Pharmacological interventions for acute pancreatitis

251 Pages·2017·1.82 MB·English

CochraneDatabaseofSystematicReviews
Pharmacological interventions for acute pancreatitis (Review)
MoggiaE,KotiR,BelgaumkarAP,FazioF,PereiraSP,DavidsonBR,GurusamyKS
MoggiaE,KotiR,BelgaumkarAP,FazioF,PereiraSP,DavidsonBR,GurusamyKS.
Pharmacologicalinterventionsforacutepancreatitis.
CochraneDatabaseofSystematicReviews2017,Issue4.Art.No.:CD011384.
DOI:10.1002/14651858.CD011384.pub2.
www.cochranelibrary.com
Pharmacologicalinterventionsforacutepancreatitis(Review)
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Figure7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Figure8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 26
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Analysis1.1.Comparison1Acutepancreatitis,Outcome1Short-termmortality. . . . . . . . . . . . . . 167
Analysis1.2.Comparison1Acutepancreatitis,Outcome2Seriousadverseevents(proportion). . . . . . . . . 174
Analysis1.3.Comparison1Acutepancreatitis,Outcome3Seriousadverseevents(number). . . . . . . . . . 176
Analysis1.4.Comparison1Acutepancreatitis,Outcome4Organfailure. . . . . . . . . . . . . . . . 179
Analysis1.5.Comparison1Acutepancreatitis,Outcome5Infectedpancreaticnecrosis. . . . . . . . . . . 182
Analysis1.6.Comparison1Acutepancreatitis,Outcome6Sepsis. . . . . . . . . . . . . . . . . . . 183
Analysis1.7.Comparison1Acutepancreatitis,Outcome7Adverseevents(proportion). . . . . . . . . . . 185
Analysis1.8.Comparison1Acutepancreatitis,Outcome8Adverseevents(number). . . . . . . . . . . . 189
Analysis1.9.Comparison1Acutepancreatitis,Outcome9Requirementforadditionalinvasiveintervention. . . . 192
Analysis1.10.Comparison1Acutepancreatitis,Outcome10Endoscopicorradiologicaldrainageofcollections. . . 195
Analysis2.1.Comparison2Acutenecrotisingpancreatitis,Outcome1Short-termmortality. . . . . . . . . . 196
Analysis2.2.Comparison2Acutenecrotisingpancreatitis,Outcome2Seriousadverseevents(proportion). . . . . 197
Analysis2.3.Comparison2Acutenecrotisingpancreatitis,Outcome3Seriousadverseevents(number). . . . . . 198
Analysis2.4.Comparison2Acutenecrotisingpancreatitis,Outcome4Organfailure. . . . . . . . . . . . 199
Analysis2.5.Comparison2Acutenecrotisingpancreatitis,Outcome5Infectedpancreaticnecrosis. . . . . . . 200
Analysis2.6.Comparison2Acutenecrotisingpancreatitis,Outcome6Sepsis. . . . . . . . . . . . . . . 201
Analysis3.1.Comparison3Severeacutepancreatitis,Outcome1Short-termmortality. . . . . . . . . . . 202
Analysis3.2.Comparison3Severeacutepancreatitis,Outcome2Seriousadverseevents(proportion). . . . . . 205
Analysis3.3.Comparison3Severeacutepancreatitis,Outcome3Seriousadverseevents(number). . . . . . . 206
Analysis3.4.Comparison3Severeacutepancreatitis,Outcome4Organfailure. . . . . . . . . . . . . . 208
Analysis3.5.Comparison3Severeacutepancreatitis,Outcome5Infectedpancreaticnecrosis. . . . . . . . . 210
Analysis3.6.Comparison3Severeacutepancreatitis,Outcome6Sepsis. . . . . . . . . . . . . . . . . 211
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Figure9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Pharmacologicalinterventionsforacutepancreatitis(Review) i
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 248
Pharmacologicalinterventionsforacutepancreatitis(Review) ii
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Pharmacological interventions for acute pancreatitis
Elisabetta Moggia1, Rahul Koti2, Ajay P Belgaumkar3, Federico Fazio4, Stephen P Pereira5, Brian R Davidson2, Kurinchi Selvan
Gurusamy2
1DepartmentofGeneralandDigestiveSurgery,IRCCSHumanitasResearchHospital,Milan,Italy.2DepartmentofSurgery,Royal
Free Campus, UCLMedical School,London, UK.3Deptof UpperGISurgery,AshfordandStPeter’sNHSTrust, Chertsey,UK.
4HPBandLiverTransplantSurgery,RoyalFreeHospital,NHSFoundationTrust,London,UK.5UCLInstituteforLiverandDigestive
Health,RoyalFreeHospitalCampus,London,UK
Contactaddress:KurinchiSelvanGurusamy,DepartmentofSurgery,RoyalFreeCampus,UCLMedicalSchool,RoyalFreeHospital,
PondStreet,London,NW32QG,[email protected].
Editorialgroup:CochraneUpperGIandPancreaticDiseasesGroup.
Publicationstatusanddate:New,publishedinIssue4,2017.
Citation: MoggiaE,KotiR,BelgaumkarAP,FazioF,PereiraSP,DavidsonBR,GurusamyKS.Pharmacologicalinterventionsforacute
pancreatitis.CochraneDatabaseofSystematicReviews2017,Issue4.Art.No.:CD011384.DOI:10.1002/14651858.CD011384.pub2.
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Inpeoplewithacutepancreatitis,itisunclearwhattheroleshouldbeformedicaltreatmentasanadditiontosupportivecaresuchas
fluidandelectrolytebalanceandorgansupportinpeoplewithorganfailure.
Objectives
Toassesstheeffectsofdifferentpharmacologicalinterventionsinpeoplewithacutepancreatitis.
Searchmethods
WesearchedtheCochraneCentralRegisterofControlledTrials(CENTRAL,2016,Issue9),MEDLINE,Embase,ScienceCitation
IndexExpanded,andtrialregisterstoOctober2016toidentifyrandomisedcontrolledtrials(RCTs).Wealsosearchedthereferences
ofincludedtrialstoidentifyfurthertrials.
Selectioncriteria
WeconsideredonlyRCTsperformedinpeoplewithacutepancreatitis,irrespectiveofaetiology,severity,presenceofinfection,language,
blinding,orpublicationstatusforinclusioninthereview.
Datacollectionandanalysis
Tworeviewauthorsindependentlyidentifiedtrialsandextracteddata.Wedidnotperformanetworkmeta-analysisasplannedbecause
ofthelackofinformationonpotentialeffectmodifiersanddifferencesoftypeofparticipantsincludedinthedifferentcomparisons,
wheninformationwasavailable.Wecalculatedtheoddsratio(OR)with95%confidenceintervals(CIs)forthebinaryoutcomesand
rateratioswith95%CIsforcountoutcomesusingafixed-effectmodelandrandom-effectsmodel.
Mainresults
Weincluded84RCTswith8234participantsinthisreview.Sixtrials(N=658)didnotreportanyoftheoutcomesofinterestfor
this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials
contributed to one or more outcomes for thisreview. The treatments assessed in these78 trials included antibiotics, antioxidants,
aprotinin,atropine,calcitonin,cimetidine,EDTA(ethylenediaminetetraaceticacid),gabexate,glucagon,iniprol,lexipafant,NSAIDs
Pharmacologicalinterventionsforacutepancreatitis(Review) 1
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(non-steroidalanti-inflammatorydrugs),octreotide,oxyphenonium,probiotics,activatedproteinC,somatostatin,somatostatinplus
omeprazole,somatostatinplusulinastatin,thymosin,ulinastatin,andinactivecontrol.Apartfromthecomparisonofantibioticsversus
control,whichincludedalargeproportionofparticipantswithnecrotisingpancreatitis,theremainingcomparisonshadonlyasmall
proportionofpatientswiththiscondition. Mosttrialsincludedeitheronlyparticipantswithsevereacutepancreatitisorincludeda
mixtureofparticipantswithmildacutepancreatitisandsevereacutepancreatitis(75trials).Overall,theriskofbiasintrialswasunclear
orhighforallbutoneofthetrials.
Source of funding:seventrials were not fundedor funded by agencies without vestedinterestin results. Pharmaceutical companies
partiallyorfullyfunded21trials.Thesourceoffundingwasnotavailablefromtheremainingtrials.
Sinceweconsideredshort-termmortalityasthemostimportantoutcome, wepresentedonlytheseresultsindetailintheabstract.
Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-
termmortalityinanyofthecomparisons(verylow-qualityevidence).Withregardstootherprimaryoutcomes,seriousadverseevents
(number)werelowerthancontrolinparticipantstakinglexipafant(rateratio0.67,95%CI0.46to0.96;N=290;1study;verylow-
qualityevidence),octreotide(rateratio0.74,95%CI0.60to0.89;N=770;5studies;verylow-qualityevidence),somatostatinplus
omeprazole(rateratio0.36,95%CI0.19to0.70;N=140;1study;low-qualityevidence),andsomatostatinplusulinastatin(rate
ratio0.30,95%CI0.15to0.60;N=122;1study;low-qualityevidence).Theproportionofpeoplewithorganfailurewaslowerin
octreotidethancontrol(OR0.51,95%CI0.27to0.97;N=430;3studies;verylow-qualityevidence).Theproportionofpeoplewith
sepsiswaslowerinlexipafantthancontrol(OR0.26,95%CI0.08to0.83;N=290;1study;verylow-qualityevidence).Therewas
noevidenceofdifferencesinanyoftheremainingcomparisonsintheseoutcomesorforanyoftheremainingprimaryoutcomes(the
proportionofparticipantsexperiencingatleastoneseriousadverseeventandtheoccurrenceofinfectedpancreaticnecrosis).Noneof
thetrialsreportedheath-relatedqualityoflife.
Authors’conclusions
Verylow-qualityevidencesuggeststhatnoneofthepharmacologicaltreatmentsstudieddecreaseshort-termmortalityinpeoplewith
acutepancreatitis.However,theconfidenceintervalswerewideandconsistentwithanincreaseordecreaseinshort-termmortalitydue
totheinterventions. Wedidnotfindconsistentclinicalbenefitswithanyintervention.Becauseofthelimitationsintheprognostic
scoringsystemsandbecausedamagetoorgansmayoccurinacutepancreatitisbeforetheyareclinicallymanifest,futuretrialsshould
consider includingpancreatitisofallseveritybutpowerthestudytomeasurethedifferencesinthesubgroup ofpeoplewith severe
acutepancreatitis.Itmaybedifficulttopowerthestudiesbasedonmortality.Futuretrialsinparticipantswithacutepancreatitisshould
considerotheroutcomessuchascomplicationsorhealth-relatedqualityoflifeasprimaryoutcomes.Suchtrialsshouldincludehealth-
relatedqualityoflife,costs,andreturntoworkasoutcomesandshouldfollowpatientsforatleastthreemonths(preferablyforatleast
oneyear).
PLAIN LANGUAGE SUMMARY
Medicaltreatmentforpeoplewithacutepancreatitis(suddeninflammationofthepancreas)
Background
Thepancreasisanorganintheabdomen(tummy)thatsecretesseveraldigestiveenzymes(substancesthatenableandspeedupchemical
reactionsinthebody)intothepancreaticductalsystembeforeitemptiesintothesmallbowel.ItalsocontainstheIsletsofLangerhans,
whichsecreteseveralhormonesincludinginsulin(helpsregulatebloodsugar).Acutepancreatitisislife-threateningillnesscharacterized
bysuddeninflammationofthepancreas,whichcanleadtofailureofotherorgans,suchasthelungsandkidneys.Thereisalotof
researchintodifferentmedicaltreatmentsforthetreatmentofacutepancreatitis,butitisnotclearwhatbenefitseachtreatmenthas,
orindeedifanymedicaltreatmentisbeneficialapartfromsupportivetreatment.Thiscareincludesbodyhydrationandintensivecare
treatmentforpeoplewithorganfailure(tosupportthefailingorgans).Wesoughttoresolvethisissuebysearchingforexistingstudies
onthetopic.Weincludedallrandomisedcontrolledtrials(clinicalstudieswherepeoplearerandomlyputintooneoftwoormore
treatmentgroups)whoseresultswerereportedto7October2016.
Studycharacteristics
Weincluded84RCTswith8234participantsinthisreview.Sixtrials(658participants)didnotreportanyoftheoutcomesofinterest
forthisreview.Intheremaining78trials,210participantswereexcludedafterrandomisation.Thus,atotalof7366participantsin
78trialscontributedtooneormoreoutcomesforthisreview.Apartfromthecomparisonofwhetherantibioticsshouldbeused,the
Pharmacologicalinterventionsforacutepancreatitis(Review) 2
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
othercomparisonsincludedonlyasmallpercentageofpeoplewithpancreaticnecrosis(anextremelysevereformofpancreatitis,which
resultsinpancreaticdestruction).Mosttrialsincludedonlythesevereformofacutepancreatitisorincludedbothmildandsevereforms
ofpancreatitis.
Sourceoffunding:seventrialswerenotfundedorwerefundedbyagencieswithoutvestedinterestinresults.Twenty-onetrialswere
partlyorfullyfundedbypharmaceuticalcompanies.Thesourceoffundingwasnotavailablefromtheremainingtrials.
Qualityoftheevidence
Theoverallqualityofevidencewaslowforallthemeasuresbecausethetrialswereatunclearorhighriskofbias(asystematicerroror
deviationfromthetruththataffectstheresults,favouringonetreatmentoveranother)andweresmalltrials.Asaresult,furtherstudies
arerequiredonthistopic.
Keyresults
Sixty-seven studies including 6638 participants reported short-term deaths. Overall, an average 12% of people who received only
supportivecaredied.Therewasnoevidencethatanyofthetreatmentsdecreasedshort-termdeaths.Therewasevidencethatvarious
treatmentsmightbebeneficialinanumberofoutcomes;however,theseresultswerenotconsistent,andwecannotmakeanyconclusions
astowhetheranyofthetreatmentsmaybebeneficial.Noneofthetrialsreportedhealth-relatedqualityoflife.
Inconclusion,basedonlowqualityevidence,thereisnoevidencethatanydrugtreatmentaddedontosupportivecaredecreasesshort-
termdeaths.Futuretrialsinparticipantswithacutepancreatitisshouldincludehealth-relatedqualityoflife,costs,andreturntowork
asoutcomesandshouldfollowpatientsforatleastthreemonths(preferablyforatleastoneyear).
Pharmacologicalinterventionsforacutepancreatitis(Review) 3
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CoPh SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
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20gic Pharmacologicalinterventionsfortreatmentofacuteseverepancreatitis(mortality)
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Cve
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chrantions Intervention:varioustreatments
efo Control:inactivecontrol
Cr
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llabocute Outcomes Illustrativecomparativerisks* (95%CI) Relativeeffect Noofparticipants Qualityoftheevidence
rp
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tionc
n.Publishreatitis(R AInsascutimveedcorinstkrol CVoarriroeusspotrnedaitnmgernistks
ee
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byiew Short-termmortality Antibiotics OR0.81 1058 ⊕(cid:13)(cid:13)(cid:13)
Joh) Follow-up:upto3months (0.57to1.15) (17studies) Verylowa,b,c
n 120per1000 99per1000
W
ile (72to135)
y
&
So Antioxidants OR2.01 163 ⊕(cid:13)(cid:13)(cid:13)
n
s, (0.53to7.56) (4studies) Verylowa,b,c
L
td 120per1000 215per1000
.
(68to508)
Aprotinin OR0.68 651 ⊕(cid:13)(cid:13)(cid:13)
(0.40to1.14) (7studies) Verylowa,b,c
120per1000 85per1000
(52to135)
Calcitonin OR0.55 125 ⊕(cid:13)(cid:13)(cid:13)
(0.15to2.00) (2studies) Verylow1,²,3
120per1000 69per1000
(20to214)
Cimetidine OR1.00 40 ⊕(cid:13)(cid:13)(cid:13)
(0.06to17.18) (1study) Verylowa,b,c
4
CP
oh
pyrarm
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t©olo 120per1000 120per1000
20gic (8to701)
1a
7l
Tin
heter EDTA OR0.94 64 ⊕(cid:13)(cid:13)(cid:13)
Coven (0.12to7.08) (1study) Verylow1,²,3
chranetionsfo 120per1000 1(1173tpoe4r9110)00
Cr
oa
llabocute Gabexate OR0.79 576 ⊕(cid:13)(cid:13)(cid:13)
rp (0.48to1.30) (5studies) Verylowa,b,c
aa
tionc 120per1000 98per1000
n.Publishereatitis(Re Glucagon (62to151) OR0.97 409 ⊕(cid:13)(cid:13)(cid:13)
dv
bie (0.51to1.87) (5studies) Verylow1,²,3
yw
Jo) 120per1000 117per1000
h
n (65to203)
W
ile
y& Iniprol OR0.14 24 ⊕(cid:13)(cid:13)(cid:13)
So (0.01to1.67) (1study) Verylowa,b,c
n
s 120per1000 19per1000
,
L
td (2to185)
.
Lexipafant OR0.55 423 ⊕(cid:13)(cid:13)(cid:13)
(0.30to1.01) (3studies) Verylow1,²,3
120per1000 70per1000
(40to121)
Octreotide OR0.76 927 ⊕(cid:13)(cid:13)(cid:13)
(0.47to1.23) (6studies) Verylowa,b,c
120per1000 94per1000
(60to143)
Probiotics OR1.70 358 ⊕(cid:13)(cid:13)(cid:13)
(0.87to3.30) (2studies) Verylowa,b,c,d
5
CP
oh
pyrarm
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t©olo 120per1000 188per1000
20gic (106to310)
1a
7l
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heter ActivatedproteinC OR8.56 32 ⊕(cid:13)(cid:13)(cid:13)
Coven (0.41to180.52) (1study) Verylowa,b,c
chranetionsfo 120per1000 5(5329tpoe9r6110)00
Cr
oa
llabocute Somatostatin OR0.57 493 ⊕(cid:13)(cid:13)(cid:13)
rapa (0.29to1.10) (6studies) Verylowa,b,c
tionc 120per1000 72per1000
n.Publishereatitis(Re Somatostatinplusomeprazo(le39to130) OR0.23 140 ⊕(cid:13)(cid:13)(cid:13)
dv
byiew (0.05to1.11) (1study) Verylowa,b,c
Jo) 120per1000 30per1000
h
n
W (6to132)
ile
y
& Somatostatinplusulinastatin OR0.43 122 ⊕(cid:13)(cid:13)(cid:13)
So (0.15to1.23) (1study) Verylowa,b,c
n
s, 120per1000 55per1000
L
td (20to144)
.
Thymosin Notestimable 24 ⊕(cid:13)(cid:13)(cid:13)
(1study) Verylowa,b,c
120per1000 notestimable
Ulinastatin OR0.45 132 ⊕(cid:13)(cid:13)(cid:13)
(0.12to1.72) (2studies) Verylowa,b,c
120per1000 58per1000
(16to190)
Long-termmortality Noneof thetrialswithinactivetreatmentinthecontrolgroupreportedlong-term mortality
Follow-up:1year
6
CP
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t©olo *Thebasis for theassumedrisk is theaveragecontrol group proportion across all comparisons. Thecorrespondingrisk(and its 95%confidence interval) is based on the
20gic assumedriskinthecomparisongroupandtherelativeeffectof theintervention(andits95%CI).
1a
7Tlin CI:confidenceintervals;OR:oddsratio;EDTA:ethylenediaminetetraaceticacid.
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Coven GRADEWorkingGroupgradesof evidence
chranetionsfo HMiogdheqrautaeliqtyu:afluitryth:efurrrtehseerarrecsheiasrcvheriysulinkleiklyeltyothoacvheaanngeimopuorrctaonntfiidmepnaccetionnthoeuresctoimnfaidteenocfeeifnfetchte.estimateof effectandmaychangetheestimate.
Cr
oa Lowquality:furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateof effectandislikelytochangetheestimate.
llabocute Verylowquality:weareveryuncertainabouttheestimate.
rp
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tionc aRiskof bias:downgradedbyonelevel.
n.Publishereatitis(Re bcdIIHmmeppterreeroccgiisseiioonnen:i:tddy:oodwwonnwggnrraagddraeedddeoodnnoeenlleeevvleeellvffeoolrrfoswrmidlaaecllcksooanmffoipdvleeenrsclaiezpeino.tfecrvoanlfsid.enceintervalsandhighI².
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