6:AcuteCoronarySyndromes

Overview
Thischapterisdividedintotwosections,thefirstfocusingonthemanagementofnonSTsegmentelevationacutecoronary syndromes(NSTEACS)unstableanginaandnonSTsegmentelevationmyocardialinfarctionandthesecondfocusingon STsegmentelevationmyocardialinfarction(STEMI).ThechapterdiscussesthepathophysiologyofACSandeachmodulewill reviewtriage,riskstratification,andinhospitalmanagementwithreferencetotheAmericanCollegeofCardiology/American HeartAssociationguidelinesasaframework.

Authors
PatrickT.O'Gara,MD,FACC EditorinChief ThomasM.Bashore,MD,FACC AssociateEditor JamesC.Fang,MD,FACC AssociateEditor GlennA.Hirsch,MD,MHS,FACC AssociateEditor JuliaH.Indik,MD,PhD,FACC AssociateEditor DonnaM.Polk,MD,MPH,FACC AssociateEditor SunilV.Rao,MD,FACC AssociateEditor

6.1:UA/NSTEMI:MyocardialInfarction:Pathophysiology
Author(s): JamesL.Januzzi,Jr,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Recognizethefactorsleadingtoatheroscleroticplaquerupture. 2. Citeeventsfollowingruptureofatheroscleroticplaques.

AcuteCoronarySyndromePathophysiology:AnHistorical Overview
Thepastdecadeshavebroughtaconsiderableshiftintheunderstandingofthe sequenceofbiologicaleventsthatleadtoacutecoronarysyndromes(ACS). Includingunstableanginapectoris(UAP),nonSTsegmentelevationmyocardial infarction(NSTEMI),andSTEMI,thevastmajorityofACSshouldnowlargelybe thoughtofasvariousexpressionsofacommonpathophysiology,alongacontinuum ofseverity.1 Earliertheoriesarguedthatcoronaryluminalcompromisefromanincreasingly severecoronarylesionwastheprimarycauseforACSsubsequently,vascular spasmaswellasinsituthrombosisgainedsupportasproximalfactorsfor progressiontoUAPandMI.However,angiographicstudiesparticularlyfollowing fibrinolysisledtoarealizationthatmorethan70%ofplaquesleadingtoACSare indeedactuallynotangiographicallysevere.2 Followingthis,moreindepthbiologicalstudiesdemonstratedthatincontrastto stablecoronarysyndromes,whichpresentmoreindolently(andduetogradual occlusionofacoronaryvesselfromalargelystable,lipidpoorplaqueFigure1), ACSaremostoftenduetoacutedisruption(or"rupture")ofaformofplaquethatis biologicallyquitedistinctfromthemorebenignstableplaque(Figure2). Indeed,this"vulnerable"plaque(knownasthethincappedfibroatheroma)isnow thoughttobetheculpritinmostformsofACSthecurrentlyheldconceptofACS pathophysiologyconnectsthe"vulnerability"forplaqueruptureandthusriskforACS moretotheunderlyingbiologyoftheplaque(andsubsequentthromboticcascade followingplaquerupture),ratherthantoantecedentangiographicseverity.

Figure1

Figure2

AStableCoronaryPlaque Figure1 Thoughpossiblyabletocauseanginathroughsupplydemandinequityrelatedtocoronarylumenobstruction,thislesionislipidpoor,andunlikely torupture.

AThinCappedFibroatheroma Figure2 Suchalesionisvulnerabletorupture,exposingitslipidrichnecroticcoretothebloodstream,triggeringtheplateletandcoagulationcascade.

VulnerablePlaqueRupture:Frequency
Remarkably,whetherthroughinvivoimagingoratautopsy,itisnowrecognizedthatthepathophysiologicallyvulnerable thincappedfibroatheromaisnotuncommon.Studiessuggestthatupto65%ofpatientswithriskfactorsforcoronary arterydisease(CAD)haveevidenceforatleastonethincappedfibroatheroma,andamongthosedyingofnoncardiac causes,asmanyas25%haveevidenceofpreviousplaquerupturewithoutknowledgeofACShistory.3 Thus,the pathophysiologicsubstrateforACSisquitecommon.

VulnerablePlaqueFormationandRupture:Pathophysiology
Intheinitialphasesofcoronarylesionformation,theplaqueareatypicallyexpands outwardsawayfromthelumenasacompensatorymechanismtoprevent narrowingofthecoronaryvessel(Figure3).Thisvascularremodelingmaycontinue untiltheareaoftheatheroscleroticplaqueexceeds4050%oftheperimeter encompassedbytheinternalelasticlamina,aconsiderableburdenofatheroma despitenoluminalcompromise. Asrevealedbyimagingstudiesofpatientswiththincappedfibroatheromataleading toACS,mostlesionsleadingtosubsequentmajorcardiaceventswerefoundin areasofthecoronaryvasculaturecharacterizedbyalargeplaqueburden,but significantangiographiccompromiseofthelumenwasnotfound(Table1).4 Similarly,locationwithinthecoronaryvesselalsoappearstoaffectriskforplaque rupture:proximallylocatedplaques(suchasthefirstthirdofthevessel)aswellas thoseatbifurcationsaremorelikelytoleadtoACS,presumablyduetomechanical forcesatthesesites.3 Inadditiontoexistinginazoneoflargeplaqueburdenandtheirlocationproximally inthevesseloratbifurcations,plaquespronetorupturehaveacharacteristic biologythatidentifiesthemas"vulnerable."Amongthebiologicalaspectsnowheld todetermineplaquevulnerabilityarethepresenceandactivityofinflammationinthe atheroscleroticlesion,thesizeofthenecroticlipidcore,thethicknessofthefibrous capoftheplaque,aswellastheabilityofsmoothmusclecellandfibroblastswithin theplaquetomaintaintheintegrityofthisfibrouscapthatseparatesthebloodpool fromtheintenselyirritatingandprothromboticlipidcore.57 Theinflammatorycellsofaplaquepronetoruptureincludelargeamountsof mononuclearandpolymorphonuclearleukocytesaswellasmastcells,allofwhich aremostoftenfoundinthe"shoulderregion"oftheplaque.Throughthereleaseof severalcompounds,includingmatrixmetalloproteinases(stimulatedbythe presenceof,amongotherthings,oxidizedlowdensitylipoproteinintheplaque), suchinflammatorycellsarethoughttoplayaroleintheeverydaymaintenanceofthe fibrouscapoftheplaquehowever,instatesofinadequatecollagensynthesisby plaquebasedsmoothmusclecellsorfibroblasts,overtweakeningofthefibrous capoccurs,usuallyatthezoneofgreatestdistributionofinflammatorycellsinthe plaqueshoulder.8 InmanycasesofACS,aproximaltriggermaybeidentified(Table2).9 Suchtriggers includefactorsthatresultinincreasedhemodynamicburdenontheplaque, promotevascularspasm,increaseendothelialdysfunction,oracombinationof theseprocesses.AcurioustriggerforACSisacuteinfectionwithinfluenza,10which hasledtotheClassIArecommendationfromthe2011AmericanCollegeof Cardiology/AmericanHeartAssociation(ACCF/AHA)FocusedUpdateIncorporated IntotheACC/AHA2007GuidelinesfortheManagementofPatientsWith UA/NSTEMItoadministertheinfluenzavaccinetoallthosewhohavebeen diagnosedwithanACS.11

Figure3

Table1

Table2

TimelineofAtherogenesis Figure3 Longitudinalsectionofcoronaryartery,depictingatimelineofatherogenesis,fromanormalartery,toearlyfattystreakformation,toplaque formationwithvascularremodeling,andultimatelycomplicatedlesionsatriskforintravascularthrombosisatthetimeofrupture. ReproducedwithpermissionfromLibbyP.Currentconceptsofthepathogenesisoftheacutecoronarysyndromes.Circulation2001104:36572.

FactorsDeterminingPlaqueVulnerability Table1

DescribedTriggersofAcutePlaqueRupture Table2 Formoreinformation,seeServossSJ,JanuzziJL,MullerJE.Triggersofacutecoronarysyndromes.ProgCardiovascDis200244:36980.

VulnerablePlaqueRupture:PlateletCascade
Whenanatheroscleroticplaqueruptures(Figure4),ittypicallyresultsinintraplaque hemorrhage,withtheexposureoflargeamountsofhighlythrombogenicmaterial (suchastissuefactor)tocirculatingbloodplatelets,triggeringoffacascadeof eventsleadingtotheformationofaplateletrichthrombusatthesiteofdisruption. Withtheexposureofthenecroticlipidrichcoreoftheplaque,whichalsocontains collagenandothercomponentsoftheadjacentsubendothelium,aplateletrich intracoronarythrombusisformedthroughplateletadhesion,activation,and aggregation.12 PlateletAdhesion Plateletadhesionismediatedbyboththeglycoprotein(GP)Ib/IXreceptor,which bindstosubendothelialvonWillebrandfactor(vWf),aswellastheGPIa/IIbreceptor, whichbindstocollagen.Followingadhesion,plateletactivationensues,which resultsinthereleaseofthecontentsofcytosolicstoragegranuleswithintheplatelet, includingprocoagulantandvasoconstrictivesubstancessuchasadenosine triphosphateandthromboxaneA2.Thesevasoactivesubstancesleadtoconstriction ofthecoronaryartery,withvariousdegreesofvascularspasminthemilieuofthe plaquerupture. PlateletActivation Followingthis,plateletactivationoccursandpropagatesviaseveralmechanisms, includingexposuretothrombin,serotonin,thromboxaneA2,andadenosine(as noted,manysubstancesthattriggerplateletsarefoundintheirowncytosolic granules).Followingactivation,criticalconformationalchangesoccurintheplatelet, leadingtothefinalcommonpathwayoftheplateletplugformation,namely aggregation. PlateletAggregation PivotaltoplateletaggregationistheGPIIb/IIIareceptor.Thereareanestimated 50,000to80,000GPIIb/IIIareceptorsonthesurfaceofeachrestingplateletthis numberincreaseswithplateletactivation,duringwhichstoredintraplateletpoolsof thereceptorareexteriorizedandrenderedreceptiveforthefunctionalligandsofthe receptor,fibrinogen,andvWF.Thebindingoftheseligandsfacilitatesthecross linkingofplateletsatthesiteofendothelialdisruption,thegrowthofanarborizing plateletrichclot,whichservesasanidealmilieuforthenowactivatedcoagulation cascadetoproceedforward.

Figure4

RupturedVulnerablePlaque Figure4 Thelesionhasrupturedattheshoulderoftheplaque(redarrow).

VulnerablePlaqueRupture:CoagulationCascadeandFormationofFibrinRichClot
Althoughbothintrinsicandextrinsiccoagulationpathwaysareparticipantsintheformationofanarterialthrombusatthe siteofplaquerupture,theintrinsic(ortissuefactor)pathwayispivotalinthisprocess.13.Themainroleofthetissuefactor pathwayistogenerateaburstofthrombinmostimportantly,givenitsprocoagulantrolerelativetoplatelets.The sequenceofstepsleadingtothrombingenerationincludes: ActivatedfactorVII(whichcirculatesinahigheramountthananyotheractivecoagulationfactor)bindstotissue factor. TheactivatedfactorVIItissuefactorcomplexactivatesfactorX. TogetherwithactivatedfactorV,activatedfactorXformstheprothrombinasecomplex,whichresultsinconversion ofprothrombinintothrombin. Thrombingenerationresultsinmorestimulatedplatelets,increasedactivationofthecoagulationcascade,and thusanongoingcycleofthrombosis. Severalfactorsdeterminethesizeoftheintracoronarythrombusthatformsatthesiteofplaquerupture.Theseinclude theabsoluteseverityofplaquerupture,aswellasfactorsintrinsictotheplaquesuchastheamountoftissuefactor generatedbystromalcellsandleukocyteswithinthelesion.Aswell,factorsintrinsictotheplateletsrespondingtothe plaquerupturemaydeterminethevolumeofthrombusthatformsithasbeensuggestedthatcertainsubgroupsof patientsmaybemorepronetoexcessiveplateletresponsesinthecontextofplaquerupture.Suchpatientstypicallyhave diffusevasculardisease,diabetesmellitus,andchronickidneydiseaseinthiscontext,plateletsmaybehyper stimulatedandmorelikelytoadhere,activate,andaggregate.Inaddition,suchpatientsmaybeathigherriskfor resistancetoantiplatelettherapies.14,15 Ultimately,inmanycasesfollowingplaquerupture,thedevelopmentofasignificantintracoronarythrombusensues,with compromiseofthecoronarylumen,andthepossibleonsetofsymptomaticACS.

MyocardialIschemiaand/orInjuryAfterPlaqueRupture
Followingplaqueruptureandintracoronarythrombusformation,dependingonthedegreeofluminalobstruction,a patientmaybeentirelyasymptomaticormaymanifestthewidespectrumofACS,includingrapidlyprogressiveUAP, NSTEMI,andsuddendeath. While,almostbydefinition,STEMIischaracterizedbycompleteocclusionoftheepicardialvesselsubtendingtheacutely injuredmyocardium,inmany(ifnotmost)casesofNSTEACS,epicardialflowisreduced,butstillpresent.Yetthepatient manifestssymptomsandsignsofmyocardialischemia,andmyocardialnecrosismayoccur.Inadditiontofocal vasospasmrelatedtomediatorselaboratedbyplateletdegranulation,thecurrentlyheldtheorytoexplainmyocardial ischemiaand/ornecrosisinthecontextofanonobstructedcoronaryisthattheabundantintracoronarythrombusthat existsatthesiteoftheplaqueruptureisunstable,exposedtonumerousstressors(suchasarterialbloodflow)aswell asendogenousfibrinolysis.Inthiscontext,frequentplateletrichembolicdebristransitstotheresistance microvasculaturethismicroembolizationthusresultsinmultifocalnecrosis,enhancingtheriskforarrhythmiaand death.16

AcuteCoronarySyndromeNotDuetoPlaqueRupture
OtherprocessesmayleadtoanACSwithoutplaquerupture(Table3).Acommon causeisincreasedmyocardialoxygendemandinthecontextofreducedsupply, suchasthatwhichoccursinthecontextofstable,butsevereepicardialcoronary stenoses.Whenthisresultsinmyocardialnecrosis,suchascenarioisreferredto asatype2(or"demandrelated")MI.17.ThisisanimportantcauseofACS,but differsconsiderablyfromapathophysiologicperspectivethanspontaneousplaque ruptureandplatelet/fibrinclotformation(atype1MI). OtheruncommoncausesofsupplydemandinequityleadingtoACSareembolito thecoronaryarteryorcoronaryvasospasm.Coronaryembolimayarisefromtheleft atrium(suchasinatrialfibrillationorinthecontextofanatrialmyxoma),from valvularstructures(asinendocarditis),ormayoriginatefromthevenoussystemand transitparadoxicallyacrosstheinteratrialseptumviaapatentforamenovaleoratrial septaldefect. Coronaryvasospasmmaybesevereenoughtoresultinabrupt,severetransmural ischemia,leadingtosocalled"variant"angina.Thoughrarelysevereenoughto resultinalargeMI,coronaryvasospasmmayresultinvaryingdegreesofmyocardial necrosisaswellasventriculararrhythmia.InWesternsocieties,coronaryspasm moreoftenthannotoccursatthesiteofacoronaryplaquepathophysiologic explanationsincludelossofnormal,endogenousnitricoxidemediated vasodilation.18 Last,upto25%ofspontaneousACSareduetosuperficialerosionofthe endotheliallayerwithoutobviousplaquedisruptioninmanycases,plaqueerosion actuallyleadstosloughingoftheendothelium,exposingtheintenselyprocoagulant subendotheliallayer.Inautopsystudies,plaqueerosionwasmorecommonlyfound inwomen,intobaccousers,andasacauseofsuddendeathsoonafterexertion.19.

Table3

CausesofAcuteCoronarySyndromeWithoutAcutePlaqueRupture Table3

FutureDirections
GiventheprimacyofthincappedfibroatheromasforthedevelopmentofACS,effortsarenowongoingtoprospectively identifytheselesions.Intracoronaryimagingtechniquessuchasintravascularultrasoundoropticalcoherence tomography,aswellastissuecharacterizationusingnearinfraredspectroscopymayofferaninvivowindowintothe biologicalriskofcoronaryplaques.Ifthisispossible,thendirectedtherapiestoreducetheriskforfutureACSmaybe possible,includingplaquesealingbystentinglesionslikelytorupture,aswellasintensivemedicalmanagementwith therapiesknowntoreducetheriskforplaquerupture,suchasstatins.

KeyPoints
MostACSresultfromdisruptionofavulnerableatheroscleroticplaquethatisnonsevereintermsofluminal obstruction. Factorsthatdetermineriskforplaqueruptureincludelocationoftheplaque,thedegreeofinflammationwithinthe plaque,andtheintegrityoftheplaquesfibrouscap. Whenthefibrouscapruptures,intenselyprocoagulantsubstancesareexposedtothebloodpool,leadingto plateletadhesion,activation,andaggregation. PlateletaggregationoccursviatheGPIIb/IIIareceptor,andallowsforthecoagulationcascadetoproceed,withthe fixationoftheprothrombinasecomplex,andthrombingeneration. Whenintracoronarythrombusforms,itmayobstructthecoronarylumenentirely,leadingtoSTEMIorsudden cardiacdeathlessersevereobstructionmayresultinnosymptoms,UAP,orNSTEMI. Myocardialnecrosisduetoanonobstructiveintracoronarythrombusmostoftenresultsfromplateletrich microaggregatesthatembolizetothemyocardialresistancevesselsdownstreamtotheepicardialplaque rupture. OthercausesofACSincludesupplydemandinequity,coronaryemboliorvasospasm,andplaqueerosion.

References
1. MartinezRumayorA,JanuzziJLJr.NonSTsegmentelevationacutecoronarysyndromes:acomprehensive review.SouthMedJ200699:110310. 2. AmbroseJA,WintersSL,AroraRR,etal.Coronaryangiographicmorphologyinmyocardialinfarction:alink betweenthepathogenesisofunstableanginaandmyocardialinfarction.JAmCollCardiol19856:12338. 3. CheruvuPK,FinnAV,GardnerC,etal.Frequencyanddistributionofthincapfibroatheromaandrupturedplaques inhumancoronaryarteries:apathologicstudy.JAmCollCardiol200750:9409. 4. StoneGW,MaeharaA,LanskyAJ,etal.Aprospectivenaturalhistorystudyofcoronaryatherosclerosis.NEnglJ Med2011364:22635. 5. FinnAV,NakanoM,NarulaJ,KolodgieFD,VirmaniR.Conceptofvulnerable/unstableplaque.ArteriosclerThromb VascBiol201030:128292. 6. MorenoPR.Vulnerableplaque:definition,diagnosis,andtreatment.CardiolClin201028:130. 7. LibbyP.Currentconceptsofthepathogenesisoftheacutecoronarysyndromes.Circulation2001104:36572. 8. LibbyP,RidkerPM,HanssonGK,onbehalfoftheLeducqTransatlanticNetworkonAtherothrombosis. Inflammationinatherosclerosis:frompathophysiologytopractice.JAmCollCardiol200954:212938. 9. ServossSJ,JanuzziJL,MullerJE.Triggersofacutecoronarysyndromes.ProgCardiovascDis200244:36980. 10. WarrenGashC,SmeethL,HaywardAC.Influenzaasatriggerforacutemyocardialinfarctionordeathfrom cardiovasculardisease:asystematicreview.LancetInfectDis20099:60110. 11. WrightRS,AndersonJL,AdamsCD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA2007 GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areport oftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines developedincollaborationwiththeAmericanAcademyofFamilyPhysicians,SocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol201157:e215367. 12. MassbergS,SchulzC,GawazM.Roleofplateletsinthepathophysiologyofacutecoronarysyndrome.Semin VascMed20033:14762. 13. SelwynAP.Prothromboticandantithromboticpathwaysinacutecoronarysyndromes.AmJCardiol200391:3H 11H. 14. AngiolilloDJ.Antiplatelettherapyindiabetes:efficacyandlimitationsofcurrenttreatmentstrategiesandfuture directions.DiabetesCare200932:53140. 15. PapathanasiouA,GoudevenosJ,TselepisAD.Aspirinresistanceincardiovasculardisease:pathogenesis, diagnosisandclinicalimpact.CurrPharmDes200915:108594. 16. YamadaDM,TopolEJ.Importanceofmicroembolizationandinflammationinatheroscleroticheartdisease.Am HeartJ2000140:S90102. 17. ThygesenK,AlpertJS,WhiteHD,onbehalfoftheJointESC/ACCF/AHA/WHFTaskForcefortheRedefinitionof MyocardialInfarction.Universaldefinitionofmyocardialinfarction.JAmCollCardiol200750:217395. 18. VanSpallHG,OvergaardCB,AbramsonBL.Coronaryvasospasm:acasereportandreviewoftheliterature.Can JCardiol200521:9537. 19. VirmaniR,BurkeAP,FarbA.Plaqueruptureandplaqueerosion.ThrombHaemost199982:13.

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6.2:UA/NSTEMI:InitialManagement,RiskAssessment,&RiskStratification
Author(s): SergioLeonardi,MD,MHS PierluigiTricoci,MD,MHS,PhD

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Summarizethekeydiagnosticstepsforpatientswithsuspectedacutecoronarysyndrome(ACS)tooptimizeinitialtriage andearlymanagement. 2. Explaintherationaleforearlyriskassessmentandstratification. 3. Discussmanagementoptionsfornonhighriskpatients. 4. Describearationalemanagementstrategyforapatientwithconfirmedunstableangina/nonSTsegmentelevation myocardialinfarction(UA/NSTEMI)accordingtothebaselinerisk.

Introduction
UAandNSTEMIarepartoftheACSspectrumofclinicalpresentation,andrepresentthemostfrequentformofACS (approximatelytwothirdsofpatientswithACS).ThediagnosisofUAismainlybasedonclinicalpresentationinthe absenceofelevationofcardiacbiomarkers.PresentationsofUAincludethreemainscenarios: Ischemicdiscomfort(chestpainorequivalent)atrest,typicallyofadurationlongerthan20minutes. New/recentonsetofexertionalanginawithmildexercisethreshold(correspondingtoaCanadianCardiovascular Society[CCS]classofIIIorIV),typicallyinthelast46weeks. Inpatientswithpreexistingexertionalangina,progressionofsymptomstoaCCSclassIIIorIV. NSTEMIisusuallycharacterizedbyischemicdiscomfortatrest,absenceofpersistentSTsegmentelevationon12lead electrocardiogram(ECG),andpositivecardiacnecrosisbiomarkers.

PrehospitalManagement
PatientswithsuspectedACSrequirearapidevaluation,whichispossiblewhenpatientsseekpromptmedicalattention. Therefore,patientswhoareconsideredatriskofdevelopingcoronaryarterydisease(CAD)(i.e.,patientswithmultiple riskfactorsorFramingham10yearrisk>20%,thosewithdiabetes,etc.)orthosewhohaveanestablishedhistoryof atheroscleroticcardiovasculardisease(i.e.,CAD,stroke,peripheralarterialdisease)shouldbeeducatedbyhealthcare providersonhowtorecognizesymptomsofACS,andtoseekimmediatemedicalattention. AkeyaspectinpatientswithknownCADistoprovideeducationonselftriagewithnitroglycerintabletsorsprays. Patientsshouldbetaughtincaseofischemicsymptomsto:1)sitandrest2)takeonenitroglycerinsprayortabletand wait5minutesforsymptomstocease3)ifsymptomsarestillpresent,takeasecondtabletorsprayofnitroglycerinand waitforsymptomstoceaseand4)ifsymptomsarestillpresent,seekemergencyevaluationbycalling911(orother localnumberforemergencymedicalservices).

InitialHospitalAssessment
TheinitialassessmentiscriticalinpatientswithsuspectedACS(Figure1).The diagnosisofACSisaclinicaldiagnosisthatreliesessentiallyonthreekey diagnostictools:1)thecharacteristicsofthepresentingsymptoms,2)theECG findings,and3)thepresenceofmyocardialnecrosis,asindicatedbyanelevationof circulatingcardiacbiomarkers. Thesethreeessentialtoolsprovidenotonlyadiagnosticassessment,butalsoa firstriskstratificationthatwillguidefundamentaldecisionsoninitialmanagement including:1)initialmedicaltherapy,2)appropriateplacement,and3)initial managementstrategy(earlycoronaryangiographyvs.earlynoninvasive assessment). Thefirstdiagnosticandprognosticevaluationsarestrictlycorrelatedandshould consequentlydrivetheinitialmanagement,withoutwaitingforafinalconfirmatory diagnosis.TheinitialdiagnosisofACS,therefore,shouldbeconsideredaworking diagnosis.The2007ACC/AHAGuidelinesfortheManagementofPatientsWith UA/NSTEMI1 recommendthatphysiciansformulateaninitialestimateonthe likelihoodofACSaslow,intermediate,orhigh(Table1).

Figure1

Table1

AlgorithmfortheAssessmentofPatientsWithSuspectedAcuteCoronarySyndromes Figure1 ACC/AHA=AmericanCollegeofCardiology/AmericanHeartAssociationACS=acutecoronarysyndromeECG=electrocardiogramLV=left ventricular. ReproducedwithpermissionfromAndersonJL,AdamsCD,AntmanEM,etal.ACC/AHA2007guidelinesforthemanagementofpatientswith unstableangina/nonSTelevationmyocardialinfarction:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForce onPracticeGuidelines(WritingCommitteetoRevisethe2002GuidelinesfortheManagementofPatientsWithUnstableAngina/NonSTElevation MyocardialInfarction)developedincollaborationwiththeAmericanCollegeofEmergencyPhysicians,theSocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeonsendorsedbytheAmericanAssociationofCardiovascularandPulmonary RehabilitationandtheSocietyforAcademicEmergencyMedicine.JAmCollCardiol200750:e1e157.

LikelihoodThatSignsandSymptomsRepresentanAcuteCoronarySyndromeSecondarytoCAD Table1 CAD=coronaryarterydiseaseCKMB=creatinekinasemyocardialbandMI=myocardialinfarctionMR=mitralregurgitationTnI=troponinI TnT=troponinT. ReproducedwithpermissionfromAndersonJL,AdamsCD,AntmanEM,etal.ACC/AHA2007guidelinesforthemanagementofpatientswith unstableangina/nonSTelevationmyocardialinfarction:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForce onPracticeGuidelines(WritingCommitteetoRevisethe2002GuidelinesfortheManagementofPatientsWithUnstableAngina/NonSTElevation MyocardialInfarction)developedincollaborationwiththeAmericanCollegeofEmergencyPhysicians,theSocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeonsendorsedbytheAmericanAssociationofCardiovascularandPulmonary RehabilitationandtheSocietyforAcademicEmergencyMedicine.JAmCollCardiol200750:e1e157.

HistoryandPhysicalExamination (1of2)
Thepatient'sdescriptionofsymptomsiscentraltothediagnosis.Thetypeofischemicsymptomsandthewayeach subjectdescribesthemcanvary.Therefore,itmakessensetorefertothesymptomsgenericallyas"ischemic discomfort."Themosttypicalischemicdiscomfortisrepresentedbyclassicanginapectoris,describedasaretrosternal chestpressureandheaviness,whichmayradiatetotheneck,jaw,epigastrium,shoulders,andoneorbotharms. AlthoughthisdescriptionofUAsymptomsmayberepresentedbynewonsetsevereischemicdiscomfort(CCSIIIIV)or accelerationofpriorexertionalangina,inNSTEACS,symptomstypicallyoccuratrestandareexacerbatedbyphysical activityorinsomecasesbyemotionalstress. Inindividualpatients,anginalepisodestendtobesimilarinqualityandlocationduringrecurrences.Thus,symptoms consistentwithpriordocumentedanginaareanimportantdiagnosticclue.Thedurationofischemicdiscomfortis typicallyseveralminutes,andmaydecreasewithrestingandnitroglycerinadministration.Ischemicdiscomfortwitha durationof>2030minutescontinuouslyisingeneralconsistentwithadiagnosisofMI,andtypicallyassociatedwith elevatedmyocardialnecrosisbiomarkers.Whilechestpainduetomyocardialischemiamayberelievedbyrestor sublingualnitroglycerin,reliefwithnitroglycerinalsohasbeendocumentedinpatientswithgastricoresophageal disorders,andhaslimiteddiagnosticvalueasatestfordeterminingmyocardialischemia.2 Somegroupsofpatients,morefrequentlyamongtheelderlyandwomen,mayhaveischemicdiscomfortthatisdifferent thanclassicangina,andalsoisreferredtoas"anginaequivalents."Theseincludedyspnea,nausea,vomiting, diaphoresis,andunexplainedfatigue.Rarely,syncopeandpalpitationsarepresentingsymptomsofACS. Ischemicdiscomfort,andinparticularchestpain,enterintodifferentialdiagnosisofothercausesofnoncardiacchest pain.Characteristicsofpainthatsuggestanoncardiacetiologyincludesharpstabbingthoracicpain,paininavery definitelocationofthechest,verybriefepisodesofpainlastingafewseconds,prolongedchestpain(i.e.,hours)not associatedwithelevatedcardiacbiomarkers,andpainexacerbatedbybreathing,movementofthechest,orreproduced withpalpation.Chestpainthatisexacerbatedbybendingdownorinthesupineposition(especiallypostprandial)may haveanesophagealetiology(i.e.,gastroesophagealrefluxdisease). AlthoughatypicalcharacteristicssubstantiallyreducetheprobabilityofACS,theyarenotsufficienttoruleoutthe diagnosis.ThepresenceoftraditionalriskfactorsforCAD(e.g.,hypertension,dyslipidemia,familyhistoryofpremature CAD,cigarettesmoking,diabetes,etc.)increasestheprobabilitythattheunderlyingsymptomsmanifestanACS,butthey arelessusefulthansymptoms,anECG,andcardiacbiomarkersforthediagnosis.Therefore,whilethepresenceor absenceoftheseriskfactorsshouldbetakenintoaccount,theyshouldnotbeusedasconfirmatoryorexclusionary factorsintheinitialdiagnosticassessment. PhysicalExamination InthemajorityofpatientswithuncomplicatedACS,thephysicalexaminationisusuallynormalandcontributestothe initialimpressionoffavorableshorttermprognosis.Thephysicalexamhasseveralimportantgoals.First,itmayhelpto disclosepotentialprecipitatingcausesofmyocardialischemiasuchasuncontrolledhypertension,anemiadueto bleeding,andthyrotoxicosis.Also,itisimportanttofindconcomitantextracardiacatherosclerosis(suchasbruits indicatingperipheralarterialdisease),aswellastoassessthehemodynamicconsequencesoftheischemicevent. Acutecoronaryischemiacancauseorexacerbateheartfailure.Signsofheartfailurearediscoveredduringaroutine physicalexam,andincludethirdcardiacsound,pulmonaryrales,elevatedjugularveinpressure,andlowextremity edema.Mitralregurgitationcanalsobeassociatedwithacutecoronaryischemia,whichcanbedetectedduringcardiac auscultation.Ifapatienthasalargeareaofischemiacausingsevereleftventricular(LV)dysfunction,physicalfindings canbedominatedbyalowoutputstatewithsinustachycardia,diaphoresis,palecoolskin,andhypotension.The presenceofheartfailureorcardiogenicshockisassociatedwithincreasedinhospitalmortality. Thephysicalexamalsomayhelptodiscloseadvancedcomorbidconditionsthatcouldimpacttherapeuticdecision making(e.g.,malignancies,orliverorpulmonaryfailure).Thephysicalexaminationisalsocriticalinthedifferential diagnosisofothercausesofcardiacchestsuchasunequalextremitypulsesoramurmurofaorticregurgitation(aortic dissection),apericardialfrictionrub(acutepericarditis),andpulsusparadoxus(cardiactamponade).Reproductionof chestpainwithpalpationindicatesanoncardiaccauseofchestpain,whichistypicallymuscularskeletalpain. Electrocardiogram TheECGisthefirstexamthatshouldbeperformedandevaluatedinpatientswithsuspectedACSwithagoalofwithin10 minutesfromfirstmedicalcontact.ECGfindingsshouldbeinterpretedinthecontextoftheclinicalpresentationtobest aiddiagnosis.Duringacutemyocardialischemia,ECGfindingshavenotonlydiagnostic,butalsoprognosticand therapeuticimplications.

Thefirstdiagnosticstepistheidentificationofchangesconsistentwithacutemyocardialischemia.ThepresenceofST segmentdeviation(elevationordepression)isthemostspecificECGsignofacuteischemia,whereasTwavechanges aresensitive,butlessspecific.PatientswithACSandpersistentSTsegmentelevation(>30minutesSTEACS)should beconsideredforimmediatemechanicalorpharmacologicalreperfusionandmanagedaccordingthe2004ACC/AHA GuidelinesfortheManagementofPatientsWithSTEMI,3 andfollowingupdates(20074 and20095 ).Importantly,this categoryalsoincludespatientswithpresumednewleftbundlebranchblock(LBBB)ortrueposteriorMI.Recognizingthe diagnosticchallengesandpotentialdelaysinlifesavingreperfusionofpatientswithtrueposteriorMI,the2007ACC/AHA GuidelinesfortheManagementofPatientsWithUA/NSTEMI1 considereditreasonabletoperformroutinelyposterior ECGleads(V7V9)inpatientswithsuspectedACSandanondiagnosticECGatpresentation. IfaSTEMIhasbeenexcluded,theECGshouldbecarefullyinspectedforthepresenceofSTsegmentdepressionsand Twaveabnormalities.DepressionsoftheSTsegmentof0.05mVareimportantindicatorsofongoingsubendocardial ischemia(especiallyifhorizontalordownsloping),andaretypicallypresentwhilethepatientissymptomatic.A prognosticallyunfavorableECGpatternistheassociationofwidespreadSTdepressionwithSTelevationinleadaVR, whichhasbeenassociatedwithextensiveischemiaduetocriticalstenosisoftheleftmaincoronaryartery.6 Twaveabnormalitiesarealsoimportanttoconsider.Tall,peakedTwavescanprecedethedevelopmentofSTelevation inpatientswithtransmuralischemia,andshouldraiseahighsuspicionofimpendingSTEACS.Ontheotherhand,T waveinversionsandTwave"pseudonormalizations"(i.e.,thedevelopmentofpositiveTwaveinpatientswithpreviously invertedTwaves)mayaidthediagnosisofUA/NSTEMI,especiallyifrecordedduringtypicalsymptomshowever,they havebeenlessconsistentlyassociatedwithmyocardialischemia. Finally,itiscriticaltorecognizethatACSpathophysiologyishighlydynamicandacompletelynormalECGdoesnot excludethepossibilityofanACS.7 Therefore,the2007ACC/AHAGuidelinesfortheManagementofPatientsWith UA/NSTEMI1 recommendperformingserialECGiftheinitialECGisnotdiagnostic,butthepatientremainssymptomatic andthereishighclinicalsuspicionforACS.AllpatientswithconfirmedUA/NSTEMIshouldundergocontinuousECG monitoringduringtheearlyhospitalphase.BeyondthediagnosticandprognosticvalueofrecordingrecurrentST segmentshifts,continuousECGmonitoringisimportantfordetectingmajorventriculararrhythmias,animportant preventablecauseofdeathintheearlyperiod. BiomarkersofMyonecrosis InconjunctionwiththeECG,theassessmentofcardiacbiomarkersistheothercornerstonetesttobeperformedinall patientswithsuspectedACS.Byvirtueofitsnearabsolutemyocardialspecificity,cardiactroponinsTandIarethe preferredmarkersofmyocardialnecrosis.Aftertroponin,creatinekinasemyocardialband(CKMB)isthenextfavored cardiacmarker,especiallyifmeasuredbyahighlysensitivemassassay. InpatientswithclinicalACSandwithoutpersistentSTelevation,thedistinctionbetweenNSTEMIandUAisdeterminedby thepresenceorabsenceofacardiacbiomarkerelevation,respectively.MostpatientswithNSTEMIhavetroponin elevatedwithin46hoursaftersymptomonset.Patientswithnegativecardiacbiomarkerswithin6hoursoftheonsetof symptomsconsistentwithACSshouldhavebiomarkersremeasured812hoursaftersymptomonset. CardiacTroponin Cardiactroponinisnowwidelyacceptedasthe"goldstandard"biomarkerfordetectionofmyocardialnecrosis.This regulatoryproteinmodulatestheactinmyosininteractioninthemyocardiumandintheskeletalmuscles,andexistsin threealternativeisoforms:I,T,andC.TroponinsIandT,butnottroponinC,haveisoformsencodedbygenesspecificfor themyocardium.Thisyieldstoproteinsthatareimmunologicallydistinctfromtheskeletalformswithepitopesthatcan betargetedbyspecificallydesignedmonoclonalantibodies. Thekineticoftroponinreleasereflectsitslocationwithinthemyocyte.Indeed,cardiactroponinsaremainlyboundto myofilaments,whileonlyasmallportionisfreeinthecytosol.Typically,troponinbloodlevelsincreaserapidlyintheinitial evolvingphaseofanMI,likelyreflectingareleaseofthefreecytoplasmicform,whiletheydecreasemoreslowlyover days/weeksafterthepeakhasbeenreached,indicatingacontinuous,moresubstantialreleasefromtheactinfilament poolofthemyocytes. Itiscurrentlyrecommendedtodefineasabnormal,atroponinlevelasavalueexceedingthe99thpercentileofa referencepopulationofapparentlyhealthysubjects.8 Also,itisrecommendedthattheinterassaycoefficientofvariation ameasureoftheanalyticalprecisionoftheassayshouldbe10%atvaluescorrespondingtothe99thpercentile. Notably,whentheserecommendationswherefirstreleased,nocommerciallyavailableassaywasabletoreachthese stringentrequirements.9 Morerecently,assaysofhighersensitivityusuallyreferredtoassensitive,highlysensitive,or ultrasensitivetroponinassayshavebeendeveloped,meetingtheserequirements. Thefollowingareimportantanalyticalissues,ofwhichcliniciansmustbeaware:First,comparedwithfirstgeneration assays,whichwerelimitedbynonspecificbindingtoskeletalmuscletroponinandsuboptimalanalyticalperformances, noveltroponinassayscombineexcellentanalyticalsensitivitywithanacceptableprecision.Severalobservationshave

shownthattroponinassaysofhighersensitivitymayimprovetheoveralldiagnosticaccuracyforACScomparedtoolder assays,andinparticular,mayacceleratethediagnosisupto3hoursfromsymptomonset.10,11 Ontheotherhand,theincreaseinanalyticalsensitivity(thelevelofdetectionwasintheorderof0.3ng/mlforatypical firstgenerationassaywhileithasreached0.0002ng/ml,aquantity>103 lower,inoneofthelatesttroponinIassays)12 hasbeeninevitablyassociatedwithalossofdiagnosticspecificity,especiallyinlowriskpatients,13whichreinforcesthe importanceofacarefulclinicaldiagnosis.Notably,inalargecohortofpatientswithstableanginawithoutACS,theuseof ahighsensitivitytroponinTassaytested"positive"(i.e.,abovethe99thpercentile)in11.1%ofpatients.14Therefore,itis criticaltorecallthatanabnormaltroponinvalueshouldbeconsideredanMIonlyinthepresenceofclinicalischemia(as indicatedbytheECGand/orthenatureofsymptoms). Thepresenceofelevatedtroponinintheproperclinicalcontext(i.e.,typicalischemicdiscomfortand/ortypicalECG changes)indicatesadiagnosisofMI.Thepresenceofanappropriateclinicalcontextisimportantbecausewhile elevatedcardiactroponinsreflectthepresenceofmyocardialnecrosis,theydonotindicatethemechanism.Infact, elevatedcardiactroponincanbedetectedinavarietyofconditionsotherthannonacutemyocardialischemia.These includephysicalmyocardialtrauma(contusion,cardioversion),heartfailure,pulmonaryembolism,apicalballooning syndrome(Takotsubocardiomyopathy),myocarditis,myocardialinfiltrativedisease,anddruginducedcardiotoxicity. Inaddition,anumberofnoncardiacconditionscanbeassociatedwithelevatedcardiactroponins,suchasrenal insufficiency,sepsis,respiratoryfailure,andsevereburns.Notablychronicallyelevatedtroponincanbeobservedin patientswithchronickidneydisease,especiallythoseundergoingdialysis.BecauseofthehighprevalenceofCADin patientswithchronickidneydisease,thisoftenposesdiagnosticuncertainty.Inthissituation,thepresenceofanew raiseandfallofatroponinpatternshouldberegardedasahigherspecificityfindingcomparedtoasingleelevatedvalue. Myocardialnecrosisandtheresultingcardiactroponinelevationdoesnotalwaysresultfromacuteinterruptionof coronaryperfusion(i.e.,coronarythrombosis).Incertainconditions(e.g.,sustainedtachyarrhythmias),anincreased myocardialblooddemandmayexceedavailablebloodsupply,resultinginmyocardialnecrosis.Thepresenceof underlyinghemodynamicallysignificantCADmayfavorthismismatch.Itisalsopossiblethatpoordeliveryofoxygento themyocardiumsuchasinthecaseofsevereacuteanemia,hypotension,severebradyarrhythmiascancausetroponin tobeelevated.Theseconditionsareclassified,accordingtotheuniversalMIdefinition,astype2orsecondaryMI.8 While theelevationoftroponinhasbeenassociatedwithworseprognosis,inconditionsoutsideACS,thetreatmentrequired forACSversussecondaryMIisdifferent. Inadditiontotheirdiagnosticrole,elevatedcardiactroponinisasignificantpredictorofbothshortandlongterm mortalityinpatientswithACS.Moreover,evidencesuggeststhatelevatedtroponinisassociatedwiththepresenceof coronarythrombosis.

HistoryandPhysicalExamination (2of2)
CreatineKinaseandCreatineKinaseMyocardialBand Duetothepoorspecificityformyocardialdamage,totalCKactivityisnolonger recommendedinthe2007ACC/AHAGuidelinesfortheManagementofPatients WithUA/NSTEMIastheprimarytestforthedetectionofmyocardialdamagein patientswithsuspectedACS.1 Theseenzymesexistasthreealternativeforms(CK MM,CKMB,andCKBB),whichmaybeseparatedbyelectrophoresis.Byvirtueofa substantiallyhigherconcentrationincardiacversusskeletalmyocytes,theCKMB isoenzymeshowssubstantiallyimprovedsensitivityandspecificitycomparedwith totalCKfordetectionofmyocardialdamage.Still,CKMBrepresents13%oftheCK inskeletalmuscle,andisalsopresentinsmallquantitiesinotherlocationssuchas theintestine,uterus,andprostate.Thismustbeaccountedforinthesettingofmajor injurytotheseorgans,especiallyskeletalmuscles. ImmunoassaysthatdetermineCKMBmass(typicallyreportedinnanogramsper milliliter)arefavoredovertraditionalassaysofCKMBactivity(expressedas internationalunits/liters)duetothehigherdiagnosticaccuracy.Troponinhas replacedCKMBasthepreferredbiomarkerforthediagnosisofMI.CKMBmustbe used,however,ifcardiactroponinsarenotavailable.Thus,whencardiactroponinis available,theroleofCKMBassessmentislimited.Onerolemaybethediagnostic evaluationinthesettingofveryearlyrecurrentMIsinpatientswithbaselineelevated troponinlevels.However,contrarytoacommonmisconception,cardiactroponins canbeusedtodiagnoserecurrentMI. OtherBiomarkers Severalbiomarkerswithdifferentputativemechanismshavebeenproposedto optimizemanagementofpatientswithACS.Theseinclude:1)markersof hemodynamicstress(suchasBtypenatriureticpeptide[BNP]orNterminalportion ofBtypenatriureticpeptide[NTproBNP]),whicharecurrentlyusedinthediagnosis ofheartfailure2)markersofearlyischemia(suchasischemiamodifiedalbumin) and3)markersofinflammation(suchasCreactiveprotein).Todate,however,there arenosufficientdatatoincorporatethesebiomarkersintheclinicaldecision making,andparticularlyinguidingtherapies. The2007ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMI considerpossiblyusefulmeasuringBNPorNTproBNPasasupplemental assessmentofglobalriskinpatientswithsuspectedACS(ClassIIb,Levelof Evidence:B).1 Natriureticpeptideshavebeenassociatedwithahigherriskof cardiovascularmortalityandheartfailureinACS,butthereisnoclearrolein establishingmanagementstrategies. RoleofAdditionalTesting AsreportedinTable1,patientscanbeclassifiedintohigh,intermediate,orlowACS likelihoodbasedonhistory,physicalexam,ECG,andbiomarkers.Inthepresenceof suspectedischemicsymptoms,ECGdynamicSTsegmentchanges,Twave inversion,orelevatedcardiacbiomarkersindicateahighlikelihoodofACS.Ifthe precedinghighlikelihoodfeaturesareabsent,apatientwouldfitintoeither intermediateorlowlikelihood.Inthesepatients,afinaldiagnosisandrisk assessmentisnotestablished,andthereisaroleforadditionalnoninvasive testing. Patientswithalowlikelihoodandwithouthighriskcharacteristicscanbe dischargedhomeandadditionalevaluationcanbeperformedasanoutpatient. Patientsatintermediateriskrequireadditionalinhospitaltriagewithnoninvasive diagnosticandriskevaluationtoassesswhetherpresentationislowriskACSor chestpainisnoncardiac. IfthepatientisabletoexerciseandbaselineECGallowstheinterpretationof exerciseinducedSTsegmentalterations,anexercisetreadmilltestshouldbe consideredfirst.CommoncausesofnoninterpretabilityoftheECGincludeLBBB,
Table1

Table2a

Table2b

pacedventricularrhythm,andrepolarizationsabnormalitiesinpatientswithLV hypertrophy. Ifanexercisetreadmilltestisnotfeasible,thenapharmacologicstresstestis recommended(i.e.,withdobutamine,adenosine,ordipyridamole).Animaging enhancedstresstest(i.e.,singlephotonemissioncomputedtomography[SPECT], magneticresonance,orechocardiogram)increasesthesensitivityandspecificityin detectingmyocardialischemiacomparedwithECGonlytesting,andis recommendedparticularlyinwomenandinpatientswithconfoundersonbaseline ECG.StrengthsandlimitationsofeachavailablestresstestarelistedinTables2a andb. Contraindicationstostresstestingarearecentrecurrenceofischemicrestpain, especiallyifassociatedwithECGchangesorothersignsofinstability (hemodynamicorsignificantarrhythmias).The2007ACC/AHAGuidelinesforthe ManagementofPatientsWithUA/NSTEMIrecommendanindividualizedapproachto thechoiceoftestbasedonpatientcharacteristics,localinstitutionalavailability,and expertiseininterpretation.1 EchocardiogramandMyocardialPerfusionImaging SPECTmyocardialperfusionimaging(MPI)andechocardiographyaretwo comparabletechniquesinthediagnosisofmyocardialischemia.Bothmodalities allowperformanceofastresstest,eitherthroughanexerciseorapharmacological agent,ifthepatientisunabletoexercise.Stressorpharmacologicagentstoprovoke ischemiaincludedobutamine(whichincreasesmyocardialoxygendemand),or adenosine/dipyridamole(whichactsdifferentlybyinducingapreferential vasodilationofnormalcoronaryarteries).MPIcanbeusedwhilethepatientis havingischemicdiscomfortatrest,todetectischemiaatrest,whichobviatesthe needforacutestresstestinginmanypatients. Thesafetyofdischargingpatientswithanegativeperfusionscanhasbeen confirmedbyalarge(2,475patients)randomizedclinicaltrial.15Thisstudyshowed thattherateofhospitalizationforpatientswithoutacutemyocardialischemiawas reducedfrom52%withstandardcareto42%withtheuseofacuteMPI,andthis reductioninhospitaladmissionwasassociatedwithanunchanged30dayclinical outcome.However,whetherthisprotocoliscosteffectiveremainsunclear. Echocardiographydetectswallmotionabnormalityinducedbyeitherexerciseor dobutamine.Normalmyocardiumrespondstoexerciseordobutaminewith increasedcontractility,andhyperkineticwallmotionobservedwith echocardiography.Exerciseordobutamineinducesischemiaintheareaof myocardiumwithsignificantcoronarystenosis,andwallmotionabnormality (hypokinesia)isdetectedwithechocardiography.Anadvantageofechocardiography overSPECTisthelackofradiationexposure. CardiacComputedTomographyAngiogram Acardiaccomputedtomographyangiogram(CTA)isatestbasedonevaluationof cardiacanatomy.Multislice(64slicesandabove)CTAhasbeenreportedtohave >90%sensitivityandspecificitytodetectobstructivecoronarydisease.CTAcan providevaluableinformationaboutcoronaryanatomyandLVfunction,whichcanbe usedintheevaluationofpatientswithsuspectedorknownCAD. Adistinctadvantageofthisimagingmodalityistheexcellentnegativepredictive value(>90%)inmostinstances,anegativecoronaryCTArulesoutsignificantCAD withahighdegreeofconfidence.However,thepositivepredictivevalueislower (80%)andthepresenceofapositivefindinghasbeenlessconsistentlyassociated withsignificantCAD.ThismaybeduetoatendencyofcardiacCTAtooverestimate diseaseseverity,particularlyinsmallerandmoredistalcoronarysegments,orin segmentswithartifactscausedbycalcificationinthearterialwalls.Another challengeofCTAisthatitprovidesanatomicratherthanfunctionalinformation therefore,itcanhelpidentifydiseaseofthecoronaryartery,butdoesnotprovethat theidentifieddiseaseisthecauseofthepatient'ssymptoms. AconceptuallyappealingapplicationforcoronaryCTAhasbeenthesocalled"triple ruleout"intheemergencydepartment(ED),whichreferstothepossibilitytoassess

(andexclude)notonlysignificantcoronaryarterystenosesasthecauseofchest pain,butalsotwootherpotentiallylifethreateningconditions:acuteaortic syndromesandpulmonaryembolism.The"tripleruleout,"however,posesspecific logisticandconceptualchallenges,andithasbeenincludedinthe"areaswithout consensus"bythe2010ExpertConsensusDocumentonCoronaryCTA.16Two importantsafetyissuesrelatedtocardiacCTAthatmustbeconsideredinthe decisionmakingprocessare:1)theamountofionizingradiationabsorbedbythe bodytissues,and2)theexposuretoiodinatedcontrastagentsthathavethe potentialtoproduceacuterenalinjuryandallergicreactions. CardiovascularMagneticResonance Cardiovascularmagneticresonance(CMR)combinesanexcellentspatialand temporalresolutionwiththesafetyofavoidingionizingradiation.CMRisa multimodalexamination,whichallowstheassessmentofcardiacfunction,anatomy, perfusion,andviabilityduringthesametest.Stress(dobutamineoradenosine) perfusionCMRprovidesexcellentdiagnosticinformationindetectingmyocardial ischemia,inthecontextofacomprehensiveassessmentofcardiacanatomyand function. Delayedenhancement(DE)CMRisahighlyaccurateandwellvalidatedtechnique todetectmyocardialscars,andisverysensitiveindetectingsmallor subendocardialinfarcts.InpatientswithsuspectedMI,particularlywhenpatients presentoutsidethediagnosticwindowofcardiactroponins,DECMRmaybe especiallyuseful.DECMRcandifferentiatebetweenischemicandvarious nonischemicformsofmyocardialinjury,andtherefore,maybehelpfulincasesof uncertaindiagnosis.InpatientswithknownMI,CMRcanbeusedtoidentify myocardialviability.Italsocanbeusedtodetectpericardialdisease(i.e., pericarditis). CMRistheimagingmodalityofchoiceinpatientswithsuspectedcoronaryartery anomalies,suchasaleftanteriordescendingorcircumflexarteryfromthe pulmonaryarteryinyoungerindividualswithsignsorsymptomsofmyocardial ischemiaandaclinicalsuspicionsuchasthepresenceofacontinuousmurmur.17

LikelihoodThatSignsandSymptomsRepresentanAcuteCoronarySyndromeSecondarytoCAD Table1 CAD=coronaryarterydiseaseCKMB=creatinekinasemyocardialbandMI=myocardialinfarctionMR=mitralregurgitationTnI=troponinI TnT=troponinT. ReproducedwithpermissionfromAndersonJL,AdamsCD,AntmanEM,etal.ACC/AHA2007guidelinesforthemanagementofpatientswith unstableangina/nonSTelevationmyocardialinfarction:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForce onPracticeGuidelines(WritingCommitteetoRevisethe2002GuidelinesfortheManagementofPatientsWithUnstableAngina/NonSTElevation MyocardialInfarction)developedincollaborationwiththeAmericanCollegeofEmergencyPhysicians,theSocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeonsendorsedbytheAmericanAssociationofCardiovascularandPulmonary RehabilitationandtheSocietyforAcademicEmergencyMedicine.JAmCollCardiol200750:e1e157.

StrengthsandLimitationsofNoninvasiveTestforDiagnosisandRiskStratificationofCoronaryArteryDisease(1of2) Table2a CAD=coronaryarterydiseaseEBCT=electronbeamcomputedtomographyEBCTA=electronbeamcomputedtomographyangiographyECG =electrocardiogramMRI=magneticresonanceimagingMSCT=multislicecomputedtomographyMSCTA=multislicecomputedtomography angiographyPET=positronemissiontomographySPECT=singlephotonemissioncomputedtomography. ReproducedwithpermissionfromBonowRO,MannDL,ZipesDP,LibbyP.BraunwaldsHeartDisease:ATextbookofCardiovascularMedicine. 9thed.Philadelphia:Saunders2011.

StrengthsandLimitationsofNoninvasiveTestforDiagnosisandRiskStratificationofCoronaryArteryDisease(2of2) Table2b CAD=coronaryarterydiseaseEBCT=electronbeamcomputedtomographyEBCTA=electronbeamcomputedtomographyangiographyECG =electrocardiogramMRI=magneticresonanceimagingMSCT=multislicecomputedtomographyMSCTA=multislicecomputedtomography angiographyPET=positronemissiontomographySPECT=singlephotonemissioncomputedtomography. ReproducedwithpermissionfromBonowRO,MannDL,ZipesDP,LibbyP.BraunwaldsHeartDisease:ATextbookofCardiovascularMedicine. 9thed.Philadelphia:Saunders2011.

RiskAssessmentandRiskStratification
Initialdiagnosticandriskassessmentlargelyoverlap.Riskassessmentiscriticalin selectingtheproperplacementforfurthercare,andtostratifytreatmentappropriately basedonbaselinerisk. Patientswithongoingischemiarefractorytoinitialmedicaltherapyandthosewith evidenceofhemodynamicorelectricalinstabilityshouldbeadmittedtoacriticalcare unitwithreadyaccesstoinvasivecardiovasculardiagnosisandtherapeutic procedures.However,mostpatientswithACSarestableandareusuallyadmittedto astepdownunitwithamonitoredbedthathascontinuousECGmonitoring(i.e., telemetry).Patientswithnohighriskfeatures(nopersistentischemia,absenceof highriskECGcriteria,andnegativecardiacbiomarkers)canbeadmittedtoan observationunit(suchasachestpainunit)forfurtherevaluationincludingserial ECGs,cardiacmarkers,andnoninvasivetesting. WhileECGsandcardiacbiomarkersarekeydiagnostictoolsandarecentralalsoin riskstratification,severalotherclinicalcharacteristicshavebeenfoundtobe significantlyassociatedwiththeriskofmortalityorotherrecurrentischemicevent.To accountformultiplefactorssimultaneouslybyusingamultivariableapproach, clinicalriskscoreshavebeendevelopedfrombothclinicaltrialandregistry databases.Twowellknownclinicallyvalidatedmultivariableriskscorealgorithms aretheThrombolysisInMyocardialInfarction(TIMI)riskscoreandtheGlobal RegistryofAcuteCoronaryEvents(GRACE)riskscore.18,19 TIMIRiskScore TheTIMIriskscoreisasimpletoolcomprisedofsevenequallyweightedrisk indicatorscollectedatpresentation,andisavailableatwww.timi.org.Theseven itemsare: 1. Age65years, 2. Presenceof3riskfactorsforCAD(i.e.,diabetes,cigarettesmoking, hypertension,highdensitylipoproteincholesterol<40mg/dl,familyhistoryof prematureCAD), 3. KnownCAD(coronaryarterystenosis50%), 4. Aspirinuseinthepast7days, 5. 2episodesofanginawithin24hours, 6. STchanges0.05mV,and 7. Positivecardiacmarkers. Theriskofallcausemortality,neworrecurrentMI,orsevererecurrentischemia promptingurgentrevascularizationwithin14daysshowedagradedincreasewith increasingTIMIriskscore.ThisscorehasbeenvalidatedinternallywithintheTIMI 11BtrialandtwocohortsofpatientsfromtheESSENCE(EfficacyandSafetyof SubcutaneousEnoxaparininUnstableAnginaandNonQWaveMyocardial Infarction)trial.18AnadvantageoftheTIMIriskscoreisitssimplicityhowever,itis associatedwitharelativelylowdiscriminatorycapacity(cstatisticinthetestcohort was0.65). GRACERiskScore TheGRACEriskmodelwasoriginallydevelopedacrossthewholespectrumofACS (i.e.,patientswithandwithoutpersistentSTelevation)in17,142patientsfromthe GRACEregistry.19Themodel,whichpredictsinhospitalmortalityanddeathorMI,is averypowerfultoolforprognostication,withexcellentdiscriminationandcalibration. AnimportantfeatureoftheGRACEriskscoreisthatitincludesrenalfunctionasa keyprognosticindicator.ThecstatisticfortheUA/NSTEMIcohortwas0.83. Additionally,themodelhasbeenextensivelyvalidatedinmultiplecontemporary registries,2022andintheTIMACS(TimingofInterventioninPatientsWithAcute CoronarySyndromes)trial,theGRACEriskscoreidentifiedpatientswhoseemedto benefitfromamoreaggressiveinvasivemanagementapproach.23 EightvariablesusedtocomputetheGRACEriskscoreare:age,Killipclass,systolic bloodpressure,STsegmentdeviation,cardiacarrestatpresentation,serum creatininelevel,positiveinitialcardiacbiomarkers,andheartrateatadmission

Figure2

(Figure2).TheGRACEclinicalapplicationtoolcanbedownloadedat www.outcomesumassmed.org/grace,tobeusedatthebedside.

GRACERiskScore Figure2 ReproducedwithpermissionfromEagleKA,LimMJ,DabbousOH,etal.Avalidatedpredictionmodelforallformsofacutecoronarysyndrome: estimatingtheriskof6monthpostdischargedeathinaninternationalregistry.JAMA2004291:272733.Copyright2004AmericanMedical Association.

EarlyInHouseManagement
GeneralMeasures Unlessthereisevidenceofclinical(hemodynamic/electrical)instability,patientswithconfirmedUA/NSTEMIareusually admittedtoamonitoredbedwithcontinuousECGmonitoring(i.e.,telemetry)andbedrestisusuallyinitiallyorderedfor patientswithUA/NSTEMIinthefirst1224hours.Ifthepatienthasbeenstableduringthisinitialphase,ambulation,as tolerated,maybeallowed.SupplementaloxygenisfrequentlyadministeredtopatientsadmittedforUA/NSTEMI,butis likelytobecosteffectiveonlyinhighriskpatients. The2007ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMIrecommendreservingsupplemental oxygentopatientswithrespiratorydistress,cyanosis,arterialhypoxemia(arterialoxygensaturation<90%measuredby pulseoximetryorbloodgas),orotherhighriskfeatures.1 Animportantinitialgoalisthereliefofsymptoms.Initialtreatmentshouldinvolvenitratesandbetablockers,butifpain persists,morphinesulfate15mgintravenouslymaybeadministeredevery530minutesasneeded,withcareful monitoringofbloodpressureandrespiratoryrate.The2007ACC/AHAGuidelinesfortheManagementofPatientsWith UA/NSTEMIhavedowngradedtherecommendationformorphineuseforpersistentischemicchestdiscomfortfrom ClassItoClassIIabecausedatafromalargeregistrysuggestedahigherriskofdeathwithmorphine.1 AntiischemicMedications Antithrombinandantiplatelettherapiesarediscussedinanothermodule(seemoduleonAncillaryTherapyI:Antiplatelet andAntithrombinTherapyinthischapter). Betablockers InUA/NSTEMI,evidenceofthebenefitofbetablockershasbeenconfirmedinmultipleclinicaltrialsandispresumedto beduetotheinhibitionofbeta1adrenergicreceptorsinthemyocardium,whichresultsinadecreaseincardiacwork andmyocardialoxygendemand.Contraindicationstobetablockadeinclude:1)significantsinusbradycardia(heartrate <50bpm),2)markedfirstdegree(PRinterval>0.24second)oranysecondorthirddegreeatrioventricular(AV)block,3) persistenthypotension,4)pulmonaryedema,5)historyofbronchospasm,and6)evidenceofalowoutputstate(e.g., oliguria). Intheabsenceofcontraindications,oralbetablockertherapyshouldbeinitiatedwithinthefirst24hours.ACC/AHA guidelinesstatethatitisreasonabletoadministerintravenous(IV)betablockerstopatientswhoarehypertensiveatthe timeofpresentation(ClassIIa).The2007ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMI1 suggestgreatercautionwiththeearlyuseofIVbetablockersduetoriskofcardiogenicshocknotedintheCOMMIT (ClOpidogrelandMetoprololinMyocardialInfarctionTrial)studyofpatientswithSTEMI,especiallyinthosewith tachycardia,hypotension,orinKillipclassIIorIII.24 ComparativestudiesamongdifferentbetablockersinUA/NSTEMIarenotavailabletoestablishapreferenceamong agentsthus,thechoiceofbetablockerforanindividualpatientisbasedprimarilyonpharmacokineticandsideeffect criteria,aswellasonphysicianfamiliarityand/orconcomitantclinicalindications. Nitrates Nitratesarehighlyeffectiveandextensivelyusedantiischemicagentswithbotharterialandvenousvasodilatationeffects thatareindependentoftheendothelium.Insymptomaticpatients,nitratesmayinitiallybegivensublinguallyorbyoral spray(0.30.6mg).Forpatientswithpersistentanginaorotherconcurrentindicationssuchasheartfailureor hypertension,IVadministrationshouldbefavored. NitratesdidnotshowanybenefitonsurvivalinpatientswithacuteMIthus,thistherapyshouldbereservedtocontrol symptomsforpatientswithrecurrentanginaorheartfailure.Dependingonwhetherapatienthasreceivedcomplete revascularizationornot,andonthelikelihoodthatanginawilloccur,therapywithstandingdoseofnitratecanbegivenat discharge.Inallpatients,sublingualorspraynitroglycerinshouldbeprescribedfornewepisodesofangina. InthesettingofUA/NSTEMI,nitratesarecontraindicatedinpatientswithsystolicbloodpressure<90mmHgoradropof 30mmHgormorecomparedwithbaseline.Also,anabsolutecontraindicationistheofuseofphosphodiesterase inhibitorsforerectiledysfunction,suchassildenafil(within24hours)ortadalafil(within48hours),whiletheappropriate timefortheadministrationofnitratesaftervardenafilhasnotbeendetermined. Calciumchannelblockers Calciumchannelblockers(CCBs)areachemicallyheterogeneousclassofdrugssharingthecommonantagonismof theLtypecalciumionchannels.Clinically,itisusefultodistinguishwithinCCBsdihydropyridinederivatives(e.g.,

amlodipine,nifedipine,orfelodipine)fromnondihydropyridinederivativeswithAVnodeinhibitoryproperties,suchas verapamilordiltiazem. AllcurrentlyavailableCCBscausearterialvasodilationandlowerbloodpressureandhaveantianginapropertieswith dihydropyridinesbeingthemostpotent,andAVnodeinhibitorycompoundsattheendofthespectrumintermsof peripheralarterialdilatoryeffects.Ontheotherhand,onlyverapamilanddiltiazemsignificantlyreduceheartrateby delayingAVconductionorcausingsinusnodedepression.Theymaybeusefulintreatingmyocardialischemia secondarytosupraventriculararrhythmias,suchasatrialfibrillation,withrapidventricularresponse. TheevidencebaseforbenefitofCCBsinUA/NSTEMIismainlylimitedtosymptomcontrol.CCBsdonotreducemortality duringorafteracuteMIandarenotcurrentlyrecommendedasroutinetherapyinpatientswithUA/NSTEMI.The2007 ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMIrecommendCCBsasasecondlinetherapyfor patientswithpersistentorrecurrentanginaaftertreatmentwithbetablockersandnitrates,orinpatientswith contraindicationstobetablockade(suchasactiveasthma)intheabsenceofclinicallysignificantLVdysfunction.1 AspecificindicationforCCBuseasfirstlinetherapyisthetreatmentofvariantangina(Prinzmetalsangina),aformofUA duetoanepicardialcoronaryvasospasmthatusuallyoccursspontaneouslyandischaracterizedbytransientST segmentelevationthatresolvesspontaneouslyorwithnitroglycerinusewithoutprogressiontoMI.Importantly, immediatereleasenifedipinehasbeenassociatedwithanincreasedriskofadverseeventsincludingmortalityin patientswithUA/NSTEMI,whichispossiblyrelatedtoareflextachycardia,andiscontraindicatedintheabsenceofa betablocker.25

ManagementStrategySelection
InvasiveVersusConservativeStrategies CoronaryangiographyrepresentsthegoldstandardforthediagnosisofCAD,and forthosewhohaveCAD,thedefinitionofcoronaryanatomyallowsthechoiceof definitivemanagement,percutaneouscoronaryintervention(PCI),coronaryartery bypassgrafting(CABG),ormedicalmanagement.Theselectionofpatientswho needtoundergoacoronaryangiographyisoneofthefundamentaldecisions derivingfromtheinitialdiagnosticandriskevaluation. InpatientswithahighlikelihoodofCADandhighriskfeatures,twoapproachesthat havebeenextensivelystudiedinrandomizedclinicaltrialsare: Aninvasivestrategyconsistingofroutinediagnosticcoronaryangiography within2448hourswiththeintenttoperformcoronaryrevascularizationifthe anatomyisamenableand Anearlyconservativeischemiaguidedstrategyconsistingofintensifying antiischemicandantithromboticmedicaltherapy,withinvasiveprocedures limitedtopatientswithrefractoryanginaorinducibleischemiaafter provocativetests. Recently,ametaanalysisofthreeoftheserandomizedclinicaltrials(FRISCII, ICTUS,andRITA3)usingpatientleveldataand5yearoutcomesprovidedevidence thataroutineinvasivestrategywasassociatedwithasignificant19%reductionin theriskofcardiovasculardeathorMI(hazardratio[HR],0.8195%confidence interval[CI],0.710.93p=0.002)withamoreprominenttreatmenteffectontheMI component,butconsistenttrendsofbenefitforcardiovasculardeaths(HR,0.83 95%CI,0.681.01p=0.068)andallcausedeaths(HR,0.9095%CI,0.771.05).26 Mostnotablyandinaccordancewithpreviousobservations,theinvasivestrategy benefitshowedagradedresponseaccordingtothebaselinerisk.Therewere2.0 3.8%absolutereductionsincardiovasculardeathorMIinthelowandintermediate riskgroups,asopposedtoa11.1%absoluteriskreductioninpatientsathighest risk. Riskstratification,therefore,istheprimarydriverforstrategyselection.The2007 ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMI,1 andthe 2011FocusedUpdate27recommendanearlyinvasivestrategyinpatientswith hemodynamicorelectricalinstability,orinpatientswithhighriskfeaturesincluding ahighriskscore(e.g.,GRACEorTIMI),positivecardiacmarkers,STsegment depression,orrefractorysymptoms.Inpatientswithouthighriskfeatures,a conservativestrategymaybeconsidered,asperphysicianand/orpatient preference. Aninvasiveapproachisrelativelycontraindicatedinpatientswithextensive comorbiditiessuchasliverorpulmonaryfailure,cancer,andacuterenal insufficiency.However,thereisnoclearguidanceonwhattypeandwhatseverityof comorbiditiesshouldrepresentanabsolutecontraindicationtocoronary angiography.Therefore,thetreatingphysicianmustmakeadecisionaboutriskand benefitofaninvasivemanagementstrategyafteraccountingforexpectedprognostic qualityoflifebenefits,aswellasindividualpatientvaluesandpreference. Anearlyinvasivestrategyisnotrecommendedinpatientswithalowlikelihoodof ACS.Additionalsubgroupsthatmaybenefitfromanearlyinvasivestrategyinclude: PatientswithahistoryofPCIwithinthepast6months,whichoftencanbe treatedeffectivelywithrepeatPCIpatientswithpriorCABGwhereusually thereisadiagnosticallychallenginginterplaybetweentheprogressionof nativecoronarydiseaseandthedevelopmentofgraftatherosclerosis PatientswithknownorsuspectedreducedLVsystolicfunction,whoarewell knowntobeathigherriskandthuspresumedtobenefitfromamore aggressivemanagementstrategyand Patientswithtroponinelevation,whichhasbeenextensivelyassociatedwith complexcoronarylesions,visiblethrombus,andimpairedcoronaryflow,and
Table3

identifiedpatientsforwhompotentantiplateletandantithrombotictherapies areeffective(Table3). Withregardtothemodalityofcoronaryrevascularization(percutaneousvs.surgical), the2007ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMI recommendCABGasthepreferredrevascularizationstrategyforpatientswith significantdisease(>50%stenosis)oftheleftmain(ClassI),patientswiththreeor twovesseldiseasewhohavesignificantproximalleftanteriordescendingartery stenosis,andeithertreateddiabetesmellitus(ClassIIa)orLVdysfunction(LV ejectionfraction<0.50ClassI).1 Intheabsenceofthesefeatures,eitherPCI(with suitablecoronaryanatomy)orCABGisrecommendedforpatientswithsingleor multivesselCADwhohavehighriskcriteriaonnoninvasivetesting(ClassI).

Selectionofmanagementstrategybasedonclinicalcharacteristics Table3 CABG=coronaryarterybypassgraftingGRACE=GlobalRegistryofAcuteCoronaryEventsHF=heartfailureLVEF=leftventricularejection fractionPCI=percutaneouscoronaryinterventionTIMI=ThrombolysisInMyocardialInfarctionTnI=troponinITnT=troponinT. ModifiedwithpermissionfromAndersonJL,AdamsCD,AntmanEM,etal.ACC/AHA2007guidelinesforthemanagementofpatientswith unstableangina/nonSTelevationmyocardialinfarction:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForce onPracticeGuidelines(WritingCommitteetoRevisethe2002GuidelinesfortheManagementofPatientsWithUnstableAngina/NonSTElevation MyocardialInfarction)developedincollaborationwiththeAmericanCollegeofEmergencyPhysicians,theSocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeonsendorsedbytheAmericanAssociationofCardiovascularandPulmonary RehabilitationandtheSocietyforAcademicEmergencyMedicine.JAmCollCardiol200750:e1e157.

TimingofInvasiveAssessment:EarlyInvasiveVersusDelayedInvasive
ThewidespreadadoptionofanearlyinvasivestrategyinpatientswithUA/NSTEMIraisedthequestionoftheoptimal timingforaninvasiveassessment.Threerandomizedclinicaltrialsaddressedtheseissues:ISARCOOL(Intracoronary StentingWithAntithromboticRegimenCoolingOff),ABOARD(AngioplastytoBlunttheRiseofTroponininAcuteCoronary SyndromesRandomizedforanImmediateorDelayedIntervention)(tworelativelysmallstudiesthatenrolled410and 352patients,respectively),28,29andmorerecently,TIMACS(TimingofInterventioninPatientsWithAcuteCoronary Syndromes),alargemulticentertrialthatwasprematurelyterminatedafter3,031patientswithNSTEACSwereenrolled forrecruitmentchallenges.TheTIMACStrialcomparedanearly(24hoursfromrandomizationmediantime14hours) versusdelayedintervention(36hoursfromrandomizationmediantime50hours)inpatientswithUA/NSTEMI.23 TheTIMACStrialfoundanonsignificant15%HRreductionintheearlyinterventiongroupfortheprimaryendpointof death,MI,orstrokeat6months(HR,0.8595%CI,0.681.06p=0.15)andasignificant28%reductioninthe prespecifiedsecondaryoutcomeofdeath,MI,orrefractoryischemiaintheearlyinterventiongroup(9.5%),ascompared withthedelayedinterventiongroup(12.9%)(HR,0.7295%CI,0.580.89p=0.003).Prespecifiedanalysesshowedthat earlyinterventionimprovedtheprimaryoutcomeintheonethirdofpatientswhowereathighestrisk(HR,0.6595%CI, 0.480.89),butnotinthetwothirdsatlowtointermediaterisk(HR,1.1295%CI,0.811.56p=0.01forheterogeneity),as definedbyaGRACEriskscore>140. Onthebasisofthisevidence,the2011FocusedUpdateoftheGuidelinesfortheManagementofPatientswith UA/NSTEMIincludedanewrecommendationforthetimingofinvasiveassessmentinpatientsforwhomanearlyinvasive strategyhasbeenselected.27IninitiallystabilizedpatientswithNSTEACSthatareathighrisk(asdefinedbyaGRACE riskscore>140),aninvasiveassessmentwithin24hoursfromhospitalpresentationistobefavored(ClassIIa,Levelof Evidence:B),whereasadelayedinvasiveapproachisreasonableinpatientswhoarenotathighrisk.

KeyPoints
PatientswithsymptomssuggestiveofACSshouldbeinstructedtocall911andreferredtoafacility(suchasan ED)thatallowsevaluationbyaphysicianandtherecordingofa12leadECGandcardiacmarkersdetermination. Transportationbyanambulanceisfavoredoverfriendsorrelatives. TheinitialassessmentofpatientswithsuspectedACSshouldprioritizetwoquestions:Arethesymptoms indicativeofanongoingACS?Ifso,whatistheshorttermriskofadverseevents? Apatientssymptomdescriptionisacriticaldiagnosticstep,andtypicalsymptomssuchaschestheaviness, oppression,andretrosternalburningarethehallmarksofangina.However,somepatients,likewomenandthe elderly,aremorelikelytopresentwithatypicalsymptomssuchasnausea,dyspnea,anddiaphoresisasangina equivalents. InallpatientswithsymptomssuggestiveofACS,a12leadECGshouldbeperformedinatimelymannerafterED arrival(withagoalofwithin10minutes)andreviewedbyanexperiencedemergencyphysician. ECGshouldbereviewedforSTsegmentdeviation(elevationordepression),whicharethemostspecificsignsof ischemia,orTwavechanges.PatientswithanondiagnosticECGatpresentationandahighsuspicionofACS shouldhaveposteriorECGleads(V7 V9 )todisclosepossibletrueposteriorSTEMItoavoiddelaysinlifesaving reperfusion. Acardiospecifictroponinisthefavoredbiomarkertodiagnosemyocardialnecrosis,andshouldbemeasuredin allpatientswithsuspectedACS.CKMB,particularlyifmeasuredbyamassassay,isalsousefulespeciallyto detectearlyrecurrentMI.Patientswithnegativecardiacmarkerswithin6hoursofsymptomonsetshouldhave biomarkersremeasuredinthetimeframeof812hoursaftersymptomonset. IfthepatientremainsasymptomaticandrepeatedECG/cardiacmarkersarenegative,astresstesttoprovoke ischemiashouldbeperformedeitherbeforedischargeoronanoutpatientbasisinatimelyfashion(within72 hours).Accordingtothe2007ACC/AHAGuidelinesfortheManagementofPatientsWithUA/NSTEMI,1 a reasonablealternative(ClassIIa)tostresstestingiscardiacCTA.CMRisanotherimagingmodalitythatis becomingincreasinglyvalidatedandthathasthecapabilitytoassesscardiacfunction,perfusion,andviability simultaneously. Earlyriskstratificationisstronglyrecommended.Earlyriskassessmentshouldfocusonclinicalexam(history andphysicalexamination),ECGfindings,andcardiacmarkers.Suchassessmentpermitsselectionofthesiteof careandmodulatestheaggressivenessoftherapy,includingselectionofthemostoptimalmanagement strategy. Optimalriskstratificationrequiresamultivariableapproachthataccountsformultipleprognosticfactors.Clinically validatedriskstratificationmodels,suchastheTIMIorGRACEriskscore,areusefultoassistindecisionmaking withregardtomanagementstrategyandtimingofinvasivenessinpatientswithsuspectedACS.

References
1. AndersonJL,AdamsCD,AntmanEM,etal.ACC/AHA2007guidelinesforthemanagementofpatientswith unstableangina/nonSTelevationmyocardialinfarction:areportoftheAmericanCollegeofCardiology/American HeartAssociationTaskForceonPracticeGuidelines(WritingCommitteetoRevisethe2002Guidelinesforthe ManagementofPatientsWithUnstableAngina/NonSTElevationMyocardialInfarction)developedincollaboration withtheAmericanCollegeofEmergencyPhysicians,theSocietyforCardiovascularAngiographyand Interventions,andtheSocietyofThoracicSurgeonsendorsedbytheAmericanAssociationofCardiovascularand PulmonaryRehabilitationandtheSocietyforAcademicEmergencyMedicine.JAmCollCardiol200750:e1e157. 2. SwamyN.Esophagealspasm:clinicalandmanometricresponsetonitroglycerineandlongactingnitrites. Gastroenterology197772:237. 3. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarctionexecutivesummary:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(WritingCommitteetorevisethe1999guidelinesforthe managementofpatientswithacutemyocardialinfarction).JAmCollCardiol200444:671719. 4. AntmanEM,HandM,ArmstrongPW,etal.2007focusedupdateoftheACC/AHA2004guidelinesforthe managementofpatientswithSTelevationmyocardialinfarction:areportoftheAmericanCollegeof Cardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines.JAmCollCardiol200851:21047. 5. KushnerFG,HandM,SmithSCJr.,etal.2009focusedupdates:ACC/AHAguidelinesforthemanagementof patientswithSTelevationmyocardialinfarction(updatingthe2004guidelineand2007focusedupdate)and ACC/AHA/SCAIguidelinesonpercutaneouscoronaryintervention(updatingthe2005guidelineand2007focused update)areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceon PracticeGuidelines.JAmCollCardiol200954:220541. 6. NikusK,PahlmO,WagnerG,etal.Electrocardiographicclassificationofacutecoronarysyndromes:areviewbya committeeoftheInternationalSocietyforHolterandNonInvasiveElectrocardiology.JElectrocardiol201043:91 103. 7. ChallaPK,SmithKM,ContiCR.Initialpresentingelectrocardiogramasdeterminantforhospitaladmissionin patientspresentingtotheemergencydepartmentwithchestpain:apilotinvestigation.ClinCardiol200730:558 61. 8. ThygesenK,AlpertJS,WhiteHD,onbehalfoftheJointESC/ACCF/AHA/WHFTaskForcefortheRedefinitionof MyocardialInfarction.Universaldefinitionofmyocardialinfarction.JAmCollCardiol200750:217395. 9. PanteghiniM,PaganiF,YeoKT,onbehalfoftheCommitteeonStandardizationofMarkersofCardiacDamageof theIFCC.Evaluationofimprecisionforcardiactroponinassaysatlowrangeconcentrations.ClinChem 200450:32732. 10. KellerT,ZellerT,PeetzD,etal.SensitivetroponinIassayinearlydiagnosisofacutemyocardialinfarction.NEngl JMed2009361:86877. 11. ReichlinT,HochholzerW,BassettiS,etal.Earlydiagnosisofmyocardialinfarctionwithsensitivecardiactroponin assays.NEnglJMed2009361:85867. 12. WuAH,AgeeSJ,LuQA,ToddJ,JaffeAS.SpecificityofahighsensitivitycardiactroponinIassayusingsingle moleculecountingtechnology.ClinChem200955:1968. 13. JanuzziJLJr,BambergF,LeeH,etal.HighsensitivitytroponinTconcentrationsinacutechestpainpatients evaluatedwithcardiaccomputedtomography.Circulation2010121:122734. 14. OmlandT,deLemosJA,SabatineMS,etal.AsensitivecardiactroponinTassayinstablecoronaryartery disease.NEnglJMed2009361:253847. 15. UdelsonJE,BeshanskyJR,BallinDS,etal.Myocardialperfusionimagingforevaluationandtriageofpatients withsuspectedacutecardiacischemia:arandomizedcontrolledtrial.JAMA2002288:2693700. 16. MarkDB,BermanDS,BudoffMJ,etal.ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT2010expertconsensusdocument oncoronarycomputedtomographicangiography:areportoftheAmericanCollegeofCardiologyFoundationTask ForceonExpertConsensusDocuments.JAmCollCardiol201055:266399. 17. FrakerTDJr,FihnSD2002ChronicStableAnginaWritingCommitteeAmericanCollegeofCardiologyAmerican HeartAssociationGibbonsRJ,AbramsJ,ChatterjeeK,etal.2007chronicanginafocusedupdateofthe ACC/AHA2002guidelinesforthemanagementofpatientswithchronicstableangina:areportoftheAmerican CollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelinesWritingGrouptodevelop thefocusedupdateofthe2002guidelinesforthemanagementofpatientswithchronicstableangina.JAmColl Cardiol200750:226474. 18. AntmanEM,CohenM,BerninkPJ,etal.TheTIMIriskscoreforunstableangina/nonSTelevationMI:Amethodfor prognosticationandtherapeuticdecisionmaking.JAMA2000284:83542. 19. EagleKA,LimMJ,DabbousOH,etal.Avalidatedpredictionmodelforallformsofacutecoronarysyndrome: estimatingtheriskof6monthpostdischargedeathinaninternationalregistry.JAMA2004291:272733. 20. ElbarouniB,GoodmanSG,YanRT,etal.ValidationoftheGlobalRegistryofAcuteCoronaryEvent(GRACE)risk scoreforinhospitalmortalityinpatientswithacutecoronarysyndromeinCanada.AmHeartJ2009158:3929. 21. FoxKA,CarruthersKF,DunbarDR,etal.Underestimatedandunderrecognized:thelateconsequencesofacute coronarysyndrome(GRACEUKBelgianStudy).EurHeartJ201031:275564.

22. MeuneC,DrexlerB,HaafP,etal.TheGRACEscore'sperformanceinpredictinginhospitaland1yearoutcome intheeraofhighsensitivitycardiactroponinassaysandBtypenatriureticpeptide.Heart2011Mar28:[Epub aheadofprint]. 23. MehtaSR,GrangerCB,BodenWE,etal.,onbehalfoftheTIMACSInvestigators.Earlyversusdelayedinvasive interventioninacutecoronarysyndromes.NEnglJMed2009360:216575. 24. ChenZM,PanHC,ChenYP,etal.Earlyintravenousthenoralmetoprololin45,852patientswithacutemyocardial infarction:randomisedplacebocontrolledtrial.Lancet2005366:162232. 25. FurbergCD,PsatyBM,MeyerJV.Nifedipine.Doserelatedincreaseinmortalityinpatientswithcoronaryheart disease.Circulation199592:132631. 26. FoxKA,ClaytonTC,DammanP,etal.Longtermoutcomeofaroutineversusselectiveinvasivestrategyin patientswithnonSTsegmentelevationacutecoronarysyndromeametaanalysisofindividualpatientdata.JAm CollCardiol201055:243545.WrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdate incorporatedintotheACC/AHA2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonST ElevationMyocardialInfarction:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeart AssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyofFamily Physicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAm CollCardiol201157:e215367. 27. WrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA2007 GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areport oftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines developedincollaborationwiththeAmericanAcademyofFamilyPhysicians,SocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol201157:e215367. 28. NeumannFJ,KastratiA,PogatsaMurrayG,etal.Evaluationofprolongedantithromboticpretreatment(cooling offstrategy)beforeinterventioninpatientswithunstablecoronarysyndromes:arandomizedcontrolledtrial.JAMA 2003290:15939. 29. MontalescotG,CaylaG,ColletJP,etal.Immediatevsdelayedinterventionforacutecoronarysyndromes:a randomizedclinicaltrial.JAMA2009302:94754.

SuggestedReading
1. AmsterdamEA,KirkJD,BluemkeDA,etal.AmericanHeartAssociationExercise,CardiacRehabilitation,and PreventionCommitteeoftheCouncilonClinicalCardiology,CouncilonCardiovascularNursing,and InterdisciplinaryCouncilonQualityofCareandOutcomesResearch.Testingoflowriskpatientspresentingtothe emergencydepartmentwithchestpain:ascientificstatementfromtheAmericanHeartAssociation.Circulation 2010122:175676. 2. O'ConnorRE,BradyW,BrooksSC,etal.Part10:acutecoronarysyndromes:2010AmericanHeartAssociation GuidelinesforCardiopulmonaryResuscitationandEmergencyCardiovascularCare.Circulation2010122(18 Suppl3):S787817.

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6.3:UA/NSTEMI:AntiplateletTherapyforNonSTSegmentElevationAcute CoronarySyndromes
Author(s): PaulA.Gurbel,MD,FACC,FSCAI,FAHA UdayaS.Tantry,PhD

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Describetheroleofplateletsinatherothrombosis. 2. ExplainthemechanismofactionofaspirinandP2Y12receptorantagonistsandglycoprotein(GP)IIb/IIIainhibitors. 3. Describetheroleofaspirin,clopidogrel,prasugrel,andticagrelortreatmentinpatientswithnonSTsegmentelevation acutecoronarysyndromes(NSTEACS). 4. Identifylimitationsofclopidogreltreatment. 5. DescribetheroleofGPIIb/IIIainhibitorsinpatientswithNSTEACS. 6. Recallthe2011AmericanCollegeofCardiologyFoundation/AmericanHeartAssociation(ACCF/AHA)FocusedUpdate IncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonSTElevation MyocardialInfarction.1

Introduction
Nearly80%ofthe1.2millionhospitalizationsforACSin2007wereforNSTEACS. NSTEACScomprisesunstableangina(UA)andnonSTsegmentelevation myocardialinfarction(NSTEMI).Basedon2007datareportedinthe2011AHAheart diseaseandstrokestatisticsupdate,NSTEMIwasthemostcommonmanifestation ofACSandwasassociatedwithanincreasedriskofcardiacdeathandsubsequent MI.2 BasedontheCRUSADE(CanRapidriskstratificationofUnstableangina patientsSuppressADverseoutcomeswithEarlyimplementationoftheACC/AHA Guidelines)registryandACTIONRegistryGWTG(AcuteCoronaryTreatmentand InterventionOutcomesNetworkGetWiththeGuidelines),5458%ofNSTEMIsare managedwithpercutaneouscoronaryintervention(PCI).3 Sinceplateletactivationandreactivityareprimarilyresponsibleforthrombus generation,antiplatelettherapyconstitutesthemainstayofinitialandlongterm pharmacologictreatmentduringbothconservativeandinvasivestrategiesofNSTE ACS.TheunderlyingpathophysiologyofNSTEACSincludesareductionin myocardialoxygensupplyresultingfromtheacutegenerationofintracoronary plateletrichthrombusatthesiteofatheroscleroticplaqueruptureand vasoconstriction.Theimmediatetreatmentgoalisthepreservationofmyocardial perfusiontopreventfurthermyocardialdamage. PlateletadhesiontoexposedcollagenandvonWillebrandfactorbyspecific receptorsandthebindingofthrombingeneratedbytissuefactortoprotease activatedreceptors(PARs)causeinitialplateletactivation.Afteractivation,adenosine diphosphate(ADP)isreleasedfromdensegranulesandthromboxaneA2 is generated.Plateletcyclooxygenase1(COX1)convertsarachidonicacid(originating frommembranephospholipids)toprostaglandin(PG)H2 andplateletspecific thromboxane(Tx)synthaseconvertsPGH2 toTxA2 .Byautocrineandparacrine mechanismsactingthroughthromboxaneandP2Yreceptors,theseagonistsare responsiblefortheactivationoftheGPIIb/IIIa(fibrinogen)receptor. TherearetwomajorADPreceptorsontheplateletsurface:P2Y1 andP2Y12.P2Y1 is coupledtoGq andisresponsibleforshapechangeandcalciummobilization,and P2Y12iscoupledtoGi andispivotalintheamplificationofplateletactivationand aggregation.Currently,theonlyADPreceptortargetedpharmacologicallyinclinical practiceisP2Y12.ADPbindingtobothP2Y1 andP2Y12isrequiredformaximal plateletactivationandaggregation.However,thecontributionofP2Y12tomaximal aggregationisfarstrongerP2Y1 contributes<10%.Mostimportantly,continuous ADPP2Y12receptorsignalingisessentialforthesustainedactivationoftheGP IIb/IIIareceptorandstablethrombusgeneration.Plateletactivationexposesthe phosphotidylserinesurface,providingbindingsitesforcoagulationfactorsandthe generationofthrombin.Thefibrinnetworkgeneratedbythrombinactivityboundto aggregatedplateletsformsthestableclotatthesiteofvascularinjury(Figure1).4 CurrentapprovedantiplateletstrategiesinNSTEACSincludeinhibitionofCOX1by aspirin,inhibitionoftheADPP2Y12interactionbyP2Y12receptorantagonists (thienopyridines,ticagrelor),andinhibitionoftheGPIIb/IIIareceptorbyGPIIb/IIIa inhibitors.SimultaneousinhibitionofCOX1andP2Y12byaspirinandclopidogrel, respectively,hasbeenshowninbothpreclinicalandlargescaleclinicalstudiesto haveamorepotentantithromboticeffectthanaspirintherapyalone.Thesepivotal findingsformthebasisforcurrenttherapeuticrecommendationsinNSTEACS. Properriskassessmentisessentialtodetermineanoptimalplateletinhibition strategythatachievesamaximalantithromboticeffectassociatedwithanacceptable bleedingrisk.

Figure1

RoleofPlateletsDuringACSandTargetsofPlateletInhibitors Figure1 ACS=acutecoronarysyndromeADP=adenosinediphosphateCOX1=cyclooxygenase1GP=glycoproteinPAR1=proteaseactivated receptor1PCI=percutaneouscoronaryinterventionTP=troponinTxA2=thromboxaneA2,vWF=vonWillebrandfactor.

Aspirin
AspirinisthebedrockofNSTEACSantiplatelettreatmentstrategies.The antithromboticpropertyofaspirinisprimarilyattributedtoirreversibleacetylationof theplateletCOX1enzyme.Subsequently,thegenerationofTxA2 andTxA2 induced plateletaggregationareinhibited.However,recentstudiesindicatethatnonCOX1 effectsofaspirininplateletsandotherpleiotropiceffectsmayalsocontributeto antithromboticproperties. Aspirinisreadilyabsorbedintheuppergastrointestinaltract,whereasenteric coatedaspirinrequiresalongertimetobeabsorbed.Peakplasmalevelsoccur within40minutesoforaladministration,andplateletinhibitionandprolongationof bleedingtimecanbeobservedwithinanhour.Althoughtheplasmahalflifeis20 minutes,irreversiblebindingandthelackofdenovosynthesisofCOX1inplatelets resultsinCOX1inhibitionforthelifespanofplatelets(~10days).Plateletinhibition hasbeenobservedevenbeforetheappearanceofaspirininthesystemic circulation,suggestingthatacetylationofplateletCOX1takesplaceinthe prehepaticcirculation.MeasurementsofTxB2 inserumandTxdependentplatelet functionareconsideredassurrogatemeasuresoftheantiplateleteffectsofaspirin.5 TheoptimalaspirindoseforNSTEACSremainscontroversial.Inametaanalysis, similarclinicalefficacyoccurredwithdailyaspirindosesbetween75and1500mg. However,therewasa50%reductioninefficacywithdoses<75mg.6 TheCURE(ClopidogrelinUnstableAnginatoPreventRecurrentEvents)trial enrolledpatientswithNSTEACSandstudiedtheeffectofdualantiplatelettherapy withaspirinandclopidogrelcomparedtoaspirinmonotherapy.AnanalysisofCURE dividedthepatientsintothreeaspirindosegroups:100mg/d,101199mg/d,and 200mg/d,anditwasdemonstratedthatmajorbleedingriskwasincreasedwith aspirindosewithorwithoutclopidogrel(Figure2).7 Basedonthisanalysis,the authorssuggestedthattheoptimaldailydoseofaspirinforNSTEACSmaybe between75and100mg. IntherecentCURRENTOASIS7(ClopidogrelandAspirinOptimalDoseUsageto ReduceRecurrentEventsSeventhOrganizationtoAssessStrategiesinIschemic Syndromes)trial,patientswererandomlyassignedina2x2factorialdesignto highversuslowdoseclopidogrelregimensandhighversuslowdoseaspirin regimens.Therewerenosignificantdifferencesinthe30dayoutcomeof cardiovasculardeath,MI,orstroke,andnodifferencesinmajorbleedingbetween 75100mgand300325mgdailydoses.8,9 Arecentmetaanalysisofsecondarypreventionstudiescontinuedtoshow significantbenefitassociatedwithaspirintreatmentinthepostMIpatient21% reductioninseriousvascularevents(p<0.00001),29%reductioninnonfatalMI(p= 0.00003),13%reductionincoronaryheartdiseaserelateddeath(p=0.04)and vasculardeath(p=0.03),20%reductioninmajorcoronaryevents(p=0.03),andno significantinfluenceonanykindofstroke(Figure3).10 Basedonpriorrandomizedtrialprotocolsandclinicalexperience,the2011 ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007Guidelinesforthe ManagementofPatientsWithUA/NSTEMIrecommendimmediatetreatmentwithan initialdoseofaspirinbetween162325mg.1 Anonentericcoatedaspirinis recommendedasinitialtherapyduetomorerapidbuccalabsorption.Aspirin therapyshouldbecontinuedindefinitely.Therecommendedmaintenancedoses areshowninTable1.Themostcommonsideeffectofaspirintreatmentis gastrointestinalintolerancethatoccursin540%ofpatients.Inpatientswhoare allergictoaspirinorwhocannottolerateaspirin,clopidogreltreatmentis recommended.Thereisastrongrationaleforconcomitantuseofaspirinevenif otherantithromboticdrugs,suchasclopidogrelorwarfarin,areadministered. Withdrawalordiscontinuationofaspirinhasbeenassociatedwithrecurrent ischemicevents,includingstentthrombosis. Concomitantadministrationofnonsteroidalantiinflammatorydrugs(NSAIDs)with aspirinshouldbeavoided,ifpossible,sinceNSAIDs,particularlyibuprofen,affect theaccessofaspirintoitsbindingsitewithinCOX1.EitheralternativeNSAIDsor

Figure2

Figure3

Table1

administrationofibuprofenshouldbedelayedatleast30minutesafterimmediate releaseaspirinoratleast8hoursbeforeaspirinadministration.1

CUREStudyAnalysis Figure2 CURE=ClopidogrelinUnstableAnginatoPreventRecurrentEventsCV=cardiovascularMI=myocardialinfarctionOR=oddsratio.

EfficacyofAspirinTreatmentinSecondaryPreventionTrials:PostMIScenario Figure3 CI=confidenceintervalMI=myocardialinfarction.

OralAntiplateletTherapy Table1 BMS=baremetalstentLD=loadingdoseMD=maintenancedosePCI=percutaneouscoronaryinterventionPES=paclitaxelelutingstent SES=sirolimuselutingstent.

AspirinResistance
Amajorcontroversyassociatedwithaspirintherapyisresistance.Aspirintherapyat81325mgdailyisassociatedwith morethan90%inhibitionofCOX1,asindicatedbyserumTxB2 levelsandsupportedbylowlevelsofarachidonicacid inducedplateletaggregation.Therefore,theprevalenceofaspirinresistanceasmeasuredbyCOX1activityis<10%. However,ahigherprevalenceofaspirinresistancereportedintheliteraturemaybeduetoanalysesbylaboratory methodsaffectedbynonCOX1pathwaysmediatingplateletreactivity. Inaddition,noncompliance,concomitantadministrationofNSAIDssuchasibuprofen,andconditionssuchasdiabetes orpostsurgerycanallinfluencetheprevalenceofaspirinresistance.Currently,laboratoryassessmentofaspirin resistanceorthealterationofaspirintherapybasedonlaboratoryfindingsisnotrecommended.11

P2Y12ReceptorBlockers
SincetheADPP2Y12interactionispivotalfortheamplificationofplateletactivationandstableplateletaggregation,an earlyfocusofantithrombotictherapytargetedinhibitionoftheP2Y12receptor.

Thienopyridines
MetabolismandMechanismofAction TheonlycurrentlyavailableP2Y12receptorblockersintheUnitedStatesarethe thienopyridines:ticlopidine,clopidogrel,andprasugrel.Duetosideeffectssuchas rash,nausea,neutropenia,andthrombocytopeniaassociatedwithticlopidine, clopidogrelbecamethefavoredthienopyridineinthelate1990sandisnowwidely implementedinclinicalpracticebasedontheclinicalefficacydemonstratedin multiplelargescaletrials. Basedonthesuperiorclinicalbenefitcomparedtoclopidogreltherapy demonstratedintheTRITONTIMI38(TrialtoAssessImprovementinTherapeutic OutcomesbyOptimizingPlateletInhibitionwithPrasugrelThrombolysisin MyocardialInfarction38)trial,prasugrelisapprovedbytheFoodandDrug AdministrationforthetreatmentofUA/NSTEMIpatientsundergoingPCI.12 Mostoftheabsorbedclopidogrel(~85%)ishydrolyzedpredominantlybyhepatic carboxyesteraseItoaninactivecarboxylicmetabolite,SR26334.Theremaining15% oftheabsorbedclopidogrelisrapidlyandextensivelymetabolizedintheliverbya CYP450dependenttwostepprocessplasmaconcentrationsoftheparent compoundarebelowthedetectionlimitbeyond2hourpostdosing.Inthefirststep, thethiopheneringofclopidogrelisoxidizedto2oxoclopidogrel,whichis subsequentlyhydrolyzedtoahighlyunstableactivemetabolite,R130964.Theactive metabolitebindsspecificallyandirreversiblytotheplateletP2Y12receptorduring passagethroughthehepaticcirculation.CYP2C19,CYP1A2,andCYP2B6are primarilyinvolvedinthefirststep,whereasCYP2C19,CYP2C9,CYP2B6,and CYP3Aareprimarilyinvolvedinthesecondstep(Figure4).13 Similartoclopidogrel,prasugrelisalsoaprodrugthatrequiresCYP450conversion toexertitsantiplateleteffects.Afteroraladministration,prasugrelisrapidlyabsorbed withmodestintraandinterrecipientvariability.Prasugrelisextensivelyhydrolyzed toR95913,aninactiveshortlivedthiolactonemetabolite,byintestinalandplasma esterases.Incontrasttothemetabolismofclopidogrel,hydrolyticproductof prasugrelisfurthermetabolizedinaonestepoxidationprocessbymainlyhepatic CYP3A4andCYP2B6,leadingtoringopeningandtheformationofthe pharmacologicallyactivemetabolite,R138727.ThesulfhydrylgroupofR138727 bindsirreversiblytotheplateletP2Y12receptor.13
Figure4

ClopidogrelMetabolism Figure4 CCB=calciumchannelblockerPPI=protonpumpinhibitor.

Clopidogrel (1of2)
CUREStudy IntheCURE(ClopidogrelinUnstableAnginatoPreventRecurrentEvents)study, therapywithclopidogrel(300mgloadingdosefollowedby75mg/d)andaspirin(75 325mg/d)inpatients(n=12,562)withNSTEACSwasassociatedwith20% reductionintheprimarycombinedendpointof12monthcardiovascularmortality, nonfatalMI,andstrokecomparedtoaspirinmonotherapy.Asignificant34%risk reductionwasobservedwithin24hoursintheclopidogrelgroup,andwas maintainedthroughoutthe12monthsofthestudyperiod.Therewasa1%absolute riskincrease(3.7%vs.2.7%,relativerisk[RR]1.38%,95%confidenceinterval[CI] 1.131.67,p=0.001)inmajorbleedingandanonsignificantincreaseinlife threatening,andfatalbleeding.Bleedingrateswerehigherinclopidogreltreated patientswhounderwentsubsequentcoronaryarterybypassgraftsurgery(CABG), buttherewasnosignificantincreaseinbleedinginpatientswhounderwentCABG morethan5daysafterinterruptionofclopidogrel.(Figure5).14 InthePCICURE(EffectsofPretreatmentWithClopidogrelandAspirinFollowedby LongTermTherapyinPatientsUndergoingPercutaneousCoronaryIntervention) study,asubsetanalysisofCURE,pretreatmentwithclopidogrelforamedianof6 daysbeforePCIwasassociatedwitha31%reductionintheprimarycomposite endpoint.15TheresultsoftheCUREtrialstronglyinfluencedthecurrentstrategyof dualantiplatelettherapyforthetreatmentoftheNSEACSpatientandestablishedat thattimethe300mgclopidogrelloadingdoseduringPCIandthe75mg maintenancedoseasthestandardofcare.Subsequentclinicaltrialsalso demonstratedtheclinicalefficacyofthisdosingregimen. CREDOStudy IntheCREDO(ClopidogrelfortheReductionofEventsDuringObservation)trial,on topofaspirintherapy,thebenefitofpretreatmentwitha300mgclopidogrelloading doseinitiated324hourspriortoanonemergentPCIwascomparedtoa75mg clopidogreldailydose.IntheCREDOtrial,patientstreatedwiththe300mgloading dosecontinuedondualantiplatelettherapyfor12months,whereasthosepatients notloadedreceiveddualantiplatelettherapyfor30days.Inthistrial,thecombined benefitofpretreatmentandprolongedclopidogreltherapyupto1yearwas associatedwitha26.9%(95%CI3.944.4,p=0.02)relativereductioninthe combinedprimaryendpointofdeath,MI,andstrokecomparedtoaspirinalone treatment.16 Takentogether,boththePCICUREandCREDOtrialsstronglysupportlongterm therapywithdualantiplatelettherapyfollowingPCI,asrecommendedinthe2011 ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007Guidelinesforthe ManagementofPatientsWithUA/NSTEMI.1 RationaleforHighClopidogrelLoadingandMaintenanceDoses Measurementsofexvivoplateletfunction,indicativeofP2Y12receptoractivity, demonstratedaslowonsetofaction,wideresponsevariability,andanabsenceof inhibition(resistance)in~30%ofpatientsundergoingPCItreatedwitha300mg clopidogreladdedtoaspirintherapy.17,18Inmultiplestudiesofpatientsundergoing PCI,highontreatmentplateletreactivitywasassociatedwithanincreasedriskof ischemiceventoccurrence.Itwasfurtherdemonstratedthatclopidogrel nonresponsivenesscouldbereducedto~10%byincreasingtheclopidogrelloading doseto600mg.17Moreover,a600mgloadingdosewasassociatedwithgreater plateletinhibition(~50%vs.~30%)andfasterinhibition(peakeffectat~8hoursvs. >12hours)thana300mgload.18 Inaddition,intheARMYDA2(AntiplatelettherapyforReductionofMYocardial DamageduringAngioplasty2)trial,a600mgloadingdoseofclopidogrelas comparedwith300mgadministered6hourspriortoPCIwasassociatedwitha
Figure5

Table1

Figure6

Figure7

significantreductionindeath,MI,ortargetvesselrevascularizationinpatients undergoingelectivePCI(12%vs.4.0%p=0.041).19Currently,inpatients undergoingPCI,a600mgloadingdoseisthemostwidelyusedstrategy(Table1). CURRENTOASIS7Trial IntheCURRENTOASIS7trial,definedearlier,astrategyofdoubledoseclopidogrel (600mgonday1,150mgondays27,then75mgdaily)wascomparedto standarddoseclopidogrel(300mgonday1,then75mgdaily)inpatientswithACS ~71%ofwhomhadNSTEACS(Figure6).Ina2x2factorialdesign,theefficacyof highversuslowdoseaspirinwasalsoassessed.The30dayprimaryoutcomeof cardiovasculardeath,MI,orstrokedidnotdifferbetweenthetwoclopidogrelgroups however,bleedingwasgreaterinthedoubledosegroup.Inaddition,clinical outcomes(ischemicorbleeding)werenotinfluencedbyaspirindose. Inananalysisof78%ofpatientswhounderwentPCI,doubledoseclopidogrel therapywasassociatedwitha14%reductionintherateoftheprimaryoutcome,and a46%reductioninthesecondaryoutcomeofdefinitestentthrombosis(Figure7). However,doubledoseclopidogrelwasnotassociatedwithanysignificantreduction inclinicaloutcomesinpatientswithNSTEACS(3.6%vs.4.2%,95%CI0.721.06,p =0.167).Doubledoseclopidogreltherapywasassociatedwithmoremajor bleedingthanstandarddoseclopidogrelintheoverallgroupandinthePCIcohort (1.6%vs.1.1%HR1.41,95%CI1.091.83,p=0.009).Interestingly,themaximum benefitinthePCIcohortwasobservedinpatientswhoweretreatedwithdouble doseclopidogrelandhighdoseaspirin(3.5%vs.4.2%,HR0.81,95%CI0.651.01, p=0.058).8,9 The2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007 GuidelinesfortheManagementofPatientsWithUA/NSTEMIreflecttheresultsof pharmacodynamicstudiesandoutcomesobservedwithdoubledoseclopidogrel therapyintheCURRENTOASIS7trial.1

CUREStudyResults Figure5 ASA=acetylsalicylicacid(aspirin)CI=confidenceintervalCURE=ClopidogrelinUnstableAnginatoPreventRecurrentEventsCV= cardiovascularMI=myocardialinfarctionRRR=relativeriskreductionTIMI=ThrombolysisInMyocardialInfarction.

OralAntiplateletTherapy Table1 BMS=baremetalstentLD=loadingdoseMD=maintenancedosePCI=percutaneouscoronaryinterventionPES=paclitaxelelutingstent SES=sirolimuselutingstent.

CURRENTOASIS7StudyDesign Figure6 ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingCAD=coronaryarterydisease CURRENTOASIS7=ClopidogrelandAspirinOptimalDoseUsagetoReduceRecurrentEventsSeventhOrganizationtoAssessStrategiesin IschemicSyndromesCV=cardiovascularECG=electrocardiogramMI=myocardialinfarctionPCI=percutaneouscoronaryinterventionSTEMI =STsegmentelevationmyocardialinfarctionTIMI=ThrombolysisInMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegment elevationmyocardialinfarction.

CURRENTOASIS7StudyDesign Figure7 CI=confidenceintervalCURRENTOASIS7=ClopidogrelandAspirinOptimalDoseUsagetoReduceRecurrentEventsSeventhOrganizationto AssessStrategiesinIschemicSyndromesCV=cardiovascularHR=hazardratioMI=myocardialinfarctionPCI=percutaneouscoronary interventionTIMI=ThrombolysisInMyocardialInfarction.

Clopidogrel (2of2)
RecentDevelopmentsinClopidogrelPharmacogenomicsandDrugDrug Interactions Thepresenceofsinglenucleotidepolymorphisms(SNPs)ofthegeneencoding CYP4502C19hasbeenshowntobeindependentlyassociatedwithreduced clopidogrelactivemetabolitegeneration,reducedinhibitionofADPinducedplatelet aggregation,andincreasedpostPCIischemicevents.Geneticsubstudiesoflarge scaleclinicalstudiesandmetaanalysesindicatedthatthepresenceofalossof function(LoF)allele(CYP2C19*2,*3,*4,and*5)wasassociatedwithincreased recurrentischemiceventoccurrence,particularlystentthrombosis,primarilyin patientstreatedwithPCI.20,21 Thecontroversysurroundingthediminishedeffectivenessofclopidogrelinpoor metabolizers(thosehavingtwoLoFCYP2C19alleles)andtheutilityofgenetictests toidentifydifferencesinCYP2C19functionhasbeenrecentlyhighlightedbythe boxedwarningissuedbytheFoodandDrugAdministration(FDA).TheFDA advisedhealthcareprofessionalstoconsideruseofotherantiplateletmedications oralternativedosingstrategiesofclopidogrelinthesepatients.22 However,arecentsubanalysisoftheGRAVITAS(GaugingResponsivenessWithA VerifyNowAssayImpactOnThrombosisAndSafety)trial,apersonalizedantiplatelet therapystudyconductedprimarilyinelectivelowriskPCIpatients,indicatedthat highdoseclopidogrel(150mgqd)wasnotanoptimalstrategytotreatpoor metabolizers40%ofpatientswithhighontreatmentplateletreactivityafter600mg clopidogrelloadingdoseremainedwithhighontreatmentplateletreactivityafter30 daysof150mgmaintenancetherapy.23 CarriageoftheLoFallelewasnotassociatedwithincreasedischemicoutcomesin thegeneticsubstudyoftheCUREtrial,wheremanypatientswerenottreatedwith PCI,andinACTIVEA(EffectofClopidogrelAddedtoAspirininPatientsWithAtrial Fibrillation),ageneticsubstudyoftheACTIVE(AtrialFibrillationClopidogrelTrial WithIrbesartanforPreventionofVascularEvents)trial,whichcomparedaspirinplus clopidogreltowarfarininpatientswithatrialfibrillation.24 Currentlyavailableevidencesupportstheconceptofathresholdforontreatment plateletreactivitytoADPinpatientstreatedwithdualantiplatelettherapythatmaybe usedtostratifypatientriskforischemic/thromboticeventsfollowingPCI,including stentthrombosis.Inarecentwhitepaper,itwasstatedthatplateletfunctiontesting maybeconsideredindetermininganantiplateletstrategyinpatientswithahistoryof stentthrombosisandinpatientspriortoundergoinghighriskPCI.However,until theresultsoflargescaletrialsofpersonalizedantiplatelettherapyareavailable,the routineuseofplateletfunctionmeasurementsinthecareofpatientswith cardiovasculardiseasecannotberecommended.25 Similarly,inthe2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA 2007GuidelinesfortheManagementofPatientsWithUA/NSTEMI,theClassIIb recommendationforpersonalizedantiplatelettherapysuggeststhataselective, limitedapproachtoplateletgenotypeassessmentandplateletfunctiontestingisthe moreprudentcourseuntilbetterclinicalevidenceexiststoprovideamore scientificallyderivedrecommendation(Tables2a,b,c,d).1 Adiminishedpharmacodynamiceffectofclopidogrelhasbeendemonstratedin patientstreatedwithprotonpumpinhibitors(PPIs),particularlyomeprazole. However,theclinicalimportanceofthispharmacodynamicinteractionremains highlycontroversial.TheACC/AmericanCollegeofGastroenterology/AHA2010 expertconsensusdocumentstatesthatroutineuseofPPIisnotrecommendedfor patientsatlowerriskofuppergastrointestinalbleeding,whohavemuchless potentialtobenefitfromprophylactictherapy.26

Table2a

Table2b

Table2c

Table2d

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2a ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction.

ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2b ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2c ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2d ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

PrasugrelintheTRITONTIMI38Trial
Prasugrel,thethirdgenerationthienopyridine,isassociatedwitharapidonsetofactionandsuperioractivemetabolite generationresultinginlessresponsevariability,alowerprevalenceofnonresponsiveness,andgreaterinhibitionofADP inducedplateletaggregationcomparedwithclopidogrel. InTRITONTIMI38,prasugrel(60mgload/10mgdailymaintenance)plusaspirintreatment(75162mg/d)was associatedwitha19%reduction(9.9%vs.12.1%,HR0.81,p=0.0004)intheprimarycompositeendpointof cardiovasculardeath,nonfatalMI,andnonfatalstrokeatamedian14.5monthfollowupcomparedwithclopidogrel(300 mgload/75mgdailymaintenance)plusaspirintreatmentinpatientswithACS(NSTEACSandSTEMI)undergoing plannedPCI.Asustainedreductionintheprimaryendpointwithprasugreltherapycomparedtoclopidogreltherapy(9.3% vs.11.2%,relativeRR18.0,95%CI7.327.4,p=0.002)wasdemonstratedamongpatientswithNSTEACS.However, thesebenefitswereassociatedwithsignificantlyincreasedkeysafetyendpointsofTIMImajorbleeding,includinglife threateningandfatalbleedinginpatientstreatedwithprasugrel(2.4%vs.1.8%.p<0.03).12 AninfluenceofLoFSNPsonclinicaloutcomeswasnotobservedduringprasugreltreatment,ascomparedwith clopidogreltreatmentinageneticsubstudyoftheTRITONtrial.ClopidogreltherapyinLoFcarrierscomparedto noncarrierswasassociatedwithanincreasedoccurrenceoftheprimaryendpoint(HR1.53,p=0.01).27,28 TheFDAhasapprovedamaintenancedoseto5mginpatients<60kgduetoapotentialincreasedriskofbleeding, althoughtheeffectivenessandsafetyofthe5mgdosehavenotbeenstudiedprospectively.Prasugrelisnot recommendedinpatientswithactivepathologicalbleedingorahistoryoftransientischemicattackorstroke.Inpatients 75yearsofage,prasugrelisgenerallynotrecommendedbecauseoftheincreasedriskoffatalandintracranial bleeding.ItisrecommendednottostartprasugreltherapyinpatientslikelytoundergourgentCABG.Whenpossible, prasugrelshouldbediscontinuedatleast7daysbeforeanysurgery.1

TicagrelorinthePLATOTrial
Ticagrelor(AZD6140),acyclopentyltriazolopyrimidinederivative,isaneworal,reversiblybinding,directactingP2Y12 inhibitor.InaphaseIIpharmacodynamicstudyinvolvingstablecoronaryarterydiseasepatients,ticagrelortherapywas associatedwitharapidonsetofaction,agreaterlevelofinhibitionthatpersistedduringmaintenancetherapy,anda morerapidoffsetofpharmacodynamicactioncomparedwithclopidogrel.29 InanotherphaseIIstudy,ticagrelortherapywasassociatedwithgreaterplateletinhibitioncomparedwithclopidogrelin bothclopidogrelrespondersandnonresponders.Ticagrelorwasextremelyeffectiveinreducingtheprevalenceofhigh plateletreactivitywithin30minutesoftherapy.30 ThePLATO(PLATeletinhibitionandpatientOutcomes)trialwasaphaseIIIrandomized,multicenter,doubleblindstudy designedtoevaluatetheefficacyofticagrelor(180mgloadingdose/90mgbid)comparedwithclopidogrel(300600mg loadingdose/75mgqd)forthepreventionofvasculareventsanddeathinpatientswithACS.Ticagrelortherapywas associatedwithasignificantreductionintheprimaryefficacyendpointcomparedtoclopidogrelat30days(4.8vs.5.4%, p=0.045)andthesuperiorityofticagrelorwasmaintainedthroughout12monthswitha16%relativeRR(9.8vs.11.7%, respectivelyp<0.001).Cardiovasculardeath(5.1%clopidogrel,4.0%ticagrelor,p=0.001)andMI(6.9%clopidogrel, 5.8%ticagrelor,p=0.005),butnotstroke(1.5%vs.1.3%,p=0.22)weresignificantlyreducedbyticagrelortreatment.A significantreductionintheprimaryendpointwasobservedinthe43%ofpatientswhohadNSTEMIinthePLATOtrial (11.9%vs.13.9%,HR0.83,95%CI0.730.94).31 Betweenticagrelorandclopidogreltreatedpatients,therewerenodifferencesintheprimarysafetyendpointofmajor bleeding,asdefinedbyeitherthestudyprotocol(ticagrelor11.6%vs.clopidogrel11.2%,p=0.43)orTIMIcriteria(7.9vs. 7.7%,p=0.57).DespitethefactthatpatientsintheticagrelortreatmentgroupwereallowedtoundergoCABGwithin24 72hoursfollowingdiscontinuationofstudymedication(comparedwith5daysintheclopidogrelgroup),CABGrelated bleedingeventratesweresimilarbetweenthetwogroups.NonCABGrelatedmajorbleedingeventrateswerehigher followingticagrelortreatment(4.5vs.3.8%,p=0.026,and2.8vs.2.2%,p=0.025,forprotocolandTIMIstudygroup definedbleedingevents,respectively).OneofthemostremarkableobservationsofthePLATOtrialwasasignificant reductioninmortalityassociatedwithticagrelortherapy.31TheUSFoodandDrugAdministrationrecentlyapproved ticagrelortoreducecardiovasculardeathandheartattackinpatientswithACS.32

Cangrelor
Cangrelor,anadenosinetriphosphateanalogue,isaparenteral,directacting,reversibleP2Y12inhibitorwithveryrapid onsetandoffsetpharmacodynamics(withinminutes).IntherecentlypublishedphaseIIIclinicaltrialsofpatients undergoingPCIwhowererandomlyassignedtotherapywitheithercangrelororplacebo,cangrelorwasnotsuperiorto placeboforreducingthecompositeoccurrenceofdeath,MI,orischemiadrivenrevascularizationat48hours,which comprisedthestudysprimaryendpoint.33,34Cangrelorcontinuestoundergodevelopment.

Elinogrel
Elinogrelisadirectacting,reversibleP2Y12receptorantagonist.Itisafirstinclasssulfonylureathatmaybe administeredeitherintravenouslyororally.Plateletinhibitionbyelinogreloccursirrespectiveofclopidogrelresponse statusandgenotype.Thechoiceofbothparenteralandoraladministrationmayfacilitateasmoothtransitionfrom immediatetolongtermtherapy.Thedirectactionofelinogrelmayalsoprovideawidertherapeuticwindowthan thienopyridinetherapy.35 IntherecentphaseIIINNOVATEPCI(IntravenousandOralElinogrel,aSelectiveandReversibleP2Y12Receptorand InhibitorinPatientsUndergoingNonurgentPCI)trial,parenteralandoralelinogreladministrationwereassociatedwith morerapidandgreaterplateletinhibitioncomparedwithstandarddosesofclopidogrel,butasimilarincidenceofmajor orminorbleeding.

ThrombinReceptorAntagonists
TheinhibitionofthethrombinPAR1interactionmayfurtherattenuateischemiceventoccurrenceinselectedpatients treatedwithdualantiplatelettherapy.TwomajorPAR1blockersarecurrentlyunderinvestigation:vorapaxarand atopaxar.Inpreclinicalstudies,inhibitionofthrombinmediatedplateletactivationbyaproteaseactivatedreceptor(PAR) 1inhibitor,ingeneral,hasaddedtotheantithromboticefficacyofaspirinandclopidogrelwithoutincreasingbleeding. However,therecentrecommendationsofthecombinedDataandSafetyMonitoringBoardforthetwophase3studiesof vorapaxarstudiesto:1)discontinuethedrugandtocloseouttheTRACERtrial(anACStrial),and2)discontinuetherapy inpatientswithstrokeenrolledintheTRA2Ptrial(asecondarypreventiontrial)suggestthatthedatafromphase2did notrevealimportantlimitationsoflongtermtherapywithvorapaxar.36 Recently,itwasdemonstratedthatatopaxarwasassociatedwithsignificantlyreducedearlyischemiaonHolter monitoringwithoutasignificantincreaseinmajororminorbleedinginpatientswithACS.Inpatientswithhighrisk coronaryarterydisease,atopaxarwasassociatedwithmarkedinhibitionofthrombinreceptoractivatingpeptide stimulatedplateletaggregation,moreminorbleeding,andnumericallyfewerischemicevents.37,38Thedevelopmentof atopaxarhasbeendiscontinuedwhereasvorapaxarcontinuetoundergodevelopment.

GlycoproteinIIb/IIIaInhibitors (1of2)

TheGPIIb/IIIareceptor,amemberoftheintegrinfamilyofreceptors,isthemost abundantplateletGPreceptor(~80,000perplatelet).TheGPIIb/IIIareceptoris composedoftheIIband3 subunits.Plateletactivationbyvariousagonistsand stimuliinducesaconformationalchangeinGPIIb/IIIareceptorthatmarkedly enhancesitsaffinityforfibrinogen. GPIIb/IIIahastwomajorsitesforligandbinding.Onesiterecognizesthearginine glycineasparticacidsequence(RGD)sequencepresentonfibrinogen,vitronectin, fibronectin,andvonWillebrandfactor,andtheotherrecognizesthelysineglycine alanineglycineasparticacidvalinesequencelocatedonfibrinogen.Thebinding sitespresentonfibrinogenaretheprimarymediatorsofplateletaggregationthe dimericfibrinogenformsabridgebetweenplatelets. ThepharmacologicalagentsthatdirectlyblockthebindingoffibrinogentotheGP IIb/IIIareceptoraremoreeffectiveininhibitingplateletaggregationthananyoral antiplateletstrategy.Markedinhibitionofplateletaggregation(>80%)hasbeen demonstratedirrespectiveoftheGPIIb/IIIainhibitor,agonisttype,oragonist concentrationinexvivostudies.Inadditiontoinhibitionofplateletaggregation,GP IIb/IIIainhibitorsalsoinduceplateletdisaggregationandmayattenuate microembolization,andreleaseofvasoconstrictors.39 Inearlystudiesoftheseagentsbeforetheeraofuniformstentingandclopidogrel pretreatment,areductioninshortandlongtermeventswasobservedinNSTEACS patientstreatedwithGPIIb/IIIainhibitorscomparedtotreatmentwithheparinor unfractionatedheparinalone.TheprimaryimpactoftheseGPIIb/IIIainhibitorswas thereductioninperiproceduralMI.ThethreeGPIIb/IIIainhibitorsapprovedfor clinicaluseabciximab,eptifibatide,andtirofibanhavedifferentpharmacodynamic properties.Theoutcomesassociatedwitheachdruginclinicaltrialshaveaffected therecommendationsinthecurrentguidelines(Tables2a,b,c,d).1 AlloftheGPIIb/IIIainhibitorshavebeenassociatedwithanincreaseinbleeding,as comparedtotreatmentwithheparinalone.However,GPIIb/IIIainhibitorsare frequentlyincorrectlydosed,andoverdosinghasbeenassociatedwithincreased bleeding.Moreover,incurrentpractice,theactivatedclottingtime(ACT)targetduring thetimeofGPIIb/IIIainhibitoruseforPCIislowerthaninearlierstudies.Efficacy andincreasedsafetyhavebeenreportedwithuseofGPIIb/IIIainhibitorsin conjunctionwithheparinatACTlevelsof200250seconds.Ithasalsobeen reportedthatduringeptifibatideorabciximabtherapy,anexcessofmajorbleeding canbeavoidedbymaintaininglowACTlevels(ACT200250seconds).40 Abciximab Abciximabisarecombinantmonoclonalantibody,thatbindstotheGPIIb/IIIa receptorwithhighaffinity,andalsotothevitronectinreceptorpresentinplatelets, smoothmusclecells,monocytes,andleukocytes,andtothemacrophage(MAC)1 receptorpresentinleukocytes.TherecommendeddosingislistedinTable3.After initialadministration,abciximabundergoesgradualredistribution(i.e.,exchange betweenoccupiedandnewplatelets),whichcontributestoaprolonged antithromboticeffect.Animportantsideeffectofabciximabaswellaseptifibatide andtirofibanisthrombocytopenia. Tirofiban Tirofibanisapeptidomimeticderivativeoftyrosinethatselectivelyandreversibly blockstheGPIIb/IIIareceptorbymimickingtheRGDsequence.Comparedto abciximab,tirofibanhaslessaffinityfortheGPIIb/IIIareceptorandashorter biologicalhalflife(90120minutes)thatdependsonrenalclearance.The recommendeddosingislistedintheTable3. Eptifibatide EptifibatideisacyclicheptapeptidewithamodifiedKGDsequence(lysineglycine aspartate)thatreversiblyblockstheGPIIb/IIIareceptor.Eptifibatidespecificallybinds totheGPIIb/IIIareceptorwithlowaffinityanddissociatesrapidlyfromthereceptor, causingplateletaggregationtoreturntobaselineinabout8hours.The recommendeddosingislistedintheTable3.

Table2a

Table2b

Table2c

Table2d

Table3

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2a ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2b ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2c ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2d ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

IntravenousGlycoproteinIIb/IIIaInhibitorTherapy Table3 IV=intravenousLD=loadingdoseMD=maintenancedosePCI=percutaneouscoronaryintervention.

GlycoproteinIIb/IIIaInhibitors (2of2)
MajorRecentClinicalTrialsofGlycoproteinIIb/IIIaInhibitorsinNSTEACS TheefficacyofGPIIb/IIIainhibitortherapyhasbeenestablishedduringPCI proceduresandinpatientswithNSTEACS,particularlyamonghighriskpatients undergoingPCIwithelevatedcardiacbiomarkers,anddiabetes.4 Mostoftheclinical trialsdemonstratingafavorablenetclinicalefficacyofGPIIb/IIIainhibitortherapy predatedtheeraofearlyinvasivetherapy,PCIwithuniformornearuniformstenting, andthienopyridinepretreatment.Theseolderstudiessupportedtheupstreamuse ofaGPIIb/IIIainhibitorincombinationwithaspirinandananticoagulantinhighrisk patientswithNSTEACS.AreviewofallofthesetrialsofGPIIb/IIIainhibitorsis beyondthescopeofthismodule. AnimportantconcernassociatedwithGPIIb/IIIainhibitoruseisincreasedbleeding risk.AmajorlimitationofallGPIIb/IIIainhibitortrialsistheabsenceofrandomization tothienopyridinetherapyorGPIIb/IIIainhibitortherapy.Contemporarytrialshave attemptedtodefinetheoptimaltimingofinitiationofGPIIb/IIIainhibitortherapyin patientswithNSTEACSandexplorethecomparativeefficacyoftreatmentwitha directthrombininhibitor,bivalirudinversusaheparinwithaGPIIb/IIIainhibitor. However,theutilityofupstream(atpresentationandbeforeangiography)or deferred(atthetimeofangiography/PCI)remainscontroversialbecausetrulyearly administration(i.e.,atthetimeofemergencydepartmentpresentation)hasnever beenachievedinaclinicaltrialdespitethegoaloftestingtheutilityofearly administration.1 ISARREACT2Study IntheISARREACT2(IntracoronaryStentingandAntithromboticRegimen:Rapid EarlyActionforCoronaryTreatment2)study,theadditionofanabciximabtoaspirin anda600mgclopidogrelloadingdoseinpatientswithNSTEACSmanagedwith anearlyinvasivestrategy,wasassociatedwithasignificantlyreducedcombined endpointofdeath,MI,ortargetvesselrevascularization(11.9vs.8.9%,p=0.03). Theseresultsweremainlyattributedtoasignificantdecreaseintherateof compositeendpointinthesubgroupoftroponinpositivepatients(Figure8).41 ACUITYTrial IntheACUITY(AcuteCatheterizationandUrgentInterventionTriagestrategY)trial, theoptimalstrategyfortheuseofGPIIb/IIIainhibitorsinmoderateandhighrisk ACSpatientsundergoingearlyinvasivetherapywasexamined.Inthistrial,patients (n=9,207)wererandomizedtooneofthreeantithromboticregimens:1) unfractionatedheparin(UFH)orenoxaparinplusGPIIb/IIIainhibitortherapy,2) bivalirudinplusGPIIb/IIIainhibitortherapy,or3)bivalirudinalone.Patientsassigned totheheparin(UFHorenoxaparin)plusGPIIb/IIIainhibitortherapyortothe bivalirudinplusGPIIb/IIIainhibitortherapywerealsorandomizedtoupstream routineGPIIb/IIIainhibitortherapyordeferredselectiveuseofGPIIb/IIIainhibitor therapyatthetimeofPCI.42 Theclopidogrelloadingdosewaslefttothediscretionofthetreatingphysician provisionalGPIIb/IIIainhibitorusewaspermittedbeforeangiographyinthedeferred groupforseverebreakthroughischemia.Bivalirudinalone,ascomparedwith heparinplusaGPIIb/IIIainhibitor,wasassociatedwithanoninferiorrateofthe compositeischemiaendpoint,significantlyreducedratesofmajorbleeding,and greaternetclinicalbenefits. IntheACUITYTimingTrial(AcuteCatheterizationandUrgentInterventionTriage StrategyTimingTrial),theupstreamadministrationofGPIIb/IIIainhibitorscompared todeferredselectiveadministrationwasassociatedwithareductioninthe compositeischemicendpointand,thus,thenoninferiorityhypothesiswasnot achieved(Figure9).TheACUITYtrialalsodemonstratedsignificantlylowermajor bleedinginthedeferredusegroupversustheupstreamgroup.
Figure8

Figure9

Figure10

Table2a

Table2b

Table2c

Table2d

Inasubanalysisofpatientswhowerenotpretreatedwithathienopyridinebefore PCI,theuseofaGPIIb/IIIainhibitorwasassociatedwithaloweroccurrenceof ischemiceventsthanbivalirudintherapy.Therelationoftheneedforadequate clopidogrelpretreatmentinbivalirudintreatedpatientsobservedintheACUITYtrial hasbeenacknowledgedintheguidelines.42 EARLYACSTrial IntheEARLYACS(EarlyGlycoproteinIIb/IIIaInhibitioninPatientsWithNonST SegmentElevationAcuteCoronarySyndrome)trial,9,492highriskNSTEACS patientswererandomizedtoreceiveeitherearlyroutineadministrationofeptifibatide (doublebolusfollowedbystandardinfusion)ordelayedprovisionaleptifibatideat thetimeofPCIinadditiontoaspirinandclopidogrel(89%ofpatientsreceiveda300 mgloadingdoseand11%received600mg).Inbothgroups,eptifibatideinfusion wasgivenfor1824hoursafterPCI.DespitethegoalofearlyGPIIb/IIIa administrationintheEARLYACStrial,themediantimefrompresentationto randomizationwas5.6hours. Therewasnodifferenceintheprimaryendpoint(acompositeofdeath,MI,recurrent ischemiarequiringurgentrevascularization,ortheoccurrenceofathrombotic complicationduringPCIthatrequiredbolustherapyoppositetotheinitialstudy groupassignment(thromboticbailout)at96hoursinpatientsintheearlytherapy armversuspatientsinthedelayedGPIIb/IIIainhibitortherapyarm(9.3%vs.10%, respectively,oddsratio0.92,95%CI0.801.06,p=0.23).Therewasa nonsignificantdecreaseinthesecondaryendpoint(allcausedeathorMIwithin30 days)inpatientsintheearlytherapyarmversuspatientsinthedelayedGPItherapy arm.However,earlyroutineeptifibatideadministrationcomparedtodelayed eptifibatidewasassociatedagreaterriskofTIMImajororminorbleeding, increasedGUSTO(GlobalUtilizationofStreptokinaseandtPAforOccluded CoronaryArteries)severeormoderatebleeding,andalsoincreasedratesofred bloodcelltransfusion(Figure10).43Thelackofsignificantefficacyandincreased bleedinginthetrialhaveaffectedtherecentguidelinerecommendationsforroutine earlyGPIIb/IIIainhibitoradministration(Tables2a,b,c,d).

ISARREACT2 Figure8 ISARREACT2=IntracoronaryStentingandAntithromboticRegimen:RapidEarlyActionforCoronaryTreatment2MI=myocardialinfarctionRR =relativeriskTn=troponinTVR=targetvesselrevascularization.

ACUITY30DayPrimaryEndpointMeasures Figure9 ACUITY=AcuteCatheterizationandUrgentInterventionTriagestrategYGPI=glycoproteinIIb/IIIainhibitorUFH=unfractionatedheparin.

EARLYACS:30DaySecondaryEfficacyResults Figure10 EARLYACS=EarlyGlycoproteinIIb/IIIaInhibitioninPatientsWithNonSTSegmentElevationAcuteCoronarySyndromeCI=confidenceinterval GUSTO=GlobalUtilizationofStreptokinaseandtPAforOccludedCoronaryArteriesMI=myocardialinfarctionMI=myocardialinfarctionTIMI= ThrombolysisinMyocardialInfarction.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2a ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2b ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2c ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

2011ACCF/AHAFocusedUpdateIncorporatedIntotheACC/AHA2007GuidelinesfortheManagementofPatientsWithUnstableAngina/NonST ElevationMyocardialInfarction Table2d ACS=acutecoronarysyndromeASA=acetylsalicylicacid(aspirin)CABG=coronaryarterybypassgraftingGP=glycoproteinHF=heart failureIV=intravenousLoE=LevelofEvidencePCI=percutaneouscoronaryinterventionTIA=transientischemicattackTIMI=Thrombolysis InMyocardialInfarctionUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarction. ReproducedwithpermissionfromWrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

FutureDirections
ThekeygoalofantiplatelettreatmentstrategiesforNSTEACSistoreduceischemiceventoccurrencewhileatthesame timeavoidingbleeding.Withimprovedinvasivetechnologiesandconcomitanttreatmentsthataddressmodifiable cardiovascularriskfactors,ischemiceventratesarefallinginclinicaltrialsand,therefore,theefficacyoftreatment strategiesuniformlyemployingmorepotentplateletinhibitionmayalsodecreaseinthefuture. Selectingthepatientfortreatmentwiththenew,morepotenttherapiesmaybeassistedbygenotypingandplatelet functiontesting.Personalizedantiplatelettherapywillbeakeyareaoffutureresearch. Understandingthemechanismsoftreatmentfailureandbleedingduringdualantiplatelettherapyisamajorareaof ongoinginvestigations.Athrombinreceptorinhibitormayprovideaddedefficacyinselectedpatientswhoexperience treatmentfailureduringdualantiplatelettherapy. TheefficacyofparenteralP2Y12receptorinhibitorsthatprovidehighlevelsofrapidandreversibleplateletinhibitionis underinvestigation.Thesepharmacodynamicpropertiesareappealingtotheinterventionalcardiologistinthetreatment ofthehighriskNSTEACSpatientwhomayrequireurgentCABGafterdefinitionofcoronaryanatomy.Thepotential benefitofearlyimplementationoftherapywiththeseagentsthataddressesevolvingcoronaryarterythrombosiswillnot carrytheliabilityassociatedwithprePCIadministrationofirreversibleP2Y12inhibitors. Finally,theuseoftheprasugelorticagrelor,P2Y12inhibitorswitharapidonsetofpotentpharmacodynamiceffects,may influencethefutureroleofGPIIb/IIIainhibitorsinthetreatmentoftheNSTEACSpatient.

KeyPoints
NSTEACSisaplateletcentricdiseasegreaterplateletinhibitionisassociatedwithreducedischemicevent occurrence. AspirinremainsthebedrockoralantiplateletagentinpatientswithNSTEACS.Theefficacyofneworalantiplatelet agentshasbeenstudiedontopofaspirininclinicaltrials.Theseagentsarealwaysprescribedinadditionto aspirinincommonclinicalpractice. DualantiplatelettherapyisthestandardofcareinpatientswithNSTEACS. TheoptimaldurationofdualantiplatelettherapyafterPCIremainscontroversial,butthereisaClassI recommendationforuninterrupteddualantiplatelettherapyfor12months. ThepharmacologicalagentsthatdirectlyblockthebindingoffibrinogentoGPIIb/IIIareceptors(GPIIb/IIIa inhibitors)aremoreeffectiveininhibitingplateletaggregationthananyoralantiplateletstrategy. TheoptimalpretreatmentantiplateletstrategyforNSTEACSpatientsundergoinganinvasivetreatmentstrategy remainscontroversial.EitherclopidogreloraGPIIb/IIIainhibitorareClassIrecommendations.Prasugrelshould beadministeredaftertheanatomyisknownanditiscertainthatthepatientwillbeundergoingPCI(ClassI recommendation).GPIIb/IIIainhibitorscanbewithheldifbivalirudinisadministeredaslongastherehasbeen adequatepretreatmentwithclopidogrel(300mgloadatleast6hoursbeforePCI,ClassIIarecommendation). Bleedingisassociatedwithworseclinicaloutcomes,andstrategiestominimizeitsoccurrencearemandatoryin thecareoftheNSTEACSpatient. Clopidogreltherapyisassociatedwithnumerouslimitations:adelayedonsetofaction,irreversiblebinding,an unpredictablepharmacodynamiceffect,andasubstantialproportionofpatientsexhibitresistance(no measurableplateletinhibition)orhighontreatmentplateletreactivitythathasbeenassociatedwithworseclinical outcomes(higherpostPCIischemiceventoccurrence). BothofthenewP2Y12inhibitorsprasugrel,anirreversible,thirdgenerationthienopyridine,andticagrelor,a reversiblybinding,directactingagentareassociatedwithafasteronsetofaction,greaterplateletinhibition,and lowerontreatmentplateletreactivitythanclopidogrel.Improvedclinicaloutcomes,includinglessstent thrombosiscomparedtoclopidogrel,havebeendemonstratedintwolargeACSclinicaltrialscomparingthese agentstoclopidogrel.However,increasedCABGandnonCABGrelatedmajorbleedingwereassociatedwith prasugreltherapyandincreasedCABGrelatedbleedingwasassociatedwithticagrelor. TicagrelortherapywasassociatedwithsignificantlylessmortalitythanclopidogreltherapyinthePLATOtrial.

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6.4:UA/NSTEMI:AnticoagulantTherapy
Author(s): AjayJ.KirtaneMD,SM,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Identifythepathophysiologicroleofanticoagulanttherapiesforthemedicalstabilizationofunstableangina/nonST segmentelevationmyocardialinfarction(UA/NSTEMI). 2. DescribethedifferentclassesofanticoagulantagentscurrentlyrecommendedintheAmericanCollegeofCardiology Foundation(ACCF)/AmericanHeartAssociation(AHA)guidelinesforthemanagementofpatientswithUA/NSTEMI.1 3. DifferentiatebetweenthecurrentlyrecommendedanticoagulantagentsforUA/NSTEMI.

Introduction
Thepathophysiologichallmarkofmostacutecoronarysyndromes(ACS)isplaqueruptureorerosionwithsuperimposed thrombosiswithinacoronaryartery.Becausethisprocessbegetsactivationandupregulationofvariousmediatorsofthe thromboticcascade,whichcanleadtoworseningischemiaandreinfarction,antithromboticandanticoagulanttherapies aregenerallyconsideredthecornerstonesofmedicaltherapyforACS.Thesetherapiesaimnotonlytopassivatethe existingthromboticprocessthathascausedACS,butalsotomoresafelyfacilitatetheuseofotherpotentially prothrombotictherapiesforACSsuchaspercutaneouscoronaryintervention(PCI),whichaimstomechanicallystabilize theACS.ThismodulewillcovertheuseofvariousanticoagulanttherapiesforACS,specificallyfocusingontheclinical scenarioofUA/NSTEMI.

UpdatedAmericanCollegeofCardiology/AmericanHeart AssociationPracticeGuidelineRecommendationsfor AnticoagulantTherapy

CurrentrecommendationsfortheuseofanticoagulanttherapyforUA/NSTEMIare elegantlysummarizedinthe2011ACCF/AHAFocusedUpdateIncorporatedIntothe ACC/AHA2007GuidelinesfortheManagementofPatientsWithUA/NSTEMI.1 Consistentwiththepracticeofmostclinicians,theseguidelinesseparate anticoagulanttreatmentrecommendationsbasedonwhetherapatientisplannedto undergoaninitialinvasivemanagementstrategy(earlydiagnosticcatheterizationto thentriagepatientsforfurthermedicaltherapy,PCI,orcoronaryarterybypass grafting[CABG])oraninitialconservativemanagementstrategy(medicaltherapy followedbynoninvasiveriskstratification). Irrespectiveofthemanagementstrategy,anticoagulantagentstypicallyshouldbe startedassoonaspossibleafterthediagnosisofACSismade,aClassI recommendationintheACCF/AHAguidelines(Table1).1 Allpatientswithsuspected ACSshouldideallyreceiveananticoagulant,withthenotableexceptionofpatients with"secondaryACS"aconditionwheretheprecipitatingconditionisnotaprimary atherothromboticprocessbutratheraprocessextrinsictothecoronaryarteries (suchasmassivebloodlossorseverehypotensioninthesettingofsepticshock). Possibleclassesofanticoagulantagentsthathavebeendemonstratedtobe effectiveinACSincludeunfractionatedheparin(UFH),lowmolecularweight heparins(LMWHs),directthrombininhibitors,andindirectfactorXainhibitors.Allof theseagentsaimtodownregulatethecycleofcoagulationandthrombosisthatcan furtherpropagateandworsentheischemiceffectsofACS. AcriticalmanagementissuerelatedtotheuseofanticoagulantagentsinACSisthe potentialtradeoffofmorepotentanticoagulation(aimedtomaximizeantiischemic efficacy)foranincreaseinbleedingcomplications.Theassociationbetween nonfatalischemiceventsandlatemortalityhasbeenhistoricallyrecognizedandwell describedinstudiesofACSinfact,thisisoneofthefundamentalprinciplesbehind theuseofanticoagulanttherapyinACS. Morerecently,astronglinkagebetweennonfatalbleedingeventsandsubsequent mortalityhasalsoemergedinbothrandomizedclinicaltrialsandobservational studiesinACS.24Thetreatingphysicianmustbeincreasinglyawareofthejoint importanceofbothischemicandbleedingcomplicationswhenselectingtheoptimal anticoagulantstrategyforpatientswithUA/NSTEMI. UseWithanInvasiveManagementStrategy Patientsundergoinganinvasivemanagementstrategytypicallyarestartedon antiplatelettherapyaswellasanticoagulanttherapyatpresentation.Catheterization usuallyisperformedwithin48hoursofpresentation.AvarietyofprePCIoptionsare availableregardinganticoagulanttherapiesinthesepatientsandinclude intravenous(IV)UFH,subcutaneouslyadministeredenoxaparin,subcutaneously administeredfondaparinux,andIVbivalirudin. TheACCF/AHAguidelinesstressthatdirect,comparativedataamongthevarious ClassIrecommendedagentsarelimitedandareinmanycasesconfoundedby changesinotheradjunctivetherapiesovertime.1 Therefore,healthsystemand physicianpreferences,modifiedbypatientspecificfactors,arelikelythemost appropriatearbitersofanticoagulantchoice.Itshouldbeemphasizedthatprotocol drivencareactuallymayreducethechanceoftreatingpatientswithmultipleagents andmayreducedosingerrors,andthusinstitutionalconsistencyamongtreating providersmaybeagoalofcareinitsownright. UA/NSTEMIpatientstreatedwithaninvasivemanagementstrategyfrequently undergoPCI.Inthissetting,thedosingofanticoagulanttherapytypicallyis increasedtomeettheincreasedanticoagulantrequirementsofPCI(Table2). Consistencyofanticoagulantagentsshouldbeemphasized,asswitching anticoagulanttherapieshasbeenassociatedinsomestudieswithincreased bleedingcomplications.5 Inrarecases(e.g.,inthetreatmentofintraprocedural
Table1

Table2

thromboticcomplications),patientsmayrequiretheuseofanadditional anticoagulantagentduringPCI.Additionally,becauseofanincreasedrateof catheterrelatedthromboticcomplicationsobservedduringPCIperformedwith fondaparinux,2 manyoperatorshaveadoptedastrategyoftreatmentwithUFHin patientsinitiallytreatedwiththisagent.6 AnticoagulanttherapyisalmostalwaysdiscontinuedimmediatelyfollowingPCI,as continuanceoftherapyusuallyisassociatedwithverylimitedantiischemicefficacy andasubstantialriskofbleeding. UseWithaConservativeManagementStrategy AmongpatientstreatedconservativelyforUA/NSTEMI,antiplateletandanticoagulant therapiesaimtopassivatetheprothromboticstatemedically,andfurther noninvasiveriskstratificationthenpromptsthemoreselectiveuseofangiographyor revascularization.Appropriateagentsincludeenoxaparin,fondaparinux,orUFH.The ACCF/AHAguidelinesdonotrecommendtheuseofbivalirudinamong conservativelymanagedpatientsduetolimiteddatawiththisagentamong conservativelymanagedpatients.Additionally,theguidelinesincludeaClassIIa indicationfavoringtheuseofeitherenoxaparinorfondaparinuxovertheuseofUFH forconservativelymanagedpatients.1 Whereasthegeneralrecommendationsforanddosingofanticoagulanttherapyare similartothatofpatientsbeingmanagedinvasively,thedurationoftherapyamong conservativelymanagedpatientsistypicallylonger.Therearelimiteddataregarding theoptimaldurationoftherapyamongconservativelymanagedpatients,butgeneral practiceistocontinuetheseagentsforatleast48hoursafterpresentation.

ACCF/AHAGuidelineRecommendations Table1 ACCF/AHA=AmericanCollegeofCardiologyFoundation/AmericanHeartAssociationCABG=coronaryarterybypassgraftingUA/NSTEMI= unstableangina/nonSTsegmentelevationmyocardialinfarctionUFH=unfractionatedheparin. ReproducedwithpermissionfromWrightRS,AndersonJL,AdamsCD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA 2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmericanAcademyof FamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol 201157:e215367.

DosingofAnticoagulantAgentsinUA/NSTEMI Table2 ACT=activatedclottingtimeaPTT=activatedpartialthromboplastintimeCrCl=creatinineclearanceFUTURA/OASIS8=FondaparinuxTrial WithUnfractionatedHeparinDuringRevascularizationinAcuteCoronarySyndromes/OASIS8GP=glycoproteinIV=intravenousPCI= percutaneouscoronaryinterventionSC=subcutaneousUA/NSTEMI=unstableangina/nonSTsegmentelevationmyocardialinfarctionUFH= unfractionatedheparin.

UnfractionatedHeparin
UFHconsistsofamixtureofpolysaccharidechainsthatexertsananticoagulant effectbyfacilitatingactivationofantithrombinIII,whichinturninactivatesfactorsIIa (thrombin),IXa,andXa.UFHactsasanindirectinhibitorofthrombinandthe coagulationcascade.ThebioavailabilityofUFHisalsolimitedbynonspecific bindingtoplasmaproteinsandcells,whichresultsinvariableactivityoftheagent withinapatient.TheanticoagulanteffectofUFHalsovariesacrosspatientsand requiresmonitoringoftheactivatedpartialthromboplastintime(aPTT)oractivated clottingtime(ACT)inordertoachievetheoptimallydesiredlevelofanticoagulation. SummaryofTrialData UFHisoneoftheoldestanticoagulantsusedinclinicalpractice,andseveraltrials havebeenconductedexaminingitsusecomparedwithaspirinaloneinUA/NSTEMI. InmetaanalysesexaminingtheeffectofaspirinplusUFHcomparedwithUFH aloneinpatientswithACS,aspirinplusUFHwasshowntoreduceearlyischemic events,includingearlydeathormyocardialinfarction(MI),albeitattheborderlineof statisticalsignificance(Figure1).7 ItshouldbenotedthattheeffectsofUFH regardingtheendpointofdeath/MIwerenotsignificantinanyoftheindividualtrials includedinthismetaanalysis.Thesetrialswereconductedpriortothemore widespreaduseofadenosinediphosphate(ADP)receptorblockerssuchas clopidogrel,whichalsoexertanantiischemiceffect,sothe"true"effectofUFHwhen usedinconjunctionwithmorepotentantiplateletagentscomparedwithnoUFHis unknown. AdditionaldatacomparingtheuseofUFHwithorwithoutotherantiplateletagents (ADPreceptorantagonistsandglycoprotein[GP]IIb/IIIainhibitors)aredescribedin themoduleonAntiplateletTherapyforNSTEACSinthischapter. DosingStrategiesandTherapeuticTargets InACS,UFHtypicallyisadministeredasanIVbolusfollowedbyacontinuousIV infusion.TraditionaldosingofUFHiswitha5000Ubolusfollowedbya1000U/hr infusion,withdosingfurtheradjustedaccordingtotheaPTT.However,more predictableanticoagulationcanbeeffectedthroughweightbaseddosing,whichis thecurrentrecommendationbytheACCF/AHA.1 TheseguidelinesrecommendanIV bolusdoseofUFH(60U/kgnottoexceed4000U)followedbyaninitial12U/kg/hr infusion(nottoexceed1000U/hr).Furtherdosingisdictatedbymonitoringofthe aPTTorACT(thelatterforpatientsundergoingPCI). BecauseofinstitutionalvariabilityinmeasurementsofaPTT,institutionalspecific nomogramsorprotocolsforUFHdosingshouldbeestablished.Typically,thegoal aPTTis1.52.0timescontrolforpatientsbeingmaintainedonIVUFH.Thisdosing isthoughttooptimizetheantiischemiceffectsofUFHwhileminimizingbleeding thatcanoccurathigherachievedlevelsofanticoagulation.8 Forpatientsundergoing PCI,additionalIVbolusestypicallyareadministeredtoattainanACTof200250 secondsforpatientsbeingconcomitantlytreatedwithaGPIIb/IIIainhibitor,with generallyhigherlevels(but<350seconds)forpatientsnottreatedwithaGPIIb/IIIa inhibitor. TheoptimaldurationofUFHtherapyinACSpatientsisunknown,buttheACCF/AHA guidelinesrecommendcontinuingdosinguptodiagnosticangiographyforpatients undergoinganinvasivemanagementstrategy.1 PatientswhoundergoPCIshould haveUFHdiscontinuedafterPCIthoseundergoingCABGshouldcontinueUFH. Patientsbeingtreatedmedicallyorthosenotundergoinganinvasivemanagement strategyshouldbetreatedwithUFHthroughtheirhospitalization(atleast48hours), atwhichpointitcanbediscontinued. UFHisareversibleanticoagulantrapidreversalofitsanticoagulanteffectcanbe producedbytheadministrationofIVprotaminesulfate.Patientswithpriorexposure tolongactinginsulinstypicallyshouldreceiveasubcutaneouslyadministeredtest dosetopreventanaphylaxistypereactionsthathavebeenreportedtooccurwhen reversingUFH.

Figure1

AdverseConsequences Asananticoagulant,UFHisassociatedwithbleedingcomplications,whichmustbe weighedagainstthepotentialantiischemiceffectsoftheagent.Althoughbleeding complicationscanoccurevenwhenUFHisdosedwithinthetherapeuticrangeof aPTT,higheraPTTvaluesareassociatedwithanexcessofbleedingcomplications. AppropriatedosingofUFHiscriticaltomaximizetheriskbenefitratioofthisagent, ashigherdosesofboththebolusandinfusionhavebeenassociatedwithadverse outcomes.9 InalargeobservationalregistryofACSpatients,excessdosingofUFH wasfoundinalmostonethirdofthepatients.10 Inadditiontobleedingcomplications,exposuretoUFHalsohasbeenassociated withthedevelopmentofheparininducedthrombocytopenia,whichcanoccurwithor withoutthrombosis.1,11Mildthrombocytopeniamayoccurin1020%ofpatients, whereassignificantthrombocytopenia(plateletcount<100,000)occursin15%of patientsandtypicallyappearsafterseveraldaysoftherapy.Thrombocytopenia typicallyresolvesafterdiscontinuationofheparin.Themoredangerouscomplication ofimmunemediatedheparininducedthrombocytopeniawiththrombosisoccurs morerarely(<0.2%).Whenitoccurs,itcanhavedevastatingconsequences, requiringbothcessationofUFHandanticoagulationwithadirectthrombininhibitor tocounterthethromboticconsequencesofthesyndrome.Finally,excessthrombin generationhasbeendescribedfollowingcessationofUFHtheactualadverse clinicalsequelaeofthiseffectarelargelyunknown.12

MetaAnalysisofUnfractionatedHeparinPlusAspirinVersusAspirinAloneinAcuteCoronarySyndrome Figure1 AdaptedwithpermissionfromOlerA,WhooleyMA,OlerJ,GradyD.Addingheparintoaspirinreducestheincidenceofmyocardialinfarctionand deathinpatientswithunstableangina.Ametaanalysis.JAMA1996276:8115. References: 1. TherouxP,OuimetH,McCansJ,etal.Aspirin,heparin,orbothtotreatacuteunstableangina.NEnglJMed1988319:110511. 2. TheRISCGroup.Riskofmyocardialinfarctionanddeathduringtreatmentwithlowdoseaspirinandintravenousheparininmenwith unstablecoronaryarterydisease:theRISCGroup.Lancet1990336:82730. 3. CohenM,AdamsPC,HawkinsL,BachM,FusterV.UsefulnessofantithrombotictherapyinrestinganginapectorisornonQwave myocardialinfarctioninpreventingdeathandmyocardialinfarction(apilotstudyfromtheAntithromboticTherapyinAcuteCoronary SyndromesStudyGroup).AmJCardiol199066:128792. 4. CohenM,AdamsPC,ParryG,etal.CombinationantithrombotictherapyinunstablerestanginaandnonQwaveinfarctioninnonprior aspirinusers:primaryendpointsanalysisfromtheATACStrial:AntithromboticTherapyinAcuteCoronarySyndromesResearchGroup. Circulation199489:818. 5. HoldrightD,PatelD,CunninghamD,etal.Comparisonoftheeffectofheparinandaspirinversusaspirinaloneontransientmyocardial ischemiaandinhospitalprognosisinpatientswithunstableangina.JAmCollCardiol199424:3945. 6. GurfinkelEP,ManosEJ,MejailRI,etal.Lowmolecularweightheparinversusregularheparinoraspirininthetreatmentofunstableangina andsilentischemia.JAmCollCardiol199526:3138.

LowMolecularWeightHeparins
LMWHsareobtainedthroughdepolymerizationofstandardUFHwithselectionof thosechainswithlowermolecularweight,withagreaterproportionaleffectagainst factorXacomparedwithfactorIIa.DifferentformulationsofLWMHhavediffering ratiosofantiXatoantiIIaactivityandthereforeslightlydifferentanticoagulanteffects. ComparedwithUFH,LMWHshaveincreasedratiosofantiXatoantiIIaactivity, exhibitlessbindingtoplasmaproteinsandcells,andhavealongerhalflife.This facilitatesmorepredictabledoseresponsestoLWMHcomparedwithUFHand allowsLMWHtobeadministeredsubcutaneouslywithtwicedailydosing.LMWH alsocanbeadministeredintravenously,whichmaybeusefulduringPCI. SummaryofTrialData TherearelimitedtrialdatacomparingLMWHversusplaceboonabackgroundof aspirinantiplatelettherapy.TheFRISC(FragminandFastRevascularizationDuring InstabilityinCoronaryArteryDisease)studyistheonlylargerandomizedtrialto compareLMWHversusplacebo.Thistrialrandomized1,506patientswithACSand showedthattheadditionofdalteparintoaspirinreducedtheriskofearlydeathorMI (inthefirst6days)from4.8%to1.8%(p=0.001)comparedwithaspirinalone.13 ThisstudyprimarilyenrolledmedicallymanagedpatientswithACS.Amongthe patientsrandomizedtodalteparin,therapywascontinuedforseveralweeks. ComparisonofLowMolecularWeightHeparinVersusUnfractionatedHeparin ThemajorityofdatawithLWMHinACSconsistsofrandomizedtrialscomparingthe useofLWMHwithUFHonabackgroundofaspirinantiplatelettherapy.Although differentpreparationsofLWMHhavebeenstudied(includingdalteparinand nadroparin),themostpositiveresultshavebeenobservedusingenoxaparin. EarlydatafromtheTIMI11B(ThrombolysisinMyocardialIschemia,Phase11B)and ESSENCE(EfficacyandSafetyofSubcutaneousEnoxaparininUnstableAnginaand NonQwaveMI)trialsdemonstratedreductionsinthecompositeofdeath,MI,or recurrentischemiawithenoxaparincomparedwithUFHthesestudieswere primarilyconductedinconservativelymanagedpatientswithACS.14Morerecent trials,includingSYNERGY(SuperiorYieldoftheNewStrategyofEnoxaparin, Revascularization,andGlycoproteinIIb/IIIaInhibitors)andAtoZ(AggrastattoZocor), haveexaminedtheuseofenoxaparincomparedwithUFHininvasivelymanaged patientswithACS. Inthe10,027patientSYNERGYtrial,therateofthecompositeischemicendpointof deathorMIwas14.0%withenoxaparinversus14.5%withUFH(nonstatistically different)however,bleedingcomplicationsweremorefrequentwithenoxaparin.15 Theuseofenoxaparininthistrialwasinadditiontoaspirinand,inapproximately halfofenrolledpatients,GPIIb/IIIainhibitors.InthesmallerAtoZtrial,inwhich patientswererandomizedtoenoxaparinversusUFHontopofabackgroundof aspirinandroutineGPIIb/IIIainhibitors,enoxaparinwasassociatedwitha nonsignificantlylowerrateofdeath,MI,orrecurrentischemiaat30days(8.4%vs. 9.4%)withnumericallygreaterratesofbleedingcomparedwithUFH.16IntheAtoZ trial,onlyhalfofthepatientsweremanagedwithanearlyinvasivestrategy,anda posthocsubgroupanalysisdemonstratedthatthebenefitofenoxaparinwaslargely confinedtopatientsmanagedconservatively. AmetaanalysisofallenoxaparinversusUFHtrialsinACSdemonstratesan approximate10%reductionindeathorMIwithenoxaparinoverUFH,withno significantdifferencesinmajorbleedingoutcomes(Figure2).5 Itshouldbenoted thatthismetaanalysisincludedanumberofpatientswhowereconservatively managed.Higherratesofbleedingoutcomeswereobservedwithenoxaparin comparedwithUFHintheSYNERGYtrial,thelargesttrialofinvasivelymanaged patientswithACS. AposthocanalysisoftheSYNERGYtrialdemonstratedthatapossibleexplanation forthehigherratesofbleedingoutcomesmayhavebeentheuseofmultiple anticoagulantagents(orswitchingofagents)inthetrial.Whetherconsistencyof

Figure2

agentsormorejudicioususeofUFHinpatientsalreadygivenenoxaparincould havemitigatedthehigherratesofbleedingobservedinthistrialisunknown.17 DifferentiationofTypesofLowMolecularWeightHeparins AlthoughdifferentformulationsofLWMHhavedifferingratiosofantiXatoantiIIa activity,itisuncleartowhatextentthesedifferencesareclinicallymeaningfulinACS. Indirectcomparisonsbetweenagentssuggestthatenoxaparinislikelythemost clinicallyusefulagent.Thereisonesmallrandomizedtrialcomparingenoxaparin versustinzaparininpatientswithunstableangina.IntheEVET(EnoxaparinVersus TinzaparininNonSTSegmentElevationAcuteCoronarySyndromes)trial,patients treatedwithenoxaparinhadsignificantlylowerratesofischemicoutcomes comparedwiththosetreatedwithtinzaparin,withsimilarratesofbleeding outcomes.18 DosingStrategies ThemeasurementofanticoagulanteffectofLWMHcanbeperformedthroughthe directmeasurementoffactorXaactivitytheaPTTisnotareliableindicatorof anticoagulanteffect.However,becauseofthemorepredictableeffectsofLMWH,itis notnecessaryinclinicalpracticetomonitorthelevelofanticoagulanteffect,making LWMHeasiertousethanintravenouslydosedUFH.ItshouldbenotedthatLMWHs aremoreaffectedbyrenaldysfunctionthanUFH,andadosereductiontoonceaday isrecommendedinpatientswithcreatinineclearance(CrCl)<30ml/min.LWMH alsocanbeadministeredintravenously,whichcanbeusefulduringthe performanceofPCI,particularlyinpatientswhohavenotreceivedpriordosesof LWMH. TheoptimaldurationofLWMHtherapyinACSpatientsisunknown,butthe ACCF/AHAguidelinesrecommendcontinuingdosinguptodiagnosticangiography forpatientsundergoinganinvasivemanagementstrategy.1 Patientswhoundergo PCIshouldhaveLWMHdiscontinuedafterPCIthoseundergoingCABGshould discontinueLWMH1224hourspriortoCABG.Patientsbeingtreatedmedicallyor thosenotundergoinganinvasivemanagementstrategyshouldbetreatedwith LWMHthroughtheirhospitalization(upto8days),atwhichpointitcanbe discontinued. AdverseConsequencesofLowMolecularWeightHeparins LWMHagents,likelyUFH,areassociatedwithbleedingcomplications,whichmust beweighedagainstpotentialantiischemicbenefits.Inlargeobservationalseriesof patientswithACS,excessdosingofLWMHagentsoccurred13.6%ofthetimeand wasassociatedwithincreasedratesofbleeding.10Inadditiontoassiduous attentiontooptimalweightbaseddosing,doseadjustmentsonthebasisof impairedkidneyfunctionareimportantfortheserenallyclearedagentsandmaybe anothercauseofbleedingcomplications. AlthoughLMWHhasbeenassociatedwiththeoccurrenceofheparinassociated thrombocytopenia,thisoccurswithamuchlowerfrequencycomparedwithUFH, andLWHMstimulatesplateletslessthanUFH.11TheuseofLWMHduringPCIhas beenassociatedwithalowbutnotablerateofepisodesofcatheterrelated thromboticcomplications,despiteadequateinhibitionoffactorXa.19This complication,althoughrare,usuallyrequirestreatmentwitheitherUFHoradirect thrombininhibitor.SimilartoUFH,a"rebound"phenomenonhasbeenobserved withcessationofLWMHtherapyitisuncleartowhatextentthisisclinicallyrelevant inthecurrentmanagementofACS,whichincludesmorepotentantiplatelettherapy thansimplyaspirinalone.

MetaAnalysisofEnoxaparinVersusUnfractionatedHeparininAcuteCoronarySyndrome Figure2 Intentiontotreatpopulation:efficacyendpointsat30daystestforheterogeneity:25=6.59,p=0.25.Blacksquaresindicateoddsratios(ORs) horizontallines,95%confidenceintervals(CIs).ThesizeofeachsquarereflectsthestatisticalweightofatrialincalculatingtheOR,andthe relativesizesofthesquaresareaccuratewithineachplotonly. ESSENCE=EfficacyandSafetyofSubcutaneousEnoxaparininNonQWaveCoronaryEventsTIMI11B=ThrombolysisinMyocardialInfarction 11BACUTEII=AntithromboticCombinationUsingTorofibanandEnoxaparinIIINTERACT=IntegrilinandEnoxaparinRandomizedAssessmentof AcuteCoronarySyndromeTreatmentAtoZ,=AggrastattoZocorstudySYNERGY=SuperiorYieldoftheNewStrategyofEnoxaparin, RevascularizationandGlycoproteinIIb/IIIaInhibitorsUFH=unfractionatedheparin. PanelBadaptedwithpermissionfromPetersenJL,MahaffeyKW,HasselbladV,etal.Efficacyandbleedingcomplicationsamongpatients randomizedtoenoxaparinorunfractionatedheparinforantithrombintherapyinnonSTsegmentelevationacutecoronarysyndromes:a systematicoverview.JAMA2004292:8996.

DirectThrombinInhibitors
DirectthrombininhibitorsofferadvantagesoverUFHandLWMHinthattheyinhibit thrombindirectlyratherthanthroughactivationofantithrombinIII.Theseagentscan inhibitbothfreeandclotboundthrombin,provideaverystablelevelof anticoagulation,anddonotcausethrombocytopenia.Hirudin,anaturallyoccurring anticoagulantderivedfromthemedicinalleech,ismadecommerciallyby recombinantDNAtechnologyinanumberofformulations(includinglepirudin, desirudin)andwasusedinearlystudiesofACS. Bivalirudin,anotherdirectthrombininhibitor,isananalogofhirudinandbinds reversiblytothrombinwithashorthalflife,inhibitingitsactivity.Bivalirudinisthe mostwidelystudieddirectthrombininhibitorinthecontemporarymanagementof ACS.Argatrobanisanothermonovalentdirectthrombininhibitorthatisapprovedfor thetreatmentofheparininducedthrombocytopeniabutisnotindicatedforthe treatmentofACSfollowingnegativestudieswiththisagentinSTEMI. SummaryofTrialData SeveralearlytrialsevaluatedrecombinanthirudinversusUFHforpatientswithACS. ThelargestofthesetrialswastheGUSTOIIb(GlobalUtilizationofStreptokinase andTPAforOccludedArteriesIIb)trial,whichenrolled12,142patientswithboth UA/NSTEMIandSTEMI,includingpatientstreatedwithfibrinolytictherapy.Inthistrial, whilethe24hourendpointofdeathorMIfavoredhirudin,the30dayrateofdeathor MIwasnotsignificantlylowerwithhirudincomparedwithUFH,andtherateof moderatebleedingwashigherwithhirudin.20Furtherevaluationofhirudin continuedinthe10,141patientOASIS2(EffectsofLongTerm,ModerateIntensity OralAnticoagulationinAdditiontoAspirininUnstableAngina)trial,whichagain demonstratedimprovedischemicoutcomeswithhirudin(butnonsignificantly)and higherratesofbleeding.21Poolingofallmajorhirudintrialshasdemonstratedan overallapproximate20%reductioninischemicevents(deathorMI)withhirudinover UFHbutatthecostofanexcessofbleedingcomplications.22Additionally,these earlytrialswereconductedonanantiplateletbackgroundofaspirinalone. Bivalirudin,asyntheticanalogueofhirudin,wasfirststudiedintheBAT(Bivalirudin AngioplastyStudy),atrialofbivalirudinversusUFHin4,098patientsundergoingPCI forunstableanginaorpostinfarctionangina.Inthistrial,bivalirudindidnot significantlyreducetheincidenceofthecompositeprimaryischemicendpoint(a combinationofearlydeath,MI,abruptvesselclosure,orclinicaldeterioration) comparedwithUFHbutwasassociatedwithareductioninbleeding.23 Asubsequentreevaluationofthedatafromthistrialwithamoreconventional ischemicendpointofdeath,MI,orrepeatrevascularizationdemonstratedabenefitto bivalirudinoverUFH(6.2%vs.7.9%,p=0.039)inthispatientpopulation,withlower ratesofbleeding.24Thesedataandotheremergingfavorabledataforbivalirudinin PCIpatientsledtoareassessmentoftheuseofbivalirudinforACSintheACUITY (AcuteCatheterizationandUrgentInterventionTriageStrategyTrial). TheACUITYrandomlyassigned13,819patientswithmoderatetohighriskACSto oneofthreeantithromboticregimens:UFH(orenoxaparin)plusaGPIIb/IIIa inhibitor,bivalirudinplusaGPIIb/IIIainhibitor,orbivalirudinmonotherapy(Figure 3).25Patientsweremanagedwithanearlyinvasivestrategyandunderwent diagnosticangiographyatamedianof19.6hoursafteradmission.Inthistrial, bivalirudinmonotherapywasassociatedwithasimilarrateofcompositeischemia (7.8%vs.7.3%,p=0.32)andsignificantlyreducedmajorbleeding(3.0%vs.5.7%,p <0.001)comparedwithUFH/enoxaparinplusaGPIIb/IIIainhibitor.Asaresult,the rateofoccurrenceofthenetclinicaloutcome(compositeischemiaplusmajor bleeding)waslowerwithbivalirudinmonotherapycomparedwithUFH/enoxaparin plusaGPIIb/IIIainhibitor(10.1%vs.11.7%,p=0.015).Althoughtheseresultswere consistentinmostmajorsubgroupsofthetrial,the30daycompositeischemic eventratewasnotablyhigherwithbivalirudinmonotherapycomparedwithUFHplus GPIIb/IIIainhibitorsamongpatientsnotpretreatedwithanADPreceptorantagonist (9.1%vs.7.1%,pforinteraction0.05).

Figure3

Ofnote,intheACUITY,treatmentwithbivalirudinplusaGPIIb/IIIainhibitorresulted insimilarratesof30daydeath,MI,orunplannedrevascularizationforrecurrent ischemiacomparedwithUFH/enoxaparinplusGPIIb/IIIainhibitors(7.7%vs.7.3%,p =0.39)andsimilarratesofmajorbleeding(5.3%vs.5.7%,p=0.38). BecauseboththeBATandACUITYtrialsemployedinvasivemanagementstrategies andinthecaseofACUITYthetimefromadmissiontorandomizationwasshorter thanthatconventionallyobservedinclinicalpractice,theACCF/AHAguidelines stressthatforpatientsexperiencingmoresignificantdelaystocatheterizationor patientswithrecurrentischemiafollowingtheinitialtreatmentstrategy, considerationshouldbemadetofurtherescalationoftheantithromboticregimen (e.g.,additionofGPIIb/IIIainhibitors).1 Infact,somehavequestionedwhetherthepotentialbenefitsofbivalirudinoverUFH alonecouldbemitigatedbymoreaggressiveoralantiplatelettherapy(suchasADP receptorblockade)inconjunctionwithUFHalone.IntheISARREACT3 (IntracoronaryStentingandAntithromboticRegimen:RapidEarlyActionforCoronary Treatment)study,thisstrategywastestedamongpatientsundergoingPCIeither electivelyorforunstableangina.Inthistrialof4,570patientspretreatedwith600mg ofclopidogrel,theratesofischemicoutcomesweresimilarforpatientstreatedwith bivalirudinorUFH,butbivalirudintreatedpatientshadasignificantlylowerrateof bleedingcomplications(3.1%vs.4.6%,p=0.008).26 DifferentiationofTypesofDirectThrombinInhibitorsandDosinginAcute CoronarySyndrome Asstatedpreviously,thetwodirectthrombininhibitorsbeststudiedinACSare bivalirudinandhirudin.However,duetolimitedischemicefficacyandincreased bleedingcomparedwithUFH,hirudinisatpresentonlyindicatedforuseinheparin inducedthrombocytopenia.Similarly,argatrobanisapprovedonlyfortheindication ofheparininducedthrombocytopenia. AlthoughnotapprovedforthisindicationinUA/NSTEMI,bivalirudinwasstudiedin moderatetohighriskinvasivelymanagedACSpatientsinthemulticenter randomizedACUITYtrial,andisgivenaClassIrecommendationforinvasively managedpatientsintheACCF/AHAguidelinesforUA/NSTEMI.1 Bivalirudinisdosed asanIVbolusfollowedbyaninfusion.Becauseoftheexcellentbioavailabilityofthis agent,noadditionalmonitoringoftherapeuticeffectisrequired. PatientsundergoingPCIreceiveanadditionalbolusandanincreasedrateof infusionthatisdoseadjustedinpatientswithdecreasedkidneyfunction(CrCl<30 ml/min).Thebivalirudininfusiontypicallyisdiscontinuedimmediatelyfollowing cardiaccatheterization(orPCI),althoughsomehaveadvocatedalongerdurationof therapy,particularlyforpatientsnotadequatelytreatedwiththienopyridines.Patients whohavebeentreatedwithbivalirudinwhoaremedicallymanagedfollowing diagnosticangiographycanhavethebivalirudinstoppedorcontinuedforupto72 hoursatthetreatingphysician'sdiscretion.PatientsscheduledtoundergoCABG shouldhavethebivalirudinstopped3hourspriortoCABGandcanthenbetreated withUFHifnecessary. AdverseEvents AdverseeventsassociatedwithdirectthrombininhibitorsusedforACSinclude bleedingcomplications,whichmustbeweighedagainstpotentialantiischemic benefits.However,bivalirudinhasbeenassociatedwithreducedbleeding comparedwithUFHaswellasLWMHinconjunctionwithGPIIb/IIIainhibitors, renderingitanattractiveagentforpatientsatriskofbleeding.UnlikeUFH,the anticoagulanteffectofdirectthrombininhibitorscannotbereversed,andbleeding complicationsmustbemanagedsupportivelyuntiltheagent'santicoagulanteffect hasdissipated.

30DayOutcomesFromtheACUITYTrialofBivalirudininAcuteCoronarySyndrome Figure3 IIb/IIIa=glycoproteinIIb/IIIaACUITY=AcuteCatheterizationandUrgentInterventionTriageStrategyTrialCABG=coronaryarterybypass graftingEnox=enoxaparinUFH=unfractionatedheparin.

FactorXaInhibitionWithFondaparinux
FactorXainhibitorsexerttheiranticoagulanteffectmoreproximallyinthecoagulation cascadeandhavedemonstratedpromiseinthetreatmentofACS.Thesynthetic pentasaccharidefondaparinuxisthebeststudiedoftheseagentsinpatientswith ACS.Fondaparinuxisstructurallysimilartotheantithrombinbindingportionof heparinsandbyreversiblybindingtoantithrombinIII,indirectlyinhibitsfactorXa. SummaryofTrialData ThelargesttrialoffondaparinuxinUA/NSTEMIistheOASIS5(FifthOrganizationto AssessStrategiesinAcuteIschemicSyndromesInvestigators)trial.Thistrial randomized20,078patientswithACStofondaparinuxversusenoxaparinboth agentswereadministeredsubcutaneouslyforameanof6days.2 Patientsinthis trialweremanagedmoreconservativelythaninothercurrentACStrials:overall, approximatelytwothirdsofpatientsunderwentdiagnosticcoronaryangiography. PatientsundergoingPCIreceivedadditionalanticoagulanttherapydependingonthe durationfromthelastadministeredstudydose(insomecasesinthefondaparinux arm,patientsreceivedadditionalintravenouslyadministeredfondaparinux).The ratesoftheprimarycompositeendpointofdeath,MI,orrefractoryischemiawere similarwithfondaparinuxandenoxaparin(5.8%vs.5.7%),butbleedingeventswere significantlydecreasedwiththeuseoffondaparinux(2.2%vs.4.1%,p<0.001). Thesebenefitspersistedat30days(Figure4)infact,30daymortalitywaslower withfondaparinuxcomparedwithenoxaparin(2.9%vs.3.5%,p=0.02). IntheOASIS5trial,inthesubsetofpatientsundergoingPCI,fondaparinuxwas associatedwithanincreasedriskofcatheterrelatedthrombus(0.9%vs.0.3%for enoxaparin),afindingthatalsowasobservedintheOASIS6(Organizationforthe AssessmentofStrategiesforIschemicSyndromes6)trialoffondaparinuxforSTEMI. Asaresult,operatorswerepermittedtouseopenlabelUFHduringPCIforpatients alreadytreatedwithfondaparinux. Asubsequenttrial,FUTURA/OASIS8(FondaparinuxTrialWithUnfractionated HeparinDuringRevascularizationinAcuteCoronarySyndromes/OASIS8),has examinedtheeffectsofUFHdosingduringPCIfor2,026patientstreatedwith fondaparinuxforACS.6 Inthistrial,therewasnodifferenceinoutcomesusingalow doseofUFHversusahigherdosetheratesofcatheterrelatedthrombusformation werelowinbothgroups. DosingStrategiesandAdverseEvents ComparedwithUFH,fondaparinuxhasapredictableanticoagulantresponsewitha longhalflifeandthuscanbesubcutaneouslyadministeredwithoncedailydosing withoutmonitoringofanticoagulanteffect.Becausefondaparinuxisrenallycleared, thedrugshouldbeavoidedinpatientswithCrCl<30ml/min. TheoptimaldurationoffondaparinuxtherapyinACSpatientsisunknown,butthe ACCF/AHAguidelinesrecommendcontinuingdosinguptodiagnosticangiography forpatientsundergoinganinvasivemanagementstrategy.1 Patientswhoundergo PCIshouldhavefondaparinuxdiscontinuedafterPCIasadirectfactorXainhibitor, fondaparinuxdoesnotresultindirectinhibitionofthrombin(factorIIa).Thus additionalUFHshouldbegivenparticularlyduringtheperformanceofPCIin fondaparinuxtreatedpatientstoavoidtheoccurrenceofcatheterrelatedthrombus formation.PatientsundergoingCABGshoulddiscontinuefondaparinux24hours priortoCABG.Patientsbeingtreatedmedicallyorthosenotundergoinganinvasive managementstrategyshouldbetreatedwithfondaparinuxthroughtheir hospitalization(upto8days),atwhichpointitcanbediscontinued. Otheradverseevents,suchasbleedingcomplications,havebeenassociatedwith treatmentwithfondaparinux,butthesewerelessfrequentlyobservedintheOASIS5 trial,leadingtotherecommendationintheACCF/AHAguidelinesfortheuseofthis agentinconservativelymanagedpatientsatriskforbleeding.1

Figure4

30DayOutcomesFromtheOASIS5TrialofFondaparinuxinAcuteCoronarySyndrome Figure4 MI=myocardialinfarctionOASIS5=FifthOrganizationtoAssessStrategiesinAcuteIschemicSyndromesInvestigators.

Warfarin
SeveralearlytrialsexaminedtheuseoftheoralanticoagulantwarfarininpatientswithACS.Warfarin'santicoagulant effectismediatedthroughinhibitionofsynthesisofvitaminKdependentclottingfactors(factorII,VII,IX,andXand proteinsCandS).Theanticoagulantactivityofwarfarinisvariable,andtheagenthasarelativelynarrowtherapeutic window,whichrequiresclosemonitoringoftheprothrombintime/internationalnormalizedratioinordertoensurethe optimallevelofanticoagulation. OralanticoagulationwithwarfarinpostACShasbeenexaminedinseveraltrials,withtherationalethatprolonged treatmentmightextendthebenefitofearlyanticoagulation.ThewarfarinsubstudyoftheOASIS2trialsubrandomized 3,712patientstocontinuedwarfarinorstandardtherapy,includingaspirin,followingtheinitialpresentationandtreatment forACS.27Inthistrial,therewerenosignificantdifferencesintherateofthecompositeofdeath,MI,orstrokewitheither therapy,butmajorbleedingwasincreasedwithwarfarintherapy(2.7%vs.1.3%,p=0.004).SubanalysesoftheOASIS2 databaseduponcountrieswithgreateradherencetowarfarintherapy(>70%compliancetotherapyat35days) demonstratedsignificantantiischemicbenefitsofwarfarinamongcountrieswithgreateradherencetowarfarintherapy buthigherrelativerisksofbleedingcomplications. Similardatahavebeenreportedfromothersmallertrials,includingpatientsatpotentiallyhigherrisksuchasSTEMI.In theWARISII(Warfarin,Aspirin,orBothAfterMyocardialInfarction)trial,whichrandomized3,630postMIpatientsto aspirinalone,warfarinalone,oraspirinpluswarfarin,treatmentwiththecombinationofaspirinandwarfarinwas associatedwiththelowestrateofdeath,MI,orthromboembolicstroke(15.0%withaspirinpluswarfarinvs.16.7%with warfarinalonevs.20%foraspirinalone,p<0.001).28However,theincidenceofnonfatalbleedingwasincreasedinboth warfaringroupscomparedwithaspirinalone. Notablecaveatstotheseearlystudiesarethattheylargelyexcludedpatientsundergoingearlyrevascularizationandwere conductedpriortomorewidespreaduseofdualantiplatelettherapy.OralantiplateletagentssuchasADPreceptor antagonistshavebeendemonstratedtoreduceischemicoutcomesovertherapywithaspirinaloneandare recommendedasstandardofcareinvirtuallyallpatientswithACS.Asthecombinationofwarfarinplusaspirinalonehas beenassociatedwithincreasedbleeding,andthecombinationofaspirin,clopidogrel(orprasugrel),andwarfarin increasesbleedingtoanevengreaterextent,theroleof"tripletherapy"isgenerallylimitedtopatientswithother indicationsforwarfarinanticoagulation(e.g.,mechanicalvalve,atrialfibrillation,stroke,ventricularthrombus,venous thromboembolism).

FutureDirections
Ongoingclinicaltrialsofneweranticoagulantagentsshouldhelptodefinebetterthe optimalanticoagulantstrategyforthefuturetreatmentofACS.Severalofthese agentsarewithintheclassesofagentsdiscussedpreviously,andotheragents belongtonovelclassesofagentswithdifferentmechanismsofaction.Clearly affectingthedevelopmentofnovelanticoagulantsistheincreasingrecognitionofthe complementaryimportanceofbothischemicandbleedingeventsinpatientswith UA/NSTEMI. Thedevelopmentofnovelanticoagulantagentshasfocuseduponattemptstoeither 1)provideincrementalgainsinantiischemicbenefitwithoutfurtherincreasesin bleedingriskor2)preservetheantiischemicbenefitsofcurrentagentswhile incrementallyloweringbleedingrisk.Inlightofthedecreasingeventratesinclinical trialsofantithrombotictherapyinACS,themarginsthroughwhichthesepotential incrementalclinicalbenefitscanbemeasuredareslim.Theclinicaltrialsizes requiredinordertodemonstratethesegainswithstatisticalconfidencealsocanbe daunting.Nonetheless,furtherstudyofnovelanticoagulantagentsremainsanarea ofactiveinterestandinvestigation(Table3).

Table3

NovelAnticoagulantAgentsUnderInvestigation Table3 ATLASACS2TIMI51=AntiXaTherapytoLowerCardiovascularEventsinAdditiontoStandardTherapyinSubjectswithAcuteCoronary SyndromeThrombolysisinMyocardialInfarction51APPRAISE2=ApixabanforPreventionofAcuteIschemicEvents2IV=intravenousPCI= percutaneouscoronaryinterventionTAO=TreatmentofAcuteCoronarySyndromeWithOtamixaban.

KeyPoints
TheACCF/AHAUA/NSTEMIguidelinesrecommendstartingallpatients(withoutcontraindications)onan anticoagulantassoonaspossibleafterpresentation(ClassI).1 FourdifferentagentsarerecommendedasClassIoptionsforUA/NSTEMIpatientsbeingmanagedwithan invasivestrategy:UFH,enoxaparin,bivalirudin,orfondaparinux. ForUA/NSTEMIpatientsbeingmanagedwithaconservativestrategy,acceptableregimensincludeenoxaparin, fondaparinux,orUFH(ClassI).Fondaparinuxisthepreferredagentinconservativelymanagedpatientsat increasedriskforbleeding.TheACCF/AHAguidelinespreferentiallygiveenoxaparinorfondaparinuxaClassIIa indicationoverUFHforconservativelymanagedpatients(exceptifCABGisplannedwithin24hours).1 PatientstreatedwithfondaparinuxwhorequirePCIshouldbetreatedwithUFHatthetimeofthePCItoavoid catheterrelatedthrombus. ThedurationofanticoagulationforpatientsundergoingPCIisupuntil(butnotafter)thePCIisperformed. ThedurationofanticoagulationforpatientsundergoingCABGisuptoCABGforpatientstreatedwithUFHupto3 hourspriortoCABGforbivalirudin(withcontinuanceofUFH)upto1224hourspriortoCABGforLMWHandup to24hourspriortoCABGforfondaparinux. Formedicallymanagedpatients(eitherconservativelymanagedpatientswhodonotundergoangiographyor invasivelymanagedpatientswhodonotundergoPCIorCABG),therecommendeddurationofanticoagulationis typicallyforaminimumof48hours(forpatientstreatedwithUFH)orthelengthofhospitalstay(upto8days)for patientstreatedwithLMWHorfondaparinux.Patientswhohavebeentreatedwithbivalirudinwhoaremedically managedfollowingdiagnosticangiographycanhavethebivalirudinstoppedorcontinuedforupto72hoursatthe physician'sdiscretion. Thebenefitsandrisksoftripleantithrombotictherapywithaspirin,clopidogrel,andwarfarinhavenotbeenclearly established,whichleavesthisrecommendationatClassIIb.Suchtherapyshouldbeselectedforclear indicationsforextendeddurationoforalanticoagulationandgivenfortheshortestdurationoftimeattheminimally effectivedosesnecessarytoachieveprotection(aspirin81mg,andwarfarintitratedtointernationalnormalized ratio2.02.5).

References
1. WrightRS,AndersonJL,AdamsCD,etal.2011ACCF/AHAfocusedupdateincorporatedintotheACC/AHA2007 GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:areport oftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines developedincollaborationwiththeAmericanAcademyofFamilyPhysicians,SocietyforCardiovascular AngiographyandInterventions,andtheSocietyofThoracicSurgeons.JAmCollCardiol201157:e215367. 2. YusufS,MehtaSR,ChrolaviciusS,etal.,onbehalfoftheFifthOrganizationtoAssessStrategiesinAcute IschemicSyndromesInvestigators.Comparisonoffondaparinuxandenoxaparininacutecoronarysyndromes.N EnglJMed2006354:146476. 3. RaoSV,EikelboomJA,GrangerCB,HarringtonRA,CaliffRM,BassandJP.Bleedingandbloodtransfusion issuesinpatientswithnonSTsegmentelevationacutecoronarysyndromes.EurHeartJ200728:11931204. 4. MehranR,PocockSJ,StoneGW,etal.Associationsofmajorbleedingandmyocardialinfarctionwiththe incidenceandtimingofmortalityinpatientspresentingwithnonSTelevationacutecoronarysyndromes:arisk modelfromtheACUITYtrial.EurHeartJ200930:145766. 5. PetersenJL,MahaffeyKW,HasselbladV,etal.Efficacyandbleedingcomplicationsamongpatientsrandomized toenoxaparinorunfractionatedheparinforantithrombintherapyinnonSTsegmentelevationacutecoronary syndromes:asystematicoverview.JAMA2004292:8996. 6. TheFUTURA/OASIS8TrialGroup.Lowdosevs.standarddoseunfractionatedheparinforpercutaneouscoronary interventioninacutecoronarysyndromestreatedwithfondaparinux.JAMA2010304:133949. 7. OlerA,WhooleyMA,OlerJ,GradyD.Addingheparintoaspirinreducestheincidenceofmyocardialinfarctionand deathinpatientswithunstableangina.Ametaanalysis.JAMA1996276:8115. 8. AnandSS,YusufS,PogueJ,GinsbergJS,HirshJ.Relationshipofactivatedpartialthromboplastintimeto coronaryeventsandbleedinginpatientswithacutecoronarysyndromeswhoreceiveheparin.Circulation 2003107:28848. 9. MelloniC,AlexanderKP,ChenAY,etal.UnfractionatedheparindosingandriskofmajorbleedinginnonST segmentelevationacutecoronarysyndromes.AmHeartJ2008156:20915. 10. AlexanderKP,ChenAY,RoeMT,etal.Excessdosingofantiplateletandantithrombinagentsinthetreatmentof nonSTsegmentelevationacutecoronarysyndromes.JAMA2005294:310816. 11. ArepallyGM,OrtelTL.Clinicalpractice.Heparininducedthrombocytopenia.NEnglJMed2006355:80917. 12. GrangerCB,MillerJM,BovillEG,etal.Reboundincreaseinthrombingenerationandactivityaftercessationof intravenousheparininpatientswithacutecoronarysyndromes.Circulation199591:192935. 13. Lowmolecularweightheparinduringinstabilityincoronaryarterydisease,FragminduringInstabilityinCoronary ArteryDisease(FRISC)studygroup.Lancet1996347:5618. 14. AntmanEM,CohenM,RadleyD,etal.Assessmentofthetreatmenteffectofenoxaparinforunstableangina/non Qwavemyocardialinfarction.TIMI11BESSENCEmetaanalysis.Circulation1999100:16028. 15. FergusonJJ,CaliffRM,AntmanEM,etal.EnoxaparinvsunfractionatedheparininhighriskpatientswithnonST segmentelevationacutecoronarysyndromesmanagedwithanintendedearlyinvasivestrategy:primaryresults ofthesynergyrandomizedtrial.JAMA2004292:4554. 16. BlazingMA,deLemosJA,WhiteHD,etal.Safetyandefficacyofenoxaparinvsunfractionatedheparininpatients withnonSTsegmentelevationacutecoronarysyndromeswhoreceivetirofibanandaspirin:arandomized controlledtrial.JAMA2004292:5564. 17. DrouetL,BalditSollierC,MartinJ.Addingintravenousunfractionatedheparintostandardenoxaparincauses excessiveanticoagulationnotdetectedbyactivatedclottingtime:resultsofthestackontoenoxaparin(stackenox) study.AmHeartJ2009158:17784. 18. MichalisLK,KatsourasCS,PapamichaelN,etal.EnoxaparinversustinzaparininnonSTsegmentelevation acutecoronarysyndromes:theEVETtrial.AmHeartJ2003146:30410. 19. DanaA,NguyenCM,CloutierS,BarbeauGR.Macroscopicthrombusformationonangioplastyequipment followingantithrombintherapywithenoxaparin.CatheterCardiovascInterv200770:84753. 20. TheGlobalUseofStrategiestoOpenOccludedCoronaryArteries(GUSTO)IIbInvestigators.Acomparisonof recombinanthirudinwithheparinforthetreatmentofacutecoronarysyndromes.NEnglJMed1996335:77582. 21. Organisationtoassessstrategiesforischemicsyndromes(OASIS2)Investigators.Effectsofrecombinant hirudin(lepirudin)comparedwithheparinondeath,myocardialinfarction,refractoryangina,andrevascularisation proceduresinpatientswithacutemyocardialischaemiawithoutSTelevation:arandomisedtrial.Lancet 1999353:42938. 22. TheDirectThrombinInhibitorTrialists'CollaborativeGroup.Directthrombininhibitorsinacutecoronary syndromes:principalresultsofametaanalysisbasedonindividualpatients'data.Lancet2002359:294302. 23. BittlJA,StronyJ,BrinkerJA,etal.Treatmentwithbivalirudin(hirulog)ascomparedwithheparinduringcoronary angioplastyforunstableorpostinfarctionangina.Hirulogangioplastystudyinvestigators.NEnglJMed 1995333:7649. 24. BittlJA,ChaitmanBR,FeitF,KimballW,TopolEJ.Bivalirudinversusheparinduringcoronaryangioplastyfor unstableorpostinfarctionangina:finalreportreanalysisofthebivalirudinangioplastystudy.AmHeartJ 2001142:9529.

25. StoneGW,McLaurinBT,CoxDA,etal.Bivalirudinforpatientswithacutecoronarysyndromes.NEnglJMed 2006355:220316. 26. KastratiA,NeumannFJ,MehilliJ,etal.Bivalirudinversusunfractionatedheparinduringpercutaneouscoronary intervention.NEnglJMed2008359:68896. 27. TheOrganizationtoAssessStrategiesforIschemicSyndromes(OASIS)Investigators.Effectsoflongterm, moderateintensityoralanticoagulationinadditiontoaspirininunstableangina.JAmCollCardiol200137:475 84. 28. HurlenM,AbdelnoorM,SmithP,ErikssenJ,ArnesenH.Warfarin,aspirin,orbothaftermyocardialinfarction.N EnglJMed2002347:96974.

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6.5:STEMI:InitialAssessmentandRiskStratification
Author(s): DavidA.Morrow,MD,MPH,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. DiscussthegoalsoftheinitialassessmentofpatientswithSTsegmentelevationmyocardialinfarction(STEMI). 2. IdentifythemajordeterminantsofriskinpatientswithSTEMI. 3. DescribenoninvasiveandinvasivetoolsthatmaybeusedtoenhanceriskassessmentinpatientswithSTEMI.

Introduction
TheinitialevaluationandmanagementofpatientswithpossibleSTEMIarefocusedon:1)rapiddiagnosis,2)expedited assessmentofrisksforreperfusiontherapy,3)timelyinitiationofreperfusiontherapy,and4)acontinuousre assessmentoftheriskforandpresenceofcomplicationsofSTEMI.Thismodulereviewstheinitialassessmentandrisk stratificationofpatientswithSTEMI.Subsequentmodulesinthischapteraddresstheselectionandinitiationof reperfusiontherapy(seemoduleonReperfusionTherapyforSTEMI),otherpharmacotherapyforSTEMI(Ancillary TherapyI:AntiplateletandAntithrombinTherapy),recognitionofmechanicalcomplications(seemoduleonMechanical ComplicationsofSTEMI),andsecondaryprevention(seemoduleonAncillaryTherapyII:SecondaryPreventionAfter STEMI).

NaturalHistory
SurvivalafterSTEMIhascontinuedtoimproveoverthepastdecade.1 Nevertheless,thecasefatalityofSTEMIremains veryhigh(>25%)forspecificsubgroupsofhighriskpatients,suchasthosewhopresentwithassociatedsevereheart failureorshock.MostdeathsinpatientswithSTEMIoccurinthefirsthourpriortoarrivingatthehospital. Amongthebroadgroupofsurvivorstohospitalpresentation,datafromtheNationalCardiovascularDataRegistry (NCDR),aninitiativeoftheAmericanCollegeofCardiology(ACC),demonstratedaninhospitalmortalityrateof5.5%in 2009.Oneyearmortalityrates,availablefromEuropeanregistries,haverangedfrom6.9%to7.6%amongpatients treatedwithprimarypercutaneouscoronaryintervention(PCI),and10.315.9%amongpatientstreatedwithafibrinolytic.2 Thesedatasummarizethepopulationaveragehowever,subsetsofpatientsareatveryhighorverylowriskofafatal complication,andtheclinicianisabletosignificantlyrefinetheestimateofriskfortheindividualusingmethods describedinthismodule. Theinhospitalincidenceofspecificcomplicationshasbeenreportedforpatientstreatedwithfibrinolysisinclinicaltrials, includingventriculararrhythmia(7%),heartfailureandshock(17%),stroke(2%),recurrentMI(4%),andrecurrent ischemia(29%).3 Notably,inpatientsundergoingprimaryPCIinalargeclinicaltrial,4 theincidenceofstroke(0.6%), recurrentischemia(2.2%),orreinfarction(1.8%),evenat30days,wasnumericallylowerthaninpreviouscumulative experiencewithfibrinolytics.

DiagnosisofSTEMI

STEMIisaclinicalsyndromedefinedbysymptomsofmyocardialischemiatogether withelectrocardiographicSTsegmentchanges,predominantlyelevation,indicative ofocclusionofacoronaryartery.ThediagnosisofMIisconfirmedbyevidenceof myocardialnecrosisbasedonbiomarkers,electrocardiography(ECG),or pathologicalexamination. InitialDiagnosticEvaluation Giventheprogressiveirreversibleinjurytocardiacmyocyteswithpersistent occlusionoftheinfarctrelatedarteryinSTEMI,theoverarchingaimofinitial managementisrapidrecognitionandimmediaterestorationofbloodflowtothe infarctzone.Forthisreason,a12leadECGshouldbeobtainedpromptly(10 minutes)inpatientspresentingwithsymptomssuspiciousformyocardial ischemia.5,6Moreover,inpatientswithaclinicalhistorythatiscompellingfor ischemiaandaninitiallynondiagnosticECG,serialtracingsshouldbeobtained every1530minutesoruntilsymptomresolution. Samplesformeasurementofbiomarkersofmyocardialnecrosis,preferablycardiac troponin,shouldbeobtainedatthetimeofpresentation.7 However,becauseST segmentchangesprecedethereleaseofdetectableconcentrationsofbiomarkers ofnecrosisbyhours,treatment,includingreperfusiontherapy,shouldnotbe delayedawaitingbiomarkerresultsinpatientswithdiagnosticSTelevation(seethe nextsectiononElectrocardiogramCriteriaandthesectiononBiomarkers,bothin thismodule). IncaseswheretheECGisnotinterpretableoruncertain,performanceofurgent bedsidetransthoracicechocardiographymaybeusefultoprovideevidenceof regionalwallmotionabnormalitiesand,thereby,tofacilitatepatienttriage. ElectrocardiogramCriteria The2007EuropeanSocietyofCardiology(ESC)/AmericanCollegeofCardiology Foundation(ACCF)/AmericanHeartAssociation(AHA)/WorldHealthFederation (WHF)ClinicalExpertConsensusDocumentontheUniversalDefinitionof MyocardialInfarction7 hasdefineddiagnosticcriteriaforSTsegmentelevation(at theJpoint)asfollows: 2mminmenor1.5mminwomeninleadsV2V3,and/or 1mminatleasttwoothercontiguouschestleadsortwolimbleads. The2009AHA/ACCF/HeartRhythmSociety(HRS)Recommendationsforthe StandardizationandInterpretationoftheECGgivesexandagespecific recommendationsforinterpretationofischemicSTsegmentchangesthatincludea higherthresholdof2.5mminleadsV2V3formen<40yearsold.8 InterpretationofSTsegmentelevationinthesettingofrightbundlebranchblock (RBBB)orfascicularblocksdoesnotrequirespecialcriteria.However,interpretation ismoredifficultinpatientswithleftbundlebranchblock(LBBB).Specialcriteriafor thediagnosisofSTEMIinpatientswithLBBBweredevelopedbySgarbossaand colleagues,9 emphasizingeitherconcordantSTsegmentelevationinanyleadwith apositiveQRSdeflectionorSTsegmentelevation>5mm(Table1). Othertypesofintraventricularconductiondelays,aswellasleftventricular(LV) hypertrophyandventricularlypacedrhythms,mayalsoconfoundECGinterpretation forSTEMI.Immediatereferralforinvasiveangiographytoguidemanagementis generallyindicatedincaseswheretheclinicalsuspicionforanacutecoronary syndrome(ACS)ishighandtheECGisdifficulttointerpretforSTelevation. AnECGwithrightprecordialleadsshouldgenerallybeperformedinpatientswith inferiorSTEMI,andposteriorleads(V7V9)maybehelpfultodetectSTEMIduetoleft circumflexarteryocclusionthatmaybesilentonastandard12leadECG.In addition,theclinicianshouldbevigilantforconcurrentSTsegmentdepressionin multipleleadsalongwithSTsegmentelevationinleadaVR,whichmaybeseenin patientswithocclusionoftheleftmainorproximalleftanteriordescending(LAD) coronaryartery.

Table1

ElectrocardiogramCriteriaforDiagnosisofSTEMIinLeftBundleBranchBlock Table1 SgarbossaandcolleaguesdevelopedcriteriafordiagnosisofSTsegmentelevationmyocardialinfarction(STEMI)inthepresenceofaleftbundle branchblock.AmetaanalysisofstudiesexploringtheutilityoftheSgarbossacriteriademonstratedthatanintegerscoreor3hadaspecificity of98%foracuteMI.However,ascoreof0didnotexcludeSTEMI. Reference(s): 1. SgarbossaEB,PinskiSL,BarbagelataA,etal.Electrocardiographicdiagnosisofevolvingacutemyocardialinfarctioninthepresenceof leftbundlebranchblock.GUSTO1(GlobalUtilizationofStreptokinaseandTissuePlasminogenActivatorforOccludedCoronaryArteries Investigators.NEnglJMed1996334:4817. 2. TabasJA,RodriguezRM,SeligmanHK,GoldschlagerNF.Electrocardiographiccriteriafordetectingacutemyocardialinfarctionin patientswithleftbundlebranchblock:ametaanalysis.AnnEmergMed200852:32936.

InitialClinicalAssessment
OnceapatientwithSTEMIhasbeenidentifiedonthebasisofsymptomsandECGfindings,theinitialclinical assessmentshouldbebriefandtargetedatevaluatingforanycontraindicationstoreperfusiontherapy,orconcomitant medicalconditionsthatmayinfluencemanagement(e.g.,cocaineuse,historyofseverebleeding).Inparallel,the clinicianshouldperformarapidpreliminaryassessmentoftheriskofmajorcomplicationsonthebasisoffeaturesofthe patient'smedicalhistory,physicalexamination,ECG,andlaboratorytesting. Decisionmakingregardingthepatient'scandidacyandmodeofreperfusiontherapy,alongwithsystemsgoalsfor implementation,arediscussedindetailinthemoduleonReperfusionTherapyforSTEMIinthischapter.However,itis worthemphasisthatthe"chainofsurvival"forSTEMIinvolvesanintegratedstrategybeginningwithpatienteducation aboutthesymptomsofSTEMI,earlycontactwiththemedicalsystem,coordinationofdestinationprotocolsinemergency medicalservicessystems,efficientpracticesinemergencydepartmentstoshortendoortoreperfusiontime,and expeditiousimplementationofthereperfusionstrategybyatrainedteam.10Criticalfactorstobeconsideredwhen selectingareperfusionstrategyinclude(seemoduleonReperfusionTherapyforSTEMIinthischapter): Thetimeelapsedsincetheonsetofsymptoms TheriskassociatedwiththeSTEMI,includingthepresenceofsevereheartfailure Theriskofadministeringafibrinolyticand Thetimerequiredtoimplementaninvasivestrategy. Assessmentofeachoftheseelementsshouldoccuraspartofasystemgoalofeitherinitiationoffibrinolytictherapy within30minutesordeploymentofthefirstinvasivecoronarydevicewithin90minutesoffirstmedicalcontact. PrehospitalEvaluation Withsophisticationofpresentemergencymedicalsystems,itispossibletoinitiatetheclinicalevaluationofpatientswith possibleSTEMIevenbeforethepatientarrivesintheemergencydepartment.InallpatientswithSTEMI,performanceofa focusedhistory,vitalsigns,andaprehospitalECGcansignificantlyreducethetimetoinitiationofreperfusiontherapy. TheabilitytotransmitsuchECGsandtoactivatetheSTEMIcareteampriortohospitalarrivalcansubstantiallyexpedite theearlyresponsetoSTEMI.11Thepotentialadvantagesandbarrierstoprehospitaladministrationoffibrinolytictherapy arediscussedinthemoduleonReperfusionTherapyforSTEMIinthischapter. HistoryandExamination Uponarrivaltothehospital,patientswithSTEMIshouldundergoafocusedclinicalhistoryandphysicalexamination. AlthoughmostpatientswithSTEMIcomplainofchestpain,pressure,ortightness,otherlesstypicalsymptomssuchas nausea,emesis,neck/arm/jawpain,dyspnea,presyncope/syncope,orseverefatiguemaypredominate,especially amongwomen,patientswithdiabetes,andtheelderly.Theclinicianshouldbealerttosignsorsymptomsofother complicatingormimickingconditionssuchasaorticdissectionorpericarditis. Evenabriefclinicalhistoryandphysicalexaminationprovidevaluableinformationforriskstratificationduringthecourse ofroutinecare,atnoadditionalcostorrisktothepatient.InpatientswithSTEMI,featuresofthepresentinghistory, includingprolongeddurationofsymptomsorthepresenceofsymptomsofheartfailure,heraldahighershorttermriskof majorcomplications.Moreover,findingsofatherosclerosisinnoncoronaryvascularbedsbyhistoryorphysical examinationportendahigherprobabilityofdiffuseseverecoronarydiseaseandahighriskofcomplicationsof procedures.12 Thepresenceofheartfailureonphysicalexaminationisamongthestrongestpredictorsofmortalityriskinpatientswith STEMI.InpatientswithacuteMI,KillipobservedthatthepresenceofralesoranS3wereassociatedwithathreetofive foldhighershorttermriskofdeath.Moreover,evenintheeraofrapidreperfusiontherapy,asimpleriskindexbasedonly thepatient'sage,alongwithbloodpressureandheartrateasmanifestationsofhemodynamiccompromise,captured 86%oftheprognosticinformationofcomplexmodels.13 Becauseofthisstrongassociation,clinicalindicatorsofheartfailureorventriculardysfunctionarecentraltomostclinical algorithmsforriskstratificationincoronaryheartdisease(seethesectiononClinicalRiskModelsinthismodule). Recognitionofthephysicalexaminationfindingsofspecificmechanicalcomplications,suchasrightventricular(RV)MI orventricularseptaldefect,arealsoessentialtooptimalmanagementofpatientswithSTEMI(seethemoduleon MechanicalComplicationsofSTEMIinthischapter). Despitetheimperativeforrapidinitiationoftherapy,theinformationgainedfromabriefsocialhistoryandassessmentof adherencetomedicaltreatmenthasemergedasapivotalelementofdecisionmakingwithrespecttostentselectionin patientsundergoingprimaryPCI.Present2009STEMIandPCIFocusedUpdateGuidelinesemphasizetheuseofbare metalstentsorballoonangioplastyinpatientswithahistoryofnonadherencetotherapy,forwhomthereisahighriskof nonadherencetoextendeddualantiplatelettherapy.6

LaboratoryTesting Inadditiontomeasurementofbiomarkersofmyocardialnecrosis,assessmentofserumelectrolytes,creatinine, hematocrit,plateletcount,andcoagulationparametersarevaluableformanagement.Hyperglycemiaatpresentation, eveninpatientswithoutrecognizeddiabetesmellitus,isassociatedwithincreasedmortalityinpatientswithSTEMI. Screeningforrecentuseofcocainemaybeappropriateinselectedcases,asitmayinfluenceselectionofmedical therapies.Evaluationoflipidprofileisgermanetosecondaryprevention(seemoduleonAncillaryTherapyII:Secondary PreventionAfterSTEMIinthischapter).

GoalsofRiskStratification
ThecentralgoalofriskassessmentinACSistoguidetherapeuticdecisionmaking and,insomecases,additionaldiagnosticevaluation(Figure1).InSTEMI,because treatmentistightlyregimentedregardlessofindividualpatientriskofrecurrent eventsorcomplicationsoftheinfarction,riskstratificationisoftenusedprimarilyto directtriagewithinthehospitalortransfertotertiarycarecenters.Aparallel evaluationoftheriskofcomplicationsoftherapy(e.g.,bleedingwithantiplatelet agents)isalsoanimportantaspectofclinicalriskstratificationandimprovesthe integratedassessmentofpotentialrisksandbenefitsoftreatment.Inpatientswith STEMI,onemayconsiderseveraldiscretephasesofriskstratification:1)earlyrisk stratificationatthetimeofpresentation,2)reassessmentaftertheinitialreperfusion strategy,and3)riskstratificationforlongtermsecondarypreventionatthetimeofor afterhospitaldischarge.Thelastoftheseconsiderationsisdescribedinthemodule onAncillaryTherapyII:SecondaryPreventionAfterSTEMIinthischapter.

Figure1

GoalsofRiskStratification Figure1 ReproducedwithpermissionfromMorrowDA.Cardiovascularriskpredictioninpatientswithstableandunstablecoronaryheartdisease. Circulation2010121:268191.

EarlyRiskStratification
ElectrocardiogramatPresentation InadditiontobeingpivotalinthediagnosisofSTEMI,theinitial12leadECG providesimportantprognosticinformation.14 MyocardialInfarctionLocationandTerritoryatRisk ThemortalityrateishigherinpatientsexperiencinganteriorwallSTEMI comparedwithinferiorSTEMI,evenwhencorrectedforinfarctsize. AhighsumoftotalSTsegmentelevationisassociatedwithanincreased mortalityrate,especiallyiftheinfarctisanteriorinlocation. STsegmentdepressionsinanteriorleadsinpatientswithinferiorinfarction areindicativeofeitherposteriorextensionofinfarctionorconcomitantLAD ischemiaand,consequently,poorerprognosis. STsegmentelevationinleadV4R,suggestingRVMIinassociationwith inferiorMI,isassociatedwithahighermortalityratethaninthosewithoutRV involvement.15 ConductionDeficits Persistentadvancedheartblock(e.g.,MobitztypeII,orthirddegree atrioventricular[AV]block)ornewintraventricularconductionabnormalities (bifascicularortrifascicular)inthecourseofaSTEMIisassociatedwith increasedmortality. Inlightoftheanatomyandvascularsupplyoftheconductionsystem,RBBB inassociationwithananteriorMIisusuallythemanifestationofalargeMI thatismorefrequentlyaccompaniedbyheartfailure,completeAVblock,and arrhythmias,andcarriesamortalityrateontheorderof3timesthatfor patientswithoutRBBB. TheevolutionofSTsegmentchangesafterreperfusiontherapyalsoprovides valuableinformationwithrespecttoprognosis(seethesectiononRiskStratification AfterReperfusionTherapyinthismodule). ClinicalRiskModels Certaindemographicandhistoricalfactorsportendaworseprognosisinpatients withSTEMI,including:1)advancedage,2)ahistoryofdiabetesmellitus,3)previous MI,and4)longdurationofsymptomspriortopresentation.Whenintegratedwiththe ECGandthephysicalexamination,inparticularthepresenceofsignsorsymptoms ofheartfailure,thesehistoricalfactorsmaybeusedtoreliablystratifypatientswith respecttoshortandlongtermmortalityrisk. IndividualClinicalRiskIndicators Withtheexceptionofpresentationwithsevereheartfailure,olderageisthe strongestpredictorofpoorprognosisinpatientswithSTEMI,exhibitinga gradedrelationshipwithoutcomethatsteepensupwardafter65years.13 Diabetesmellitusconfersa>40%increaseinadjustedriskofdeathby30 daysafterSTEMI.16Asaresultofacceleratedatherosclerosisandhigher riskofthrombosis,survivingdiabeticpatientsalsoexperienceamore complicatedpostMIcourseincludingagreaterincidenceofpostinfarction angina,infarctextension,andheartfailure.12 Clinicalsignsofheartfailure,includingtachycardiaandhypotension,arethe strongestpredictorsofpoorsurvivalandareincludedinthemajorityof clinicalscoresdevelopedforriskassessmentinpatientswithSTEMI. RiskScores Severalclinicalriskstratificationtoolshavebeendevelopedandvalidated,andmay beusedatpresentationtoassesstheshortandlongtermriskofdeathafter STEMI.12TheTIMIRiskIndexrequiresonlythepatient'sage,heartrate,andsystolic bloodpressureatpresentation,andmaybeeasilyperformedbyprehospitalor
Table2

Table3

Figure2

Figure3

Figure4

paramedicalpersonnel,identifyinga20foldgradientofincreasedmortalityacross quintiles(0.817.4%,p<0.001)(Table2).13 TheTIMI(ThrombolysisinMyocardialInfarction)riskscoreforSTEMIisasimple integerscorethatcanbecalculatedbyhand(score014)atthebedsidebasedon thehistoryandphysicalexamination(Table3).17TheGRACE(GlobalRegistryof AcuteCoronaryEvents)riskscoreisacontinuousscore(range0263)thatmaybe calculatedusingawebbasedcalculatorusingthehistory,physicalexamination, andlaboratorydata(Figure2).18 These,andotherriskscoresforpatientswithSTEMI,placethegreatestweighton thepatient'sageandfindingssuggestiveofhemodynamicsignificanceoftheMI:1) hypotension,2)tachycardia,3)presenceofrales,or4)presenceofanS3. Biomarkers InitiationofareperfusionstrategyinpatientswithSTEMIshouldnotbedelayeduntil laboratorydata,includingbiomarkers,areavailable(Seetheprecedingsectionon DiagnosisofSTEMI).5 Nevertheless,serumorplasmabiomarkers,onceavailable, complementtheotherclinicaldata,offeringinsightsintothetimingoftheSTEMI,the extentofnecrosis,andthepatient'sprognosis. MarkersofMyocardialNecrosis Inadditiontoestablishingthepresenceofcardiomyocytenecrosis,thereby confirmingthediagnosisofMI,biomarkersofnecrosis(cardiactroponinand creatinekinasemyocardialband[CKMB]),whenelevatedatinitialpresentation,are associatedwithhighermortalityriskthaninpatientswithSTEMIwhohavenormal concentrationsonthefirstsample. IntheGUSTOIII(GlobalUseofStrategiesToOpenOccludedCoronaryArteries) trial,patientswhopresentedwithdetectablecardiactroponinT(8.9%ofentire population)hadasignificantlyhighermortalityrateat30days(15.7%)compared withpatientswithnodetectabletroponinatpresentation(6.2%,p<0.001).19This associationmostlikelyreflectstheintegratedinfluenceofthetiming(later presentationwithhighervalues)andextentofmyocardiuminjeopardy. CKMBandtroponinconcentrationspeakearlieranddeclinemorerapidlyif successfulreperfusionisachievedlikelybecausereflowofbloodallowsfaster clearanceofthenecroticproteinswhereasthereleaseisslowerintheabsenceof successfulreperfusion(Figure3).Cardiactroponinsarethepreferredmarkerto confirmthepresenceofMIbecauseofbothgreaterclinicalsensitivityandtissue specificitytoCKMB.7 Theareaundertheconcentrationcurveandpeakvaluefor eithercardiactroponinandCKMBmaybeusedasanoninvasiveindicatorofthe sizeoftheinfarction.AmongpatientsundergoingprimaryPCI,theconcentrationof cardiactroponinapproximately3daysaftertheonsetofsymptomshasbeen suggestedtoofferthebestestimationoftotalinfarctsizeusingnuclearimagingas thestandard(Figure4).20 BiomarkersofInflammation SeveralbiomarkersofinflammationhavebeenevaluatedinpatientswithMI, includingSTEMI.Ofbiomarkersthatareclinicallyavailable,bothCreactiveprotein andmyeloperoxidasehavebeenassociatedwithmortalityinriskinpatientswith STEMI.21Thisrelationshipmayreflectboththeunderlyinginflammatory contributionstothepathobiologyofatherothrombosis,andtheintensityofthe inflammatoryresponsetonecrosis.Althoughthese,andotherbiomarkers,remain ofpotentialresearchinterest,particularlyasnovelantiinflammatorytherapeuticsare explored,thereispresentlynoestablishedroleforroutineclinicaluseinpatients withSTEMI.22 BiomarkersofHemodynamicStress Becauseofthesubstantialprognosticimportanceofheartfailureinpatientswith STEMI,biomarkersofhemodynamicstresshavewellstudiedasriskmarkersin patientswithSTEMI.Btypenatriureticpeptide(BNP)andtheNterminalpeptideof

itsprecursor(NTproBNP)aremarkersofventricularwallstressthatarestrongly associatedwiththeriskofdeathandneworworseningheartfailureinpatientswith STEMI. Forexample,inonestudy,aconcentrationofBNP>80pg/mlatpresentationwas associatedwithasevenfoldhigher30dayriskofdeath(oddsratio7.2,95% confidenceinterval2.124.5,p=0.001).Inaddition,anelevatedconcentrationof BNPatpresentationisassociatedwithimpairedcoronaryflowatangiography,and failedmicrovascularreperfusionafterfibrinolysis.22 InitialRiskStratificationandClinicalDecisionMaking Itisnotclearwhetherthewidespreadapplicationofeitherclinicalriskscoresor novelbiomarkerscanimprovedecisionmakingforpatientswithSTEMI. Nevertheless,theyfacilitatethecoreprincipleofACSmanagementoftargeting interventionsinamannerthatisappropriatetotheriskofadverseoutcomesandthe potentialforclinicalbenefit.Thesetoolsforenhancedriskstratificationdoprovide estimatesofriskthatmaybeusefulinthetailoringoftherapyforindividualpatients, particularlywithrespecttounderstandingthepotentialabsoluteriskreductions possibleinaverylowversusahighriskpatient.5 Asanexample,inameta analysisofprimaryPCIversusfibrinolytictherapy,thosepatientsathighestoverall mortalityriskhadthegreatestabsolutebenefitfromprimaryPCI.23Inaddition,early identificationofhighriskpatientsmayfacilitateearlyconsiderationoftransfertoa tertiarycarefacility,andrecognitionofpatientswhoarenotcandidatesforearly hospitaldischargeafterSTEMI.

TIMIRiskIndex Table2 MethodforcalculationoftheTIMI(ThrombolysisinMyocardialInfarction)riskindex.Followsteps1,2,and3. D=daysH=hoursHR=heartrateSBP=systolicbloodpressure. ReproducedwithpermissionfromMorrowDA,AntmanEM,GiuglianoRP,etal.AsimpleriskindexforrapidinitialtriageofpatientswithST elevationmyocardialinfarction:anInTIMEIIsubstudy.Lancet2001358:15715.

TIMIRiskScoreforSTEMI Table3 TheThrombolysisinMyocardialInfarction(TIMI)riskscoreforSTsegmentelevationmyocardialinfarction(STEMI),calculatedastheweighted sumofeightpresentingcharacteristics(age6574or75,systolicbloodpressure(SBP)<90mmHg,heartrate(HR)>100bpm,KillipclassIIIV, anteriorSTsegmentelevation(STE)orleftbundlebranchblock(LBBB),priordiabetesmellitus(DM),hypertension(HTN),orhyperlipidemia, weight<67kg,timetotreatment(Rx)>4hours)wasderivedinaclinicaltrialpopulationandvalidatedinalargepopulationbasedregistry,and showedaclearstepwiseincreaseinmortalitywithincreasedriskscore.Therewasnodifferenceindiscriminationoftheriskscoreintermsof initialreperfusionstrategy(cstatistic=0.79forfibrinolysistreatedpatientsand0.80forPCItreatedpatients)however,itdidnotperformas wellforpredictingmortalityamongpatientswhoreceivednoreperfusiontherapy(cstatistic=0.65). ReproducedwithpermissionfromMorrowDA,AntmanEM,CharlesworthA,etal.TIMIriskscoreforSTelevationmyocardialinfarction:A convenient,bedside,clinicalscoreforriskassessmentatpresentation:AnintravenousnPAfortreatmentofinfarctingmyocardiumearlyIItrial substudy.Circulation2000102:20312037,andMorrowDA,AntmanEM,ParsonsL,etal.ApplicationoftheTIMIriskscoreforSTelevationMIin theNationalRegistryofMyocardialInfarction3.JAMA2001286:13569.

GRACERiskCalculatorfor6MonthMortality Figure2 GRACE=GlobalRegistryofAcuteCoronaryEvents ReproducedwithpermissionfromEagleKA,LimMJ,DabbousOH,etal.,onbehalfoftheGRACEInvestigators.Avalidatedpredictionmodelfor allformsofacutecoronarysyndrome:estimatingtheriskof6monthpostdischargedeathinaninternationalregistry.JAMA2004291:272733.

PatternofCKMBandTroponinRiseFollowingSTEMIinPatientsWithandWithoutSuccessfulReperfusion Figure3 CKMB=creatinekinasemyocardialbandSTEMI=STsegmentelevationmyocardialinfarctionURL=upperreferencelimit ReproducedwithpermissionfromAntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithST elevationmyocardialinfarction:AreportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines (CommitteetoRevisethe1999GuidelinesfortheManagementofPatientsWithAcuteMyocardialInfarction).JAmCollCardiol200444:E1E211.

CorrelationofCardiacTroponinTDrawn3DaysAfterSTEMIandInfarctSizebySPECTandEjectionFraction Figure4 CorrelationofcardiactroponinT(cTnT)drawn3daysafterSTsegmentelevationmyocardialinfarction(STEMI)andinfarctsizebysinglephoton emissioncomputedtomography(SPECT)(PanelA),andleftventricularejectionfraction(LVEF)(PanelB).ROCcurveanalysisforcTnTonday4, cTnTpeak,andareaunderthecurve(AUC)cTnTforpredictionofinfarctmassabovemedianbymagneticresonanceimaging(PanelC). ReproducedwithpermissionfromPanteghiniM,CucciaC,BonettiG,GiubbiniR,PaganiF,BoniniE.SinglepointcardiactroponinTatcoronary careunitdischargeaftermyocardialinfarctioncorrelateswithinfarctsizeandejectionfraction.ClinChem200248:14326,andGiannitsisE, SteenH,KurzK,etal.Cardiacmagneticresonanceimagingstudyforquantificationofinfarctsizecomparingdirectlyserialversussingletime pointmeasurementsofcardiactroponinT.JAmCollCardiol200851:30714.

RiskStratificationAfterReperfusionTherapy (1of2)
Thesecondmajorphaseofriskstratificationisthereassessmentofriskafter reperfusiontherapy.Thisreassessmentintegratesthesizeoftheinfarction,the successofreperfusiontherapy,theextentofanyresidualcoronaryarterydisease, thesusceptibilitytoseriousventriculararrhythmias,andthedevelopmentof complicationsoftheMI(e.g.,heartfailureorischemicstroke)ortreatment(e.g., bleeding). Avarietyofnoninvasiveandinvasivestudiesareusefulforfacilitatingthis assessmentincludingtheECG,echocardiography,stresstesting,stressnuclear imaging,cardiacmagneticresonance(CMR)imaging,coronaryangiographyand ventriculography,anddynamicuseofriskscoresthatincorporatetheclinicalcourse ofcomplicationsoftheMI. NoninvasiveTesting Electrocardiogram
Figure7

Figure5

Figure6

Thesuccessofreperfusionoftheculpritepicardialcoronaryarteryanddistal microvasculaturemaybeassessednoninvasivelyusingtheECG.Severalrelated measuresoftheoverallextentofresolutionofSTsegmentelevationhavebeenwell validatedforthispurpose. STSegmentResolution:STsegmentresolution(STRES)issimple surrogateforbothepicardialandmyocardialreperfusion.Thepercentageof STresolutioncanthenbecalculatedfrombaselinetosometimepointafter reperfusiontypically60180minutesafterfibrinolysisorimmediatelyafter primaryPCI.STRESisusuallycategorizedaseitherpresent(>50%)or absent(<50%)orasathreewaycategorization:complete(>70%resolution), partial(3070%resolution),ornone(<30%resolution). PatientswithgreaterSTRESareatalowerriskofdeath,heartfailure,and havingreducedLVfunctioncomparedtopatientswithpartialornoSTRES. Forexample,intheGISSI2(GruppoItalianoperloStudiodella Sopravvivenzanell'Infartomiocardicoacuto2)trial,patientswith>50%ST resolutionwereatmuchlowerriskofdeathcomparedtothosewith<50% resolutionat30days(3.5vs.7.4%,hazardratio0.46,95%confidenceinterval 0.370.57).24ThecalculationofSTRESandtheassociatedmortalityratesby threewaycategoryaredemonstratedinFigure5. STResolutionandEvidenceofReperfusion:Amongpatientsundergoing fibrinolysis,thosewhoachievecompleteSTRES(>70%resolution)aremuch morelikelytohavenormalTIMIgrade3flowonangiographycomparedto thosewitheitherpartialornoSTRES.IntheTIMI14(Thrombolysisin MyocardialInfarctionTrial,Phase14)andHIT4(HirudinforImprovementof Thrombolysis)trials,forexample,>90%ofpatientswithcompleteSTRES hadapatentinfarctrelatedartery,and7080%achievedTIMI3flow(Figure 6). Studiesutilizingmyocardialcontrastechocardiographyorangiographic measurestoassesstissuelevelperfusionhaveshownthatSTRES correlateswiththedegreeoftissueandmicrovascularreperfusionachieved, eveninthesettingofnormalflowintheepicardialartery.Theseobservations helpexplainwhypatientswhoachieveTIMI3flow,butfailtoachieve completeSTRESafterreperfusionstillexperiencesignificantmyonecrosis andhavepooreroutcomesdespiteanopenepicardialculpritartery.25Itisfor thesereasonsthatSTRESalsoprovidesprognosticinformationinpatients treatedwithprimaryPCI. MaximalSTElevation:ThetotalextentofpersistentSTelevationatasingle timepointafterinitialreperfusiontherapyisamoreconvenientand potentiallystrongerECGmarkerofpoorprognosisthancalculationofthe percentageofSTresolution.Inastudyof2,719patientswithSTEMI,maximal

Table4

Figure8

STelevationidentifiedinasinglelead90minutesafterfibrinolysiswasa betterpredictorofdeaththanpercentageofSTRES.Patientswiththemost residualSTelevationinasinglelead(>5mmpersistentSTelevationfor largeMI,>3mmforasmallanteriorMI,or>2mmforaninferiorMI)hadmuch higher6monthmortalityrate(16.2%)comparedtointermediateSTelevation (7.1%)ornopersistentSTelevation(<2mmforalargeMI,<1mmforsmall anteriorMI,or<1mmforinferiorMI)(3.1%)(Figure7). SingleECGLeadAssessment:Severalstudiesdemonstratethattheless cumbersomemethodofdeterminingmaximalSTelevationintheleadwith greatestSTdeviationprovidesasimilarassessmentofreperfusionandthe risktousingthesumacrossall12leads.26Forexample,afinalSTsegment elevation1mmforinferiorinfarctionsand2mmforanteriorinfarctionsin theleadwithgreatestelevationonadmissionhadapositivepredictivevalue of91%forapatentinfarctrelatedarteryfollowingfibrinolysis. AssessmentofLeftVentricularFunction HospitalmortalityfromSTEMIistightlytiedtotheseverityofLVdysfunction.5 Forthis reason,alongwithtiestopreventionofsuddencardiacdeath(seethesectionon RiskAssessmentforSuddenDeathinthismodule),itisaClassIrecommendation toassessLVfunctionafterSTEMI,eitherusingleftventriculographyatthetimeof catheterization(afterreperfusion),usingnucleargatedimagingatthetimeofstress imaging,usingCMRimaging,ormostcommonly,byechocardiography.5,6Because nostudyhasclearlyshownoneimagingmodalitytobesuperiortoothers,clinicians shouldbeguidedintheirselectionofventricularimagingtechniquebytheavailability andlevelofexpertisewithagivenmodalityattheirlocalinstitution.Similarly,the optimaltimingofmeasurementofassessmenthasnotbeenestablished. EvaluationforIschemia BecauseoftheadverseconsequencesofrecurrentMIafterSTEMI,itisimportantto assessapatient'sriskforfutureischemiaandinfarction.Recommendationsfrom theACCF/AHAGuidelinesontheManagementofPatientsWithSTEMIareshownin Table4.Inpatientstreatedwithfibrinolytictherapyalone,apredischargeevaluation forischemiaallowsclinicianstoselectpatientswhomightbenefitfrom catheterizationandrevascularizationfollowinginitialreperfusion. InpatientsmanagedwithprimaryPCI,selectedpatientswithresidualnonculprit coronaryarterydiseasemaybecandidatesforprovocativetestingforischemiato guidedecisionsregardingadditionalrevascularization.However,noprospective randomizedstudieshaveaddressedthisissue.Additionally,exercisetestingcanbe usefultoformulateanexerciseprescription,andmaybehelpfulinsupporting patients'confidenceintheirabilitytoconducttheirdailyactivitiesafterdischarge. Patientswhoareunabletoexercisecanbeevaluatedbytheuseofa pharmacologicalstressprotocol,suchaswithadenosine.5 Inselectedcases,clinicaldecisionmakingregardingrevascularizationafterthe initialreperfusionstrategymaybedependentondistinguishingbetweenirreversibly damaged,stunned,orhibernatingmyocardium.Singlephotonemissioncomputed tomography(SPECT),positronemissiontomography,andCMRimagingare alternativetechniquestodefineischemicand/orviablemyocardiumversusscarin thepostinfarctionsetting(seemoduleonInitialAssessmentandRiskStratification inthischapter).CMRisemergingasausefultechniquethatcanprovideinformation regardingthetimingofinfarction,ventricularfunction,theextentofinjury,residual viability,andtheextentofischemia.27 CatheterizationandAngiography AfterSTEMI,theseverityandextentoftheobstructivelesionsinthecoronaryvascular bedsupplyingresidualviablemyocardiumaffecttherisksofrecurrentinfarction, extensionofmyocardialdamage,andseriousventriculararrhythmias.Inpatients treatedwithpharmacologicalreperfusiontherapy,flowintheculpritarteryafter fibrinolysisisassociatedwithsubsequentmortality.TheTIMItrialgradingsystemis describedinFigure8.Theextentofmyocardialtissuelevelreperfusion,theultimate goalofreperfusion,maybecharacterizedbyangiographyandgradedusingtheTIMI

myocardialperfusiongrade.Abnormalitiesofmyocardialperfusioncorrelatewith mortalityriskevenafteradjustingforthepresenceofTIMIgrade3flow.

CalculationofSTSegmentResolution Figure5 ReproducedwithpermissionfromdeLemosJA,AntmanEM,GiuglianoRP,etal.STsegmentresolutionandinfarctrelatedarterypatencyand flowafterthrombolytictherapy.ThrombolysisinMyocardialInfarction(TIMI)14investigators.AmJCardiol200085:299304,andSchroderK, WegscheiderK,ZeymerU,TebbeU,SchroderR.ExtentofSTsegmentdeviationinasingleelectrocardiogramlead90minafterthrombolysisas apredictorofmediumtermmortalityinacutemyocardialinfarction.Lancet2001358:147986.

SuccessofReperfusionoftheInfarctRelatedArteryCategorizedbySTResolutionCategory Figure6 TIMI14=ThrombolysisinMyocardialInfarctionTrial,Phase14HIT4=HirudinforImprovementofThrombolysis. ReproducedwithpermissionfromdeLemosJA,BraunwaldE.STsegmentresolutionasatoolforassessingtheefficacyofreperfusiontherapy. JAmCollCardiol200138:128394.

MaximalSTElevationandMortalityAfterSTEMI Figure7 ReproducedwithpermissionfromSchroderK,WegscheiderK,ZeymerU,TebbeU,SchroderR.ExtentofSTsegmentdeviationinasingle electrocardiogramlead90minafterthrombolysisasapredictorofmediumtermmortalityinacutemyocardialinfarction.Lancet2001358:1479 86.

2004ACC/AHAGuidelinesfortheManagementofSTEMI:RecommendationsforUseofExerciseTesting Table4 ACC/AHA=AmericanCollegeofCardiology/AmericanHeartAssociationCHF=congestiveheartfailureECG=electrocardiogramSTEMI=ST segmentelevationmyocardialinfarction ReproducedwithpermissionfromAntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithST elevationmyocardialinfarction:AreportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines (CommitteetoRevisethe1999GuidelinesfortheManagementofPatientsWithAcuteMyocardialInfarction).JAmCollCardiol200444:E1E211.

DescriptionofTIMIFlowGrade Figure8

RiskStratificationAfterReperfusionTherapy (2of2)
RiskAssessmentforSuddenDeath AfterSTEMI,patientsareatgreatestriskforthedevelopmentofsignificantventricular arrhythmiasinthefirst2448hours,3 withpersistentriskofsuddencardiacdeath thatremainshighinrelativetermsoverthefirst30days,anddiminishesoverthe courseofthefirst1to2years,withalowersubsequentrate(Figure9).28The managementofpatientswithsustained,hemodynamicallycompromising arrhythmiasisdiscussedinthemoduleonVentricularArrhythmiasinStructural HeartDiseaseinChapter14. Avarietyofnoninvasiveapproacheshavebeenusedtoattempttoidentifypatientsat highriskforarrhythmicevents.Forthemostpart,thesestrategiesareaimedat detectingeitherexcessiveactivationoftheautonomicnervoussystem,oraltered impulseconductionthroughtheinfarctzone.Thus,inadditiontothedetectionof spontaneoushighgradeasymptomaticventricularectopy,candidatenoninvasive indicatorsofarrhythmiariskinclude:1)changesinventricularrepolarization,2) alterationsofautonomictone,and3)delayedanddisorderedmyocardial conduction. Thebeststudiedtechniquesare:1)ambulatoryECGrecordingsfordetectionof ventriculararrhythmias(Holtermonitoring),2)signalaveragedorhighresolution ECG,3)heartratevariability,4)baroreflexsensitivity,and5)Twavealternans.To date,neitherthesenoninvasiveapproachesnorinvasiveelectrophysiological testinghaveprovedtobesufficientlyusefulenoughtorecommendtheirroutineuse inpractice.29 InpatientECGtelemetryorambulatoryHoltermonitoring:Theprognostic significanceofventriculararrhythmiasafterSTEMIvariesaccordingtothe timing,duration,andhemodynamicconsequenceofthearrhythmia. Sustainedventriculartachycardia(VT)orventricularfibrillation(VF)withinthe first~48hoursafterMIhasbeenassociatedwithhigherinhospitalorearly mortality,butnotwithlongtermsurvivalinhospitalsurvivors.Sustained VT/VFinthesubacuteorchronicphaseafterSTEMIistypicallyassociated withLVdysfunction.However,becausenonsustainedVTbyitselfisnotan indicatorforintervention,routineHoltermonitoringforriskassessmentinthe earlypostMIperiodhasnotbeentiedtospecificchangesinclinical management. SignalaveragedECG29usescomputerizedaveragingofcomplexesto detectsmall(microvolt)signals(latepotentials)thatreflectslow (fragmented)conductionthroughmyocardiumdisruptedbyinfarction, inflammation,oredema.Theseabnormalitiesconstituteunderlying substratethatpredisposesthepatienttoreentrantVT,andhavevariably beenassociatedwithanincreasedriskforsuddendeathinpatientspostMI. Heartratevariability29isareflectionofthebeattobeatvariationincycle length,thatlargelyreflectssympathovagaltone.Lowheartratevariability, indicativeofdecreasedvagaltone,isapredictorofincreasedmortality, includingsuddendeath,afterMI. Baroreceptorsensitivity29alsoquantifiestheinfluenceofcardiac parasympathetictoneusingtheslopeofaregressionlinerelatingbeatto beatchangesinheartrateinresponsetoachangeinbloodpressure, typicallyaccomplishedbyadministeringphenylephrine.Reductionsin baroreflexsensitivityhavebeenassociatedwithanincreasedsusceptibility toarrhythmiceventsandsuddendeath. Twavealternans29isdefinedbymicrovoltalterationsofTwaveamplitude thatreflectheterogeneityinventricularrepolarization,andareassociatedwith ahigherriskofsuddendeath. Decelerationcapacityandheartrateturbulenceareinvestigationalmetrics thatreflectdiminisheddecelerationofheartrate,andcyclelength perturbationsofsinusrhythmafterisolatedprematureventricularcomplexes (heartrateturbulence).30Bothofthesephenomenareflectarelative
Figure9

decreaseinvagalactivity,andhavebeenassociatedwithahigherriskof cardiovasculardeath.Asanexample,studiedin7,054patientspostMI acrosssevenstudies,abnormalheartrateturbulencecorrelatedwitha consistent3foldhigherriskofdeath,withariskrelationshipthatwas similartothatforlowejectionfraction.30 Althougheachofthesetechniqueshaveevidencethattheyofferprognostic informationregardingsuddendeath,thetherapeuticimplicationsarenot established.29Inaddition,becauseofthelowpositivepredictivevalue(<30%)of thesetests,theirusefulnessislimitedwhenviewedinisolation.Giventhebenefits ofestablishedroutinetherapiessuchasaspirin,betablockers,andangiotensin convertingenzymeinhibitors,coupledwithconcernsabouttheefficacyandsafetyof antiarrhythmicdrugsandthecostofimplanteddefibrillators,thereisconsiderable uncertaintyaboutthetherapeuticimplicationsofanabnormalnoninvasivetestfor electricalinstabilityinanasymptomaticpatient. Themostvalidatedriskindicatorsuponwhichtodirectaninterventionforreduction insuddencardiacdeathareLVdysfunctionandtheoccurrenceof(late)sustained ventriculararrhythmias.Intheabsenceofareversiblecause,latesustainedVT/VF wouldbeanindicationforICDtherapyforsecondarypreventionofsuddencardiac death,aswouldpersistentLVdysfunction(>40days)afteranMI(seethemodule onDeviceTherapy:ICDsinChapter14).

RiskofSuddenDeathAfterMyocardialInfarctionAccordingtoLeftVentricularEjectionFraction(LVEF) Figure9 ReproducedwithpermissionfromSolomonSD,ZelenkofskeS,McMurrayJJ,etal.,onbehalfoftheValsartaninAcuteMyocardialInfarctionTrial (VALIANT)Investigators.Suddendeathinpatientswithmyocardialinfarctionandleftventriculardysfunction,heartfailure,orboth.NEnglJMed 2005352:25818.

DynamicRiskStratification
Riskassessmentisadynamicprocessthatincorporatesnewdataasitemerges (e.g.,peakbiomarkers,ventricularfunction,extentofresidualcoronarydisease, presenceofprovokableischemia),successfulprocedures,aswellasnewclinical events,suchasrecurrentischemia,mechanicalcomplications,orbleedingevents. Spontaneousrecurrentischemiceventsareassociatedwithincreasedmortality,31 asarebleedingevents.32Riskmodelsthatareupdatedbasedonclinicalevents thatoccurduringhospitalizationhavebeendevelopedforpatientsundergoing fibrinolytictherapy.Suchmodelsdemonstratethatbyday2afterSTEMI, complicationssuchasheartfailureorstrokedominatetheprognosisrelativetothe presentingcharacteristics(Figure10).

Figure10

DynamicRiskStratification:ChangingInfluence(%ofRisk)ExplainedbyClinicalRiskPredictorsAccordingtoDayAfterSTEMI Figure10 CHF=congestiveheartfailureECG=electrocardiogramSTEMI=STsegmentelevationmyocardialinfarctionTIMI=ThrombolysisinMyocardial Infarction ReproducedwithpermissionfromChangWC,KaulP,FuY,etal.,onbehalfoftheASSENT3Investigators.Forecastingmortality:dynamic assessmentofriskinSTsegmentelevationacutemyocardialinfarction.EurHeartJ200627:41926.

FutureDirectionsforRiskStratificationinSTEMI
Investigationofnewtoolsforriskstratificationandnewclinicalapplicationsofexistingtoolsisongoing.Particularareas ofinterestinclude: Developmentofnewbiomarkersofischemiathatcanprovideearlierdetectionofischemiaatthetimeof presentation. Evolutionofimprovedcardiacimagingtechniqestononinvasivelycharacterizeresidualischemicandviable myocardium,aswellasvulnerableatheroscleroticlesions. Applicationofcurrentandemergingtoolsforriskassessmenttoidentifypatientswhoshouldroutinelybe transferredfromnonPCItoPCIhospitalsafterpresentingwithSTEMI. Applicationofcurrentandemergingtoolsforriskassessmenttoidentifypatientswhoarecandidatesforlower levelsofinhospitalcare(e.g.,stepdownunitratherthanintensivecareunit)andearlyhospitaldischargeafter STEMI.

KeyPoints
TheinitialevaluationandmanagementofpatientswithpossibleSTEMIarefocusedon: Rapiddiagnosis, Expeditedassessmentofrisksforreperfusiontherapy, Timelyinitiationofareperfusionstrategy,and Continuousreassessmentoftheriskforandpresenceofcomplications. DiagnosisofSTEMIisdependentonrecognitionofSTsegmentelevation,alongwithclinicalsymptomsof ischemia.BecauseSTsegmentchangesprecedethereleaseofdetectableconcentrationsofbiomarkersof necrosisbyhours,treatment,includingreperfusiontherapy,shouldnotbedelayedawaitingbiomarkerresultsin patientswithdiagnosticSTelevation. Symptoms,signs,andbiomarkersofheartfailurearethestrongestpredictorsofmortalityinpatientspresenting withSTEMI.EarlyECGindicatorsofhighriskarethosethatreflectaparticularlylargeterritoryatrisk(e.g.,extreme magnitudeofSTelevation,posteriorextension,involvementoftheconductionsystem). Riskstratificationaftertheinitialreperfusionstrategyshouldincludeassessmentofthesuccessofreperfusion (epicardialandmicrovascular),detectionofheartfailureormechanicalcomplications,assessmentforrecurrent spontaneousoreasilyprovokableischemia,andevaluationofLVfunction. Thepresenceoffrequentventricularectopy,lowheartratevariability,reducedbaroreflexsensitivity,andTwave alternansareallassociatedwithahigherriskofsuddendeathafterSTEMI.However,todate,neitherthese noninvasiveapproachesnorinvasiveelectrophysiologicaltestinghaveprovedtobesufficientlyusefulenoughto recommendtheirroutineuseinpractice.LVdysfunctionandtheoccurrenceof(late)sustainedventricular arrhythmiasarethemostimportantindicatorsofahigherriskofsuddendeath,andarelinkedtospecific therapeuticrecommendations.

References
1. KrumholzHM,WangY,ChenJ,etal.ReductioninacutemyocardialinfarctionmortalityintheUnitedStates:risk standardizedmortalityratesfrom19952006.JAMA2009302:76773. 2. StenestrandU,LindbckJ,WallentinL,RIKSHIARegistry.Longtermoutcomeofprimarypercutaneouscoronary interventionvsprehospitalandinhospitalthrombolysisforpatientswithSTelevationmyocardialInfarction.JAMA 2006296:174956. 3. NewbyLK,HasselbladV,ArmstrongPW,etal.Timebasedriskassessmentaftermyocardialinfarction. Implicationsfortimingofdischargeandapplicationstomedicaldecisionmaking.EurHeartJ200324:1829. 4. StoneGW,WitzenbichlerB,GuagliumiG,etal.,onbehalfoftheHORIZONSAMITrialInvestigators.Bivalirudin duringprimaryPCIinacutemyocardialinfarction.NEnglJMed2008358:221830. 5. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarctionexecutivesummary:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(WritingCommitteetorevisethe1999guidelinesforthe managementofpatientswithacutemyocardialinfarction).JAmCollCardiol200444:671719. 6. KushnerFG,HandM,SmithSCJr.,etal.2009focusedupdates:ACC/AHAguidelinesforthemanagementof patientswithSTelevationmyocardialinfarction(updatingthe2004guidelineand2007focusedupdate)and ACC/AHA/SCAIguidelinesonpercutaneouscoronaryintervention(updatingthe2005guidelineand2007focused update):areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeartAssociationTaskForceon PracticeGuidelines.JAmCollCardiol200954:220541. 7. ThygesenK,AlpertJS,WhiteHD,onbehalfoftheJointESC/ACCF/AHA/WHFTaskForcefortheRedefinitionof MyocardialInfarction.Universaldefinitionofmyocardialinfarction.JAmCollCardiol200750:217395. 8. WagnerGS,MacfarlaneP,WellensH,etal.AHA/ACCF/HRSrecommendationsforthestandardizationand interpretationoftheelectrocardiogram:partVI:acuteischemia/infarction:ascientificstatementfromtheAmerican HeartAssociationElectrocardiographyandArrhythmiasCommittee,CouncilonClinicalCardiologytheAmerican CollegeofCardiologyFoundationandtheHeartRhythmSociety.EndorsedbytheInternationalSocietyfor ComputerizedElectrocardiology.JAmCollCardiol200953:100311. 9. SgarbossaEB,PinskiSL,BarbagelataA,etal.Electrocardiographicdiagnosisofevolvingacutemyocardial infarctioninthepresenceofleftbundlebranchblock.GUSTO1(GlobalUtilizationofStreptokinaseandTissue PlasminogenActivatorforOccludedCoronaryArteriesInvestigators.NEnglJMed1996334:4817. 10. JacobsAK,AntmanEM,FaxonDP,GregoryT,SolisP.DevelopmentofsystemsofcareforSTelevation myocardialinfarctionpatients:executivesummary.Circulation2007116:21730. 11. GrangerCB.AcceleratingSTsegmentelevationmyocardialinfarctioncare:emergencymedicalservicestake centerstage.JACCCardiovascInterv20092:3479. 12. MorrowDA.Cardiovascularriskpredictioninpatientswithstableandunstablecoronaryheartdisease.Circulation 2010121:268191. 13. MorrowDA,AntmanEM,GiuglianoRP,etal.AsimpleriskindexforrapidinitialtriageofpatientswithSTelevation myocardialinfarction:anInTIMEIIsubstudy.Lancet2001358:15715. 14. PetrinaM,GoodmanSG,EagleKA.The12leadelectrocardiogramasapredictivetoolofmortalityafteracute myocardialinfarction:currentstatusinaneraofrevascularizationandreperfusion.AmHeartJ2006152:118. 15. PfistererM.Rightventricularinvolvementinmyocardialinfarctionandcardiogenicshock.Lancet2003362:3924. 16. DonahoeSM,StewartGC,McCabeCH,etal.Diabetesandmortalityfollowingacutecoronarysyndromes.JAMA 2007298:76575. 17. MorrowDA,AntmanEM,CharlesworthA,etal.TIMIriskscoreforSTelevationmyocardialinfarction:aconvenient, bedside,clinicalscoreforriskassessmentatpresentation:anintravenousnPAfortreatmentofinfarcting myocardiumearlyIItrialsubstudy.Circulation2000102:20317. 18. EagleKA,LimMJ,DabbousOH,etal.Avalidatedpredictionmodelforallformsofacutecoronarysyndrome: estimatingtheriskof6monthpostdischargedeathinaninternationalregistry.JAMA2004291:272733. 19. OhmanEM,ArmstrongPW,WhiteHD,etal.,onbehalfoftheGUSTOIIIInvestigators.Riskstratificationwitha pointofcarecardiactroponinTtestinacutemyocardialinfarction.GlobalUseofStrategiesToOpenOccluded CoronaryArteries.AmJCardiol199984:12816. 20. PanteghiniM,CucciaC,BonettiG,GiubbiniR,PaganiF,BoniniE.SinglepointcardiactroponinTatcoronarycare unitdischargeaftermyocardialinfarctioncorrelateswithinfarctsizeandejectionfraction.ClinChem 200248:14326. 21. SciricaBM,MorrowDA,CannonCP,etal.,onbehalfoftheThrombolysisinMyocardialInfarction(TIMI)Study Group.ClinicalapplicationofCreactiveproteinacrossthespectrumofacutecoronarysyndromes.ClinChem 200753:18007. 22. MorrowDA,CannonCP,JesseRL,etal.NationalAcademyofClinicalBiochemistryLaboratoryMedicinePractice Guidelines:Clinicalcharacteristicsandutilizationofbiochemicalmarkersinacutecoronarysyndromes. Circulation2007115:e35675. 23. ZahnR,SchieleR,SchneiderS,etal.Primaryangioplastyversusintravenousthrombolysisinacutemyocardial infarction:canwedefinesubgroupsofpatientsbenefitingmostfromprimaryangioplasty?Resultsfromthe pooleddataoftheMaximalIndividualTherapyinAcuteMyocardialInfarctionRegistryandtheMyocardialInfarction

Registry.JAmCollCardiol200137:182735. 24. MauriF,MaggioniAP,FranzosiMG,etal.Asimpleelectrocardiographicpredictoroftheoutcomeofpatientswith acutemyocardialinfarctiontreatedwithathrombolyticagent.AGruppoItalianoperloStudiodellaSopravvivenza nell'InfartoMiocardico(GISSI2)DerivedAnalysis.JAmCollCardiol199424:6007. 25. van'tHofAW,LiemA,SuryapranataH,HoorntjeJC,deBoerMJ,ZijlstraF.Angiographicassessmentof myocardialreperfusioninpatientstreatedwithprimaryangioplastyforacutemyocardialinfarction:myocardial blushgrade.ZwolleMyocardialInfarctionStudyGroup.Circulation199897:23026. 26. ZeymerU,SchroderK,WegscheiderK,SengesJ,NeuhausKL,SchroderR.STresolutioninasingle electrocardiographiclead:asimpleandaccuratepredictorofcardiacmortalityinpatientswithfibrinolytictherapy foracuteSTelevationmyocardialinfarction.AmHeartJ2005149:917. 27. KimHW,FarzanehFarA,KimRJ.Cardiovascularmagneticresonanceinpatientswithmyocardialinfarction: currentandemergingapplications.JAmCollCardiol201055:116. 28. SolomonSD,ZelenkofskeS,McMurrayJJ,etal.Suddendeathinpatientswithmyocardialinfarctionandleft ventriculardysfunction,heartfailure,orboth.NEnglJMed2005352:25818. 29. GoldbergerJJ,CainME,HohnloserSH,etal.AmericanHeartAssociation/AmericanCollegeofCardiology Foundation/HeartRhythmSocietyScientificStatementonNoninvasiveRiskStratificationTechniquesfor IdentifyingPatientsatRiskforSuddenCardiacDeath.AscientificstatementfromtheAmericanHeartAssociation CouncilonClinicalCardiologyCommitteeonElectrocardiographyandArrhythmiasandCouncilonEpidemiology andPrevention.JAmCollCardiol200852:117999. 30. BauerA,MalikM,SchmidtG,etal.Heartrateturbulence:standardsofmeasurement,physiologicalinterpretation, andclinicaluse:InternationalSocietyforHolterandNoninvasiveElectrophysiologyConsensus.JAmCollCardiol 200852:135365. 31. GibsonCM,KarhaJ,MurphySA,etal.Earlyandlongtermclinicaloutcomesassociatedwithreinfarctionfollowing fibrinolyticadministrationintheThrombolysisinMyocardialInfarctiontrials.JAmCollCardiol200342:716. 32. PocockSJ,MehranR,ClaytonTC,etal.Prognosticmodelingofindividualpatientriskandmortalityimpactof ischemicandhemorrhagiccomplications:assessmentfromtheAcuteCatheterizationandUrgentIntervention TriageStrategytrial.Circulation2010121:4351.

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6.6:STEMI:ReperfusionTherapyforSTEMI
Author(s): HenryE.Kim,MD,MPH,FACC AkshayKhandelwal,MD,FACC,FSCAI

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. DefinethedifferentreperfusionstrategiesinSTsegmentelevationmyocardialinfarction(STEMI). 2. Demonstrateknowledgeoftherisksandbenefitsofthedifferentreperfusionstrategiesandemploytheminarational approachforSTEMIcare. 3. Identifythevariousadjunctivedevicesintheperformanceofprimarypercutaneouscoronaryintervention(PPCI). 4. Compareandcontrastthedifferentfibrinolyticagents. 5. Discussthemanagementofpatientsnotreceivingearlyreperfusiontherapy.

Introduction:TimeisMuscle
ImmediaterecognitionofSTEMIwithpromptrestorationofThrombolysisin MyocardialInfarctiongrade3(TIMI3)flowintheoccludedinfarctrelatedarteryis associatedwithimprovedshortandlongtermoutcomes.Infarctsizehasbeen showninanimalstobedirectlyproportionaltothedurationofcoronaryartery occlusion.Myocardialischemicinjuryoccursasawavefrontofcelldeaththatmay begininaslittleas20minutesaftercoronaryocclusionwithnearcompletionafter6 hours.1 Themaximthat"timeismuscle"hasbeenbornfromnumerousstudies investigatingthetimetoreperfusionanditsimpactonclinicaloutcomes.The effectivenessofreperfusiontherapyandtheextentofmyocardialsalvageforacute STEMIaredirectlyafunctionofischemictime,withthegreatestbenefitaccruingto thosewiththeshortesttimefromsymptomonsettorestorationofcoronaryblood flow(Figure1).Infarctsizeandleftventricular(LV)functionmeasuredbyejection fraction(EF)followingmyocardialinfarction(MI)aresignificantlyassociatedwith mortality.2,3

Figure1

HypotheticalConstructoftheRelationshipAmongtheDurationofSymptomsofAcuteMIBeforeReperfusionTherapy,MortalityReduction,and ExtentofMyocardialSalvage Figure1 Mortalityreductionasabenefitofreperfusiontherapyisgreatestinthefirst23hoursaftertheonsetofsymptomsofacuteMI,mostlikelya consequenceofmyocardialsalvage. MI=myocardialinfarction. ReproducedwithpermissionfromGershBJ,StoneGW,WhiteHD,HolmesDRJr.Pharmacologicalfacilitationofprimarypercutaneouscoronary interventionforacutemyocardialinfarction:istheslopeofthecurvetheshapeofthefuture?JAMA2005293:97986.

GeneralFactorsintheSelectionofReperfusionStrategy
PatientspresentingwithSTEMIwhoreceiveeitherthrombolytictherapyorPPCIhave betterclinicaloutcomescomparedwiththosewhodonotreceivesuchtherapies. Thedecisionregardingthemethodofreperfusionmustconsiderseveralimportant factors:1)thetimefromonsetofsymptoms,2)theriskleveloftheSTEMI,3)therisk ofbleeding,and4)theavailabilityandtimerequiredfortransportingthepatienttoa skilledPCIfacility. TimeFromOnsetofSymptoms Theefficacyofreperfusionandclinicalbenefitaredependentuponthetimefrom onsetofsymptomstotherapy.Theadministrationoffibrinolytictherapyearlyinthe courseofsymptomonsetsignificantlyreducesinfarctsizeanddecreasesmortality. However,theefficacyoffibrinolytictherapyinlysingthrombusandrestoringcoronary flowmarkedlydiminishesastimepasses. Patientspresentingwithin3hoursofsymptomonsetwithsuccessfulprompt restorationofmyocardialperfusioninacuteSTEMIderivethegreatestbenefitin termsofmyocardialsalvageanddecreasedmortality.Theabilityoffibrinolytic administrationtolysethrombusandrestorecoronaryarteryflowisgreatestwithin thefirst3hoursofsymptomonset.4 Incontrast,successfulrestorationofcoronary flowandmyocardialperfusionismuchlessdependentonthetimeofsymptom onsetinthesettingofPCI.However,theoverallclinicalbenefitderivedfromeither revascularizationstrategyisstronglycorrelatedwiththetimefromsymptomonsetto treatment.5 Accordingly,patientspresentingwithSTEMIwithin3hoursofsymptomonsetwho cannotreceivePPCIrevascularizationwithin90minutesshouldbeconsideredfor fibrinolytictherapy.IfthereisnosignificanttimedelaytoPCI(doortoballoon[DTB] minusdoortoneedletime<60minutes),PPCIispreferredgiventhesignificant advantageofthisstrategyinachievingcoronarypatencyandperfusionover fibrinolytictherapy.6 However,inpatientswhereaccesstoaPPCIfacilityisnot readilyavailableorthereareanticipatedsignificantdelaystoPCI(DTBminusdoor toneedle>60minutes),fibrinolytictherapyshouldbegiven. Inpatientspresenting312hoursaftersymptomonset,PPCIisthepreferred strategy.Therisk/benefitratiooffibrinolytictherapyfavorsPPCIgiventhereduced bleedingandstrokeriskandenhancedsuccessofrestoringcoronarybloodflow withthisstrategy.However,thegoalshouldremainaDTBtimeof<90minutes (Table1). Apatientpresenting>12hoursfromtheonsetofsymptomsisunlikelytoderive significantbenefitfromfibrinolytictherapywhilebeingsubjectedtotherisksofthat treatment.However,itisreasonabletoperformPPCIinpatientspresentingwiththe onsetofsymptomswithinthepast1224hoursifoneormoreofthefollowingare present:severecongestiveheartfailure(CHF),hemodynamicorelectricalinstability, orpersistentischemicsymptoms.Asymptomaticpatientspresenting>12hours fromtheonsetofsymptomsshouldnotundergoPPCIiftheyarehemodynamically andelectricallystable.7 HighRiskSTSegmentElevationMyocardialInfarction ThebenefitofPPCIoverafibrinolyticstrategyforacuteSTEMIisgreatestinthe patientpresentingwithhighriskfeatures.PatientspresentingwithacuteSTEMIand concomitanthighriskfeatures,includinghemodynamicorelectricalinstability, pulmonaryedema,orTIMIriskscore5,shouldpreferentiallyreceivePPCI,even withmodestlyincreaseddegreesofPCIrelateddelays. TheDANAMI2(DanishTrialinAcuteMyocardialInfarction2)randomized1,572 STEMIpatientstofrontloadedalteplaseorPPCIwithstenting.Themajorityofthese patientswereinitiallyevaluatedinnonPCIcentersandtransferredifrandomizedto PPCI.Thedurationofsymptomstopresentationhadtobe<12hours,andtransferto aPCIcenterhadtobedonewithin3hours.Thestudywasstoppedprematurely
Figure2

Table1

Table2

Figure3

becauseofanobservedsignificantreductionintheprimaryendpointsofdeath, reinfarction,andstrokeat30dayswithPPCI(8.0%vs.13.7%).Amortalitybenefit wasseenonlyinthesubgroupofTIMIriskscore5.8 Thismortalitybenefitinthe highTIMIriskscorecohortpersistedat3yearfollowup(25.3%vs.36.2%).9 TheTIMIriskscoreforSTEMIisavalidatedbedsideclinicaltoolusing10variables topredicttheshortandintermediatetermriskofmortalityinfibrinolyticeligible patientspresentingwithSTEMI.Scorescanrangefrom0to14,withriskof30day mortalityrangingfrom0.8%(TIMIriskscore0)to35.9%(TIMIriskscore>8)(Figure 2).10SeveralothervalidatedmodelsofSTEMIriskalsohavebeendeveloped,and allprovidecliniciansamethodtoassessmortalityriskinpatientspresentingwith STEMI.1113 HighriskSTEMIfeaturesinpatientswhoshouldbeconsideredfortransferassoon aspossibletoaPCIcapablefacilitywherePCIcanbeperformedeitherwhen neededoraspartofapharmacoinvasivestrategyarelistedinTable2. Considerationofapharmacoinvasivestrategyforhighriskpatientspresentingtoa nonPCIcapablefacilityisaddressedinaseparatesection. RiskofBleeding Theselectionofreperfusionstrategyalsomaybesignificantlyimpactedbythe patient'sriskofbleeding.Historyofintracranialhemorrhage(ICH),activebleeding, suspectedaorticdissection,knownstructuralcerebralvascularmalformation,and+ knownmalignantintracranialneoplasm(primaryormetastatic)areabsolute contraindicationstofibrinolytictherapy.Theriskofbleedingcomplicationsfrom fibrinolytictherapymustbeweighedagainstthepotentialbenefitofpharmacologic reperfusion.Whenbothreperfusionstrategiesareavailable,PCIshouldbe increasinglyfavoredastheriskofbleedingincreases. TimeforTransporttoaSkilledPercutaneousCoronaryInterventionFacility MostpatientswithacuteSTEMIpresenttohospitalswithoutonsitePPCIcapability. Evencenterswithinterventionalcardiologyfacilitiesmaynothavetheexperience, expertise,orabilitytoprovidearoundtheclockcoverageforPPCIrevascularizationof STEMI.The2009AmericanCollegeofCardiologyFoundation/AmericanHeart Association(ACC/AHA)STEMIandPCIfocusedupdatesemphasizedthe importanceofdevelopingSTEMIsystemsofcaretodevelopprocessesfor prehospitalidentificationofSTEMI,processesforpatientstobesentforPPCI,and destinationprotocolsforSTEMIreceivingcenters.14 ThedecisionbetweenfibrinolytictherapyorimmediatetransferforPPCIdependson patientspecificfactorsandthepresentingclinicalsituation,asdiscussedpreviously (Figure3).However,STEMIpatientsundergoingaPPCItreatmentstrategyshould achieveamedicalcontacttoballoontimeof<90minuteswhethertheypresenttoa PCIcapablefacilityornot.FibrinolyticeligiblepatientsshouldnotexperienceaPCI relateddelay(DTBminusdoortoneedle/fibrinolytic)of>60minutes.PCIrelated delaysof>60minutesresultedinnosurvivaladvantageofPPCIoverfibrinolytic therapy.15 PatientswhomaybenefitmostfromimmediatetransferforPPCIarethosewho presentwithhighriskfeatures,havehigherriskofbleedingfromfibrinolytictherapy, andpresentrelativelylatefromsymptomonset(>3hours).14Marginallylongerdelay timestoPPCImaybeacceptableforselectpatientsathighrisk,buteveryeffortmust bemadetoachieveaDTBtimeof<90minutes.Therapiesincorporatinga pharmacoinvasivestrategywithtransfertoaPCIcapablefacilityarediscussedina subsequentsection.

AssessmentofReperfusionOptionsforPatientsWithSTEMI Table1 DTB=doortoballoonPCI=percutaneouscoronaryinterventionPPCI=primarypercutaneouscoronaryinterventionICH=intracranial hemorrhageSTEMI=STsegmentelevationmyocardialinfarction. AdaptedwithpermissionfromAntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarctionexecutivesummary:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceonPractice Guidelines(WritingCommitteetorevisethe1999guidelinesforthemanagementofpatientswithacutemyocardialinfarction).JAmCollCardiol 200444:671719.

TIMIRiskScoreforSTEMIforPredicting30DayMortality Figure2 HTN=hypertensionLLBB=leftbundlebranchblockSTE=STsegmentelevationSTEMI=STsegmentelevatioinmyocardialinfarctioinTIMI= ThrombolysisinMyocardialInfarction. ReproducedwithpermissionfromMorrowDA,AntmanEM,CharlesworthA,etal.TIMIriskscoreforSTelevationmyocardialinfarction:A convenient,bedside,clinicalscoreforriskassessmentatpresentation:AnintravenousnPAfortreatmentofinfarctingmyocardiumearlyIItrial substudy.Circulation2000102:20317.

HighRiskFeaturesofSTEMIinPatientsWhoShouldBeConsideredforTransferasSoonasPossibletoaPCICapableFacility Table2 HR=heartrateLBBB=leftbundlebranchblockLVEF=leftventricularejectionfractionMI=myocardialinfarctionRV=rightventricularSBP= systolicbloodpressureSTE=STsegmentelevation. AdaptedwithpermissionfromDiMarioC,DudekD,PiscioneF,etal.Immediateangioplastyversusstandardtherapywithrescueangioplasty afterthrombolysisintheCombinedAbciximabREteplaseStentStudyinAcuteMyocardialInfarction(CARESSinAMI):anopen,prospective, randomised,multicentretrial.Lancet2008371:55968,andCantorWJ,FitchettD,BorgundvaagB,etal.Routineearlyangioplastyafter fibrinolysisforacutemyocardialinfarction.NEnglJMed2009360:270518.

TriageandTransferforPCI Figure3 EachcommunityandeachfacilityinthatcommunityshouldhaveanagreedonplanforhowSTEMIpatientsaretobetreatedthatincludeswhich hospitalsshouldreceiveSTEMIpatientsfromemergencymedicalservicesunitscapableofobtainingdiagnosticelectrocardiograms,management attheinitialreceivinghospital,andwrittencriteriaandagreementsforexpeditioustransferofpatientsfromnonPCIcapabletoPCIcapable facilities.Considerationshouldbegiventoinitiatingapreparatorypharmacologicalregimenassoonaspossibleinpreparationforandduring patienttransfertothecatheterizationlaboratory.Theoptimalregimenisnotyetestablished,althoughpublishedstudieshaveusedvarious combinationsofthefollowing:anticoagulant,oralantiplateletagents,intravenousantiplatelet. CABG=coronaryarterybypassgraftLOE=levelofevidencePCI=percutaneouscoronaryinterventionSTEMI=STsegmentelevation myocardialinfarction. *TimesinceonsetofsymptomsriskofSTEMIrisksassociatedwithfibrinolytictherapytimerequiredfortransporttoaskilledPCIlaboratory. ReproducedwithpermissionfromKushnerFG,HandM,SmithSC,Jr.,etal.2009focusedupdates:ACC/AHAguidelinesforthemanagementof patientswithSTelevationmyocardialinfarction(updatingthe2004guidelineand2007focusedupdate)andACC/AHA/SCAIguidelineson percutaneouscoronaryintervention(updatingthe2005guidelineand2007focusedupdate)areportoftheAmericanCollegeofCardiology Foundation/AmericanHeartAssociationTaskForceonPracticeGuidelines.JAmCollCardiol200954:220541.

PrimaryPercutaneousCoronaryIntervention
MultiplerandomizedtrialshavedemonstratedthatPPCIisthepreferred revascularizationstrategyinpatientspresentingwithacuteSTEMIwhenperformed expeditiouslyinhighvolumecentersbyexperiencedoperators.1619Comparedwith fibrinolysis,PPCIissuperiorinrestoringTIMI3flowintheinfarctrelatedartery (>90%vs.6070%withfibrinolytictherapy),withsignificantlyimprovedmortalityand lowerratesofICHandreinfarction.6,20Inaddition,upto2030%ofpatientsmaynot becandidatesforfibrinolytictherapyforacuteSTEMI,makingPPCIthestrategyof choice.21 Ametaanalysisof23randomizedtrialscomparingtheshortandlongterm outcomesofpatientsreceivingPPCIversusfibrinolytictherapiesrevealedthatPCI wassuperiorinreducingshorttermdeath,nonfatalreinfarction,stroke,andthe combinedendpointofdeath,nonfatalreinfarction,andstroke(Figure4).6 The numberneededtotreatwithPPCIinsteadoffibrinolytictherapytosaveonelifeand preventtwolifethreateningcomplications,includingstrokeandreinfarction,was50. However,thebenefitofPPCIdiminishesasthetimefrompresentationtoPCI increases.DatafromtheNationalRegistryofMyocardialInfarctionshowedastrong relationshipbetweenDTBtimeandinhospitalmortalityamong29,222patientswho underwentPCIwithin6hoursofpresentation.22AsDTBtimeincreasedfrom<90 minutesto91120minutes,121150minutes,and>150minutes,inhospital mortalityincreasedfrom3.0%to4.2%,5.7%,and7.4%,respectively(Figure5). Unfortunately,aspreviouslynoted,mostacuteSTEMIpatientspresentinitiallyto nonPCIcapablefacilities.OfthosepatientstransferredforPPCI,only4%ofSTEMI patientsfromthatsameregistryachievedDTBtimesof<90minutes.23 ArecentstudyfromtheACTIONRegistryGWTGanalyzed14,821patientswho initiallypresentedtoanonPCIcapablefacilityandweretransferredtoanother hospitalforPPCI.Only11%ofthesepatientshaddoorintodoorout(DIDO)timesof <30minutes.PatientswithDIDO<30minutesweremuchmorelikelytoreceivean overallDTB<90minutescomparedwithpatientswithDIDO>30minutes(60%vs. 13%,p<0.001).Observedinhospitalmortalitywasmuchhigherinthepatientswith DIDO>30minutescomparedwithpatientswithDIDO<30minutes(5.9%vs.2.7%,p <0.001,oddsratio[OR]1.56).24 ThesefindingshighlightthegreatimportanceofachievingrapidPCI revascularizationandtheneedtocriticallyandrealisticallyevaluatetheabilityofa giventransferandcatheterizationlabactivationprocesstoachieveDTBtimesof<90 minutesbeforeselectingaparticularreperfusionstrategy.

Figure4

Figure5

ShortTermandLongTermClinicalOutcomesinIndividualsTreatedWithPrimaryPTCAorThrombolyticTherapy Figure4 PTCA=percutaneoustransluminalcoronaryangioplasty.*Datanotavailable. ReproducedwithpermissionfromKeeleyEC,BouraJA,GrinesCL.Primaryangioplastyversusintravenousthrombolytictherapyforacute myocardialinfarction:aquantitativereviewof23randomisedtrials.Lancet2003361:1320.

InHospitalMortalityandDoortoBalloonTime Figure5 p<0.001fortrend ReproducedwithpermissionfromMcNamaraRL,WangY,HerrinJ,etal.EffectofdoortoballoontimeonmortalityinpatientswithSTsegment elevationmyocardialinfarction.JAmCollCardiol200647:21806.

BleedingComplicationsinPrimaryPercutaneousCoronaryInterventionandRelationshipto Outcomes
Thedevelopmentanduseofnewantiplateletandantithrombotictherapiesinconcertwithinvasivestrategiesinthe managementofacutecoronarysyndromeshavegreatlyimprovedoutcomesinthisgroupofpatients.However,the combinationofthesenewtherapieswithPCIalsocomeswithincreasedriskofbleeding.Theincidenceofbleedingin thesepatientshasbeenreportedtobeashighas31%,butmorerecentstudieshavebeeninthe110%range.2528 Bleedingisconsistentlyassociatedwithshortandlongtermadverseoutcomes,includingdeath,MI,stroke,andstent thrombosis.2932 Assuch,strategiesassociatedwithreducedbleedingriskappeartobeassociatedwithreducedmortality.Forexample, theHORIZONSAMI(HarmonizingOutcomesWithRevascularizationandStentsinAcuteMyocardialInfarction)trial randomlyassigned3,602patientswithSTEMIpresentingwithin12hoursofsymptomonsetundergoingPPCItoeither heparinwithaplannedglycoprotein(GP)IIb/IIIainhibitororbivalirudinwithprovisionalGPIIb/IIIainhibitor.Patients assignedtothebivalirudinstrategyhadlower30dayadverseclinicaleventscomparedwiththoseassignedtothe heparinplusGPIIb/IIIainhibitorstrategy(9.2%vs.12.1%relativerisk[RR],0.7695%confidenceinterval[CI],0.630.92 p=0.005)thiswasattributableprimarilytoasignificantlylowerrateofmajorbleeding(4.9%vs.8.3%RR,0.6095%CI, 0.460.77p<0.001).Althoughtherewasincreasedstentthrombosisinthefirst24hoursinthebivalirudingroup,no differencewasseenat30days.Patientsassignedtobivalirudinalsohadsignificantlylower30daymortalityfromcardiac causes(1.8%vs.2.9%RR,0.6295%CI,0.400.95p=0.03)anddeathfromallcauses(2.1%vs.3.1%RR,0.6695% CI,0.441.00p=0.047).33Followupdatafromthisstudywererecentlyreportedandconfirmeddurabilityofthese findingsoutto3years.34 Similarly,theuseofthetransradialratherthanthetransfemoralapproachforcoronaryangiographyandPCImaylargely mitigatetheriskofperiproceduralbleedingandimproveclinicaloutcomes.35TheRIVAL(RadialVersusFemoralAccess forCoronaryIntervention)trialrandomlyassigned7,021patientswithacutecoronarysyndrometocoronaryangiography eitherbyradialorfemoralaccess.IntheprespecifiedSTEMIcohort,patientsrandomizedtoradialaccesshada significantlylowerprimarycompositeendpointofdeath,MI,stroke,ornoncoronaryarterybypassgraftrelatedmajor bleedingat30days(3.1%vs.5.2%hazardratio[HR],0.60CI,0.380.94p=0.026).Thesecondaryendpointsofdeath (1.3%vs.3.2%HR,0.39CI,0.200.76p=0.006)andmajorvascularcomplications(1.3%vs.3.5%HR,0.36CI,0.19 0.70p=0.002)alsoweresignificantlydecreasedinSTEMIpatientsrandomizedtoradialaccess.36 Whilebleedingmaybeamarkerformoresystemicdisease,everyeffortshouldbemadetoconsidertheriskofbleeding inthetherapeuticstrategyofpatientspresentingwithMI.37

AdjunctiveDevicesforPercutaneousCoronaryIntervention
DistalEmbolicProtection TheinfarctrelatedarteryinSTEMIoftenmaycontainalargethrombusburdencomplicatingtheperformanceofPPCIwith distalembolizationoffragmentedthrombus,plaqueandlipidcore,andplateletaggregate,resultinginslowornoreflow phenomenon.EventherestorationofTIMI3epicardialbloodflowdoesnotnecessarilyequatewithnormalmyocardial perfusionatthemicrovascularlevel.Patientswithimpairedmicrocirculatoryperfusionhaveworsemyocardialsalvage, lowerLVfunction,andconsequentlyhighershortandlongtermmortality.38 Therewasconsiderableinterestinutilizingdevicesthatpreventdistalembolization.Thesedevicesconsistofeithera distalfilterthat"catches"debrisoraballoonthatoccludesthearterydistaltotherupturedplaqueandacatheterthat aspiratesdebris.However,useofthevariousdistalembolicprotectiondevicesdesignedtopreventdistalembolization hasbeendisappointinginthesettingofPPCIforSTEMI,showingnosignificantdifferenceintheratesofangiographic endpoints,infarctsize,orsurvival.39 Basedontheresultsoftheserandomizedtrialsandthemetaanalysis,theroutineuseofdistalprotectioninthesetting ofSTEMIisnotfelttobebeneficialandisnotrecommended. Aspiration/Thrombectomy Severalmetaanalyseshavebeenperformedandsupporttheuseofaspirationthrombectomyinthesettingofacute STEMI.3942Accordingly,theACC/AHAguidelineshavebeenupdatedtoincorporatethesedata.The2009ACC/AHA FocusedUpdates:STEMIandPCIGuidelineshavegivenaspirationthrombectomyaClassIIa,LevelofEvidenceB, indicationinpatientsundergoingPPCIforSTEMI,indicatingthat"itisreasonabletouseaspirationthrombectomyin patientsundergoingPPCI."14WhetheraspirationthrombectomyisbeneficialinallpatientswithSTEMIisunresolvedat thistime.Certainlyitisreasonabletoconsiderthatastrategyofmanualaspirationmaybemostbeneficialinpatients withshortischemictimesandlargethrombusburden. TrialsofmechanicalthrombectomyinSTEMIhavebeendisappointingtodateandhavenotshownbenefitinclinical outcomes.Thelargestmechanicalthrombectomytrial,AiMI(AngioJetRheolyticThrombectomyinPatientsUndergoing PrimaryAngioplastyforAcuteMyocardialInfarction),randomized480patientsandutilizedtheAngioJetrheolytic thrombectomydevice.Patientsreceivingmechanicalthrombectomyhadlargerinfarctsizewithhigher30daymajor adversecardiacevents.43 Stents Previousstudieshaveshownthattheuseofstentscomparedwithballoonangioplastydoesnotdecreasemortality however,stentshavebeenshowntosignificantlydecreasetheneedfortargetvesselrevascularization(TVR)and possiblyrecurrentMI.44,45TheCADILLAC(ControlledAbciximabandDeviceInvestigationtoLowerLateAngioplasty Complications)trialstudiedtheuseofabciximabandstentsina2x2factorialdesignin2,082patientswithSTEMI.Six monthangiographicrestenosiswas41%intheangioplastyalonegroupand22%inthestentgroup(p<0.001).TVR wassignificantlylowerinthegroupsreceivingstentimplantation(p<0.001).46 TheSTENTPAMI(StentPrimaryAngioplastyinMI)trialwasaprospectivemulticentertrialwith900STEMIpatients randomlyassignedtoballoonangioplastyorheparincoatedstentimplantation.SixmonthischemiadrivenTVRwas significantlylowerinthestentversusangioplastygroup(7.7%vs.17.0%,p<0.01).Angiographicrestenosiswas significantlylowerinthestentgroupversustheangioplastygroup(20.3%vs.33.5%,p<0.001).47

StentSelection:BareMetalVersusDrugElutingStents
Drugelutingstents(DES)havebeenshowntodecreasetheincidenceof angiographicandclinicalrestenosisandtheneedforTVR.However,issueswith respecttostentthrombosisandtheneedforprolongedthienopyridinetherapyhave forcedoperatorstobecircumspectandselectiveinitsuse.Additionally,data regardingthesafetyandefficacyofDESspecificallyinSTEMIhavebeenlimitedin sizeandfollowup. TheHORIZONSAMItrialrandomlyassigned,ina3:1ratio,3,006patients presentingwithSTEMItoeitherapaclitaxelDES(2,257patients)oranotherwise identicalbaremetalstent(BMS)(749patients).Therewasnodifferenceinthe12 monthcompositesafetyendpointofdeath,reinfarction,stroke,orstentthrombosis betweenthetwogroups(8.1%vs.8.0%).TheDESarmhadsignificantlylower ischemiadrivenTVR(5.8%vs.8.7%HR,0.6595%CI,0.480.89p<0.006)at12 monthfollowup,drivenpredominantlybysignificantlylowertargetlesion revascularization.48 Ametaanalysisof13randomizedtrials(n=7,352patients)comparingDESversus BMSinSTEMIovera2yearfollowupperiodwasconsistentwiththeHORIZONSAMI trialandshowedbenefitwithDESinsignificantlydecreasingTVR(RR,0.4495%CI, 0.350.55).Therewasnoincreaseindeath,MI,orstentthrombosis.Eighteen registries(n=26,521patients)alsowereanalyzedinthissamepaperandshowed significantlydecreasedTVRandnodifferenceindeath,MI,orstentthrombosisover a2yearfollowup(Figures6a,b).49 The2009ACC/AHAFocusedUpdates:STEMIandPCIGuidelinesaddressedthe issueoftheuseofDESinthesettingofSTEMIandstatethatitisreasonabletouse aDESasanalternativetoaBMSforPPCIinSTEMI.14Itisveryimportantthatthe decisiontoimplantaDESbemadewithconsiderationofthepatient'sabilityto complywiththerequirementforextendedthienopyridineantiplatelettherapyfor1 year,includingtheriskofbleeding,possibilityofsurgeryinthenearfuture,andany financialconstraintsonmedicationadherence.

Figure6a

Figure6b

OutcomesinRandomizedTrialsofDESvs.BMSinSTEMI Figure6a Sizeofdatamarkersindicatestheweightofthestudy. BMS=baremetalstentCI=confidenceintervalDES=drugelutingstentTVR=targetvesselrevascularization. ReproducedwithpermissionfromBrarSS,LeonMB,StoneGW,etal.Useofdrugelutingstentsinacutemyocardialinfarction:asystematic reviewandmetaanalysis.JAmCollCardiol200953:167789.

OutcomesinRandomizedTrialsofDESvs.BMSinSTEMI Figure6b Sizeofdatamarkersindicatestheweightofthestudy. BMS=baremetalstentCI=confidenceintervalDES=drugelutingstentTVR=targetvesselrevascularization. ReproducedwithpermissionfromBrarSS,LeonMB,StoneGW,etal.Useofdrugelutingstentsinacutemyocardialinfarction:asystematic reviewandmetaanalysis.JAmCollCardiol200953:167789.

PrimaryPercutaneousCoronaryInterventionWithoutOnSiteCardiacSurgery
ThebenefitoftimelyandmorereliablereperfusionwithPPCIatfacilitieswithoutonsitecardiacsurgerymustbeweighed againsttheriskofPCIcomplicationwithoutcardiacsurgerysupportandthesmallriskofdelayinpatienttransporttoa PCIcapablefacilitywithcardiacsurgerybackup. TheCPORT(AtlanticCardiovascularPatientOutcomesResearchTeamTrial)studywasaprospectiverandomizedtrial comparingastrategyofPPCIinhospitalswithoutonsitecardiacsurgerybackupversusfibrinolytictherapy.A6month followuprevealedasignificantlylowerrateofthecompositeendpointofdeath,recurrentMI,andstrokeinthePPCIgroup (12.4%vs.19.9%,p=0.03).50 The2004ACC/AHAGuidelinesfortheManagementofPatientsWithSTEMImandatethefollowingaspartofitsClassIIb, LevelofEvidenceBrecommendation7 : Aprovenplanshouldbeinplaceforrapidtransporttoafacilitywithcardiacsurgery. Operatorsshouldperform75PCIproceduresannually. Hospitalsshouldperform36PPCIproceduresannually. DTBtimeshouldbe<90minutes.

FibrinolyticTherapy
Perspective TwodevelopmentsledtotheconceptoffibrinolysisforthetreatmentofSTEMI.The firstwasthediscoverythatbetahemolyticstreptococcipossessedpowerful fibrinolyticcapabilities,aconceptthatwassuccessfullytestedinadulthumans.51 Thesecondwastherealizationthatoccludedcoronaryarterieswereresponsiblefor transmuralinfarctions.52Theseadvancesmeantthatanacutelyoccludedcoronary artery,deprivingthesubtendedmyocardiumofoxygenandnutrients,couldbe reopenedorreperfusedpharmacologically,therebysavingthemyocardiumfrom furthernecrosisandreducingcardiovascularmorbidityandmortalityifperformed promptly. Mechanism Plaqueruptureorerosionleadstoactivationandaggregationofplateletsaspartof aninitialorprimaryhemostasis.Tissuefactorreleasedsimultaneouslyactivatesthe extrinsicpathway,andactivatedfactorXconvertsprothrombinintothrombin. Thrombinisresponsibleforconvertingfibrinogenintofibrin,activatingfactorXIII (whichhelpscrosslinkexistingfibrin),andfurtheractivatingplatelets.Naturally occurringplasminogenisconvertedviavariousactivators,includingtissuetype plasminogenactivator(TPA),toplasmin,whichdegradescrosslinkedfibrinand leadstoclotlysis.Thislatterstepofanaturallyoccurringprocessisamplified significantlybyexogenouslyadministeredfibrinolyticagentsandhelpstoexplainits benefitsaswellasharm.Plasminactsnotonlyonclotboundfibrinbutalsoon fibrinogen,whichcanleadtoastateofsystemiclysisandseriousbleeding. Plasminogenactivatorinhibitor1(PAI1)inhibitstheconversionofplasminogento plasmin(Figure7). Streptokinase PharmacologicProfile Streptokinase(SK)isafirstgenerationfibrinolyticthatisderivedfrombetahemolytic streptococcus.Itisuniqueamongthefibrinolyticagentsinthatitdoesnotpossess anyenzymaticactivityrather,itbindswithplasminogen.TheSKplasminogen complexesconverttoSKplasmincomplexes,whichactasplasmin.Itisgivenasan infusionof1.5millionunits(U)over3060minutes.Itisnotfibrinspecific,which meansitalsodegradesfibrinogenandthuscaninduceasystemiclysisstate. SKcancauseallergicmanifestationssuchasfever,rash,serumsickness, hypotension,andbronchospasm.Becauseithasantigenicproperties,priorSK administrationisacontraindicationforrepeatuse.Anistreplase,oranisoylated plasminogenstreptokinaseactivatorcomplex(APSAC),isanotherfirstgeneration fibrinolyticthatwhileavailableasasinglebolusisasexpensiveasTPAwithout beingassafeandthushaslargelyfallenoutoffavor. PivotalTrials SKwasthefirstfibrinolyticstudiedinalarge,multicenter,randomizedclinicaltrial, theGISSI(GruppoItalianoperloStudiodellaSopravvivenzanell'InfartoMiocardico) study.53Morethan11,000patientswhopresentedwithSTEMIwithin12hourswere randomizedtoSKorplacebo.Therewasasignificantreductionin30day(10.7%vs. 13.0%)and1yearmortality(17.2vs.19.0%)infavorofSK.TheISIS2(International StudyofInfarctSurvival2)randomized17,187patientstoSK,aspirin,both,orneither anddemonstratedthatwhileaspirinorSKsignificantlyreduced5weekmortality whencomparedwithplacebo(10.7%and10.4%respectively,vs.13.2%forplacebo, p<0.001forbothinteractions),mortalitywasfurtherreducedbythecombinationof boththerapies(8.0%,p<0.001)(Figure8).54 Alteplase PharmacologicProfile
Figure11 Figure7

Figure8

Figure9

Figure10

Table3

Alteplase(recombinantTPA)isaserineproteaseorenzymethatisnaturally occurringbutmanufacturedusingrecombinantDNAtechnology.Itisasinglechain thatcontainsa"finger"regionandtwo"kringle"loops(Figure9)thesehelpincrease thespecificityforfibrin,andalthoughitisactivewithout,fibrinincreasesitspotency severalfold.Itisadministeredasabolusandintravenous(IV)infusionover3hours, althoughan"accelerated"or"frontloaded"90minuteinfusionwasdevelopedthat ledtoincreasedarterypatencyrates(Figure10). PivotalTrials Morethan41,000patientswereenrolledinGUSTO1(TheGUSTOVRandomised Trial),whichcomparedfourtreatmentregimens:SKwithsubcutaneousheparin,SK withIVheparin,frontloadedTPAwithIVheparin,andacombinationofTPAandSK withIVheparin.55Forthepurposesofthisdiscussion,weconcentrateoncomparing theTPAwithIVheparinandSKwithIVheparinarms.Therewasasignificant reductionin30daymortalitywithTPAasopposedtoSK(6.3%vs.7.4%,p=0.005). AlthoughtherewasaslightincreaseinintracerebralhemorrhagewithTPA(0.5%vs. 0.7%,p=0.03),therewas"netclinicalbenefit"(deathorsignificantstroke)favoring TPA(7.9%vs.6.9%,p=0.006)(Figure11).Inanangiographicsubstudy,greater infarctarterypatencywasnotedwithTPA(81%vs.54%,p<0.001).56Similar outcomeswereseeninTIMI4.Becauseofthesesuperiorresultsofincreasedfibrin specificityandlackofantigenicity,TPAquicklybecameapreferredagentforthose whocouldaffordthehighercost. Reteplase PharmacologicProfile Reteplase(recombinantplasminogenactivator[rPA])issimilartoTPA,butwithout thefingerregionandfirstkringle.Thisreducesthefibrinspecificity,andthusthe potency,butincreasesthehalflife,allowingrPAtobeadministeredastwoboluses of10U,30minutesapart. PivotalTrials TheRAPIDI(RecombinantPlasminogenActivatorAngiographicPhaseII InternationalDosefindingStudy)andRAPIDII(ReteplasevsAlteplasePatency InvestigationDuringMyocardialInfarction)trialsdemonstratedaslightadvantagein termsofarterypatencyofrPAoverTPA.57,58TheGUSTO3(GlobalUtilizationof StreptokinaseandTPAforOccludedArteriesIII)study,however,showedthatthere wasnodifferenceinstrokeratesor30daymortalitybetweenthetwo.59Whilethere isnoclinicalbenefitofrPAoverTPA,itseaseofadministrationremainsattractive. Tenecteplase PharmacologicProfile Tenecteplase(TNKrecombinantTPA[TNKTPA])issimilartoTPA,buthas substitutionsatthreelocations,theaminoacidsthreonine(T),asparagine(N),and lysine(K),whichgiverisetoitsname.Thisimprovesthefibrinspecificityaswellas resistancetoPAI1.Perhapsmoreimportantly,itallowsTNKTPAtobe administeredasasinglebolus.Itisgivenas0.5mg/kgIVinincrementsof5mg, from30mguptoamaximumof50mg. PivotalStudies TheASSENT2(AssessmentoftheSafetyandEfficacyofaNewThrombolytic:TNK TPA)trialcomparedTNKTPAwithacceleratedTPAinastudyofalmost17,000 patients.60TNKTPAwasfoundtobeequivalenttoTPAintermsofoverallmortality (6.2%vs.6.2%),intracerebralhemorrhage(0.9%vs.0.9%),andstroke(1.8%vs. 1.7%)(allp=NS).Therewasasuggestionofincreasedarterypatencyinpatients whopresented4hoursaftersymptomonset,andincreasedsafety,becausethere wasreducedmajorbleeding,transfusions,andintracerebralhemorrhageinhigh riskpatients. AcomparisonoffibrinolyticagentsissummarizedinTable3.

CoagulationCascade Figure7 AT=antithrombinFDP=FibrinDegradationproductsPA=plasminogenactivatorPC/PS=proteinC/proteinSPI=plasminPT=prothrombin TFPI=tissuefactorpathwayinhibitor. ReproducedwithpermissionfromSchaferAI:theprimaryandsecondaryhypercoagulablestates,originallyinSchaferAI[ed]Molecular MechanismsofHypercoagulableSates.AustinTX.LandesBioscience1997p148.AcccessfromBraunwald'sHeartdisease8thedition,p 2053.

ResultsFromISIS2 Figure8 ResultsfromISIS2suggestingnotonlywereaspirinandstreptokinasesimilarwithrespecttomortalityinSTEMIbutthattogethertheywere significantlybetter. ReproducedwithpermissionfromRandomisedtrialofintravenousstreptokinase,oralaspirin,both,orneitheramong17,187casesofsuspected acutemyocardialinfarction:ISIS2.ISIS2(SecondInternationalStudyofInfarctSurvival)CollaborativeGroup.Lancet19882:34960.

MolecularStructureofAltepase,Reteplase,andTNK,DemonstratingtheKringleLoops Figure9 EGF=epidermalgrowthfactorSK=streptokinaserPA=recombinantplasminogenactivatorTNK=tenecteplaseTPA=tissuetype plasminogenactivator ModifiedwithpermissionfromBrenerSJ,TopolEJ:Thirdgenerationthrombolyticagentsforacutemyocardialinfarction.InTopolEJ[ed]Acute CoronarySyndromes.NewYork,MarcelDekker1998p169.AccessfromBraunwaldsHeartDisease8thEdition,p1246.

ThirtyDayMortalityintheFourTreatmentGroups Figure10 ThegroupreceivingacceleratedtreatmentwithTPAhadlowermortalitythanthetwostreptokinasegroups(p=0.001)andthaneachindividual treatmentgroup:streptokinaseandSCheparin(p=0.009),streptokinaseandIVheparin(p=0.003),andTPAandstreptokinasecombinedwith IVheparin(p=0.04). IV=intravenousSC=subcutaneousTPA=tissuetypeplasminogenactivator ReproducedwithpermissionfromAninternationalrandomizedtrialcomparingfourthrombolyticstrategiesforacutemyocardialinfarction.The GUSTOinvestigators.NEnglJMed1993329:67382.

KaplanMeierCurvesforthePrimaryEndpointat30Days Figure11 Theprimaryendpointwasthecompositeofdeath,reinfarction,worseningheartfailure,orcardiogenicshockwithin30days. PCI=percutaneouscoronaryintervention. ReproducedwithpermissionfromCantorWJ,FitchettD,BorgundvaagB,etal.Routineearlyangioplastyafterfibrinolysisforacutemyocardial infarction.NEnglJMed2009360:270518.

SummaryComparisonofFibrinolyticAgents Table3 ICH=intracranialhemorrhageIV=intravenousrPA=recombinantplasminogenactivatorSK=streptokinaseTNK=tenecteplaseTPA=tissue typeplasminogenactivatorU=unit.

CandidatesforFibrinolysis
Decidingbetweenfibrinolysis(pharmacologic)andPCI(mechanical)reperfusion strategiescanbeasourceofsomecommongroundanddebate.Thisisaddressed furtherunderpharmacoinvasivestrategies.However,importantabsoluteandrelative contraindicationsexistregardingfibrinolyticadministration,assummarizedinTable 4.7 Ingeneral,fibrinolytictherapyisindicatedwhenthereis: STsegmentelevation(STE)0.1mVintwocontiguousleads,evidenceof posteriorinfarction,orevidenceofnewonsetleftbundlebranchblock(LBBB) inthesettingofanacutecoronarysyndrome. Timefromonsetofchestpainis<12hours(betterwithin6hours,bestwithin 3hours). Absenceofcontraindications,aslistedinTable4.

Table4

AbsoluteandRelativeContraindicationsforFibrinolyticAdministration Table4 APSAC=anisoylatedplasminogenstreptokinaseactivatorcomplexCPR=cardiopulmonaryresuscitationDBP=diastolicbloodpressureSBP= systolicbloodpressureSK=streptokinase.

RisksofFibrinolysis:IntracranialHemorrhage
OneofthemajorlimitingdrawbackstotheuseoffibrinolytictreatmentistheriskofICH.Althoughthisonlyoccursata rateof0.50.7%inthemajorfibrinolytictrials,itisadevastatingcomplicationassociatedwithsignificantpermanent disabilities.Whenclinicallysuspected,allanticoagulantandantiplatelettherapiesmustbestopped,emergency computedtomographyscanningofthebrainshouldbearranged,andappropriatereversalagentsshouldbe administered(e.g.,cryoprecipitateforfibrinolytics,platelettransfusionforanyantiplatelettherapygiven,protaminesulfate forheparin,andfreshfrozenplasma).7 Emergentneurosurgicalconsultationisalsonecessaryforsuspectedorproven ICH.TheriskforICHincreaseswithageandincreasessignificantlywith>75years.Importantly,agealoneisnota contraindicationtofibrinolyticsasreperfusiontherapy.

PrehospitalFibrinolysis
Becausereperfusiontherapyistimedependent,prehospitalfibrinolysisisapotentiallyattractivemanagementstrategy. Severalstudieshaveshownthatthemediantimefromsymptomonsettofibrinolyticadministrationissignificantly reduced.Ametaanalysisofthesestudiesdemonstratedthatthistranslatedintoimprovedsurvival.61 TheCAPTIM(ComparisonofAngioplastyandPrehospitalThrombolysisinAcuteMyocardialInfarction)studycompared prehospitalfibrinolysisagainstprimaryangioplasty,withtheideathatearlyadministrationoffibrinolyticsbytrained medicalpersonnelbeforehospitalpresentationmightsignificantlyshortenthetimetoreperfusionandimproveclinical outcomes.62Althoughtherewasareductioninthemediantimeofsymptomonsettotreatmentofabout35%,thisdidnot translateintoimprovedcombinedprimaryendpointofdeath,nonfatalMI,andnonfatalstrokeat30days.These differencespersistedthrougha5yearfollowup.63Interestingly,therewasatrendtowardbetteroutcomesiffibrinolytics wereadministeredwithin2hoursofsymptomonset.RegistrydatafromFrancewhereprehospitalthrombolysisis commonsuggestamortalitybenefitfavoringthisstrategy.64Thisstrategymaybepreferredifemergencymedicalservice iscapableofrecognizingSTEMIandadministeringfibrinolytictherapy.65

RescuePercutaneousCoronaryIntervention
Ifthereis<50%resolutionofSTE90minutesafterfibrinolyticadministration,apatientisdeemedtohave electrocardiographicallyfailedfibrinolytictherapy.OptionsincludereferralforPCI,readministrationoffibrinolytics,or continuedmedicaltherapyandobservation.TheREACT(RapidEarlyActionforCoronaryTreatment)studyaswellasa metaanalysisofeightrescuePCIstudiesrevealedthatrescuePCIinmoderatetohighriskpatientsisclearlysuperiorto theothertwostrategies.66,67Therefore,patientswhofailtoachieveelectrocardiographicevidenceofreperfusion90 minutesafteradministrationoffibrinolysis,havepersistentsymptoms,orareelectricallyorhemodynamicallyunstable shouldbereferredforrescuePCI.14

CombinationTherapies
Therehasbeenconsiderableinterestincombiningdifferentpharmacologic strategieswithorwithoutPCI.Therationaleistoleveragethedifferentadvantagesof pharmacologicagentstoincreasethelikelihoodofcoronarypatencyandtocombine thebenefitsofearlymedicaltherapywiththeadvantagesofsubsequentPCI. However,somestrategieshavebeendisappointingwithrespecttoclinical outcomes. CombiningFibrinolysisWithParenteralAntiplateletAgents AddingapotentantiplateletsuchasaGPIIb/IIIainhibitortofibrinolytictherapyis theoreticallybeneficialduetotheactivationofplateletsthatoccurswhenfibrinolysis isadministered.AbciximabhasbeenbetterstudiedthanthesmallmoleculeGP IIb/IIIainhibitoragents.Twostudies,GUSTOV(TheGUSTOVRandomisedTrial) andASSENT3(TheAssessmentoftheSafetyandEfficacyofaNewThrombolytic Regimen(ASSENT)3Investigators.EfficacyandSafetyofTenecteplasein CombinationWithEnoxaparin,Abciximab,orUnfractionatedHeparin:TheASSENT3 RandomizedTrialinAcuteMI),foundthatcombininghalfdosefibrinolysisand abciximabimprovedacombinedendpointofdeath,stroke,andnonfatalMI.This waslargelydrivenbyareductioninreinfarctionandcameatthecostofasignificant increaseinbleeding.68,69 FacilitatedTherapy Facilitatedtherapyreferstohalforfulldosefibrinolytictherapyfollowedbyroutine "immediate"PCI.TheASSENT4PCI(AssessmentoftheSafetyandEfficacyofa NewTreatmentStrategyforAcuteMyocardialInfarction)trialrandomizedpatients withSTEMItofulldosetenecteplasefollowedbyPCIwithin13hoursversusPPCI withunfractionatedheparin.GPIIb/IIIainhibitorswereadministeredonlyforbailout, andclopidogrelwasgivenonlyifastentwasplaced.70Despiteplannedenrollment for4,000patients,thestudywasstoppedearlyafterenrollingapproximately1,700 patientsbecausetherewasincreasedinhospitaldeath(6%vs.3%,p<0.05) TheFINESSE(FacilitatedInterventionWithEnhancedReperfusionSpeedtoStop Events)trialrandomized2,452STEMIpatientsundergoingPCItoabciximabplus halfdosereteplase,versusearlyabciximab,versusstandardPPCI.71Therewasno differenceintheprimary,broadcompositeoutcomeofallcausemortality,ventricular fibrillationat48hours,cardiogenicshock,orcongestiveheartfailureat90days acrossthethreegroups.TheratesofnonintracranialTIMImajororminorbleeding werelowestinthestandardPPCIarm.Becauseofthelackofbenefitandincreased harmdemonstratedbythesetwostudies,thestrategyoffacilitatedPCI(with fibrinolyticsfollowedbymandatedimmediatePCI)isnotrecommended. PharmacoinvasiveTherapy AlthoughfacilitatedPCIwitheitherlowdoselyticsplusGPIIb/IIIainhibitorsorearly upstreamGPIIb/IIIainhibitorsisnolongerrecommended,severalstudiessuggest thatearlyplannedPCI(butnotimmediate,unlessitisrescuePCI)inpatients postfibrinolysiswithin24hoursofadministrationyieldsbetterresults. TheCARESSinAMI(CombinedAbciximabReteplaseStentStudyinAcute MyocardialInfarction)included600patientswithhighriskfeatureswhopresented withSTEMIwithin12hoursofsymptomonsetatanonPCIcapablehospital.These patientswererandomizedtoeitherhalfdosereteplaseandabciximabfollowedby routineearly(butnotimmediate)PCIortothesamepharmacologicstrategy followedbyPCIonlyforfailureofreperfusion.72Additionally,patientsmetatleast onehighriskcriterion:extensiveSTE,newonsetLBBB,previousMI,Killipclass>II, orLVEF?35%.Thisstudydemonstratedthatastrategyofhalfdosereteplaseand abciximabfollowedbyroutineearlyPCI,whencomparedwithrescueonly angioplastyafterthesamepharmacologiccocktail,resultedinareductioninthe compositeendpointofdeath,reinfarction,orrepeatischemiawithin30days(4.4% vs.10.7%,p=0.005).
Table2

Figure10

Similarly,theTRANSFERAMI(TrialofRoutineAngioplastyandStentingAfter FibrinolysistoEnhanceReperfusioninAcuteMyocardialInfarction)enrolled1,030 highriskpatientspresentingwithin12hoursofSTEMIatanonPCIcapable hospitalandtreatedwithTNKfibrinolytictherapy.Patientswerethenrandomizedto mandatedtransfertoaPCIcenterwithin6hoursortostandardpostfibrinolytic managementwithonlyselectivetransferforrescuePCIwhenindicated.73Highrisk wasdefinedasatleast2mmSTEinatleasttwocontiguousanteriorleadsorat least1mmofinferiorSTEintwocontiguousleadswithoneofthefollowing:systolic bloodpressure<100mmHg,heartrate(HR)>100bpm,KillipclassIIorIII,ST depression2mmintheanteriorleads,orSTE1mminV4Rsuggestingright ventricularinvolvement. Cardiaccatheterizationwasperformedin98.5%ofpatientsrandomizedto immediatetransfer,withamediantimefromrandomizationtocatheterizationof2.8 hours.Only88.7%ofpatientsrandomizedtoconservativetherapyunderwent catheterization,withamediantimefromrandomizationtocatheterizationof32.5 hours.Althoughtherewasnodifferenceinmortality,therewasareductioninthe combinedendpointofdeath,MI,recurrentischemia,neworworsenedheartfailure (HF),andcardiogenicshock(11.0%vs.17.2%,p=0.004)(Figure10). ThesedataarecorroboratedbytheNORDISTEMI(NorwegianStudyonDistrict TreatmentofSTElevationMyocardialInfarction),inwhichastrategyofroutineearly transferafterfibrinolysisalsodidnotshowasignificantreductioninmortalitybutdid demonstrateasignificantreductionin12monthcombinedendpointofdeath,MI, andstroke(6%vs.16%,p=0.01).74Inthisstudy,99%ofpatientsrandomizedto earlytransferreceivedPCI,withamediantimefromfibrinolyticadministrationto catheterizationof130minutes.Ninetyfivepercentofpatientsrandomizedto ischemiadriventherapyreceivedPCI,withamediantimefromfibrinolytic administrationtocatheterizationof5.5days. Inallstudies,deathandreinfarctionwerereducedwithminimalimpactonbleeding. Thiswasconfirmedbyametaanalysisthatincludedearliertrialsaswellasthese morecontemporarystudies.75Itshouldbenotedthatthesestudiesdidnothavea PPCIcomparatorarm. Thuspatientsundergoingfibrinolysis,eitherfulldoseorhalfdoseincombination withabciximab,canbenefitfromroutineimmediatetransfertoaPCIcapablecenter andconsiderationofPCIaspartofa"pharmacoinvasive"strategy.Whileroutine immediatePCIisnotrecommendedforpatientswhohavebeenadministered fibrinolysis,a"dripandship"withaplannedearlyinvasivestrategyisconsidered reasonableandpotentiallyeffective(ACC/AHAClassIIarecommendation)forthose patientsathigherrisk(Table2).

ThirtyDayMortalityintheFourTreatmentGroups Figure10 ThegroupreceivingacceleratedtreatmentwithTPAhadlowermortalitythanthetwostreptokinasegroups(p=0.001)andthaneachindividual treatmentgroup:streptokinaseandSCheparin(p=0.009),streptokinaseandIVheparin(p=0.003),andTPAandstreptokinasecombinedwith IVheparin(p=0.04). IV=intravenousSC=subcutaneousTPA=tissuetypeplasminogenactivator ReproducedwithpermissionfromAninternationalrandomizedtrialcomparingfourthrombolyticstrategiesforacutemyocardialinfarction.The GUSTOinvestigators.NEnglJMed1993329:67382.

HighRiskFeaturesofSTEMIinPatientsWhoShouldBeConsideredforTransferasSoonasPossibletoaPCICapableFacility Table2 HR=heartrateLBBB=leftbundlebranchblockLVEF=leftventricularejectionfractionMI=myocardialinfarctionRV=rightventricularSBP= systolicbloodpressureSTE=STsegmentelevation. AdaptedwithpermissionfromDiMarioC,DudekD,PiscioneF,etal.Immediateangioplastyversusstandardtherapywithrescueangioplasty afterthrombolysisintheCombinedAbciximabREteplaseStentStudyinAcuteMyocardialInfarction(CARESSinAMI):anopen,prospective, randomised,multicentretrial.Lancet2008371:55968,andCantorWJ,FitchettD,BorgundvaagB,etal.Routineearlyangioplastyafter fibrinolysisforacutemyocardialinfarction.NEnglJMed2009360:270518.

PatientsWithDelayedPresentationorNotReceivingEarlyReperfusionTherapy
STEMIpatientsnotreceivingprimaryreperfusiontherapyareatsignificantlyincreasedriskforfuturecardiovascular eventsanddeath.54Asdiscussedpreviously,fibrinolytictherapyisunlikelytoprovidesignificantoutcomesbenefitin patientspresenting>12hoursfromtheonsetofsymptoms.However,itisreasonabletoperformcoronaryangiography andPPCIinappropriatelesionsinpatientspresentingwiththeonsetofsymptomswithinthepast1224hoursifoneor moreofthefollowingarepresent:severeCHF,hemodynamicorelectricalinstability,andpersistentischemicsymptoms. Asymptomaticpatientspresenting>12hoursfromtheonsetofsymptomsshouldnotundergoPPCIiftheyare hemodynamicallyandelectricallystable.7 Theopenarteryhypothesisproposedthatlatepatencyofaninfarctarteryinthosepatientsnotreceivingearlyreperfusion therapywouldderivebenefitinimprovedLVfunctionwithlessdeleteriouspostinfarctionremodeling,enhancedelectrical stability,andfewerfutureadverseclinicalevents.TheOAT(OccludedArteryTrial)studyincluded2,166patientsmeeting highriskcriteria(EF<50%orproximalocclusion)withanoccludedinfarctrelatedartery328daysafterSTEMI determinedbycardiaccatheterization.ExclusioncriteriaincludedNewYorkHeartAssociationClassIII/IVHF,shock, serumcreatinine>2.5mg/dl,significantleftmain/threevesselcoronaryarterydisease,anginaatrest,andsevere ischemiaonstresstesting.PatientswererandomizedtoPCIwithstentplacementandoptimalmedicaltherapyor optimalmedicaltherapyalone.Thecompositeprimaryendpointofdeath,reinfarction,andClassIVHFwasnot statisticallydifferentbetweenthetwogroups(17.2%inthePCIgroup,15.6%inthemedicaltherapyalonegroup)at4 years.76 BasedontheOATtrial,the2007FocusedUpdateoftheACC/AHA2004GuidelinesfortheManagementofPatientsWith STEMImakethefollowingstatement:PCIofatotallyoccludedinfarctartery>24hoursafterSTEMIisnotrecommendedin asymptomaticpatientswithoneortwovesseldiseaseiftheyarehemodynamicallyandelectricallystableanddonot haveevidenceofsevereischemia.65

KeyPoints
ImmediaterecognitionofSTEMIwithtimelyinitiationofreperfusiontherapiessignificantlydecreases cardiovascularmorbidityandmortality. TheselectionofreperfusionstrategyinSTEMI(pharmacologicvs.invasivevs.pharmacoinvasive)isdependent uponthetimefromonsetofsymptoms,mortalityriskofSTEMI,bleedingrisk,andtimefortransporttoaskilled PCIfacility. PPCIissuperiorintherestorationofTIMI3flow,haslowerratesofreinfarctionandmortality,andhasless intracranialbleedingcomparedwithfibrinolytictherapy. BleedingisanimportantoutcomemeasureinPCIandissignificantlyassociatedwithmortality. AspirationthrombectomyisreasonableandmaybebeneficialinPPCI.Filterdistalprotectionandmechanical thrombectomyarenotrecommendedinPPCI. TheuseofDESinPPCIisareasonablealternativetoBMSanddecreasesTVR. Fibrinolyticagentshavesignificantdifferencesinfibrinspecificity,pharmacokinetics,efficacy,andsafety. Whilecombinationtherapyandfacilitatedtherapycannolongerberecommended,apharmacoinvasivestrategy forreperfusionwithfibrinolyticsandearlydirectedangiographyisapreferredstrategy. Asymptomaticpatientspresenting>12hoursfromtheonsetofsymptomsshouldnotundergoPPCIiftheyare hemodynamicallyandelectricallystable.

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6.7:STEMI:AncillaryTherapyI:AntithrombinandAntiplateletTherapy
Author(s): AmyLeighMiller,MD,PhD TracyWang,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. EvaluatetheevidenceunderlyingtheuseofancillaryantithrombinandantiplatelettherapyforpatientswithSTsegment elevationmyocardialinfarction(STEMI). 2. DiscusstheappropriateindicationsandcontraindicationstoantithrombinandantiplatelettherapyforSTEMIpatients. 3. DiscussspecialconsiderationsforantithrombinandantiplatelettherapyselectionanduseamongSTEMIpatients.

Introduction
AlthoughreperfusionisthemainstayofSTEMImanagement,antithrombinandantiplateletagentsareessentialancillary therapiestoimprovepatientoutcomes.Useoffibrinolyticagentsresultsinthrombinliberationandplateletactivation, creatingahypercoagulablestatethatcanbeamelioratedbyancillaryantithrombinandantiplatelettherapytoprevent reocclusionoftheinfarctvessel.Similarly,whenmechanicalreperfusionwithprimarypercutaneouscoronaryintervention (PCI)isselected,antithrombinandantiplateletagentsminimizetherisksofintraproceduralcatheterthrombosisand earlyinstentthrombosis. Whileantithromboticandantiplateletagentsplayanimportantroleinincreasingthesuccessofrevascularization,they alsocarryanincreasedriskofbleeding.Therelativeefficacy(preservationofvesselpatencyandpreventionofrecurrent thrombosis)andsafety(bleedingcomplications)varyacrossagents,aswellasacrosspatientpopulations.Continued effortstofindagentsthatmaximizeefficacywithoutalossofsafetyhaveledtoarapidexpansionoftherepertoireof availablemedications.

AntithrombinAgentsinSTEMI (1of2)
UnfractionatedHeparin Althoughunfractionatedheparin(UFH)istheantithrombinagentbestrepresentedintheSTEMIliterature,itsfuturein fibrinolysisofSTEMIisunclear.WhilegreaterinfarctvesselpatencyhasbeendemonstratedwithadjunctiveUFHuseat thetimeoffibrinolysis(earlypatencyrates82%vs.52%withaspirinalone,1 and3daypatencyratesof71%vs.43%in controls2 ),demonstrableclinicalbenefitremainselusive.EarlyfibrinolytictrialscomparingsubcutaneousUFHwith standardtherapydemonstratedanearlybutnotlongtermmortalitybenefit,aswellasanincreaseinbleedingrisk. IntheGISSI2(GruppoItalianoperloStudiodellaSopravvivenzanell'Infartomiocardicoacuto2)trial,useofheparin increasedtheriskofmajor(relativerisk[RR],1.6495%confidenceinterval[CI],1.092.45)andminor(RR,1.8895%CI, 1.642.14)bleedingwhilereducingtheriskofsystemicthromboembolism(RR,0.5495%CI,0.350.84),withno differenceinoverallmortality.3 WhileGISSI2foundnoincreaseinhemorrhagicstrokeswithheparin,3 intheISIS3 (InternationalStudyofInfarctSurvival3)trial,heparinwasassociatednotonlywithincreasedoverallbleedingrisk,but alsowithanincreaseintheriskofintracerebralhemorrhage.4 InbothGISSI2andISIS3,heparinappearedtoreduce mortalityduringtheperiodofinfusion,butthisprotectivebenefitwassubsequentlylost,suchthat30daymortalitywasno differentinheparintreatedpatientsversuscontrols.3,4 Smallertrialsoffixeddoseintravenous(IV)heparinfoundsimilartrendsofincreasedbleeding(14%vs.12%intheISIS [InternationalStudyofInfarctSurvival]pilotstudy,5 17.6%vs.15.1%intheEuropeanCooperativeStudyGrouptrial6 ) withoutmortalitybenefit.Vesselpatencyrates,however,weresignificantlyimprovedwithIVheparin(RR,0.6695%CI, 0.470.63).5,6Despitethelackofdefinitiveevidencesupportinglongtermbenefit,the2007FocusedUpdateofthe AmericanCollegeofCardiology/AmericanHeartAssociation(ACC/AHA)2004GuidelinesfortheManagementofPatients WithSTEMIstillrecommendthatUFHbeusedinconjunctionwithtissuetypeplasminogenactivator(TPA)based fibrinolysisamongSTEMIpatients(seelaterdiscussionfordosing).7 AnadditionalconsiderationwithUFHistheriskofheparininducedthrombocytopenia(HIT).WhileHITispossiblewith otheragents,theincidenceishigherforUFHthanforlowmolecularweightheparin(LMWH).8 GiventheconcernforHIT, thedurationofUFHinfusionisgenerallylimitedto48hours. IntheExTRACTTIMI25(EnoxaparinandThrombolysisReperfusionforAcuteMyocardialInfarctionTreatment)trial,a48 hourUFHinfusionwasinferiortoLMWHtreatmentadministeredforthedurationofthehospitalization,with superimposedendpointcurvesuntilUFHwasdiscontinuedat48hours(rateofdeath/nonfatalmyocardialinfarction[MI] at48hours,4.7%inpatientstreatedwithenoxaparinvs.5.2%inpatientstreatedwithUFHRR,0.9095%CI,0.801.01). After48hours,eventcurvesdiverged,withlowerdeath/nonfatalMIratesforLMWHat8days(7.2%vs.9.3%,RR,0.77 95%CI,0.710.85)andat30days(9.9%vs.12.0%,RR,0.8395%CI,0.770.90)comparedwithUFH.9 Riskofmajor bleedingwashigherwithprolongedLMWHexposurecomparedwitha48hourUFHinfusion:1.4%versus1.0%at48 hours(RR,1.4495%CI,1.121.86),1.8%versus1.2%at8days(RR,1.4995%CI,1.191.87),and2.1%versus1.4%at 30days(RR,1.5395%CI,1.231.89).9 Thesedatasuggestthatlongeranticoagulationmayprovidetherapeuticbenefit atthecostofgreaterbleedingrisk. CurrentSTEMIACC/AHAguidelinesrecommendUFHdosedat60U/kgbolus(maximumbolus4000U)plusaninitial infusionof12U/kg/hr(maximuminfusionrateof1000U/hr)amongSTEMIpatientsreceivingTPAbasedfibrinolytic agents.7 TheSTEMIACC/AHAguidelinesrecommendthatinfusionsofUFHbeadministeredroutinelyfor48hoursand beadministeredforalongerperiodonlyinpatientswithanongoingindicationforanticoagulation(e.g.,atrialfibrillation, mechanicalvalve,venousthrombosisrequiringanticoagulation),giventheriskofHITwithcontinuedinfusion.7 Incontrasttothesettingoffibrinolysis,antithrombinagentshavebeenwellstudiedinprimaryPCI.UFHwasthemainstay antithromboticagentforthefirsttwodecadesofbothurgentandelectivePCI.Onlyinthepastdecadehaveneweragents beguntocompetewithUFHinthesettingofcatheterization.ThedownsidesofUFHincludetheneedforperiodic monitoringandbleedingcomplicationsthatlikelyareattributableinparttothevariabilityindrugconcentrationandeffect overtime,aswellasthepotentialforplateletactivation.Consequently,thereissignificantinterestinagentsthatprovide reliable,consistentefficacy(seediscussionlater). ForpatientsundergoingprimaryPCIwhohavealreadybeenreceivingUFH,additionalUFHbolusesshouldbe administeredasneededtomaintaintherapeuticactivatedclottingtimelevels,takingintoaccountwhetherglycoprotein (GP)IIb/IIIareceptorantagonistshavebeenadministered.7 ThedurationofUFHinfusioninthePCIpopulationisnot addressedintheACC/AHASTEMIguidelines.Inpatientswhodonotreceiverevascularization,anticoagulationwithUFH orLMWHforatleast48hoursisgivenaClassIIarecommendation.10

LowMolecularWeightHeparin IncontrasttoUFH,LMWHagentsmorespecificallyinhibitfactorsXaandIIa.Inearlytrials,adjunctiveenoxaparinwas showntobesuperiortoplaceboamongSTEMIpatientstreatedwithfibrinolysis(compositeendpointof30day death/reinfarctionangina13%withenoxaparin,21%withplacebo).11EnoxaparinhadefficacysuperiortothatofUFH (compositeendpointofinhospitalreinfarction/inhospitalrefractoryischemia/30daymortality14.2%withenoxaparinvs. 17.3%withUFH),butwasassociatedwithincreasedbleedingriskrelativetoUFH,predominantlyinpatients>75 years.12 IntheASSENT3(AssessmentoftheSafetyandEfficacyofaNewThrombolyticRegimen3)trial,fulldosetenecteplase withenoxaparinhadgreaterefficacy(combinedendpoint30daymortality/inhospitalreinfarction/inhospitalrefractory ischemia)thandidfulldosetenecteplasewithweightadjustedUFH(15.4%eventratevs.11.4%forenoxaparin)and similarefficacytohalfdosetenecteplasewithlowdoseweightadjustedUFHandabciximab(11.1%eventrate). Bleedingrateswerehighestwithabciximab(39.7%),intermediatewithenoxaparin(25.6%),andlowestwithUFH (21.1%),withriskofbleedingagainhighestinpatients>75years.13 Thisobservationledtotheexclusionofpatients>75inthemorerecentExTRACTTIMI25(EnoxaparinandThrombolysis ReperfusionforAcuteMyocardialInfarctionTreatment)trial,whichagainfoundhighertherapeuticefficacyforenoxaparin (17%riskreductionin30daydeath/MIrate).Themajorbleedingratewassignificantlyhigherwithenoxaparinrelativeto UFH(2.1vs.1.4%,p<0.001)eveninthisagerestrictedpopulation.9 Whileearlypilotworkwithdalteparinwaspromising,14subsequentworksuggestedanincreaseinthromboticevents shortlyafterdrugdiscontinuationthatappearedtooffsetanybenefit.15IntheCREATE(CanadianCardiacRandomized EvaluationofAntidepressantandPsychotherapyEfficacy)trial,reviparininadditiontousualcarereducedtherateofthe combinedendpointofdeath/MI/strokeat7days(9.6%vs.11.0%,hazardratio[HR],0.87)withanincreaseinbleeding events(0.2%lifethreateningbleedingeventsvs.0.1%).16A2005metaanalysisfoundthatLMWHreducedreinfarction (oddsratio[OR],0.7295%CI,0.580.90)anddeath(OR,0.9095%CI,0.800.99)relativetoplacebo,whereasIVUFH didnot(OR,1.0495%CI,0.621.78fordeathOR,1.0895%CI,0.581.99forreinfarction),althoughminorbleedingwas morefrequentwithLMWH(OR,1.2695%CI,1.121.43).17However,thecombinationofmultipleLMWHagentsand heparindosinginthisanalysismaybeasignificantconfounder. TheLMWHliteratureinSTEMIpatientsundergoingPCIcontinuestoevolve.InthepopulationofExTRACTTIMI25patients whounderwentPCI,areducedriskof30daydeath/recurrentMIwasseenwithLMWHcomparedwithUFH(10.7%vs. 13.8%)withoutasignificantincreaseinmajorbleeding(1.4%vs.1.6%).18Morerecently,aprospectivesinglecenter nonrandomizedcomparisonofoutcomesinSTEMIpatientsundergoingprimaryPCIsimilarlyfoundareductioninin hospitalmortalitywithLMWHcomparedwithUFH(OR,0.3295%CI,0.120.85),aswellasareductionin30daymortality (OR,0.495%CI,0.170.99)withoutanincreaseinmajor(6.8vs.4.3%,p=0.34)orminor(10.1vs.9.0%,p=0.65) bleeding.19 Therandomized,openlabelATOLL(AcuteMyocardialInfarctionTreatedWithPrimaryAngioplastyandIntravenous EnoxaparinorUnfractionatedHeparintoLowerIschemicandBleedingEventsatShortandLongTermFollowUp)trial comparedtreatmentwithUFHand0.5mg/kgenoxaparinpriortoprimaryPCIandfoundnodifferencein30daymortality, majorbleeding,orproceduralfailure.Thestudydidfindthatthecompositeendpoints,deathorcomplicationofMI, death/recurrentMI/urgentrevascularization,occurredlessfrequentlywithLMWHthanUFH(RR,0.63and0.60, respectively).20 AnadditionalroleconsideredforLMWHinSTEMIwasasanancillarytherapyamongpatientsineligibleforreperfusion. TheTETAMI(TreatmentofEnoxaparinandTirofibaninAcuteMyocardialInfarction)trialrandomizedpatientswhowerenot eligibleforreperfusiontoUFHorenoxaparin,bothwithorwithoutGPIIb/IIIainhibitors.21Whilenobenefitwasobserved withtirofiban(30daydeath/reinfarction/recurrentanginarate16.6%vs.16.4%withplacebo),enoxaparinhadasimilar efficacy(30daydeath/reinfarction/recurrentanginarateof15.7%vs.17.3%)andsafety(majorhemorrhagerate1.5%vs. 1.3%)comparedwithUFH.ThissuggeststhatenoxaparinwasareasonablealternativetoUFHforthemedical managementofreperfusionineligibleSTEMIpatients. Easieradministrationanddosing,aswellasalowerriskofinducingHIT,makeLMWHproductsattractivealternativesto UFH.TheseattractivefeaturesarepartiallyoffsetbytheirreversiblenatureofLMWH.IncontrasttoUFH,whichcanbe acutelyreversedwithprotamine,LMWHeffectsareonlypartiallyreversiblebyprotamine.Inmostpatients,LMWHdoes notrequiremonitoringofclinicaleffect.Infact,thetestscommonlyusedtomonitorUFHeffects(partialthromboplastin timeandactivatedclottingtime)arenotusefulmetricsofLMWHeffect,whichisinsteadmonitoredusinganantifactorXa assay.Inpatientswithsignificantrenaldysfunction(LMWHisrenallycleared)orsevereobesity(bodyweight>100kg), antifactorXalevelmonitoringisnecessarytoensuresafeandtherapeuticdosing. WhilemultipleLMWHagentshavebeenexaminedinpatientswithacutecoronarysyndrome(ACS),todate,sufficient datatogarneranACC/AHASTEMIguidelinerecommendationonlyexistforenoxaparin.Theuseofenoxaparinis recommendedforpatients<75yearsandinwhomserumcreatininelevelsare<2.5mg/dlformalesand2.0mg/dlfor

females.7 TherecommendeddurationofenoxaparinparallelstheExTRACTTIMI25trial,withcontinuoustreatmentfor thedurationoftheindexhospitalization(uptoamaximumof8days).CurrentACC/AHASTEMIguidelinesadvisean additional0.3mg/kgdoseofenoxaparininpatientswhoselastdoseofenoxaparinwasreceived>8hourspriortoPCI. Patientswhohavereceivedtreatmentdoseenoxaparinwithin8hoursofPCIdonotrequireadditionalantithrombotic therapy.7

AntithrombinAgentsinSTEMI (2of2)

DirectThrombinInhibitorBivalirudin Incontrasttoheparinproducts,directthrombininhibitors(DTIs)arenotassociatedwithHIT.Recentstudiesshowedthat DTIsareassociatedwithamorefavorablebleedingprofile.WhilethereareanumberofclinicallyavailableDTIs, bivalirudinistheagentthathasbeenbeststudiedinthesettingofACS.Furthermore,ametaanalysiscomparingresults forthevariousDTIsinthesettingofMIfoundareductionofdeath/MIwithbivalirudinorhirudinbutnotwithotheragents, aswellasincreasedriskofbleedingwithhirudinbutnotbivalirudin.22 TheHERO2(HirulogandEarlyReperfusionorOcclusionTrial)examinedstreptokinaseadministrationwithbivalirudinor UFHadjunctivetherapy.Thestudyfounda30%lowerriskofreinfarctionwithbivalirudin,aswellasaslightlyincreased bleedingriskwithbivalirudincomparedwithUFH.23Therewasnodifferenceinmortality(10.5%forbivalirudinvs.10.9% forUFHRR,0.9695%CI,0.861.07p=0.46). TheHORIZONSAMI(HarmonizingOutcomesWithRevascularizationandStentsinAcuteMyocardialInfarction)study randomizedabout3,600STEMIpatientsundergoingprimaryPCItoUFH/GPIIb/IIIareceptorinhibitorversusbivalirudin withprovisionaluseofGPIIb/IIIareceptorinhibitors.Therewasasignificantlylowerrateof30daynetadverseclinical eventsdefinedasthecompositeofdeath,recurrentMI,targetvesselrevascularization(TVR),ormajorbleedingwith bivalirudinuse(9.2%vs.12.1%RR,0.7695%CI,0.630.92p=0.005).Thiswaslargelydrivenbythesignificant reductioninmajorbleedingevents(4.9%vs.8.3%,p=0.001).Overallmortality(2.1%vs.3.1%RR,0.6695%CI,0.44 1.00)andcardiovascular(CV)mortalityrates(1.8%vs.2.9%RR,0.6295%CI,0.400.95p=0.03)werealsomodestly reduced.24Acute(within24hoursofprimaryPCI)stentthrombosisrateswere,however,higherwithbivalirudin(1.3%vs. 0.3%,p<0.001).Ofnote,morethanonehalfofthepatientsintheHORIZONSAMIstudyhadreceivedUFHpriorto randomization. Subsequentanalysishasshownthatprerandomizationheparinandhigher(600mg)clopidogrelloadingdoseswere associatedwithlowerstentthrombosisratesinpatientstreatedwithbivalirudin.25CurrentACC/AHASTEMIandPCI guidelinesrecommend(ClassII,LevelofEvidenceA)considerationofbivalirudinforSTEMIpatientsathighriskof bleedingwhoareundergoingPCI.26 Bivalirudinispartiallyrenallycleared,necessitatingreduceddosinginpatientswithcreatinineclearance<30ml/minute. WhilenotstudiedexplicitlywithintheSTEMIpopulation,retrospectiveanalysisofdoseadjustedbivalirudinindialysis dependentpatientsundergoingPCIfoundnodifferenceinmajorbleedingorclinicalendpointswhencomparedwithUFH inthesamepopulation.27 FactorXaInhibitorFondaparinux Fondaparinux,asyntheticpentasaccharidethatinhibitsfactorXa,iscurrentlytheonlyclinicallyavailablefactorXainhibitor forACStreatmentintheUnitedStates.28FondaparinuxwasstudiedamongSTEMIpatientsintheOASIS6(Organization fortheAssessmentofStrategiesforIschemicSyndromes6)trial,whichcompareda7daycourseoffondaparinuxwith 48hoursofUFH.Thestudyfoundthatfondaparinuxreducedrisksof30daydeath/MI(9.7vs.11.2%HR,0.8695%CI, 0.770.96),withanonsignificanttrendtowardless30dayThrombolysisinMyocardialInfarction(TIMI)majorbleeding(1.0 vs.1.3%,p=0.13).However,anincreasedriskofcatheterassociatedthromboticeventsatPCI(22eventsinthe fondaparinuxgroupcomparedwithnoneintheUFHgroup,p<0.001)significantlyattenuatedthebenefitoffondaparinux inpatientsundergoingPCI.28 SubsequentanalysishassuggestedthatthebenefitoffondaparinuxinOASIS6isthesameacrossagegroups.29 Furthermore,inthesubsetofpatientsfromOASIS6whounderwentfibrinolysis,fondaparinuxreducedtherateof30day death/MI(HR,0.7995%CI,0.680.92),withsignificantreductionsinbothcomponentsofthatcomposite,aswellasin majorbleedingevents(HR,0.6295%CI,0.400.94),relativetousualcare.30However,theobservedcatheterthrombosis eventsatPCIareasignificantconsiderationforpatientsundergoingPCI.Consequently,currentACC/AHASTEMI guidelinesadviseadditionalIVantithromboticagentadministrationforSTEMIpatientswhohavereceivedfondaparinux priortoPCI.7 LikeDTIs,theantithromboticeffectsoffondaparinuxcannotbeacutelyreversed.Invitrostudieshaveshown nointeractionbetweenfondaparinuxandHITantibodies,31makingfondaparinuxanattractivetherapyinpatientswith priorhistoryofHIT,arolethatiscurrentlybeinginvestigatedinPhaseIItrials. Apixaban,anoralfactorXainhibitorcurrentlyavailableinEurope,wasstudiedinhighriskACS(NSTEMIorSTEMI) patientsintheAPPRAISE2(ApixabanforPreventionofAcuteIschemicEvents2)trial,inwhichapixabanorplacebowas addedtostandardantiplatelettherapy.32Patientswererandomizedamedianof2days(interquartilerange24)after parenteralantithrombotictherapyhadbeendiscontinued.WhiletherewasnodifferenceintheprimarycompositeofCV death/MI/ischemicstroke(7.5%vs.7.9%withplacebo,p=0.51),majorbleedingeventsweresignificantlymorecommon withapixaban(1.3%vs.0.5%HR,2.59p=0.001).32

AntiplateletAgentsinSTEMI
Aspirin ThetherapeuticbenefitofaspirinintheacuteMIsettingwaslargelydemonstratedintheISIS2(InternationalStudyof InfarctSurvival2)trial,inwhichpatientswererandomizedtoaspirin,streptokinaseinfusion,streptokinaseandaspirin,or control.SignificantreductionsinCVmortalitywereobservedwithbothstreptokinasealoneandaspirinalone,and combinationtherapydemonstratedadditivebenefit.33Subsequenttrialsshowedsimilarbenefitinassociationwithother fibrinolyticagents.34WhileISIS2onlymandateda1monthdurationofaspirintherapy,subsequenttrialsdefinitively demonstratedthebenefitoflongtermaspirintherapyinabroadrangeofpatientpopulations.35 CurrentACC/AHASTEMIandPCIguidelinesrecommendthat162325mgaspirinbegiventoallSTEMIpatientsreceiving fibrinolysisforSTEMIandcontinuedindefinitelyatadoseof75162mg/day.26Patientswhoreceivecoronaryarterystents withoutincreasedriskofbleedingshouldreceiveaspirin162325mg/dayforatleast1monthafterbaremetalstent implantation,3monthsaftersirolimuselutingstentimplantation,and6monthsafterpaclitaxelelutingstentimplantation, afterwhichlongtermaspirinuseshouldbecontinuedindefinitelyatadoseof75162mg/day.36 AdenosineDiphosphateReceptorInhibitors Thepastfewyearshaveseenarapidincreaseintherangeofavailableadenosinediphosphate(ADP)receptor inhibitors.Theliteraturecomparingtheseagentsisrapidlyevolvingandlikelywillcontinuetodosofortheforeseeable future.Anotherareaofcontinuedresearchandevolutionistheappropriatedurationofdualantiplatelettherapyinpatients afterPCI.Factorsthatinfluencethisdecisionincludepatientspecificfactors(e.g.,age,historyofmajorbleedingevents), lesionspecificcharacteristics(e.g.,vessel/stentdiameter),lesioncomplexity(e.g.,bifurcation),andpriorhistoryofstent thrombosis.37 Ticlopidine TiclopidinewasthefirstADPreceptorinhibitoravailableforclinicaluse.Whileitsplateletinhibitionreducesadverse eventsinpatientswithMIwithefficacysimilartoclopidogrelinSTEMIpatientsundergoingPCI,ticlopidineislesswell tolerated.38Gastrointestinalintoleranceiscommon,butmoreimportantly,ticlopidinecanrarelybeassociatedwith thromboticthrombocytopenicpurpura,aplasticanemia,andneutropenia.Duetothelowertoleranceofticlopidine,which canresultinprematurediscontinuationoftherapy,combinedwiththehematologicrisksassociatedwiththedrug,ithas largelybeenreplacedbyclopidogrelinclinicalpractice.Withtheavailabilityofprasugrelandthelikelyfutureclinical availabilityofotherADPreceptorinhibitors,theroleofticlopidineinthispopulationalmostcertainlywillcontinueto decline. Clopidogrel Thetherapeuticefficacyofdualantiplatelettherapywithaspirinandclopidogrelinassociationwith"usualtherapy"for STEMIwasdemonstratedintheCOMMIT/CCS2Clopidogrel(Randomized,PlaceboControlledTrialofAdding ClopidogreltoAspirinin46,000AcuteMyocardialInfarctionPatients)trialthatdidnotinvolvealoadingdosefor clopidogrel,39andtheCLARITYTIMI28(ClopidogrelasAdjunctiveReperfusionTherapy)trialthatutilizeda300mg clopidogrelloadingdose.40AllpatientsinCLARITYTIMI28receivedfibrinolysis.Inthispopulation,clopidogrelreduced thecompositeendpointof30dayCVdeath,recurrentMI,orrecurrentischemiaby20%.40Bleedingeventsinthetrial werelowandsimilarbetweengroups. IntheCOMMIT/CCS2trial,morethan40,000STEMIpatientswererandomizedto162mgofaspirinoraspirinand75 mg/dayofclopidogrel(withnoloadingdoseadministered),andmorethanhalfweretreatedwithfibrinolysis.At28days, theprimarycompositeendpointofdeath,reinfarction,orstrokewasdecreasedby9%intheclopidogrelarm,anda7% RRreduction(RRR)inmortalitywasobserved.Therewasnosignificantinteractionwithfibrinolyticagentuse.Overall bleedingrateswereagainlowandsimilarbetweengroups. TheuseofclopidogrelinSTEMIpatientsundergoingprimaryPCIisnotwellstudied.ThePCICLARITY(Clopidogrelas AdjunctiveReperfusionTherapy:PercutaneousCoronaryInterventionSubgroupStudy)trialtestedadjunctiveclopidogrel therapyamong1,863patientsundergoingPCIafterfibrinolysis.Theprimarycompositeoutcomeof30dayCVdeath,MI, orstrokefromPCIwassignificantlyloweramongpatientswhoreceivedclopidogrelversusplacebo(3.6%vs.6.2%OR, 0.5495%CI,0.350.85p=0.008).41AmongclopidogreltreatedSTEMIpatientsintheTRITONTIMI38(TrialtoAssess ImprovementinTherapeuticOutcomesbyOptimizingPlateletInhibitionwithPrasugrel),theprimaryendpoint(CV death/nonfatalMI/nonfatalstroke)occurredin9.5%ofpatientsby30days,withaTIMImajorbleedingunrelatedto coronaryarterybypassgrafting(CABG)rateof1.3%.42 CurrentACC/AHAPCIandSTEMIguidelinesrecommendaloadingdoseof300600mgclopidogrelbeforeorduringPCI

orafterreceivingfibrinolysisifnothienopyridinewasgiven.26Therecommendeddurationoftherapyis12monthsfor patientswhohavereceivedacoronarystent,regardlessoftype,withcontinuationbeyond15monthsreceivingaClassII, LevelofEvidenceBrecommendationinpatientswhoreceiveadrugelutingstent.26 Prasugrel Clinicalindicationsandutilizationofprasugrelarebasedonasinglelargescaletrial,TRITONTIMI38,which randomized13,608ACSpatientsundergoingPCItoprasugrelversusclopidogrel.Prasugrelproduceda2.2%absolute and19%RRRforthecompositeendpointofCVdeath/nonfatalMI/nonfatalcerebrovascularaccident,withnonfatalMI drivingtheobserveddifference.Theseprotectiveeffectswereoffsetbyanincreaseinsignificantbleedingevents(TIMI majorbleedingratesof2.4%withprasugrelvs.1.8%withclopidogrel).Inposthocanalysis,benefitsofprasugrelwere notobservedinpatients<60kg,75years,orwithahistoryofstroke.Subsequentpharmacokineticstudieshave demonstratedincreasedactivemetaboliteexposureinlighterbodyweightandolderpopulations.43 Ofthe13,608patientsintheTRITONTIMI38study,3,534hadSTEMI.44InasecondaryanalysisofSTEMIpatients undergoingeitherprimaryorsecondaryPCI,prasugrelagaindemonstratedriskreductioncomparedwithclopidogrel (HR0.68forthecompositeendpointofCVdeath/nonfatalMI/nonfatalstroke),withprotectivebenefitspresentby30days andpersistentat15months.42TIMImajorbleedingafterCABGwasmorefrequentwithprasugrel,butotherbleeding eventrateswerenodifferentbetweentreatmentgroups.Ofnote,TRITONwasastudyofprasugrelinthesettingofPCI, andthus,nodataexistsupportingprasugreluseinthesettingoffibrinolysis.Consequently,currentACC/AHASTEMIand PCIguidelinesadvocateclopidogrelasthethienopyridineofchoiceinthesettingoffibrinolysis.Eitherclopidogrelor prasugrelcanbeconsidered(ClassIrecommendation)forprimaryPCI,withaminimumdurationof12monthsin patientswhoreceiveastent.26 Ticagrelor TicagrelorisanoralP2Yreceptorantagonist,whichwascomparedwithclopidogrelinthePLATO(PlateletInhibitionand PatientOutcomes)trial.11,45TicagrelorreducedthecompositeendpointofCVdeath/MI/strokeby16%,relativeto clopidogrel.Whiletherewasnooveralldifferenceinmajorbleeding,ticagrelorresultedinahigherincidenceoffatal intracranialbleeding.AswiththeTRITONTIMI38trial,thePLATOtrialenrolledapopulationofSTEMIpatientsforwhom primaryPCIwasplanned.ForSTEMIpatientsundergoingPCI,ticagrelorreducedthecompositeendpointby13%, withoutadifferenceinmajorbleedingunrelatedtoCABG(4.5%vs.3.8%)orintracranialhemorrhage(0.3%vs.0.2%).46 Aswithprasugrel,todatethereisnolargescalestudyexaminingtherole,ifany,ofticagrelorasanadjunctto thrombolysis. GlycoproteinIIb/IIIaReceptorInhibitors GPIIb/IIIareceptorinhibitorsareaheterogeneousclass,forwhichgeneralizabilityofresultsobservedwithasingleagent islimited.GPIIb/IIIareceptorinhibitorsaregenerallydividedintotwogroups:abciximaband"smallmolecule"(tirofiban, eptifibatide).Historically,theSTEMIliteraturefocusedprimarilyonabciximab.Itwasonlyin2009thatsufficientdatafor tirofibanandeptifibatideexistedintheliteraturefortheACC/AHAPCIandSTEMIguidelinesforSTEMItoupgradethem fromaClassIIbtoClassIIarecommendationinthesettingofprimaryPCI.26 TrialsexaminingGPIIb/IIIareceptorinhibitorsinassociationwiththrombolysishaveingeneralemployedhalfdose fibrinolyticsinpatientsreceivingGPIIb/IIIareceptorinhibitorspriortocardiaccatheterization,astrategytermedfacilitated PCI.TheGUSTOV(TheGUSTOVRandomisedTrial)comparedabciximabplushalfdosereteplasewithfulldose reteplaseandfounddecreasednonfatalreinfarctanddecreasedarrhythmiccomplicationswiththeGPIIb/IIIareceptor inhibitortreatmentgroup,offsetbyanincreaseinmoderate/severebleeding.47 TheASSENT3trialagainfoundlowerreinfarctionandhigherbleedingratesforabciximabplushalfdosetenecteplase relativetofulldosetenecteplase.13TheFINESSE(FacilitatedInterventionWithEnhancedReperfusionSpeedtoStop Events)trialfoundthatpatientstreatedwithabciximabplushalfdosereteplasehadmorerapidSTsegmentelevation resolution,butnosignificantclinicalbenefitintermsofmortalityoradverseclinicaleventscomparedwithabciximab alone.48Onthebasisofthesestudies,facilitatedPCIcurrentlygarnersaClassIIbrecommendationintheACC/AHA STEMIandPCIguidelines,buthaslargelyfallenoutofpracticeintheUnitedStatesduetothefocusonimprovingdoor toballoontimes.26 Incontrast,intheprimaryPCIsetting,earlystudiesofabciximabconsistentlydemonstratedbenefit.TheADMIRAL (PlateletGlycoproteinIIb/IIIaInhibitionWithCoronaryStentingForAcuteMyocardialInfarction)studyrandomized300 STEMIpatientstoabciximaborplacebopriortoprimaryPCI.The30daycompositeprimaryendpointof death/reinfarction/urgentTVRoccurredin6.0%ofpatientstreatedwithabciximab,comparedwith14.6%ofcontrol patientsRRsforthethreecomponentsofthecompositeendpointwere0.51(95%CI,0.171.52)fordeath,0.51(95%CI, 0.092.81)forreinfarction,and0.20(95%CI,0.040.94)forurgentTVR.49At6months,urgentTVRremainedsignificant (RR,0.3095%CI,0.080.99).49InaEuropeanstudy,30daycompositedeath/reinfarction/TVRrateswere4.5%with

abciximabversus10.5%withplacebo(OR,0.4195%CI,0.170.97).50Importantly,thesetrialsprecededthedual antiplatelettherapyeraofPCI. Intrialssupportedbydualantiplatelettherapy,theadditionofGPIIb/IIIareceptorinhibitorsprovidednosignificantefficacy orbleedingcomparedwithplacebo,regardlessoftheagentstudied.51,52Whileeptifibatidehasnotbeencomparedwith placebointhesettingofdualantiplateletagents,UFHwitheptifibatidewasshowntobeinferiortobivalirudinin theHORIZONSAMIstudy.24Thus,whileallthreeGPIIb/IIIareceptorinhibitorshaveaClassIIarecommendationinthe settingofPCIforSTEMI,thisrecommendationisfortheirusein"selectedpatients."26Theyarenotcurrentlyconsidered "usualtherapy"intheSTEMIpopulationbutarelikelyofbenefitonlyinselectedhighriskpatients.

SpecialConsiderations

STEMIPatientsRequiringInterhospitalTransfer IntheUnitedStates,primaryPCIisthepreferredreperfusionstrategyforSTEMIpatientswhenfeasible.Unfortunately, <25%ofUShospitalshaveroundtheclockcapabilitiesforprimaryPCI.53Forpatientspresentingtofacilitiesthatdonot offerprimaryPCI,theappropriatemanagementstrategydependsonwhenthepatientpresentsrelativetosymptomonset andtheanticipatedtimerequiredfortransfertothenearestPCIcapablefacility.Whenthedelayfromarrivalto mechanicalreperfusion(doortoballoontime)exceeds90minutes,fibrinolysisatthereceivinghospitalisadvisable.54In recentyears,however,therehasbeenincreasedattentiontomanagementafterfibrinolyticadministration,withattention totheroleofimmediateversusdelayedtransfertoPCIcapableinstitutions. TheCARESS(ClopidogrelandAspirinforReductionofEmboliinSymptomaticCarotidStenosis)trialexaminedhalf dosereteplase/abciximab/UFHadministrationinpatientspresentingtoanonPCIfacility,withpatientsrandomizedto immediatetransfertoaPCIcapablefacilityforPCIversustransferonlyasneeded.55Thecompositeendpointofall causemortality/reinfarction/refractoryischemiawassignificantlylower(4.4%vs.10.7%,HR,0.4095%CI,0.210.76)for thegrouptransferredimmediatelytothePCIcapableinstitution,withnodifferenceinmajorbleedingratesbetween groups(3.4%vs.2.3%,p=0.49). TheTRANSFERAMI(TrialofRoutineAngioplastyandStentingAfterFibrinolysistoEnhanceReperfusioninAcute MyocardialInfarction)randomizedSTEMIpatientsreceivingfibrinolysis(tenecteplasewithaspirinandUFHorenoxaparin) tostandardtreatmentorimmediatetransferforPCIwithin6hours.56AsintheCARESStrial,thecompositeendpointof death/reinfarction/recurrentischemia/CHF/cardiogenicshockoccurredlessfrequently(11%vs.17.2%,RR,0.6495%CI, 0.470.87)inpatientsrandomizedtoearlyPCI,withoutadifferenceinmajorbleeding(7.4%vs.9.0%,RR,0.8395%CI, 0.551.24). Thesetwotrialsstronglysupportastrategyofimmediatetransferofanypatientsreceivingthrombolysisatfacilities withoutPCIcapabilities.Thisstrategyshouldbedistinguished,however,from"facilitatedPCI"inwhichreduceddose thrombolyticsorGPIIb/IIIareceptorinhibitorsareadministeredasanintentionalbridgestrategytodefinitivereperfusion byPCI.WhileanumberofdifferentpharmacologicstrategiestofacilitatedPCIhavebeenattempted,nonehaveshown benefit. Infact,theASSENT4PCI(AssessmentoftheSafetyandEfficacyofaNewTreatmentStrategyforAcuteMyocardial Infarction)trial,atrialoftenecteplaseforfacilitatedPCIcomparedwith"standardPCI"withananticipateddelayof13 hours(forpatientspresentingwithSTEMIof<6hourduration),wasstoppedprematurelyforincreasedinhospital mortality(6%vs.3%)inthefacilitatedPCIgroup.57InametaanalysiscomparingfacilitatedPCIwithprimaryPCI, fibrinolytictherapywasassociatedwithincreasedmortality,reinfarction,urgentTVR,stroke,andmajorbleeding,whereas GPIIb/IIIareceptorinhibitorshadnoeffectonefficacyorsafety.58 RoleofPlateletFunctionTesting WhileclopidogrelhasthegreatestevidencebaseamongallADPreceptorinhibitorsusedinthetreatmentofACS,recent attentionhashighlightedthevariabilityinresponseacrosstreatedpatients.Highontreatmentplateletreactivityhasbeen demonstratedinapproximatelyonethirdofclopidogreltreatedpatients.59Multiplestudiesnowshowanassociation betweenhighreactivityandadverseclinicaloutcomes.6062 ClopidogrelisaprodrugrequiringatwostepmetabolicconversionbyCYP450toformanactivemetabolitethatinhibits plateletaggregation.GeneticpolymorphismsoftheCYP2C19geneencodingtheCYP450enzymescontributetothe variableplateletinhibitionresponse,variabilityinabsorption,olderage,diabetes,anddecreasedmedicationadherence. AFoodandDrugAdministration"boxedwarning"wasrecentlyissued,highlightingthisassociation.However,the therapeuticresponseofpatientswhoaregeneticallypoormetabolizersisunclear. ApointofcareP2Y12assayhasbeendevelopedthatassessesplateletresponsetoclopidogrelbymeasuringplatelet aggregation.Theresultsofthispointofcaretesthavebeenwellcorrelatedwithtraditionallighttransmission aggregometry,andathreshold>235240P2Y12reactionunitshasbeendemonstratedtopredictadverseischemic events.63However,nodataareavailabletosupportachangeintherapyamongpatientswithdemonstratedhighon treatmentplateletreactivity. TheGRAVITAS(GaugingResponsivenesswithAVerifyNowAssayImpactonThrombosisAndSafety)studyrandomized 2,214patientswithP2Y12reactionunits>230tostandardclopidogreldosing(75mg/day)versusdoubleclopidogrel dosing(150mg/day)for6monthsandobservednosignificantdifferenceintheprimaryendpointof6monthCVdeath,MI, andstentthrombosis(2.3%vs.2.3%HR,1.0195%CI,0.581.76).64However,STEMIpatientswere<1%ofthisstudy population.Severalongoingrandomizedstudieswillexaminethepotentialbenefitoftailoredantiplatelettherapy,whether tailoredtoplateletreactivityorgenotype,usingnovel,morepotent,antiplateletagentssuchasprasugrelandticagrelor.

FutureDirections
Whilethereisnoclearconsensusonthebestantithrombinandantiplatelettreatmentstrategy,researchinthepast decadehassignificantlyadvancedourunderstandingofwhattherapiesareandarenoteffectiveinpatientswithSTEMI.A pointofcontinuedevaluationistherelativebalanceofefficacyandbleedingrisks,whichvariesacrossagentsaswellas acrosspatientpopulations.Givendifferencesinthisrisk/benefitratioasafunctionofpatientcharacteristics,itislikelythat patientspecifictailoringofantithrombinandantiplateletregimenswillprovethemosteffectiveapproachtooptimizing therapy.Thephenotypicandpharmacogenomicstudieswithclopidogrelarerepresentativeofthetypeofworkthatwillbe requiredtoenablepatientspecifictailoringoftherapy.

KeyPoints
UFHisrecommendedinassociationwithfibrinolysis.Recommendeddurationofinfusionshouldnotexceed48 hoursintheabsenceofanongoingindicationforanticoagulationgiventheriskofHIT. UtilityofLMWHinthesettingofthrombolysisislimitedbyexcessbleedingwiththeseagents. WhileUFHhaslongbeenthestandardantithromboticincardiaccatheterization,UFHwithGPIIb/IIIareceptor inhibitorswasinferiortobivalirudininSTEMIpatientsundergoingPCIintheHORIZONSAMItrial. FondaparinuxtreatmentisassociatedwithimprovedoutcomesinSTEMIpatientsbutrequiresancillary antithrombotictherapyduringcardiaccatheterizationgiventheincreasedriskofcatheterthrombosiswith fondaparinuxalone. AllSTEMIpatientsshouldreceiveaspirinandanADPreceptorinhibitor.Prasugreliscontraindicatedinpatients withpriorstroke,weight<60kg,or75years. Geneticpolymorphismsinfluenceresponsetoclopidogrel,buttheroleofgenetictestingorplateletfunction testinghasyettobedefined. STEMIpatientspresentingtofacilitieswithoutinterventionalcapabilitieswhoreceivethrombolysisshouldbe transferredimmediatelytoareferralcenterwithacardiaccatheterizationlaboratory.

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StegPG,JamesS,HarringtonRA,etal.TicagrelorversusclopidogrelinpatientswithSTelevationacutecoronary syndromesintendedforreperfusionwithprimarypercutaneouscoronaryintervention:aPlateletInhibitionand PatientOutcomes(PLATO)Trialsubgroupanalysis.Circulation2010122:213141. 47. Reperfusiontherapyforacutemyocardialinfarctionwithfibrinolytictherapyorcombinationreducedfibrinolytic therapyandplateletglycoproteinIIb/IIIainhibition:theGUSTOVrandomisedtrial.Lancet2001357:190514. 48. EllisSG,TenderaM,deBelderMA,etal.FacilitatedPCIinpatientswithSTelevationmyocardialinfarction.NEngl JMed2008358:220517. 49. MontalescotG,BarraganP,WittenbergO,etal.PlateletglycoproteinIIb/IIIainhibitionwithcoronarystentingfor acutemyocardialinfarction.NEnglJMed2001344:18951903.

50. AntoniucciD,RodriguezA,HempelA,etal.Arandomizedtrialcomparingprimaryinfarctarterystentingwithor withoutabciximabinacutemyocardialinfarction.JAmCollCardiol200342:187985. 51. van'tHofAWJ,tenBergJ,HeestermansT,etal.PrehospitalinitiationoftirofibaninpatientswithSTelevation myocardialinfarctionundergoingprimaryangioplasty(OnTIME2):amulticentre,doubleblind,randomised controlledtrial.Lancet2008372:53746. 52. MehilliJ,KastratiA,SchulzS,etal.AbciximabinpatientswithacuteSTsegmentelevationmyocardialinfarction undergoingprimarypercutaneouscoronaryinterventionafterclopidogrelloading:arandomizeddoubleblindtrial. Circulation2009119:193340. 53. JacobsAK.RegionalizedcareforpatientswithSTelevationmyocardialinfarction:it'scloserthanyouthink. Circulation2006113:115961. 54. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarction:AreportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceon PracticeGuidelines(CommitteetoRevisethe1999GuidelinesfortheManagementofPatientsWithAcute MyocardialInfarction).JAmCollCardiol200444:E1E211. 55. DiMarioC,DudekD,PiscioneF,etal.Immediateangioplastyversusstandardtherapywithrescueangioplasty afterthrombolysisintheCombinedAbciximabREteplaseStentStudyinAcuteMyocardialInfarction(CARESSin AMI):anopen,prospective,randomised,multicentretrial.Lancet2008371:55968. 56. CantorWJ,FitchettD,BorgundvaagB,etal.Routineearlyangioplastyafterfibrinolysisforacutemyocardial infarction.NEnglJMed2009360:270518. 57. AssessmentoftheSafetyandEfficacyofaNewTreatmentStrategywithPercutaneousCoronaryIntervention (ASSENT4PCI)Investigators.Primaryversustenecteplasefacilitatedpercutaneouscoronaryinterventionin patientswithSTsegmentelevationacutemyocardialinfarction(ASSENT4PCI):randomisedtrial.Lancet 2006367:56978. 58. KeeleyEC,BouraJA,GrinesCL.Comparisonofprimaryandfacilitatedpercutaneouscoronaryinterventionsfor STelevationmyocardialinfarction:quantitativereviewofrandomisedtrials.Lancet2006367:57988. 59. BonelloL,TantryUS,MarcucciR,WorkingGrouponHighOnTreatmentPlateletR.Consensusandfuture directionsonthedefinitionofhighontreatmentplateletreactivitytoadenosinediphosphate.JAmCollCardiol 201056:91933. 60. MatetzkyS,ShenkmanB,GuettaV,etal.Clopidogrelresistanceisassociatedwithincreasedriskofrecurrent atherothromboticeventsinpatientswithacutemyocardialinfarction.Circulation2004109:31715. 61. GurbelPA,BlidenKP,HiattBL,O'ConnorCM.Clopidogrelforcoronarystenting:responsevariability,drug resistance,andtheeffectofpretreatmentplateletreactivity.Circulation2003107:290813. 62. BarraganP,BouvierJL,RoquebertPO,etal.Resistancetothienopyridines:clinicaldetectionofcoronarystent thrombosisbymonitoringofvasodilatorstimulatedphosphoproteinphosphorylation.CatheterCardiovascInterv 200359:295302. 63. PriceMJ,EndemannS,GollapudiRR,etal.Prognosticsignificanceofpostclopidogrelplateletreactivity assessedbyapointofcareassayonthromboticeventsafterdrugelutingstentimplantation.EurHeartJ 200829:9921000. 64. PriceMJ,BergerPB,TeirsteinPS,etal.Standardvshighdoseclopidogrelbasedonplateletfunctiontestingafter percutaneouscoronaryintervention.JAMA2011305:1097105.

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6.8:STEMI:AncillaryTherapyII:SecondaryPreventionAfterSTSegment ElevationMyocardialInfarction
Author(s): VenuMenon,MBBS,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Reviewtheresultsoflandmarkclinicaltrialssupportingtheutilizationofestablishedadjunctivemedicaltherapiesinthe periinfarctionandpostinfarctionclinicalsetting. 2. RecognizepharmacologicinterventionsthatareefficaciousandrecommendedforthetreatmentofpatientswithST segmentelevationmyocardialinfarction(STEMI). 3. Identifytheindicationsandcontraindicationsforspecificadjunctivemedicaltherapiesintheindividualpatientfollowing STEMI.

Introduction
Despiteoptimalandtimelyreperfusionstrategies,patientsremainatheightenedriskforrecurrentcardiovascular(CV) eventsbothintheacuteandconvalescentphasefollowinganacuteSTEMI.Theunderlyingmechanismoftheseevents maybeischemicduetoresidualorprogressionofatheroscleroticcoronaryarterydisease(CAD),arrhythmicsecondary tothetriggeroflatentischemiaorarisingfromthereentrantsubstrateprovidedbytheinfarctscar,orrelatedtoheart failure(HF)secondarytothedeleteriousconsequencesofadverseventricularremodelingfollowingtheprimaryinfarction event. Inthispopulation,thegoalofmedicalinterventionisfocusedonreducingtheriskofCVdeath,recurrentmyocardial infarction(MI),theburdenofangina,andtheadverseconsequencesofasymptomaticandsymptomaticleftventricular (LV)dysfunction.Wellpoweredrandomizedclinicaltrialshaveestablishedthebenefitofanumberofmedical interventionsinthissetting. Thismodulewillreviewthedatafromclinicaltrialsthatserveastheevidencebaseguidingmedicaltherapeuticsafter acuteMI(AMI),andtherelevantconsensusrecommendationsfromthe2004AmericanCollegeofCardiology/American HeartAssociation(ACC/AHA)GuidelinesfortheManagementofPatientsWithSTEMIandthe2008FocusedUpdate.13It willsummarizetheroleofbetablockers,angiotensinconvertingenzyme(ACE)inhibitors(ACEIs),angiotensinreceptor blockers(ARBs),aldosteroneblockers,nitrates,calciumchannelblockers(CCBs),andstatintherapyinthissetting. Detailedinformationregardingtheuseofantiplatelettherapieswillbepresentedinanalternatemodule.Chapter14: Arrhythmiashighlightstheprimaryandsecondaryindicationsorpacingandintracardiacdefibrillatorplacementfollowing STEMI.

BetaBlockers
Betablockersshouldbeadministeredinboththeacutepatientandthe postdischargemanagementofpatientswithSTEMI.Theseagentsdecreaseheart rate,systemicbloodpressure,andmyocardialcontractility,allofwhichare determinantsofincreasedmyocardialoxygendemand.Earlytrialsinthe prereperfusionerashowedadecreaseininfarctsize,areducedriskofreinfarction, andadeclineinthefrequencyofsignificantventriculartachyarrhythmiawiththese agents.Initialtrialsutilizingintravenous(IV)betablockadewereassociatedwitha mortalitybenefit.IntheISIS1(FirstInternationalStudyofInfarctSurvival)trial(n= 16,000),administrationof510mgofIVatenolol,followedbyongoingtreatmentwith 100mgdailyinpatientswithsuspectedMI,wasassociatedwithmortalitybenefitat 24hoursthatwasmaintainedat1week(6livessavedper1,000treated).4 IntheMIAMI(MetoprololinAcuteMyocardialInfarction)trial,IVinitiationofmetoprolol (three5mginjectionsat2minuteintervals),followedbyoraldosing(200mgdaily) within24hoursofonsetofsymptoms,wascomparedwithplaceboamong5,778 patientshospitalizedwithAMI.5 After15days,therewasanonsignificant13%lower rateofdeath(p=0.29)inthemetoprololgroup.Onsubgroupanalysis,therewasa 29%lowermortalityamongtheonethirdofhighriskpatients(definedasthe presenceof>3ofthefollowingeightbaselinevariables:age>60years,presenceof abnormalelectrocardiogram[ECG],historyofMI,hypertension,anginapectoris, congestiveheartfailure[CHF],diabetes,diuretic/digoxinutilization),whereaslow riskpatientsderivednobenefit. Currentevidence,however,doesnotsupportthesystematicearlyutilizationofIV betablockadeforallSTEMIsubjects.IntheCOMMIT/CCS2(Randomized,Placebo ControlledTrialofAddingClopidogreltoAspirinin46,000AcuteMyocardialInfarction Patients)megatrial(n=54,852),randomizationtometoprolol(5mgIVx3)within24 hoursofsuspectedMI,followedby200mgoflongactingmetoprolol,was associatedwithadecreaseinreinfarction(5per1,000treated)andtheneedfor ventriculardefibrillation(5per1,000treated),butalsoresultedinanincreaseinthe ratesofobservedcardiogenicshock(11per1,000treated)withnooverallmortality benefitwhencomparedtoplacebo.6 Asaresult,routineIVbetablockadeshouldnotbeadministeredtopatientswiththe following:1)signsofacuteHF,2)evidenceofalowoutputstate,3)increasedrisk forcardiogenicshock,or4)relativecontraindicationstobetablockade(prolonged PR>0.24seconds,secondorthirddegreeheartblock,activeasthma,orreactive airwaydisease).IVtreatmentmaybeconsideredinpatientswhoarehypertensive andinsubjectswithrapidventricularratesorongoingischemia,intheabsenceof severeLVdysfunctionormedicalcontraindications.Ametaanalysisexcluding COMMITpatientsatriskforcardiogenicshockshowedanoveralltreatmentbenefit forIVbetablockadeinthispopulation(Figure1).6 Intheabsenceofcontraindications,allpatientsfollowingSTEMIshouldbeplaced onoralbetablockadeduringthesubacuteandconvalescentphasefollowing STEMI.PatientswhobenefitmaximallyincludethosewithimpairedLVfunction, clinicalHF,andventriculararrhythmiaandthosenottreatedwithreperfusiontherapy. IntheBHAT(BetaBlockerHeartAttackTrial),thenonselectivebetablocker propranololwasinitiatedorally521daysfollowingMIin3,837participants.7 Ata mean25monthfollowup,ahighlysignificant26%reductionintotalmortalitywas notedamongpatientsrandomizedtopropranolol(7.2%vs.9.8%),andsimilar resultswerealsonotedwithtimololintheNorwegianNifedipineMultiCenterTrial.8 TheCAPRICORN(CarvedilolPostInfarctSurvivalControlledEvaluation)trial comparedcarvedilol,anonselectivebetablockerwith1 adrenergicreceptor blockingactivity,initiated321daysafterMI(at6.25mgorallytwicedailyand increasedto25mgtwicedailyover46weeks),withplaceboin1,959patientsafter AMIwithdocumentedLVejectionfraction(LVEF)of40%.9 Atmeanfollowupof15 months,allcausemortalitywas23%lowerinthecarvedilolgroupthaninthe placebogroup(p=0.03).A59%reductionintheoccurrenceofatrialfibrillationor atrialflutteranda76%reductionintheoccurrenceofventriculartachycardiaor

Figure1

ventricularfibrillationwithcarvediloltreatmentwerealsoreported.Althoughlong termdatabeyond23yearsarelacking,itappearsreasonabletocontinuebeta blockadeindefinitelyifthemedicationiswelltolerated. Asaspecialcircumstance,coronaryvasoconstrictionmayplayadominantrolein cocaineinducedMI.Betablockadehasbeennotedtopotentiatevasospasminthis settingandshouldbeavoided.10Labetalol,whichhasalphaandbetablocking properties,however,hasbeenshowntodecreasesystemicbloodpressureinthis settingwithoutincreasingcoronaryvascularresistance.11 ACC/AHASTEMIGuidelinesforBetaBlockers ClassI Oralbetablockertherapyshouldbeinitiatedinthefirst24hoursforpatientswhodo nothaveanyofthefollowing:1)signsofHF,2)evidenceofalowoutputstate,3) increasedriskforcardiogenicshock,or4)otherrelativecontraindicationstobeta blockade(PR>0.24seconds,secondorthirddegreeheartblock,activeasthma,or reactiveairwaydisease).(ClassI,LevelofEvidenceB.) Patientswithearlycontraindicationswithinthefirst24hoursofSTEMIshouldbere evaluatedforcandidacyforbetablockertherapyassecondaryprevention.(ClassI, LevelofEvidenceC.) PatientswithmoderateorsevereLVfailureshouldreceivebetablockertherapyas secondarypreventionwithagradualtitrationscheme.(ClassI,LevelofEvidenceB.) ClassIIa ItisreasonabletoadministeranIVbetablockeratthetimeofpresentationtoSTEMI patientswhoarehypertensiveandwhodonothaveanyofthefollowing:1)signsof HF,2)evidenceofalowoutputstate,3)increasedriskforcardiogenicshock,or4) otherrelativecontraindicationstobetablockade(PR>0.24seconds,secondor thirddegreeheartblock,activeasthma,orreactiveairwaydisease).(ClassIIa,Level ofEvidenceB.) ClassIII IVbetablockersshouldnotbeadministeredtoSTEMIpatientswhohaveanyofthe following:1)signsofHF,2)evidenceofalowoutputstate,3)increasedriskfor cardiogenicshock,or4)otherrelativecontraindicationstobetablockade(PR>0.24 seconds,secondorthirddegreeheartblock,activeasthma,orreactiveairway disease).(ClassIII,LevelofEvidenceA.) Riskfactorsforcardiogenicshockincludeage>70years,systolicbloodpressure (SBP)<120mmHg,sinustachycardia>110bpmorheartrate<60bpm,and increasedtimesinceonsetofsymptomsofSTEMItopresentation(thegreaterthe numberofvariablespresent,thegreatertherisk).

MetaAnalysisoftheEffectsofEarlyBetaBlockerTherapyAfterAMI Figure1 Metaanalysisoftheeffectsofintravenousandthenoralbetablockertherapyondeath,reinfarction,andcardiacarrestduringthescheduled treatmentperiodstestedinmorethan50,000patientsin26smallrandomizedtrials,theMIAMItrial,theISIS1trial,andthesubsetofpatientsinthe COMMITtrialatlowriskfordevelopingshock.Notethesignificantbenefitforpatientsnotathighriskforcardiogenicshock.(99%confidence intervals[CIs]areusedfortheindividualtrials,whereasa95%CI,representedbyadiamond,isusedforoverallresults.) SE=standarderror. ReproducedwithpermissionfromChenZM,PanHC,ChenYP,etal.Earlyintravenousthenoralmetoprololin45,852patientswithacute myocardialinfarction:randomisedplacebocontrolledtrial.Lancet2005366:162232.

RenalAngiotensinSystemBlockade
AngiotensinConvertingEnzymeInhibitors AngiotensinIIisapotentvasoconstrictorthatisformedbytheconversionof angiotensinItoangiotensinIIbyACEinthekidney.Inhibitionofthisenzymeresults insystemicvasodilationandareductioninLVafterload.Thesehemodynamic effects,aswellasputativelocaltissueleveleffectswithinthemyocardiumand vasculature,promotebeneficialeffectsonLVwallstressandattenuatedeleterious remodeling. AlargebodyofevidencesupportstheutilizationofACEIsinpatientswithLV dysfunctioninthesettingofSTEMI.BenefitswerefirstnotedintheSAVE(Survival andVentricularEnlargement)trial(n=2,231)thatrandomizedpatientswithanLVEF of<40%(butwithoutovertHForsymptomsofmyocardialischemia)316days (mean11days)afterindexMItoreceivecaptopril(2550mgthreetimesdaily)or placebo,withasubsequentmeanclinicalfollowupof42months.12Thecaptopril groupshowedasignificant19%reductioninallcausemortalityanda37% reductioninthedevelopmentofsevereCHF. TheSMILE(SurvivalofMyocardialInfarctionLongTermEvaluation)trialevaluated zofenoprilin1,556subjectswithanteriorwallMIrandomizedtoACEinhibition versusplacebowithin24hoursofinfarction.13At1year,relativemortalitywith zofenoprilwassignificantlydecreasedby29%(14vs.10%p=0.011).TheAIRE (AcuteInfarctionRamiprilEfficacyStudy)randomized2,006subjectswithclinicalHF complicatingMIatameanof5daystoramiprilversusplacebo.14Atanaverageof 15monthsfollowup,allcausemortalitywasreducedby27%withramipril(17vs. 23%p=0.002).TheTRACE(TheTrandolaprilCardiacEvaluationTRACEStudy) randomized2,606patientswithLVEF<35%totrandolaprilorplaceboatamedianof 4daysfollowingMI.15Theobservedmortalitywithtrandolaprilwas34%compared with42%withplaceboduringthestudyperiod(p=0.001). SystematicACEinhibitioninitiatedwithinthefirst24hoursfollowingSTEMIisalso associatedwithclinicalbenefit.TheGISSI3(EffectsofLisinoprilandTransdermal GlycerolTrinitrateSinglyandTogetheron6weekMortalityandVentricularFunction afterAMI)trialrandomized19,394patientswithMItolisinopril(5mginitialdoseand then10mgdaily)orplaceboandreportedasignificant12%reductionin6week mortalitywithACEinhibition.16TheISIS4(FourthInternationalStudyofInfarct Survival)randomized58,050patientsatamedianof8hoursfollowingSTEMIto captopril(6.25mginitialdosetitratedupto50mgtwicedaily)orplaceboand reportedasignificant7%reductionin5weekmortalitywithcaptopriltreatmentthat translatedintoapproximately5livessavedper1,000treated.17 Inaggregate,randomizedclinicaltrialsinvolving>100,000patientshave demonstratedthatACEIuseamongpatientswithAMIwithoutcontraindications significantlyreducestheriskofdeathandmajornonfatalCVevents.17Thegreatest benefitsareseenwithlongtermACEItherapyinhighriskpatientswithLV dysfunction,signsorsymptomsofCHF,orboth(Figure2). WhilerandomizedtrialshavedemonstratedabenefitoforalACEIsafterMI,IVACEIs arenotrecommendedintheSTEMIsetting.ThisisbasedontheCONSENSUSII (TheEffectsoftheEarlyAdministrationofEnalaprilonMortalityinPatientswithAcute myocardialinfarction:ResultsoftheCooperativeNewScandin)trial,inwhich6,090 patientspresentingwithSTEMIwererandomizedwithin24hoursofsymptomonset toreceiveIVenalaprilatfollowedbyoralenalaprilorplacebo.18Therewasno significantdifferenceinallcausemortalityat6monthsbytreatmentassignment, andtheincidenceofdeathduetoprogressiveHFwasincreased26%inthe enalaprilgroup(p=0.06).Theharmfuleffectsobservedinthistrialhavebeen attributedtoearlyhypotension,anadversereactionthatwassignificantlymore frequentintheenalaprilattreatedgroup. AlthoughinitialtrialsofACEinhibitionfocusedprimarilyonthefavorableeffectsof ACEinhibitiononventricularremodeling,the25%reductioninrecurrentMIobserved
Figure2

Figure3

Figure4

intheSAVEtrialresultedintheconductofclinicaltrialsinsubjectswithestablished CAD,butwithoutclinicalHF.Thesetrialswereperformedinthesettingofstable CADbutmaybeextrapolatedtosecondarypreventioninpatientsfollowingSTEMI. TheHOPE(HeartOutcomesPreventionEvaluationStudy)randomized9,297 subjects(52%withapriorMI)toramipril10mg/dayversusplaceboover46years andobservedrelativeriskreductionof20%,32%,and16%ontheindividual endpointsofMI,stroke,andallcausemortality,respectively.19 TheEUROPA(EuropeanTrialonReductionofCardiacEventswithPerindoprilin StableCoronaryArteryDisease)trialevaluated13,655patientswithCADand withoutCHFtoperindopril8mg/daycomparedwithplacebo.20Overameanfollow upof4.2years,arelativeriskreductionof20%wasobservedonthecombined endpointofnonfatalMI,CVmortality,andresuscitatedcardiacarrest.Incontrast, thePEACE(PreventionofEventsWithAngiotensinConvertingEnzymeInhibition Trial)randomized8,290patientswithstableCADtotrandolapril(4mg/day)or placebo.21Morethan72%ofsubjectshadundergonerevascularizationpriorto randomization.Overameanfollowupperiodof4.8years,theincidenceofthe primaryendpoint,acompositedeathfromCVcauses,MI,orcoronary revascularization,wassimilar. Insummary,patientswithSTEMIandLVdysfunctionshouldbetreatedwithanACEI intheabsenceofcontraindications.DiabeticsshouldalsobetreatedwithanACEI giventhefavorableeffectsonrenovascularprotection.ACEIsalsomaybeutilizedto treathypertensivesubjectstotheirtreatmentgoal.Finally,datafromtrialsofpatients withstableCADsuggestthatACEinhibitionshouldbestronglyconsideredinall patientsfollowingMI. ACC/AHASTEMIGuidelinesforAngiotensinConvertingEnzymeInhibition ClassI.ACEIsshouldbestartedandcontinuedindefinitelyinallpatientsrecovering fromSTEMIwithLVEF40%andinthosewithhypertension,diabetes,orchronic kidneydisease,unlesscontraindicated.(ClassI,LevelofEvidenceA.) ClassI.ACEIsshouldbestartedandcontinuedindefinitelyinpatientsrecovering fromSTEMIwhoarenotlowerrisk(lowerriskdefinedasthosewithnormalLVEFin whomCVriskfactorsarewellcontrolledandrevascularizationhasbeenperformed), unlesscontraindicated.(ClassI,LevelofEvidenceB.) ClassIIa.AmonglowerriskpatientsrecoveringfromSTEMI(i.e.,thosewithnormal LVEFinwhomCVriskfactorsarewellcontrolledandrevascularizationhasbeen performed),useofACEIsisreasonable.(ClassIIa,LevelofEvidenceB.) AngiotensinReceptorBlockers IthasbeenrecognizedthatACEIsarecapableofblockingonlypartofthetotal productionofangiotensinIIintheCVsystem.Therefore,considerationwasgivento theconceptthatagentsthatdirectlyblocktheangiotensintypeIreceptor,orARBs, mighttheoreticallyprovidesuperiorresults.Further,despitetheirprovenclinical efficacyforpatientswithCHFandAMI,notallpatientstolerateACEIs(e.g.,some patientsdevelopintractablecough),andreplacementagentsinthissettingare warranted. IntheOPTIMAAL(EffectsofLosartanandCaptoprilonMortalityandMorbidityin HighRiskPatientsAfterAcuteMyocardialInfarction)trial,5,477patientswithCHF afterAMIwererandomlyassignedtolosartan(50mg/day)orcaptopril(50mgthree timesdaily).22Althoughlosartanwassignificantlybettertoleratedthancaptopril,at anaverageof2.7years,therewasanonsignificant(p=0.07)relative13%increase intherateofallcausedeathandasignificantincreaseintherateofdeathfromCV causesseeninthelosartangroup. IntheVALIANT(ValsartaninAcuteMyocardialInfarctionTrialInvestigators)trial,the ARBvalsartanwascomparedwithcaptoprilandthecombinationofvalsartanand captoprilbyrandom1:1:1assignmentof14,808patientswithAMIcomplicatedbyLV systolicdysfunction,CHF,orboth.23Treatmentwasinitiatedat0.510daysafterAMI. At25months,therewasnosignificantdifferencebetweenvalsartanandcaptopril withrespecttoallcausemortalityorintherateoffatalandnonfatalCVevents (Figure3).Thecombinationstrategyofvalsartanwithcaptoprilresultedinan

increasedrateofadverseeventswithoutimprovingsurvival.Ofnote,valsartanmet theprespecifiedcriteriafornoninferioritycomparedwithcaptopril,andthestudy concludedthatvalsartanstartedafterAMIwasaseffectiveascaptopril. TheCHARMAlternative(CandesartaninHeartFailureAlternativeTrial)also supportstheutilizationofcandesartaninthesettingofACEIintoleranceinpatients withHFfollowingAMI.24UnlikeVALIANT,intheCHARMAdded(Candesartanin HeartFailureAddedTrial),thecombinationofcandesartanatatargetdoseof32mg inadditiontoanACEIwasnotedtobesuperiortoplacebowhentestedonpatients withLVEF<40%andsymptomaticHFwitha4%absolutereductioninpreventingCV deathandreadmissionforHF.25 ACC/AHASTEMIGuidelinesforUtilizationofAngiotensinReceptorBlockers ClassI.UseofARBsisrecommendedinpatientswhoareintolerantofACEIsand haveHForhavehadanMIwithLVEF40%.(ClassI,LevelofEvidenceA.) ItisbeneficialtouseARBtherapyinpatientswhoareACEIintolerantandhave hypertension.(ClassI,LevelofEvidenceB.) ClassII.ConsideringtheuseincombinationwithACEIsinsystolicdysfunctionHF maybereasonable.(ClassII,LevelofEvidenceB.) AldosteroneAntagonists AldosteroneappearstoaffectmultipleprocessesthatmaybedeleterioustoCV physiology,includingplasmavolumehomeostasis,electrolytebalance, inflammation,collagenformation,andmyocardialfibrosisandremodeling.The aldosteroneblockerspironolactonewasshowntoreduceadverseevents,including death,inpatientswithsevereHFduetochronicLVsystolicdysfunctionintheRALES (RandomizedAldactoneEvaluationStudy).26 TheEPHESUS(EplerenonePostAMIHeartFailureEfficacyandSurvivalStudy) testedtheuseoftheselectivealdosteroneblockereplerenoneinpatientswithAMI complicatedbyLVsystolicdysfunction.27IntheEPHESUSstudy,6,632patients3 14daysafterAMIwithanLVEF40%andCHFdocumentedbyralesoranLVS3 on examorchestxray,orthoughttobeathighriskbythepresenceofdiabetes,were included.Patientswithserumcreatinine>2.5mg/dl,withserumpotassium>5.0 mmol/L,orreceivingapotassiumsparingdiureticwereexcluded.Atameanfollow upof16months,assignmenttoeplerenonewasassociatedwithahighlysignificant 15%lowerrateofallcausemortalityand21%reductioninsuddencardiacdeath whencomparedwithplacebo(Figure4).Eplerenonereducedtheriskofsudden cardiacdeathamongallincludedpatientsby37%(p=0.051)andamongthoseat veryhighrisk(EF30%)by58%(p=0.008). ThebenefitofeplerenoneintheEPHESUSstudywasobservedamongpatients whowerealreadytreatedoptimallywithACEIs,ARBs,diuretics,andbetablockersat thetimeofrandomization,suggestingthattheadditionofeplerenonetooptimal medicaltherapycanreducemortalityandmorbidityamongpatientswithAMI complicatedbyLVdysfunctionandsignsofCHFordiabetes,withasmallbut significantriskofserioushyperkalemia.Carefullaboratorymonitoringiswarranted astherateofserioushyperkalemiawasincreasedbyabsolute1.6%inthe eplerenonegroup.Independentbaselinepredictorsofhyperkalemiaincluded serumpotassium>4.3mEq/L,estimatedglomerularfiltrationrate<60ml/min/1.73 m 2 ,ahistoryofdiabetesmellitus,andprioruseofantiarrhythmics. ACC/AHASTEMIGuidelinesforUtilizationofAldosteroneAntagonists ClassI.UseofaldosteroneblockadeinpostMIpatientswithoutsignificantrenal dysfunctionorhyperkalemiaisrecommendedinpatientswhoarealreadyreceiving therapeuticdosesofanACEIandbetablocker,haveanLVEF40%,andhaveeither diabetesorHF.(ClassI,LevelofEvidenceA.)

EffectofEarlyACEITherapyonMortalityAfterAMI Figure2 SystematicoverviewoftheeffectsonshorttermmortalityofstartingACEIsearlyinAMItestedin>100,000patientsinrandomizedtrials.(99% CIsareusedfortheindividualtrials,whereasa95%CI,representedbyadiamond,isusedfortheoverallresult.). ACEIs=angiotensinconvertingenzymeinhibitorsAMI=acutemyocardialinfarctionCEI=convertingenzymeinhibitorCIs=confidence intervalsSD=standarddeviation. Reproducedwithpermissionfrom[Noauthorslisted].ISIS4:arandomizedfactorialtrialassessingearlyoralcaptopril,oralmononitrate,and intravenousmagnesiumsulphatein58,050patientswithsuspectedAMI.ISIS4(FourthInternationalStudyofInfarctSurvival)Collaborative Group.Lancet1995345:66985.

EffectsofValsartan,Captopril,orBothAfterAMIintheVALIANTTrial Figure3 KaplanMeierestimatesoftherateofdeathfromanycause(PanelA)andtherateofdeathfromcardiovascularcauses,reinfarction,or hospitalizationforheartfailure(PanelB),accordingtotreatmentwithvalsartan,captopril,orbothintheVALIANTtrial(p=notsignificantforall comparisons). ReproducedwithpermissionfromMassachusettsMedicalSociety.PfefferMA,McMurrayJJ,VelazquezEJ,etal.Valsartan,captopril,orbothin myocardialinfarctioncomplicatedbyheartfailure,leftventriculardysfunction,orboth.NEnglJMed2003349:1893906.Copyright2003, MassachusettsMedicalSociety.Allrightsreserved.

EffectofAldosteroneblockadewithEplerenoneComparedtoOpyimalMedicalTherapyinPatientswithAMIComplicatedbyLeftVenticular Dysfunction Figure4 KaplanMeierestimatesoftherateofdeathfromanycause(PanelA),therateofdeathfromcardiovascularcausesorhospitalizationfor cardiovascularevents(Panelb),andtherateofsuddendeathfromcardiaccauses(PanelC)fortreatmentwitheplerenoneversusplaceboin theEPHESUStrial. RR=relativeriskCI=confidenceinterval. ReproducedwithpermissionfromMassachusettsMedicalSociety.PittB,RemmeW,ZannadFetal.Eplerenone,aSelectiveAldosteroneBlocker, inPatientswithLeftVentricularDysfunctionafterMyocardialInfarction.NEnglJMed2003348:130921.Copyright2003,Massachusetts MedicalSociety.Allrightsreserved.

Nitrates
Nitratesdilatevenousandarterialsmoothmuscle,resultinginareductioninventricularfillingpressuresandarterial bloodpressure,effectsthatreducemyocardialoxygendemandandreducemyocardialischemia.Nitratesalsodirectly dilatecoronaryarteries,favorablyimpactoncollateralflow,andrelievevasoconstriction.Theireffectonmortalityinthe fibrinolyticerawastestedintwolargescalerandomized,controlled,factorialdesigntrials,theGISSI316andISIS4.17 IntheGISSI3trial,19,394AMIpatientswithin24hoursofsymptomonsetwererandomlyassignedtotreatmentwith nitratetherapy(IVglyceryltrinitrate[GTN]forthefirst24hoursfollowedbytransdermalGTN10mgdaily)oropencontrol. At6weekfollowup,GTNdidnotsignificantlyimproveoutcome,resultinginanonsignificant6%lowerallcausemortality. InISIS4,58,050patientsupto24hoursaftertheonsetofsuspectedAMIwererandomizedtoreceive1monthoforal controlledreleasemononitrate(30mginitialdosetitratedupto60mgoncedaily)orplacebo.At5weekfollowup,there wasnosignificantreductioninmortalitybyassignmenttomononitrate. Asubsequentpooledanalysisof>80,000patientstreatedintravenouslyororallywithnitratessuggestedasignificant 5.5%relativereductioninshorttermmortalitybynitratetherapy.Thiseffecttranslatesinto34fewerdeathsforevery 1,000treatedpatients.17Inthecurrentreperfusionera,themortalitybenefitwithnitratesisuncertain. ACC/AHASTEMIGuidelinesforUtilizationofNitrates ClassI Patientswithongoingischemicdiscomfortshouldreceivesublingualnitroglycerin(0.4mg)every5minutesforatotalof3 doses,afterwhichanassessmentshouldbemadeabouttheneedforIVnitroglycerin.(ClassI,LevelofEvidenceC.) IVnitroglycerinisindicatedforthereliefofongoingischemicdiscomfort,controlofhypertension,ormanagementof pulmonarycongestion.(ClassI,LevelofEvidenceC.) ClassIII NitratesshouldnotbeadministeredtopatientswithSBP<90mmHgor>30mmHgbelowbaseline,severebradycardia (lessthan50bpm),tachycardia(>100bpm),orsuspectedrightventricularinfarction.(ClassIII,LevelofEvidenceC.) Nitratesshouldnotbeadministeredtopatientswhohavereceivedaphosphodiesteraseinhibitorforerectiledysfunction withinthepast24hours(48hoursfortadalafil).(ClassIII,LevelofEvidenceB.)

CalciumChannelBlockers
CCBshaveestablishedefficacyintreatinganginaandhypertension.Agentswithinthisclass,tovariabledegrees,cause vasodilation,mayslowatrioventricular(AV)nodalconduction,andmayreducemyocardialcontractility.CCBsarenotfirst linetherapy,anddatainthesettingofSTEMIaremorethantwodecadesold.Theeffectofearlyadministrationofthe shortactingdihydropyridineCCBnifedipineonoutcomeafterAMIwascomparedwithplacebointworandomizedtrials involving1,177patients.28,29Notably,inpooledresultsfromthesetwotrials,theshorttermmortalitywassignificantly increasedby60%inthenifedipinetreatedpatients.Shortactingnifedipineshould,therefore,notbeadministeredto patientsintheearlyphaseofSTEMI. TheeffectsofthenondihydropyridineCCBsverapamilanddiltiazeminitiatedlaterafterAMIwerestudiedintheDAVITII (DanishStudyGrouponVerapamilinMI)trial30andtheMDPIT(MulticenterDiltiazemPostInfarctionTrial),31respectively, anddiltiazemwasalsostudiedinthesettingofnonQwaveMI.32IntheDAVITIItrial,1,775patients715daysafterAMI wererandomlyassignedtoverapamilorplacebo.Atameanfollowupof16months,therewasanonsignificant20% lowerrateofdeathintheverapamilgroup.Insubgroupanalysis,amongpatientswithoutHFintheintensivecareunit,the mortalityratewasreducedby36%withverapamiltreatment(p=0.02).TheMulticenterDiltiazemPostinfarctionTrial ResearchGrouprandomized576patients2472hoursfollowinganonQwaveMItodiltiazemversusplacebo.31Over twoweeks,assignmenttodiltiazemtreatmentwasassociatedwithasignificant51.2%reductionintheincidenceof reinfarctionand49.7%reductioninthefrequencyofrefractorypostinfarctionangina. InMDPIT,2,466patientswererandomlyassignedtoreceivediltiazemorplaceboat315daysafterAMIandfollowedfora meanof25months.Overallmortalityandadversecardiaceventsweresimilarinthediltiazemandplacebogroups,buta significantinteractionwasobservedbetweendiltiazemtreatmentandpulmonarycongestion(detectedradiographically) orLVsystolicdysfunction(EF<40%).Amongthe>75%oftrialparticipantswithoutpulmonarycongestion,diltiazem treatmentconferredbenefitwithasignificant23%reducedrateofadversecardiacevents.Inthenearly20%ofpatients withpulmonarycongestionorLVdysfunction,diltiazemwasassociatedwithhazard,withasignificant41%increasein therateofadversecardiacevents. Inaggregate,theseresultssuggestthatthenondihydropyridineCCBsverapamilanddiltiazemmaybebeneficialafter AMIforpatientswithnosignsofCHFandpreservedLVsystolicfunctionbutshouldbeavoidedforanypatientwithCHFor LVsystolicdysfunction.EvenamongpatientswithpreservedEFafterAMI,theweightofevidencefavorslongtermuseof betablockersoverCCBsforallpatientswithoutcontraindications. ACC/AHASTEMIGuidelinesforUtilizationofCalciumChannelBlockers ClassIIa Itisreasonabletogiveverapamilordiltiazemtopatientsinwhombetablockersareineffectiveorcontraindicated(e.g., bronchospasticdisease)forreliefofongoingischemiaorcontrolofarapidventricularresponsewithAForatrialflutter afterSTEMIintheabsenceofCHF,LVdysfunction,orAVblock.(ClassIIa,LevelofEvidenceC.) ClassIII DiltiazemandverapamilarecontraindicatedinpatientswithSTEMIandassociatedsystolicLVdysfunctionandCHF. (ClassIII,LevelofEvidenceA.) Nifedipine(immediatereleaseform)iscontraindicatedinthetreatmentofSTEMIbecauseofthereflexsympathetic activation,tachycardia,andhypotensionassociatedwithitsuse.(ClassIII,LevelofEvidenceB.)

GlucoseControlinPatientsWithAcuteMyocardialInfarction
ThemanagementofhyperglycemiainthesettingofAMIisunclear.PriorguidelinesgaveaclassIbrecommendationto theuseofIVinsulininfusioninpatientswithacomplicatedcoursefollowingSTEMIwithagoalofnormalizingblood glucose.ThesefindingswerelargelybasedonresultsfromtheDIGAMI(DiabeticInsulinGlucoseInfusioninAcuteMI) studythatrandomized620diabeticpatientstointensiveinsulintherapywithaninsulinglucoseinfusionfor24hours followedby3monthsofsubcutaneousinjectionsofinsulin4timesdailyorusualcare.33Inthisstudy,theuseof continuousinsulininfusiondecreasedbloodglucoselevelsinthefirst24hoursfrom15.4to9.6mmol/Lintheinfusion groupcomparedwithareductionfrom15.7to11.7mmol/Linthecontrolgroup(p<0.0001).Thesebiochemicaleffects wereassociatedwithatrendtowardlower30daymortalityandsignificantlylower1yearmortality(18.6%vs.26.1%,p= 0.027). Trialsconductedintheintensivecaresettinghavearrivedatdifferingconclusions.Inastudyofintensivecareunit patients,alargeproportionofwhomhadundergonecoronaryarterybypassgraftsurgery,the12monthmortalityrates werereducedfrom8.0%to4.6%(p<0.04n=1,548)utilizingatargetof80110mg/dlofglucosecomparedwith standardcare.34ThewidespreadacceptanceofthisstudyhasbeentemperedbytheresultsoftheNICESUGAR (NormoglycemiainIntensiveCareEvaluationSurvivalUsingGlucoseAlgorithmRegulation)trial.35Inthistrialof6,014 criticallyillpatients,intensiveglucoselowering(targetglucose81108mg/dl)wasassociatedwithanabsoluteincreased riskofdeathat90daysof2.6%,translatingtoanumberneededtoharmof38andincreasedratesofhypoglycemia comparedwithconventionalglucosecontrolwithatargetof<180mg/dlandhasledtoamodificationofthecurrent guidelines. ACC/AHASTEMIGuidelinesforUtilizationofIntravenousInsulin ClassIIa Itisreasonabletouseaninsulinbasedregimentoachieveandmaintainglucoselevels<180mg/dlwhileavoiding hypoglycemiaforpatientswithSTEMIwitheitheracomplicatedoruncomplicatedcourse.(ClassIIa,LevelofEvidenceB.) DiabeticpatientswithSTEMIareathighriskforrecurrentCVevents.Informationregardingthechoiceofglucoselowering agentondischargecanbeextrapolatedfromtheBARI2D(BypassAngioplastyRevascularizationInvestigation2 Diabetes)trial.36Thisstudyrandomized2,368patientswithbothtype2diabetesandheartdiseasetoundergoeither insulinsensitizationorinsulinprovisiontherapy.At5years,ratesoffreedomfromthecompositeofdeath,MI,andstroke were77.7%intheinsulinsensitizationgroupand75.4%intheinsulinprovisiongroup(p=0.13),suggestingsimilar outcomes.TheglycemicgoalsoftreatmentfollowingdischargewithanMIshouldbemodest. TheACCORD(ActiontoControlCardiovascularRiskinDiabetes)trialrandomized10,251patientswithtype2diabetes mellitus(meanage62.2years)withamedianglycatedhemoglobin(HbA1c)levelof8.1%onenrollmenttoastrategyof intensivetherapy(HbA1cgoalof<6.0%)orstandardtherapy(HbA1cof7.07.9%).37At3.5yearsoffollowup,intensive treatmentresultedinatrendtowarddetrimentaloutcomesforthecompositeofdeath,MI,andstroke(hazardratio[HR], 0.9095%confidenceinterval[CI],0.781.04p=0.16)withincreasedhazardfordeath(HR,1.2295%CI,1.011.46p= 0.04).Similarly,noCVbenefitswereobservedwithintensiveglucosecontrolintheVADT(VeteransAffairsDiabetes Trial),38andtheADVANCE(ActioninDiabetesandVascularDisease:PreteraxandDiamicronModifiedRelease ControlledEvaluation)37trial.

LipidTherapy
InthehospitalphaseoftreatmentofAMI,determinationofapatient'slipidprofileand initiationofinterventionstomanagedyslipidemiaandpromotesecondaryprevention arepartofroutinemanagementthatarestronglysupportedbyclinicaltrialevidence. Inparticular,theuseofhydroxymethylglutarylcoenzymeAreductaseinhibitors (statins)hasbeenextensivelyinvestigatedandisestablishedasanimportantdrug classforbothloweringatherogeniclipidsandreducingfutureadverseCVevents. Severaltrialshavespecificallystudiedtheeffectofstatinsonoutcomeinpatients followingacutecoronarysyndromes(ACSs)orAMI.IntheCARE(Cardiac AngiographyinRenallyImpairedPatients)trial,4,159patientswithplasmatotal cholesterollevelsof<240mg/dlwereenrolledbetween3and20monthsafterAMI andrandomizedtopravastatin40mg/dayorplacebo.39Afteramedianfollowupof5 years,therateoffatalcoronaryeventsornonfatalMIwasreducedby24%(p= 0.003),thefrequencyofstrokewasreducedby31%(p=0.03),therateofcoronary arterybypassgraftsurgerywasreducedby26%(p=0.005),andtherateofcoronary angioplastywasreducedby23%(p=0.01). ThepotentialbenefitarisingfromearlystatintreatmentwasfirstnotedintheMIRACL (EffectsofAtorvastatinonEarlyRecurrentIschemicEventsinAcuteCoronary Syndromes.TheMIRACLStudy:ARandomizedControlledTrial)thatenrolled3,086 patientswithnonSTelevationACSwhowererandomlyassignedbetween24and 96hoursafteradmissiontotreatmentwithhighdoseatorvastatin(80mg/day)or placebo.40At16weekfollowup,atorvastatinreducedlowdensitylipoprotein(LDL) cholesterolbyanaverageof52%.Theprimarycompositeendpointofdeath, nonfatalAMI,cardiacarrestwithresuscitation,orrecurrentsymptomaticmyocardial ischemiawasreduced16%(p=0.048)byatorvastatin. BenefitsofearlystatininitiationafterAMIwerealsoobservedinaprospective, nonrandomizedcohortstudyusingtheSwedishRegisterofCardiacIntensiveCare (RIKSHIA).41Thestudypopulationconsistedofnearly20,000patientswithafirst AMI,ofwhom5,528receivedstatinsatorbeforedischargeand14,071didnot.Early statintreatmentinitiatedpriortohospitaldischargewasassociatedwitha25% reductionin1yearmortality(p=.001).Inanobservationalstudyusingdataon patientswithACSsfromtheGUSTOIIB(GlobalUtilizationofStreptokinaseandTPA forOccludedArteriesIIb)andPURSUIT(PlateletGlycoproteinIIb/IIIainUnstable Angina:ReceptorSuppressionUsingIntegrilinTherapy)trials,theadjustedmortality rateat6monthswas33%loweramongthe3,653patientsdischargedonlipid loweringagentscomparedwiththe17,156patientswhowerenot(p=0.023).42 Threetrialshaveaddressedtheroleofintensivestatintherapycomparedwithmore moderatedosingregimensinthesettingofACSs.4345ThePROVEITTIMI22Lipid LoweringResults(PravastatinorAtorvastatinEvaluationandInfectionTherapy: ThrombolysisinMyocardialInfarction)trialenrolled4,162patientswithin10daysof hospitalizationforanACSwhowererandomlyassignedto40mgofpravastatinor 80mgofatorvastatin.43Duringthetrial,themediancholesterollevelsofthe pravastatinandatorvastatingroupswere95mg/dland62mg/dl,respectively.By2 years,therewasasignificant16%reduction(p=0.005)inthecompositeofdeath fromanycause,MI,unstableanginarequiringrehospitalization,revascularization, andstrokeinfavorofpatientsassignedtoatorvastatintreatment(Figure5). TheAZ(AggrastattoZocor)trialevaluatedclinicaloutcomesin4,497patientswith ACSrandomizedtosimvastatin40mguptitratedto80mgat1monthcomparedwith 20mgdailyinitiatedat4monthsover2yearsoffollowup.45At8months,the medianLDLintheintensivetreatmentandconservativegroupwas63mg/dland77 mg/dl,respectively.UnlikethePROVEIT(PravastatinorAtorvastatinEvaluationand InfectionTherapy)trial,theoveralleventsrates(acompositeofCVdeath,nonfatal MI,readmissionforACS,andstroke)weresimilarinbothgroups(HR,0.8995%CI, 0.761.04p=.14).Inametaanalysis,intensivetreatmentwithstainsinthesetting ofanACSwasassociatedwithareductioninallcausemortalityrelativerisk0.75 (95%CI,0.610.91p=0.005),translatinginto119patientstobetreatedfor1yearto prevent1CVdeath.46

Figure5

Thesedatasuggestthatearlyinitiationofintensivelipidloweringtherapywith statinsinthehospitalforpatientswithACSs,includingAMI,andcontinued postdischargeusetoachievetargetLDLlevelsofsubstantially<100mg/dlare associatedwithreducedshortandlongtermadverseCVevents.Themodified AdultTreatmentPanelIIIguidelinessuggestthatforhighriskpatients,the recommendedLDLcholesterol(LDLC)treatmentgoalis<100mg/dl47however,a targetof<70mg/dlrepresentsareasonabletherapeuticoptionforpersons consideredtobeatveryhighrisk,suchaspatientsafterAMI. ACC/AHASTEMIGuidelinesforLipidTherapyinSettingofSTEMI ClassI Afastinglipidprofileshouldbeassessedinallpatientsandwithin24hoursof hospitalizationforthosewithanacuteCVorcoronaryevent.(ClassI,Levelof EvidenceA.) Forhospitalizedpatients,lipidloweringmedicationisrecommendedbefore discharge.LDLCshouldbe<100mg/dl.FurtherreductionofLDLCto<70mg/dlis reasonable.(ClassI,LevelofEvidenceA.) IfbaselineLDLCis100mg/dl,LDLloweringdrugtherapyshouldbeinitiated. (ClassI,LevelofEvidenceA.) IfontreatmentLDLCis100mg/dl,intensifyingLDLloweringdrugtherapy(may requireLDLloweringdrugcombination)isrecommended.(ClassI,Levelof EvidenceA.) ClassI Startingdietarytherapyisrecommendedforallpatients.Reduceintakeofsaturated fats(<7%oftotalcalories),transfattyacids,andcholesterol(<200mg/day).(ClassI, LevelofEvidenceB.) Promotionofdailyphysicalactivityandweightmanagementisrecommended. (ClassI,LevelofEvidenceB.) Iftriglyceridesare150mg/dlorhighdensitylipoproteincholesterol(HDLC)is<40 mg/dl,weightmanagement,physicalactivity,andsmokingcessationshouldbe emphasized.(ClassI,LevelofEvidenceB.) Iftriglyceridesare200499mg/dl,nonHDLCtargetshouldbe<130mg/dl.(ClassI, LevelofEvidenceB.) ClassI Iftriglyceridesare500mg/dl,therapeuticoptionsthatareindicatedandusefulto preventpancreatitisarefibrateorniacinbeforeLDLloweringtherapytreatLDLCto goalaftertriglycerideloweringtherapy.AchievingnonHDLC<130mg/dlis recommended.(ClassI,LevelofEvidenceC.) ClassIIa FurtherreductionofLDLCto<70mg/dlisreasonable.(ClassIIa,LevelofEvidence A.) Addingplantstanolsorsterols(2g/day)orviscousfiber(>10g/day)isreasonableto furtherlowerLDLC.(ClassIIa,LevelofEvidenceA.) ClassIIa IfbaselineLDLCis70100mg/dl,itisreasonabletotreattoLDLC<70mg/dl. (ClassIIa,LevelofEvidenceB.) Iftriglyceridesare200499mg/dl,furtherreductionofnonHDLCto<100mg/dlis reasonable.(ClassIIa,LevelofEvidenceB.) Fibratetherapy(afterLDLCloweringtherapy)canbebeneficial.(ClassIIa,Levelof EvidenceB.)

ClassII Itmaybereasonabletoencourageincreasedconsumptionofomega3fattyacidsin theformoffishorincapsules(1g/day)forriskreduction.Fortreatmentofelevated triglycerides,higherdosesareusuallynecessaryforriskreduction.(ClassII,Level ofEvidenceB.)

EffectofIntensiveversusModerateLipidLoweringinPROVEITTIMI22 Figure5 KaplanMeierestimatesoftheincidenceoftheprimaryendpointofdeathfromanycauseoramajorCVeventaccordingtointensivevs. moderatelipidloweringinthePROVEIT/TIMI22trial.Intensivelipidloweringwiththe80mgdoseofatorvastatin,ascomparedwithmoderatelipid loweringwiththe40mgdoseofpravastatin,reducedtheHRfordeathoramajorCVeventby16%. CV=cardiovascularHR=hazardratio. ReproducedwithpermissionfromMassachusettsMedicalSociety.CannonCP,BraunwaldE,McCabeCH,etal.Intensiveversusmoderatelipid loweringwithstatinsafteracutecoronarysyndromes.NEnglJMed2004350:1495504.Copyright2004,MassachusettsMedicalSociety.All rightsreserved.

Warfarin
TheuseoforalanticoagulationwithwarfarinforsecondarypreventionfollowingAMIhasbeenstudiedinrandomized clinicaltrialsfollowingfibrinolysis.4851Ingeneral,thesetrialsshowedmodestbenefitforwarfarinwithrespectto reductionofcompositeischemicendpoints,butnoneshowedareductioninmortalityandallreporteda2035%rateof drugdiscontinuationandahigherrateofbleedingwithwarfarintherapy. Thereisnoroleforroutinewarfarintherapyinpatientsfollowingprimarypercutaneouscoronaryintervention(PCI).The useofwarfarinshouldonlybeconsideredwhenthereareprimaryindicationsforanticoagulationsuchasAF,prosthetic metallicheartvalves,documentedmuralLVthrombus,oralargeakineticordyskineticLVsegment.Forthelattertwo indications,treatmentforatleast3monthsisrecommended. Whenwarfarinisusedalone,aninternationalnormalizedratio(INR)of2.53.5isrecommended.Whenwarfarinis combinedwithaspirin,thedoseofaspirinshouldbekeptlow(75162mg),andtheINRshouldbemaintainedinthe rangeof2.03.0.Therisksofbleedingcomplicationsshouldbeweighedagainstthepotentialforbenefitbefore administration.Observationalstudiesexaminingtheuseofwarfarincombinedwithbothaspirinandclopidogrel(e.g.,for patientsrecoveringafterstentingofaleftanteriordescending[LAD]arterywithalargeanteriorMI)havesuggestedahigh riskofbleeding.Accordingtothecurrentguidelines,suchpatientsshouldreceivelowdoseaspirin(7581mg)andno morethan75mg/dayofclopidogrelandmaintainanINRof2.02.5. ACC/AHASTEMIGuidelinesforUtilizationofCoumadin ClassIa ManagingwarfarintoanINRequalto2.03.0forparoxysmalorchronicatrialfibrillationorflutterisrecommended,andin postMIpatientswhenclinicallyindicated(e.g.,atrialfibrillation,LVthrombus). ClassIb Useofwarfarininconjunctionwithaspirinorclopidogrelisassociatedwithanincreasedriskofbleedingandshouldbe monitoredclosely.

KeyPoints
Earlyadministrationofbetablockers,especiallyintravenouslyinSTEMIpatientswithhighriskcharacteristics (olderage,hemodynamicinstability,increasedheartrate,lowerbloodpressure,andsignsofCHF),mayincrease theriskofcardiogenicshockandshockrelateddeath. LongtermtreatmentwithbetablockersisbeneficialafterSTEMIforreductionofdeathandrecurrentadverse events. BetablockersshouldbeavoidedinpatientswithSTEMIassociatedwithcocaineuse. AmongpatientswithSTEMIwithandwithoutLVsystolicdysfunction,earlyinitiation(within24hours)oforalACEIs andcontinuedlongtermtreatmentsignificantlyreducemortalityandrecurrentCVevents. AllpatientsfollowingSTEMIshouldbeconsideredforACEItherapy.Thegroupsthatareleastlikelytobenefit includethosewithpreservedLVfunctioninthesettingofadequaterevascularization. PatientswhoareintolerantofACEIsmaybetreatedwithARBs. ThealdosteroneblockereplerenonehasbeenshowntoreducemortalityforpostSTEMIpatientswithanLVEF 40%withoutsignificantrenaldysfunctionorhyperkalemiawhoarealreadyreceivingtherapeuticdosesofan ACEIandhaveeithersymptomaticCHFordiabetes. NitratesmaybeusefulintheconvalescentphaseafterSTEMIforthetreatmentofrecurrentangina,but randomizedtrialdatasuggestthattheydonotsignificantlyreducemortalitynitrateuseshouldnotprecludethe useofbetablockersorACEIs. CCBsmaybehazardousandincreaseadverseeventsincertainpatientsafterSTEMI.Verapamilanddiltiazem shouldbeavoidedinSTEMIpatientswithLVsystolicdysfunctionandCHF,andshortactingnifedipineisgenerally contraindicatedinthetreatmentofSTEMI. CertainCCBsmaybeusefulforthetreatmentofangina,hypertension,andatrialtachyarrhythmiasinselect patientsafterSTEMIwhenbetablockers(ornitrates)areineffective,nottolerated,orcontraindicatedandin patientswhohavenosignsofCHF,LVdysfunction,orAVblock. ThegoalofintensiveglucosecontrolwithIVinsulininthesettingofanAMIshouldbetomaintainbloodglucose levels<180mg/dlandtoavoidhypoglycemia. LongtermintensiveglucosecontrolwithanHbA1cgoalof<6isassociatedwithincreasedratesofhypoglycemia anddetrimentalclinicaloutcomes.

References
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heartfailure,leftventriculardysfunction,orboth.NEnglJMed2003349:1893906. 24. GrangerCB,McMurrayJJ,YusufS,etal.Effectsofcandesartaninpatientswithchronicheartfailureandreduced leftventricularsystolicfunctionintoleranttoangiotensinconvertingenzymeinhibitors:theCHARMAlternativetrial. Lancet2003362:7726. 25. McMurrayJJ,OstergrenJ,SwedbergK,etal.Effectsofcandesartaninpatientswithchronicheartfailureand reducedleftventricularsystolicfunctiontakingangiotensinconvertingenzymeinhibitors:theCHARMAddedtrial. Lancet2003362:76771. 26. PittB,ZannadF,RemmeWJ,etal.Theeffectofspironolactoneonmorbidityandmortalityinpatientswithsevere heartfailure.RandomizedAldactoneEvaluationStudyInvestigators.NEnglJMed1999341:70917. 27. PittB,RemmeW,ZannadF,etal.Eplerenone,aselectivealdosteroneblocker,inpatientswithleftventricular dysfunctionaftermyocardialinfarction.NEnglJMed2003348:130921. 28. GoldbourtU,BeharS,ReicherReissH,etal.Earlyadministrationofnifedipineinsuspectedacutemyocardial infarction.TheSecondaryPreventionReinfarctionIsraelNifedipineTrial2Study.ArchInternMed1993153:345 53. 29. MullerJE,MorrisonJ,StonePH,etal.Nifedipinetherapyforpatientswiththreatenedandacutemyocardial infarction:arandomized,doubleblind,placebocontrolledcomparison.Circulation198469:7407. 30. [Noauthorslisted].Effectofverapamilonmortalityandmajoreventsafteracutemyocardialinfarction(theDanish VerapamilInfarctionTrialIIDAVITII).AmJCardiol199066:77985. 31. [Noauthorslisted].Theeffectofdiltiazemonmortalityandreinfarctionaftermyocardialinfarction.TheMulticenter DiltiazemPostinfarctionTrialResearchGroup.NEnglJMed1988319:38592. 32. GibsonRS,BodenWE,TherouxP,etal.DiltiazemandreinfarctioninpatientswithnonQwavemyocardial infarction.Resultsofadoubleblind,randomized,multicentertrial.NEnglJMed1986315:4239. 33. MalmbergK,RydenL,EfendicS,etal.Randomizedtrialofinsulinglucoseinfusionfollowedbysubcutaneous insulintreatmentindiabeticpatientswithacutemyocardialinfarction(DIGAMIstudy):effectsonmortalityat1year. JAmCollCardiol199526:5765. 34. vandenBergheG,WoutersP,WeekersF,etal.Intensiveinsulintherapyinthecriticallyillpatients.NEnglJMed 2001345:135967. 35. FinferS,ChittockDR,SuSY,etal.Intensiveversusconventionalglucosecontrolincriticallyillpatients.NEnglJ Med2009360:128397. 36. FryeRL,AugustP,BrooksMM,etal.Arandomizedtrialoftherapiesfortype2diabetesandcoronaryartery disease.NEnglJMed2009360:250315. 37. GersteinHC,MillerME,ByingtonRP,etal.Effectsofintensiveglucoseloweringintype2diabetes.NEnglJMed 2008358:254559. 38. DuckworthW,AbrairaC,MoritzT,etal.Glucosecontrolandvascularcomplicationsinveteranswithtype2 diabetes.NEnglJMed2009360:12939. 39. SacksFM,PfefferMA,MoyeLA,etal.Theeffectofpravastatinoncoronaryeventsaftermyocardialinfarctionin patientswithaveragecholesterollevels.CholesterolandRecurrentEventsTrialinvestigators.NEnglJMed 1996335:10019. 40. SchwartzGG,OlssonAG,EzekowitzMD,etal.Effectsofatorvastatinonearlyrecurrentischemiceventsinacute coronarysyndromes:theMIRACLstudy:arandomizedcontrolledtrial.JAMA2001285:171118. 41. StenestrandU,WallentinL.Earlystatintreatmentfollowingacutemyocardialinfarctionand1yearsurvival.JAMA 2001285:4306. 42. AronowHD,TopolEJ,RoeMT,etal.Effectoflipidloweringtherapyonearlymortalityafteracutecoronary syndromes:anobservationalstudy.Lancet2001357:10638. 43. CannonCP,BraunwaldE,McCabeCH,etal.Intensiveversusmoderatelipidloweringwithstatinsafteracute coronarysyndromes.NEnglJMed2004350:1495504. 44. ColivicchiF,TubaroM,MociniD,etal.FulldoseatorvastatinversusconventionalmedicaltherapyafternonST elevationacutemyocardialinfarctioninpatientswithadvancednonrevascularisablecoronaryarterydisease.Curr MedResOpin201026:127784. 45. deLemosJA,BlazingMA,WiviottSD,etal.Earlyintensivevsadelayedconservativesimvastatinstrategyin patientswithacutecoronarysyndromes:phaseZoftheAtoZtrial.JAMA2004292:130716. 46. MillsEJ,O'ReganC,EyawoO,etal.Intensivestatintherapycomparedwithmoderatedosingforpreventionof cardiovascularevents:ametaanalysisof>40000patients.EurHeartJ201132:140915. 47. GrundySM,CleemanJI,MerzCN,etal.ImplicationsofrecentclinicaltrialsfortheNationalCholesterolEducation ProgramAdultTreatmentPanelIIIguidelines.Circulation2004110:22739. 48. HurlenM,AbdelnoorM,SmithP,ErikssenJ,ArnesenH.Warfarin,aspirin,orbothaftermyocardialinfarction.N EnglJMed2002347:96974. 49. MeijerA,VerheugtFW,WerterCJ,LieKI,vanderPolJM,vanEenigeMJ.Aspirinversuscoumadininthe preventionofreocclusionandrecurrentischemiaaftersuccessfulthrombolysis:aprospectiveplacebocontrolled angiographicstudy.ResultsoftheAPRICOTStudy.Circulation199387:152430. 50. vanEsRF,JonkerJJ,VerheugtFW,DeckersJW,GrobbeeDE.Aspirinandcoumadinafteracutecoronary syndromes(theASPECT2study):arandomisedcontrolledtrial.Lancet2002360:10913. 51. [Noauthorslisted].Effectoflongtermoralanticoagulanttreatmentonmortalityandcardiovascularmorbidityafter myocardialinfarction.AnticoagulantsintheSecondaryPreventionofEventsinCoronaryThrombosis(ASPECT) ResearchGroup.Lancet1994343:499503.

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6.9:STEMI:MechanicalComplicationsofMyocardialInfarction
Author(s): EmmanouilS.Brilakis,MD,PhD,FACC SubhashBanerjee,MD,FACC

LearnerObjectives
Uponcompletionofthismodule,thereaderwillbeableto: 1. Explainthetypesofmechanicalcomplicationsthatmayoccurafteranacutemyocardialinfarction(AMI)(i.e.,freewall rupture,ventricularseptaldefect,severemitralregurgitation[MR],rightventricular[RV]infarction). 2. DescribediagnosticandtreatmentstrategiesforthemechanicalcomplicationsofAMI.

Introduction
ThreemajormechanicalcomplicationscanoccurafteranAMI:1)freewallrupture, 2)ruptureoftheinterventricularseptum,and3)severeMR(whichcanbedueto papillarymuscleruptureorothercauses)(Figure1).RVinfarctioncanalsohave severehemodynamicconsequences,andwillalsobediscussedinthismodule (Table1).Thesecomplicationsaretheresultofmyocardialnecrosis,dysfunction, andpossibleruptureattheareaofinfarctionandcanallleadtocardiogenicshock, whichisdiscussedseparately. MechanicalAMIcomplicationshavebeenencounteredlessfrequentlyinrecent years,possiblyduetoadministrationofearlierreperfusiontherapy.13Inan internationalmulticenterregistryof231postAMIpatientswithcardiogenicshock, ventricularseptalruptureoracutesevereMRwerepresentin8%ofthepatients,and RVinfarctionin2%.4 ForallthreemajormechanicalAMIcomplications(freewallrupture,ruptureofthe interventricularseptum,andpapillarymusclerupture),the2004AmericanCollegeof Cardiology/AmericanHeartAssociation(ACC/AHA)GuidelinesfortheManagement ofPatientsWithSTSegmentElevationMyocardialInfarction(STEMI)recommend "urgentcardiacsurgicalrepair,unlessfurthersupportisconsideredfutilebecause ofthepatient'swishesorcontraindications/unsuitabilityforfurtherinvasivecare" (ClassIrecommendation).3 Thesameguidelinesalsorecommend"coronaryartery bypassgraftingatthesametimeassurgicalrepair"(alsoaClassI recommendation).3

Figure1

Table1

MechanicalComplicationsofAcuteMyocardialInfarction:TheTypeofComplicationDependsontheRuptureSite Figure1

ComparisonofDifferentMechanicalComplicationsofAcuteMI Table1 MI=myocardialinfarctionRV=rightventricular.

FreeWallRupture
IncidenceandTiming Freewallrupture(Figure2)occursinapproximately16%ofAMIs,butaccountsfor upto15%ofearlymortality.1,2,5,6Thepeakincidenceoffreewallrupturewasat5 daysafterMIintheprefibrinolyticera,butwithearlyreperfusion,freewallrupture occursearlier,usuallywithin48hoursfrompresentation.7 Freewallruptureappears tooccurmoreofteninolderpatients,women,andpatientswhoreceivelate reperfusion.2,7Earlyreperfusionbythrombolysis1 orprimarypercutaneouscoronary intervention(PCI)2 appeartobeprotective. Location Freewallruptureusuallyoccursatsiteswheremyocardialnecrosisistransmural, oftenafterhemorrhagictransformationoftheinfarctedzone.Freewallrupturemay occurinanylocation,butmaybemorelikelytooccurinthelateralleftventricular(LV) wall.8 Freewallruptureisinfrequentinpatientswithrightcoronaryarteryocclusion.6 Presentation Freewallruptureisusuallyarapidlyfatalevent.Mostpatientsdevelopcardiac tamponadefollowedbypulselesselectricalactivity.Rarely,freewallrupturemaybe contained,formingaventricularpseudoaneurysm(Figure3).BecauseLV pseudoaneurysmsalsohavehighriskforrupture,urgentsurgicalrepairis recommendedaswell.Somepatients(21%inoneseries)8 maypresentwithan abrupttransientepisodeofhypotensionandbradycardia,whichislikelyduetothe initialtearingoftheepicardium,witharesultantsmallhemopericardium.8 Diagnosis Echocardiographycanconfirmthediagnosis,byshowingapericardialeffusion,or highdensityintrapericardialechocardiogramssuggestiveofbloodclots.5 Presence of10mmpericardialeffusionpostSTEMIisassociatedwithhighriskof subsequentrupture.9 Echocardiographymayalsoshowsignsoftamponade,such asrightatrialorRVwallcompressionwithdiastolicRVcollapseandsignificant inspiratorydecreaseinmitralinflowvelocities.Ifapseudoaneurysmiscreated,color Dopplerimagingcanillustrateflowinandoutofthepseudoaneurysm(Figure3 Videos1a,b). Treatment Aggressiveintravenousfluidadministrationandinotropeadministrationmayhelp stabilizethepatient,butdelayingsurgerytoperformcoronaryangiographyisnot recommended.Emergentpericardiocentesisisusuallyrequiredforinitialpatient stabilization,followedbyemergentsurgicalrepair.Ontheotherhand,ifapatientis hemodynamicallystablewithacontainedrupture,pericardiocentesisshouldbe avoided,becauseitmaydecreasethetamponadeeffectandincreasebloodflow fromthesiteofrupture.Insuchcases,thepatientshouldgoimmediatelytosurgery withoutpericardiocentesis. Althoughemergentsurgerycarrieshighrisk,itoffersthebestchanceforsurvival.3 Surgeryisindicatedevenifapseudoaneurysmisfound,becauseoftheriskof delayedrupture.Surgicalrepairmaybedifficultbecausethenecroticmyocardial tissuemaynotaccommodatesutureswell,butcanoftenbeaccomplishedwiththe useofapatchstabilizedwithsuturesorcyanoacrylateglue.Ifneeded,coronary arterybypassgraftsurgery(CABG)isalsoperformedatthesametime.3 Althoughearlyclosureoffreewallruptureisgenerallyadvocated,somepatients maybeconsideredtobeatprohibitiveriskforsurgery.Alternativetreatmentsin thesepatientsincludeuseofventricularassistdevices,percutaneousclosureofthe defect,orintrapericardialinfusionoffibringlue,althoughthoseapproacheshave hadvariableresults.
Figure2

Figure3

PostinfarctionCardiacRupture Figure2 Freewallrupturewithhemopericardium. ReproducedwithpermissionfromEdwardsWD.Appliedanatomyoftheheart.In:BrandenburgRO,FusterV,GiulianiER,etal.Cardiology: FundamentalsandPractice.Vol.1.Chicago:YearBookMedicalPublishers1987:47112.

CaseofPostinfarctionLeftVentricularPseudoaneurysmina59YearOldManWithaPriorInferiorSTEMI Figure3 Magneticresonanceimagingdemonstratingaleftventricularlateralwalllargepseudoaneurysmduringdiastole(panelA)andsystole(panelB). Transthoracicechocardiographyalsodemonstratesthepseudoaneurysm(panelC)withflowintotheaneurysmalcavityusingcolorDoppler imaging(panelD). STEMI=STsegmentelevationmyocardialinfarction. MagneticresonanceimagingandechocardiographicimagescourtesyofDr.ChristopherGallagherandDr.AmitKhera,UTSouthwesternMedical Center,Dallas,TX.

VentricularSeptalRupture
IncidenceandTiming Ventricularseptalruptureoccurredinapproximately13%ofAMIpatientsbeforethe reperfusionera(Figure4),10,11butislesscommoninpatientsreceiving reperfusion.Itoccurredin84of41,021(0.2%)patientsenrolledintheGUSTOI (GlobalUseofStrategiesToOpenoccludedcoronaryarteries)trial.12 InAMIpatientsnotreceivingfibrinolytictherapy,ventricularseptalrupturetypically occursduringday1orbetweendays3and5,whereasinpatientsreceiving reperfusion,itusuallyoccursduringthefirst24hoursfrompresentation.12,13 RiskFactors VentricularseptalruptureisusuallyassociatedwithlargeMIs,especiallyinelderly patientsandinwomen.13Persistentocclusionoftheinfarctrelatedarteryandthe lackofcollateralcirculationmayalsopredisposetoventricularseptalrupture.11 Location Ventricularseptalruptureassociatedwithananteriorinfarctisusuallylocatedinthe apicalseptum,whereasruptureassociatedwithinferiorinfarctsislocatedinthe posterobasalseptum.10 Presentation Patientswhodevelopventricularseptalruptureusuallypresentwithchestpain, dyspnea,andmaydevelophypotensionandcardiogenicshock.Theseverityof symptomsdependsonthesizeofthedefect,withlargerdefectscausingmoreleft torightintracardiacshuntingandmoreseveresymptoms.Comparedtopapillary muscleruptureorLVfreewallrupture,ventricularseptaldefectisusuallyeasierto identifyonphysicalexaminationbecauseofthepresenceofloudholosystolic murmur.10ManypatientshaveathrilloranRVlift. Diagnosis Anewloudholosystolicmurmurcanoftenpointearlytothediagnosisofventricular septalrupture.Transthoracicechocardiography(TTE)withcolorflowDoppler imagingcanconfirmthediagnosisandshowthelefttorightshuntthroughthe ventricularseptum(Videos2a,b,c).Alternatively,leftventriculographyintheleft anteriorobliqueprojectioncandemonstratethelefttorightshuntduringsystole. Rightheartcatheterizationshowsanincrease,or"stepup"inoxygensaturationat theleveloftheRV,asoxygenatedbloodfromtheLVmixeswithdesaturatedbloodin theRV. Treatment Althoughitcarrieshighrisk,immediatesurgicalcorrectionoftheventricularseptal ruptureoffersthebestchanceforsurvival.Evenifpatientswithventricularseptal ruptureappeartobestable,ortheystabilizewithintensivemedicaltherapy,theystill needtobeoperatedurgentlybecausetheventricularseptalrupturemayacutely enlarge,resultinginsuddendeteriorationanddeath.3,11 Initialstabilizationcanbeachievedbyintraaorticballooncounterpulsationand inotropicsupport.Ifpatientsarehemodynamicallystable,thenafterloadreduction withnitroprussidemayreducethemagnitudeoflefttorightshunting.11Surgical repairusuallyconsistsofdebridementofthenecroticareaandreconstructionusing prostheticmaterial.CABGiscommonlyperformedatthesametime. Percutaneousclosureoftheventricularseptalrupturehasbeenreportedhowever,it hasseverallimitations.14Deliveringtheclosuredevice,suchastheAmplatzer device(AGAMedicalCorporation,MapleGrove,MN)mayresultinenlargementofthe defect,sincethesurroundingtissueisnecroticandfragile.Placementofadevice
Figure4

couldalsodistortthegeometryoftheventricleorcausefreewallperforation.Septal ruptureduetorightcoronaryarteryocclusionisusuallylocatedintheinferobasal septum,anddeployingadeviceinthislocationmayimpingeonthetricuspidor mitralvalvecausingregurgitation.Deviceembolization(bothimmediateordelayed) andincompletesealingareotherpotentialcomplications.14 AMIpatientswhodevelopventricularseptalrupturehaveapoorprognosis.Ina seriesfromtheGUSTOItrial,overall30daymortalitywas74%,butwaslowerin patientswhounderwentsurgicalrepair(47%)comparedtopatientswhowere treatedconservatively(94%),althoughthiscouldreflectselectionbias.12 InananalysisfromtheSHOCK(SHouldweemergentlyrevascularizeOccluded CoronariesincardiogenicshocK?)trialregistry,mortalityofcardiogenicshock patientswithventricularseptalrupturewas87%mortalitywas81%inpatientswho underwentsurgerycomparedto96%inthosetreatedconservatively.13Thirtyday mortalitywas65%inaseriesof29patientsundergoingpercutaneousclosure.14 However,inpatientswhosurvivepast30days,prognosisisrelativelygood.12

VentricularSeptalRupture Figure4 ReproducedwithpermissionfromEdwardsWD.Pathologyofmyocardialinfarctionandreperfusion.In:GershBJ,RahimtoolaSH,eds.Acute MyocardialInfarction(CurrentTopicsinCardiology).NewYork:ElsevierScience1990:1448.

PapillaryMuscleRupture
MRoftencomplicatesAMI,andisassociatedwithincreasedmortality.15Papillary musclerupture(Figures5,6)isonlyoneofthemechanismsleadingtoMRinthe postAMIpatient.Othermechanismsinclude:1)LVdilatation,2)severeregionalwall motionabnormalityadjacenttoapapillarymuscle,and3)ischemicpapillarymuscle dysfunction.10 ThissectionfocusesonMRduetopapillarymusclerupture,whichaccountsfor approximately5%ofAMIdeaths.10 Mechanism PapillarymuscleruptureinAMIpatientsisduetoischemicnecrosis.Therearetwo papillarymuscles:theanterolateralandtheposteromedial.16Theanterolateral papillarymusclereceivesdualbloodsupplyfromboththeleftanteriordescending coronaryarteryandthecircumflexcoronaryartery.Incontrast,theposteromedial papillarymuscleusuallyreceivesbloodsupplyonlyfromtheposteriordescending artery,andistherefore,moresusceptibletoinfarctionandruptureinpatientswithan inferiorAMI. Incontrasttofreewallandseptalrupture,alargeinfarctisnotrequiredforpapillary musclerupture.Afocal,preciselylocalizedinfarctcanleadtorupture.Rupturecan becomplete,leadingtosevereMR,orpartial,leadingtolesssevereregurgitation. Becausebothpapillarymusclesareattachedviachordaetoboththeanteriorand posteriormitralleaflets,adisruptionoftheposteromedialpapillarymusclecan resultindysfunctionofeithertheanterior(Figure6)orposterior(Videos3a,b,c) mitralleaflet,17leadingtoeitherposteriorlyoranteriorlydirectedMRjets, respectively. Arecentmagneticresonanceimagingstudyrevealedhighfrequencyofpapillary muscleinfarctioninSTEMIpatients(40%),mainlynonanteriorMIshowever,most papillarymuscleinfarctionswereclinicallylatent.18 IncidenceandTiming Papillarymuscleruptureusuallyoccurs27daysafteraninferiorAMI,in approximately1%ofAMIpatients.3,10 Presentation Mostpatientswithpapillarymusclerupturepresentinacutepulmonaryedemaand cardiogenicshock.19Onphysicalexamination,patientshaveelevatedjugular venouspressureandcongestedlungs.10AlthoughaholosystolicMRmurmurmay bepresent,itcanbeverysoftorabsentbecauseoftherapidequalizationoftheLV andleftatrialpressuresduringsystole.Thisiswhyemergentechocardiographymay beneededtomakethediagnosis. Diagnosis TTEusuallyshowsaflailsegmentofthemitralvalveandtherupturedpapillary muscleheadmovingfreelywithintheLVandoftenprolapsingintotheleftatrium (Figure6Videos3a,b,c).LVsystolicfunctionmayappearhyperdynamicdueto bloodregurgitationintotheleftatrium.Insomepatients,thepapillarymusclemay notprolapseintotheleftatrium,necessitatingtransesophagealechocardiographyto establishthediagnosis(Figure6Videos3a,b,c).Pulmonaryarterialcatheterization typicallydemonstrateslargevwavesinthepulmonarycapillarywedgepressure measurementsthatmayalsobeseeninthepulmonaryarterywaveforms. Treatment Althoughpatientswithpapillarymusclerupturemayinitiallystabilize,theyremainat veryhighriskforfurtherdeteriorationanddeath.20Earlysurgicalrepairis recommendedtooptimizesurvival.3,16,21,22Initialhemodynamicstabilizationcan
Figure6

Figure5

beachievedbyafterloadreduction(usingnitroprussideoranintraaorticballoon pump),incombinationwithinotropicsupport.Althoughmitralvalvereplacementis oftenrequired,sometimestherupturedpapillarymusclecanberepaired,avoiding theneedforaprostheticvalve.CABGisalsoperformedatthesametimewithmitral valverepair/replacement.Patientswhosurvivesurgeryhaveexcellentlongterm outcomes.22

PathologicSpecimenWithCompleteTranssectionofPapillaryMuscleBecauseofInferiorWallMI Figure5 Pathologicspecimenwithcompletetranssectionofpapillarymuscle(left)andcloseupview(right)becauseofinferiorwallmyocardialinfarction (MI).Severemitralregurgitationanddeathresulted. ReproducedwithpermissionfromReederGS,GershBJ.Acutemyocardialinfarction.In:SteinJH,ed.SteinsInternalMedicine.St.Louis:Mosby YearBook1994:16989.

CaseofPapillaryMuscleRupture Figure6 Coronaryangiographyofapatientwithacuteinferiormyocardialinfarctionshowingocclusionofthedistalrightcoronaryarterywith intracoronarythrombus(arrow,panelA)withdiffuselydiseasedbutpatentleftanteriordescendingandleftcircumflexartery(panelB). Transesophagealechocardiographyindiastoleshowstheposteromedialpapillarymuscleintheleftventricle(panelC)however,insystole,the anteriormitralleafletisflailandtheposteromedialpapillarymuscleprolapsesintotheleftatrium(arrow,panelD).ColorDopplerimagingshows severeposteriorlydirectedmitralregurgitation(arrow,panelE).Thepatientunderwentemergencymitralvalvereplacementandcoronaryartery bypassgraftsurgeryandsurvivedtohospitaldischarge. EchocardiographicimagescourtesyofDr.LauraCollinsandDr.ManishaShah,UTSouthwesternMedicalCenter,Dallas,TX.

RightVentricularInfarction
IncidenceandTiming Althoughalmost50%ofpatientswithinferiorMIhaveRVinvolvement, hemodynamicallysignificantRVdysfunction(Figure7)occursinonly1015%of thosepatients,usuallyinthefirstfewhoursafterpresentation.3 Mechanism AlthoughtheRVisresistanttoischemia,whentherightcoronaryarteryisoccluded proximaltotheoriginoftheacutemarginalbranches,significantRVischemia occurs,oftenleadingtoacuteRVdilatation(Figure7)andhypocontractility.Because oftherapidincreaseinRVsize,thepericardiumdoesnothaveenoughtimeto stretch,resultinginincreasedintrapericardialpressure.Moreover,the interventricularseptummayshifttowardtheLV,furtherreducingLVdiastolicfilling. Thoseactionsmaydecreasebloodreturntotherightatrium,RV,andLV,resultingin decreasedstrokevolume,cardiacoutput,andsystemicbloodpressure.3 TheeffectsofRVinfarctioncanbeexacerbatedbyfactorsthatfurtherdecreaseRV cardiacoutput,suchashypovolemia,administrationofnitrates,lossofrightatrial contraction(forexample,inpatientswithatrialfibrillationorwithoutatrioventricular [AV]synchrony),andincreasedpulmonarycapillarywedgepressuredueto concomitantLVdysfunction.Patientswithapatentforamenovalemaydevelop severesystemichypoxemiaduetoincreasedrightatrialpressureandrighttoleft shunting. Presentation Theclassictriadofhypotension,elevatedjugularvenouspressure,andclearlungs isstronglysuggestiveofRVinfarctioninpatientswithinferiorAMIhowever,itisnot verysensitive.Somepatientsmaydevelopseveresystemichypoxemiaduetoright toleftshuntingthroughapatentforamenovale. Diagnosis InpatientswithinferiorAMIandhypotension,RVinfarctioncanoftenbesuspected whenSTsegmentelevationisseeninRVelectrocardiographicleads,especially leadV4R.TheyshouldalsoundergoTTE,whichmayshowRVenlargementand shiftingoftheLVseptumtowardtheLV.Rightatrialpressure>10mmHgandaratio ofrightatrialtopulmonarycapillarywedgepressureof0.8ormore,alsosuggestthe presenceofRVinfarction. Treatment Volumeloading,inotropicsupport,andearlyreperfusion,23arethemainstaysofRV infarcttreatment.3,10Vasodilatingagentssuchasnitratesordiureticsshouldbe avoided,astheycanprecipitateseverehypotension.Patientswhodevelopcomplete AVblockshouldreceiveAVpacing(topreserveAVsynchronyandmaintainadequate cardiacoutput).Patientswhodevelopatrialfibrillationshouldundergourgent cardioversion,alsotorestoreAVsynchrony. EarlyreperfusionwitheitherfibrinolytictherapyorprimaryPCIcanresultinrapidRV recovery.IfCABGisneededand>46hourshaveelapsedsincepresentation,itmay bebesttoacutelytreattheinfarctrelatedarteryanddelayCABGfor4weeks,toallow forrecoveryofRVfunction.IfCABGisperformedearly,severepostoperativeRV dysfunctionoftenensues,requiringextensivesupportandcarryingveryhigh mortality. AlthoughpatientsincardiogenicshockduetoRVinfarctionhavelowerrisk characteristicscomparedtoLVinfarctionpatients,theyhavehighmortalitysimilarto patientswithLVinfarction.24
Figure7

ExtensiveRVInfarctionAssociatedWithInferiorWallInfarction Figure7 Severerightventricular(RV)failureresultedinpatientsdeath. ReproducedwithpermissionfromReederGS,GershBJ.Acutemyocardialinfarction.In:SteinJH,ed.SteinsInternalMedicine.St.Louis:Mosby YearBook1994:16989.

UnusualMechanicalComplicationofAcuteMyocardialInfarction
DynamicLeftVentricularOutflowObstruction SomepatientswithsmallAMIswhopresentwithanewmurmurandcardiogenicshockmaybefoundtohavedynamicLV outflowtractobstruction.25ThisusuallyoccurswithacuteanteroapicalMI,andechocardiographyshowsapicalakinesis withhyperdynamicfunctionoftheinferobasalsegment.DynamicLVoutflowobstructionshouldbedifferentiatedfrom othercausesofsystolicmurmurinAMIpatients,suchasventricularseptalruptureorpapillarymusclerupture).Dynamic LVoutflowtractobstructionisusuallytreatedwithbetablockeradministration.

KeyPoints
Freewallruptureusuallymanifestsastamponade,pulselesselectricalactivity,anddeath. Reperfusiontherapydecreasestheriskoffreewallrupture. Echocardiographyshowshyperechoicpericardialeffusionwithsignsoftamponade. Emergentsurgicalrepairoftheruptureoffersthebestchanceforsurvival. Ventricularseptalruptureusuallypresentsaschestpainandcardiogenicshock. Usuallypatientshavealoudholosystolicmurmur. Rightheartcatheterizationshowsanincrease,orstepupinoxygensaturationattheleveloftheRV. Emergentsurgicalrepairisthetreatmentofchoice,evenifthepatientishemodynamicallystable.Patientswho survivesurgeryhavegoodprognosis. Papillarymuscleruptureusuallyinvolvestheposteromedialpapillarymusclethatreceivesperfusionfromtheright coronaryartery,whereastheanterolateralpapillarymusclehasdualbloodsupply. Papillarymuscleruptureusuallypresentswithacutepulmonaryedemaandcardiogenicshock. PatientsmayhaveasoftorabsentsystolicmurmurduetorapidequalizationofpressuresintheLVandtheleft atriumduringsystole. Echocardiographycanconfirmthediagnosisanddemonstratethesiteofrupture. Emergentsurgicalrepairisthetreatmentofchoice.Afterloadreductionwithintraaorticballoonpumpand nitroprussideadministrationmayserveasbridgetosurgery. Theclassictriadofhypotension,elevatedjugularvenouspressure,andclearlungsisstronglysuggestiveofRV infarctioninpatientswithinferiorAMI. AdministrationofnitroglycerinorotherpreloadreducingagentscancauseprofoundhypotensioninRVinfarction patients. Volumeloading,inotropicsupport,andearlyreperfusionarethemainstaysofRVinfarctiontreatment.

References

1. BeckerRC,GoreJM,LambrewC,etal.AcompositeviewofcardiacruptureintheUnitedStatesNationalRegistry ofMyocardialInfarction.JAmCollCardiol199627:13216. 2. MorenoR,LopezSendonJ,GarciaE,etal.Primaryangioplastyreducestheriskofleftventricularfreewallrupture comparedwiththrombolysisinpatientswithacutemyocardialinfarction.JAmCollCardiol200239:598603. 3. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswithSTelevation myocardialinfarctionexecutivesummary.AreportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(WritingCommitteetorevisethe1999guidelinesforthe managementofpatientswithacutemyocardialinfarction).JAmCollCardiol200444:671719. 4. HochmanJS,BolandJ,SleeperLA,etal.Currentspectrumofcardiogenicshockandeffectofearly revascularizationonmortality.ResultsofanInternationalRegistry.SHOCKRegistryInvestigators.Circulation 199591:87381. 5. LopezSendonJ,GonzalezA,LopezdeSaE,etal.Diagnosisofsubacuteventricularwallruptureafteracute myocardialinfarction:sensitivityandspecificityofclinical,hemodynamicandechocardiographiccriteria.JAmColl Cardiol199219:114553. 6. SlaterJ,BrownRJ,AntonelliTA,etal.Cardiogenicshockduetocardiacfreewallruptureortamponadeafteracute myocardialinfarction:areportfromtheSHOCKTrialRegistry.Shouldweemergentlyrevascularizeoccluded coronariesforcardiogenicshock?JAmCollCardiol200036:111722. 7. BeckerRC,HochmanJS,CannonCP,etal.Fatalcardiacruptureamongpatientstreatedwiththrombolyticagents andadjunctivethrombinantagonists:observationsfromtheThrombolysisandThrombinInhibitioninMyocardial Infarction9Study.JAmCollCardiol199933:47987. 8. OlivaPB,HammillSC,EdwardsWD.Cardiacrupture,aclinicallypredictablecomplicationofacutemyocardial infarction:reportof70caseswithclinicopathologiccorrelations.JAmCollCardiol199322:7206. 9. FiguerasJ,BarrabesJA,SerraV,etal.Hospitaloutcomeofmoderatetoseverepericardialeffusioncomplicating STelevationacutemyocardialinfarction.Circulation2010122:19029. 10. BrilakisES,ReederGS,GershBJ.Modernmanagementofacutemyocardialinfarction.CurrProblCardiol 200328:7127. 11. BirnbaumY,FishbeinMC,BlancheC,SiegelRJ.Ventricularseptalruptureafteracutemyocardialinfarction.N EnglJMed2002347:142632. 12. CrenshawBS,GrangerCB,BirnbaumY,etal.Riskfactors,angiographicpatterns,andoutcomesinpatientswith ventricularseptaldefectcomplicatingacutemyocardialinfarction.GUSTOI(GlobalUtilizationofStreptokinase andTPAforOccludedCoronaryArteries)TrialInvestigators.Circulation2000101:2732. 13. MenonV,WebbJG,HillisLD,etal.Outcomeandprofileofventricularseptalrupturewithcardiogenicshockafter myocardialinfarction:areportfromtheSHOCKTrialRegistry.SHouldweemergentlyrevascularizeOccluded CoronariesincardiogenicshocK?JAmCollCardiol200036:11106. 14. ThieleH,KaulferschC,DaehnertI,etal.Immediateprimarytranscatheterclosureofpostinfarctionventricular septaldefects.EurHeartJ200930:818. 15. PicardMH,DavidoffR,SleeperLA,etal.Echocardiographicpredictorsofsurvivalandresponsetoearly revascularizationincardiogenicshock.Circulation2003107:27984. 16. NishimuraRA,GershBJ,SchaffHV.Thecaseforanaggressivesurgicalapproachtopapillarymusclerupture followingmyocardialinfarction:"Fromparadiselosttoparadiseregained".Heart200083:6113. 17. CzarneckiA,ThakrarA,FangT,etal.Acuteseveremitralregurgitation:considerationofpapillarymuscle architecture.CardiovascUltrasound20086:5. 18. TanimotoT,ImanishiT,KitabataH,etal.Prevalenceandclinicalsignificanceofpapillarymuscleinfarction detectedbylategadoliniumenhancedmagneticresonanceimaginginpatientswithSTsegmentelevation myocardialinfarction.Circulation2010122:22817. 19. BonowRO,CarabelloBA,ChatterjeeK,etal.ACC/AHA2006guidelinesforthemanagementofpatientswith valvularheartdisease:areportoftheAmericanCollegeofCardiology/AmericanHeartAssociationTaskForceon PracticeGuidelines(writingCommitteetoRevisethe1998guidelinesforthemanagementofpatientswith valvularheartdisease)developedincollaborationwiththeSocietyofCardiovascularAnesthesiologistsendorsed bytheSocietyforCardiovascularAngiographyandInterventionsandtheSocietyofThoracicSurgeons.JAmColl Cardiol200648:e1148. 20. NishimuraRA,SchaffHV,ShubC,GershBJ,EdwardsWD,TajikAJ.Papillarymusclerupturecomplicatingacute myocardialinfarction:analysisof17patients.AmJCardiol198351:3737. 21. NishimuraRA,SchaffHV,GershBJ,HolmesDRJr,TajikAJ.Earlyrepairofmechanicalcomplicationsafteracute myocardialinfarction.JAMA1986256:4750. 22. KishonY,OhJK,SchaffHV,MullanyCJ,TajikAJ,GershBJ.Mitralvalveoperationinpostinfarctionruptureofa papillarymuscle:immediateresultsandlongtermfollowupof22patients.MayoClinProc199267:102330. 23. BowersTR,O'NeillWW,GrinesC,PicaMC,SafianRD,GoldsteinJA.Effectofreperfusiononbiventricularfunction andsurvivalafterrightventricularinfarction.NEnglJMed1998338:93340. 24. JacobsAK,LeopoldJA,BatesE,etal.Cardiogenicshockcausedbyrightventricularinfarction:areportfromthe SHOCKregistry.JAmCollCardiol200341:12739. 25. HaleyJH,SinakLJ,TajikAJ,OmmenSR,OhJK.Dynamicleftventricularoutflowtractobstructioninacutecoronary syndromes:animportantcauseofnewsystolicmurmurandcardiogenicshock.MayoClinProc199974:9016.

PrintablePDF
Thisportionoftheactivityisnotconducivetoprinting.Pleasevisittheonlineversionofthisproducttoseethisitem.

Chapter6Exam
Visittheonlineversionoftheproducttoseethecorrectanswerandcommentary. 1. Allofthefollowingarefactorsthatdeterminethevulnerabilityofacoronaryplaqueto ruptureandcauseanACSEXCEPT: A. Thinfibrouscap. B. Largeamountofinflammatorycellswithintheplaqueshoulder. C. Smalllipidcore. D. Proximallocationwithinthecoronaryvessel. E. Largeplaqueburden.

2. WhichofthefollowingisTRUEregardingplaqueerosion? A. Itismorecommoninmen. B. Itisassociatedwithtobaccouse. C. Ittypicallyoccursinthecontextofathincappedfibroatheromarupturing open. D. Itmaybeassociatedwithapatentforamenovale. E. ItisnottypicallyassociatedwithACS.

3. Whichofthefollowingagentsisabletodirectlyinhibitthestepofplatelet aggregation? A. Aspirin. B. Clopidogrel. C. Selectiveserotoninreuptakeinhibitors. D. Abciximab. E. Bivalirudin.

4. WelldescribedtriggersforplaqueruptureandACSincludeallofthefollowing EXCEPT: A. Influenzainfection.

B. Exposuretononsteroidalantiinflammatorydrugs. C. Mentalstress. D. Sexualactivity. E. Anger.

5.Itis11:00p.m.onaSaturdaynightandyouareinchargeatthelocalED.Mr.John, a63yearoldman,presentswithchiefcomplaintsofchestheaviness.Hetellsyou aboutanepisodeinthemorningthatsubsidedspontaneouslyafter10minutes,and anewepisode2hoursbeforepresentationthatlastedabout30minutes.Nowheis asymptomatic,buthiswifeinsistedonbringinghimtotheED.Hehasbeendiabetic forthelast15yearsandtreatedwithmetforminandglimepiride.Hehasalsobeen prescribedamlodipinetocontrolhisbloodpressure. Hisbloodpressureisnow145/90mmHg,hisheartrateis62bpm,andcreatinine is1.12mg/dl.Thephysicalexamisunremarkable.Hesmokesabout10cigarettes perday.HisECGisnearnormalandonthefirstset,histroponinTis0.06ng/ml (99thpercentile,0.01ng/ml).YoucalculateaGRACEscoreof106andTIMIscoreof 3. WhichofthefollowingistheoptimalmanagementforMr.John? A. Hehasmultipleriskfactorsandapositivetroponin.Anearlyinvasivestrategy isthebestchoiceinthissetting.Coronaryangiographymustbeperformed within12hoursorsooner. B. Adelayedinvasivestrategywithadiagnosticangiographyperformedthenext Mondaymorningisreasonableforthispatient,shouldheremainclinically stable. C. Thepatientisstableandnolongersymptomatic.Aconservative,ischemia guidedapproachistheoptimalstrategyinthissituation. D. OrderanechocardiographytoassessLVfunctionandregional abnormalitiestodecidetheoptimalmanagementstrategy. E. ThepatientisasymptomaticandhasaninterpretableECG.Orderan exercisetreadmilltestintheED.

6. WhichoneofthefollowingagentsisNOTaP2Y12receptorinhibitor? A. Ticlopidine. B. Clopidogrel. C. Cangrelor. D. Atopaxar. E. Ticagrelor. F. Elinogrel.

7. WhichoneofthefollowingP2Y12receptorblockersisassociatedwithasignificant mortalitybenefit? A. Ticlopidine. B. Clopidogrel. C. Ticagrelor. D. Vorapaxar. E. Cagrelor.

8. Inthe2011ACCF/AHAFocusedUpdateGuidelinesfortheManagementofPatients WithUA/NSTEMI,itisaClassIrecommendationistoadminister60mgprasugrel promptlyandnolaterthan1hourafterPCIoncethecoronaryanatomyisdefined andadecisionismadetoproceedwithPCI.Trueorfalse? A. True. B. False.

9. Inthe2011ACCF/AHAFocusedUpdateGuidelinesfortheManagementofPatients WithUA/NSTEMI,patientswithdefiniteUA/NSTEMIatmediumorhighriskandin whomaninitialinvasivestrategyisselected,thechoiceofsecondantiplateletagent atthetimeofPCIisclopidogrel,prasugrel,oraGPIIb/IIIainhibitor.Trueorfalse? A. True. B. False.

10.A79yearoldmancallsemergencymedicalservices,complainingofcrushing chestpainforthepast15minutes.Uponarrivaltotheemergencyroom,symptoms havebeenpresentfor35minutes.Medicalhistoryisnotableforhypertensionanda 40pack/yeartobaccohistory.ECGuponarrivaldemonstratesanteriorSTelevations. Bloodpressureis95/55mmHg,andheartrateis82bpm.Routinelaboratories, drawnbyhisprimarycarephysician3daysprior,demonstratenormalbaseline creatinine.Thereceivingfacilitydoesnothaveacardiaccatheterizationlaboratory. Transfertoafacilitywithinterventionalcapabilitieswillrequireatleast120minutes. Whichofthefollowingisanappropriatemanagementstrategyforthispatient? A. 325mgaspirin/60mgprasugrel/TPA,followedbyimmediatetransfertothe PCIcapablefacility. B. 325mgaspirin/300mgclopidogrel/transferforprimaryPCI. C. 325mgaspirin/heparin/reteplase,followedbyimmediatetransfertothePCI

capablefacility. D. 325mgaspirin/abciximab/halfdosetenecteplaseandtransferforPCI. E. 325mgaspirin/tenecteplase/enoxaparinwithouttransferforPCI.

11. WhichofthefollowinganticoagulantsusedinUA/NSTEMIiscorrectlyclassifiedby itsrouteofadministrationandmechanismofaction? A. BivalirudinIVdirectthrombininhibitor. B. EnoxaparinIVorsubcutaneouslyadministereddirectfactorXainhibitor. C. UFHIVorsubcutaneouslyadministeredfactorIXinhibitor. D. FondaparinuxsubcutaneouslyadministeredLMWH.

12. Whichofthefollowinganticoagulantregimensshouldbeusedinpatients undergoingPCIforthemanagementofUA/NSTEMI? A. OralwarfarinduringPCIforapatientpreviouslytreatedwithIVbivalirudin. B. SubcutaneousenoxaparinduringPCIforapatientpreviouslytreatedwithIV UFH. C. UFHduringPCIforapatientpreviouslytreatedwithfondaparinux. D. AdditionalIVargatrobanduringPCIforapatientpreviouslytreatedwith argatroban.

13. Whichofthefollowingisaspecificcomplicationassociatedwiththelisted anticoagulantagent? A. UFHcatheterrelatedthrombosisduringPCI. B. Fondaparinuxskinnecrosis. C. Enoxaparinexcessdosinginchronickidneydisease. D. Bivalirudinheparininducedthrombocytopeniawiththrombosis.

14.A66yearoldmanwithnoknownpriormedicalhistory,takingnomedications, developschestpainat11:00a.m.whileworkinginhisbasement.Hebelievesitto beindigestionanddoesnotseekcareuntilthefollowingdayat8:00a.m.whenthe

painispersistentandhebeginstofeelshortofbreath.Onpresentation,hisresting heartrateis52bpmandbloodpressureis90/55mmHg.Hisjugularvenous pressureis14cmofwaterandhehasbasilarcracklesonauscultationofhischest. ThereisnoS3.HisECGshowssinusbradycardiawithfirstdegreeAVblockand3 mmofSTsegmentelevationinleadsII,III,andF. Whichofthefollowingisthemostappropriatenextstep? A. Administeraspirin81mgbymouth. B. Initiateintravenousnitroglycerin. C. Administermetoprolol15mgbymouth. D. ObtainanECGwithrightsidedprecordialleads.

15.A62yearoldwomanwithahistoryoflongstandingtype2diabetesmellitus presentswith1hourofseveresubsternalchestpainanddiaphoresis.Onexam,her pulseis92bpmandbloodpressureis155/82mmHg.Herlungsareclearand thereisnoS3ormurmur.AnECGshows34mmofSTelevationinleadsV25.His labs,includingcompletebloodcellcountandcoagulationparameters,arenormal. Theclosesthospitalwithacathlabis2hoursaway. Youadministerafulldosefibrinolyticalongwithweightbaseddosingofaheparin. At90minutesafteradministrationofthefibrinolytic,herECGshows3mmofST elevationinleadsV25.Herpainisalmostcompletelyrelieved,butshestillhasa lingeringslightachingsensationoverherleftchest. Whichofthefollowingisthenextbeststepforthispatient? A. Administeranotherdoseofthefibrinolytic. B. AdministeraglycoproteinIIb/IIIareceptorantagonist. C. ArrangeforimmediatetransfertoaPCIcapablehospital. D. Admitherandobserveforanadditional180minutes.

16.A56yearoldfemalewithsymptomaticrheumatoidarthritisisstatus/posta recentanteriorwallMIandaresidualLVEFof55%withasmallapicalwallmotion abnormalityonechocardiogram.Onangiography,shehassinglevesseldisease withanulcerated95%midLADlesionthatwasstentedwithaDES.Her postreperfusioncourseinthehospitalwasuneventful. Whichofthefollowingmedicalinterventionsmostlikelywilltranslateintoapotential mortalitybenefit? A. Treatmentwithatorvastatin80mg/day. B. Treatmentwithtrandolapril8mg/day. C. Treatmentwithnadolol40mg/day. D. Treatmentwithaldactone25mg/day. E. Treatmentwithanonsteroidalantiinflammatorydrugwithcyclooxygenase2 (COX2)selectivity.

17. InapatientwithanacutemitralregurgitationasaconsequenceofSTsegment elevationMI,whichofthefollowingisthemostlikelyculpritcoronaryartery? A. Leftmaincoronaryartery. B. Leftanteriordescendingcoronaryartery. C. Circumflexartery. D. Rightcoronaryartery.

18. InapatientwithacuteSTEMIcomplicatedbyacutemitralregurgitationfrompapillary musclerupture,whichofthefollowingisconsidereddefinitivetreatment? A. Insertionofanintraaorticballoonpump. B. Administrationofdopamine. C. Administrationofnitroprusside. D. Surgicalrepairorreplacementoftherupturedpapillarymuscle. E. Alloftheabove.

19. A75yearoldmanpresentswithaninferiorSTsegmentelevationAMI.Initialblood pressureintheemergencyroomis110/60mmHgandheartrateis80bpmwithout anygallopsormurmurs.Lungsarecleartoauscultationandjugularvenous pressureis20mmHg.Afteradministrationofsublingualnitroglycerin,systolicblood pressuredecreasesto60mmHg.Whichofthefollowingtreatmentoptionsis contraindicatedinthispatient? A. Administrationofintravenousnormalsaline. B. Administrationofdopamine. C. Administrationofmorphine. D. Administrationofthrombolytics. E. PrimaryPCI.

20.A65yearoldfemalepatientpresents2hoursaftertheonsetofchestpain. Electrocardiogram(ECG)reveals2mmofSTEinIIandIII,arteriovenousfistula (AVF),and2mmofSTdepressioninV1V3withuprightTwaves.Herblood pressure(BP)is160/90mmHg,andHRis90bpm.Herlungsareclearto

auscultation,andS1andS2areheardwithoutmurmurs.ThenearestPCIcapable facilityis60minutesaway. Inadditiontoaspirinandclopidogrel,whichofthefollowingisthebest revascularizationstrategy? A. Heparin4000units(U)IVbolusandimmediatetransferforPPCI. B. 10Uofreteplase30minutesapart,heparin4000UIVbolus,andtransferfor immediateangiography. C. 10Uofreteplase30minutesapart,heparin4000UIVbolus,andtransfer followedbyangiographywithin24hours. D. 10Uofreteplase30minutesapart,heparin4000UIVbolus,and admission.TransfertoaPCIcapablefacilityforangiographyonlyifthepatient failstoreperfuseorisfoundtohaveischemiaonsymptomlimitedstress testing. E. 10Uofreteplase30minutesapart,abciximabIVbolus,heparin4000UIV bolus,andtransferfollowedbyimmediateangiography.

21. Whichofthefollowingpatientsisthemostappropriatetoreceivefibrinolytictherapy? A. A45yearoldfemalewhopresentswithananteriorSTEMIwithin2hoursof symptomonset,isactivelymenstruating,andis2hoursawayfromthenearest PCIcapablehospital. B. A74yearoldmalewhopresentswithananteriorSTEMIincardiogenic shock12hoursaftersymptomonsetandis2hoursawayfromthenearestPCI capablehospital. C. A69yearoldfemalewhopresentswithananteriorSTEMIwithin2hoursof symptomonsetandis40minutesawayfromthenearestPCIcapablehospital. D. A63yearoldmalewhopresentswithaninferiorSTEMIwithin3hoursof symptomonset,hasactivepepticulcerdisease,andis2hoursawayfromthe nearestPCIcapablehospital. E. A54yearoldfemalewhopresentswithaninferiorSTEMIwithin2hoursof symptomonset,hasahistoryofafracturedorbitandmandiblefromacar accident2monthsago,andis2hoursawayfromthenearestPCIcapable hospital.

22.A52yearoldmalepresents2daysaftertheonsetofpersistentchestpain.He currentlyhasnomorechestpainandisinnodistress.HisBPis150/70mmHg,his HRis85bpm,andhis02saturationis98%onroomair.Hishistoryissignificantfor diabetes,hypertension,andhyperlipidemia.Onphysicalexamination,hehasasoft S3gallopandminimalralesatbothlungbases.A12leadECGreveals2mmof STEinleadsII,III,AVF,I,andaugmentedvoltageleftarm. AtwodimensionalechocardiographyrevealsnormalLVchambersizewithno aneurysmorintracavitarythrombus,mildLVhypertrophy,akinesisoftheinferolateral wallwithanejectionfractionof45%,andmildtomoderatemitralregurgitation.He undergoescoronaryangiography,whichrevealsanormalleftmain,minorluminal irregularitiesoftheleftanteriordescending(LAD),a70%stenosisofalargesecond obtusemarginal,anda100%occlusionwithhazythrombusatthemidsegmentofa

largerightcoronaryartery(RCA).TherearesmallcollateralsfromtheLADtothe distalRCA. Whichofthefollowingisthenextbeststepinmanagement? A. PlacementofaBMSintheRCA. B. PlacementofaDESintheRCA. C. PlacementofaDESinthesecondobtusemarginal. D. BeginabciximabGPIIb/IIIainhibitortherapyandperformaspiration thrombectomy. E. Optimizemedicaltherapy.

PleasevisittheonlineversiontoengageinthisExam. 1.ThecorrectanswerisC.Vulnerableplaquestypicallyhavealarge,necroticlipidcore.Each oftheotherfactorsdescribedarecharacteristicofavulnerableplaque,whichtypicallyhasa verythinfibrouscap(<30microns),alargeamountofinflammatorycells,andisproximally locatedincoronaryvesselssufferingfromalargeplaqueburden. 2.ThecorrectanswerisB.PlaqueerosionisarelativelycommonsecondarycauseofACS, andisoftenfoundinpatientsdyingsuddenly.DistinctpathophysiologicallyfromACSdueto ruptureofavulnerablethincappedfibroatheroma,erosionismorecommoninwomen,andis typicallyfoundinsmokers.ACSinassociationwithpatentforamenovaleismoreoftendueto paradoxicalembolism. 3.ThecorrectanswerisD.Thethirdstepoftheplateletcascadeisaggregation,whichfollows adhesionandactivation.Aspirin,clopidogrel,andserotoninreuptakeinhibitorsallaffect activation,butdonothaveadirecteffectonaggregation,whichismediatedthroughtheGPIIb/IIIa receptor,andisthusblockedbyabciximab.Bivalirudin,throughitsantithrombineffectshasa modestantiplateleteffect,largelythroughreductioninactivation. 4.ThecorrectanswerisB.Whileeachoftheotherfactorslistedhavebeenwelldescribedto triggerACS,exposuretononsteroidalagentshasbeenlargelycircumstantiallyassociatedwith cardiovascularevents,andthemechanismofsucheventsremainsunclear. 5.ThecorrectanswerisB.OptionAisincorrect.Althoughthisoptionisnotunreasonable,the riskprofileofthispatientdoesnotwarrantanemergentcatheterization.Ifthecardiac catheterizationlaboratoryisavailableontheweekend,inthissituation,thereisnostrong evidenceindicatingthatacatheterizationshouldbepostponeduntilMonday.The2011Focused UpdatedoftheGuidelinesfortheManagementofPatientswithUA/NSTEMI1 consider reasonableanearlyinvasivemanagementstrategywithin24hoursinthecaseofhighrisk criteriaorclinicalinstability,butasaClassIIarecommendation,andoneshouldtakeinto accountresourceavailability. OptionBiscorrect.Thispatientisdiabeticandhaspositivetroponin,bothofwhichfavoran invasiveapproach.However,ifthecardiaccatheterizationlaboratoryisavailableontheweekend, inthissituation,thereisnostrongevidenceindicatingthatacatheterizationshouldbepostponed untilMonday. OptionCisincorrect.Inapatientthatisdiabeticandtroponinpositive,aninvasiveapproach shouldbefavored. OptionDisincorrect.Atthistime,anechocardiographyisnotapriority,andthus,itisnot necessarytodecidetheoptimalmanagementstrategy. OptionEisincorrect.ThispatienthasaconfirmedNSTEMIandastresstesttoprovokeischemia inthissettingisnotdiagnosticallyusefulandisunsafe.

References
1. WrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintothe ACC/AHA2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevation MyocardialInfarction:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeart AssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmerican AcademyofFamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andthe SocietyofThoracicSurgeons.JAmCollCardiol201157:e215367.

6.ThecorrectanswerisD.Atopaxarisathrombinreceptor(PAR1)inhibitor. 7.ThecorrectanswerisC.InthePLATOtrial,ticagrelorwasassociatedwithasignificant reductioninmortalitycomparedtoclopidogrel. 8.ThecorrectanswerisA.However,itisaClassIIbrecommendationthat60mgprasugrel maybeconsideredinUA/NSTEpatientsinwhomPCIisplanned,beforedefinitionofcoronary anatomy,ifboththeriskforbleedingislowandtheneedforCABGisconsideredunlikely(Level ofEvidence:C). References

1. WrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocusedupdateincorporatedintothe ACC/AHA2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevation MyocardialInfarction:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeart AssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmerican AcademyofFamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andthe SocietyofThoracicSurgeons.JAmCollCardiol201157:e215367.

9.ThecorrectanswerisA.TheuseofupstreamGPIIb/IIIainhibitorsmaybeconsideredin highriskUA/NSTEMIpatientsalreadyreceivingaspirinandathienopyridinewhoareselectedfor aninvasivestrategy,suchasthosewithelevatedtroponinlevels,diabetes,orsignificantST segmentdepression,andwhoarenototherwiseathighriskforbleeding(ClassIIb recommendation.LevelofEvidence:B). References

1. WrightRS,AndersonJL,Adams,CD,etal.2011ACCF/AHAfocused

updateincorporatedintotheACC/AHA2007GuidelinesfortheManagement ofPatientswithUnstableAngina/NonSTElevationMyocardialInfarction:a reportoftheAmericanCollegeofCardiologyFoundation/AmericanHeart AssociationTaskForceonPracticeGuidelinesdevelopedincollaboration withtheAmericanAcademyofFamilyPhysicians,Societyfor CardiovascularAngiographyandInterventions,andtheSocietyofThoracic Surgeons.JAmCollCardiol201157:e215367.

10.ThecorrectanswerisC.Giventhetimethatwouldberequiredfortransfertooccur,the patientshouldundergofibrinolysisattheinitialfacility,ratherthanawaitingdefinitive managementaftertransfer.Expeditioustransfershouldnonethelessfollowlysis,giventhe resultsoftheCARESSandTRANSFERAMItrialshence,whilethemedicaltherapiesinoptionE arereasonable,thepatientshouldthenbetransferred.Prasugrel(optionA)hasnotbeen studiedinthesettingoffibrinolytics,andthus,shouldnotbeemployedinthissetting.The loadingdoseofclopidogrel(optionB)isreasonable,buttransferforPCIpriortoattempted reperfusionviafibrinolysisisinadvisableinthissetting.FacilitatedPCIwithreduceddoselytic administeredpriortoplannedPCIwasstudiedintheASSENT4trial,andwasassociatedwith increasedinhospitalmortalitythus,optionDisincorrect. References
1. DiMarioC,DudekD,PiscioneF,etal.Immediateangioplastyversusstandardtherapywithrescue angioplastyafterthrombolysisintheCombinedAbciximabREteplaseStentStudyinAcuteMyocardial Infarction(CARESSinAMI):anopen,prospective,randomised,multicentretrial.Lancet 2008371:55968. 2. CantorWJ,FitchettD,BorgundvaagB,etal.Routineearlyangioplastyafterfibrinolysisforacute myocardialinfarction.NEnglJMed2009360:270518. 3. AssessmentoftheSafetyandEfficacyofaNewTreatmentStrategywithPercutaneousCoronary

Intervention(ASSENT4PCI)investigators.Primaryversustenecteplasefacilitatedpercutaneous coronaryinterventioninpatientswithSTsegmentelevationacutemyocardialinfarction(ASSENT4 PCI):randomisedtrial.Lancet2006367:56978.

11.ThecorrectanswerisA.Anticoagulantshaveseveralpotentialmechanismsofactionby whichtheyexerttheirantithromboticeffects.Althoughtherehasbeeninterestinoral anticoagulantsforuseinUA/NSTEMI,themajorityofagentscurrentlyrecommendedinthe ACCF/AHAguidelinesareeitherintravenouslyorsubcutaneouslyadministered.Bivalirudinisan intravenouslyadministereddirectthrombininhibitorthathasaClassIrecommendationfor invasivelymanagedpatientswithUA/NSTEMI.Enoxaparincanbeadministeredthrougheither subcutaneousorIVroutes(thelatterduringPCI),andisanLMWH,whichexertsitsanticoagulant effectbypotentiatingtheactivityofantithrombinIII.UFHalsoactsviapotentiationofantithrombin IIIseffectandistypicallyadministeredinUA/NSTEMIviaIVadministration,althoughitalsocan beadministeredsubcutaneously.Fondaparinuxisadministeredsubcutaneouslyandreversibly bindstoantithrombinIII,indirectlyinhibitingfactorXa.Enoxaparin,UFH,andfondaparinuxalso haveaClassIindicationforuseinUA/NSTEMI(inbothinvasivelyandconservativelymanaged patients). References
1. WrightRS,AndersonJL,AdamsCD,etal.2011ACCF/AHAfocusedupdateincorporatedintothe ACC/AHA2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevation MyocardialInfarction:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeart AssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmerican AcademyofFamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andthe SocietyofThoracicSurgeons.JAmCollCardiol201157:e215367.

12.ThecorrectanswerisC.AnticoagulantagentsusedduringPCIforUA/NSTEMIareinmost caseskeptconsistentwiththeinitialagentsusedpriortoPCI,asthestacking/switchingof anticoagulantagentshasinsomecasesbeenassociatedwithanincreasedriskofbleeding complications.Anotableexceptiontothisisthecaseofapatienttreatedwithfondaparinux,an agentthathasbeenobservedtoberelatedtoalowbutdefiniteincidenceofcatheterrelated thrombusformationduringPCI.TheACCF/AHAguidelinesthusrecommendtheuseofUFH duringPCIforpatientsinitiallytreatedwithfondaparinux. WarfarinisnottypicallyindicatedforuseinUA/NSTEMI,particularlyduringPCI.Subcutaneously administeredenoxaparincanbeusedforthemedicaltreatmentofUA/NSTEMI,butifused specificallyasananticoagulantforPCIshouldbeintravenouslyadministered.Additionally,the useofbothenoxaparinandUFHinpatientswithACShasbeenassociatedwithanincreased rateofbleedingcomplications.Argatrobanisnotindicatedorrecommendedforusein UA/NSTEMI. References
1. WrightRS,AndersonJL,AdamsCD,etal.2011ACCF/AHAfocusedupdateincorporatedintothe ACC/AHA2007GuidelinesfortheManagementofPatientswithUnstableAngina/NonSTElevation MyocardialInfarction:areportoftheAmericanCollegeofCardiologyFoundation/AmericanHeart AssociationTaskForceonPracticeGuidelinesdevelopedincollaborationwiththeAmerican AcademyofFamilyPhysicians,SocietyforCardiovascularAngiographyandInterventions,andthe SocietyofThoracicSurgeons.JAmCollCardiol201157:e215367.

13.ThecorrectanswerisC.Commoncomplicationsrelatedtoanticoagulantagentsinclude potentialbleedingcomplications,whichmustbeweighedagainsttheantiischemiceffectsof theseagents.Specificcomplicationsrelatedtotheseagentsarealsoimportanttoconsider whenadministeringtheseagents.BothUFHandLMWHs,includingenoxaparin(althoughtoa muchlesserextentthanUFH),havebeenassociatedwiththeoccurrenceofheparinassociated thrombocytopenia,withorwithoutthrombosis.Fondaparinuxhasbeenassociatedwithcatheter relatedthrombosisduringPCI.Asadirectthrombininhibitor,bivalirudincanbeusedforthe treatmentofheparininducedthrombocytopenia.Becausebivalirudinisrenallycleared,the infusiondosemustbeadjustedinthesettingofrenaldysfunction.Enoxaparinandfondaparinux arealsorenallycleared,andenoxaparinshouldbedoseadjustedinpatientswithCrCl<30 ml/min,whereasfondaparinuxistypicallyavoidedinthesepatients. 14.ThecorrectanswerisD.ThefindingsareconsistentwithaninferiorSTEMIwithelevated rightandleftsidedfillingpressures.AnRVMIshouldbeconsideredandadministrationof nitroglycerinmayprecipitateworseninghypotension.Rightsidedprecordialleadsshould

generallybeperformedinpatientswithinferiorSTEMI.Inthiscase,therelativehypotensionand elevatedjugularvenouspressureareofconcern.Theappropriatedoseofaspirinis325mg.A betablockershouldnotbeadministeredatpresentationinpatientswithSTEMIwithevidenceof heartfailure(classIII). 15.ThecorrectanswerisC.ThisisawomanwithalargeanteriorSTEMIwhohaspresented earlyaftersymptomonsetwithnocontraindicationstofibrinolysisandananticipatedtransfer time>2hourstogettoacathlabforprimaryPCI.At90minutesafterreceivingthefibrinolytic,she hasnoresolutionofSTsegmentelevation.Ataminimum,thisfindingplacesherinahigherrisk group.Inaddition,shehasa>50%likelihoodofnothavingrestorednormalflowintheculprit vessel. Therefore,itisreasonabletoreferherimmediatelytoaPCIcapablehospital,wherecoronary angiographycanbeperformedifherSTelevationandchestsymptomspersistonarrival,with rescuePCIperformedifneeded.RescuePCIissuperiortoreadministrationofafibrinolyticin thiscircumstance.AdministrationofaglycoproteinIIb/IIIaantagonistisassociatedwithamarked increaseinbleedingandisnotrecommendedinthissetting.Additionaldelayattheinitial hospitalisnotadvisable.IfthereisSTresolutionbythetimeofarrivalatthePCIhospital,then urgentPCIcanbedeferred. 16.ThecorrectanswerisA.ThepotentialmortalitybenefitswithabetablockeroranACEIina completelyrevascularizedsubjectwithpreservedLVfunctionarelikelysmalltonegligible.There isnocurrentdatatosupporttheinitiationofanAldosteroneantagonistinthepostSTEMIsetting withpreservedLVEF.TheuseofCOX2agentsisassociatedwithincreasedCVmortalityin vulnerablepatientsubsets.Earlyinitiationofstatintherapyisassociatedwithaprovenmortality benefitinthissetting. 17.ThecorrectanswerisD.Theposteromedialpapillarymuscleismorelikelytorupture comparedtotheanterolateralpapillarymuscle,becauseitusuallyreceivesbloodsupplyonly fromtherightposteriordescendingartery,whichisabranchoftherightcoronaryartery.In contrast,theanterolateralpapillarymusclereceivesdualbloodsupply(fromboththeleftanterior descendingandthecircumflexartery)andis,therefore,lesslikelytorupture. References
1. BonowRO,CarabelloBA,ChatterjeeK,etal.ACC/AHA2006guidelinesforthemanagementof patientswithvalvularheartdisease:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(writingCommitteetoRevisethe1998guidelinesfor themanagementofpatientswithvalvularheartdisease)developedincollaborationwiththeSociety ofCardiovascularAnesthesiologistsendorsedbytheSocietyforCardiovascularAngiographyand InterventionsandtheSocietyofThoracicSurgeons.JAmCollCardiol200648:e1148.

18.ThecorrectanswerisD.Patientswithrupturedpapillarymuscleshouldundergoemergent surgicalrepairormitralvalvereplacement,alongwithCABG.Beforesurgery,measuresthatcan stabilizethepatientincludeinotropicsupportanddecreaseoftheafterloadwithintraaortic ballooncounterpulsation(orwithnitroprussideadministrationifthesystemicbloodpressureis notverylow). References

1. BonowRO,CarabelloBA,ChatterjeeK,etal.ACC/AHA2006guidelinesforthemanagementof patientswithvalvularheartdisease:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(writingCommitteetoRevisethe1998guidelinesfor themanagementofpatientswithvalvularheartdisease)developedincollaborationwiththeSociety ofCardiovascularAnesthesiologistsendorsedbytheSocietyforCardiovascularAngiographyand InterventionsandtheSocietyofThoracicSurgeons.JAmCollCardiol200648:e1148. 2. NishimuraRA,GershBJ,SchaffHV.Thecaseforanaggressivesurgicalapproachtopapillary musclerupturefollowingmyocardialinfarction:"Fromparadiselosttoparadiseregained".Heart 200083:6113.

19.ThecorrectanswerisC.ThispatientmostlikelyhasRVinfarctioncomplicatinghisinferior STEMI,assuggestedbytheclearlungsandtheelevatedjugularvenouspressure,aswellasthe profoundhypotensioncausedbynitroglycerinadministration.Hypotensioninsuchpatientscan betreatedbyintravenousfluidadministration,suchasnormalsaline(optionA)andinotropic support(optionB).Promptreperfusion,eitherwiththrombolyticadministration(optionD)orwith primaryPCI(optionE),isalsorequired.Morphinehasvenousvasodilatingpropertiesandmay

furtherdecreasecardiacpreloadtherefore,itshouldnotbeadministeredtopatientswithRV infarction. References

1. BonowRO,CarabelloBA,ChatterjeeK,etal.ACC/AHA2006guidelinesforthemanagementof patientswithvalvularheartdisease:areportoftheAmericanCollegeofCardiology/AmericanHeart AssociationTaskForceonPracticeGuidelines(writingCommitteetoRevisethe1998guidelinesfor themanagementofpatientswithvalvularheartdisease)developedincollaborationwiththeSociety ofCardiovascularAnesthesiologistsendorsedbytheSocietyforCardiovascularAngiographyand InterventionsandtheSocietyofThoracicSurgeons.JAmCollCardiol200648:e1148.

20.ThecorrectanswerisC.ThepatientispresentingwithanacuteinferoposteriorMI.PPCIis notthebestmanagementstrategybecauseDTBdoortoneedletimewillexceed60minutes, andtherearenocontraindicationstofibrinolytictherapy.Administrationoffibrinolytictherapyis thebestinitialstrategy.BasedonCARESSinAMIandTRANSFERAMI,immediatetransferis warrantedsinceaninferoposteriorMIwouldbeconsideredhighrisk.RoutineuseofGPIIb/IIIa inhibitorswithfulldosefibrinolyticsisnotbeneficialandmaybeharmful. References

1. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswith STelevationmyocardialinfarctionexecutivesummary:areportoftheAmericanCollegeof Cardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines(WritingCommitteeto revisethe1999guidelinesforthemanagementofpatientswithacutemyocardialinfarction).JAm CollCardiol200444:671719. 2. KushnerFG,HandM,SmithSCJr.,etal.2009focusedupdates:ACC/AHAguidelinesforthe managementofpatientswithSTelevationmyocardialinfarction(updatingthe2004guidelineand 2007focusedupdate)andACC/AHA/SCAIguidelinesonpercutaneouscoronaryintervention (updatingthe2005guidelineand2007focusedupdate):areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines.JAmColl Cardiol200954:220541. 3. CantorWJ,FitchettD,BorgundvaagB,etal.RoutineEarlyAngioplastyafterFibrinolysisforAcute MyocardialInfarction.NEnglJMed2009360:270518. 4. DiMarioC,DudekD,PiscioneF,etal.ImmediateAngioplastyversusStandardTherapywithRescue AngioplastyafterThrombolysisintheCombinedAbciximabREteplaseStentStudyinAcute MyocardialInfarction(CARESSinAMI):AnOpen,Prospective,Randomised,MulticentreTrial.Lancet 2008371:55968.

21.ThecorrectanswerisA.FibrinolysisisthepreferredreperfusionstrategyforacuteMIifthe DTBdoortoneedleis>60minutesandespeciallyifthepatientpresentswithin3hours. However,thepatientinchoiceBisalatepresenteranteriorSTEMIcomplicatedbycardiogenic shock.ThesepatientsarebestmanagedwithPPCIevenifthereisamodestdelay.Thepatient inchoiceCislikelytoachieveaDTBof90minutesandthusshouldbemanagedwithPPCI. Activepepticulcerdiseaseisarelativecontraindicationtofibrinolysis,thusmakingthepatientin choiceDasuboptimalcandidate.ThepatientinchoiceEhashadarecenthead/facialfracture. Fibrinolysisiscontraindicatedwithin3monthsofasignificantclosedheadorfacialtrauma. Whileactivebleedingisacontraindicationtofibrinolysistherapy,mensesisnot,makingpatient Athebestanswertoreceivefibrinolysistherapy. References
1. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswith STelevationmyocardialinfarctionexecutivesummary:areportoftheAmericanCollegeof Cardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines(WritingCommitteeto revisethe1999guidelinesforthemanagementofpatientswithacutemyocardialinfarction).JAm CollCardiol200444:671719. 2. KushnerFG,HandM,SmithSCJr.,etal.2009focusedupdates:ACC/AHAguidelinesforthe managementofpatientswithSTelevationmyocardialinfarction(updatingthe2004guidelineand 2007focusedupdate)andACC/AHA/SCAIguidelinesonpercutaneouscoronaryintervention (updatingthe2005guidelineand2007focusedupdate):areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines.JAmColl Cardiol200954:220541.

22.ThecorrectanswerisE.PCIofatotallyoccludedinfarctartery24hoursafterSTEMIisnot recommendedinasymptomaticpatientswithoneortwovesseldiseaseiftheyare hemodynamicallyandelectricallystableanddonothaveevidenceofsevereischemia.TheOAT

trialtestedthehypothesisthatlatepatencyofaninfarctrelatedarterywouldbeassociatedwith improvedLVremodeling,greaterelectricalstability,andprotectionagainstfuturecardiovascular events.PatientswererandomizedtoPCIwithstentplacementandoptimalmedicaltherapyor optimalmedicaltherapyalone.Thecompositeprimaryendpointofdeath,reinfarction,andclass IVHFwasnotstatisticallydifferentbetweenthetwogroupsat4years. WhenPCIinSTEMIisindicated,theuseofstents,GPIIb/IIIainhibitors,andaspiration thrombectomyhasbeenshowntobebeneficialinthesettingofSTEMIPCI.The2009ACC/AHA FocusedUpdates:STEMIandPCIGuidelinesaddressedtheissueoftheuseofDESinthe settingofSTEMIandstatethatitisreasonabletouseaDESasanalternativetoaBMSforPPCI inSTEMI.PCIofanoninfarctrelatedarteryisnotindicated. References
1. AntmanEM,AnbeDT,ArmstrongPW,etal.ACC/AHAguidelinesforthemanagementofpatientswith STelevationmyocardialinfarctionexecutivesummary:areportoftheAmericanCollegeof Cardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines(WritingCommitteeto revisethe1999guidelinesforthemanagementofpatientswithacutemyocardialinfarction).JAm CollCardiol200444:671719. 2. AntmanEM,HandM,ArmstrongPW,etal.2007focusedupdateoftheACC/AHA2004guidelinesfor themanagementofpatientswithSTelevationmyocardialinfarction:areportoftheAmericanCollege ofCardiology/AmericanHeartAssociationTaskForceonPracticeGuidelines.JAmCollCardiol 200851:21047. 3. KushnerFG,HandM,SmithSCJr.,etal.2009focusedupdates:ACC/AHAguidelinesforthe managementofpatientswithSTelevationmyocardialinfarction(updatingthe2004guidelineand 2007focusedupdate)andACC/AHA/SCAIguidelinesonpercutaneouscoronaryintervention (updatingthe2005guidelineand2007focusedupdate):areportoftheAmericanCollegeof CardiologyFoundation/AmericanHeartAssociationTaskForceonPracticeGuidelines.JAmColl Cardiol200954:220541. 4. HochmanJS,LamasGA,BullerCE,etal.Coronaryinterventionforpersistentocclusionafter myocardialinfarction.NEnglJMed2006355:2395407.