A clinical evaluation to compare the safety efficacy and performance of the Absorb everolimuseluting bioresorbable vascular scaffold system against the XIENCE everolimuseluting coronary stent system in the treatment of subjects wit ID: 10146
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ABSORBIIrandomizedcontrolledtrial.Aclinicalevaluationtocomparethesafety,efficacy,andperformanceoftheAbsorbeverolimus-elutingbioresorbablevascularscaffoldsystemagainsttheXIENCEeverolimus-elutingcoronarystentsysteminthetreatmentofsubjectswithischemicheartdiseasecausedbydenovonativecoronaryarterylesions:RationaleandstudydesignRobertoDiletti,MD,a,fPatrickW.Serruys,MD,PhD,FESC,a,fVasimFarooq,MBChB,MRCP, FromtheThoraxcenter,ErasmusMC,Rotterdam,TheNetherlands,DepartmentofCardiology,InstitutHospitalierJacquesCartier,Massy,France,AbbottVascular,Diegem, SubmittedMarch17,2012;acceptedAugust17,2012. TheAbsorbeverolimus-elutingbioresorbablevascularscaffold(AbsorbBVS)wasdevelopedtoprovideanovelapproachtotreatcoronaryarterylesionswithtransientvesselsupportanddrugdelivery.Preclinicalevaluationinanimalmodeldemonstratedsubstantialpolymerdegradationat2-yearspostBVSimplantation,withcompletedisappearanceoftheAbsorbBVSstrutimplantationinthevesselwallwithina4-yearperiod,withnosignificantinflam-matoryresponseassociatedwithBVSimplantationatshortorlong-termfollow-up.Thefirst-generationAbsorbBVSwastestedintheABSORBCohortATrialanddemonstratedpromisingresultswithalowclinicaleventrateat4-yearfollow-up.Thedevicewas,however,limitedbyslightlyhigherlaterecoilcomparedwithconventionalmetallicplatformImprovementsindesignwerethereforeintro-ducedinthesecond-generationAbsorbBVS:notablyanenhancedmechanicalstrength,moredurablesupporttothevesselwall,areducedmaximumcircularunsup-portedsurfacearea,andamoreuniformstrutdistributionanddrugdelivery.Theperformanceofthisnext-generationAbsorbBVSwassubsequentlyinvestigatedintheABSORBCohortBTrialwhichreportedexcellentclinicalresultsupto1-yearfollow-up.Todate,thetreatmentofcoronaryarterydiseasewiththesecond-generationAbsorbBVShasbeeninvestigatedinalimitednumberofpatientswithrelativelysimplecoronarylesioncomplexity.Furthermore,norandomizedcomparisonbetweentheAbsorbBVSandtheconven-tionalmetallicdrug-elutingstenthasyetbeenundertaken.Therefore,theABSORBIIcontrolledrandomizedtrial(ClinicalTrials.govNCT01425281)comparingthemetal-liceverolimus-elutingstentXIENCEwiththeAbsorbBVSwillbeinitiated,andtreatmentwillbeexpandedtoincludesubjectswithsmalltargetvesseldiameterandlonglesionlength.InvestigationaldeviceThesecond-generationAbsorbBVS(AbbottVascular,SantaClara,CA)isaballoon-expandabledeviceconsistingofapolymerbackboneofpoly--lactide(PLLA)coatedwithathinlayerofa1:1mixtureofanamorphousmatrixofpoly--lactide(PDLLA)polymerand100g/cmoftheantiproliferativedrugeverolimus.TwoplatinummarkerslocatedateachAbsorbBVSedgeallowforaccuratevisualizationoftheradiolucentAbsorbBVSduringangiog-raphyorotherimagingmodalities.ThePDLLAcontrolsthereleaseofeverolimus,80%ofwhichiselutedwithinthefirst30days.BothPLLAandPDLLAarefullybioresorbable.Thepolymersaredegradedviahydrolysisoftheesterbonds,andtheresultinglactateanditsoligomersarequicklytransformedtopyruvateandmetabolizedintheKrebsenergycycle.Smallparticles,lessthan2mindiameter,havealsobeenshowntobephagocytizedanddegradedbymacrophages.Accordingtopreclinicalstudies,thetimeforcompletebioresorptionofthepolymerbackboneis2to3years.ControldeviceThecontroldevicetobeusedinthetrialisaCEMarkedeverolimuselutingcoronarystentsystemfromtheXIENCEfamilyofstents(manufacturedbyAdvancedCardiovascularSystems,Inc.,asubsidiaryofAbbottVascular,Inc)referredtohereafterasXIENCEstent.TheXIENCEstentisaballoon-expandablemetallicplatformstentmanufacturedfromaflexiblecobaltchromiumalloywithamulticellulardesignandcoatedwithathinnonadhesive,durable,biocompatibleacrylic,andfluorinatedeverolimus-releasingcopolymer.ThedeliverysystemtobeusedinbotharmsofthetrialwillusethesameprincipleofoperationasotherAbbottVascularRapidExchangecoronarystentsystemsandcoronarydilationcatheters.TreatmentstrategyQuantitativeassessmentoftargetvesseldiameterbyonlinequantitativecoronaryangiography(QCA)isrequiredatbaselineafternitroglycerinforappropriateAbsorbBVSorXIENCEstentsizeselection.TherequiredrangefortargetvesseldiameterisassessedintermsoftheonlineQCAparametersdistalDmaxandproximalDmax,whichrefertomaximumlumendiameterevaluatedbeforepredilatationupto5to10mmdistalandproximaltotheboundariesofthelesionlengthdefinedbyQCA.A3.5mmABSORBBVSorXIENCEshouldbeusedwhenboththeproximalanddistalmeanlumendiameterare TableI.Devicesizestobeusedinthestudyaccordingtothemaximumlumendiameter(Dmax)byonlineQCAonlyLesionandDeviceSizesLesionlengthABSORBBVSScaffolddiameter2.5mm2.25and3.0mm48mmScaffoldlength:18,28mm3.0mm2.5and3.3mm48mmScaffoldlength:18,28mm3.5mm3.0and3.8mm48mmScaffoldlength:12,18,28mmXIENCEStentdiameter2.5mm2.25and3.0mm48mmScaffoldlength:18,28mm3.0mm2.5and3.3mm48mmScaffoldlength:18,28mm3.5mm3.0and3.8mm48mmScaffoldlength:12,18,28mmDilettietalAmericanHeartJournalVolume164,Number5 withintheupperlimitof3.8mmandthelowerlimitof3.0mm.3.0-mmAbsorbBVSorXIENCEstentmustbeusedwhenboththeproximalanddistalmeanlumendiametersarewithintheupperlimitof3.3mmandthelowerlimitof2.5mm.A2.5-mmAbsorbBVSorXIENCEstentmustbeusedwhenboththeproximalandthedistalmeanlumendiametersarewithintheupperlimitof3.0mmandthelowerlimitof2.25mm.Boththeproximalmeanlumendiameterandthedistalmeanlumendiameterneedtobewithintheupperandlowerlimitsspecifiedforthescaffold/stentsize.Overlapwillbeallowed(TableIDual-antiplatelettherapyAllsubjectswillreceive75mgofaspirindailyaftertheindexprocedureandthroughoutthelengthoftheclinicalinvestigation.Allsubjectswillbemaintainedataminimumof75mgofclopidogreldailyoraminimumof10mgofprasugreldailyforaminimumof180daysaftertheprocedure,leadingtoadual-antiplatelettherapyforaminimumof180days.Ifasubjectdevelopssensitivitytoclopidogrelorprasugrel,theymaybeswitchedtoticlopidineaccordingtostandardhospitalpractice.Theantiplatelettherapycanbehaltedforclinicalindi-cationsifrequired;however,itmustberesumedassoonaspossibleper-physiciandiscretion.TrialdesignandobjectiveTheABSORBIIrandomizedcontrolledtrial(RCT)isintendedtocontinuetoevaluatethesafetyandefficacyoftheAbsorbBVSandtodirectlycompareittothemetallicdrug-elutingstentXIENCEstent.XIENCEstentandAbsorbBVSsharethesamebasicMULTI-LINKdesign,andbothdevicesaresimilarintermsofdrug,drugdosedensity,andelutionprofile.TheABSORBIIRCTisaprospective,randomized,active-controlled,single-blinded,parallel2-arm,multicen-terclinicaltrial.Atotalofapproximately501subjects(334intheAbsorbBVSgroupand167intheXIENCEstentgroup)willberandomizedinapproximately40sitesinEuropeandNewZealand.Thetrialprotocolallowsthetreatmentofupto2denovonativecoronaryarterylesions,eachlocatedindifferentmajorepicardialvessels,withamaximallumendiameterbetween2.25and3.8mmasassessedbyonlineQCAandamaximumlesionlengthof48mm.Allsubjectswillbescreenedpertheprotocolinclusionandexclusioncriteriabeforeenrollment.Subjectswillhaveclinicalfollow-upat30and180daysandat1,2,and3years.Allsubjectswillundergocoronaryangiography,intravascularultrasound(IVUS),andIVUSvirtualhistol-ogy(VH)imagingpredeviceandpostdeviceimplanta-tionandat2yearspostindexprocedure.SubjectsfromtheErasmusMedicalCentre(MC)Rotterdam,theNetherlands,willalsoundergointravas-cularimagingwithnear-infraredspectroscopysystem(Lipiscan,InfraReDx,Burlington,USA)preandpostdeviceimplantationandat2yearspostindexprocedure.AllsubjectsallocatedtotheAbsorbBVSarmwillundergomultislicecomputedtomography(MSCT)imag-ingat3yearspostindexprocedure.Subjectswillbeunblindedafterthecompletionofthe2-yearfollow-upforthecoprimaryendpoints.TheprimaryobjectiveoftheABSORBIIRCTistocom-parethesafety,efficacy,andperformanceofAbsorbBVSagainsttheXIENCEstentinthetreatmentforsubjectswithischemicheartdiseasecausedbydenovonativecoronaryarterylesions.TheABSORBIIRCTisintendedtoshowsuperiorityofAbsorbBVSvsXIENCEstent,intermsoftheprimaryendpointofvasomotorreactivityasassessedbythechangeinmeanlumendiameterprenitrateandpost-nitrateandat2-yearinvasivefollow-upwithQCA,andnoninferiority(reflextosuperiority)intermsofthecoprimaryendpointofminimumlumendiameter(MLD) TableII.InclusioncriteriaGeneralInclusionCriteriaSubject'sagemustbeatleast18and85ySubjectmustagreenottoparticipateinanyotherclinicalinvestigationforaperiodof3yaftertheindexprocedure.Thisincludesclinicaltrialsofmedicationandinvasiveprocedures.Questionnaire-basedstudiesorotherstudiesthatarenoninvasiveanddonotrequiremedicationareallowed.Subjectisabletoverballyconfirmunderstandingofrisks,benefits,andtreatmentalternativesofreceivingtheAbsorbBVSandhe/sheorhis/herlegallyauthorizedrepresentativeprovideswritteninformedconsentbeforeanyclinicalinvestigation-relatedprocedure,asapprovedbytheappropriateethicscommitteesSubjectmusthaveevidenceofmyocardialischemia(eg,stableorunstableangina,silentischemiaSubjectmustbeanacceptablecandidateforcoronaryarterybypassgraftsurgerySubjectmustagreetoundergoallclinicalinvestigationplan-requiredfollow-upvisits,exercisetesting,blooddraw,andadherencetoESCguidelinesandcompletionofqualityoflifequestionnairesandofasubjectdiarytocollectinformationincludingbutnotlimitedtotobaccouse,foodintake,dailyexercise,andbodyweightsAngiographicinclusioncriteria1or2denovonativelesionseachlocatedinadifferentepicardialvesselIf2treatablelesionsmeettheeligibilitycriteria,theymustbeinseparatemajorepicardialvessels(LeftAnteriorDescending(LAD)withseptalanddiagonalbranches,Circumflex(CX)withobtusemarginaland/orramusintermediusbranches,andRightCoronaryArtery(RCA)andanyofitsbranches).Lesion(s)musthaveavisuallyestimateddiameterstenosisof50%and100%withaTIMIflowofLesion(s)mustbelocatedinanativecoronaryarterywithDmaxbyonlineQCAof2.25and3.8mm.Lesion(s)mustbelocatedinanativecoronaryarterywithlesion(s)lengthbyonlineQCAof48mm.Percutaneousinterventionsforlesionsinanontargetvesselareallowedifdone30dbeforeorifplannedtobedone2yaftertheindexprocedure.Percutaneousinterventionforlesionsinthetargetvesselisallowedifdone6mobeforeorifplannedtobedone2yaftertheindexprocedure.DilettietalAmericanHeartJournalNovember2012 at2yearspostnitrateminusMLDpostprocedurepostni-tratebyQCA.Allinvasiveproceduresmaybedeferredto3years,dependingontheresultsoftheABSORBCohortBTrial.ThistrialwillbeconductedinaccordancewiththeClinicalInvestigationalPlan,theDeclarationofHelsinki,ISO14155standards,andtheappropriatelocallegislation(s).Theconductofthetrialwillbeapprovedbytheappropriateethicscommitteeoftherespectiveclinicalsiteandasspecifiedbylocalregulations.PatientselectionSubjectsenrolledintotheclinicaltrialwillbemaleorfemalederivedfromthegeneralinterventionalcardiologypopulation.Theclinicaltrialwillrandomizeuptoapproxi-mately501subjects.Subjectsmeetingthegeneralinclusionandexclusioncriteria(TablesIIandIII)willbeaskedtosignaninformedconsentform.Nonroutinelaboratoryassess-mentsspecifictotheclinicalinvestigationwillnotbeperformedbeforeaninformedconsentformhasbeensigned.Screeningfailureswillbecapturedonapaper-screeninglog.Aftersuccessfulpredilatationofthefirsttargetlesion,subjectID,randomizationnumber,andtreatmentarmwillbeassignedbyacentralallocationservice(interac-tivevoice/interactiveWeb-basedrandomizationservice).Subjectswillberandomizedina2:1ratiotoAbsorbBVSvsXIENCEstent.Randomizationwillbefurtherstratifiedbydiabetesmellitusstatusandnumberofplannedtargetlesions.Follow-upscheduleSubjectswillbeobservedfora3-yearperiodpostindexprocedurewithclinicalandinvasiveimagingfollow-up(Clinicalfollow-upClinicalvisitfollow-upincludingbloodsamplingwillbeperformedinallpatientsat30and180daysandat1,2,and3yearspostprocedure.Acentrallaboratorywillbeusedfor TableIII.ExclusioncriteriaGeneralexclusioncriteriaKnownhypersensitivityorcontraindicationtoaspirin,bothheparinandbivalirudin,antiplateletmedicationspecifiedforuseinthestudy(clopidogrelandprasugrelandticlopidine,inclusive),everolimus,PLLA,PDLLA,cobalt,chromium,nickel,tungsten,acrylicandfluoropolymers,orcontrastsensitivitythatcannotbeadequatelypre-medicated.Subjecthasaknowndiagnosisofacutemyocardialinfarctionatanytimeprecedingtheindexprocedure,andrelevantcardiacenzymes(accordingtolocalstandardhospitalpractice)havenotreturnedwithinnormallimitsatthetimeofprocedure.EvidenceofongoingacutemyocardialinfarctioninelectrocardiogrambeforeprocedureSubjecthascurrentunstablearrhythmias.LeftventricularejectionfractionSubjecthasreceivedahearttransplantoranyotherorgantransplantorisonawaitinglistforanyorgantransplant.Subjectisreceivingorscheduledtoreceivechemotherapyofmalignancywithin30dbeforeoraftertheprocedure.Subjectisreceivingimmunosuppressanttherapyand/orhasknownimmunosuppressiveorautoimmunedisease(eg,humanimmunodeficiencyvirus,systemiclupuserythematosus,rheumatoidarthritis,severeasthmarequiringimmunosuppressivemedication,etc).Subjectisreceivingchronicanticoagulationtherapythatcannotbestoppedandrestartedaccordingtolocalhospitalstandardprocedures.Electivesurgeryisplannedwithin2yaftertheprocedurethatwillrequirediscontinuingeitheraspirin,clopidogrel,prasugrel,orticlopidine.Subjecthasaplateletcount100,000cells/mm700,000cells/,awhitebloodcellcountof3,000cells/mm,ordocumentedorsuspectedliverdisease(includinglaboratoryevidenceofhepatitis).Knownrenalinsufficiency(eg,estimatedGlomerularFiltrationRate60mL/min/1.73morserumcreatininelevelof2.5mg/dL,orsubjectondialysis)HistoryofbleedingdiathesisorcoagulopathyorwillrefusebloodSubjecthashadacerebrovascularaccidentortransientischemicneurologicalattackwithinthepast6mo.Pregnantornursingsubjectsandthosewhoplanpregnancyintheperiodupto3yafterindexprocedure(Femalesubjectsofchild-bearingpotentialmusthaveanegativepregnancytestdonewithin28dbeforetheindexprocedureandcontraceptionmustbeusedduringparticipationinthistrial.)Othermedicalillness(eg,cancerorcongestiveheartfailure)orknownhistoryofsubstanceabuse(alcohol,cocaine,heroinetc)asperphysicianjudgmentthatmaycausenoncompliancewiththeprotocolorconfoundthedatainterpretationorisassociatedwithalimitedlifeexpectancySubjectisalreadyparticipatinginanotherclinicalinvestigationthathasnotyetreacheditsprimaryendpoint.Subjectisbelongingtoavulnerablepopulation(perinvestigator'sjudgment,eg,subordinatehospitalstafforsponsorstaff)orsubjectunabletoreadorwrite.AngiographicexclusioncriteriaTargetlesionthatpreventsadequate(residualstenosisattargetlesion(s)is40%byvisualassessment)coronarypredilatation.TargetlesioninleftmaintrunkAorto-ostialtargetlesion(within3mmoftheaortajunction)Targetlesionlocatedwithin2mmoftheoriginoftheLADorLCXTargetlesionlocateddistaltoadiseased(vesselirregularityperangiogramand20%stenosedlesion)arterialorsaphenousveingraftTargetlesioninvolvingabifurcationlesionwithsidebranch2mmindiameter,orwithasidebranch2mmindiameterrequiringguide-wireprotectionordilatationTotalocclusion(TIMIflow0),beforewirecrossingExcessivetortuosity(2ormore45°angles)orextremeangulation90°)proximaltoorwithinthetargetlesion RestenoticfrompreviousinterventionHeavycalcificationproximaltoorwithinthetargetlesionTargetlesioninvolvesmyocardialbridge.TargetvesselcontainsthrombusasindicatedintheangiographicAdditionallyclinicallysignificantlesion(s)(40%diameterstenosisbyvisualassessment)forwhichPCImayberequired2yaftertheindexSubjecthasreceivedbrachytherapyinanyepicardialvessel(includingsidebranches).Subjecthasahighprobabilitythataprocedureotherthanpredilatationandstudydeviceimplantationand(ifnecessary)postdilatationwillberequiredatthetimeofindexprocedurefortreatmentofthetargetvessel TableIII.continuedDilettietalAmericanHeartJournalVolume164,Number5 bloodanalysisoftroponin,creatinekinase,creatinekinaseMB,fastingtotalcholesterol,fastinglow-densitylipoproteincholesterol,fastinghigh-densitylipoproteincholesterol,fastingtriglycerides,hemoglobinA1c,andfastingbloodglucoselevels.Thesebloodsamplesforcentrallaboratorywillbeobtainedbeforeoratthetimeoftheprocedure;theresultswillnotbereviewedattheproceduretime.Localanalysesmaybeperformedinparalleltoanybloodresultsthatarerelevantforappropriateprotocolcompliance,subjectcare,andtreatmentoptimization.Exercisetestingwillberequiredat180daysandat1,2,and3yearspostprocedure,tobeperformedbeforeanyrequiredimagingprocedureandafterbloodsampling.Exercisetestswillbeperformedateachinvestigationalsiteaccordingtolocalclinicalpractice.AllpatientsandtreatingphysicianswillbeaskedtoadheretotheEuropeanSocietyofCardiology(ESC)intermsoftobaccousage,exercise,healthyfoodintake,maintaininganadequateweight(bodymassindex)andwaistcircumference,achievingtargetbloodlipidlevels,andbloodpressurecontrol.Theseparameterswillbeevaluatedatpreprocedure,30and180days,andat1,2,and3yearspostprocedure.QualityoflifequestionnaireswillbeundertakenintheABSORBIIRCTtoprovideacomplementaryevaluationoftheeffectivenessoftheAbsorbBVSsystem.Thequestionnaireswillbecollectedatpreimplantation,at180-day,andat1,2,and3-yearfollow-upandwillincludeboththeoverallhealthstatus,assessedusingtheSF-12HealthSurveyandtheEuroQoLEQ-5Dsurvey Figure Clinicalinvestigationflowchart.*ClinicalLaboratory:bloodsample(tobeobtainedbeforeexercisetesting)toaidintheadjustmentofmedicaltreatmentandadherencetoESCguidelines.**QoL:qualityoflifeusingtheSAQ,theSF-12HealthSurvey,andtheEuroQoLEQ-5DHealthSurvey.Thisinformationwillbecollectedattheindicatedtimepoints.***LipiscananalysiswillbedoneattheErasmusMConly.****Exercisetesttobedonebeforeanyrequiredimagingprocedureandafterblooddraws.Theofficeimagingvisitat2years(includingexercisetesting,coronaryangiogram,IVUS,IVUS-VH,Lipiscan,SF12,EuroQoLEQ-5D,andSAQ)maybechangedto3years,dependingoncohortB2-yearimagingdata.Inthatcase,the2yearimagingvisitwouldbereplacedbyanofficevisitwhereexercisetesting,SF12,EuroQoLEQ-5D,SAQ,adherencetoESCguidelinesperprotocolmedication,concomitantmedication,andadverseeventswouldbereviewed.DilettietalAmericanHeartJournalNovember2012 disease-specificqualityoflife,assessedusingtheSeattleAnginaQuestionnaire(SAQ).Intravascularimagingfollow-upAngiography.Allsubjectswillundergocoronaryangiographyatpredeviceandpostdeviceimplantationandat2-yearfollow-up.GreyScaleIVUS-VH.BothIVUSandIVUS-VHassess-mentswillbeperformedinallpatientsaftercoronaryangiography,atpreimplantation,postimplantationandat2-yearfollow-up.PreproceduralIVUSandIVUS-VHwillbeperformedbeforepredilatationofeachtargetlesion.Ifnottechnicallyfeasible(ie,theIVUScathetercannotcrossthelesion),predilatationwithasmallballoondilatationcatheterisallowedforIVUScatheteraccess.BothIVUSandIVUS-VHareintendedfordocumentarypurposesonlyandnotforvesselsizing;thus,thiswillnothaveanimpactoninclusion/exclusiondecision-makingprocesses.Incaseof2targetlesions,preproceduralIVUSandIVUS-VHwillbe TableIV.Clinicalangiographicandimagingendpoints.ClinicalendpointsAcutesuccessDevicesuccess(lesionbasedanalysis)Proceduralsuccess(subjectbasedanalysis)Clinicalendpoint(at30-and180-dandat1,2,and3-yfollow-up)death(cardiac,vascular,noncardiovascular)Myocardialinfarction(MI:QwaveMyocardialInfarction(QMI)QMIandNonQwaveMyocardialInfarctionNQMI)Targetlesionrevascularization(TLR)ClinicallyindicatedTLR(CI-TLR)NotclinicallyindicatedTLR(NCI-TLR)ClinicallyindicatedTVR(CI-TVR)NotclinicallyindicatedTVR(NCI-TVR)targetvesselrevascularization(NTVR)ClinicallyindicatedNTVR(CI-NTVR)NotclinicallyindicatedNTVR(NCI-NTVR)AllcoronaryrevascularizationCompositeendpointsDeath/AllMICardiacdeath/TV-MI/CI-TLR(targetlesionfailure)(device-orientedendpoint)Cardiacdeath/allMI/CI-TLR(majoradversecardiacevents)Cardiacdeath/allMI/CI-TVR(targetvesselfailure)Death/AllMI/allrevascularization(subject-orientedendpoint)Scaffold/StentthrombosisTiming(acute,subacute,late,andverylate)Evidence(definite,probable,andpossible)Qualityoflife(QoL)relatedendpointsHealthstatuswillbeassessedusingtheSF-12HealthSurveyandtheEuroQoLEQ-5Datpreimplantation,at180-d,andat1-,2-,and3-yDisease-specificQoLwillbeassessedusingtheSAQatpreimplantation,at180-d,andat1-,2-,and3-yfollow-up.AngiographicendpointsIn-segmentLateLoss(LL)LLpostnitrateat2)yProximalLL(proximaldefinedaswithin5mmoftissueproximaltoscaffold/stentplacement)postnitrateat2yDistalLL(distaldefinedaswithin5mmoftissuedistaltoscaffold/stentplacement)postnitrateat2yIn-scaffold/in-stent,in-segment,proximalanddistalMLDpostnitratepostprocedureandat2yIn-scaffold/in-stent,in-segment,proximalanddistal%diameterstenosis(DS)postnitratepostprocedureandat2yIn-scaffold/in-stent,in-segment,proximalanddistalangiographicbinaryrestenosisratepostnitrateat2yIn-scaffold/in-stentnetgain(beingthechangeinMLDbetween2yvspreimplantation)postnitrateChangeinmeanandminimallumendiametersat2-yfollow-upfromprenitratetopostnitratebyangiographyIn-scaffold/in-stent%DSat2yprenitrateandpostnitratebyConformabilityassessedbychangeincurvatureandangulationbetweenpreprocedure,postprocedure,andfollow-upIVUSendpointsMinimallumenarea(MLA)byIVUSpostnitrateat2yPercentageofpatientswithlategain(IVUSMLApostprocedurepostnitrateIVUSMLA2-yfollow-uppostnitrate)withoutIVUSChangeoftotalplaque(tissuebetweenlumenandexternalelasticmembrane)withinscaffold/stentbyIVUSpostnitratebetweenpostimplantationand2y Mean/Minimalvesseldiameter/area/volumepreprocedure,postprocedure,andat2yMean/Minimalscaffold/stentdiameter/area/volumepreprocedure,postprocedure,and(ifanalyzable)at2yMean/Minimallumendiameter/area/volumepreprocedure,postprocedure,andat2y,includingchangeinMLAbetweenpostprocedureandfollow-upPlaquebehindmetallicstentarea/volumepostprocedureandat2yPlaquebehindpolymericscaffoldarea/volumepostprocedureandat2y(ifanalyzable)Mean/maximalneointimahyperplasiainthemetallicstentarea/volume/percentageat2yMean/maximalneointimahyperplasiainthepolymericscaffoldarea/volume/percentageat2y(ifanalyzable)Incompleteapposition(postimplantation),persistingincompleteapposition,lateacquiredincompleteapposition,andresolvedincompleteappositionat2y(ifanalyzable)Totalplaquearea/volumepreprocedure,postprocedure,andat2y,includingchangeintotalplaquebetweenpreprocedureandfollow-upIVUS-VHendpointsDensecalciumvolume,area,percentage,preprocedure,postprocedure,andat2yNecroticcorevolume,area,percentage,preprocedure,postprocedure,andat2yFibrofattyvolume,area,percentage,preprocedure,postprocedure,andat2yFibrousvolume,area,percentage,preprocedure,postprocedure,andat2yNear-infraredspectroscopyendpoint(substudyinErasmusMC)Changeinlipidcoreburdenindexfrompreimplantationtopostimplantationand2-yfollow-upMSCTendpoints(subjectsintheAbsorbBVSarmonly)ThefollowingMSCTendpointswillbeexaminedintheAbsorbBVSarmDescriptiveanalysisofvascularandscaffoldmorphologyat3yMeasurementoflumenareaanddiameter(minimum,maximum,mean),%DS,and%areastenosisat3y TableIV.DilettietalAmericanHeartJournalVolume164,Number5 performedforthesecondlesionafterthetreatmentofthefirstlesion.Near-infraredspectroscopy(Lipiscan).Anear-infraredspectroscopysubstudywilltakeplaceinErasmusMConly.Analyseswillbeperformedatpreandpostdeviceimplantationandat2-yearfollow-up.Near-infraredspectroscopyassessmentwillbeperformedafterIVUSandIVUS-VHateachtimepoint.Allinvasiveimagingproceduresat2yearsmaybedeferredto3years,dependingontheresultsoftheABSORBCohortB2-yearimagingfollow-updata.Multislicecomputedtomography(MSCT).AMSCTscanismandatoryforallsubjectsintheAbsorbBVSarmat3-yearfollow-up.EndpointsPrimaryendpointsandrationaleThecoprimaryendpointsoftheclinicaltrialareasfollows:(1)vasomotionassessedbychangeinmeanlumendiameterbetweenprenitrateandpostnitrateat2yearsbyQCA(superiority)and(2)MLDat2yearspostnitrateminusMLDpostprocedurepostnitratebyQCA(noninferiority,reflextosuperiority)(TableIVSecondaryclinicalandimagingendpointsarereportedTableIVStatisticalconsiderationsSamplesizecalculationsandassumptions.samplesizecalculationisbasedonthefirstcoprimaryendpoint(superiorityforvasomotionassessedbychangeinmeanlumendiameterbetweenprenitrateandpostnitrateat2yearsbyQCA).Thefollowingassumptionswereconsidered:(1)2-tailedsuperioritytest,(2)=0.05,(3)power=90%,(4)randomizationratio2:1(AbsorbBVS/XIENCEstent),(5)basedonpreviousvasomotiondataat2yearsafterBVSimplantation,thetruechangeinmeanlumendiameterbetweenprenitrateandpostnitrateat2-yearfollow-upisassumedtobe0.07mmforAbsorbBVSand0mmforXIENCEstent),and(6)thestandarddeviationisassumedtobe0.20mm.Basedontheaboveassumptions,260lesionsintheAbsorbBVSarmand130lesionsintheXIENCEstentarmwillberequiredforthestudy.TheattritionrateobservedinABSORBCohortAandSPIRITIIat2yearswas24%;weexpectanadditionallossof5%forunmatchedprenitrateandpostnitrateandabout10%ofpatientswithduallesions.Therefore,approximately501subjectswillberandomizedinABSORBII,withapproximately334intheAbsorbBVSarmand167intheXIENCEstentarm.Consideringthe390lesionsavailableforQCAassess-ments,thestudyhasmorethan89%powertodetectnoninferiorityinthesecondcoprimaryendpointofMLDat2yearspostnitrateminusMLDpostprocedurepost-nitratebyQCA(assumingthetruemeansareequalinbothgroupswithastandarddeviationof0.45mmandanoninferioritymargin()of0.14mm).ThepowercalculationswereperformedusingPASS11(NCSS,LLC,Kaysville,Utah,USA).Coprimaryendpointsanalysis.Thecoprimaryendpointswillbeanalyzedfortheintent-to-treatpopulation,onalesionbasis.Fortheendpointofvasomotionassessedbychangeinmeanlumendiameterbetweenprenitrateandpostnitrateat2yearsbyQCA,thecom-parisonwillbetestedusinga2-sidedtestatthe0.05significancelevel.FortheendpointofMLDat2yearspostnitrateminusMLDpostprocedurepostnitratebyQCA,noninferioritywillbetestedusinga1-sidedasymptotictestatthe0.05significancelevel,consideringthenoninferioritymarginof0.14mm.IfnoninferiorityismetwithhighervalueintheAbsorbBVSarm,thensuperioritywillbetestedusinga2-sidedtestatthe0.05significancelevel.Ifthenormalityassumptionisunten-able,nonparametrictestsmaybeconsidered.Forthetrialtobesuccessful,thecriteriaforsuperiorityshouldbemetforthecoprimaryendpointofvasomotionandthecriteriafornoninferiorityshouldbemetforthecoprim-aryendpointofMLDat2yearspostnitrateminusMLDpostprocedurepostnitrate.Inaddition,asasecondaryanalysis,thecoprimaryendpointswillbeanalyzedontheper-treatment-evaluablepopulation.Secondaryendpointanalyses.Analysesofothersecondaryendpointswillbedescriptiveandwillbeperformedonboththeintent-to-treatandper-treatment-evaluablepopulations.Forbinaryvariablessuchastargetvesselfailure,targetlesionrevascularization,andclinicalproceduresuccess,counts,percentages,andexact95%confidenceintervalsusingClopper-Pearsonmethodwillbecalculated.Forcontinuousvariablessuchasdiameterstenosis,means,standarddeviations,and95%confidenceintervalsforthemeanusingtheGaussianapproximationwillbecalculated.StudymanagementTheABSORBIItrialisfundedbyAbbottVascular.TheDataSafetyMonitoringBoardwillmonitorthesafetyofsubjectsand/orefficacythroughoutthesubjectenrollmentandonanongoingbasis.TheClinicalEventsCommitteewillcomprisequalifiedphysicianswhoarenotinvestiga-torsinthetrial.TheClinicalEventsCommitteewillberesponsibleforadjudicatingallmajoradversecardiaceventrelatedendpoints.Centrallaboratorycardiacenzymesvalueswillbeusedforeventadjudication(incasecentrallaboratoryvalueswouldnotbeavailable,thelocallaboratoryresultswillbeused).Imagingacquisitionswillbeevaluatedbyanindependentcorelaboratory(Cardialysis,Rotterdam,theNetherlands).Theintroductioninthelastdecadeofdrug-elutingcoronarystentsmarkedanimportantprogressintheDilettietalAmericanHeartJournalNovember2012 fieldofcoronaryarterydiseasetreatment.Theinhibi-tionofneointimalgrowthbylocallydeliveringanti-proliferativedrugstranslatedintoareductioninintrastentrestenosisloweringtheneedforrepeatedHowever,metallicstentplacementisnotdevoidofimportantlong-termlimitations.Themetallicimplantresultsinapermanentcagingofthevessel,preventinglatelumenenlargement,jailingsidebranches,precludingnoninvasiveimaging,andfurthersurgicalrevasculariza-tionofstentedsegments.Moreover,despitethebeneficialeffectofneointimalinhibition,theantiproli-ferativedrugelutionhasbeenshowntointerferewiththevascularhealingprocesses,thusprovidingthebackgroundforphenomenasuchasdelayedstrutcoverageandpersistentoracquiredmalapposition,implicatedincausinglateandverylatestentGiventhisbackground,theneweverolimus-elutingbioresorbablevascularscaffoldshavebeenintroducedintheattempttoovercomethepreviouslymentionedlimitationsand,intheABSORBIItrial,willbecomparedwiththecurrentstandardofmetaldrug-elutingstent.Vasomotionplaysanimportantroleintheregulationofcoronarybloodflow,ensuringthemaintenanceofanappropriatecoronaryflowpressure,andimpairedvasomotoractivityofcoronaryvesselshasbeenshowntobeassociatedwithanincreasedriskoffuturecardiovascularevents.Restorationofvasomotoractivityisthereforedesirableafterpercutaneousrevas-cularizationandisasuitableendpointfortheevaluationofcoronaryarterydiseasetreatmentwithdrug-elutingstents/scaffoldsinrandomizedtrials.Minimumlumendiameterat2yearsminuspostproce-duralMLDisameasurementofneointimalhyperplasiaandthereforeamechanisticmeasurementofprocedural-relatedhemodynamicnarrowing;theoreticallyandclini-callycorrelatedwithbinaryrestenosisandtargetvesselrevascularization(TVR).22-24Consequently,theMLDat2yearsminusthepostimplantationMLDatbaselineisconsideredasuitableendpointforevaluationoftheperformanceofdrug-elutingstents/scaffoldsinthepresentrandomizedtrial.Inadditiontothetheoreticaladvantages,namely,thepossibilityforfurthersurgicalrevascularizationandapotentialreductionineventssuchaslatescaffoldthrombosisafterthecompletescaffoldbioresorption,theimplantationoftheAbsorbBVShaspreviouslybeendemonstratednottoprecludethenoninvasiveimagingofthetreatedarteriesatanystageofpatientfollow-andtherestorationofcoronaryvasomotionwasobservedtoreturnafter1yearpostscaffoldimplanta-Moreover,theAbsorbBVSplacementhasbeenassociatedwiththeformationofaneointimallayerthatmaypotentiallyrepresentadenovocircumferentialplaquethickcap,afterscaffoldbioresorption,withthepotentialfunctionofplaquestabilization.Fromaphysiologicalperspective,completescaffoldbioresorptionexposesthevesselwalltothecyclicalstrainofbloodpulsatility.Previousstudieshavesuggestedthatthemechanicalstimuliinducedbyapulsatilebloodflowincreasethereleaseofnitricoxideandprostacyclinandisassociatedwithareductionofmonocyteadhesion,providingafundamentalatheropro-tectiveeffect.Biomechanicalstimulialsomodulateendothelialcellmorphology,proliferation,apoptosis,elongationandextracellularmatrixproduction,inflammatorysignals.Pulsatileflowanditsmechanicalactiononvesselwallareassociatedwithadown-regulationofNADPHoxidaseactivity,presentintheendothelium,vascularsmoothmusclecells,fibroblasts,andmonocytes,withaconsequentreductioninreactiveoxygenspeciesPreviousreportshavedemonstratedthatreactiveoxy-genspeciessuchassuperoxideandhydrogenperoxideinactivatesnitricoxideandprovokestheformationofoxidantsthatinducesbothlow-densitylipoproteinoxidationandexpressionofmonocytechemoattractantproteinsonendothelialcellswithsubsequentmonocytebindingandtransendothelialmigration,whicharebothfundamentalprocessesinatherogenesis.Therestorationofthebeneficialcyclicalstraintheconsequentreductioninreactiveoxygenspeciesformationmaythereforehaveanimpactonbothendothelium-dependentvasodilationandatherogenesis.Inaddition,thepreviouslymentionedphenomenawilltakeplaceinamicroenvironmenttreatedwiththemammaliantargetofrapamycin(mTOR)inhibitorever-olimus.TheproteinmTORisakeyserine-threoninekinaseplayingacentralroleintheregulationofcellgrowth,proliferation,andsurvival.Onamolecularlevel,everolimusformsacomplexwiththecytoplasmicproteinFKBP-12;thiscomplexbindstomTORandinhibitsitssignalingfunction,thusinhibitinggrowthstimulatedproliferationofvascularsmoothmusclecells,whichistriggeredbyinjurytoendothelialcellsandleadstoneointimaformation.Inthenewscenarioofacoronaryvesselfreeofmetalliccaging,theconcomitantscaffolddrugelutionatearlystages,medicaltherapy,andchangesinlife-mayallplayakeyadditionalroletofacilitatephenomenasuchasplaqueregression,expansiveremo-deling,andlateluminalenlargement.Ananalysisofvasoreactivityinscaffoldedsegmentsat12-and24-monthfollow-upwithbothendothelial-dependentandendothelial-independentagentshasbeenrecentlyreported,showingthatendothelialdys-functioninthoseregionsiscorrelatedtotheamountofplaqueburdenandnecroticcorecontent.DilettietalAmericanHeartJournalVolume164,Number5 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