overlapping (OL) stents*. % Endotheliazation Percent Endothelialization1 7 to 180 days Days Days 7 28 90 180 7 28 90 180 Single Stents Overlapping (OL) Stents % Endotheliazation * Study Number FS102 FS99 FS100 FS11 Study Number FS102 FS99 FS100 FS11 Percent Endothelialization1 7 to 180 days *CVPath, Dr Renu Virmani

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Preserved Endothelial Function In Vivo Assessment of Endothelial Function in Porcine Models: eNOS Staining Endeavor Driver Immunohistochemistry Staining for Presence of eNOS

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Preserved Endothelial Function In Vivo Assessment of Endothelial Function Porcine Model: Active Vasoreactivity Driver Endeavor Distal Vessel Vasoreactivity Following Acetylcholine (Ach) Challenge

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Endeavor Clinical Program Overview 9m 2yr 3yr 4yr ENDEAVOR I ENDEAVOR II ENDEAVOR II CA ENDEAVOR III ENDEAVOR IV ENDEAVOR PK Single Arm First-in-Man (n=100) 4yr 1:1 RCT vs. BMS (E=598,D=599) PK (n=106) 3yr Continued Access Single Arm (n=296) 2yr 3:1 RCT vs. Cypher® (E=323,C=113) 2yr 1:1 RCT vs.Taxus® (E=773,T=775) 12mo Pharmacokinetic Study (n=43) 9mo Single Arm (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 (n=2000) Proposed Ongoing Premarket Safety and Efficacy Package

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Current DES Insights Efficacy measures The relationship between LL and TLR is non-linear and moderate LL may still result in low TLR Angiographic follow-up has a profound impact on TLR Safety considerations DES safety evaluations can no longer be confined to 1 year, as very late stent thrombosis is increased compared with BMS Clinical trial design Larger non-inferiority RCTs vs. approved DES and even larger “real world” studies (both with longer follow-up) are now required to discern clinical safety and efficacy

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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 Clinical Trial Design Co PIs: Martin B. Leon and David E. Kandzari 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%)

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Endeavor IV Study Endpoints Primary Target vessel failure (TVF) at 9 months (pre-specified non-inferiority margin 3.8%) Secondary In-segment late lumen loss at 8 months (pre-specified non-inferiority margin 0.2mm) Angiographic binary restenosis at 8 months Clinical outcomes - TVF, MACE, death, MI, TVR, TLR, and stent thrombosis (protocol and ARC definitions) at 9, 12, 24, 36, 48, and 60 months

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Endeavor IV Key Inclusion Criteria Clinical evidence of ischemic coronary disease Single de novo lesion in native coronary artery Target lesion =27mm in length, diameter stenosis =50% and <100%, and target reference vessel diameter =2.5mm and =3.5mm Target vessel TIMI flow =2 Patient able to take dual anti-platelet therapy (ASA + thienopyridine) for at least 6 months

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Endeavor IV Key Exclusion Criteria Acute MI within 72 hours of index procedure Previous PCI of target vessel within 9 months pre-procedure Planned PCI of any vessel within 30 days post-procedure Hx stroke or TIA within 6 months Active PUD or UGIB within 6 months LVEF <30% Target vessel containing thrombus or with excessive tortuosity Target lesion in ostial or left main location, >45° bend, severe calcification, or involving a bifurcation

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Endeavor IV Study Administration QCA Core Lab Brigham and Women’s Hospital, Boston, MA, USA Jeffrey J. Popma, MD IVUS Core Lab Stanford Interventional Cardiology, CA, USA Peter Fitzgerald, MD ECG Core Lab Harvard Clinical Research Institute, Boston, MA, USA Peter Zimetbaum, MD Data Coordinating Center Harvard Clinical Research Institute, Boston, MA, USA Laura Mauri, MD Clinical Events Committee/DSMB Harvard Clinical Research Institute, Boston, MA, USA Donald Cutlip, MD

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Endeavor IV Patient Flowchart Angio F/U (8 mo) 135/164 82.3% Patients Enrolled N = 1548 Randomized Endeavor n = 773 Taxus n = 775 Angio F/U (8 mo) 144/164 87.8% Clinical F/U (9 mo) 758/773 98.1% Clinical F/U (9 mo) 749/775 96.6% (12 mo) 749/773 96.9% (12 mo) 741/775 95.6%

Slide 19 :

Endeavor IV - Top Enrollers

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Endeavor IV Patient Demographics

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Endeavor IV Clinical CAD History

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Endeavor IV Lesion Characteristics (QCA)

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Endeavor IV Post-Procedure QCA

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Endeavor IV 8 Month QCA

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Endeavor IV 8 Month QCA

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Endeavor IV Restenosis at 8 Months (QCA)

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Endeavor IV Clinical Events at 30 days

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Endeavor IV Clinical Events at 30 days

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Endeavor IV Peri-procedural MIs (CKMB rises) CKMB Rises (xULN) 8/17 (47%) of Taxus non-Q MIs with CKMB rises ?10X ULN =5X<8X =8X<10X =10X 1 1 0 1 2 8 Number Patients

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Endeavor IV Primary Endpoint Result at 9 months Target Vessel Failure TVF Rate P for Non-Inferiority < 0.001 ?=3.8% Taxus (n=54/749) Endeavor (n=50/758) 7.2% 6.6%

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Endeavor IV Clinical Events at 9 months *Day 83, 145, 171

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Endeavor IV Clinical Events at 12 months *Day 83, 145, 171

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Endeavor IV Target Vessel Failure Endeavor (50/758) Taxus (54/749) Endeavor (58/749) Taxus (70/741) P = 0.685 9 months 12 months Rate P = 0.267 6.6% 7.2% 7.7% 9.4%

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Endeavor IV Death and MI at 9 months Card Death Non-Q Rate 0.7% 0.8% P =0.772 P =1.000 P =1.000 P =0.117 0.3% 0.4% 2.4% 1.5% P =0.194 0.3% 0.1% 1.2% 2.3% Death All MI All Q-wave Endeavor (n=758) Taxus (n=749)

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Endeavor IV Death and MI at 12 months Card Death Non-Q Rate 1.1% 1.1% P =1.000 P =1.000 P =1.000 P =0.131 0.5% 0.5% 2.6% 1.6% P =0.208 0.3% 0.1% 1.3% 2.4% Death All MI All Q-wave Endeavor (n=749) Taxus (n=741)

Slide 36 :

Endeavor IV Target Vessel Revascularization Endeavor (41/758) Taxus (37/749) Endeavor (47/749) Taxus (50/741) P = 0.728 9 months 12 months Rate P = 0.753 5.4% 4.9% 6.3% 6.7%

Slide 37 :

Endeavor IV Target Lesion Revascularization Endeavor (31/758) Taxus (20/749) Endeavor (34/749) Taxus (24/741) P = 0.154 9 months 12 months Rate P = 0.228 4.1% 2.7% 4.5% 3.2%

Slide 38 :

Endeavor IV Relative Changes in Clinical Endpoints from 9 to 12 Months TVR Percent Increase 17% 31% 37% 17% 10% 19% 25% 50% TVF TLR Non TL-TVR

Slide 39 :

Endeavor IV ALL TLR Events at 12 months All Clinically Driven Non-clinically Driven TLR Rate 44 40 34 24 10 16 P =0.737 P =0.228 P =0.241 Endeavor (n=749) Taxus (n=741)

Slide 40 :

Endeavor IV TVR by Angiographic Follow-up at 12 months TVR Rate 14/141 9/133 33/608 41/608 Endeavor Taxus Endeavor Taxus Angiographic Follow-up Clinical Follow-up P =0.389 P =0.401 9.9%

Slide 41 :

Endeavor IV TLR by Angiographic Follow-up at 12 months TLR Rate 12/141 4/133 22/608 20/608 Endeavor Taxus Endeavor Taxus Angiographic Follow-up Clinical Follow-up P =0.070 P =0.875

Slide 42 :

Freedom from TVF 100% 85% 0 30 60 90 120 150 180 210 240 270 300 330 360 Time after Initial Procedure (days) 90% 95% TVF-free 92.3% 90.6% 0.243 Endeavor Taxus P (log rank) Endeavor IV TVF Free Survival to 360 days

Slide :

Slide 46 :

Endeavor IV - Diabetics TVF and TLR at 12 months Rate 20/233 24/223 16/233 13/223 Endeavor Taxus Endeavor Taxus P =0.526 P =0.704 8.6% TVF TLR 477 diabetics (30.8% of E IV patients)

Slide 47 :

Endeavor IV TVF (9M) – Post Hoc Subgroup Analysis Diabetes Non-diabetes RVD ?2.5mm >2.5 <3.0mm ?3.0mm Lesion Length ?10mm >10 <20mm ?20mm Single Stent Multiple Stents Favors Endeavor Favors Taxus 0.1 1 10

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Endeavor IV Cardiac Death/MI (9M) – Post Hoc Subgroup Analysis Diabetes Non-diabetes RVD ?2.5mm >2.5 <3.0mm ?3.0mm Lesion Length ?10mm >10 <20mm ?20mm Single Stent Multiple Stents Favors Endeavor Favors Taxus 0.1 1 10

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Endeavor IV TVR (9M) – Post Hoc Subgroup Analysis Diabetes Non-diabetes RVD ?2.5mm >2.5 <3.0mm ?3.0mm Lesion Length ?10mm >10 <20mm ?20mm Single Stent Multiple Stents Favors Endeavor Favors Taxus 0.1 1 10

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Endeavor IV TLR (9M) – Post Hoc Subgroup Analysis Diabetes Non-diabetes RVD ?2.5mm >2.5 <3.0mm ?3.0mm Lesion Length ?10mm >10 <20mm ?20mm Single Stent Multiple Stents Favors Endeavor Favors Taxus 0.1 1 10

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Endeavor IV at 12 months Multivariate TLR Predictors for All patients

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Endeavor IV at 12 months Multivariate TLR Predictors for Endeavor and Taxus

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The Endeavor DES, compared with the Taxus DES, demonstrated… Endeavor IV Conclusions Reduced peri-procedural non-Q MIs, and a similar overall safety profile (death, Q-MI, and stent thrombosis) through 12 months follow-up Higher angiographic late loss at 8 months follow-up Similar TVF (1ry endpoint) through 12 months follow-up Similar TVR/TLR in subsets of interest (including diabetics) through 12 months follow-up, especially in the clinical FU patient cohort

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