Synergy: Short DAPT Study Jeffrey J. Popma, MD Professor of Medicine Harvard Medical School Director, Interventional Cardiology Beth Israel Deaconess Medical Center Boston, MA

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. Financial Relationship Company Institutional Grants Medtronic Medical Advisory Board Boston Scientific Consultant Direct Flow Medical Abbott Vascular 2 2 2

PCI: It has been quite a ride . . . . 1977 POBA: Getting Artery Open 1994 BMS: Keeping Artery Open 2003 DES Decrease Restenosis 2015+ Future DES: Optimize Healing PCI EVOLUTION Continuous improvement in platform design and acute performance Lower late events rates – ST, TLR Reduced need for prolonged DAPT Reduced risk of neoatherosclerosis

Freedom from stent thrombosis Long term efficacy Now as a “recreational” interventionalist with lots of STEMI call, how do I chose what DES to use? Deliverability Freedom from stent thrombosis Long term efficacy Decisions are not always data driven but more visceral based on incomplete knowledge about the patient 4 4 4

DES design affects procedural success and clinical outcomes Elements of DES Design DES design affects procedural success and clinical outcomes Scaffold Delivery System Polymer Drug

Platinum Chromium (PtCr) Alloy Platinum has over twice the density of Iron or Cobalt (improved radiopacity) Platinum provides increased strength when alloyed with stainless steel Specifically developed for coronary stents Biocompatible

Durable Polymer Coated Distribution / thickness Contemporary DES Platforms Strut and Coating Thickness In Perspective Durable Polymer Coated Bioabsorbable Polymer Coated Xience CoCr-EES Resolute Biomatrix Nobori Ultimaster SYNERGY MiStent Orsiro Promus PtCr-EES CoNi-ZES 316L-BES CoCr-SES PtCr-EES Strut thickness 81 µm 0.0032” 89 µm 0.0035” 120 µm 0.0046” 125 µm 0.0047” 80 µm 0.0031” 74 µm 0.0029” 64 µm 0.0025” 61 µm 0.0024” Polymer PVDF BioLINX PLA PDLLA + PCL PLGA PLLA Probio* Distribution / thickness Conformal 7-8µm / side 6µm / side Abluminal 10 µm 20 µm 15 µm 4 µm 5 µm / 15 µm 3.5 µm / 7.5 µm *silicon carbide

PtCr Element™ Platform Architecture Wider peaks focus strain to minimize recoil Short and increased segments per length improve conformability and minimize gaps on a bend Helical, two-connector design for maximum flexibility and conformance to the vessel Nested peaks minimize strut-to-strut contact on bends and enhance deliverability

PtCr Element™ Platform Improved radial strength, flexibility, and resistance to recoil Bench Test Data Radial Strength Flexibility/Conformability Recoil Improved radial strength Reduced Recoil Improved flexibility Percent (%) Recoil Newtons/mm N=10 Newtons·mm N=15 N=10 N=15 N=10 N=15 N=10 PROMUS Element™ Stent Xience V™ Stent PROMUS Element™ Stent Xience V™ Stent PROMUS Element™ Stent Xience V™ Stent Data on file at Boston Scientific. 2.5mm diameter stents. Bench test results may not be indicative of clinical performance.

(Pre-procedure minus Post-procedure) Vessel Angulation and Straightening Change in angulation significantly lower with PROMUS Element All Lesions Single Stents Only P=0.01 P=0.01 P=0.02 P=0.03 (Pre-procedure minus Post-procedure) Change in Angulation (50) (50) (50) (50) (48) (41) (48) (41) Xience V™ Stent PROMUS Element™ Stent (lesions)

Stent Fracture Associated with DES Restenosis Human autopsy analysis EES implanted in LOM, 6 months Proximal Distal Foerst et al. JACC 2012;5(3): 239-242.

DES design affects procedural success and clinical outcomes Elements of DES Design DES design affects procedural success and clinical outcomes Scaffold Delivery System Polymer Drug

How may an abluminally coated bioabsorbable polymer DES be optimal for healing? Uncoated surface on luminal side to promote cell coverage and adhesion Vessel Lumen Strut Freedom from long-term polymer exposure once coating is absorbed Arterial Wall Targeted drug delivery reduces risk of restenosis and inflammation

SYNERGY Stent Synchronous Drug Release & Polymer Absorption Preclinical evaluation in porcine model Everolimus Arterial Tissue Concentration ng/mg Everolimus Mass Remaining PLGA Mass Remaining Limit of Quantitation (LOQ) Wilson, G. J., et al. Cathet. Cardiovasc. Intervent. doi: 10.1002/ccd.25993

Time Course For Polymer Bioabsorption Not all bioabsorbable technologies are the same Drug Release Bioabsorbable Polymer References: SYNERGY: Presented by I Meredith at TCT 2012 Abluminus: Presented by S. Dani at TCT 2012 Elixir Desyne BD and Elixir DESolve: Presented by A. Abizaid at TCT 2012 Firehawk: Presented by Bo Xu at TCT 2014 Biomatrix and Nobori: Company brochure on website SVELTE: Presented by M Pomeranz at EuroPCR 2012 Orsiro: Presented by S Windecker at TCT 2012 BVS: Serruys et al, Lancet 2009; 373: 897-910 Reva: Presented at CRT April 2006 ART: Presented by John Ormiston at ACC 2013 MiStent: Presented by Alexandra Lansky, MD at CRT 2014 BioMime: Presented by Martin Leon, MD at TCT 2013 DREAMS: Garg et al Nat. Rev. Cardiol. 10, 248–260 (2013); Time (Months) Non-head to head trials not for comparative purposes. Provided for educational information only.

SYNERGY is associated with a high degree of intimal coverage and Early healing assessment with OCT of SYNERGY at 3 and 6 months after implant A-D: Different Case Examples of SYNERGY at 3 months E-H: Different Case Examples of SYNERGY at 6 months 3 MONTH 6 MONTH SYNERGY is associated with a high degree of intimal coverage and apposition at 3 months post implant with additional increase at 6 months De la Torre Hernandez, et al. Catheterization and Cardiovascular Interventions DOI 10.1002/ccd. Case study not necessarily representative of all cases. Results in other cases may vary.

DES design affects procedural success and clinical outcomes Elements of DES Design DES design affects procedural success and clinical outcomes Scaffold Delivery System Polymer Drug

EVOLVE Trial Design and Methods Patients with de novo native coronary lesions ≤ 28 mm in length, RVD ≥2.25 mm ≤ 3.5, %DS>50% (excluded LM disease, CTO, AMI or recent MI) Randomized 1:1:1 at 29 sites (Europe, Australia, New Zealand) PROMUS Element N=98 SYNERGY N=94 SYNERGY ½ Dose N=99 Single-blind, noninferiority design Primary Clinical Endpoint: TLF (TV-CD, TV-MI, or TLR) at 30 days Primary Angiographic Endpoint: In-stent late loss at 6 months Per protocol patients were treated with clopidogrel, ticlopidine or prasugrel for at least 6 months following the index procedure Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362

EVOLVE Trial Key Results 6 Months 5 Years P=0.19 P=0.65 P=0.56 P=0.60 Patients, % mm Late Loss TLF ST (Def/Prob) PROMUS Element (n=98) SYNERGY (n=94) SYNERGY Half Dose (n=99) Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362.; Presented by Meredith at EuroPCR 2016. Intent-to-treat; P values are versus PROMUS Element (Fisher exact test)

Protocol-required angiogram Late Events with Permanent vs. Bioabsorbable Polymer DES 5-year Target Lesion Failure in EVOLVE Trial SYNERGY vs PE HR 0.77 [0.24, 2,42] P=0.65 SYNERGY ½ vs PE HR 0.74 [0.23, 2.32] P=0.60 20 Protocol-required angiogram TLF (%) 7.2% …………….. 5.5% 5.2% 1 2 3 4 5 Years Numbers at risk PE 98 93 92 67 SYNERGY 90 86 83 82 61 SYNERGY ½ Dose 99 88 65 Safety Population; KM Event Rate; log-rank P values. Presented by Meredith at EuroPCR 2016.

Protocol-required angiogram Late Events with Permanent vs. Bioabsorbable Polymer DES 5-year TLR in EVOLVE Trial SYNERGY vs PE HR 0.18 [0.02, 1.47] P=0.07 SYNERGY ½ vs PE HR 0.17 [0.02, 1.40] P=0.06 20 Protocol-required angiogram TLR (%) 6.1% 1.1% 1.0% 1 2 3 4 5 Years Numbers at risk PE 98 93 92 68 SYNERGY 90 87 84 83 61 SYNERGY ½ Dose 99 95 91 67 Safety Population; KM Event Rate; log-rank P values. Presented by Meredith at EuroPCR 2016.

EVOLVE II Pivotal Trial Design Patients with ≤3 native coronary artery lesions in ≤ 2 major epicardial vessels; lesion length ≤ 34 mm, RVD ≥2.25 mm ≤ 4.0, %DS≥50<100 (excluded LM disease, CTO, SVG, ISR or recent STEMI) Randomized Cohort (RCT) PK Substudy 125 global sites PROMUS Element Plus N=838 SYNERGY N=846 SYNERGY N=21 Diabetes Substudy RCT Design Multicenter noninferiority trial Pivotal, single-blind, 1:1 randomization Primary Endpoint: TLF (CD, TV-MI, or TLR) at 12 mo Follow-up through 5 years SYNERGY N=203 DAPT (ASA + clopidogrel, ticlopidine, prasugrel, ticagrelor) ≥ 6 months or longer as tolerated Kereiakes, et al. Circ Cardiovasc Interv. 2015;8:e002372. DOI: 10.1161/CIRCINTERVENTIONS.114.002372.

EVOLVE II TLF at 2 years TLF (%) 9.4% 6.7% 8.5% 6.5% 6 12 24 PROMUS Element Plus vs SYNERGY 1 Endpoint: 12 months ITT Pnoninferiority=0.0005 16 2 years HR 1.10 [0.79, 1.52] P=0.57 12 TLF (%) 9.4% 6.7% 8.5% 8 4 6.5% No. at risk 6 12 24 PE+ 838 790 772 538 SYNERGY 846 807 794 553 Months ITT Population; Patients who did not receive a study stent were censored at 1 year; KM Event Rates; log-rank P values Presented by Kereiakes ACC 2016

EVOLVE II Stent Thrombosis at 2 years Definite/Probable : ITT Population Acute (≤1 d) Subacute (2-30 d) Late (30 d – 1 y) Very Late (1 – 2 y) N=5 (2 Definite/3 Probable) N=1 (Def) 0.8% (N=6) P=0.31 N=2 (Definite) N=1 (Prob) 0.4% (N=3) No definite ST in the SYNERGY arm after 24 hours Presented by Kereiakes ACC 2016

ST Landmark Analysis Definite/Probable ST after 24 hours PROMUS Element Plus vs SYNERGY >24 h Landmark HR 0.16 [0.02, 1.37] P=0.056 4 3 Definite/Probable ST (%) 2 1 0.8% * 0.1% 1d 6 mo 12 mo 24 mo ‡Day 715 – Definite ST: Patient was not compliant to aspirin and was not taking at P2Y12 inhibitor at time of presentation ST occurring between 0 and 1 years have been previously reported in Kereiakes et al. Circ Cardiovasc Interv 2015 ITT; Patients who did not receive a study stent were censored at 1 year; KM Event Rate; log-rank P values Presented by Kereiakes ACC 2016

SYNERGY: BSC Clinical Trials EVOLVE EVOLVE II RCT EVOLVE II QCA EVOLVE China EVOLVE Short DAPT First Human Use Trial. 291 patients. PROMUS Element vs. SYNERGY vs. SYNERGY Half-Dose (1:1:1). Primary Endpoint: 6 month Late Loss + Composite Safety @ 30 days Global IDE Trial. 1684 patients, 125 sites, 16 countries . PROMUS Element Plus vs. SYNERGY (1:1) single-blind trial. Primary Endpoint: 12 month TLF Quantitative Angiography. 100 Patient Registry, 12 sites (Australia, Japan, New Zealand, Singapore). Primary Endpoint: 9 month in-stent Late Loss China regulatory approval trial (SFDA). 400 patients, up to 15 sites. PROMUS Element Plus vs. SYNERGY (1:1) Primary Endpoint: 9 month Late Loss 3/12 Month DAPT. Prospective, Multi-center, Global,~1500 patients. Primary Endpoint: Cardiac Death/ MI Enrolling

EVOLVE Short DAPT Study Design Prospective, N=2000, ~100 global sites Key Inclusion Criteria Patients considered by the treating physician to be at high risk for bleeding ≥75 years of age and high bleeding risk long term anticoagulation therapy history of major bleeding stroke, or renal insufficiency/failure (excluded LM disease, ostial lesions, >2 lesions, CTO, SVG, ISR, NSTEMI or STEMI) P2Y12 + ASA ASA Only (for patients eligible for discontinuation of P2Y12) 3m 15m Co-primary Endpoints: Death or MI, ARC def/prob ST Secondary Endpoint: Rate of major bleeding (BARC bleeding classification 2,3,5) Primary and secondary endpoints evaluated between 3 and 15 months Propensity adjusted comparison to historical control patients treated with standard DAPT will be performed Presented by Mauri at TCT 2015. 27

SYNERGY Clinical Trials Ongoing and Upcoming Trials Multi-vessel Disease SYNERGY Clinical Trials Ongoing and Upcoming Trials Bifurcation Lesions SYNTAX II BIORESORT SWEET IDEAL Left Main SORT OUT VIII MULTISTARS AMI SCAAR SYNERGY research program studying >20,000 patients. CTO SYNTAX II SWEET BIORESORT CELTIC OCT/GSI SCAAR ACS SYNTAX II CONSISTENT Diabetes SENIOR BIORESORT SWEET TRANSFORM OCT SORT OUT VIII MULTISTARS AMI SCAAR Long Lesions BIORESORT SWEET SCAAR EVOLVE II SYNTAX II BIORESORT SWEET SCAAR EVOLVE II DAPT Imaging / Healing SENIOR EVOLVE Short DAPT POEM Addressing full spectrum of cardiovascular disease complexity BSC Core Trials TIMELESS MOVES TRANSFORM OCT SORT OUT VIII GREEK PLATELET EVOLVE EVOLVE II EVOLVE China EVOLVE Short DAPT BSC Sponsored Trials Investigator Sponsored Research

Summary The SYNERGY Stent design goals are to address needs surrounding complex PCI Best in class deliverability and acute performance Optimal healing / rapid endothelialization Thin struts Abluminal coating Low polymer load Synchronous drug release and polymer absorption Short-term polymer exposure Drug present in artery while polymer degrades May allow short DAPT without risk of ST