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1 The Next ERA: COMBO Dual Therapy Stent The Unmet Need Roxana Mehran, MD Mount Sinai i School of Medicine i

2 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 Grant/Research Support to Institution Company Sanofi/BMS- Significant The Medicines Company Consulting Fees/Honoraria Astra Zeneca, Abbott Vascular, Regado Biosciences, Janssen

3 Late Cypher Stent Thrombosis After 3 Years Baseline Late Stent Thrombosis at 3.5 yrs After 2 Cypher Stents

4 Definition of Stent Thrombosis Definite Stent Thrombosis Cutlip D et al. Circulation 2007 Angiographic or pathologic confirmation of partial or total thrombotic occlusion within the peri-stent region AND at least ONE of the following, additional criteria: - Acute ischemic i symptoms - Ischemic ECG changes - Elevated cardiac biomarkers Probable Stent Thrombosis - Any unexplained death within 30 days of stent implantation - Any myocardial infarction, which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause Possible Stent Thrombosis - Any unexplained death beyond 30 days

5 PYRAMID OF RISK and BENEFIT w/ ADP Receptor Antagonism: Acute Stent Thrombosis 24 Hours (Incidence 0.5%) Subacute Stent Thrombosis Ischemic Events Days to weeks (Incidence 3%) Ischemic Events Up to 12 months (Incidence 15%) Ischemic Events Due to Progression of Diffuse Atherothrombotic Disease?????????? > 1 Year (Incidence 20%) Adapted from Bhatt DL. J Invasive Cardiol. 2003;15:3B

6 Incidence of Stent Thrombosis Bare Metal Stents Drug-Eluting Stents Mean = 1.4% Mean = 1.2% % % Ong 2005 Iakovou 2005 Kuchulakanti 2006 Rodriguez 2006 Urban 2006 Park 2006 Daemen Karrillon 1996 Moussa 1997 Schühlen 1998 Cutlip 2001 Serruys 2001 Orford 2002 Wenaweser 2005 N=24,087 N=32,648

7 Late Stent Thrombosis and Bare Metal Stents N Early 1.2% (N=71) Late 0.4% (N=24) Study population ,058 patients undergoing g PCI with BMS Wenaweser et al. EHJ Days 3 Overall ST Late ST Wang Heller Calver Wenaweser N=1,191 N=1,855 N=361 N=6,058

8 First Generation Drug-Eluting Stents and dv Very Late Stent tth Thrombosis Bern-Rotterdam Cohort 4 Years Wenaweser P et al. J Am Coll Cardiol 2008, 52(14): ,146 consecutive patients treated with 1 st generation DES Stent Thrombosis Risk of very late stent thrombosis % 0.5% per year

9 Multifactorial Nature of Stent Thrombosis Device factors -Surface -Drugs -Polymer -Stent overlap Lesion factors -Vessel size/length -Thrombus -Plaque characteristics -Bifurcation -Calcification -Total occlusions Procedural factors -Dissection -Incomplete stent apposition and stent expansion - Brachytherapy STENT THROMBOSIS Stent-Artery- Interaction -Late Malapposition - Hypersensitivity reaction Patient factors -Drug response/interactions -Gene polymorphism -LV function -Acute coronary syndrome -Renal failure -Diabetes Platelet and Coagulation factors -Coagulation activity -Inhibition of platelet aggregation -Inadequate response to anti-platelet therapy -Premature anti-platelet therapy discontinuation

10 BR-Cohort 5 Years Onuma Y. et al. ESC 2009

11 Hypersensitivity Associated With Drug-Eluting Stents RADAR registry 262 of 5,783 DES related reports with hypersensitivity y symptoms 17 cases probably or certainly related to DES 4 cases of fatal stent thrombosis with focal hypersensitivity on autopsy (eosinophilic infiltrates) Clinical manifestations Rash, hives, dyspnea, myalgia/arthralgia, itching Laboratory findings Eosinophilia Elevated IgE titers Virmani R et al. Circulation 2004;109:701-5 Nebeker J et al. JACC 2006;47:175-81

12 Optimal Platelet Inhibition Prevention of Early ST Optimal Procedural Result Extent of platelet inhibition Excess of bleeding Prevention of early ST No residual dissection Stent length as short as possible and as long as needed Complete stent expansion

13 STENT ANALYSIS Death Following ST Mortality During Follow up (%) Post-Stent Thrombosis Subje ects % of HR 13.1 ( ) P< Stent Thrombosis 2.6 No Stent Thrombosis N=210 N=12634

14 New P2Y12 in PCI for STEMI: Death New P2Y12 Clopidogrel Death Major Bleeding Bellemain-Appaix A. et al. JACC 2011

15 HORIZONS-STENT STENT THROMBOSIS: 2-year Events Effect of DES Use bosis (%) ent Thromb ef/prob Ste De Any DES BMS only Time in Months 4.4% HR: 1.00 [95% CI: 0.68, 1.46] p= Number at risk Any DES BMS only Dangas et al, Circulation 2011

16 HORIZONS-STENT STENT THROMBOSIS: 2-Year Events Independent d Predictors of fany Definite/Probable it bl ARC ST Variables H.R. (95% C.I.) p Insulin-Treated Diabetes 2.88 ( 1.64, 5.07) Angiographic Aneurysm 2.54 ( 1.04, 6.22) History of Previous PCI 2.36 ( 1.53, 3.64) Angiographic Ulceration 2.25 ( 1.04, 4.86) Current Smoking 1.66 ( 1.16, 2.38) Baseline flow grade TIMI 0/ ( 1.07, 2.36) Baseline Platelet Count ( , ) <.0001 Pre-Randomization Heparin 0.55 ( 0.39, 0.79) Dangas et al, Circulation 2011 rev

17 Prevention of Late ST New Stent Technology New Generation DES with smaller strut thickness Biodegradable polymers Polymer free surface Bioabsorbable stents Concepts facilitating endothelial coverage (e.g. endothelial progenitor cell capture) Use of antithrombotic stent surface

18 Genous

19 Combo Dual Therapy Stent Design features: Abluminal biodegradable polymer matrix Sirolimus elution Genous technology for accelerated endothelial coverage Abluminal Sirolimus Release Matrix 316L Stainless Steel Stent Strut Cross-sectionsection Outer Immobilized Anti-CD34 Antibody Treatment 3-5 μm Antibody Monolayer; nanometers thick Vessel Side Lumen Side 100 μm

20 Stent Surface Coverage by SEM in Stented Arteries at 3 and 14 Days Genous 3 Days 14 Days tion by SEM Cypher + Anti-CD34 Cypher % Endot thelializa *p<0.05; **p<0.01; ***p<0.001 Genous Combo Cypher Combo ** 3 Days 14 Days Cypher Timepoint * **

21 Drug Sirolimus Combo Stent Sirolimus Drug Elution Polymer - biodegradable Surmodics SynBiosys proprietary blend of urethane-linked block co-polymers of lactide, glycolide, and ε-caprolactone; degradation time <90 days Drug content is 5 µg/mm stent length, approximately half the dose of CYPHER but with a similar release profile 100 % Elution over time Combo Cypher Time (days) In vitro elution of Combo and CYPHER (% of total drug eluted over time) Granada et al., Circ Cardiovasc Intervent. 2010; 3:

22 Stent Thrombosis Baber, et al. JACC 2011

23 Timing of First Discontinuation of Thienopyridine Within 2 Years After XIENCE V Treatment (n=2454) Discontinued after 6 months n=849 (34.6%) Discontinued before 6 months n=145 (5.9%) Never discontinued n=1460 (59.5%) SE Rev A.

24 Timing of First Discontinuation of Thienopyridine and Subsequent Stent Thrombosis after XIENCE V Treatment N=1457 N=123 Never Discont. D/C <6 months D/C >6 months SE Rev A.

25 Multivariable Predictors of ARC Definite or Probable 2-Year Stent Thrombosis: XIENCE V Patients Variable Hazard Ratio Hazard Ratio P [95% CI] [95% CI] Value First discontinuation of thienopyridine before 6 months (Yes vs. Never Discontinued) 8.06 [1.79, 36.22] First discontinuation of thienopyridine after 6 months (Yes vs. Never discontinued) 1.06 [0.24, 4.73] SE Rev A.

26 Conclusions The safety profile of current DES technologies can still be enhanced- shorter duration of DAPT without risk for ST The additive effect of EPC recruitment with DES seems promising and needs further evaluation in large scale studies to evaluate this safety benefit The COMBO O stent t is the only stent t that has employed this combination therapy, with early promising studies in humans