Reduction of Intraocular Pressure and Glaucoma Progression

ObjectiveTo provide the results of the Early Manifest Glaucoma Trial, which compared the effect of immediately lowering the intraocular pressure (IOP), ... ReductionofIntraocularPressureandGlaucomaProgression:ResultsFromtheEarlyManifestGlaucomaTrial|Glaucoma|JAMAOphthalmology|JAMANetwork Ourwebsiteusescookiestoenhanceyourexperience.Bycontinuingtouseoursite,orclicking"Continue,"youareagreeingtoourCookiePolicy | Continue [SkiptoNavigation] fulltexticon FullText contentsicon Contents figureicon Figures/Tables multimediaicon Multimedia attachicon SupplementalContent referencesicon References relatedicon Related commentsicon Comments DownloadPDF TopofArticle Abstract Methods Results Comment ArticleInformation References Figure1. ViewLargeDownloadPatientflowchart.Moststudypatientswererecruitedfromapopulation-basedmassscreening.Attritionrateswerelow,andfollow-upisindicatedasofSeptember2001.Figure2. ViewLargeDownloadProgressionacrosstimeofallpatientsbystudygroup.Thecumulativeprobabilityofpatientswithprogressionwaslargerinthecontrolgroupthanthetreatmentgroup(P=.007).Thenumberofpatientsatriskforglaucomaprogressioninthetreatmentgroupandcontrolgroupareshownbelowthex-axis.Figure3. ViewLargeDownloadProgressionacrosstimestratifiedaccordingtobaselinecovariates:patientswithanintraocularpressurelessthan21mmHg(A)and21mmHgorgreater(B),withexfoliation(C)andwithout(D),withmeandeviationvaluesbetterthan−4.5dB(E)andworse(F),andwhoareyoungerthan68years(G)and68yearsorolder(H).Thenumbersofpatientsatriskforglaucomaprogressioninthetreatmentgroupandcontrolgroupareshownbelowthex-axes.Thesenumbersdecreasesignificantlywithlengthoffollow-upandweresmallfromthebeginningintheexfoliationgroup.Figure4. ViewLargeDownloadLensOpacitiesClassificationSystem(LOCS)IIscoresof2andhigherbystudygroupduringthefirst48monthsoffollow-up. Table1. ViewLargeDownloadBaselineCharacteristicsofAllStudyPatientsbyStudyGroup*Table2. ViewLargeDownloadProgressionbyStudyGroup*Table3. ViewLargeDownloadChangeofMeanDeviationValuesandNumberofHighlySignificantTestPointLocationsUntilTimeofProgressioninProgressedEyesorUntilLastVisitinNonprogressedEyes,byStudyGroup*Table4. ViewLargeDownloadAdverseEventsandSelf-reportedConditionsbyStudyGroup* 1.Strömberg  U Ocularhypertension.  ActaOphthalmol(Copenh).1962;40suppl69S1- S75GoogleScholar2.Hollows  FCGraham  PA Intraocularpressure,glaucoma,andglaucomasuspectsinadefinedpopulation.  BrJOphthalmol.1966;50570- 586GoogleScholarCrossref3.Bengtsson  B Theprevalenceofglaucoma.  BrJOphthalmol.1981;6546- 49GoogleScholarCrossref4.Nørskov  K Routinetonometryinophthalmicpractice,II:five-yearfollow-up.  ActaOphthalmol(Copenh).1970;48873- 895GoogleScholarCrossref5.Perkins  ES TheBedfordglaucomasurvey,I:long-termfollow-upofborderlinecases.  BrJOphthalmol.1973;57179- 185GoogleScholarCrossref6.Kitazawa  YHorie 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 B Screening:relationshiptodiagnosisandtherapy. Duane  TDed. ClinicalOphthalmology.Philadelphia,PaHarperandRow1994;1- 19GoogleScholar28.USPreventiveServicesTaskForce, GuidetoClinicalPreventiveServices. 2ndAlexandria,VaInternationalMedicalPublishing1996;29.Leske  MCHeijl  AHyman  LBengtsson  B EarlyManifestGlaucomaTrial:designandbaselinedata.  Ophthalmology.1999;1062144- 2153GoogleScholarCrossref30.Åsman  PHeijl  A GlaucomaHemifieldTest:automatedvisualfieldevaluation.  ArchOphthalmol.1992;110812- 819GoogleScholarCrossref31.Åsman  PHeijl  A EvaluationofmethodsforautomatedHemifieldanalysisinperimetry.  ArchOphthalmol.1992;110820- 826GoogleScholarCrossref32.Heijl  ALindgren  GLindgren  A  etal.  Extendedempiricalstatisticalpackageforevaluationofsingleandmultiplefieldsinglaucoma:StatpacII. Mill  RPHeijl  Aeds. PerimetryUpdate1990/91.Amsterdam,NYKuglerPublications1991;303- 315GoogleScholar33.Heijl  ALindgren  GOlsson  J Apackageforthestatisticalanalysisofvisualfields. Greve  ELHeijl  Aeds. SeventhInternationalVisualFieldSymposium,1986.Dordrecht,theNetherlandsMartinusNijhoff/DrW.Junk1987;153- 168GoogleScholar34.Chylack  LT  JrLeske  MCMcCarthy  DKhu  PKashiwagi  TSperduto  R LensopacitiesclassificationsystemII(LOCSII).  ArchOphthalmol.1989;107991- 997GoogleScholarCrossref35.TheAge-RelatedEyeDiseaseStudyResearchGroup, TheAge-RelatedEyeDiseaseStudy(AREDS)systemforclassifyingcataractsfromphotographs:AREDSreportno.4.  AmJOphthalmol.2001;131167- 175GoogleScholarCrossref36.Mangione  CMLee  PPGutierrez  PRSpritzer  KBerry  SHays  RD Developmentofthe25-itemNationalEyeInstituteVisualFunctionQuestionnaire.  ArchOphthalmol.2001;1191050- 1058GoogleScholarCrossref37.Brandt  JDBeiser  JAKass  MA  etal.  CentralcornealthicknessintheOcularHypertensionTreatmentStudy(OHTS).  Ophthalmology.2001;1081779- 1788GoogleScholarCrossref38.Bengtsson  BLindgren  AHeijl  A  etal.  Perimetricprobabilitymapstoseparatechangecausedbyglaucomafromthatcausedbycataract.  ActaOphthalmolScand.1997;75184- 188GoogleScholarCrossref39.Bengtsson  BKrakau  CE Flickercomparisonoffundusphotographs:atechnicalnote.  ActaOphthalmol(Copenh).1979;57503- 506GoogleScholarCrossref40.Heijl  ABengtsson  B Diagnosisofearlyglaucomawithflickercomparisonsofserialdiscphotographs.  InvestOphthalmolVisSci.1989;302376- 2384GoogleScholar41.Kalbfleisch  JDPrentice  RL Thestatisticalanalysisoffailuretimedata. NewYork,NYJohnWiley&SonsInc1980;42.Lipsitz  SRKim  KZhao  L Analysisofrepeatedcategoricaldatausinggeneralizedestimatingequations.  StatMed.1994;131149- 1163GoogleScholarCrossref43.Cox  DR Regressionmodelsandlife-tables(withdiscussion).  JRoyalStatSoc.1972;34187- 220GoogleScholar44.Breslow  NE Covarianceanalysisofcensoredsurvivaldata.  Biometrics.1974;3089- 100GoogleScholarCrossref45.Begg  CCho  MEastwood  S  etal.  Improvingthequalityofreportingofrandomizedcontrolledtrials:theCONSORTstatement.  JAMA.1996;276637- 639GoogleScholarCrossref46.Altman  DGSchulz  KFMoher  D  etal.  TherevisedCONSORTstatementforreportingrandomizedtrials:explanationandelaboration.  AnnInternMed.2001;134663- 694GoogleScholarCrossref47.Drance  SAnderson  DRSchulzer  MandtheCNTGSGroup, Riskfactorsforprogressionofvisualfieldabnormalitiesinnormal-tensionglaucoma.  AmJOphthalmol.2001;131699- 708GoogleScholarCrossref48.TheAGISInvestigators, TheAdvancedGlaucomaInterventionStudy(AGIS),I:studydesignandmethodsandbaselinecharacteristicsofstudypatients.  ControlClinTrials.1994;15299- 325GoogleScholarCrossref49.TheAGISInvestigators, Theadvancedglaucomainterventionstudy,VI:effectofcataractonvisualfieldandvisualacuity.  ArchOphthalmol.2000;1181639- 1652GoogleScholarCrossref50.Leske  MCWu  SYNemesure  BHennis  A Riskfactorsforincidentnuclearopacities.  Ophthalmology.2002;1091303- 1308GoogleScholarCrossref51.Gordon  MOKass  MA TheOcularHypertensionTreatmentStudy:designandbaselinedescriptionoftheparticipants.  ArchOphthalmol.1999;117573- 583GoogleScholarCrossref52.Kass  MAHeuer  DKHigginbotham  EJ  etal.  TheOcularHypertensionTreatmentStudy:arandomizedtrialdeterminesthattopicalocularhypotensivemedicationdelaysorpreventstheonsetofprimaryopen-angleglaucoma.  ArchOphthalmol.2002;120701- 713GoogleScholarCrossref53.StatisticsSweden, StatisticalYearBookofSweden:2000. 86Stockholm,SwedenStatisticsSweden1999;54.Musch  DCLichter  PRGuire  KEStandardi  CL TheCollaborativeInitialGlaucomaTreatmentStudy:studydesign,methods,andbaselinecharacteristicsofenrolledpatients.  Ophthalmology.1999;106653- 662GoogleScholarCrossref55.TheAGISInvestigators, Theadvancedglaucomainterventionstudy(AGIS),VII:therelationshipbetweencontrolofintraocularpressureandvisualfielddeterioration.  AmJOphthalmol.2000;130429- 440GoogleScholarCrossref56.Lichter  PRMusch  DCGillespie  BW  etal.  InterimclinicaloutcomesintheCollaborativeInitialGlaucomaTreatmentStudycomparinginitialtreatmentrandomizedtomedicationsorsurgery.  Ophthalmology.2001;1081943- 1953GoogleScholarCrossref57.Heijl  ALindgren  ALindgren  G Test-retestvariabilityinglaucomatousvisualfields.  AmJOphthalmol.1989;108130- 135GoogleScholar58.Grødum  KHeijl  ABengtsson  B Acomparisonofglaucomapatientsidentifiedthroughmassscreeningandinroutineclinicalpractice.  ActaOphthalmolScand.Inpress.GoogleScholar MENINGIOMASARISINGFROMTHETUBERCULUMSELLAE Article January1,1929 Harvey Cushing, M.D.;Louise Eisenhardt, M.D. LIGHTINGANDTHEHYGIENEOFTHEEYE Article July1,1929 C.E.FERREE,Ph.D.;GERTRUDERAND,Ph.D. ExpectationsFromClinicalTrials Editorial October1,2002 PaulR.Lichter,MD SeeMoreAbout GlaucomaOphthalmology SelectYourInterests SelectYourInterests CustomizeyourJAMANetworkexperiencebyselectingoneormoretopicsfromthelistbelow. 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ArchOphthalmol.2002;120(10):1268-1279.doi:10.1001/archopht.120.10.1268 visualabstracticon VisualAbstract editorialcommenticon EditorialComment relatedarticlesicon RelatedArticles authorinterviewicon Interviews multimediaicon Multimedia Editorial ExpectationsFromClinicalTrials PaulR.Lichter,MD Article MENINGIOMASARISINGFROMTHETUBERCULUMSELLAE Harvey Cushing, M.D.;Louise Eisenhardt, M.D. Article LIGHTINGANDTHEHYGIENEOFTHEEYE C.E.FERREE,Ph.D.;GERTRUDERAND,Ph.D. Abstract Objective  ToprovidetheresultsoftheEarlyManifestGlaucomaTrial,whichcomparedtheeffectofimmediatelyloweringtheintraocularpressure(IOP),vsnotreatmentorlatertreatment,ontheprogressionofnewlydetectedopen-angleglaucoma.Design  Randomizedclinicaltrial.Participants  Twohundredfifty-fivepatientsaged50to80years(median,68years)withearlyglaucoma,visualfielddefects(medianmeandeviation,−4dB),andamedianIOPof20mmHg,mainlyidentifiedthroughapopulationscreening.PatientswithanIOPgreaterthan30mmHgoradvancedvisualfieldlosswereineligible.Interventions  Patientswererandomizedtoeitherlasertrabeculoplastyplustopicalbetaxololhydrochloride(n=129)ornoinitialtreatment(n=126).StudyvisitsincludedHumphreyFullThreshold30-2visualfieldtestsandtonometryevery3months,andopticdiscphotographyevery6months.Decisionsregardingtreatmentweremadejointlywiththepatientwhenprogressionoccurredandthereafter.MainOutcomeMeasures  Glaucomaprogressionwasdefinedbyspecificvisualfieldandopticdiscoutcomes.Criteriaforperimetricprogressionwerecomputerbasedanddefinedasthesame3ormoretestpointlocationsshowingsignificantdeteriorationfrombaselineinglaucomachangeprobabilitymapsfrom3consecutivetests.Opticdiscprogressionwasdeterminedbymaskedgradersusingflickerchronoscopyplusside-by-sidephotogradings.Results  Afteramedianfollow-upperiodof6years(range,51-102months),retentionwasexcellent,withonly6patientslosttofollow-upforreasonsotherthandeath.Onaverage,treatmentreducedtheIOPby5.1mmHgor25%,areductionmaintainedthroughoutfollow-up.Progressionwaslessfrequentinthetreatmentgroup(58/129;45%)thanincontrols(78/126;62%)(P=.007)andoccurredsignificantlylaterintreatedpatients.TreatmenteffectswerealsoevidentwhenstratifyingpatientsbymedianIOP,meandeviation,andageaswellasexfoliationstatus.Althoughpatientsreportedfewsystemicorocularconditions,increasesinclinicalnuclearlensopacitygradingswereassociatedwithtreatment(P=.002).Conclusions  TheEarlyManifestGlaucomaTrialisthefirstadequatelypoweredrandomizedtrialwithanuntreatedcontrolarmtoevaluatetheeffectsofIOPreductioninpatientswithopen-angleglaucomawhohaveelevatedandnormalIOP.Itsintent-to-treatanalysisshowedconsiderablebeneficialeffectsoftreatmentthatsignificantlydelayedprogression.Whereasprogressionvariedacrosspatientcategories,treatmenteffectswerepresentinbotholderandyoungerpatients,high-andnormal-tensionglaucoma,andeyeswithlessandgreatervisualfieldloss. STARTINGINTHE1960s,epidemiologicalstudiesdemonstratedthatnormal-tensionglaucomawasmuchmorecommonthanpreviouslythoughtandthatocularhypertension,orelevatedintraocularpressure(IOP)withoutglaucomatousvisualfielddefectsoropticdisccupping,wasmorecommonthanglaucoma.1-3Subsequentstudiesshowedthatrelativelyfewpatientswithocularhypertensiondevelopedsignsofglaucomatousdamageduringfollow-upperiodsofupto20years,eveniftheconditionwasleftuntreated.4-8TheearlierconceptthatbasicallyequatedelevatedIOPwithglaucomabecameobsolete,resultinginuncertaintyoftheeffectsofglaucomatreatment. Giventhisbackground,severalrandomizedtrialswereinitiatedintheearly1980stoevaluatetherelationshipbetweenglaucomaandthereductionofIOP.9-12TherelationshipwasstudiedsomewhatindirectlybyinvestigatingwhetherIOPreductioncouldreducetheincidenceofglaucomadamageinpatientswithocularhypertension.Atthattime,conductingastudytoaddressthesubjectmoreunequivocally(ie,acarefullydesignedrandomizedtrialofpatientswithglaucomathatincludedanuntreatedcontrolarm)wouldprobablyhavebeenconsideredunethical. Controversycontinuedregardingwhen,howaggressively,andwhetherornottotreat,13andtheuncertaintyoftreatmenteffectswasoutlinedinareportpresentedtotheNationalLeadershipCommissiononHealthCare.14ThedevelopmentandwidespreaduseofcomputerizedperimetryandtheimprovedunderstandingofearlyopticdiscchangesinglaucomahaddemonstratedacomplexrelationshipbetweenIOPandglaucomadamage.Researchersandprofessionalorganizationsemphasizedanewglaucomaconceptinwhichthediseasewasdescribedasanopticneuropathy,withIOPasonlyoneofseveralriskfactors.15,16Thisviewhasnowbecomethestandard,andmodernglaucomadefinitionsoftendonotevenmentionIOP.17,18 Whenourtrialwasplannedintheearly1990s,severalcontrolledstudiesusingtimololmaleateinpatientswithocularhypertensionhadbeeninprogressformanyyearsbuthadnotshownthatsuchtreatmenteffectivelypreventedglaucomadamage.Giventherelativelylowincidenceofthisdamageinpatientswithocularhypertension,thesamplesizesandstatisticalpowerofthesetrialswereprobablyinsufficient.Only1controlledtrialinvolvingtreatedanduntreatedpatientswithglaucomahadbeenpublished,andwithnegativeresults.19TheCollaborativeNormal-TensionGlaucomaStudy(CNTGS)wasunderwayatthattime.20,21In1993,Rossettietal22concludedinasystematicliteraturereviewthat"[p]racticingophthalmologistsshouldbeawarethattheeffectivenessofpressure-loweringagentsinthetreatmentofprimaryopenangleglaucomaisstilltobedetermined,"andthatcontrolledtrialswithfunctionalendpointsandsufficientdurationwereurgentlyneeded. Becausetheeffectivenessofsuchtreatmenthadneverbeenshowninarandomizedclinicaltrial,severalclinicalimplicationsinfluencedglaucomamanagement:Whatpriceintermsofadverseeffects,inconvenience,andcostcouldbeconsideredacceptablewhentreatmenteffectswereuncertain?Effortstodetectcasesofglaucomathatremainedundetected(approximately50%)2,3,23-25couldhardlybeadvocatedbecauseaneffectivetreatmentforaparticulardiseaseisconsideredaprerequisiteforscreening.26-28Theneedforknowledgeinthisareawasclear.Thedevelopmentofimprovedmethodsforcomputerizedvisualfieldtestingandrecognitionofmildglaucomaprogressionenhancedthefeasibilityofsuchtrials.Hence,arandomizedstudywithacontrolarm,inwhichpatientsunderwentfollow-upwithouttreatmentaslongasprogressiondidnotoccur,wouldnotexposestudypatientstounacceptablerisks. TheEarlyManifestGlaucomaTrial(EMGT)beganin1992.ItisacontrolledclinicaltrialevaluatingtheeffectivenessofreducingIOPinpatientswithnewlydetected,previouslyuntreatedglaucoma.Thestudydesignandbaselinedatawerereportedin1999.29 ThepurposeofourarticleistoreporttheEMGTresultspertainingtotheprimaryaimofthetrial,namelytocomparetheeffectofimmediatetherapytolowertheIOP,vsnotreatmentorlatertreatment,ontheprogressionofnewlydetectedopen-angleglaucomaasmeasuredbyincreasingvisualfieldlossoropticdiscchanges. Methods Ourpreviouslypublishedarticle29containsadetaileddescriptionofthestudymethods.Thefollowingisacondenseddescription,whichshouldenablethereadertounderstandandinterprettheresults. Inclusionandexclusioncriteria Studypatientshadnewlydetected,previouslyuntreatedopen-angleglaucoma.Allpatientsfulfilledthefollowingeligibilitycriteria: Adiagnosisofearlymanifestopen-angleglaucoma,includingprimaryopen-angleglaucoma,normal-tensionglaucoma,orexfoliationglaucoma.Reproducibleglaucomatousvisualfielddefectsinatleastoneeye.Agebetween50and80years. Todetermineeligibility,glaucomatousvisualfielddefectsweredocumentedwithcomputerizedstaticperimetryusingtheFullThreshold24-2programoftheHumphreyperimeter.Eligibilityrequiredaclassificationof"outsidenormallimits"involvingthesamevisualfieldareaat2initialpostscreeningvisitsusingtheglaucomahemifieldtest30,31oftheStatpacIIprogramforcomputer-assistedvisualfieldinterpretation.32A"borderline"classificationwasacceptableonlyifobviouslocalizedglaucomatousopticdisccuppingwaspresentinanareacorrespondingtothevisualfielddefect. Exclusioncriteriawereasfollows: Advancedvisualfielddefects(meandeviation[MD]worsethan−16dB)33orathreattofixation,definedasdifferentiallightsensitivityof10dBorworseateitherorbothtestpointsclosesttothepointoffixationinboththeupperandlowerhemifields.Ifbotheyeswereeligible,theMDhadtobebetterthan−10dBinatleastoneeye.Visualacuitylessthan0.5(Monoyer-Granström),correspondingto20/40,inanyeye.MeanIOPgreaterthan30mmHgoranyIOPgreaterthan35mmHginatleastoneeye.Anyconditionprecludingreliableresultsofperimetryoropticdiscphotography,theuseofstudyinterventions,or4yearsoffollow-up.CataractouslenschangesexceedinggradingsofN1,C2,orP1accordingtotheLensOpacitiesClassificationSystem(LOCS)II.34 ThestudywasconductedaccordingtothetenetsoftheDeclarationofHelsinki.Allsubjectsgaveinformedconsent,andthestudywasapprovedbytheEthicsCommitteeoftheUniversityofLund(Lund,Sweden)andtheCommitteeonResearchInvolvingHumanSubjectsattheStateUniversityofNewYorkatStonyBrook. Randomization,treatment,andmasking Eligibilitywasindependentlyconfirmedatthedatacenter.Eligiblepatientswererandomizedevenlybetweentreatmentandnontreatmentgroupsaccordingtoapermutedblockrandomizationschemestratifiedbytheclinicalandsatellitecenters.Alleyesrandomizedtotreatmentreceivedafull360°trabeculoplastyplusbetaxololhydrochlorideeyedropsatadoseof5mg/mL(Betoptic;Alcon,FortWorth,Tex)twicedaily.Eyesstayedintheirallocationarmsunlesssignificantprogressionoccurred.If,however,theIOPintreatedeyesexceeded25mmHgat2consecutivefollow-upvisitsor35mmHgincontroleyes,latanoprosteyedropsatadoseof50µg/mL(Xalatan;Pharmacia,Uppsala,Sweden)weregivenoncedaily.Whendefiniteprogressionoccurred,patientswereinformedandoptionswerediscussed;decisionsonsubsequentclinicalmanagementweremadewiththeircooperationandfollowingtheusualpatternsofglaucomatreatment. Aspartofthequalitycontrolprotocolforthetrial,allstudypersonnelcompletedatrainingperiodaccordingtothemanualofprocedurespriortodatacollection,whichwasfollowedbyaformalcertificationprocessimplementedbythedatacenter.Regularsitevisitsanddataauditswereconducted.Studyoutcomesweredeterminedeitherthroughnumerical,predeterminedobjectivecriteria(visualfieldtests)orbymaskedgradersatthediscphotographyreadingcenter.Studypersonnelmeasuringvisualacuity,IOP,andvisualfieldsweremaskedtopatients'studygroup,butpatientsandtreatingphysicianswerenotmasked.AnindependentDataSafetyandMonitoringCommittee(DSMC),whichincludesmembersfrombothSwedenandtheUnitedStates,hasbeenresponsibleformonitoringallaspectsofthetrialsinceitsinception.TheDSMCmeetsyearlytoreviewpatientsafety,evaluatedataqualityandtheresultsofinterimanalyses,andsupervisetheoverallconductofthestudy. Patientvisits Theprotocolrequired2postscreeningvisitsprecedingthe2baselinevisits.Theseearlyvisitswereusedtosubstantiatethediagnosis,ascertaineligibility,minimizetheeffectsofperimetriclearning,andprovideinformationaboutthetrial.BothbaselineexaminationsincludedvisualfieldtestingandthemeasurementofIOP(Goldmannapplanationtonometry).Aftereligibilitywasconfirmedatthesecondbaselinevisit,informedconsentwasobtainedandpatientswererandomized.Patientsreceivedfollow-upat3-monthintervals.Arecentmedicalandophthalmologichistory,includingadverseeventsandcompliance,wasobtainedateachvisit.ExaminationsincludedvisualacuitytestingwithMonoyer-Granströmstandarddecimalchartsfollowingsubjectiverefraction,Goldmannapplanationtonometry,computerizedvisualfieldtesting(Humphrey30-2Full-Thresholdprogram),ophthalmoscopy,andslitlampexaminationwithlensclassificationusingtheLOCSIIsystem.34Opticdiscphotographswereobtainedevery6months. Additionstothestudyprotocol TofurtherassessdifferencesinnuclearclinicalLOCSIIgradings34betweenstudygroups,theDSMCapprovedaproposaltoobtainnuclearlensphotographswithslitlampcamerasspecificallyadaptedforthispurpose.Afterstandardizationandcertificationofthephotographers,lensphotographswereobtainedtwice:(1)betweenDecember1999andMarch2000,and(2)betweenMarch2001andJuly2001.The2setsofslitlampphotographswereevaluatedconcurrently,followingarandomorder,atareadingcenterattheDepartmentofOphthalmology,UniversityofWisconsin–Madison.Thegradersweremaskedandappliedastandardizedsystem.35 Furtheradditionstotheprotocoloncethestudybeganincludedvisualfunction-relatedquality-of-lifeassessmentwiththeNationalEyeInstitute'sVisualFunctionQuestionnaire36andcornealpachymetrymeasurements.37 Outcomes Thestudyoutcomewasprogressionofeitherglaucomatousvisualfielddefectsoropticdisccupping,eachaccordingtopredeterminedobjectivecriteria.Foreachpatient,oneorbotheyescouldbeincludedinthestudy,basedoneligibilityatbaseline.Apatientwasconsideredtohaveprogressionwhenthefirsteligibleeyemetprogressioncriteria. Todeterminevisualfieldprogression,allfollow-upresultsofvisualfieldtestswerecomparedwithanaverageofthosefromthe2baselinetestsfromthesameeyeusingglaucomachangeprobabilitymaps(GCPMs).ThesemapsdifferentiatebetweensignificantprogressionatP<.05andrandomtest-retestfluctuationsateachof74testpointlocationsinthevisualfield.theemgtusedpatternde viationgcpmsbasedonpointwisepatterndeviationsfromtheage-correctednormalthresholdvalues38ratherthanth estandardtotaldeviationgcpms.patterndeviationmapslimittheeffectsofincreasinghomogeneouslossofdiffere ntiallightsensitivity todetermineopticdiscprogression statisticalanalysis thesamplesizecalculationswerebasedonassuming4-yearprogressionratesof40 univariatecomparisonsbetweentreatmentandcontrolgroups results recruitmentandretention recruitmenthaspreviouslybeendescribedindetail.29alargepopulationscreeningof44 baselinecharacteristics themeanageofthepatientswas68years iopchangesafterbaseline themeaniopinthetreatmentgroupdecreasedfrom20.6mmhgatbaseline>25mmHg)occurredinfrequently(4patients,or3%),whereasnountreatedpatientsreachedthe35mmHglimitrequiringtopicalmedicationbeforeprogression. Inthecontrolgroup,IOPvalueswereunchanged(20.9and20.8mmHgatbaselineandthe3-monthvisit,respectively),withsmallchangesthereafter(medianchange=0.0%from3monthsuntilprogressionorthelastvisit).Themean±SDdifferencefrombaselinetoallvisits,censoredforprogression,was0.0±1.9mmHg. Mainoutcomes BySeptember1,2001,theproportionofpatientswhoshoweddefinitevisualfieldandopticdiscprogressionwaslargerinthecontrolgroupthanthetreatmentgroup:78(62%)of126vs58(45%)of129,respectively(P=.007)(Table2).Allpatientswithprogressionmetthevisualfieldoutcomecriteriawith1exception,whomettheopticdisccriteriononly.InaccordancewiththespecificEMGTcriteriatodefineopticdiscprogression,fewoftheseoutcomeswereobserved. Life-tableanalysesshowthattheseparationbetweenstudygroupsappearedearlyandwasmaintainedduringtheentirefollow-upperiod;theyalsoshowthatprogressionincreasedconsiderablywithtime,inthetreatmentgroupaswellasthecontrolgroup(Figure2).Progressionwasmorecommoninthecontrolgroupatanypointduringfollow-up;inotherwords,progressionoccurredearlierincontrolsthaninthetreatmentgroup.Whereasthemediantimetoprogression(usingtheKaplan-Meiercumulativesurvivalfunction)was48monthsincontrols,itwas66monthsintreatedpatients,indicatingadelayinprogressioncausedbytreatment.Accordingtothelife-tableresultsat48months,whichwastheminimumplannedperiodoffollow-up,62controls(49%)hadprogressedcomparedwith39(30%)inthetreatmentgroup(difference=19%;95%confidenceinterval,7%-23%;P=.004).Thedifferencesbetweenstudygroupsandapparenttreatmenteffectswerealsoobservedwhenstratifyingaccordingtothebaselinecovariates(Figure3).Allofthesecurvesshowaclearandpersistentseparationbetweentreatmentandcontrolgroups,andthecovariatesweresignificantlyrelatedtoprogressioninmultivariateanalyses(M.C.L.,A.H.,M.H.,B.B.,L.H.,andE.Komaroff,PhD,unpublisheddata,2002).Intheseanalyses,eachmillimeterofmercuryofdecreasedIOPwasrelatedtoanapproximately10%loweringofrisk,andtheresultsshowednosignificanttreatmenteffectsbeyondthoserelatedtoIOPreduction. TheregressionanalysesofMDandnumberofhighlysignificantlydepressedtestpointlocations(P<.5 adverseeventsandself-reportedadverseeffects asseenintable4 data-monitoringanalysesindicatedanunexpectedincreasedincidenceofnuclearopacitiesevidentinthelocsiicl inicalgradings.thepercentagesoflocsiigradingsof2orhigherbystudygroupduringtheinitiallyplanned4-yearf ollow-upperiodareshowninfigure4.therewasaclearandsignificantlymorerapiddevelopmentofnuclearopacities inthetreatmentgroup lensphotographsweretakentofurtherevaluatetheseclinicalfindings morepatientsdiedinthetreatmentgroupthaninthecontrolgroup:15of22 dataquality therateofmissedvisitswas5.9 reviewbythedsmc nopatientsafetyissueswereidentifiedbythedsmc comment modernevidence-basedmedicinerecognizesthatthebestproofoftreatmenteffectivenesscomesfromrandomizedcon trolledtrialsthatarenotonlywelldesignedandexecutedbutalsothoroughlyandaccuratelyreported.beginningin effectsoftreatmentonglaucomaprogression theemgtshowedclearbeneficialeffectsoftreatmentondelayingtheonsetofprogression themediantimetoprogressionwas18monthslongerinthetreatmentgroupthanthecontrolgroup.thisobservationsho uldnotbeinterpretedtomeanthattheonlybenefitoftreatment theiopreductionachievedbytheemgttreatmentwassubstantialandwasnotassociatedwithadverseeffectsassignif icantasthosetypicallyencounteredafterfilteringsurgeryanddocumentedinthecntgs.20 timetoprogressionvariedgreatlyamongtreatedpatientsaswellasuntreatedonesandwassometimesrathershort.th isindicatesthatthestandardizedtreatmentwasinsufficientinmanyrapidlyprogressingpatients.ontheotherhan d adverseevents inouropinion analysisofnuclearphotogradingscoresalsoshowedassociationswithtreatment itiswellknownthatglaucomafilteringsurgeryisassociatedwithamarkedriseincataractincidenceandthattopica lirreversiblecholinesteraseinhibitorscausedcataract.thereportsofthecntgshaveemphasizedthefrequentocc urrenceofcataractsurgeryinitstreatedgroup20 everythingconsidered thedifferenceindeathratebetweengroupsisworthattention.therateobservedinthetreatedpatientswasasexpect edaccordingtothepopulationstatisticsofsweden possiblemechanisms intheemgt eventhoughtheemgtclearlysupportsthebeneficialeffectofiopreductiononopen-angleglaucoma comparisonwithothertrials sincethestartoftheemgt mostimportantisthecntgs althoughtrialsinvolvingpatientswithocularhypertensionaddressasomewhatdifferentsubject strengthsandlimitations interpretationoftheemgtresultsmustconsiderseveralmethodologicstrengthsofthetrial.thatonly2.4 dataonbothvisualfieldandopticdiscoutcomeswereobtainedbymaskedobserversfollowingstandardizedandunbias edmethods.visualfieldcriteriaweredefinedusingmodernstatisticalprogramsforvisualfieldanalysisandweret hereforenumericalandobjective.glaucomachangeprobabilitymapsprovidedearlyyetspecificdetectionofvisual fieldprogression.thesemapswerebasedonpatterndeviationratherthantotaldeviation becauseglaucomacaseswerenewlydetectedandpreviouslyuntreated interpretationoftheemgtresultsmustalsoconsiderpotentiallimitationsofthestudy.onesuchlimitationisthat thestudyinvolvedaspecific>30mmHg)oradvancedvisualfieldloss.Anothernecessarylimitationwasthattheinitialrandomizationtotreatmentornotreatmentwasmaintainedonlyaslongasprogressiondidnotoccur;thisshortenedtheascertainmentperiodoftheglaucoma'snaturalhistory,whichwasasecondaryEMGTaim.Thestudy,therefore,doesnotincludelong-termfollow-upofuntreatedpatientsbeyondEMGTprogression. TheEMGTusedanewcriteriontodefinevisualfieldprogression,whichwasunchangedthroughouttheentirestudy.TheEMGTdefinitionallowedthedetectionofsmallamountsofprogression,animportantsafetyaspectofthetrial.Thiscriterionwasbasedonknowledgegatheredduringthe1980sonthenatureofrandomvariabilityinglaucomatousvisualfields57andpermittedanearlierseparationbetweentreatmentarmsthanmoreconventionalcriteria(eg,linearregressionofMDvaluesorchangesinnumbersoftestpointlocationsdevelopingsignificantorabsolutevisualfieldloss).However,theEMGTvisualfieldcriterionisnotasintuitivelycomprehensibleasothersimplercriteria.Toaddressthisissueandtoprovideabasisforalaterarticlethatwillpresentclinicallyusefulconclusionsfromthestudyresults,wehavecomparedtheEMGTcriterionwithothercriteriainaseparatereport(A.H.,M.CL.,B.B.,B.B.,andM.H.,fortheEMGTGroup,unpublisheddata,2002). TheEMGT'svisualfieldprogressioncriterionshowedexcellentsensitivityandspecificityinacomparisonoftheperformanceofsuchcriteriausedintheEMGT,AGIS,andCIGTS.Inthispilotstudy,theEMGTcriteriadetectedprogressionin20of20seriesofvisualfieldsfromEMGTpatientswhohadbeendeemedtohavedefiniteprogressionby2independentglaucomaexperts.Progressionwassustainedin90.8%ofvisitsfollowingthevisitwhendefiniteprogressionwasfirstfound.Specificitywasdeterminedfromanother20seriesofvisualfieldsthathadbeenclassifiedasstablebythesameexperts.Itwasfoundtobehigh;noneofthe20stablevisualfieldswerefalselylabeledasprogressingwiththeEMGT'scriterion(A.H.,M.C.L.,B.B.,B.B.,andM.H.,fortheEMGTGroup,unpublisheddata,2002). Implicationsofstudyresults TheEMGTisthefirstrandomizedstudyprovidingalong-termcomparisonofprogressionbetweentreatedanduntreatedpatientswithprimaryopen-angleglaucoma,normal-tensionglaucoma,andexfoliationglaucomathatshowsadefinitepositiveeffectofIOPreduction.Thisinformationisvaluablebecausetreatmenteffectsinchronicopen-angleglaucomahavebeenlargelyunknown,andthereisverylittleinformationaboutthenaturalhistoryofglaucoma. Althoughtheseresultsprovidequantitativedatadirectlyapplicabletomostpatientswithglaucoma,oureligibilitycriterialedtoastudypopulationwithearlierdiseasethanatypicalclinicalglaucomapopulation.58Atthepopulationscreening,19%ofpatientswithnewlydetectedearlymanifestglaucomawereineligiblefortheEMGTbecausetheirIOPexceededtheinclusioncriteria(meanIOP>30mmHgoranyIOP>35mmHg),andanadditional10%couldnotparticipatebecausethevisualfielddamageexceededourlimitsforinclusion.TheEMGTresultsprovidelittleinformationdirectlypertainingtopatientswithadvancedglaucomaandhighIOPlevels;however,asmentionedearlier,futureanalyseswilllikelyshowthatthecurrentresultsareindeedapplicabletosuchpatients. TheEMGTdatahaveimportantclinicalimplications.TheresultsnotonlyconfirmpreviousbeliefsthatIOPreductionisbeneficialbutalsoprovidenewknowledgeonratesofdiseaseprogression,withandwithouttreatment,inpatientswithvariouscharacteristics.Ourresultsthereforestrengthentherationaleforcurrentstandardclinicalmanagement.Inaddition,theyaffordabasisforincreasedeffortstoachieveearlierdetectionofthediseaseandfortailoringtheclinicalmanagementofglaucomatotheneedsoftheindividualpatient.Thelatterissuesareworthspecialconsiderationandwillbeaddressedseparately. SubmittedforpublicationJune24,2002;finalrevisionreceivedAugust1,2002;acceptedAugust5,2002. ThisstudywassupportedbygrantsU10EY10260andU10EY10261fromtheNationalEyeInstitute,Bethesda,Md,andgrantK2002-74X-10426-10AfromtheSwedishResearchCouncil,Stockholm. DrugsweredonatedbyAlconLaboratoriesInc,FortWorth,Tex,andPharmacia,Uppsala,Sweden. EarlyManifestGlaucomaTrialGroup ClinicalCenter DepartmentofOphthalmology,MalmöUniversityHospital,Malmö,Sweden:AndersHeijl,MD,PhD(studydirector);BoBengtsson,MD,PhD(screeningdirector);KarinWettrell,MD,PhD(ophthalmologist;1992-2000);PeterÅsman,MD,PhD,(ophthalmologist);BoelBengtsson,PhD(investigator;since2001);MargaretaWennberg,BA(cliniccoordinator);GertieRanelycke(technician);MonicaWollmer,RN(technician);GunillaLundskog,RN(technician);KatarinaMagnusson(secretary). DataCenter DepartmentofPreventiveMedicine,StateUniversityofNewYorkatStonyBrook:M.CristinaLeske,MD,MPH(director);LeslieHyman,PhD(deputydirector);MohamedHussein,PhD(seniorbiostatistician);QimeiHe,PhD(biostatistician;since2001);EugeneKomaroff,PhD(biostatistician;since2001);Ling-YuPai,MA(datamanager);LisaArmstrong(assistantdatamanager;since1999). SatelliteClinicalCenter DepartmentofOphthalmology,HelsingborgHospital,Helsingborg,Sweden:KerstinSjöström,MD(director);LenaBrenner,MD(ophthalmologist);GöranSvensson,MD(ophthalmologist);IngridAbrahamson,RN(headnurse);Nils-ErikAhlgren,RN(technician);UllaAndersson,RN(technician);AnnetteEngkvist,RN(technician);LilianHagert(secretary/cliniccoordinator). DiscPhotographyReadingCenter DepartmentofOphthalmology,LundUniversityHospital,Lund,Sweden:AndersBergström,MD(director;since1997);CatharinaHolmin,MD(director;1993-1997);AnnaGlöck,RN(photograder);CatharinaDahlingWesterberg,RN(photograder);IngerKarlsson,RN(centercoordinator). NationalEyeInstitute,Bethesda,Md CarlKupfer,MD(until2000);DonaldEverett,MA(programdirector). SteeringCommittee BoBengtsson,MD,PhD;DonaldEverett,MA;AndersHeijl,MD,PhD;LeslieHyman,PhD;M.CristinaLeske,MD,MPH. DataSafetyandMonitoringCommittee CurtFurberg,MD,PhD(chairman);RichardBrubaker,MD;BeritCalissendorff,MD,PhD;PaulKaufman,MD;MaureenMaguire,PhD;HelgeMalmgren,MD,PhD. Correspondingauthorandreprints:AndersHeijl,MD,PhD,DepartmentofOphthalmology,MalmöUniversityHospital,SE-20502Malmö,Sweden(e-mail:[email protected]). 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