1. ISAR-TEST-2 Trial Two-year Clinical and Angiographic Outcomes from a Randomized Trial of Polymer-Free Dual Drug-Eluting Stents versus Polymer-Based Cypher and Endeavor Drug-Eluting Stents Robert A. Byrne, MB MRCPI Adnan Kastrati, MD; Klaus Tiroch, MD; Stefanie Schulz, MD; Jürgen Pache, MD; Susanne Pinieck; Steffen Massberg, MD; Melchior Seyfarth, MD; Karl-Ludwig Laugwitz, MD; Katrin A. Birkmeier, MD; Albert Schömig, MD; Julinda Mehilli, MD ACC/i2 2010 – LBCT III Deutsches Herzzentrum & 1. Med. Klinikum rechts der Isar Technische Universität Munich Germany

2.  First generation DES systems deliver high antirestenotic efficacy in comparison with BMS but do so at the cost of a delay in structural and functional healing of stented segment  This pathophysiological process underlies the surfeit of late adverse events seen with this technology  Polymer residue seems to play a key role Background

3.  Avoidance of polymer imposes efficacy limitations related to suboptimal drug release kinetics  The incorporation of a second active agent targeted at a different element of the restenotic response cascade is a potential option to enhance anti-restenotic performance  Probucol is a potent lipophilic antioxidant which has proven effects in reducing restenosis Background

4. to compare the anti-restenotic efficacy of: polymer-free sirolimus+probucol-eluting stent (Dual-DES) with permanent polymer sirolimus-eluting stent (Cypher) and permanent polymer zotarolimus-eluting stent (Endeavor) in patients with coronary artery disease Aim of ISAR-TEST-2 Study

5. 1007 pts randomized Dual-DES 333 pts Endeavor 339 pts Cypher 335 pts 286 pts with 6-8-mo. angiogram 268 pts with 6-8-mo. angiogram 274 pts with 6-8-mo. angiogram Clinical follow-up data to 2 years was available for all but 65 of 1007 enrolled patients Among patients without 2-yr FU, median FU was 21 [20-22] months 162 pts with 2 year angiogram 164 pts with 2 year angiogram 167 pts with 2 year angiogram ISAR-TEST-2 Study Flow

6. Inclusion Criteria  “De novo” lesions in native coronary arteries  Written informed consent Exclusion Criteria  Left main lesion  Cardiogenic shock  Comorbidities with a life expectancy < 12 months  Contraindication to aspirin, limus agents, probucol, stainless steel, thienopyridines  Pregnancy Patient Selection

7. Two-year Safety Endpoints:  Composite of death and myocardial infarction  Definite stent thrombosis Two-year Efficacy Endpoints:  Target lesion revascularization (TLR) due to restenosis in the presence of symptoms or signs of ischemia  Delta-TLR between 1 and 2 years  Composite binary restenosis at 2 years based on latest available angiogram available (whether at 6-8 months or 2 years) ISAR-TEST-2 Study Endpoints

8. Sirloimus-eluting stent with permanent polymer (Cypher) Sirolimus+probucol- eluting stent (Dual-DES) Zotarolimus-eluting stent with permanent polymer (Endeavor) Microporous thin-strut (87 μm) 316L Stainless Steel Polymer-free; dual drug-eluting Developed in setting of ISAR Project 100 µm 10 µm ISAR-TEST-2 Study Stent Types

9. Study hypothesis:  Cypher, Dual-DES and Endeavor stents would have different anti-restenotic efficacy based on an angiographic endpoint (binary restenosis) at 6-8 months  Additional analyses are exploratory in nature and should be regarded as hypothesis generating Statistical Analysis

10. Baseline Clinical Characteristics Dual-DES n=333 Endeavor n=339 Data are percentage or mean ± standard deviation; Percentages may not total 100 due to rounding Cypher n=335 Hypercholesterolemia6366 69 Current smoker2018 17 Diabetes2926 27 Arterial hypertension6568 64 Women2325 23 67 ±11 Age, years 67± 11 History of MI2526 30

11. LV ejection fraction (%) Stable angina Unstable angina Acute MI Dual-DES n=333 53 ±12 58 30 12 Endeavor n=339 55 ±10 56 30 15 Cypher n=335 52 ±12 61 25 13 Data are percentage or mean ± standard deviation; Percentages may not total 100 due to rounding Baseline Clinical Characteristics

12. Target vessel LAD LCx RCA Complex lesions Multivessel disease Total occlusions Data are percentage; percentages may not total 100 due to rounding Dual-DES n=427 70 81 31 25 44 12 Cypher n=419 73 86 26 25 49 12 Endeavor n=420 75 83 29 31 41 12 Angiographic Characteristics

13. QCA Measurements Dual-DES n=427 Cypher n=419 Endeavor n=420 Vessel size, mm 2.75 ±.46 2.71 ±.49 2.69 ±.52 Lesion length, mm 14.8 ±8.3 14.7 ±8.0 14.0 ±8.2 MLD after PCI, mm 2.55 ±.43 2.51 ±.47 2.49 ±.48 DS after PCI, % 10.8 ±5.7 10.7 ±7.0 11.6 ±5.0 Data are mean ± standard deviation

14. ISAR-TEST-2 Primary Results

15. ISAR-TEST-2 Eur Heart J 2009 ISAR-TEST-2

16. EndeavorCypher Dual-DES p=0.003 6-8 months % p=0.68p=0.002 Binary Angiographic Restenosis

17. ISAR-TEST-3 Two-year Results

18. 0 10 20 30 40 50 024681012141618202224 % mos Dual-DES Endeavor Cypher p=0.61 Death or myocardial infarction

19. Incidence, % P = ns Dual-DES Endeavor Cypher Definite Stent Thrombosis - 2 years -

20. 1 yr 2 yrs Δ = 3.5%Δ = 0.7%Δ = 0.9% Endeavor Cypher Dual-DES p=0.009p=0.72 1 yr 2 yrs % Target Lesion Revascularization

21. 6-8 m 2 yrs* % Δ = 6.8%Δ = 1.6%Δ = 2.9% p=0.016p=0.28 6-8 m 2 yrs* Binary restenosis Endeavor Cypher Dual-DES * 2-year composite

22.  The occurrence of safety events beyond 1 year was rare; there was no signal of a differential safety profile between the Cypher, Dual-DES and Endeavor out to 2 years  The anti-restenotic efficacy of both Dual-DES and Endeavor remained durable between 1 and 2 years with Dual-DES maintaining an advantage  There was evidence of a slight decrement in anti- restenotic efficacy with Cypher Conclusions

23. ISAR-TEST-2 Trial Deutsches Herzzentrum, Munich. Germany Thank You