Immunosuppres- sants for the prophylaxis of corneal graft rejection after penetratin

39 Pages·2017·0.88 MB·English

CochraneDatabaseofSystematicReviews
Immunosuppressants for the prophylaxis of corneal graft
rejection after penetrating keratoplasty (Review)
AbudouM,WuT,EvansJR,ChenX
AbudouM,WuT,EvansJR,ChenX.
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty.
CochraneDatabaseofSystematicReviews2015,Issue8.Art.No.:CD007603.
DOI:10.1002/14651858.CD007603.pub2.
www.cochranelibrary.com
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review)
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 36
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) i
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Immunosuppressants for the prophylaxis of corneal graft
rejection after penetrating keratoplasty
MinawaerAbudou1,TaixiangWu2,JenniferREvans3,XueyiChen4
1TheEyeDepartmentoftheFirstAffiliatedHospital,XinjiangMedicalUniversity,Xinjiang,China.2ChineseClinicalTrialRegistry,
ChineseEthicsCommitteeofRegisteringClinicalTrials,WestChinaHospital,SichuanUniversity,Chengdu,China.3CochraneEyes
andVisionGroup,ICEH,LondonSchoolofHygiene&TropicalMedicine,London,UK.4EyeDepartment,FirstAffiliatedHospital
ofXinjiangMedicalUniversity,Xinjiang,China
Contact address: Xueyi Chen, Eye Department, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China.
[email protected].
Editorialgroup:CochraneEyesandVisionGroup.
Publicationstatusanddate:New,publishedinIssue8,2015.
Reviewcontentassessedasup-to-date: 18May2015.
Citation: AbudouM,WuT,EvansJR,ChenX.Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetrating
keratoplasty.CochraneDatabaseofSystematicReviews2015,Issue8.Art.No.:CD007603.DOI:10.1002/14651858.CD007603.pub2.
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Penetratingkeratoplastyisacornealtransplantation procedureinwhichafull-thicknesscorneafromthehostisreplacedbyagraft
fromadonor.Theuseofvariousimmunosuppressantstopreventgraftrejection,themostcommoncauseofgraftfailureinthelate
postoperativeperiod,isincreasing.
Objectives
Toassesstheeffectivenessofimmunosuppressantsintheprophylaxisofcornealallograftrejectionafterhigh-andnormal-riskkerato-
plasty.
Searchmethods
WesearchedCENTRAL(whichcontains theCochraneEyesandVision GroupTrialsRegister)(2015, Issue4),OvidMEDLINE,
OvidMEDLINE In-Processand OtherNon-Indexed Citations, OvidMEDLINE Daily,OvidOLDMEDLINE (January 1946 to
May2015),EMBASE(January1980toMay2015),ChinaNationalKnowledgeInfrastructure(CNKI)(January1913toFebruary
2015), VIPdatabase (January 1989 toFebruary 2015), Wanfang Data(www.wanfangdata.com)(January 1990 toFebruary 2015),
theISRCTNregistry(www.isrctn.com/editAdvancedSearch),ClinicalTrials.gov(www.clinicaltrials.gov),andtheWorldHealthOrga-
nization(WHO)InternationalClinicalTrialsRegistryPlatform(ICTRP)(www.who.int/ictrp/search/en).Wedidnotuseanydateor
language restrictions intheelectronicsearchesfortrials.WelastsearchedtheEnglishlanguage databases on18May 2015 andthe
Chineselanguagedatabaseson20February2015.
Selectioncriteria
We included allrandomised controlledtrials (RCTs) assessing theuse of immunosuppressants inthe prevention of graft rejection,
irrespectiveofpublicationlanguage.
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 1
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Datacollectionandanalysis
Weusedstandard proceduresexpectedbyCochrane. Theprimary outcome wascleargraftsurvival at12 monthsafterpenetrating
keratoplasty. Secondary outcomes included graft rejection, best-corrected visual acuity, and quality of life. We defined ’high-risk
keratoplasty’asrepeatkeratoplastyandotherindicationsofreducedgraftsurvival.
Mainresults
We included six studies conducted in Germany (three studies), Iran, India, and China. Three studies were conducted in people
undergoing high-risk keratoplasty and investigated threedifferentcomparisons: systemicmycophenolate mofetil (MMF) versusno
MMF;systemicMMFversussystemiccyclosporineA(CsA);andtopicalCsAversusplacebo.Onestudycomparedtopicaltacrolimus
totopicalsteroidinpeoplewithnormal-riskkeratoplasty,andtwostudiescomparedtopicalCsAtoplaceboinpeopleexperiencing
graftrejectionafternormal-riskkeratoplasty.Overall,weconsideredthetrialstobeatunclearorhighriskofbias.
MMFmaynotimprovecleargraftsurvival(riskratio(RR)1.06,95%confidenceinterval(CI)0.84to1.33,1RCT,87participants,
low-qualityevidence)butmayreducetheriskofgraftrejection(RR0.49,95%CI0.22to1.08,1RCT,87participants,low-quality
evidence)comparedtonoMMF.Visualacuitywasnotreported.
In1studyof52peoplecomparingsystemicMMFandsystemicCsA,therewerenograftfailuresinthefirstyearoffollow-up.Data
fromthelongestfollow-up(threeyears)suggestthattheremaybelittledifferenceintheeffectofthesetwotreatmentsoncleargraft
survival(RR1.10,95%CI0.90to1.35,low-qualityevidence).Therewaslow-qualityevidenceofanincreasedriskofgraftrejection
withsystemicMMFcomparedtosystemicCsA,butwithwideCIscompatiblewithincreasedriskwithsystemicCsA(RR1.48,95%
CI0.56to3.93,low-qualityevidence).Visualacuitywasnotreported.
Onestudyof84peoplecomparingtopicalCsAtoplacebodidnotreportcleargraftsurvivalat1year,whichsuggeststhatallgrafts
survivedto1year.ThisstudysuggeststhattheuseoftopicalCsAprobablyleadstolittleornodifferenceingraftrejection(RR1.00,
95%CI0.39to2.58,moderate-qualityevidence).Atoneyear,themeandifference(MD)betweenthetwogroupsinvisualacuitywas
0.07(95%CI-0.01to0.15,moderate-qualityevidence).
TopicalCsAprobablydoesnothaveaneffectoncleargraftsurvivalinpeopleexperiencinggraftrejectionafternormal-riskkeratoplasty
comparedtoplacebo(RR1.03,95%CI0.96to1.10,2RCTs,283participants,moderate-qualityevidence).Therewereinconsistent
findingsongraftrejection,withonestudyreportingareducedincidenceofgraftrejectionintheCsAgroup(RR0.35,95%CI0.14
to0.87,230participants)buttheotherstudyreportingahigheraveragenumberofepisodesofgraftrejectioninpeopletreatedwith
CsA(MD1.30, 95%CI0.39to2.21, 43participants). Overall,wejudgedthistobelow-quality evidenceduetoriskofbiasand
inconsistency.Therewasnoevidenceforadifferenceinvisualacuitybetweenthe2groupsatfinalfollow-up(approximately18months,
range2to33months)(MD0.04,95%CI-0.10to0.18,1RCT,43participants,low-qualityevidence).
In 1 study comparing topical tacrolimus to topical steroid, the graft survived in all of the 12 treated participants and 20 control
participantsat6months.Graftrejectionwasrare(0outof12versus2outof20)(RR0.32,95%CI0.02to6.21,low-qualityevidence).
Visualacuitywasnotreported.
Noneofthestudiesreportedonqualityoflife.Weidentifiedanunpublishedtrialofbasiliximab(Simulect)(NCT00409656),probably
completedin2005.
Authors’conclusions
Current evidence on the effectof immunosuppressants in the prevention of graft failure and rejection after high- and normal-risk
keratoplastyislargelylowqualitybecausethenumberoftrialswaslimited,and,ingeneral,thetrialsweresmallandatriskofbias.
Futuretrialsshouldbelargeenoughtodetectimportantclinicaleffects,conductedwithaviewtominimisingtheriskofbias,andthey
shouldmeasureoutcomesimportanttopatients.
PLAIN LANGUAGE SUMMARY
Immunosuppressantstopreventcornealgraftrejectionafterpenetratingkeratoplasty
Background
The cornea is the transparent front part of the eye that if damaged, can be replaced by a corneal transplant (keratoplasty) using
healthycorneatissue fromadonor. Apenetrating keratoplastyinvolves replacing allthe damaged cornea. It isnecessary toprevent
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 2
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
thetransplantedmaterial(graft)frombeingrejected.Thecurrentstrategiesforpreventinggraftrejectionaretopicalandoralsteroids.
TheuseofcyclosporineA(CsA),tacrolimus,mycophenolatemofetil(MMF),sirolimus,andleflunomideisincreasing.However,the
benefitsandadversereactionsoftheseimmunosuppressantshavenotyetbeensystematicallyreviewed.
Searchdate
TheevidenceisuptodatetoMay2015.
Keyfindings
Weincludedsixrandomisedcontrolledtrialsthatenrolledatotalof561people.ThetrialswereconductedinGermany(threetrials),
Iran,India,andChina.
Inpeoplewithhigh-riskkeratoplasty,one study comparedsystemicMMF withplacebo, one study comparedsystemicMMF with
systemicCsA,andonestudycomparedCsAeyedropsversusplacebo.
Inpeoplewith normal-riskkeratoplasty,one study comparedtacrolimuseyedropstosteroideyedrops,and twostudiescompared
CsAeyedropstoplaceboinpeopleexperiencingrejectionafterkeratoplasty.Allstudiesreportedcleargraftsurvival,incidenceofgraft
rejection,andadverseeffects.
Weareuncertainastotheeffectsofimmunosuppressantsinthepreventionofgraftfailureandrejectionafterhigh-andnormal-risk
keratoplasty,asthenumber of trialsislimited,and, ingeneral,thetrialsaresmallandatriskof bias. Future trialsshouldbe large
enoughtodetectimportantclinicaleffects,conductedwithaviewtominimisingtheriskofbias,andtheyshouldmeasureoutcomes
importanttopatients.
Studyfundingsources
Threeofthestudiesweresupportedbythepharmaceuticalindustry.
Qualityofevidence
Wejudgedthequalityoftheevidencetobelowtomoderate.Therewasriskofbiasintheincludedstudies;theresultsweresometimes
imprecisebecauseofthesmallnumberofstudiesandsmallnumberofpeopleenrolledinthesestudies;andinsomeanalysestheresults
ofindividualtrialswereinconsistent.
BACKGROUND riorsegmentsurgery,preoperativeglaucoma, quadrants of ante-
riorsynechiae,quadrantsofstromalvessels,aprimarydiagnosis
ofchemicalburn,andbloodgroupABOincompatibility.Insuch
Descriptionofthecondition cases,knownashigh-riskkeratoplasty,thegraftrejectionratemay
behigherthan60%(Maguire1994).
Penetratingkeratoplastyisacornealtransplantationprocedurein
whichafull-thicknesscorneafromthehostisreplacedbyagraft
fromadonor.Ithasbeenperformedinmanyeyediseases,includ-
Preventionofcornealallograftrejection
ingpseudophakiccornealoedema,keratoconus, aphakiccorneal
oedema, and stromal corneal dystrophies (Dobbins 2000; Liu Theeyehaspropertiesthatpermitthelong-termsurvivaloftissue
1997;Ramsay1997).Survivaloffirst-timegraftsis90%at5years graftsthatarenormallyrejectedatextraocularsites.Thisocular
and82%at10years,withreportedallograftrejectionratesfollow- immuneprivilegewasoriginally attributedtoaputativeseques-
ingpenetratingkeratoplasty rangingfrom5%to18%(Tabbara trationofantigensintheeyeasaresultoftheconspicuousabsence
2007).Initialregraftshavesignificantlylower5-and10-yearsur- of intraocular lymphatic drainage channels (Niederkorn 2003).
vivalrates,53%and41%,respectively(Thompson2003). However, arecent multivariate analysis suggests thereis no dif-
Theriskfactorsforgraftfailureafterkeratoplastyareyoungrecip- ferencebetweenthelong-termoutcomesofcornealtransplanta-
ientage,thenumberofpreviousgrafts,historyofpreviousante- tionandthoseofotherformsoftransplantation(Williams2006).
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 3
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Theanteriorsegmentoftheeyeisstillregardedasanimmune- rejection following high-risk corneal transplantation (Reinhard
privilegedsite because of theabsence of vascular andlymphatic 2005;Reis1999),butinferiortosystemictacrolimusinpreventing
supplytothecornea.Cell-mediatedimmunityincornealallograft graftrejection(Reis1998a).
rejectioncanresultfromtheactivationoflimbalLangerhanscells
and from T-cellsactivation by antigens releasedin the aqueous Sirolimus isa bacterial macrolide with both antifungal and im-
humoroftheanteriorchamber(Yamagami2005).Nevertheless, munosuppressiveproperties.Itiscommonlyusedinconjunction
theimmunologyofcornealtransplantationisnotfullyunderstood with CsA or tacrolimus after solid-organ transplantation. Simi-
(Perez 2013). Furthermore, corneal graft rejection remains the lartoMMF,sirolimusisfetotoxic,althoughnotteratogenic,and
mostcommoncauseofgraftfailureinthelatepostoperativepe- shouldbeusedwithcautionincornealtransplantationinpregnant
riod,andprophylaxisforallograftrejectionisneeded(Ing1998). women(Guerra2007).
Descriptionoftheintervention
Howtheinterventionmightwork
Avarietyofstrategiestopreventcornealallograftrejectionhave
Immunosuppressantspreventcornealgraftrejectionbyinhibiting
been explored and include the use of several immunosuppres-
theimmunityofthehost.Differentdrugshavedifferenttargets.
santsthroughvariousdeliverysystems;humanleukocyteantigens
ThemechanismofCsA prophylaxisofcorneal graftrejectionis
matching;andmanipulationofantigenexpression.Immunosup-
mainlybyselectivelyinhibitingcellularimmunity,whichprimar-
pressantsincludesteroids,cyclosporineA(CsA),tacrolimus,my-
ilyinhibitstheproliferationandactionofT-cells(Utine2010).
cophenolatemofetil(MMF),sirolimus,andleflunomide.Topical
MMF prevents the replication of T- and B-lymphocytesby in-
andoralsteroidsarecurrentlythegoldstandard forroutine use
hibitingthedenovopathwayofpurinesynthesis(Siconolfi1996).
inthepreventionofgraftrejection(Hill1991;Randleman2006;
Tacrolimus,acalcineurininhibitor,isamacrolideantibioticwith
Tabbara 2007), and the use of topical cyclosporine for routine
potentimmunosuppressive activity(Pillans2006).Steroidshave
managementofhigh-riskgraftsisincreasing(Randleman2006).
anantiproliferativefunction(Taylor2005).
CsA is afungal proteinthat has ahigh degree of specificity for
T-celllymphocytesandasacalcineurininhibitorpreventsT-cell-
mediatedimmuneresponses.ItisbelievedthatsystemicCsAsig-
nificantly increasestherateofgraftsurvival inhigh-riskcorneal Whyitisimportanttodothisreview
transplantation whenusedprophylacticallyfollowing transplan-
Immunosuppressants are widely used for the prophylaxis of
tation.However,thistherapyalsocarriessignificantrisks,includ-
corneal graft rejection after high- and normal-risk keratoplasty.
inghypertension,renaltoxicity,hepatotoxicity,neurotoxicity(Hill
However,thebenefitsandadversereactionsfromtheirusehave
1989; Hill 1994), and post-transplant lymphoproliferative dis-
notyetbeensystematicallyreviewed.
orders(Algros2002).Althoughevidence ontheeffectivenessof
topicallyadministeredCsAinthepreventionofgraftrejectionis
increasing(Belin1990),studieshaveyieldedinconsistentresults.
Forexample,investigatorsfoundthattheuseofacombinationof
topicalCsAandsteroidsisbetterthansteroidsaloneinpreventing
OBJECTIVES
episodesofrejection(Cosar2003;Inoue2000).However,other
investigatorsfoundthattopicalCsAdidnotdemonstrateanysig- Ourprimaryobjectivewastoassesstheeffectivenessofimmuno-
nificantimprovementinpreventingcornealgraftrejection(Price suppressantsintheprophylaxisofcornealallograftrejectionafter
2006;Shepherd1980). high-andnormal-riskkeratoplasty.
Tacrolimushasbeenshowntobeeffectiveinpreventingcorneal
allograftrejection(Reinhard2005;Sloper2001),causingalower
incidence ofside effectsrelatedtotoxicity or over immunosup-
METHODS
pressionatamuchlowerdosagethanCsA(Reis1998b).System-
aticadverseeffectssuchashypertensionandrenaltoxicitymaybe
encounteredwithoraltacrolimus(Sloper2001).
Criteriaforconsideringstudiesforthisreview
MMF is thought to be a safe and effective immunosuppressive
agent following renal transplantation due to less nephrotoxicity
(Guerra 2007; Land 2005), but is teratogenic and is unsafe for
Typesofstudies
useinpregnantwomen(Jackson2009;Klieger-Grossmann2010).
MMFhasbeenshowntobeaseffectiveasCsAinpreventingacute Weincludedrandomisedcontrolledtrials(RCTs)only.
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 4
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Typesofparticipants Searchmethodsforidentificationofstudies
We included people undergoing high- and normal-risk kerato-
plastyandevaluatedthemastwoseparategroups.Wedefinedthe
term’high-riskkeratoplasty’asrepeatkeratoplasty,graftposition Electronicsearches
closetothelimbus,presenceofthreeorfourquadrantswithdeep We searched CENTRAL (which contains the Cochrane Eyes
vascularisation,transplantationofahighlyimmunogenicgraft(for andVision GroupTrialsRegister)(2015, Issue4), OvidMED-
examplecentrallimbo-keratoplasty),severeatopicdermatitis,and LINE,OvidMEDLINEIn-ProcessandOtherNon-IndexedCi-
steroid-responseglaucoma. tations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (Jan-
uary 1946 to May 2015), EMBASE (January 1980 to May
2015), China National Knowledge Infrastructure (CNKI)(Jan-
Typesofinterventions uary 1913 to February 2015), VIP database (January 1989 to
February2015),WanfangData(www.wanfangdata.com)(January
Weincludedtrialsinwhichsystemicortopicalimmunosuppres-
1990toFebruary2015),theISRCTNregistry(www.isrctn.com/
sants such as CsA, tacrolimus, sirolimus, and MMF were com-
editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov),
paredtoplacebo,corticosteroids,orotherimmunosuppressants.
andtheWorldHealthOrganization(WHO)InternationalClini-
calTrialsRegistryPlatform(ICTRP)(www.who.int/ictrp/search/
en).Wedidnotuseanydateorlanguagerestrictionsintheelec-
Typesofoutcomemeasures tronic searchesfor trials. We lastsearchedthe English language
databaseson18May2015andtheChineselanguagedatabaseson
20February2015.
See: Appendices for details of search strategies for CENTRAL
Primaryoutcomes
(Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix
1. Cleargraftsurvival12monthsafterpenetrating 3),ChinaNationalKnowledgeInfrastructure(CNKI)(Appendix
keratoplasty. 4),VIPdatabase(Appendix5),WanfangData(Appendix6),IS-
RCTN (Appendix 7), ClinicalTrials.gov (Appendix 8), and the
ICTRP(Appendix9).
Secondaryoutcomes
1. Graftrejection12monthsafterpenetratingkeratoplasty. Searchingotherresources
Wedefinedrejectionasanyimmunereactionrequiringachange
Wesearchedreferencelistsofidentifiedtrialreportstofindaddi-
intherapy.
tionaltrials.WealsosearchedtheSocialScienceCitationIndexto
2. Best-correctedvisualacuity.
findstudiesthathadcitedtheidentifiedtrials.
3. Qualityoflifemeasuredusingavalidatedquestionnaire.
4. Cost-effectiveness.Thisincludesthecostofthedrugsand
otherpalliativemedications,theneedforbedrestor
Datacollectionandanalysis
hospitalisationversusoutpatientcare,andthelengthofhospital
stay.
5. Adverseeffects
i) Epithelialkeratitis Selectionofstudies
ii) Highintraocularpressureasdefinedbystudy Tworeviewauthors(MA,TXW)scannedthetitles,abstracts,and
investigators keywordsofeveryrecordretrievedtofindstudiesthatmetourin-
iii) Majorcalcineurin-inhibitortoxicity(e.g.new-onset clusioncriteria.Weretrievedfull-textcopiesofthestudiesforfur-
diabetesorrenalfailure) therassessmentiftheinformationgivensuggestedthatthestudies:
iv) Minorcalcineurin-inhibitortoxicity(e.g.tremor, 1. includedparticipantsafterpenetratingkeratoplasty;
gingivitis,orhirsutism) 2. comparedimmunosuppressantssuchasCsA,tacrolimus,
v) Dosereductionsduetoadverseevents andMMFwithcorticosteroidsonly;
vi) Withdrawalsanddropoutsduetoadverseevents 3. assessedoneormorerelevantclinicaloutcomemeasures;
Wemeasuredmostoutcomesduringa1-year,2-year,5-year,and 4. usedrandomallocationforthecomparisongroups.
10-year follow-up where possible. For those studies where the Afterreviewingthefulltext,weincludedonlythosestudiesthat
aforementionedfollow-upwasnotavailableevenaftercorrespon- fulfilledthe inclusion criteria. We excluded studies if they used
dencewiththeprincipalinvestigator,weincludedthenearesttime a false randomisation procedure or included participants com-
pointavailableinthegeneralandsubgroupanalyses. plicated with other diseases. We listed excluded studies in the
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 5
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Characteristicsofexcludedstudiessectionwithreasonsforexclu- Unitofanalysisissues
sion.
Participantswererandomlyallocatedtotreatmentinallstudies.
Any disagreements were resolved through discussion or, if re-
Intwostudiesitwasstatedthatoneeyeperpersonwasincluded
quired,throughconsultationwithathirdreviewauthor.
(Javadi2010;Sinha2010);intheotherstudiesthiswasnotclear.
Dataextractionandmanagement Dealingwithmissingdata
Two review authors (MA, TXW) independently extracted data Weassessedandreportedthepresenceorabsenceoranintention-
concerning details of study population, intervention used, and to-treat(ITT)analysisinthefollowingway(ITTanalysisrefers
outcomes using a data extraction form and then entered into totheanalysisofoutcomesbasedonthetreatmentarmtowhich
RevMan2014.Theformincludedthefollowingitems. participants wererandomly allocated,ratherthan thetreatment
1. Generalinformation:setting,country,yearofpublication, theyactuallyreceived):
sponsor • Yes:SpecificallyreportedbyauthorsthatITTanalysiswas
2. Trialcharacteristics:design,durationoffollow-up,method undertakenandconfirmedonstudyassessment.
ofrandomisation,allocationconcealment,masking(blinding) • Yes:Notspecificallyreported,butconfirmedonstudy
(participants,peopleadministeringtreatment,outcomeassessors) assessment.
3. Intervention(s):intervention(s)(dose,route,timing), • No:NotreportedandlackofITTanalysisconfirmedon
comparisonintervention(s)(dose,route,timing),co- studyassessment(participantswhowererandomisedwerenot
medication(s)(dose,route,timing) includedintheanalysisbecausetheydidnotreceivethestudy
4. Participants:exclusioncriteria,totalnumberandnumberin intervention,theywithdrewfromthestudy,orwerenotincluded
comparisongroups,age(adults),baselinecharacteristics, becauseofprotocolviolation).
diagnosticcriteria,similarityofgroupsatbaseline(includingany • No:Statedbutnotconfirmedonstudyassessment.
comorbidity),assessmentofcompliance,withdrawals/lossesto • Unclear:Notreportedandnotclearfromstudyassessment.
follow-up(reasons/description),subgroups
5. Outcomes:outcomesspecifiedinthisreview,anyother
outcomesassessed,otherevents,lengthoffollow-up,qualityof Assessmentofheterogeneity
reportingofoutcomes
WeexaminedheterogeneitybytheChi2test,andthesignificance
6. Results:foroutcomes(includingameasureofvariation)
wassetatPgreaterthan0.1;I2 isusedtoestimatetotalvariation
andtimesofassessment
acrossstudiesthatisduetoheterogeneityusingpercentages.I2less
MAandTXWindependentlyabstractedoriginalreportsoftrial
than 40% is considered as not having important heterogeneity,
results.We contactedauthors oftheprimary studies forfurther
30%to60%asmoderateheterogeneity,50%to90%assubstantial
information.Therewerenodisagreementsinthisstep.
heterogeneity, and 75% to 100% as considerable heterogeneity
Forbinaryoutcomes,weextractedthenumberofeventsandtotal
asoutlinedinChaper9oftheCochraneHandbookforSystematic
number in each group. For continuous outcomes, we extracted
Reviews of Interventions (Deeks 2011). If there was evidence of
themean,standarddeviation,andsamplesizeofeachgroup.
heterogeneity, we planned to explore it and perform subgroup
analysistodeterminethepossiblereason.Weperformedsensitivity
analysistoexplorewhetherornottheheterogeneitywasdueto
Assessmentofriskofbiasinincludedstudies
low-qualitytrials.Ifso,weexcludedthelowestqualitytrials.
Weassessedthequalityofreportingforeachtrialbasedlargelyon
thecriteriaspecifiedbyChapter8oftheCochraneHandbookfor
SystematicReviewsofInterventions(Higgins2011).SeeAppendix Assessmentofreportingbiases
10forfurtherdetails. Wedidnotassesspotential publication bias usingafunnelplot
We also planned to explore the influence of individual quality asplannedasweincludedonlysixstudies.SeeChapter10ofthe
criteriainasensitivityanalysis. CochraneHandbookforSystematicReviewsofInterventions(Sterne
2011).
Measuresoftreatmenteffect
Datasynthesis
For dichotomous data, we usedrisk ratios and 95% confidence
intervals.Forcontinuousdata,weusedmeandifferenceand95% Weperformedstatisticalanalysesaccordingtothestatisticalguide-
confidenceintervalstoexpresstheeffectsifwecouldextractthe linesinChapter8oftheCochraneHandbookforSystematicReviews
dataasmeanandstandarddeviation. ofInterventions(Higgins2011).
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 6
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Whendatawerereportedinvariousformsthatcouldnoteasily foreachcomparison,wedidnotincludesuchatableinthecurrent
beconvertedintoastandardmeasure,wesummarisedthedatain versionofthereview.
anarrativeformat,andanalyseddifferentcomparisonsseparately. Wegradedtheoverallqualityof theevidence foreachoutcome
Weincludeddatainameta-analysisiftheywereofsufficientqual- usingtheGRADEclassification(www.gradeworkinggroup.org/).
ityandsufficientlysimilar.Weusedafixed-effectmodelbecause Infutureupdates,wewillincludethefollowingoutcomesinthe
lessthanthreetrialswereincludedineachanalysis. ’Summaryoffindings’table.
1. Cleargraftsurvival
2. Graftrejection
Subgroupanalysisandinvestigationofheterogeneity
3. Best-correctedvisualacuity
We didnot performsubgroup analyses inthisreview. In future 4. Qualityoflife
updatesweplantoconductsubgroupanalysiswiththefollowing: 5. Adverseeffects
• Normal-versushigh-riskkeratoplasty Follow-up:12monthsafterpenetratingkeratoplasty
• Differentdosageofimmunosuppressants
Sensitivityanalysis
RESULTS
Wewereunabletoconductourplannedsensitivityanalysisdueto
onlyoneortwostudiesbelongingtoeachsubgroup.Ifmoretrials
areincludedinfutureupdatesofthisreview,weplantoconduct
Descriptionofstudies
sensitivity analysistoassesshowrobustthereview resultsare to
keydecisionsandassumptions madeduringthereview.Wewill
repeatanalysisofdatawiththefollowingadjustments.
Resultsofthesearch
1. Exclusionofstudieswithhighriskofbias;studieswithlow
riskofbiasweredefinedashavingadequateallocation Theelectronicsearchesyieldedatotalof6660records.TheTri-
concealmentanda’reasonablyexpectedlosstofollow-up’ alsSearchCo-ordinatorrantheelectronicsearchesandidentified
classifiedaslessthan20%,giventhestatedimportanceof 577records,andweransearchesontheVIPandChinaNational
attritionasaqualitymeasure(Tierney2005). KnowledgeInfrastructureChinesedatabasesandidentified6023
2. Exclusionofunpublishedstudies. records. See Figure 1 for details of the screening process of the
3. Comparingthedifferencebetweenthecombinedanalysis searchresults.Weobtainedfull-textrecordsof20reportsforfur-
resultsfromtherandom-effectsmodelandthefixed-effectmodel. therinvestigation.Weincluded9reportsof6studiesandexcluded
10 reports of 9 studies. See Characteristics of included studies;
Characteristics of excluded studies. We have also included one
Summaryoffindingstable
studyinOngoingstudiesthatiscompletedbuttheresultshave
Inamodificationtoourpublishedprotocol,weplannedtoprepare notyetbeenpublished(NCT00409656).Wetriedbutfailedto
a’Summaryoffindings’tablepresentingrelativeandabsoluterisks makecontacttheinvestigatorsofthisstudytoobtainthedata;we
fortheoutcomeslistedbelow.However,asthedatawerelimited willaddthisstudytothereviewifthedatabecomesavailable.
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 7
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Figure1. Studyflowdiagram
Immunosuppressantsfortheprophylaxisofcornealgraftrejectionafterpenetratingkeratoplasty(Review) 8
Copyright©2015TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.