心内科冠心病临床试验终点事件定义

ClinicalEndPointsinCoronaryStentTrials冠状动脉支架试验中的临床终点Background-Althoughmostclinicaltrialsofcoronarystentshavemeasurednominallyidenticalsafetyandeffectivenessendpoints,differencesindefinitionsandtimingofassessmenthavecreatedconfusionininterpretation.背景——虽然大多数冠状动脉支架的临床实验已经评价了完全相同的安全性终点和疗效终点，但多种定义以及评估时间的不同已然造成阐述问题时的困扰。MethodsandResults'-TheAcademicResearchConsortiumisaninformalcollaborationbetweenacademicresearchorganizationsintheUnitedStatesandEurope.Twomeetings,inWashington,DC,inJanuary2006andinDublin,Ireland,inJune2006,sponsoredbytheAcademicResearchConsortiumandincludingrepresentativesoftheUSFoodandDrugAdministrationandalldevicemanufacturerswhowereworkingwiththeFoodandDrugAdministrationondrug-elutingstentclinicaltrialprograms,werefocusedonconsensusendpointdefinitionsfordrug-elutingstentevaluations.Theeffortwaspursuedwiththeobjectivetoestablishconsistencyamongendpointdefinitionsandprovideconsensusrecommendations.Onthebasisofconsiderationsfromhistoricallegacytokeypathophysiologicalmechanismsandrelevancetoclinicalinterpretability,criteriaforassessmentofdeath,myocardialinfarction,repeatrevascularization,andstentthrombosisweredeveloped.Thebroadlybasedconsensusendpointdefinitionsinthisdocumentmaybeusefullyappliedorrecognizedforregulatoryandclinicaltrialpurposes.方法和结果——美国学术研究联合会（ARC）是美国和欧洲之间的一个非正式的学术研究机构。在2006年1月华盛顿和2006年6月爱尔兰都柏林召开的由美国学术研究联合会赞助的两个会议，包括美国食品药品监督管理局和所有与食品药品监督管理局在药物洗脱支架临床试验项目器材厂商在内，都一致关注药物洗脱支架（DES）评估中的临床终点的定义。其努力追求的目标是建立起终点定义的共识，从而提供一致的建议。基于对传统依据、关键病理生理学机制以及临床解释能力的考虑，对死亡、心肌梗塞、再次血运重建以及支架血栓形成的评估标准会取得实质性进展。在这篇文章中的终点定义是基于广泛共识的。它也许会在应用于管理或临床试验的目的时有所帮助。Conclusion—Althoughconsensuscriteriawillinevitablyincludecertainarbitraryfeatures,consensuscriteriaforclinicalendpointsprovideconsistencyacrossstudiesthatcanfacilitatetheevaluationofsafetyandeffectivenessofthesedevices.结论：虽然一致的标准会不可避免的包含特定的任意性的特点，但一致的临床终点标准提供了跨越研究的一致性，从而有利于这些器材安全性和疗效的评估。KeyWords:restenosisstentsthrombosisclinicaltrials关键词：再狭窄支架血栓形成临床试验Clinicaltrialsdesignedtoevaluatethesafetyandeffectivenessofdrug-elutingcoronarystents（DES）playpivotalrolesinbothnewdeviceapprovalandintheiradoptionforclinicaluse.Althoughsurrogatemarkersmayhavesomeroleinthedefinitionofdeviceperformance,directmeasuresofclinicaloutcomesarepreferableintheunderstandingoftheresponseofhumansubjects,exposuretothesecombinationdrug-deviceproducts.很多临床试验是为评估药物洗脱支架（DES）的安全性和疗效而设计的，这些试验在新器材的批准使用以及在临床应用中被接受的过程中起到了关键作用。虽然替代品制造者也许在器材性能的定义中起到了一定作用，但临床转归的测量更倾向于直接测量受试者暴露于这些药物与器材的结合产品后的反应。Theselectedendpointsmustserveseveralpurposes.Theymusthavebothshort-andlong-termpathophysiologicalrelevancetodeviceperformance,theymustrepresentclinicallymeaningfulevents,andtheymustbesufficientlydefined,preferablythroughblindedprocesses,tobesubjectedtostatisticalanalysis.Becauseoftheintrinsiclimitationsintheabilitytoobtainhistology,serialexaminations,orothermechanisticdetailfromhumansubjects,clinicalendpointsforDESstudiesareboundtoincludecertainarbitraryassumptionsandwillfrequentlyvaryacrossclinicaltrialsastheresultofdifferentapproachestosuchassumptions.Variabilityinendpointdefinitions,however,createsaformidablebarriertotheunderstandingofresultsacrossclinicaltrialsorthepoolingofresultsforthedetectionofraresafetysignals.入选的终点必须适用于多种目的，它们必须从短期和长期来看都有与器材性能在病理生理学上的相关性；必须能够代表临床上有意义的时间；必须足够明确，最好能经过盲审，能够服从于数据分析。由于其在获取组织学、系列检查或其他机制上细节的固有限制，DES研究中的临床终点必然包含一些任意的假设，并且会在各种针对这些假设的不同方法的临床试验结果中频繁变化。然而，终点定义的变化对不同临床试验的结果的理解以及对罕见安全信号探测结果的合并造成了不可忽视的障碍。Withtherecognitionthatconsistencyacrosswellconsideredendpointdefinitionsiscriticaltothisprocess,4academicresearchorganizationsinvolvedinthedesignandmanagementofcurrentDESclinicaltrialscombinedeffortsinaninformalcollaborationtermedtheAcademicResearchConsortium(ARC)toorchestrateasetofconsensusdefinitionsforDESstudyendpoints.TwomeetingsthatalsoincludedrepresentativesoftheUSFoodandDrugAdministration(FDA)anddevicemanufacturersthatworkedatthetimewiththeFDAonDESclinicaltrialprogramswereheldinWashington,DC,inJanuary2006andinDublin,Ireland,inJune2006(seetheonline-onlyDataSupplement).Thechargefortheconsortiumwastoselectappropriateindividualclinicalendpoints,definethecriteriatodeterminetheoccurrenceoftheendpoint,andconsiderthepotentialtogroupindividualendpointsintomeaningfulcompositesofbothdevice-orientedandpatient-orientedoutcomes.Importantly,themissionofthisfirstARCeffortwastoachievewell-consideredconsensusdefinitionswithoutdetailingperseallaspectsofhowthesedefinitionsshouldbeappliedfortrialdesignsorotherrelatedanalyses.认识到详尽周全的不同终点定义的一致性对于DES研究的重要性后，4家学术研究组织与一家名为美国学术研究协会(ARC)的非正式组织合力，参与到目前的DES临床试验的设计和管理中，以编写一系列的DES研究终点定义的共识。2006年1月和2006年6月，分别在华盛顿和爱尔兰都柏林举行了两场会议，美国FDA代表以及与FDA在DES临床试验项目上合作过的器材厂商参会。这个团队的任务是选择合适的独立临床终点，明确这个终点的发生标准，而后考虑将独立终点组合成有意义的面相器材、面相患者的结果。重要的是，第一届ARC的主要任务是完成详尽周全的定义共识，本身没有对这些定义是如何应用到试验设计或其他相关分析进行详尽描述。GeneralCriteriaforDESClinicalEndPointDefinitionsThreegeneralcriteriawereconsideredforeachendpointdefinition.First,theendpointdefinitionsshouldsupportthecharacterizationofdeviceeffectivenessorsafety.Inthefollowingdiscussion,itistheARCconsensusthatsafetyendpointsrepresentanyadverseoutcomewhetherspecificallyrelatedtotheuseofthedeviceornot,andeffectivenessendpointsreferspecificallytomaintenanceofcoronaryarteryluminalpatency.Second,theendpointdefinitionsshouldrelatetothepathophysiologicalmechanism(s)mostlikelyresponsiblefortheclinicaloutcome.Finally,theproposedcriteriashouldbalancetheneedforconsistencywiththelegacyofpublishedliteratureagainsttheneedforadaptationofdefinitionsbasedonnewlyemergingknowledge.DES临床终点定义的一般标准每个终点定义要考虑3个一般标准。第一，终点的定义应该支持对器材疗效和安全性的描述。在下面的讨论中，是ARC认为安全性终点代表了任何不良结果，不管与应用器材与否有无明确关系，而疗效终点则特指维持冠状动脉的开放。第二，终点的定义应该与导致临床结局的病理生理学机制相关。最后，所提出的标准应该在两种需要之间保持平衡，一种是与已发表的文章保持一致的需要，一种是适应以新出现的知识为基础的定义的需要。ClinicalEndPointMeasuresofDeviceSafety:GeneralConsiderations器材安全性临床终点测量的一般原则DES-relatedsafetyissuesaregovernedtosomedegreebytime.Adverseoutcomeswithin30daysofimplantationaregenerallyconsideredtemporallyrelatedtotheprocedure.Inthesettingofaprogressiveentitysuchascoronarydisease,thelaterthatadverseeventsoccur,themorelikelytheyaretorepresentaninteractionbetweenthedeviceandthediseaseortorepresentnewdiseaseactivityaltogether.DES相关的安全问题某种程度上受制于时间。30日内移植的不良结局通常被认为与手术相关。在像冠心病这样的逐步进展的疾病中，不良事件发生的越晚，就越有可能代表器材与疾病之间有相互作用，或者表示完全新发疾病。Eventdefinitionsmayalsovaryinrelationtothetreatedpopulation.Forexample,periproceduralmyocardialinfarction(MI)orsuddendeathwithin30daysinelectivepatientsmayclearlybedevice-orprocedure-related,whereasinpatientswithacuteorevolvingMIsuchrelationshipmaynotbeclear.事件的定义也许也会随着被治疗人群的变化而有所不同。例如，入选患者围手术期心梗01)或30天内的突然死亡也许是明显与器材或手术相关的，然而急性或慢性MI的病人，这种关系就不是十分明朗了。ClinicalEndPointMeasuresofDeviceEffectiveness:GeneralConsiderations器材疗效临床终点测量总论DESareimplantedforthetreatmentofobstructivecoronaryarterydisease.Theireffectivenessismeasuredbythereliefofsuchflow-limitingobstructions,initiallythroughstructuralmechanismsandlaterwithpreservationoftheluminaldimensionthroughinhibitionofneointimalhyperplasiaorrestenosis.DES的植入是用来治疗阻塞性冠状动脉疾病的。他们的疗效通过对这种限制血流的阻塞的开通，首先通过结构机理，而后通过防止内膜增生或再狭窄来保护血管腔的大小。Effectivenessclinicalendpointsaredesignedtoassessclinicallysignificantrestenosis,assessedobjectivelyasarequirementforischemia-drivenrepeatrevascularization,eitherofthestentedsegmentitself(targetlesionrevascularization[TLR])2orofthestentedvesseloritssidebranches(targetvesselrevascularization).Targetvesselfailure,proposedasanytargetvesselrevascularization,death,orMIattributedtothetargetvessel,isanevenbroadermetricoffailedeffectivenessandadjustsforthepotentialbiasintroducedwhenpatientswhodieorsustainMIbeforetheendoftheTLRendpointtimeareconsideredtobefreefromTLR.Ostensibly,onemightalsoconsiderpersistenceorrecurrenceofanginaduringfollow-upasevidenceoffailedeffectiveness(becausenotallepisodesofclinicalrestenosiswillleadtorepeatrevascularization),butwebelievethatthisendpointdoesnotlenditselfasreadilytoastheotherproposedendpointsandisbettermeasuredasastand-aloneendpointwiththeuseofformal,validatedhealthstatusinstruments.疗效临床重点被设计用来评估临床上有意义的再狭窄，是客观评价由于局部缺血所进行的血运重建的需要，而不是植入支架部分本身(靶病变血运重建，TLR)或植入支架的血管或它的侧支循环。靶血管的血运重建、死亡或归因于靶血管的心肌梗死时被提及的靶血管狭窄，用来表达失败的疗效，或适应由于患者死亡或在TLR终点之前忍受MI而被认为可以避免TLR而引入的潜在的偏差时，是个更宽泛的概念。表面上看，也许会有人认为随访期持续或再发心绞痛试疗效失败的证据(因为部分临床再狭窄的发生会进行再次血运重建)，但我们相信这个终点并不会同样容易地适用于其他提出的终点，而更应在应用正式的、经过验证的健康状态工具的基础上作为一个独立终点被测量。Patient-Oriented(Global)CardiovascularEndPoints:GeneralConsiderations面向患者的心血管终点总论TheoptimalbasisforDESevaluationshouldbeoverallcardiovascularoutcomesfromthepatient,sperspective,includingalldeath,MI,andrepeatrevascularizationprocedures.Theseoutcomesreflectthecomplexinterplaybetweendeviceperformance,revascularizationstrategy,secondaryprevention,andkeypatientdescriptors.BoththetimecourseandthecompositeselectedshouldcharacterizepatientwellbeingrelatedtothepathophysiologyoftheimplantedDESdeviceanditsimpactonunderlyingcoronaryarterydiseaseoutcome.Forexample,whetheradeviceimprovesfunctionalcapacityandqualityoflife,butdoesnotaffectMIratesormortality-asisthecaseforpercutaneousinterventioninelectivecases-shouldbeclearsothatregulatoryauthorities,clinicians,andreimbursementagenciescancarefullyweighthenetbenefitagainstpossiblesafetyconcerns.最理想的评估DES的基础应该是患者视角中全部心血管结局，包括死亡、MI以及再次血运重建治疗。这些结局反应了器材性能、血运重建策略、二级预防和患者主诉之间的复杂的相互影响。时间进程和综合选择应该描述患者与植入的DES病理生理机制、对正在发生的冠状动脉疾病结局的影响相关的健康特征。例如，作为被选择的经皮冠状动脉介入术的案例，不管器材是否提高了患者的生存质量和生活能力，只要其不影响MI的患病率和死亡率，应该十分明确，这样监管部门、临床医生以及赔偿机构才能认真地权衡利弊。ProposedSafetyandEfficacyEndPoints提议的安全性和疗效终点Death死亡Deaththatoccursafteracoronarystentproceduremaybyclearlyrelatedtoadevice-orprocedure-relatedcomplication,inwhichcasetheroleofthedeviceisclear.Deathmayalsooccurunexpectedlyduringthefollowupperiod,eitherasaresultofanevidentcardiacevent,unexplainedsuddendeath,ornoncardiaccause.ARCconsidersal-causemortalitythemostunbiasedmethodtoreportdeathsinaclinicaltrialorobservationalstudy,eventhoughitmaybelessspecificthandeathsadjudicatedascardiacinorigin(Table1).发生在冠状动脉支架过程中的死亡也许明确地与器材相关或手术相关并发症有关，在其中器材的角色是明确的。死亡也许会在随访期突然发生，既不是有明显证据的心血管事件导致的无法解释的猝死，也不是非心血管事件原因。ARC认为全因死亡率是在临床试验或观察研究中最不会出现偏差的方法，即使这种方法也许相比宣判心源性死亡缺少特异性(表1)。Fortimeswhenattributiontocardiacversusnoncardiaccausesisdesired,suchasduringlong-termfollow-upstudies,ARCproposesaconservativeapproach(Table1).Specifically,alldeathsareconsideredcardiacunlessanunequivocalnoncardiaccausecanbeestablished.Cardiacdeathsshouldincludealleventsrelatedtoacardiacdiagnosis,acomplicationoftheprocedure,treatmentforacomplicationoftheprocedure,oranunexplainedcause.Unexpecteddeatheveninpatientswithcoexistingandpotentiallyfatalnoncardiacdisease(eg,cancer,infection)shouldbeclassifiedascardiacunlesshistoryrelatedtothenoncardiacdiagnosissuggestsdeathwasimminent.Mortalityshouldthenbereportedasall-causeaswellascardiacmortalityversusnoncardiac.Itmayalsobedesirabletosubcategorizenoncardiacdeathbyvascularversusnonvascularcauses.很长时间以来我们需要把死亡原因归于心源性或非心源性，比如在进行长期的随访期研究的过程中，因此ARC提出另一个保守的方法(表1)。特别的是，所有死亡都被认为是心源性的，除非明确的非心源性病因能够成立。心源性死亡应包括与心血管诊断、治疗中的并发症以及对并发症的治疗等相关的所有事件。意外死亡，甚至在共存或潜在的致命的非心脏病(如癌症、感染)的患者，都应被归类为心源性的，除非有相关的非心脏病诊断提示即将死亡。此时死亡率应该报告全因死亡率与心源性而不是非心源性死亡率。也可以被描述为下一级的分类：非心源性死亡中的血管性与非血管性原因。TABLE1.ClassificationsofDeath表1死亡的分类Cardiacdeath心源性死亡Anydeathduetoproximatecardiaccause(eg,MI,low-outputfailure,fatalarrhythmia),unwitnesseddeathanddeathofunknowncause,andallprocedure-relateddeaths,includingthoserelatedtoconcomitanttreatment,willbeclassifiedascardiacdeath.任何由于近期的心脏因素(例如，心梗、低输出量性心力衰竭、致命性心律失常)，未察觉的死亡，未知原因的死亡以及所有治疗相关的死亡，包括哪些与移植治疗相关的死亡，都应被归为心源性死亡。Vasculardeath血管性死亡Deathcausedbynoncoronaryvascularcauses,suchascerebrovasculardisease,pulmonaryembolism,rupturedaorticaneurysm,dissectinganeurysm,orothervasculardiseases.非冠状动脉血管导致的死亡，例如脑血管疾病、肺栓塞、主动脉瘤破裂或其他的血管性疾病。Noncardiovasculardeath非血管性死亡Anydeathnotcoveredbytheabovedefinitions,suchasdeathcausedbyinfection,malignancy,sepsis,pulmonarycauses,accident,suicide,ortrauma.任何不适由于上述定义导致的死亡，如感染、败血症、肺因素、事故、自杀或创伤。Alldeathsareconsideredcardiacunlessanunequivocalnoncardiaccausecanbeestablished.Specifically,anyunexpecteddeathev^ninpatientswithcoexistingpotentiallyfatalnoncardiacdisease(eg,cancer,infection)shouldbeclassifiedascardiac.所有死亡都被认为是心源性的，除非明确的非心源性病因能够成立。特别的是，在共存或潜在的致命的非心脏病(如癌症、感染)的患者，都应被归类为心源性的。MyocardialInfarction心肌梗塞MIduringaclinicaltrialofapercutaneouscoronaryintervention(PCI)devicemayoccurduringtheimmediateperiproceduralperiodasaresultoftheindexstudyprocedureorlongaftertheprocedure,asaresultofspontaneousMIorlatecomplicationsofthestudydeviceorsubsequentrevascularizationprocedures.EventhemostrecentDESclinicaltrialshavereliedonoldermodifiedWorldHealthOrganizationcriteriatoestablishthediagnosisofMI,withthresholdvaluesoftotalcreatinekinase2timestheupperlimitofnormalratherthanmoresensitiveandspecificbiomarkers.Furthermore,thesedefinitionshavenotincludedmorevariablethresholdstodistinguishperiproceduralfromspontaneousMI.RepresentativesoftheEuropeanSocietyofCardiologyandtheAmericanCollegeofCardiologyhaveprovidedrecommendationstoredefinediagnosticcriteriaforMI7,8andtogetherwiththeAmericanHeartAssociationandWorldHeartFederationhaverecentlyupdatedtheseguidelinestocallforauniversaldefinitionforclinicalaswellasinvestigationaltrialuse.Initsmostrecentdocument,thisglobaltaskforcestronglyencouragesclinicaltrialiststoadopttheproposeddefinitionsforconsistentapplicationacrossinvestigationalstudies(Tables2and3).经皮冠状动脉介入治疗(PCI)器材的临床试验中出现的MI也许会在围手术期立即发生，可能是指数研究过程或其后发生的结果，或是自发性MI,或研究器材以及血运重建治疗的晚期并发症。即使最近的DES临床试验也要依赖早些时候的WHO改进版标准来确立MI的诊断，即肌酸激酶阈值高于2倍最大正常值，而不是更具敏感性和特异性的生物指标。不仅如此，这些定义不包括更可变的阈值来区分围术期MI和自发性MI。欧洲心脏病学会和美国心脏病学会的一些代表提供了重新定义MI诊断标准的一些建议，并且联合美国心脏协会和世界心脏联盟最近更新了指南来呼吁一个临床和试验通用的定义。在其最近的文献中，这个全球性的任务深深的鼓励了临床研究者来适应为不同调查研究提出的定义的共识。Aftercarefulconsideration,theARCagreeswiththisaddedlevelofconsensusandproposesaclassificationsystemthatisconsistentwiththeglobaltaskforcerecommendationandhighlightsareasthatrequireadditionalconsideration.TheglobaltaskforcerecommendstheestablishmentofcriteriabasedontroponinorcreatinekinaseMb(CKMB)butnotesthepreferencefortroponininallcases.ForeithertroponinorCKMB,theupperrangelimitisdefinedasthe99thpercentileofthenormalrange.Theperiproceduralperiodincludesthefirst48hoursafterPCIandfirst72hoursaftercoronaryarterybypassgrafting(CABG).经过认真考虑，ARC认可将这种认同提高等级，提出了一个与全球专题小组一致的强烈推荐的分类系统，并重点关注需要额外关注的部分。全球专题小组提到，这项标准是在肌钙蛋白或肌酸激酶MB(CK-MB)的基础上建立起来的，但在所有案例中更倾向于肌钙蛋白。不管是肌钙蛋白还是CK-MB，其参考值上限都是定义在正常值范围的99个百分点内。围术期包括PCI术后的48小时以及冠状动脉旁路移植术(CABG)后。TABLE2,MyocardialInfarctionClassificationandCriteiiaforDiagnosis*ClassiliDaticnBiomarkerCriteriatAdditionalCriteriaPtriprOCedurdPCITropunin>3limesURLarCKMB>3timesURL%鸵Memue<URLPaiprcbcedurdCABGTropunin>5limesURLarCKMB>5timesURL1%鸵lin日value<URLaridanyM(hefoilowing;newpalhologlcQwaves^t)rLBBB,newnativeargraftve$.sellDcdusiun.imagjri^evidenceol依屿ofviablem^DcardiunniSpontan^o<j5Trvpunin>URLwCKMB>URLSuddend^aihDeathbeforehiomwkersobtainedorbeforeexpectedtobe目川社tedSymptomssuggestiveofIschemiaandanyofthefoUowing:newST回的湖口。norLBBE、documentedIhrornbusbyan-gioyraplhyGrdulop^yReintarctionStableordecreasingvalueson2samplesard2C%Increase3to6hoursaftersecondsampleIfbiomarkersincreasingorpeaknotreachedthenIrsufficienldatalodiagnoserecurfenlML(AdaptedfrrmGlabalTaskrare.9URLindicateduppnrrelEiencfilimit,dtimed配99tfripEirenlileofnonnalreferencerange；LB8B.leftbundlehranchNock;右ndST』stentthrombosis.Waseiiiebiomarkervaluesquiredbeforestudyprocedureandpresumes3typicalriseand招II.tQwavesmaybedefinedaccordingtotheGlobaJTaskForca,3MinneEtitacode,arFJovacode.表2心肌梗塞分类及诊断标准分类生物标志物标准附加标准PCI围手术期心梗肌钙蛋白＞3倍参考值上限，或CK-MB＞3倍参考值上限基础值＜参考值上限CABG围手术期心梗自发性心梗肌钙蛋白＞5倍参考值上限，或CK-MB＞5倍参考值上限肌钙蛋白＞参考值上限，或CK-MB＞为值上限基础值＜参考值上限，及下列任意1项：新出现的病理性Q波或左束支传导阻滞，新出现的自身或移植血闭塞，心肌失活的影像学证据猝夕匕生物标志物结果获得前或升高前死亡提示缺血的症状或下.列任意一项：新出现的支架内血栓或左束支传导阻滞，由血管造影或尸体解剖发现的血栓。再梗死 2份稳定或升高的样本，以及在第2份样本3〜6个小若生物标志物升高或未达峰值，那时后有20%的升高 么缺乏足够证据诊断再发心梗来自全球专题小组。URL指参考值上限，定义为正常参考值的99个百分点内。LBBB，左束支传导阻滞。ST，支架血栓。*生物标志物基础值需要在研究过程之前，并能推测典型的升高和降低。**Q波可根据全球专题小组，明尼苏达或Nova编码。PresentationofMlOuleum照inClinicalTriallReportsPrimaryendpointTotalofMisdefinedbyanyoffthedassiUcationsinTable2.TroponinrectjinmendedasthepreferredbiornarkeratalltimepointsSecondaryanalysesAlldatafo「troponinandCKNBshouldbetabulatedfu「eachCla&sificatiorltoincludeatleadihefallowingoftheURLbytreatmentgroups：<1h1to2,2to3h3to5d5to10,aM>10CumullativefrequencydistributionoftroponinandCKWIBbytreatment卯加口表3临床试验报告中MI结局的呈现主要终点―I—一、八、、所有在表2中确定的MI分类。肌钙蛋白在所有时间点都被推荐为首选生物标志物。次级分析所有肌钙蛋白和CK-MB的数据都应列表与每个分类对应，治疗组至少包括下列参考值上限的倍数：<1，1〜2，2〜3，3〜5，5〜10，>10。治疗组的肌钙蛋白和CK-MB累计频率分布。PeriproceduralMIAfterPCIPCI围术期MIForperiproceduralMIafterPCI,itisimportanttodistinguisheventsdefinedbyathresholdlevelofenzymeorbiomarkerelevationwherethedegreeofelevationhasaprovenrelationshiptoothermoremeaningfulclinicaloutcomes.Althoughtheglobaltaskforcenotestheabsenceofsolidscientificevidencefortheestablishmentofsuchathreshold,theyhaverecommendedavalue3timestheupperrangelimit.SeveralinvestigatorshavereportedcorrelationofelevatedCKMBof3,5,or8timesnormalwithincreasedmortality,buttherehasbeenreluctancetousetroponininthissettingbecauseofconcernsoveritsextremesensitivityasameasure.In1study,manymorepatientsreachedthethresholdof3timesthenormalrangefortroponinthanforCKMB(22%versus4%).Althoughevenminimallyelevatedtroponinhasbeenassociatedwithincreasedlatemortality,thepositivepredictivevalueremainslow(10%).Nevertheless,theuseofamoresensitivemarkertodiagnoseanyMIofpotentialclinicalsignificancemaybeuseful,asthereappearstobeastrongcorrelationoftroponinlevelsandmeasurementsofinfarctsize.对于PCI围术期MI,4肌酶谱或生物标志物可能升高在某个临界值水平，升高程度可能被证实与其他更有意义的临床结局有关，区分这几种事件是很重要的。虽然全球专题小组提到目前缺乏确凿的科学依据来建立这样的临界值，但他们已经提出3倍与参考值上限的数值。某些调查者报告了CK-MB升高至3、5、8倍正常值与死亡率升高之间的相关性，肌钙蛋白由于其极高的敏感性则显得有些勉强。在研究中，很多患者达到了3倍肌钙蛋白或CK-MB正常范围的临界值（分别是22%与4%）。虽然即使最低限度的肌钙蛋白升高也与死亡率的升高有关，但其阳性预测值仍低（10%）。虽然如此，一个更加敏感的标志物来诊断任何MI或潜在的临床意义是有益的，因为看来肌钙蛋白与梗死大小的衡量是有关联的。TheARCremainsconcernedwhether3timesthenormalrangefortroponinwillprovetobeoverlysensitiveandfailtodiscriminateamongdeviceswithvariableriskforclinicallysignificantperiproceduralMI.Weagreewiththeglobaltaskforcethatclinicaltrialsshouldreportcompletebiomarkerdatawithdifferentmultiplesoftheupperrangelimitaswellasthetotaldistribution.Thispracticemayallowforimproveddiscriminatoryabilityifhigherlevelsaremorefrequentforaparticulardeviceandwillprovideinvestigatorswithabilitytotranslateacrossstudiesifdifferentthresholdsareused.ItmayalsobeadvisabletocollectCKMBdatawheneverpossibleuntilmoreexperiencehasbeenacquiredwiththeevaluationofoutcomesonthebasisoftroponin,especiallyincaseswherecomparisonswithhistoricalcontrolsareneeded.TheARCrecognizesthattheFDAandindividualtrialsponsorsmayprefertheuseoftotalcreatinekinaseorCKMBdefinitionsincaseswherehistoricalcomparisonsarecritical,butinthesecasesweencourageCKMBratherthantotalcreatinekinase.ARC仍然关心3倍正常范围的肌钙蛋白是否会被证明过于敏感而不能区别不同器材变化多样的临床上有意义的围术期MI。我们认同全球专题小组的观点：临床试验应该报告完整的生物标志物数据，包括不同倍数的参考值上限以及总体分布。若不同的临界值对于一个特定的器材较高水平频繁出现，这项实践也许会考虑改进分辨能力，并且会对不同研究之间的相互转化能力进行调查研究。随时收集全部CK-MB的数据直至获取更多基于肌钙蛋白评估结局的经验，尤其是在需要与历史对照对比的案例中ARC意识到FDA和独立试验者更倾向于在历史对照处于临界值的案例中使用总肌酸激酶或CK-MB，但这些案例我们更鼓励使用CK-MB而不是总肌酸激酶。PeriproceduralMIAfterCABGCABG围术期MIThediagnosisofMIafterCABGmaybeanissueduringfollow-upinPCItrialsoratthetimeoftheindextreatmentinstudieswhereCABGiscomparedwithDES.AlthoughstudieshavereportedassociationsofadverseoutcomeandCKMBelevations5,10,or20timestheupperratelimit,theinterpretationofisolatedbiomarkerelevationafterCABGisdifficultbecauseseveralsourcesofsuchelevationcanbeanticipated,includingcardiacmanipulation,ventricularventing,andsutureplacement.TheARCconcurswiththeglobaltaskforcethatbiomarkerelevationaloneisinadequateforthediagnosisofperiproceduralMIafterCABGandacceptstheproposeddefinitionoftroponinorCKMB5timestheupperratelimitwhenassociatedwithnewpathologicalQwavesorleftbundle-branchblock,angiographicallydocumentednewgraftornativevesselocclusion,orimagingevidenceofnewlossofviablemyocardium.CABG相关MI的诊断是在PCI试验随访期或CABG与DES对比研究中指数治疗时的一个问题。虽然各项研究已报道不良结局与CK-MB在5倍、10倍或20倍于参考值上限的升高之间的关系，但CABG术后独立的生物标志物升高的判读是非常困难的，因为这种升高可以来源于几种情况，包括心脏操作、心室射血、缝合位置。ARC同意全球专题小组提出的单独的生物标志物的升高不足以诊断CABG围术期MI，以及认可其提出的定义：肌钙蛋白或CK-MB升高至参考范围上限5倍，伴新出现的病理学Q波、左束支传导阻滞、新出现的自身或移植血闭塞、心肌失活的影像学证据。SpontaneousMI自发性MIMIaftertheperiproceduralperiodmaybesecondarytolatestentcomplicationsorprogressionofnativedisease.PerformanceofECGandangiographysupportsadjudicationtoeitheratargetornontargetvesselinmostcases.Withtheuniqueissuesandpathophysiologicalmechanismsassociatedwiththeselatereventsaswellasthedocumentedadverseimpactonshort-andlong-termprognosis,theARCproposesamoresensitivedefinitionthanforperiproceduralMIandsupportstheglobaltaskforcecriterionofanyelevationoftroponinabovetheupperrangelimit.ForthepurposesofevaluationofresultsofPCIclinicaltrials,wedonotfinditusefultodistinguishspontaneouseventscausedbyacutecoronaryischemiceventsfromthoserelatedtoincreaseddemandorothercausesfordecreasedsupplyasproposedbythetaskforce,andwewillconsideralllateeventsthatarenotassociatedwitharevascularizationproceduresimplyasspontaneous.围术期后的MI可能为次级的支架晚期并发症或原发疾病的进展。ECG表现以及血管造影在大多数案例中支持靶血管或非靶血管的判定。对于与这些后期事件相关的不同问题及病理生理学机制以及有记载的对短期或长期预后不良影响，ARC提出了比围术期MI更加敏感的定义，并且支持全球专题小组任何肌钙蛋白水平升高高于参考范围上限的标准。出于对PCI临床试验结果进行评估的目的，我们并没有发现像专题小组提出来的那样，在区分急性冠状动脉缺血时间导致的自发性时间与那些需氧增加相关或其他原因导致的供氧减少时的作用。我们认为所有与血运重建治疗无关的晚期事件都是单纯的自发性事件。SpecialSituations特殊情况TheglobaltaskforceaddressesotherspecificsituationsthatareapplicabletothediagnosisofMIinPCIclinicaltrials.Theimportanceofbaselinebiomarkersishighlightedtoexcludeelevationbeforetheindexprocedure.RecurrentMIorreinfarctionmaybediagnosedwhenbiomarkerlevelsarestableon2samplesthatare6hoursapartorareindeclineifasubsequentvalue3to6hoursaftertheprocedureisincreasedby20%fromthebaselinesample.Ifthebaselinevalueisnotstable,theninsufficientdataexisttorecommendbiomarkercriteriafordiagnosis,andtheARCrecommendsthattheseeventsbeconsideredaspreprocedureMI.TheglobaltaskforcealsoaddressestheroleofECGfordiagnosisofMI.PathologicalQwavesaredefinedaccordingtoamplitude,location,anddepthifpresentinatleast2contiguousleads;otherclassifications,suchasMinnesotacodeandNovacode,arealsoacceptablefordiagnosis.ThepresenceofQwavesasdefinedmaybeusedtodiagnoseintervalorpriorMIandhavealsobeenusedtosubclassifyperiproceduralandspontaneousMIasQwaveornon-Qwave.ECGinterpretationbyablindedcorelaboratoryisrecommended.Finally,theglobaltaskforceaddressespatientswhosuffersuddendeathbeforebiomarkerdatacanbeobtainedorbeforetheappearanceofcardiacbiomarkersintheblood.Inthepresenceofsupportingdata,suchasischemicsymptoms,newST-segmentelevation,newleftbundle-branchblock,ordocumentedvesselthrombusMIshouldbediagnosed.全球专题小组提出其他适用于诊断PCI临床试验中MI的特殊情况。生物标志物基础值的重要性是被特别关注的，它可以排除指数治疗前的升高。诊断心梗复发或再梗死需要在2份相隔6小时的生物标志物水平稳定或下降的基础上，治疗后3~6小时升高大于样本基础值的20%。若基础值不稳定，那么不充分的数据的存在就要提出生物标志物诊断标准，因此ARC提出这些事件应被认为是围术期MI。全球专题小组也提出MI诊断中ECG的地位。病理性Q波是根据振幅、位置、深度来考虑的，至少存在于2个连续导联；其他分类，比如明尼苏达码或Nova码在诊断中也是被接受的。病理性Q波的出现，已经明确被用来诊断陈旧性或现有MI，并且已被用于与将围术期及自发性MI归为Q波性或非Q波性。还提到双盲核心实验室对ECG的判读。最后，全球专题小组提到了在获取生物标志物之前猝死或心脏生物标志物升高之前猝死的病人。在支持数据缺乏时，缺血症状、新的ST段抬高，新的左束支传导阻滞或血管栓塞等均可诊断MI。RepeatRevascularization再次血运重建AssessmentofClinicalEffectiveness,ReductionofRestenosis临床疗效、减少再狭窄的评估ClearandconsistentdefinitionofTLRiscrucialtotheunderstandingofvariationsinDESeffectiveness,whetheracrossdifferentpatientpopulations,lesioncategories,orthedevicesthemselves.CriteriaforTLRshoulddefineproceduresthatareperformedforclinicallysignificantrenarrowingandthusinclude2fundamentalcomponents:theluminalmeasurementandtheclinicalcontext.Luminalrenarrowingprovidesanatomicevidenceofdeviceperformancefailure.TLR的明确、一致的定义对于理解DES疗效的变异是十分重要的，不论是什么样的病人群体、病变分类或器材本身。TLR的标准应该明确为有临床意义的再狭窄而进行的手术治疗，因此应包括两个基本的部分：血管腔的测量以及临床背景。血管腔的再狭窄为器材治疗失败提供解剖学证据。Theclinicalstatusofthepatientprovidesamoredirectreflectionoftheclinicaloutcomeassociatedwithanineffectivedevice-basedintervention.TheARCdefinitionrequiressymptomsorfunctionalevidenceofischemiaaswellaslesionseverityof50%diameterstenosisdeterminedbyanindependentquantitativecoronaryangiographiccorelaboratory(Table4).TheARCrecommendationextendstoencouragingDESstudydesignstorequirecompletionofclinicalevaluationsatapointintimebeforeanyprotocolrecatheterization,intravascularultrasound,orotherimaging.Implicittothisapproachisthatallintervalcatheterizations,andhe