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CLOPIDOGREL(PLAVIX)

OBJECTIVE:

Todescribetheclinicalpharmacologyandtherapeuticapplicationofclopidogrel.
Todiscussdrugdosing,durationoftherapy,geneticpolymorphismsaffectingdrugmetabolism,
andpotentialdruginteractionswithprotonpumpinhibitors.

BACKGROUND:
Clopidogrel(Plavix)isanoralplateletinhibitorthathasdemonstratedcardiovascularprotectionas
monotherapyorwhenaddedtoacetylsalicylicacid(ASA)inpatientswithacutecoronarysyndrome
(ACS)treatedmedically,surgicallyorwithpercutaneouscoronaryintervention(PCI)aswellasin
thosewithsymptomaticperipheralarterialandcerebrovasculardisease.

MECHANISMOFACTIONOFCLOPIDOGREL:
ClopidogreliscategorizedasathienopyridinewhichirreversiblyblockstheP2Y12adenosine
diphosphate(ADP)receptorandtherebyinhibitsADPinducedplateletaggregation.Clopidogrelisa
prodrugwhichismetabolizedintotheactiveagentintwostepsbythehepaticcytochromeP450
enzymesystem(3A4and2C19).

INDICATIONSFORCLOPIDOGREL:

Clopidogrelisatreatmentoptionforthesecondarypreventionofatherothromboticevents
(myocardialinfarction,strokeorvasculardeath)inpatientswithatherosclerosisthatmanifest
clinicallyasstroke,acutecoronarysyndromeorperipheralarterydisease.
Clopidogrelisindicated,incombinationwithASA,forthesecondarypreventionof
atherothromboticeventsinpatientswithACS.Clopidogrelisusuallyadministered,incombination
withASA,for1yearfollowinganepisodeofACS.
FornonACSstentedpatients,clopidogrelcombinedwithASAisrecommendedfor1year,withat
least3monthsoftreatmentfordrugelutingstentpatientsand1monthforbaremetalstent
patientsiftheyareunabletotolerateyearlongdualtherapy.Clopidogrelmaybeusedas
monotherapyinpatientsnotconsideredcandidatesforASAmonotherapy(e.g.thosewithASA
allergiesorahighriskofASArelatedgastrointestinalbleeding).
Clopidogrelisatreatmentoptionforsecondarypreventionofrecurrentatherothromboticevents
inpatientswhodevelopanischemicstrokeortransientischemicattack(TIA)whilereceivingASA
therapy.
Inpatientswithatrialfibrillation(AF)whohaveriskfactorsthatwarrantanticoagulanttherapy,
butarenotsuitablefortreatmentwithananticoagulant,clopidogrel(75mgdaily)incombination
withASA(81mgdaily)isindicatedforthepreventionofatherothromboticandthromboembolic
events.Notethatthebleedingriskofcombinedantiplatelettherapymaynotbeverydifferent

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fromoralanticoagulantmonotherapy.Formostpatientswithatrialfibrillation,anticoagulationis
preferredbecauseitissignificantlymoreeffectiveatpreventingstroke.

DOSINGFORCLOPIDOGREL:

Acutecoronarysyndrome:300600mgloadingdosefollowedby75mgdaily.Adoseof150mg
dailymaybeconsideredforthefirstweekinpatientstreatedbyPCI.
Forallotherindicationsthedoseis75mgoncedaily.
Thereisadelayofapproximately4daystopeakantiplateletactivityifaloadingdoseof
clopidogrelisnotgiven.Therefore,inselectedpatientsatveryhighriskforthrombosis,aloading
doseof300or600mgshouldbeconsidered.

MONITORINGOFCLOPIDOGREL:
Itisadvisabletoobtainabaselinecompletebloodcountpriortoinitiatingclopidogrel.Ongoing
monitoringofcoagulationparametersinpatientstakingclopidogrelisnotrequired.

ADVERSEEFFECTSOFCLOPIDOGREL:
Themostcommonadversereactiontoclopidogrelisanincreasedrateofbruisingandbleeding.The
riskofbleedingisincreasedwhenclopidogrelistakenwithASAandparticularlyincreasedwhen
clopidogrelistakenwithananticoagulant.Gastrointestinalbleedinghasbeenreported.Skinrashis
uncommon.Blooddisorderssuchasagranulocytosis,granulocytopenia,aplasticanemia,neutropenia,
andthrombocytopeniahavebeenreported,butarerareevents.

PERIPROCEDURALMANAGEMENTOFPATIENTSTAKINGCLOPIDOGREL:
Clopidogrelshouldbediscontinued57dayspriortoaninvasiveprocedure,and710dayspriorto
procedureswithahighbleedingrisk.However,cautionshouldbeusedindiscontinuingclopidogrelin
patientsathighriskofthromboticevents,includingthosewithrecentlyimplantedcoronarystents,
andconsultationwithaspecialistisadvised.Thereisincreasedriskofstentthrombosiswhen
antiplatelettherapyisdiscontinuedpriorto1yearfollowingstentimplantation.Theriskisgreaterin
patientswithdrugelutingstentsversusbaremetalstents.Ifpossible,itisrecommendedtodefer
surgeryforatleast612monthsafterdrugelutingstentplacement,andtodefersurgeryforatleast6
weeksafterbaremetalstentplacement.Forpatientswhorequirenonemergencysurgerywithin6
monthsofadrugelutingstentorwithin6weeksofabaremetalstent,oneofthreeapproachesis
used(consultationwithaspecialistisadvised):
1. Continuethedualantiplatelettherapywithoutinterruption(especiallyifrecentstent)
2. Continueaspirinandholdclopidogrel5dayspreop
3. Holdtheoralantiplatelettherapy5dayspreop,admitthepatientandstartintravenous
eptifibatide

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SPECIALCONSIDERATIONS:
Geneticpolymorphismsoftheenzymesthatactivatetheprodrug,clopidogrel,toitsactive
metabolitemayleadtoreducedbenefitofclopidogrel.However,specifictestingforthesevariantsis
notrecommended.
Protonpumpinhibitors:Someprotonpumpinhibitorsarestrong2C19inhibitorsthatcanreducethe
effectofclopidogrelonplateletaggregationandcanincreasetheriskofrecurrentcardiovascular
events.Pantoprazoleisnotastrong2C19inhibitorandshouldbeusedwheneveraprotonpump
inhibitorisrequired.
ComparedtotheotherP2Y12plateletinhibitors:Prasugrelandticagrelorhavefasterandgreater
plateletinhibitionthanclopidogrelaswellaslessinterindividualvariabilityintheireffect.Ingeneral,
theyarealsomoreeffectivethanclopidogrel,resultinmorebleedingandaremorecostly.

OTHERRELEVANTTHROMBOSISCANADACLINICALGUIDES:

AcetylSalicylicAcid(ASA)
NonSTElevationAcuteCoronarySyndrome:OutpatientAntithromboticManagement
PeripheralArterialDisease
Prasugrel(Effient)
STElevationMyocardialInfarction:OutpatientAntithromboticManagement
StrokePreventioninAtrialFibrillation
Ticagrelor(Brilinta)

REFERENCES:
Verma,Atul,etal.2014focusedupdateoftheCanadianCardiovascularSocietyguidelinesforthe
managementofatrialfibrillation.CanadianJournalofCardiology30.10(2014):11141130.
BellAD,etal.Theuseofantiplatelettherapyintheoutpatientsetting:CanadianCardiovascular
SocietyGuidelines.CanJCardiol2011;27(SupplA):S1S59.
ChuaD,NishiC.Newantiplateletagentsforcardiovasculardisease.CMAJ2013;185(16):14051411.
DouketisJD,etal.Perioperativemanagementofantithrombotictherapy:AntithromboticTherapyand
PreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidenceBasedClinical
PracticeGuidelines.Chest2012;141(2Suppl):e326S50S.
JuurlinkDN,etal.Apopulationbasedstudyofthedruginteractionbetweenprotonpumpinhibitors
andclopidogrel.CMAJ2009;180(7):713718.
MehtaSR,etal.Dosecomparisonsofclopidogrelandaspirininacutecoronarysyndromes.NEnglJ
Med2010;363(10):930942.

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DateofVersion:2015Oct10
Pleasenotethattheinformationcontainedhereinisnottobeinterpretedasanalternativetomedicaladvice
from your doctor or other professional healthcare provider. If you have any specific questions about any
medical matter, you should consult your doctor or other professional healthcare providers, and as such you
shouldneverdelayseekingmedicaladvice,disregardmedicaladviceordiscontinuemedicaltreatmentbecause
oftheinformationcontainedherein.

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