住院患者质子泵抑制剂过度使用英文Word文档格式.docx

住院患者质子泵抑制剂过度使用英文Word文档格式.docx

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Protonpumpinhibitors（PPIs）havebecomeoneofthemostcommonlyprescribeddrugclasseswithannualexpendituresin2009estimatedatUS$13.5billionintheUnitedStatesandUS$24billionworldwide.1 

SeveralPPIsarecurrentlyapprovedbytheUSFoodandDrugAdministration（FDA）fordiseasestatessuchasgastricorduodenalulcer,erosiveesophagitis,andgastroesophagealrefluxdisease（GERD）.2–6 

Additionally,currentguidelinessuggesttheuseofPPIsforthefollowingreasons:

preventingulcercomplicationsrelatedtouseofnonsteroidalanti-inflammatorydrugs（NSAIDs）,managinggastroesophagealrefluxdiseaseandulcerbleeding,prophylaxisofstressulcers,andpreventinggastrointestinalrisksinpatientsreceivinganticoagulation.7–11 

Themaximumrecommendedtreatmentdurationformanyoftheseindicationsis4to8weeks.Inordertopreventprolongedinappropriateuse,evaluationofsymptomresolutionandneedforcontinuedtherapyshouldbeperformed.Despitetreatmentrecommendations,severalstudiesfromcountriesoutsideoftheUnitedStateshaveshownthatPPIsareoftenexcessivelyandinappropriatelyusedintheinpatientsetting.12–15

PPIshavebeengenerallyregardedassafe,withthemostcommonadversereactionsbeingheadache,abdominalpain,nausea,diarrhea,vomiting,andflatulence.2–6,16 

Thisperceivedsafetyandtolerabilityhasmostlikelycontributedtotheirincreaseduseandpotentialoveruse.Alarmingly,morerecentevidencehassuggestedthatPPIuseisnotasbenignasoriginallybelieved.Infact,studieshavelinkedPPIusewithmoreseriousadverseeffectssuchasincreasedriskof 

Clostridiumdifficile 

（C.difficile）infections,community-acquiredandhospital-acquiredpneumonia,andosteoporoticfracture,includinghipfracture.17 

Inadditiontoadversereactions,riskswithPPItherapyalsoincludedrug-druginteractionsanddrug-nutrientinteractions,whichmayleadtovitamindeficiencies.Adruginteractionwithclopidogrelhasbeendescribed,however,theclinicalsignificanceofthisinteractionisquestionable.Othercommondrug-nutrientinteractionsincludereducedabsorptionofcalcium,iron,andvitaminB12.17

Duetoincreasingreportsofpotentiallyseriousadverseeffectsanddrug-druginteractions,thepossiblewidespreaduseofPPIinhospitalizedpatientsrequiresfurtherexamination.ThepurposeofthisreviewwastoevaluatetheappropriatenessofusewithPPIsinhospitalizedgeneralmedicalpatientsintheUnitedStatesandoutlinepotentialconsequencesassociatedwiththeuseofPPIs.

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Methods

AliteraturesearchwasconductedusingMEDLINE®

（1946toJuly,week3,2012）andEMBASE®

（1980to2012,week29）.KeywordsandMedicalSubjectHeadings（MeSH）usedincludeprotonpumpinhibitorsandhospitalization.ResultswerelimitedtostudiesconductedinadultsubjectsandpublishedintheEnglishlanguage.StudieswereselectedforinclusioniftheyevaluatedtheuseofprotonpumpinhibitorsinthegeneralmedicalinpatientpopulationintheUnitedStates.StudieswerealsoonlyincludedifthemajorityofpatientsinthestudyweretakingaPPI（versusahistamine2 

receptorantagonist）.StudieswereexcludediftheywereconductedoutsideoftheUnitedStates,oriftheystudiedonlypatientsinthecriticalcaresetting.Referencesofselectedarticles,reviewarticles,andtreatmentguidelineswerealsoexaminedforpertinentarticles.

Mechanismofaction,metabolism,andpharmacokineticprofile

PPIsareabsorbedintheproximalsmallbowelandachievepeakconcentrationsofapproximately0.5to2mg/mL.18 

AllPPIsundergolowratesofhepaticfirst-passmetabolismandthushavehighoralbioavailability;

oralbioavailabilityrangesfrom77%forpantoprazoleto90%forlansoprazole.18 

PPIsarehighlyproteinbound,witheachbinding95%orgreater.ThoughPPIsareknowntoinhibitacidsecretionforupto36hours,theireliminationhalf-lifeisshort,rangingfrom30minutesto2hours.19

ThemechanismofactionofPPIsleadstoareductioningastricacidproductionviatheadenosinetriphosphateases（H+,K+-ATPase）pumps,whichareresponsiblefortheregulationofgastricpH.PPIsselectivelyandirreversiblybindtoH+,K+-ATPasepumps,alsoreferredtoasprotonpumps,inhibitingbothbasalandstimulatedsecretionofgastricacid.19

PPIsaremetabolizedprimarilythroughthecytochromeP450（CYP）enzymes2C19and3A4.ThoughallPPIsutilizetheCYPsystem,itshouldbenotedthattherearedifferencesintheextenttowhichtheirdegradationdependsonthegivenCYP.18 

Forexample,onlyasmallpercentageofrabeprazoleutilizesCYP2C19andCYP3A4formetabolism.Further,omeprazole,esomeprazole,andpantoprazolepredominantlyrelyonCYP2C19formetabolism,lansoprazolesignificantlyreliesonbothCYP2C19andCYP3A4.

Clinicalstudies

StudiesevaluatingoveruseofPPItherapyonly

TherearetwopublishedstudiesevaluatingthesoleuseofPPIsinthehospitalizedsetting.ThefirstofthesestudieswasconductedbyReidetalasaretrospectivereviewfromtwodatabasesfromuniversity-affiliatedhospitalsinColorado（Table1）.20 

Thisstudywasconductedinrandomlyselectedadultpatientsaged18to90yearsadmittedformedicalservices.AppropriatenessofPPItherapywasdeterminedusingInternationalClassificationofDiseases,9thRevision（ICD-9）codes.Interestingly,resultsfromtheevaluationofbothdatabasesfoundthat40%ofpatientsinonedatabaseand14%ofpatientsintheotherwereprescribedPPIsduringhospitalization.OfthosethatwereprescribedPPItherapy,39%and27%ofpatientsinthesedatabases,respectively,wereclassifiedashavingvalidindicationsforPPIuse.Arandomchartreviewof5%ofpatientsindicatedthatutilizationofICD-9codesmaybeinaccurateandrevealeda19%errorrate.Adjustingthedataaccordingtothisadministrativeerrorrateresultedin>

50%failingtomeetproperindicationsforPPItherapy.Further,safetyinformationwasalsocollected,andpatientsreceivingPPIsinbothdatabasepopulationshadahigherrateofconcurrent 

C.difficileinfection:

1.16%inthePPIpopulationversus0.44%inthenon-PPIgroupinonedatabaseand1.32%versus0.003%,respectively,intheseconddatabase（P 

<

0.001）.Increasedconcurrentdiagnosisofpneumoniawassignificantlygreaterinonepopulation（8.2%inthePPIgroupversus5.3%inthenon-PPIgroup;

P 

0.001）andatrendtowardsignificanceintheotherpopulation（10.1%inthePPIgroupand8.7%inthenon-PPIgroup;

=0.023）.AftercorrectionusingtheBonferronimethod,a 

value<

0.01wasdeemedstatisticallysignificant.Theresultsofthisstudyindicatethatthereisover-useofPPIinhospitalizedpatients.However,investigatorsutilizedretrospectivechartreview,whichledtoaself-reportedadministrativeerrorrateof19%.ThismayhaveoriginatedfromtheuseofICD-9codestodetermineappropriatenessoftherapy,asICD-9codestendtohavehighspecificitybutlowsensitivityincapturingallinpatientdiagnoses.Further,thedataonoverutilizationofPPIfromthetwodatabasesweredrasticallydifferentdespitesimilarmethodsemployed,bringingintoquestiontheaccuracyofthesefindings.

Table1

Studiesevaluatingtheuseofprotonpumpinhibitorsinhospitalizedadultpatients.

AstudyconductedbyThomasetalevaluatedappropriateinitiationofPPIsduringhospitalizationusingICD-9codes（Table1）.21 

TheinvestigatorsalsoevaluatedthecostassociatedwithinappropriateprescribingofPPItherapyinhospitalized,non–criticallyillpatientsusingmedicalandpharmacyclaimsfromalargemanagedcaredatabase.Informationwasgatheredthroughclaimsbasedon“placeofservice”fieldtoonlyincludeinformationfrominpatientclaims.PPItherapywasonlyconsideredappropriateifthepatientwasusingPPItherapypriortohospitalizationorifusewasconsistentwithdiagnoses.Atotalof20,197（68.8%）patientswerecategorizedasinappropriateusersofPPItherapy.Whencomparingcriticallyillpatientsversusmedicalpatients,therewasnostatisticallysignificantdifferencefoundwithrespecttoinappropriateuse（68.7%and68.9%,respectively）.EvaluationofPPIoverusewasconductedcontinuouslyover4years;

overuseofPPIsdecreasedslightlyduringthistime.However,therewasnosignificantdifferenceovertime.SimilartothestudybyReidetal,concernsregardingtheaccuracyofresultsmayhavebeenlimitedbytheretrospectivenatureofthedesignofthisstudy.Additionally,miscodingorinaccuratediagnosiswaslikelygiventhatthereisnoICD-9codeforstressulcerprophylaxis（SUP）.AuthorsmaynothaveaccountedforpotentialinaccuraciesinfindingswhenusingICD-9codes;

however,thefindingsreportedaresignificantandcannotbeoverlooked.

InadditiontothetwopreviousstudiesthatexaminedtheuseofPPIs,severalotherstudiesincludedpatientswhoweretakingPPIsaswellasthosetakingotheracidsuppressivetherapy.Forthepurposesofthisreview,studieswereonlyincludedifthemajorityofpatientsweretakingaPPI.

Guptaetallookedatthefrequencywithwhichinappropriateadministrationofacidsuppressivetherapy（AST）（eitherahistamine-2 

receptorantagonist[H2RA]oraPPI）occurredduringhospitaladmissionandathospitaldischarge（Table1）.22 

PatientsadmittedtothegeneralmedicineunitofauniversityhospitalandwhoreceivedatleastonedoseofASTwereeligibleforthestudy.Patientswereexcludediftheyweretransferredfromtheintensivecareunit（ICU）orhadbeenprescribedASTpriortoadmission.Twohundredandseventy-ninepatientswererandomlyselectedovera3-monthperiodand