ISAR-TEST 5: Randomized, Non-inferiority Trial of Rapamycin/Probucol- and Zotarolimus-Eluting Stents J. Mehilli, MD A. Kastrati, R.A. Byrne, S. Massberg, K. Tiroch, S. Schulz, J. Pache, M. Fusaro, K-L. Laugwitz, A. Schömig Deutsches Herzzentrum & 1. Med. Klinik rechts der Isar Technische Universität Munich Germany

Disclosure Statement of Financial Interest I, (Julinda Mehilli) DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Background In comparison with BMS, DES are associated with a small excess of late events occurring more than one year after intervention * The pathological substrate underlying these events is delayed arterial healing and inflammatory response to DES permanent polymer coatings

Dual-DES: Rapamycin – probucol – natural resin No polymer Microporous stainless steel stent platform  developed in the settings of the ISAR-Project supported by the Bayerische Forschungsstiftung 100 µm 10 µm Zotarolimus-eluting stent (ZES): (Endeavor Resolute stent) BioLinx polymer system Co-Cr alloy stent platform Avoidance or modifications of polymer stent coatings offer potential to improve arterial healing and decrease late adverse events Background

mm Endeavor Resolute Xience Leon et al. JACC 2010 Serruys et al., NEJM 2010 EndeavorCypherDual-DES mm P=0.78 P<0.001 Byrne et al. EHJ 2009 Background Late Lumen Loss

…to compare the efficacy of a rapamycin-probucol eluting polymer-free stent against the permanent polymer-based zotarolimus-eluting stent (Endeavor resolute) – in a trial powered for clinical events Objective of ISAR-TEST 5

Inclusion criteria Patients with ischemic symptoms or evidence of myocardial ischemia in the presence of ≥50 % de novo stenosis located in native coronary arteries Informed, written consent Inclusion & Exclusion Criteria Exclusion criteria Age < 18 years Cardiogenic shock Target lesion located in the left main stem Target lesion located in the bypass graft Malignancies with life expectancy <1 year Allergies to study medication

Composite of cardiac death, target vessel-related myocardial infarction target lesion revascularization at 1-year post index PCI Primary Endpoint

Secondary Endpoints All cause mortality All cause mortality Incidence of definite/probable stent thrombosis Incidence of definite/probable stent thrombosis at 1-year post index PCI In-segment binary restenosis In-segment binary restenosis In-stent late luminal loss In-stent late luminal loss at follow-up angiography

Sample Size Calculation Hypothesis: Rapamycin/Probucol-eluting stent (Dual-DES) is not inferior to zotarolimus-eluting stent (Endeavor Resolute) in terms of device-oriented major adverse cardiac events Assumptions: Incidence of primary endpoint in both groups 10% Margin of non-inferiority 3% Power of 80% One-sided  -level of 0.05 Random sequence 2:1 Needed total # of patients: 3000 (accounting for possible losses at follow-up)

Rapamycin/Probucol-Eluting DES (Dual-DES)n=2002 Zotarolimus-Eluting DES (ZES)n= patients with de novo lesions Intracoronary Stenting and Angiographic Results: Test Efficacy of Rapamycis/Probucol- and Zotarolimus-Eluting STents - 5 ISAR-TEST-5 6 to 8-month repeat angiogram 12-month clinical follow-up

Dual-DES: Rapamycin – probucol – natural resin No polymer Microporous stainless steel stent platform  developed in the settings of the ISAR-Project supported by the Bayerische Forschungsstiftung 100 µm 10 µm Study DES Types Zotarolimus-eluting stent (ZES): (Endeavor Resolute stent) BioLinx polymer system Co-Cr alloy stent platform

serial CK + CKMB measurements 600 mg Clopidogrel PCI ASS 500 mg 0 repeat angiography (76%) clinical follow-up (98%) 6-8 mo. 12 mo. Follow-Up Protocol 30 d clinical follow-up (100%) Clopidogrel2x75 mg/day until discharge 75 mg at least 6 months after index PCI Aspirin200 mg/d indefinitely

Dual-DESn=2002ZESn=1000 Age, years 67.7± ± 10.8 Female, % 2424 Art. hypertension, % 6767 Diabetes, % 2930 Current smoker, % 1817 Prior bypass surgery, % 910 Prior MI, % 2930 Hyperlipidemia, % 6365 Baseline clinical characteristics

Dual-DESn=2002ZESn=1000 Clinical presentation, % acute MI 1110 unstable angina 3033 stable angina 5957 Multivessel disease, % 8286 Multilesion PCI, % 3638 LV ejection fraction, % 52.6± ± 11.4 Baseline clinical characteristics

Angiographic characteristics Dual-DESn=2912ZESn=1479 Target vessel, % left anterior descending 4545 left circumflex 2426 right coronary artery 3129 Bifurcation, % 2729 Complex morphology, % 7474 Lesion length, mm 16.4± ± 10.0 Vessel size, mm 2.78± ± 0.50

30-Day Clinical Outcomes % ZES Dual-DES P=.61P=.55P=.52P=.41 Cardiac deathTV-related myocardial infarction Target-lesion revascularization Device-oriented combined endpoint* * device-oriented combined endpoint of cardiac death, target vessel myocardial infarction or target lesion revascularization target vessel myocardial infarction or target lesion revascularization

Months After Randomization % 40 ZES 4.4% Dual-DES 3.6% P=0.31 RR 0.82 [ ] All-Cause Death at 1 Year

Months After Randomization Stent Thrombosis at 1 Year % 4 0 ZES 1.2% Dual-DES 1.1% P=0.91 RR 0.94 [ ] Definite/Probable

Months After Randomization Cardiac Death or MI at 1 Year % 40 ZES 4.4% Dual-DES 4.1% P=0.73 RR 0.94 [ ]

Months After Randomization Target Lesion Revascularization % 40 ZES 10.0% Dual-DES 10.3% P=0.94 RR 0.99 [ ]

Angiographic Restenosis mm ZESDual-DES P=.62 In-stent late lumen loss % In-segment binary restenosis P=.81

Months After Randomization Cardiac Death/TV-related MI/TLR % 40 ZES 13.1% Dual-DES 13.1% P=0.83 RR 1.03 [ ]

>67.8 yrs Women ≤67.8 yrs <2.79 mm ≥2.79 mm Men Age Sex Vessel size Yes No Diabetes 0.91 (0.69, 1.20) 1.40 (0.87, 2.26) 1.12 (0.81, 1.55) 0.95 (0.71, 1.27) 1.07 (0.78, 1.47) 0.90 (0.71, 1.14) P interaction (0.80, 1.31) All 0.97 (0.69, 1.36) 1.02 (0.77, 1.34) 0.82 Relative Risk (95% CI) Dual-DESbetter ZESbetter Primary Endpoint in Different Subgroups

Summary Out to 12 months polymer-free rapamycin/probucol- eluting stent is non-inferior to the permanent polymer-based zotarolimus-eluting stent in a large- scale study powered for clinical endpoints. Their performance was comparable with regard to hard clinical endpoints – stent thrombosis, death or MI – as well as clinical and angiographic parameters of restenosis.