临床试验文献评价

,第四节临床文献评价真实性重要性实用性,临床科研设计书的主要内容1.研究题目：主要研究问题和次要研究问题，说明课题的科学性与可行性。2.样本含量估计：计算方法和本研究采用样本量的依据。3.研究对象的诊断、纳入、排除标准。4.设计方案、随机方法和研究地点。5.效应指标和测量方法。6.控制偏倚的措施。7.统计分析。8.医德问题。,一、真实性评价1.研究证据是否来源于真正的随机对照试验？2.研究对象是否明确限定？3.防治措施的具体内容是否明确？4.是否观察、报告了全部临床结果？5.报道的结果是否包括了全部纳入的病例？6.统计方法的使用是否合适？是否注意了统计学意义与临床意义？,（一）研究证据是否来源于真正的随机对照试验？随机分组的方法是否交代、是否恰当、是否采用了隐匿？试验组和对照组例数是否相等或接近？两组的基线资料和其它非试验因素是否可比？分层随机的分层因素是否合适？分层各组的样本量要仔细计算。,（二）研究对象是否明确限定？诊断标准纳入标准排除标准,（三）防治措施的具体内容是否明确？1.药物：剂量、剂型、给药方法与途径、疗程、相应的配套治疗。2.保证防治措施的正确实施。3.沾染和干扰的预防。4.依从性的检查。,（四）是否观察、报告了全部临床结果？效益和危害-治疗作用与毒副反应效应指标及其观察时间、空间和测量方式是否合适是否合适的采用盲法,（五）报道的结果是否包括了全部纳入的病例？确保失访（lostfollow)率10%。如失访率20%，没有多大的临床价值。失访率在10%-20%之间：采用意愿治疗分析(intention-to-treatanalysis)试验组失访人数按无效计算对照组失访人数按有效计算,（六）统计方法的使用是否合适？是否注意了统计学意义与临床意义？统计学意义只表明试验组与对照组之间的差异来自防治措施的本身，只能评价这种差异的真实程度，但并不表明疗效差异大小的临床意义。CERARRNNT的应用。,二、重要性评价真正的阴性结果真正的尚有争议的结果真实有效的结果,（一）效果究竟有多大？明确试验组与对照组事件发生率（如治愈率、死亡率、不良反应等）各有多大，以及组间的差值，对这些差值的临床意义做出评价。,（二）试验效果的准确度如何？常用95%的可信区间表示（95%CIconfidenceinterval)可信区间越小，可信度越靠近真值，反之可信度就要差一些。,三、实用性评价患者的情况是否与我们的相一致？可行性如何？干预措施的“利”与“弊”,（一）试验的证据是否与我们经治的患者情况一致？根据患者的病情、病理损害程度、社会人口特点（人种、性别、年龄等）、亚组的分析特点“对号入座”。,（二）试验结果的可行性如何？技术的可行性病人接受的可行性经济的可行性,（三）试验结果的“利”与“弊”对试验结果施加给病人后可能获得多大程度的效果和引起不良反应的风险度要权衡比较，只有在确定“利”肯定大于“弊”时才能接受、实践这种试验结果。LikelihoodofbeinghelpedversusharmedLHH,AMulticenterStudyofGrepafloxacin(格雷沙星）andClarithromycinintheTreatmentofPatientsWithCommunity-AcquiredPneumonia*S.Moola,MBChB;LarsHagberg,MD,PhD;GavinA.Churchyard,MBBCh;JoeS.Dylewski,MDCM;SangeetaSedani,BScandHeatherStaley,BScChest.1999;116:974-983.,Studyobjectives:Tocomparetheefficaciesof10-dayregimensofgrepafloxacin(GFX)(RaxarorVaxar;GlaxoWellcome;Greenford,UK),600qd,andclarithromycin(CLA)(Klacid,Biaxin,orKlaracid;AbbottLaboratories;Chicago,IL),500mgbid,inpatientswithcommunity-acquiredpneumonia(CAP),onthebasisofclinicalresponse,includingradiographicevidence,andbacteriologicefficacy.,PatientPopulationandStudyDesignThiswasaphaseIIIb,double-blind,randomized,prospective,parallel-group,comparativestudy(protocolGFXB3003)conductedat58centersin11countries(Australia,Canada,CzechRepublic,Germany,Italy,Israel,NewZealand,Poland,SouthAfrica,Spain,andSweden).Regulatoryapprovalwasobtainedwhereappropriate,andthestudywasapprovedbylocalethicscommittees.Written,informedconsentwasobtainedforeachparticipantinaccordancewithnationalguidelinesandtheDeclarationofHelsinki(HongKongamendment,1989).,Patientswithchestradiographstakenwithin2daysofthestartofstudymedicationconfirmingpulmonaryinfiltrationorconsolidation（实变）likelytobecausedbypneumonia,andpatientspresentingwithoneormoreoftheclinicalsignsandsymptomsconsistentwithCAPpleuriticchestpain,cough,fever(38C),andauscultatoryfindingssuchasralesand/orevidenceofconsolidationwereincludedinthestudy.,Sputumproductionwasnotarequirementforstudyentry;however,whenpatientswereproducingsputum,asamplewascollectedforculture.Patientscouldbetreatedinthecommunityorcouldbeadmittedtothehospital,dependingonthestandardmedicalpracticeindifferentcountries.,Patientswereexcludediftheyhadnosocomial（院内）pneumonia;requiredimmediateIVantibiotictherapy;hadreceivedantibiotictherapywithin3daysbeforestudyentry;orhadbronchialcarcinoma,empyema（脓胸）,lungabscess,uncontrolledasthma,pulmonarytuberculosis,orcysticfibrosis.,Aswellasotherstandardexclusioncriteriaforclinicaltrials,patientswithanimmunocompromisedstatus,malabsorption（吸收障碍）syndromes,hepaticorrenalimpairment,andhistoryofseizure（癫痫）disorderswereexcluded,aswerethosewithknownsensitivitytoanyquinoloneormacrolideantibiotic.,PatientswererandomizedtoreceiveeitheroralGFX,600mgqdfor10days(251patients)ororalCLA,500mgbidfor10days(253patients).Inadditiontotheactivemedication,patientsreceivedconcurrentplaceboforstudy-blindingpurposes.Administrationofadditionalantimicrobialswasnotpermittedforthedurationofthestudy,andarecordwaskeptofanymedicationtakenconcomitantly.,AssessmentsAfterentryintothestudyandpretreatmentassessment,patientswerereassessedduringtreatment(4to6daysaftertreatmentinitiation),aftertreatment(1to3daysaftercompletion),andatfollow-up(28to35daysaftertreatmentcompletion).Ateachassessment,patientswereevaluatedforresolutionofsignsandsymptomsofpneumonia.Beforetreatmentandatfollow-up(orwithdrawal),chestradiographyandphysicalexaminationswereperformed.,Ateachassessment,sputumsampleswerecollected(ifavailable)forGramsstain,culture,andsusceptibilitytesting(onlysamplesmeetingtherecognizedcriteriaof25neutrophilsand10epithelialcellsperlow-powerfieldwerecultured).Bloodwascollectedforcultureatthepretreatmentassessment,andiftheresultswerepositiveorifthesubjectremainedfebrile,bloodwascollectedforcultureattheposttreatmentandfollow-upassessments.,Primaryidentificationofisolatedpathogenswasperformedusingroutinelaboratoryculturemethods.BacterialisolatesweretestedbydiskdiffusionforsusceptibilitytoGFXandCLA;inaddition,theminimalinhibitoryconcentrationwasdetermined.Productionof-lactamasewasdeterminedbythenitrocefinmethodwhereappropriate.ForSpneumoniaeisolates,susceptibilitytestingtopenicillinwasperformed.,Inaddition,serologywasperformedbyacentrallaboratoryonpretreatmentandfollow-upbloodorurinesamplesfordetectionoftheatypicalrespiratorypathogensMycoplasmapneumoniae,Chlamydiapneumoniae（衣原体）,andLpneumophila.ThepresenceofChlamydiaandMycoplasmasppwasestablishedusingindirectfluorescentantibodyassaykitsforbothIgGandIgM(MRLDiagnostics;Cypress,CAandZeusScientific;Raritan,NJ).Testswereinterpretedfromcomparisonsofpretreatmentandfollow-upsamplesaccordingtotheinstructionsofthemanufacturer.,Atleastafourfoldriseinreciprocal(互补）valuetiterforIgGorIgMfrompretreatmenttofollow-upwasrequiredtoindicateapositivetestresult.ForMpneumoniae,anIgGtiterof1:128wasrequiredunlessafourfoldincreaseinIgMwasalsopresent,whenatiterof1:64wasacceptable.Legionellasppweredetectedusingradioimmuneassays(Bimax;Portland,ME)ofurinesamples.,C-reactiveprotein(CRP)determinationsweremadeonbloodsamplestakenbeforeandaftertreatmenttoevaluatethistestasanadditionalsurrogate（替代）markertoindicatethepresenceofbacterialinfection.ThenumberofpatientswithaCRPvalue50mg/Latthepretreatmentandposttreatmentassessmentswasdeterminedandwasalsoanalyzedinconjunctionwithclinicaloutcome.,Detailsofadverseeventsandanyotherproblemselicitedbynonspecificquestioningwererecordedateachvisit.,EfficacyMeasuresTheprimarymeasureofefficacywastheclinicalandradiographicresponseatfollow-up;thiswasassessedforallpatientsandforpatientswithdocumentedinfectionwitheithertypicaloratypicalpathogens.,Table1.DefinitionsofClinicalResponsesClinicalResponsesDefinitionsCureImprovementorresolutionofclinicalsignsandsymptomsaftertreatmentandabsence,includingradiographicevidence,atfollow-upImprovementImprovementbutincompleteresolutionofclinicalsignsandsymptoms,includingradiographicevidence,atfollowFailureNoimprovementduringoraftertreatmentordiscontinuationoftherapybecauseofadrug-relatedadverseeventRecurrenceResolutionorimprovementaftertreatmentwithrecurrenceofclinicalsymptoms,includingradiographicevidence,atfollow-upUnabletobeSignificantdeviationsfromprotocolevaluated,Togradetheclinicaloutcome,theradiographicresponsewasclassifiedatfollow-upasresolved(areasofinfiltrationorconsolidationcompletelyclear),improved(areasofinfiltrationorconsolidationstillexistbutshowevidenceofclearing),orunchangedorworse(areasofinfiltrationorconsolidationunchangedorshowevidenceofspreadorincreaseddensity).,Table2.DefinitionsofBacteriologicResponsesBacteriologicResponsesDefinitionsCureInitialpathogeneradicatedPresumedcureClinicalcureorimprovementintheabsenceofsputumorbloodcultureCurewithsuperinfectionEradicationofinitialpathogenwithisolationofneworganism(s)associatedwithclinicalsymptomsofinfectionCurewithcolonizationEradicationofinitialpathogenwithisolationofnewnonpathogenicorganism(s)notassociatedwithclinicalsymptomsofinfectionRecurrenceInitialbacteriologiccurewithreisolationoforiginalpathogenatfollow-upFailureInitialpathogennoteradicatedduringtreatmentPresumedfailureClinicalfailureintheabsenceofsputumorbloodcultureFailurewithsuperinfectionInitialpathogennoteradicatedplusisolationofnewpathogen(s)FailurewithresistanceInitialpathogen(s)developingresistanceduringtherapyUnabletobeevaluatedInabilitytoidentifyorculturepretreatmentpathogens,andanyotherdeviationfromprotocol,StatisticalAnalysisAsatisfactoryresponserate(clinicalcureorimprovement)of80to89%atfollow-upwithabroad-spectrumantibioticwasassumed.Assuminganinabilitytoevaluaterateof25%,atleast450patientswererequiredtoestablishequivalenceinboththeintent-to-treat(ITT,patientswhowererandomlyassignedandreceivedatleastonedoseofthestudymedication)andclinicallyevaluatedpopulations(eg,patientswhowereabletobeclinicallyevaluated(CE)inaccordancewiththestudyprotocolcriteria),usinga95%confidenceinterval(CI)calculatedforatwo-tailedtestofsignificanceatthe15%levelwith90%power.9Equivalencewasdemonstratedifthelowerlimitofthe95%CIofthedifferenceinresponserateamongpatientsreceivingGFXminustheresponseratetoCLAwas-15%.,PrimaryefficacydatawereanalyzedfortheITTandCEpopulations.Analyseswerealsoperformedonthemicrobiologicintent-to-treat(MITT;patientsintheITTpopulationwhohadapathogenisolatedonstudyentry)andthemicrobiologicallyandclinicallyevaluated(MCE;patientsintheMITTpopulationwhowereabletobeclinicallyevaluated)studypopulations.,Results:1.PatientDemographicsandDisposition2.PrimaryAssessmentofClinicalResponseattheFollow-UpVisit3.PosttreatmentAssessmentofClinicalResponse4.AssessmentofClinicalResponseinPatientsWithConfirmedInfection5.BacteriologicResponse6.PathogensIsolatedandAntibioticSusceptibility7.Safety,ResultsPatientDemographicsandDispositionPatientswererecruitedat58centersin11countries;43%ofthepatientsweretreatedinthecommunitysetting(generalpracticeoroutpatientclinic),and57%ofpatientswerehospitalizedinaccordancewiththestandardmedicalmanagementofsuchpatientsindifferentcountries.,Patientdemographicsweresimilarwithrespecttoage,sex,andethnicoriginbetweenthetwostudygroups(Table3).Themajorityofpatients,73%,were35yearsold,with23%being65yearsold.Sixty-twopercentofpatientshadapreexistingmedicalconditiononentryintothestudy,withcardiovascular(23%)andrespiratory(17%)conditionsbeingthemostcommon.Themostcommonlyreportedpretreatmentsymptomswerecoughandadventitialsounds,recordedfor95%and85%ofthepatients,respectively.,Table3.SummaryofDemographicandBaselineCharacteristics*PatientCharacteristicsGFX,n=251CLA,n=253Total,n=504SexFemale106(42.2)98(38.7)204(40.5)Male145(57.8)155(61.3)300(59.5)Age,yr47.717.949.218.048.518.0EthnicoriginAsian4(1.6)7(2.8)11(2.2)Black40(15.9)41(16.2)81(16.1)White198(78.9)202(79.8)400(79.4)Other9(3.6)2(1.2)12(2.4)Height,cm169.89.4170.39.6170.19.5Weight,kg72.8916.3673.4516.5473.1716.43,Atotalof504patientswererecruitedtothestudy(ITTpopulation),ofwhom251patientswererandomizedtoreceiveGFXand253toreceiveCLA.Therewere106withdrawals(21%)fromthestudy(51GFX,55CLA;p=0.78)becauseoflackofefficacy(4%),adverseevents(7%),failuretoreturnforassessment(4%),orotherreasons(6%;Fig1).Compliancewasgood,with99%ofurinetestresultsbeingpositiveforthepresenceofantibioticand84%ofpatientstakingtheirmedicationinaccordancewiththeprotocol.,HELPwithhighresolutionimageviewingReturntoArticleFigure1.Patientflowthroughtrial.*TwopatientsintheGFXgroupandfourintheCLAgrouphadbothtypicalandatypicalpathogenspresentbeforetreatment.ReturntoArticle,Radiographicfindingsandthenatureandseverityofsignsandsymptomswerecomparableinthetwotreatmentgroups.Atthepretreatmentassessment,78%,43%,48%,and48%ofpatientsreportedmoderateorseverecough,dyspnea,pleuriticchestpain,andchills,respectively,comparedwith3%,3%,1%,and1%ofpatientsatfollow-up.Nodifferencesweredemonstratedbetweenthetwotreatmentgroups.Likewise,adventitialsounds,dullnesstopercussion,frictionrub,arthralgia,andmyalgiaweremarkedlyreducedatfollow-up.Sputumwaspurulentormucopurulentin43%ofpatientsatpretreatmentandinonly3%ofpatientsatfollow-up,PretreatmentCRPmeasurementswereobtainedfor462patients.Awiderangeofvalueswasobtained,from1to577mg/L,withamedianof109mg/LandSDof141mg/L.However,ofthe462patients,68%hadavalue50mg/L,suggestingthepresenceofactiveinfection;valueswerecomparableforthetwotreatmentgroups.Forthe126patientsinwhomapretreatmentpathogenwasconfirmedandCRPmeasured,76%ofpatientshadavalue50mg/L.Theproportionofpatientswithapretreatmentvalue50mg/Lwassimilarforpatientswithtypicalandatypicalpathogens,althoughthemedianvaluewashigherfortheformer,171mg/Lcomparedwith97mg/L.,PrimaryAssessmentofClinicalResponseattheFollow-UpVisitAssessmentoftheprimaryefficacyendpointofthestudywasmadeusingtheCEpopulationatfollow-up.Clinicalsignsandsymptomsandradiographicevidencewereusedtoassessoutcome.Ofthe504patientsintheITTpopulation,174(35%)wereunabletobeclinicallyevaluatedbecauseofalackofplannedposttreatmentorfollow-upassessments,consumptionofprohibitedmedication,adverseeffectsunrelatedtothestudydrug,orothersignificantprotocolviolations(Fig1).Thus,330patientscomposedtheCEpopulation(163GFX,167CLA).,Atthefollow-upvisit,147of163CEpatients(90%)receivingGFXand148of167CEpatients(89%)receivingCLAhadasatisfactoryclinicalresponse(p=0.78;95%CI,-6to9%;Fig2).Hence,formalequivalencewasdemonstratedbetween10-daytreatmentregimensofGFX,600mgqd,andCLA,500mgbid,inthetreatmentofpatientswithradiographicallyconfirmedCAP.Similarly,equivalencebetweenthetwotreatmentgroupswasdemonstratedintheITTpopulation,inwhich75%and76%showedasatisfactoryresponserateforGFXandCLA,respectively(p=0.88;95%CI,-9to7%;Fig2),HELPwithhighresolutionimageviewingReturntoArticleFigure2.Responsebypathogentypeaftertreatmentandatfollow-up(MCEpopulation).Responses(bacteriologic)fortypicalpathogensarebasedonanassessmentofpresumedcureorfailure,takingintoaccountclinicalsignsandsymptomsbecauseofveryfewvalidposttreatmentsamplessuitableforbacteriology.Responses(clinical)foratypicalpathogensdetectedbyserologicmethodsarefromclinicalandradiographicdata.ReturntoArticle,ClinicalequivalencebetweentheGFXandCLAtreatmentgroupswasdemonstratedinallfourstudypopulations.However,somedifferencesintheratesofsatisfactoryclinicalandradiographicresponsewereobservedincertainsubpopulationsofpatientsabletobeevaluated,althoughthesewerenotstatisticallysignificant,RatesofsatisfactoryclinicalresponsewereslightlybetterforbothGFXandCLAinyoungerpatients,withthisage-relateddifferencemoreapparentintheCLAtreatmentgroup.Responseratesforpatients50mg/L.Incontrast,forpatientswhodidnothaveasatisfactoryclinicaloutcome,CRPvaluesrangedfrom4to377mg/L,withamedianof74mg/LandSDof105mg/L,with58%havingaCRPvalue50mg/L.Resultsweresimilarforthetwotreatmentgroups.,AssessmentofClinicalResponseinPatientsWithConfirmedInfectionPatientsfromwhomapathogenwasculturedorwhohadpositiveserologicevidenceofLegionella,Chlamydia,orMycoplasmainfectionrespondedsatisfactorily(MITTpopulationn=131).Statisticalequivalenceofsatisfactoryclinicalresponseincorporatingradiographicevidencewasdemonstratedinthispopulation(p=0.67;95%CI,-11to20%),with80%and76%ofpatientsintheGFXandCLAtreatmentgroups,respectively,classifiedascuredorimprovedatfollow-up.,Therewasnoevidencetosuggestthatpatientswithconfirmedpathogensonentryintothestudyhadapooreroutcomeatfollow-upcomparedwithpatientsforwhomnopathogenwasdetected.Ofthe80patientsconfirmedashavingatypicalpathogenbeforetreatment,30(75%)intheGFXgroupand29(73%)intheCLAgroupshowedasatisfactoryclinicalandradiographicresponseatfollow-up.IntheCEsubpopulation,23of26patients(88%)respondedsatisfactorilytoGFXcomparedwith24of26patients(92%)intheCLAgroup.,Incomparison,inthesubgroupofpatientswithatypicalpathogensonentry(MITTatypicalgroupn=57),thosetreatedwithGFXshowedahigherclinicalresponserate,91%,comparedwitharesponserateof82%(p=0.58)forthosereceivingCLA.However,therelativelysmallsamplesizemeansthatthisdifferencewasnotstatisticallysignificant.IntheCEsubpopulation,thetrendwassimilar,with18of18patients(100%)respondingsatisfactorilytoGFXcomparedwith23of26patients(88%)respondingtoCLA(p=0.39;Fig2).,Forthe126of131patientsinwhomapretreatmentpathogenwasconfirmedandCRPmeasured,76%ofpatientshadaCRPvalue50mg/L.Mostvalueswereveryhigh(median,145.5mg/L).Aftertreatment,inpatientswithasatisfactoryresponse,themedianvaluefellto4mg/L.PatientswithanunsatisfactoryresponsemaintainedahighCRPvaluewithamedianof146mg/L.Posttreatmentresultsweresimilarforthetwotreatmentgroupsandforpatientswithtypicaloratypicalpretreatmentpathogens.,BacteriologicResponseMostoftheassessmentsofbacteriologicresponseforpatientswithtypicalpathogenswerebasedoneitherpresumedcureorpresumedfailure,takingintoaccountclinicalsignsandsymptoms.Despitetherelativelysmallnumbersofpatients,equivalencebetweentheGFXandCLAgroupswasdemonstratedwithintheMITTpopulationaftertreatmentbutwithhigherresponseratesobtainedforGFX.,Ofthe40patientsinthetypicalMITTpopulationreceivingGFX,80%showedasatisfactoryresponse(cure,presumedcure,orcurewithcolonization)comparedwith73%ofthe40patientsreceivingCLA(p=0.60;95%CI,-14to29%).IntheMCEpopulation,24of26patients(92%)respondedsatisfactorilytoGFXand22of24patients(92%)respondedtoCLA(Fig2).,PathogensIsolatedandAntibioticSusceptibilityPretreatmentpathogenswereconfirmedin131patients(MITTpopulation),withtypicalpathogensisolatedin80patients(40GFX,40CLA)andatypicalpathogensin57patients(23GFX,34CLA).Sixpatientshadbothanatypicalandatypicalpathogenpresent.Twenty-fivebacterialpathogenswereisolatedfrompretreatmentbloodcultures(11intheGFXgroupand14intheCLAgroup)and67fromsputum(33intheGFXgroupand34intheCLAgroup).,Spneumoniaewasthemostprevalentorganismandwasrecoveredfrom15of25bloodsamplesand18of67sputumsamples.Theotherbloodcultureisolateswerecoagulase-negativeStaphylococcusspp(fiveisolates),Streptococcusspp(threeisolates),Proteusmirabilis(oneisolate),andEscherichiacoli(oneisolate).,Spneumoniaewasthemostfrequentlyisolatedtypicalpathogen,followedbyHinfluenzae(26isolates;Fig3).Allisolatesweresusceptibletothestudydrugs,correlatingwithahighnumberofpatientsexperiencingasatisfactorybacteriologicresponserate(cure,presumedcure,andcurewithcolonization).ForpatientswithSpneumoniaeisolatedfrompretreatmentbloodcultures,sevenofeightintheGFXgroupandsixofsevenintheCLAgrouphadasuccessfulclinicalandradiologicoutcome.,HELPwithhighresolutionimagevi