Patrick W. Serruys, MD PhD Imperial College London, United Kingdom - PowerPoint PPT Presentation

Late-Breaking Trials 2, Co-Sponsored by Circulation A Randomized Trial Evaluating an Ultra-thin Strut Bioresorbable Polymer-based Coronary Drug Eluting Stent in an All-comers Patients Population Patrick W. Serruys, MD PhD Imperial College London, United Kingdom Erasmus University, Rotterdam, the Netherlands Azfar Zaman, Robbert J de Winter, Upendra Kaul On behalf of the TALENT Investigators Saturday, Sep 22, 2018, 12:40 PM – 12:52 PM, Main Arena 1

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 • • Grant/Research Support Abbott • • Consulting Fees/Honoraria Biosensors • Medtronic • Micell • Sinomedical Sciences Technology • Philips/Volcano • Xeltis • HeartFlow All TCT 2018 faculty disclosures are listed online and on the App. 2

Background ▪ A recent meta-analysis showed that ultra-thin strut DES (<70 μm ) reduced the incidence of TLF compared with contemporary thicker strut DES. * ▪ Safety and efficacy of Supraflex SES (technology from India) with ultra-thin struts and biodegradable polymer were compared with Xience EES in an all- comers population. ▪ Since clinical outcomes of contemporary drug- eluting stents are reaching a “safety” plateau, it is likely that cost effectiveness will influence in the near future “the stent market”. * Bangalore S, Circulation. 2018 Jun 26.doi: 10.1161/CIRCULATIONAHA.118.034456. [Epub ahead of print] 3

The price cap of coronary stent in India • The Indian stent market is around 0.55 million stents annually, with more than 90% DES (values about 531 million USD). • The market is growing around 15% annually . • It is expected to become the 2 nd largest international market after China by 2020. Stent price in India DES BMS $1800 New pricing policy $670 Feb 2017 $440 $110 DES BMS DES BMS pre post - Positive impact - • More people can afford PCI. • More patients with multivessel disease will opt for PCI instead of CABG. • Boost for domestic industry and made in India DES. A regulation required for Indian companies to demonstrate that their product is > non-inferior to other proven stents, by outcomes data in RCT TALENT Kaul U, Eurointervention 2017 Jun 20;13(3):267-268 4

Trial organization (investigator-initiated trial) • Sponsor: European Clinical Research Institute (www. ECRI -trials.com) • Grant giver: • SMT (Supraflex SES) • Clinical Research Organization: Cardialysis • Statistical analysis: Cardialysis • Clinical event committee (CEC) - Prof. W. Rutsch (Catheterisation Laboratories Charité, University Clinic Berlin, Germany) - Dr. S. Garg (Central Manchester & Manchester children’s Foundation Trust, East Lancashire NHS Trust United Kingdom) - Dr. J-P. R. Herrman (Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands) - Dr. B. Rensing (St. Antonius Ziekenhuis, Nieuwegein, the Netherlands) • Data and Safety Monitoring Board (DSMB) - Prof. S. James (DSMB Chairman, Uppsala University, Sweden) - Prof. H. Boersma (DSMB Biostatistician, Erasmus Medical Center, Rotterdam, the Netherlands) - Dr. J. ten Berg (DSMB member, St. Antonius Hospital, Nieuwegein, the Netherlands) 5

Supraflex SES Platform Stent material CoCr (L605) with highly flexible ‘S–link’ interconnector Strut 60 μ m across all stent diameters (2.0 to thickness 4.5mm) Carrier Biodegradable Top layer - polymer 0% drug • matrix Protective layer (PVP: poly-vinylpyrrolidone ) • Base layer - PVP 100% drug (Sirolimus) • PLLA/PLGA PLLA and PLGA • with Sirolimus Coating Circumferential The average thickness: 4-5 μ m Drug Sirolimus 1.4 μ g/mm 2 Release 1. Initial burst profile 70% released within 7 days - Aiming to prevent excessive cell - growth 2. Sustained release up to 48 days 6

Hypothesis and sample size calculation • Hypothesis Non-inferiority of device-oriented endpoint (DOCE) – a composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularization – in the Supraflex arm compared with the Xience arm at 12 months post-procedure. • Sample size calculation  Expected DOCE rate of Xience at 12 months: 8.3% (Resolute All-comers (Xience arm))*  Non-inferiority margin of 4.0%  One-sided type I error of 0.05  85% power to detect non-inferiority  Assume lost to follow-up of 3% ->a total of 1435 subjects were to be randomized. 7 *Serruys PW, N Engl J Med 2010 Jul 8;363(2):136-46

TALENT study flow chart All-comers patient population “All - comers” 1435 patients from 23 enrolling sites population Randomization (1:1) • Any ischemic coronary syndrome (STEMI, NSTEMI, Supraflex SES Xience EES UAP,SAP) N=720 N=715 • Any type of lesions ✓ Left main ✓ SVG 11 withdrew consent 7 withdrew consent ✓ CTO 1 lost follow up ✓ Bifurcation Primary Endpoint: non-inferiority comparison of ✓ ISR 709 (98.4%) 707 (98.8%) DOCE at 12 months ✓ etc. - included in ITT analysis - included in ITT analysis • Unrestricted use of * Intention-to-treat analysis DES DOCE is defined as a composite of cardiac death, target vessel myocardial (number, length) infarction**, and clinically-indicated target lesion revascularization **Definition of MI: SCAI consensus for periprocedural MI with 48 hours after index PCI and 3 rd Universal definition later than 48 hours after the index procedure. 8 10

Baseline characteristics Characteristic Supraflex (n=720) Xience (n=715) Percentage difference (95% CI) Age (years) 65.0±10.3 64.7±10.1 0.3 (-0.8 to 1.3) 75.8% Male 76.5% -0.7% (-5.1 to 3.7%) BMI (kg/m 2 ) 28.3±4.8 28.3±4.6 0.0% (-0.5 to 0.5%) Risk factors Current smoker 24.5% 24.1% 0.4% (-4.0 to 4.9%) 21.8% Diabetes mellitus 24.9% -3.1% (-7.5 to 1.3%) Insulin dependent 6.7% 9.4% -2.7% (-5.5%, 0.1%) Hypertension 65.3% 66.1% -0.8% (-5.7 to 4.1%) 61.8% Hypercholesterolemia 60.2% 1.6% (-3.4 to 6.7%) Family history of CAD 46.3% 45.2% 1.2% (-4.1 to 6.5%) History of Previous MI 18.9% 17.9% 1.0% (-3.0 to 5.0%) PVD 7.1% 9.0% -1.9% (-4.7 to 0.9%) 24.3% Previous PCI 21.4% 2.9% (-1.4 to 7.2%) < Previous CABG 4.6% 7.7% -3.1% (-5.6 to -0.6%) Heart Failure 4.7% 6.9% -2.1% (-4.5 to 0.3%) 2.8% Renal Insufficiency* 2.0% 0.8% (-0.8 to 2.4%) Indication 40.4% Stable angina 43.4% 3.0% (-2.1 to 8.1%) ACS 59.6% 56.6% UAP 16.1% 13.8% 2.3% (-1.4 to 6.0%) NSTEMI 26.9% 26.4% 0.5% (-4.1 to 5.1%) STEMI 16.5% 16.4% 0.2% (-3.7 to 4.0%) 9 Data are mean±SD (n) or n (%) *Renal insufficiency is defined as serum creatinine >2.5 mg/dL or creatinine clearance ≤ 30mL/min.

Lesion and procedural characteristics Lesion characteristics (Patient level) Procedural characteristics (Lesion level) Supraflex Xience Supraflex Xience P-value P-value n=1046 lesions N=1030 lesions n=1046 lesions N=1030 lesions Vessel location: 0.070 77.2% 75.9% 0.509 Pre-dilatation LAD 44.7% 41.9% 13.6±4.3 13.5±4.1 0.677 Max pressure (atm) > 21.0% 23.0% LCX Max balloon diameter (mm) 2.52±0.43 2.46±0.43 0.006 32.3% 31.8% RCA Stent characteristics (per lesion) 1.4% 1.6% Left main 1.2±0.5 1.2±0.5 0.592 Number of stents used 0.5% 1.7% Bypass graft Total stent length (mm) 25.7±14.5 26.0±14.5 0.623 Number of lesions treated 1.45±0.77 1.44±0.74 0.760 Overlapping stents 21.1% 19.5% 0.361 per patient Total stented length per 37.2±27.4 37.2±27.0 0.961 Stent length (mm) 21.3±8.3 21.8±8.8 0.120 patients (mm) Nominal Stent diameter TIMI flow pre 0.122 3.0±0.5 3.0±0.5 0.186 (mm) Flow 0 13.7% 10.9% Post balloon dilatation 52.0% 52.2% 0.918 Flow 1 3.8% 4.1% Max pressure (atm) 17.1±4.3 17.5±3.9 0.096 Flow 2 6.3% 8.2% Max balloon diameter (mm) 3.30±0.58 3.29±0.60 0.804 Flow 3 72.5% 72.2% 4.2% 4.1% 0.883 Restenotic lesion 40.2% 40.2% 0.999 Small vessel (≤ 2.75 mm) 49.7% 49.6% 0.964 Long lesion (> 18 mm) 10 16.0% 15.2% 0.650 Bifurcation involved Data are mean±SD (n) or n (%)

Device success and components Supraflex Xience Difference n=720 patients n=715 patients p value (95% CI) n=1046 lesions n=1030 lesions Operators attempted to • The crossovers to non-allocated stent - in total 21 lesions out of implant the allocated 997 lesions 1003 lesions -2.1% (-3.7 to -0.5%) 0.014 1046 in the Supraflex arm (12 lesions crossovered to the Xience stent arm, 9 lesions crossovered to non-study stents) - were clustered No stent was able to 1 (0.1%) 3 (0.3%) - 0.2% (-0.6 to 0.2%) 0.371 in 7 out of the 23 centers. cross the lesion • Some investigators had a tendency to quickly crossover to a Stent dislodgement familiar stent technology. and failure to 1 (0.1%) 0 (0.0%) 0.1% (-0.1 to 0.3%) 1.000 retrieve Cross over Allocated stent did > 21 (2.0%) 1 (0.1%) 1.9% (1.0 to 2.8%) <0.0001 not cross the lesion XIENCE: 12 (57%) Supraflex: 1 (100%) Others: 9 (43%) In-stent residual 1 (0.1%) 1 (0.1%) -0.0% (-0.3 to 0.3%) 1.000 stenosis ≥30% Device success 97.6% 99.5% < -1.9% (-3.0 to -0.9%) 0.0003 (per lesion) (973/997) (998/1003) 11