四种第二代抗组胺药物的卫生技术评估

q小【目衍I止『，、学泉忠》2003q。9N菜3卷希3期越第lo刺 ⋯ ——一 业型竺业型竺坠!型坐塑型型坠型业旦塑些旦————二望三二 ·论著· Articles Healthtechnologyassessmentoffournon-sedatingantihista_ minesforallergicdiseases SUNXin，．CAOLi．ya·，MATao2，I,ANFen。，LIXia2，XIAOAi—li4，CHENXin‘zn2，LIYou。ping⋯ r，Ke3Lab一7Yan,、plantEngineeringandlmmu¨olog?"tMinisto’o／Health，China)，West ChinaHospital，Si(hua’lUni。’8‘vi(r, Che，Jgd“．610041，China；2WeYtChinaSchoolo，ClinicalMedicine．Sichuanu姗ersity,Chengdu，6j004j，Chi’㈨3ttwChine’9 cf，ehrlinpCenterWestChinaHospital,SichanUn}、，ersity,Chengdu．610041．China；4．CenterforDrugRe。evahtatiott，State Food 口ndDrugAdmini，tration盯ChinaBeijin9100038．China,"8('orresponditlgauthor) Abstract：ObjectivesThisreviewcomparedclinicaleltecliveness，cardiac‘afetyandeconouncsofastemizole．10tata— dine，cetirizineandterfenadinctoprovideevidenceforadjuMmentofEssentialDrugListinChina．SearchstrategyWe scarchedMedlinc．CochraneLiblarvEmbaseandChineseBiomedicalDatabase．Fourteendatabasesfordrugsafetyand Dharmaccuticalecollomicswereadditionallysearched．SelectionCriteriaRandomizedcontrolledtrialsaudsystematic -?，ieI，apublip,hedinEnglishandChineseandcomparingtwoornloreofthesefourantihistaminesforallergicrhinitis andunicariawereincludedforstudyofeffectivenessNon—randomizedclinicaltrialswereadditionallyincludedforeco— nomicevaluationCardiacsafetystudiesofantihistaminesforallergicdiseasesolanytypewereincludedQuality AppraisalJadadscalewasprimarilyappliedtorandomizedcontrolledtrialsAllocationconcealmentandintention—to treatanalysiswarealsoappraisedTheQUOROMstatementwasappliedInsystematicreviews andmeta—analysisDatz extractionandanalysesForthestudyofeffectiveness．compositedatawereprimarilyextractedandanalyzedbyfixed efleetmodelSensilivityanalysisVeasdunetoexploretheheterogeneityForthestudyofcardiacsafety，casesofadverse drugreactionsanddeathweresummarizedDifferenceofoccurrencerateinsexandagewereanalyzeditpossible Electrocardiugraphyandcliaic'AsymptomsweresummarizedResultsNostudiesoneconomicevaluationwereidenti— fled27and6randomizedcontrolledtrialsincluding3227participants，forallergicrhinitisandurticariawereidentified CetiriTinewassuperiortoloratadine(n=709)insynlptomscoreandonsetofaction．superiortotefl、enadine(n=645)in QualityofLjfeandsuperiortoastemizolefn-=498)inpatientsatisfactionandonsetofaction73h-ADRcaseswcreiden— tiffed1T1 astemizole．27casesinterfenadine，lcaseinIoratadineandnoneincetirizineNodeathswcreidentified Combinationofterfenadineplusgrapefruit1uice(n=lS)，itraconazole("=6)，nefazodone研=67)，andloratadineadminis— trationconcomitantwithcemitidine(n=30)significantlyprolongedQTcinterval．ConclusionsCetirizinewassuperiortO otherthreeantihistaminesintermsofclinicaleffectivenessanddrugsafetyAstemizoleandterfenadinecouldcauseslg— nificantlyvnorccardiac—relatedadversereactionsthancetifidneandIoratadine． Keywords：Astemizole：loratadine；lerfenadine；cetirizine：allergicrhtuttis；urticaria；healthtechnologyassessmenl CLCnumber：R，115，R976Documentcode：AArticleID：1672—2531(20t)3)03—0195一I2 Allergicrhinitisisoneofthemostfrequentlyoccurred allergicdiseasesandtheprevalencewasestimatedat5 l【122percentinlheUnitedStates(anestimated20to 40millionpeople1’1)．Itisclassifiedasseasonalor perennialsubtype．dependinguponwhethersymptoms ReceIreddate．2003一心-l，Reviseddam：2003—0h-1S Foundaliorlitem：Thispmgramw扒Ioinlly3ponsnredbyCemmfo]Drug ReevaluationalStateFoodandDrugAdministrationandtheChinese CochrancCeiiIPL BiogaphYsUNXiiimale(1079)Re～earchA、^lMalltre’|carch interests：healthtcchnL，ll’时ass“‘nlcflt、pharnlaceullculeconomics aresuflf；eredatcertaintimesthroughouttheyear121．In 2000，oversixbillionUSdollarswerespentOilpre— scriptionmedicationsforthisdiseaseI”Urticariaisa verycommondiseaseandmayaffectpeopleofall agesItisestimatedthat15to20percentofthepopu— laltonexperiencesallurticarialillnessintheirJires t2] Clinically，atttihislaminesarethefirst—linemedica— lionsintreatmentofallergicrhinitisandurticarian As thebesl—doctlmeritedchemicalmediator for urticaria，theyarethemainstayoftherapy151． 万方数据 ：竖： 竺坐型型坚竺!!望!竺竺兰塑!竺坐型苎坐竖兰竺竺竖竺————一 Thesecond—generationantihistamines，suchasasteml— zole，cetirizine．terfenadineandloratadine．represent anadvanceintherapeuticsAlrecommendeddoses， theyvirtuallydonotenterthecentralnervoussystem (CNS)andproducerelativelyslightsomnolence However,someagentswerereportedtobeassociated withprolongationoftheQTcintervalanddevelop— mentoftorsadesdepointes，apotentiallyfatalventfic— ulararrhythmia．WHOUppsalaCenterreportedthat morethan100casesofdeathcausedbythesecond— generationantihistantineswereidentifiedfrom1986 t01996． Thoughdrugmanufacturerswithdrewterfenadineand Astemizolefrominternationalmarketinl998and 1999．thesetwodrugsarestilllistedasessentialmedi— cinesinChina．Physiciansbecameconfusedjnclini— calpracticeduetodiscrepancyinclinicaleftective— heSSandsafetyconcernHowever,statisticsfrom45 hospitalsinShanghaishowedtheCOStofconsumption ofloratadinewasover4750thousandUSdollarsin 1997and5560thousandUSdollarsin1998 Atpresent．noevidenceisavajlabletomakeclear explanationonthesafely．comparativeeffectiveness andeconomicsoftheseagentsforwell—informeddin— icalpracliceandhealthdecision—makingControversy existedthroughselectionofessentialdrugsinChina． Therefore，Itisurgentandimportanttoassessthese pharmaceuticalagentsintermsofeffectiveness，safety andpharmaceuticaleconomicsThisstudyreviewed ThetypeofsilMy astemi，olc．Ioratadine，terfenadineandcetirizine．aim— ingatprovidingthebestevidenceforadjnslmenlof EssentialDrugListandimprovementofclinicalprac— tice． Methods 1 SearchStrategy Medline(1966—20022)，Embase(1974—2002．2／，The CochraneLibraryf2002IssueNo4)andChinese BiomedicalDatabase(1979—20022)weresearched forstudiesonclinicaleffectiveness．cardiac—related adversedrugreactions(h—ADRs)14additional data- basesandjournalsfordrugsafetyandeconomiceval— uationsweresearchedforh—ADRs Thekeywordsincludedsystematicreview，lneta— analysis，randomizedconlrollcdtrial(s)．clinicalcon— trolledtrial(s)，clinical—trial．clinicalstudy'，cohort study，casereport．caseseries．allergicrhiniIis． urticaria．adversedrugreactions，astemizole，lorata— dine，tefenadine，cetirizine，arrhythmia，!achycardia， cost—effectivenessandCOSt—utilityCombinationot wordswouldbedifferentlyappliedinseparatedata— basesbasedontheselectioncriteria 2SelectionCriteria 21 SelectionCriteriaforeffectivenessandh—AI)R study SelectionCriteriaforeffectivenessandh—ADRstudy werebasicallysimilar，detailsofwhichwereshowed intable1．PublishedstudiesjnEnglishlindChinese wouldbeincluded Table1Selectioncrileriaforstudyoileffectlvenc蟠andh-ADRs Effectivenessstudy h-ADRstudy Systematicre～Jewsmeta-analysi、，randumlzedcon— trofledtrialswithJadadscorcnolessthanthree SystenlalicmvlewsllqCtaanalysisrandomizedC()lllloiledtrialscnn trolledclinicalIrialscohortstudycase‘cricsandcRsercputI、、h¨uId beincluded ThetypeofparticipantsIncludehealthyvolunteelxandpatientssufferingfromallergicrbinitisorumcariaexcepl easesNorestrictionwasappliedt0ageand，ex Thetypeofintervention ThelypeofoHtcoroe Anyoffouranlihislamineswereadministrated|0rallergicdl、eases E1cc【roc¨dlograph”parameters unytypc Clinicalsymptoms；and Endpoinlparametm：death ：至Ⅲ舡 州㈣时㈣⋯ 燃～ 裟嬲一璧囊一篡爱||篇勰淼毓一至薰裟篇黧揣Ⅷ 万方数据 *tltl目掘证lX毕泉，岂》200Y；t。|．9jI帮3锰第3蹦总铺10州 ⋯， n·竺!Jo【一型坐竺：!!竺!：!!!!!竺型型!!型竺塑!!堕塑I：i塑立里型坠11——二!兰L， 22SelectionCriteriaforeconornicevaluation Prospectiveandrclrospuctiveeconomicstudiesshould beincludedHealthyvolunteersandpatientssuffering fromallergicrhinitisandurticariawerequalifiedfor inclusion． 3Qualityappraisal TworeviewersassessedthetrialsindependentlyAny discrepancieswereresolvedbydiscussionorbya thirdparty． 3．1Qualityappraisalofsystematicreview／meta— analysis QUOROMStatementwasprimaftlyappliedtoassess thequalityofsystematicreviewandmeta—analysis Eachitemwouldbeassessedonilsreliabilityorvalid— itydependingonthenatureofindividualitemThe majoritemsrelatedtostudyqualityincludedatabases， selectioncriteria，studyperformance(datainclusion andexclusion，dataextraction)．analysismethods， studyresultsandclinicalimplication 3．2Quality'appraisalofrandomizedcontrolledtrials Jadadscalewasprimarilyadaptedtoassessthestudy qualityofrandomizedcontrolledtrials．Arangescore systemfromonetofivepointswasestablishedbased 011thateachitemreceives1 pointifadequateother- wiseapointwasdeductedifinadequate．Studieswith Jadadscoreslessthanthreepointswereconsidered lowinquality．Allocationconcealmentandintention— to—treatanalysis(inclusionofdataoflostparticipants inanalyses)wereadditionallyappliedforassessment ofstudyquality．fA：adequatelydescribedB：inade— quatclydescribedC：unknown) 3．3Qualityappraisalofeconomicevaluation Itemstobeassessedinclude11cleardefinitionofclin— icalandeconomicquestions，2)adequatedescription ofinterveutions．3)definitiveeffectiveness，4)accu— ratemcasurelnentofcostandoutcomes，5)reliability ofCOStandoutcomes，and6)sensitivityanalysis Foreachidentifiedtrial．fourgradescaubemade accordingtoeachitem： A=adequateB。partiallyadequateC=inadequate D=unknown 4Dataextraction 4．1Dataexlractionstrategy Compositedatawereextractedforanalyses．One reviewerindependentlyextracteddatafromstudy． withre—examinationfollowedbyanotherreviewer AnYproblemsweresolvedbasedonarticle． 0therwise，authorswerecontacted 4．2Iternstobeextracted Majoritemstobeextractedincludebaselinecharac— teristicsofsubjects．comparalorandintervention (drug，dosageandduration)，lossoffolio'#,'一upout— comemeasureandoutcomes Dataforeconom{cevaluationwereadditionally extracted，whichincludedcountryofstudy，perspec— live，compositionofCOSt，modelforanalyses(Markov ChainModel)，discount，(incremental)COSt—effective— nessratio，(incremental)cost—utilityratioandsensitiv— ityanalysis。 5Dataanalyses 5．fStudyofeffectiveness Resultsofeligiblestudieswerestatisticallysynthe— sized(Meta—analysis)ifpossibleusingReview Manager4．1 Fordichotomousvariables．thePeto oddsratiowerecalculatedusingthefixedeffect inndelwith95％confidenceintervalsF0rcontinuous variables，weightedmeandifferenceswerecalculated usingthefixedeffectmodelwith95％coilfidence interval．Afixeeffectsmodelwasusedfortheprima— ryanalyseswheneverpossible Heterogeneitybetweentrialresultswastestedinall analysesChi—squaretestsforheterogeneitywereused totestforgrossstatisticalheterogeneity,betweenall trials．Ifheterogenekyexisted，sensitivityanalysisand analysisbyrandomeffectmodelwereapplied． Sensitivityanalyseswereperformedtoexplorethe influencebystudyquality,verylongorlargestudies 10establishhowmuchtheydominatetheresultsand studieswithhighrate(>lO％)oflossoffollow一“p 52h—ADRsstudy Meta—analyses wereconductedifpossible．as describedaboveCasestudiesofindividualantibista。 mineswereseparatelysummarizedbythenumberof casesofh-ADR，casesofdeath，clinicalsympton'ts， 万方数据 ：竖‘ 型型业型堕型!翌竺竺型竺!!：!竺塑竺竺坐竺型型竺竺L———一 andelectrocardiographexaminationAdjustedrelative riskwascalculatedifpossible，aimingatcomparison ofdeathrateandmorbidityratewithinfour,'mtihista— mines．Subgroupsummarywasdoneaccordingtoage andsexofvictimstoinvestigatesexandagespecific correlationswithantihistmnines clinlcaltrIals AR＆URT R 192 Results 1PrimaryselectionofData 270trials wereidentifiedbyreadingtitlesand abstracts，detailsofwhichareshownintable2 After finalselection．27RCTsforallergicrhinitis and6 RCTsforurticariawereidentifiedNosystematic reviewswereavailable衙eitherdiseaseconditions． "table2Resultsofprimaryselection 6 3 65 10tdI 10” 195 65 +Syxtemaucrevi6wsinterfllSofeffectivenessandsafetyo～erlappedAR(allergicrhinitis)URT(urticaria 2Studyofeffeetiveness Nosystematicreviewswereincludedforanalysis27 trialsforallergicrhinitiswereidentified．22ofwhich studiedseasonalallergicrhinitis2trialsscoredfive pointsbyJadadscale．13trialsscoredfourandl2td— alsscoredthreeInaddition．Horak1⋯andCarpio⋯ adequatelydescribedallocationconcealmentand8tri— alsappliedintention—to—treatanalysis． ExcepttrialsbyGutkowski⋯andJames128I．astemi— zole．10ratadineandcetirizinewasadministrated10mg oncedaily,tertenadineas120meoncedailyor60mg twicedailyLengthofstudyvariedfromonedayto twomonths．Totally，3227participantswereprimarily includedintrials．226ofwhichfailedtofollowup． SeveraItrialsdidnotreportpatientnumberswho withdrewfromtrialsLuigi⋯reporteda40percent 10ssrate， 3Efiectivenessoffonrantihistaminesforallergle rhinitis 3．1Terfenadinevs．Astemizole⋯”埘 Sixtrials(n=222，28lossoffollowup)comparedter— fenadineandastemizole．inwhichBolandstudied perennialallergicrhinitis．StudybyLuigireporteda highlossofrate(40percent)Nosignificantdiffer— eDcewasidentifiedforseverityofsymptoms．except studybyWoodHI／thatshowedterfenadineissuperior toastemizolejnphysicianassessment．G{rard129’ reportedthatterfenadineisfarmorerapidthanastern— izoleinonsetofaction，comparing3hoursagainst48 hours【P<005jBolandstudiedtheoverallefficacyof treatment(OEOT)bypatients，whichshowedastemi— zolewassuperiortoterfenadine[P=O．02]．However， combinationofstudiesonOEOTbyphysiciansindi— catednostatjsticaldifferencebetweenthe1wo IP=05]． 32Loratadinevs．"rerfenadinem’1’ Fourtrials(n=320，5710SSoffollowu口)wereidenti— fled，inwhichGeorgesstudiedperennialallergic rhinitis．GutkowskiandGeorgesassessednasaland non—nasalsymptomsbysymptomscoringscale． HorakandCarpioassessednasalandnon—nasalsever— itybyeveryscoringscale．Resultsindicatednosignif- icancebetweenthesetwoagents．Fourtrialscompared twoagentsbyOEOT．Combinedestimatesshowed loratadinewassignificantlysuperiortoterfenadine {OR=1．41P=O．03) 3．3Cetirizinevs．Loratadine【“”4。i Threetrials(n=709．571ASSoffollowup)wereinclud— edDay⋯andMeltzer⋯comparedcetirizineand loratadinebymajorsymptom(MSC)scoreandtotal symptomscore(TSC)Resultsshowedthatcetirizine wassignificantlysuperiortoIoratadinefP≤O．01． P