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Activegastrointestinalorgenitourinarybleeding
Majorsurgeryortraumawithin7days
Dissectinganeurysm
Relativecontraindications
Remotehistoryofgastrointestinalbleeding
Remotehistoryofgenitourinarybleeding
Remotehistoryofpepticulcer
Otherlesionwithpotentialforbleeding
Recentminorsurgeryortrauma
Severe,uncontrolledhypertension
Coexistinghemostaticabnormalities
Pregnancy

THROMBOLYTICTHERAPYFORSTROKE
Strokeisthethirdleadingcauseofdeath,andtheleadingcauseofseriousdisabilityintheUnitedStates.323Its
incidencehasbeendeclininginrecentyearsduetocontrolofriskfactors,buttotalnumbersareincreasingasa
consequenceofagingofthepopulation.Althoughaspirinandanticoagulantsmaybeusefulinprevention,
thrombolytictherapyistheonlyavailableinterventionduringtheacutestage.
Theappropriateuseofthrombolytictherapyforstrokeisbasedonanunderstandingofitspathogenesis.
Ischemicstrokeismostcommonlycausedbyruptureofanatheroscleroticplaquewithinalargeormedium
sizedarteryintheneckorcranium.Inaddition,transientischemicattacks(TIAs)andstrokesinvolvingsmall
arteriescanresultfromembolizationofplateletfibrinthrombithatformonatheroscleroticvesselsintheneck
andascendingaorta,orfromembolizationofthrombithatformintheheartinassociationwithatrialfibrillation,
valvedysfunction,artificialvalves,orendocardialthrombi.Upto30percentofstrokeshavenodefined
etiology.
Currentapproachestothrombolytictherapyforstrokearebasedonimagingtodefinetheetiology,resultsof
clinicaltrials,andtheexperiencewiththrombolysisforacutemyocardialinfarction.Moderncomputed
tomography(CT)imagingandmagneticresonanceimaging(MRI)canidentifyischemicareasandlocalize
areasofhemorrhagequiteearly.Additionally,arteriographycanidentifyobstructedvesselsandfollowthe
courseofrecanalizationduringthrombolytictherapy.Clinicalstudieshavegenerallyfollowedthesuccessful
designsusedformyocardialinfarctionthatdemonstratedthecriticalpathologicroleoftheoccludedvessel,the
importanceofearlyrecanalizationinpreservingmyocardium,andtheimpressivedecreaseinmorbidityand
mortalityresultingfromearlyreperfusion.Theyhavealsocharacterizedthebleedingrisk.
Theexperiencewiththrombolytictreatmentforstrokealsohighlightsimportantdifferencesfrommyocardial
infarction.Thearterialanatomyofthebrainismorecomplex,thetimefromonsetofischemiatoirreversible
necrosisisshorter,theriskandconsequencesofbleedingaregreater,andthereismorevariabilityinthe
thrombo(embolic)occludinglesion.Further,theocclusiveplateletfibrinthrombusthatprecipitatesamyocardial
infarctionisquitesmall,whereastheocclusivelesioncausingischemicstrokemaybealargeinsituthrombus,
smallplateletfibrinembolus,orlargeembolusofvaryingageandcompositionoriginatingfromtheleftatrium.
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Thrombolysishashadasmallerimpactforstrokethanithasformyocardialinfarction,basedlargelyonthese
differences.
EarlyThrombolyticStudies

Thecurrenttherapeuticapproachbeganwithsmall,openlabelstudiesthatusedintravenousorintraarterial
streptokinase,urokinase,andtPAtodeterminedose,recanalizationrate,hemorrhagicpotential,andclinical
predictorsofresponse.324339Thesestudiesdemonstratedthatrecanalizationcouldbeachieved,thatearly
treatmentwasessential,andthattherateofintracranialhemorrhageandhemorrhagictransformationwithinthe
ischemicareawashigh.PhaseIIstudiesdefinedtheoptimumdosageandtimewindowforintravenoustPAand
servedasthebasisforlargerphaseIIItrialsthatledtothecurrenttPAbasedapproachtothrombolytictherapy
forstroke(Table1355).Atpresent,theonlyFDAapprovedtherapyforacutestrokeisintravenousalteplase
(recombinanttPA)givenwithin3hoursofsymptomonset.
Table1355.MajorFibrinolyticTherapyTrialsinStroke
Thrombolytic
No.of
Study
Time Drug
MainEfficacyResult
Patients
Dose*
tPA,
NINDS
624
3h
0.9mg/kg
Reduceddisabilityat3months
IV
tPA,
ECASSI 620
6h
1.1mg/kg
Nosignificantdifference
IV
tPA,
ECASSII 800
6h
0.9mg/kg
Nosignificantdifference
IV
tPA,
ECASSIII 821
34.5h
0.9mg/kg
Improvedoutcomeat3months
IV
tPA,
ATLANTIS 613
0.9mg/kg
Nosignificantdifference
6h IV
SITS
11,865 3vs. tPA,
0.9mg/kg
Nosignificantdifference
#
vs.664 34.5h IV
ISTR
1.5million
ASK
340
4h
SK,IV
Increasedmorbidityandmortality
units
SK,
1.5million
MASTI
622
6h
Increasedmortality

units
IV
SK,
1.5million
MASTII 310
6h
Increasedmortality

units
IV
pro
PROACT
180
6h
Improved3monthoutcome
UK,|| 9mg
II
IA
uPA,
Nosignificantdifferenceinfavorableoutcome
MELT
114
6h
variable
IA
significantdifferenceinexcellentfunctionaloutcome
ASK,AustralianStreptokinaseATLANTIS,AlteplaseThrombolysisforAcuteNoninterventionalTherapyin
IschemicStrokeECASS,EuropeanCooperativeAcuteStrokeStudyIA,intraarterialMAST,Multicentre
AcuteStrokeTrialMELT,TheMiddleCerebralArteryEmbolismLocalFibrinolyticInterventionTrial
NINDS,NationalInstituteofNeurologicalDisordersandStrokeProUK,prourokinasePROACTII,Prolyse
inAcuteCerebralThromboembolismIISITSISTR,SafeImplementationofTreatmentsinStroke
InternationalStrokeThrombolysisRegistrySK,streptokinasetPA,tissuetypeplasminogenactivatoruPA,
urokinaseplasminogenactivator.

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*Allplacebocontrolled.
Allgivenover1hexceptPROACTII,whichwas2h.
547/613within35h.
#Observationalstudywithoutplaceboarm.
22factorialdesignwithacetylsalicylicacid(ASA)300mg/day.
Acetylsalicylicacid(ASA)100mg/day.
||ProUKandplacebogroupalsoreceivedheparin.
< MeandosesofuPAinpatientswithgoodandpooroutcomewere555,000IUand789,000IU.
TissuePlasminogenActivatorTherapy

TheNationalInstituteofNeurologicalDisordersandStroke(NINDS)Studywasatwopartrandomized,
doubleblind,placebocontrolledstudy340totestwhethertPAimprovedclinicaloutcomeat24hoursand3
months.Allpatientsweretreatedwithin3hoursofsymptomonsetwithatotaldoseof0.9mg/kgoftPA.The
combinedresultsshoweda30percentimprovementinclinicaloutcomesat3monthsandthebenefitpersistedat
12months,despitea10foldincreaseinearlysymptomaticintracranialhemorrhage.At3months,therewasno
differenceinmortalitybetweenthegroups.ThisstudyformedthebasisoftheapprovalbytheFDAof
intravenoustPAforstrokein1996.
EarlyrandomizedtrialsofIVtPAdidnotshowclearbenefitforpatientstreatedbeyond3hoursafterstroke
onset.IntheEuropeanCooperativeAcuteStrokeStudy(ECASS)Study,subjectswithmoderatetosevere
symptomswererandomizedtoplaceboortPAwithin6hoursofsymptomonset341resultsshowedno
significantdifferenceineithertheprimaryendpointoffunctionalstatusat90daysorin30daymortality.Inthe
ECASSII,inwhichpatientswererandomizedandstratifiedforpresentationupto3hoursaftersymptomonset
orbetween3and6hours,therewasnosignificantbenefitofthrombolytictherapyusingtheprimaryendpoint
offunctionalcapacityof90days.342TheAlteplaseThrombolysisforAcuteNoninterventionalTherapyin
IschemicStroke(ATLANTIS)StudyevaluatedthesafetyofrecombinanttPA(rtPA)inadoubleblind,placebo
controlledstudywithadministrationofdrugbetween3and5hoursaftersymptomonset,343andtheprimary
endpointofexcellentneurologicalrecoverywasobservedin32percentofplaceboand34percentofrtPA
treatedpatients.Earlysymptomaticintracranialhemorrhageoccurredin1.1percentofcontroland7.0percentof
rtPAtreatedpatients.TherewasanonsignificanttrendtowardincreasedmortalitywithrtPAtreatmentat90
days(6.9percentvs.11.0percent,p=0.09).AmetaanalysispoolingdatafromNINDS,ATLANTIS,and
ECASSIIpatientswhoreceivedeitheralteplaseorplacebowithin6hoursshowedthattheoddsofafavorable
3monthoutcomedecreasedastheintervalfromstrokeonsettothestartofalteplasetreatmentincreased.
Furthermore,thestudyalludedtothepotentialbenefitofextendingthetreatmentwindowto4.5hourswith
favorablebutdecreasingoddsratioforalteplasetreatmentbeyond3hours.344
ThebenefitofIVtPAfortreatmentbeyondthe3hourwindowwasestablishedbytheECASSIIItrial.345This
studyshowedthatIVtPAtreatmentinitiatedat3to4.5hoursafterischemicstrokeonsetledtoamodest
improvementinthe3monthoutcome.MorepatientshadafavorableoutcomewithtPAthanwithplacebo(52.4
percentvs.45.2percentoddsratio:1.3495percentCI1.02to1.76).Whiletheincidenceofintracranial
hemorrhagewashigherwithtPAtreatment(2.4percentvs.0.2percentp=0.008),therewasnodifferencein
mortalitybetweenthetwogroups.

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Theeffectofalteplasegivenbeyond3hoursafterstrokeoninfarctgrowthandreperfusionwasstudiedinthe
EchoplanarImagingThrombolyticEvaluationTrial(EPITHET)trial.346Alteplasewasshowntobesignificantly
associatedwithincreasedreperfusioninpatientswhohadmismatchatbaseline(p=0.001),betterneurologic
outcome(p<0.0001),andbetterfunctionaloutcome(p=0.010).TheobservationalSafeImplementationof
TreatmentinStrokeInternationalStrokeThrombolysisRegister(SITSISTR)studyfurthersupportedthesafety
ofadministeringIVtPAbetween3and4.5hoursafteracuteischemicstroke.347,348Comparedtopatients
treatedwithinlessthan3hours(n=11,865),thosetreatedat3to4.5hours(n=664)hadsimilarratesof
independence,symptomaticintracranialhemorrhage,andmortality.AnupdatedpooledanalysisofECASS,
ATLANTIS,NINDS,andEPITHETtrialscontinuestodemonstratethatpatientswithischemicstroke,selected
byclinicalsymptomsandCT,benefitfromintravenousalteplasewhentreatednolaterthan4.5hours.349
StreptokinaseTherapy

Streptokinasehasbeenevaluatedinthreelargestroketrials.TheAustralianStreptokinase(ASK)studyshowed
anincreaseindeathrateat90daysinstreptokinasetreatedpatients,andthestudywasprematurely
terminated.350TheMulticentreAcuteStrokeTrialItaly(MASTI)studyexaminedbenefitsandrisksof
streptokinasetreatmentwithorwithoutaspirininpatientswithacuteischemicstrokewhopresentedwithin6
hoursofsymptomonset.351Aninterimanalysisresultedinearlyterminationbecausestreptokinasetreatment
wasassociatedwitha2.7foldincreaseinfatalityat10daysamongpatientsreceivingbothstreptokinaseand
aspirin.IntheMulticenterAcuteStrokeTrialEurope(MASTE)trial,themortalityrateat10dayswashigherin
patientswhoreceivedstreptokinase(34.0percent)comparedwithplacebo(18.2percent,p<0.02)primarily
becauseofhemorrhagictransformationofinfarcts.352
TenecteplaseTherapy

TenecteplaseisageneticallymodifiedandgeneticallyengineeredrecombinanttPAithasahigherfibrin
specificityandgreaterresistancetoinactivationbyitsendogenousinhibitor(PAI1)comparedtonativetPA.In
aphaseIIBstudy,therewerenosignificantdifferencesinintracranialbleedingorotherseriousadverseeventsin
patientsreceivingalteplaseversustenecteplase.353However,thetwotenecteplasegroupshadgreater
reperfusion(p=0.004)andclinicalimprovement(p<0.001)at24hourscomparedwiththealteplasegroup.The
studyoutcomesupportsongoingphaseIIIIItrialsoftenecteplaseversusalteplaseinthetimewindowthatis
currentlyapprovedforstrokethrombolysis(NCT01472926andNCT01949948).
IntraarterialThrombolysis

IntraarterialadministrationallowsdeliveryofahighconcentrationofaPlgactivatorinproximitytothe
thrombus,moreaccurateanatomicdiagnosis,theabilitytoobservethecourseofrecanalization,andlowertotal
dosesofdrugthatmightreduceintracranialhemorrhage.Ontheotherhand,thisapproachrequiresspecialized
facilitiesandexperiencedpersonneltoperformarteriographyandselectivecatheterization,whichmaydelay
treatment.Severalsmallopenlabeltrialsobservedahighrateofrecanalizationandapparentclinicalbenefit
withintraarterialtherapyusingurokinase,streptokinaseortPA,buthemorrhagictransformationwasafrequent
problem.327,331,334,337,354,355,356,357,358,359,360
TheProlyseinAcuteCerebralThromboembolism(PROACT)andPROACTIItrialsevaluatedrecombinant
humanprourokinasebycatheterdirectedintraarterialadministration.361,362InthePROACTtrial,a
significantlyhigherrecanalizationratewasobservedwithprourokinasetreatmentwithnoincreasein
intracranialhemorrhage.ThisledtothelargerPROACTIItrial,whichrevealedasignificantlyhigher
recanalizationratewithprourokinase(66percentvs.18percent,p<0.001),andsuperiorfunctional
improvementat90days.363,364Symptomaticintracranialhemorrhageoccurredin10percentofpatientstreated
withprourokinaseand2percentofcontrols.Althoughpromising,theseresultsdidnotleadtoFDAapprovalof
intraarterialprourokinasefortreatmentofstroke.
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Athirdstudy,theMiddleCerebralArteryEmbolismLocalFibrinolyticInterventionTrial(MELT),was
underpoweredbecauseofprematurestudyclosure.365Afavorable,butnotstatisticallysignificant,outcomeat
90dayswasmorelikelywithintraarterialurokinasecomparedwithplacebo.Theproportionofpatientswithan
excellentfunctionaloutcomewassignificantlybetterintheintraarterialurokinasegroup(42percentvs.23
percent,p=0.045).Intracerebralhemorrhagewithin24hoursoftreatmentoccurredin9percentand2percent,
respectively(p=0.206).Thisstudysuggestedthatintraarterialfibrinolysishasthepotentialtoincreasethe
likelihoodofexcellentfunctionaloutcomeinappropriateclinicalsettings.
Overall,thesestudiesshowthattreatmentofacutestrokewiththrombolytictherapycanleadtorecanalizationof
theoccludedarteryandimprovementinclinicaloutcomes.Theneedforearlytreatment,whichimproves
outcome,iscurrentlythesinglelargestlimitationtogreaterapplicationofthrombolytictherapyforstroke,and
lessthan5percentofstrokepatientscurrentlyreceivetPAtreatment,indicatingtheneedforfocused
communityeducationalefforts.366,367,368RandomizedstudieswithrtPAhaveshownthatintravenous
thrombolytictherapycanbesafelyextendedto4.5hoursaftersymptomonsetinselectedpatients,whereas
streptokinasewasassociatedwithanunacceptablyhighrateofintracranialhemorrhage.344,345,347Inaddition,
intracranialhemorrhagecanbereducedbyidentifyingpatientsatgreatestriskusingMRIdiffusionperfusion
mismatchtoidentifyreversibleischemia.346,369,370,371Thecombinationofpotentantiplatelettherapyusinga
glycoproteinIIb/IIIaantagonistwithalowerdoseofathrombolyticagentmayimprove
results.372,373,374,375,376,377
Insummary,currentrecommendationslimitthrombolytictherapyforstroketopatientspresentingwithin3hours
ofsymptomonset.378,379,380Theapprovedtherapyiswith0.9mg/kg(maximum:90mg)oftPAadministered
intravenouslywith10percentasaninitialbolusandtheremainderinfusedover60minutes.Thebestresultsare
obtainedinpatientswhomeetstricteligibilityrequirements(Table1356).Patientsshouldbecloselymonitored
forbleedingcomplications,especiallyintracranialhemorrhage,andcarefulattentionshouldbepaidtoblood
pressureandothercomorbidities.
Table1356.GuidelinesforTissueTypePlasminogenActivatorTherapyinStroke
Eligibility
Timefromsymptomonsettotherapy3hours
ResultsfromEuropeanCooperativeAcuteStrokeStudy(ECASS)IIItrialsuggesttreatmentwithin4.5h
ofonsetisbeneficial
Exclusions
Priorintracranialhemorrhage
Majorsurgerywithin14days
Gastrointestinalorurinarytractbleedingwith21days
Arterialpunctureinnoncompressiblesite
Recentlumbarpuncture
Intracranialsurgery,seriousheadtrauma,orpriorstrokewithin3months
Minorneurologicdeficit
Seizureattimeofstrokeonset
Clinicalfindingsofsubarachnoidhemorrhage
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Activebleeding
Persistentsystolicbloodpressure(BP)>185and/ordiastolicBP>110orrequiringaggressivetreatment
Arteriovenousmalformationoraneurysm
Evidenceofhemorrhageoncomputedtomographyscan
Platelets<100,000/L
Internationalnormalizedratio>1.5onwarfarin
Elevatedpartialthromboplastintimeonheparin
Bloodglucose<40or>400mg/dL
ECASSIIIadditionallyexcludedpatients>80yearsold,patientswithacombinationofpreviousstroke
anddiabetesmellitus,andpatientswithanNationalInstitutesofHealthStrokeScalescoreof>25.

PERIPHERALVASCULARDISEASE
Acuteperipheralarterialocclusionpresentswiththesuddenonsetofnew,severelegsymptomsoracute
worseningofchronicischemia,andofteninvolvesembolicorthromboticocclusionoflegarteries.Thegoalsof
treatmentaretopreservelimbfunctionthroughrestorationofflow.Anticoagulationisusefultoprevent
thrombusextension,whilethrombolytictherapyorsurgerycanrestoreperfusion.
Earlyapproachestoacuteperipheralarterialocclusioninvolvedstreptokinase.Severalsmallstudies
demonstratedreperfusioninapproximately40percentofpatients,withgreatestsuccesswhenocclusionswere
recentbleedingcomplicationsoccurredinuptoonethirdofsubjects.381Followingthereportin1974by
Dotter382ofsuccessfulthrombolysisinperipheralarterialocclusionusinglocallyadministeredthrombolysis,
practicemovedprogressivelytothenearlyexclusiveuseoflocalintraarteriallyadministeredtreatment.
Advantagesincludedeliveryofahighconcentrationofdrugdirectlytothesiteofthrombosis,theabilityto
followthecourseoftreatmentusingthetreatmentcatheter,andidentificationoflocalvascularlesionsrequiring
endovascularorsurgicaltreatmentafterrecanalization.
Treatmentinvolvesarterialaccessfromaremotesitefollowedbyfluoroscopicguidanceofthecatheterto
administerdrugdirectlyintothethrombus.Therapyisdeliveredbycontinuousinfusionoverhourstodaysand
requiresclosemonitoringandalargedoseofthrombolyticagent.Successfulreperfusionoccursin
approximatelythreequartersofcases.383Ourielandcolleagues384reportedthatthrombolytictherapyresulted
ina70percentrecanalizationrate,andafrequencyoflimbsalvagethatmirroredthatofoperativeintervention.
Therewas,however,asurvivaladvantageinpatientsreceivingprimarythrombolytictherapyresultingprimarily
fromadecreaseintheoccurrenceofinhospitalcomplications.TheSurgeryversusThrombolysisforIschemia
oftheLowerExtremity(STILE)trial,whichcomparedtheoptimalsurgicalproceduretocatheterdirected
thrombolysiswitheithertPAorurokinase,wasterminatedprematurelybecauseofongoingorrecurrent
ischemiaat30daysinsurgicallytreatedpatients.385Morethanhalfofpatientsreceivingthrombolysishada
decreaseinthemagnitudeofthesurgicalprocedureeventuallyrequired,withsignificantreductionsinthe1year
rateofmajoramputation.Inaddition,therewasnodifferenceinoutcomewithtPAversusurokinase.
TheThrombolysisorPeripheralArterialSurgery(TOPAS)Istudycomparedrecombinanturokinaseorsurgery
forinitialtherapyofacutelowerextremityischemiaoflessthan14daysduration.386The1yearmortalityand
amputationfreesurvivalweresimilarintheurokinaseandsurgerygroups.Therewasasignificantreductionin
thefrequencyandmagnitudeofsurgicalinterventionseventuallyrequiredinpatientsrandomizedtoinitial
thrombolysis.ThelargerTOPASIIstudyshowedrecanalizationin80percentofpatientswhoreceived
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