Drug Eluting Stents: Looking Forward Janine Lane Director Clinical Communication and Education Medtronic Vascular

Components of the Endeavor Stent Cobalt Alloy Modular stent Strut thickness 0.0036’’ Biocompatible PC Technology (phosphorylcholinepolymer) Delivery based on discrete, secure Technology Zotarolimus (Sirolimus analogue) 10 g/mm stent dosage

Lessons Learned Antiproliferative drugs consistently reduce need for repeat intervention Current drug eluting stents are associated with varied angiographic results Perception of the cost benefit of drug eluting stents is not uniform

Unanswered Questions Impact of current drug eluting stents on long-term safety? Stent Thrombosis Myocardial Infarction Death Ideal length of dual anti-platelet therapy?

= increased necessity for prolonged dual antiplatelet regimens Stent Thrombosis Factors to Consider The polymer Inflammatory Thrombogenic The drug Delayed Endothelization Late incomplete apposition The patient (more complex lesions = more thrombogenic milieu) = increased necessity for prolonged dual antiplatelet regimens Late Stent Thrombosis (“LST”) is a well known, potentially life threatening complication of PCI/Stenting. There are four widely suspected underlying causes of LST: discontinuation of anti-platelet therapy, late incomplete apposition, polymer hypersensitivity/inflammation and delayed endothelialization. As you will see in the following slides, Endeavor effectively reduces the risk of each of these causes of LST This is reflected in the excellent Endeavor clinical program results with 0% LST after 10 days in more than 1200 pts.

*Antiplatelet Therapy Discontinuation Stent thrombosis Rates According to Select Patient Characteristics *Antiplatelet Therapy Discontinuation Prior Brachy Renal Failure Bifurcations ULM Diabetes UA The incidence of stent thrombosis according to selected patient characteristics was 29% in pts with premature antiplatelet therapy discontinuation, 8.7% in prior brachytherapy at the target vessel, 5.5% with renal failure, 3.5% in bifurcations, 3.2% in unprotected left main treated, 2.6% in diabetes, and 1.3% in unstable angina *Premature discontinuation From Milan/Sieburg Experience ACC 05.

Usually associated with minor Late Stent thrombosis After Anti-platelet Discontinuation CYPHER TAXUS 335 343 375 442 Usually associated with minor surgical procedures 100 200 300 400 500 Day McFadden EP et al. Lancet 2004; 364:1519–21

At-Risk Patient Noncompliance Adherence to Antiplatelet Medication In at-risk patients from Western Europe over 24 months: Dual antiplatelet therapy Other agents (i.e. PLAVIX) Aspirin Alone ≥1 antiplatelet agent 78% 62% Percent of Population 27% 11% Bhatt DL et al. JAMA 2006; 295(2):180-188

Safety Profile: No Late Stent Thrombosis in Over 1,300 Patients EI EII Days Post Procedure 1 2 3 12 13 14 30 100 150 270 200 365 720 EI n=100 = 1% EII n=598 = 0.5% EII CA n=296 = 0.0% EIII n=323 = 0.0% Defined as angiographic thrombus or subacute closure within the stented vessel at the time of the clinically driven angiographic restudy for documented ischemia (chest pain and ECG changes). Any death not attributed to a non-cardiac cause within the first 30 days is considered a surrogate for stent thrombosis in the absence of documented angiographic stent patency. Overall Thrombosis = 0.3%

Unanswered Questions Long term benefits (health care economics) Stent design itself: Elution characteristics Ideal drug or drugs Ideal delivery mechanism Patient responses: healing times of complex disease states why current drug eluting stents sometimes fail Can we improve safety while maintaining aggressive neointimal suppression

Unmet Clinical Needs Clinically unmet needs in the DES era Diffuse Disease Long Lesions Smaller Diameter Vessels Bifurcation Lesions Left Main AMI Diabetics Multi-Vessel Disease

Migration/Proliferation Unmet Clinical Needs Extended Drug Exposure (% Response) Extracellular Matrix Production Smooth Muscle Cell Migration/Proliferation Inflammation Reabsorption 90 Thrombosis 3 14 440 1000 Elution Duration Drug In Tissue

Potential Solutions One new drug eluting stent: Multiple/combination drugs Different delivery mechanism Choice of drug eluting stents from one supplier Indication specific drug eluting stents One drug eluting stent with different versions

Next Generation DES Pipeline Endeavor Controlled Response (CR) Novel, Medtronic designed polymer coating Tunable elution kinetics to match the breadth of healing needs in complex lesions Capability to deliver multiple drugs

Medtronic RESOLUTE Clinical Trial Single De Novo Native Coronary Artery Lesions Stent Diameters: 2.5, 3.0, 3.5mm Stent Lengths: 18, 24, 30mm (8/9mm bailout) Lesion Length: 14-27mm Drug Dose: 1.6 g/mm2 stent surface area Pre-dilatation required 100 Patients (includes 30 PK Sub-Study Patients) 12 Sites (New Zealand and Australia) Endeavor CR Stent Clinical/MACE 30d 6mo 9mo 12mo 2yr 3yr 4 yr 5 yr Angio/IVUS (all patients) Primary Endpoint: Late lumen loss (in-stent) at 9 mo Secondary Endpoints: 1. MACE rate at 30 day and 6, 9, 12 mo 2. Acute success (device, lesion, procedure) 3. Angiographic parameters at 9 mo (%DS, LL, LL index, ABR, MLD) 4. TVF at 9 mo 5. Clinically driven TLR at 9 mo 6. Neointimal hyperplastic volume and percent volume obstruction (%VO) at 9 mo 7. PK Sub-Study Pharmacokinetic parameters (Cmax, Tmax, AUC, CL corresponding to AUC)

Conclusion Many more questions than answers Durability and safety Medtronic is assessing the theory of delayed healing with the Endeavor CR program