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NEUROLOGY/CLINICALPOLICY
Clinical Policy: Use of Intravenous tPA for the Management of
Acute Ischemic Stroke in the Emergency Department
This clinical policy is the result of a collaborative project of the American College of Emergency Physicians and the
American Academy of Neurology.
Development Panel Robert L. Wears, MD, MS (Methodologist; Department
Jonathan A. Edlow, MD (Department of Emergency of Emergency Medicine, University of Florida,
Medicine, Beth Israel Deaconess Medical Center, Jacksonville, FL)
Harvard Medical School, Boston, MA) Wyatt W. Decker, MD (Vice President and Trustee Mayo
Eric E. Smith, MD, MPH (Department of Clinical Clinic, CEO Mayo Clinic Arizona, Scottsdale, AZ)
Neurosciences, Hotchkiss Brain Institute [E.E.S.],
Providing Project Support:
University of Calgary, Foothills Medical Centre, Rhonda R. Whitson, RHIA, Clinical Practice Manager,
Calgary, Canada) American College of Emergency Physicians
LathaGantiStead,MD,MS,MBA(ProfessorofEmergency Thomas S. D. Getchius, Associate Director, Clinical
MedicineandNeurologicalSurgery;Director,Centerfor Practice, American Academy of Neurology
BrainInjuryResearchandEducation,Universityof
Florida,Gainesville,FL)
GaryGronseth,MD(DepartmentofNeurology,Universityof
Approved by the ACEP Board of Directors, June 13,
KansasMedicalCenter,KansasCity,KS) 2012
StevenR.Messé,MD(DepartmentofNeurology,Hospital Endorsed by the American Academy of Neurology,
oftheUniversityofPennsylvania,Philadelphia,PA) December 6, 2012
Andy S. Jagoda, MD (Professor and Chair, Department Supported by the Emergency Nurses Association,
of Emergency Medicine Mount Sinai School of December 11, 2012
Medicine; Medical Director, Emergency Department, Endorsed by the Neurocritical Care Society, January 4,
Mount Sinai Hospital, New York, NY) 2013
Policy statements and clinical policies are the official policies of the American College of Emergency
Physiciansand,assuch,arenotsubjecttothesamepeerreviewprocessasarticlesappearingintheprint
journal.PolicystatementsandclinicalpoliciesofACEPdonotnecessarilyreflectthepoliciesandbeliefs
of Annals of Emergency Medicine and its editors.
0196-0644/$-seefrontmatter
Copyright©2012bytheAmericanCollegeofEmergencyPhysicians.
http://dx.doi.org/10.1016/j.annemergmed.2012.11.005
[AnnEmergMed.2013;61:225-243.] treatedbetween3to4.5hoursaftersymptomonset?
Evidencewasgradedandrecommendationsweregiven
ABSTRACT basedonthestrengthoftheavailabledatainthemedical
literature.
Thispolicywasdevelopedbyajointwritingpanelofthe
AmericanCollegeofEmergencyPhysiciansandtheAmerican
AcademyofNeurology.Thepanelreviewedtheliteratureto INTRODUCTION
deriveevidence-basedrecommendationstohelpclinicians Itisestimatedthatthereare795,000newstrokesinthe
answerthefollowingcriticalquestions: UnitedStateseachyear.1Strokeisthethirdleadingcauseof
(1)Isintravenoustissueplasminogenactivator(tPA) deathintheUnitedStates,causing1ofevery17deathsin
safeandeffectiveforacuteischemicstrokepatientsif 2005.1
givenwithin3hoursofsymptomonset?(2)Isintravenous In1996,theFoodandDrugAdministration(FDA)
tPAsafeandeffectiveforacuteischemicstrokepatients approvedintravenous(IV)tissueplasminogenactivator(tPA)as
Volume,. : February Annalsof EmergencyMedicine 225
ClinicalPolicy
atreatmentforacuteischemicstroke.Sincethen,theuseofIV formulatakingintoaccountdesignandqualityofstudy
tPAforstrokehasbeenoneofthemostcontentiousmedical (AppendixB).Articleswithfatalflawsweregivenan“X”grade
treatments. andnotusedinformulatingrecommendationsinthispolicy.
Evidencegradingwasdonewithrespecttothespecificdata
METHODOLOGY
beingextractedandthespecificcriticalquestionbeingreviewed.
AjointdevelopmentpanelwasappointedbytheAmerican Thus,thelevelofevidenceforanyonestudymayvary
CollegeofEmergencyPhysicians(ACEP)andtheAmerican accordingtothequestion,anditispossibleforasinglearticleto
AcademyofNeurology(AAN)toproduceaclinicalevidence– receivedifferentlevelsofgradingasdifferentcriticalquestions
basedguidelineontheuseoftPAforacuteischemicstroke. areanswered.Question-specificlevelofevidencegradingmaybe
Thisclinicalpolicywascreatedaftercarefulreviewand foundintheEvidentiaryTableincludedattheendofthis
criticalanalysisofthemedicalliterature.Multiplesearchesof
policy.
MEDLINEandtheCochraneDatabaseforarticlespublished
Clinicalfindingsandstrengthofrecommendationsregarding
betweenJanuary1999andMay2011wereperformedusinga
patientmanagementwerethenmadeaccordingtothefollowing
combinationofkeywords,including“cerebrovascular
criteria:
accident,”“tissueplasminogenactivator,”“tPA,”“thrombolytic
LevelArecommendations.Generallyacceptedprinciplesfor
therapy,”“stroke,”“intracerebralhemorrhage,”“subarachnoid
patientmanagementthatreflectahighdegreeofclinical
hemorrhage,”“emergencydepartment,”“emergencyservice,”
certainty(ie,basedonstrengthofevidenceClassIor
“emergencyroom,”“therapyinemergencydepartment,”and
overwhelmingevidencefromstrengthofevidenceClassII
“treatmentinemergencydepartment.”Thesearcheswere
studiesthatdirectlyaddressalloftheissues).
limitedtotheEnglishlanguageandhumanstudies.Additional
LevelBrecommendations.Recommendationsforpatient
articleswerereviewedfromthebibliographiesofstudiescited.
managementthatmayidentifyaparticularstrategyorrangeof
Panelmemberssuppliedarticlesfromtheirownknowledgeand
managementstrategiesthatreflectmoderateclinicalcertainty
files,andmorerecentarticlesidentifiedduringtheprocesswere
(ie,basedonstrengthofevidenceClassIIstudiesthatdirectly
alsoincluded.
addresstheissue,decisionanalysisthatdirectlyaddressesthe
ThereasonsfordevelopingACEP’sclinicalpoliciesandthe
issue,orstrongconsensusofstrengthofevidenceClassIII
approachesusedintheirdevelopmenthavebeenenumerated.2
studies).
Expertreviewcommentswerereceivedfromemergency
LevelCrecommendations.Otherstrategiesforpatient
physicians,neurologists,andindividualmembersofthe
managementthatarebasedonClassIIIstudies,orinthe
AmericanAcademyofFamilyPhysicians,AmericanCollegeof
absenceofanyadequate,publishedliterature,basedonpanel
Physicians,EmergencyNursesAssociation,AmericanStroke
consensus.
Association,NationalStrokeAssociation,NeurocriticalCare
Therearecertaincircumstancesinwhichthe
Society,andtheSocietyforAcademicEmergencyMedicine.
recommendationsstemmingfromabodyofevidenceshouldnot
Theirresponseswereusedtofurtherrefineandenhancethis
beratedashighlyastheindividualstudiesonwhichtheyarebased.
policy;however,theirresponsesdonotimplyendorsementof
Factorssuchasheterogeneityofresults,uncertaintyabouteffect
thisclinicalpolicy.Commentswerealsoreceivedfrominternal
magnitudeandconsequences,andpublicationbias,amongothers,
ACEPandAANcommitteesandworkgroups.ACEPclinical
mightleadtosuchadowngradingofrecommendations.
policiesarescheduledforrevisionevery3years;however,
Whenpossible,clinicallyorientedstatistics(eg,likelihood
interimreviewsareconductedwhentechnologyorthepractice
ratios,numberneededtotreat)willbepresentedtohelpthe
environmentchangessignificantly.ACEPandAANarethe
readerbetterunderstandhowtheresultscanbeappliedtothe
fundingsourceforthisclinicalpolicy.
Thesearchesresultedin1,140articles,ofwhich303were individualpatient.Forfurtherdefinitionofthesestatistical
selectedforadditionalreviewandgrading.Allarticlesusedin concepts,seeAppendixC.
theformulationofthisclinicalpolicywereindependently Thispolicyisnotintendedtobeacompletemanualonthe
gradedbyatleast2panelmembersforstrengthofevidenceand evaluationandmanagementofadultpatientswithacute
classifiedbythepanelmembersinto3classesofevidenceonthe ischemicstrokebutratherafocusedexaminationofcritical
basisofthedesignofthestudy,withdesign1representingthe issuesthathaveparticularrelevancetothecurrentpracticeof
strongestevidenceanddesign3representingtheweakest emergencymedicine.Itisthegoalofthispaneltoprovidean
evidencefortherapeutic,diagnostic,andprognosticclinical evidence-basedrecommendationwhenthemedicalliterature
reports,respectively(AppendixA).Articleswerethengradedon providesenoughqualityinformationtoansweracritical
6dimensionsthoughttobemostrelevanttothedevelopmentof question.Whenthemedicalliteraturedoesnotcontainenough
aclinicalguideline:blindedversusnonblindedoutcome qualityinformationtoansweracriticalquestion,themembers
assessment,allocation,directorindirectoutcomemeasures, ofthepanelbelievethatitisequallyimportanttoalert
biases(eg,selection,detection,transfer),externalvalidity(ie, physicianstothisfact.Recommendationsofferedinthispolicy
generalizability),andsufficientsamplesize.Articlesreceiveda arenotintendedtorepresenttheonlydiagnosticand
finalgrade(ClassI,II,III)onthebasisofapredetermined managementoptionsthatthephysicianshouldconsider.ACEP
226 Annalsof EmergencyMedicine Volume,. : February
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andAANclearlyrecognizetheimportanceoftheindividual symptomonsetwererandomized1:1toplaceboversusIV
physician’sjudgment.Rather,thisguidelinedefinesforthe treatmentwith0.9mg/kgofthehumanrecombinanttPA
physicianthosestrategiesforwhichmedicalliteratureexiststo alteplase,with10%ofthetotaldoseadministeredasabolus
providesupportforanswerstothecriticalquestionsaddressed andtheremaining90%infusedover60minutes(maximum
inthispolicy. dose90mg).Randomizationwasstratifiedbyclinicalcenter
ScopeofApplication.Thisguidelineisintendedfor andbytimefromtheonsetofstroketotreatment(0to90
physiciansworkinginhospital-basedemergencydepartments minutesand91to180minutes).Theprespecifiedprimary
(EDs). outcomeofNINDSpartI(n(cid:1)291)wasearlyclinical
InclusionCriteria.Thisguidelineisintendedforadult
improvement,definedascompleteresolutionofthestroke
patientspresentingtotheEDwithacuteischemicstroke.
symptomsoranimprovementintheNationalInstitutesof
ExclusionCriteria.Thisguidelineisnotintendedtobe
HealthStrokeScale(NIHSS)(Figure1)scoreby4ormore
appliedtochildrenyoungerthan18years.
pointsat24hours.Therewasnodifferenceinearlyclinical
improvementinthetPAgroupcomparedwiththeplacebo
CRITICALQUESTIONS
group(relativerisk1.2;95%confidenceinterval[CI]0.9to
1. IsIVtPAsafeandeffectiveforacuteischemicstroke 1.6;P(cid:1).21).TheprespecifiedprimaryoutcomeofNINDS
patientsifgivenwithin3hoursofsymptomonset? partII(n(cid:1)333)wasafavorableoutcomeat3months,
2. IsIVtPAsafeandeffectiveforacuteischemicstroke
determinedusing4assessmentscales:theBarthelIndex
patientstreatedbetween3to4.5hoursaftersymptom
(Figure2),modifiedRankinScale(Table1),Glasgow
onset?
OutcomeScale(Table2),andNIHSS(Figure1).Totestthe
primaryhypothesis,aglobalendpointwasderivedfromthe
PatientManagementRecommendations
individualscaleswiththeuseofscale-specificcutpoints.The
LevelArecommendations.Inordertoimprovefunctional
oddsratio(OR)forafavorableoutcomeinthetPAgroup,
outcomes,IVtPAshouldbeofferedtoacuteischemicstroke
definedasminimalornodisabilityat90days,was1.7(95%
patientswhomeetNationalInstituteofNeurologicalDisorders CI1.2to2.6;P(cid:1).008).AfavorableoutcomeforthetPA
andStroke(NINDS)inclusion/exclusioncriteriaandcanbe
groupwasobservedoneachofthe4assessmentscales
treatedwithin3hoursaftersymptomonset.*
(P(cid:1).02to.03),withabsolutepercentagedifferencesbetween
LevelBrecommendations.Inordertoimprovefunctional
tPAandplaceborangingfrom11%to13%.Forexample,a
outcomes,IVtPAshouldbeconsideredinacuteischemicstroke
modifiedRankinScalescoreoutcomeof0or1,indicating
patientswhomeetEuropeanCooperativeAcuteStrokeStudy
noresidualdisablingstrokesymptoms,wasachievedin39%
(ECASS)IIIinclusion/exclusioncriteriaandcanbetreated
oftPA-treatedpatientsversus26%ofplacebo-treated
between3to4.5hoursaftersymptomonset.*
patients.Therewasa12%absoluteincreaseinthenumber
*TheeffectivenessoftPAhasbeenlesswellestablishedin
ofpatientswithminimalornodisabilityinthetPAgroup,
institutionswithoutthesystemsinplacetosafelyadministerthe
medication. definedbytheglobalstatistic.Thiscorrespondstoanumber
Note:Withinanytimewindow,oncethedecisionismadeto neededtotreatof8.3,meaningthat8.3patientswouldneed
administerIVtPA,thepatientshouldbetreatedasrapidlyas tobetreatedfor1additionalpatienttoachieveafavorable
possible.Asofthiswriting,tPAforacuteischemicstrokeinthe outcomewithessentiallynostroke-relateddisability.A
3-to4.5-hourwindowisnotFDAapproved. subsequentreanalysisofthetrialdatasuggestedthatthe
LevelCrecommendations.Nonespecified. numberneededtotreattoproducea1-pointshiftinthe
RankinScale,includingfromstatesofseveredisabilityto
Mostischemicstrokesinadultsarecausedbythrombotic
moremoderatedisability,maybeaslowas3.6
orembolicocclusionsofanartery.WithtPA,inactive
CombinedanalysisofpartsIandIIoftheNINDSstudy
plasminogenisconvertedintotheactiveformplasmin,
showedaconsistenteffectofIVtPAonfavorableoutcomeat90
whichpromotesthrombolysisbycleavingfibrin.In1995,the
days.3Thisbeneficialeffectwasobservedinboththe0-to90-
NINDStPAStrokeStudyGrouppublisheda2-part
minuteandthe91-to180-minutetimestrata.Mortalitywas
randomizedcontrolledtrialshowingthathuman
recombinanttPAimprovedoutcomesafterischemicstroke.3 similarinbothgroups(17%fortPAversus21%forplacebo;
P(cid:1).30).Therewas,however,anincreaseinsymptomatic
ThispublicationledtoFDAapprovalin1996.Reactionto
theavailabilityoftPAforacuteischemicstrokehasranged intracerebralhemorrhageinthetPA-treatedgroupduringthe
fromskepticism4tounbridledenthusiasm.5 first36hours(6%versus0.6%intheplacebogroup;P(cid:2).001).
TheClassININDStPAstudywasdividedinto2parts.3 ManyofthesetPA-relatedhemorrhageswerefatal(45%).
Eachpartwasperformedinaunique,independentlyenrolled Therefore,theimproved90-dayoutcomesinthetPAgroup
populationofpatientswithacuteischemicstrokebutwith (withoutanincreasedoverallmortality)occurreddespitethe
differentprespecifiedprimaryoutcomes.Inbothparts,acute excessmortalityinpatientswhohadsymptomaticintracerebral
ischemicstrokepatientspresentingwithin3hoursof hemorrhage.
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National Institutes of Health Stroke Scale.
Level of consciousness 1a–1c: 6. Motor Leg: Raise leg to 30 degrees and hold for 5
1a. Alertness seconds; test both sides.
0=alert and responsive 0=No drift x 5 seconds
1=arousable to minor stimulation 1=Drift but does not hit bed
2=arousable only to painful stimulation 2=Some antigravity effort but cannot sustain
3=reflex responses or unarousable 3=No antigravity effort, but even minimal movement
counts
1b. Orientation: Ask the patient his or her age and the 4=No movement at all
month; answers must be exact. X=Unable to assess because of amputation, fusion,
0=Both correct fracture, etc
1=One correct (or dysarthria, intubated, foreign language) Left or Right
2=Neither correct
7. Limb Ataxia: Check finger to nose and heel to shin
1c. Commands: Ask the patient to open/close eyes and to (only scoring + if out of proportion to weakness).
grip/release the nonparetic hand (or other 1-step command). 0=No ataxia (or aphasic, hemiplegic)
Grip and release nonparetic 1=Ataxia in 1 limb
0=Both correct (OK if impaired by weakness) 2=Ataxia in 2 limbs
1=One correct X=Unable to assess because of amputation, fusion,
2=Neither correct fracture, etc
Left or Right
2. Best Gaze: Only horizontal eye movements are checked
by voluntary movement or reflective movement (Doll’s 8. Sensory: Use safety pin.
eyes, not by calorics). Check grimace or withdrawal if stuporous. Score only
0=Normal stroke-related losses.
1=Partial gaze palsy 0=Normal
2=Forced eye deviation or total paresis that cannot be 1=Mild to moderate unilateral loss but patient aware of
overcome by Doll’s eyes touch (or aphasic, confused)
2=Total loss, patient unaware of touch, coma, bilateral loss
3. Visual Field: Test using confrontation (or visual threat if
necessary). 9. Best Language: Describe cookie jar picture, name
0=No visual loss objects, and read sentences (these standard items can be
1=Partial hemianopia, quadrantanopia, extinction found on the Web and at the American Heart Association
2=Complete hemianopia Web site).
3=Bilateral hemianopia or blindness (including cortical 0=Normal
blindness) 1=Mild to moderate aphasia (partly comprehensible)
2=Severe aphasia (almost no information exchanged)
4. Facial Palsy: If stuporous, check symmetry of grimace 3=Mute, global aphasia, coma.
to pain.
0=Normal 10. Dysarthria: Read list of words.
1=Minor paralysis, flat nasolabial fold or asymmetric smile 0=Normal
2=Partial paralysis (lower face) 1=Mild to moderate, slurred but intelligible
3=Complete paralysis (upper and lower face) 2=Severe, unintelligible or mute
X=Intubation or mechanical barrier
5. Motor Arm: arms outstretched 90 degrees (patient
sitting) or 45 degrees (patient supine) for 10 seconds. 11. Extinction/Inattention: Simultaneously touch patient
Encourage patient for best effort. Assess both sides. on both hands, show fingers in both visual fields, ask
0=No drift x 10 seconds whether patient recognizes own left hand.
1=Drift but does not hit bed 0=Normal, none detected (visual loss alone)
2=Some antigravity effort but cannot sustain 1=Neglects or extinguishes to double simultaneous
3=No antigravity effort, but even minimal movement stimulation in any modality
counts (visual, auditory, sensory, special or body parts)
4=No movement at all 2=Profound neglect in more than 1 modality, does not
X=Unable to assess because of amputation, fusion, recognize own left hand
fracture, etc
The NIHSS is an 11-part scale that measures the neurologic examination in a codified manner. The scale ranges from 0 to 42. A
score of less than 5 indicates a small stroke, and greater than 20 indicates a large stroke. Physicians can learn to perform the
NIHSS on a training module on the Internet. Standard pictures (eg, the cookie jar picture) and lists of words can also be
downloaded from the Internet.
Figure 1. National Institutes of Health Stroke Scale.
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Barthel Index.*
Activity
Feeding Toilet Use
0=unable 0=dependent
5=needs help cutting, spreading butter, etc or requires modified diet 5=needs some help, but can do something alone
10=independent 10=independent (on and off, dressing, wiping)
Bathing Transfers (bed to chair and back)
0=dependent 0=unable, no sitting balance
5=independent (or in shower) 5=major help (1 or 2 people, physical), can sit
10=minor help (verbal or physical)
Grooming 15=independent
0=needs help with personal care
5=independent face/hair/teeth/shaving (implements provided) Mobility (on level surfaces)
0=immobile or <50 yards
Dressing 5=wheelchair independent, including corners, >50 yards
0=dependent 10=walks with help of 1 person (verbal or physical) >50 yards
5=needs help but can do about half unaided 15=independent (but may use any aid; for example, stick) >50 yards
10=independent (including buttons, zips, laces, etc)
Stairs
Bowels 0=unable
0=incontinent (or needs to be given enemas) 5=needs help (verbal, physical, carrying aid)
5=occasional accident 10=independent
10=continent
TOTAL (0-100):
Bladder
0=incontinent, or catheterized and unable to manage alone
5=occasional accident
10=continent
*Mahoney FI, Barthel D. Functional evaluation: the Barthel Index. Maryland State Med J. 1965;14:56-61. Used with permission.
The Barthel ADL Index: Guidelines
1. The index should be used as a record of what a patient does, not as a record of what a patient could do.
2. The main aim is to establish degree of independence from any help, physical or verbal, however minor and for
whatever reason.
3. The need for supervision renders the patient not independent.
4. A patient's performance should be established using the best available evidence. Asking the patient, friends/relatives,
and nurses are the usual sources, but direct observation and common sense are also important. However, direct testing is
not needed.
5. Usually the patient's performance over the preceding 24 to 48 hours is important, but occasionally longer periods will
be relevant.
6. Middle categories imply that the patient supplies over 50 percent of the effort.
7. Use of aids to be independent is allowed.
The Barthel Index measures a person's ability to function in terms of the activities of daily living and mobility. It consists of 10
items, and scores range from 0 to 100. The higher the score, the more independent a patient is.
Figure 2. Barthel Index.
SecondarysubgroupanalysesofthecombinedNINDS StrokeTrial–Italy,9MulticenterAcuteStrokeTrial–Europe,10
partIandpartIIstudiesfailedtofindevidenceofadifferent andECASSI.11Allofthesestudiesfailedtodemonstratea
effectoftPAaccordingtoage,sex,strokeseverity,andstroke benefitofthrombolysisforstroke,andsomewerehalted
type.7 earlybecauseofexcessivemortalityinthetreatmentarm.9,10
In1995and1996,severalotherlargerandomizedtrialsof AllofthesestudiesweredifferentfromtheNINDSstudyinthat
thrombolyticagentsinacuteischemicstrokewerepublished, theyuseddifferentthrombolyticagents(streptokinase),8-10
includingtheAustralianStreptokinasetrial,8MulticenterAcute differenttimeperiodsfortreatment(upto6hours),higher
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Table1.ModifiedRankinScale.*(Usedwithpermission). protocolwasmodifiedandanewtrial,enrollingpatients0to5
Score Description hoursafterstrokeonset,wasbegun(ATLANTISPartB).In
ATLANTISPartB,613patientswererandomized1:1to0.9
0 Nosymptoms
mg/kgtPAorplacebo.14After31patientswereenrolled,the
1 Nosignificantdisabilitydespitesymptoms;abletocarryoutall
usualdutiesandactivities timewindowwaschangedto3to5hoursaftersymptomonset
2 Slightdisability;unabletocarryoutallpreviousactivitiesbut becauseofFDAapprovalforIVtPAin1996.Theprimary
abletolookafterownaffairswithoutassistance
outcomewastheproportionofpatientswithanexcellent
3 Moderatedisability;requiringsomehelpbutabletowalk
recovery,definedasanNIHSSscoreof0or1at90days.There
withoutassistance
4 Moderatelyseveredisability;unabletowalkwithout wasnodifferenceintheprimaryoutcomebetweentPA-treated
assistanceandunabletoattendtoownbodilyneeds patientsandplacebocontrols(34%versus32%;P(cid:1).65).Inthe
withoutassistance tPA-treatedgroup,therewasahigherrateofsymptomatic
5 Severedisability;bedridden,incontinent,andrequiring intracerebralhemorrhage(7%versus1%;P(cid:2).001)andatrend
constantnursingcareandattention
towardhighermortality(11%versus6.9%;P(cid:1).09).14Themean
6 Dead
timetotreatmentinthisstudywas4hours28minutes.Amongthe
RankinJ.Cerebralvascularaccidentsinpatientsovertheageof60.II.Progno-
sis.ScottMedJ.1957;2:200(cid:3)215.©Copyright1957RoyalSocietyofMedi- 61patientsrandomizedwithin3hours,ofwhom23were
cinePress,UK. randomizedtotPAand38wererandomizedtoplacebo,moretPA-
*ThemodifiedRankinScaleisa6-pointclinicaloutcomescalethatmeasuresa treatedpatientsachievedtheprimaryoutcome(61%oftPAversus
patient’sfunctionandindependence.Alowerscoreindicatesabetteroutcome. 26%ofplacebo;P(cid:1).01)andhadsymptomaticintracerebral
hemorrhage(13%oftPAversus0%ofplacebo;P(cid:1).05).15
Table2.GlasgowOutcomeScore.*(Usedwithpermission).
TheNINDSpartIIstudyisthereforeuniqueinshowinga
5 GoodRecovery Resumptionofnormallifedespiteminor
benefitinthepreselectedprimaryoutcomefor0.9mg/kgtPA
deficits.
forpatientswithischemicstrokeoflessthan3hours’duration.3
4 ModerateDisability Disabledbutindependent.Canworkin
shelteredsetting. Thereproducibilityofthefindingissupportedbythereanalysis
3 SevereDisability Consciousbutdisabled.Dependentfor oftheNINDSstudy,whichfoundthat90-dayoutcomeswere
dailysupport. againsignificantlyimproved,withoutadifferenceinmortality
2 Persistentvegetative Minimalresponsiveness
rates.16Furthermore,aClassIIpatient-levelmeta-analysisthat
1 Death
includesdatafromtheNINDS,ECASS,ATLANTIS,and
JennettB,BondM.Assessmentofoutcomeafterseverebraindamage.Lancet.
EchoplanarImagingThrombolyticEvaluationTrial
1975;1:480-484.©Copyright1975,withpermissionfromElsevier.
*TheGlasgowOutcomeScoreisanothersimplemeasureoffunctionaloutcome. (EPITHET)studiesofpatientstreatedwithin3hoursalso
supportstheefficacyoftPA.17Theincreasednumberof
patientsinthismeta-analysisprovidedamoreprecise
dosesoftPA(1.1mg/kg),11orallowedotherconcomitant estimateofthepotentialeffectoftreatment,andthe
antithrombotics(aspirin).9 calculated95%CIssuggestedthattPA’sbenefitdiminished
overtimebutremainedsignificantupto4.5hoursafter
OtherrandomizedtrialsofIVtPA,usingthesamedosebutwith
onsetofsymptoms.17
longertimeperiods,generatedmixedoutcomes.TheClassI
TwoindependentgroupshavereanalyzedtheNINDStrial
ECASSIItestedtPA(0.9mg/kg)versusplaceboinacuteischemic
strokeoflessthan6hours’duration.12Theprimaryendpointwas data.First,anindependentcommitteewascommissionedbythe
NINDStoverifythevalidityoftheNINDStrialresultsandto
theproportionofpatientswithafavorableoutcomeonthe
addresstheconcernthatanimbalanceinstrokeseverityat
modifiedRankinScale,definedasascoreof0or1.Therewasno
differenceinthisoutcomebetweentPA-treatedandplacebo baselinemayhaveconfoundedtheanalysisoftherelationship
controlsintheoverallcohort(40%versus37%;P(cid:1).28)andin betweenIVtPAandthelikelihoodofagoodoutcome.16
patientstreatedwithin3hours(42%versus38%;P(cid:1).63), AlthoughthemedianbaselineNIHSSscorewasnotdifferentin
althoughlessthan20%ofpatientsweretreatedwithinthattime thetPAandplacebogroups(P(cid:1).10),thereweremorepatients
period.Parenchymalhemorrhageonposttreatmentcomputed inthe91-to180-minutestratumwithbaselineNIHSS0to5
tomography(CT)wasobservedin12%oftPAand3%ofplacebo whowererandomizedtotPAratherthanplacebo(29patients
patients(P(cid:2).001).The90-daymortalityratewasequal(11%)for totPAversus7patientstoplacebo).Thecommitteefoundthat
boththetPAandplacebogroups(P(cid:1).99). therelationshipbetweentPAuseandgoodoutcomeremained
TheAlteplaseThrombolysisforAcuteNoninterventional robust(OR2.1;95%CI1.5to2.9)afteradjustmentfor
TherapyinIschemicStroke(ATLANTIS)trialalsotestedIV baselineNIHSSandotherfactorsrelatedtostrokeoutcome,
tPA(0.9mg/kg)versusplaceboinpatientswithstroke usingdatafromNINDSpartIandpartII.16Second,an
symptomsoffewerthan6hours’duration.13Thetrialwas independentauthorgroupreanalyzedthedatawithgraphic
stoppedprematurelyafterenrolling142patientsbecauseof analysisbutwithoutstatisticaltesting.18Theyconcludedthat
increasedsymptomaticintracerebralhemorrhageinpatients tPAhadonlyasmalleffectonthechangeinNIHSSscore
enrolled5to6hoursafterstrokesymptomonset.Thetrial betweenbaselineandday90.TheNIHSSchangewasnota
230 Annalsof EmergencyMedicine Volume,. : February
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primaryoutcomeoftheNINDSpartIItrial,however,andthe States,Canada,andtheEuropeanUnionmandatedphaseIV
authorsdidnotdisputethattPAhadastatisticallysignificant studiestodeterminewhetheroutcomesinclinicalpractice
effectontheprimarytrialoutcome. matchedthoseachievedinthetrials.Single-center(orin1case,
DatahavebeenaccumulatingaddressingtheuseofIVtPA singlesystem21)studiesfromearlyadopterssuggestedcausefor
within3to4.5hoursafteronsetofsymptoms.Asnotedabove, concern,withmajorprotocolviolationsoccurringin9%to
theClassIImeta-analysisofstudiesusing0.9mg/kgoftPA 67%oftreatedpatients.21-26Mostviolationswererelatedto
confirmedabenefitfortPAwithin3hoursofonsetof timecriteria,bloodpressuremonitoringandcontrol,or
symptomsandsuggestedthatthebenefitremainedsignificant provisionofantithromboticsoranticoagulantswithin24hours
upto4.5hoursfromsymptomonset.17Thebenefitof0.9mg/ oftPAadministration.Somestudiesfoundthatprotocol
kgtPAbetween3to4.5hoursaftersymptomonsetwasdirectly violationswereassociatedwithahigherrateofsymptomatic
testedintheClassIECASSIIIrandomizedcontrolledtrial.19 intracerebralhemorrhage22andmortality.24
Thetrialusedthesamedosingregimenandinclusion/exclusion Thefirstlargepostmarketingmulticenterstudy,mandatedby
criteriaastheNINDSprotocol(Figure3),withadditional theFDA,wastheClassIIIStandardTreatmentwithAlteplase
exclusions:agegreaterthan80years,baselineNIHSSscore toReverseStroke(STARS)study.27Mostoftheparticipating
greaterthan25,anyoralanticoagulantuse(regardlessofthe
centershadpreviouslyenrolledpatientsinclinicaltrialsoftPA
internationalnormalizedratio),andthecombinationofa
forstroke.TheadministrationoftPAfollowedtheNINDS
previousstrokeanddiabetesmellitus.Inaddition,incontrastto protocol.3OutcomesweresimilartothoseinthetPAarmofthe
theNINDSprotocol,patientswerepermittedtoreceive
NINDStrial(seeEvidentiaryTable).Twolargerregistriesfrom
parenteralanticoagulantsforprophylaxisofdeepvenous
CanadaandEuropefoundthattPAadministeredinclinical
thrombosiswithinthefirst24hoursaftertreatmentwithtPA.
practicehadratesofsymptomaticintracerebralhemorrhageof
ThefrequencyoftheprimaryefficacyoutcomeinECASSIII
4%to5%andratesofdisabilityandmortalitysimilartothat
(definedasmodifiedRankinScalescore0to1at90daysafter
observedintheNINDStrial.28,29TheClassIICanadian
treatment)wassignificantlygreaterwithtPA(291/418;52.4%)
AlteplaseforStrokeEffectivenessStudy(CASES)28tracked
thanplacebo(182/403;45.2%)(OR1.34;95%CI1.02to
outcomesof1,135tPA-treatedpatients,whichtheauthors
1.76;riskratio1.16;95%CI1.01to1.34;P(cid:1).04).Mortality
estimatedtorepresent84%ofalltreatedpatientsinCanada
rateswereequivalent(7.7%fortPA-treatedpatientsversus
duringthestudyperiod.Usingmultivariable-adjustedpredictive
8.4%forplacebo-treatedpatients).Symptomaticintracranial
modeling,theauthorsfoundnodifferencebetweentheobserved
hemorrhage,asdefinedbythecriteriausedintheNINDS
rateofagoodoutcomeandtheexpectedratebasedonamodel
study,wasreportedin33subjectstreatedwitht-PA(7.9%)and
derivedfromtheNINDSdataset.TheClassIISafe
in14subjectsgivenplacebo(3.5%)(OR2.38;95%CI1.25to
4.52;P(cid:1).006).Thehemorrhagerateswereslightlyhigherfor ImplementationofThrombolysisinStroke-MonitoringStudy
(SITS-MOST)trackedoutcomesof6,442tPA-treatedpatients
bothplaceboandtPA-treatedpatientscomparedwiththatin
from285centersinEurope.29Theproportionwithgood
theNINDSstudy,whichmaybeattributabletotheearlyuseof
outcomewas38.9%,andsymptomaticintracerebral
parenteraldeepvenousthrombosisprophylaxisallowedinthis
hemorrhage,definedaccordingtocriteriausedinECASSII,12
study.ThebenefitinECASSIIIwasmoremodestthanthat
was4.6%.
observedintheNINDStrials,andthenumberneededtotreat
TherearefewerdataontheuseoftPAinclinicalpracticein
toachieve1excellentoutcomewas14inthisstudy.Thisis
the3-to4.5-hourtimeperiod.TheClassIIISafe
consistentwiththetPAmeta-analysiswithinthistimeframeand
ImplementationofTreatmentsinStroke–InternationalStroke
reinforcestheconceptthatearliertimetotreatmenthasalarge
ThrombolysisRegistry(SITS-ISTR)3-to4.5-hourstudywasa
impactonlikelihoodofgoodoutcomewithinanydefined
timeframe.Therefore,althoughthetimewindowfortPA posthocassessmentofdataacquiredbetweenDecember2002
treatmentmayhavebeenlengthenedbasedontheECASSIII andFebruary2010fromanongoinginternationalregistry.30
results,theaggregatedatastronglysuggestthatpatientoutcomes Thisstudyreportedoutcomesin2,317patientstreatedwith
willbeoptimizedbytheearliestpossibleadministrationoftPA tPAbetween3to4.5hoursafteronset.Mostpatientswere
afterasafeandthoroughclinicalandbrainimagingevaluation. treatedafterpublicationoftheECASSIIItrialinOctober
Thenotionthatthereis“plentyoftime”toevaluatepatients 2008.Therewere44.5%withgoodoutcome(modifiedRankin
andadministertPAcouldleadtodelaysthatreducethe Scalescore0or1),whereas7.4%hadsymptomaticintracranial
effectivenessofthedrug.20 hemorrhagebytheNINDStrialdefinitionand12.0%diedby
Thesubstantialincreasedrateofsymptomaticintracerebral 3months.ComparedwiththeECASSIIItPA-treatedarm,the
hemorrhageamongtPA-treatedpatientshastempered proportionwithgoodoutcomewassomewhatlowerandthe
enthusiasmfortherapidadoptionoftPAasroutinecare,inpart proportionwithmortalitywassomewhathigher,probably
becauseoftheconcernthattreatmentmaybelesssafeinroutine becausepatientsintheSITS-ISTRregistryhadhigherinitial
clinicalpracticethaninthehighlymonitoredsettingofa strokeseverityandmoremedicalcomorbiditiesthanthe
clinicaltrial.Asaresult,regulatoryagenciesintheUnited patientsenrolledintheECASSIIItrial.
Volume,. : February Annalsof EmergencyMedicine 231
ClinicalPolicy
NINDS and ECASS III inclusion and exclusion criteria for intravenous tPA for acute ischemic
stroke.
NINDS Criteria3 ECASS III Criteria19
Inclusion: Inclusion:
Acute ischemic stroke with clearly defined time Acute ischemic stroke with a clearly defined
of onset (who could be treated <3 hours of time of onset (who could be treated between 3-
symptom onset) 4.5 hours from symptom onset)
Measurable deficit on the NIH stroke scale Age 18-80 years
Baseline brain CT scan that showed no evidence Stroke symptoms present for at least 30 minutes
of hemorrhage. without significant improvement prior to
treatment.
Exclusion:* Baseline brain imaging that showed no evidence
Another stroke or serious head injury within the of hemorrhage.
preceding 3 months
Major surgery within prior 14 days Exclusion:*
History of intracranial hemorrhage Same as NINDS plus the following additional
Systolic BP >185 mm Hg or diastolic BP >100 criteria:
mm Hg Age >80 years
Rapidly improving or minor symptoms Severe stroke (NIHSS >25) or by appropriate
Symptoms suggestive of subarachnoid imaging techniques (defined as >1/3 of the
hemorrhage middle cerebral artery territory)
Gastrointestinal or genitourinary hemorrhage Combination of previous stroke and diabetes
within the previous 21 days mellitus
Arterial puncture at a noncompressible site Any oral anticoagulant use (regardless of INR
within the previous 7 days or PT).
Seizure at onset of stroke
Use of anticoagulation: *Exclusions (or cautions) to tPA use that
patients receiving heparin within the 48 were not specifically mentioned in either
hours preceding the onset of stroke who have an study but are generally used:
elevated PTT, Myocardial infarction within previous 3 months
patients with a PT >15 seconds (or INR (AHA 2007 guidelines)
>1.6), Pregnancy and early postpartum period
patients with a platelet count <100,000 Known bleeding diathesis, recent pericarditis,
Glucose level of <50 mg/dL or >400 mg/dL. recent lumbar puncture (Brain Attack Coalition
http://www.stroke-
site.org/guidelines/tpa_guidelines.html, accessed
March 1, 2012).
AHA, American Heart Association; BP, blood pressure; CT, computed tomography; ECASS, European
Cooperative Acute Stroke Study; INR, International Normalized Ratio; NIH, National Institutes of
Health; NIHSS, National Institutes of Health stroke scale; NINDS, National Institute of Neurological
Disorders and Stroke; PT, prothrombin time; PTT, partial thromboplastin time; tPA, tissue plasminogen
activator.
Figure 3. NINDS and ECASS III inclusion and exclusion criteria for intravenous tPA for acute ischemic stroke.
PuttingtheEvidenceIntoClinicalContext stroke,includingrapidaccesstolaboratorytestresults,brain
SafeandeffectiveadministrationoftPAreliesonahospital imaging,andaccurateimageinterpretation.Protocolsmustbe
havingasysteminplacefortreatingstrokepatients.Patients inplacefordrugadministration,closeclinicalmonitoring,
mustundergorapidandaccuratediagnosisofacuteischemic activebloodpressuremanagement,andtreatmentof
232 Annalsof EmergencyMedicine Volume,. : February
ClinicalPolicy
hemorrhagiccomplications(systemicorintracerebral)ifthey “hypodensitygreaterthanonethirdofthecerebral
occur.Ifagivenhospitalisunabletoprovidethisinfrastructure, hemisphere”anda“caution”forthepresenceofmajor
protocolsshouldbeinplacefortransferringpatientstoafacility deficits,40andtheAmericanCollegeofChestPhysicians
thatcan.Whateverahospital’sapproachis,anongoingquality guidelinesrecommendagainsttreatmentwhenclearly
assuranceprogramoughttobeinplace.Physicianexpertiseand identifiablehypodensityispresentingreaterthanonethird
writtenprotocolsarethereforehypothesizedtobeimportantfor ofthemiddlecerebralarteryterritorywhilenotdisallowing
useoftPA31butmaybeinshortsupplyinsmallercenters treatmentinthepresenceofearlyischemicchangessuchas
withoutanabundanceofstrokespecialists.TheCASESand subtlelossofgray-whitedifferentiationorsulcaleffacement
SITS-MOSTstudies,whichincludedabroadselectionof withouthypodensity.41Patientswiththesecharacteristics
academicandcommunityhospitals,showedresultssimilarto havebeenexcluded,underrepresented,ornotreportedonin
thoseobservedintheNINDStrial.Additionally,bothstudies themajorobservationalstudies;therefore,dataonoutcomes
failedtofindadifferenceinoutcomesinpatientstreatedat inthesepatientsubgroupsinclinicalpracticearelacking.
moreexperiencedcenters,definedbytPAcasevolume, Theexceptionisadvancedage,forwhichseveralstudies
comparedwithlessexperiencedcenters.TheSITS-MOST reportgenerallyworseoutcomescomparedwithyounger
subjectsbutnoincreasedriskofsymptomaticintracerebral
findingsmustbetreatedwithsomecaution,however,because
hemorrhage.42-44Thisisnotasurprisingfinding,giventhatage
allcenterswererequiredtohaveaneurologistorotherphysician
with“considerableexperienceinstrokecare.”29Adequate isawell-establishedriskfactorforpooroutcomeregardlessof
intervention.Althoughitisappropriatetoexercisecaution
physicianacutestrokecareexpertisehasnotbeenrigorously
whenconsideringtreatmentforthesesubgroupswithpoor
definedintheliterature,basedoneithercredentialordegreeof
prognosis,aposthocanalysisofthe1995NINDStrialfailedto
experience,orstudiedinclinicaltrials.Thedefinitionshould
showevidenceofadifferentialeffectoftPAaccordingtopatient
notberestrictedtoneurologistsandshouldincludeemergency
subgroups,includingthosewithadvancedage,severeclinical
physiciansorotherphysicianswithexpertiseandexperiencein
deficits,andmoreextensiveCTchanges.45
strokecare,accordingtorecommendationsfromtheBrain
AttackCoalition31andtheCanadianStrokeConsortium.32
Forcenterswithouton-siteacutestrokespecialists,telestroke
Addendum
technologyoffersameanstoobtainremoteconsultationabout
Afterthisdocumentwascompleted,theInternational
theadministrationofIVtPA.InastudybyFisher,33the
StrokeTrial3(IST-3)waselectronicallypublishedin
formationof“telestroke”networksallowedinexperienced Lancet.46IST-3wasdesignedtoevaluatetheeffectsoftPA
centerstoobtainexpertmedicalandradiologicconsultationby
onpatientswithischemicstrokeupto6hoursfrom
remotevideolinkage.Accumulatingdatashowthatthismodel
symptomonsetinwhombenefitwasdeemedtobeuncertain
ofstrokecareproducesresultssimilartothoseobtainedbyon-
(thevastmajorityofwhomhadcontraindicationstotPA
siteconsultationwithstrokeexperts.34-36AClassIIIstudyfrom definedbyNINDScriteriainthe0-to3-hourwindowor
anetworkofhospitalsinBavaria,Germany,foundthat115 ECASS-3criteriainthe3-to4.5-hourwindow).IST-3
patientstreatedwithtPAatremotesitesusingtelestrokehad lookedatadifferentcohortofpatientsthanthoseonwhich
similarinhospitalratesofsymptomatichemorrhage(7.8%)and thispolicyfocuses.Thepublishedtrialdatawerecarefully
mortality(3.5%)comparedwithlocallytreatedpatientsatthe reviewedbythewritingpanel,anditwasdeterminedthatthe
academicstrokecenters.37Arandomizedcontrolledtrialshowed study’smethodologywassuchthatthefindingsdidnotaffect
thatmoreaccuratedecisionsaremadewhenvideoconsultation, therecommendationsmadeinthispracticeguideline.
ratherthantelephoneconsultation,isused.38TheAmerican
HeartAssociationpublishedrecommendationsontheuseof Disclosures
telemedicineforacutestrokecare.39 Dr.EdlowservesontheExecutiveCommitteeofthe
Therehasbeenclinicalconcernabouttreatmentof FoundationforEducationandResearchinNeurologic
patientgroupswhowouldmeetNINDScriteriabuthavea Emergencies,coeditedthetextbookofNeurological
poorprognosisforgoodoutcome,irrespectiveoftPAuse, EmergenciesforOxfordUniversityPress,andservesonthe
includingthosewithadvancedage,severeclinicaldeficits, editorialboardoftheJournalofInternalandEmergency
andCThypodensityinalargeportionofthemiddlecerebral MedicineandtheInternationalJournalofEmergency
arteryterritoryorhemisphere.TheSITS-MOSTandSITS- Medicine.Healsoreviewsmedicalmalpracticecasesforboth
ISTRtreatmentprotocolexcludedpatientsolderthan80 plaintiffanddefense.
years,withNIHSSscoregreaterthanorequalto25,orwith Dr.Smithservedonascientificadvisoryboardfor
“severestroke”onCT.29,30TheCanadianguidelineslistCT Genentechin2010,receivedspeakerhonorariafromthe
evidenceofinfarctioninvolvingmorethanonethirdofthe CanadianConferenceonDementia,servesasanassistanteditor
middlecerebralarteryterritoryasanexclusioncriterion.32 forStroke,hasservedonspeakers’bureausforQuantiaMDand
TheAmericanHeartAssociation/AmericanStroke BMJBestPractice,isontheDataandSafetyMonitoringBoard
AssociationguidelinesincludethatCTdoesnotshowa fortheMRWitnesstrialfundedbytheNationalInstitutesof
Volume,. : February Annalsof EmergencyMedicine 233
ClinicalPolicy
Health(NIH)/NINDS,andreceivesresearchsupportfromthe methodandapplicationtothrombolytictherapyforacutestroke.
NIH/NINDS,CanadianInstitutesforHealthResearch, ArchNeurol.2004;61:1066-1070.
7. TheNINDSt-PAStrokeStudyGroup.Generalizedefficacyoft-PA
CanadianStrokeNetwork,theAlbertaHeritageFundfor
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8. DonnanGA,DavisSM,ChambersBR,etal.Streptokinasefor
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9. MulticentreAcuteStrokeTrial–Italy(MAST-I)Group.Randomised
NeurologyNow,servesonaspeakers’bureauforBoehringer
controlledtrialofstreptokinase,aspirin,andcombinationofboth
Ingelheim,andreceiveshonorariafromBoehringerIngelheim
intreatmentofacuteischaemicstroke.Lancet.1995;346:1509-
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withrecombinanttissueplasminogenactivatorforacute
AdjudicationCommittee),NationalHeart,Lung,andBlood
hemisphericstroke.TheEuropeanCooperativeAcuteStroke
Institute(NHLBI)(1R01HL084375-01A2,subinvestigator,
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neurologicassessments),NINDS(U01NS40406-04,local
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principalinvestigator),andNIH(HHSN268200800003C, placebo-controlledtrialofthrombolytictherapywithintravenous
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inNeurologicEmergencies,servesontheadvisoryboardforthe
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BrainTraumaFoundation,andisaconsultantforBanyan
to6-houracutestroketrial,partA(A0276g):resultsofadouble-
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EmergencyMedicine.
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