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Cardiovascular and Congenital Safety Evaluation of Antiobesity Agents, Including Topiramate: A Pharmacovigilance Analysi...
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Title: Cardiovascular and Congenital Safety Evaluation of Antiobesity Agents, Including Topiramate: A Pharmacovigilance Analysis of the Adverse Event Reporting System.
Physical Description: Conference Papers
Creator: Ayad K. Ali
Conference: ISPOR 15th Annual European Congress
Publisher: International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
Place of Publication: USA
Publication Date: November 6, 2012
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Abstract: OBJECTIVES: A myriad of pharmacologic agents are developed in attempts to control obesity, including the extension of the antiepileptic topiramate as an antiobesity agent. However, concerns about the safety of such agents are mounting. This study aimed at evaluating the cardiovascular and congenital (CC) safety of marketed antiobesity agents, including topiramate. METHODS: A pharmacovigilance analysis of adverse event reports spontaneously submitted to the US Food and Drug Administration’s Adverse Event Reporting System (AERS) from 2004 to 2011 was conducted. The Proportional Reporting Ratio (PRR) data mining algorithm is used to detect signals of CC adverse events that are reported for orlistat, phentermine, sibutramine, and topiramate. Safety signals are detected for PRR values >2. The values are compared within antiobesity class and to all drugs in AERS. RESULTS: A total of 41,930 adverse event reports for antiobesity agents were submitted to the AERS during the study period. About 4% and 1% of the reports were for cardiovascular and congenital problems, respectively. Compared to all drugs in AERS, antiobesity agents didn’t show higher than expected reporting of cardiovascular events (PRR 0.71, 95%CI 0.68-0.74). However, they showed significant safety signals regarding congenital anomalies (PRR 7.45, 95%CI 6.82-8.0), which were mostly attributed by topiramate. Compared to other antiobesity agents, sibutramine was associated with higher cardiovascular reporting rates (PRR 4.42, 95%CI 4.0-4.85), e.g. cardiac arrhythmias, pulmonary hypertension, hypertension, coronary artery disease, and stroke. Phentermine was associated with valvular heart disease (VHD), pulmonary hypertension, and stroke. Topiramate was associated with congenital anomalies and VHD. CONCLUSIONS: Antiobesity agents should be prescribed with caution to patients with cardiovascular risk factors. Regulatory authorities should define cardiovascular safety surveillance requirements for antiobesity agents at postmarketing stages of product’s lifecycle. An alternative to topiramate should be prescribed to females of childbearing age. Epidemiological studies are warranted to test the generated hypotheses.
Acquisition: Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Ayad K Ali.
Publication Status: Published
General Note: Suggested Citation: Ali AK. Cardiovascular and Congenital Safety Evaluation of Antiobesity Agents, Including Topiramate: A Pharmacovigilance Analysis of the Adverse Event Reporting System. Value in Health. 2012;15(7):A508 Abstract No. PSY1
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Source Institution: University of Florida Institutional Repository
Holding Location: University of Florida
Rights Management: Applicable rights reserved.
System ID: IR00001291:00001

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switch(OR 1.6;1.2-2.1)anddiscontinuation(OR 1.8;1.5-2.1).Heartfailurewasassociatedwithaugmentation(OR 1.6;1.0-2.5)anddiscontinuation(OR 1.7;1.2-2.4).Agewas inverselyassociatedwithaugmentationanddiscontinuationandtimesincediabetesdiagnosiswasalsoinverselyassociatedwithaugmentation. CONCLUSIONS: HbA1cisa cleardriveroftreatmentregimenchangesalthoughthereareotherfactorsalso independentlyrelatedtochangesuchasage,heartfailureandbaselineOAD. PDB79 TREATMENTPATTERNSOFORALANTI-DIABETICDRUGSINTHEUKMaguireA1,MitchellB2 1UnitedBioSourceCorporation,London,UK,2EliLillyandCompany,Indianapolis,IN,USAOBJECTIVES: IntheUK,OralAnti-DiabeticdrugsOADŽareadministeredtocontrol hyperglycaemiaintype2diabeteswhenHbA1cexceeds48mmol/mol.Treatment guidelinesdetermineinitialOADandsubsequentchangesinregimendependon HbA1cresponse.Hence,theaimofthisstudyistoquantifyOADtreatment patterns. METHODS: AllpatientswhoinitiatedanOAD(exceptrosiglitazone)with “rstuseasindexdate,intheGPRDdatabasebetween1/1/2006and25/2/2011were included.Periodsofcontinuousandoverlappingprescribing(Rx)wereusedto de“nediscontinuation,switchingandaugmentation;agapof60dayssinceexpiry ofRxde“neddiscontinuation. RESULTS: Of63060patientscommencingOAD,88% startedonmetforminand8%ongliclazidebothasmonotherapy.Hence,allother OADregimenscomprisedonly4%ofallpatients.Comparedtometformin,the gliclazidepatientgroupwasolder(meanage67vs.61years)andhadhighermedianbaselineHbA1c(70(IQR60-95)vs.64(IQR56-74)mmol/mol).TherateofdiscontinuationofbaselineOADatoneyearwas32%whilstthediscontinuationofall OADwas26%.ItwasrarefordiscontinuationofOADtobepermanent;only3.3%of patientswhodiscontinuedinthe1st12monthsdidnotrestartduring4years.The rateofswitchingwas6.4%andtherateofaugmentationwas15%overthe“rstyear. TheseratesdifferedaccordingtobaselineOAD.Comparedtometforminthediscontinuationrateofgliclazidewashigher(41%vs.30%),aswasswitching(8.4%vs. 6.1%)andaugmentation(23%vs.14%).Lastly,insulinuptakewasjust2%byone yearsinceOADinitiation;againthiswashigherinthegliclazidegroupcomparedto metformin(7%vs.1.4%). CONCLUSIONS: Mostpatientsinitiatedonmetformin, whilstforthoseinitiatingongliclazide,discontinuation,switching,augmentation andinsulininitiationwereallhigher.MostpatientswhodiscontinuedOADsubsequentlyrestarted. SYSTEMICDISORDERS/CONDITIONS-ClinicalOutcomesStudies PSY1 CARDIOVASCULARANDCONGENITALSAFETYEVALUATIONOFANTIOBESITY AGENTS,INCLUDINGTOPIRAMATE:APHARMACOVIGILANCEANALYSISOF THEADVERSEEVENTREPORTINGSYSTEMAliAK UniversityofFlorida,Gainesville,FL,USAOBJECTIVES: Amyriadofpharmacologicagentsaredevelopedinattemptstocontrolobesity,includingtheextensionoftheantiepileptictopiramateasanantiobesityagent.However,concernsaboutthesafetyofsuchagentsaremounting.This studyaimedatevaluatingthecardiovascularandcongenital(CC)safetyofmarketedantiobesityagents,includingtopiramate. METHODS: Apharmacovigilance analysisofadverseeventreportsspontaneouslysubmittedtotheUSFoodand DrugAdministrationsAdverseEventReportingSystem(AERS)from2004to2011 wasconducted.TheProportionalReportingRatio(PRR)dataminingalgorithmis usedtodetectsignalsofCCadverseeventsthatarereportedfororlistat,phentermine,sibutramine,andtopiramate.SafetysignalsaredetectedforPRRvalues 2. ThevaluesarecomparedwithinantiobesityclassandtoalldrugsinAERS. RESULTS: Atotalof41,930adverseeventreportsforantiobesityagentsweresubmittedtotheAERSduringthestudyperiod.About4%and1%ofthereportswerefor cardiovascularandcongenitalproblems,respectively.Comparedtoalldrugsin AERS,antiobesityagentsdidntshowhigherthanexpectedreportingofcardiovascularevents(PRR0.71,95%CI0.68-0.74).However,theyshowedsigni“cantsafety signalsregardingcongenitalanomalies(PRR7.45,95%CI6.82-8.0),whichwere mostlyattributedbytopiramate.Comparedtootherantiobesityagents,sibutraminewasassociatedwithhighercardiovascularreportingrates(PRR4.42,95%CI 4.0-4.85),e.g.cardiacarrhythmias,pulmonaryhypertension,hypertension,coronaryarterydisease,andstroke.Phenterminewasassociatedwithvalvularheart disease(VHD),pulmonaryhypertension,andstroke.Topiramatewasassociated withcongenitalanomaliesandVHD. CONCLUSIONS: Antiobesityagentsshouldbe prescribedwithcautiontopatientswithcardiovascularriskfactors.Regulatory authoritiesshouldde“necardiovascularsafetysurveillancerequirementsforantiobesityagentsatpostmarketingstagesofproductslifecycle.Analternativeto topiramateshouldbeprescribedtofemalesofchildbearingage.Epidemiological studiesarewarrantedtotestthegeneratedhypotheses. PSY2 PRELIMINARYVALIDATIONOFCOLLECTSCALE:ACO-MORBIDITY ASSESSMENTTOOLFORPATIENTSWITHCHRONICLYMPHOCYTICLEUKAEMIAGiraldoP1,LopezA2,RiosE3,Gonzalez-GrandeI4,RosetM5,Castro-GomezA6,DeLa SernaJ7,CarbonellF8 1HospitalUniversitarioMiguelServet,Zaragoza,Spain,2HospitalUniversitariValledHebron, Barcelona,Spain,3HospitalVirgendeValme,Sevilla,Spain,4RocheFarma,S.A.,Madrid,Spain,5IMSHealth,Barcelona,Spain,6Roche,Madrid,Spain,7HospitalUniversitario12deOctubre, Madrid,Spain,8ConsorciHospitalGeneralUniversitariValencia,Valencia,SpainOBJECTIVES: COLLECTscalewasdevelopedtoassessthelevelofcomorbiditywith animpactontreatmentdecisionforpatientswithChronicLymphocyticLeukaemia(CLL)in5steps:1.-Literaturereview,2.-FocusGroup,3.-Pilotstudytoevaluate scalefeasibility,4.-Scaledesign,5.-Scalevalidationinanobservational,prospectivephaseIVstudy(evaluatingsafetypro“leofRituximabinCLL).ThiscommunicationpresentsthepreliminaryvalidationoftheCOLLECTscale. METHODS: Atotal of219patientswereincluded.Thescaleistobeful“lledbeforeinitiatingCLL treatmentanditcollatesandratesthepresenceof11relevantcomorbidities.The rangeofthescoregoesfrom0to57points.Fourscoringclusterswereprede“ned: 0-3points(lowcomorbidity),4-6(mildcomorbidity),7-10(moderatecomorbidity) and 10(highcomorbidity). RESULTS: Datafrom218patientsof47hospitalswere analyzed.MostfrequenttherapeuticschemewasRituximab-Fludarabine-Cyclophosphamide(R-FC)(41.3%),followedbyRituximab-Bendamustine(R-B)(29.6%) andRituximab-Chlorambucil(R-Cl)orschemesincludingalkylatingagents(21.1%). COLLECTmedianscore(SD)was4(0-21)withameanof4.8(3.1)points.39.2%of patientsscoredbetween4-6and33%between0-3.Statisticallysigni“cantdifferenceswereobservedinCOLLECTscoreaccordingtoage(p 0.01)andEGOG (p 0.01):thegreatertheageandECOG,thegreaterthescore.Theelectionofinmunochemotherapytreatmentdiffereddependingonthescorecluster(p 0.002): 50.6%and32,9%ofpatientstreatedwithR-FChadlowandmildcomorbiditylevel respectively.40,0%ofpatientsreceivingR-Bhadmediumand26.5%highcomorbiditylevel.50%ofpatientstreatedwithR-Clscoredbetween4-6andthe23.5% between7-10. CONCLUSIONS: COLLECTscaleallowsde“ning4levelsofcomorbidities,withaverygoodcorrelationtoageandECOGstatus.Althoughtheaimof thescaleisnottodrivetreatmentdecision,thestudyshowsatrendtoassociate comorbidityscorewithintensityoftreatment. PSY3 DISEASEACTIVITYINDICES(DAIS)INSYSTEMICLUPUSERYTHEMATOSUS (SLE)WyrwichK1,WinnetteR2,OglesbyA3,NarayananS4 1UnitedBioSourceCorporation,Bethesda,MD,USA,2UnitedBioSourceCorporation,London,UK,3GlaxoSmithKline,ResearchTrianglePark,NC,USA,4HumanGenomeSciences,Inc.,Rockville, MD,USAOBJECTIVES: Reviewthedevelopmentandpropertiesofsystemiclupuserythematosus(SLE)diseaseactivityindices(DAIs)usedinclinicaltrials,observational studies,andcasestudies. METHODS: Astructuredsearchwasconductedtoidentifypublishedarticlesin2005-2011throughkeyliteraturedatabases(EMBASEand MEDLINE/PUBMED).Conferenceabstractsfromtargetedrheumatology,outcomes researchandquality-of-lifescienti“cmeetingsin2009-2011wereincluded.SLE therapyclinicaltrialswithinthepast“veyearswereidenti“edthroughtheClinicalTrials.govdatabase. RESULTS: Thesearchresultedinmorethan15different DAIs,withthemostfrequentlyusedbeingtheBritishIslesLupusAssessment GroupScale(BILAG),EuropeanConsensusLupusActivityMeasure(ECLAM),SystemicLupusActivityMeasure(SLAM),SLAM-revised(SLAM-R),SystemicLupus ErythematosusDiseaseActivityIndex(SLEDAI),SLEDAI-2K,SafetyofEstrogenin LupusErythematosusNational-SLEDAI(SELENA-SLEDAI),andSLEDAI-2K-50(SRI50).Thenumberofitems(24-97),timetocomplete(5-20mins; 20minsforsome toolsincaseoflessphysiciantraining/familiarity),scoring(noglobalscoreor 0-105),organ/systemsassessed(8-24),andsubscalesobservedinthesemeasures variedwidely.TheseeightDAIsalldemonstratedsubstantialinter-raterreliability (ICC .61-1.0)andhadmoderatetostrongcorrelationswitheachother(r 0.430.97).MeasuresinallbutBILAGwereweighted.Allofthesetoolsrequireperiodic laboratoryassessmentssuchashemoglobin,whitecellcount,complementlevels, orincreasedDNAbinding.Abilitytodiscriminatebetween-patientandbetweenvisitdifferencesvariedacrossthetools. CONCLUSIONS: BILAGandSELENA-SLEDAIorinstrumentsderivedfromthesetoolsareusedwidelyinSLEclinicalresearch.However,giventhecomplexity,cliniciantimerequiredforaccurate completion,andneedforlabassessmentstocompletethesetools,furtherinvestigationisneededtoassesstheirfeasibilityforuseoutsideoftheresearcharenain routineclinicalpracticeforoptimalSLEmanagement. PSY4 LENALIDOMIDEORBORTEZOMIBFORTHETREATMENTOF RELAPSED/REFRACTORYMULTIPLEMYELOMA(MM):ACOMPARATIVE EFFECTIVENESSANALYSISUSINGINDIRECTSTATISTICALTECHNIQUESKauraS1,DranitsarisG2 1CelgeneCorporation,Summit,NJ,USA,2AugmentiumPharmaConsulting,Toronto,ON,CanadaOBJECTIVES: Lenalidomide(LEN)andbortezomib(BORT)arebotheffectiveforthe treatmentofrelapsed/refractoryMM.Theformerisadministered25mg/dayorally ondays1-21ofrepeated28-daycycles.Thelatterasa1.3mg/m2intravenousdose ondays1,4,8and11foreight,threeweekcycles.Currently,therearenodatafrom headtoheadrandomizedtrialscomparingLENandBORT.Intheabsenceofsuch data,anindirectcomparisonbetweenLENandBORTwasperformedintherelapsed/refractoryMMsetting.Suchananalysiswasfeasiblebecausecomparable controlswereusedinthepivotalrandomizedtrialsandpatientshadsimilarbaselinecharacteristics. METHODS: ThreepivotalrandomizedtrialswithLEN(n 2) andBORT(n 1)intherelapsed/refractorysettingwereidenti“ed.Patientswithin eachtrialhadsimilardiseasecharacteristics.Dataintermsofresponserate(RR), timetoprogression(TTP)andoverallsurvival(OS)wereextractedfromthepivotal trials.AnindirectstatisticalcomparisonbetweenLENandBORTwasthenperformedontheseendpointsusingthemethodofBucheretal.(1997),whichpartly maintainsthebene“tsofrandomizationonthemagnitudeofbene“t. RESULTS: Theanalysisidenti“edsigni“cantdifferencesinef“cacybetweenthesedrugs.PatientstreatedwithLENweresigni“cantlymorelikelytoachieveadiseaseresponse (OR 1.92;95%CI:1.15-3.20)andtohaveaprolongationinTTP(HR 0.64;95%CI: 0.44-0.91).Theanalysisalsoidenti“edatrendforanOSbene“tinpatientsreceivingtreatmentwithLENoverBORT(HR 0.71;95%CI:0.46-1.11). CONCLUSIONS:A508VALUEINHEALTH15(2012)A277…A575