心內(nèi)科冠心病臨床試驗(yàn)終點(diǎn)事件定義

ClinicalEndPointsinCoronaryStentTrials冠狀動(dòng)脈支架試驗(yàn)中的臨床終點(diǎn)Background-Althoughmostclinicaltrialsofcoronarystentshavemeasurednominallyidenticalsafetyandeffectivenessendpoints,differencesindefinitionsandtimingofassessmenthavecreatedconfusionininterpretation.背景——雖然大多數(shù)冠狀動(dòng)脈支架的臨床實(shí)驗(yàn)已經(jīng)評(píng)價(jià)了完全相同的安全性終點(diǎn)和療效終點(diǎn)，但多種定義以及評(píng)估時(shí)間的不同已然造成闡述問(wèn)題時(shí)的困擾。MethodsandResults'-TheAcademicResearchConsortiumisaninformalcollaborationbetweenacademicresearchorganizationsintheUnitedStatesandEurope.Twomeetings,inWashington,DC,inJanuary2006andinDublin,Ireland,inJune2006,sponsoredbytheAcademicResearchConsortiumandincludingrepresentativesoftheUSFoodandDrugAdministrationandalldevicemanufacturerswhowereworkingwiththeFoodandDrugAdministrationondrug-elutingstentclinicaltrialprograms,werefocusedonconsensusendpointdefinitionsfordrug-elutingstentevaluations.Theeffortwaspursuedwiththeobjectivetoestablishconsistencyamongendpointdefinitionsandprovideconsensusrecommendations.Onthebasisofconsiderationsfromhistoricallegacytokeypathophysiologicalmechanismsandrelevancetoclinicalinterpretability,criteriaforassessmentofdeath,myocardialinfarction,repeatrevascularization,andstentthrombosisweredeveloped.Thebroadlybasedconsensusendpointdefinitionsinthisdocumentmaybeusefullyappliedorrecognizedforregulatoryandclinicaltrialpurposes.方法和結(jié)果——美國(guó)學(xué)術(shù)研究聯(lián)合會(huì)（ARC）是美國(guó)和歐洲之間的一個(gè)非正式的學(xué)術(shù)研究機(jī)構(gòu)。在2006年1月華盛頓和2006年6月愛(ài)爾蘭都柏林召開的由美國(guó)學(xué)術(shù)研究聯(lián)合會(huì)贊助的兩個(gè)會(huì)議，包括美國(guó)食品藥品監(jiān)督管理局和所有與食品藥品監(jiān)督管理局在藥物洗脫支架臨床試驗(yàn)項(xiàng)目器材廠商在內(nèi)，都一致關(guān)注藥物洗脫支架（DES）評(píng)估中的臨床終點(diǎn)的定義。其努力追求的目標(biāo)是建立起終點(diǎn)定義的共識(shí)，從而提供一致的建議?；趯?duì)傳統(tǒng)依據(jù)、關(guān)鍵病理生理學(xué)機(jī)制以及臨床解釋能力的考慮，對(duì)死亡、心肌梗塞、再次血運(yùn)重建以及支架血栓形成的評(píng)估標(biāo)準(zhǔn)會(huì)取得實(shí)質(zhì)性進(jìn)展。在這篇文章中的終點(diǎn)定義是基于廣泛共識(shí)的。它也許會(huì)在應(yīng)用于管理或臨床試驗(yàn)的目的時(shí)有所幫助。Conclusion—Althoughconsensuscriteriawillinevitablyincludecertainarbitraryfeatures,consensuscriteriaforclinicalendpointsprovideconsistencyacrossstudiesthatcanfacilitatetheevaluationofsafetyandeffectivenessofthesedevices.結(jié)論：雖然一致的標(biāo)準(zhǔn)會(huì)不可避免的包含特定的任意性的特點(diǎn)，但一致的臨床終點(diǎn)標(biāo)準(zhǔn)提供了跨越研究的一致性，從而有利于這些器材安全性和療效的評(píng)估。KeyWords:restenosisstentsthrombosisclinicaltrials關(guān)鍵詞：再狹窄支架血栓形成臨床試驗(yàn)Clinicaltrialsdesignedtoevaluatethesafetyandeffectivenessofdrug-elutingcoronarystents（DES）playpivotalrolesinbothnewdeviceapprovalandintheiradoptionforclinicaluse.Althoughsurrogatemarkersmayhavesomeroleinthedefinitionofdeviceperformance,directmeasuresofclinicaloutcomesarepreferableintheunderstandingoftheresponseofhumansubjects,exposuretothesecombinationdrug-deviceproducts.很多臨床試驗(yàn)是為評(píng)估藥物洗脫支架（DES）的安全性和療效而設(shè)計(jì)的，這些試驗(yàn)在新器材的批準(zhǔn)使用以及在臨床應(yīng)用中被接受的過(guò)程中起到了關(guān)鍵作用。雖然替代品制造者也許在器材性能的定義中起到了一定作用，但臨床轉(zhuǎn)歸的測(cè)量更傾向于直接測(cè)量受試者暴露于這些藥物與器材的結(jié)合產(chǎn)品后的反應(yīng)。Theselectedendpointsmustserveseveralpurposes.Theymusthavebothshort-andlong-termpathophysiologicalrelevancetodeviceperformance,theymustrepresentclinicallymeaningfulevents,andtheymustbesufficientlydefined,preferablythroughblindedprocesses,tobesubjectedtostatisticalanalysis.Becauseoftheintrinsiclimitationsintheabilitytoobtainhistology,serialexaminations,orothermechanisticdetailfromhumansubjects,clinicalendpointsforDESstudiesareboundtoincludecertainarbitraryassumptionsandwillfrequentlyvaryacrossclinicaltrialsastheresultofdifferentapproachestosuchassumptions.Variabilityinendpointdefinitions,however,createsaformidablebarriertotheunderstandingofresultsacrossclinicaltrialsorthepoolingofresultsforthedetectionofraresafetysignals.入選的終點(diǎn)必須適用于多種目的，它們必須從短期和長(zhǎng)期來(lái)看都有與器材性能在病理生理學(xué)上的相關(guān)性；必須能夠代表臨床上有意義的時(shí)間；必須足夠明確，最好能經(jīng)過(guò)盲審，能夠服從于數(shù)據(jù)分析。由于其在獲取組織學(xué)、系列檢查或其他機(jī)制上細(xì)節(jié)的固有限制，DES研究中的臨床終點(diǎn)必然包含一些任意的假設(shè)，并且會(huì)在各種針對(duì)這些假設(shè)的不同方法的臨床試驗(yàn)結(jié)果中頻繁變化。然而，終點(diǎn)定義的變化對(duì)不同臨床試驗(yàn)的結(jié)果的理解以及對(duì)罕見(jiàn)安全信號(hào)探測(cè)結(jié)果的合并造成了不可忽視的障礙。Withtherecognitionthatconsistencyacrosswellconsideredendpointdefinitionsiscriticaltothisprocess,4academicresearchorganizationsinvolvedinthedesignandmanagementofcurrentDESclinicaltrialscombinedeffortsinaninformalcollaborationtermedtheAcademicResearchConsortium(ARC)toorchestrateasetofconsensusdefinitionsforDESstudyendpoints.TwomeetingsthatalsoincludedrepresentativesoftheUSFoodandDrugAdministration(FDA)anddevicemanufacturersthatworkedatthetimewiththeFDAonDESclinicaltrialprogramswereheldinWashington,DC,inJanuary2006andinDublin,Ireland,inJune2006(seetheonline-onlyDataSupplement).Thechargefortheconsortiumwastoselectappropriateindividualclinicalendpoints,definethecriteriatodeterminetheoccurrenceoftheendpoint,andconsiderthepotentialtogroupindividualendpointsintomeaningfulcompositesofbothdevice-orientedandpatient-orientedoutcomes.Importantly,themissionofthisfirstARCeffortwastoachievewell-consideredconsensusdefinitionswithoutdetailingperseallaspectsofhowthesedefinitionsshouldbeappliedfortrialdesignsorotherrelatedanalyses.認(rèn)識(shí)到詳盡周全的不同終點(diǎn)定義的一致性對(duì)于DES研究的重要性后，4家學(xué)術(shù)研究組織與一家名為美國(guó)學(xué)術(shù)研究協(xié)會(huì)(ARC)的非正式組織合力，參與到目前的DES臨床試驗(yàn)的設(shè)計(jì)和管理中，以編寫一系列的DES研究終點(diǎn)定義的共識(shí)。2006年1月和2006年6月，分別在華盛頓和愛(ài)爾蘭都柏林舉行了兩場(chǎng)會(huì)議，美國(guó)FDA代表以及與FDA在DES臨床試驗(yàn)項(xiàng)目上合作過(guò)的器材廠商參會(huì)。這個(gè)團(tuán)隊(duì)的任務(wù)是選擇合適的獨(dú)立臨床終點(diǎn)，明確這個(gè)終點(diǎn)的發(fā)生標(biāo)準(zhǔn)，而后考慮將獨(dú)立終點(diǎn)組合成有意義的面相器材、面相患者的結(jié)果。重要的是，第一屆ARC的主要任務(wù)是完成詳盡周全的定義共識(shí)，本身沒(méi)有對(duì)這些定義是如何應(yīng)用到試驗(yàn)設(shè)計(jì)或其他相關(guān)分析進(jìn)行詳盡描述。GeneralCriteriaforDESClinicalEndPointDefinitionsThreegeneralcriteriawereconsideredforeachendpointdefinition.First,theendpointdefinitionsshouldsupportthecharacterizationofdeviceeffectivenessorsafety.Inthefollowingdiscussion,itistheARCconsensusthatsafetyendpointsrepresentanyadverseoutcomewhetherspecificallyrelatedtotheuseofthedeviceornot,andeffectivenessendpointsreferspecificallytomaintenanceofcoronaryarteryluminalpatency.Second,theendpointdefinitionsshouldrelatetothepathophysiologicalmechanism(s)mostlikelyresponsiblefortheclinicaloutcome.Finally,theproposedcriteriashouldbalancetheneedforconsistencywiththelegacyofpublishedliteratureagainsttheneedforadaptationofdefinitionsbasedonnewlyemergingknowledge.DES臨床終點(diǎn)定義的一般標(biāo)準(zhǔn)每個(gè)終點(diǎn)定義要考慮3個(gè)一般標(biāo)準(zhǔn)。第一，終點(diǎn)的定義應(yīng)該支持對(duì)器材療效和安全性的描述。在下面的討論中，是ARC認(rèn)為安全性終點(diǎn)代表了任何不良結(jié)果，不管與應(yīng)用器材與否有無(wú)明確關(guān)系，而療效終點(diǎn)則特指維持冠狀動(dòng)脈的開放。第二，終點(diǎn)的定義應(yīng)該與導(dǎo)致臨床結(jié)局的病理生理學(xué)機(jī)制相關(guān)。最后，所提出的標(biāo)準(zhǔn)應(yīng)該在兩種需要之間保持平衡，一種是與已發(fā)表的文章保持一致的需要，一種是適應(yīng)以新出現(xiàn)的知識(shí)為基礎(chǔ)的定義的需要。ClinicalEndPointMeasuresofDeviceSafety:GeneralConsiderations器材安全性臨床終點(diǎn)測(cè)量的一般原則DES-relatedsafetyissuesaregovernedtosomedegreebytime.Adverseoutcomeswithin30daysofimplantationaregenerallyconsideredtemporallyrelatedtotheprocedure.Inthesettingofaprogressiveentitysuchascoronarydisease,thelaterthatadverseeventsoccur,themorelikelytheyaretorepresentaninteractionbetweenthedeviceandthediseaseortorepresentnewdiseaseactivityaltogether.DES相關(guān)的安全問(wèn)題某種程度上受制于時(shí)間。30日內(nèi)移植的不良結(jié)局通常被認(rèn)為與手術(shù)相關(guān)。在像冠心病這樣的逐步進(jìn)展的疾病中，不良事件發(fā)生的越晚，就越有可能代表器材與疾病之間有相互作用，或者表示完全新發(fā)疾病。Eventdefinitionsmayalsovaryinrelationtothetreatedpopulation.Forexample,periproceduralmyocardialinfarction(MI)orsuddendeathwithin30daysinelectivepatientsmayclearlybedevice-orprocedure-related,whereasinpatientswithacuteorevolvingMIsuchrelationshipmaynotbeclear.事件的定義也許也會(huì)隨著被治療人群的變化而有所不同。例如，入選患者圍手術(shù)期心梗01)或30天內(nèi)的突然死亡也許是明顯與器材或手術(shù)相關(guān)的，然而急性或慢性MI的病人，這種關(guān)系就不是十分明朗了。ClinicalEndPointMeasuresofDeviceEffectiveness:GeneralConsiderations器材療效臨床終點(diǎn)測(cè)量總論DESareimplantedforthetreatmentofobstructivecoronaryarterydisease.Theireffectivenessismeasuredbythereliefofsuchflow-limitingobstructions,initiallythroughstructuralmechanismsandlaterwithpreservationoftheluminaldimensionthroughinhibitionofneointimalhyperplasiaorrestenosis.DES的植入是用來(lái)治療阻塞性冠狀動(dòng)脈疾病的。他們的療效通過(guò)對(duì)這種限制血流的阻塞的開通，首先通過(guò)結(jié)構(gòu)機(jī)理，而后通過(guò)防止內(nèi)膜增生或再狹窄來(lái)保護(hù)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.療效臨床重點(diǎn)被設(shè)計(jì)用來(lái)評(píng)估臨床上有意義的再狹窄，是客觀評(píng)價(jià)由于局部缺血所進(jìn)行的血運(yùn)重建的需要，而不是植入支架部分本身(靶病變血運(yùn)重建，TLR)或植入支架的血管或它的側(cè)支循環(huán)。靶血管的血運(yùn)重建、死亡或歸因于靶血管的心肌梗死時(shí)被提及的靶血管狹窄，用來(lái)表達(dá)失敗的療效，或適應(yīng)由于患者死亡或在TLR終點(diǎn)之前忍受MI而被認(rèn)為可以避免TLR而引入的潛在的偏差時(shí)，是個(gè)更寬泛的概念。表面上看，也許會(huì)有人認(rèn)為隨訪期持續(xù)或再發(fā)心絞痛試療效失敗的證據(jù)(因?yàn)椴糠峙R床再狹窄的發(fā)生會(huì)進(jìn)行再次血運(yùn)重建)，但我們相信這個(gè)終點(diǎn)并不會(huì)同樣容易地適用于其他提出的終點(diǎn)，而更應(yīng)在應(yīng)用正式的、經(jīng)過(guò)驗(yàn)證的健康狀態(tài)工具的基礎(chǔ)上作為一個(gè)獨(dú)立終點(diǎn)被測(cè)量。Patient-Oriented(Global)CardiovascularEndPoints:GeneralConsiderations面向患者的心血管終點(diǎn)總論TheoptimalbasisforDESevaluationshouldbeoverallcardiovascularoutcomesfromthepatient,sperspective,includingalldeath,MI,andrepeatrevascularizationprocedures.Theseoutcomesreflectthecomplexinterplaybetweendeviceperformance,revascularizationstrategy,secondaryprevention,andkeypatientdescriptors.BoththetimecourseandthecompositeselectedshouldcharacterizepatientwellbeingrelatedtothepathophysiologyoftheimplantedDESdeviceanditsimpactonunderlyingcoronaryarterydiseaseoutcome.Forexample,whetheradeviceimprovesfunctionalcapacityandqualityoflife,butdoesnotaffectMIratesormortality-asisthecaseforpercutaneousinterventioninelectivecases-shouldbeclearsothatregulatoryauthorities,clinicians,andreimbursementagenciescancarefullyweighthenetbenefitagainstpossiblesafetyconcerns.最理想的評(píng)估DES的基礎(chǔ)應(yīng)該是患者視角中全部心血管結(jié)局，包括死亡、MI以及再次血運(yùn)重建治療。這些結(jié)局反應(yīng)了器材性能、血運(yùn)重建策略、二級(jí)預(yù)防和患者主訴之間的復(fù)雜的相互影響。時(shí)間進(jìn)程和綜合選擇應(yīng)該描述患者與植入的DES病理生理機(jī)制、對(duì)正在發(fā)生的冠狀動(dòng)脈疾病結(jié)局的影響相關(guān)的健康特征。例如，作為被選擇的經(jīng)皮冠狀動(dòng)脈介入術(shù)的案例，不管器材是否提高了患者的生存質(zhì)量和生活能力，只要其不影響MI的患病率和死亡率，應(yīng)該十分明確，這樣監(jiān)管部門、臨床醫(yī)生以及賠償機(jī)構(gòu)才能認(rèn)真地權(quán)衡利弊。ProposedSafetyandEfficacyEndPoints提議的安全性和療效終點(diǎn)Death死亡Deaththatoccursafteracoronarystentproceduremaybyclearlyrelatedtoadevice-orprocedure-relatedcomplication,inwhichcasetheroleofthedeviceisclear.Deathmayalsooccurunexpectedlyduringthefollowupperiod,eitherasaresultofanevidentcardiacevent,unexplainedsuddendeath,ornoncardiaccause.ARCconsidersal-causemortalitythemostunbiasedmethodtoreportdeathsinaclinicaltrialorobservationalstudy,eventhoughitmaybelessspecificthandeathsadjudicatedascardiacinorigin(Table1).發(fā)生在冠狀動(dòng)脈支架過(guò)程中的死亡也許明確地與器材相關(guān)或手術(shù)相關(guān)并發(fā)癥有關(guān)，在其中器材的角色是明確的。死亡也許會(huì)在隨訪期突然發(fā)生，既不是有明顯證據(jù)的心血管事件導(dǎo)致的無(wú)法解釋的猝死，也不是非心血管事件原因。ARC認(rèn)為全因死亡率是在臨床試驗(yàn)或觀察研究中最不會(huì)出現(xiàn)偏差的方法，即使這種方法也許相比宣判心源性死亡缺少特異性(表1)。Fortimeswhenattributiontocardiacversusnoncardiaccausesisdesired,suchasduringlong-termfollow-upstudies,ARCproposesaconservativeapproach(Table1).Specifically,alldeathsareconsideredcardiacunlessanunequivocalnoncardiaccausecanbeestablished.Cardiacdeathsshouldincludealleventsrelatedtoacardiacdiagnosis,acomplicationoftheprocedure,treatmentforacomplicationoftheprocedure,oranunexplainedcause.Unexpecteddeatheveninpatientswithcoexistingandpotentiallyfatalnoncardiacdisease(eg,cancer,infection)shouldbeclassifiedascardiacunlesshistoryrelatedtothenoncardiacdiagnosissuggestsdeathwasimminent.Mortalityshouldthenbereportedasall-causeaswellascardiacmortalityversusnoncardiac.Itmayalsobedesirabletosubcategorizenoncardiacdeathbyvascularversusnonvascularcauses.很長(zhǎng)時(shí)間以來(lái)我們需要把死亡原因歸于心源性或非心源性，比如在進(jìn)行長(zhǎng)期的隨訪期研究的過(guò)程中，因此ARC提出另一個(gè)保守的方法(表1)。特別的是，所有死亡都被認(rèn)為是心源性的，除非明確的非心源性病因能夠成立。心源性死亡應(yīng)包括與心血管診斷、治療中的并發(fā)癥以及對(duì)并發(fā)癥的治療等相關(guān)的所有事件。意外死亡，甚至在共存或潛在的致命的非心臟病(如癌癥、感染)的患者，都應(yīng)被歸類為心源性的，除非有相關(guān)的非心臟病診斷提示即將死亡。此時(shí)死亡率應(yīng)該報(bào)告全因死亡率與心源性而不是非心源性死亡率。也可以被描述為下一級(jí)的分類：非心源性死亡中的血管性與非血管性原因。TABLE1.ClassificationsofDeath表1死亡的分類Cardiacdeath心源性死亡Anydeathduetoproximatecardiaccause(eg,MI,low-outputfailure,fatalarrhythmia),unwitnesseddeathanddeathofunknowncause,andallprocedure-relateddeaths,includingthoserelatedtoconcomitanttreatment,willbeclassifiedascardiacdeath.任何由于近期的心臟因素(例如，心梗、低輸出量性心力衰竭、致命性心律失常)，未察覺(jué)的死亡，未知原因的死亡以及所有治療相關(guān)的死亡，包括哪些與移植治療相關(guān)的死亡，都應(yīng)被歸為心源性死亡。Vasculardeath血管性死亡Deathcausedbynoncoronaryvascularcauses,suchascerebrovasculardisease,pulmonaryembolism,rupturedaorticaneurysm,dissectinganeurysm,orothervasculardiseases.非冠狀動(dòng)脈血管導(dǎo)致的死亡，例如腦血管疾病、肺栓塞、主動(dòng)脈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.任何不適由于上述定義導(dǎo)致的死亡，如感染、敗血癥、肺因素、事故、自殺或創(chuàng)傷。Alldeathsareconsideredcardiacunlessanunequivocalnoncardiaccausecanbeestablished.Specifically,anyunexpecteddeathev^ninpatientswithcoexistingpotentiallyfatalnoncardiacdisease(eg,cancer,infection)shouldbeclassifiedascardiac.所有死亡都被認(rèn)為是心源性的，除非明確的非心源性病因能夠成立。特別的是，在共存或潛在的致命的非心臟病(如癌癥、感染)的患者，都應(yīng)被歸類為心源性的。MyocardialInfarction心肌梗塞MIduringaclinicaltrialofapercutaneouscoronaryintervention(PCI)devicemayoccurduringtheimmediateperiproceduralperiodasaresultoftheindexstudyprocedureorlongaftertheprocedure,asaresultofspontaneousMIorlatecomplicationsofthestudydeviceorsubsequentrevascularizationprocedures.EventhemostrecentDESclinicaltrialshavereliedonoldermodifiedWorldHealthOrganizationcriteriatoestablishthediagnosisofMI,withthresholdvaluesoftotalcreatinekinase2timestheupperlimitofnormalratherthanmoresensitiveandspecificbiomarkers.Furthermore,thesedefinitionshavenotincludedmorevariablethresholdstodistinguishperiproceduralfromspontaneousMI.RepresentativesoftheEuropeanSocietyofCardiologyandtheAmericanCollegeofCardiologyhaveprovidedrecommendationstoredefinediagnosticcriteriaforMI7,8andtogetherwiththeAmericanHeartAssociationandWorldHeartFederationhaverecentlyupdatedtheseguidelinestocallforauniversaldefinitionforclinicalaswellasinvestigationaltrialuse.Initsmostrecentdocument,thisglobaltaskforcestronglyencouragesclinicaltrialiststoadopttheproposeddefinitionsforconsistentapplicationacrossinvestigationalstudies(Tables2and3).經(jīng)皮冠狀動(dòng)脈介入治療(PCI)器材的臨床試驗(yàn)中出現(xiàn)的MI也許會(huì)在圍手術(shù)期立即發(fā)生，可能是指數(shù)研究過(guò)程或其后發(fā)生的結(jié)果，或是自發(fā)性MI,或研究器材以及血運(yùn)重建治療的晚期并發(fā)癥。即使最近的DES臨床試驗(yàn)也要依賴早些時(shí)候的WHO改進(jìn)版標(biāo)準(zhǔn)來(lái)確立MI的診斷，即肌酸激酶閾值高于2倍最大正常值，而不是更具敏感性和特異性的生物指標(biāo)。不僅如此，這些定義不包括更可變的閾值來(lái)區(qū)分圍術(shù)期MI和自發(fā)性MI。歐洲心臟病學(xué)會(huì)和美國(guó)心臟病學(xué)會(huì)的一些代表提供了重新定義MI診斷標(biāo)準(zhǔn)的一些建議，并且聯(lián)合美國(guó)心臟協(xié)會(huì)和世界心臟聯(lián)盟最近更新了指南來(lái)呼吁一個(gè)臨床和試驗(yàn)通用的定義。在其最近的文獻(xiàn)中，這個(gè)全球性的任務(wù)深深的鼓勵(lì)了臨床研究者來(lái)適應(yīng)為不同調(diào)查研究提出的定義的共識(shí)。Aftercarefulconsideration,theARCagreeswiththisaddedlevelofconsensusandproposesaclassificationsystemthatisconsistentwiththeglobaltaskforcerecommendationandhighlightsareasthatrequireadditionalconsideration.TheglobaltaskforcerecommendstheestablishmentofcriteriabasedontroponinorcreatinekinaseMb(CKMB)butnotesthepreferencefortroponininallcases.ForeithertroponinorCKMB,theupperrangelimitisdefinedasthe99thpercentileofthenormalrange.Theperiproceduralperiodincludesthefirst48hoursafterPCIandfirst72hoursaftercoronaryarterybypassgrafting(CABG).經(jīng)過(guò)認(rèn)真考慮，ARC認(rèn)可將這種認(rèn)同提高等級(jí)，提出了一個(gè)與全球?qū)ｎ}小組一致的強(qiáng)烈推薦的分類系統(tǒng)，并重點(diǎn)關(guān)注需要額外關(guān)注的部分。全球?qū)ｎ}小組提到，這項(xiàng)標(biāo)準(zhǔn)是在肌鈣蛋白或肌酸激酶MB(CK-MB)的基礎(chǔ)上建立起來(lái)的，但在所有案例中更傾向于肌鈣蛋白。不管是肌鈣蛋白還是CK-MB，其參考值上限都是定義在正常值范圍的99個(gè)百分點(diǎn)內(nèi)。圍術(shù)期包括PCI術(shù)后的48小時(shí)以及冠狀動(dòng)脈旁路移植術(shù)(CABG)后。TABLE2,MyocardialInfarctionClassificationandCriteiiaforDiagnosis*ClassiliDaticnBiomarkerCriteriatAdditionalCriteriaPtriprOCedurdPCITropunin>3limesURLarCKMB>3timesURL%鴕Memue<URLPaiprcbcedurdCABGTropunin>5limesURLarCKMB>5timesURL1%鴕lin日value<URLaridanyM(hefoilowing;newpalhologlcQwaves^t)rLBBB,newnativeargraftve$.sellDcdusiun.imagjri^evidenceol依嶼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心肌梗塞分類及診斷標(biāo)準(zhǔn)分類生物標(biāo)志物標(biāo)準(zhǔn)附加標(biāo)準(zhǔn)PCI圍手術(shù)期心梗肌鈣蛋白＞3倍參考值上限，或CK-MB＞3倍參考值上限基礎(chǔ)值＜參考值上限CABG圍手術(shù)期心梗自發(fā)性心梗肌鈣蛋白＞5倍參考值上限，或CK-MB＞5倍參考值上限肌鈣蛋白＞參考值上限，或CK-MB＞為值上限基礎(chǔ)值＜參考值上限，及下列任意1項(xiàng)：新出現(xiàn)的病理性Q波或左束支傳導(dǎo)阻滯，新出現(xiàn)的自身或移植血閉塞，心肌失活的影像學(xué)證據(jù)猝夕匕生物標(biāo)志物結(jié)果獲得前或升高前死亡提示缺血的癥狀或下.列任意一項(xiàng)：新出現(xiàn)的支架內(nèi)血栓或左束支傳導(dǎo)阻滯，由血管造影或尸體解剖發(fā)現(xiàn)的血栓。再梗死 2份穩(wěn)定或升高的樣本，以及在第2份樣本3?6個(gè)小若生物標(biāo)志物升高或未達(dá)峰值，那時(shí)后有20%的升高 么缺乏足夠證據(jù)診斷再發(fā)心梗來(lái)自全球?qū)ｎ}小組。URL指參考值上限，定義為正常參考值的99個(gè)百分點(diǎn)內(nèi)。LBBB，左束支傳導(dǎo)阻滯。ST，支架血栓。*生物標(biāo)志物基礎(chǔ)值需要在研究過(guò)程之前，并能推測(cè)典型的升高和降低。**Q波可根據(jù)全球?qū)ｎ}小組，明尼蘇達(dá)或Nova編碼。PresentationofMlOuleum照inClinicalTriallReportsPrimaryendpointTotalofMisdefinedbyanyoffthedassiUcationsinTable2.TroponinrectjinmendedasthepreferredbiornarkeratalltimepointsSecondaryanalysesAlldatafo「troponinandCKNBshouldbetabulatedfu「eachCla&sificatiorltoincludeatleadihefallowingoftheURLbytreatmentgroups：<1h1to2,2to3h3to5d5to10,aM>10CumullativefrequencydistributionoftroponinandCKWIBbytreatment卯加口表3臨床試驗(yàn)報(bào)告中MI結(jié)局的呈現(xiàn)主要終點(diǎn)―I—一、八、、所有在表2中確定的MI分類。肌鈣蛋白在所有時(shí)間點(diǎn)都被推薦為首選生物標(biāo)志物。次級(jí)分析所有肌鈣蛋白和CK-MB的數(shù)據(jù)都應(yīng)列表與每個(gè)分類對(duì)應(yīng)，治療組至少包括下列參考值上限的倍數(shù)：<1，1?2，2?3，3?5，5?10，>10。治療組的肌鈣蛋白和CK-MB累計(jì)頻率分布。PeriproceduralMIAfterPCIPCI圍術(shù)期MIForperiproceduralMIafterPCI,itisimportanttodistinguisheventsdefinedbyathresholdlevelofenzymeorbiomarkerelevationwherethedegreeofelevationhasaprovenrelationshiptoothermoremeaningfulclinicaloutcomes.Althoughtheglobaltaskforcenotestheabsenceofsolidscientificevidencefortheestablishmentofsuchathreshold,theyhaverecommendedavalue3timestheupperrangelimit.SeveralinvestigatorshavereportedcorrelationofelevatedCKMBof3,5,or8timesnormalwithincreasedmortality,buttherehasbeenreluctancetousetroponininthissettingbecauseofconcernsoveritsextremesensitivityasameasure.In1study,manymorepatientsreachedthethresholdof3timesthenormalrangefortroponinthanforCKMB(22%versus4%).Althoughevenminimallyelevatedtroponinhasbeenassociatedwithincreasedlatemortality,thepositivepredictivevalueremainslow(10%).Nevertheless,theuseofamoresensitivemarkertodiagnoseanyMIofpotentialclinicalsignificancemaybeuseful,asthereappearstobeastrongcorrelationoftroponinlevelsandmeasurementsofinfarctsize.對(duì)于PCI圍術(shù)期MI,4肌酶譜或生物標(biāo)志物可能升高在某個(gè)臨界值水平，升高程度可能被證實(shí)與其他更有意義的臨床結(jié)局有關(guān)，區(qū)分這幾種事件是很重要的。雖然全球?qū)ｎ}小組提到目前缺乏確鑿的科學(xué)依據(jù)來(lái)建立這樣的臨界值，但他們已經(jīng)提出3倍與參考值上限的數(shù)值。某些調(diào)查者報(bào)告了CK-MB升高至3、5、8倍正常值與死亡率升高之間的相關(guān)性，肌鈣蛋白由于其極高的敏感性則顯得有些勉強(qiáng)。在研究中，很多患者達(dá)到了3倍肌鈣蛋白或CK-MB正常范圍的臨界值（分別是22%與4%）。雖然即使最低限度的肌鈣蛋白升高也與死亡率的升高有關(guān)，但其陽(yáng)性預(yù)測(cè)值仍低（10%）。雖然如此，一個(gè)更加敏感的標(biāo)志物來(lái)診斷任何MI或潛在的臨床意義是有益的，因?yàn)榭磥?lái)肌鈣蛋白與梗死大小的衡量是有關(guān)聯(lián)的。TheARCremainsconcernedwhether3timesthenormalrangefortroponinwillprovetobeoverlysensitiveandfailtodiscriminateamongdeviceswithvariableriskforclinicallysignificantperiproceduralMI.Weagreewiththeglobaltaskforcethatclinicaltrialsshouldreportcompletebiomarkerdatawithdifferentmultiplesoftheupperrangelimitaswellasthetotaldistribution.Thispracticemayallowforimproveddiscriminatoryabilityifhigherlevelsaremorefrequentforaparticulardeviceandwillprovideinvestigatorswithabilitytotranslateacrossstudiesifdifferentthresholdsareused.ItmayalsobeadvisabletocollectCKMBdatawheneverpossibleuntilmoreexperiencehasbeenacquiredwiththeevaluationofoutcomesonthebasisoftroponin,especiallyincaseswherecomparisonswithhistoricalcontrolsareneeded.TheARCrecognizesthattheFDAandindividualtrialsponsorsmayprefertheuseoftotalcreatinekinaseorCKMBdefinitionsincaseswherehistoricalcomparisonsarecritical,butinthesecasesweencourageCKMBratherthantotalcreatinekinase.ARC仍然關(guān)心3倍正常范圍的肌鈣蛋白是否會(huì)被證明過(guò)于敏感而不能區(qū)別不同器材變化多樣的臨床上有意義的圍術(shù)期MI。我們認(rèn)同全球?qū)ｎ}小組的觀點(diǎn)：臨床試驗(yàn)應(yīng)該報(bào)告完整的生物標(biāo)志物數(shù)據(jù)，包括不同倍數(shù)的參考值上限以及總體分布。若不同的臨界值對(duì)于一個(gè)特定的器材較高水平頻繁出現(xiàn)，這項(xiàng)實(shí)踐也許會(huì)考慮改進(jìn)分辨能力，并且會(huì)對(duì)不同研究之間的相互轉(zhuǎn)化能力進(jìn)行調(diào)查研究。隨時(shí)收集全部CK-MB的數(shù)據(jù)直至獲取更多基于肌鈣蛋白評(píng)估結(jié)局的經(jīng)驗(yàn)，尤其是在需要與歷史對(duì)照對(duì)比的案例中ARC意識(shí)到FDA和獨(dú)立試驗(yàn)者更傾向于在歷史對(duì)照處于臨界值的案例中使用總肌酸激酶或CK-MB，但這些案例我們更鼓勵(lì)使用CK-MB而不是總肌酸激酶。PeriproceduralMIAfterCABGCABG圍術(shù)期MIThediagnosisofMIafterCABGmaybeanissueduringfollow-upinPCItrialsoratthetimeoftheindextreatmentinstudieswhereCABGiscomparedwithDES.AlthoughstudieshavereportedassociationsofadverseoutcomeandCKMBelevations5,10,or20timestheupperratelimit,theinterpretationofisolatedbiomarkerelevationafterCABGisdifficultbecauseseveralsourcesofsuchelevationcanbeanticipated,includingcardiacmanipulation,ventricularventing,andsutureplacement.TheARCconcurswiththeglobaltaskforcethatbiomarkerelevationaloneisinadequateforthediagnosisofperiproceduralMIafterCABGandacceptstheproposeddefinitionoftroponinorCKMB5timestheupperratelimitwhenassociatedwithnewpathologicalQwavesorleftbundle-branchblock,angiographicallydocumentednewgraftornativevesselocclusion,orimagingevidenceofnewlossofviablemyocardium.CABG相關(guān)MI的診斷是在PCI試驗(yàn)隨訪期或CABG與DES對(duì)比研究中指數(shù)治療時(shí)的一個(gè)問(wèn)題。雖然各項(xiàng)研究已報(bào)道不良結(jié)局與CK-MB在5倍、10倍或20倍于參考值上限的升高之間的關(guān)系，但CABG術(shù)后獨(dú)立的生物標(biāo)志物升高的判讀是非常困難的，因?yàn)檫@種升高可以來(lái)源于幾種情況，包括心臟操作、心室射血、縫合位置。ARC同意全球?qū)ｎ}小組提出的單獨(dú)的生物標(biāo)志物的升高不足以診斷CABG圍術(shù)期MI，以及認(rèn)可其提出的定義：肌鈣蛋白或CK-MB升高至參考范圍上限5倍，伴新出現(xiàn)的病理學(xué)Q波、左束支傳導(dǎo)阻滯、新出現(xiàn)的自身或移植血閉塞、心肌失活的影像學(xué)證據(jù)。SpontaneousMI自發(fā)性MIMIaftertheperiproceduralperiodmaybesecondarytolatestentcomplicationsorprogressionofnativedisease.PerformanceofECGandangiographysupportsadjudicationtoeitheratargetornontargetvesselinmostcases.Withtheuniqueissuesandpathophysiologicalmechanismsassociatedwiththeselatereventsaswellasthedocumentedadverseimpactonshort-andlong-termprognosis,theARCproposesamoresensitivedefinitionthanforperiproceduralMIandsupportstheglobaltaskforcecriterionofanyelevationoftroponinabovetheupperrangelimit.ForthepurposesofevaluationofresultsofPCIclinicaltrials,wedonotfinditusefultodistinguishspontaneouseventscausedbyacutecoronaryischemiceventsfromthoserelatedtoincreaseddemandorothercausesfordecreasedsupplyasproposedbythetaskforce,andwewillconsideralllateeventsthatarenotassociatedwitharevascularizationproceduresimplyasspontaneous.圍術(shù)期后的MI可能為次級(jí)的支架晚期并發(fā)癥或原發(fā)疾病的進(jìn)展。ECG表現(xiàn)以及血管造影在大多數(shù)案例中支持靶血管或非靶血管的判定。對(duì)于與這些后期事件相關(guān)的不同問(wèn)題及病理生理學(xué)機(jī)制以及有記載的對(duì)短期或長(zhǎng)期預(yù)后不良影響，ARC提出了比圍術(shù)期MI更加敏感的定義，并且支持全球?qū)ｎ}小組任何肌鈣蛋白水平升高高于參考范圍上限的標(biāo)準(zhǔn)。出于對(duì)PCI臨床試驗(yàn)結(jié)果進(jìn)行評(píng)估的目的，我們并沒(méi)有發(fā)現(xiàn)像專題小組提出來(lái)的那樣，在區(qū)分急性冠狀動(dòng)脈缺血時(shí)間導(dǎo)致的自發(fā)性時(shí)間與那些需氧增加相關(guān)或其他原因?qū)е碌墓┭鯗p少時(shí)的作用。我們認(rèn)為所有與血運(yùn)重建治療無(wú)關(guān)的晚期事件都是單純的自發(fā)性事件。SpecialSituations特殊情況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?qū)ｎ}小組提出其他適用于診斷PCI臨床試驗(yàn)中MI的特殊情況。生物標(biāo)志物基礎(chǔ)值的重要性是被特別關(guān)注的，它可以排除指數(shù)治療前的升高。診斷心梗復(fù)發(fā)或再梗死需要在2份相隔6小時(shí)的生物標(biāo)志物水平穩(wěn)定或下降的基礎(chǔ)上，治療后3~6小時(shí)升高大于樣本基礎(chǔ)值的20%。若基礎(chǔ)值不穩(wěn)定，那么不充分的數(shù)據(jù)的存在就要提出生物標(biāo)志物診斷標(biāo)準(zhǔn)，因此ARC提出這些事件應(yīng)被認(rèn)為是圍術(shù)期MI。全球?qū)ｎ}小組也提出MI診斷中ECG的地位。病理性Q波是根據(jù)振幅、位置、深度來(lái)考慮的，至少存在于2個(gè)連續(xù)導(dǎo)聯(lián)；其他分類，比如明尼蘇達(dá)碼或Nova碼在診斷中也是被接受的。病理性Q波的出現(xiàn)，已經(jīng)明確被用來(lái)診斷陳舊性或現(xiàn)有MI，并且已被用于與將圍術(shù)期及自發(fā)性MI歸為Q波性或非Q波性。還提到雙盲核心實(shí)驗(yàn)室對(duì)ECG的判讀。最后，全球?qū)ｎ}小組提到了在獲取生物標(biāo)志物之前猝死或心臟生物標(biāo)志物升高之前猝死的病人。在支持?jǐn)?shù)據(jù)缺乏時(shí)，缺血癥狀、新的ST段抬高，新的左束支傳導(dǎo)阻滯或血管栓塞等均可診斷MI。RepeatRevascularization再次血運(yùn)重建AssessmentofClinicalEffectiveness,ReductionofRestenosis臨床療效、減少再狹窄的評(píng)估ClearandconsistentdefinitionofTLRiscrucialtotheunderstandingofvariationsinDESeffectiveness,whetheracrossdifferentpatientpopulations,lesioncategories,orthedevicesthemselves.CriteriaforTLRshoulddefineproceduresthatareperformedforclinicallysignificantrenarrowingandthusinclude2fundamentalcomponents:theluminalmeasurementandtheclinicalcontext.Luminalrenarrowingprovidesanatomicevidenceofdeviceperformancefailure.TLR的明確、一致的定義對(duì)于理解DES療效的變異是十分重要的，不論是什么樣的病人群體、病變分類或器材本身。TLR的標(biāo)準(zhǔn)應(yīng)該明確為有臨床意義的再狹窄而進(jìn)行的手術(shù)治療，因此應(yīng)包括兩個(gè)基本的部分：血管腔的測(cè)量以及臨床背景。血管腔的再狹窄為器材治療失敗提供解剖學(xué)證據(jù)。Theclinicalstatusofthepatientprovidesamoredirectreflectionoftheclinicaloutcomeassociatedwithanineffectivedevice-basedintervention.TheARCdefinitionrequiressymptomsorfunctionalevidenceofischemiaaswellaslesionseverityof50%diameterstenosisdeterminedbyanindependentquantitativecoronaryangiographiccorelaboratory(Table4).TheARCrecommendationextendstoencouragingDESstudydesignstorequirecompletionofclinicalevaluationsatapointintimebeforeanyprotocolrecatheterization,intravascularultrasound,orotherimaging.Implicittothisapproachisthatallintervalcatheterizations,andhe