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Laserphotocoagulationforproliferativediabeticretinopathy
Review

Intervention

JenniferREvans , ManueleMichelessi, GianniVirgili

Firstpublished:
24November2014

EditorialGroup:
CochraneEyesandVisionGroup

DOI:
10.1002/14651858.CD011234.pub2 View/savecitation

Citedby:
0articles Citationtools

Abstract
Background
Diabeticretinopathyisacomplicationofdiabetesinwhichhighbloodsugarlevelsdamagetheblood
vesselsintheretina.Sometimesnewbloodvesselsgrowintheretina,andthesecanhaveharmfuleffects
thisisknownasproliferativediabeticretinopathy.Laserphotocoagulationisaninterventionthatis
commonlyusedtotreatdiabeticretinopathy,inwhichlightenergyisappliedtotheretinawiththeaimof
stoppingthegrowthanddevelopmentofnewbloodvessels,andtherebypreservingvision.

Objectives
Toassesstheeffectsoflaserphotocoagulationfordiabeticretinopathycomparedtonotreatmentor
deferredtreatment.

Searchmethods
WesearchedCENTRAL(whichcontainstheCochraneEyesandVisionGroupTrialsRegister)(2014,Issue
5),OvidMEDLINE,OvidMEDLINEInProcessandOtherNonIndexedCitations,OvidMEDLINEDaily,
OvidOLDMEDLINE(January1946toJune2014),EMBASE(January1980toJune2014),the

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metaRegisterofControlledTrials(mRCT)(www.controlledtrials.com),ClinicalTrials.gov
(www.clinicaltrials.gov)andtheWorldHealthOrganization(WHO)InternationalClinicalTrialsRegistry
Platform(ICTRP)(www.who.int/ictrp/search/en).Wedidnotuseanydateorlanguagerestrictionsinthe
electronicsearchesfortrials.Welastsearchedtheelectronicdatabaseson3June2014.

Selectioncriteria
Weincludedrandomisedcontrolledtrials(RCTs)wherepeople(oreyes)withdiabeticretinopathywere
randomlyallocatedtolaserphotocoagulationornotreatmentordeferredtreatment.Weexcludedtrialsof
lasersthatarenolongerinroutineuse.Ourprimaryoutcomewastheproportionofpeoplewholost15or
moreletters(3lines)ofbestcorrectedvisualacuity(BCVA)asmeasuredonalogMARchartat12months.
Wealsolookedatlongertermfollowupoftheprimaryoutcomeattwotofiveyears.Secondaryoutcomes
includedmeanbestcorrecteddistancevisualacuity,severevisualloss,meannearvisualacuity,
progressionofdiabeticretinopathy,qualityoflife,pain,lossofdrivinglicence,vitreoushaemorrhageand
retinaldetachment.

Datacollectionandanalysis
WeusedstandardmethodsasexpectedbytheCochraneCollaboration.Tworeviewauthorsselected
studiesandextracteddata.

Mainresults
Weidentifiedalargenumberoftrialsoflaserphotocoagulationofdiabeticretinopathy(n=83)butonlyfive
ofthesestudieswereeligibleforinclusioninthereview,i.e.theycomparedlaserphotocoagulationwith
currentlyavailablelaserstono(ordeferred)treatment.ThreestudieswereconductedintheUSA,one
studyintheUKandonestudyinJapan.Atotalof4786people(9503eyes)wereincludedinthesestudies.
Themajorityofparticipantsinfourofthesetrialswerepeoplewithproliferativediabeticretinopathyone
trialrecruitedmainlypeoplewithnonproliferativeretinopathy.Fourofthestudiesevaluatedpanretinal
photocoagulationwithargonlaserandonestudyinvestigatedselectivephotocoagulationofnonperfusion
areas.Threestudiescomparedlasertreatmenttonotreatmentandtwostudiescomparedlasertreatment
todeferredlasertreatment.Allstudieswereatriskofperformancebiasbecausethetreatmentandcontrol
weredifferentandnostudyattemptedtoproduceashamtreatment.Threestudieswereconsideredtobe
atriskofattritionbias.
At12monthstherewaslittledifferencebetweeneyesthatreceivedlaserphotocoagulationandthose
allocatedtonotreatment(ordeferredtreatment),intermsoflossof15ormorelettersofvisualacuity(risk
ratio(RR)0.99,95%confidenceinterval(CI)0.89to1.118926eyes2RCTs,lowqualityevidence).
Longertermfollowupdidnotshowaconsistentpattern,butonestudyfounda20%reductioninriskof
lossof15ormorelettersofvisualacuityatfiveyearswithlasertreatment.Treatmentwithlaserreduced
theriskofseverevisuallossbyover50%at12months(RR0.46,95%CI0.24to0.869276eyes4RCTs,
moderatequalityevidence).Therewasabeneficialeffectonprogressionofdiabeticretinopathywith
treatedeyesexperiencinga50%reductioninriskofprogressionofdiabeticretinopathy(RR0.49,95%CI
0.37to0.648331eyes4RCTs,lowqualityevidence)andasimilarreductioninriskofvitreous
haemorrhage(RR0.56,95%CI0.37to0.85224eyes2RCTs,lowqualityevidence).
Noneofthestudiesreportednearvisualacuityorpatientrelevantoutcomessuchasqualityoflife,pain,
lossofdrivinglicenceoradverseeffectssuchasretinaldetachment.

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Wedidnotplananysubgroupanalyses,buttherewasadifferenceinbaselineriskinparticipantswithnon
proliferativeretinopathycomparedtothosewithproliferativeretinopathy.Withthesmallnumberofincluded
studieswecouldnotdoaformalsubgroupanalysiscomparingeffectinproliferativeandnonproliferative
retinopathy.

Authors'conclusions
Thisreviewprovidesevidencethatlaserphotocoagulationisbeneficialintreatingproliferativediabetic
retinopathy.Wejudgedtheevidencetobemoderateorlow,dependingontheoutcome.Thisispartly
relatedtoreportingoftrialsconductedmanyyearsago,afterwhichpanretinalphotocoagulationhas
becomethemainstayoftreatmentofproliferativediabeticretinopathy.
FutureCochraneReviewsonvariationsinthelasertreatmentprotocolareplanned.Futureresearchon
laserphotocoagulationshouldinvestigatethecombinationoflaserphotocoagulationwithnewertreatments
suchasantivascularendothelialgrowthfactors(antiVEGFs).

Plainlanguagesummary English

Laserphotocoagulationforproliferativediabeticretinopathy
Reviewquestion
Islaserphotocoagulationaneffectivetreatmentfordiabeticretinopathy?
Background
Diabeticretinopathy(DR)isacommonproblemforpeoplewithdiabetesandcanleadtolossofvision.The
backoftheeye(retina)candevelopproblemsbecauseofdiabetes,includingthegrowthofharmfulnew
bloodvessels(proliferativeDR,referredtohereas'PDR').Laserphotocoagulationisacommonlyused
treatmentforDRinwhichtheeyedoctorusesalaseronthebackoftheeyetostopsomeoftheharmful
changes.
Studycharacteristics
Wefoundfivestudies.ThesearchesweredoneinApril2014.ThreestudiesweredoneintheUSA,one
studyintheUKandonestudyinJapan.Atotalof4786people(9503eyes)wereincludedinthesestudies.
MostparticipantshadPDR.
Keyresults
Wefoundthatmoderatevisionlossat12monthswassimilarineyestreatedwithlaserandeyesthatwere
nottreated,butsimilarassessmentsmadeatalaterdateshowedthateyestreatedwithlaserwereless
likelytohavesufferedmoderatevisionloss.Treatmentwithlaserreducedtheriskofseverevisuallossby
over50%at12months.TherewasasimilareffectontheprogressionofDR.Noneofthestudiesreported
patientrelevantoutcomessuchaspainorlossofdrivinglicence.
Qualityoftheevidence
Wedidnotfindverymanystudiesandthosewefoundweredonequitealongtimeagowhenstandardsof
trialconductandreportingwerelower.Wejudgedthequalityoftheevidencetobelow,withtheexception
oftheresultsforseverevisualloss,whichwejudgedtobemoderatequalityevidence.

Summaryoffindings (Explanation)

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Summaryoffindingsforthemaincomparison.Laserphotocoagulationcomparedtocontrolfor
diabeticretinopathy

Laserphotocoagulationcomparedtonotreatment(ordeferredtreatment)fordiabeticretinopathy

Patientorpopulation:peoplewithdiabeticretinopathy
Settings:Ophthalmologyclinics
Intervention:laserphotocoagulation
Comparison:notreatmentordeferredtreatment

Outcomes Illustrativecomparativerisks*(95%CI) Relative Noof Qualityof Comments

effect participants the
Assumed Correspondingrisk (95% (studies) evidence
risk* CI) (GRADE)

Notreatment Laserphotocoagulation
ordeferred
treatment

Lossof15ormore Lowrisk(nonproliferativeDR) RR0.99 8926 ThepooledRR

lettersBCVA (0.89to (2RCTs) LOW 1,2 0.99(0.89to
1.11) 1.11)isderived
Followup:12 100per1000 99per1000 fromonestudy
months (89to111) withmainlylow
riskpopulation
RR1.07(0.92to
Highrisk(proliferativeDR) 1.23)andone
studywith
250per1000 248per1000 mainlyhighrisk
(223to278) population0.86
(0.71to1.04)

BCVAmeasured Themean ThemeanBCVAat12 36

usinglogMARacuity BCVAat12 monthsintheintervention (1RCT) LOW 1,3
(0=6/6visualacuity, monthsinthe groupwas0.02logMAR
controlgroup unitshigher(worse0.23
higherscoreis
was0.12 lowerto0.27higher)
worsevisualacuity)
logMAR
Followup:12
months

Severevisualloss Lowrisk(nonproliferativeDR) RR0.46 9276

(BCVA<6/60) (0.24to (4RCTs) MODERATE
0.86) 1,4
Followup:12 10per1000 5per1000
(2to9)
months

Highrisk(proliferativeDR)

50per1000 23per1000
(12to43)

Progressionof Lowrisk(nonproliferativeDR) RR0.49 8331

diabeticretinopathy (0.37to (4RCTs) LOW 1,5
100per1000 49per1000 0.64)
(37to64)

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Followup:12
months Highrisk(proliferativeDR)

400per1000 196per1000
(148to256)

Qualityoflife Seecomment Seecomment Nostudies

reportedthis
Followup:12
outcome
months

Pain Seecomment Seecomment Nostudies

reportedthis
Followup:attimeof
outcome
treatment

Lossofdriving Seecomment Seecomment Nostudies

licence reportedthis
outcome
Followup:within
threemonthsof
treatment

*Thebasisfortheassumedrisk(e.g.themediancontrolgroupriskacrossstudies)isprovidedinfootnotes.The
correspondingrisk(andits95%confidenceinterval)isbasedontheassumedriskinthecomparisongroupandtherelative
effectoftheintervention(andits95%CI).
CI:ConfidenceintervalDR:diabeticretinopathyBCVA:Bestcorrectedvisualacuity

GRADEWorkingGroupgradesofevidence
Highquality:furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
Moderatequality:furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmay
changetheestimate.
Lowquality:furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikely
tochangetheestimate.
Verylowquality:weareveryuncertainabouttheestimate.

*Estimatesofassumedriskareindicativeonly,asestimatesat12monthswerenotavailableinallstudies.Forthelowrisk
populationstheywereestimatedfromETDRS(butacknowledgingthatthecontrolgroupreceiveddeferredlaser)andforthe
highriskpopulationstheywereestimatedfromDRSandHercules1977.

1 Downgradedforriskofbias(1):studieswerenotmaskedandtreatmentgroupsdifferent

2 Downgradedforinconsistency(1):I2 =69%andeffectestimateswereindifferentdirections.Seecommentsfordetails

3 Downgradedforimprecision(1):wideconfidenceintervals

4 Therewasheterogeneity(I2 =70%)butalleffectestimatesfavouredlaserphotocoagulationsowedidnotdowngradefor
inconsistency

5 Downgradedforindirectness(1):studyresultswerereportedat1,3,4and5years

Background
Descriptionofthecondition
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Diabeticretinopathy(DR)isamicrovascularcomplicationofdiabetesinwhichhighbloodsugarlevelsdamage
thebloodvesselsintheretina(Davidson2007).Thesebloodvesselsmaybecomeblocked,whichleadstoa
reductionorcessationofbloodsupplytotheretina(nonproliferativediabeticretinopathy).Sometimesthe
vesselsswellupandleakfluid(macularoedema)andsometimesnewvesselsgrow(neovascularisation)on
theretinaandvitreous(alsocalledthevitreoushumour)thisisknownasproliferativediabeticretinopathy
(PDR).
Ingeneral,theearlystagesofthediseasearenotassociatedwithanysymptoms.Diseaseprogressionis
associatedwithvisuallossandblindness,ifleftuntreated.DRisanimportantcauseofvisualimpairment
worldwide.Anestimated285millionpeoplearevisuallyimpairedandoftheseapproximately39millionpeople
areblind(Pascolini2012).DRisbelievedtoaccountforapproximately1%ofvisualimpairmentandblindness,
meaningnearlythreemillionpeopleworldwidearevisuallyimpairedduetothiscondition.Thetotalnumberof
peoplewithdiabetesisprojectedtoincreasefrom171millionpeoplein2000to366millionin2030(Wild
2004).
ThisCochraneReviewisconcernedwiththetreatmentofDR,bothproliferativeandnonproliferative,butnot
macularoedemawhichisaddressedinanotherreview(Jorge2013).

Descriptionoftheintervention
Laserphotocoagulationinvolvesapplyinglightenergytotheretina.Thisisabsorbedbytheretinalpigments,
whichheatupandcausethermaldamagetotheretinaltissues.Thereareseveraltypesoflaser:gas(argon,
krypton),diode,dyeandYAG(RCOphth2012).

Typeoflaser Wavelengthinnm(colour) Comments

Argon 488(blue)514(green)

Krypton 568(yellow)647(red)

Dyelaser 570to630,577(yellow)often
used

Diodelaser 810(infrared) Micropulsemodeavailable

Frequencydoubledyttriumaluminiumgarnet(YAG) 532(green)oftenused Patternscanlaser(PASCAL)often

laser used

Laserapplicationmayfocusonmicroaneurysmsorbedeliveredinagridpatternaroundthecentreofthe
maculainpeoplewithdiabeticmacularoedema(DMO).Whendeliveredtotheperipheralretina,itmaybe
focal,directedtoneovasculartufts,ormorecommonlyscattered,whichisalsoknownaspanretinal
photocoagulation(PRP)andinwhich1200to2000burnsareappliedtotheperipheralretina.Laser
photocoagulationmaybeappliedinonesessionormaybedeliveredoverseveralsessionstoreducetherisk
ofadverseeffects.
Peripheralorpanretinallasertreatmentiscommonlydeliveredtoischaemicareas(i.e.thosewithlowoxygen
levels)intheretinalperiphery,withtheaimsofcausingregressionofretinalneovascularisationandprevention
ofvisuallossduetovitreoushaemorrhage,tractionalretinaldetachment,orneovascularglaucoma,whichare
themaincausesofvisuallossinpatientswithendstagePDR.Panretinalperipherallasertreatmentwasalso
initiallyproposedasatreatmentthatmightpreventtheoccurrenceofPDR.

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Howtheinterventionmightwork
Theaimoflaserphotocoagulationistoslowdownthegrowthofnewbloodvesselsintheretinaandthereby
preventtheprogressionofvisualloss(Ockrim2010).Focallaserphotocoagulationusestheheatoflightto
sealordestroyabnormalbloodvesselsintheretina.Individualvesselsaretreatedwithasmallnumberof
laserburns.
PRPaimstoslowdownthegrowthofnewbloodvesselsinawiderareaoftheretina.Manyhundredsoflaser
burnsareplacedontheperipheralpartsoftheretinatostopbloodvesselsfromgrowing(RCOphth2012).It
isthoughtthattheanatomicandfunctionalchangesthatresultfromphotocoagulationmayimprovethe
oxygensupplytotheretina,andsoreducethestimulusforneovascularisation(Stefansson2001).Againthe
exactmechanismsareunclear,butitispossiblethatthedecreasedareaofretinaltissueleadstoimproved
oxygenationandareductioninthelevelsofantivascularendothelialgrowthfactor.Areductioninlevelsof
antivascularendothelialgrowthfactormaybeimportantinreducingtheriskofharmfulnewvesselsforming.

Whyitisimportanttodothisreview
LaserphotocoagulationisawellestablishedcommontreatmentforDRandtherearemanydifferentpotential
strategiesfordeliveryoflasertreatmentthatarelikelytohavedifferenteffects.Asystematicreviewofthe
evidenceforlaserphotocoagulationwillprovideimportantinformationonbenefitsandharmstoguide
treatmentchoices.Withtheadventofnewtreatments,especiallytheantivascularendothelialgrowthfactor
(antiVEGF)agents,laserphotocoagulationmaybecomelesscommonlyusedinhigherincomecountries,but
maystillhaverelevanceasapotentiallycosteffectivetreatmentinotherpartsoftheworld.Thisreviewshould
bereadinconjunctionwithrelatedCochraneReviewsoftreatmentofDR,includinglaserphotocoagulationfor
diabeticmacularoedema(Jorge2013),antiVEGFforproliferativeretinopathy(MartinezZapata2014),anti
VEGFfordiabeticmacularoedema(Virgili2012),andsteroidsfordiabeticmacularoedema(Grover2008).
Thisisthefirstinaseriesofplannedreviewsonlaserphotocoagulation.Futurereviewswillcomparedifferent
photocoagulationtechniques.

Objectives
Toassesstheeffectsoflaserphotocoagulationfordiabeticretinopathycomparedtonotreatmentordeferred
treatment.

Methods
Criteriaforconsideringstudiesforthisreview

Typesofstudies

Weincludedrandomisedcontrolledtrials(RCTs)irrespectiveofthelanguageinwhichtheywerepublished,or
publicationstatus(publishedorunpublished).

Typesofparticipants

Peoplewithpreproliferative(DR)orproliferativediabeticretinopathy(PDR).Weexcludedtrialswherethe
primaryaimwastotreatdiabeticmacularoedemaasthisiscoveredinaseparateCochraneReview(Jorge

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2013).

Typesofinterventions

Weconsideredtrialsofperipherallaserphotocoagulationwithanyophthalmiclaseratanywavelength,either
focalorpanretinal.Wecomparedthistonotreatment,shamtreatmentordeferredtreatment.
Weincludedstudiesusinganytypeoflaser,butnotstudiesusingxenonarcphotocoagulationorrubylaser,
sincetheselasershavenotbeenusedfordecadesbecauseofanobservedincreaseintheriskofside
effects,suchasperipheralfielddamageandmaculartraction(DRS1981).
Weexcludedtrialsthatcompareddifferenttypes(wavelength)oflaser,laserapplicationatdifferentpowersor
fordifferentexposuretimes,andtrialsthatcompareddifferentregimensfortheapplicationofthelaser(e.g.
comparedthenumber,patternorlocationofburns,orcompareddifferentnumbersoftreatmentsessions)as
thesewillbeconsideredinfutureCochraneReviews.
ThisreviewshouldbereadinconjunctionwithrelatedCochraneReviewsthataddressthecomparison
betweenlaserphotocoagulationandothertreatmentssuchasantiVEGF(MartinezZapata2014Virgili
2012),andsteroids(Grover2008).

Typesofoutcomemeasures

Primaryoutcomes

Proportionofpeoplewholose15ormoreletters(3lines)ofbestcorrectedvisualacuity(BCVA)as
measuredonalogMARchart.

Secondaryoutcomes

1. Meandistancevisualacuity(BCVA).

2. Meannearvisualacuity(NVA).

3. Severevisualloss(BCVA<6/60).

4. Progressionofdiabeticretinopathy,asdefinedbytrialinvestigators.

5. Qualityoflifemeasuredusinganyvalidatedquestionnaire.

6. Adverseevents:pain,lossofdrivinglicence,vitreoushaemorrhage,retinaldetachment.

Withtheexceptionofadverseevents,weaimedtocollectdataontheseoutcomesatoneyearafterinitiation
oftreatment,whichwedefinedastheperiodbetweensixand18months.Weconsideredadverseeventsat
anytimepoint,butthesearemostlikelytooccurwithinthreemonthsoftreatment.Wealsoplannedtoreport
theprimaryoutcomeatlongertimeperiodstwotofiveyearsinordertocommentonwhetheranyeffects
observedaresustainedinthelongterm.
Wemadesomeamendmentstotheoutcomesfromtheprotocol.SeeDifferencesbetweenprotocoland
review.

GoTo

Searchmethodsforidentificationofstudies

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Electronicsearches

WesearchedCENTRAL(whichcontainstheCochraneEyesandVisionGroupTrialsRegister)(2014,Issue
5),OvidMEDLINE,OvidMEDLINEInProcessandOtherNonIndexedCitations,OvidMEDLINEDaily,Ovid
OLDMEDLINE(January1946toJune2014),EMBASE(January1980toJune2014),the meta Registerof
ControlledTrials( m RCT)(www.controlledtrials.com),ClinicalTrials.gov(www.clinicaltrials.gov)andtheWorld
HealthOrganization(WHO)InternationalClinicalTrialsRegistryPlatform(ICTRP)
(www.who.int/ictrp/search/en).Wedidnotuseanydateorlanguagerestrictionsintheelectronicsearchesfor
trials.Welastsearchedtheelectronicdatabaseson3June2014.
See:AppendicesfordetailsofsearchstrategiesforCENTRAL(Appendix1),MEDLINE(Appendix2),EMBASE
(Appendix3), m RCT(Appendix4),ClinicalTrials.gov(Appendix5)andtheICTRP(Appendix6).

Searchingotherresources

Wesearchedthereferencelistsofincludedstudiesandotherreviewsidentifiedbythesearches.

Datacollectionandanalysis

Selectionofstudies

Tworeviewauthors(JE,MM)independentlyscreenedthesearchresultsandselectedtrialsforinclusion.We
resolveddisagreementsthroughdiscussion.
Wescreenedthelistofcitationsandabstractsandclassifiedrecordsinto'possiblyrelevant'and'definitelynot
relevant'.Fortherecordsweidentifiedas'possiblyrelevant'weobtainedthefulltextarticles.Followingthe
Criteriaforconsideringstudiesforthisreviewweclassifiedtrialsinto'tobeincluded'or'tobeexcluded'.We
documentedexcludedtrialsinthecategoryintheCharacteristicsofexcludedstudiessection.

Dataextractionandmanagement

Twoauthors(JE,MM)independentlyextracteddatafromtrialreportsandenteredthedataintoReview
Manager(RevMan2014).Weresolvedanydifferencesinopinionthroughdiscussion.Weusedadata
collectionspreadsheet.WeobtainedEnglishtranslationsofanytrialreportedinalanguageotherthanEnglish
beforeextractingdata.
WecollecteddataontrialcharacteristicsasdetailedinAppendix7.
WeobtainedthefollowingdataonoutcomesspecifiedinTypesofoutcomemeasures:fordichotomous
outcomes,wecollecteddataonthenumberofeventsandtotalparticipantsfollowedupineachtrialarmfor
continuousoutcomes,wecollecteddataonthemeanandstandarddeviationineachtrialarm.
Wedidnotattempttoobtainfurtherinformationfromtrialists.

Assessmentofriskofbiasinincludedstudies

WeassessedriskofbiasusingtheCochraneCollaboration'stoolforassessingtheriskofbiasasdescribedin
Chapter8oftheC ochraneHandbookforSystematicReviewsofInterventions (Higgins2011).

GoTo
Measuresoftreatmenteffect

Wecalculatedtheriskratio(RR)foralldichotomousvariables.Thiswasavariationontheprotocolsee
Differencesbetweenprotocolandreview.
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Forcontinuousvariables(onlydataondistancevisualacuitywereavailable)wecalculatedthemean
difference.
Allmeasuresofeffectwerereportedwith95%confidenceintervals(CIs).

Unitofanalysisissues

Fourofthefivestudieswerewithinpersonstudiesbutwerereportedasunmatched.Wehaveusedthese
dataasreported,whichisaconservativeanalysis.Onetrialconsideredoneeyeperpersononly,butitwas
notclearhowthateyewasselectedforinclusioninthetrial.

Dealingwithmissingdata

Wedocumentedfollowupbyinterventiongroup.Weaimedtocollectdataonreasonsforlosstofollowup,but
thisinformationwasnotusuallyavailable.Wedocumentedwhenlosstofollowupwashigh(over20%),or
unbalancedbetweentreatmentgroups,asapotentialsourceofattritionbias.Weplannedtoconductan
intentiontotreat(ITT)analysisifthiswasreportedbythetrialists,butwehaveconductedanavailablecase
analysisbecausethemajorityoftrialsdidnotreportanITTandtheonesmalltrialthatdidonlyreportedone
outcomeasanITTanalysis(Sato2012).Anavailablecaseanalysismakestheassumptionthatthetreatment
effectinpeoplelosttofollowupwasthesameasthatinpeoplewhowereobserved(assessed).

Assessmentofheterogeneity

WeassessedheterogeneitybyvisualinspectionoftheforestplotsandbycalculatingtheI 2 value(Higgins
2002).WealsoconsideredtheChi 2 testforheterogeneity,butthismayhavelowpowerasfewtrialsmetthe
inclusioncriteria.

Assessmentofreportingbiases

Wewereunabletolookatsmalltrialeffectsaswehadplannedbecausetherewereonlyfiveincludedtrials.
Weconsideredselectiveoutcomereportingbiasaspartoftheassessmentofriskofbiasintheindividual
studies(seeAssessmentofriskofbiasinincludedstudiessection).

Datasynthesis

Wepooleddatausingarandomeffectsmodel,unlesstherewerethreeorfewertrials,inwhichcaseweused
afixedeffectmodel.
Therewasconsiderableheterogeneity,andformanyanalysestheI 2 statisticwasover50%.Inmostanalyses
alleffectestimateswereinthesamedirectionandwereportapooledvalue.TheexceptionwasAnalysis1.1,
butastheeffectestimateswererelativelycloseto1wehavereportedapooledestimate.Thisisavariation
fromourprotocolseeDifferencesbetweenprotocolandreview.

Subgroupanalysisandinvestigationofheterogeneity

Wedidnotplananysubgroupanalysisattheprotocolstage,buttherewasconsiderableheterogeneityin
termsofbaselineriskinparticipantswithnonproliferativeretinopathyandthosewithproliferativeretinopathy.

GoTo
Therewasnotenoughevidencetodosubgroupanalysisbasedonthesegroups,andnewtrialsinfutureare
unlikely.

Sensitivityanalysis
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Weplannedtorepeattheanalysesexcludingstudiesathighriskofselection,ordetectionbias,orboth.In
mostanalysestrialsweresimilarwithrespecttotheseriskofbiasdomainsandsoasensitivityanalysiswas
notpossible.WedidonesensitivityanalysisfortheoutcomeprogressionofDR.
Summaryoffindings

Wereportabsoluterisksandmeasuresofeffectina'Summaryoffindings'table,providinganoverall
assessmentofthequalityoftheevidenceforeachoutcomeusingtheGRADEsystem(Guyatt2011).Two
reviewauthors(JE,GV)independentlyperformedtheGRADEassessment.
Ourprespecifiedoutcomemeasureswere:
1. proportionofpeoplewholose15ormoreletters(3lines)ofBCVAasmeasuredonalogMARchart

2. meanlogMARvisualacuity

3. averseevent:lossofdrivinglicence

4. adverseevent:severevisualloss(BCVA<6/60)

5. adverseevent:pain

6. qualityoflifemeasuredusingavalidatedquestionnaire.

Weplannedtoreportoutcomes1,2and6atoneyear,outcomes3and4withinthreemonthsoftreatment
andoutcome5attimeoftreatment.
Wemodifiedtheprotocoltoincludeseverevisuallossasaneffectivenessoutcomemeasuredatoneyear.
SeeDifferencesbetweenprotocolandreview.

Results
Descriptionofstudies

Resultsofthesearch

Theelectronicsearchesyieldedatotalof3517references(Figure1).TheTrialsSearchCoordinator
removed545duplicaterecords,screenedtheremaining2972recordsandremoved2660referencesthat
werenotrelevanttothescopeofthereview.Wescreenedatotalof312referencesanddiscarded173
reportsasthesewerenotrelevanttothescopeofthereview.Wereviewed139fulltextreportsandincluded
30reportsoffivestudiesthatwereeligibleforinclusioninthereview.Wewereunabletoassess13reports,
eitherbecausethefulltextcopywasunavailableorbecauseatranslationwasneeded.Thesereportsare
listedintheStudiesawaitingclassificationsection,butareunlikelytobeeligibletrials.Wealsoexcluded96
reportsthatreferredto78trials,seeCharacteristicsofexcludedstudiesfordetails.

GoTo

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Figure1.
Openinfigureviewer

GoTo
Resultsfromsearchingforstudiesforinclusioninthereview

Includedstudies

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Weidentifiedfivestudiesthatcomparedlaserphotocoagulationtoacontrol.Threestudieswereconductedin
theUSA(DRS1978ETDRS1991Yassur1980),onestudyintheUK(Hercules1977),andonestudyin
Japan(Sato2012).
FourstudieswerewithinpersonRCTsi.e.oneeyewasrandomlyallocatedtolaserphotocoagulationandthe
othereyetothecontrol(DRS1978ETDRS1991Hercules1977Yassur1980).Sato2012randomly
allocatedpeopletotreatmentandonlyoneeyewasincludedinthestudyitwasunclearhowtheeyewas
selected.
Thenumberofparticipantsenrolledrangedfrom45inYassur1980to3711inETDRS1991.Theaverageage
ofparticipantsrangedfrom41yearsinHercules1977to60yearsinSato2012.Moststudiesrecruited
participantsagedapproximately18to70yearswithanaverageageofaround45years.Thepercentageof
womenenrolledrangedfrom25%inSato2012to48%inYassur1980,butonaveragebetween40%and
45%oftheparticipantsineachtrialwerewomen.
TwostudiesenrolledpeoplewithPDRonly(Hercules1977Yassur1980)twostudiesenrolledpeopleeither
withmoderateorseverenonproliferativeDRorPDR(DRS1978ETDRS1991)andonestudyenrolled
participantswithpreproliferativeDR(Sato2012).IntheDRS1978studyapproximately80%ofparticipants
hadPDRintheETDRS1991studyapproximately20%ofparticipantshadPDR.
MoststudiesusedPRPwithargonlaser(Table1).TheexceptionwasSato2012,whichevaluatedselective
photocoagulationofnonperfusionareas.Threestudiescomparedlasertonotreatment(DRS1978Hercules
1977Yassur1980)twostudiescomparedlasertodeferredlasertreatment(ETDRS1991Sato2012i.e.
controlparticipantsreceivedlaserwhenseverenonproliferative(ETDRS1991)orPDR(ETDRS1991Sato
2012)developed).
Table1.Characteristicsoflaserphotocoagulation

Study Typeof Typeofphotocoagulation Number(size)of Intensity Exposuretime Numberof

laser burns (seconds) sessions

DRS Argon Panretinal 8001600(500m) Notreported 0.1 1(usually)

1978 or
Focaltreatmentofnewvessels
5001000(1000m)

ETDRS Argon Panretinal Full:12001600 Moderate 0.1 Full:2or

1991 (500m) more
Mild:400650(500 Mild:1
m)

Hercules Argon Panretinal 800to3000(200 Minimalretinal Notreported Upto6

1977 mand500m) blanching

Sato Not Selectivephotocoagulationof (400m500m) Notreported Notreported

2012 reported nonperfusionareas

Yassur Argon Panretinal AsforDRS1978 AsforDRS AsforDRS AsforDRS

1980

1978 1978 GoTo
1978

Excludedstudies

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SeeCharacteristicsofexcludedstudies.

Riskofbiasinincludedstudies
SeeFigure2.

Figure2.
Openinfigureviewer GoTo

Riskofbiassummary:reviewauthors'judgementsabouteachriskofbiasitemforeachincluded
study.

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Allocation

Generationoftheallocationsequencewasconsideredadequateintwotrials(DRS1978Sato2012)andwas
notclearlydescribedintherest.Asmostofthestudieswerewithinpersonstudies,allocationconcealment
wasnotjudgedtobeaproblem(asallparticipantsreceivedbothinterventionandcontrol).Intheoneparallel
groupstudytheallocationwasclearlydescribedandjudgedtobeatlowriskofbias(Sato2012).

Blinding

Wejudgedthestudiesthatmeasuredandreportedvisualacuitytobeatahighriskofbiasbecausethe
treatmentandcontrolgroupswereobviouslydifferentandpatientknowledgeofinterventioncouldaffectthe
measurementofvisualacuity.However,theextentofthebiasisdifficulttojudge,andsomestudieshad
specificprotocolstoimprovetheaccuracyofthemeasurementofvision,suchasencouragingpatientstoread
asfardownthechartaspossible(DRS1978).Ingeneral,wejudgedthatpatientandcarerknowledgeof
assignmentwouldnotaffecttheprogressionofDR.

Incompleteoutcomedata

Wejudgedwithinpersonstudiestobeatlowriskofattritionbiasbydefinitionbecause,althoughtheremaybe
attritioninpatientfollowup,thefollowupbetweeninterventionandcontrolgroups,i.e.betweeneyes,will
alwaysbeequal.However,twostudiesselectivelyremovedparticipantswhoreceivedtreatmentinthecontrol
eye(Hercules1977Yassur1980),whichweconsideredtobeapotentialsourceofbiasfortheeffect
estimate.Theoneparallelgroupstudyhadconsiderablelosstofollowup(Sato2012).

Selectivereporting

Ingeneralreportingbiaswasdifficulttojudgewiththeinformationavailable.Noneofthestudiesreportedall
ourreviewoutcomes.

Otherpotentialsourcesofbias

TheSato2012studywasstoppedearly.

Effectsofinterventions
See:SummaryoffindingsforthemaincomparisonLaserphotocoagulationcomparedtocontrolfor
diabeticretinopathy
1.1Lossof15ormorelettersBCVAat12months

Forthisoutcomewefoundtworelevanttrials(DRS1978ETDRS1991:n=8926Figure3Analysis1.1).
Oneofthesestudiesreportedlossof10ormorelettersratherthanlossof15ormoreletters(DRS1978).
Therewasconsiderableheterogeneityofeffect(I 2 =69%Pvalue=0.07).IntheDRS1978studyfewereyes
givenlaserphotocoagulationlost10ormoreletterscomparedtountreatedeyes,buttherewasuncertainty
andtheconfidenceintervalsincluded1(RR0.86,95%CI0.71to1.04).IntheETDRS1991studymoreeyes
treatedwithlaserphotocoagulationlost15ormorelettersover12monthscomparedtoeyesgivendeferred

GoTo
treatment,butagaintherewasuncertaintyandtheconfidenceintervalsincluded1(RR1.07,95%CI0.92to
1.23).

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Figure3.
Openinfigureviewer

Forestplotofcomparison:1Laserphotocoagulationversuscontrol,outcome:1.1Lossof15or
morelettersBCVAat12months

1.2Lossof15ormorelettersBCVAatlongerfollowuptimes

Twotrialsreportedthisoutcomeattwoyears(DRS1978ETDRS1991:n=8306Analysis1.2).Fewereyes
givenlaserphotocoagulationlost15(or10)ormorelinesofvisualacuityattwoyearscomparedtountreated
(DRS1978),ordeferredtreatmenteyes(ETDRS1991RR0.88,95%CI0.80to0.97).Therewas
considerableheterogeneityI 2 =73%,Pvalue=0.06).However,asbotheffectestimateswereinthesame
direction(0.74and0.92)wehavereportedapooledestimate.
Twotrialsreportedthisoutcomeatthreeyears(ETDRS1991Sato2012:n=7458Analysis1.3).Moreeyes
receivinglaserphotocoagulationlost15ormorelettersBCVAatthreeyearscomparedtoeyeswithdeferred
treatment,buttherewasuncertaintyintheresultandtheconfidenceintervalsincluded1(RR1.07,95%CI
0.93to1.23).TheresultsofthetwotrialswerereasonablyconsistentI 2 =14%.
Notrialsreportedthisoutcomeatfouryears.
Onestudyreportedthisoutcomeatfiveyears(ETDRS1991n=7422).Eyesreceivinglaser
photocoagulationwerelesslikelytolose15ormoreletterscomparedtoeyesreceivingdeferredtreatment
(RR0.79,95%CI0.72to0.85).

1.3MeanBCVAat12months

OnestudyreportedmeanlogMARBCVAatthreeyears(Sato2012).Thedifferencebetweenthegroupswas
smallanduncertain(MD0.02,95%CI0.23to0.27n=36).

2MeanNVAat12months

GoTo
Noneofthestudiesreportednearvisualacuity.

3Severevisualloss(BCVA<6/60)

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Fortheoutcomeofseverevisualloss(BCVA<6/60)wefoundfourrelevanttrials(DRS1978ETDRS1991
Hercules1977Sato2012:n=9276Figure4Analysis1.4).Eyesreceivinglaserphotocoagulationwereless
likelytoexperienceseverevisuallosscomparedtountreatedeyesoreyesthatreceiveddeferredtreatment
(RR0.46,95%CI0.24to0.86).Thisoutcomehadhighlevelsofheterogeneity(I 2 =70%,Pvalue=0.02),but
asalltheeffectestimateswereinthesamedirectionwereportapooledestimate.Suchheterogeneity
seemedduetoHercules1977,asmallstudyincludingonlypatientswithproliferativeretinopathy,which
recordedthelargestbenefitwithlaser.

Figure4.
Openinfigureviewer

Forestplotofcomparison:1Laserphotocoagulationversuscontrol,outcome:1.4Severevisualloss
(BCVA<6/60)

4Progressionofdiabeticretinopathy

FortheoutcomeofprogressionofDRwefoundfourrelevanttrials(DRS1978ETDRS1991Sato2012
Yassur1980:n=8331Figure5Analysis1.5).

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Figure5.
Openinfigureviewer

Forestplotofcomparison:1Laserphotocoagulationversuscontrol,outcome:1.5Progressionof
diabeticretinopathy

IntheDRS1978studyprogressionwasbasedongradingoffundusphotographs.Eyesweregradedfornew
vesselsandseveritywasgradedbycomparisonwithstandardimages.Thefollowingcategorieswereused
andprogressionwasdefinedaschangeofoneormoregradesfromnonewvesselstomoderateorsevere
NVD(NVDmeansnewvesselsonorwithin1discdiameteroftheopticdiscNVEmeansnewvessels
elsewhere):
1. nonewvessels

2. mildNVE,noNVD

3. moderateorsevereNVE,noNVD

4. mildNVD

5. moderateorsevereNVD.

IntheETDRS1991studyprogressionwasdefinedasthedevelopmentof'highriskproliferativediabetic
retinopathy'.ThiswasdefinedasPDRwithhighriskcharacteristicsasdefinedbyDRS1978.Thesewerenew
vesselsonorwithin1discdiameteroftheopticdiscworsethanastandardphotograph,withorwithout
vitreousorpreretinalhaemorrhageorvitreousorpreretinalhaemorrhageaccompaniedbynewvessels,
eitherNVD(lessthanstandardphotograph)orNVEgreaterthanorequaltoaquarterofthediscarea.
InSato2012progressionwasdefinedasthedevelopmentofPDR,i.e.thegrowthofnewvessels(detectedby
ophthalmoscopyorfluoresceinangiography),orpreretinal/vitreoushaemorrhage.

GoTo
Yassur1980consideredonlynewvesselsonorneartheopticdisc.Theseweregradedintofivegradesof
severitybasedonthenumberofinvolveddiscquadrants,calibreofthenewvessels,densityof
neovascularisation(NVD)orfibrousproliferationatthedisc(FPD),totalareaofNVDorFPDproliferation,

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planeofNVDorFPDproliferation,andfluoresceinleakagefromNVD.Progressionwasdefinedasincreasein
severityofoneormoregrades.
Thetimeframesatwhichtheseoutcomeswerereportedweredifferentrangingfrom12monthstofive
years,andtheseareindicatedonthefigure.
DRwaslesslikelytoprogressineyesthatreceivedlaserphotocoagulation(RR0.49,95%CI0.37to0.64).
TherewasconsiderableheterogeneityI 2 =63%,Pvalue=0.05)butalleffectestimateswereinthesame
direction,sowereportapooledestimate.

5Qualityoflife

Noneoftheincludedstudiesreportedqualityoflife.

6.1Adverseevents:pain

Noneoftheincludedstudiesreportedpain.

6.2Adverseevents:lossofdrivinglicence

Noneoftheincludedstudiesreportedpatientoutcomessuchaslossofdrivinglicence.

6.3Adverseevents:vitreoushaemorrhage

Forthisoutcomeofvitreoushaemorrhagewefoundtworelevanttrials(Hercules1977Sato2012:n=224
Analysis1.6).Peoplereceivinglaserphotocoagulationwerelesslikelytodevelopvitreoushaemorrhage(RR
0.56,95%CI0.37to0.85I 2 =0%).

6.4Adverseevents:retinaldetachment

Noneofthestudiesreportedretinaldetachmentbyinterventiongroup.

Sensitivityanalysis

ForAnalysis1.5progressionofdiabeticretinopathy,exclusionoftwotrialsathighriskofselectionordetection
biasresultedinaRRof0.55(95%CI0.48to0.64participants=8183studies=2I 2 =41%Sato2012
Yassur1980).Thisisnotdissimilartotheanalysisofallfourtrials(RR0.49,95%CI0.37to0.64participants
=8331studies=4I 2 =63%).

Discussion
Summaryofmainresults
SeeSummaryoffindingsforthemaincomparison.
Weidentifiedfivetrials.Inthemajorityofthesestudies(4trials,99%ofallparticipants)theinterventionwas
panretinalphotocoagulation(PRP)usinganargonlaser.Thereweredifferencesinthepatientpopulation
includedinthesestudies.Twotrialsincluded94%oftheparticipantsinthisreview(DRS1978ETDRS1991).

GoTo
ThesetwostudieswereconductedintheUSpopulationandwerecomplementary:DRS1978assessed
whetherPRPiseffectivecomparedtonotreatmentinpeoplemostlyaffectedbyproliferativediabetic
retinopathy(PDR)ETDRS1991assessedwhetherearlierperipherallasertreatmentofdiabeticretinopathy

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(DR)initsnonproliferativeorearlyproliferativestageisbeneficial,comparedtoastrategyinwhichlaseris
usedatalaterstage,inhighriskPDR.Thus,anybenefitinETDRS1991shouldhavebeenlessthanthat
seeninDRS1978aslaserisalsopartofthecontrolstrategyintheformer.Inmostoftheanalysestheeffects
observedinETDRS1991wereindeedlowerthanDRS1978butnotsignificantlyso.Eventhoughtherewas
evidenceforstatisticalheterogeneity,effectsweregenerallyinthesamedirection,sowepooledtheresultsto
obtain(approximate)overallestimatesofeffect.
At12monthstherewaslittledifferencebetweeneyesreceivinglaserphotocoagulationandthoseallocatedto
notreatment(ordeferredtreatment),intermsoflossof15ormorelettersofvisualacuity.Longertermfollow
updidnotshowaconsistentpattern,butETDRS1991reporteda20%reductioninriskoflossof15ormore
lettersofvisualacuityatfiveyears.
Treatmentwithlaserreducedtheriskofseverevisuallossbyover50%at12months.
TherewasabeneficialeffectonprogressionofDRwithtreatedeyesexperiencinga50%reductioninriskof
progressionandasimilarreductioninriskofvitreoushaemorrhage.
Noneofthestudiesreportednearvisualacuity,qualityoflife,pain,orpatientrelevantoutcomessuchasloss
ofdrivinglicenceoradverseeffectssuchasretinaldetachment.

Overallcompletenessandapplicabilityofevidence
Overallthereisnotalargeamountofevidencefromrandomisedcontrolledtrials(RCTs)onlaser
photocoagulationcomparedtonotreatmentordeferredtreatment.Theevidenceisdominatedbytwolarge
studiesconductedintheUSpopulation(DRS1978ETDRS1991).
Reflectingthefactthatthestudieswereconductedsometimeago,therewasalackofdatareportedformany
ofourcurrentprespecifiedreviewoutcomes,inparticularpatientrelevantoutcomessuchasqualityoflife.
Wedidnotconsiderlasersthatarenotcommonlyusedtodaybutthetreatmentparametersusedinthe
includedtrialsweredifferenttothoseincurrentuse,inparticular,smallersizeandshorterdurationburnsare
nowused(RCOphth2012).
OveralltheevidenceisapplicabletopeoplepresentingwithmoderatetoseverepreproliferativeandPDR,
however,thefactthatrelativelyfewtrialswereidentified,andthatthesewereallconductedsometimeagoin
highincomecountriesleavesalackofevidenceforlowerandmiddleincomecountriesanddifferentpartsof
theworld.However,wehavenoreasontosupposethattheeffectivenessofthesetreatmentswouldbe
differentinlowerincomecountries.
Theintroductionofantivascularendothelialgrowthfactor(antiVEGF)therapyfortreatingseveral
chorioretinalvasculardiseaseshasmadeitpossibletoachievearapid,buttransient,regressionofnew
vesselsinPDR,especiallytotrytoclearvitreoushaemorrhage,butalsotolimitsideeffectsofPRPregarding
theoccurrenceofdiabeticmacularoedemainpatientsatrisk.Moreover,antiVEGFtherapyissometimes
usedinpreparationofvitrectomywhichincludesuseofanendolaserinadvancedPDR.However,useof
antiVEGFinPDRmayhaveadverseeffectsandrequiresmultipletreatments.OtherCochraneReviews
comparetheeffectivenessofantiVEGFandlasertreatmentforPDR(MartinezZapata2014),anddiabetic
macularoedema(Virgili2012).

Qualityoftheevidence

GoTo
OverallthereisnotalargeamountofevidencefromRCTsontheeffectsoflaserphotocoagulationcompared
tonotreatmentordeferredtreatment.TheevidenceisdominatedbytwolargestudiesconductedintheUS
population(DRS1978ETDRS1991).Thesetwostudiesweregenerallyjudgedtobeatloworunclearriskof

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bias,withtheexceptionofinevitableunmaskingofpatientsduetodifferencesbetweeninterventionand
control.
Fourofthestudieswerewithinperson(i.e.pairmatched),butnoneofthestudiesreportedtheresultstaking
intoaccountthematching.Thismeansthattheresultswillbeconservative(confidenceintervalswiderthanif
matchinghadbeentakenintoaccount).Onestudyreportedthattheyhadrepeatedtheanalysestakinginto
accountthepairmatchingandthatignoringthepairmatchingwasindeedaconservativeapproach(ETDRS
1991).
Overallwejudgedthequalityoftheevidencetobemoderateorlow(Summaryoffindingsforthemain
comparison),reflectingthefactthatthestudiescontributingtothereviewwereconductedsometimeago,
whenstandardsoftrialconductandreportingwerelowerheterogeneitywasalsopresent.

Potentialbiasesinthereviewprocess
WefollowedstandardmethodsexpectedbytheCochraneCollaboration.Allchangesfromprotocolare
documentedinDifferencesbetweenprotocolandreview.

Agreementsanddisagreementswithotherstudiesorreviews
Incurrentclinicalguidelines,e.g.RCOphth2012,PRPisrecommendedinhighriskPDR.The
recommendationisthat "asretinopathyapproachestheproliferativestage,laserscattertreatment(PRP)
shouldbeincreasinglyconsideredtopreventprogressiontohighriskPDR" basedonotherfactorssuchas
patients'complianceorplannedcataractsurgery.
Theserecommendationsneedtobeinterpretedwhileconsideringtheriskofvisuallossassociatedwith
differentlevelsofseverityofDR,aswellastheriskofprogression.SincePRPreducestheriskofsevere
visualloss,butnotmoderatevisuallossthatismorerelatedtodiabeticmaculopathy,mostophthalmologists
judgethatthereislittlebenefitintreatingnonproliferativeDRatlowriskofseverevisualdamage,aspatients
wouldincurtheknownadverseeffectsofPRP,which,althoughmild,includepainandperipheralvisualfield
lossandtransientDMO.Theresultsofthisreviewwouldconfirmthisapproach.

Authors'conclusions

Implicationsforpractice

Thisreviewprovidesevidencethatlaserphotocoagulationisbeneficialintreatingdiabetic
retinopathy.Therewasnotenoughevidencetojudgewhethertheeffectoftreatmentisdifferent
innonproliferativeandPDR,butbasedonthebaselineriskofprogressionofthedisease,and
riskofvisualloss,thecurrentapproachofcautionintreatingnonproliferativeDRwithlaserwould
appeartobejustified.

Bycurrentstandardsthequalityoftheevidenceisnothigh,however,theeffectsonriskof
progressionandriskofseverevisuallossarereasonablylarge(50%relativeriskreduction).

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Implicationsforresearch

FutureCochraneReviewswillexaminespecificquestionsregardingthetreatmentprotocolfor
laserphotocoagulation.

Futuretrialsonlaserphotocoagulationshouldfocusonthecombinationwith,andcomparisonto,
newerinterventions,suchasantivascularendothelialgrowthfactor(antiVEGF)treatment.

Acknowledgements
TheCochraneEyesandVisionGroup(CEVG)createdandexecutedtheelectronicsearchstrategies.We
thankCateyBunce,ChristianFau,NoemiLoisandRichardWormaldfortheircommentsontheprotocoland
DavidYorston,AndrewEldersandChristianFaufortheircommentsonthereview.WethankAnupaShah,the
ManagingEditor,forherassistancethroughoutthereviewprocess.

Dataandanalyses
Downloadstatisticaldata
Comparison1.Laserphotocoagulationversuscontrol

No.of No.of
Outcomeorsubgrouptitle Statisticalmethod Effectsize
studies participants

1Lossof15ormorelettersBCVAat12 2 8926 RiskRatio(MH,Fixed,95% 0.99[0.89,

months CI) 1.11]

2Lossof15ormorelettersBCVAat2 2 8306 RiskRatio(MH,Fixed,95% 0.88[0.80,

years CI) 0.97]

3Lossof15ormorelettersBCVAat3 2 7458 RiskRatio(MH,Fixed,95% 1.07[0.93,

years CI) 1.23]

4Severevisualloss(BCVA<6/60) 4 9276 RiskRatio(MH,Random, 0.46[0.24,

95%CI) 0.86]

5Progressionofdiabeticretinopathy 4 8331 RiskRatio(MH,Random, 0.49[0.37,

95%CI) 0.64]

6Vitreoushaemorrhage 2 224 RiskRatio(MH,Fixed,95% 0.56[0.37,

CI) 0.85]

GoTo
Appendices

Appendix1.CENTRALsearchstrategy
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#1MeSHdescriptor:[DiabeticRetinopathy]explodealltrees
#2diabet*near/3retinopath*
#3proliferat*near/3retinopath*
#4diabet*near/3maculopath*
#5neovasculari?ation
#6#1or#2or#3or#4or#5
#7MeSHdescriptor:[LightCoagulation]explodealltrees
#8photocoagulat*
#9photonextcoagulat*
#10(focalorgrid)near/3laser*
#11coagulat*orargonorkryptonorYAGordiodeormicropulseorpanretinal
#12#7or#8or#9or#10or#11
#13#6and#12

Appendix2.MEDLINE(OvidSP)searchstrategy
1.randomizedcontrolledtrial.pt.
2.(randomizedorrandomised).ab,ti.
3.placebo.ab,ti.
4.dt.fs.
5.randomly.ab,ti.
6.trial.ab,ti.
7.groups.ab,ti.
8.or/17
9.expanimals/
10.exphumans/
11.9not(9and10)
12.8not11
13.expdiabeticretinopathy/
14.(diabet$adj3retinopath$).tw.
15.(proliferat$adj3retinopath$).tw.
16.(diabet$adj3maculopath$).tw.
17.neovasculari?ation.tw.
18.or/1317
19.explightcoagulation/
20.photocoagulat$.tw.
21.(photoadj1coagulat$).tw.
22.((focalorgrid)adj3laser$).tw.
23.(coagulat$orargonorkryptonorYAGordiodeormicropulseorpanretinal).tw.
24.or/1923
25.18and24
26.12and25
ThesearchfilterfortrialsatthebeginningoftheMEDLINEstrategyisfromthepublishedpaperbyGlanvilleet
GoTo

al(Glanville2006).

Appendix3.EMBASE(OvidSP)searchstrategy
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1.exprandomizedcontrolledtrial/
2.exprandomization/
3.expdoubleblindprocedure/
4.expsingleblindprocedure/
5.random$.tw.
6.or/15
7.(animaloranimalexperiment).sh.
8.human.sh.
9.7and8
10.7not9
11.6not10
12.expclinicaltrial/
13.(clin$adj3trial$).tw.
14.((singl$ordoubl$ortrebl$ortripl$)adj3(blind$ormask$)).tw.
15.expplacebo/
16.placebo$.tw.
17.random$.tw.
18.expexperimentaldesign/
19.expcrossoverprocedure/
20.expcontrolgroup/
21.explatinsquaredesign/
22.or/1221
23.22not10
24.23not11
25.expcomparativestudy/
26.expevaluation/
27.expprospectivestudy/
28.(control$orprospectiv$orvolunteer$).tw.
29.or/2528
30.29not10
31.30not(11or23)
32.11or24or31
33.expdiabeticretinopathy/
34.(diabet$adj3retinopath$).tw.
35.(proliferat$adj3retinopath$).tw.
36.(diabet$adj3maculopath$).tw.
37.neovasculari?ation.tw.
38.or/3337
39.explasercoagulation/
40.argonlaser/
41.photocoagulat$.tw.
42.(photoadj1coagulat$).tw.
43.((focalorgrid)adj3laser$).tw. GoTo

44.(coagulat$orargonorkryptonorYAGordiodeormicropulseorpanretinal).tw.
45.or/3944

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46.38and45
47.32and46

Appendix4. meta RegisterofControlledTrialssearchstrategy

diabeticretinopathyAND(laserORphotocoagulationORcoagulationORargonORkryptonORYAGOR
diodemicropulseORpanretinal)

Appendix5.ClinicalTrials.govsearchstrategy
diabeticretinopathyAND(laserORphotocoagulationORcoagulationORargonORkryptonORYAGOR
diodemicropulseORpanretinal)

Appendix6.ICTRPsearchstrategy
diabeticretinopathy=ConditionANDlaserORphotocoagulationORcoagulationORargonORkryptonOR
YAGORdiodemicropulseORpanretinal=Intervention

Appendix7.Dataextractionsheetontrialcharacteristics

Tableheadingin Subheadingsfor Comment

RevMan2014 CEVGreviews

Methods Trialdesign ParallelgroupRCT(i.e.peoplerandomisedtotreatment)

PairedeyeorintraindividualRCT(i.e.eyesrandomisedtotreatment)
ClusterRCT(i.e.communitiesrandomisedtotreatment)
CrossoverRCT
Other,specify

Eyes Oneeyeincludedintrial
Specifyhoweyeselected
Botheyesincludedintrial,eyesreceivedsametreatment
Brieflyspecifyhowanalysed(best/worst/average/bothandadjustedforwithinperson
correlation/bothandnotadjustedforwithinpersoncorrelation)
Specifyifmixtureoneeyeandtwoeye
Botheyesincludedintrial,eyesreceiveddifferenttreatments(pairmatched)
Specifyifcorrectpairmatchedanalysisdone

Participants Country

Numberof
participants

%women GoTo

Averageage

Agerange

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Inclusioncriteria

Exclusioncriteria

Interventions Intervention Includingnumberofparticipantsrandomlyallocatedtoeach

Comparator

Outcomes List Outcomesreportedinmethodsandresults,identifyprimaryoutcomeifspecified

Notes Dateconducted Datesofrecruitmentofparticipantsmonth/yeartomonth/year

Sourcesof Ifreported
funding

Declarationof Ifreported
interest

What'snew

Date Event Description

7August2015 Amended EditsmadetotheSummaryoffindingstableandadditionalsourceofsupportadded

Contributionsofauthors
JEpreparedafirstdraftoftheprotocol,whichwasrevisedbyGV.
JEandMMscreenedsearchresultsandextracteddata.GVandMMreviewedandcommentedonvarious
draftsofthereview.

Declarationsofinterest
JE:noneknown
MM:noneknown
GV:noneknown

Sourcesofsupport
Internalsources
Nosourcesofsupportsupplied

GoTo

Externalsources

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ItalianMinistryofHealthandFondazioneRoma,Italy.
ThecontributionoftheIRCCSFondazioneBiettiinthispaperwassupportedbytheItalianMinistry
ofHealthandbyFondazioneRoma,Italy

NationalInstituteforHealthResearch(NIHR),UK.
RichardWormald,CoordinatingEditorfortheCochraneEyesandVisionGroup(CEVG)
acknowledgesfinancialsupportforhisCEVGresearchsessionsfromtheDepartmentof
HealththroughtheawardmadebytheNationalInstituteforHealthResearchtoMoorfields
EyeHospitalNHSFoundationTrustandUCLInstituteofOphthalmologyforaSpecialist
BiomedicalResearchCentreforOphthalmology.

TheNIHRalsofundstheCEVGEditorialBaseinLondon.

TheCochraneReviewIncentiveSchemeprovidedfundingforJenniferEvanstoassistwith
completionofthisreview.

Theviewsexpressedinthispublicationarethoseoftheauthorsandnotnecessarilythoseofthe
NIHR,NHS,ortheDepartmentofHealth.

Differencesbetweenprotocolandreview
Title
Ontherecommendationofaclinicalpeerreviewerwechangedthetitleofthisreviewfrom"laser
photocoagulationfordiabeticretinopathy"to"laserphotocoagulationforproliferativediabeticretinopathy".The
reviewerfeltthatcliniciansseeingthebroadertitlewouldexpecttoseediabeticmacularoedema(DMO)
includedinthisreviewbutthisisspecificallyexcludedasthereisaseparatereviewlookingatlaserforDMO
(Jorge2013).

Outcomes
Wechanged'distancecorrectednearvisualacuity'to'nearvisualacuity'.Wedidnotfindanydataonnear
visualacuity,eitherdistancecorrectedornot.
Wemovedtheoutcome'severevisualloss'outofadverseeffectsandfurtherupthelist,refectingtheuseof
thisoutcomegenerallyasameasureofeffectratherthananadverseeffectasoriginallydefinedinour
protocol.Weconsideredthisoutcomeatoneyearfollowupasfortheothereffectivenessoutcomes(andnot,
asoriginallyplanned,withinthreemonthsoftreatment).
Weremovedtheoutcome'secondarychoroidalneovascularisation'forfutureupdates.Thisoutcomeismore
ofaconcernaftertreatmentfordiabeticmacularoedema.Wedidnotfindanydataonthisoutcome.

Measuresofeffect
Weplannedtocalculatetheriskratiofordichotomousvariableswheretheeventriskwasgreaterthan10%,

GoTo
theoddsratiofordichotomousvariableswheretheeventriskwaslessthan10%andforveryrareevents
(lessthan1%)thePetooddsratio.Infactformostanalysestheeventriskinthecontrolgroupwasgreater
than,orapproximately,10%andwefeltthatitwouldbeconfusingtoreportanoddsratioforonlyone
outcome(severevisualloss)wheretheeventratewas4%.Wehavethereforeonlyusedtheriskratioasthe

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measureofeffectfordichotomousvariables.Thisdecisionhasnotaffectedtheconclusionsdrawn.Forthe
outcomeofseverevisuallossthereportedriskratiowas0.46(95%CI0.24to0.86)andthisissimilartothe
oddsratioof0.40(95%CI0.18to0.88).

Datasynthesis
Weplannedthat,incasesofsubstantialheterogeneity,forexampledifferencesindirectionofeffect,orwhere
theI 2 statisticwasgreaterthan50%andtheChi 2 statisticlessthan0.1,suchthatthepooledresultdidnot
summarizetheindividualtrialresultsadequately,wewouldnotprovideapooledestimate,unlessvisual
inspectionoftheforestplotindicateditmightbeappropriatetodoso(forexample,ifalleffectestimateswere
inthesamedirection).Foroneanalysis,Analysis1.1,theeffectestimateswerereasonablycloseto1andwe
reportapooledestimateeventhoughtheeffectestimateswerenotinthesamedirection.

Characteristicsofstudies
Characteristicsofincludedstudies[orderedbystudyID]

DRS1978

Methods WithinpersonRCTbotheyesincludedinstudy,eyesreceiveddifferenttreatments

Participants Country:USA
Numberofparticipants(eyes):867(1734)
%women:44%
Averageage(range):43years(1569)
Inclusioncriteria:
BCVA20/100orbetterineacheye

PDRinatleastoneeyeorseverenonproliferativeDRinbotheyes

Exclusioncriteria:
Unilateralaphakia

Oneorbothlensesremovedwithin3monthsofinitialvisit

Anticoagulanttherapythatcouldnotbediscontinuedduringtreatment

Highorlowbloodpressure

Myocardialinfarctionwithin6monthsofinitialvisit

Activetuberculosisorhistoryofhemoptysiswithin12monthsofinitialvisit

Interventions Intervention(n=867eyes)
argonlaser
GoTo

Comparator(n=867eyes)

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notreatment

Thistrialalsoconsideredxenonarclaserbutthishasnotbeenconsideredinthisreview

Outcomes Primaryoutcome:
visualacuity

Secondaryoutcomes:
visualfields

morphologicchangesintheretinaandvitreous

Followup:every4monthsfor5years

Notes Dateconducted:April1972September1975
Sourcesoffunding:NIH
Declarationofinterest:notreported

Riskofbias

Bias Authors' Supportforjudgement

judgement

Random Lowrisk "Oneeyeofeachpatientwasrandomlyassignedtoimmediatephotocoagulationand

sequence theothertofollowupwithouttreatment..." Page583,reportnumber8
generation
Furtherdetailsofsequencegenerationareonpage158ofreportnumber6
(selectionbias)

Allocation Lowrisk "Thesealedenvelopecontainingtheassignedtreatmentwasnottobeopenedinthe

concealment clinicuntilafinaldeterminationhadbeenmadeofthepatient'seligibilityandthepatient
(selectionbias) hadsignedtheconsentformatthesecondinitialvisit" Page158,reportnumber6

Blindingof Highrisk Patientsandpersonnelwillhaveknownwhicheyewastreated

participantsand
personnel
(performance
bias)
Visualacuity

Blindingof Lowrisk Wejudgeditunlikelythatpatientorcarerknowledgeoftreatmentassignmentwould

participantsand impactontheprogressionofdiabeticretinopathy
personnel
(performance
bias)
Progressionof
diabetic
retinopathy

GoTo
Blindingof Lowrisk "...measurementofbestcorrectedvisualacuitybyexaminerswhodidnotknowthe
outcome identifyofthetreatedeyeandwhoattemptedtoreducepatientbiasbyurgingthepatient
assessment toreadasfardownthechartaspossiblewitheacheye,guessingatlettersuntilmore
thanonelinewasmissed". Page584,reportnumber8

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(detectionbias)
Visualacuity

Blindingof Unclear
outcome risk
assessment
(detectionbias)
Progressionof
diabetic
retinopathy

Incomplete Lowrisk Attritioninpatientsbutnotinunitofanalysis(eyes)

outcomedata
(attritionbias)
Alloutcomes

Selective Unclear Noaccesstoprotocol

reporting risk
(reportingbias)

Otherbias Unclear
risk

ETDRS1991

Methods WithinpersonRCTbotheyesincludedinstudy,eyesreceiveddifferenttreatments

Participants Country:USA
Numberofparticipants(eyes):3711(7422)
%women:44%
Averageage48years(estimatedrange1870)
Inclusioncriteria:
aged1870years

DRinbotheyes

eacheyeeither:
nomacularoedema,visualacuity20/40orbetterandmoderateorseverenonproliferativeorearly
PDR,or

macularoedema,visualacuityof20/200orbetterandmild,moderateorseverenonproliferativeor
earlyPDR

Exclusioncriteria:

Interventions Intervention(n=3711eyes)
earlyargonlaser

GoTo
Comparator(n=3711eyes)
deferredargonlaser

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Fortheinterventiongroup,eyeswerealsorandomlyallocatedto'full'or'mild'PRP.Forthe
comparatorgroup,argonlaserwasappliedifhighriskPDRwasdetected

Outcomes Primaryoutcome:
developmentofseverevisuallosswhichwasdefinedasvisualacuity<5/200attwoconsecutive
followupvisits.Followupvisitswere4monthsapart.VisualacuitywasmeasuredusinganETDRS
chartatadistanceof4metresandat1metreifvisualacuity<20/100

Secondaryoutcomes:
visualfields

colourvision

severityofretinopathyandmacularoedema

Followup:every4monthsforanunknownnumberofyears

Notes Dateconducted:April1980toJune1985
Sourcesoffunding:NEI
Declarationofinterest:notreported

Riskofbias

Bias Authors' Supportforjudgement

judgement

Random Unclear "Therandomizationschedulesweredesignedtoprovidebalancein:...thenumberof

sequence risk rightandlefteyesassignedtoearlyphotocoagulation". Page746,reportnumber7
generation
(selectionbias)

Allocation Lowrisk "Attherandomizationvisit,theClinicalCenterophthalmologistandstaffreviewedthe

concealment patient's...eligibility...ThesealedmailerfromtheCoordinatingCentercontainingthe
(selectionbias) descriptionofthephotocoagulationstrategy...wasthenopened." Page746,report
number7

Blindingof Highrisk Treatmentswerequitedifferentandpatients'perceptionoftreatmentmaywellhave

participantsand affectedassessmentofvisualacuity
personnel
(performance
bias)
Visualacuity

Blindingof Lowrisk Wejudgeditunlikelythatpatientorcarerknowledgeoftreatmentassignmentwould

participantsand impactontheprogressionofdiabeticretinopathy
personnel
(performance
bias)
Progressionof GoTo

diabetic
retinopathy

Blindingof Unclear "Theprotocolspecifiedthatvisualacuityexaminersbetrainedandcertified,thatthey

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outcome risk bemaskedfromtreatmentassignmentthattheyfollowstandardproceduresfor

assessment encouragingpatientstomakethemaximumefforttoreadasmanylettersaspossible
(detectionbias) witheacheye". Page747,reportnumber7
Visualacuity

Blindingof Unclear "FundusPhotographReadingCenterstaff,withoutknowledgeoftreatment

outcome risk assignmentsandclinicaldata,followedastandardizedproceduretogradefundus
assessment photographsandfluoresceinangiogramsforindividuallesionsofdiabeticretinopathy "
(detectionbias) Page748,reportnumber7
Progressionof
diabetic
retinopathy

Incomplete Lowrisk Attritioninpatientsbutnotinunitofanalysis(eyes)

outcomedata
(attritionbias)
Alloutcomes

Selective Unclear Noaccesstoprotocol

reporting risk
(reportingbias)

Otherbias Unclear
risk

Hercules1977

Methods WithinpersonRCTbotheyesincludedinstudy,eyesreceiveddifferenttreatments

Participants Country:UK
Numberofparticipants(eyes):94(188eyes)
%women:40%
Averageage(range):41years(1865)
Inclusioncriteria:
botheyesofparticipantweresimilarlyaffectedbyaproliferativediabeticprocess
involvingtheopticdisc

observablefeaturesoftheretinopathyhadtobewithinthesamegradewheneach
eyewasclassified

visualacuityatinitialassessmentdidnotdifferbymorethantwolinesontheSnellen
chartandwasatleast6/24intheworseeye

Exclusioncriteria:
70yearsorolder

lifeexpectancywaspossiblytooshortforsubsequentassessments

previouspituitaryablation

GoTo
eithereyehadreceivedpreviousxenonarcphotocoagulation

presenceofintercurrentoculardisease

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visualacuitywasadverselyaffectedbyopacitiesofthemediaandvisualpathways,
makingretinalphotographyandtreatmentunsatisfactory

proliferationintheretinahadreachedthelatecicatricialstagewithlocalisedtraction
detachment

Interventions Intervention(n=94)
argonlaser

Comparator(n=94)
notreatment

Outcomes Outcomes:
visualacuity:BCVA

appearanceoftheopticdiscs6monthsaftertreatmentandyearlyfromthatpoint
(colourphotographsandfluoresceinangiograms)

vitreoushaemorrhageandothercomplicationsincludinguveitis,glaucoma,and
retinaldetachment

blindness:PDRand/orvitreoushaemorrhageinvolvingreductioninvisualacuityto
lessthan6/60ontheSnellenchartonatleasttwoconsecutivevisits

Followup:6months

Notes Dateconducted:notreportedbuttrial'initiated'in1973
Sourcesoffunding:notreported
Declarationofinterest:notreported

Riskofbias

Bias Authors' Supportforjudgement

judgement

Randomsequencegeneration Unclear Notreported

(selectionbias) risk

Allocationconcealment Lowrisk Notmentioned,butunlikelytobeaprobleminawithinpersonstudy

(selectionbias)

Blindingofparticipantsand Highrisk Treatmentsarequitedifferentandpatients'perceptionoftreatmentmay

personnel(performancebias) wellaffectassessmentofvisualacuity
Visualacuity

GoTo
Blindingofparticipantsand Unclear
personnel(performancebias) risk
Progressionofdiabetic
retinopathy
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Blindingofoutcome Lowrisk "...bestcorrectedvisualacuitieswereobtainedateachvisit,on

assessment(detectionbias) subjective
Visualacuity testing,byarefractionistwhowasnotawareofthepreviousvisualacuity
northetreatedeye" Page557

Blindingofoutcome Unclear
assessment(detectionbias) risk
Progressionofdiabetic
retinopathy

Incompleteoutcomedata Highrisk "Eightpatientssubsequentlyreceivingtreatmenttothe'control'eye

(attritionbias) wereremovedfromthestudyatthatpoint." Page556
Alloutcomes

Selectivereporting(reporting Unclear Noaccesstoprotocol

bias) risk

Otherbias Unclear
risk

Sato2012

Methods ParallelgroupRCT.Oneeyeperpersonenrolledunclearhoweyeselected

Participants Country:Japan
Numberofparticipants(eyes):69(69)
%women:25%
Averageage:60years
Inclusioncriteria:
preproliferativediabeticretinopathy

nopreviousphotocoagulation

multiplenonperfusionareaslargerthanonediscareaonfluoresceinangiographyimages

Exclusioncriteria:
clearfluoresceinangiographyimagescouldnotbeobtainedduetoopaquemedia

fluoresceinangiographycouldnotbeperformed(e.g.duetoallergy)

pasthistoryofintraocularsurgery(exceptif3ormoreyearsaftercataractsurgery)

PRPindicated

Interventions Intervention(n=32)
selectivephotocoagulationofnonperfusionareas

GoTo

Comparator(n=37)
deferredpanretinallaserphotocoagulation

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Forthecomparatorgroup: "WheneverPDRdeveloped,PRPwasperformed.ThedevelopmentofPDR
wasdefinedasthedetectionofanyofthefollowing:neovascularizationdetectedbyophthalmoscopeor
FAandpreretinalhemorrhageorvitreoushemorrhage.Therefore,inthisstudy,PDRincludesnotonly
highriskPDRbutalsoearlyPDRasdescribedbytheEarlyTreatmentDiabeticRetinopathyStudy
ResearchGroup(ETDRS)" Page53
Inbothinterventionandcomparatorgroups: "...photocoagulationformacularedemawaspermitted
whentheophthalmologistinchargeofthisstudyconsidereditnecessary" .Page53/54

Outcomes Primaryoutcome:
developmentofproliferativediabeticretinopathy

Secondaryoutcomes:
highriskPDR

severevisualloss(BCVA<0.025)

vitreoushaemorrhage

Followup:3years

Notes Dateconducted:February2004December2008
Sourcesoffunding: "ThisstudywassupportedbyaGrantinAidforScientificResearchC(no.
17591856),2005,fromtheJapanSocietyforthePromotionofScience.Thefollowingauthorshave
indicatedthattheyhavereceivedgrantsfromtheJapaneseGovernment:SadaoHoriandNaohito
Yamaguchi." Page59
Declarationofinterest:notreported

Riskofbias

Bias Authors' Supportforjudgement

judgement

Random Lowrisk "PatientdataandFAimagesinthosepatientsconsideredtobeappropriatesubjectsbythe

sequence ophthalmologistsinchargeofthisstudyateachinstitutionweresenttotheDataCenterin
generation theDepartmentofPublicHealth,TokyoWomensMedicalUniversity.AttheDataCenter,a
(selection designatedophthalmologistconfirmedwhethereachpatientsdataandFAimageswere
bias) appropriate.Afterconfirmation,thepatientswererandomlyassignedtoeitherthe
nonphotocoagulationgroup(nonPCgroup)ortothephotocoagulationgroup(PCgroup)
usingrandomnumbertables,andtheophthalmologistsinchargeofthisstudywere
informedofthegroupsintowhichtheirpatientshadbeenrandomized." Page53

Allocation Lowrisk "PatientdataandFAimagesinthosepatientsconsideredtobeappropriatesubjectsbythe

concealment ophthalmologistsinchargeofthisstudyateachinstitutionweresenttotheDataCenterin
(selection theDepartmentofPublicHealth,TokyoWomensMedicalUniversity.AttheDataCenter,a
bias) designatedophthalmologistconfirmedwhethereachpatientsdataandFAimageswere
appropriate.Afterconfirmation,thepatientswererandomlyassignedtoeitherthe
nonphotocoagulationgroup(nonPCgroup)ortothephotocoagulationgroup(PCgroup) GoTo
usingrandomnumbertables,andtheophthalmologistsinchargeofthisstudywere
informedofthegroupsintowhichtheirpatientshadbeenrandomized." Page53

Blindingof Highrisk Notreportedandtreatmentsdifferent

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participants
and
personnel
(performance
bias)
Visualacuity

Blindingof Lowrisk Wejudgeditunlikelythatpatientorcarerknowledgeoftreatmentassignmentwouldimpact

participants ontheprogressionofdiabeticretinopathy
and
personnel
(performance
bias)
Progression
ofdiabetic
retinopathy

Blindingof Highrisk Notreportedandtreatmentsdifferent

outcome
assessment
(detection
bias)
Visualacuity

Blindingof Highrisk Notreportedandtreatmentsdifferent

outcome
assessment
(detection
bias)
Progression
ofdiabetic
retinopathy

Incomplete Highrisk "WhenwediscontinuedthestudyinDecember2009,thecoursesof17patients(8inthe

outcome nonPCgroupand9inthePCgroup)hadnotyetbeenobservedforthewhole36months,
data(attrition althoughthesepatientscouldpotentiallycontinuetobeobservedforthe36months.Ofthe
bias)
69patients,36(23inthenonPCgroupand13inthePCgroup)completedthe36month
Alloutcomes
followupinDecember2009.Another16patients(6inthenonPCgroupand10inthePC
group)haddroppedoutofthestudyforthefollowingreasons:10stoppedcomingtothe
hospital,3switchedhospitals,1developedseverevisuallossduetocentralretinalartery
occlusion,1died,and1developedanallergytofluorescein.Asthenumberofpatientswho
droppedoutofthestudywassomewhatlargerinthePCthaninthenonPCgroup,we
conductedtheanalysisusingtheintenttotreatmethodinall69patients,aswellasthe
treatmentmethodin36patients". Page54
Outcomesofrelevancetothisreviewwerelargelyreportedonthe36patientsfollowedup
tothreeyears.DevelopmentofPDRwasreportedinall69patientsaswell.

Selective Unclear Noaccesstoprotocol

reporting risk
(reporting
bias)

Otherbias Highrisk
"ThestudywasdiscontinuedinDecember2009.AnanalysisperformedinOctober2009 GoTo
revealedasignificantlyhigherincidenceofPDRinthenonPCgroup.Thus,theData
MonitoringCommitteesuggestedthatcontinuingthestudywithoutprovidingtheresultsto
thepublicwouldbeamajordisadvantagetothepatientsrandomizedtothenonPC
group." Page54

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Yassur1980

Methods WithinpersonRCTbotheyesincludedinstudy,eyesreceiveddifferenttreatments

Participants Country:USA
Numberofparticipants(eyes):45(90)
%women:48%
Averageage(range):notreported(1672)
Inclusioncriteria:notreportedbutparticipantshad"neovascularisationofthedisc"i.e.PDR
Exclusioncriteria:notreported

Interventions Intervention(n=45)
argonlaser

Comparator(n=45)
notreatment

Outcomes Primaryoutcome:
newproliferationonthedisc

Followup:4years

Notes Dateconducted:19731974
Sourcesoffunding:notreported
Declarationofinterest:notreported

Riskofbias

Bias Authors' Supportforjudgement

judgement

Randomsequence Unclear "...onlyoneeyewasrandomlyassignedtotreatment" Page78

generation risk
(selectionbias)

Allocation Lowrisk Notmentioned,butunlikelytobeaprobleminawithinpersonstudy

concealment
(selectionbias)

Blindingof Unclear
participantsand risk GoTo
personnel

(performancebias)
Visualacuity

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Blindingof Lowrisk Wejudgeditunlikelythatpatientorcarerknowledgeoftreatmentassignmentwould

participantsand impactontheprogressionofdiabeticretinopathy
personnel
(performancebias)
Progressionof
diabeticretinopathy

Blindingofoutcome Unclear
assessment risk
(detectionbias)
Visualacuity

Blindingofoutcome Highrisk Maskingnotmentionedandtreatmentsquitedifferent

assessment
(detectionbias)
Progressionof
diabeticretinopathy

Incompleteoutcome Highrisk "Initiallywereviewedtherecordsof83consecutivepatientsassignedfora4year

data(attritionbias) followup,but16patientsdroppedoutatvariousstagesbecauseofdeath,
Alloutcomes inadequatefollowup,orbecausethe'control'eyewasalsotreated." Page78

Selectivereporting Unclear Noaccesstoprotocol

(reportingbias) risk

Otherbias Unclear
risk

BCVA:bestcorrectedvisualacuity
DR:diabeticretinopathy
ETDRS:EarlyTreatmentDiabeticRetinopathyStudyResearchGroup
FA:fluoresceinangiography
NEI:NationalEyeInstitute
NIH:NationalinstitutesforHealh
PDR:proliferativediabeticretinopathy
PRP:panretinalphotocoagulation
a AbbreviationsRCT:randomisedcontrolledtrial

Characteristicsofexcludedstudies[orderedbystudyID]

Study Reasonforexclusion

AlHussainy2008 Nountreatedordeferredlasercontrolgroup

GoTo
Atmaca1995 Nountreatedordeferredlasercontrolgroup

Bandello1993 Nountreatedordeferredlasercontrolgroup

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Bandello1996 Nountreatedordeferredlasercontrolgroup

Bandello2001 Nountreatedordeferredlasercontrolgroup

Bandello2012 NotanRCT

Beetham1969 Lasernolongerinuse

BirchCox1978 NotRCT

Blankenship1987 Nountreatedordeferredlasercontrolgroup

Blankenship1989 Nountreatedordeferredlasercontrolgroup

Brancato1990 Nountreatedordeferredlasercontrolgroup

Brancato1991 Nountreatedordeferredlasercontrolgroup

BritishMulticentreStudyGroup1975 Lasernolongerinuse

Buckley1992 Nountreatedordeferredlasercontrolgroup

Canning1991 Nountreatedordeferredlasercontrolgroup

Capoferri1990 Nountreatedordeferredlasercontrolgroup

Chaine1986 Nountreatedordeferredlasercontrolgroup

Chen2013 Nountreatedordeferredlasercontrolgroup

Crick1978 Nountreatedordeferredlasercontrolgroup

Doft1982 Nountreatedordeferredlasercontrolgroup

Doft1992 Nountreatedordeferredlasercontrolgroup

Dong1997 NotanRCT

Elsner2005 Nountreatedordeferredlasercontrolgroup

Emi2009 NotanRCT

Fankhauser1972a Nountreatedordeferredlasercontrolgroup

Fankhauser1972b Nountreatedordeferredlasercontrolgroup

Francois1977 Nountreatedordeferredlasercontrolgroup

Gerke1985 Nountreatedordeferredlasercontrolgroup

GoTo
Haas1999 Nountreatedordeferredlasercontrolgroup

Hamilton1981 Nountreatedordeferredlasercontrolgroup

Ivanisevic1992 Nountreatedordeferredlasercontrolgroup
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Ivanisevic1992 Nountreatedordeferredlasercontrolgroup

KARNS1988 Nountreatedordeferredlasercontrolgroup

Khosla1994 Nountreatedordeferredlasercontrolgroup

Klemen1985 Nountreatedordeferredlasercontrolgroup

Kovacic2007 Nountreatedordeferredlasercontrolgroup

Kovacic2012 Nountreatedordeferredlasercontrolgroup

Li1986 Nountreatedordeferredlasercontrolgroup

Liang1983 Nountreatedordeferredlasercontrolgroup

Lim2009 NotanRCT

Lopez2008 Nountreatedordeferredlasercontrolgroup

MAPASS2010 Nountreatedordeferredlasercontrolgroup

McLean1972 Unabletolocatereference

Menchini1990 Nountreatedordeferredlasercontrolgroup

Menchini1995 Nountreatedordeferredlasercontrolgroup

MirkiewiczSieradzka1988 NotanRCT

Mirshahi2013 Nountreatedordeferredlasercontrolgroup

Misra2013 NotanRCT

Mody1983 Nountreatedordeferredlasercontrolgroup

Muraly2011 Nountreatedordeferredlasercontrolgroup

Nagpal2010 Nountreatedordeferredlasercontrolgroup

NeiraZalentein2011 NotanRCT

Okuyama1995 Nountreatedordeferredlasercontrolgroup

Pahor1998 Nountreatedordeferredlasercontrolgroup

Pahor1999 NotanRCT

Peng2013 Nountreatedordeferredlasercontrolgroup

GoTo
Perez2008 Nountreatedordeferredlasercontrolgroup

PETERPANStudy2013 Nountreatedordeferredlasercontrolgroup

Plumb1982 Nountreatedordeferredlasercontrolgroup
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Plumb1982 Nountreatedordeferredlasercontrolgroup

Salman2011 Nountreatedordeferredlasercontrolgroup

Schiodte1983 Nountreatedordeferredlasercontrolgroup

Seiberth1986 NotanRCT

Seiberth1987 NotanRCT

Seiberth1993 Nountreatedordeferredlasercontrolgroup

Seymenoglu2013 Nountreatedordeferredlasercontrolgroup

Shimura2003 Nountreatedordeferredlasercontrolgroup

Shimura2009 NotanRCT

Stanga2010 Nountreatedordeferredlasercontrolgroup

Tewari2000 Nountreatedordeferredlasercontrolgroup

Theodossiadis1990 Nountreatedordeferredlasercontrolgroup

Townsend1980 Lasernolongerinuse

Uehara1993 Nountreatedordeferredlasercontrolgroup

VeraRodriguez2008 Nountreatedordeferredlasercontrolgroup

Wade1990 Nountreatedordeferredlasercontrolgroup

Wiznia1985 NotanRCT

Wroblewski1991 Nountreatedordeferredlasercontrolgroup

Wroblewski1992 Nountreatedordeferredlasercontrolgroup

Zaluski1986 Nountreatedordeferredlasercontrolgroup

a AbbreviationRCT:randomisedcontrolledtrial

Characteristicsofstudiesawaitingassessment[orderedbystudyID]

Francois1971

Methods

GoTo
Participants

Interventions

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Outcomes

Notes Currentlyunabletosourceacopyofthearticle

Gaudric1987

Methods

Participants

Interventions

Outcomes

Notes Currentlyunabletosourceacopyofthearticle

Guo2014

Methods

Participants

Interventions

Outcomes

Notes Awaitingatranslationofthereportofthestudy

Kaluzny1985

Methods

Participants

Interventions

Outcomes

Notes Awaitingatranslationofthereportofthestudy

Krill1971

Methods

Participants
GoTo

Interventions

Outcomes
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Notes Currentlyunabletosourceacopyofthearticle

Leuenberger1975

Methods

Participants

Interventions

Outcomes

Notes Currentlyunabletosourceacopyofthearticle

Li1987

Methods

Participants

Interventions

Outcomes

Notes Awaitingatranslationofthereportofthestudy

Lund1971

Methods

Participants

Interventions

Outcomes

Notes Awaitingatranslationofthereportofthestudy

Mella1976

Methods

Participants

GoTo
Interventions

Outcomes

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Notes Awaitingatranslationofthereportofthestudy

Mirzabekova2004

Methods

Participants

Interventions

Outcomes

Notes Awaitingatranslationofthereportofthestudy

Okun1968

Methods

Participants

Interventions

Outcomes

Notes Currentlyunabletosourceacopyofthearticle

Pahor1997

Methods

Participants

Interventions

Outcomes

Notes Awaitingatranslationofthereportofthestudy

Palacz1988

Methods

Participants

Interventions GoTo

Outcomes

Notes Awaitingatranslationofthereportofthestudy

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