2010 Trombolisis Isquemia Cerebral

7/30/2019 2010 Trombolisis Isquemia Cerebral

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www.ntisin. October 2010 | Volume 1 | Article 139 | 1

Review ARticlepublished: 29 October 2010

doi: 10.3389/neur.2010.00139

Thrombolysis for cerebral ischemia

Jennifer E. Fugate, Elias A. Giraldo and Alejandro A. Rabinstein*

Department of Neurology, Mayo Clinic, Rochester, MN, USA

The care or patients with acute ischemic stroke has been revolutionized by the clinical applicationo brinolysis. Intravenous recombinant tissue plasminogen activator (rt-PA) has been proven

to improve unctional outcomes ollowing acute ischemic stroke and can be administered

to a select group o patients up to 4.5 h ater symptom onset. Time rom symptom onset to

thrombolysis is the most important determinant o the success o treatment, with greatest

ecacy i given within 90 min. Hospitals should implement standardized processes and protocols

or acute stroke to guide immediate patient assessment, brain imaging, drug administration,

and post-thrombolysis care. In this article we review the clinical application o thrombolysis,

care o acute stroke patients, current evidence regarding brinolysis, and uture direction o

penumbral imaging to select candidates or reperusion therapies.

Kyws: act stk, cbvascla, thmblysis, t-PA

Edited by:

S. Andrew Josephson, University of

California at San Francisco, USA

Reviewed by:

Jose Biller, Loyola University Medical

Center, USA

Kevin N. Sheth, University of Maryland

School of Medicine, USA

*Correspondence:

Alejandro A. Rabinstein, 200 First

Street SW, Rochester, MN 55905,

USA.

e-mail: [email protected]

rhage, which occurred in 6.4% o patients treated with rt-PA versus0.6% o patients who received placebo, but it did not result in an

increase in mortality among rt-PA-treated patients. Ecacy wasgreatest or patients treated within 90 min o symptom onset. Forpatients treated within 90 min the odds ratio or complete recoverywas 2.11 compared with an odds ratio o 1.69 or patients treatedwithin 91180 min (Marler et al., 2000). Functional benet wassustained at 1 year (Kwiatkowski et al., 1999). Subgroup analyses

conrmed that the ecacy o intravenous rt-PA extended to allpatients meeting the trial inclusion and exclusion criteria, includingolder patients with severe strokes at presentation (NINDS rt-PAStroke Study Group , 1995).

Shortly ater publication o the NINDS trial, rt-PA was

approved or intravenous use in patients with acute ischemicstroke in the USA mostly ollowing the patient selection crite-

ria o NINDS study. An additional radiological exclusion crite-rion was added based on the nding that the presence o largeearly ischemic changes on baseline CT scan was associated withhigher risk o symptomatic intracranial hemorrhage and resultsrom earlier European studies that suggested poorer outcomes inpatients with multilobar low attenuation changes(von Kummer

and Hacke, 1992) which had led to the exclusion o these patientsrom subsequent European trials. Since then, treatment withintravenous rt-PA has gained acceptance across the globe andits eectiveness has been conrmed in multiple post-marketingobservational studies.

The largest o these observational studies has been the SITS-MOST (Wahlgren et al., 2007), which enrolled nearly 6,500 patientsrom 14 European countries. Intravenous brinolysis with rt-PAwas at least as sae and eective in routine clinical practice as it hadbeen in the randomized trials (Wahlgren et al., 2007; Wahlgren et al.,2008b). Over three-quarters o treated patients had moderate tosevere strokes at baseline and 55% were independent at 3 months

despite only 10.6% being treated within 90 min (versus hal o thert-PA group in the NINDS trial). Even centers with limited experi-ence on the administration o brinolysis or acute stroke achievedgood results when adhering to the accepted indications and con-

The concept o pharmacological brinolysis or the treatmento acute ischemic stroke developed rom the nding that earlyreperusion improved outcomes in various experimental animalmodels o intracranial vessel occlusion and the recognition thatthe mechanisms or endogenous brinolysis in humans are oteninsucient to prevent brain inarction in many patients (Meschiaet al., 2002). The clinical application o brinolysis revolutionized

ischemic stroke care by oering an eective treatment or a diseasein which previously all medical eorts were ocused on preventiono recurrent events, avoidance o secondary complications, andrehabilitation.

MechanisMs of fibrinolysis

When a clot is ormed, a plasma protein called plasminogen getstrapped within it. The injured tissues and vascular endotheliumthen slowly release tissue plasminogen activator (t-PA) which inturn converts plasminogen to plasmin. Plasmin is a potent pro-

teolytic enzyme that digests brin (the main protein componento the clot) into soluble ragments (brin degradation products).This process ensures the clot dissolution and protects blood fow,particularly in the microcirculation.

fibrinolysis for the treatMent of ischeMic stroke

the evidence

Early intravenous administration o recombinant tissue plasmino-gen activator (rt-PA, Alteplase) has been proven to improve unc-

tional outcome ater acute ischemic stroke (Adams et al., 2007). Thepivotal trial leading to the international approval o intravenousrt-PA or the treatment o cerebral ischemia was the NINDS rt-PAStroke Study (NINDS rt-PA Stroke Study Group , 1995). In thistrial, 624 patients were randomized to receive intravenous rt-PA(0.9 mg/kg, maximum 90 mg) or placebo within 3 h o stroke

symptom onset. Treatment with intravenous rt-PA was associatedwith at least 30% increase in the chances o achieving unctionalindependence with complete or nearly complete neurologicalrecovery at 3 months (NINDS rt-PA Stroke Study Group , 1995).The main risk o treatment was symptomatic intracerebral hemor-


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Fntis in Nly | Neurocritical and Neurohospitalist Care October 2010 | Volume 1 | Article 139 | 2

Fugate et al. Thrombolysis or cerebral ischemia

tion and treatment. Hospitals should monitor their perormance torecognize areas or improvement and to ensure consistent compli-ance with the recommended time metrics (Table 1).

Strict adherence to the prescribed criteria or patient selectionis crucial to avoid complications and optimize the likelihood obenet rom intravenous brinolysis. Table 2 presents the indi-

cations and contraindications or treatment with intravenous

rt-PA. Notice that some additional contraindications should berespected when contemplating the use o rt-PA between 3 and 4.5 h.Treatment in patients without a suspected coagulopathy (e.g., no

traindications. The risk o intracranial hemorrhage, dened usingvarious criteria, was acceptably low. Substantial neurological declinerom brain hemorrhage only occurred in 1.7% o patients.

Although intravenous brinolysis has become standard o care

or emergency treatment o patients with acute ischemic stroke,only a small minority o these patients receive the therapy. Themain reason or the limited application o this eective intervention

in clinical practice is that patients oten arrive to the EmergencyDepartment too late. As a consequence, there has been a lot ointerest in extending the therapeutic window or acute reperusion

therapies, including intravenous rt-PA.A pooled analysis o six major trials evaluating the eectiveness

o intravenous rt-PA or acute ischemic stroke within up to 6 hrom symptom onset suggested that brinolysis could produceclinical benet when administered beyond 3 h (Hacke et al., 2004).In act, this analysis showed that the benet was much greater

over the rst 90 min rom symptom onset, but much more simi-lar when time to treatment was 91180 and 181270 min. Thesendings provided the rationale or the design o the ECASS IIItrial, a multi-center, randomized trial conducted in Europe to

evaluate intravenous rt-PA versus placebo administered between3 and 4.5 h ater onset o ischemic stroke symptoms (Hacke et al.,

2008). A total o 821 patients were enrolled, nearly one-third morethan in the NINDS trial. Treatment with rt-PA was associatedwith a signicant improvement in the rate o avorable unctionaloutcome using various scales. Overall, the chances to regain ullindependence were 28% higher among patients treated with rt-PAand 14 patients had to be treated or one additional patient toachieve a avorable outcome. Mortality was not signicantly di-

erent between the groups, but slightly higher in the placebo arm.The rate o symptomatic intracranial hemorrhage as dened bythe NINDS criteria was 7.9% in the rt-PA group (versus 6.4% inthe NINDS trial), but only 2.4% o them were considered to have

worsened because o the bleeding. A subsequent analysis con-rmed the ecacy o rt-PA in various subgroups treated within

the 34.5 h window, including patients o older age and acrossall severities o stroke (Bluhmki et al., 2009). Intravenous bri-nolysis with rt-PA within 3 and 4.5 h was also shown to be sae inlarge European observational study (SITS-ISTR) which includedover 650 patients treated in that time window (Wahlgren et al.,2008a). Thereore, intravenous rt-PA should be considered or

selected patients with symptom duration between 3 and 4.5 h. Itshould be noted that there are additional exclusion criteria orthe 34.5 h time window, as patients with certain characteristicswere not studied. These include age >80 years, very severe decitsat onset (NIHSS >25), combination o history o previous stroke

and diabetes mellitus, and oral anticoagulation regardless o INRat presentation.

Patient evaluation and selection

Acute stroke patients must be evaluated emergently or consid-eration o reperusion treatments. Hospitals need to implement astroke code process to streamline immediate patient assessment,

brain imaging, and drug administration. Development o criticalcare pathways (ideally starting rom assessment in the eld by para-medics or other rst responders), easily accessible written protocols,and order sets is highly useul to ensure rapid and eective evalua-

Tabl 1 | Tat tims m act stk psntatin t fbinlytic

tatmnt.

Stp ca Tat tim

Evaluation by physician 10 min

Brain imaging 25 min

Interpretation o brain imaging (door-to-interpretation) 45 min

Start o brinolysis (door-to-needle) 60 min

Tabl 2 | Inicatins an cntainicatins intavns t-PA in act

ischmic stk.

Inicatins

Diagnosis o ischemic stroke causing a measurable neurological decit

Onset o symptoms 1/3 o the cerebral hemisphere

Labaty

Oral anticoagulation with INR >1.7*

Heparin within previous 48 h with elevated current aPTT

Platelet count 25)

Combination o previous stroke and diabetes mellitus

*Oral anticoagulation regardless of current INR should be considered a contrain-

dication for treatment between 3 and 4.5 h.


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and sulcal eacement. However, these signs do not have the sameimplication as areas o denite hypodensity because they probablyindicate ocal tissue edema rather than established inarction (Muir

et al., 2006). Interpretation o brain imaging should be perormedby a physician with expertise reading brain scans, but ormal train-ing in neuroradiology is not required.

Adequate control o blood pressure beore, during and ateradministration o intravenous brinolysis must be achieved toreduce the risk o intracranial bleeding. Table 3 summarizes the

recommendations or blood pressure control. Most stroke special-ists deem administration o brinolysis unsae or patients who

require sodium nitroprusside inusion to lower the blood pressurebelow 185/110 mm Hg in the Emergency Department.

adMinistration of fibrinolysis and Post-fibrinolysis care

Inusion o the brinolytic agent should be started in the EmergencyDepartment without delay as soon as the patient is determinedto be a good treatment candidate. The dose o rt-PA is 0.9 mg/

kg (maximum 90 mg) over 60 min with 10% o the total dosegiven as a bolus over 1 min. Ater brinolysis, the patient shouldbe admitted to a Stroke Unit or strict neurological monitoringby specialized nurses. Post-brinolytic management should be

recent or current administration o anticoagulants, no history othrombocytopenia, end-stage liver disease or hematologic disorder)should not be delayed or laboratories with long turnaround times.Thrombolysis can be saely administered in these patients beore

the results o clotting tests are available (Rost et al., 2009). Otherneurologic conditions can mimic ischemic stroke (e.g., migraine,seizure, or conversion disorder), but ear o misdiagnosis should

not prevent initiation o intravenous thrombolysis i the clini-cian has reasonable concern or acute ischemic stroke. The risk ointracranial hemorrhage in those treated with intravenous rt-PA

who present with acute neurologic symptoms that are ound to becaused by other conditions is not well studied, but appears to below. A recent retrospective study ound zero instances o intrac-ranial hemorrhage in patients with stroke mimics (Chernyshevet al., 2010).

The importance o careul determination o time o symptomonset cannot be overemphasized. Current guidelines on rt-PA

administration are based on the denition o symptom onset asthe last time that the patient was symptom-ree or at his/her previ-ous baseline (Adams et al., 2007). For patients who wake up with

symptoms, the time o onset is considered the last time the patientwas awake and without the symptoms. A recent transient ischemicattack similar to the current symptoms is generally not considered

a contraindication or brinolysis; the clock can be reset to the timeo onset o the new symptoms as long as there is clear knowledgethat the previous symptoms resolved ully.

Some actors initially listed among the exclusion criteria orintravenous brinolysis in the seminal trials are no longer consid-ered to be contraindications in practice. For instance, the report

o a seizure at the onset o decits should not preclude brinolysisas long as the treating physician is convinced that the persist-ent decits are secondary to a stroke and not merely a postictalphenomenon (Adams et al., 2007). A similar reasoning might

applied to hypoglycemic patients who ail to improve ater admin-istration o dextrose. One should also be careul when deciding

not to treat a stroke patient with brinolysis because o mild orrapidly improving symptoms. All too oten, these patients sub-sequently suer permanent disability rom those strokes (Barberet al., 2001).

Interpretation o brain imaging in the emergency setting hasthe primary objective o excluding intracranial hemorrhage. Non-

contrast CT scan o the head is sucient or this goal and emer-gency treatment should not be delayed in order to obtain moreadvanced imaging modalities (such as multimodality MRI andmultimodality CT) (Adams et al., 2007). Apart rom hemorrhage,only the presence o multilobar hypodensity (involving more than

1/3 o the cerebral hemisphere) should be considered a radiologi-cal contraindication or brinolysis (Figure 1). Other CT ndingsmay have prognostic value but they do not negate the benet obrinolysis and should not preclude its use (Figure 2). For instance,the presence o a hyperdense middle cerebral artery sign is associ-ated with worse prognosis (Qureshi et al., 2006) and higher risk ohemorrhage ater brinolysis (Derex et al., 2005), but intravenousrt-PA can still be useul or these patients (Qureshi et al., 2006).

Other early signs o brain ischemia can oten be seen when the CTscan is assessed in detail, such as loss o insular ribbon, obscurationo the lenticular nucleus, loss o graywhite matter dierentiation,

FIgure 1 | CT scan th ha witht cntast shwin mltilba

hypnsity in th iht hmisph (aws).

FIgure 2 | (A) Axial non-contrast CT o the head demonstrates a let

hyperdense middle cerebral artery sign indicative o acute thrombus (arrow).

(B) CT scan o the head without contrast showing eacement o sulci and

Sylvian ssure (arrowhead) and loss o distinction o the margins o the let

lenticular nucleus (arrow).


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Hyperglycemia and ever have been independently associated withincreased risk o poor outcome in the setting o acute ischemicstroke. Any ever should be investigated or source as it may bethe rst sign o an inectious complication such as pneumonia.Follow-up brain imaging should be obtained at 24 h ater treat-ment, prior to the initiation o antithrombotics (antiplatelet agents

or anticoagulants).

Additional complications rom rt-PA include angioedema, whichmay cause partial airway obstruction, and, very rarely, myocardialrupture in patients with previous large myocardial inarctions.

Predictors of outcoMe after intravenous fibrinolysis

Older age, worse neurological decits (i.e., higher NIHSS score) anddisturbances o consciousness at presentation, higher admission

blood glucose level, and early ischemic changes and hyperdensemiddle cerebral artery sign on baseline CT scan are the main pre-dictors o poor outcome upon initial evaluation (NINDS rt-PAStroke Study Group , 1995; Bruno et al., 2002; Heuschmann et al.,2004; Qureshi et al., 2006; Wahlgren et al., 2008b; Mateen et al.,2009). Time to brinolysis has a strong inverse association with

unctional outcome across strokes o dierent severity (Marleret al., 2000; Hacke et al., 2004). Hyperglycemia and intracranialhemorrhage predict hyperacute clinical worsening ater brinolysis(Leigh et al., 2004). Lack o improvement at 24 h portends worseoutcome at 3 months (Saposnik et al., 2004). Hyperglycemia, timeto brinolytic therapy, and cortical involvement have been asso-ciated with lack o improvement during the rst day (Saposnik

et al., 2004). The detrimental eects o hyperglycemia may be atleast partially explained by lower rates o recanalization, probablyrelated to a hyperglycemia-induced decrease in brinolytic activity(Ribo et al., 2005).

The main predictors o symptomatic intracranial hemorrhageare older age although intravenous rt-PA can be administered

to selected octogenarians and even non-egenarians with accept-able saety (Sylaja et al., 2006; Mateen et al., 2010), higher initialNIHSS, larger area o ischemia, and higher blood glucose lev-els (Kidwell et al., 2002; Hacke et al., 2004; Albers et al., 2006 ).Longer time to brinolysis has been associated with higher risk ointracranial hemorrhage in some(Kidwell et al., 2002) but not all

studies (Hacke et al., 2004). Higher systolic blood pressure mayalso increase the risk o intracranial hemorrhage (Wahlgren et al.,2008b), but especially when currently recommended parametersor blood pressure controlled are not respected. Other protocolviolations, most notably the use o antithrombotic agents dur-ing the rst 24 h, can markedly increase the risk o hemorrhage

(Katzan et al., 2000).

novel strategies for intravenous fibrinolysis

selection of candidates for intravenous fibrinolysis using

PenuMbral iMaging

There is strong physiological rationale to support the concept thatimaging o the ischemic penumbra with MRI diusion-weighted(DWI) and perusion-weighted (PWI) or CT perusion (CTP) can

extend the therapeutic window or reperusion therapies, includingbrinolysis. Proponents o this model argue that documentation opersistent ischemic penumbra (i.e., hypoperused but salvageabletissue) should represent a solid indication or reperusion treatments

ideally guided by a written protocol to ensure optimal care andavoid risks. Patients should be kept on cardiac telemetry or atleast the rst 24 h.

Neurologic assessments and blood pressure measurements shouldbe perormed every 15 min during the inusion, ollowed by every30 min or the rst 6 h, and then hourly until 24 h ater treatment. Therationale or such close blood pressure monitoring is that excessive

hypertension in patients treated with intravenous rt-PA is associatedwith the development o symptomatic hemorrhagic transormation.

Hypertension in the 24 h post-brinolysis is preerably treated withintravenous labetalol or nicardipine inusion. I systolic blood pres-sure exceeds 230 mm Hg or diastolic blood pressure exceeds 120 mmHg, intravenous continuous inusions o antihypertensives (e.g.,sodium nitroprusside) should be considered. I the patient devel-ops severe headache, vomiting, or acute reractory hypertension

(BP >180/110), an emergency head CT should be obtained.Bleeding complications in general and intracranial hemorrhage

in particular are the most common and eared adverse events aterintravenous brinolysis. Yet, disabling or atal intracranial hemor-rhages ater brinolysis typically occur in older patients with severe

decits and large areas o ischemia at presentation (Albers et al.,2006; Saver, 2007). In other words, severe brain hemorrhages usu-ally complicate brinolytic therapy in patients who already had verypoor prognosis rom presentation. As a consequence, ew patientsare actually harmed by intravenous rt-PA (number needed to harmhas been estimated to be 126 or disabled or atal outcome and36.5 or worsened outcome among patients treated within 3 h o

symptom onset) (Saver, 2007).Strict monitoring o blood glucose (with insulin as needed

to maintain levels between 140 and 180 mg/dL) and avoid-ance o hyperthermia are essential measures o supportive care.

Tabl 3 | Manamnt atial hyptnsin in patints with act

ischmic stk wh a caniats fbinlysis.

B fbinlysis

I SBP >185 mm Hg or DBP >110 mm Hg

Labetalol 1020 mg IV over 12 min (may repeat once)

or

Nicardipine inusion at 515 mg/hI BP controlled, administer brinolysis

I BP still >185/110 mm Hg, do NOT proceed with brinolysis

At fbinlysis

I SBP 180230 mm Hg or DBP 105120 mm Hg

Labetalol 1020 mg IV over 12 min,

may repeat every 1020 min up to 300 mg over 24 h

or

Labetalol 1020 mg IV ollowed by inusion at 28 mg/min

or

Nicardipine inusion at 515 mg/h

I SBP >230 mm Hg or DBP >120 mm Hg

Sodium nitroprusside inusion at 0.53 mcg/kg/min (doses o upto 10 mcg/kg/min can be saely administered or up to 10 min)

This protocol also applies to other forms of reperfusion therapy apart from

intravenous rt-PA.

BP, blood pressure; SBP, systolic blood pressure; DBP, diastol ic blood pressure.


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come (dened as modied Rankin score 2 at 90 days). The rateo symptomatic intracranial hemorrhage was quite low (4%) andthe risk o this complication did not correlate with baseline volumeo restricted diusion. In addition to DWI-PWI mismatch, therehas been some interest in whether a clinical-diusion mismatch(CDM, the comparison o severity o clinical decits measured by

NIHSS and area o restricted diusion on MRI) can select patients

or thrombolytic therapy. This was not supported in a substudy oEPITHET, in which there was no increased benet rom rt-PA inpatients with CDM (Ebinger et al., 2009).

A recent study compared intravenous tenecteplase administeredbetween 3 and 6 h rom symptom onset on patients with docu-

mented penumbra (dened by MRI with DWI-PWI or CTP) andvessel occlusion (dened by non-invasive angiogram) versus controlpatients treated with intravenous rt-PA within 3 h according to cur-rent guidelines (Parsons et al., 2009). Although the relatively smallsize o the study (n= 50, included only 15 treated with tenecteplase)and methodological limitations preclude denite conclusions, the

high degrees o reperusion (74%) and rates o recanalization (10/15cases) among patients selected on the basis o penumbral imaging

was promising. Pilot trials testing intravenous desmoteplase between3 and 9 h rom symptom onset in patients with DWI-PWI mis-match on baseline MRI had shown encouraging results (Hacke et al.,2005; Furlan et al., 2006). However, the larger DIAS-2 study did not

conrm this benet (Hacke et al., 2009). A preponderance o mildstrokes with small core lesions and mismatch volumes may havelimited the power o DIAS-2 to detect some therapeutic eect.

An ongoing trial (MR RESCUE) is assessing the value o endovas-cular reperusion within 38 h o symptom onset among patientswith DWI-PWI mismatch on MRI. At this point, we still do not

have sucient inormation to recommend the use o penumbralimaging to select patients or brinolysis in clinical practice.

intra-arterial fibrinolysis and bridging theraPyThe study and application o endovascular reperusion therapies oracute ischemic stroke has strong advocates. Unortunately, availableevidence is highly promising but not conclusive. Thereore, endovas-cular interventions or acute brain ischemia cannot be considered

standard o care. This is a brie review o the most important inor-mation on intra-arterial brinolysis and combined intravenous andintra-arterial therapy (also known as bridging therapy).

The PROACT II study provides the best evidence that intra-arterial brinolysis can improve patient outcomes (Furlan et al.,1999). This was a rigorously designed, multi-center (54 centers in

USA and Canada), randomized, open-label study with blinded out-come assessment which enrolled 180 patients with angiographically

proven middle cerebral artery occlusion and stroke symptoms orless than 6 h to receive intra-arterial pro-urokinase over 2 h plusintravenous heparin versus intravenous heparin alone (all patientsreceived heparin or 4 h). Mechanical disruption o the clot was

not allowed. Intra-arterial brinolysis resulted in recanalization in66% o cases. Favorable unctional outcome (dened as modiedRankin score o2) at 90 days occurred in 40% o patients treatedwith intra-arterial brinolysis versus 25% o patients in the controlgroup (P= 0.04; number needed to treat = 7). These results werequite remarkable considering that participating patients had severe

decits at presentation (median NIHSS = 17). The rate o symp-

regardless o duration o symptoms. A comparison o CTP sequences

o mean transit time, cerebral blood fow, and cerebral volume mayidentiy whether there is salvageable ischemic penumbra or i theinarct has been completed (Figure 3). Assuming that brain imagingcan reliably recognize penumbral tissue and discriminate patients atexcessive risk or bleeding in the inarct core, the concept should bevalid. However, these assumptions remain to be proven.

DEFUSE was a prospective observational study o 74 patientstreated with intravenous rt-PA between 3 and 6 h ater symp-tom onset (Albers et al., 2006). All patients underwent MRI withDWI-PWI and MR angiogram beore and a ew hours ater bri-nolysis, but all patients were treated regardless o the radiologi-cal ndings. The investigators ound that patients with a target

mismatch prole (i.e., large areas o hypoperusion with much

smaller areas o restricted diusion) beneted greatly rom bri-nolysis i they achieved recanalization. Conversely, patients withvery large areas o restricted diusion had unacceptably high riskso intracerebral bleeding.

The randomized trial EPITHET assigned 101 patients to receive

intravenous rt-PA or placebo 36 h ater stroke onset (Davis et al.,2008). All patients were studied with MRI with DWI-PWI beoreand a ew days ater treatment, but the radiological ndings didnot aect treatment assignment. DWI-PWI was present in 86% opatients. Reperusion occurred in 39% o mismatch patients andthese patients had less inarct growth and better unctional out-

FIgure 3 | CT psin scan th ha mnstats fnins

cnsistnt with la ischmic pnmba.Decreased cerebral blood fow

(A), preserved cerebral blood volume (B), and prolonged time to peak (C) and

mean transit time (d) in the let middle cerebral and bilateral anterior cerebral

artery distributions are shown.


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and Hacke, W. (2006). Dose escalation

o desmoteplase or acute ischemic

stroke (DEDAS): evidence o saety

and ecacy 3 to 9 hours ater stroke

onset. Stroke37, 12271231.

Hacke, W., Albers, G., Al Rawi, Y.,

Bogousslavsky, J., Davalos, A., Eliasziw,

M., Fischer, M., Furlan, A., Kaste, M.,

Lees, K. R., Soehngen, M., and Warach,

S. (2005). The desmoteplase in acute

ischemic stroke trial (DIAS): a phase

II MRI-based 9-hour window acutestroke thrombolysis trial with intrave-

nous desmoteplase. Stroke36, 6673.

Hacke, W., Donnan, G., Fieschi, C., Kaste,

M., von Kummer, R., Broderick, J. P.,

Brott, T., Frankel, M., Grotta, J. C.,

Haley, E. C. Jr., Kwiatkowski, T., Levine,

S. R., Lewandowski, C., Lu, M., Lyden,

P., Marler, J. R., Patel, S., Tilley, B. C.,

Albers, G., Bluhmki, E., Wilhelm, M.,

and Hamilton, S. (2004). Association

o outcome with early stroke treat-

ment: pooled analysis o ATLANTIS,

tom onset. Patients treated in this multi-center, open-label, single armpilot study had better outcomes than the rt-PA-treated patients in theNINDS study despite longer time to start o intravenous brinoly-sis and much worse initial stroke severity. The rate o symptomaticintracranial hemorrhage was nearly 10%, but 3 month mortality wasactually lower than expected (16%). IMS III is randomizing patients

to standard intravenous rt-PA versus combined intravenous/intra-

arterial approach (including mechanical embolectomy).

clinical Pearls

Intravenous brinolysis is an effective treatment for acute

ischemic stroke or up to 4.5 h ater symptom onset. Timefromsymptomonsettobrinolytictherapyisthemost

important determinant o the success o treatment; the chan-ces o avorable recovery diminish with each minute lost.

Strictadherencetotheprescribedprotocolfortheadministra-tion o rt-PA and post-brinolytic care is crucial to minimizethe risk o hemorrhagic complications.

rt-PA remains the only brinolytic agentreliably proven to

improve the outcomes o stroke patients ater intravenousadministration.

Selection of candidates for reperfusion therapies using

penumbra imaging (MRI with DWI-PWI or CTP) is a promi-sing albeit yet unproven strategy to widen the therapeuticwindow or acute treatment o brain ischemia.

Correction of hyperglycemia might improve the results of

brinolysis and should be considered as part o the acute careo stroke patients undergoing reperusion therapies.

tomatic intracranial hemorrhage was 10% among patients treatedwith the brinolytic agent (versus 2% among controls), but there

were no dierences in mortality. Following the conclusion o thestudy, pro-urokinase was not approved or clinical use in stroke andits manuacturer stopped producing it. Over the subsequent years,clinical use o intra-arterial rt-PA has been ound to be sae.

The Japanese MELT study had a similar design to PROACT

II, albeit using urokinase as the brinolytic agent (Ogawa et al.,2007). It was prematurely aborted ater enrollment o 114 patientsbecause o the approval o intravenous rt-PA treatment in Japan.Clinical outcomes were more avorable with intra-arterial brinoly-sis, especially in terms o the number o patients achieving excel-lent unction and minimal or no decits at 90 days. Symptomaticintracranial hemorrhage occurred in 9% o brinolyzed patients(versus 2% o controls).

The combined results o PROACT II and MELT provide strongsupport or the clinical use o intra-arterial brinolysis. Yet, theadvent o mechanical embolectomy aorded by the introduction oclot retrieving and suctioning catheters has changed the eld. Today,endovascular reperusion procedures start with attempts to remove

the clot and brinolysis is usually only attempted as an adjuvant ther-apy when the clot cannot be mechanically retrieved or suctioned.

Bridging therapy consists o administering intravenous brinoly-sis and then proceeding to endovascular treatment i the patient ailsto improve and there is persistent major intracranial vessel occlu-sion. The IMS II trial tested this strategy on 81 stroke patients withsevere decits at presentation (median NIHSS o 19) (The IMS II

Trial Investigators , 2007). Intravenous rt-PA (0.6 mg/kg) was startedwithin 3 h and intra-arterial rt-PA (up to 22 mg) within 5 h o symp-


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