10/14/2015

ColchicinefortheHeart
AlyssaKeatingVora,PharmD,BCPS,ClinicalPharmacist,DukeUniversityHospitalKristenBova
Campbell,PharmD,CPP,BCPS(AQCardiology),ClinicalPharmacist,DukeUniversityHospital,Senior
ResearchAssociate,DivisionofElectrophysiology

Topic:
Resultsfrommultipletrialssuggestaroleforcolchicineinthepreventionandmanagementofpostoperative
atrialfibrillation(POAF).

Background:
ColchicineisFDAapprovedfortreatmentoffamilialMediterraneanfeverandacutegoutandforprophylaxis
againstgoutyarthritis.1Colchicineexhibitsbothantiproliferativeandantiinflammatoryactions,primarilyvia
inhibitionofmicrotubuleselfassemblythroughtheformationoftubulincolchicinecomplexes.Thisinhibits
movementofintercellulargranulesandsecretionofinflammatorysubstances.Colchicinealsoimpairs
neutrophiladhesiontovascularendothelium.Importantly,colchicineshowsapreferentialconcentrationfor
leukocytes,decreasingleukocytemotilityandbluntingtheinflammatoryresponse.Peakconcentrationsin
leukocytesmaybemorethan10timesthatseeninplasmatherefore,atherapeuticeffectcanbeseenat
relativelyloworaldoses.2

POAFisthemostcommoncomplicationaftercardiacsurgeryitisreportedin10%to65%ofcasesdepending
onthetypeandcomplexityofsurgeryperformed.2TheincidenceofPOAFappearstobeincreasingduetothe
escalatingnumberofcardiacsurgeriesbeingperformedinelderlypatientswithmultipleriskfactorsand
comorbidities.DevelopmentofPOAFislikelymultifactorial,involvingpericardialinflammation,autonomic
imbalance,excessiveproductionofcatecholamines,andfluidshifts.AsubstudyoftheColchicineforthe
PreventionofthePostpericardiotomySyndrome(COPPS)trialdemonstratedasignificantdecreaseinthe
incidenceofPOAFaswellasashorterinhospitalstayinpatientswhoreceivedcolchicinepostoperatively.3

NewInformation:
TheColchicineforthePreventionofPostpericardiotomySyndromeandPostoperativeAtrialFibrillation
(COPPS2)trialsoughttoevaluatetheincrementalefficacyofcolchicineprophylaxisinitiatedinthe
preoperativeperiod.Thisdoubleblind,placebocontrolled,randomizedtrialevaluated360cardiacsurgery
patientswhoreceivedcolchicineorplacebostartingbetween48and72hoursbeforesurgeryandcontinuedfor
1monthaftersurgery.Colchicinewasdosedat0.5mgtwicedailyinpatientsweighing70kgormoreor0.5
mgoncedailyinpatientsweighinglessthan70kg.Theprimaryendpointofpostpericardiotomysyndrome
(PPS)within3monthswassignificantlyreducedinthecolchicinegroup(19.4%vs.29.4%95%CI,1.1%to
18.7%NNT10).TherewasnosignificantdifferenceinthesecondaryendpointofPOAF(33.9%vs.41.7%
95%CI,2.2%to17.6%).ThereductioninPOAFwassignificantintheprespecifiedontreatmentanalysisof
patientswhotoleratedcolchicine(27%vs.41.2%95%CI3.3%to24.7%).Adverseeffectsweremore
frequentinthecolchicinegroup(20%vs.11.7%95%CI,0.76%to15.9%),butdiscontinuationrateswere
similar(21.7%vs.17.8%95%CI,1.4%to14.3%).Adverseeffectsanddiscontinuationincreasedtwofold
comparedtotheCOPPStrialthisisthoughttobeduetopatientvulnerabilityduringtheperioperativephase.
Theauthorsconcludedthatroutinepreoperativecolchicinetreatmentisnotwarrantedatthistime.4

InterpretationandApplication:
DataforpreventionofPOAFincardiacsurgeryremaininconclusivefurtherlargescalestudieswithaprimary
endpointofPOAFarewarranted.Considerationshouldbegiventodoselimitingfactorssuchassideeffects
anddrugdruginteractions.Gastrointestinalsideeffectsofcolchicinearecommon,andsomepatientsmaynot
bewillingtocontinuetherapyiftheyoccur.Furthermore,drugsthatinhibitCYP3A4mayincreasecolchicine
concentrations(andsideeffects)becauseitisasubstrateofthesamemetabolicpathway.CommonCYP3A4
inhibitorsincludediltiazem,verapamil,azithromycin,andketoconazole.
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Perhapsthebiggesthurdleinexpandingcolchicineuserelatestoitscost.EventhoughtheFDArecently
grantedapprovalofgenericcolchicinetocompetewithColcrys,thepriceisstillabout$4.00(U.S.)per
tablet.Theimpactofwidergenericdrugdistributionisyettobedeterminedhowever,costsareexpectedto
decrease.Providersshouldconsiderthiscostwhenprescribingcolchicineforofflabelindications.
1.KesselheimAS,SolomonDH.Incentivesfordrugdevelopmentthecuriouscaseofcolchicine.NEnglJ
Med2010362:20452047.[PubMed:20393164]
2.DeftereosS,GiannopouloG,PapoutsidakisN,etal.Colchicineandtheheart.JAmCollCardiol
201362:18171825.[PubMed:24036026]
3.ImazioM,BrucatoA,FerrazziPetal.Colchicinereducespostoperativeatrialfibrillation.Circulation
2011124:22902295.[PubMed:22090167]
4.ImazioM,BrucatoA,FerrazziPetal.Colchicineforpreventionofpostpericardiotomysyndromeand
postoperativeatrialfibrillation:theCOPPS2randomizedclinicaltrial.JAMA2014312:10161023.
[PubMed:25172965]
5.Fay,Matthew.Genericcolchicine:victoryinonebattleondrugprices.RheumatologyNetwork.Web.20Jan
2015.
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