GDao - APAP and Asthma - University Blog...
Transcript of GDao - APAP and Asthma - University Blog...
10/15/16
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From“A”to“Wheeze”Acetaminophen’sRoleintheAsthmaEpidemic
GretchenDao,PharmDCommunityPharmacyPGY1ResidentH-E-B/UniversityofTexasatAusGn October21,2016
+A7-year-oldchildoncontrollertherapyforasthmahasatemperatureof100.1°FandanewprescripEonforananEbioEc.Hermothertellsyouthatthepediatricianrecommendedthatsheshouldalsoget“somethingOTCforthefever”.
Doyourecommend:
A. Acetaminophen?
B. Ibuprofen?
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+LearningObjecEves
n Discusstheroleofacetaminophen(APAP)intheasthmaepidemicinchildren
n EvaluatesafetyofotheralternaGves
n Provideappropriateanalgesic/anGpyreGcrecommendaGonsforchildrenwithasthma
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+BackgroundAsthma
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+AsthmaStaEsEcs
Data,StaGsGcs,andSurveillance.CenterforDiseaseControlandPrevenGon.(2016)
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10.5millionphysicianoffice
visits
$50+billionspentperyear
1.8millionEDvisits
49%ofchildrenwithasthma
missed>1dayofschool
Data,StaGsGcs,andSurveillance.CenterforDiseaseControlandPrevenGon.(2016)
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Data,StaGsGcs,andSurveillance.CenterforDiseaseControlandPrevenGon.(2016)
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8.4%
Data,StaGsGcs,andSurveillance.CenterforDiseaseControlandPrevenGon.(2016)
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+Whatcausesasthma?
n Environmentaltriggers
n AirwayinfecGons
n GeneGcs
n “HygieneHypothesis”
WhatIsAsthma?U.S.NaGonalLibraryofMedicine.(2014)
???APAP???
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+Whatisasthma?
Image:Haderer&Muller,illustratedfortheAmericanCollegeofChestPhysicians.(2016)
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Cellmediatedimmunity&DelayedhypersensiEvity AllergicinflammaEonVarnerAE,BusseWW,LemanskeRF.AnnAllergyAsthmaImmunol.(1998)
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Pathophysiology
COX-2
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+APAPandAsthmaThreeMainQuesGons
1. DoesfrequentAPAPuseleadtoasthmainchildren?
2. DoesfrequentAPAPuseworsensymptomsinchildrenwhoalreadyhaveasthma?
3. ArethealternaGves(i.e.ibuprofen)anysafer?
Litonjua.NEnglJMed.(2016)
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+From“A”to“Wheeze”ObservaGonalStudies
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+TheFirstHypothesis:Varner,etal.(1998)
NoEcedin1980s:Pediatricaspirin(ASA)usedecreased
✚Childhoodasthmaprevalenceincreased
VarnerAE,BusseWW,LemanskeRF.AnnAllergyAsthmaImmunol.1998;81(4):347-51.
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DecreaseduseofASAmaybeafactorinfacilitaGngallergicsensiGzaGonand
asthma.Hypothesis
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Cellmediatedimmunity&DelayedhypersensiEvity AllergicinflammaEonVarnerAE,BusseWW,LemanskeRF.AnnAllergyAsthmaImmunol.1998;81(4):347-51.
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TheFirstHypothesis:Varner,etal.(1998)
COX-2
ASA
êé
APAP?
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VarnerAE,BusseWW,LemanskeRF.AnnAllergyAsthmaImmunol.1998;81(4):347-51.
TheFirstHypothesis:Varner,etal.(1998)
CorrelaEon?Coincidence?
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+TheFirstHypothesis:Varner,etal.(1998)n Conclusion:n EliminaGonofpediatricASAmaybeanimportantcontributor
n RelaGonshipbetweenAPAPandasthmaisunproven,furtherinvesGgaGonisneeded
VarnerAE,BusseWW,LemanskeRF.AnnAllergyAsthmaImmunol.1998;81(4):347-51.
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+EpidemiologicalEvidence:Shaheen,etal.(2000)
n Background:n AnimalstudiesshowedthatAPAPdepletesglutathione(GSH)inlungs
n GSHisananGoxidantthatmaydefendagainstoxidaGvestressofasthmainflammaGon
n IncreasedGSHlevelsinairwaysofadultswithasthma
Shaheen,etal.Thorax.2000;55(4):266-70.
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FrequentAPAPuseisassociatedwithasthma.Hypothesis
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+EpidemiologicalEvidence:Shaheen,etal.(2000)
Shaheen,etal.Thorax.2000;55(4):266-70.
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• PopulaGonbasedcase-control• SurveyonfrequencyofASA/APAPuseinpeoplewithasthmavs.without
• Controlledforconfoundingriskfactors
Design
• Aged16-49y• Defined“asthmaGc”or“non-asthmaGc”basedonscreeningquesGons
• N=1574(664casesvs.910controls)ParEcipants
+EpidemiologicalEvidence:Shaheen,etal.(2000)
Shaheen,etal.Thorax.2000;55(4):266-70.
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+EpidemiologicalEvidence:Shaheen,etal.(2000)
Shaheen,etal.Thorax.2000;55(4):266-70.
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+EpidemiologicalEvidence:Shaheen,etal.(2000)n Conclusion:n Frequent(daily/weekly)APAPuse,possiblyoveruse,posiGvelyassociatedwithasthman Dose-relatedresponse-causal?
n UnlikelythatrelaGonshipisauributabletohigherprevalenceofco-morbidity
n ASAavoidancecanonlyexplainpartoftheassociaGon,notall
Shaheen,etal.Thorax.2000;55(4):266-70.
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+AnEcologicalLook:Newson,etal.(2000)
Sofar:
n Varner:êASAàéAPAPàéasthma?
n Shaheen:frequentAPAPçèasthma?
Newson,etal.EurRespirJ.2000;16(5):817-23.
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CountrieswithhighernaGonalAPAPsalesareassociatedwithhigherasthma
symptomprevalence.Hypothesis
+AnEcologicalLook:Newson,etal.(2000)
Newson,etal.EurRespirJ.2000;16(5):817-23.
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• Linearregressionanalysis:• InternaGonalsymptom-prevalencedata• NaGonalper-capitaAPAPsales
Design
• Aged6-7y,13-14y• N=?(22countries)ParEcipants
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+AnEcologicalLook:Newson,etal.(2000)
Newson,etal.EurRespirJ.2000;16(5):817-23.
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+AnEcologicalLook:Newson,etal.(2000)
Newson,etal.EurRespirJ.2000;16(5):817-23.
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English-speakingcountries
+AnEcologicalLook:Newson,etal.(2000)
n “Anglophoneeffect”n English-speakingWesterncountriestendtohave:n Highestprevalenceofasthmasymptomsn HighestAPAPsales
n Posthocanalysis:n AllassociaGonsbetweenAPAPandasthmasymptomsàabolishedornon-significant
Newson,etal.EurRespirJ.2000;16(5):817-23.
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+AnEcologicalLook:Newson,etal.(2000)
n Conclusion:n NaGonalAPAPsalesposiGvelyassociatedwithprevalenceofasthmasymptoms
n “Anglophoneeffect”n LikelyduetoconfounderstronglyassociatedwithEnglish-speakingcountries
n WarrantsfurtherinvesGgaGon
Newson,etal.EurRespirJ.2000;16(5):817-23.
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+LimitaEonstoObservaEonalStudiesn Weakstrengthofevidence
n ConfoundingbyindicaGonn CausalassociaGonisdifficulttodetermine
n Exposuredatanotlinkedtoindividuals
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+Pu_ngItAllTogetherMeta-Analysis
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+Meta-Analysis:Garcia-Marcos,etal.(2011)
n 41sub-studiesn Infants,children,adults,pregnantwomenn Longitudinal,cross-secGonal
n PooledOR=1.48n “…nomacerwhattypeofstudy,age,orEmeofexposure,thereisalwaysaposiEveassociaEonbetweenexposureandrespiratorysymptoms”
Garcia-MarcosL,Sanchez-SolisM,Perez-FernandezV.CurrOpinAllergyClinImmunol.2011;11(3):162-73.
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+Meta-Analysis:Garcia-Marcos,etal.(2011)
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Garcia-MarcosL,Sanchez-SolisM,Perez-FernandezV.CurrOpinAllergyClinImmunol.2011;11(3):162-73.
+WhatAboutAlternaEves?APAPvs.Ibuprofen
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+FirstRandomizedControlledTrial:Lesko,etal.(2002)
Lesko,etal.Pediatrics.2002;109(2):E20.
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• Short-termuseofibuprofenincreasesasthmamorbidityinchildrenHypothesis
• Randomized,double-blind,APAP-controlled• MeasuredhospitalizaGonandoutpaGentvisitsforasthma
Design
+FirstRandomizedControlledTrial:Lesko,etal.(2002)
Lesko,etal.Pediatrics.2002;109(2):E20.
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• Aged6m-12ywithasthmaandfever
• N=1879ParEcipants
• APAP12mg/kg,ibuprofen5mg/kg,ibuprofen10mg/kg
• Followedx4weeksIntervenEon
+FirstRandomizedControlledTrial:Lesko,etal.(2002)
Lesko,etal.Pediatrics.2002;109(2):E20.
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• NodifferenceinhospitalizaGonrates• OutpaGentvisitssignificantlylowerinibuprofengroup
Results
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Cellmediatedimmunity&DelayedhypersensiEvity AllergicinflammaEon
FirstRandomizedControlledTrial:Lesko,etal.(2002)
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COX-2
ASA
êé
APAP?
Ibu
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+FirstRandomizedControlledTrial:Lesko,etal.(2002)n Conclusion:n ComparedtoAPAP,ibuprofenhaslowerriskofasthmamorbidity
n Duetonoplacebo-control,cannotdeterminewhetherdifferenceisduetoAPAPincreasingriskoribuprofendecreasingrisk
Lesko,etal.Pediatrics.2002;109(2):E20.
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+AVICATrialSheehan,etal.(2016)
Sheehan,etal.NEnglJMed.2016;375(7):619-30.
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• AsthmamorbidityishigherinAPAPvs.ibuprofeninchildrenwithmildpersistentasthma
Hypothesis
• MulGcenter,prospecGve,double-blind,parallel-group
• 48weeks,measuredexacerbaGonfrequencies
Design
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+AVICATrialSheehan,etal.(2016)
Sheehan,etal.NEnglJMed.2016;375(7):619-30.
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• Aged1-5ywithmildpersistentasthma
• N=300ParEcipants
• APAP15mg/kgq6hprn• Ibuprofen9.4mg/kgq6hprnIntervenEon
+AVICATrialSheehan,etal.(2016)
Sheehan,etal.NEnglJMed.2016;375(7):619-30.
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• NosignificantdifferenceinexacerbaGonratesbetweengroups
Results
+AVICATrialSheehan,etal.(2016)
n Conclusion:n Nosignificantdifferencedoesnotnecessarilymeanthattheyareequal(RRCI=0.69-1.28)
n Resultsmaynotbegeneralizableto:n Higherseverityofasthman Non-adherentchildren
n Duetonoplacebo-control,cannotexcludepossibilitythatbothibuprofenandAPAPmaybeassociated
Sheehan,etal.NEnglJMed.2016;375(7):619-30.
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+WhatDoYouThink?RevisiGngthePaGentCase
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+A7-year-oldchildoncontrollertherapyforasthmahasatemperatureof100.1°FandanewprescripEonforananEbioEc.Hermothertellsyouthatthepediatricianrecommendedthatsheshouldalsoget“somethingOTCforthefever”.
Doyourecommend:
A. Acetaminophen?
B. Ibuprofen?
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+Reviewer’sThoughts
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+EvidenceChecklist
q Exposureprecedesonsetofdisease
q Plausiblebiologicalmechanism
q Consistencyacrossdifferentstudysewngs
q TemporalrelaGonshiptoexposure
q IdenGficaGonofdose-responseeffect
q SpecificitytocausaGveagentwithnoconvincingalternaGveexplanaGon
q ReversibilityofthecausaleffectWeatherall,etal.ClinExpAllergy.2015;45(1):108-13.
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✔✔✔✔✔✔
+Conclusion
n MulGpleobservaGonalstudiessuggest:n Dose-relatedrelaGonshipbetweenAPAPuse(possiblyAPAPoveruse)andasthma
n Plausiblemechanism(s)
n ExisGngRCTssuggest:n IbuprofenisnotnecessarilyabeueralternaGve
n MoreRCTsneededtostrengthenevidencen Lackingdataonreversibilityofeffect
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+Acknowledgements
n Dr.NathanPope
n H-E-B/UTResidents&Preceptors
Evaluator:Prof.MarciaKiger
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+Bibliography
n Data,StaGsGcs,andSurveillance.CenterforDiseaseControlandPrevenGon.hups://www.cdc.gov/asthma/asthmadata.htm.PublishedSeptember8,2016.AccessedOctober3,2016.
n Garcia-MarcosL,Sanchez-SolisM,Perez-FernandezV.Earlyexposuretoacetaminophenandallergicdisorders.CurrOpinAllergyClinImmunol.2011;11(3):162-73.
n LeskoSM,LouikC,VezinaRM,MitchellAA.Asthmamorbidityayertheshort-termuseofibuprofeninchildren.Pediatrics.2002;109(2):E20.
n LitonjuaAA.AcetaminophenandAsthma--ASmallSighofRelief?.NEnglJMed.2016;375(7):684-5.
n NewsonRB,ShaheenSO,ChinnS,BurneyPG.Paracetamolsalesandatopicdiseaseinchildrenandadults:anecologicalanalysis.EurRespirJ.2000;16(5):817-23.
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+Bibliography
n ShaheenSO,SterneJA,SonghurstCE,BurneyPG.Frequentparacetamoluseandasthmainadults.Thorax.2000;55(4):266-70.
n SheehanWJ,MaugerDT,PaulIM,etal.AcetaminophenversusIbuprofeninYoungChildrenwithMildPersistentAsthma.NEnglJMed.2016;375(7):619-30.
n VarnerAE,BusseWW,LemanskeRF.Hypothesis:decreaseduseofpediatricaspirinhascontributedtotheincreasingprevalenceofchildhoodasthma.AnnAllergyAsthmaImmunol.1998;81(4):347-51.
n WeatherallM,IoannidesS,BraithwaiteI,BeasleyR.TheassociaGonbetweenparacetamoluseandasthma:causaGonorcoincidence?.ClinExpAllergy.2015;45(1):108-13.
n WhatIsAsthma?U.S.NaGonalLibraryofMedicine.hups://www.nhlbi.nih.gov/health/health-topics/topics/asthma.PublishedAugust4,2014.AccessedOctober3,2016.
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From“A”to“Wheeze”Acetaminophen’sRoleintheAsthmaEpidemic
GretchenDao,PharmDCommunityPharmacyPGY1ResidentH-E-B/UniversityofTexasatAusGn October21,2016