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Resuscitation
j o ur na l h o me p a g e:ww w . e l s e v i er . c o m / l o c a t e / r e s u s c i t a t i o n
European
Resuscitation
Council
Guidelines
for
Resuscitation
2015
Section
8.
Initial
management
of
acute
coronary
syndromes
Nikolaos
I.
Nikolaou
a,∗,
Hans-Richard
Arntz
b,
Abdelouahab
Bellou
c,
Farzin
Beygui
d,
Leo
L.
Bossaert
e,
Alain
Cariou
f,
on
behalf
of
the
Initial
management
of
acute
coronary
syndromes
section
Collaborator
1aCardiologyDepartment,KonstantopouleioGeneralHospital,Athens,Greece
bDepartmentofEmergencyMedicine,Charité,UniversityMedicineBerlin,CampusBenjaminFranklin,Berlin,Germany
cUniversityofRennes,France&DepartmentofEmergencyMedicine,BethIsraelDeaconnesMedicalCenter,HarvardMedicalSchool,
Boston,MA,USA
dInterventionalCardiologyUnit,CaenUniversityHospital,Caen,France
eDepartmentofMedicineandHealthSciences,UniversityofAntwerp,Antwerp,Belgium
fMedicalIntensiveCareUnit,CochinUniversityHospital(APHP)&ParisDescartesUniversity,Paris,France
Summaryofmainchangessince2010guidelines
Thefollowingisasummaryofthemostimportantviewsand changesinnewrecommendationsforthediagnosisandtreatment ofacutecoronarysyndromes(ACS)sincethelastERCguidelinesin 2010.
DiagnosticinterventionsinACS
• Pre-hospitalrecordingofa12-leadelectrocardiogram(ECG) is recommendedinpatientswithsuspectedSTsegmentelevation acutemyocardialinfarction(STEMI).ForthosewithSTEMIthis expeditesprehospitalandin-hospital reperfusionandreduces mortality for both those planned for primary percutaneous coronaryintervention(PPCI)andthosewhoreceivefibrinolytic therapy.
• Non-physicianECGSTEMIinterpretationwithorwithouttheaid ofcomputerinterpretationissuggestedifadequatediagnostic performance can be maintained through carefully monitored qualityassuranceprograms.
• Pre-hospitalSTEMIactivationofthecatheterisationlaboratory may not only reduce treatment delays but may also reduce patientmortality.
• Theuseofnegativehigh-sensitivitycardiactroponins(hs-cTn) duringinitialpatientevaluationcannotbeusedasastandalone measuretoexcludeanACS,butinpatientswithverylowrisk scoresmayjustifyearlydischarge.
TherapeuticinterventionsinACS
• Adenosinediphosphate(ADP)receptorantagonists(clopidogrel, ticagrelor,orprasugrel-withspecificrestriction),maybegiven
∗ Correspondingauthor.
E-mailaddress:nikosnik@otenet.gr(N.I.Nikolaou).
1 TheInitialmanagementofacutecoronarysyndromessectionCollaboratoris
listedintheCollaboratorsection.
eitherpre-hospitalorintheEDforSTEMIpatientsplannedfor primaryPCI.
• Unfractionatedheparin(UFH)canbeadministeredeitherinthe pre-hospitalorin-hospitalsettinginpatientswithSTEMIanda plannedprimaryPCIapproach.
• Pre-hospitalenoxaparinmaybeusedasanalternativeto pre-hospitalUFHforSTEMI.
• PatientswithacutechestpainwithpresumedACSdonotneed supplementaloxygenunlesstheypresentwithsignsofhypoxia, dyspnoea,orheartfailure.
ReperfusiondecisionsinSTEMI
• Reperfusiondecisionshavebeenreviewedinavarietyofpossible localsituations.
• Whenfibrinolysisistheplannedtreatmentstrategy,we recom-mendusingpre-hospitalfibrinolysisincomparisontoin-hospital fibrinolysisfor STEMIwhere transport timesare>30minand pre-hospitalpersonnelarewelltrained.
• IngeographicregionswherePCIfacilitiesexistandareavailable, directtriageand transportfor PCIispreferredtopre-hospital fibrinolysisforSTEMI.
• PatientspresentingwithSTEMIintheemergencydepartment (ED)ofanon-PCIcapablehospitalshouldbetransported imme-diatelytoaPCIcentreprovidedthattreatmentdelaysforPPCI arelessthan120min(60to90minforearlypresentersandthose withextendedinfarctions),otherwisepatientsshouldreceive fib-rinolysisandbetransportedtoaPCIcentre.
• Patients who receive fibrinolytic therapy in the emergency departmentofanon-PCIcentreshouldbetransportedifpossible forearlyroutineangiography(within3to24hfromfibrinolytic therapy)ratherthanbetransportedonlyifindicatedbythe pres-enceofischemia.
• PCIinlessthan3hfollowingadministrationoffibrinolyticsis notrecommendedandcanbeperformedonlyincaseoffailed fibrinolysis.
http://dx.doi.org/10.1016/j.resuscitation.2015.07.030
Hospitalreperfusiondecisionsafterreturnofspontaneous circulation(ROSC)
• We recommend emergency cardiaccatheterisation lab evalu-ation(and immediatePCIif required),in a mannersimilarto patientswithSTEMI without cardiac arrest, in selectedadult patientswithROSCafterout-of-hospitalcardiacarrest(OHCA) ofsuspectedcardiacoriginwithST-elevationonECG.
• InpatientswhoarecomatoseandwithROSCafterOHCAof sus-pectedcardiacoriginwithoutST-elevationonECGItisreasonable toconsideranemergencycardiaccatheterisationlabevaluation inpatientswiththehighestriskofcoronarycausecardiacarrest.
Introduction
TheincidenceofacuteST-elevationmyocardialinfarction(AMI) is decreasingin many European countries;1 however, the inci-denceofnon-STEMIacutecoronarysyndrome(non-STEMIACS) isincreasing.2Althoughin-hospitalmortalityfromSTEMIhasbeen reducedsignificantlybymodernreperfusiontherapyandimproved secondary prophylaxis,theoverall 28-day mortalityis virtually unchanged because about two thirds of those who die do so beforehospitalarrival,mostlyfromlethalarrhythmiastriggered byischaemia.3 Thus,thebestwayofimprovingsurvivalfroman ischaemicattackisreducingthedelayfromsymptomonsettofirst medicalcontactandtargetedtreatmentstartedintheearlyout-of hospitalphase.
Thetermacutecoronarysyndrome(ACS)encompassesthree differententitiesoftheacutemanifestationofcoronaryheart dis-ease(Fig.8.1):STelevationmyocardialinfarction(STEMI),non-ST elevationmyocardialinfarctionandunstableanginapectoris(UAP). Non-STelevationmyocardialinfarctionandUAPareusually com-binedinthetermnon-STEMI-ACS.Thecommonpathophysiologyof ACSisarupturedorerodedatheroscleroticplaque.4 Electrocardio-graphic(ECG)characteristics(absenceorpresenceofSTelevation) differentiateSTEMIfromnon-STEMIACS.Thelattermaypresent withSTsegmentdepression,nonspecificSTsegmentwave abnor-malities,orevenanormalECG.IntheabsenceofSTelevation,an increaseintheplasmaconcentrationofcardiacbiomarkers, partic-ularlytroponinTorIasthemostspecificmarkersofmyocardial cellnecrosis,indicatesnon-STEMI.
Acutecoronarysyndromesarethecommonestcauseof malig-nantarrhythmiasleadingtosuddencardiacdeath.Thetherapeutic goalsaretotreatacutelife-threateningconditions,suchas ven-tricularfibrillation(VF)orextremebradycardia,andtopreserve leftventricularfunctionandpreventheartfailurebyminimising theextentofmyocardialdamage.Thecurrentguidelinesaddress thefirsthoursafteronsetofsymptoms.Out-of-hospitaltreatment andinitialtherapyintheemergencydepartment(ED)mayvary accordingtolocalcapabilities,resourcesandregulations.Thedata supportingout-of-hospitaltreatmentareoftenextrapolatedfrom studiesofinitialtreatmentafterhospitaladmission;therearefew high-qualityout-of-hospitalstudies.TheEuropeanSocietyof Car-diologyandtheAmericanCollegeofCardiology/AmericanHeart Associationhavepublishedcomprehensiveguidelinesforthe diag-nosisand treatmentofACSwithand withoutSTelevation.The currentrecommendationsareinlinewiththeseguidelines.5,6 Diagnosisandriskstratificationinacutecoronary
syndromes
SignsandsymptomsofACS
Typically ACS appears with symptoms such as radiating chestpain,shortnessofbreathand sweating;however,atypical
Fig.8.1.Definitionsofacutecoronarysyndromes(ACS);ECG,electrocardiogram; LBBB,leftbundlebranchblock;STEMI,ST-elevationmyocardialinfarction;NSTEMI, non-ST-elevationmyocardialinfarction;ctroponin,cardiactroponin;UAP,unstable anginapectoris;TIMI,thrombolysisinacutemyocardialinfarction;GRACE,global registryofacutecoronaryevents.
symptomsorunusualpresentationsmayoccurintheelderly,in females,andindiabetics.NoneofthesesignsandsymptomsofACS canbeusedaloneforthediagnosisofACS.Areductioninchestpain afternitroglycerinadministrationcanbemisleadingandisnot rec-ommendedasadiagnosticmanoeuvre.7Symptomsmaybemore intenseandlastlongerinpatientswithSTEMIbutarenotreliable fordiscriminatingbetweenSTEMIandnon-STEMI-ACS.5,8–10
Thepatient’shistoryshouldbeevaluatedcarefullyduringfirst contactwithhealthcareproviders.Itmayprovidethefirstcluesfor thepresenceofanACS,triggersubsequentinvestigationsand,in combinationwithinformationfromotherdiagnostictests,canhelp inmakingtriageandtherapeuticdecisionsintheout-ofhospital settingandtheemergencydepartment(ED).
TheclinicalrecognitionofACSisachallengeemphasisingthat trainingofemergencyprovidersincludingEMSdispatchers, doc-tors and non-doctors depending onthe type of EMS systemis essential.Clinical pathwayprotocolsarestronglyrecommended and mustbeavailableforemergency teamsworkingin thepre hospitalsettingandtheemergencydepartment(ED).
12-leadECG
A12-leadECGisthekeyinvestigationforassessmentofanACS. InthecaseofSTEMI,itindicatestheneedforimmediate reper-fusion therapy(i.e.primarypercutaneouscoronaryintervention (PCI)orpre-hospitalfibrinolysis).WhenanACSissuspected, print-outofa12-lead-ECGshouldbeacquiredandinterpretedassoon aspossibleafterfirstpatientcontact,tofacilitateearlier diagno-sisandtriage.6,8,10STEMIistypicallydiagnosedwhenST-segment
elevation,measuredattheJpoint,fulfillsspecificvoltagecriteria intheabsenceofleftventricular(LV)hypertrophyorleftbundle branchblock(LBBB).5Inpatientswithclinicalsuspicionofongoing myocardialischaemiawithneworpresumednewLBBB,consider promptreperfusiontherapy,preferablyusingprimaryPCI(PPCI). VentricularpacingmayalsomaskthepresenceofanevolvingMI andmayrequireurgentangiographytoconfirmdiagnosisand ini-tiatetherapy.
Rightprecordialleadsshouldberecordedinallpatientswith inferiorSTEMIinordertodetectrightventricularMI.Isolated ST-depression≥0.05mVinleadsV1throughV3representsSTEMIin theinferobasalportionoftheheartwhichmaybeconfirmedby STsegmentelevationinposteriorleads(V7–V9).Pre-hospitalor EDECGyieldsusefuldiagnosticinformationwheninterpretedby trainedhealthcareproviders.
Recordingofa12-leadECGout-of-hospitalenablesadvanced notificationtothereceivingfacilityandexpeditestreatment deci-sions afterhospital arrival. In many studies, using pre-hospital 12-leadECG,thetimefromhospitaladmissiontoinitiating reper-fusiontherapyisreducedby10to60min.Thisisassociatedwith shortertimestoreperfusionandimprovedpatientsurvivalinboth patientswithPCIandthoseundergoingfibrinolysis.11–19
TrainedEMSpersonnel(emergencyphysicians,paramedicsand nurses)canidentifySTEMI,definedbySTelevationof≥0.1mV ele-vationinatleasttwoadjacentlimbleadsor>0.2mVintwoadjacent precordialleads,withahighspecificityandsensitivitycomparable todiagnosticaccuracyinthehospital.20,21Itisthusreasonablethat paramedicsandnursesbetrainedtodiagnoseSTEMIwithoutdirect medicalconsultation,aslongasthereisstrictconcurrentprovision ofqualityassurance.
Ifinterpretationofthepre-hospitalECGisnotavailableon-site, computerinterpretation22,23 or fieldtransmission oftheECG is reasonable.14,22–29Recordingandtransmissionofdiagnostic qual-ityECGstothehospitalusuallytakeslessthan5min.Whenused fortheevaluationofpatientswithsuspectedACS,computer inter-pretationoftheECGmayincreasethespecificityofdiagnosisof STEMI,especiallyforcliniciansinexperiencedinreadingECGs.The benefitofcomputerinterpretationhowever,isdependentonthe accuracyoftheECGreport.Incorrectreportsmaymislead inexpe-riencedECGreaders.Thuscomputer-assistedECGinterpretation shouldnotreplace,butmaybeusedasanadjunctto,interpretation byanexperiencedclinician.
Biomarkers,rulesforearlydischargeandchestpainobservation protocols
IntheabsenceofST elevationontheECG,thepresenceof a suggestivehistoryandelevatedconcentrationsofbiomarkers (tro-ponins,CKandCKMB)characterisenon-STEMIanddistinguishit fromSTEMIandunstableangina,respectively.Measurementofa cardiac-specifictroponinis usedroutinelybecauseof itshigher sensitivityandspecificity.Elevatedconcentrationsoftroponinare particularly helpful in identifying patients at increased risk of adverseoutcome.30,31
Inordertousethemeasuredbiomarkeroptimally,clinicians shouldbefamiliarwiththesensitivity,precisionandinstitutional normsof theassay,and alsotherelease kineticsand clearance. Highlysensitive(ultrasensitive)cardiactroponinassayshavebeen developed.Theycanincreasesensitivityandacceleratediagnosis ofMIinpatientswithsymptomssuspiciousofcardiacischaemia.32 Cardiacbiomarkertestingshouldbepartoftheinitial evalua-tionofallpatientspresentingtotheEDwithsymptomssuggestive ofcardiacischaemia.However,thedelayinrelease of biomark-ersfromdamagedmyocardiumpreventstheiruseindiagnosing myocardialinfarctioninthefirsthoursaftertheonsetofsymptoms. Forpatientswhopresentwithin6hofsymptomonset,andhavean
initialnegativecardiactroponin,biomarkersshouldbemeasured againbetween2and3andupto6hlaterforhs-cTn(12hwith regu-lartroponin).ThemajorityofpatientswithpossibleACSdonothave anACSbuttheidentificationofthosewithACSischallenging.The recentlyreportedrateofpatientswitha‘missed’diagnosisofACSin theEDisupto3.5%withsignificantmorbidityandmortality.33–35 Withtheimplementationofhigh-sensitivity(hs)-assays,many hs-cTnbasedpathwaysforrapiddecision-makinghavebeentested whichresultedinaproliferationofproposeddiagnosticalgorithms intheEDincludingECG,troponin,andTIMIriskscore.Datafrom largeobservationalmulticentrestudiesshowedanexcellent per-formanceof2hrule-outprotocolsthatcombinehs-cTnvalueswith clinicalinformation,butalsofora1hrule-outandrule-inprotocol exclusivelybasedonhs-cTnTvalues.36–39
Itisnotrecommendedtousehighsensitivitycardiactroponins asastand-alonemeasureat0and2htoexcludethediagnosisof ACS,definedas<1%30-daymajoradversecardiacevents(MACE).40 Negativehs-cTnImeasuredat0and2hmaybeusedtogetherwith lowriskstratification(TIMIscoreof0or1)toexcludethediagnosis ofACS.AlsonegativecTnIorcTnTmeasuredat0and3–6htogether maybeusedinconjunctionwithverylowriskstratification (Van-couverscoreof0orNorthAmericanCPscoreof0andage<50)to excludethediagnosisofACS.
Thereisnoevidencetosupporttheuseoftroponin point-of-caretesting(POCT)inisolationasaprimarytestinthepre-hospital settingtoevaluatepatientswithsymptomssuspiciousofcardiac ischaemia.32IntheED,useofpoint-of-caretroponinassaysmay helptoshortentimetotreatmentandlengthofEDstay.41Until fur-therrandomisedcontroltrialsareperformed,otherserumassays shouldnotbeconsideredfirst-linestepsinthediagnosisand man-agementofpatientspresentingwithACSsymptoms.42–44
Riskassessmentscoresandclinicalpredictionalgorithmsusing clinicalhistory,physicalexamination,ECG,andcardiactroponins havebeendevelopedtohelpidentifypatientswithACSatincreased riskofadverseoutcome(s).Bothaccuratediscriminationand cali-brationareneededfromariskpredictionequation.Cliniciansneed toknowwhichACSpatientsareathighestrisksotheycanbe priori-tisedforearlierandmoreaggressivetreatment.Buttheyalsoneed toknowwhattheabsoluteriskis,sopatientscanbeadvisedabout theriskandbenefitsofvarioustreatmentoptions,andtosupport theminmakingrationalcost-benefitdecisions.GlobalRegistryof AcuteCoronaryEvents(GRACE)andThrombolysisInMyocardial Infarction(TIMI)riskscorearethemostcommonlyused.Inarecent meta-analysis,TIMIandGRACEriskscoresweretheonlyones val-idatedinmultipleclinicalsetting,withGRACEshowinga better performancewithanareaunderthecurve(AUC)around0.85.45
TheGRACEscoreidentifiedasizablelow-riskcohortpotentially safeforearlyEDdischargewithoutpatientassessmentwithhigh sensitivityandnegativepredictivevalue;howeverthe complex-ityofthistoolmaylimititsutility.46,47Itcouldbedifficulttouse thesescoresinthecontextofapre-hospitalsettingwhere biolog-icalparameters(biomarkersandcreatinine)arenotavailable.This isprobablythereasonwhylittleattentionhasbeenfocusedonthe pre-hospitalaspectsofcareinnon-STEMIdespiteitscommonality anddominantroleasthemajoroverallcontributortomortality from myocardial infarction.Whether implementation of a pre-hospitalregionalprogramofearly-riskstratification,initiationof evidence-basedcare,anda timelyinvasivestrategydeliveredto patientswithnon-STEMIatmoderatetohighriskwouldenhance outcomesstillneedsinvestigation.48ThenewversionoftheGRACE riskscore(GRACE2.0)usesnon-linearfunctionsandseemstobe moreaccuratethantheoriginalversion.Itisnowvalidatedoverthe longerterm(to1and3years)andwithsubstitutionspossiblefor creatininevaluesandKillipclassGRACE2.0willenablerisk stratifi-cationatthepatientpresentationwhereverthemanagementcare willstart.49
Fig.8.2.Treatmentalgorithmforacutecoronarysyndromes;ECG,electrocardiogram;SBP,systolicbloodpressure;STEMI,ST-elevationmyocardialinfarction; Non-STEMI-ACS,non-ST-elevationacutecoronarysyndrome;PCI,percutaneouscoronaryintervention.
In patients suspected of an ACS the combination of an unremarkablepasthistoryandphysicalexaminationwithnegative initialECGandbiomarkers cannotbeusedtoexcludeACS reli-ably.Thereforeafollowupperiodismandatoryinordertoreacha diagnosisandmaketherapeuticdecisions.
Chestpainobservationprotocolsarerapidsystemsfor assess-mentofpatientswithsuspectedACS.Theyshouldgenerallyinclude ahistoryandphysicalexamination,followedbyaperiodof obser-vation,duringwhichserialelectrocardiographyandcardiacmarker measurementsareperformed.AtsomepointafterAMIisexcluded, theevaluationofthepatientshouldbecomplementedbyeither a non-invasive evaluation for anatomical coronary disease or provocativetestingforinduciblemyocardialischaemia.These pro-tocolsmaybeusedtoimprove accuracyin identifyingpatients requiringinpatientadmissionorfurtherdiagnostictestingwhile maintainingpatientsafety,reducinglengthofstayandreducing costs.50
Inpatientspresenting totheEDwitha historysuggestiveof ACS,butnormalinitialworkup,chestpain(observation)unitsmay representasafeandeffectivestrategyforevaluatingpatients.The potentialtherapeuticanddiagnosticyieldofprovocativetesting maytakeonanincreasinglycentralroleindeterminingthe useful-nessofprovocativetestingforlow-riskandmoderate-riskpatients withchestpainevaluatedinaccelerateddiagnosticprotocols. Mul-ticentrestudiesareneededtodemonstrate theimpactofchest pain(observation)unitsintheuseofprovocativetesting.51They mayberecommendedasameanstoreducelengthofstay,hospital admissionsandhealthcarecosts,improvediagnosticaccuracyand improvequalityoflife.52Thereisnodirectevidence demonstrat-ingthatchestpainunitsorobservationprotocolsreduceadverse cardiovascularoutcomes,particularlymortality,forpatients pre-sentingwithpossibleACS.
Imagingtechniques
Effective screeningof patientswithsuspected ACS,but with negative ECG and negative cardiac biomarkers, remains chal-lenging. Non invasive imaging techniques (CT angiography,53 cardiacmagneticresonance,myocardialperfusionimaging,54and echocardiography55)havebeenevaluatedasmeansofscreening theselow-riskpatientsandidentifyingsubgroupsthatcanbe dis-chargedhomesafely.31,56–58 Furthermore,differentialdiagnoses suchas aortic dissection,pulmonary embolism, aorticstenosis, hypertrophiccardiomyopathy,pericardialeffusion,or pneumoth-orax may be identified. Therefore, echocardiography should be routinelyavailableinED,andusedinallpatientswithsuspected ACS.Studiesareneededtoevaluatetheimpactofechocardiography inthepre-hospitalsetting.Althoughtherearenolargemulticentre trials,existingevidenceindicatesthatthesediagnosticmodalities enableearlyandaccuratediagnosiswithareductioninlengthof stayandcostswithoutincreasingcardiacevents.Boththe expo-suretoradiationandiodinatedcontrastshouldbeconsideredwhen usingmyocardialperfusionimagingandmulti-detectorcomputer tomographycoronaryangiography(MDCTCA).
MDCTCAhasbeenrecentlyproposedinthemanagementacute chestpainintheED.Itisaccuratecomparedwithinvasivecoronary angiography,enablingdifferentialdiagnosis,anditisfeasibleand practicalintheED.53,59–63MDCTCAhasahighabilitytoruleout obstructivecoronaryarterydisease(CAD).64,65Earlyuseofcardiac MDCTCAinpatientspresentingtotheEDwithchestpainandalow tointermediateriskofACSquicklyidentifiesagroupofparticularly low-riskpatients(<1%riskofadverseeventswithin30days)and enablessafeandexpediteddischarge.Bypreventingunnecessary admissionsandprolongedlengthsofstay,astrategybasedonearly cardiacMDCTCAhasbeenshowntobeefficient.66–68Inasignificant
numberoflow-riskACSpatients,MDCTCAdetectsseverecoronary lesionsandenablesdedicatedfurtherdiagnosticandtherapeutic intervention.Inarecentmeta-analysis,MDCTCAdemonstrateda highsensitivityandalownegativelikelihoodratioof0.06,andwas effectiveinrulingoutthepresenceofACSinlowtointermediate riskpatientspresentingtotheEDwithacutechestpain.69Butthe inabilityofanatomicalfindingstoprovethepresenceofischaemia, thecancerriskinducedbyradiationexposureandpotentialoveruse stillraiseconcernsabouttherelevanceofthisstrategy.
Treatmentofacutecoronarysyndromes—Symptoms
Nitrates
Glyceryltrinitrateisaneffectivetreatmentforischaemicchest painandhasbeneficialhaemodynamiceffects,suchasdilationof thevenouscapacitancevessels,dilationofthecoronaryarteries and, to a minor extent, the peripheral arteries. Glyceryl trini-trate maybe consideredif the systolicblood pressure (SBP) is above90mmHgandthepatienthasongoingischaemicchestpain (Fig.8.2).Glyceryltrinitratecanalsobeusefulin thetreatment ofacute pulmonary congestion.Do not usenitrates inpatients withhypotension(SBP≤90mmHg),particularlyifcombinedwith bradycardia,andinpatientswithinferiorinfarctionandsuspected rightventricularinvolvement.Useofnitratesunderthese circum-stancescandecreasetheblood pressureandcardiacoutput.Do notusenitratesif5-phosphodiesteraseinhibitorshavebeenused recently(<48h).5,9,70,71
Giveglyceryl trinitrate0.4mgsublingualorequivalentevery 5minupto3dosesasSBPallows.BeginIVdosingat1010 micro-gramsmin−1 in persistentpain orpulmonaryedema;titrateto desiredBPeffect.
Analgesia
Morphineistheanalgesicofchoicefornitrate-refractorypain and also has calming effects on the patient making sedatives unnecessaryinmostcases.Sincemorphineisadilatorofvenous capacitance vessels, it may have additional benefit in patients with pulmonary congestion. Give morphine in initial doses of 3–5mgintravenouslyandrepeateveryfewminuntilthepatientis pain-free.Cautionisneededinpresenceoflethargy,hypotension, bradycardiaorknownhypersensitivity.5,9,71Avoid non-steroidal anti-inflammatorydrugs(NSAIDs)foranalgesiabecausetheyhave pro-thromboticeffects.72
Oxygen
Evidenceisaccumulatingaboutthequestionableroleof supple-mentaloxygenincardiacarrest,afterROSCandinacutecoronary syndromes.PatientswithacutechestpainwithpresumedACSdo notneedsupplementaloxygenunlesstheypresentwithsignsof hypoxia,dyspnoeaorheartfailure.Thereisincreasingevidence suggestingthathyperoxiamaybeharmfulinpatientswith uncom-plicatedmyocardialinfarction.73–76
In ACS complicated with cardiac arrest, hypoxia develops rapidly.Ischaemicbraininjuryisamajordeterminantfor neurolog-icallyintactsurvival.ThereforeduringCPRadequateoxygenationis essential.AfterROSC,avoidbothhypoxiaandhyperoxia(seepost resuscitationcare).77Use100%inspiredoxygenuntilthearterial oxygensaturationcanbemeasuredreliably.Assoonasthe arte-rialbloodoxygensaturationcanbemeasuredreliably,titratethe inspiredoxygenconcentrationtoachievearterialbloodoxygen sat-urationintherangeof94–98%,or88–92%inchronicobstructive pulmonarydisease.5,71
Treatmentofacutecoronarysyndromes—Cause
Inhibitorsofplateletaggregation
Platelet activation and aggregation following atherosclerotic plaquerupturearecentralpathophysiologicmechanismsofacute coronarysyndromesandantiplatelettherapyisapivotaltreatment ofACS whetherwithorwithout STsegment elevation,withor withoutreperfusionandwithorwithoutrevascularisation. Acetylsalicylicacid(ASA)
Largerandomisedcontrolledtrialsindicatedecreased mortal-itywhenASA(75–325mg)isgiventohospitalisedpatientswith ACS independent of the reperfusion or revascularisation strat-egy. A few studies have suggested reduced mortalityif ASA is given earlier.78–80 Therefore, give an oral loading dose of ASA (150to300mgof a non-entericcoated formulation)or150mg ofanIVpreparationassoonaspossibletoallpatientswith sus-pectedACSunless thepatienthasa knowntrueallergytoASA orhasactivebleeding.ASAmaybegivenbythefirsthealthcare provider,bystanderorbydispatcherassistanceaccordingtolocal protocols.
ADPreceptorinhibitors
Theinhibition oftheplateletADPreceptor bythe thienopy-ridinesclopidogrelandprasugrel(irreversibleinhibition)andthe cyclo-pentyl-triazolo-pyrimidineticagrelor(reversibleinhibition) leadstofurtherinhibitionofplateletaggregationinadditiontothat producedbyASA.Incontrasttoclopidogrel,theeffectofprasugrel andticagrelorarelargelyindependentofageneticallydetermined variabilityofdrugmetabolismandactivation.Therefore prasug-relandticagrelor(reversible)leadtoamorereliable,fasterand strongerinhibitionofplateletaggregation.
Alargerandomisedstudycomparingaloadingdoseof300mg clopidogrelfollowedby75mgdailywithprasugrel(loadingdose 60mg, followedby 10mg daily)in patientswithACS (see spe-cificremarksonnon-STEMI-ACSbelow)plannedforPCIresultedin fewerMACEwithprasugrel;thebleedingratewashigher,however. Bleedingriskwasincreasedmarkedly in patientsweighing less than60kgandthoseolderthan75years.81Asignificantlyincreased intracranialbleedingratewasobservedinpatientswithahistoryof transientischaemicattack(TIA)and/orstrokeinassociationwith prasugrel.Inanotherstudy,ticagrelor(loadingdose180mg, fol-lowedby90mgtwicedaily)provedtobesuperiortoclopidogrel (loadingdose300–600mgfollowedby75mgdaily)withrespectto mortalityandMACEinthegeneralsettingofACSbutalsoassociated withhigherrisksofbleeding.82
ADP-receptorinhibitorsinnon-STEMI-ACS.
Clopidogrel. IfgiveninadditiontoheparinandASAin high-risknon-STEMI-ACSpatients,clopidogrelimprovesoutcome.83Ifa conservativeapproachisselected,givealoadingdoseof300mg; withaplannedPCIstrategy,aninitialdoseof600mgmaybe pre-ferred.Thereisnolarge-scalestudyinvestigatingpre-treatment withclopidogrel,comparedwithperi-interventionalapplication– eitherwitha300mgor600mgloadingdose.
Prasugrel. Prasugrel (60mg loading dose) may be given to patientswithhigh-risknon-STEMI-ACSandplannedPCIonlyafter angiography,providedthatcoronarystenosesaresuitableforPCI. Contraindications(historyofTIA/stroke)andthebenefit–risk bal-anceinpatientswithhighbleedingrisk(weight<60kg,age>75 years)shouldbeconsidered.ARCT,comparingpreversus post-angiographytreatmentby prasugrelin non-STEMI-ACSshowed thatpre-treatmentwasassociatedwithhigherriskofmajor bleed-ingwithoutreducingthromboticeventsexcludingprasugrelfrom
anypossiblepre-treatmentstrategyin non-STEMI-ACSwhether initiatedinoroutofhospitalbeforecoronaryanatomyisknown.84 Ticagrelor. AccordingtothelatestESCguidelines,6ticagrelor (180mgloadingdose)shouldbegivenin additiontoASAinall patientswithmoderatetohigh-risknon-STEMI-ACSwhetheran invasivestrategyisplannedornot.Inpatientswithnon-STEMI-ACS plannedforaconservativeapproach,giveticagrelororclopidogrel assoonasthediagnosisisconfirmed.Thereisinsufficientevidence torecommendfororagainstpre-treatmentwiththeseagentswhen PCIistheinitialstrategy.
ADP-receptorinhibitorsinSTEMI.
Clopidogrel. Pre-hospitalversusin-hospitaladministrationof clopidogrel hasbeenassessedin two smallstudieswhich have shownitssafetybutnoevidentclinicalbenefit.85,86However,a meta-analysis of pre-PCI versus post-PCI (and not pre-hospital versus in-hospital)administration of clopidogrel in STEMI sub-group of patients has shown a significant benefit in terms of mortalityreduction andMIrateswithoutableedingexcessrisk in associationwithpre-treatment.87 Althoughthere is nolarge studyontheuseofclopidogrelforpre-PCItreatmentofpatients presentingwithSTEMIandplannedPCI,itislikelythatthis strat-egyisbeneficial.Sinceplateletinhibitionismoreprofoundwitha higherdose,a600mgloadingdosegivenassoonaspossiblemay beconsideredforpatientspresentingwithSTEMIandplannedPCI. Twolargerandomisedtrialsstudiedclopidogrelcomparedwith placebo in patients withSTEMI treated conservatively or with fibrinolysis.88–90Onestudyincludedpatientsupto75years,treated withfibrinolysis, ASA, an anti-thrombin and a loadingdose of 300mgclopidogrel.88Treatmentwithclopidogrelresultedinfewer occludedculpritcoronaryarteriesatangiographyand fewer re-infarctions,withoutanincreasedbleeding risk.Theotherstudy investigatedSTEMIpatientswithoutagelimitstobetreated con-servativelyorwithfibrinolysis.Inthistrial,clopidogrel(noloading, 75mgdaily)comparedwithplaceboresultedinfewerdeathsanda reductionofthecombinedendpointofdeathandstroke.89 There-forepatientswithSTEMItreatedwithfibrinolysisshouldbetreated withclopidogrel(300mgloadingdoseuptoanageof75yearsand 75mgwithoutloadingdoseif>75yearsofage)inadditiontoASA andanantithrombin.
Prasugrel. Prasugrelwithaloadingdoseof60mgupto24h before, atthetime of,or evenafter,PCI maybegiven in addi-tiontoASAandanantithrombintopatientspresentingwithSTEMI withplannedPCI.91Contraindications(historyofTIA/stroke),and relationof bleedingrisk versus benefitin patientswitha body weight<60kgor aged>75 years shouldbe takeninto account. Thereisnodataonprehospitaltreatmentwithprasugrelandno dataonprasugrelifusedinthecontextoffibrinolysis.
Ticagrelor. Ticagrelor may begiven with a loading dose of 180mgtopatientspresentingwithSTEMIandplannedPCI.The benefitofpre-hospitalversusin-catheterisationlaboratory admin-istrationofticagrelor(180mgloadingdose)wasassessedinaRCT including1862STEMIpatientspresentingwithin6haftersymptom onsetandplannedforprimaryPCI.Thestudyshowednobenefit intermsofangiographiccoronaryarteryfloworSTsegment ele-vationresolution(primaryend-point)ormajorclinicalendpoints. Thestudyalsoshowedthatpre-hospital administrationof tica-grelorwasassociatedwithareducedrateofdefiniteacutestent thrombosis(OR0.19,95%CI0.04–0.86)withoutexcessintheriskof bleeding.92However,thisend-pointwasnotpre-specifiedandthe findingshouldbeconsideredashypothesisgeneratingonly.There arenodataonticagrelorwhenusedinthecontextoffibrinolysis.
Therelativebenefitofpre-hospitaladministeringanADP antag-onist routinely in patients planned for PCI for STEMI may be marginalandoffsetbyadditionalharmsthatshouldbeevaluated inlargerRCTsthatincludeadditionalpatient-orientedoutcomes.
However,theuseofADPantagonistsin patientstransferredfor primaryPCI maybeconsideredaftercautious evaluationof the risk-benefitbalanceforeachpatient.
Glycoprotein(Gp)IIB/IIIAinhibitors
Glycoprotein (Gp)IIB/IIIA receptoractivationis thecommon final linkof plateletaggregation.Eptifibatideandtirofiban lead to reversible inhibition, while abciximab leads to irreversible inhibitionoftheGpIIB/IIIAreceptor.Olderstudiesfromthe pre-stenteramostlysupporttheuseofthisclassofdrugs.93 Recent studiesmostlydocumentneutralorworseoutcomes94withthe exception oftherecently publishedON-TIME-2trialcomparing pre-hospitalsystematicversusin-hospitalprovisional administra-tion of tirofiban associated with secondary PCI and showing a benefitofpre-treatmentwithGpIIB/IIIAreceptorblockersonthe primarythrombotic endpointwithnorelevantexcessin bleed-ingrisk.95 Alsoarecentmeta-analysis studyingtheresultsof7 randomisedtrialsincluding722patientscomparingearlyversus lateadministrationofabciximabinthesettingofprimaryPCIfor STEMIshowedabenefitofearlystrategyoncoronaryarterypatency translatingtoabenefitintermsofmortality.96However,inalmost allsupporting,neutraloropposingstudies,bleedingoccurredin morepatientstreatedwithGpIIB/IIIAreceptorblockers.Thereare insufficientdatatosupportroutinepre-treatmentwithGpIIB/IIIA receptorblockersinpatientswithSTEMIornon-STEMI-ACS.Itisnot recommendedtogiveGpIIB/IIIAreceptorblockersbeforecoronary anatomy is known.For high-riskpatientswithnon-STEMI-ACS, in-hospital pre-treatment witheptifibatide or tirofiban may be acceptablewhereasabciximabmaybegivenonlyinthecontextof PCI.TakingintoaccounttheincreasedbleedingriskwithGpIIB/IIIA receptorblockerswhenusedwithheparins,alternativetreatment strategieswiththeuseofADPantagonistsshouldbeconsidered.97 Antithrombins
Unfractionatedheparin(UFH)isanindirectinhibitorof throm-bin,which incombination withASAis usedasanadjunctwith fibrinolytictherapyorPPCIandisanimportantpartoftreatment ofunstableanginaandSTEMI.Limitationsofunfractionated hep-arininclude its unpredictableanticoagulant effect in individual patients,theneedtogiveitintravenouslyandtheneedto mon-itoraPTT.Moreover,heparincaninducethrombocytopaenia.Since publicationofthe2010ERCguidelinesonACS,severalrandomised trials have been performed testing alternative antithrombins versusUFHfor thetreatmentofpatientswithACS.98–100 These alternativesarecharacterisedbyamorespecificfactorXa activ-ity (low molecularweight heparins [LMWH], fondaparinux) or aredirectthrombininhibitors(bivalirudin).Withthelatter anti-thrombins,thecoagulationsystemdoesnotneedbemonitored andtheriskofthrombocytopeniaisreduced.Therearenostudies evaluatingprehospitalversusdelayedin-hospitaladministrationof anti-thrombinsotherthanUFH.Rivaroxaban,apixabanandother oraldirectthrombinantagonistsmayhaveanindicationafter sta-bilisationinspecificpatientgroupsbutnotintheinitialtreatment ofACS.101
Antithrombinsinnon-STEMI-ACS
Parenteralanticoagulation,in additiontoanti-plateletdrugs, is recommended atthe time ofdiagnosis becauseit effectively reducestherateofMACEinpatientswithnon-STEMI-ACS.Even ifthereisarationaleinuseofearlytreatmenttoavoidMACE,there isnoscientificproofofsuperiorityofpre-hospitaloverin-hospital initiationofanti-thrombintherapy.
Compared withUFH(70–100IUkg−1 IV), enoxaparin(30mg IV followed by 1mgkg−1 every 12h) reduces the combined
endpoint of mortality, myocardial infarction and the need for urgentrevascularisation,ifgivenwithinthefirst24–36hofonset ofsymptomsofnon-STEMI-ACS.102,103Althoughenoxaparincauses moreminorbleedingthanUFH,theincidenceofseriousbleedingis notincreased.AdditionalActivatedClottingTime(ACT)-activated IVbolusesofUFHmaybeconsideredfollowinginitialUFH treat-ment.
BleedingworsenstheprognosisofpatientswithACS.104 Fonda-parinux(2.5mgscdaily)andbivalirudin(0.1mgkg−1ivfollowed bya0.25mgkg−1 infusion)causelessbleedingthanUFH.105–107 Fondaparinux is recommended as having the most favourable efficacy—safety profile regardless of the management strategy. SincecatheterthrombiwereobservedinpatientsundergoingPCI additionalUFHduringPCIisnecessary.105
EnoxaparinorUFHarerecommendedwhenfondaparinuxisnot available.Inthetrialsonpatientspresentingwithnon-STEMI-ACS, UFH,fondaparinux,enoxaparinand bivalirudinweregiven only afterhospitaladmission;itthereforemaybeinvalidtoextrapolate theresultstothepre-hospitalorEDsetting.
Because of the reduced risk of bleeding, fondaparinux may bethe preferredanticoagulant. Because enoxaparinand fonda-parinuxmayaccumulateinpatientswithrenalimpairment,dosing mustbeadjusted.Forpatientswithaplannedinvasiveapproach, bivalirudinandenoxaparinarereasonablealternativestoUFH.The bleedingrisk maybeincreasedbyswitching betweenUFHand enoxaparin.108ConsiderstoppinganticoagulationafterPCIunless otherwiseindicated.
AntithrombinsinSTEMI
Antithrombinsforpatientstobetreatedwithfibrinolysis.
Enoxaparin-UFH. It is reasonable to give UFH for patients treatedwithpre-hospitalfibrinolysisforSTEMI.
Severalrandomised studiesofpatientswithSTEMI undergo-ingfibrinolysis,however,have shownthatadditionaltreatment withenoxaparininstead ofUFH resultedin betterclinical out-comes(irrespectiveofthefibrinolyticused)butaslightlyincreased bleeding rate in elderly (>75 years) and low weight patients (BW<60kg).109Reduceddosesofenoxaparininelderlyandlow weightpatientsmaintainedtheimprovedoutcomewhilereducing thebleedingrate.110
Dosingof enoxaparin: in patients<75 years, give an initial bolus of 30mg IV followed by 1mgkg−1 SC every 12h (first SC dose shortly after the IV bolus). Treat patients >75 years with 0.75mgkg−1 SC every 12h without an initial IV dose. Patientswithknownimpairedrenalfunction(creatinineclearance <30ml−1min−1)maybegiven1mgkg−1enoxaparinSConcedaily ormaybetreatedwithUFH.Thereareinsufficientdatato recom-mendotherLMWH.
Fondaparinux. Severalstudiesshowsuperiorityorneutral out-comewhenfondaparinuxwascomparedwithUFHasanadjunct forfibrinolysisinSTEMIpatients.105Fondaparinux(initially2.5mg SCfollowedby2.5mgSCdaily)maybeconsideredspecificallywith non-fibrin-specificfibrinolytics(i.e.streptokinase)inpatientswith aplasmacreatinineconcentration<3mgdl−1 (250micromoll−1). IncaseofplannedPPCI,enoxaparinorUFHarepreferred.
Bivalirudin. There are insufficient data to recommend bivalirudin insteadof UFHor enoxaparinin STEMI patientsto betreated withfibrinolysis. Since switching theanticoagulants mayincreasebleedingrisk,theinitialagentshouldbemaintained, with the exception of fondaparinux, where additional UFH is necessaryifanadditionalinvasiveprocedureisplanned.108 Anti-thrombinsfor STEMI patientsto betreated with primaryPCI (PPCI). AninjectableanticoagulantmustbeusedinprimaryPCIfor STEMI.AfterpublicationoftheERC2010Guidelines,studieshave been performed comparing different antithrombin treatments
withpre-hospitalinitiationforpatientswithSTEMIandplanned PPCI.98,99,111 Withexemption ofUFH(F),however, thereis still apaucity ofstudiescomparingtheefficacyofpre-hospital with in-hospital initiationof treatment withthesame anticoagulant i.e.theroleof earlierstartof therapy.Therefore treatment rec-ommendationsforthesesettingshavetobeextrapolatedmainly fromin-hospitalinvestigationswithoutproofofadvantageof pre-hospitalinitiationoftherapy,untilmorespecificstudyresultsare available.
UFH. In one observational study pre-hospital injection of 500mgaspirintogetherwith>5000IUUFHledtoasignificantly higher rate of TIMI flow 2 and 3 and TIMI flow 3 at initial angiography.112 Therewas,however,noimprovementininfarct sizeor30daymortality.
Enoxaparin. Inonelargerrandomisedstudyenoxaparinwas comparedwithUFHinplannedPPCIforSTEMI.In71%ofpatients anticoagulantswerestartedintheambulance.99Thestudyrevealed nodifferenceintheprimarycombinedendpointofdeath, proce-durefailureormajorbleeding,butreductionsinseveralsecondary combinedendpointssuchasdeath,recurrentACSandurgent revas-cularisation.Severalregistriesandsmallerstudiesalsodocumented favourableorneutral outcomewhenenoxaparinwascompared withUFHforPPCI(withbroaduseofthienopyridinesand/orGp IIB/IIIAreceptorblockers).113Therefore,enoxaparinisasafeand effectivealternativetoUFHandmaybepreferredoverUFHalsoin thepre-hospitalsetting.Thereareinsufficientdatatorecommend anyLMWHotherthanenoxaparinforPPCIinSTEMI.Switchingfrom UFHtoenoxaparinorviceversamayleadtoanincreased bleed-ingriskandthereforeshouldbeavoided.108Doseadjustmentof enoxaparinisnecessaryforpatientswithrenalimpairment.
Bivalirudin. Twolarge randomised studiesdocumented less bleedingandareductioninshortandlongtermmortalitywhen bivalirudinwascomparedwithUFHplusGpIIB/IIIAreceptor block-ersinpatientswithSTEMIandplannedPCI.114,115Severalother studiesandcaseseriesshowedalsobetterorneutralresultsandless bleedingwhenbivalirudinwascomparedwithUFH.Feasibilityand safetyofpre-hospitaladministrationaswellasreducedbleeding rateswereshowninnon-randomisedstudieswhencomparedwith historicalcontrols.100,111Innewertrialstestingbivalirudinagainst UFHwithlessextensiveadditionofGpIIb/IIIareceptorblockers,ora modifiedantiplateletstrategydifferencesinmajorbleedingswere onlyminor,whereasresultsinischaemicendpointswereneutral or even inferior with bivalirudin.116,117 A further study tested prehospitalinitiationofbivalirudinvs.UFHplusoptionalGpIIB/IIIa receptorantagonists,whichwasgivenin69%ofpatients.Bleedings butnotdeathweresignificantlyreducedwithbivalirudin;therate ofstentthromboseswithinthefirst24hafterPCIwashigherwith bivalirudinasinotherstudies.98,118 Weighingreduced bleeding ratesagainsthigherratesofstentthrombosisbivalirudinmaystill beconsideredasanalternativetoUFHinPPCIforSTEMI.
Fondaparinux. When compared with UFH, fondaparinux resultedinsimilarclinicaloutcomesbutlessbleedingwhenusedin thecontextofPPCI;105however,thrombusformationoncatheters requiredtreatmentwithadditionalUFH.Thereforefondaparinuxis notrecommendedforplannedPPCIofSTEMI.
ReperfusionstrategyinpatientspresentingwithSTEMI
ReperfusiontherapyinpatientswithSTEMIisthemost impor-tantadvanceinthetreatmentofmyocardialinfarctioninthelast 30years.ForpatientspresentingwithSTEMIwithin12hof symp-tomonset,reperfusionshouldbeinitiatedassoonaspossibleusing themostappropriateavailablestrategy.119–122Reperfusionmaybe achievedwithfibrinolysis,withPPCI,oracombinationofboth. Effi-cacyofreperfusiontherapyisprofoundlydependentonthetime
Table8.1
Contraindicationsforfibrinolysis
Absolutecontraindications
Haemorrhagicstrokeorstrokeofunknownoriginatanytime Ischaemicstrokeinthepreceding6months
Centralnervoussystemdamageorneoplasms
Recentmajortrauma/surgery/headinjury(withinthepreceding3weeks) Gastro-intestinalbleedingwithinthelastmonth
Knownbleedingdisorder Aorticdissection Relativecontraindications
Transientischaemicattackinpreceding6months Oralanticoagulanttherapy
Within1weekpost-partum Non-compressiblepunctures Traumaticresuscitation
Refractoryhypertension(systolicbloodpressure>180mmHg) Advancedliverdisease
Infectiveendocarditis Activepepticulcer
AccordingtotheguidelinesoftheEuropeanSocietyofCardiology
intervalfromsymptomonsettoreperfusion.Fibrinolysisis
effec-tivespecificallyinthefirst2to3haftersymptomonset;PPCIisless
timesensitive.
Fibrinolysis
Ameta-analysisof3RCTsincluding531patientsshowedbenefit
ofprehospitalversusinhospitalfibrinolysisintermsofsurvivalto
hospitaldischargewithoutevidenceofadditionalharmintermsof
majororintracranialbleeding.123–125Aneffectiveandsafesystem
forout-of-hospitalfibrinolytictherapyrequiresadequatefacilities forthediagnosisandtreatmentofSTEMIanditscomplications. Fibrinolytictherapy can begiven safely bytrained paramedics, nursesorphysiciansusinganestablishedprotocol,comprehensive trainingprograms,andqualityassuranceprogramswithmedical oversight.126Ideally,thereshouldbeacapabilityof communicat-ingwithexperiencedhospitaldoctors.(e.g.emergencyphysicians orcardiologists).Therealadvantageofprehospitalfibrinolysisis wheretherearelongtransport times,i.e.>30–60min.TheRCTs thatshowedbenefitwithpre-hospitalfibrinolysiswereconducted in healthcare settingswith a meandifference intime between pre-hospital treatmentandin hospital treatmentof33–52min. Additionally,transporttimestohospitalwereameanof38–60min. Asthetransport timeshortens, anyexpectedadvantage islost. Thus,givingfibrinolyticsout-of-hospitaltopatientswithSTEMIor signsandsymptomsofanACSwithpresumednewLBBBis benefi-cial.Theefficacyisgreatestearlyafteronsetofsymptoms.Patients withsymptomsofACSandECGevidenceofSTEMI(orpresumably newLBBBortrueposteriorinfarction)presentingdirectlytothe EDshouldbegivenfibrinolytictherapyassoonaspossibleunless thereistimelyaccesstoPPCI.
Risksoffibrinolytictherapy
Healthcareprofessionalswhogivefibrinolytictherapymustbe awareofitscontraindications(Table8.1)andrisks.Patientswith largeAMIs(e.g.indicatedbyextensiveECGchanges)arelikelyto gainmostfromfibrinolytictherapy.Benefitsoffibrinolytictherapy are less impressive in inferior wallinfarctions than in anterior infarctions.Olderpatientshaveanabsolutehigherriskofdeath, buttheabsolutebenefitoffibrinolytictherapyissimilartothat of younger patients. Patients over 75 years have an increased riskofintracranialbleedingfromfibrinolysis;thus,theabsolute benefit of fibrinolysisis reduced by this complication.The risk of intracranial bleeding is increased in patientswith a systolic blood pressure ofover 180mmHg; this degreeof hypertension isa relative contraindication tofibrinolytictherapy. Therisk of
intracranialbleedingisalsodependentonthechosenfibrinolytic, antithrombinandantiplatelettherapy.Analternative,whileusing enoxaparin,ishalving thedosefortenecteplasein patients>75 years,whichreducestherateofintracranialbleedingwithoutloss ofefficacy.127,128
Primarypercutaneousintervention
Coronary angioplasty with or without stent placement has become the first-line treatment for patients with STEMI. PPCI performed with a limited delay to first balloon inflation after firstmedicalcontact,atahigh-volumecentre,byanexperienced operator who maintains an appropriate expert status, is the preferred treatmentas it improvesmorbidity and mortalityas comparedwithimmediatefibrinolysis.129
FibrinolysisvsprimaryPCI
PrimaryPCIhasbeenlimitedbyaccesstocatheterlaboratory facilities, appropriately skilledclinicians and delay to first bal-looninflation.Fibrinolysistherapyisawidelyavailablereperfusion strategy.Bothtreatmentstrategiesarewellestablishedandhave beenthesubjectoflargerandomisedmulticentretrialsoverthe lastdecades.TimefromonsetofsymptomsandPPCIrelateddelay (diagnosistoballoonintervalminusthediagnosistoneedle inter-val) arekey in selectingthemostappropriate revascularisation strategy.
Fibrinolytic therapy is most effective in patients presenting within 2–3h from onset of ischaemic symptoms. It compares favourablywithPPCIwhenstartedwithin2hfromsymptomonset andiscombinedwithrescueordelayedPCI.40,130,131Inthe ran-domised studies comparing PPCI with fibrinolytic therapy, the typicaldelay fromdecision tothebeginning of treatmentwith eitherPPCIorfibrinolytictherapywaslessthan60min.Inregistries that reflect standard practice more realistically the acceptable PPCI-relateddelay(i.e.thediagnosistoballoonintervalminusthe diagnosistoneedleinterval)tomaintainthesuperiorityofPPCI over fibrinolysis varied considerablybetween 45 and >180min depending on the patients’ conditions (i.e. age, localisation of infarction,anddurationofsymptoms).InSTEMIregistries,system delaystoPCImayexceed120mininasmanyas58%ofpatientswith STEMI.132Thuscontinuousmonitoringofsystemperformanceis neededtoassureoptimalperformanceandoutcomesforpatients withSTEMI.
Inearlypresenters,patientsofyoungerageandlargeanterior infarctions, PPCI related delays of 60minmay be unacceptable whileinlatepresenters(>3hfromtheonsetofsymptoms)PPCI relateddelaysofupto120minmaybeacceptable.133
ThepresenceofcertaincomorbiditiessuchaspreviousCABG, diabetesandrenalfailureareadditionalfactorstobeconsidered fortheselectionofthemostappropriatetherapy.134
TimedelaytoPPCImaybesignificantlyshortenedbyimproving thesystemsofcare135,136:
• Apre-hospitalECGshouldbeacquiredassoonaspossibleand interpretedforthediagnosisofSTEMI.Thiscanreducemortality inbothpatientsplannedforPPCIandfibrinolytictherapy. • STEMIrecognitionmaybeaccomplishedbyECGtransmissionor
onsiteinterpretationbyphysicians,orhighlytrainednursesor paramedics,withorwithouttheaidofcomputerECG interpreta-tion.
• When PPCI is theplannedstrategy, pre-hospital activationof catheterisationlaboratoryforPPCIwillcontributetoamortality benefit.40
Additionalelementsforaneffectivesystemofcareinclude: • Requiring the catheterisation laboratory to be ready within
20minavailable24/7.
• Providingreal-timedatafeedbackontherealtimecoursefrom symptomonsettoPCI.
Forthosepatientswithacontraindication tofibrinolysis,PCI shouldstillbepursueddespitethedelay,ratherthannotproviding reperfusiontherapy atall. For those STEMIpatients presenting inshock,primaryPCI (orcoronaryarterybypasssurgery)isthe preferred reperfusion treatment. Fibrinolysis should only be consideredifthereisasubstantialdelaytoPCI.
Triageandinter-facilitytransferforprimaryPCI
ThemajorityofpatientswithanongoingSTEMIwillbefirst diagnosedeitherinthepre-hospitalenvironmentorinthesetting oftheEDofanon-PCIcapablehospital.Thereforedecisionshaveto bemadeasforthemostappropriatestrategyforrevascularisation. In thepre-hospital setting thereis evidence suggesting that although pre-hospital fibrinolysis is not inferior to immediate transfer for primary PPCI in terms of mortality, it is associ-ated with increased risk for intracranial haemorrhage. When PCI can be performed within a time limit of 60–90min, then direct triage and transport for PCI is preferred to pre-hospital fibrinolysis.40,127,137–139
WhenthepatientwithSTEMIfirstappearsintheemergency departmentofanonPCIhospital,datafrom8RCTs140–147enrolling 3119patientsindicatethatimmediatetransferforPPCIissuperior tolocalfibrinolytictherapyandtransferonlyforrescuePCIinterms ofmortality,reinfarction andstrokewithoutevidencefor addi-tionalharm.Therefore,foradultpatientspresentingwithSTEMI intheEDofanon-PCIcapablehospitalemergenttransferwithout fibrinolysistoaPCIcentreshouldbeconsideredprovidedthatPPCI canbeperformedwithinacceptabletimedelays.
Itislessclearwhetherimmediatefibrinolytictherapy(in-or out-of-hospital)ortransferforPPCIissuperiorforyoungerpatients presentingwithanterior infarctionandwithin ashort duration of<2–3h.133TransferofSTEMIpatientsforPPCIisreasonablefor thosepresentingmorethan3hbutlessthan12haftertheonsetof symptoms,providedthatthetransfercanbeachievedrapidly. Combinationoffibrinolysisandpercutaneouscoronary
intervention
FibrinolysisandPCImaybeusedinavarietyofcombinations torestoreandmaintaincoronarybloodflowandmyocardial per-fusion.Thereareseveralwaysinwhichthetwotherapiescanbe combined.Thereissomelackofuniformityinthenomenclature usedtodescribePCIintheseregimens.FacilitatedPCIisusedto describePCIperformedimmediatelyafterfibrinolysis,a pharmaco-invasivestrategyreferstoPCIperformedroutinely3to24hafter fibrinolysis,andrescuePCIisdefinedasPCIperformedforafailed reperfusion(asevidencedby<50%resolutionofSTsegment ele-vationat60to90minaftercompletionoffibrinolytictreatment). ThesestrategiesaredistinctfromaroutinePCIapproach where theangiographyandinterventionisperformedseveraldaysafter successfulfibrinolysis.
Routine immediate angiography post fibrinolytic therapy is associated with increased intracranial haemorrhage (ICH) and majorbleedingwithoutofferinganybenefitintermsofmortality orreinfarction.148–152
ItisreasonabletoperformangiographyandPCIwhennecessary inpatientswithfailedfibrinolysisaccordingtoclinicalsignsand/or insufficientST-segmentresolution.153
Incaseofclinicallysuccessfulfibrinolysis(evidencedbyclinical signsandST-segmentresolution>50%),angiographydelayedby severalhoursafterfibrinolysis(thepharmaco-invasiveapproach) hasbeenshowntoimproveoutcome.Thisstrategyincludesearly transferforangiographyandPCIifnecessaryafterfibrinolytic treat-ment.
AnalysisofdataformsevenRCTs138,146,154–158enrolling2355 patientsshowbenefitintermsoflessreinfarctionsinimmediate routinetransferforangiographyat3–6h(orupto24h)infirst 24hafterEDfibrinolysisversusonlytransferforrescuePCIafter inhospitalfibrinolysis(OR0.57;95%CI0.38–0.85).Therewasno evidenceofbenefitintermsofshorttermand1yearmortalityor foradditionalharmintermsofmajorhaemorrhageorintracranial bleeding.
Data from two RCTs138,159 and one non RCT160 indicate no benefitfromtransfertoimmediatePCIincomparisontofibrinolytic therapyfollowedbyroutinetransferforPCI3to24hlater. There-foreincasePPCIcannotbeachievedinduetime,onsitefibrinolysis andtransferforangiography3to24hlaterisareasonable alterna-tive.
Specialsituations Cardiogenicshock
Acute coronarysyndrome (ACS) is the most commoncause ofcardiogenicshock,mainlythroughalargezoneofmyocardial ischaemia or a mechanical complication of myocardial infarc-tion.Althoughuncommon,theshort-termmortalityofcardiogenic shockis upto40%161 contrastingwithagood qualityof lifein patientsdischargedalive.Anearlyinvasivestrategy(i.e.primary PCI,PCIearlyafterfibrinolysis)isindicatedforthosepatientswho aresuitableforrevascularisation.162Observationalstudiessuggest thatthisstrategycouldbealsobeneficialinelderlypatients(over 75years).Evenifcommonlyusedinclinicalpractice,thereisno evidencesupportingtheuseofIABPincardiogenicshock.161
Suspect right ventricularinfarction in patients withinferior infarction,clinicalshockandclearlungfields.STsegmentelevation ≥0.1mVinleadV4Risausefulindicatorofrightventricular infarc-tion.Thesepatientshaveanin-hospitalmortalityofupto30%and manybenefitgreatlyfromreperfusiontherapy.Avoidnitratesand othervasodilators,andtreathypotensionwithintravenousfluids. ReperfusionaftersuccessfulCPR
Asitisoftenaccompaniedbyanacutecoronaryartery occlu-sionorbyahighdegreestenosis,acutecoronarysyndrome(ACS) is a frequent cause of out-of-hospitalcardiac arrest (OHCA) In a recentmeta-analysis,the prevalenceof acutecoronary artery lesionrangedfrom59%to71%inOHCApatientswithoutan obvi-ousnon-cardiaccause.163Sincethepublicationofthepioneering study,164manyobservationalstudieshaveshownthatemergent cardiac catheter laboratoryevaluation, including early percuta-neous coronary intervention (PCI), is feasible in patients with returnofspontaneouscirculation(ROSC)aftercardiacarrest.165 Theinvasivemanagement(i.e.earlycoronaryangiography(CAG) followedbyimmediatePCIifdeemednecessary)ofthispatient group,particularlypatientsafterprolongedresuscitationand hav-ingnonspecificECG changes,hasbeencontroversial duetothe lackofspecificevidenceandsignificantimplicationsonresource utilization(includingtransferofpatientstoPCIcentres).
PCIfollowing ROSC with ST-elevation. Thehighest prevalenceof acute coronary lesion is observed in patientswith ST segment elevation(STE)orleftbundlebranchblock(LBBB)onpost-ROSC electrocardiogram(ECG).Thereisnorandomisedstudybutasmany observationalstudies reporteda benefit regarding survival and neurologicaloutcome,itishighlyprobablethatthisearlyinvasive
managementisastrategyassociatedwithaclinicallyrelevant ben-efitinpatientswithSTsegmentelevation.Arecentmeta-analysis indicatesthat earlyangiographyisassociated withreduction of hospitalmortality[OR0.35(0.31to0.41)]andincreased neuro-logicallyfavourablesurvival[OR2.54(2.17to2.99)].40However patientsthatunderwentearlyangiographywerehighlyselected populationswithhigherprevalenceofmalegender,VF,witnessed arrest,therapeutichypothermiaandmoreintenseLVsupport. Dia-betesmellitus,renalandheartfailurewerelessprevalentinthese patients.
Basedontheavailabledata,emergentcardiaccatheterisation labevaluation(andimmediatePCIifrequired)shouldbeperformed inselectedadultpatientswithROSCafterOHCAofsuspected car-diacoriginwithSTsegmentelevationonECG.166
Observationalstudiesalsoindicatethatoptimaloutcomesafter OHCAareachievedwithacombination oftargetedtemperature management and PCI, which can be combined in a standard-isedpost–cardiac-arrestprotocolaspartofanoverallstrategyto improveneurologicallyintactsurvivalinthispatientgroup. PCIfollowingROSCwithoutST-elevation. Incontrasttotheusual presentationofACSinnoncardiacarrestpatients,recommended toolstoassesscoronaryischaemiaarelessaccurateinthissetting. Bothsensitivityandspecificityofclinicaldata,ECGand biomark-erstopredictanacutecoronaryarteryocclusionasthecauseof OHCAaredebatable.167 Inparticularseverallargeobservational seriesshowedthatabsenceof STEmayalsobeassociated with ACSinpatientswithROSCfollowingOHCA.168 Inthesenon-STE patients,dataareconflictingregardingthepotentialbenefitofan emergentcardiaccatheterisationlabevaluation,allcomingfrom observationalstudies,169,170orsubgroupanalysis.171Itis reason-abletodiscussanemergentcardiaccatheterisationlabevaluation afterROSCinpatientswiththehighestriskofcoronarycauseofCA. Avarietyoffactorssuchaspatientage,durationofCPR, haemo-dynamicinstability,presentingcardiacrhythm,neurologicstatus uponhospitalarrival,andperceivedlikelihoodofcardiacaetiology caninfluencethedecisiontoundertaketheintervention.Arecent consensusstatementfromtheEuropeanAssociationfor Percuta-neousCardiovascularInterventions(EAPCI)hasemphasisedthatin OHCApatients,cardiaccatheterisationshouldbeperformed imme-diatelyinthepresenceofST-elevationandconsideredassoonas possible(lessthantwohours)inotherpatientsintheabsenceof anobviousnon-coronarycause,particularlyiftheyare haemody-namicallyunstable.172Inpatientswhopresentinanon-PCIcentre transferforangiographyandPPCIifindicatedshouldbeconsidered onanindividualbasis,weighingtheexpectedbenefitsfromearly angiographyagainsttherisksfrompatienttransport.
Preventiveinterventions
PreventiveinterventionsinpatientspresentingwithACSshould beinitiatedearlyafterhospitaladmissionandshouldbe contin-uedifalreadyinplace.Preventivemeasuresimproveprognosisby reducingthenumberofmajoradversecardiacevents.Prevention with drugs encompasses beta-blockers, angiotensin converting enzyme(ACE)inhibitors/angiotensinreceptorblockers(ARB)and statins, as well as basic treatment with ASA and, if indicated, thienopyridines.
Beta-blockers
Severalstudies,undertakenmainlyinthepre-reperfusionera, indicateadecreasedmortality,incidenceofreinfarctionand car-diacruptureaswellasalowerincidenceofventricularfibrillation andsupraventriculararrhythmiainpatientstreatedearlywitha beta-blocker.173Beta-blockerstudiesareveryheterogeneouswith
respect to time of start of treatment.There is paucity of data onadministrationin thepre-hospital orED settings.Moreover, studies indicatean increased risk ofcardiogenic shock withIV beta-blockersinpatientswithSTEMI,eveniftherateofsevere tach-yarrhythmiaisreducedbybeta-blockade.174Thereisnoevidence tosupportroutineintravenousbeta-blockersinthepre-hospital orinitialEDsettings.EarlyIVuseofbeta-blockersis contraindi-catedinpatientswithclinicalsignsofhypotensionorcongestive heartfailure.Itmaybeindicatedinspecialsituationssuchassevere hypertensionortachyarrhythmiasintheabsenceof contraindica-tions.Itisreasonabletostartoralbeta-blockersatlowdosesonly afterthepatientisstabilised.
Otheranti-arrhythmics
Apartfrombeta-blockers,thereisnoevidencetosupportthe useof anti-arrhythmicprophylaxisafterACS. Ventricular fibril-lation(VF)accountsformostoftheearlydeathsfromACS;the incidenceofVFishighestinthefirsthoursafteronsetofsymptoms. Thisexplainswhynumerousstudieshavebeenperformedwith theaimofdemonstratingtheprophylacticeffectofantiarrhythmic therapy.175Theeffectsofantiarrhythmicdrugs(lidocaine, magne-sium,disopyramide,mexiletine,verapamil,sotalol,tocainamide) given prophylactically to patients with ACS have been stud-ied.Prophylaxis withlidocaine reducestheincidenceofVFbut may increase mortality.176 Routinetreatment withmagnesium in patients with AMI does not reduce mortality. Arrhythmia prophylaxisusingdisopyramide,mexiletine,verapamil,orother anti-arrhythmicsgivenwithinthefirsthoursofanACSdoesnot improve mortality. Therefore prophylactic anti-arrhythmics are notrecommended.
Angiotensin-convertingenzymeinhibitors,angiotensinreceptor blockers
OralACEinhibitors reducemortalitywhengiven topatients withAMIwithorwithoutearlyreperfusiontherapy.Thebeneficial effectsaremostpronouncedinpatientspresentingwithanterior infarction,pulmonarycongestionorleftventricularejection frac-tion<40%.DonotgiveACEinhibitorsifthesystolicbloodpressureis lessthan100mmHgonadmissionorifthereisaknown contraindi-cationtothesedrugs.Atrendtowardshighermortalityhasbeen documentedifanintravenousACEinhibitorisstartedwithinthe first24hafteronsetofsymptoms.Thistherapyissafe,well toler-atedandassociatedwithasmallbutsignificantreductionin30-day mortality.177Therefore,giveanoralACEinhibitorwithin24hafter symptomonsetinpatientswithAMIregardlessofwhetherearly reperfusiontherapyisplanned,particularlyinthosepatientswith anteriorinfarction,pulmonarycongestionoraleftventricular ejec-tionfractionbelow40%.DonotgiveintravenousACEinhibitors within24hofonsetofsymptoms.178,179Giveanangiotensin recep-torblocker(ARB)topatientsintolerantofACEinhibitors.180 Lipid-loweringtherapy
Statins reduce the incidence of major adverse cardiovascu-lareventswhengivenearlywithinthefirstdaysafteronsetan ACS.181,182Considerstartingstatintherapyinallpatientswithin 24hofonsetofsymptomsofACSunlesscontraindicated.Ifpatients arealreadyreceivingstatintherapy,donotstopit.183
Collaborator
NicolasDanchin,DepartmentofCardiology, HôpitalEuropéen GeorgesPompidou,Paris,France.
Conflictsofinterest
NikolaosNikolaou ResearchgrantFouriertrial-AMGEN AlainCariou SpeakershonorariumBARD-France
FarzinBeygui SpeakershonorariumAstraZeneca,Lilly,Daichi-Sankyo
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