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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
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
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
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