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Gosling, R., Yazdani, M., Parviz, Y. et al. (5 more authors) (2017) Comparison of P2Y12 inhibitors for mortality and stent thrombosis in patients with acute coronary syndromes: Single center study of 10 793 consecutive ‘real-world’ patients. Platelets. ISSN 0953-7104

https://doi.org/10.1080/09537104.2017.1280601

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1

ComparisonofP2Y12inhibitorsformortalityandstentthrombosisinpatientswithacute

coronarysyndromes:singlecentrestudyof10,793consecutive‘real-world’patients

Authors:RebeccaGosling1,2,MominaYazdani

2,YasirParviz

1,IanRHall

1,EverDGrech

1,

JulianPGunn1,2,RobertFStorey

1,2,JavaidIqbal

1

Authors’affiliations:

1SouthYorkshireCardiothoracicCentre,NorthernGeneralHospital,Sheffield,UK

2DepartmentofInfection,ImmunityandCardiovascularDisease,UniversityofSheffield,UK

RunningTitle:ComparisonofP2Y12inhibitorsinACSpatients

Keywords:acutecoronarysyndromes,clopidogrel,ticagrelor,prasugrel,percutaneous

coronaryintervention,stentthrombosis

CorrespondingAuthor:

ProfessorRobertF.Storey,

CardiovascularResearchUnit,

CentreforBiomedicalResearch,

NorthernGeneralHospital,

HerriesRoad,Sheffield,S57AU,UnitedKingdom

Tel:+441142159554

Fax:+441142711863

Email:r.f.storey@sheffield.ac.uk

2

ABSTRACT

Threeoral platelet P2Y12 inhibitors, clopidogrel, prasugrel and ticagrelor, are available for

reducing the risk of cardiovascular death and stent thrombosis in patients with acute

coronarysyndromes(ACS).Wesoughttocomparetheefficacyoftheseantiplateletdrugsin

contemporarypractice.

Datawerecollectedfor10,793consecutiveACSpatientsundergoingcoronaryangiography

at Sheffield, UK (2009-2015). Since prasugrel use was mostly restricted to the STEMI

subgroup,clopidogrelandticagrelorwerecomparedforallACSpatientsandallthreeagents

were compared in the STEMI subgroup. Differences in outcomes were evaluated at 12

monthsbyKMcurvesandlog-ranktestafteradjustmentforindependentriskfactors.

Of 10,793 patients with ACS (36% STEMI), 43% (4653) received clopidogrel, 11% (1223)

prasugreland46%(4917)ticagrelor,withaspirinforall.Intheoverallgroup,ticagrelorwas

associatedwithlowerall-causemortalitycomparedwithclopidogrel(adjustedhazardratio

(adjHR)0.82,95%confidenceintervals(CI)0.71-0.96,p=0.01).IntheSTEMIsubgroup,both

prasugrelandticagrelorwereassociatedwithalowermortalitycomparedwithclopidogrel

(prasugrelvsclopidogrel:adjHR0.65,CI0.48-0.89,p=0.007;ticagrelorvsclopidogrel:adjHR

0.70, CI 0.61-0.99, p = 0.05). Of the 7,595 patients who underwent PCI, 78 (1.0%) had

definite stent thrombosis by 12 months. Patients treated with ticagrelor had a lower

incidence of definite stent thrombosis compared with clopidogrel (0.6% vs. 1.1%; adjHR

0.51, CI 0.29-0.89, p=0.03). In the STEMI subgroup, there was no significant difference

betweenthethreegroups(ticagrelor1.0%,clopidogrel=1.5%,prasugrel=1.6%;p=0.29).

In conclusion, ticagrelor was superior to clopidogrel for reduction of both mortality and

stent thrombosis in unselected invasively-managed ACS patients. In STEMI patients, both

3

ticagrelor and prasugrelwere associatedwith lowermortality comparedwith clopidogrel

buttherewasnosignificantdifferenceintheincidenceofstentthrombosis.

4

INTRODUCTION

Antiplateletagentsarethemainstayoftreatmentforpatientswithacutecoronary

syndromes(ACS)[1].ThemajorityofpatientswithACSundergocoronaryrevascularization

withpercutaneouscoronaryintervention(PCI)or,lessfrequently,coronaryarterybypass

graftsurgery(CABG)[2,3].Antiplatelettherapyisvitalinthesepatientstopreventfuture

ischaemiceventsand,inPCI-treatedpatients,stentthrombosis[4-8].Thechoiceof

antiplateletagentsforpatientswithACS,especiallythosewithST-segmentelevation

myocardialinfarction(STEMI),remainsdebatable.Itisrecommendedthatallthesepatients

shouldreceivedualantiplatelettherapyforatleast12months[1].Aspirinshouldbe

continuedindefinitelyandlowdose(75-100mgdaily)ispreferredoverhigherdoses.

Clopidogrel,aP2Y12inhibitor,wasthecommonlyused2ndantiplateletagentinthelast

decade.However,itisapro-drugwhichrequireshepaticactivationbythecytochromeP450

systemandsomepatientsproduceineffectivelevelsofactivemetaboliteleadingtopoor

pharmacodynamicresponseor‘resistance’[9].Consequently,newerP2Y12inhibitors,

prasugrelandticagrelor,havebeendevelopedinrecentyears[9].Prasugreltherapy,

comparedwithclopidogrel,inACSpatientsundergoingPCIhassignificantlyreducedratesof

ischaemicevents,includingstentthrombosis,butwithanincreasedriskofbleedingandno

significanteffecton1-yearmortality[10].Ticagrelor,anon-thienopyridineP2Y12inhibitor,is

anactivedrug,which,followingintestinalabsorption,canrapidlyachieveadequatelevelsof

plateletinhibition.ThePLATOtrialhasshownthatticagrelorreduces1-yearmortalityin

patientswithACS,comparedwithclopidogrel[11].InPLATO,therewasnodifferencein

CABG-relatedbleedingwithticagrelorcomparedwithclopidogrelbuttherelativeincreasein

non-CABG-relatedbleeding,includingthosemanagedwithplannedinvasivestrategy,was

similartothatseenpreviouslywithprasugrel[11,12].However,thereisverylimiteddataon

5

comparisonofnewerP2Y12inhibitorswithclopidogrelinunselectedACSpatients[13].

Furthermore,onlyoneclinicaltrialwithamodestsamplesize(1230patients)hasdirectly

comparedprasugrelwithticagrelorandthishasshownnodifferenceinoutcomes,althoughit

wasterminatedearlyforfutility[14],andtheresultsoffurthercomparativeefficacystudies

areawaited[15].Weaimedtoinvestigatetheeffectoftheintroductionofprasugreland

ticagreloronall-causemortalityandstentthrombosisinthislargesingle-centre,all-comers

registry.

METHODS

Studydesignandpopulation

Datawerecollectedprospectivelyforconsecutivepatientsattendingthecardiac

catheterizationlaboratoryofSouthYorkshireCardiothoracicCentreandundergoing

coronaryangiographybetweenJan2009andJune2015forthemanagementofACS.This

centreistheonlyoneprovidingaPCIandCABGservicetothepopulationinandaround

Sheffield,atotalof1.8millionpeople.ForpatientsundergoingPCI,theprocedureand

adjunctivepharmacotherapywasatthediscretionoftheoperator,butadheredtorelevant

local,national,andinternationalguidelines.Consequently,therewasagradualevolutionof

treatmentduringthecourseofthestudyfromuseofclopidogrelastheonlyP2Y12inhibitor

in2009tointroductionoftheoptionofprasugrelin2010,predominantlyforSTEMI,

followedbytheintroductionofticagrelorasfirst-linetherapyinFebruary2012,accordingto

ourpreviouslypublishedprotocolsthatincludedtheprescriptionofhigh-intensitystatin

therapy,angiotensinpathwayinhibitorsandbeta-blockersthroughoutthestudyperiod

6

[16].Ofparticularnote,dualantiplatelettherapyfor12monthsforallACSpatientswasthe

defaultapproachthroughoutthestudyperiod.After12months,patientswereprescribed

aspirinindefinitelyandso,tostudytheimpactofdualantiplatelettherapyonclinical

outcomes,follow-upwaslimitedto12months.Dataonadherenceandswitchingof

antiplatelettherapywerenotcollectedandthereforeouranalysiswasbasedonthe

intentiontotreatpatientswithdualantiplatelettherapyfor12months.Thegroupswere

definedaspertheantiplateletagentprescribedonadmissiontothecatheterlaboratory.

Anypatientwhohadaneventwhilstinhospitalresultinginachangeofantiplateletwere

definedaspertheoriginalantiplateletprescribed.Intra-proceduralunfractionatedheparin,

andnotbivalirudin,wasthedefaultanticoagulationtherapy,alongwithselectiveuseofa

glycoproteinIIb/IIIainhibitor,attheoperators’discretion.Allpatientsweretreatedwith2nd

generationdrug-elutingstentsorbare-metalstents,attheoperators’discretion.Therewere

noexclusioncriteria.TherewasincreasingprovisionofaprimaryPCIservicetothe

populationduringthecourseofthestudy,accountingforahigherproportionofpatients

withSTEMIinthelateryears.

DataCollection

Demographic,clinical,andangiographicdatawerecollectedprospectively.Renalfailurewas

definedascreatininelevelof>200μmol/Landcardiogenicshockassystolicbloodpressure

<100mmHgalongwithsignsorsymptomsofhypoperfusion.Theoutcomedatawere

collectedusingthenationalmortalitydatabaseandthehospitalelectronicdatabaseand

patientrecordsforSouthYorkshireCardiothoracicCentre.Otherpatientrecordswerenot

availableforthisanalysisandsowewerenotabletoassessnon-fatalischaemicand

bleedingoutcomes.TheAcademicResearchConsortium(ARC)criteriawereusedtodefine

7

definitestentthrombosis[17]andourdatawerebasedontheassumptionthatsurvivorsof

stentthrombosiswouldpresentorbereferredbacktoourcatheterlaboratorysincethisis

theonlyPCIcentrefortheregionandtherewasnochangeinthisarrangementduringthe

courseofthedatacollection.Thecaseswereadjudicatedbyreviewoftheangiographyfilms

bytwocardiologistsindependentlyand,incasesofdifferenceofopinion,byathird

cardiologistasareferee.

Dataanalysis

Dataarepresentedasmean±SDoraspercentages(proportions)unlessstatedotherwise.

AnalysiswascarriedoutusingStudent’st-testorone-wayANOVAforcontinuousvariables

andChi-squaredorFisher’sexacttestforcategoricalvariables.Variableswithsignificant

trend(p≤0.1)wereenteredinaCoxproportionalhazardsmodeltoidentifyfactors

independentlyassociatedwithmortalityandstentthrombosis.Differenceinoutcomes

amongpatientsreceivingdifferentP2Y12inhibitorswasevaluatedbyKaplan-Meiersurvival

curvesandlog-ranktest.ClopidogrelandticagrelorwerecomparedforallACSpatientsand

allthreeagentswerecomparedintheSTEMIsubgroup.Allstatisticalanalyseswere

performedusingSPSSversion21(IBMSPSSInc.,NewYork,USA)andRsoftwareversion-

2.13.1(RFoundationforStatisticalComputing,Vienna,Austria).

RESULTS

PatientCharacteristics

Duringthestudyperiod,10,793patientswithACSunderwentcoronaryangiography.The

meanagewas63.6±12.7years;70%ofthepatientsweremalesand15%haddiabetes.

8

Abouttwo-thirds(64%)oftheprocedureswereperformedfornon-STelevationacute

coronarysyndrome(NSTE-ACS)andtheremaining(36%)wereforSTEMI.OfallACS

patients,43%(n=4653)receivedclopidogrel,46%(n=4917)receivedticagrelorand11%

(n=1223)receivedprasugrel.Oftheprasugrel-treatedpatients,93%(n=1136)hadSTEMI

andonly7%(n=87)hadNSTE-ACSsoonlytheSTEMIcohortwasincludedintheanalyses.

ACSpatientstreatedwithclopidogrelwereslightlyolderbutlessfrequentlyhadSTEMIor

renalfailurecomparedtothosetreatedwithticagrelor(Table1).Thispartlyreflectedan

increasingprovisionofprimaryPCIforSTEMIduringtheyearsinwhichprasugrelandthen

ticagrelorwereintroducedasoptions.

Ofthe3920(36%)ofpatientswhounderwentcoronaryangiographyforSTEMI,themean

agewas62.9±12.9,73%weremaleand12%haddiabetes.29%(n=1130)received

clopidogrel,29%(n=1136)prasugreland42%(n=1654)ticagrelor.Differenceswerenotedin

someclinicalcharacteristicsbetweenthethreegroups(Table2):prasugrel-treatedpatients

wereyoungerandclopidogrel-treatedpatientsolderthanthosetreatedwithticagrelor;

priorhistoryofstroke/TIAwasmorecommoninclopidogrel-treatedpatients;and

cardiogenicshockwasmorecommoninticagrelor-treatedpatients.

All-causemortalityatoneyear

Ofthe10,793patientswithACS,787(7.3%)diedwithinoneyear.Theuseofticagrelorwas

associatedwithsignificantlylowerall-causemortalityat1-yearcomparedwithclopidogrel

(Figure1A).Theuseofclopidogrelwasanindependentriskfactorformortalityinmultiple

regressionanalysis(Table3).Afteradjustmentfortheindependentriskfactors,therewas

stilllowermortalityinpatientstreatedwithticagrelor(Figure1B).

9

Ofthe3920patientswithSTEMI,340(8.7%)diedwithinoneyear.Theuseofprasugreland

ticagrelor(vsclopidogrel)wasassociatedwithsignificantlylowerall-causemortalityat1-

year(Figure1C).Afteradjustmentforindependentriskfactors,therewasstilllower

mortalityinpatientstreatedwithprasugrelandticagrelorcomparedwithclopidogrel

(Figure1D).

Incidenceofdefinitestentthrombosis

OutofallACSpatients,7595(70%)weretreatedwithPCI.Outofthesepatients,2880(38%)

patientsreceivedclopidogreland3493(46%)ticagrelor.Theremaining1222(16%)received

prasugrel.

AmongPCI-treatedACSpatients,78(1.0%)developeddefinitestentthrombosiswithin12

months.Ofthese,24(31%)wereacute(<24hours),32(41%)subacute(1-30days)and22

(28%)late(31-365days).Halfofthestentthrombosiseventsinpatientstreatedwith

prasugrelorticagrelorwereacutewhereasaboutone-quarteroftheseeventswereacutein

clopidogrel-treatedpatients(Table4).

Theuseofticagrelorwasassociatedwithalowerincidenceofdefinitestentthrombosisat

oneyearcomparedwithclopidogrel(Figure2A).Clopidogrelwasanindependentriskfactor

fordefinitestentthrombosisinmultipleregressionanalysis(Table5).Afteradjustmentfor

independentriskfactors,therewasstilllowerriskofstentthrombosisinticagrelor-treated

patients(Figure2B).

Ofthe3881patientsundergoingPCIforSTEMI,51(1.3%)developedstentthrombosis

within12months.Therewasnosignificantdifferenceintheincidenceofstentthrombosis

betweenclopidogrel-,prasugrel-andticagrelor-treatedpatientsinunadjusted(Figure2C)or

10

adjustedanalysis(Figure2D).

DISCUSSION

Inthis'real-world'registryof10,793patientswithACS,wefoundthatticagrelorwas

associatedwithareductioninmortalitycomparedwithclopidogrelininvasively-managed

ACSpatients,includingafterwehadadjustedfordifferencesinbaselinecharacteristicsthat

wereattributabletoincreasingprovisionofprimaryPCIforSTEMIduringthestudyperiod

andcontraindicationstotheuseofticagrelororprasugrel.Additionally,bothticagrelorand

prasugrelwereassociatedwithareductioninmortalitycomparedtoclopidogrelinthe

STEMIcohort.InallACSpatients,ticagrelorwasalsoassociatedwithlowerratesofstent

thrombosiscomparedtoclopidogrel;however,therewasnosignificantdifferenceinthe

STEMIsubgroup.

DualantiplatelettherapyintheformofaspirinandaP2Y12inhibitordecreasestherisksof

myocardialinfarction,recurrentischaemiaandcardiovasculardeathinabroadspectrumof

ACSpatientsandreducestheriskofstentthrombosisanditssequelaeinPCI-treated

patients[18,19].Theoriginaldualantiplateletregimenconsistedofaspirinplusticlopidine,

whichshowedsuperioritytoaspirinaloneoraspirinpluswarfarin[20,21].Ticlopidinefell

outoffavourduetohaematologicalside-effectsandwasreplacedbythesaferandequally

effectivealternativeofclopidogrel[18,22].However,morecontemporaryconcernsof

resistanceanddrug-druginteractionswithclopidogrelhaveledtothedevelopmentofthe

neweroralP2Y12antagonists,prasugrelandticagrelor[23,24].Prasugrelisapro-drug

metabolizedtoitsactiveformbyCYP3A4andCYP2B6withamorerapidonsetandhigher

11

meanlevelofplateletinhibitioncomparedtoclopidogrel.PatientswithACSundergoingPCI

andtreatedwithdualantiplateletincludingprasugrelhadlowerratesofmyocardial

infarction,urgenttarget-vesselrevascularization,andstentthrombosisascomparedtodual

antiplatelettherapywithclopidogrelat15-monthsfollow-upoftheirindexPCIinTRITON-

TIMI-38[10].Thisbenefitwasmostlyrelatedtoareductionintheratesofnon-fatal

myocardialinfarction(7.4%withprasugrelvs9.7%withclopidogrel;HR0.76;95%CI0.67to

0.85;P<0.001)andlowerratesofstentthrombosis(1.1%vs2.4%;P<0.001).Ticagrelorisa

direct-acting,reversibly-bindingagentwithsimilarlyrapidonsetofactioncomparedto

clopidogrelandrequirestwice-dailyadministration.InthePLATOstudy,amongpatients

withACStreatedwithorwithoutaninvasivestrategy,therewasareductioninthe

compositeendpointofdeathfromvascularcauses,myocardialinfarctionorstrokewhen

ticagrelorwasincludedinthedualantiplatelettherapyregimenascomparedtoclopidogrel

(9.8%forticagrelorvs11.7%withclopidogrel;HR0.84;95%CI0.77to0.92;p<0.001)[11].

Ticagreloralsosignificantlyreducedtherateofstentthrombosis[25].Arecentmeta-

analysisoftherandomizedtrialshasalsoshownthebeneficialeffectofnewP2Y12inhibitors

overclopidogrel[26].TheSWEDEHEARTregistryconfirmedthebenefitofticagrelor(vs

clopidogrel)inareal-worldregistryof45,073patientsalbeitwithahigherbleedingrate

[13].Ourdatafromalargeall-comerspopulationhavefurtherconfirmedthebenefitof

ticagrelorinallACSpatientsonbothmortalityandstentthrombosisthatwasseeninthe

clinicaltrialsandrecentregistry.

Bothprasugrelandticagrelorwereassociatedwithreducedmortalitycomparedto

clopidogrelinpatientswithSTEMI,howevertherewasnosignificantdifferencebetweenthe

twoneweragents(Figures1Dand2D).ForpatientswithNSTE-ACS,ticagreloris

12

recommendedinpreferencetoclopidogrelregardlessoftreatmentstrategy[1].Inthe

PLATOtrial,ticagrelorwassuperiortoclopidogrelforpatientswithNSTE-ACSwhether

treatedmedicallyorwithrevascularization[27,28].WhereastheTRITON-TIMItrialshowed

benefitsofprasugrelcomparedtoclopidogrelinpatientswithNSTE-ACStreatedwithPCI,

theTRILOGYACStrialfoundnobenefitwithprasugrelcomparedtoclopidogrelinpatients

withmedically-treatedACS[29].Consequently,prasugrelisonlyrecommendedforNSTE-

ACSmanagedwithPCI.ForpatientswithSTEMImanagedwithprimaryPCI,bothprasugrel

andticagrelorarerecommendedinpreferencetoclopidogrelforpatientswithout

contraindications[3,30].StudiesofplateletreactivityinSTEMIpatientshaveshownsimilar

onsetsofactionofprasugrelandticagrelorloadingdoses,withevidenceofbothbeing

delayedinsomeofthesepatients,atleastpartlyduetomorphinetreatment[31-34].We

foundnosignificantdifferenceinstentthrombosisratesintheSTEMIgroupwiththenewer

P2Y12inhibitors(prasugrelandticagrelor)comparedtoclopidogrel.Furthermore,ahigher

proportionofthestentthrombosisseeninSTEMIoccurredacutely(<24hours)(STEMI45%,

allACS31%).Thismayinpartbeexplainedbytheincreasedadministrationofmorphinein

thesepatients.TheremaypotentiallybearoleofintravenousP2Y12inhibitorsinthese

patients[35,36].

OurresultsarealsoconsistentwiththePRAGUE-18study[14],where1230patients

undergoingprimaryPCIforACSwererandomlyassignedtoprasugrelorticgarelor.There

wasnosignificantdifferenceintheprimaryoutcomecomprisingdeath,re-infarction,urgent

targetvesselrevascularization,stroke,orseriousbleedingobservedat30days.Currently

mostcentresareusingoneorothernewerP2Y12inhibitorforpatientswithSTEMItreated

withprimaryPCI;however,itmaybeappropriatetohavebothdrugsavailableanduseone

13

ortheotherbasedonclinicalprofileofindividualpatientsandrelativecontraindicationsor

sideeffectsofthesedrugs.Prasugrelisgenerallynotrecommendedinolder(>75years)

patientsandiscontraindicatedinthosewithahistoryofstroke,whereasticagrelormaybe

avoidedinpatientswithsinoatrialnodedysfunctionuntreatedwithpermanentpacemaker

orwithintolerabledyspnoearelatedtoticagrelor.

Studylimitations:Thisisanobservationalstudy,withthedataderivedfromaprospectively

compiledregistry.Dataforbleedingcomplications,myocardialinfarctionorstrokewerenot

availableandwereliedonreferralofsurvivorsofstentthrombosisbacktoourPCIcentre

forrecordingofthiscomplication.Inaddition,someaspectsofthedatawereunconfirmed;

forexample,wedidnotevaluatepatients’adherencetotheirantiplatelettreatmentand

ourresultsarebasedonantiplateletprescriptionatindexadmission.Ratesofstent

thrombosisintheSTEMIsubgroupwerelowmakinginterpretationdifficult.Becauseofthe

natureoftheregistry,wedidnotincludeACSpatientswhodidnotundergocoronary

angiographyandsoourresultsonlyprovidedataonACSpatientswhoaremanaged

invasively.

Conclusion:Ticagrelorisassociatedwithimprovedsurvivalandareductioninstent

thrombosiscomparedwithclopidogrelininvasively-managedACSpatients.Bothticagrelor

andprasugrelareassociatedwithreducedmortalityintheSTEMIcohortcomparedwith

clopidogrelbutnosignificantdifferenceinstentthrombosiswasseeninthisgroup.Further

head-to-headcomparisonofprasugrelandticagrelorforSTEMIpatientsiswarrantedinan

adequatelypoweredclinicaltrial.

14

ACKNOWLEDGMENTS

WearegratefultoalltheinterventionalcardiologistsatSouthYorkshireCardiothoracic

Centre.WewouldalsoliketothankLouisaAlcockforhelpwithdataextraction.

DECLARATIONOFINTERESTSTATEMENT

RFStoreyreportsresearchgrants,consultancyfees,andhonorariafromAstraZeneca;

researchgrantsandconsultancyfeesfromPlaqueTec;andconsultancyfeesfromAspen,

Bayer,ThermoFisherScientific,Bristol-MyersSquibb/Pfizeralliance,andTheMedicines

Company.Theotherauthorsreportnoconflictsofinterest.

15

FIGURELEGENDS

Figure1.Cumulativeincidenceofall-causemortalityover1yearshowing(A)unadjusted

ratesinallACSpatientstreatedwitheitherclopidogrelorticagrelor,(B)adjustedratesinall

ACSpatientstreatedwitheitherclopidogrelorticagrelor,(C)unadjustedratesinSTEMI

patientstreatedwithclopidogrel,prasugrelorticagrelor,and(D)adjustedratesinSTEMI

patientstreatedwithclopidogrel,prasugrelorticagrelor.HR:hazardratio;CI:confidence

intervals.

Figure2.Cumulativeincidenceofdefinitestentthrombosisover1yearshowing(A)

unadjustedratesinallACSpatientstreatedwitheitherclopidogrelorticagrelor,(B)

adjustedratesinallACSpatientstreatedwitheitherclopidogrelorticagrelor,(C)

unadjustedratesinSTEMIpatientstreatedwithclopidogrel,prasugrelorticagrelor,and(D)

adjustedratesinSTEMIpatientstreatedwithclopidogrel,prasugrelorticagrelor.HR:hazard

ratio;CI:confidenceintervals.

16

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Table1:ClinicalcharacteristicsofallACSpatientsstratifiedbyantiplatelet.

Characteristic Clopidogrel

N=4653

Ticagrelor

N=4917

P

Age(years) 64.4(+/-12.9) 63.5(+/-12.7) <0.001

Male 3166(68%) 3466(70%) 0.009

STEMI 1130(24%) 1654(34%) <0.001

Renalimpairment 45(1%) 107(2%) <0.001

Diabetesmellitus 687(15%) 798(16%) 0.05

Previousstroke/TIA 143(3%) 144(3%) 0.68

PreviousPCI 320(7%) 359(7%) 0.42

PreviousCABG 149(3%) 141(3%) 0.34

GPIIb/IIIainhibitor 581(12%) 634(13%) 0.55

LMS>50% 340(7.3%) 226(4.6%) <0.001

Hypertension 1882(40%) 2140(44%) 0.002

Dyslipidaemia(treated) 2144(46%) 1903(39%) <0.001

3-vesseldisease 1002(22%) 745(15%) <0.001

PCI 2880(62%) 3353(68%) <0.001

No.ofvesselsattempted 1.2+/-0.48 1.2+/-0.47 0.801

No.ofstentsused 1.59+/-0.92 1.47+/-0.87 <0.001

ReferredforCABG 458(10%) 292(6.2%) <0.001

STEMI:ST-elevationmyocardialinfarction;TIA:transientischaemicattack;PCI:

percutaneouscoronaryintervention;CABG:coronaryarterybypassgraftsurgery;

GP:glycoprotein;LMS:Leftmainstem

21

Table2:ClinicalcharacteristicsofST-elevationmyocardialinfarctionpatientsaccordingto

antiplatelettherapy.

TIA:transientischaemicattack;PCI:percutaneouscoronaryintervention;CABG:coronary

arterybypassgraftsurgery;LMS:Leftmainstem;GP:Glycoprotein

Characteristic Clopidogrel

N=1130

Prasugrel

N=1136

Ticagrelor

N=1654

P

Age(years) 65.2+/-13.7 60.8+/-11.7 62.8+/-12.9 <0.001

Male 804(71%) 870(77%) 1189(72%) 0.005

Renalimpairment 12(1%) 7(1%) 23(1%) 0.144

Diabetesmellitus 141(13%) 121(11%) 216(13%) 0.147

Hypertension 413(37%) 388(34%) 593(36%) 0.477

Dyslipidaemia 444(39%) 419(37%) 470(29%) <0.001

Previousstroke/TIA 57(5%) 32(2.8%) 40(2%) <0.001

PreviousPCI 76(7%) 78(7%) 139(8%) 0.172

PreviousCABG 19(2%) 16(1%) 24(1%) 0.805

Cardiogenicshock 23(2%) 18(2%) 64(4%) <0.001

GPIIb/IIIainhibitors 391(35%) 364(32%) 529(32%) 0.299

LMS>50% 61(5.4%) 31(2.7%) 53(3.2%) 0.001

3-vesseldisease 234(21%) 181(16%) 208(13%) <0.001

PCI 1130(100%) 1135(100%) 1616(98%) <0.001

No.ofvesselsattempted 1.12+/-0.39 1.10+/-0.35 1.09+/-0.39 0.139

No.ofstentsused 1.54+/-0.81 1.50+/-0.82 1.35+/-0.77 <0.001

ReferredforCABG 0(0%) 0(0%) 7(0.4%) <0.001

22

Table3:Independentpredictorsofmortalityinallacutecoronarysyndromepatients

Variable HR 95%CI p

Cardiogenicshock 7.006 5.247-9.353 <0.001

Renalimpairment 3.048 2.199–4.226 <0.001

Emergencyprocedure 2.396 1.959–2.929 <0.001

LMSdisease 1.693 1.350–2.124 <0.001

3-vesseldisease 1.358 1.054-1.750 0.02

Clopidogrel 1.188 1.020-1.382 0.03

Age(years) 1.057 1.050–1.064 <0.001

STEMI 0.805 0.649-0.999 0.05

Dyslipidaemia(treated) 0.796 0.681–0.932 0.004

LMS:leftmainstem;STEMI:ST-elevationmyocardialinfarction

23

Table4:Incidenceandtimingofdefinitestentthrombosisaccordingtoantiplatelettherapy

Clopidogrel Prasugrel Ticagrelor Pvalue

AllPCI-treatedACSpatients,n 2880 - 3353

DefiniteST,n(%) 33(1.1%) - 21(0.6%) 0.02

Acute(%oftotal) 11(33%) - 6(29%)

Sub-acute(%oftotal) 15(45%) - 5(24%)

Late(%oftotal) 7(21%) - 10(48%)

AllPCI-treatedSTEMIpatients,n 1130 1136 1654

DefiniteST,n(%) 17(1.5%) 18(1.6%) 16(1%) 0.29

Acute(%oftotal) 6(26%) 11(61%) 6(38%)

Sub-acute(%oftotal) 7(48%) 5(28%) 4(25%)

Late(%oftotal) 4(26%) 2(11%) 6(38%)

PCI:percutaneouscoronaryintervention;ACS:acutecoronarysyndromes;ST:stent

thrombosis;STEMI:ST-elevationmyocardialinfarction

24

Table5:Independentpredictorsofdefinitestentthrombosiswithin12months

Variable HR 95%CI p

STEMI 2.232 1.286-3.872 0.004

Diabetes 2.191 1.189-4.037 0.01

Clopidogrel 2.057 1.187-3.565 0.01

Age 0.967 0.947-0.987 0.001

STEMI:ST-elevationmyocardialinfarction

25

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