2-year outcome of the 3-arm BIO-RESORT - PowerPoint Presentation

1. 2-year outcome of the 3-arm BIO-RESORT randomized trial in all-comer patients treated with contemporary DESMarlies M. Kok, MDThoraxcentrum Twente, MST, Enschede, the NetherlandsOn behalf of the BIO-RESORT Investigators (PI: C. von Birgelen, MD, PhD, FESC)

2. Potential conflicts of interest Speaker's name : Marlies M. Kok, MD – Enschede, the Netherlands☑ I have the following potential conflicts of interest to report:Receipt of grants / research supports: Institutional research grants from Biotronik, Boston Scientific and MedtronicBIO-RESORT

3. BackgroundModern biodegradable coating DES, such as the sirolimus-eluting Orsiro and everolimus-eluting Synergy stents, combine flexible thin-strut designs with thin bioresorbable drug-eluting coatings. The polymer coating of the Synergy stent is resorbed within 4 months, while the coating of the Orsiro stent degrades after >12 months, which is why the present follow-up of this randomized clinical trial beyond de primary clinical endpoint at 12 months is of great interest.The present, large scale BIO-RESORT randomized trial has demonstrated non-inferiority of the biodegradable polymer Orsiro and Synergy stents versus the durable polymer Resolute Integrity stent at 1-year follow-up. At 1-year follow-up 85.6% of the patients were on DAPT1.1. von Birgelen et al. BIO-RESORT 1-Year Outcome. Lancet 2016; 388:2607-2617 / LBCT session TCT 2016, Washington DC (USA)BIO-RESORT

4. Aim of the studyTo evaluate in all-comer PCI patients the 2-year safety and efficacy of treatment with contemporary very thin-strut biodegradable polymer Synergy and Orsiro versus thin-strut Resolute Integrity DES.BIO-RESORT

5. Durable Polymer DESBiodegradable Polymer DESResolute IntegrityCoCr-ZESSynergyPtCr-EESOrsiroCoCr-SESThickness (µm) of uncoated strutData from manufacturers’ information (modified, extended) * Synergy‘s platinum chromium strut thickness is 74 µm for stent diameters ≤ 2.5 mm, 79 µm for stent diameters 3.0 – 3.5 mm, and 81 µm for stent diameter 4.0 mm. ** Orsiro‘s cobalt chromium strut thickness is 60 µm for stent diameters ≤ 3.0 mm, and 80 µm for stent diameters > 3.0 mm; Orsiro has an asymmetrical, conformal distribution of the PLLA coating (abluminal coating is thicker) on a very thin passive coating of silicon carbide.Distribution, type and thickness (µm) of polymer coatingCircumfer. 6/sideBioLinxTMAbluminal 4PLGA, PCL Circumfer. 4-7/sidePLLA**91 74*60**We assessed the 2-year clinical outcome of the BIO-RESORT all-comers, who were treated with very thin strut Synergy and Orsiro biodegradable polymer DES versus Resolute Integrity durable polymer DES.Synergy and Orsiro stents use highly dissimilar biodegradable coatings (i.e. different type, amount and degradation speed of polymer).BIO-RESORTBIO-RESORT: Study Devices

6. BIO-RESORTBIO-RESORT: Study Devices SYNERGY RESOLUTE INTEGRITY ORSIRO Coating characteristicsBiodegradableAbluminalDurableCircumferential SymmetricalBiodegradableCircumferentialAsymmetrical Bare strut thickness, μm74(3.0 – 3.5 mm: 79,4.0 mm stent: 81)9160(≥ 3.5 mm stents: 80) Coating thickness, μm45.67.4 / 3.5 (ab-/luminal) Coated strut thickness, μm (of smallest stent)7810271 MetalPlatinum-chromiumCobalt-chromiumCobalt-chromium Polymer PLGA (poly [lactic-co-glycolic acid] polymer) coating BioLinx®, a blend of hydrophobic C10, hydrophilic C19, and poly-vinyl pyrrolidonePLLA (poly [L-lactide] acid) (BIOlute®), on thin amorphous silicon carbide (proBIO®) DrugEverolimusZotarolimusSirolimus Drug release time, mo.363.3 Degradation time, mo.4 ---< 24

7. BIO-RESORT: Trial Design Primary endpoint Target Vessel Failure (composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization) to test 2 independent hypotheses that the safety and efficacy of both ORSIRO and SYNERGY is non-inferior to the reference device RESOLUTE INTEGRITY Secondary endpoints Death ∙ myocardial infarction (MI) ∙ repeat revascularization ∙ stent thrombosis ∙ TLF ∙ etc.Investigator-initiated, multicenter, assessor and patient-blinded, three-arm, randomized, non-inferiority trial ∙ Visits to outpatient clinic, questionnaire or telephone follow-up ∙ No routine angiographic follow-up ∙ Independent monitoring and clinical event adjudication (CEC) ∙ Supervision by DSMB30 days 1 year 5 years 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 another drug or device RCT before reaching primary EP; life expectancy < 1 year; planned surgery < 6 mo’s unless DAPT maintained; known pregnancy; known intolerance to DES, anticoagulants or antiplatelet drugs preventing DAPT3,514 all-comers were 1:1:1 randomized to DES type and assessed All-comer patients: any patient who requires a percutaneous coronary intervention with DES implantation Patients with any clinical syndrome, number of target lesions or vessels, any lesion length, vessel size, etc.2 years 3 years 4 years Zotarolimus-eluting Resolute IntegrITYSirolimus-eluting ORSIROEverolimus-eluting SYNERGYBIO-RESORT Study Sites: Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede ∙ Rijnstate Hospital, Arnhem ∙ Haga Hospital, The Hague ∙ Albert Schweitzer Hospital, Dordrecht; all in the Netherlands ∙ Enrollment from December 21, 2012 to August 24, 2015 ∙ PI: C. von Birgelen, MD PhD, TC Twente, Enschede, the Netherlands. This investigator-initiated study is equally funded by Biotronik, Boston Scientific & Medtronic. 3,472 patients (98.8%) completed 2-year follow-up or had died. 11 Patients lost to follow-up, 31 patients withdrew consentBIO-RESORT

8. BIO-RESORTBIO-RESORT: Baseline PatientsSynergyn = 1,172Resolute Integrityn = 1,173Orsiron = 1,169Mean age at randomization64.0 years63.6 years64.2 yearsMen72.1 %72.3 %73.1 %Women27.9 %27.7 %26.9 %Clinical syndrome at index PCIAny ACS69.6 %69.5 %70.0 % STEMI32.2 %27.8 %31.7 % NSTEMI21.1 %23.0 %20.4 % Unstable angina16.4 %18.7 %17.9 %Stable angina30.4 %30.5 %30.0 % Lesions and proceduresSynergyn = 1,532 lesionsResolute Integrityn = 1,580 lesionsOrsiron = 1,551 lesionsSimple target lesions (types A or B2)29.0 %27.8 %26.3 %Complex target lesions (types B2 or C)71.0 %72.2 %73.7 %Severely calcified target lesions19.3 %20.7 %20.4 %Direct stenting performed (no pre-dilation)22.3 %20.4 %23.0 %Post-dilation of stent performed77.7 %73.3 %74.0 %

9. Results: Target Vessel FailureBIO-RESORTLancet 2016; 388: 2607–17 1-year follow-up

10. Results: Target Vessel FailureBIO-RESORT

11. Results: TVF ComponentsAt 2-year follow-up, there was no statistically significant difference between DES groups in the components of target vessel failure (TVF)Cardiac death at 2 yearTarget vessel myocardial infarction at 2 yearTarget vessel revascularisation at 2 yearBIO-RESORT

12. Target lesion failure (TLF) at 2-year f’up Landmark analysis of TLFLandmark analyses between 1 and 2 year follow-up showed a significantly lower rate of the secondary endpoint TLF (composite of cardiac death, any MI or clinically driven TLR) in patients of the SES arm versus the ZES armBIO-RESORTResults: Target Lesion Failure

13. Target lesion revascularisation (TLR) at 2-year f’up Landmark analysis of TLRLandmark analyses between 1 and 2 year follow-up showed a significantly lower rate of TLR in the SES arm versus the ZES armBIO-RESORTResults: TLR

14. Definite-or-probable stent thrombosis rates were low and similar among groupsDefinite-or-probable stent thrombosis at 2-year follow-upBIO-RESORTResults: Stent Thrombosis

15. Why is this study important?Reliable outcome data of contemporary DES in all-comers are of significant interest, particularly considering the use of different biodegradable DES with dissimilar polymers and degradation times.BIO-RESORT is the first randomized clinical trial that examines the everolimus-eluting Synergy stent in all-comers. Low TVF rates were observed in a complex all-comers population that includes a huge proportion of patients with acute coronary syndromes (70%) and more than 30% of all patients presenting with STEMI. Landmark analyses provided a signal that the use of the Orsiro sirolimus-eluting stent might reduce the risk of repeat revascularisation after the first year of follow-up.BIO-RESORT

16. Summary & ConclusionsVery thin-strut biodegradable polymers DES have flexible designs and refined coatings to promote re-endothelialization and reduce the risk of ischemic coronary events. The randomised, multicentre BIO-RESORT trial compared in 3,514 all-comers the 2-year outcome data (98.8% follow-up) after treatment with the very thin-strut Orsiro and Synergy biodegradable polymer DES versus the thin-strut Resolute Integrity durable polymer DES.The combination of very thin strut stents with biodegradable polymers was associated with a safety and efficacy that during the first 2 years from implantation in all-comers was similar to DES with durable polymer coating. The landmark analyses provided a signal that use of the biodegradable polymer sirolimus-eluting Orsiro stent might reduce the risk of repeat revascularisation after the first year of follow-up. Further long-term data will be of great interest.BIO-RESORTKok M.M. et al. EuroIntervention 2018; simultaneously online published (DOI: 10.4244/EIJ-D-18-00336)

17. The investigator-initiated randomized BIO-RESORT trial was equally funded by Biotronik, Boston Scientific and Medtronic.BIO-RESORTBIO-RESORTTrial OrganizationStudy Centers and Local PIsThoraxcentrum Twente, Enschede C. von Birgelen, MD PhDRijnstate Hospital, Arnhem P. Danse, MD PhDHaga Hospital, Den Haag C. Schotborgh, MDAlbert Schweitzer Hospital, Dordrecht M. Scholte, MDStudy CoordinationCRE, Enschede M. Kok, MD G. Zocca, MD R. Buiten, MD L. van der Heijden, MD, PhD K. Tandjung, MD PhDSteering Committee C. von Birgelen, MD PhD (Study PI) P. Danse, MD PhD M. Hartmann, MD PhD K. van Houwelingen, MD J. Louwerenburg, MD F. de Man, MD PhD M. Scholte, MD C. Schotborgh, MD M. Stoel, MD PhDStatistical Analysis M. Kok, MD G. Zocca, MD L. van der Heijden, MD, PhD C. Doggen, PhD (Statistical supervisor) Data Management, Analysis and Follow-upCRE, EnschedeMonitoring and Organization ofClinical Event AdjudicationDiagram, ZwolleKok M.M. et al. EuroIntervention 2018; in press – simultaneously online published (2-year follow-up)von Birgelen C. et al. Lancet 2016; 388: 2607–17 (1-year follow-up)

18. Manuscript with further details is free available on the homepage of EuroInterventionDOI: 10.4244/EIJ-D-18-00336Two-year clinical outcome of all-comers treated with three highly dissimilar contemporary coronary drug-eluting stents in the randomised BIO-RESORT trial Marlies M. Kok, MD1*, Paolo Zocca, MD1*, Rosaly A. Buiten, MD1, Peter W. Danse, MD PhD2, Carl E. Schotborgh, MD3, Martijn Scholte, MD4, Marc Hartmann, MD PhD1, Martin G. Stoel, MD PhD1, K. Gert van Houwelingen, MD1, Gerard C.M. Linssen, MD PhD5, Carine J.M. Doggen, PhD6, Clemens von Birgelen, MD PhD1,6Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, the NetherlandsDepartment of Cardiology, Rijnstate Hospital, Arnhem, the NetherlandsDepartment of Cardiology, Haga Hospital, The Hague, the NetherlandsDepartment of Cardiology, Albert Schweitzer Hospital, Dordrecht, the NetherlandsDepartment of Cardiology, Hospital Group Twente, Almelo and Hengelo, the NetherlandsDepartment of Health Technology and Services Research, MIRA – Institute of Technical Medicine and Biomedical Technology, University of Twente, Enschede, the Netherlands * M.M. Kok and P. Zocca contributed equally to this manuscript.

19. Summary & ConclusionsVery thin-strut biodegradable polymers DES have flexible designs and refined coatings to promote re-endothelialization and reduce the risk of ischemic coronary events. The randomised, multicentre BIO-RESORT trial compared in 3,514 all-comers the 2-year outcome data (98.8% follow-up) after treatment with the very thin-strut Orsiro and Synergy biodegradable polymer DES versus the thin-strut Resolute Integrity durable polymer DES.The combination of very thin strut stents with biodegradable polymers was associated with a safety and efficacy that during the first 2 years from implantation in all-comers was similar to DES with durable polymer coating. The landmark analyses provided a signal that use of the biodegradable polymer sirolimus-eluting Orsiro stent might reduce the risk of repeat revascularisation after the first year of follow-up. Further long-term data will be of great interest.BIO-RESORTKok M.M. et al. EuroIntervention 2018; simultaneously online published (DOI: 10.4244/EIJ-D-18-00336)