Non-absorbable disaccharides versus placebo/no intervention and lactulose versus lactitol for the

163 Pages·2016·1.79 MB·English

CochraneDatabaseofSystematicReviews
Non-absorbable disaccharides versus placebo/no intervention
and lactulose versus lactitol for the prevention and treatment
of hepatic encephalopathy in people with cirrhosis (Review)
GluudLL,VilstrupH,MorganMY
GluudLL,VilstrupH,MorganMY.
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepaticen-
cephalopathyinpeoplewithcirrhosis.
CochraneDatabaseofSystematicReviews2016,Issue4.Art.No.:CD003044.
DOI:10.1002/14651858.CD003044.pub3.
www.cochranelibrary.com
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepatic
encephalopathyinpeoplewithcirrhosis(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 25
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Analysis1.1.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome1Mortality. . . 111
Analysis1.2.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome2Mortalityintrials
withalowriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Analysis 1.3. Comparison 1 Non-absorbable disaccharides versus placebo/no intervention, Outcome 3 Hepatic
encephalopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Analysis1.4.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome4Seriousadverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Analysis1.5.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome5Qualityoflife:
sicknessimpactprofile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Analysis1.6.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome6Non-seriousadverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Analysis1.7.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome7Numberconnection
test,endoftreatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Analysis1.8.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome8Ammoniaendof
treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Analysis1.9.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome9Ammoniachange
frombaseline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Analysis1.10.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome10Mortalityin
worst-casescenarioanalyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Analysis1.11. Comparison 1Non-absorbable disaccharidesversusplacebo/nointervention, Outcome11 Hepatic
encephalopathyworst-casescenarioanalysis. . . . . . . . . . . . . . . . . . . . . . . . 124
Analysis1.12.Comparison1Non-absorbabledisaccharidesversusplacebo/nointervention,Outcome12Seriousadverse
eventsworst-casescenarioanalysis. . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Analysis2.1.Comparison2Preventiontrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome1
Mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Analysis2.2.Comparison2Preventiontrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome2
Mortalityandbiascontrol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Analysis2.3.Comparison2Preventiontrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome3
Hepaticencephalopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepatic i
encephalopathyinpeoplewithcirrhosis(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Analysis2.4.Comparison2Preventiontrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome4
Seriousadverseevents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Analysis2.5.Comparison2Preventiontrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome5
Non-seriousadverseevents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Analysis3.1.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome1
Mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Analysis3.2.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome2
Mortalityintrialswithalowriskofbias. . . . . . . . . . . . . . . . . . . . . . . . . 136
Analysis3.3.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome3
Mortalityinacuteorchronichepaticencephalopathy. . . . . . . . . . . . . . . . . . . . . 138
Analysis3.4.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome4
Hepaticencephalopathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Analysis3.5.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome5
Acuteorchronichepaticencephalopathy. . . . . . . . . . . . . . . . . . . . . . . . . 140
Analysis3.6.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome6
Seriousadverseevents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Analysis3.7.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome7
Seriousadverseeventsinacuteorchronichepaticencephalopathy. . . . . . . . . . . . . . . . . 143
Analysis3.8.Comparison3Treatmenttrials:non-absorbabledisaccharidesversusplacebo/nointervention,Outcome8
Non-seriousadverseevents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Analysis4.1.Comparison4Lactuloseversuslactitol,Outcome1Mortality. . . . . . . . . . . . . . . . 145
Analysis4.2.Comparison4Lactuloseversuslactitol,Outcome2Hepaticencephalopathy. . . . . . . . . . 146
Analysis4.3.Comparison4Lactuloseversuslactitol,Outcome3Seriousadverseevents. . . . . . . . . . . 147
Analysis4.4.Comparison4Lactuloseversuslactitol,Outcome4Non-seriousadverseevents. . . . . . . . . 148
Analysis4.5.Comparison4Lactuloseversuslactitol,Outcome5NumberConnectionTest:endoftreatment. . . . 150
Analysis4.6.Comparison4Lactuloseversuslactitol,Outcome6NumberConnectionTest:changefrombaseline. . 151
Analysis4.7.Comparison4Lactuloseversuslactitol,Outcome7Venousbloodammonia:endoftreatment. . . . 151
Analysis4.8.Comparison4Lactuloseversuslactitol,Outcome8Venousbloodammonia:changefrombaseline. . . 152
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 160
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepatic ii
encephalopathyinpeoplewithcirrhosis(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Non-absorbable disaccharides versus placebo/no intervention
and lactulose versus lactitol for the prevention and treatment
of hepatic encephalopathy in people with cirrhosis
LiseLotteGluud1,HendrikVilstrup2,MarshaYMorgan3
1Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. 2Departmentof Hepatology and
Gastroenterology,AarhusKommunehospital,AarhusC,Denmark.3UCLInstituteforLiver&DigestiveHealth,DivisionofMedicine,
RoyalFreeCampus,UniversityCollegeLondon,London,UK
Contactaddress:LiseLotteGluud,Gastrounit,MedicalDivision,CopenhagenUniversityHospitalHvidovre,KettegaardsAlle,Hvi-
dovre,2650,[email protected].
Editorialgroup:CochraneHepato-BiliaryGroup.
Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue4,2016.
Reviewcontentassessedasup-to-date: 19October2015.
Citation: Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides versus placebo/no intervention and lactulose versus
lactitolforthepreventionandtreatmentofhepaticencephalopathyinpeoplewithcirrhosis.CochraneDatabaseofSystematicReviews
2016,Issue4.Art.No.:CD003044.DOI:10.1002/14651858.CD003044.pub3.
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Non-absorbabledisaccharides(lactuloseandlactitol)arerecommendedasfirst-linetreatmentforhepaticencephalopathy.Theprevious
(second)versionofthisreviewincluded10randomisedclinicaltrials(RCTs)evaluatingnon-absorbabledisaccharidesversusplacebo/
nointerventionandeightRCTsevaluatinglactuloseversuslactitolforpeoplewithcirrhosisandhepaticencephalopathy.Thereview
foundnoevidencetoeithersupportorrefutetheuseofthenon-absorbabledisaccharidesandnodifferencesbetweenlactuloseversus
lactitol.
Objectives
Toassessthebeneficialandharmfuleffectsofi)non-absorbabledisaccharidesversusplacebo/nointerventionandii)lactuloseversus
lactitolinpeoplewithcirrhosisandhepaticencephalopathy.
Searchmethods
WecarriedoutelectronicsearchesoftheCochraneHepato-BiliaryGroupControlledTrialsRegister,theCochraneCentralRegister
of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October
2015;manualsearchesofmeetingsandconferenceproceedings;checksofbibliographies;andcorrespondencewithinvestigatorsand
pharmaceuticalcompanies.
Selectioncriteria
WeincludedRCTs,irrespectiveofpublicationstatus,language,orblinding.
Datacollectionandanalysis
Tworeviewauthors,workingindependently,retrieveddatafrompublishedreportsandcorrespondencewithinvestigators.Theprimary
outcomesweremortality,hepaticencephalopathy,andseriousadverseevents.Wepresentedtheresultsofmeta-analysesasriskratios
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepatic 1
encephalopathyinpeoplewithcirrhosis(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
(RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using ’Grading of
RecommendationsAssessmentDevelopmentandEvaluation’(GRADE)andbiascontrolusingtheCochraneHepato-BiliaryGroup
domains.Ouranalysesincludedregressionanalysesofpublicationbiasandothersmallstudyeffects,TrialSequentialAnalysestodetect
type1andtype2errors,andsubgroupandsensitivityanalyses.
Mainresults
Weincluded38RCTswithatotalof1828participants.EightRCTshadalowriskofbiasintheassessmentofmortality.Alltrials
hadahighriskofbiasintheassessmentoftheremainingoutcomes.Random-effectsmeta-analysisshowedabeneficialeffectofnon-
absorbabledisaccharidesversusplacebo/nointerventiononmortalitywhenincludingallRCTswithextractabledata(RR0.59,95%
CI0.40to0.87;1487participants;24RCTs;I2 =0%;moderatequalityevidence)andintheeightRCTswithalowriskofbias(RR
0.63,95%CI0.41to0.97;705participants).TheTrialSequentialAnalysiswiththerelativeriskreduction(RRR)reducedto30%
confirmedthefindingswhenincludingallRCTs,butnotwhenincludingonlyRCTswithalowriskofbiasorwhenwereducedthe
RRRto22%. Comparedwithplacebo/nointervention, thenon-absorbable disaccharides wereassociated withbeneficial effectson
hepaticencephalopathy(RR0.58,95%CI0.50to0.69;1415participants;22RCTs;I2=32%;moderatequalityevidence).Additional
analysesshowedthatnon-absorbabledisaccharidescanhelptoreduceseriousadverseeventsassociatedwiththeunderlyingliverdisease
includingliverfailure,hepatorenalsyndrome,andvaricealbleeding(RR0.47,95%CI0.36to0.60;1487participants;24RCTs;I
2 =0%;moderatequalityevidence).WeconfirmedtheresultsinTrialSequentialAnalysis.Testsforsubgroupdifferencesshowedno
statistical differencesbetweenRCTs evaluating prevention, overt,or minimal hepaticencephalopathy.The evaluation of secondary
outcomesshowedapotentialbeneficialeffectofthenon-absorbabledisaccharidesonqualityoflife,butwewerenotabletoinclude
thedatainanoverallmeta-analysis(verylowqualityevidence).Non-absorbabledisaccharideswereassociatedwithnon-serious(mainly
gastrointestinal)adverseevents(verylowqualityevidence).NoneoftheRCTscomparinglactuloseversuslactitolevaluatedqualityof
life.Thereviewfoundnodifferencesbetweenlactuloseandlactitolfortheremainingoutcomes(verylowqualityevidence).
Authors’conclusions
ThisreviewincludesalargenumberofRCTsevaluatingthepreventionortreatmentofhepaticencephalopathy.Theanalysesfound
evidencethatnon-absorbable disaccharidesmaybeassociatedwithabeneficialeffectonclinicallyrelevantoutcomescomparedwith
placebo/nointervention.
PLAIN LANGUAGE SUMMARY
Arenon-absorbabledisaccharidesassociatedwithbeneficialorharmfuleffectsinpeoplewithcirrhosisandhepaticencephalopa-
thy?
Background
Cirrhosisisachronicdisorderoftheliver.Peoplewithcirrhosismaydevelophepaticencephalopathy,aconditionthatresultsinpoor
brainfunctioning.Hepaticencephalopathymaybeclinicallyobvious(overt)withchangesincludingpoorconcentration,tremor,and
alterationsinconsciousness.Othershavenoobviousclinicalchanges(minimal)but,whentested,someaspectsofbrainfunctionsuch
asattentionandtheabilitytoperformcomplextasksareimpaired.
Thereasonwhypeopledevelophepaticencephalopathyiscomplex.Theaccumulationofammoniaplaysakeyrole.Thenon-absorbable
disaccharides,lactuloseandlactitol,areindigestiblesugarsthatreducethelevelsofammoniaintheblood.
Reviewquestion
Weinvestigatedtheuseofnon-absorbable disaccharidesforthepreventionandtreatmentofhepaticencephalopathyinpeoplewith
cirrhosisbyreviewingrandomisedclinicaltrials(RCTs).
Searchdate
ThesearchdatewasOctober2015.
Studyfundingsources
SevenRCTsreceivedfinancialsupportand11RCTsreceivedlactitolorinactiveplacebofreeofchargefromapharmaceuticalcompany.
Studycharacteristics
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepatic 2
encephalopathyinpeoplewithcirrhosis(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Weincluded29RCTscomparingnon-absorbable disaccharideswithinactiveplaceboornointerventionandnineRCTscomparing
lactulosewithlactitol.SevenoftheincludedRCTsevaluatedthepreventionofhepaticencephalopathyand31evaluatedthetreatment
ofhepaticencephalopathy.SixteenofthetreatmentRCTsincludedpeoplewithoverthepaticencephalopathywhile15includedpeople
withminimalhepaticencephalopathy.Thedurationoftreatmentvarieddependingonthetypeofhepaticencephalopathyfromfive
daystooneyear.
Keyresults
Peoplewhoreceivednon-absorbabledisaccharideswerelesslikelytodiethanpeoplegivenaplaceboornotreatment.Theywerealso
lesslikelyto developserious complications of their liverdisease such asliver failure, bleeding, and infections. The non-absorbable
disaccharideswerealsoeffectiveinpreventingthedevelopmentofhepaticencephalopathyandincreasedthenumberofparticipants
whorecoveredfromhepaticencephalopathy.Therewassomeevidencefromasmallnumberoftrialsthatlactulosehasabeneficialeffect
onthequalityoflife,butwewereunabletoincludethedatainanoverallanalysis.Thenon-absorbabledisaccharideswereassociated
withadverseeventsincludingdiarrhoea,nausea,bloating,andflatulence.NoneoftheRCTscomparinglactuloseversuslactitolreported
qualityoflife.Theanalysesshowednodifferencesbetweenthetwointerventionsfortheremainingoutcomes.
Qualityoftheevidence
Inthecomparisonofnon-absorbabledisaccharidesversusplacebo/nointervention,wefoundmoderatequalityevidenceofbenefitfor
theoutcomesofdeath,hepaticencephalopathy,andseriouscomplications.Theevidencefortheremainingoutcomeswasofverylow
quality.
Non-absorbabledisaccharidesversusplacebo/nointerventionandlactuloseversuslactitolforthepreventionandtreatmentofhepatic 3
encephalopathyinpeoplewithcirrhosis(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
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raneCoithcirrhesversu 1Meovrtidaelintyceiswdhoenwnwgeralidmeidtedonteheleavneallytsois’mtoodinercalutedqeuoanliltyyRevCiTdsenwcei’thbaecloauwsreistkhoefTbriiaasl.Sequential Analysis found insufficient
llaboration.Puosis(Review)splacebo/noin ii32nnSHettehhrpieeoaouotisvvceeaerrdaanvllclleeaarpssshsesaeeelssovsspemmantteehsnnyitts..isddoowwnnggraraddeeddoonneelelevveellttoo’m’mooddeerraatteeqquuaalilittyyeevviiddeennccee’’bbeeccaauusseennoonneeoofftthheeRRCCTTsshhaaddaalloowwrriisskkooffbbiiaass
blishedby tervention b54NQiauosan,l-iisit)eytrhoioefulhsifeeatedisrvoedgroseweneneigvtryeanwdteasdsiscthdoronesweindlegevrraaedblseledt,oath’nvrdeereyiiill)oewwveeqlsuwateolirte’yvueervnyiadlboewnleceqt’oubacelioctymauebvsiiendeei)ntchneeo’bndeeactoaafuitsnheeain)innocovluendreaeoldlfaRtnhCaeTlyisnschislau.ddeadloRwCTrisskhaodf
Jo a a low risk of bias,ii) the confidence intervals were wide (uncertainty),and iii) we were only ableto include data from nine
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