BIONYX (TWENTE IV) A Randomized Trial Evaluating a Thin Composite Wire Strut Durable - PowerPoint Presentation

1. BIONYX (TWENTE IV)A Randomized Trial Evaluating a Thin Composite Wire Strut Durable Polymer-Based DES Compared with an Ultra-Thin Strut Bioresorbable Polymer-Based DES in an All-Comers Patient PopulationClemens von Birgelen, MD PhD FESCThoraxcentrum Twente, MST, Enschede, the NetherlandsOn behalf of the BIONYX InvestigatorsBIONYX

2. Disclosure Statement of Financial InterestPersonal Grant/Research SupportConsulting Fees/HonorariaMajor Stock Shareholder/EquityRoyalty IncomeOwnership/FounderIntellectual Property RightsOtherInstitutional Grant/Research SupportnonenonenonenonenonenonenoneAbbott Vascular, Biotronik, Boston Scientific, MedtronicWithin 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:

3. The majority of contemporary DES use platforms from cobalt-chromium alloy which has a limited radiographic visibility.Resolute Onyx was developed to improve visibility using a novel thin strut composite wire platform which has a dense platinum-iridium core.The novel strut material allows lowering strut thickness, which might reduce stent thrombosis while preserving radial strength.The range of stent diameters (2.0–5.0 mm) is the widest currently available, which might reduce suboptimal stent expansion and incomplete stent apposition.Background

4. Study DevicesResolute OnyxOrsiroCoating characteristicsDurableBioresorbableBare strut thickness, μm81 / 91 (≤ 4.0 / ≥ 4.5 mm stents)60 / 80 (≤ 3.0 / ≥ 3.5 mm stents)Coating thickness, μm5.6 (conformal) 7.4 / 3.5 (ab-/luminal) Coated strut thickness*, μm 9271Stent platformswaged shape core wire from platinum-iridium surrounded by cobalt-chromium alloycobalt-chromium alloyPolymerBioLinx®, a blend of hydrophobic C10, hydrophilic C19, and poly-vinyl pyrrolidonePLLA (poly [L-lactide] acid) (BIOlute®), on thin amorphous silicon carbide (proBIO®)DrugZotarolimus Sirolimus Drug release time, months63.3Degradation time, months– < 24 Available stent diameters2.0 – 5.02.25 – 4.0* of the smallest stent

5. To assess at 1-year follow-up, whether the safety and efficacy of the novel Resolute Onyx stent is non-inferior to the reference Orsiro stentAim

6. Primary Endpoint Target Vessel Failure (TVF)A composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization at 1-yearSample Size Assuming a TVF rate of 6% at 1-year (based on previous data)1, 2,470 study participants would yield at least 80% power to detect non-inferiority (pre-specified margin 2.5%) with an upper 1-sided alpha of 0.05, allowing for 3% loss to follow-upPrimary Endpoint and Sample Size1. von Birgelen et al. Lancet. 2014;383:413-23Primary Endpoint Target Vessel Failure (TVF)A composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization at 1-yearSample Size Assuming a TVF rate of 6% at 1-year (based on previous data),1 2,470 study participants would yield at least 80% power to detect non-inferiority (pre-specified margin 2.5%) with an upper 1-sided alpha of 0.05, allowing for 3% loss to follow-up

7. 1-year primary endpoint report: von Birgelen C. et al. Lancet 2018; online published on Sept. 22, 2018 ∙ LBCT presentation at TCT 2018, San Diego, CA, USA Study design paper: van der Heijden L.C., Kok M.M. et al. Am Heart J 2018; 198: 25-32 (doi: 10.1016/j.ahj.2017.12.011) BIONYX: Trial Design Inclusion criteria: Pat. ≥ 18 yrs.; PCI with DES required; informed consent; ability and willingness to comply with study procedures and follow-up Exclusion criteria: Participation in RCT of CV devices, DAPT, antithrombotics or anticoagulants before reaching primary EP; life expectancy < 1 year; planned surgery <3 mo. preventing maintenance of DAPT; known pregnancy; known intolerance to DES, anticoagulants or antiplatelet drugs, preventing DAPT2,488 patients were 1:1 randomized All-comer patients Primary endpoint: Target Vessel Failure, a composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization, to test the hypothesis that the safety and efficacy of RESOLUTE ONYX is non-inferior to the reference device ORSIRO Secondary endpoints: Death ∙ MI ∙ revascularization ∙ stent thrombosis ∙ TLF ∙ MACE ∙ PoCE ∙ etc. 1-year follow-up: 2,478 patients (99.6%) completed 1-year follow-up or had died (7 were lost to follow-up ∙ 3 withdrew consent)International, multi-center, assessor- and patient-blinded, investigator-initiated, prospective, randomized clinical trial ∙ Systematic (serial) assessment of cardiac markers and ECG ∙ No routine angiographic follow-up ∙ Analyses based on intention-to-treat ∙ Visits to outpatient clinic, questionnaire, or telephone follow-up ∙ Independent monitoring ∙ Independent clinical event adjudication (CEC) ∙ Supervision by DSMB30 days 1 year 2 years Zotarolimus-eluting Resolute ONYXSirolimus-eluting ORSIROPatients were enrolled from October 7, 2015 to December 23, 2016 at 7 study sites, located in the Netherlands: Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede ∙ Treant Zorggroep, Scheper Hospital, Emmen ∙ Haga Hospital, The Hague ∙ Rijnstate Hospital, Arnhem ∙ Belgium: Centre Hospitalier Universitaire de Charleroi, Charleroi ∙ Jessa Hospital, Hasselt ∙ and Israel: Rambam Medical Center, Haifa ∙ PI: C. von Birgelen, MD PhD, Enschede, the Netherlands ∙ Equally funded by Biotronik and Medtronic

8. Study Sites Enrolling Study Sites CoordinatorsPts. enrolledThoraxcentrum Twente, MST, Enschede, the NetherlandsC. von Birgelen (PI)925Treant Zorggroep, Scheper Hospital, Emmen, the NetherlandsG.A.J. Jessurun556Haga Hospital, The Hague, the NetherlandsC. Schotborgh431Rambam Medical Center, Haifa, IsraelA. Roguin199Jessa Hospital, Hasselt, BelgiumE. Benit138Rijnstate Hospital, Arnhem, the NetherlandsP.W. Danse126Centre Hospitalier Universitaire de Charleroi, Charleroi, BelgiumA. Aminian113

9. Baseline CharacteristicsAll patientsn = 2,488Resolute Onyxn = 1,243 Orsiron = 1,245Age (yrs.)64.0 ± 11.064.1 ± 10.963.9 ± 11.2Women 23.9 %23.9 %23.9 %BMI (kg/m²)27.9 ± 4.427.9 ± 4.428.0 ± 4.4Current smoker30.6 %30.6 %30.7 %Family history of coronary artery disease43.5 %44.7 %42.2 %Diabetes, medically treated20.5 %20.9 %20.1 %Hypertension51.5 %49.8 %53.2 %Hypercholesterolemia45.9 %45.4 %46.4 %Previous myocardial infarction16.1 %15.6 %16.5 %Previous percutaneous revascularization21.7 %21.1 %22.3 %Previous coronary bypass surgery7.1 %6.4 %7.8 %Acute coronary syndrome70.9 %70.8 %71.1 %Acute myocardial infarction51.2 %50.4 %52.1 % STEMI25.0 %22.7 %27.2 % NSTEMI26.3 %27.7 %24.9 %Unstable angina19.7 %20.4 %19.0 %Stable angina or silent ischemia29.1 %29.2 %28.9 %Data are % or mean (± SD)

10. Lesion CharacteristicsAll lesionsn = 3,239Resolute Onyxn = 1,646Orsiron = 1,593Target lesion coronary artery Left main 1.5 %1.5 %1.4 % Left anterior descending41.4 %41.2 %41.6 % Left circumflex23.8 %24.3 %23.4 % Right coronary artery33.1 %32.9 %33.3 % Bypass graft1.4 %1.2 %1.6 %ACC/AHA lesion class3,2351,6441,591 A/B130.3 %30.4 %30.2 % B2/C69.7 %69.6 %69.8 %Bifurcation31.9 %31.3 %32.5 %Severe calcification15.5 %15.0 %16.0 %In-stent restenosis2.3 %2.9 %1.8 %Chronic total occlusion3.5 %3.1 %4.0 %Number of stents per lesion1.26 ± 0.561.27 ± 0.551.26 ± 0.57Implantation of assigned stents only98.3 %98.6 %98.0 %Data are % or mean (± SD)

11. Procedural Data (Patient based)All patientsn = 2,488Resolute Onyxn =1,243Orsiron = 1,245Total number of lesions treated per patient1 lesion75.2 %73.5 %76.9 %2 lesions20.1 %21.2 %19.1 %3 or more lesions4.7 %5.4 %4.0 %Multivessel treatment17.7 %19.0 %16.5 %At least one chronic total occlusion4.5 %4.0 %5.0 %At least one bifurcation lesion39.4 %39.0 %39.8 %At least one in-stent restenosis2.9 %3.5 %2.2 %At least one small-vessel (RVD < 2.75 mm)52.3 %54.3 %50.3 %At least one long lesion (> 27 mm)21.0 %19.7 %22.3 %Total stent length (mm) per patient30 (18-48)30 (18-49)30 (18-48)Radial approach73.1 %73.5 %72.6 %Data are % or mean (IQR)

12. Procedural Data (Lesion based)All lesionsn = 3,239 lesionsResolute Onyxn = 1,646Orsiron = 1,593PreproceduralLesion length (mm)15.4 (11.3-23.2)15.3 (10.9-22.9)15.6 (11.2-23.7)Minimum lumen diameter (mm)0.75 (0.46-1.05)0.75 (0.48-1.04)0.74 (0.43-1.06)Reference vessel diameter (mm)2.81 (0.56)2.79 (0.57)2.83 (0.56)Stenosis (lumen diameter, %)72.3 (61.5-83.0)72.0 (61.2-82.1)72.7 (61.8-84.4)ProceduralImplantation of study stents only98.3 %98.6 %98.0 %Number of stents implanted per lesion1.26 (0.56)1.27 (0.55)1.26 (0.57)Postdilatation64.0 %63.5 %64.5 %PostproceduralMinimum lumen diameter (mm)2.41 (0.53)2.41 (0.54)2.41 (0.52)Stenosis (lumen diameter, %)12.7 (8.2-18.3)12.4 (8.1-17.8)13.0 (8.5-18.9)Acute gain in segment (mm)1.67 (0.63)1.65 (0.62)1.68 (0.64)Device success 98.1 %98.4 %97.8 %Lesion success 99.7 %99.7 %99.6 %Data are % or mean (IQR or ± SD)

13. Primary Endpoint TVFTarget Vessel Failure (TVF) is a composite of cardiac death, target vessel-related MI, or clinically driven target vessel revascularization.Events displayed in the graph were calculated by Kaplan-Meier methods and compared with the log-rank test. 1-year fup rate = 99.6 %

14. Primary Endpoint TVFTarget Vessel Failure (TVF) is a composite of cardiac death, target vessel-related MI, or clinically driven target vessel revascularization.Events displayed in the graph were calculated by Kaplan-Meier methods and compared with the log-rank test. 1-year fup rate = 99.6 % HR 0.75 (0.66 – 1.37), Log-rank p = 0.77

15. Primary Endpoint TVFTarget Vessel Failure is a composite of cardiac death, target vessel-related MI, or clinically driven target vessel revascularization.Non-inferiority margin 2.5 %- 0.500.53.52.02.53.0- 1.01.01.5- 1.5- 2.0ORSIRO = 4.7 %RESOLUTE ONYX = 4.5 %Absolute risk difference = - 0.2 %Upper 1-sided 95% CI = 1.1 % P non-inferiority = 0.0005P superiority = 0.77

16. Components of TVFCardiac DeathTV-related MIClinically indicated TVREvents displayed in the graph were calculated by Kaplan-Meier methods and compared with the Log-rank test.TV-related MI was defined by the extended historical definition. At 1-year follow-up, there was no statistically significant difference between stent groups in the components of Target Vessel Failure (TVF).

17. Composite Clinical EndpointsTLF = Target Lesion Failure (cardiac death, target vessel MI, or clinically indicated target lesion revascularization). MACE = major adverse cardiac event (any death, any MI, clinically indicated target lesion revascularization). POCE = patient-oriented composite endpoint (any death, any MI, any revascularization). p = 0.77p = 0.68p = 0.71p = 0.41

18. Antithrombotic MedicationThere were no significant differences in medication between the stent groups, expect for triple therapy at 1-year (1.1% vs. 0.4%,p=0.04, for Resolute Onyx vs. Orsiro stent groups, respectively. DAPT = dual antiplatelet therapy; OAC = oral anticoagulation.

19. Definite or Probable Stent ThrombosisDefinite stent thrombosis: 0.1% vs. 0.6%, HR 0.14 (0.02 – 1.16), Log-rank p = 0.03, p based on Wald test = 0.07Stent thrombosis defined according to the Academic Research Consortium (ARC)

20. Subgroup Analysis of TVF

21. BIONYX is the first randomized study of the Resolute Onyx stent, and the first assessment of its safety and efficacy in all-comers.In BIONYX, the study population included many patients with increased clinical, lesion-related, or procedural risk, suggesting that it reflects well the wide spectrum of patients treated in routine clinical practice.The reference stent used in BIONYX – the Orsiro stent – has shown excellent safety and efficacy outcomes in three all-comer trials,1-3 and it most recently outperformed the former best-in-class everolimus-eluting stent in the BIOFLOW V trial4.Discussion 1/21. Pilgrim et al. Lancet. 2014;384:2111–22 3. von Birgelen et al. Lancet. 2016;388:2607–17 2. Jensen et al. Circ Cardiovasc Interv. 2016;9:e003610 4. Kandzari et al. Lancet. 2017;390:1842-52

22. The rate of the primary endpoint was lower than assumed, but substantial underreporting appears unlikely considering the systematic biomarker and ECG assessment, the follow-up of 99.6%, and the independent monitoring and event adjudication.While the non-inferiority margin was lower than in most other stent trials, it was more than half of the primary endpoint rate.As the study is not powered for rare adverse events, such as stent thrombosis, these data are hypothesis generating only and should be interpreted with great caution. Discussion 2/2

23. Twente is the name of a region in the Eastern Netherlands, well-known for its beautiful landscapes, stately castles, ground-breaking technology, and infectiously innovative spirit. The center for cardiac interventions in Twente, Thoraxcentrum Twente, is located in the hospital Medisch Spectrum Twente in the heart of Enschede, the largest city of the region. The research department of Thoraxcentrum Twente conducts the TWENTE trials in cooperation with other medical centers and the University of Twente.Where or What is TWENTE ?The Netherlands TwenteSource of images: panels on the left-hand side : Wikipedia; panels on the right-hand side: MST, Enschede, the Netherlands.BIONYXBIO-RESORT

24. BIO-RESORTBIONYXThe Series of TWENTE Randomized Trials

25. The investigator-initiated randomized BIONYX trial was equally funded by Biotronik and Medtronic.BIONYXTrial OrganizationStudy Centers and Local PIsThoraxcentrum Twente, Enschede, NL C. von BirgelenTreant Zorggroep, Emmen, NL G. JessurunHaga Hospital, Den Haag, NL C. SchotborghRambam Medical Center, Haifa, IL A. RoguinJessa Hospital, Hasselt, BE E. BenitRijnstate Hospital, Arnhem, NL P. DanseCentre Hospitalier Univ. de Charleroi, Charleroi, BE A. AminianStudy Coordination CRO Stichting Cardiovascular Research and Education, Enschede, NL P. Zocca R. Buiten M. Kok L. van der Heijden M. LöwikSteering Committee C. von Birgelen (PI) K. van Houwelingen M. Stoel M. Hartmann F. de Man J. LouwerenburgStatistical Analysis P. Zocca R. Buiten C. Doggen (supervisor)Data Management and Follow-upCRO Stichting Cardiovascular Research and Education, Enschede, NLData and Safety Monitoring BoardE. Kedhi (chair)M. Brusse-Keizer (statistician)G. Kant (member)Monitoring CRO Diagram, Zwolle, NL R. DekkerAngiographic Analysis Angiographic Core Lab ofCRO Stichting Cardiovascular Research and Education, Enschede, NL J. Jonge Poerink I. Valkenburg R. Wiggers-van der Leest L. Oldenhof-JanssenBIONYXClinical Event Adjudication R. de Winter, AMC, Amsterdam, NL J. Wykrzykowska, AMC, Amsterdam, NL K. Koch, AMC, Amsterdam, NL

26. BIONYX (TWENTE IV)BIONYX manuscript online available on homepage of The Lancet

27. The novel Resolute Onyx stent was non-inferior to the reference Orsiro stent for the primary endpoint of safety and efficacy at 1-year.Secondary outcomes were favorable, representing a safety signal for both stents.The observed very low rate of stent thrombosis in the Resolute Onyx arm warrants further clinical investigation.ConclusionThe BIONYX manuscript is online available on the homepage of The Lancet: www.thelancet.com

28. The novel Resolute Onyx stent was non-inferior to the reference Orsiro stent for the primary endpoint of safety and efficacy at 1-year.Secondary outcomes were favorable, representing a safety signal for both stents.The observed very low rate of stent thrombosis in the Resolute Onyx arm warrants further clinical investigation.ConclusionThe BIONYX manuscript is online available on the homepage of The Lancet: www.thelancet.com