BIOFLOWVComparison ofUltraThin Sirolimus-Eluting

BioresorbablePolymer with Thin Everolimus-Eluting DurablePolymer Stents

DavidEKandzari,MD;LauraMauri,MD,MSc;JacquesKoolen,MD,PhD;JosephMMassaro,PhD;GheorgheDoros,PhD;HectorMGarcia-Garcia,MD,PhD;DonaldECutlip,MD;RonWaksmanMD,for

theBIOFLOWVInvestigators

Clinicaltrials.gov IdentifierNCT02389946

DrugElutingStentInnovationPerspective• Persistenceofadverseeventswithbothfirstgenerationandcontemporary

permanentpolymer-basedDESpresentsanopportunityforiterativeimprovement

• Advancementsincludethinnerstruts,stentdesignmodifications,improvementinpolymerbiocompatibilityandmostrecentlythedevelopmentofbioresorbablepolymers

– BPcontroldrugreleasewhileallowingsimultaneous(orsubsequent)dissolutionofthepolymermaterial,eliminatingthestimulusforchronicinflammationandhypotheticallyrestoringthestentphenotypetoaninertbaremetalstent

• Althoughpreviouscomparativestudieshavereportedstatisticalnon-inferioritybetweenbioresorbableandpermanentpolymerDES,nostudytodatehasdemonstratedastatisticallymeaningfuldifferenceinclinicaloutcomes

Orsiro UltraThin Strut(BPSES)StentSystemStent material L-605Cobalt-Chromium

Strutthickness 60µm*

Polymer material Poly-L-lactic acid(PLLA)

Polymer type

Bioresorbable,asymmetriccircumferential thickness;scissionbeginsimmediatelywith 24month completedegradation

Passivecoating Amorphous siliconcarbide

Antiproliferative drug Sirolimus (1.4µg/mm2),>80%elutedinfirst90days

*For2.25mmto3.0mmdiameterstents,80µmfor>3.0mmdiameterstents

Randomised ClinicalTrialsInvolvingOrsiro BPSESBIOFLOW II BIOFLOW IV BIOSCIENCE BIO-RESORT

Location Europe Europe,Japan Switzerland Netherlands

Design Randomised 2:1vs.XiencePrime

Randomised 2:1vs.XiencePrime/Xpedition

Randomised (1:1vsXience Prime)

Randomised (1:1:1, Orsiro,Synergy,ResoluteIntegrity)

PrimaryEndpoint LLL@9 Months TVF@12Months TLF@12Months TVF@12 Months

Enrollment 452(298Orsiro,154Xience) 579(387Orsiro,192Xience)

2,119 (1,063Orsiro,1,056Xience)

3,514(1,172 Synergy,1,169Orsiro,1,173ResoluteIntegrity)

Inclusion 1to2denovolesionsSeparatearteries

1to 2denovolesionsSeparatearteries

All-comers All-comers

Follow-up 1,6,12months and2to5yearclinical9monthclinicalandangiographic(60IVUSpatients)

1,6,12monthsand2to5yearclinical

1,6,12monthsand2to5yearclinical

1 and12monthand2to5yearclinical

BIOFLOWVTrialLeadershipandOrganizationSteeringCommittee Ron Waksman,MD(Chairman),DavidEKandzari,MD(USPrincipal

Investigator),JacquesKoolen,MD(EUPrincipalInvestigator),LauraMauri,MD,JosephJMassaro,PhD

CoreLaboratory HectorGarcia-Garcia,MedStar CardiovascularResearchNetwork,AngiographicCoreLaboratory,Washington,DC,USA

StudyManagement,DataMonitoringandAnalysis

Baim InstituteforClinicalResearch,Boston, MAUSA

DataSafetyMonitoringBoard

WilliamWeintraub(Chairman)Baim InstituteforClinicalResearch,Boston,MAUSA

ClinicalEventsCommittee

DonaldECutlip,MD (Chairman)Baim InstituteforClinicalResearch,Boston,MAUSA

Sponsor BIOTRONIK,Inc.andBIOTRONIKAG

BIOFLOWVTrialDesign

BIOFLOWVPrimaryandSecondaryEndpointsPrimaryEndpoint TargetLesionFailure(TLF)at12months: cardiovasculardeath,targetvessel-related

myocardialinfraction(MI),orischaemia-drivenTLRNoninferioritydesign,Eventrate7.0%,Delta3.85%,Power89%

SecondaryEndpoints

Major AdverseCardiacEvents(MACE):all-causedeath,MI,orischaemia-drivenTLR

TargetVessel Failure(TVF):cardiacdeath,targetvessel-relatedMI,orischaemia drivenTVR

Individualcomponentsofcompositeendpointsat30daysand12months

Definite /probablestentthrombosis

DeviceSuccess:achievementof<30%diameterstenosisofthetargetlesionwithinthestudystent

ProcedureSuccess: finaldiameterstenosis<30%withtheassigned stentandwithnoin-hospitalMACE

KeyEnrollmentCriteriaInclusionCriteria• Age≥18years• IHD,stableorunstableangina,orsilent

ischaemia• ≤3denovotargetlesionsin≤2native

targetvessels(TV)• RVD≥2.25mmand≤4.0mm• LL≤36mm• TIMIflow>1• EligibleforDAPTtherapy(aspirin+P2Y12)• Providedinformedconsent

ExclusionCriteria• Recent(<72hourspriortoprocedure)STEMIor

hemodynamicallyunstableNSTEMI/ACSpatients

• Chronictotalocclusions,bypassgrafts• Bifurcationswithsidebranch>2.0mm• In-stentrestenosisoractivestentthrombosis• LVEF<30%• PriorPCIwithin30days(non-TV)orwithin9

months(TV).• PlannedstagedPCIpost-procedure• Renalimpairment>2.5mg/dL or221µmol/Lor

dialysisdependent• Excessivelytortuous/angulatedorseverely

calcified(operatorvisualassessment)

BIOFLOWVEnrollment

• 1,334patientsrandomised betweenMay2015andMarch2016– 884Orsiro and450Xience

• Patientsenrolledin13countriesinNorthAmerica(665),Europe(390),Israel(231),Asia(36),andAustraliaandNewZealand(12)

• 12monthfollow-upcompletedMay2017

LeadingEnrollmentSitesInstitution Country NumberenrolledUZ Leuven– CampusGasthuisberg Belgium 57RambamMedicalCenter Israel 55KaplanMedicalCenter(Clalith HealthServices) Israel 52RabinMedicalCenter Israel 48Universitares Herzzentrum Hamburg Germany 44Ein-Kerem MedicalCenter Israel 43CharlestonAreaMedicalHealthSystems USA 39FloridaHospitalPepinHeartInstitute USA 35CardiovascularAssociates,Ltd. USA 34ColumbiaPresbyterianUniversityMedicalCenter USA 33Sourasky MedicalCenterTelAviv Israel 33ThomasHospital USA 31UniversityHospitalLausanne Switzerland 31

PatientDisposition

1,334Patientsenrolled

884AllocatedtoBPSES 450AllocatedtoDPEES

833Evaluableforprimaryendpoint97.3%Follow-up

427Evaluableforprimaryendpoint96.7%Follow-up

4,772Patientsscreened

48Didnotcompletea12-monthvisit24Missedthe12-monthvisit10Withdrewconsent6Werelosttofollow-up7Died1Wasexitedforotherreasons

29Didnotcompletea12-monthvisit14Missedthe12-monthvisit7Withdrewconsent2Werelosttofollow-up6Died

BayesianAnalysis• SubjectsfromBIOFLOWIIandBIOFLOWIVmeetingallBIOFLOWV

inclusion/exclusioncriteriaandhavingeitheranendpointeventorcompletingatleast330daysoffollow-up

• Toensureconsistencyandvalidityofpooledevents,allBIOFLOWIIandBIOFLOWIVeventswerere-adjudicatedbytheBIOFLOWVCEC,includingadditionaleventsnotpreviouslyadjudicatedforthosestudies

BayesianPopulation BPSES DPEES

BIOFLOW II 418 279 139BIOFLOWIV 530 354 176BIOFLOWV 1,260 833 427Total 2,208 1,466 742

ClinicalCharacteristics BPSES(N=884) DPEES(N=450)

Age, years 64.5± 10.3 64.6± 10.7

Female 25.3% 27.1%

Hypertension 79.7% 80.5%

Hyperlipidemia 78.9% 82.4%

Diabetesmellitus 34.0% 37.0%

Prior MI 27.4% 25.9%

PriorPCI 36.8% 33.0%

PriorCABG 7.1% 5.2%

Currentsmoking 23.6% 22.7%

Clinicalpresentation

Stableangina 48.4% 47.4%

Acutecoronarysyndrome 51.4% 49.6%

AngiographicCharacteristics BP SES(N=1,051lesions) DPEES(N=561lesions)Target lesionvessel

Leftanterior descending 41.0% 41.2%Left circumflex 26.6% 26.0%Right coronaryartery 32.4% 32.8%

Thrombus 1.0% 0.9%Bifurcationlesion 14.8% 15.0%Moderate/severecalcification 24.0% 26.7%Moderate/severetortuosity 58.8% 61.5%ACC/AHAlesionclassB2/C 72.6% 75.9%

Angiographic/ProceduralResults BP SES(N=1,051lesions) DPEES(N=561lesions)Lesionlength 13.3± 7.6 13.2± 7.7Referencevesseldiameter 2.6± 0.5 2.6± 0.6No.targetlesions/pt* 1.2± 0.4 1.3± 0.5%diameterstenosis, pre 55.4± 13.3 55.9± 13.5%diameterstenosis, post 7.1± 9.8 7.4± 9.8Post-dilationperformed 47.7% 46.2%No. stents/lesion* 1.07± 0.3 1.13± 0.4Stentlength/lesion 20.8± 9.1 21.8± 10.5Overlapping stents* 9.4% 15.0%*P<0.05forcomparison

BIOFLOWVProceduralOutcomes

BPSES DPEES P value

Lesionsuccess* 1102/1107(99.5%) 579/583(99.3%) 0.505

Devicesuccess† 1082/1107(97.7%) 566/583(97.1%) 0.415

Proceduresuccess‡ 827/881(93.9%) 401/445(90.1%) 0.019

*Lesionsuccessdefinedasattainmentof<30%residualstenosisofthetargetlesionusinganypercutaneousmethod.†Devicesuccessdefinedasattainmentof<30%residualstenosisofthetargetlesionusingtheassignedstudystentonly.‡Proceduresuccessdefinedasattainmentof<30%residualstenosisofthetargetlesionusingtheassignedstudystentonlywithoutoccurrenceofin-hospitalmajoradversecardiacevents(MACE;compositeofall-causedeath,Q-waveornon-Q-waveMI,andanyclinical-drivenTLR).

BPSES(N=884) DPEES(N=450) P value

All-causedeath 0.1% 0.2% 1.000

MyocardialInfarction 4.3% 6.9% 0.050

In-Hospital MI 3.9% 6.7% 0.029

TLR 0.5% 0.7% 0.694

StentThrombosis 0.3% 0.2% 1.000

TLF 4.2% 7.1% 0.026

TVF 4.3% 7.1% 0.037

BIOFLOWV30DayOutcomes

Alldatarepresentedasintentiontotreat

OrsiroBPSES(n=884)

XienceDPEES(n=450)

P value

Targetlesion failure 6.2% 9.6% 0.040

Cardiacdeath 0.1% 0.7% 0.115

Target-vesselMI 4.7% 8.3% 0.016

Clinically-driven TLR 2.0% 2.4% 0.686

BIOFLOWVPrimaryEndpoint:12MonthTargetLesionFailure

Alldatarepresentedasintentiontotreat

OrsiroBPSES(n=1466)

XienceDPEES(n=742)

Ratedifference Posteriorprobability

Target-lesionfailure(Bayesiananalysis)

Non-inferioritymargin3.85%

Superiority(post-hoc)

12-MonthRate,posteriormean± estimateofSD(%),95% CredibleInterval

6.3± 0.8(4.9, 7.9)

8.9± 1.2(6.7, 11.4)

-2.6(-5.5,0.1) 100.0% 96.9%

BIOFLOWVPooledBayesianAnalysis:BIOFLOWV,IIandIVTrials

BIOFLOWVPrimaryEndpoint:12MonthTargetLesionFailure

BIOFLOWVLandmarkAnalysis:TargetVesselMI,30Daysto12Months

BPSES(N=884) DPEES(N=450) P valueStentThrombosis

AnyStentThrombosis 0.5% 1.2% 0.175

Definite 0.5% 0.7% 0.694

Definite/Probable 0.5% 0.7% 0.694

Timing ofEvent(Definite/ProbableST)Acute(≤24hours) 0.1% 0.0% 1.000

Sub-acute(>24hoursand≤30days) 0.2% 0.2% 1.000

Late(>30daysand ≤1year) 0.1% 0.5% 0.264

Timing ofEvent(AnyST)Acute(≤24hours) 0.1% 0.0% 1.000

Sub-acute(>24hoursand≤30days) 0.2% 0.2% 1.000

Late(>30daysand ≤1year) 0.1% 0.9% 0.047

BIOFLOWVStentThrombosis 12MonthDAPTAdherence:92.1%BPSES, 91.2%DPEES

BIOFLOWVTargetLesionFailureat12MonthsbySubgroups

*Small vessels defined as ≤ 2.75mm.†ACS defined as: subjects with unstable angina or any elevated cardiac enzymes at baseline (any pre procedure CK, CK MB or Troponin out of normal range).

• Inaninternational,randomised trial,treatmentwiththeultra-thinstrutOrsiro BPSESwassuperiortotheXience DPEESregarding12monthTLFandMI

– DifferencesinMIobservedearlybutpersistedinlandmarkanalysis

• RevascularizationwithOrsiro BPSESwasassociatedwithfavorablylowTLRandstentthrombosis

• BayesianpooledanalysisincludingpatientleveloutcomesfromBIOFLOWIIandIVtrialsdemonstratedunequivocalnon-inferioritywithmeanTLFtreatmentdifferenceof-2.6%favoringOrsiro andposteriorprobabilityofsuperiority96.9%

• TheseresultsendorsethesafetyandefficacyoftheultrathinOrsiro BPSESinpatientsrepresentativeofthosetreatedinclinicalpracticeandadvanceanewstandardforDEScomparison

BIOFLOWVConclusions

Publishedonline,26August2017