Adjuvant antithrombotic therapy in ST-elevation myocardial infarction : a narrative review

(1)

www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

REVIEW

ARTICLE

Adjuvant

antithrombotic

therapy

in

ST-elevation

myocardial

infarction:

A

narrative

review

Daniel

Caldeira

a_,b_,c_,d_,_∗

_,

_Hélder

_Pereira

a_,b

a_Cardiology_Department,_Hospital_Garcia_de_Orta,_Almada,_Portugal

b_Centro_{Cardiovascular}_da_Universidade_de_Lisboa,_CCUL,_Faculdade_de_Medicina,_Universidade_de_Lisboa,_Portugal c_Laboratório_de_Farmacologia_Clínica_e_{Terapêutica,}_Faculdade_de_Medicina,_Universidade_de_Lisboa,_Portugal d_Instituto_de_Medicina_Molecular,_Faculdade_de_Medicina,_Universidade_de_Lisboa,_Portugal

Received2January2018;accepted13May2018

KEYWORDS Myocardialinfarction; Antiplatelet; Anticoagulant; Antithrombotic; Adjuvant

Abstract Thisarticlereviewsthemajorpharmacologicfeaturesof,andclinicalevidenceon, adjuvantmedicaltherapyinpatientswithST-elevationmyocardialinfarction(STEMI)treated withprimarypercutaneouscoronaryintervention.Thesedrugsincludeoralantiplatelets(aspirin and P2Y12 inhibitors suchas clopidogrel,prasugrel andticagrelor),intravenous antiplatelet

agents(theP2Y12inhibitorcangrelor,GPIIb/IIIainhibitorssuchasabciximab,eptiﬁbatideand

tiroﬁban),andintravenousanticoagulantagents(unfractionatedheparin,lowmolecularweight heparinandbivalirudin).

Terapêuticaantitrombóticaadjuvantenoenfartedomiocárdio comsupra-desnivelamentodosegmentoST:revisãonarrativa

Resumo Nesteartigoforamanalisadasasprincipaiscaracterísticasfarmacológicasea evidên-cia clínica douso de terapêuticamédica adjuvante em doentes comenfarte do miocárdio comsupradesnivelamentodosegmentoSTtratadoscomangioplastiaprimária.Essesfármacos incluemantiagregantesorais(ácidoacetilsalicílicoeinibidoresdeP2Y12,taiscomoclopidogrel, prasugrel,ticagrelor),antiagregantesendovenosos(oinibidorP2Y12cangrelor,inibidores GpI-IbIIIa,comooabciximab,eptiﬁbatideetiroﬁban)eagentesanticoagulantesdeusoendovenoso (heparinanãofracionada,heparinadebaixopesomolecularebivalirudina).

∗_{Corresponding}_author.

E-mailaddress:dgcaldeira@hotmail.com(D.Caldeira).

https://doi.org/10.1016/j.repc.2018.05.020

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Introduction

The acute standard of care for ST-elevation myocardial

infarction (STEMI)1---3 _includes _activation _of _a _STEMI _care

network,administrationof adjuvantmedicaltherapy,and

reperfusionbyprimarypercutaneouscoronaryintervention

(PCI).

Developmentsin organizationalaspectsofhealth care,

suchastheStentforLifeinitiative,andinreperfusion

ther-apy,haveestablishedprimaryPCIasthecurrentﬁrstoption

forthetreatmentofpatientswithSTEMI,duetoitsimpact

onprognosis.4,5

The improvements nowseen in STEMIcare areclosely

relatedtoadvancesinadjuvantmedicaltherapyinrecent

decades,particularlyantithrombotictherapy.

Inthisarticle,wepresentanarrativereviewdescribing

themainpharmacologiccharacteristicsof,andclinical

evi-denceon,adjuvantmedicaltherapyusedintheacutephase

ofSTEMI.

Review

Aspirin(AcetylsalicylicAcid)

Aspirin acts as a platelet inhibitor at lower doses

(75-325mg),buthasantipyreticandanti-inﬂammatoryeffects

athigherdoses.

Thelandmarktrialforantiplatelettreatmentinpatients

withacutemyocardialinfarction(MI)wasthe1988Second

InternationalStudyofInfarctSurvival(ISIS-2).6

Inthis trial, theadministrationof162.5 mgaspirin for

30daysachieveda21%relativeriskreduction(RRR)in

vas-cular mortality compared with placebo (Figure 1), which

wassimilartotheeffectofstreptokinasealone(RRR23%).

Areductionof39%invascularmortalitywasobservedwhen

aspirinwasaddedtostreptokinase.6_Overall,_aspirin

treat-mentshowedanabsoluteriskreductioninvascularmortality

of2.4%andanumberneededtotreatof42patientswithin

ﬁveweekstopreventone vascular death, comparedwith

placebo.

Duringthe acutepresentation of STEMI,the guidelines

recommendaloadingdoseofaspirinof150-300mgorallyor

80-150mgintravenouslywithlysineacetylsalicylateinorder

toensureinhibitionofserumthromboxaneB2synthesis.1,3,7

The issue ofaspirin dosingwasfurtheranalyzed inthe

Clopidogrel and Aspirin Optimal Dose Usage to Reduce

RecurrentEvents−SeventhOrganizationtoAssessStrategies

in Ischemic Syndromes 7 (CURRENT-OASIS 7) trial, which

included 25 086 patients with acute coronary syndromes

(29%ofwhom,about7000patients,presentedwithSTEMI).8

Patientsrandomizedtohigh-doseaspirin(300-325mgdaily)

forsevendaysshowedsimilarratestothelow-dosegroup

(75-100mgdaily)forthecompositeoutcomeof30-day

car-diovascularmortality,non-fatalMIornon-fatalstroke.The

secondaryoutcomeswerealsosimilarbetweenthe

interven-tions,withtheexceptionofalowerincidenceofrecurrent

ischemiainthehigh-doseaspirinarm.Minorbleedingevents

wereincreasedwithhigh-doseaspirinbuttheriskofmajor

bleedingwassimilarwiththedifferentdoses.8

P2Y₁₂inhibitors:clopidogrel,prasugrel,ticagrelor andcangrelor

Clopidogrel

Thebeneﬁtsoftheadditionofasecondantiplateletagent

inadditiontoaspirininSTEMIpatientsareclearly

demon-strated by clopidogrel.Clopidogrelis a second-generation

memberofthethienopyridinedrugclass,whichinhibit

bind-ingofADPtoP2Y12 receptorsinplateletsandthusprevent

ADP-relatedglycoprotein(GP)IIb/IIIareceptoractivation.

Clopidogrelis a prodrug and requires a two-step

acti-vation process in the liver in which it is converted by

cytochrome P450 (CYP) enzymes into an intermediate

metabolite and a ﬁnal active metabolite. CYP2C19 is

one of the most important CYPs involved in clopidogrel

metabolism. The concomitant use of CYP2C19 inhibitors

(omeprazole, ﬂuoxetine, orazole antifungalagents) leads

todecreasedlevelsoftheactivemetabolite,buttheclinical

relevanceofthisdecreasehasnotbeenclearlydetermined.9

Thus, alternative drugs should be considered before

pre-scribingCYP2C19inhibitors.

ClopidogrelasAdjunctiveReperfusionTherapy-

Throm-bolysis In Myocardial Infarction (CLARITY-TIMI 28) was a

placebo-controlled trial designed to determine whether

clopidogrel added to standard antiplatelet therapy with

aspirin (loading dose plus maintenance dose of

75-162mg/day)wouldfurtherimprovetheprognosisof adult

patients (18-75 years old) managed with ﬁbrinolysis.10

A total of 3491 patients presenting within 12 hours of

MI intended for treatment with a ﬁbrinolytic agent were

enrolledandrandomizedtoreceiveeitheraspirinaloneor

aspirinplusclopidogrel(300mgloadingdosefollowedby75

mg/day).Theadditionofclopidogreltoaspirinshowedan

RRRof36%foroccludedinfarct-relatedartery,deathorMI

bythetimeofangiography,anda20%RRRfor

cardiovascu-larmortality,MIorurgentrevascularizationduetorecurrent

ischemiaat30days.10

The PCI-CLARITY study was a subgroup analysis of

CLARITY-TIMI28,with1863patientsundergoingPCIamedian

ofthreedaysafterrandomization. Allpatientsinthis

sub-group received a loading dose of 300 mg, then 75 mg

oncedaily of open-labelclopidogrel beforePCI.

Pretreat-mentwithclopidogrelafterﬁbrinolytictherapyandbefore

PCI resulted in a46% RRR of the compositeof

cardiovas-cular death, recurrent MI or stroke compared to placebo

(Figure1).11

The clopidogrel arm of ClOpidogrel and Metoprolol in

Myocardial Infarction Trial/Second Chinese Cardiac Study

(COMMIT-CCS2)12_enrolled₄₅₈₅₂_patients_with_MI_(93%_with

STEMIor MI withleftbundle branchblock)randomizedto

receiveeitherclopidogrelorplaceboinadditiontoaspirin

162mg/dailyuntildischargeoruptofourweeksinhospital.

Clopidogrelsigniﬁcantlyreducedall-causemortalityandthe

composite outcome of death, reinfarction or stroke, with

RRRs of 7% and 9%, respectively, after a meantreatment

periodoftwoweeks.

The rates of major bleeding found in these two trials

(CLARITY-TIMI28 andCOMMIT-CCS2)were notsigniﬁcantly

(3)

Study

Estimate (RR/OR/HR) Estimate (RR/OR/HR)

95% CI 95% CI

Aspirin ISIS-2(1) P2Y12 inhibitors

PCI-CLARITY (2)

TRITON-TIMI 38 (STEMI subgroup) (3) PLATO (STEMI subgroup ) (4)

CHAMPION PHOENIX(STEMI subgroup) (5) GP IIb/IIIa inhibitors

De Luca et al. [meta-analysis] (6) On-TIME 2 (7)

EVA-AMI (8)

(1) Aspirin vs. placebo; 1-month cardiovascular mortality (2) Clopidogrel vs. placebo; 1-month CV death, MI or stroke (3) Prasugrel vs. clopidorel; CV death, MI or stroke (4) Ticagrelor vs. clopidogrel; CV death, MI or stroke

(5) Cangrelor vs. placebo; death, MI, ischemic-driven revascularization or stent thrombosis (6) Abciximab vs. control; 6 month-1 year mortality

(7) Tirofiban vs. placebo; thrombotic bail-out (secondary outcome) (8) Eptifibatide vs. abciximab; death, MI or TVR (secondary outcome)

0.79 [0.73, 0.86] 0.54 [0.35, 0.85] 0.79 [0.64, 0.97] 0.87 [0.75, 1.01] 0.75 [0.45, 1.25] 0.69 [0.52, 0.92] 0.70 [0.56, 0.88] 0.93 [0.54, 1.59] 0.5

Favors intervention Favors control

0.7 1 1.5 2

Figure1 ResultsofselectedtrialsassessingantiplateletagentsinpatientswithST-segmentelevationmyocardialinfarction.CI: conﬁdenceinterval;CV:cardiovascular;GP:glycoprotein;HR:hazardratio;MI:myocardialinfarction;OR:oddsratio;RR:relative risk;STEMI:ST-segmentelevationmyocardialinfarction;TVR:targetvesselrevascularization.

Clopidogrel loading doses (600 mg vs. 300 mg) were

comparedin 201STEMIpatientsundergoingprimaryPCIin

theAntiplatelettherapy forReductionofMYocardial

Dam-ageduringAngioplasty-MyocardialInfarction(ARMYDA-6MI)

trial.13 _The _primary _outcome, _the _area _under _the _curve

ofcardiacbiomarkersasasurrogateofmyocardialinfarct

size,wassigniﬁcantlylowerwiththe600mgloadingdose

thanwiththe300mgloadingdose.Therewerealsofewer

30-day major adverse cardiovascular events but bleeding

complications were similarbetween the different loading

doses.13

The CURRENT-OASIS 7 trial (see section on aspirin,

above),witha2-by-2factorialdesign,alsoassessedthe

clin-icalimpactofhigh-doseclopidogrel(loadingdose600mg,

sixdaysat 150 mg/day, followedby 75 mg/day)vs.

stan-darddose(loadingdose300mg,followedby75mg/day).8

Overall, high-dose clopidogrel didnot reduce 30-day

car-diovascularmortality,MIor stroke,but inthesubgroupof

patientswhounderwentPCI(STEMIandnon-STEMI)therisk

ofthesemajoradversecardiovasculareventswas

signiﬁcan-tlydecreased,mainlyduetothereductionofMI.High-dose

clopidogrelincreasedtheriskofmajorbleeding.8

Prasugrel

Prasugrel,anothermemberofthethienopyridinedrugclass,

is an irreversible P2Y12 inhibitor that overcomes some

of clopidogrel’s limitations, particularly the degree of its

antiplateleteffectandtimetoonset.

Prasugrel is rapidly hydrolyzed toa thiolactonein the

intestine,andthenafterabsorptionisconvertedbyCYP3A4

andCYP2B6andtoalesserextentbyCYP2C9andCYP2C19to

theactivemetabolite,whichreachespeakplasma

concen-tration30minafteradministration.

Thebeneﬁtsofprasugrel(loadingdose60mg,followed

by10 mgoncedaily)instead ofclopidogrel inadditionto

aspirin(atanydosefrom75to162mg)wereshownbythe

TRITON-TIMI38 trial,which enrolled 13608 patients with

acutecoronarysyndromesmanagedinvasivelywithPCI.14

Prasugrelreducedtherelativeriskofthecomposite

out-come of cardiovascular death, non-fatal MI and non-fatal

strokeby19%comparedwithclopidogrel.Theresultswere

mainlydrivenby reduced riskfor non-fatal MI (RRR 24%),

andtheoverallclinicalimpactofprasugrelwasnot

differ-entwithinthe subgroup of 3534STEMI patients (p=NSfor

interaction);theRRRinthissubgroupwas21%.Therewas

nomortality beneﬁt withprasugrel and the bleeding risk

wassigniﬁcantlyhigheraccordingtothestudydeﬁnitionof

majorbleeding(TIMImajorbleedingnotrelatedtocoronary

artery bypassgrafting [CABG]).14 _The _risk _of _death,

non-fatalMI,non-fatalstrokeandnon-CABG-relatedTIMImajor

bleedingwassigniﬁcantlyhigherinpatients withahistory

ofstrokeortransientischemicattack,andthusprasugrelis

notindicatedforthesepatients.Othersubgroupsforwhich

speciﬁcconcernswereraised weretheelderly(≥75years

old)andlow-weightindividuals(<60kg),particularly

regard-ingtheirbleedingrisk with10mgprasugreldaily.Current

regulatorydocumentsrecommendacarefulindividual

ben-eﬁt/riskassessmentandifprescribedthemaintenancedose

shouldbe5mgdailyforsuchpatients.

Ticagrelor

Ticagrelor is an oral cyclopentyltriazolopyrimidine that

reversiblyandnon-competitivelyinhibits ADP-induced

sig-naling downstream of P2Y12 receptors. Compared to

clopidogrel,ticagrelorshowedafavorableproﬁleregarding

timetoonsetanddegreeofantiplateleteffect.

Ticagrelorreaches peakplasma levelsbetween 90 min

andthreehoursandpeakplateletinhibitionintwohours.

ThepivotaltrialofticagrelorinACSwasPLATO(aStudy

(4)

antiplatelettreatmentwithaspirinandticagrelorwas

com-paredwithaspirinandclopidogrel.Thetrialincludedatotal

of18624patientswithACS.BothP2Y12inhibitorsweregiven

inaloadingdose(ticagrelor180mg;clopidogrel300-600mg)

andamaintenancedose(ticagrelor90mgtwicedaily;

clopi-dogrel 75 mgonce daily). Ticagrelorshowed a signiﬁcant

16%RRRincardiovascularmortality,MIandstroke,dueto

decreasesincardiovascularmortalityandMI.Overallmajor

bleedingriskwasnotsigniﬁcantlyincreased,but

non-CABG-relatedmajorbleedingwassigniﬁcantlyincreased.

This trial included 7544 patients with STEMI, and the

subgroup’sresultwassimilartothe non-STEMIpopulation

(p=0.29forinteraction).Itisnoteworthythatticagrelorhad

lesseffectinNorthAmericathanintherestoftheworld.15

Otherthanchancealoneoratrueregionaldifference,one

possibleexplanationisthefactthattheaspirinmaintenance

dosewasonaveragehigherinNorthAmerica.Asigniﬁcant

statisticalinteractionwasobservedfavoringtheinteraction

oflow-doseaspirinwithticagrelor.Therecommendeddose

ofaspirintobetakenwithticagreloris75-150mg,

prefer-ablylowerdoses.

Themain adverseevents associatedwithticagrelorare

dyspneaand bradyarrhythmias. The incidence of dyspnea

intheticagrelorarm in thePLATOtrial was13.8%.It was

usually non-severe, transient and not related to cardiac,

pulmonaryormetabolicfactors.

Ventricularpausesof>3s,assessedbyHoltermonitoring,

weremore frequent withticagrelorthan withclopidogrel

intheacute phaseofthe coronaryevent(duringtheﬁrst

week), but not at 30 days after randomization. The risk

ofheart block,syncope andpacemakerimplantation with

ticagrelorwasnotsigniﬁcantlydifferentfromclopidogrel.

In addition to P2Y12 signal blockade, ticagrelor also

inhibits equilibrative nucleoside transporter-1 (ENT-1),

which is implicated in the cellular uptake of endogenous

adenosine.16---18 _The _above _adverse _drug _reactions _may_be

relatedtothismechanism.

The Administration of Ticagrelor in the Cath Lab or

inthe Ambulancefor NewST ElevationMyocardial

Infarc-tiontoOpentheCoronaryArtery(ATLANTIC)trialassessed

the potential beneﬁts of the prehospital administration

of ticagrelor compared with in-hospital administration.19

In this study involving 1862 STEMI patients, the median

timefromrandomizationtocoronaryangiogramwas48min

andthemediantimedifferencebetween pre-hospitaland

in-hospitaladministrationoftheticagrelorloadingdosewas

31min.Theprimaryoutcomes,surrogatesofantithrombotic

efﬁcacyrelatedtopre-PCIcoronaryreperfusion(resolution

ofST-segmentelevationandtheproportionofcoronaryTIMI

ﬂow<3),werenotimprovedbyearlypre-hospitalticagrelor

administration. The risk of deﬁnite stent thrombosis was

lowerwithpre-hospitalticagreloradministration.19

Cangrelor

Cangreloris an intravenousreversibleP2Y12 inhibitor.The

mainadvantagesofthisdrugarerapidonset(within2min

ofabolusfollowedbyaninfusion)andoffset(onehourafter

stoppingdruginfusion)ofantiplateleteffects.20

The drugismetabolizedin theplasma intoaninactive

metabolitewhichiseliminatedthroughrenalanddigestive

routes.Thus,cangrelordoesnotrequiredose adjustments

inrenalorliverimpairment.

Cangrelorhasbeenapprovedforpatientswithcoronary

disease undergoingPCI whodid notreceive an oral P2Y12

inhibitor priortotheprocedure andin whomcurrentoral

therapywithP2Y12inhibitorsisnotfeasible(e.g.absenceof

oralroute)ordesirable(e.g.bridgingtoCABGsurgery).20

ThepivotalCHAMPIONPHOENIX(Cangrelorversus

Stan-dard TherapytoAchieve OptimalManagement of Platelet

Inhibition PHOENIX) trial comparedcangrelorand placebo

in 10 942 patients treated witha 300- or 600-mg loading

dose ofclopidogrelbeforePCI.21 _This _trial_showed_an_RRR

of22%and15%inthecompositeendpointofmortalityand

ischemic events (MI, ischemia-driven revascularization or

stent thrombosis) at 48 hours and 30 days of follow-up,

respectively. This beneﬁt was mainly driven by a

signiﬁ-cantRRRof38%instentthrombosis(intraproceduralstent

thrombosisindependentlyadjudicatedbytheangiographic

corelaboratorycommittee,ordeﬁnitestentthrombosisas

deﬁned by the Academic ResearchConsortium criteria22_).

CHAMPIONPHOENIXincluded1992patientswithSTEMIand

no interaction was observed regarding treatment effect

accordingtoclinicalpresentation(STEMIandnon-STEMI).21

Thebeneﬁtsof cangrelorarelikelyrelatedtoitsrapid

antiplateletactioncomparedtootheroralP2Y12 inhibitors

suchasclopidogrel.

GlycoproteinIIb/IIIainhibitors

Thisclassincludesthreedrugs,administeredintravenously,

thatdisableﬁbrinogenandvonWillebrandfactorbybinding

totheGPIIb/IIIareceptor:abciximab,tiroﬁbanand

eptiﬁ-batide.

Abciximab

Abciximabisanantigen-bindingfragmentofachimeric

mon-oclonal antibody that binds to GPIIb/IIIa and vitronectin

receptors. Abciximab’santiplatelet effect is seen 10 min

after bolus administration and platelet function typically

recovers24-48hoursafterdrugwithdrawal.23---25

Mostof the evidence supporting the use of GP IIb/IIIa

inhibitorsinSTEMIarisesfromtrialswithabciximabinthe

eraofballoonangioplastyandbeforetheroutine

implemen-tationofdualantiplatelettherapyinthesepatients.DeLuca

etal.publishedasystematicreviewontheclinicalimpact

of abciximabinSTEMIpatients treatedwithﬁbrinolysisor

primaryPCI.26_In_this_review_abciximab_reduced_both_30-day

andlong-term(sixmonthstooneyear)all-causemortalityby

31%and32%,respectively.Nosigniﬁcantincreaseinmajor

bleedingrisks,includingintracranialhemorrhage,wasnoted

(Figure1).26

Themainadverseeventratherthanbleeding(majoror

minor)isthrombocytopenia,which usuallydevelopsinthe

ﬁrst24hours.Theincidenceofthrombocytopeniais2.9%for

ﬁrstadministrationand5%forrepeatadministrations.27,28

Tiroﬁban

Tiroﬁbanisanon-competitivenon-peptideGPIIb/IIIa

recep-torantagonist.Thisdrug’santiplateleteffectbegins15min

(5)

ofplateletaggregationis<50%fourhoursaftercessationof

druginfusion.30

IntheOn-TIME2trial,936STEMIpatientswere

random-ized to high-dosetiroﬁban or placebo in the pre-hospital

setting,ontopofaspirin500mg,clopidogrel600mg,and

unfractionated heparin 5000 IU.31 _The _trial _was _designed

to assess ST-elevation resolution, and tiroﬁban

signiﬁcan-tlydecreased theextent of residualST-segmentdeviation

one hour after PCI. The rates of the composite of

death,recurrentMIortargetvesselrevascularization,and

major bleeding were not signiﬁcantly different between

interventions.Therewassigniﬁcantlylessneedfor

throm-boticbail-outduetoTIMIﬂowgrade0-2andabruptclosure

of the culprit vessel in the tiroﬁban arm (Figure 1).

In-hospitalthrombocytopeniawasnotsigniﬁcantlyhigher(2.0%

withtiroﬁbanand1.8%withplacebo).

Eptiﬁbatide

Eptiﬁbatide is a synthetic heptapeptide that reversibly

andcompetitivelyinhibitsGPIIb/IIIareceptors.Itis given

throughan initial double intravenous bolus (separatedby

10min)of180 ␮g/kgfollowedbyacontinuousinfusionof

2 ␮g/kg/min for up to72 hours. The antiplatelet effects

areobservedafterthebolusandplateletfunctionrecovers

fourhoursaftercessationofinfusion.Because50%of

epti-ﬁbatide clearance is kidney-dependent, the infusion dose

shouldbehalvedinpatientswithmoderatechronickidney

disease(estimatedglomerularﬁltrationrate30-50ml/min).

Themaindataoneptiﬁbatideuseinacutecoronary

syn-dromescome fromthePURSUITtrial, whichenrolledonly

patients without persistent ST-segment elevation.32

PUR-SUIT was a randomized, double-blind assessment of the

efﬁcacyandsafetyofeptiﬁbatideversusplacebofor

redu-cingmortality and MI in patients with unstable angina or

non-Q-wave MI and included 13.8% of patients with

non-persistent ST segment elevation or persistent ST-segment

elevationof0.5-0.9mm.ThistrialshowedaRRRof10%in

mortalityor MIat 30days.Asigniﬁcant increase inmajor

and/or minor bleedingevents wasobserved in the

eptiﬁ-batidearm.Theriskofthrombocytopeniawitheptiﬁbatide

wasnotsigniﬁcantlydifferentfromplacebo.

InthecontextofSTEMI,theEptiﬁbatideVersusAbciximab

in Primary PCI for Acute Myocardial Infarction (EVA-AMI)

trialrandomized427STEMIpatientstoeptiﬁbatide(double

bolusand24-hourinfusion)orabciximab(bolusand12-hour

infusion) as adjuncts to primary PCI.33 _The _primary

out-comewascompleteST-segmentresolution60minafterPCI.

Theelectrocardiographicandclinicalimpactofeptiﬁbatide

wassimilartoabciximab(Figure1).Non-randomizedstudies

showsimilarﬁndings.34,35

Heparins

Unfractionatedheparin

Unfractionatedheparin(UFH)isapolysaccharidethatbinds

to plasma proteins, including antithrombin, enhancing its

action,whichincludes inactivationofthrombinandfactor

Xa. The heparin-antithrombin complex also inhibits other

coagulation factors including VIIa, XIa and XIIa. UFH also

enhancesendogenousﬁbrinolysis.UFHisusuallygiven

intra-venously,includinginthecontextofSTEMI.

This drug hastwo independentclearancemechanisms:

asaturable pathwayin which rapid depolymerization

fol-lows binding to endothelial cells, macrophages and local

proteins;andanon-saturablerenalclearancepathway.The

half-lifeofUFHis90-120 mindepending onthe clearance

mechanism.The existenceofthesetwoclearance

mecha-nismscanleadtointra-andinter-individualvariabilityinthe

pharmacodynamiceffectsofUFH,whichisalimitationonits

useduetotheunpredictabilityofitsanticoagulanteffects,

whichnecessitatemonitoringbymeasurementofactivated

partialthromboplastintimeoractivatedclottingtime.

Although therehave been noplacebo-controlledtrials,

thevalueofUFHwashighlightedbytheOASIS-6trialon

fon-daparinux,inwhich UFHwasadministeredtosomeofthe

controlgroup.36_In_the_subgroup_of_patients_with_STEMI_who

underwentprimaryPCI,UFHreducedtheriskofthrombotic

bailout or catheter thrombosis,none of the latter

occur-ringwithUFH.Therewasalsoatrendtowardsanincreased

riskofdeathorreinfarctioninprimaryPCIpatientstreated

withfondaparinuxcomparedtoUFHat30daysand90-180

days,withasigniﬁcantsubgroupinteraction(primaryPCIvs.

non-primaryPCI,trendingforafavorableeffectofUFHin

theprimaryPCIsubgroup,andasigniﬁcantfavorableeffect

of fondaparinux in the non-primary PCI subgroup).36 _For

thesereasonsfondaparinuxisnotrecommendedforpatients

withSTEMIundergoingPCI,butisavalidanticoagulantfor

STEMIpatients treatedwithﬁbrinolysis.3 _UFH_is_an _option

forparenteralanticoagulantsinthissettingaccordingtothe

EuropeanSocietyofCardiology(ESC)guidelines.1

Regarding dosage of UFH, the initial bolus should be

weight-adjusted, and should be as follows according to

expectationoftheuseofGPIIb/IIIainhibitors:UFH70-100

IU/kgwhennoGPIIb/IIIainhibitorisplanned,orUFH50-60

IU/kgwhentheuseofGPIIb/IIIainhibitorsisexpected.1

The main safetyissuesarebleedingevents and

throm-bocytopenia. For bleeding events, protamine can be

administeredto reverse the anticoagulant effectof UFH.

The incidenceof heparin-inducedthrombocytopenia (HIT)

ranges from 0.1% to 5.0% and at least one quarter of

thesepatientsdevelopthromboticcomplications.InHIT,the

plateletcount fall is 50% or more and the nadiris above

20×109_/l.37 _It _usually _occurs _after _5-10 _days _of _exposure

toUFHor soonerifthe patientwasexposedinthe

previ-ous30days.37 _Both_HIT _and_HIT-related_thrombotic_events

arerelatedtothedevelopmentofimmunoglobulinsagainst

complexesofplateletfactor4andUFH.37

Lowmolecularweightheparins

Lowmolecularweightheparins(LMWH)aresmall

antithrom-bin polysaccharides derived from UFH. LMWH have more

anti-Xa than anti-IIa activity and enhance the release of

tissuefactor pathway inhibitors. These drugs donot bind

to endothelial cells or macrophages, and hence have a

predictabledose-effectrelationshipusingbolus

administra-tions.Theirbioavailabilityisalsohigher,enablingeffective

subcutaneous administration. Regarding safety issues,the

rate of HIT is lower with LMWH than with UFH, but in

bleedingconditions the antidote protamine is less

effec-tive, sinceit only partially neutralizesthe anti-Xa effect

ofLMWH.Thenewanti-factorXaantidoteandexanetalfa

(6)

Study ATOLL (1) HORIZONS-AMI (2) MATRIX (STEMI subgroup) (3)

VALIDATE-SWEDEHEART (STEMI subgroup) (4)

(1) Enoxaparin vs. UFH; death, MI, PCI failure, or major bleeding (2) Bivalirudin vs. UFH+iGP IIb/IIIa] major bleeding (co-primary outcome) (3) Bivalirudin vs. UFH; major bleeding (secondary outcome)

(4) Bivalirudin vs. UFH; death, MI, or major bleeding

Estimate (RR/OR/HR) Estimate (RR/OR/HR)

95% CI 0.83 [0.68, 1.01] 0.60 [0.46, 0.77] 0.60 [0.39, 0.92] 0.95 [0.78, 1.17] 0.5 0.7 1 1.5 2

Favors intervention Favors control

95% CI

Figure2 ResultsofselectedtrialsassessinganticoagulantagentsinpatientswithST-segmentelevationmyocardialinfarction. CI:conﬁdenceinterval;CV:cardiovascular;GP:glycoprotein;HR: hazard ratio;MI:myocardialinfarction; OR:odds ratio;PCI: percutaneouscoronaryintervention;RR:relative risk;STEMI: ST-segmentelevationmyocardialinfarction; UFH:unfractionated heparin.

patientsrequiringrapidhemostasis.38_However,_the

Andex-anetAlfa,aNovelAntidotetotheAnticoagulationEffectsof

FXAInhibitors4(ANNEXA-4)trialonlyenrolledfourpatients

with major bleeding treated with enoxaparin (out of

67patientstreatedwithfactorXainhibitors).38

ThemainclinicalevidencefortheuseofLMWHinSTEMI

patients derives from the Acute STEMI Treated with

pri-mary angioplasty and intravenous enoxaparin Or UFH to

Lowerischemicandbleedingeventsatshort-andLong-term

follow-up study (ATOLL).39 _Compared _to _UFH, _enoxaparin

(intravenousbolusof0.5mg/kg followedbysubcutaneous

injections every 12 hours) did not signiﬁcantly (p=0.06)

reduce theprimary compositeoutcome of death,

compli-cation of MI, procedure failure, or major bleedingin 910

STEMI patients (Figure 2). However, secondary outcomes

includingdeath, recurrent acute coronarysyndrome, and

urgentrevascularizationweresigniﬁcantly decreased(41%

RRR) with enoxaparin.39 _No _differences _were _observed _in

majorbleeding.Basedontheseﬁndings,theESCguidelines

statethatLMWHmaybeconsideredinsteadofUFH(classIIb

recommendation).1_Another_advantage_of_LWMH_over_UFH_is

thelowerriskofHIT.

Bivalirudin

Bivalirudin is a polypeptide that is a direct thrombin

inhibitor,bindingbothcirculatingandclot-boundthrombin.

The Harmonizing OutcomesWith Revascularizationand

Stents in Acute Myocardial Infarction (HORIZONS-AMI)

trial compared UFH plus a GP IIb/IIIa inhibitor with

bivalirudinalone(0.75mg/kgintravenousbolusfollowedby

1.75mg/kg/hour infusion) inpatients undergoing primary

PCI.40

In 3602 STEMI patients undergoing primary PCI,

bivalirudin,comparedtoUFHplusGPIIb/IIIainhibitors(52%

abciximab,46%tiroﬁban),showedanRRRof24%within30

daysinnetadverseclinicalevents,acompositeof

cardio-vasculardeath,MI,targetvesselrevascularization,strokeor

majorbleeding,mostlyduetothe40%RRRinmajor

bleed-ing(Figure2).40_An_increased_risk_of_stent_thrombosis_within

24hourswasobservedinthebivalirudingroup.

The European Ambulance Acute Coronary Syndrome

Angiography(EUROMAX) trial studied 2218 STEMI patients

transportedfor primaryPCIandrandomizedtobivalirudin

(bolus and infusion for at least four hours after PCI at

0.25 mg/kg/hour)or UFH(and optional use of GP IIb/IIIa

inhibitors).41 _The _primary _outcome _of _death _and _major

bleedingwassigniﬁcantlydecreased,duetothe57%RRRin

majorbleeding.41 _Similarly_to_the_HORIZONS-AMI_trial,_the

riskofacutestentthrombosiswassigniﬁcantlyhigher.

TheMinimizingAdverseHemorrhagicEventsby

Transra-dial Access Site and Systemic Implementation of Angiox

(MATRIX) trial also compared bivalirudin with UFH (with

GPIIb/IIIainhibitorsonlyinbail-outcircumstances).42_This

trial included 7213 ACS patients, 4010 (56%) with STEMI.

The results for the STEMI group were not different from

the overall study results.43 _The _risk _of _death, _non-fatal

MI and non-fatal stroke was similar between groups, but

there was a signiﬁcant 40% RRR in major bleeding with

bivalirudinintheSTEMIgroup(Figure2).TheMATRIXstudy

also assessed the potential impactof post-PCI bivalirudin

infusion;thisstrategydidnotimproveanyoutcome,

includ-ingstentthrombosis.42

TheBivalirudin versus Heparin inST-Segmentand

Non-ST-Segment ElevationMyocardial Infarction in Patientson

Modern Antiplatelet Therapy in the Swedish Web System

forEnhancementandDevelopmentofEvidence-basedCare

in Heart Disease Evaluated according to Recommended

TherapiesRegistryTrial(VALIDATE-SWEDEHEART)wasa

ran-domized open-labelregistry-basedcontrolled clinicaltrial

that compared bivalirudin and UFH monotherapy in 6006

patientswithMI(3001 withSTEMI).The clinicalimpactof

bivalirudinwassimilartoUFHinmonotherapyinthe

over-all cohort as well as in the STEMI subgroup in terms of

the compositeprimaryendpoint of all-causemortality, MI

or majorbleedingduring180daysoffollow-up(Figure2).

Nosigniﬁcantdifferenceswereobservedinanyofthe

sec-ondaryendpoints.

Discussion

STEMIis an acutethrombus-drivenevent.The importance

ofthispathophysiologicallinkishighlightedinthisreview,

inwhichthemainpharmacokinetic,pharmacodynamicand

clinicaldataonantithromboticdrugsinSTEMIarereviewed.

These adjuvant medical agents, particularly antiplatelet

drugs, have signiﬁcantly improved the prognosis of this

patientgroup.Afteraspirin(withISIS-2),6_the_breakthrough

(7)

Table 1 2017 European Society of Cardiology recommendations for antithrombotic therapy in patients with ST-elevation myocardialinfarctionundergoingprimarypercutaneousintervention.3

Classof recommendation (wording) I (Isrecommended) IIa (Shouldbe considered) IIb (Maybe considered) III (Isnot recommended) Antiplateletagents OralorIVaspirin

P2Y12inhibitorinadditionto aspirin

Ticagrelor

Prasugrel(clopidogrel-naïve patientsaged<75years;no historyofstrokeorTIA) Clopidogrelwhenticagreloror prasugrelareunavailableor contraindicated

GPIIb/IIIa inhibitorsas bailouttherapyin patientswithhigh thrombotic burden,slowﬂow orno-reﬂow GPIIb/IIIa inhibitorsas upstreamtherapy inhigh-risk patients transferredfor primaryPCI RoutineuseofGP IIb/IIIainhibitors inadditiontoUFH inprimaryPCI

-Anticoagulantagents BivalirudinoverroutineUFHwith GPIIb/IIIainhibitors

UFHinprimaryPCIpatientsnot receivingbivalirudinorenoxaparin

- Enoxaparinover

UFH

Fondaparinuxin primaryPCI patients

GP:glycoprotein;IV:intravenous;PCI:percutaneouscoronaryintervention;TIA:transientischemicattack;UFH:unfractionatedheparin.

IntheSTARStrialthecombinationofticlopidineandaspirin

instentedpatients(patientswithrecentMIwereexcluded)

showedadecreaseinstentthrombosis-relatedevents

com-paredtoaspirinaloneandaspirincombinedwithwarfarin.44

In the ISAR trial the combination of aspirin and

ticlopi-dine (24%of the patientsin this grouphad hadacuteMI)

wassuperior to aspirin withphenprocoumon (a vitamin K

antagonist).45_The _former_reduced_the_composite_endpoint

of cardiovascular mortality, non-fatal MI or

revasculariza-tion,aswellasthromboticstentocclusion.45_{Consequently,}

theadventofGPIIb/IIIainhibitorscontributedsigniﬁcantly

totheperception that dualantiplatelet therapywas

nec-essary in acute coronary syndromes. The process of PCI,

includinginterventioninSTEMIandthe evolutionto

drug-elutingstentsandradialaccess,andinhibitionoftheP2Y12

receptorpathwaywithclopidogrel,prasugrelandticagrelor,

have sincebeen furtherstudied andoptimized.Nowadays

themainstayforantiplatelettherapyinSTEMIisaspirinand

apotentP2Y12inhibitor(usuallyticagrelororprasugrel).GP

IIb/IIIainhibitorsarereservedforbailoutsituations,while

cangrelormayplayaroleduetoitsrapidantiplateletaction

incaseswherethepharmacodynamiceffectsofthenewer

andfaster P2Y12 inhibitorsarenot optimal. InSTEMI, the

ﬁbrin-richthrombi that occludearteries arethe resultof

plateletactivationandalsoofthereleaseoftissuefactor

bythedamagedvesselthatleadstoactivation,ampliﬁcation

andpropagationofthecoagulationcascade.Anticoagulants

inthissettingaregiventopreventexpansionand

enhance-mentofthrombi.Furthermore,contemporarymanagement

withprimary PCI requires a suitable antithrombotic

envi-ronment to prevent catheter thrombosis, which may be

achievedwithUFH,enoxaparinorbivalirudin.Fondaparinux

was found to decrease the risk of death or MI,

particu-larly in patients managed medically or in those receiving

ﬁbrinolysis (mostly streptokinase). In patients undergoing

primary PCI, fondaparinux increased the risk of catheter

thrombosis and no clinical beneﬁt was noted regarding

otheroutcomes.Fondaparinuxisthereforecontraindicated

in patients undergoing primary PCI. Regarding the other

anticoagulants,UFHremainsthegoldstandardintravenous

anticoagulant,althoughitsanti-ischemicefﬁcacywas

chal-lenged by enoxaparin in one trial (ATOLL39_), _and _despite

concerns of increased risk of stent thrombosis the major

bleedingriskwasshowntobelowerwithbivalirudin.

The2017EuropeanSocietyofCardiology recommendationsforantithrombotictherapyin patientswithST-elevationmyocardialinfarction undergoingprimarypercutaneousintervention3 Antiplateletdrugs

- Aspirinisrecommended(classI).

- A P2Y12 inhibitor is recommended inaddition toaspirin

(classI),particularly ticagrelor(classI)or prasugrel(in

clopidogrel-naïvepatientsaged<75yearsorwithno

his-toryofstrokeortransientischemicattack---classI).

- GP IIb/IIIa inhibitors should be considered for bailout

therapy in patients with high thrombotic burden or

complications,includingslowﬂoworno-reﬂow(classIIa).

- GPIIb/IIIainhibitorsmaybeconsideredforupstream

ther-apyinhigh-risk patientsundergoingtransferfor primary

PCI(classIIb),orasroutineadjunctantiplatelettherapy

inpatientstreatedwithUFH(classIIb).

Anticoagulantdrugs

- Bivalirudin is recommended over routine UFH with GP

IIb/IIIainhibitors(classI).

- EnoxaparinmaybepreferredtoUFH(classIIa).

- UFHshouldbeusedinSTEMIpatientsundergoingprimary

PCInotreceivingbivalirudinorenoxaparin(classI).

- FondaparinuxiscontraindicatedinSTEMIpatients

(8)

Table 1 summarizes the recommendations and their

classes regarding antithrombotic therapy in patients with

STEMItreatedwithprimaryPCI.

Conclusions

Advancesin antithrombotic treatment have led to

signiﬁ-cantimprovementsintheprognosisofpatientswithSTEMI

treatedby primaryPCI. The growingbody ofevidence on

eachofthesetherapeuticoptionsposesnewchallengesin

termsofdrugcombinations.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

References

1.TaskForceonthemanagementofST-segmentelevationacute myocardial infarction of the European Societyof Cardiology (ESC),StegPG,JamesSK,AtarD,etal.ESCGuidelinesforthe managementofacutemyocardialinfarctioninpatients present-ingwithST-segmentelevation.EurHeartJ.2012;33:2569---619.

2.Yanamala CM, Bundhun PK, Ahmed A. Comparing mortal-ity between ﬁbrinolysis and primary percutaneous coronary intervention in patients with acute myocardial infarction: a systematic review and meta-analysis of 27 randomized-controlledtrials including11429patients.CoronArtery Dis. 2017;28:315---25.

3.IbanezB,JamesS,AgewallS,etal.ESCGuidelinesforthe mana-gementofacutemyocardialinfarctioninpatientspresenting withST-segmentelevation:TheTaskForceforthemanagement ofacutemyocardialinfarctioninpatientspresentingwith ST-segmentelevationoftheEuropeanSocietyofCardiology(ESC). EurHeartJ.2017:2017.

4.PereiraH,PintoFJ,CaleR,etal.StentforLifeinPortugal:this initiativeisheretostay.RevPortCardiol.2014;33:363---70.

5.KaifoszovaZ,KalaP,WijnsW.TheStentforLifeInitiative:quo vadis?EuroIntervention.2016;12:14---7.

6.Randomised trial of intravenous streptokinase, oral aspirin, both,orneitheramong17,187casesofsuspectedacute myocar-dial infarction: ISIS-2. ISIS-2 (Second International Study of InfarctSurvival)CollaborativeGroup.Lancet.1988;2:349---60.

7.BuerkeM,PittroffW,MeyerJ,etal.Aspirintherapy:optimized platelet inhibition with different loading and maintenance doses.AmHeartJ.1995;130:465---72.

8.CURRENT-OASIS7Investigators,MehtaSR,BassandJP, Chrolavi-ciusS, etal. Dose comparisonsofclopidogreland aspirinin acutecoronarysyndromes.NEnglJMed.2010;363:930---42.

9.Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or withoutomeprazoleincoronaryarterydisease.NEnglJMed. 2010;363:1909---17.

10.SabatineMS,CannonCP,GibsonCM,etal.Additionof clopido-greltoaspirinandﬁbrinolytictherapyformyocardialinfarction withST-segmentelevation.NEnglJMed.2005;352:1179---89.

11.SabatineMS,CannonCP,GibsonCM,etal.Effectof clopido-grelpretreatmentbeforepercutaneouscoronaryintervention inpatientswithST-elevationmyocardialinfarctiontreatedwith ﬁbrinolytics:thePCI-CLARITYstudy.JAMA.2005;294:1224---32.

12.ChenZM,JiangLX,ChenYP,etal. COMMIT(ClOpidogreland MetoprololinMyocardialInfarctionTrial)collaborativegroup. Additionofclopidogreltoaspirinin45,852patientswithacute myocardial infarction: randomised placebo-controlled trial. Lancet.2005;366:1607---21.

13.PattiG,BarcziG,OrlicD,etal.Outcomecomparisonof 600-and300-mgloadingdosesofclopidogrelinpatients undergo-ingprimarypercutaneouscoronaryinterventionforST-segment elevationmyocardialinfarction:resultsfromtheARMYDA-6MI (AntiplatelettherapyforReductionofMYocardialDamage dur-ingAngioplasty-MyocardialInfarction)randomizedstudy.JAm CollCardiol.2011;58:1592---9.

14.WiviottSD, BraunwaldE,McCabeCH, etal.Prasugrel versus clopidogrelinpatientswithacutecoronarysyndromes.NEngl JMed.2007;357:2001---15.

15.MahaffeyKW, Wojdyla DM, Carroll K, et al. Ticagrelor com-pared withclopidogrel bygeographic regionin the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124:544---54.

16.ArmstrongD,SummersC,EwartL,etal.Characterizationofthe adenosinepharmacologyofticagrelor revealstherapeutically relevantinhibition ofequilibrative nucleoside transporter1. JCardiovascPharmacolTher.2014;19:209---19.

17.vanGiezenJJ,SidawayJ,GlavesP,etal.Ticagrelorinhibits adenosineuptakein vitro and enhancesadenosine-mediated hyperemiaresponsesinacaninemodel.JCardiovascPharmacol Ther.2012;17:164---72.

18.NylanderS, Femia EA, Scavone M, et al. Ticagrelor inhibits humanplateletaggregationviaadenosineinadditiontoP2Y12 antagonism.JThrombHaemost.2013;11:1867---76.

19.MontalescotG, van’tHofAW, LapostolleF,etal.Prehospital ticagrelorinST-segmentelevationmyocardialinfarction.NEngl JMed.2014;371:1016---27.

20.Marcano AL, Ferreiro JL. Role of new antiplatelet drugs on cardiovascular disease: update on cangrelor. Current AtherosclerosisReports.2016;18:66.

21.BhattDL,StoneGW,MahaffeyKW,etal.Effectofplatelet inhi-bitionwithcangrelorduringPCIonischemicevents.NEnglJ Med.2013;368:1303---13.

22.ApplegateRJ,SacrintyMT,LittleWC,etal.Incidenceof coro-narystentthrombosisbasedonacademicresearchconsortium deﬁnitions.AmJCardiol.2008;102:683---8.

23.Tcheng JE, Ellis SG, George BS, et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet anti-body Fab 7E3 in high-risk coronary angioplasty. Circulation. 1994;90:1757---64.

24.Simoons ML, de Boer MJ, van den Brand MJ, et al., Euro-peanCooperativeStudyGroup.RandomizedtrialofaGPIIb/IIIa plateletreceptorblockerinrefractoryunstableangina. Circu-lation.1994;89:596---603.

25.MadanM,Berkowitz SD,Christie DJ, etal. Determinationof platelet aggregationinhibition duringpercutaneous coronary interventionwiththeplateletfunctionanalyzer PFA-100.Am HeartJ.2002;144:151---8.

26.De LucaG, Suryapranata H, Stone GW, et al. Abciximab as adjunctivetherapytoreperfusioninacuteST-segmentelevation myocardial infarction:a meta-analysis of randomized trials. JAMA.2005;293:1759---65.

27.Kereiakes DJ, Berkowitz SD, Lincoff AM, et al. Clinical correlates and course of thrombocytopenia during percu-taneous coronary intervention in the era of abciximab plateletglycoproteinIIb/IIIablockade.AmHeartJ.2000;140: 74---80.

28.TchengJE, Kereiakes DJ,Lincoff AM,et al. Abciximab read-ministration:resultsoftheReoProReadministrationRegistry. Circulation.2001;104:870---5.

29.Summary of Product Characteristics of Tiroﬁban - Aggras-tat50 mg/mlSolution for infusion. https://www.medicines. org.uk/emc/product/566[accessedApril2018].

30.Kereiakes DJ, Kleiman NS, Ambrose J, et al. Random-ized,double-blind, placebo-controlled dose-ranging study of tiroﬁban (MK-383) platelet IIb/IIIa blockade in high risk

(9)

patientsundergoingcoronary angioplasty.J AmCollCardiol. 1996;27:536---42.

31.Van’tHofAW, Ten BergJ, Heestermans T, etal. Prehospital initiation of tiroﬁban in patients with ST-elevation myocar-dialinfarctionundergoingprimary angioplasty(On-TIME2):a multicentre,double-blind,randomisedcontrolledtrial.Lancet. 2008;372:537---46.

32.PlateletGlycoproteinIIb/IIIainUnstableAngina:Receptor Sup-pressionUsingIntegrilinTherapy(PURSUIT)TrialInvestigators. Inhibition of platelet glycoprotein IIb/IIIa with eptiﬁbatide in patients with acute coronary syndromes. N Engl J Med. 1998;339:436---43.

33.ZeymerU,MargenetA,HaudeM,etal.Randomizedcomparison ofeptiﬁbatideversusabciximabinprimarypercutaneous coro-naryinterventioninpatientswithacuteST-segmentelevation myocardialinfarction:resultsoftheEVA-AMITrial.JAmColl Cardiol.2010;56:463---9.

34.Akerblom A, James SK, Koutouzis M, et al. Eptiﬁbatide is noninferior to abciximab in primary percutaneous coro-naryintervention:resultsfrom theSCAAR (SwedishCoronary Angiography and Angioplasty Registry). J Am Coll Cardiol. 2010;56:470---5.

35.Singh HS, Dangas GD, Guagliumi G, et al. Comparison of abciximab versus eptiﬁbatide during percutaneous coronary intervention in ST-segment elevation myocardial infarction (from the HORIZONS-AMI trial). Am J Cardiol. 2012;110: 940---7.

36.YusufS,MehtaSR,ChrolaviciusS,etal.Effectsoffondaparinux onmortalityandreinfarctioninpatientswithacuteST-segment elevationmyocardialinfarction:theOASIS-6randomizedtrial. JAMA.2006;295:1519---30.

37.WarkentinTE.ThinkofHIT.HematologyAmSocHematolEduc Program.2006:408---14.

38.ConnollySJ,MillingTJJr,EikelboomJW,etal.Andexanetalfa foracutemajorbleedingassociatedwithfactorXainhibitors. NEnglJMed.2016;375:1131---41.

39.MontalescotG,ZeymerU,SilvainJ,etal.Intravenous enoxa-parin or unfractionated heparin in primary percutaneous coronaryintervention for ST-elevationmyocardialinfarction: theinternationalrandomisedopen-labelATOLL trial.Lancet. 2011;378:693---703.

40.StoneGW,WitzenbichlerB,GuagliumiG,etal.Bivalirudin dur-ingprimaryPCIinacutemyocardialinfarction.NEnglJMed. 2008;358:2218---30.

41.Steg PG, van’tHof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369:2207---17.

42.ValgimigliM,FrigoliE,LeonardiS,etal.Bivalirudinor unfrac-tionatedheparininacutecoronarysyndromes.NEnglJMed. 2015;373:997---1009.

43.Leonardi S, Frigoli E, Rothenbuhler M, et al. Bivalirudin or unfractionated heparinin patientswith acute coronary syn-dromes managed invasively with and without ST elevation (MATRIX):randomisedcontrolledtrial.BMJ.2016;354,i4935.

44.LeonMB,Baim DS, PopmaJJ,et al. Aclinicaltrial compar-ingthreeantithrombotic-drugregimens aftercoronary-artery stenting.StentAnticoagulationRestenosisStudyInvestigators. NEnglJMed.1998;339:1665---71.

45.Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334:1084---9.