This is a repository copy of Choices for Potent Platelet Inhibition in Patients With Diabetes

Mellitus.

White Rose Research Online URL for this paper:http://eprints.whiterose.ac.uk/107507/

Version: Accepted Version

Article:

Storey, R.F. orcid.org/0000-0002-6677-6229 and Parker, W.A.E. orcid.org/0000-0002-7822-8852 (2016) Choices for Potent Platelet Inhibition in Patients With Diabetes Mellitus. Circulation, 134 (11). pp. 793-796. ISSN 0009-7322

https://doi.org/10.1161/CIRCULATIONAHA.116.023835

eprints@whiterose.ac.ukhttps://eprints.whiterose.ac.uk/

Reuse

Unless indicated otherwise, fulltext items are protected by copyright with all rights reserved. The copyright exception in section 29 of the Copyright, Designs and Patents Act 1988 allows the making of a single copy solely for the purpose of non-commercial research or private study within the limits of fair dealing. The publisher or other rights-holder may allow further reproduction and re-use of this version - refer to the White Rose Research Online record for this item. Where records identify the publisher as the copyright holder, users can verify any specific terms of use on the publisher’s website.

Takedown

If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing eprints@whiterose.ac.uk including the URL of the record and the reason for the withdrawal request.

Choices for potent platelet inhibition in patients with diabetes mellitus Robert F. Storey1,2, MD, DM, William A.E. Parker1,2, MD 1Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom 2Directorate of Cardiology and Cardiothoracic Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom Corresponding author: Professor Robert F. Storey, MD, DM Department of Infection, Immunity and Cardiovascular Science University of Sheffield Beech Hill Road Sheffield, S10 2RX United Kingdom Telephone +44-114-2712052 Fax +44-114-2711863 Email r.f.storey@sheffield.ac.uk Funding: None. Disclosures Robert F Storey: institutional research grants from AstraZeneca and PlaqueTec; consultancy fees from AstraZeneca, Aspen, ThermoFisher Scientific, Correvio, PlaqueTec and The Medicines Company; honoraria from AstraZeneca and Medscape; travel support from Medtronic. William AE Parker: honorarium from Medscape.

Diabetesmellitusprovideschallengestocliniciansseekingtooptimizethe

efficacyofpharmacologicaltherapiesforthemanagementandpreventionof

atherothromboticevents.Ontheonehand,itdrivestheprogressionof

atherosclerosis,leadingtothehighlythrombogenicruptureanderosionof

plaques,atthesametimeasincreasingthethrombogenicityofbloodthrough

modulationofplateletreactivity,enhancementofplasmacoagulabilityand

impairmentofendogenousfibrinolysis.[1]Ontheotherhand,itisassociated

withreducedpharmacodynamicactionoftraditionaloralantiplatelettherapies,

aspirinandclopidogrel,throughincreasedplateletturnoverand,inthecaseof

clopidogrel,impairmentofhepaticactivemetabolitegeneration,thusrendering

thesetherapieslesseffectivedespitetheclinicalimperativeformoreeffective

treatment.[1]Itwasthereforeinevitablethatmoreeffectivetreatmentsshould

bedevelopedfordiabetespatientsaswellasothersathighriskof

atherothromboticevents.Thisconceptiswellillustratedintheworkof

Angiolilloandcolleagueswhoherehavecomparedthepharmacodynamic

propertiesofprasugrelandticagrelorindiabetespatients.[2]

Akeycomponentoftherationaleforcomparingprasugrel’sandticagrelor’s

effectsindiabetespatientsisthedifferentpatternsofbenefitsseeninthe

diabetessubgroupsinthepivotalphase3studiesofthesedrugscomparedto

clopidogrel.[3,4]Withprasugrel,aparticularlymarkedearlybenefitinreduced

thromboticeventswasseeninthediabetessubgroupwhereas,withticagrelor,

therewasamoreprogressiveaccrualofbenefitover1year,including

progressivereductioninmortality.However,differencesinstudydesigncan

explainmuchofthedifferenceinthepatternsofearlybenefit:theclopidogrel

regimenwassubstantiallydifferentbetweenthetwostudies,withprasugrel

beingcomparedtoa300-mgloadingdoseofclopidogrel,oftengivenafter

completionofpercutaneouscoronaryintervention(PCI),whereasticagrelorwas

comparedtopretreatmentwithaclopidogrelloadingdoseof300to600mg.

Giventhehigherthromboticriskandlesserefficacyofclopidogrelindiabetes

patients,itisclearthata300mgloadingdoseadministeredafterPCIis“toolittle,

toolate”sowouldbepredictedtodriveahighereventratecomparedtomore

effectivepretreatmentregimens.Nevertheless,itwasimportanttoestablish

whetherornotanydifferencesinearlyandsustainedplateletinhibitionexist

betweenprasugrelandticagrelorindiabetespatients.

Thephase3resultsforbothprasugrelandticagrelorpointtobreakthroughsin

oralantiplatelettherapy.Thekeytoprasugrel’ssuccessisitsmoreefficient

productionofactivemetabolitecomparedtovariableandunreliableclopidogrel

activemetaboliteproduction.[5]Althoughthesecondstepinprasugrelactive

metaboliteformationreliesonhepaticcytochromeP450(CYP)enzymes,inthe

samewaythatbothstepsinclopidogrelactivemetaboliteformationdo,the

availabilityofseveraldifferentCYPpathwaysforgeneratingprasugrelactive

metaboliteandthelackofalternativepathwaysforinactivationofprasugreland

itsintermediatemetabolitemeanthatsufficientlevelsofthisactivemetabolite

canbeproducedinordertobindirreversiblytomostoftheP2Y12receptorson

circulatingplatelets.Thisirreversibleinhibitionmustoccurbeforetheactive

metabolitelevelsfalltosubtherapeuticlevelswithinafewhoursafterprasugrel

absorptionasaconsequenceofitsshortdistributionhalf-life(about30-60

minutes)(Figure1).

Theexplanationforticagrelor’ssuccessisdifferent.Ticagrelorbelongstoaclass

ofdrugthatisdistinctfromthethienopyridinesprasugrelandclopidogreland

reliesonsustainedplasmalevelsofbothticagrelorand,toalesserextent,its

activemetabolitetoprovidepotentplateletP2Y12inhibition(Figure1).[5]Asa

consequenceofitsreversiblebindingtoanallostericsiteonP2Y12distinctfrom

theADPbindingsite,itsinhibitoryeffectsresolvewhenplasmalevelsof

ticagreloranditsactivemetabolitefalltosubtherapeuticlevelssuchthatthe

inhibitorsdissociatefromtheplateletP2Y12receptors.Plasmahalflivesof6to

12hoursforbothinhibitorymoleculesensuresconsistentandsustainedP2Y12

inhibitionwithtwice-dailyticagrelordosing.[6,7]BeyondP2Y12inhibition,

ticagreloralsopossessesasecondproperty,whichisaweakinhibitionofcellular

adenosineuptakeviaequilibrativenucleosidetransporter1(ENT-1).[8]How

muchthiscontributestotheclinicaleffectsofticagrelorremainstobe

establishedbutitmayexplainsomeoftheclinicalefficacyaswellassomeofthe

adverseeffectssuchasdyspnea.

Intheirstudy,Angiolilloetaldemonstratehowthedifferentpharmacokinetic

characteristicsofprasugrelandticagrelorlead,inbothcases,toahighmean

levelofplateletP2Y12inhibitionat2hoursafteraloadingdoseindiabetes

patients.Despitethis,aminorityofthepatientsexhibitedhighplateletreactivity

atthistimepointindicatingthattheyhadnotyetreachedasteadystatelevelof

plateletinhibition.Inthecaseofprasugrel,previousstudieshavesuggested

sloweronsetofactioninstablepatientpopulations[9,10]comparedtothe

healthyvolunteerstudiesthatindicateimpressiveeffectat1hourandsteady

stateinhibitionat2hoursafterloadingdose.[11]Previousworksuggested

ticagrelorachievessteadystateinhibitionby2hoursinpatientswithstable

coronaryarterydisease,[7]sotheresultsinthecurrentstudyraisethequestion

astowhetherdiabetesmellitusmightbeassociatedwithslowerabsorptionof

ticagrelorinsomepatients.Thisisdistinctfromtheeffectofmorphinewhich

delaysgastricemptyingandthereforedelaystheintestinalabsorptionandonset

ofactionofprasugrelandticagrelorinpatientswithST-elevationmyocardial

infarctionundergoingprimarypercutaneouscoronaryintervention(PPCI)

(Figure1).[10,12,13]Therateofonsetofactionofprasugrelorticagreloris

particularlyimportantinPPCIpatientsandthevariousfactorsthatleadto

delayedonsetofactioninthesepatientssupporttheuseofparenteral

antithrombotictherapytocoverthetimeperiodduringwhichthedrugsare

absorbedinordertopreventacutestentthrombosis.

Somedoubtsareraisedinthecurrentstudyastowhetherornotticagrelor

providesgreaterplateletP2Y12inhibitionduringmaintenancetherapycompared

toprasugrel.WeareinclinedtotrusttheresultsoftheVerifyNowP2Y12assay

thatshowedaslightlygreaterlevelofinhibitionwithticagrelor.Thereare

multiplestrandsofevidenceunderlyingthisopinion.Firstly,therewasa

deliberatedecisiontodevelopa10-mgdailymaintenancedoseofprasugrel

comparedtoprasugreldosesof15mgorgreaterinordertominimizetheexcess

ofbleedingcomparedtoclopidogreltherapy[14]andthisexplainsoffsetofsome

oftheplateletinhibitionaftertheeffectsoftheprasugrelloadingdosehaveworn

off.[9]Thiscontrastswiththedecisiontodevelopamaintenancedoseof

ticagrelorthatsustainsthehighlevelsofplateletinhibitionseenfollowinga

loadingdose.[6][7]Secondly,severalstudieshavepreviouslyobservedhigher

levelsofplateletP2Y12inhibitionwithticagrelorcomparedtoprasugrel

maintenancetherapy,includinginpatientswithdiabetesmellitus.[15]Thirdly,

wehavefoundtheVerifyNowP2Y12assaytobeparticularlydiscriminatingand

reliableinassessingtherapeuticlevelsofplateletP2Y12inhibitioncomparedto

someoftheotherassays.[6,16]Whethertheobserveddifferencesinlong-term

levelsofplateletP2Y12inhibitionwiththetwodrugstranslateintorelevant

differencesinefficacyandsafetyoutcomesisunknown,particularlyinviewof

potentialoractualdifferencesineffectsunrelatedtoP2Y12inhibition,andthis

requiressufficientlypoweredhead-to-headstudies.

AngiolilloetaldemonstratehowprasugrelandticagrelorinhibitnotonlyADP-

inducedplateletaggregationbutalsoplateletaggregationinducedbyagonists

activatingthereceptorpathwaysforcollagen,thromboxaneA2andthrombin.

ThisreflectsthecentralroleoftheplateletP2Y12receptorinamplifyingthe

responsesmediatedbynumerousreceptorpathwaysandexplainswhythis

receptorhasproventobesuchasuccessfultargetinthemanagementof

cardiovasculardisease(Figure1).[5]Whilstitistemptingtoinferthatthismight

meanaspirincanbeabandonedasaco-medicationwithprasugrelorticagrelor,

suchaninferencemustbecautionedagainstinhigh-riskpatients,suchasthose

withdiabetesandhistoryofacutecoronarysyndrome.Theeffectsofaspirinare

additivetothoseofaP2Y12inhibitor,particularlywithregardtocollagen-

inducedplateletactivation(Figure1),andtheeffectsofP2Y12inhibitioncanbe

overwhelmedbyhighlevelsofplateletactivation.Consequentlyitisimportantto

waitfortheresultsofclinicalstudiesassessingP2Y12inhibitormonotherapy

and,furthermore,tolookcriticallyatresultsinsubgroupsatdifferentlevelsof

riskbeforejudgingthataspirincanbesafelyabandonedinhigh-riskindividuals.

References

1. ParkY,FranchiF,RolliniF,AngiolilloDJ.AntithromboticTherapyfor

SecondaryPreventioninPatientsWithDiabetesMellitusandCoronary

ArteryDisease.CircJ.2016;80:791-801.

2. FranchiF,RolliniF,AggarwalN,HuJ,KuretiM,DurairajA,DuarteV,Cho

JR,BeenL,ZenniMM,BassTA,AngiolilloDJ.APharmacodynamic

ComparisonofPrasugrelversusTicagrelorinPatientsWithType2

DiabetesMellitusandCoronaryArteryDisease:TheOPTIMUS

(OptimizingAntiplateletTherapyinDiabetesMellitus)-4study.

Circulation.2016;inpress.

3. WiviottSD,BraunwaldE,AngiolilloDJ,MeiselS,DalbyAJ,VerheugtFW,

GoodmanSG,CorbalanR,PurdyDA,MurphySA,McCabeCH,AntmanEM,

fortheTriton-TimiInvestigators.GreaterClinicalBenefitofMore

IntensiveOralAntiplateletTherapyWithPrasugrelinPatientsWith

DiabetesMellitusintheTrialtoAssessImprovementinTherapeutic

OutcomesbyOptimizingPlateletInhibitionWithPrasugrel-Thrombolysis

inMyocardialInfarction38.Circulation.2008;118:1626-1636.

4. JamesS,AngiolilloDJ,CornelJH,ErlingeD,HustedS,KontnyF,MayaJ,

NicolauJC,SpinarJ,StoreyRF,StevensSR,WallentinL.Ticagrelorvs.

clopidogrelinpatientswithacutecoronarysyndromesanddiabetes:a

substudyfromthePLATeletinhibitionandpatientOutcomes(PLATO)

trial.EurHeartJ.2010;31:3006-3016.

5. AhmadS,StoreyRF.Developmentandclinicaluseofprasugreland

ticagrelor.CurrPharmDes.2012;18:5240-60.

6. StoreyRF,AngiolilloD,PatilS,DesaiB,EcobR,HustedS,EmanuelssonH,

CannonC,BeckerR,WallentinL.InhibitoryEffectsofTicagrelor

ComparedtoClopidogrelonPlateletFunctioninPatientswithAcute

CoronarySyndromes:thePLATOPLATELETSubstudyJAmCollCardiol.

2010;56:1456-62.

7. GurbelPA,BlidenKP,ButlerK,TantryUS,GesheffT,WeiC,TengR,

AntoninoMJ,PatilSB,KarunakaranA,KereiakesDJ,ParisC,PurdyD,

WilsonV,LedleyGS,StoreyRF.RandomizedDouble-BlindAssessmentof

theONSETandOFFSetoftheAntiplateletEffectsofTicagrelorversus

ClopidogrelinPatientswithStableCoronaryArteryDisease:The

ONSET/OFFSETStudy.Circulation.2009;120:2577-85.

8. ArmstrongD,SummersC,EwartL,NylanderS,SidawayJE,vanGiezenJJJ.

CharacterizationoftheAdenosinePharmacologyofTicagrelorReveals

TherapeuticallyRelevantInhibitionofEquilibrativeNucleoside

Transporter1.JournalofCardiovascularPharmacologyandTherapeutics.

2014;19:209-219.

9. WiviottSD,TrenkD,FrelingerAL,O'DonoghueM,NeumannF-J,

MichelsonAD,AngiolilloDJ,HodH,MontalescotG,MillerDL,Jakubowski

JA,CairnsR,MurphySA,McCabeCH,AntmanEM,BraunwaldE,fortheP-

TI.PrasugrelComparedWithHighLoading-andMaintenance-Dose

ClopidogrelinPatientsWithPlannedPercutaneousCoronary

Intervention:ThePrasugrelinComparisontoClopidogrelforInhibitionof

PlateletActivationandAggregationThrombolysisinMyocardial

Infarction44Trial.Circulation.2007;116:2923-2932.

10. ThomasMR,MortonAC,HossainR,ChenB,LuoL,ShahariNN,HuaP,

BenistonRG,JudgeHM,StoreyRF.Morphinedelaystheonsetofactionof

prasugrelinpatientswithpriorhistoryofST-elevationmyocardial

infarction.ThrombHaemost.2016;116:96-102.

11. BrandtJ,PayneC,WiviottS,WeerakkodyG,FaridN,SmallD,Jakubowski

J,NaganumaH,WintersK.Acomparisonofprasugrelandclopidogrel

loadingdosesonplateletfunction:magnitudeofplateletinhibitionis

relatedtoactivemetaboliteformation.AmHeartJ.2007;153:66.e9-e16.

12. AlexopoulosD,XanthopoulouI,GkizasV,KassimisG,TheodoropoulosKC,

MakrisG,KoutsogiannisN,DamelouA,TsigkasG,DavlourosP,HahalisG.

RandomizedAssessmentofTicagrelorVersusPrasugrelAntiplatelet

EffectsinPatientswithST-Segment–ElevationMyocardialInfarction.

Circulation:CardiovascularInterventions.2012;5:797-804.

13. SilvainJ,StoreyRF,CaylaG,EsteveJB,DillingerJG,RousseauH,Tsatsaris

A,BaradatC,SalhiN,HammCW,LapostolleF,LassenJF,ColletJP,Ten

BergJM,Van'tHofAW,MontalescotG.P2Y12receptorinhibitionand

effectofmorphineinpatientsundergoingprimaryPCIforST-segment

elevationmyocardialinfarction.ThePRIVATE-ATLANTICstudy.Thromb

Haemost.2016;116:online.

14. WiviottSD,AntmanEM,GibsonCM,MontalescotG,RiesmeyerJ,

WeerakkodyG,WintersKJ,WarmkeJW,McCabeCH,BraunwaldE.

Evaluationofprasugrelcomparedwithclopidogrelinpatientswithacute

coronarysyndromes:designandrationalefortheTRialtoassess

ImprovementinTherapeuticOutcomesbyoptimizingplateletInhibitioN

withprasugrelThrombolysisInMyocardialInfarction38(TRITON-TIMI

38).AmHeartJ.2006;152:627-635.

15. AlexopoulosD,XanthopoulouI,MavronasiouE,StavrouK,SiapikaA,

TsoniE,DavlourosP.RandomizedAssessmentofTicagrelorVersus

PrasugrelAntiplateletEffectsinPatientsWithDiabetesMellitus.Diabetes

Care.2013;36:2211-6.

16. StoreyRF,AngiolilloDJ,BonacaMP,ThomasMR,JudgeHM,RolliniF,

FranchiF,AhsanAJ,BhattDL,KuderJF,StegPG,CohenM,MuthusamyR,

BraunwaldE,SabatineMS.PlateletInhibitionwithTicagrelor60mg

Comparedwith90mgTwice-dailyinthePEGASUS-TIMI54study.JAm

CollCardiol.2016;67:1145-54.

Figurelegend

Figure1.Absorptionandeffectsoftheorally-activeantiplateletdrugsaspirin,

clopidogrel,prasugrelandticagrelor.A2A-Adenosinereceptor2A;AA–

Arachidonicacid;ADP–Adenosinediphosphate;CAM–Clopidogrelactive

metabolite;CIM–Clopidogrelinactivemetabolite;ENT1–Equilibrative

nucleosidetransporter1;GPVI–GlycoproteinVIreceptor;P2Y12-PlateletP2Y12

ADPreceptor;PAM–Prasugrelactivemetabolite;PAR1–Protease-activated

receptor1;PAR4–Protease-activatedreceptor4;TAM–Ticagreloractive

metabolite;TPα–Thromboxanereceptor[αisoform];TxA2–ThromboxaneA2.

Figure1