2-year outcome of the 3-arm BIO-RESORT randomized trial in all-comer patients

treated with contemporary DES

Marlies M. Kok, MDThoraxcentrum Twente, MST, Enschede, the Netherlands

On behalf of the BIO-RESORT Investigators (PI: C. von Birgelen, MD, PhD, FESC)

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 Medtronic

BIO-RESORT

Background

• Modern 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, the coating of the Orsiro stent degrades after >12 months, which is why the present follow-up of this randomized clinical trial beyond the 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

Aim of the study

• To evaluate in all-comer PCI patients the 2-year safety and efficacy of treatment with contemporary very thin-strut biodegradable polymer Synergy and Orsiroversus thin-strut Resolute Integrity DES.

BIO-RESORT

Durable Polymer DES

Biodegradable Polymer

DES

Resolute Integrity

CoCr-ZES

Synergy

PtCr-EES

Orsiro

CoCr-SES

Thickness (µm) of uncoated strut

Data 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 stentdiameters > 3.0 mm; Orsiro has an asymmetrical, conformal distribution of the PLLA coating (abluminal coatingis thicker) on a very thin passive coating of silicon carbide.

Distribution, type and thickness (µm) of polymer coating

Circumfer. 6/side

BioLinxTM

Abluminal 4

PLGA, PCL

Circumfer.

4-7/side

PLLA**

91 74* 60**

Synergy and Orsiro stents use highly dissimilar biodegradablecoatings (i.e. different type, amount and degradation speed of polymer).

BIO-RESORTBIO-RESORT: Study Devices

BIO-RESORTBIO-RESORT: Study Devices

SYNERGY RESOLUTE

INTEGRITY

ORSIRO

Coatingcharacteristics

BiodegradableAbluminal

DurableCircumferential

Symmetrical

BiodegradableCircumferentialAsymmetrical

Bare strut thickness, μm

74(3.0 – 3.5 mm: 79,4.0 mm stent: 81)

91 60(≥ 3.5 mm stents: 80)

Coating thickness, μm 4 5.6 7.4 / 3.5 (ab-/luminal)

Coated strut thickness, μm (of smallest stent)

78 102 71

Metal Platinum-chromium Cobalt-chromium Cobalt-chromium

Polymer PLGA (poly [lactic-co-glycolic acid]

polymer) coating

BioLinx®, a blend of hydrophobic C10,

hydrophilic C19, and poly-vinyl pyrrolidone

PLLA (poly [L-lactide] acid) (BIOlute®), on thin

amorphous siliconcarbide (proBIO®)

Drug Everolimus Zotarolimus Sirolimus

Drug release time, mo. 3 6 3.3

Degradation time, mo. 4 --- < 24

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 DSMB

30 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 DAPT

3,514 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

SYNERGY

BIO-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 consent

BIO-RESORT

Patients & Lesions

PatientsSynergy

n = 1,172Resolute Integrity

n = 1,173Orsiro

n = 1,169

Mean age at randomization 64.0 years 63.6 years 64.2 years

Men 72.1 % 72.3 % 73.1 %

Women 27.9 % 27.7 % 26.9 %

Clinical syndrome at index PCIAny ACS 69.6 % 69.5 % 70.0 %

STEMI 32.2 % 27.8 % 31.7 %

NSTEMI 21.1 % 23.0 % 20.4 %

Unstable angina 16.4 % 18.7 % 17.9 %

Stable angina 30.4 % 30.5 % 30.0 %

Lesions and proceduresSynergy

n = 1,532 lesionsResolute Integrityn = 1,580 lesions

Orsiron = 1,551 lesions

Simple 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 lesions 19.3 % 20.7 % 20.4 %

Direct stenting performed (no pre-dilation) 22.3 % 20.4 % 23.0 %

Post-dilation of stent performed 77.7 % 73.3 % 74.0 %

BIO-RESORT

Results: Target Vessel FailureBIO-RESORT

Lancet 2016; 388: 2607–17 1-year follow-up

Results: Target Vessel FailureBIO-RESORT

Results: TVF Components

At 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 year

Target vessel myocardial infarction at 2 year Target vessel revascularisation at 2 year

BIO-RESORT

Target lesion failure (TLF) at 2-year Landmark analysis of TLF

Landmark analysis 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 arm

BIO-RESORTResults: Target Lesion Failure

Target lesion revascularisation (TLR) at 2-year Landmark analysis of TLR

Landmark analysis between 1 and 2 year follow-up showed a significantly lower rate of TLR in the SES arm versus the ZES arm

BIO-RESORTResults: TLR

Definite-or-probable stent thrombosis rates were low and similar among groups

Definite-or-probable stent thrombosis at 2-year follow-up

BIO-RESORT Results: Stent Thrombosis

Why is this study important?

• Reliable outcome data of contemporary DES in all-comers are of significant interest, particularly considering the use of differentbiodegradable DES with dissimilar polymers and degradationtimes.

• 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 Orsirosirolimus-eluting stent might reduce the risk of repeat revascularisation after the first year of follow-up.

BIO-RESORT

Summary & Conclusions

Very thin-strut biodegradable polymers DES with flexible designs and refined coatings promotere-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 polymerDES versus the thin-strut Resolute Integrity durable polymer DES.

Conclusion

• The combination of very thin strut stents with biodegradablepolymers 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 reducethe risk of repeat revascularisation after the first year of follow-up. Further long-term data will be of great interest.

BIO-RESORT

The investigator-initiated randomized BIO-RESORT trial was equally funded by Biotronik, Boston Scientific and Medtronic.

BIO-RESORT

BIO-RESORTTrial Organization

Study 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, MD

Study CoordinationCRE, Enschede

M. Kok, MDG. Zocca, MDR. Buiten, MDL. van der Heijden, MD, PhDK. Tandjung, MD PhD

Steering CommitteeC. von Birgelen, MD PhD (Study PI)P. Danse, MD PhDM. Hartmann, MD PhDK. van Houwelingen, MDJ. Louwerenburg, MDF. de Man, MD PhDM. Scholte, MDC. Schotborgh, MDM. Stoel, MD PhD

Statistical AnalysisM. Kok, MDG. Zocca, MDL. van der Heijden, MD, PhDC. Doggen, PhD (Statistical supervisor)

Data Management, Analysis and Follow-upCRE, Enschede

Monitoring and Organization ofClinical Event AdjudicationDiagram, Zwolle

Kok 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)

Manuscript with further details is free available on the homepage of EuroIntervention

DOI: 10.4244/EIJ-D-18-00336

Two-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 PhD1,6

1 Department of Cardiology, Thoraxcentrum Twente, Medisch Spectrum Twente, Enschede, the Netherlands

2 Department of Cardiology, Rijnstate Hospital, Arnhem, the Netherlands3 Department of Cardiology, Haga Hospital, The Hague, the Netherlands4 Department of Cardiology, Albert Schweitzer Hospital, Dordrecht, the Netherlands5 Department of Cardiology, Hospital Group Twente, Almelo and Hengelo, the Netherlands6 Department 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.

Summary & Conclusions

Very thin-strut biodegradable polymers DES with flexible designs and refined coatingspromote 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 biodegradablepolymers 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 reducethe risk of repeat revascularisation after the first year of follow-up. Further long-term data will be of great interest.

BIO-RESORT