ISAR-LEFT MAIN 2 Randomized Trial Zotarolimus- vs ISAR-LEFT MAIN 2 Randomized Trial Zotarolimus- vs. Everolimus-Eluting Stents for Treatment of Unprotected Left Main Coronary Artery Lesions Julinda Mehilli, MD Klinikum der Universitaet Munich Deutsches Herzzentrum Munich Germany

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Lecture fees Abbott Vascular Daichii Sankyo/Lilly The Medicines Terumo

PCI vs. CABG Surgery for uLMCA Meta-analysis of Randomized Controlled Studies Similar Risk of Death or Myocardial Infarction Higher Risk of Revascularization Capodanno et al., J Am Coll Cardiol 2011

First Generation DES for uLMCA Similar Clinical & Angiographic Performance ISAR-LEFT MAIN Mehilli et al., J Am Coll Cardiol 2009

Second Generation DES for uLMCA Improved Clinical Performance PRECOMBAT 2 trial Ischemia-driven TVR MACE Kim YH et al., J Am Coll Cardiol, Interv 2012

Second Generation DES for All-Comers Resolute All Comers trial Serruys et al., New Engl J Med 2010 5

ISAR-LEFT MAIN 2 DESIGN: Randomized, multi-center trial OBJECTIVE: To evaluate the relative performance of two 2nd generations DES – zotarolimus- and everolimus-eluting stents – in patients with uLMCA lesions STEERING COMMITTEE Adnan Kastrati, MD (Chair) Julinda Mehilli, MD (principal investigator) Josef Dirschinger, MD PARTICIPATING CENTERS Deutsches Herzzentrum & Klinikum rechts der Isar, Munich, Germany PI: J. Mehilli & K-L Laugwitz Bad Segeberger Kliniken, Bad Segeberg, Germany PI: G Richart Department of Cardiology, University of Ferrara, Italy PI: M Valgimigli 6

Inclusion Criteria Patients with ischemic symptoms or evidence of myocardial ischemia in the presence of ≥50 % stenosis located in unprotected LMCA who are unable to undergo CABG because of cardiac surgeons’ refusal (poor surgical candidates) or their own unwillingness

Exclusion Criteria Age < 18 years Cardiogenic shock ST-Elevation Acute Myocardial Infarction In-stent Restenosis Prior coronary artery bypass surgery Malignancies with life expectancy <1 year Planned staged PCI within 30 days from index PCI Planned elective surgical procedure necessitating interruption of clopidogrel during the first six months after PCI Pregnancy

Primary Endpoint Incidence of major adverse cardiac events defined as the composite of death myocardial infarction target lesion revascularization at 1-year follow-up

Secondary Endpoints left main area analysis Angiographic restenosis at 8-month FU angiogram, defined as diameter stenosis ≥50% measured by QCA in the area from left main ostium to 5-mm proximal segments of LAD, LCx as well as of R. intermedius if the latter has a reference diameter >2 mm ARC-defined stent thrombosis at 1-year follow-up

Sample Size Calculation Hypothesis: Endeavor Resolute stent is not inferior to Xience stent in terms of major adverse cardiac events Assumptions: Incidence of MACE 25% in both stent groups Margin of non-inferiority 9% Power of 80% -level of 0.05 Rate of lost to follow-up 5% Planed number of patients for each group: 300

ISAR-LEFT MAIN 2 Trial 650 patients with uLMCA lesions pre-treated with 600 mg clopidogrel Zotarolimus-eluting stent (Endeavor Resolute) N= 324 Everolimus-eluting stent (Xience) N= 326 Angiographic follow-up at 8 months in 73% (N=237) Angiographic follow-up at 8 months in 69% (N=226) Clinical follow-up at 12 months in 100% (N=324) Clinical follow-up at 12 months in 100% (N=326)

Baseline Characteristics Resolute n=324 Xience n=326 Age, years 69.4±10.4 70.2±9.4 Women, % 27 23 Art. hypertension, % 68 70 Diabetes, % 28 29 Current smoker, % 15 13 Hypercholesterolemia, % 69 76

Baseline Characteristics Resolute n=324 Xience n=326 Acute Coronary Syndrome, % 38 33 History of MI, % 32 29 Prior PCI, % 52 54 Creatinine serum level, mg/dl 1.09±0.71 1.09±0.70 Parsonnet Score 13.3±10.3 13.7±11.0 EuroSCORE 5.1±3.7 5.0±3.7 Malignancies, % 22 24

Angiographic Characteristics Resolute n=324 Xience n=326 LV ejection fraction, % 52.1±11.9 53.8±11.4 Coronary artery dominance right left balanced 84 10 6 9 7 RCA ≥50% stenosis, % 69 74 Dominant RCA occlusion, % 11 R. intermedius >2.0 mm, % 16

Left Main Area Lesion Location % Distal Midshaft Ostium Resolute n=324 Xience n=326

Stenting Technique % Single stenting Culotte stenting T-stenting Crush stenting Resolute n=324 Xience n=326

Incidence of Stent Thrombosis - secondary endpoint - % Probable stent thrombosis Definite stent thrombosis Resolute n=324 Xience n=326

Major Adverse Cardiac Events - primary endpoint - 100 RR 1.26 (95% CI 0.85-1.85) P= .25 80 60 Resolute Cumulative incidence, % Xience 40 17.5% 20 14.3% 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization

Death or Myocardial Infarction 100 RR 1.28 (95% CI 0.70-2.34) P= .42 80 60 Resolute Cumulative incidence, % Xience 40 20 7.5% 5.9% 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization

Death or Myocardial Infarction or Stroke 100 RR 1.26 (95% CI 0.71-2.23) P= .43 80 60 Resolute Cumulative incidence, % Xience 40 20 8.1% 6.5% 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization

Cumulative incidence, % All-Cause Mortality 100 RR 1.01 (95% CI 0.52-1.94) P= .98 80 60 Resolute Cumulative incidence, % Xience 40 20 5.6% 5.6% 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization

LMCA Area Restenosis Resolute P=.20 P=.35 Xience % Angiographic restenosis Clinical restenosis

Target Lesion Revascularization Resolute RR 1.26 (95% CI 0.78-2.06) P= .35 Xience % TLR Repeat PCI Bypass surgery

MACE in Different Subgroups Resolute Xience Relative Risk (95% CI) P Value for Interaction No. of Events/Total (%) Diabetes 0.96 Yes 24/92 (26.2) 20/93 (21.9) No 32/232 (14.0) 26/233 (11.3) Parsonnet score 0.68 >15 28/120 (23.7) 24/115 (21.0) ≤15 28/204 (13.9) 22/211 (10.6) EuroSCORE 0.52 ≥6 29/140 (20.7) 23/120 (19.5) <6 27/184 (15.0) 23/206 (11.3) 0.5 1 1.5 2 2.5 3 Resolute better Xience better

Summary The use of 2nd gen. DES in unprotected LMCA lesions in relatively unselected patients is safe and effective. Both Endeavor Resolute and Xience stents provide similar clinical and angiographic outcomes at one-year follow-up in this high risk patient population.