Drug Eluting Stents: Past, Future & Dual Anti-Platelet Therapy When is Stopping Safe

Disclosure Statement of Financial Interest Drug Eluting Stents: Past, Future & Dual Anti-Platelet Therapy When is Stopping Safe Louis A. Cannon, MD, FACC, FSCAI, FACP Program Director, Heart & Vascular Institute of Northern Michigan Hospital Founder, President, The Cardiac & Vascular Research Center of Northern Michigan Lub Dub 214 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 Abbott Vascular Fogarty Foundation McLaren Northern Michigan Consulting Fees/Honoraria Boston Scientific Abbott Vascular Medtronic Covidien Major Stock Shareholder/Equity BioStar Ventures CVRCNM Ownership/Founder BioStar Ventures CVRCNM Ownership KONA CVI Ablative Solutions Guided Delivery Systems MiCardia Cardiac MD / Phoenix Royalty Income, Intellectual Property Rights, Other Financial Benefit None The Problem of Dual Antiplatelet Therapy (DAPT) and Anticoagulation Patient: Mr John Average CHADS2VASC -- <8< 8mm focal RCA 2.5 mm in diameter with distal haze likely fractured plaque LL.? Multiple Issues & Multiple studies at Different Times with Different Stents, s and Drugs with Differing Populations BMS DES?? BMS? Which DES? Which Anti-Plt Agent How Long? Study Support and the Challenge of Medical Legend DES: ION 2.5 mm / 14 mm post to 26 atm with NCB Smaller diameter and diabetes = DES benefit GOAL: Correct diameter sizing complete apposition and circular strut expansion Normal artery to normal artery 1

The Problem of Dual Antiplatelet Therapy (DAPT) and Anticoagulation S.P., 86 y/o male, arterial hypertension / diabetes mellitus Stenting January 21 st 213 Did not agree to ablation for atrial flutter Telephone follow-up May 13 th 213: free of symptoms RECOMMENDATION:4 weeks triple therapy with ASA 81 mg/d + Clopidogrel 75 mg/d and Rivaroxaban 15 mg/d for 4 weeks Then Clopidogrel discontinued Traditional Predictors of Restenosis Predicted in-stent restenosis rates 1 Diabetes, Long Lesions & Small Vessels, contribute to Restenosis Lesion Length MLD 1 mm 15 mm 2 mm 25 mm Diabetics 2.5 mm 35% 39% 43% 46% 3. mm 23% 26% 3% 33% 3.5 mm 15% 17% 19% 22% 4. mm 9% 1% 12% 14% Non-Diabetics 2.5 mm 27% 3% 33% 37% 3. mm 17% 19% 22% 25% 3.5 mm 1% 12% 14% 16% 4. mm 6% 7% 8% 1% 1 Ho, AHA, 1998. Looking From The Inside Out? Metal to Surface Area vs. Restenosis Diameter 2.5 mm Metal to Surface Area 22.4 % 3. mm 19. % 3.5 mm 16.4 % TCT: Moussa, Columbia Univ Med Ctr, CRF Late Loss by Vessel Size & % Diameter Stenosis --Small Vessels Lose Big RVD 4. mm 3.5 mm 3. mm mm 4.mm 2.5 mm 2. mm.45mm.45mm.45mm.45mm.45mm Late Loss.9 mm.9 mm.9 mm.9 mm.9 mm Diameter Stenosis 23% 26% 3% 36% 45% TCT: Moussa, Columbia Univ Med Ctr, CRF What s the literature on small vessels Doctor 1998: Small Vessels (SV) were < 3. mm 1,2 TLR rates are SV 3.mm SV binary restenosis rates 3 Pts with SV often have complexity: a) DM b) Long c) Tapered d) calcium 21: Small Vessels are 2.5 mm 1 Columbo, et al., J of Invasive Cardiol., Vol. 13, No. 6, June 21.2 Scheile et al, Catheterization and Cardiovascular Diagnosis 44: 77-82, 1998 3 Fitzgerald, P. et al., Contribution of Localized Calcium Deposits to Dissection after Angioplasty, Circulation 1992, Vol. 86, No. 1. 4 Mintz, American Journal of Cardiology, 1998. 5.ACC/AHA Guidlines 2

Balance of Efficacy and Healing Premature Discontinuation of Anti-Platelet Therapy FPO Premature Discontinuation of Anti-Platelet Therapy is the most important predictor of stent thrombosis after implantation * Stent struts not covered by neointima Too Little?? Optimal? Too Much?? Higher rates of TLR Results: At 9 month follow-up, 29 pts had stent thrombosis (1.3%) Among the 29 patients, 13 died (case fatality rate 45%) Negative Late Loss Common reasons for discontinuation include: Noncompliance Follow on procedures: surgery, dental, biopsies Resistance to clopidogrel, aspirin.1.4 In-stent Late Loss (mm).6 *Lakovou et al. Incidence, predictors, and outcomes of thrombosis after successful implantation of drug-eluting stents. JAMA. May 25. 14 Late Stent Thrombosis Factors to Consider Of the 15 DES thrombosis cases, 6 (4%) were LST. This could be related to delayed stent endothelialisation, late stent malapposition...and even a localized sensitivity to the polymer. * Late Stent thrombosis: After Anti-platelet Discontinuation CYPHER TAXUS 335 343 375 442 Delayed Endothelialization Late Stent Thrombosis Late Incomplete Apposition Usually associated with minor surgical procedures! Hypersensitivity/ Inflammation 1 2 3 4 5 Day *Moreno et al. Drug-eluting stent thrombosis, results from a pooled analysis including 1 randomized studies. Madrid, Spain; (JACC 25). 15 16 McFadden EP et al. Lancet 24; 364:1519 21 Applying Guidelines on John Average All randomized Controlled medical studies published in the literature do NOT apply to Mr John Average Age Exclusion 5 year follow up NSTEMI Exclusion with troponin bump risk of thrombus and follow MACE Pt on Rivaroxaban tooo high a bleeding risk contributing to MACE (interactions unknown) Depressed EF < 35% (longevity and MACE secondary to other causes Real World studies?? Are Not Randomized, Controlled, Blinded studies Are Ethnically disparate, Genetically diverse, When published,. they are already historical studies What is the Minimum Duration of DAPT Duration after PCI with DES in Patients with Stable CAD? 25: 6-12 months 21: 6-12 months 27: 12 months 211: at least 12 months Why the Difference?? The Stent, s, Drug is different we are Europeans Hx 3

Fully published randomized studies for DAPT duration after the guidelines have been finalized: Every month of DAPT prolongation counts for increased bleeds REAL/ZEST LATE (21) EXCELLENT (212) PRODIGY (213) DAPT Duration 1 year vs. 2 years 6 months vs. 1 y 6 months vs. 2 y Message no advantage of 2 years (probably worse) no signif. difference no advantage of longer DAPT,91,92,93,94,95 24 mo DAPT (PP) 1 mo DAPT (BMS) 6 mo DAPT (PP) DAPT Bleeding risk: 3.8%/y ASA bleeding risk: 1.21-1.37%/y Bleeding hazard.2%/month Guidelines are Guidelines based on Medical Legends and can be used for the average patient in the average practice by the average physician in the average situation, yesterday In an average patient on average,96 ASA mono-tx,97,98 ASA mono-tx,99 1, 5 1 15 2 25 3 35 4 45 5 55 6 65 7 75 Survival Time (Days) SO, lets call all the patients in our practices and D/C DAPT if longer than 6 months Prodigy and others were in 3 rd 4 th generation stents Exclusion criteria for most studies: Anti coagulants, age, poor EF Multiple stents Lesion length and diameter Intra Coronary Thrombus Need for Overlapping stents Major side Branches Saphenous vein bypass graft to epicardial vessel Any patient with a diseased saphenous vein graft Hold the phone call ION Stent Strut Thickness compared to other DES ION, TAXUS Express, TAXUS Liberte Stents are trademarks of Boston Scientific Corporation; XIENCE V is a trademark of Abbott Laboratories group of companies; Cypher is a trademark of Cordis Corp.; Endeavor is a trademark of Medtronic Inc. Everolimus-Eluting Stents Everolimus concentration: 1 ug/cm 2 : PBMA & PVDF-HFP (7mm thickness) XIENCE V / PROMUS (CoCr-EES) PROMUS Element (PtCr-EES) 18% Chromium 33% Platinum 3% Iron 1% Nickel 15% Tungsten 52% Cobalt 2.6% Molybdenum 9% Nickel.5% Manganese 37% Iron 2% Chromium 1.5% Manganes e PtCr Stent Platform Clinical Program: Paclitaxel and Everolimus ION * Paclitaxel PERSEUS Study Program 1-year Results ACC 21 2-year Results TCT 211 PROMUS Element Plus Everolimus PLATINUM Study Program 9 month QCA TCT 21 1-year RCT Results ACC 211 PBMA=poly (n-butyl methacrylate) (primer layer); PVDF-HFP=poly (vinylidene fluoride-co-hexafluoropropylene) (drug matrix layer) 23 *The ION Stent is commercialized as the TAXUS Element Stent outside the U.S. The PERSEUS and PLATINUM studies are sponsored by Boston Scientific Corporation. The PROMUS Element Plus Stent is an investigational device. Limited by United States Federal Law to investigational use in the U.S. Not for sale in the U.S. 4

Event Rates (per Patient, %) Micron (µ) BSC JNJ ABT MDT 7/8/214 PERSEUS WH (Overall Study) 12-Month Clinical Outcomes in All Patients 15 1 5 6.1 TAXUS Express Stent (N=32) 5.6 7.7 7.4 4.5 TLF: ischemia-driven TLR, or MI/cardiac death related to the target vessel. MACE: MI, TVR, cardiac death 3.8.6 TLF MACE TLR All-Cause Death ION * Stent (N=942) P=.78 P=.86 P=.6 P>.99 P=.34 P=.17 P>.99 Overall MI.7.5. (19/313) (52/922) (24/313) (68/922) (14/313) (35/922) (2/314) (6/922) (/313) (5/922) Q-MI 2.9 P=.48 T. Express 2.9% ION 2.2% 1.6 (9/313) (15/922) NQWMI.3.4 (1/313) (4/918) ST (ARC Def/Prob) 12m DAPT compliance 89%, both groups U.S. Drug-Eluting Stent Launches 211 through 217+ Projections* 21 211 212 213 ION PtCr Stent PROMUS 2.25mm Xience V Nano PROMUS Element Plus PtCr NEVO launch date may change. Oct 19, 21, J&J announced suspension of enrollment for OUS NEVO II clinical trial citing balloon catheter performance issues. Enrollment began in Aug 21, Xience Prime Endeavor Resolute TM 214 215 216 217+ OMEGA TM PtCr BMS Nevo * Resolute TM Integrity TM SYNERGY Program***? ThinMan TM * Metallic Bioabsorbable Stent Program*** Bioabsorbable Stent Program*** BVS * Presented by Louis Cannon, MD at TCT 21. *The ION Stent is commercialized as the TAXUS Element Stent outside the U.S. The PERSEUS WH and PERSEUS SV studies are sponsored and funded by Boston Scientific Corporation. Introduction: Bioabsorbable polymer Durable polymer coatings on drug-eluting stents have been associated with chronic inflammation and impaired healing. SYNERGY Stent Abluminal Bioabsorbable and Drug Bioabsorbable polymer (PLGA) Applied only to the abluminal surface (rollcoat) Thin strut PtCr Stent Potential advantages of bioabsorbable polymer stents: Reduced polymer load Short-term polymer exposure may Decrease risk of late events including ST and TLR Reduce required duration of DAPT and risk if interrupted Durable Permanent + Drug 36 Around Stent Current Durable Abluminal Bioabsorbable PLGA Bioabsorbable + Everolimus * on Abluminal Side of Stent * 2 doses of everolimus evaluated: one similar to PROMUS Stent and one that is half the dose Presented by Ian Meredith, MBBS, PhD at TCT 21 Study sponsored by Boston Scientific Corporation. Not for sale. Abluminal Bioabsorbable Relative Thickness Percutaneous Coronary Intervention Multivariate correlates of cumulative late mortality (7,16 patients discharged alive post PCI, followed 1.4+/- ½ years) Hazard Ratio ± 95% CI (p<.5) 6 5 4 3 2 1 ~5µ 6-8µ ~15µ 14µ 5-12µ Renal Impairment Diabetes mellitus CK elevation (8xULN)* Saphenous vein graft Prior MI Unstable angina Left main PCI Elevated cholesterol Current smoker Advanced age Bioabsorbable Abluminal (Thickness) Red Cell (Diameter) TAXUS Liberté (Thickness) Neutrophil (Diameter) Human Hair (Thickness) *In the absence of new Q waves 4 3 2 1-1 CAUTION: Under Development. Not for sale. Stone et al Circ 21;14:642-647. 5

Patients (%) Target Lesion Failure (%) Event Rates (per Patient, %) 7/8/214 SPIRIT IV: Impact of Diabetes (TLF 1-yr) Sites of action of rapamycin and paclitaxel PROMUS (Xience V ) Stent TAXUS Express Stent Type II Diabetes P<.1 P=.8 Hyperglycemia Free Fatty Acids Insulin Receptor Hyperinsulinemia ROS PKC IKKb IRS-1 Shc PI 3 kinase PDK-1 Akt mtor Sos Ras Olimi Akt p 7S6K Cell Cycle Effectors Raf 52/1652 55/815 49/761 26/379 enos S6 MAPKK TLF=Cardiac Death, Target Vessel MI, or ischemia driven TLR 1 year = 365 ± 28 days NO Protein synthesis Vasodilation Inhibits SMC Migration Anti-thrombotic MAPK (ERK1,2, p38, JNK) Vasoconstriction Mitogenesis Pro-inflammatory factors Paclitaxel Stone, G. N Engl J Med 21;362:1663-74. The PROMUS Stent is a private-labeled XIENCE V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE V is a trademark of Abbott Laboratories group of companies. Caution: The safety and effectiveness of the TAXUS Stent Systems, ION Stent and PROMUS Stent have not been established in patients with diabetes mellitus. Caution: The safety and effectiveness of the TAXUS Stent Systems and ION Stent have not been established in patients with diabetes mellitus. In high glucose: Inhibition of SMC migration by Paclitaxel is preserved; Sirolimus loses effects The IC5 for sirolimus on migration is <.1 ng/ml, but > 1 ng/ml under high glucose conditions. The effect of sirolimus to inhibit smooth muscle migration is thus reduced by at least 1-fold. PERSEUS Diabetes Substudy Unadjusted 12-Month Outcomes ION *Stent-Treated Patients 2 Non-Diabetic (N=852) Diabetic (N=314) Patterson C, Arteriosclerosis, Thrombosis, and Vascular Biology, 26;26;1473-148 3 3 15 1 5 P=.17 P=.11 P=.29 P=.6 P=.95 P=.61 5.4 7.6 7.5 1.5 3.8 5.3.5 TLF ** MACE TLR All-Cause Death **TLF: ischemia-driven TLR, or MI/cardiac death related to the target vessel. MACE: MI, TVR, cardiac death Baseline Lesion Differences Non-Diabetic (N=852) 1.7 1.9 2. (45/836) (23/34) (63/836) (32/34) (32/836) (16/34) (4/837) (5/33) (16/836) (6/34) MI Diabetic (N=314).4 P Value RVD (mm) 2.67±.51 2.58±.55.2 Length (mm) 13.53±5.86 14.4±6.33.3.7 (3/834) (2/299) ST (ARC Def/Prob) Presented by Louis Cannon, MD at TCT 21. *The ION Stent is commercialized as the TAXUS Element Stent outside the U.S. The PERSEUS study is sponsored by Boston Scientific Corporation. Caution: The safety and effectiveness of the ION Stent have not been established in patients with diabetes mellitus. Stent Thrombosis - ARC Def/Prob 3-Year Follow-up No. at risk CoCr-EES (N=749) PtCr-EES (N=758) HR [95% CI] = 1.23 [.33, 4.57] P =.76 CoCr-EES 749 744 74 732 723 PtCr-EES 758 751 747 742 736 PtCr- EES CoCr- EES Months Since Index Procedure 716 73 ARC Definite Stent Thrombosis* Early (<3d) Late (3d -1yr) Very Late (1-3 yrs) 73 722 P>.99 n=1 n=2 n=2 n=3 n=1.7% (N=5/77).6% (N=4/675).7%.5% 5 516 Antiplatelet Medication Usage Medication CoCr-EES PtCr-EES P (N=749) Discharge (N=758) value Aspirin 99.6% 98.9%.14 Thienopyridine 99.2% 98.9%.61 Aspirin + Thienopyridine 98.9% 98.%.15 1 Year Aspirin 93.7% 94.7%.41 Thienopyridine 82.7% 84.8%.29 Aspirin + Thienopyridine 8.5% 83.4%.13 2 Years Aspirin 92.7% 94.8%.9 Thienopyridine 5.8% 53.7%.25 Aspirin + Thienopyridine 48.% 51.4%.19 *There were no adjudicated ARC probable ST events through 3 years of follow-up; binary rates Aspirin + Thienopyridine 42.9% 42.7%.93 CoCr-EES: 1 ST occurred during 1-2 years; PtCR-EES: 1 ST occurred during 1-2 years and 1 during 2-3 years ARC=Academic Research Consortium; Def/Prob=definite/probable; ST=stent thrombosis 2 12 3 Years Aspirin 95.2% 95.3%.94 Thienopyridine 46.5% 46.%.84 6

Delayed Endothelialization Overlap more than Doubles the Toil and Troubles Crush Technique SES PES Try to re-cross two layers of struts into the SB, and finish up with kissing balloons BMS Overlap BMS Overlap Results will vary, depending on the angulation of the SB Conclusions: BMS showed far greater endothelialization than DES Lack of coverage highlighted in areas of overlap Less surface coverage by endothelial cells in PES 37 than SES Finn AV. Circulation. 25;112:27-278 Ormiston 23 Crush Technique Position both stents simultaneously. Deploy the SB first, then crush it with the main branch stent Inflammation Overlapping SES vs PES Conclusions: DES further delays arterial healing and promote inflammation Compared to SES, PES induce greater: Fibrin deposition Medial cell loss WBC Infiltration Late Neointimal Hyperplasia Ormiston 23 Finn AV. Circulation. 25;112:27-278 4 Mr John Average Deserves : Guideline Based Medical Care Patient: Mr John Average Not so average Guidelines do not apply (including CHADS2VASC hx) In Conclusion: Stents have been in Rapid Evolution: - Smaller diameter, enhanced flexibility, trackability, Visibility - Less recoil, Less non-biodegradable (inflammatory) polymer Studies are very controlled protocol based populations Patients exist in uncontrolled populations Medicine is not pre-programmed robotics Many Guidelines are Medical Legends Studies of yesterday do not reflect practice of today, especially in the USA, when worldwide studies do not reflect current average drugs, our genetics, our diet, exercise pattern or our practices, or the US average patient, on average THANK YOU 7

3.5% upper boundary non-inferiority margin 7/8/214 PERSEUS WH, ATLAS and SPIRIT Trials Data Sets in Absence of Small Vessels TAXUS ATLAS WH 15% 1% 5% 12.3% 12.5% RVD 2.5mm p=.94 6% 4% 2% SPIRIT III 4.4% 5.1% RVD > 2.775mm subset RR = 1.17 [.46, 2.97] Primary Endpoint Target Lesion Failure at 12 Months Population Difference [2-sided 95% CI] (1-sided UCB) CoCr- EES (N=762) PtCr- EES (N=768) P Difference Value [2-sided 95% CI] (noninferiority) (superiority) % 6% 4% 2% % (n=978) 4.7% (n=867) 12 month MACE* (n=45) SPIRIT IV 3.9% (n=91) 12 month TLF* TAXUS Express Stent *Cardiac Death, MI, or ischemia-driven TVR RVD > 2.75 mm subset HR =.83 [.49, 1.41] *Cardiac Death, target-vessel MI, or ischemia-driven TLR TAXUS Liberté Stent % 8% 5% 3% % (n=137) 12 month MACE* PERSEUS WH 6.1% (n=313) (n=274) 5.6% (n=922) 12 month TLF* Xience V (PROMUS ) Stent *Cardiac Death, MI, or ischemia-driven TLR RVD 2.75mm P=.78 *Target Vessel Cardiac Death, targetvessel MI, or ischemia-driven TLR ION Stent ATLAS WH: BSC Data on File; SPIRIT III: Gregg Stone, et. Al. JAMA: 28 April (299)16:193-13. SPIRIT IV: Presented by Gregg W. Stone, MD, TCT 29 ( + total patient N= 1351 reported only). The PROMUS Stent is a private-labeled XIENCE V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE V is a trademark of Abbott Laboratories group of companies. SPIRIT is sponsored by Abbott. *The ION Stent is commercialized as the TAXUS Element Stent outside the U.S. The PERSEUS WH and PERSEUS SV studies are sponsored and funded by Boston Scientific Corporation. Per protocol (1º endpt) Intentto-treat -5-4 -3-2 -1 PtCr-EES better 2.13% 1-sided UCB 2.1% 1-sided UCB 1 2 3 4 5 CoCr-EES better 2.9% 3.4%.5%.1 (21/714) (25/731) [-1.3%, 2.3%].6 3.2% 3.5%.3%.9 (23/727) (26/742) [-1.5%, 2.2%].72 UCB=upper confidence bou1n1d 8

TAXUS V Trial IVUS Enriching the Understanding Of Efficacy and Healing Control Stent 31.8 % Net Volume Obstruction TAXUS Express 2TM Stent 13.1 % Net Volume Obstruction 59% reduction 9

Balance of Efficacy and Healing Incomplete Apposition DES studies with available IVUS follow-up FPO 6 5 4.8 Stent struts not covered by neointima Too Little?? Optimal? Too Much?? Higher rates of TLR % I A 5 4 3 2 9.9 Incomplete Apposition 2 1. 2 1 8. Negative Late Loss.1.4 In-stent Late Loss (mm).6 1 5. 1 2.6 1 1.5 8.7 9. 1 5.9 6.5 4. 3. 4. T AXUS I I T AXUS I V T AXUS V RAVEL1 SI RI US1E- SI RI US2 DI ABET ES3 n=15/119 n=4/99 n=17/148 n=1/41 n=18/14 n=nr n=nr P=ns P=ns P=ns P=nr P=nr P=.7 P=.1 1. Cypher Stent DFU 2. E-SIRIUS IVUS presentation, AHA 23 3.Pilar, Jimaenez-Quevedo, et. al. The DIABETES Trial. 9 month IVUS,, ACC 25 TAXUS TAXUS Control Cypher TM Cypher TM Control For reference purposes only. Late-Incomplete Apposition Potential for Stent Thrombosis Baseline Follow-up In a Taxus and Cypher study of patients with late incomplete apposition upon clopidogrel discontinuation: Late-Incomplete Apposition Potential Mechanisms Baseline Follow-up No Remodeling No Remodeling 2% had stent thrombosis* Positive Remodeling Positive 59 6 * Study by Dr. Abizaid, presented at TCT 25. Remodeling Source: Dr. Peter Fitzgerald 1

Late Stent Thrombosis Factors to Consider Discontinuation of Anti-Platelet Therapy Delayed Endothelialization Late Stent Thrombosis Late Incomplete Apposition Thank you Hypersensitivity/ Inflammation 61 11