intravitreal bevacizumab injection alone or combined with

Journal of ophthalmic and Vision research 2014;Vol.9,No.4 453

IntravitrealBevacizumabInjectionAloneorCombinedwithTriamcinoloneVersusMacularPhotocoagulationInBilateralDiabeticMacularEdema;ApplicationofBivariate

GeneralizedLinearMixedModelwithAsymmetricRandomEffectsinaSubgroupofaClinicalTrial

Mehdi Yaseri1, PhD; Hojjat Zeraati1, PhD; Kazem Mohammad1, PhD; Masoud Soheilian2, MD Alireza Ramezani2,3, MD; Medi Eslani4, MD; Gholam A. Peyman5, MD

1Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran2Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3Department of Ophthalmology, Imam Hossein Medical Center, Tehran, Iran4Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, USA

5Department of Ophthalmology, University of Arizona Health Science Center, Tucson, Arizona, USA

AbstractPurpose: Tocomparetheefficacyofintravitrealbevacizumab(IVB)injectionaloneorwithintravitrealtriamcinoloneacetonide(IVB/IVT)versusmacularphotocoagulation(MPC)inbilateraldiabeticmacularedema(DME).Methods:Inthisstudywerevisiteddatafromasubsetofsubjectspreviouslyenrolledinarandomizedclinicaltrial.Theoriginalstudyincluded150eyesrandomizedtothreetreatmentarms:1.25mgIVBalone,combinedinjectionof1.25mgIVBand2mgIVT,andfocalormodifiedgridMPC.Toeliminatethepossibleeffectsofsystemicconfounders,weselectedfelloweyesofbilaterallytreatedsubjectswhohadundergonedifferenttreatments;eventually30eyesof15patientswerere‑evaluatedatbaseline,6,12,18,and24months.Usingmixedmodelanalysis,wecomparedthetreatmentprotocolsregardingvisualacuity(VA)andcentralmacularthickness(CMT).Results: ImprovementinVAintheIVBgroupwassignificantlygreatercomparedtoMPCatmonths6and12(P=0.037andP=0.035,respectively)butthisdifferencedidnotpersistthereafterupto24months.OtherlevelsofVAwerecomparableatdifferentfollow‑upintervals(allP>0.05).TheonlysignificantdifferenceinCMTwasobservedinfavoroftheIVBgroupascomparedtoIVB/IVTgroupat24months(P=0.048).Conclusion: OverallVAwassuperiorinIVBgroupascomparedtoMPCupto12months.AlthoughtheIVBgroupshowedsuperiorityregardingCMTreductionover24monthsascomparedtoIVB/IVTgroup,itwascomparabletotheMPCgroupthroughthesameperiodoffollowup.

Keywords:AsymmetricRandomEffects;BivariateGeneralizedLinearMixedModel;DiabeticMacularEdema

Correspondence to: HojjatZeraati,PhD.DepartmentofEpidemiologyandBiostatistics,TehranUniversityofMedicalSciences,PoursinaSt.,Tehran14155,Iran. E‑mail:[email protected]

Received:12‑08‑2013 Accepted:17‑05‑2014

J Ophthalmic Vis Res2014;9(4):453‑460.

Access this article online

Quick Response Code:Website: www.jovr.org

DOI: 10.4103/2008‑322X.150818

Original Article

INTRODUCTION

Diabeticmacularedema(DME)is themaincauseofvisual impairment in diabetic patients.[1] Commonthinkingwasthatsincemacularlaserphotocoagulation

(MPC)reducedthepossibilityofmoderatevisuallossby 50%, such therapy entails a beneficial effect onDME.[2]

454 Journal of ophthalmic and Vision research 2014;Vol.9,No.4

IVB with or without IVT versus Laser for Bilateral DME; Yaseri et al

The Diabetic Retinopathy Clinical ResearchNetwork (DRCRnet) reported improvement ofmorethan5lettersinvisualacuity(VA)byMPCat1,2,and3years of follow‑up in 51%, 47%, and62%of cases,respectively.[3‑5] Alternative or adjunct treatmentsforDME such as anti‑vascular endothelial growthfactor(VEGF)therapy[3,6‑10]andintravitrealtriamcinoloneacetonide (IVT)[3,11‑15] have been evaluated inmostrecent studies.DRCRnet disclosed that in spite ofan early beneficial effect from 4mg intravitrealtriamcinolone (IVT) on retinal thickening andVAat 4months as compared to 1mg IVTor focal/gridphotocoagulation,finalmeanVAat24and36monthswas better in theMPCgroup.[4,5] Some reports haveshownapromisingeffect fromintravitrealanti‑VEGFagentsfortreatmentofDME.[3,6‑10,16,17]TheVAoutcomewassignificantlybetterwithranibizumabascomparedtoMPC forDME at 6months[17] and 24months.[18] In a previous trial,wehave shown that intravitrealbevacizumab(IVB) injectionwithorwithout IVThadabettertherapeuticeffectonVAinDMEincontrasttoMPCat3months[19]theeffectofwhichwasmaintainedupto24months.[20‑22]

Somestudieshaveshownthatpatientcharacteristicssuchasage,typeofdiabetescontrolandHbA1Clevels,in the pre‑treatment, treatment and post‑treatmentperiodcouldaffecttheresponsetomedicationsusedfortreatmentofdiabeticretinopathy(DR).[23‑26]Furthermore,otherstudieshavereportedtheeffectofgeneticfactorsand other patient characteristics on the response tointravitrealranibizumabtherapyinage‑relatedmaculardegeneration(ARMD).[27‑29]Thus,comparingtheefficacyof variousDME treatment protocols, baseline andsystemicindividualfactorsshouldbetakenintoaccount.However, asmost of these studies are randomizedclinicaltrials,oneassumesinsufficientsamplesizeforconsideringallofthem.Onepossiblewaytoovercometheproblemofsystemic

andbaselineindividualfactorsistocomparedifferenttreatmentsinsubjectswithbilaterallyinvolvedeyes,thuspatientcharacteristicswhichmayaffecttheresultsarecontrolledandmatched.Ontheotherhand,bilateraleyesareexpectedtobecorrelatedandfrequentmeasurementsalsoaddanotherlevelofcorrelationtothesedata.Therearesomestatisticalmethodsconsiderthesecorrelations.Thegeneralizedlinearmixedmodels(GLMMs)arewellknown statisticalmethodsused tohandle suchdatasets.[30]Inaddition,multivariatemixedmodelscantackleboththecorrelationcausedbyintra‑subjectorgansandrepeatedmeasurements.[31‑34]Normalitydistributionofrandomeffectsisoneofthemostimportantassumptionsinthesemodels.Violationofthisassumptioncanresultinseriousmisleadinginference.[35‑40]Somehavesuggestedrandom effectmodelswith asymmetric aswell assymmetricdistributiontoavoidsuchproblems.[41‑43]

In this studyusing thebivariategeneralized linearmixedmodelwith asymmetric random effects,weattemptedtoeliminatetheroleofpossibleconfoundersin comparing three treatments forDMEandconsiderthecorrelationinfelloweyesofthesamesubjectfromasubsetofpatientsalreadyreportedinapreviouspaper.[22] Herein,weselectedpatientswithbilateralinvolvementreceivingdifferenttreatmentsforeacheye.

METHODSThisclinicaltrialwasapprovedbytheEthicsCommitteeof theOphthalmicResearchCenter, ShahidBeheshtiUniversityofMedical Sciences.The trial registrationnumberwasNCT00370669.Thestudyadhered to thetenets of theDeclaration ofHelsinki and informedconsentwasobtainedfromallparticipants.Detailsofthepatientsandmethodsofthetrialhavebeenpublishedpreviously.[19,20,22] The present study is a subgroupanalysisofpatientswithbilateraleyeinvolvement.This randomized, double‑blind clinical trialwas

performed at LabbafinejadMedicalCenter betweenSeptember 2005 andMay 2007.All naive eyeswithclinically significantDMEbasedonEarlyTreatmentDiabetic Retinopathy Study (ETDRS) criteriawereincluded. Exclusion criteriawere previous focal orpanretinallaserphotocoagulation,historyofintraocularinjection,glaucomaorocularhypertension,intraocularsurgery, significantmedia opacity,VAworse than20/300 or better than 20/40, iris neovascularization,andhigh risk for proliferative diabetic retinopathy.Other exclusion criteriawerepregnancy,monocularstatus, uncontrolled diabetesmellitus and serumcreatinine≥3mg/dL.Primarily,150eyesof129patientswere enrolled and randomly allocated to one of thethreestudyarmsusingtherandomblockpermutationmethodwith randomblock lengths of 4 and 6. Thestudygroupswereasfollowing:(1)0.05mL(1.25mg)bevacizumab (Avastin;Genentech, Inc., South SanFrancisco,CA,USA[madeforF.Haffmann‑LaRoche,Ltd.,Basel, Switzerland]) injectionnamedas the IVBgroup;(2)bevacizumabinjectionplus0.05mL(2mg)triamcinolone(HEXALPharmaceuticals,Holzkirchen,Germany)knownastheIVB/IVTgroup,and(3)theMPCgroup.The felloweyes inbilateralcaseswere treated1‑weekapart.AccordingtoETDRScriteriaandprovidedthatVAwasnot better than 20/40, retreatmentwasperformedforpersistentclinicallysignificantmacularedemaat 12‑week intervalswith the assigned initialtreatment.Asdescribedintheoriginalprotocol,[22]ifbotheyes

of apatientmet the inclusion criteria, each eyewasrandomized individually, hence itwas possible forbotheyesofbilateralcasestobeallocatedintothesametreatmentgroup.Inthepresentsubgroupanalysisstudy,wechoseonlybilateralcaseswhounderwentdifferent



treatments in fellow eyes.Therefore, only 30 eyes of15patientswererecruitedforthisstudy.Changeinbest‑correctedvisualacuity(BCVA)and

CMTmeasuredbyopticalcoherencetomography(OCT)weretheprimaryoutcomemeasures.UsingstandardSnellencharts,BCVAwasrecordedinthelogarithmoftheminimumangleofresolution(logMAR)notations.OCT mapping was achieved by a time‑domaindevice (Zeiss,Dublin, CA,USA).Measurement ofretinalthicknesswasperformedina3.5mmdiametercirclecenteredonthefixationpoint.CMTwasmeasuredasmeanthicknessonthe1‑mmcirclecenteredonthefovea.Topreserveinvestigatormasking,procedureswere

carriedoutbystaffotherthanthestudyinvestigators.A20sshamlaserprocedurewasperformedusinganaimingbeamoflaseronthemaculaofeyesintheIVBandIVB/IVTgroups.AshaminjectionwasdoneintheMPCgroup,withaneedlelesssyringepressedagainstthe conjunctiva. BCVAmeasurement andOCTwereperformedbymaskedexaminers.

Statistical methodsTocompareVAandCMTatfollowupperiodswithbaselinevalueswithineachgroup,weutilizedageneralmixedmodel.Inaddition,anothermixedmodelwasused to compare CMT and VA in the treatment

groups after adjustment for baseline values and toconsider correlationbetween felloweyesofpatientsat each followup. Benjamin andHochbergmethodwasemployedforformultiplecomparisons.[44]Inthelast step, to obtain an overall comparison betweentreatment responses throughout the studydurationconsideringthetwolevelsofcorrelationinsubjectsandfollow‑up,abivariategeneralizedlinearmixedmodelwith asymmetric random effectswas used. P <0.05wereconsideredasstatisticallysignificant.StatisticalanalysiswasperformedusingRSoftware(version3.0.0,R Foundation for Statistical Computing, Vienna,Austria).

RESULTS

The24‑monthresultsofthistrialhavebeenpreviouslypublished.[22]Outof21patientswithbilaterallyenrolledfellow eyes, 6 patientswho had received the sametypeoftreatmentinbotheyeswereexcluded.Overall,15 eligiblepatientswere evaluated at 6, 12, 18, and24months,ofwhom4(27%)subjectsreceivedIVBinoneeyeandIVB/IVTinfelloweye;4(27%)receivedIVBinoneeyeandMPCintheothereye;and7(46%)patients received IVB/IVT in one eye andMPC inthe fellow eye [Figure 1]. Baseline characteristics ofpatientswho completed the study are summarized

Figure 1.Flowchartforenrolledsubjectsthroughoutthetrial.



inTable1.Uptothelastfollowup,retreatmentwiththeassignedregimenwasrequired inalleyes in theIVB,IVB/IVTgroups[Table2].Themeannumberofretreatments foreacharmwas1.87±0.93,2.0±1.05and1.36±0.76intheIVB,IVB/IVTandMPCgroups,respectively(P=0.198).Table 2 demonstrates the mean and median

proportionsof improvement inVAateach follow‑upinterval in the study groups. The results ofmixed

effectsmodeling showed that compared to baselinevalues,VA improvementwas significantlydifferentamong the groups up to 12months (P = 0.037 and P =0.035 at 6 and 12months, respectively) in favorof IVB.Within thegroups, analysis showed thatVAimprovementwas significant only in the IVBgroupup to12months (P=0.027and P =0.022atmonth6and12, respectively). In the courseof the study,VAimprovedintheIVB/IVTgroupanddecreasedinthe

Table 1. Patient characteristics in each combination group

Parameter Total IVB+IVB/IVT IVB+MPC IVB/IVT+MPC

SexFemale/male 5/10 3/1 1/3 1/6

Age(years)Mean±SD 61±4 59±3 64±3 60±4Median(range) 60(55‑67) 60(55‑61) 64(60‑67) 60(55‑66)

Diabetesduration(years)Mean±SD 11±3 11±1 13±3 9±2Median(range) 10(6‑16) 12(10‑12) 13(10‑16) 9(6‑11)

IOP(mmHg)Mean±SD 14.2±2.4 14.2±2.9 16±0 13.3±2.3Median(range) 13.5(11‑18) 14(11‑18) 16(16‑16) 12.5(12‑18)

VA(logMAR)Mean±SD 0.63±0.33 0.71±0.37 0.67±0.33 0.55±0.3Median(range) 0.48(0.1‑1.4) 0.69(0.22‑1.4) 0.54(0.4‑1.3) 0.4(0.1‑1.22)

CMT(µm)Mean±SD 328±145 343±170 312±154 329±136Median(range) 283(117‑651) 261(195‑651) 230(199‑605) 301(117‑556)

IVB, intravitrealbevacizumab injection; IVT, intravitreal triamcinolone injection;MPC,macular laserphotocoagulation; IOP, intraocularpressure;VA,visualacuity;logMAR,logarithmoftheminimumangleofresolution;CMT,centralmacularthickness;SD,standarddeviation

Table 2. Mean BCVA (logMAR) changes from baseline and median proportions of change for each group during follow‑up

IVB IVB/IVT MPC P‡ Multiple comparison

Baseline(mean±SD) 0.84±0.37 0.66±0.29 0.44±0.226months 0.62±0.28 0.65±0.42 0.66±0.47 0.037 IVBversusMPC0‑6months −0.22±0.14 −0.01±0.24 0.23±0.4Relativechange% −26 2 52Pwithin† 0.027 0.973 0.04

12months 0.54±0.33 0.61±0.42 0.56±0.36 0.035 IVBversusMPC0‑12months −0.3±0.13 −0.05±0.18 0.13±0.36Relativechange% −36 −8 30Pwithin† 0.022 0.973 0.179

18months 0.69±0.43 0.59±0.44 0.52±0.25 0.117 ‑0‑18months −0.16±0.27 −0.07±0.22 0.08±0.3Relativechange% −19 −11 18Pwithin† 0.355 0.973 0.339

24months 0.81±0.54 0.61±0.46 0.46±0.23 0.444 ‑0‑24months −0.04±0.49 −0.05±0.26 0.02±0.3Relativechange% −5 −8 5Pwithin† 0.858 0.973 0.79

‡Adjustedforbaselinebasedonmixedmodel;†Basedonmixedmodel.AdjustmentformultiplecomparisonsperformedbyBenjaminandHochbergmethod.IVB,intravitrealbevacizumabinjection;IVT,intravitrealtriamcinoloneinjection;MPC,macularlaserphotocoagulation;BCVA,best‑correctedvisualacuity;logMAR,logarithmoftheminimumangleofresolution;SD,standarddeviation



MPCgroup,althoughnoneofthesechangesreachedasignificantlevel[Figure2].ThepercentageofeyeswithVAimprovementofequalorbetterthan2Snellenlineswas38%,9%,and18%intheIVB,IVB/IVT,andMPCgroupsat 12months, respectively.Thesepercentageswere42.9%,37.5%and33.3%intheIVB,IVB/IVT,andMPCgroupsat24months,respectively.AlthoughVA improvement at 6 and 12months

was significantly in favor of IVB as compared toMPC, the difference did not remain significantthereafterupto24monthsbasedonintentiontotreatanalysis (P=0.177and P =0.444at18and24months,

correspondingly).TheIVB/IVTgroupshowedbetterVA improvement than theMPC group, however,thisdifferencewasnotstatisticallysignificantatanyfollow‑up interval (all P > 0.05). All comparisonswere repeated byper protocol analysis but showedno change appeared in the results. The bivariategeneralizedlinearmixedmodelshowedthattheIVBgroupdemonstratedgreaterimprovementinVA(0.33logMAR,95%credibleinterval:0.23–0.44)ascomparedtotheMPCgroupandalsotheIVB/IVTgroup(0.23logMAR,95%credibleinterval:0.12–0.33)throughoutthe study period.On the other hand, the IVB/IVTgroupshowedanegligibledifferencewith theMPCgroupthroughthestudy(0.11logMAR,95%credibleinterval:−0.01–0.20)PerformingthesamecomparisonforCMTchanges,

theIVBgrouphadasignificantlygreaterCMTreductionthan the IVB/IVT group at 24months [Table 3, P =0.048].Also,CMThadanincreasingtrendinIVB/IVTgroup(P<0.001)throughthestudy.ThechangeinCMTofIVBgroupwasdifferentcomparedtotheIVB/IVTgroup (108µ, 95%credible interval: 59–157)andMPCgroup(51µ,95%credibleinterval:4–100)throughthestudyfollowups.Also,theIVB/IVTgroupshowedsomeincreaseinCMTascomparedtotheMPCgroup(−57µ,95%credibleinterval:−96to−17)[Figure3].

DISCUSSION

InthecurrentstudyusingthegeneralizedlinearmixedmodelonbilateralDMEcaseswhohadreceiveddifferent

Table 3. Mean CMT changes from baseline and median proportions of change for each group during follow‑up

IVB IVB/IVT MPC P‡ Multiple comparison

Baseline(mean±SD)(µm) 364±188 324±132 305±1316months 278±115 334±194 327±133 0.462 ‑0‑6months −86±172 10±115 22±53Relativechange% −24 3 7Pwithin† 0.493 0.899 0.983

12months 287±94 380±192 335±142 0.233 ‑0‑12months −77±186 56±125 30±68Relativechange% −21 17 10Pwithin† 0.558 0.78 0.983

18months 340±121 396±190 303±107 0.145 ‑0‑18months −24±96 72±123 −2±97Relativechange% −7 22 −1Pwithin† 0.783 0.78 0.983

24months 302±103 420±215 304±117 0.048 IVBversusIVB/IVT0‑24months −62±151 96±147 −1±101Relativechange% −17 30 0Pwithin† 0.612 0.78 0.983

‡Adjustedforthebaselinebasedonmixedmodel;†Basedonmixedmodel.AdjustmentformultiplecomparisonsperformedbyBenjaminandHochbergmethod.IVB,intravitrealbevacizumabinjection;IVT,intravitrealtriamcinoloneinjection;MPC,macularlaserphotocoagulation;CMT,centralmacularthickness;SD,standarddeviation;µm,micron

Figure 2.Mean best‑corrected visual acuity changes inrelationtobaselinevaluesinthelogarithmoftheminimumangleofresolutionnotationsinthethreegroupsatdifferenttimepoints. IVB, intravitreal bevacizumab injection; IVB/IVT,IVB/intravitrealtriamcinoloneinjection;MPC,macularphotocoagulation; BCVA, best‑corrected visual acuity;logMAR,logarithmoftheminimumangleofresolution.



treatmentsforeacheye,thedifferencebetweenIVBandMPCat 6 and12monthswas statistically significantin terms of VA improvement. Other intergroupdifferencesregardingVAdidnotreachasignificantlevel.ConsideringCMTchanges,thedifferencebetweenthegroupswassignificantonlyat24monthsinfavoroftheIVBgroupascomparedtotheIVB/IVTgroup.Moreover,using bivariate generalized linear mixedmodelwith asymmetric randomeffects,we found thatVAimprovementwassuperiorintheIVBgroupascomparedtotheIVB/IVTandMPCgroupsanditdemonstratedbetteroutcomesregardingCMTascomparedtotheIVB/IVTandMPCgroupsthroughthestudy.Comparingtheseresultswiththoseoftheoriginal

study, a similar pattern of differencewasdetected.In the original trial, the significant superiority ofVA improvement in the IVBgroup,whichhadbeennoted atmonth 6,was not sustained thereafter upto 24months and the difference among the groupswasnot significant at anyvisit.However,meanVAimprovementwasgreater in the IVBgroup than theothergroupsandintheIVB/IVTgroupascomparedtotheMPCgroup.Inthecurrentstudy,conductedonlyonbilateraltreatedeyesusingdifferentinterventions,the difference between IVB andMPC at 6 and12monthswasstatisticallysignificantintermsofVAimprovement.On the contrary, in the original trialdifferenceinimprovementofVAbetweengroupswasstatisticallysignificantonlyat6months.Participatingonlybilateralcasesinthisstudyalongwithapplyingbivariategeneralizedlinearmixedmodelarepossiblereasons for thediscrepancybetween this study andthe original one. These two reasons could increasethe homogeneity between the groups, decreasethe confounding effects of dissimilarities betweentreatmentgroupsandincreasethepowerofstatisticaltests.Insomeotherstudies,theefficacyofIVBlastedfor 6months[45,46] and its superiority overMPCwas

reportedtopersistfor6[17,18,47]and12months[3,10] after intervention.However,theeffectofIVBandIVB/IVTwasnotdifferentafter12monthsanotherstudy.[48]

ConcerningCMTchangesinthisstudy,thedifferenceamongthegroupswassignificantat24monthsinfavoroftheIVBgroupincomparisontocombinedIVB/IVT.WeobservedCMTreductionof24%intheIVBgroupandonthecontrary,aCMTincreaseof30%inthecombinedgroup.However,noneof thesimilarcomparisonswasstatisticallysignificantintheoriginalstudy.[22]AreviewofliteratureshowedcontroversialresultsregardingtheeffectofthesetreatmentsonCMT;somestudiesshowedthatMPCwasmoreeffectivethananti‑VEGFtreatments,[17,49] othersrevealedthesuperiorityofintravitrealinjectionsincludingIVBaloneorcombinedwithIVTascomparedtoMPC[47]andsomewerenotabletodetectanydifference.[48]

Our study was powered by eliminating theconfoundingeffectofsystemicparametersviacomparingtwoeyesofthesameindividualreceivingtwodifferenttreatments at the same time. It hasbeen shown thatsystemic factors such as blood sugar levels, bloodpressure,blood lipids, etc., couldaffect the treatmentresponse.[23,25‑29]Keepingalloftheseparametersundercontrol throughout a studyandmaking themsimilaramongall thegroups ina trial arealmost impossiblepractically.Therefore,comparingtwoeyesofthesamesubjectmay compensate for such correlationsmoreideally.However, as far as intravitreal injections areconcerned, thepossibilityof systemicabsorptionandfelloweyeeffectmayinterferewiththeresultsandcanbeconsideredasasourceofbiasinthisstudy.Amixedmodelwasused in thepresent study to

comparetreatmentoutcomes; this isawayfor intentiontotreatanalysisinclinicaltrials.[50,51]Oneoftheimportantassumptionsof thesemodels isnormaldistribution forrandomeffectsfacilitatingtheirimplementation.Simulationstudieshave shown thatalthoughdeviation from thisassumptiondoesnothaveasevereimpactontheregressioncoefficient,[38‑40]itcanaffectthevarianceoftheirestimationandconsequentlyleadtobiasedinference.[36,37]Weappliedabivariategeneralizedlinearmixedmodelwithasymmetricdistribution for randomeffects to compare the resultsthroughoutthestudycompensatingforthecorrelationoffelloweyesandrepeatedmeasurementssimultaneouslyandcoveringskewedandsymmetricdistributionsforrandomeffects.Despitethesmallsamplesizeinthecurrentstudy,whichcanreduceitspower,somenewdifferenceswerefoundascomparedtotheoriginalsurveyincludingmoreprolongedIVBeffectonbothVAandCMTthanothertreatments.Thejustificationforthiscouldbesimplychanceobservation.Sinceallobserveddifferencesintheoriginaltrialweredetectedagaininthisstudy,itmightbeconcludedthat theconfoundingeffectsofsystemic factorsdidnotsignificantlyimpactthepreviouslypublishedresults.Insummary,theresultsofthisstudyusingbivariate

generalized linearmixedmodelwith asymmetric

Figure 3.Meancentralmacularthicknesschangesinrelationtobaselinevaluesinmicroninthethreegroupsatdifferenttimepoints.IVB,intravitrealbevacizumabinjection;IVB/IVT,IVB/intravitrealtriamcinoloneinjection;MPC,macularlaserphotocoagulation;CMT,centralmacularthickness.



randomeffectonbilateralDMEcasesreconfirmedtheresultsofourpreviousclinicaltrial.Inotherwords,thesuperiorityof repeated IVB injectionsover combinedIVB/IVTandMPCtreatmentuptoonly24monthswasreconfirmed.However, thisresultneedstobeprovenin larger studies using different treatment agentssimultaneouslyinbilateralDMEcases.

ACKNOWLEDGEMENTS

TheauthorswouldliketothanktheSchoolofPublicHealthandtheInstituteofPublicHealthResearch,TehranUniversityofMedicalSciencesfortheirfinancialsupport.

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How to cite this article: Yaseri M, Zeraati H, Mohammad K, Soheilian M, Ramezani A, Eslani M, et al. Intravitreal bevacizumab injection alone or combined with triamcinolone versus macular photocoagulation in bilateral diabetic macular edema; application of bivariate generalized linear mixed model with asymmetric random effects in a subgroup of a clinical trial. J Ophthalmic Vis Res 2014;9:453-60.

Source of Support: The authors would like to thank the School of Public Health and the Institute of Public Health Research, Tehran University of Medical Sciences for their financial support. Conflict of Interest: None declared.

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