Intraarterial Thrombolysis Trials in Acute Ischemic Stroke

7/28/2019 Intraarterial Thrombolysis Trials in Acute Ischemic Stroke

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Intraarterial Thrombolysis Trials in AcuteIschemic StrokePerry P. Ng, MD, Randall T. Higashida, MD, Sean P. Cullen, MD, Reza Malek, MD, Christopher F. Dowd, MD,

and Van V. Halbach, MD

Stroke is a common cause of death and disability in industrialized nations. Technical advances and the increasedavailability of noninvasive brain imaging techniques have permitted precise and early diagnosis of acute cerebralischemia. This has made emergent thrombolytic therapy for rapid restoration of cerebral perfusion increasinglypossible. Herein, the authors present a review of the clinical trials investigating acute stroke treatment with intraar-terial thrombolysis.

J Vasc Interv Radiol 2004; 15:S77S85

Abbreviations: ATLANTIS Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke, ECASS European Cooperative Acute StrokeStudy, IA intraarterial, ICH intracranial hemorrhage, IV intravenous, MCA middle cerebral artery, NIHSS National Institutes of Health Stroke Scale,NINDS National Institute for Neurologic Disorders and Stroke, PROACT Prolyse in Acute Cerebral Thromboembolism, r-proUK recombinant pro-urokinase, r-tPA recombinant tissue-type plasminogen activator, TIMI thrombolysis in myocardial infarction

STROKE is the third most commoncause of death in the United Statesafter heart disease and cancer and isthe single most common reason forpermanent disability (13). More than700,000 new strokes occur each year inthe United States alone, accounting for

more than $45 billion in medical ex-penses, rehabilitation costs, and loss ofemployment (4,5).

Cerebral infarction may ensue withinminutes of a critical reduction in cere-

bral blood flow. Conservative manage-ment of nonhemorrhagic stroke resultsin severe neurologic deficit or death in alarge proportion of patients, with mor-tality rates after 30 days and 5 yearsapproximating 17% and 40%, respec-tively (1). Up to 78% of patients withacute stroke due to middle cerebral ar-

tery (MCA) occlusion die or become se-verely disabled (6).

In the International Stroke Trial (7),the rates of death or dependency at 6months after therapy for patients whounderwent traditional treatment withanticoagulation or aspirin were not

any different than those for controlsubjects in whom aspirin and heparinwere withheld. Intravenous (IV)thrombolysis trials have demonstratedthat thrombolytic drugs enable recan-alization of occluded segments morerapidly than heparin alone, with someimprovement in clinical outcome (811). Local intraarterial (IA) thrombol-ysis for acute stroke has shown en-couraging results, with even higherrecanalization rates and superior clin-ical outcome (12). Although thesestudies have helped determine appro-priate inclusion criteria, to our knowl-edge the dose and time window fortreatment and the optimal parametershave yet to be elucidated.

IMAGING OF ACUTE STROKE

Computed Tomography (CT)

CT is readily available and permitsrapid diagnosis of intracranial hemor-rhage and alternative abnormalities inpatients who are clinically suspected

of having acute ischemic stroke (13).The European Cooperative AcuteStroke Study (ECASS) trials demon-strated a predictably higher rate ofhemorrhagic conversion in patientstreated with IV thrombolysis who hadsigns of acute ischemia on their base-

line CT scans involving more thanone-third of the MCA territory (8).

CT perfusion can help determinecerebral blood flow, cerebral bloodvolume, and time to peak enhance-ment, which allows depiction of tissueat risk of irreversible brain injury. Thisischemic penumbra represents poten-tially salvageable tissue, and its pres-ervation is the goal of acute stroketherapy.

Magnetic Resonance (MR) Imaging

Acutely ischemic regions can beidentified on MR diffusion imagesmuch earlier than parenchymal changescan be seen on conventional CT or MRimages. Alterations in diffusion can beevident within minutes of arterial oc-clusion indicative of infarction (14).

MR perfusion imaging, like CT per-fusion, can help define regions of ce-rebral hypoperfusion. The mismatch

between the perfusion and diffusionimages represents the ischemic pen-umbra (15,16).

From the Division of Interventional Neuroradiol-ogy, Room L352, University of California at SanFrancisco Medical Center, 505 Parnassus Avenue,San Francisco, California 94143-0628. Received andrevision requested January 14, 2003; revision re-ceived and accepted April 7. Address correspon-dence to R.T.H.; E-mail: [email protected]

None of the authors have identified a potential con-flict of interest.

SIR, 2004

DOI: 10.1097/01.RVI.0000107490.61085.10

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Catheter Angiography

Diagnostic cerebral angiography inpatients with acute stroke can betterdefine the degree of occlusion by theoffending thrombus, thrombus mor-phology, and presence or absence ofcollateral pathways. The degree ofvessel occlusion has been classified byusing a scale adopted from the cardi-ology literature known as the throm-

bolysis in myocardial infarction (TIMI)score. TIMI 0 is complete occlusion,TIMI 1 is contrast material passagethrough the clot with minimal perfu-sion, TIMI 2 is partial flow and/orrecanalization, and TIMI 3 is completeflow and/or recanalization (17). Someauthors have recently referred to a

TICI score in stroke studies, specify-ing cerebral rather than myocar-dial perfusion with correspondinggrade definitions.

Although angiography carries a fi-nite risk of complications due to theprocedure itself, the relative risk isconsidered to be low in the setting ofacute stroke (18 20).

THROMBOLYTIC AGENTS

Thrombolytic agents differ in sta-bility, half-life, and fibrin selectivity.

The best thrombolytic drug for use inacute stroke has yet to be determined.Most recent investigations have con-centrated on recombinant prouroki-nase (r-proUK) and recombinant tis-sue-type plasminogen activator (r-tPA). The thrombolytic effect ofurokinase is augmented with heparin(18,19).

IV THROMBOLYSIS TRIALS

The National Institute for Neuro-logical Disorders and Stroke (NINDS)

study used evidence of intracranialhemorrhage (ICH) as the only CT ex-clusion criteria (11). Patients who pre-sented within 3 hours of ictus receivedIV administration of either 0.9 mg oftPA per kilogram of body weight(maximum, 90 mg) or placebo over 60minutes. Compared with the placebogroup, patients given tPA were 30%more likely to have minimal or no dis-ability at 3 months. Although symp-tomatic ICH occurred within 36 hoursin 6.4% of patients who received tPAand 0.6% of those who received pla-

cebo, there was no statistically signifi-

cant difference in 3-month mortalitybetween the two groups.

Subsequent trials, including ECASSI and II (8,9) and Alteplase Thrombol-ysis for Acute Noninterventional Ther-

apy in Ischemic Stroke (ATLANTIS)(10), investigated the extension of thetherapeutic window to 6 hours aftersymptom onset. The use of intrave-nous thrombolysis did not confer anysignificant benefit in terms of clinicaloutcome at 90 days, as determinedwith assessment scales including themodified Rankin scale (21). The risk ofsymptomatic ICH was substantiallyhigher than that in the NINDS study.Consequently, the time window fortreatment of acute stroke with IVthrombolysis is now considered to be

3 hours.

IA THROMBOLYSIS TRIALS

Technical advances in the design ofsofter, more compliant microcathetersand steerable guide wires have madeintracranial endovascular access in-creasingly feasible and safe. Small caseseries exploring the use of locally in-fused thrombolytics for acute stroketherapy have appeared in the litera-ture since the late 1980s.

The theoretical advantages of IA

thrombolysis include direct infusionof the medication into the occludingthrombus with higher local drug con-centrations, lower systemic concentra-tion of thrombolytic agent with lessrisk of extracranial hemorrhagic com-plications, precise depiction of the ar-terial anatomy including morphologyof thrombus, assessment of treatmenteffect and extent of collateral circula-tion, and the possible use of mechani-cal means to disrupt the clot with useof the guide wire, microcatheter, orother devices.

The disadvantages of this approachinclude additional time delays re-quired for angiography and micro-catheter placement before therapy iscommenced (22) and additional risksof the endovascular procedure itself.These include intracranial arterial em-

bolization, subarachnoid hemorrhage,arterial perforation, hemorrhagic in-farction, retroperitoneal hematoma,and groin hematoma (23). Such com-plications occur in less than 5% of pa-tients treated (23).

The results of early trials of IA

thrombolysis in the carotid territory

were encouraging. In these trials, in-vestigators used urokinase in doses ofup to 2 million U or tPA in doses of upto 80 mg (22,2437); in most cases,patients were treated within 6 hours

of stroke onset. Of the 174 patientstreated, complete clot lysis wasachieved in 39% and partial lysis wasachieved in 36%. Symptomatic ICHwas apparent in approximately 4% ofpatients. The inclusion and exclusioncriteria used for these studies, how-ever, are looser than those used in sub-sequent larger studies (eg, Prolyse inAcute Cerebral Thromboembolism[PROACT] trials), which makes directcomparison difficult. Their small pa-tient populations also prevented defi-nite conclusions with regard to safety

and efficacy of treatment to be drawn.

PROACT I

The PROACT I study (38), whichwas conducted in 1994 to 1995, wasthe first randomized, double-blinded,multicenter trial in which the safety,recanalization frequency, and clinicalefficacy of direct IA infusion ofr-proUK was compared with that ofplacebo in patients with symptomaticMCA occlusion of less than 6 hoursduration.

Clinical inclusion criteria requiredpatients to have (a) new focal neuro-logic signs consistent with MCA terri-tory occlusion within 6 hours of strokeonset, (b) a National Institutes ofHealth Stroke Scale (NIHSS) score orgreater than 4, and (c) an age of 18 to85 years. Clinical exclusion criteria in-cluded an NIHSS score or more than30, coma, minor stroke symptoms, his-tory of stroke within 6 weeks, seizuresat stroke onset, suspected lacunarstroke, clinical suggestion of subarach-noid hemorrhage, history of ICH or

intracranial tumor, uncontrolled hy-pertension, presumed septic embolusor endocarditis, surgery or traumawithin 30 days, head trauma within 90days, active or recent hemorrhagewithin 14 days, bleeding diathesis,and oral anticoagulation with an inter-national normalized ratio or morethan 1.5.

CT exclusion criteria included ICH,substantial mass effect with midlineshift, and intracranial tumor (exceptsmall meningioma).

Patients who met the clinical and

CT inclusion criteria underwent diag-

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nostic cerebral angiography of thesymptomatic carotid territory. Angio-graphic inclusion criteria were com-plete occlusion (TIMI grade 0) or con-trast material penetration withminimal perfusion (TIMI grade 1) ofeither the M1 or M2 segments of theMCA.

Eligible patients were randomized

to receive 6 mg of r-proUK or salineplacebo at 30 mL/hour via a micro-catheter embedded in the proximalthird of the thrombus or in close prox-imity to the clot within the M1 seg-ment if the former was not achievable(Fig 1). The infusion was given over 2hours, and a diagnostic angiogram

was obtained after 1 hour to help de-

termine the effect of treatment. Ran-domization was organized so that pa-tients were assigned in a ratio of 2:1into the r-proUK group versus placebogroup to limit the exposure of patientsto placebo while permitting assess-ment of risk due to the delivery sys-tem. Mechanical disruption of the

thrombus by using the guide wire

Figure 1. Angiograms obtained in a 78-year-old woman whopresented with sudden onset of right hemiparesis and dys-phasia. (a) Frontal projection of a left internal carotid arteryinjection shows complete occlusion of the superior division ofthe MCA (arrow). (b) The microcatheter tip (black arrow) was

positioned immediately proximal to the thrombus (white ar-row), and 9 mg of r-proUK was infused over 2 hours. (c) An-giogram of the common carotid artery obtained after treat-ment reveals almost complete recanalization. The patientmade a good clinical recovery.

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or microcatheter was specificallyprohibited.

All patients were given IV heparinfor 4 hours after angiographic verifica-tion of an occluding thrombus. The

first 16 patients were treated with ahigh-dose heparin regimen consistingof a bolus of 100 IU per kilogram bodyweight followed by infusion of 1,000IU/hour. Because 73% of patients whowere treated with the high-dose hepa-rin regimen experienced ICH within24 hours, subsequent patients weretreated with a low-dose regimen ofheparin consisting of a bolus of 2,000IU (regardless of body weight) fol-lowed by an infusion of 500 IU/hourfor 4 hours.

The degree of vessel recanalization

at 120 minutes was determined an-giographically by neuroradiologistsblinded to treatment assignment andclinical status. Results were reportedaccording to the TIMI scale. CT wasperformed in all patients after 24hours to assess for ICH.

Clinical outcome was measured byphysicians blinded to treatment allo-cation with use of the NIHSS, modi-fied Rankin scale, and Barthel index(21,39) 7, 30, and 90 days aftertreatment.

Of 1,314 patients screened for eligi-

bility, 105 met the clinical and CT in-clusion criteria and underwent an-giography. Of these patients, 46 hadcomplete occlusions of the M1 or M2segments and were randomized intotreatment groups. Six patients ulti-mately did not receive study medica-tions for various reasons; thus, 40 pa-tients completed treatment andfollow-up. Twenty-six patients re-ceived r-proUK and 14 receivedplacebo.

Partial or complete recanalizationwas evident 120 minutes after treat-

ment onset in 15 of 26 patients (58%)treated with r-proUK and two of 14patients (14%) who received placebo(P .0085). Five patients (19%) whoreceived r-proUK had complete recan-alization; none of the patients who re-ceived placebo demonstrated a com-plete response.

Hemorrhagic transformation within24 hours of treatment occurred in 42% ofthe r-proUK group and 7% of the pla-cebo group. These hemorrhages weresymptomatic in 15% and 7% of patientsin the r-proUK and placebo groups, re-

spectively. There was no statistically sig-

nificant difference in the frequency ofICH between the two groups when fol-lowed up for 90 days (50% and 36%,respectively). All five patients who re-ceived r-proUK and had evidence of

ischemia involving more than one-thirdof the MCA territory at baseline CT de-veloped ICH within 24 hours.

A substantial reduction in the fre-quency of patients with ICH after r-proUK administration was achieved

by lowering the dose of heparin given.There was, however, a correspondingdecrease in the recanalization ratefrom 82% to 40%with reducedanticoagulation.

There was a 10%12% absolute in-crease in positive neurologic outcomein the r-proUK group compared with

the placebo group at 90 days.Sixteen adverse events occurred in14 patients who underwent angiogra-phy, including catheter-induced vaso-spasm of the cavernous carotid artery,seizure, groin hematoma, worseningof chronic renal insufficiency, and as-piration pneumonia.

PROACT II

The PROACT II study was a ran-domized, multicenter, open-label clin-ical trial with blinded follow-up in-

volving 54 North American andCanadian centers (12). One-hundredeighty patients with acute ischemicstroke of less than 6 hours durationdue to angiographically proved occlu-sion of the MCA were randomized toreceive 9 mg IA r-proUK and low-doseheparin as used in PROACT I or low-dose heparin alone (control group). In-fusion of saline as a placebo was notundertaken in this study due to ethicalconcerns raised in PROACT I. Inclu-sion and exclusion criteria were simi-lar to those used in PROACT I, with

the addition of the ECASS CT exclu-sion criteria (hypoattenuation or sulcaleffacement in more than one-third ofthe MCA territory).

Of the 12,323 patients with acutestroke who underwent screening, 474underwent angiography and 180 weresubsequently randomized into r-proUKand control groups in a ratio of 2:1.Diagnostic angiography was per-formed 120 minutes after infusion,and CT scans were obtained at base-line, 24 hours, and 7 to 10 days. Clin-ical efficacy was assessed at 7 to 10

days, 30 days, and 90 days after treat-

ment by using the modified Rankinscore, NIHSS, and Barthel index(21,39).

Of the 180 patients, 121 receivedr-proUK and 59 were given only low-

dose heparin. The median baselineNIHSS score was 17. The median timeto initiation of thrombolytic therapywas 5.3 hours. The recanalization ratewas 66% for the r-proUK patients and18% for the control patients (P .001),with complete recanalization achievedin 19% and 2%, respectively (P .003).The higher r-proUK dose of 9 mg ver-sus 6 mg in the PROACT I studyhelped improve recanalization effi-ciency by 26%, but the symptomaticICH rate increased by 4%.

Good clinical outcomes (modified

Rankin score 2) at 90 days were seenin 40% of r-proUK patients and 25% ofcontrol patients (P .043), which rep-resents an absolute benefit of 15% anda relative benefit of 58%.

Hemorrhagic transformation oc-curred within 24 hours in 35% of r-proUK patients and 13% of control pa-tients, with neurologic deterioration

being evident in 10% and 2% of pa-tients, respectively. The incidence ofICH at 10 days was similar, occurringin 68% of r-proUK patients and 57% ofcontrol patients. Patients with a blood

glucose level higher than 200 mg/dL(11 mmol/L) at stroke onset had ahigher frequency of symptomatic ICHafter thrombolysis (40).

COMBINED IV AND IATHROMBOLYSIS TRIALS

The time delay required for cere-bral angiography and microcatheterpositioning before the commencementof IA thrombolysis has been consid-ered a disadvantage of this techniquecompared with IV thrombolysis. This

has prompted investigators to com-bine the two therapies so that IV ther-apy can be initiated as soon as thedecision to proceed with thrombolysisis made and adjunctive IA therapy can

be instigated within the 6-hour timewindow.

In the Emergency Management ofStroke Bridging Trial (41), 35 patientswith acute stroke of less than 3 hoursduration were randomized and giveneither a loading dose of 0.6 mg/kg IVtPA or placebo followed by cerebralangiography and IA thrombolysis

with an additional 20 mg tPA if the



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vessel remained occluded. After IVtPA administration, a residual throm-

bus was identified at angiography in70% of patients. Complete MCA re-canalization was more frequent in pa-

tients who received IV and IA throm-bolysis than in patients who receivedIA tPA alone (55% vs. 10%, respec-tively). The frequency of life-threaten-ing hemorrhagic complications in theIV and IA tPA group was 11.8%,which is similar to that observed withIA tPA alone. The authors concludedthat clinical outcomes were not im-proved despite a higher recanalizationrate with combined IV and IA therapy.

In the Interventional Managementof Stroke trial (42), 62 patients with a

baseline NIHSS score of at least 10

were given 0.6 mg of IV tPA per kilo-gram body weight; 44 of these patientswere also treated with 0.6 mg of IAtPA per kilogram body weight. Goodclinical outcomes were achieved in56% of patients, and symptomatic

brain hemorrhages occurred in 14% ofpatients.

In a series by Keris et al (43), 45patients with acute onset of a hemi-spheric stroke without CT features ofmajor cerebral infarction were ran-domized to receive combined IV andIA thrombolysis or IV heparin alone.All patients received IV heparin at aninitial dose of 5,000 U followed by5,000 U twice daily for several daysunless ICH occurred, after which hep-arin administration was ceased.

Twelve patients were treated with25 mg IA rtPA via a microcatheter em-

bedded in the clot, without attempts atmechanical clot disruption. This studydiffered with the Emergency Manage-ment of Stroke and InterventionalManagement of Stroke trials in that IVtPA (25 mg) was given afterwards in

the intensive care unit as an infusionover 60 minutes. Intracranial hemor-rhage occurred in 17% of patientstreated with combined IA and IVthrombolysis and 6% of patients in thecontrol group, but there was no in-crease in mortality or symptomaticICH between the two groups. Goodclinical outcomes (modified Rankinscore, 0 3) were seen at 1 month ineight of 12 patients (67%) who under-went combined IA and IV thromboly-sis and seven of 33 patients (21%) inthe control group. At 12 months, good

outcomes were apparent in 83% and

33% of patients in each group,respectively.

Abciximab is a monoclonal anti-body that inhibits platelet aggregationby binding to the platelet fibrinogen

receptor glycoprotein IIb/IIIa. In astudy by Lee et al (44), 16 patientsreceived IA urokinase alone and 20patients received IV abciximab (0.25mg per kilogram of body weight as a

bolus) as soon as thrombolytic therapywas planned; this was followed by amaintenance infusion of 0.125 g/kg/minute. Heparin was not adminis-tered. IA urokinase was continued un-til there was acceptable restoration ofvessel patency (TIMI 2 or 3), when1,000,000 U of urokinase had been ad-ministered, or if there was evidence of

ICH. CT was performed immediatelybefore and after thrombolytic therapy.Nine of 10 patients (90%) in the

combined urokinase and abciximabgroup demonstrated arterial recanali-zation compared with seven of 16 pa-tients (44%) who received urokinasealone. A lower dose of urokinase wasrequired for recanalization when usedin conjunction with abciximab (meandose of 828,000 vs. 418,000 U). Therewas no statistically significant differ-ence in the incidence of symptomaticICH. The patients treated with uroki-

nase and abciximab displayed a trendtoward better functional outcome(80% vs. 50%).

VERTEBROBASILARTHROMBOLYSIS

Vertebrobasilar occlusion usuallyportends a grim prognosis, with over-all mortality rates of 70% 80% (23).Despite a lack of large, randomizedstudies, a number of case series have

been published since 1986 involvingsome 300 patients treated with local IA

infusion of urokinase or tPA (22,45 49).

Successful recanalization, eitherpartial or complete, was achieved inapproximately 70% of patients after amedian infusion time of 120 minutes(22,23), with survival rates of55%70%. Survival rates in cases ofuntreated or persistent vertebrobasilarocclusion have been reported to be0%10% (46,48). All survivors in theuntreated group were at least moder-ately disabled, whereas two-thirds ofthose treated aggressively had good

clinical outcomes.

Distal occlusions that likely repre-sented emboli were easier to lyse thanwere more proximal thromboses,which were often superimposed onunderlying atherosclerotic plaques.

These latter lesions often necessitatedadjuvant treatment with angioplasty,stent placement, and antiplatelet med-ication after recanalization. Paradoxi-cally, these lesions, although more dif-ficult to treat, can stimulate thedevelopment of extensive collateralvessels that can prolong the time win-dow for thrombolytic therapy.

Although the appropriate timeframe for successful therapy has yet to

be determined, given the almost uni-formly poor prognosis of vertebrobasi-lar occlusion many operators have ex-

tended the treatment window beyondthe 6 hours accepted for MCA occlu-sion. Many series have included pa-tients up to 24 hours (46,50), 48 hours(48,51), and even 72 hours (46,52) aftersymptom onset.

A relationship between time totreatment and clinical outcome has

been suggested in some series (53) butnot in others (47,48). The presence ofcoma or tetraparesis for several hoursportends a poor prognosis despite suc-cessful recanalization. Some authorshave acknowledged that patients with

signs of brain stem infarction at CT arepoor candidates for thrombolysis(46,48), whereas others have found nocorrelation with neurologic outcome(47,52).

CURRENT STATUS OF IASTROKE THROMBOLYSIS

The results of clinical trials ofthrombolysis for acute stroke havechanged our algorithm for the man-agement of acute ischemic stroke fromsystemic anticoagulation and/or aspi-

rin alone to include the judicious useof more aggressive thrombolytictherapy.

IV thrombolysis appears to be bet-ter suited to recanalization of smallerdistal emboli as opposed to large in-tracranial vessel occlusions that can besuccessfully lysed with local IA infu-sion (54). Rates of recanalization in theproximal MCA are higher with IAthrombolysis than with IV thromboly-sis, with recanalization rates of 70%and 31%, respectively (55). The supe-rior recanalization efficacy of IA

thrombolysis may in part explain the



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Figure 2. Images in a 55-year-old woman who presented with cranial nerve palsies and rapidly became comatose. (a) Towne projectionof a left vertebral artery injection shows occlusion of the distal basilar artery. Note additional thrombus in the distal vertebral artery(black arrow) and posterior inferior cerebellar artery (white arrows). (b) A microcatheter was embedded into the distal, occlusivethrombus (arrow), and 900,000 U of urokinase was infused over 2 hours. (c) Left vertebral artery angiogram obtained after treatmentshows recanalization of the distal basilar artery and filling of the posterior cerebral arteries bilaterally. (d) CT scan and (e) coronalfluid-attenuated inversion-recovery MR image obtained the following day reveal extensive infarction in the left cerebellar hemisphereand thalami (arrows in d) as well as diffuse subarachnoid hemorrhage. The patient was discharged with hemiplegia and dysmetria, and

prolonged rehabilitation was required.



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longer therapeutic window for IAtreatment.

IA thrombolysis requires a lowertotal dose of thrombolytic agent andmay be safer in patients with a high

bleeding risk (eg, those in the periop-erative period after open heart sur-gery) (56).

The PROACT II study has providedgood evidence that, in carefully se-lected patients, IA thrombolysis ofacute M1 and/or M2 occlusions with 9mg r-proUK over 2 hours can signifi-cantly improve outcome if performedwithin 6 hours of symptom onset.Seven patients must be treated to pre-vent one patient from death ordependence.

The higher rate of symptomatic

ICH in the PROACT II study (10.2%)compared with IV tPA studiesin-cluding ECASS II (8.8%), NINDS(6.4%), and ATLANTIS (7.2%) can

be explained by the higher baselinestroke severity in the PROACT IIstudy (median NIHSS of 17 comparedwith 11 in ECASS II and ATLANTISand 14 in NINDS). There was also alonger median time to treatment andhigher recanalization rate achieved inthe PROACT II study.

A universal theme in essentially allIA thrombolysis studies is that, de-

spite the higher incidence of early(36 h) hemorrhagic transformationin patients treated with thrombolytics,the overall rates of ICH (especiallythose associated with neurologic dete-rioration) any time in the study periodare not significantly different fromthose in patients treated less aggres-sively. This likely reflects delayedspontaneous recanalization and perfu-sion into irreversibly damaged brainat a later time in patients treated moreconservatively. Therefore, the in-creased risk of early hemorrhagic con-

version appears acceptable, as theoverall prognosis is not worse com-pared with the natural history ofstroke.

Poor clinical outcomes may be pre-dicted in intracranial vascular occlu-sions with poor collateral circulation.For example, a carotid T saddle em-

bolus that occludes antegrade flow inthe ipsilateral A1 and M1 segmentsminimizes the likelihood of effectiveleptomeningeal collateral circulation,which would serve to maintain or pro-long tissue viability and deliver the

thrombolytic agent beyond the oc-

cluded segment (57). Some authorspropose excluding such patients fromthrombolytic therapy after diagnosisof such occlusions with ultrasound,CT, or MR imaging (43). Conversely,

for vertebrobasilar occlusions, a para-doxical outcome has been observed inthat patients with staggering, pro-longed clinical courses may actuallydo better clinically than patients withabrupt onset of coma, presumably dueto the presence of better collateral cir-culation in patients with pre-existing

basilar stenoses.Recanalization success with an-

giography does not always correlatewith the observed clinical benefit afterthrombolysis (Fig 2). An artery may bereopened yet not function efficiently

(22,58), whereas good clinical out-comes may be achieved despite persis-tent occlusion in the presence ofthrombolysed collateral vessels thatperfuse the affected cerebral territory(59,60). Some studies, however, haveshown a statistically significant corre-lation between recanalization successand clinical outcome (57). A worseoutcome has been correlated with ad-vanced age.

The use of IA thrombolysis foracute stroke is currently limited by theavailability of centers with an inter-

ventional neuroradiology service thatoperates 24 hours a day, 7 days aweek. It has been estimated that 1% ofall patients with ischemic stroke and2% of patients presenting to hospitalswithin 3 hours of stroke are treatedwith thrombolytic drugs (23). Educa-tion of the public, general practitio-ners, and emergency room physiciansthat newer therapies are currently avail-able will help expedite suitable candi-dates to centers with neurointerven-tional services and stroke expertise.

The additional cost and risk related

to the procedure can be justified evenif only one in seven patients benefit, assuggested by the PROACT II studyresults. A financial savings of almost$8 million per 1,000 patients treatedwith IV thrombolysis in terms of hos-pital, rehabilitation, and social welfarecosts has been demonstrated (23). Sim-ilar savings can be expected with IAthrombolysis.

Further evidence about the efficacyand safety of IA thrombolysis foracute stroke is being collected throughthe International Stroke Outcomes

Registry. Future developments in me-

chanical clot retrieval devices and neu-roprotective drugs may also reducethe need for and dose of thrombolyticdrugs and extend the time window fortreatment, respectively.

CONCLUSION

Clinical trials have demonstrated abenefit of IA thrombolysis in selectedpatients with acute stroke in both theanterior and posterior cerebral circula-tions. The overall risk of symptomatichemorrhagic transformation associ-ated with thrombolytic therapy is notincreased despite a higher frequencyof early ICH and should not dissuadephysicians from using such therapy inappropriate candidates. Education of

the community and physicians alongwith further research about thrombol-ysis protocols and the development ofnewer techniques and medicationswill help ensure that prognosis afterstroke continues to improve.

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