Update on Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke

REVIEW

Update on Intravenous Recombinant TissuePlasminogen Activator for Acute Ischemic Stroke
Jennifer E. Fugate, DO, and Alejandro A. Rabinstein, MD
Abstract

The controversial field of interventional stroke neurology has attracted considerable interest within thestroke community, but no endovascular interventional therapies have proved to be superior to intravenous(IV) recombinant tissue plasminogen activator (rtPA), the standard of care for patients with acute ischemicstroke. In this article, we review the evidence and background of IV thrombolysis for stroke, the clinicalapplication of IV rtPA in practice, and the management of potential complications after thrombolysis. Weconducted this review using a search of PubMed for articles published from January 1, 1995, to October31, 2013, with the following terms: ischemic stroke, tissue plasminogen activator, TPA, alteplase, thrombolysis,and intracranial hemorrhage. Articles were also identified through searches of reference lists and the au-thors’ files. In nearly 2 decades since the publication of the transformative National Institute of Neuro-logical Disorders and Stroke trials, the efficacy and safety of IV rtPA has been consistently verified ininternational real-world clinical practice. Time from stroke symptom onset to thrombolysis is crucial andprobably the most important determinant of success of IV therapy. Thus, optimal care of patients withacute stroke should include community education and standardized protocols to guide immediate patientassessment and triage to medical centers with capability for efficient neurologic assessment, brain imaging,drug administration, and specialized postthrombolysis care.

ª 2014 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2014;nn(n):1-13

From the Division ofCritical Care Neurology,Mayo Clinic, Rochester,MN.
T he availability of intravenous (IV) re-
combinant tissue plasminogen activator(rtPA) has dramatically transformed the

approach to acute ischemic stroke. As recently asjust 2 decades ago, no emergent therapies forstroke were proven to be safe or effective inimproving outcomes, and patient care wasfocused on supportive measures, rehabilitation,and secondary stroke prevention. Progress inpreventive measures for cerebrovascular diseaseand in acute care have helped lower stroke fromthe third to the fourth leading cause of death inthe United States, but it remains a major cause oflong-term disability.1 The cumulative poststrokedisability burden is likely to become a growingproblem for society as an increasing number ofpeople survive their strokes because of develop-ments in the medical field. Since the publicationof the pivotal National Institute of NeurologicalDisorders and Stroke (NINDS) IV rtPA trials in1995,2 IV rtPA has become standard therapyfor patients presenting within 3 hours of onsetof acute ischemic stroke. Recent advances inthe field center around interventional strokeneurology and direct intra-arterial therapies,which have captured considerable interest of

Mayo Clin Proc. n XXX 2014;nn(n):1-13 n http://dx.doi.org/10.1016www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for M

researchers, clinicians, and medical device com-panies. Yet despite a sound pathophysiologicrationale and promising results from non-randomized studies, treatment of patients withendovascular therapy has not proved to be supe-rior in improving patient outcomes comparedwith IV rtPA.3,4

In this article, we review the evidence andbackground of IV thrombolysis for stroke, theclinical application of IV rtPA in practice, andthe management of potential complicationsafter thrombolysis. We conducted this reviewusing a search of PubMed for articles pub-lished from January 1, 1995, to October 31,2013, with the following terms: ischemic stroke,tissue plasminogen activator, TPA, alteplase,thrombolysis, and intracranial hemorrhage. Arti-cles were also identified through searches ofreference lists and the authors’ files.

REVIEWING THE EVIDENCEResults of the NINDS rtPA Stroke Study2da trialof 624 patients randomized to receive IV rtPA(0.9 mg/kg, maximum 90 mg) or placebo within3 hours of ischemic stroke onsetdrevealed thatIV rtPA increases the chance of achieving a

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ARTICLE HIGHLIGHTS

n Intravenous (IV) recombinant tissue plasminogen activator(rtPA) remains the only proven therapy for acute ischemicstroke and is most effective when given early.

n There is evidence that the “therapeutic window” for IV rtPA canbe extended to 4.5 hours for most patients with stroke who areless than 80 years old, but efficacy and safety are greatest whenthrombolytic therapy is administered within the first 3 hours.

n Factors most predictive of prognosis include onset to treatmenttime, stroke severity (National Institutes of Health Stroke Scalescore), age, and blood glucose levels.

n The most feared complication of IV rtPA is symptomaticintracranial hemorrhage, which occurs in 2% to 6% of patients.

n Postthrombolysis intracranial hemorrhage should promptneurosurgical evaluation, strict blood pressure control, andconsideration of antifibrinolytic agents, cryoprecipitate, andplatelet transfusion.

MAYO CLINIC PROCEEDINGS

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3-month complete or nearly complete neurologicrecovery by at least 30%. The proportion ofpatients achieving 3-month favorable outcome(modified Rankin Scale score of �1) was 39%in the rtPA group and 26% in the placebo group(P¼.019). Intracranial hemorrhage (ICH) oc-curred more often in the rtPA-treated group(6.4% vs 0.6%), and the rate of severe systemichemorrhage was less than 1%. Mortality rateswere not significantly different between thegroups (21% vs 17%). Absence of hemorrhageon noncontrast computed tomography (CT)was the only radiologic condition for proceedingwith thrombolysis in this trial. However, on USFood and Drug Administration approval of IVrtPA for acute stroke, an additional radiologicexclusion criterion, the presence of multilobarlow-attenuation changes on baseline CT, wasadded on the basis of exclusion criteria fromthe early European Cooperative Acute StrokeStudy (ECASS) trials.5-7 Intravenous rtPA ismost effective when given shortly after symptomonset. In the NINDS study sample, after adjust-ment for stroke severity, patients treated within90 minutes had significantly increased odds ofimprovement at 24 hours and favorable 3-month outcome compared with patients treatedbeyond 90 minutes (odds ratio [OR], 2.11 vs1.69).8 This result has been consistently foundin subsequent studies. In a recent analysis of

Mayo Clin Proc. n XXX 20

58,353 IV rtPAetreated patients from the na-tional Get With The GuidelineseStroke registry,faster onset to treatment time, in 15-minute in-crements, was associated with reduced mortality(OR, 0.96; 95% CI, 0.95-0.98), reduced symp-tomatic ICH (OR, 0.96; 95% CI, 0.95-0.98),and increased rate of independent ambulationat hospital discharge (OR, 1.04; 95% CI, 1.03-1.05).9

Following approval of IV rtPA for the treat-ment of acute ischemic stroke by the US Foodand Drug Administration in 1996, rtPA gainedinternational acceptance, and its effectivenessand safety have been repeatedly confirmed byseveral postmarketing observational studies ofreal-world clinical practice. One of the largestwas SITS-MOST (Safe Implementation ofThrombolysis in Stroke-Monitoring Study),which included 6483 patients from nearly 300centers in 14 European countries.10 The rate ofsymptomatic ICH (sICH) in this population at24 hours was only 1.7%, and the 3-month mor-tality rate was 11.3%. These unfavorable eventsoccurred at lower rates than those reported inthe pooled analysis of earlier randomized trialsof IV thrombolysis for stroke, and even centerswith very limited IV thrombolysis experienceachieved good results. The lower rate of sICHis likely due to a different definition of sICH inthis study (parenchymal hemorrhage in >30%of infarcted area with substantial mass effectcombined with neurologic deterioration of �4points on the National Institutes of HealthStroke Scale [NIHSS] or leading to death).10

Although treatment with IV rtPA has becomestandard of care for patients with acute ischemicstroke, only 3% to 5% actually receive the ther-apy.11-13 Utilization is increased in academicteaching medical centersdparticularly thosewith neurology training programsdbut still isgenerally less than 5%.14 The main reason forthis low rate is that many patients present formedical attention beyond 3 hours after symp-tom onset. This delay has led to interest inexpanding the therapeutic window for IV rtPA.In 2004, a pooled analysis of 6 trials of IV rtPAadministered up to 6 hours after symptom onsetsuggested that a clinical benefit may exist evenwhen rtPA was administered beyond 3 hours.15

This analysis confirmed that efficacy is greatestwhen IV rtPA is given within 90 minutes ofsymptom onset but showed similar efficacy be-tween time to treatment of 91 to 180 and 181

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INTRAVENOUS THROMBOLYSIS FOR STROKE

to 270 minutes. Subsequently, results of theECASS III trial, a Europeanmulticenter random-ized trial that evaluated rtPA vs placebo admin-istered between 3 and 4.5 hours after strokesymptom onset, was published.7 In this studyof 821 patients, the odds of regaining full inde-pendence were 28% higher among rtPA-treatedpatients, and these results led to internationalrecommendations to expand the time windowfor thrombolysis to 4.5 hours. The mortalityrate was slightly higher in the placebo arm, butthere was not a statistically significant differencebetween the groups. Symptomatic ICHdasdefined by NINDS criteriadoccurred in 7.9%in the rtPA group but caused neurologic wors-ening in only 2.4%. It should be noted that addi-tional exclusion criteria were used in ECASS III,including age greater than 80 years, the combi-nation of previous stroke and diabetes mellitus,anticoagulation regardless of internationalnormalized ratio, and NIHSS score greaterthan 25. Thus, when recommending treatmentwith IV rtPA for this extended time window itis prudent to consider these factors as possiblecontraindications.

The large European observational studySITS-ISTR (Safe Implementation of Treatmentin Stroke-International Stroke Thrombolysis Reg-ister) confirmed that IV rtPA is effective whenadministered 3 to 4.5 hours after ischemic strokesymptom onset.16 An analysis of 29,618 patientswith acute ischemic stroke from SITS-ISTR dur-ing 2002-2011 revealed that patients treatedwithin 3 to 4.5 hours had rates of functional in-dependence of 63%, sICH of 1.8%, andmortalityof 11%.17 There was no significant difference inthese rates compared with those treated with IVthrombolysis within 3 hours, although this com-parison was not controlled for initial strokeseverity. Furthermore, in this registry, patientstreated within 4.5 to 6 hours had outcomes com-parable to those of patients treated within 3hours.17 However, when onset to treatmenttime was analyzed as a continuous variable, itwas significantly associated with higher sICHrates and unfavorable 3-month outcomes, againhighlighting the well-established value of earlytreatment. Treatment between 3 and 4.5 hoursafter symptom onset has been supported and rec-ommended by many international regulatoryagencies, but the US Food and Drug Administra-tion did not approve its use in this time frame.The basis for that decision was kept confidential,

Mayo Clin Proc. n XXX 2014;nn(n):1-13 n http://dx.doi.org/10.1016www.mayoclinicproceedings.org

but it is thought that they believed the evidencesupporting rtPA efficacy within this windowwas inconclusive. Conversely, the AmericanHeart Association (AHA) has recommendedtreatment with IV rtPA to eligible patients within3 and 4.5 hours after symptom onset with theadditional exclusion criteria listed in ECASSIII.18 At Mayo Clinic in Rochester, Minnesota,we typically adhere to these additional exclusioncriteria as well and offer off-label rtPA to eligiblepatients who present within this extended timewindow.

The third International Stroke Trial (IST-3)was a multicenter randomized trial from 12countries that tested the efficacy and safety ofIV rtPA only in patients in whom there was clin-ical uncertainty about its usefulness.19 Thus, ifpatients with acute stroke had clear indicationsor contraindications for treatment with IVthrombolysis, theywere not included. If the clini-cian was convinced that the patient should orshould not be treated with IV rtPA , then the pa-tient was not randomized. Randomizationoccurred only if the patient met eligibility criteriaand the clinician was truly uncertain about therisks and benefits of rtPA for that individual. Pa-tients undergoing thrombolysiswere treated rela-tively late in this study, with a median time fromsymptom onset to treatment of 4.2 hours (3.2-5.2 hours). The study enrolled 3035 patientsbut was underpowered to detect a difference be-tween groups for its primary outcome (6000 pa-tients were needed by estimated sample size).This was a primarily negative trial because at 6months, 37% of rtPA-treated patients were aliveand independent vs 35% of the control group(P¼.18). There was a favorable shift in 6-month functional outcomes for those receivingthrombolysis (OR, 1.27 for outcome rangingfrom no disability to moderate disability forrtPA group vs control group), but the shift anal-ysis was not planned at the beginning of the trial.Subgroup analysis suggested benefit in elderlypatients (age >80 years) and in patients treatedbetween 4.5 and 6 hours.19 However, the lowerbenefit observed in younger patients and the lackof significant benefit in patients treated withinthe 3- to 4.5-hour timewindow incited questionsover the reliability of these subgroup analyses.Functional outcomes of patients in major throm-bolysis stroke studies are shown in Figure 1.

Our knowledge about safe candidates andhow to optimize the effect of IV rtPA continues

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0%

NINDS

ECASS II

ECASS III

ATLANTIS

SITS-MOST

SITS-ISTR

IST-3

10% 20%

Propor

FIGURE 1. Outcomes wRankin Scale was used fTrial (IST-3),19 which usbars, the top bar indicatcombinant tissue plasmrepresents patients in theof Treatments in Strokegroups. The IV rtPA wasNational Institute of Neu(NINDS),2 the SITS-MInternational Stroke Throthe European Cooperatito 5 hours for the AlteTherapy in Ischemic StroECASS III.7 Note that ISTuncertain whether IV rtP


4

to grow and will be enhanced by results ofongoing trials. A large area of ongoing researchinvolves the possible extension of IV lysis to pa-tients historically excluded, such as patients whowake up from sleep with stroke symptoms. Twotrials are currently recruiting patients to studythis population: one is studying the effect andsafety of giving IV rtPA to patients within 3 hoursof waking,21 and the other, the WAKE-UP trial,will treat patients with a mismatch in visibilityof an acute ischemic lesion between diffusion-weighted magnetic resonance imaging andfluid-attenuated inversion recovery magneticresonance imaging (“DWI-FLAIR mismatch”)performed within 4.5 hours of awakening.22

Additionally, sonothrombolysis, the use of trans-cranial Doppler ultrasonography to enhance clot

30% 40% 50% 60% 70% 80% 90% 100%

tion of patients by functional outcome group

mRS*0-1 2-3 4-5 6

ere assessed at 90 days after stroke. *Modifiedor all studies except the third International Strokeed the Oxford Handicap Scale. In studies with 2es those who were treated with intravenous re-inogen activator (IV rtPA), and the bottom barplacebo or control arm. The Safe Implementation(SITS) studies were observational without controlgiven within 0 to 3 hours of symptom onset for therological Disorders and Stroke rtPA Stroke Studyonitoring Study (SITS-MOST),10 and the SITS-mbolysis Register (SITS-ISTR)16; 0 to 6 hours forve Acute Stroke Study (ECASS) II6 and IST-319; 3plase Thrombolysis for Acute Noninterventionalke (ATLANTIS) study20; and 3 to 4.5 hours for-3 included only patients in whom clinicians wereA would be beneficial.


dissolution following administration of IV lysis,has had promising results. Meta-analyses ofsonothrombolysis studies have revealed safety,improved recanalization rates, and better clinicaloutcomes comparedwith IV rtPA alone, but withwide confidence intervals.23,24 Results of theCLOTBUST-ER trial (Combined Lysis ofThrombus With Ultrasound and Systemic tPAfor Emergent Revascularization in AcuteIschemic Stroke), a phase 3 randomized trialthat is currently recruiting, will shed light onthe usefulness of this adjunct.25 Eptifibatide, aglycoprotein IIb/IIIa antagonist, is also underinvestigation as an adjunctive treatment to IVrtPA. In a multicenter double-blind safety study(CLEAR-ER [Combined Approach to Lysis Uti-lizing Eptifibatide and rt-PA in Acute IschemicStrokeeEnhanced Regimen]), patients withstroke were randomized to a lower dose ofrtPA (0.6 mg/kg) in combination with eptifiba-tide (bolus and 2-hour infusion) comparedwith treatment with standard IV rtPA (0.9 mg/kg).26 Symptomatic ICH occurred in 2 of 101patients (2%) in the combined treatment groupcompared with 3 of 25 patients (12%) in thestandard rtPA group (OR, 0.15; 95% CI,0.01-1.40). However, an earlier phase 3 trialof abciximabdanother glycoprotein IIb/IIIaantagonistdwas prematurely terminatedbecause of an unfavorable benefit-risk profile(5.5% of abciximab-treated and 0.5% ofplacebo-treated patients had sICH).27 Recruit-ment is ongoing for another trial randomizingpatients to full-dose IV rtPA in combinationwith eptifibatide or standard IV rtPA alone.28

One of the biggest barriers to more wide-spread use of rtPA is that a substantial propor-tion of the population does not live near ahospital with rtPA capability. The delay causedby the need to transfer patients from these areasto another hospital often shifts these patientsoutside the therapeutic window. As a result,there has been recent interest in developingand expanding practices using audiovisual tele-medicine so that thrombolysis can be adminis-tered to more patients in their communitywith real-time interaction between local practi-tioners, patients, and stroke experts.29,30 Onerandomized trial of 234 patients with acutestroke found that the decision to administerrtPA was “correct”more often in those evaluatedby telemedicine than by telephone (98% vs82%; P<.001) consultation.31 There were no




TABLE 1. Contraindications to Administration of IV rtPA for Acute IschemicStroke Within 3 Hours of Symptom Onset

Clinical contraindicationsMajor head trauma or stroke within the previous 3 moSustained hypertension >185 mm Hg systolic or >110 mm Hg diastolicActive internal bleedingBlood glucose level <50 mg/dL (2.7 mmol/L) and symptoms resolve with admin-

istration of dextroseHistory of intracranial hemorrhageMajor surgery or serious trauma within the previous 14 dAcute bleeding diathesis

Platelet count <100 � 109/LHeparin received within 48 h resulting in elevated apTTAnticoagulation resulting in INR >1.7Current use of direct thrombin inhibitors or factor Xa inhibitors with elevated

laboratory test results (eg, apTT, TT, ECT, or factor Xa activity assays)PregnancyGastrointestinal or urinary tract hemorrhage within the previous 21 dAcute myocardial infarction within the previous 3 mo

Radiographic contraindicationsMultilobar infarction (hypodensity of more than one-third of the MCA territory)Intracranial hemorrhage

apTT ¼ activated partial thromboplastin time; ECT ¼ ecarin clotting time; INR ¼ internationalnormalized ratio; IV rtPA ¼ intravenous recombinant tissue plasminogen activator; MCA ¼ middlecerebral artery; TT ¼ thrombin time.


statistically significant differences in rates ofgood functional outcome, mortality, or rates ofICH between the groups.

Intravenous thrombolysis is not only effec-tive in clinical trials and in real-world practicebut also produces economic benefits byreducing societal and health care costs.32-34

Although rtPA use results in extra costs in theacute care setting (cost of rtPA itself, stay inan intensive care unit, additional brain imaging,and increased overall length of stay), these costsare more than offset by the ultimate reductionin long-term disability costs.32 One analysis ofexpected cost savings from rtPA use in theUnited States estimated that $7.4 million canbe saved for every 2% increase in rtPA-treatedpatients.33 Another model derived from a sys-tematic review found that rtPA use in theUnited States is associated with $60 million indirect savings to society and an additional7510 quality-adjusted life-years, for a totalbenefit of $363 million.32

PATIENT SELECTIONPatients with acute ischemic stroke requireemergent medical evaluation because braincells die rapidly without adequate blood flow,and IV rtPA is most effective for acute strokewhen given early. Hospitals need to implementprotocols to triage patients quickly to medicalcenters with the capability of rapid neurologicassessment and treatment of acute stroke.Within very efficient systems, it is possible toreduce the time to IV thrombolysis to as shortas 20 minutes on average.35 Methods thatreduce delays to treatment include premixingrtPA before patient arrival and taking the pa-tient directly to the CT suite, where the briefneurologic examination takes place, blood iswithdrawn, and rtPA bolus is given.35 Further-more, treatment can be accelerated by en-hancing prehospital care through education ofdispatchers, direct communication betweenparamedics and stroke specialists,35 and eventransporting CT scanners and neurologists tothe field in ambulances.36 Many of the contra-indications to IV thrombolysis (Table 1) arederived from exclusion criteria of early majorrandomized trials. The rationale underlyingmany of the criteria is based on data from smallobservational studies or expert opinion, andthe contraindications for IV rtPA vary slightlyamong the AHA guidelines, the European


Stroke Initiative recommendations, and thealteplase package insert.37 For example, rapidlyimproving or minor symptoms are considereda relative contraindication in the alteplase pack-age insert and the AHA guidelines but are notlisted as contraindications in the Europeanguidelines.18,38 Recent myocardial infarctionis a contraindication in the AHA guidelinesbut not in the European guidelines or the alte-plase package insert.

The single most important part of the acutestroke history is determination of the time ofsymptom onset. Current AHA guidelines definesymptom onset as the last time that the patientwas at his or her previous baseline or in asymptom-free state.18 Neurologic examinationshould be brief, timely, and focused. The useof a standardized examination such as theNIHSS (Supplementary Table, available onlineat http://www.mayoclinicproceedings.org) al-lows rapid quantification of deficits and facili-tates communication among health careprofessionals in addition to providing early in-formation about prognosis.18

Only a few diagnostic tests are absolutelynecessary before administering IV rtPA for acutestroke. Required tests include noncontrast head

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CT (to exclude ICH and large established infarc-tion) and blood glucose measurement. For mostacute ischemic stroke evaluations, clinicians donot need to await the results of laboratorytestsdexcept for blood glucose concentrationdbefore administering IV rtPA.18 If patients arecurrently taking or have recently taken anti-coagulants or if they have a history of throm-bocytopenia, end-stage liver disease, orhematologic disorders, then the activatedpartial thromboplastin time and prothrombintime/international normalized ratio need tobe checked before administration. Theincreasing use of direct thrombin inhibitorsand factor Xa inhibitors adds complexity tothe assessment of patients because routinecoagulation parameters are not reliable indi-cators of the anticoagulation effect of theseagents. The AHA guidelines recommendagainst treating patients currently takingthese novel oral anticoagulants if more sensi-tive laboratory values are elevated (eg,thrombin time, ecarin clotting time, factorXa activity assays).18 This is an area of currentuncertainty that demands research. Othertests such as electrocardiography, chest radi-ography, and measurement of serum electro-lytes and hemoglobin level are reasonable toobtain in the emergency setting, but throm-bolysis should not be delayed while awaitingresults of these tests.18

Fear of misdiagnosis of a possible “strokemimic” such as seizure, migraine, or functionaldisorder should not prevent the administrationof IV rtPA if there is reasonable concern for acuteischemic stroke. The risk of sICH in patientswith these disorders is exceedingly low,39-43

and the consequences of missing the opportu-nity to treat acute ischemic stroke could bedevastating. In fact, some of the traditional con-traindications such as seizure at onset of symp-toms or minor or resolving stroke symptomsare no longer considered absolute contraindica-tions.18,44 Observational studies have found thatapproximately 25% to 30% of patients who donot undergo thrombolysis because of mild orimproving symptoms have unfavorable out-comes, including permanent disability.45,46

PRACTICALITIES: ADMINISTRATION ANDPOSTTHROMBOLYSIS CAREIntravenous rtPA should be administered asquickly as possible once a patient with a


potentially disabling deficit has been deemedeligible. The dose is 0.9 mg/kg (maximum,90 mg) with 10% given as a bolus over 1 min-ute and the remainder infused over 1 hour.The patient should be admitted to a special-ized stroke unit or neurocritical care intensivecare unit for postthrombolysis care. Protocol-guided care may be useful to standardize andoptimize care and to avoid risks. Patientsshould be monitored with cardiac telemetryfor at least 24 hours. Neurologic examinationsshould be performed and vital signs should bemonitored every 15 minutes for the first 2hours, followed by every 30 minutes for thenext 6 hours and then hourly until 24 hoursfollowing treatment. Optimal management ofarterial blood pressure (ABP) after acuteischemic stroke is complex, particularly if therecanalization status of an occluded artery isunknown. Although exact blood pressuregoals are not derived from rigorous data,marked hypertension in IV rtPAetreated pa-tients has been associated with sICH.47 Intra-venous labetalol or nicardipine infusions areeffective agents for most patients. Guidelinesrecommend smoothly lowering ABP to lessthan 185/110 mm Hg before thrombolysisand maintaining ABP at less than 180/105mm Hg thereafter.18 Intravenous labetalol(10- to 20-mg bolus doses) and/or a contin-uous IV nicardipine infusion (5-15 mg/h) aresufficient for most hypertensive stroke pa-tients. If hypertension is severe and/or resis-tant to these measures, an infusion ofsodium nitroprusside can be considered. Ithas been deemed prudent to avoid invasiveprocedures during the first 24 hours afterrtPA administration. This includes the place-ment of nasogastric feeding tubes or urinarycatheters, but we consider it reasonable toplace these devices if necessary after severalhours given that the initial half-life of alteplaseis less than 5 minutes. The optimal timing ofmobilizing patients after rtPA administrationis not clear, but it is often avoided for 24hours. A small pilot study mobilized 10 pa-tients between 12 and 24 hours after adminis-tration of rtAP and found that only 1 patienthad an adverse event (orthostatic hypoten-sion).48 A difficult circumstance arises whena patient requires decompressive hemicraniec-tomy for treatment of malignant edema fromlarge middle cerebral artery infarcts. One





study compared 20 patients undergoingdecompressive hemicraniectomy who hadreceived IV rtPA with 20 patients who hadnot been treated with rtPA and underwentthe procedure.49 Craniectomy was performedan average of 44 hours after stroke onset,and 2 patients in each group experiencednew ICH or worsening of preexisting ICH.The optimal interval to wait before a majorprocedure such as this is performed is uncer-tain, and risks and benefits must be assessedon an individual basis. It may be reasonableto wait at least 24 hours after rtPA administra-tion if possible.

The most feared complication after IVthrombolysis for acute stroke is ICH. Thispotentially devastating development occursmost commonly in older patients with severedeficits and large areas of ischemia at presenta-tion.50,51 Reperfusion injury is broadly consid-ered to be the most common pathophysiologicmechanism causing sICH. Thus, patients whoare at greatest risk of this complication alreadyhave a poor prognosis with high likelihood ofdisability. As a consequence, few patients areactually harmed by IV rtPA (number neededto harm has been estimated to be 126 fordisabled or fatal outcome).51

Other complications of IV rtPA are muchless frequent. Angioedema occurs in about1.3% to 5% of cases, is more common in pa-tients taking angiotensin-converting enzyme in-hibitors, and often involves the orolingualregions ipsilateral to the side of hemiparesis.52

The mainstays of treatment are antihistaminesand corticosteroids. Although evidence-basedrecommendations regarding the dose and dura-tion of these treatments are not available, weconsider it reasonable to administer diphenhy-dramine at 25 to 50 mg IV, ranitidine at 50mg IV, and dexamethasone at 6 to 10 mg IVand monitor the clinical response. Treatmentscan be continued for 24 to 72 hours as dictatedby the severity and resolution or persistence ofsymptoms. Airway safety must be carefullymonitored because the angioedema can occa-sionally involve the posterior laryngeal struc-tures and lead to airway obstruction. Rarely,other life-threatening complications such asmyocardial wall rupture or aortic dissectionhave occurred.

Prompt initiation of measures to preventearly recurrent stroke are important, and


antiplatelet agents and anticoagulants can beadministered (or resumed) 24 hours after theadministration of IV rtPA. It is generally safe tobegin treatment with antiplatelet agents at 24hours, but anticoagulation may need to be with-held longer depending on the risk of hemor-rhage, which depends largely on the ultimatesize of brain infarction. Notably, urgent anticoa-gulation, or “bridging” with full therapeuticdoses of unfractionated heparin or low-molecular-weight heparin, is not recommendedfor patients with acute ischemic stroke whorequire anticoagulation (eg, patients with atrialfibrillation).18 In our experience, most patientswho require anticoagulation can begin treatmentwith vitamin K antagonists within days of thestroke, targeting therapeutic anticoagulationwithin 1 to 2 weeks from the event. However,early anticoagulation should be avoided whenthe infarction is large or in the presence of un-controlled hypertension or bleeding diatheses.Direct thrombin inhibitors and factor Xa antag-onists are alternatives to vitamin K antagonists,but reliable data regarding their efficacy andsafety in very early secondary stroke prevention,particularly after the administration of IV rtPA,are currently unavailable.

OUTCOME PREDICTIONThe fundamental clinical predictors of poor out-comes in patients with acute ischemic stroke areadvanced age, worse neurologic deficits (higherNIHSS score), disturbed consciousness at onset,and hyperglycemia.16,53,54 More recently, renalfunction has also been indentified as a predictorof outcome after acute stroke. Low estimatedglomerular filtration rate is independently asso-ciated with poor outcomes, death, and sICH.55

Radiographic predictors of poor outcomeinclude early ischemic changes and hyperdensemiddle cerebral artery sign on baseline noncon-trast CT.56 As previously discussed, the timefrom symptom onset to administration of IVrtPA is strongly associated with outcomes, withearlier time to treatment predicting better clin-ical outcomes.9 Over the past few years, severalscales have been developed to quantify risk andassist with outcome prediction in patients withstroke (Table 2).57-60 The DRAGON score57

was designed to predict outcome for patientstreated with IV thrombolysis and ranges from0 to 10 points. The higher the score, the higherthe likelihood a patient will have a poor

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TABLE 2. Scales to Predict Functional Outcome After Acute Ischemic Strokea

Scale orscore Variables Derivation cohort Scoring paradigms Favorable outcome AUC

DRAGON57 Hyperdense MCA or CT signs of earlyinfarct, prestroke mRS score, age,glucose level, onset to treatmenttime, NIHSS score

1319 Stroke patientstreated with IV lysis inHelsinki, Finland

2 Points: 88% favorableoutcome

8 Points: 70% “miserableoutcome”b

mRS score 0-2 at 3 mo 0.84

ASTRAL58 Age, severity of stroke (NIHSS score),time from stroke onset toadmission, range of visual fields,glucose level, level of consciousness

1645 Stroke patients fromthe Acute StrokeRegistry in Lausanne,Switzerland

Score �23: 80% favorableoutcome



SPAN-10059 Age, NIHSS score 624 Stroke patients fromNINDS tPA trials

Score <100: 55% favorableoutcome


Composite:mRS score 0-1,NIHSS

score �1, Barthelindex score �95,and GOS score 1 at3 mo

0.64

THRIVE60 Age, NIHSS score, hypertension,diabetes mellitus, atrial fibrillation

5724 Stroke patients fromVISTA

Score 0-2: w70% goodoutcome

Score 6-9: w10% goodoutcome


aAUC ¼ area under the receiver operating characteristic curve; CT ¼ computed tomography; GOS ¼ Glasgow Outcome Scale; IV ¼ intravenous; MCA ¼ middle cerebralartery; mRS ¼ modified Rankin Scale; NIHSS ¼ National Institutes of Health Stroke Scale; NINDS ¼ National Institute of Neurological Disorders and Stroke; tPA ¼ tissueplasminogen activator; VISTA ¼ Virtual International Stroke Trials Archive.bmRS score 5-6.

TABLE 3. Scales to Predict Postthrombolysis ICHa

Scale orscore Variables Derivation cohort Scoring paradigms Findings

SPAN-10059 Age, NIHSS score 624 Stroke patientsfrom NINDS trials(312 received IVrtPA)

Score <100:12% ICHScore �100: 42% ICH

ORb (95% CI)Any ICH: 4.93 (2.64-9.6)sICH: 3.5 (1.45-8.46)Fatal ICH: 5.0 (1.4-17.8)

THRIVE60 Age, NIHSS score,hypertension, diabetesmellitus, atrial fibrillation

5724 Stroke patientsfrom VISTA

Score 0-2:w3% ICHScore 6-9:w10% ICH

Each 1-point increase in score wasassociated with an OR (95% CI) of1.29 (1.16-1.43) for hemorrhage

HAT61 NIHSS score, diabetes mellitusor blood glucose <200 mg/dL, hypodensity on initialhead CT

302 rtPA-treatedpatients fromNINDS trials

ICH rate:Score 0, 6%Score 1, 16%Score 2, 23%Score 3, 36%Score >3, 78%

C statistic (95% CI):Any ICH, 0.70 (0.61-0.79)sICH, 0.68 (0.56-0.81)Fatal ICH, 0.75 (0.63-0.87)

SITS62 NIHSS score, blood glucose,age, body weight, time fromstroke onset to treatment,antiplatelet agents,hypertension

13,908 patients treatedwith rtPA fromSITS-ISTR

sICH rate:Score 0-2, 0.4%Score 3-5, 1.5%Score 6-8, 3.6%Score �9, 9.2%

C statistic:sICH, 0.67

aCT ¼ computed tomography; ICH ¼ intracerebral hemorrhage; IV ¼ intravenous; NIHSS ¼ National Institutes of Health Stroke Scale; NINDS ¼ National Institute ofNeurological Disorders and Stroke; OR ¼ odds ratio; rtPA ¼ recombinant tissue plasminogen activator; sICH ¼ symptomatic ICH; SITS-ISTR ¼ Safe Implementation ofTreatments in Stroke-International Stroke Thrombolysis Register; VISTA ¼ Virtual International Stroke Trials Archive.bFor patients with a positive SPAN-100 (score �100) vs a negative SPAN-100 score.


8 Mayo Clin Proc. n XXX 2014;nn(n):1-13 n http://dx.doi.org/10.1016/j.mayocp.2014.03.001www.mayoclinicproceedings.org



FIGURE 2. Example of postthrombolysis intracranial hemorrhage. Non-contrast computed tomography (CT) of the head shortly after infusion ofrecombinant tissue plasminogen activator shows intraparenchymal hem-orrhage in the left inferior frontal lobe (A) and diffuse subarachnoidhemorrhage over the left cerebral hemisphere (B). Tranexamic acid (1000mg intravenously), cryoprecipitate (2 U), and fresh frozen plasma (2 U)were administered. Repeated CT the following day showed minimal evo-lution of hemorrhage and hypodensity in the left middle cerebral arteryterritory consistent with ischemic infarction (C, D).


outcome. In the initial cohort, the proportions ofpatients with good outcome (modified RankinScale score of 0-2 at 3 months) were 96%,88%, 74%, and 0% for scores of 0 to 1, 2, 3,and 8 to 10, respectively. The ASTRAL score58

incorporates 6 variables: age, NIHSS score,time from stroke onset to admission, visualfields, glucose level, and level of consciousness.This score did not take thrombolysis intoconsideration but was validated in external pop-ulations. The Stroke Prognostication using Ageand NIH Stroke Scale (SPAN)-100 index59 is asimple method to estimate the clinical responseof patients with stroke who are treated withthrombolysis. The index, calculated bycombining age and NIHSS score, is consideredpositive if the total is 100 or higher.59 TheTotaled Health Risks in Vascular Events(THRIVE) score60 incorporates age, NIHSSscore, and medical comorbidities of hyperten-sion, diabetes mellitus, or atrial fibrillation. Itpredicts clinical outcomes, mortality, and riskof ICH.

Many of the same features that predict clin-ical outcomes also predict the occurrence ofsICH: higher NIHSS score at presentation, largerareas of ischemia, and higher blood glucoselevels (Table 3).59-62 Additional factors includelonger time to thrombolysis and higher systolicblood pressure at presentation.15,16,50,63 It isnotable that although elderly patients with acutestroke have favorable outcomes less frequentlythan younger patients (regardless of whetherIV rtPA is given), the rates of sICH after IVthrombolysis are comparable, and the best avail-able evidence indicates that the benefit from IVrtPA is not diminished in elderly patients.19,64,65

The SPAN-10059 and THRIVE60 scores predictnot only functional outcome but also risk ofICH after thrombolysis. Among patientsreceiving rtPA in the NINDS trial, ICH rateswere higher for SPAN-100epositive patientsvs SPAN-100enegative patients (42% vs 12%;P<.001).59 Each 1-point increase in THRIVEscore is associated with a 29% increased chanceof hemorrhage after rtPA (OR, 1.29; 95% CI,1.16-1.43).60 Other scores have been developedspecifically to predict ICH after IV rtPA. Thehemorrhage after thrombolysis (HAT) score isa 5-point scale based on the NIHSS score, hypo-density on CT, baseline glucose level, and his-tory of diabetes. The proportion of patients inwhom ICH develops after rtPA increases with


higher HAT scores (C statistic, 0.70).61 A largercohort of 31,627 patients treated with IV rtPAfrom the SITS Registry formed the basis of thedevelopment of the SITS symptomatic intracere-bral hemorrhage risk score.62 In this database, 9independent risk factors for sICH were identi-fied: NIHSS score, glucose level, systolic bloodpressure, age, body weight, stroke onset to treat-ment time, aspirin or combined aspirin and clo-pidogrel, and history of hypertension. The scoreranges from 0 to 12 points, and there was amorethan 70-fold increase in the rate of sICH forthose with a score of 10 or more pointscompared with patients with no points.Although these prediction scales are useful tostratify those patients at highest risk of

/j.mayocp.2014.03.001 9



Emergenthead CT

No ICH

Suspected ICH(neurologic worsening,

HA, n/v)

Check fibrinogen, PT,pTT, platelet count;

determine blood type andscreen for antibodies

DiscontinuertPA infusion

Consultneurosurgery

Maintain SBP at≤160 mm Hg

If fibrinogen is<150 mg/dL,

give cryoprecipitate(0.15 U/kg) and

recheck in 30 min

Consider platelettransfusion if

platelets <100 × 109/Lor dysfunction

suspected

Considerantifibrinolytic

(eg, tranexamicacid 1000 mg)

ICH

FIGURE 3. Algorithm for evaluation of postthrombolysis intracranial hemorrhage.


10

hemorrhagic complications and poor outcome,they should not be used to make therapeutic de-cisions because patients with high scores whoare eligible for rtPA should still be treated.66

MANAGING HEMORRHAGICCOMPLICATIONSMost sICHs after IV thrombolysis for strokeoccur in the first 24 hours. If a patient experi-ences neurologic deterioration after thromboly-sis, emergency CT should be performed toexclude ICH. If it is still being administered,the infusion of rtPA should be discontinuedand a complete blood cell count, fibrinogenlevels, coagulation parameters, and blood typeand antibody screen should be obtained.Depending on the size and extent of hemorrhage,there may be reason to consider reversing thefibrinolytic effect of rtPA. Generally, small pete-chial hemorrhagesdparticularly when foundincidentallydor microhemorrhages on gradientecho sequences should be monitored but donot require active intervention. Larger paren-chymal hematomas, subarachnoid hemorrhage,and the presence ofmass effect or intraventricular


hemorrhage are factors thatmay prompt reversal.There is no universally accepted standardizedguideline for reversal of thrombolysis-associatedhemorrhages, but many protocols advise admin-istering cryoprecipitate iffibrinogen levels are low(<150mg/dL). Antifibrinolytics, such as tranexa-mic acid or aminocaproic acid, havenotbeenwellstudied, but their use is backed by solid patho-physiologic rationale. Tranexamic acid competi-tively inhibits the activation of plasminogen andmay stabilize hemorrhage expansion.67 Figure 2depicts an example of a patient with postthrom-bolysis ICH who was treated with tranexamicacid, fresh frozen plasma, and cryoprecipitateand had no further hemorrhage expansion ordeterioration. Surgical evacuation of hema-tomas can be considered on the basis of thesize and location of the ICH and the patient’soverall medical condition and capacity forrehabilitation. A suggested algorithm for man-agement of sICH after IV thrombolysis foracute ischemic stroke is shown in Figure 3,but it is empirical rather than data based.Further studies are warranted to determinethe optimal management strategy.





FUTURE DIRECTIONSThe introduction of IV rtPA nearly 2 decades agomarked the end of one era, in which ischemicstroke was generally considered untreatable,and the beginning of another, in which we areonly beginning to recognize the impact that treat-ments can have in improving stroke outcomes. Itis likely that as we continue to gain experience,the inclusion and exclusion criteria for IV rtPAwill be relaxed, and this changedin combinationwith the increasing use of telemedicinedwillallow more patients with ischemic stroke to beconsidered for treatment. Some fibrinolytic alter-natives, such as tenecteplase, show promise68

and may be even more effective than alteplase.The use of advanced brain imaging techniques(CT perfusion, magnetic resonance imagingperfusion, arterial spin-labeled perfusion) mayassist in refining our selection of the optimal can-didates for emergent revascularization therapies.The organization of prehospital care systems inwhich neuroprotectants can be studied andadministered opens up myriad opportunities.The future of acute stroke treatment appearsbright with abundant opportunities to improveour ability to salvage ischemic brain tissue andimprove patient outcomes.

Abbreviations and Acronyms: ABP = arterial bloodpressure; AHA = American Heart Association; CT =computed tomography; ECASS = European CooperativeAcute Stroke Study; ICH = intracranial hemorrhage; IV =intravenous; NIHSS = National Institutes of Health StrokeScale; NINDS = National Institute of Neurological Disordersand Stroke; OR = odds ratio; rtPA = recombinant tissueplasminogen activator; sICH = symptomatic ICH; SPAN-100 = Stroke Prognostication using Age and NIH StrokeScale; THRIVE = Totaled Health Risks in Vascular Events

Correspondence: Address to Jennifer E. Fugate, DO, Divi-sion of Critical Care Neurology, Mayo Clinic, 200 First StSW, Rochester, MN 55905 ([email protected]).

REFERENCES1. Towfighi A, Saver JL. Stroke declines from third to fourth lead-

ing cause of death in the United States: historical perspectiveand challenges ahead. Stroke. 2011;42(8):2351-2355.

2. National Institute of Neurological Disorders and Stroke rt-PAStroke Study Group. Tissue plasminogen activator for acuteischemic stroke. N Engl J Med. 1995;333(24):1581-1587.

3. Broderick JP, Palesch YY, Demchuk AM, et al; InterventionalManagement of Stroke (IMS) III Investigators. Endovasculartherapy after intravenous t-PA versus t-PA alone for stroke[published correction appears in N Engl J Med. 2013;368(13):1265]. N Engl J Med. 2013;368(10):893-903.

4. Ciccone A, Valvassori L, Nichelatti M; SYNTHESIS ExpansionInvestigators. SYNTHESIS expansion: design of a nonprofit,


pragmatic, randomized, controlled trial on the best fast-trackendovascular treatment vs. standard intravenous alteplase foracute ischemic stroke. Int J Stroke. 2011;6(3):259-265.

5. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysiswith recombinant tissue plasminogen activator for acute hemi-spheric stroke: the European Cooperative Acute Stroke Study(ECASS). JAMA. 1995;274(13):1017-1025.

6. Hacke W, Kaste M, Fieschi C, et al; Second European-Australasian Acute Stroke Study Investigators. Randomiseddouble-blind placebo-controlled trial of thrombolytic therapywith intravenous alteplase in acute ischaemic stroke (ECASS II).Lancet. 1998;352(9136):1245-1251.

7. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators.Thrombolysis with alteplase 3 to 4.5 hours after acute ischemicstroke. N Engl J Med. 2008;359(13):1317-1329.

8. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associ-ated with better outcome: the NINDS rt-PA Stroke Study.Neurology. 2000;55(11):1649-1655.

9. Saver JL, Fonarow GC, Smith EE, et al. Time to treatment withintravenous tissue plasminogen activator and outcome fromacute ischemic stroke. JAMA. 2013;309(23):2480-2488.

10. Wahlgren N, Ahmed N, Dávalos A, et al; SITS-MOSTInvestigators. Thrombolysis with alteplase for acute ischaemicstroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study[published correction appears in Lancet. 2007;369(9564):826].Lancet. 2007;369(9558):275-282.

11. Kleindorfer D, de los Rios La Rosa F, Khatri P, Kissela B,Mackey J, Adeoye O. Temporal trends in acute stroke manage-ment. Stroke. 2013;44(6, suppl 1):S129-S131.

12. Nasr DM, Brinjikji W, Cloft HJ, Rabinstein AA. Utilization ofintravenous thrombolysis is increasing in the United States. IntJ Stroke. 2013;8(8):681-688.

13. de Los Ríos la Rosa F, Khoury J, Kissela BM, et al. Eligibility forintravenous recombinant tissue-type plasminogen activatorwithin a population: the effect of the European CooperativeAcute Stroke Study (ECASS) III Trial. Stroke. 2012;43(6):1591-1595.

14. Moradiya Y, Crystal H, Valsamis H, Levine SR. Thrombolytic uti-lization for ischemic stroke in US hospitals with neurology res-idency program. Neurology. 2013;81(23):1986-1995.

15. Hacke W, Donnan G, Fieschi C, et al; ATLANTIS Trials Inves-tigators; ECASS Trials Investigators; NINDS rt-PA Study GroupInvestigators. Association of outcome with early stroke treat-ment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774.

16. Wahlgren N, Ahmed N, Dávalos A, et al; SITS Investigators.Thrombolysis with alteplase 3-4.5 h after acute ischaemicstroke (SITS-ISTR): an observational study. Lancet. 2008;372(9646):1303-1309.

17. Ahmed N, Kellert L, Lees KR, Mikulik R, Tatlisumak T, Toni D;SITS Investigators. Results of intravenous thrombolysis within 4.5 to 6 hours and updated results within 3 to 4.5 hours of onsetof acute ischemic stroke recorded in the Safe Implementationof Treatment in Stroke International Stroke Thrombolysis Reg-ister (SITS-ISTR): an observational study. JAMA Neurol. 2013;70(7):837-844.

18. Jauch EC, Saver JL, Adams HP Jr, et al; American Heart Associ-ation Stroke Council; Council on Cardiovascular Nursing;Council on Peripheral Vascular Disease; Council on ClinicalCardiology. Guidelines for the early management of patientswith acute ischemic stroke: a guideline for healthcare profes-sionals from the American Heart Association/American StrokeAssociation. Stroke. 2013;44(3):870-947.

19. IST-3 Collaborative Group. The benefits and harms of intrave-nous thrombolysis with recombinant tissue plasminogen acti-vator within 6 h of acute ischaemic stroke (the thirdInternational Stroke Trial [IST-3]): a randomised controlled trial[published correction appears in Lancet. 2012;380(9843):730].Lancet. 2012;379(9834):2352-2363.

/j.mayocp.2014.03.001 11

mailto:[email protected]




12

20. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP,Hamilton S. Recombinant tissue-type plasminogen activator(Alteplase) for ischemic stroke 3 to 5 hours after symptomonset: the ATLANTIS study; a randomized controlled trial.JAMA. 1999;282(21):2019-2026.

21. Safety of Intravenous Thrombolysis forWake-up Stroke (Wake-Up Stroke). ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT01183533?term¼wake-up&rank¼2. Updated May7, 2013. Accessed February 22, 2014.

22. Efficacy and Safety of MRI-based Thrombolysis in Wake-upStroke (WAKE-UP). ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT01525290?term¼wakeþupþtrial&rank¼2.Updated May 27, 2013. Accessed February 22, 2014.

23. Saqqur M, Tsivgoulis G, Nicoli F, et al. The role of sonolysis andsonothrombolysis in acute ischemic stroke: a systematic reviewand meta-analysis of randomized controlled trials and case-control studies [published online ahead of print April 22,2013]. J Neuroimaging. http://dx.doi.org/10.1111/jon.12026.

24. Tsivgoulis G, Eggers J, Ribo M, et al. Safety and efficacy ofultrasound-enhanced thrombolysis: a comprehensive reviewand meta-analysis of randomized and nonrandomized studies.Stroke. 2010;41(2):280-287.

25. Phase 3, Randomized, Placebo-Controlled, Double-BlindedTrial of the Combined Lysis of Thrombus With Ultrasoundand Systemic Tissue Plasminogen Activator (tPA) for EmergentRevascularization in Acute Ischemic Stroke (CLOTBUST-ER).ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT01098981?term¼ClotbustþER&rank¼1. Updated July11, 2013. Accessed February 22, 2014.

26. Pancioli AM, Adeoye O, Schmit PA, et al; CLEAR-ER Investiga-tors. Combined approach to lysis utilizing eptifibatide and re-combinant tissue plasminogen activator in acute ischemicstroke-enhanced regimen stroke trial. Stroke. 2013;44(9):2381-2387.

27. Adams HP Jr, Effron MB, Torner J, et al; AbESTT-II Investigators.Emergency administration of abciximab for treatment of pa-tients with acute ischemic stroke: results of an internationalphase III trial; Abciximab in Emergency Treatment of StrokeTrial (AbESTT-II). Stroke. 2008;39(1):87-99.

28. Study of the CombiPatentTherapy of Rt-PA and Eptifibatideto Treat Acute Ischemic Stroke (CLEAR-FDR). ClinicalTrials.gov website. http://clinicaltrials.gov/ct2/show/NCT01977456?term=Study+of+the+Combination+Therapy+of+Rt-PA+and+Eptifibatide+to+Treat+Acute+Ischemic+Stroke+%28CLEAR-FDR%29&rank=1. Updated December 5, 2013. AccessedFebruary 22, 2014.

29. Demaerschalk BM, Miley ML, Kiernan TE, et al; STARR Coin-vestigators. Stroke telemedicine [published correction appearsin Mayo Clin Proc. 2010;85(4):400]. Mayo Clin Proc. 2009;84(1):53-64.

30. Rubin MN, Demaerschalk BM. The use of telemedicine in themanagement of acute stroke. Neurosurg Focus. 2014;36(1):E4.

31. MeyerBC, RamanR,HemmenT, et al. Efficacyof site-independenttelemedicine in the STRokE DOC trial: a randomised, blinded,prospective study. Lancet Neurol. 2008;7(9):787-795.

32. Johnston SC. The economic case for new stroke thrombolytics.Stroke. 2010;41(10, suppl):S59-S62.

33. Demaerschalk BM, Yip TR. Economic benefit of increasing uti-lization of intravenous tissue plasminogen activator for acuteischemic stroke in the United States. Stroke. 2005;36(11):2500-2503.

34. Fagan SC, Morgenstern LB, Petitta A, et al. Cost-effectiveness oftissue plasminogen activator for acute ischemic stroke: NINDSrt-PA Stroke Study Group. Neurology. 1998;50(4):883-890.

35. Meretoja A, Strbian D, Mustanoja S, Tatlisumak T, Lindsberg PJ,Kaste M. Reducing in-hospital delay to 20 minutes in strokethrombolysis. Neurology. 2012;79(4):306-313.

36. Weber JE, Ebinger M, Rozanski M, et al; STEMO-Consortium.Prehospital thrombolysis in acute stroke: results of thePHANTOM-S pilot study. Neurology. 2013;80(2):163-168.


37. Fugate JE, Rabinstein AA. Contraindications to intravenous rtPAfor acute stroke: a critical reappraisal. Neurol Clin Pract. 2013;3(3):177-185.

38. European Stroke Organisation (ESO) Executive Committee;ESO Writing Committee. Guidelines for management ofischaemic stroke and transient ischaemic attack 2008. Cerebro-vasc Dis. 2008;25(5):457-507.

39. Chernyshev OY, Martin-Schild S, Albright KC, et al. Safety oftPA in stroke mimics and neuroimaging-negative cerebralischemia. Neurology. 2010;74(17):1340-1345.

40. Selim M, Kumar S, Fink J, Schlaug G, Caplan LR, Linfante I.Seizure at stroke onset: should it be an absolute contraindica-tion to thrombolysis? Cerebrovasc Dis. 2002;14(1):54-57.

41. Winkler DT, Fluri F, Fuhr P, et al. Thrombolysis in strokemimics: frequency, clinical characteristics, and outcome. Stroke.2009;40(4):1522-1525.

42. Zinkstok SM, Engelter ST, Gensicke H, et al. Safety of throm-bolysis in stroke mimics: results from a multicenter cohortstudy. Stroke. 2013;44(4):1080-1084.

43. Tsivgoulis G, Alexandrov AV, Chang J, et al. Safety and out-comes of intravenous thrombolysis in stroke mimics: a 6-year,single-care center study and a pooled analysis of reported se-ries. Stroke. 2011;42(6):1771-1774.

44. Re-examining Acute Eligibility for Thrombolysis (TREAT) TaskForce, Levine SR, Khatri P, Broderick JP, et al; NINDS rt-PA StrokeTrial Investigators. Review, historical context, and clarifications ofthe NINDS rt-PA stroke trials exclusion criteria, part 1: Rapidlyimproving stroke symptoms. Stroke. 2013;44(9):2500-2505.

45. Smith EE, Fonarow GC, Reeves MJ, et al. Outcomes in mild orrapidly improving stroke not treated with intravenous recombi-nant tissue-type plasminogen activator: findings from Get WithThe Guidelines-Stroke. Stroke. 2011;42(11):3110-3115.

46. Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Whyare stroke patients excluded from TPA therapy? an analysis ofpatient eligibility. Neurology. 2001;56(8):1015-1020.

47. Ahmed N, Wahlgren N, Brainin M, et al; SITS Investigators.Relationship of blood pressure, antihypertensive therapy, andoutcome in ischemic stroke treated with intravenous thrombol-ysis: retrospective analysis from Safe Implementation of Throm-bolysis in Stroke-International Stroke Thrombolysis Register(SITS-ISTR). Stroke. 2009;40(7):2442-2449.

48. Freeman WD, Chavez OS, Meschia J. Letter by Freeman et alregarding article, “Very early mobilization after stroke fast-tracksreturn to walking: further results from the phase II AVERT ran-domized controlled trial.” Stroke. 2011;42(5):e375.

49. Takeuchi S, Wada K, Nawashiro H, et al. Decompressivecraniectomy after intravenous tissue plasminogen activatoradministration for stroke. Clin Neurol Neurosurg. 2012;114(10):1312-1315.

50. Albers GW, Thijs VN, Wechsler L, et al; DEFUSE Investigators.Magnetic resonance imaging profiles predict clinical response toearly reperfusion: the diffusion and perfusion imaging evaluationfor understanding stroke evolution (DEFUSE) study. Ann Neu-rol. 2006;60(5):508-517.

51. Saver JL. Hemorrhage after thrombolytic therapy for stroke: theclinically relevant number needed to harm. Stroke. 2007;38(8):2279-2283.

52. Fugate JE, Kalimullah EA, Wijdicks EF. Angioedema after tPA:what neurointensivists should know. Neurocrit Care. 2012;16(3):440-443.

53. Bruno A, Levine SR, Frankel MR, et al; NINDS rt-PA StrokeStudy Group. Admission glucose level and clinical outcomesin the NINDS rt-PA Stroke Trial. Neurology. 2002;59(5):669-674.

54. Kammersgaard LP, Jørgensen HS, Reith J, Nakayama H,Pedersen PM, Olsen TS. Short- and long-term prognosis forvery old stroke patients: the Copenhagen Stroke Study. AgeAgeing. 2004;33(2):149-154.

55. Gensicke H, Zinkstok SM, Roos YB, et al. IV thrombolysis andrenal function. Neurology. 2013;81(20):1780-1788.


http://clinicaltrials.gov/ct2/show/NCT01183533?term=wake-up%26rank=2




http://clinicaltrials.gov/ct2/show/NCT01525290?term=wake+up+trial%26rank=2






http://dx.doi.org/10.1111/jon.12026

http://ClinicalTrials.gov

http://clinicaltrials.gov/ct2/show/NCT01098981?term=Clotbust+ER%26rank=1







http://clinicaltrials.gov/ct2/show/NCT01977456?term=Study+of+the+Combination+Therapy+of+Rt-PA+and+Eptifibatide+to+Treat+Acute+Ischemic+Stroke+%28CLEAR-FDR%29%26rank=1







56. Moulin T, Cattin F, Crépin-Leblond T, et al. Early CT signs inacute middle cerebral artery infarction: predictive value for sub-sequent infarct locations and outcome. Neurology. 1996;47(2):366-375.

57. Strbian D, Meretoja A, Ahlhelm FJ, et al. Predicting outcome ofIV thrombolysisetreated ischemic stroke patients: theDRAGON score. Neurology. 2012;78(6):427-432.

58. Ntaios G, Faouzi M, Ferrari J, Lang W, Vemmos K, Michel P. Aninteger-based score to predict functional outcome in acuteischemic stroke: the ASTRAL score. Neurology. 2012;78(24):1916-1922.

59. Saposnik G, Guzik AK, Reeves M, Ovbiagele B, Johnston SC.Stroke Prognostication using Age and NIH Stroke Scale:SPAN-100. Neurology. 2013;80(1):21-28.

60. Flint AC, Faigeles BS, Cullen SP, et al; VISTA Collaboration.THRIVE score predicts ischemic stroke outcomes and throm-bolytic hemorrhage risk in VISTA. Stroke. 2013;44(12):3365-3369.

61. Lou M, Safdar A, Mehdiratta M, et al. The HAT score: a simplegrading scale for predicting hemorrhage after thrombolysis.Neurology. 2008;71(18):1417-1423.

62. Mazya M, Egido JA, Ford GA, et al; SITS Investigators. Predictingthe risk of symptomatic intracerebral hemorrhage in ischemic


stroke treated with intravenous alteplase: Safe Implementationof Treatments in Stroke (SITS) symptomatic intracerebral hem-orrhage risk score [published correction appears in Stroke.2012;43(9):e102]. Stroke. 2012;43(6):1524-1531.

63. Kidwell CS, Saver JL, Carneado J, et al. Predictors of hemorrhag-ic transformation in patients receiving intra-arterial thromboly-sis. Stroke. 2002;33(3):717-724.

64. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plas-minogen activator for acute ischaemic stroke: an updated sys-tematic review and meta-analysis. Lancet. 2012;379(9834):2364-2372.

65. Guillan M, Alonso-Canovas A, Garcia-Caldentey J, et al. Off-la-bel intravenous thrombolysis in acute stroke. Eur J Neurol. 2012;19(3):390-394.

66. Rabinstein A, Rundek T. Prediction of outcome after ischemicstroke: the value of clinical scores [editorial]. Neurology. 2013;80(1):15-16.

67. French KF, White J, Hoesch RE. Treatment of intracerebralhemorrhage with tranexamic acid after thrombolysis with tissueplasminogen activator. Neurocrit Care. 2012;17(1):107-111.

68. Parsons M, Spratt N, Bivard A, et al. A randomized trial of ten-ecteplase versus alteplase for acute ischemic stroke. N Engl JMed. 2012;366(12):1099-1107.

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Update on Intravenous Recombinant Tissue Plasminogen Activator for Acute Ischemic Stroke