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. Copyright©201encephalopathyNon-absorbable SNoUn-MabsMorbAabRleYdisaOcchFariFdeIsNverDsusINplaGcebSo/nFoiOnteRrvenTtioHnfEortMheApreIvNentioCnaOndMtrePatAmeRntIofShOepaNtice[Enxcpelpahnaaltoipoant]hyinpeoplewithcirrhosis 6Theinpeodisacc Population:preventionandtreatmentof hepaticencephalopathyinpeoplewithcirrhosis Cph ochlewarid Intervention:non-absorbabledisaccharides(lactuloseandlactitol) raneCollaboration.ithcirrhosis(Reviewesversusplacebo/no hODSCeeuuoptrtntacatiotnrtiiomgocl:n:eeipsnnolc-fahecfopoeshlbplaooiltw/oanp-loua(optinhv:tyetehrrtIevlhleudensupttriaroaattniticoivneendcceoeppmehpnaadloreapdtaiovthneytr)hisaekntsdy*po(eu9to5pf%aetCineIcn)etp(hmailnoipmaathlRhyeelwaptiatihvtiec5eedfnfaceyecsptfhoarloapcautthey,N7ao4ndodfapypresavrfetoincrtiicpohanrnottrnsiiacl,s7)0dQauysalfitoyromfitnhimeeavl,idaenndc2e07Cdoamymsefonrtspreventionof Pu)in (95%CI) (studies) (GRADE) blishedby tervention Assumedrisk Correspondingrisk Jo a hn nd Control Non-absorbabledisac- W lac charides iley tulo versus placebo/no in- & s So eve tervention n r s, su L s Mortality Studypopulation RR 0.59 (0.40 to 0. 1487 ⊕⊕⊕(cid:13) TrialSequentialAnaly- td la . c 87) when including all (24studies) moderate1 sis: tito RCTs; RR 0.63 (0.41 The Trial Sequential l for to0.97)whenincluding Analysis found a ben- the RCTs withalow risk of eficial effect of the in- p r bias tervention including all e v e RCTs, but when the n tio 88per1000 49per1000 analysis only included n a (32to75) RCTs withalow risk of n d tr bias e a Moderate Assessment method: tm e Assessedbasedonthe n to 20per1000 11per1000 total numberof partici- f h (7to17) pantswhodied e p a tic 4 CeN opyright©201ncephalopathyon-absorbable Htheypatic encephalopa- Studypopulation R(0R.50t.o580.69) 1(24215studies) ⊕m⊕od⊕er(cid:13)ate2 Tsirsia:lSequentialAnaly- 6Theinpeodisacc TAhnealysTisriaflouSnedquaenbteina-l CochraneCoplewithcirrhharidesversu etRaefnCriacvTliesyan,sltiiesobfnufoetnicnltycwoluhifndectinnhlugedteihandel-l llaboration.osis(Reviewsplacebo/no RbAiCsasTsesswsmithenatlowmeritshkoodf: Pu)in 469per1000 272per1000 Assessedbasedonthe blishedby tervention Moderate (234to323) dRtiecCfiTpinsainti(tonsnuwsmitbihneoruintocaflucpdlaeinrd-- Joh an icallyrelevant improve- n d W la 423per1000 245per1000 ment of hepatic en- c ile tu (211to292) cephalopathy) y lo & s e Son ver Seriousadverseevents Studypopulation RR0.47 1487 ⊕⊕⊕(cid:13) TrialSequentialAnaly- s,L sus (0.36to0.6) (24studies) moderate3 sis: td. lac The Trial Sequential tito Analysis found a ben- l fo eficial effect of the in- r th tervention including all e pr RCTs, but when the e ve analysis only included n tio RCTs withalow risk of n a bias n d Assessment method: tr ea Assessed and defined tm as any untoward medi- e n t cal occurrence that led o fh todeath,waslifethreat- e pa ening, or required hos- tic pitalisation or prolon- 5 CeN opyright©201ncephalopathyon-absorbable gtiaotnio(nICHo-fGChPos2p0i0ta7l)i.sa- 6Theinpeodisacc 207per1000 97per1000 Cochplewharid (75to124) raneCoithcirrhesversu Moderate llaboration.Puosis(Review)splacebo/noin Quality of life (sec- 142per1000 6N(57o1pteoor8v1e50r)0al0l estimate ⊕(cid:13)(cid:13)(cid:13) Wewereunabletocom- blishedby tervention ondaryoutcome) available verylow4 bounivneaercactlelhpeatnadaballyytsaihsiigndhtuoeheatton- Jo a erogeneity h n nW dla Assessmentmethod: c ile tu Basedonthequalityof y& los lifequestionnaires. e So ve n r s, su Non-serious adverse Studypopulation RR2.47 739 ⊕(cid:13)(cid:13)(cid:13) Assessment method: L s td la events(secondaryout- (1.24to4.93) (9studies) verylow5 The outcome includes . c tito come) 106per1000 261per1000 all adverse events that l fo (131to521) do not fulfil thecriteria r th for ’serious’ (ICH-GCP e p Moderate 2007). r e v e n tio 63per1000 156per1000 n (78to311) a n d tre *The basis for the assumedrisk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95%confidence interval) is a tm basedontheassumedriskinthecomparisongroupandtherelativeeffectof theintervention(andits95%CI). e nt CI:confidenceinterval;RCT:randomisedclinicaltrial;RR:riskratio o f h e p a tic 6 CeN opyright©201ncephalopathyon-absorbable GHRigAhDqEuWaloitryk:inFgurGthroeurpregsreaadrecshoisfveevridyeunncliekelytochangeourconfidenceintheestimateof effect. 6Theinpeodisacc MLoowdeqruaatleitqyu:aFluitryth:eFrurrethseerarrcehseisarvcehryislilkikeelylytotohhaavveeaannimimppoortratannttimimppaaccttoonnoouurrccoonnfifdideenncceeininththeeeesstitmimaateteooffeefffefeccttaannddismlaikyeclyhtaongcehatnhgeeetshtiemeastteim. ate. Cochplewharid Verylowquality:Weareveryuncertainabouttheestimate. 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 h n n d RCTsinourmeta-analysis. W la c ile tu y lo & s e So ve n r s, su L s td la . c tito l fo r th e p r e v e n tio n a n d tr e a tm e n t o f h e p a tic 7