Context Intravenous tissue-type plasminogen activator can be beneficial to some
patients when given within 3 hours of stroke onset, but many patients present
later after stroke onset and alternative treatments are needed.
Objective To determine the clinical efficacy and safety of intra-arterial (IA)
recombinant prourokinase (r-proUK) in patients with acute stroke of less than
6 hours' duration caused by middle cerebral artery (MCA) occlusion.
Design PROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized,
controlled, multicenter, open-label clinical trial with blinded follow-up
conducted between February 1996 and August 1998.
Setting Fifty-four centers in the United States and Canada.
Patients A total of 180 patients with acute ischemic stroke of less than 6 hours'
duration caused by angiographically proven occlusion of the MCA and without
hemorrhage or major early infarction signs on computed tomographic scan.
Intervention Patients were randomized to receive 9 mg of IA r-proUK plus heparin
(n = 121) or heparin only (n = 59).
Main Outcome Measures The primary outcome, analyzed by intention-to-treat, was based on the
proportion of patients with slight or no neurological disability at 90 days
as defined by a modified Rankin score of 2 or less. Secondary outcomes included
MCA recanalization, the frequency of intracranial hemorrhage with neurological
deterioration, and mortality.
Results For the primary analysis, 40% of r-proUK patients and 25% of control
patients had a modified Rankin score of 2 or less (P
= .04). Mortality was 25% for the r-proUK group and 27% for the control group.
The recanalization rate was 66% for the r-proUK group and 18% for the control
group (P<.001). Intracranial hemorrhage with neurological
deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of
control patients (P = .06).
Conclusion Despite an increased frequency of early symptomatic intracranial hemorrhage,
treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke
caused by MCA occlusion significantly improved clinical outcome at 90 days.
Intravenous (IV) tissue-type plasminogen activator (tPA) improves outcomes
after acute ischemic stroke but must be given within 3 hours of onset.1 Six randomized trials have failed to show an overall
benefit for IV thrombolytic therapy initiated within 6 hours of stroke onset.2-7
A number of factors have contributed to this failure, but stroke heterogeneity
has been cited as a main cause.8,9
A focused trial of a homogeneous stroke population provides an alternative
to the traditional large, randomized clinical trial.9
Intra-arterial (IA) thrombolysis lends itself to such a design in selected
patients with acute ischemic stroke.10-16
The recanalization efficacy and safety of IA recombinant prourokinase
(r-proUK) in patients with acute ischemic stroke of less than 6 hours' duration
caused by middle cerebral artery (MCA) occlusion were demonstrated in the
first Prolyse in Acute Cerebral Thromboembolism (PROACT I) trial.17 Prolyse (nasaruplase beta) is a glycosolated 411–amino
acid single-chain proenzyme precursor of urokinase (UK) derived from transfected
murine SP2/0 hybridoma cells.18 Single-chain
r-proUK is activated to 2-chain UK at the thrombus surface by fibrin-associated
plasmin.19 The thrombolytic effect of r-proUK
is augmented by heparin, possibly through thrombin neutralization or by stimulating
tPA release from the endothelium.20,21
Based on PROACT I, we performed a multicenter, randomized trial to determine
the clinical efficacy and safety of IA r-proUK in patients with acute ischemic
stroke of less than 6 hours duration caused by MCA occlusion. In PROACT II,
we increased the total dose of r-proUK from 6 mg to 9 mg given over 2 hours
while using the same low heparin dose as in PROACT I in an attempt to improve
recanalization while limiting symptomatic brain hemorrhages.
Between February 1996 and August 1998, 54 North American centers screened
patients with suspected acute stroke for the study. The study protocol and
all amendments were approved by the institutional review board at each center.
The clinical inclusion criteria were (1) new focal neurological signs
in the MCA distribution allowing initiation of treatment within 6 hours of
the onset of symptoms; (2) a minimum National Institutes of Health Stroke
Scale (NIHSS)22 score of 4, except for isolated
aphasia or hemianopia; and (3) age 18 through 85 years. Clinical exclusion
criteria included an NIHSS score greater than 30; coma; rapidly improving
neurological signs at any point prior to administration of study drug; history
of stroke within the previous 6 weeks; seizures at onset; clinical presentation
suggestive of subarachnoid hemorrhage; previous history of intracranial hemorrhage
at any time, neoplasm, or subarachnoid hemorrhage; septic embolism; suspected
lacunar stroke; surgery, biopsy of a parenchymal organ, trauma with internal
injuries or lumbar puncture within 30 days; head trauma within 90 days; active
or recent hemorrhage within 30 days; known hemorrhagic diathesis, baseline
international normalized ratio greater than 1.7, activated partial thromboplastin
time more than 1.5 times normal, or baseline platelet count less than 100
× 109/L (100 × 103/µL); known contrast
sensitivity; and uncontrolled hypertension defined by a blood pressure greater
than 180 mm Hg systolic or greater than or equal to 100 mm Hg diastolic on
3 separate occasions at least 10 minutes apart or requiring continuous IV
therapy.
Computed tomographic (CT) scan exclusion criteria were intracranial
tumors except small meningioma, hemorrhage of any degree or location, significant
mass effect with midline shift, and acute hypodense parenchymal lesion or
effacement of cerebral sulci in more than one third of the MCA territory (European
Cooperative Acute Stroke Study [ECASS] criteria2).
Patients who met all clinical and CT scan criteria and for whom signed
informed consent was obtained underwent diagnostic cerebral angiography of
the symptomatic MCA territory. Angiographic inclusion criteria were complete
occlusion (TIMI [Thrombolysis in Myocardial Infaction] grade 0)23
or contrast penetration with minimal perfusion (TIMI grade 1) of either the
M1 segment or an M2 division of the MCA. Angiographic
exclusion criteria were arterial dissection, arterial stenosis precluding
safe passage of a microcatheter into the MCA, nonatherosclerotic arteriopathy,
no visible occlusion, or occlusion of an artery other than the M1
or M2 MCA. All patients with an angiographic exclusion were observed
for 24 hours or until an alternative stroke therapy was initiated, whichever
came first.
Eligible patients were randomized to receive 9 mg total of IA r-proUK
over 2 hours plus IV heparin or IV heparin alone, in a ratio of 2:1. Randomized
treament was to be initiated within 6 hours of stroke onset. The randomization
was stratified by baseline stroke severity into 3 NIHSS strata: (1) 4 through
10, (2) 11 through 20, and (3) 21 through 30. A blinded randomization code
was assigned via telephone independent of the sponsor by Paragon Biomedical
Inc, Irvine, Calif. A computer-generated master randomization schedule using
a random block size ranging from 3 to 12 was used. The schedule was not stratified
by clinical center to preclude knowledge of the distribution of future treatment
assignments at a given center.
All randomized patients received a 2000 U bolus and a 500 U/hr infusion
of IV heparin for 4 hours beginning at the time of angiography.17
Heparin flush solutions for angiography contained 1 U/mL heparin in 0.9% sodium
chloride and were infused at 60 mL/h. Otherwise, antithrombotic agents were
prohibited for the first 24 hours.
An infusion microcatheter (<3.0 F) with a single end hole was placed
into the proximal one third of the MCA thrombus using a steerable microguidewire.
If intrathrombus positioning of the infusion catheter was not possible, the
tip of the catheter was to be placed as close to the proximal face of the
thrombus as possible for r-proUK infusion. A superselective angiogram was
performed through the microcatheter to document catheter placement (Figure 1). Mechanical disruption of the clot
was not permitted. Recombinant prourokinase was infused at a rate of 30 mL/h.
After 1 hour of r-proUK infusion (4.5 mg), another angiogram was performed
through the microcatheter. If any of the proximal thrombus had dissolved,
the interventionalist advanced the microcatheter tip into the proximal portion
of any remaining clot in the MCA. Even if complete lysis occurred in the first
hour, the remaining 4.5 mg of r-proUK was infused into the proximal MCA over
the subsequent 1 hour. Another diagnostic carotid angiogram was performed
at 2 hours in both r-proUK and control patients to assess final vessel patency.
All CT scans and 2-hour angiograms were assessed by a neuroradiologist
at a core facility who was blinded to treatment assignment and clinical status.
Computed tomographic scans were obtained at baseline, 24 hours, and 7 to 10
days after initial treatment. Hemorrhagic infarction was defined as any area
of petechial or small confluent hemorrhages within larger regions of hypodense
ischemic injury. Parenchymatous hematoma was defined as more homogeneous areas
of hemorrhage, with or without mass effect or intraventricular extension.
Complete recanalization was defined as complete (TIMI 3) flow in both the
M1 segment and M2 divisions of the MCA. Partial recanalization
was defined as partial (TIMI 2) flow in either MCA segment.
Clinical efficacy was assessed at 7 to 10 days, 30 days, and 90 days
following initial treatment based on the modified Rankin scale, NIHSS score,
and Barthel index.24 Follow-up examinations
were standardized and blinded. All follow-up examinations were to be performed
by the same board-certified or eligible blinded neurologist. At the time of
randomization, centers were required to designate a neurologist who was to
remain blinded to treatment assignment and angiographic results for the duration
of the trial. The principal investigator at each site was responsible for
ensuring the integrity of the blinded follow-up examinations. All examiners
were required to pass certifying tests for both the NIHSS and Barthel index.
An NIHSS recertification examination had to be passed after approximately
6 months.
The primary efficacy outcome was the percentage of patients achieving
a modified Rankin score of 2 or less at 90 days following the initial therapy;
this score signifies slight or no disability. The interobserver agreement
for differences of 1 grade on the modified Rankin scale is 0.56 and for 2
grades, 0.91.25
The secondary efficacy outcomes were the percentage of patients reaching
an NIHSS score of 1 or less at 90 days and the rate of angiographic recanalization.
Other preplanned analyses included the percentage of patients achieving a
50% or greater reduction from baseline NIHSS score at 90 days, and the percentage
of patients achieving a Barthel index score of 60 or greater and a Barthel
index score of 90 or greater at 90 days.
The primary and secondary clinical efficacy analyses were performed
on an intent-to-treat basis. For living patients who missed the 90-day assessment,
the most recent assessment prior to 90 days was used. The upper limit for
the 90-day visit data was prospectively set at 120 days. For living patients
with no data, the scale value corresponding to failure was imputed. The principal
analyses of the NIHSS and Barthel index total scores were performed with imputations
for mortality of 42 for the NIHSS and 0 for the Barthel index.
Modified Rankin score, Barthel index, and NIHSS score analyses were
performed using the Cochran-Mantel-Haenszel method with baseline stroke severity
as the stratification factor. The analysis for the primary end point, stratified
by center, revealed no significant treatment by center interaction and is
not presented.
Procedural complications were analyzed for all randomized patients.
All other safety analyses were performed on patients treated as randomized,
ie, r-proUK patients who received the drug and control patients who did not
receive a thrombolytic agent. The primary safety outcome was hemorrhagic transformation
causing neurological deterioration within 24 hours of treatment. Guidelines
for neurological deterioration were a 4-point or greater increase in the NIHSS
score or a 1-point deterioration in level of consciousness. An external safety
committee was commissioned to recommend termination of the trial if predefined
rates of hemorrhagic transformation with neurological deterioration were reached.
The percentage of patients experiencing hemorrhagic transformation with neurological
deterioration within 24 hours of treatment was compared between treatment
groups using the Fisher exact test for 2 × 2 tables. Adverse events
and nonintracranial bleeding complications were analyzed using the Fisher
exact test for 2 × 2 tables.
Based on the results of PROACT I,17 100
r-proUK patients and 50 control patients provided a power of 80% at the 2-sided
.05 α level for detecting a difference in the primary efficacy outcome
between r-proUK and control. To adjust for patients who were randomized but
who might not receive the study drug, approximately 120 r-proUK and 60 control
patients needed to be enrolled.
Site management, data monitoring, and data management were performed
independently of the sponsor by ClinTrials Research Inc, Cary, NC. A preplanned
futility assessment was performed after the first 75 patients completed the
90-day follow-up. The futility assessment and the analyses in this report
were performed independently of the sponsor by the Clinical Trials Methodology
Group, Hamilton Civic Hospitals Research Centre, McMaster University, Hamilton,
Ontario.
During the study, 12,323 patients with acute stroke were screened, of
whom 474 (4%) underwent diagnostic cerebral angiography at a median of 4.5
hours from stroke onset. There were angiographic exclusions in 294 patients.
The remaining 180 patients were randomized (Figure 2).
The 121 r-proUK and 59 control patients were generally well-matched
for medical history (Table 1)
and baseline characteristics (Table 2).
There was an excess history of diabetes among control patients and more ECASS
CT scan protocol violations among r-proUK patients. A total of 20% (11/54)
of control patients vs 8% (9/108) of r-proUK patients received some heparin
within 5 to 23 hours after the start of the initial protocol-specified 4-hour
infusion. The total rate of ECASS CT scan protocol violations was 8% (14/177).
The median baseline NIHSS score was 17 in both groups. The median time to
initiation of r-proUK treatment was 5.3 hours.
For the primary efficacy analysis, 40% of r-proUK patients and 25% of
control patients had a modified Rankin score of 2 or less at 90 days after
stroke onset (P = .04; absolute benefit, 15%; relative
benefit, 58%; number needed to treat to benefit, 7 (Table 3 and Figure 3).
All secondary clinical outcome trends favored r-proUK at all time points,
although there were no statistically significant differences between treatment
groups at 90 days (Table 4). Patients
treated with r-proUK achieved independence in activities of daily living earlier
as measured by a Barthel index score of 90 or higher at 7 to 10 days (22%
vs 10%, P = .04), although this difference did not
maintain statistical significance at 90 days (P =
.24).
Among all randomized patients, 13 r-proUK patients did not receive any
r-proUK for the following reasons: no M1 or M2 occlusion
(4); treatment not initiated within 6 hours of onset of symptoms (3); technical
difficulties (2); and agitation, neurological deterioration, pharmacy error,
and improper informed consent (1 each). Five control patients received thrombolytic
agent (2 received r-proUK by pharmacy error; 3, at patient/family insistence),
3 of whom experienced intracranial hemorrhage with neurological deterioration.
If these 18 patients are removed from the intention-to-treat analysis there
is still a 15% absolute benefit (42% vs 27%, P =
.053) for the primary outcome in favor of r-proUK.
Procedural complications for randomized patients in the r-proUK and
control groups included worsening of neurological symptoms, 1% (1/121) vs
0%; anaphylaxis, 1% (1/121) vs 0%; and systemic hemorrhage (primarily minor
hemorrhages at the catheter site), 7% (9/121) vs 17% (4/59).
Among patients treated as randomized, intracranial hemorrhage within
24 hours occurred in 35% (38/108) of the r-proUK patients and 13% (7/54) of
control patients (P = .003). By 10 days, the rates
for all intracranial hemorrhages were 68% (73/108) and 57% (31/54), respectively
(P = .23).
Intracranial hemorrhage with neurological deterioration within 24 hours
occurred in 10% (11/108) of r-proUK patients and 2% (1/54) of control patients
(number needed to treat to harm, 12) (Figure
4). All symptomatic intracranial hemorrhages occurred in patients
with a baseline NIHSS score of 11 or higher (NIHSS 11-20, 11%; NIHSS >20,
13%). The median activated partial thromboplastin time at the end of the 4-hour
heparin infusion was 34.9 seconds for r-proUK patients and 36.5 seconds for
control patients.
There was no difference in the NIHSS stratum–adjusted 90-day mortality
rate, which was 25% for r-proUK patients and 27% for control patients (intent-to-treat
analysis, Table 4, Figure 3).
For patients treated as randomized, the NIHSS stratum–adjusted
recanalization rates (TIMI 2 + 3) on the 2-hour angiogram were 66% in r-proUK
patients and 18% in control patients (P<.001).
The 2-hour complete (TIMI 3) recanalization rates were 19% and 2%, respectively
(P<.003) (Figure
5).
PROACT II is the first randomized multicenter trial to demonstrate the
clinical efficacy of IA thrombolysis in patients with acute stroke of less
than 6 hours' duration caused by MCA occlusion. Compared with patients receiving
low-dose IV heparin only, patients with ischemic stroke caused by MCA occlusion
treated with 9 mg of IA r-proUK plus low-dose heparin a median of 5.3 hours
from symptom onset were 58% more likely to have slight or no neurological
disability at 90 days. The 15% absolute increase in favorable outcome with
IA r-proUK (P = .04) means that, on average, for
every 7 patients treated with IA r-proUK, 1 will benefit.
PROACT I and PROACT II are the only randomized, multicenter stroke trials
to restrict patient selection to MCA occlusion. We selected MCA occlusion
because of its poor natural history26 and because
the MCA is the most frequent site of arterial occlusion in patients with severe
stroke of less than 6 hours' duration.27 To
further increase homogeneity between the 2 study arms, PROACT II prospectively
stratified for initial stroke severity. In contrast to the National Institute
of Neurological Disorders and Stroke (NINDS) tPA trial,1
we chose slight or no neurological disability (modified Rankin score ≤2)
as the primary outcome measure rather than complete recovery (modified Rankin
score ≤1) because of the anticipated high baseline stroke severity in patients
with MCA occlusion. A modified Rankin score of 2 or less has been used as
an indicator of functional independence in other thrombolysis stroke trials.4,5
Intra-arterial thrombolysis poses other unique stroke trial design issues.28,29 PROACT I used a double-blind design;
control patients received IA saline placebo. In PROACT II we changed to an
open design with blinded follow-up because of ethical concerns about infusing
a placebo into the MCA through a microcatheter for 2 hours with little likelihood
of any benefit and to create a control group more closely reflecting the natural
history of MCA occlusion.
We demonstrated a benefit with IA r-proUK despite the use of a conservative
interventional technique. To demonstrate the pharmacological effect of r-proUK
and to standardize delivery technique across centers, we prohibited mechanical
clot manipulation in PROACT I and PROACT II. The low TIMI 3 recanalization
rate in PROACT II indicates that residual thrombus was frequently present
2 hours after IA r-proUK thrombolyis. Advances in catheter technology, imaging
techniques, mechanical clot removal, and thrombolytic agents should lead to
faster and more complete recanalization and potentially even better patient
outcomes.
Although the treatment groups were generally well-balanced, the small
sample size resulted in some differences in baseline variables by chance.
Two of these, baseline CT hypodensity30,31
and diabetes,32 have been correlated with stroke
outcome, but we have limited our initial report to the prespecified analysis
plan.
The higher r-proUK dose in PROACT II improved recanalization efficacy
by 26% compared with PROACT I, but the symptomatic brain hemorrhage rate also
increased by 4%. It is not clear if low-dose heparin contributed to the intracranial
hemorrhage risk in either group. The median activated partial thromboplastin
times were not prolonged by low-dose heparin, and symptomatic brain hemorrhage
was not clinically apparent until several hours after it was discontinued.
Treatment with IA r-proUK was beneficial despite an increased risk of
early intracranial hemorrhage with neurological deterioration. There was no
significant difference in the rates of total intracranial hemorrhage by day
10. This may reflect delayed recanalization in the control group with hemorrhagic
transformation, whereas the higher early rate with r-proUK reflected drug-induced
recanalization and reperfusion hemorrhage. The total intracranial hemorrhage
rates were consistent with those previously reported in patients with embolic
stroke.33-35 Most
of these hemorrhages were small and clinically irrelevant and were detected
only because of the protocol-mandated CT scans.
The higher rate of intracranial hemorrhage with neurological deterioration
with IA r-proUK (10.2%) compared with IV tPA in NINDS (6.4%),1
Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke
(ATLANTIS) (7.2%),7 and ECASS II (8.8)6 reflects the greater baseline stroke severity and
time to treatment in PROACT II. Baseline stroke severity was first associated
with intracranial hemorrhage risk in ECASS I2
and NINDS.36 The patients in PROACT II had
the greatest baseline stroke severity of any randomized acute stroke trial.
The median baseline NIHSS score of 17 in PROACT II contrasts with a median
NIHSS score of 11 in both ECASS II6 and ATLANTIS,7 and 14 in the NINDS trial.1
Direct comparisons of hemorrhage rates and clinical outcomes between
PROACT II and the IV thrombolysis trials are difficult. Patients with acute
ischemic stroke have a variety of arterial occlusion sites despite similar
clinical presentations.37 Since neither the
sites of arterial occlusion nor the recanalization rates are known in the
IV thrombolysis trials, including NINDS, the efficacy of IV thrombolysis in
patients with MCA occlusion cannot be specifically determined from those trials.
While the NINDS study supports the use of IV tPA in a less than 3-hour window,
limited data suggest that IV tPA may be relatively ineffective in the subset
of patients with MCA occlusion. The Thrombolytic Therapy of Acute Thrombotic/Thromboembolic
Stroke Study (TTATTS)38 suggests a recanalization
rate of no more than 30% for large vessel occlusion with 0.8 mg/kg or 1.0
mg/kg of IV tPA. Tomsick et al39 reported that
a baseline NIHSS score greater than 10 and a hyperdense MCA sign on CT scan
(signifying MCA occlusion) predicted a poor clinical outcome for patients
treated with IV tPA given less than 3 hours from stroke onset.
Although MCA recanalization rates may be superior with IA thrombolysis,
there was an average 3-hour delay between patient arrival at hospital and
initiation of the IA r-proUK infusion. We treated only 1 patient with r-proUK
less than 3 hours from stroke onset. When the 2-hour drug infusion time is
added, up to 5 hours elapsed in some patients during which brain infarction
continued. A door-to-drug time of 1 hour similar to that recommended for IV
tPA40 is more difficult to achieve with IA
thrombolysis but was met in a few patients in PROACT II. It may also be feasible
to give IA thrombolysis to patients with persistent MCA occlusion after IV
tPA.41-43
There has been significant controversy over the therapeutic window in
acute human ischemic stroke.44,45
Recent diffusion and perfusion magnetic resonance studies suggest that as
many as two thirds of patients with acute MCA distribution stroke have brain
tissue at risk even 24 hours after stroke onset, but the clinical relevance
of these observations is uncertain.46,47
PROACT II has demonstrated that the therapeutic window for a significant number
of patients with major stroke due to MCA occlusion may extend to at least
6 hours. The challenge is to build on the results of PROACT II and other thrombolysis
trials by refining patient selection, reducing the risk of hemorrhage, optimizing
delivery techniques, and combining treatment strategies to further improve
outcomes for patients with acute stroke.
1.The National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. Tissue plasminogen activator for acute ischaemic stroke.
N Engl J Med.1995;333:1581-1587.Google Scholar 2.Hacke W, Kaste M, Fieschi C.
et al. Intravenous thrombolysis with recombinant tissue plasminogen activator
for acute hemispheric stroke: the European Cooperative Acute Stroke Study
(ECASS).
JAMA.1995;274:1017-1025.Google Scholar 3.Donnan GA, Davis SM, Chambers BR.
et al. Streptokinase for acute ischemic stroke with relationship to time of
administration.
JAMA.1996;276:961-966.Google Scholar 4.The Multicenter Acute Stroke Trial—Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke.
N Engl J Med.1996;335:145-150.Google Scholar 5.The Multicenter Acute Stroke Trial–Italy (MAST–I) Group. Randomised controlled trial of streptokinase, aspirin and combination
of both in treatment of acute ischaemic stroke.
Lancet.1995;346:1509-1514.Google Scholar 6.Hacke W, Kaste M, Fieschi C.
et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy
with intravenous alteplase in acute ischaemic stroke (ECASS II).
Lancet.1998;352:1245-1251.Google Scholar 7.Clark WM, Albers GW.for the ATLANTIS Stroke Investigators. The Atlantis rt-PA (Alteplase) Acute Stroke Trial: final results [abstract].
Stroke.1999;30:234.Google Scholar 8.Muir KW, Grosset DG. Neuroprotection for acute stroke: making clinical trials work.
Stroke.1999;30:180-182.Google Scholar 9.Sandercock P, Hennerici MG, Orgogozo JM, Davis SM, Gorelick PB. Mega trials versus small trials in stroke. In: Fisher M, Bogousslavsky J, eds. Current Review
of Cerebrovascular Disease. Boston, Mass: Butterworth-Heinemann; 1999:217-222.
10.Gonner F, Remonda L, Mattle H.
et al. Local intra-arterial thrombolysis in acute ischemic stroke.
Stroke.1998;29:1894-1900.Google Scholar 11.del Zoppo GJ, Ferbert A, Otis S.
et al. Local intra-arterial fibrinolytic therapy in acute carotid territory
stroke: a pilot study.
Stroke.1988;19:307-313.Google Scholar 12.Theron J, Courtheoux P, Casasco A.
et al. Local intraarterial fibrinolysis in the carotid territory.
AJNR Am J Neuroradiol.1989;10:753-765.Google Scholar 13.Mori E, Tabuchi M, Yoshida T.
et al. Intracarotid urokinase with thromboembolic occlusion of the middle
cerebral artery.
Stroke.1988;19:802-812.Google Scholar 14.Zeumer H, Freitag HJ, Zanella F.
et al. Local intra-arterial fibrinolytic therapy in patients with stroke:
urokinase versus recombinant tissue plasminogen activator (r-TPA).
Neuroradiology.1993;35:159-162.Google Scholar 15.Hacke W, Zeumer H, Ferbert A.
et al. Intra-arterial thrombolytic therapy improves outcome in patients with
acute vertebrobasilar occlusive disease.
Stroke.1988;19:1216-1222.Google Scholar 16.Pessin M, del Zoppo GJ, Furlan AJ. Thrombolytic treatment in acute stroke: review and update of selective
topics. In: Moskowitz MA, Caplan LR, eds. Cerebrovascular
Diseases: Nineteenth Princeton Stroke Conference. Boston, Mass: Butterworth-Heinemann;
1995:409-418.
17.del Zoppo GJ, Higashida RT, Furlan AJ.
et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by
direct arterial delivery in acute middle cerebral artery stroke.
Stroke.1998;29:4-11.Google Scholar 18.Kasai S, Arimura H, Nishida M, Suyama T. Primary structure of single-chain pro-urokinase.
J Biol Chem.1985;260:12382-12389.Google Scholar 19.Pannell R, Gurewich V. Pro-urokinase: a study of its stability in plasma and of a mechanism
for its selective fibrinolytic effect.
Blood.1986;44:217-228.Google Scholar 20.Tebbe U, Windeler J, Boesl I.
et al. Thrombolysis with recombinant unglycosylated single-chain urokinase-type
plasminogen activator (saruplase) in acute myocardial infarction: influence
of heparin on early patency rate (LIMITS Study).
J Am Coll Cardiol.1995;26:365-373.Google Scholar 21.Gurewich V, Liu J. Intra-arterial pro-urokinase in ischemic stroke [letter].
Stroke.1998;29:1255.Google Scholar 22.Brott T, Adams Jr HP, Olinger CP.
et al. Measurements of acute cerebral infarction: a clinical examination scale.
Stroke.1989;20:864-870.Google Scholar 23.TIMI Study group. Special report: the Thrombolysis in Myocardial Infarction (TIMI) trial.
N Engl J Med.1985;312:932-936.Google Scholar 24.Wolfe CD, Taub NA, Woodrow BA, Burney PG. Assessment of scales of disability and handicap for stroke patients.
Stroke.1991;22:1242-1244.Google Scholar 25.van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients.
Stroke.1988;19:604-607.Google Scholar 26.Furlan AJ. Natural history of atherothromboembolic occlusion of cerebral arteries:
carotid versus vertebrobasilar territories. In: Hacke W, del Zoppo GJ, Hirschberg M, eds. Thrombolytic Therapy in Acute Ischemic Stroke. New York, NY: Springer-Verlag;
1991:71-76.
27.del Zoppo GJ, Poeck K, Pessin MS.
et al. Recombinant tissue plasminogen activator in acute thrombotic and embolic
stroke.
Ann Neurol.1992;32:78-86.Google Scholar 28.Ferguson RD, Ferguson JG. Cerebral intraarterial thrombolysis at the crossroads: is a phase III
trial advisable at this time?
AJNR Am J Neuroradiol.1994;15:1201-1216.Google Scholar 29.del Zoppo GJ, Higashida RT, Furlan AJ. The case for a phase III trial of cerebral intraarterial fibrinolysis.
AJNR Am J Neuroradiol.1994;15:1217-1222.Google Scholar 30.Moulin T, Cattin F, Crepin-Leblond T.
et al. Early CT signs in acute middle cerebral artery infarction: predictive
value for subsequent infarct locations and outcome.
Neurology.1996;47:366-375.Google Scholar 31.von Kummer R, Allen KL, Holle R.
et al. Acute stroke: usefulness of early CT findings before thrombolytic therapy.
Radiology.1997;205:327-333.Google Scholar 32.Toni D, De Michele M, Fiorelli M.
et al. Influence of hyperglycemia on infarct size and clinical outcome of
acute ischemic stroke patients with intracranial arterial occlusion.
J Neurol Sci.1994;123:129-133.Google Scholar 33.Lodder J, Krijne-Kubat B, Broekman J. Cerebral hemorrhagic infarction at autopsy: cardiac embolic causes
and the relationship to cause of death.
Stroke.1986;17:626-629.Google Scholar 34.Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction—a prospective study.
Stroke.1986;17:179-185.Google Scholar 35.Okada Y, Yamaguchi T, Minematsu K.
et al. Hemorrhagic transformation in cerebral embolism.
Stroke.1989;20:598-603.Google Scholar 36.The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic
stroke.
Stroke.1997;28:2109-2118.Google Scholar 37.Wolpert SM, Bruckmann H, Greenlee R.
et al. Neuroradiology evaluation of patients with acute stroke treated with
recombinant tissue plasminogen activator.
AJNR Am J Neuroradiol.1993;14:3-13.Google Scholar 38.Genentech, applicant. Summary basis for approval: activaseTM for acute ischemic stroke. New Drug Application. PLA96-0350.
39.Tomsick T, Brott T, Barsan W.
et al. Prognostic value of the hyperdense middle cerebral artery sign and
stroke scale score before ultraearly thrombolytic therapy.
AJNR Am J Neuroradiol.1996;17:79-85.Google Scholar 40.Marler JR, Jones PW, Emr M. Rapid Identification and Treatment of Acute Stroke: Proceedings of a National Symposium. Bethesda, Md: National Institutes of Health; 1997. NIH Publication
97-439.
41.Ueda T, Sakaki S, Nochide I.
et al. Angioplasty after intra-arterial thrombolysis for acute occlusion of
intracranial arteries.
Stroke.1998;29:2568-2574.Google Scholar 42.Emergency Management of Stroke (EMS) Investigators. Combined intra-arterial and intravenous tPA for stroke [abstract].
Stroke.1997;28:273.Google Scholar 43.Pannell R, Black J, Gurewich V. The complementary modes of action of tissue plasminogen activator (t-PA)
and pro-urokinase (pro-UK) by which their synergistic effect on clot lysis
may be explained.
J Clin Invest.1988;81:853-859.Google Scholar 44.Fisher M, Garcia JH. Evolving stroke and the ischemic penumbra.
Neurology.1996;47:884-888.Google Scholar 45.Baron JC, von Kummer R, del Zoppo GJ. Treatment of acute ischemic stroke—challenging the concept of
a rigid and universal time window.
Stroke.1995;26:2219-2221.Google Scholar 46.Fisher M, Prichard JW, Warach S. New magnetic resonance techniques for acute ischemic stroke.
JAMA.1995;274:908-911.Google Scholar 47.Staroselskaya IA, Baird AE, Linfante I.
et al. Correlations between MR diffusion-perfusion studies and MRA in acute
stroke.
Neurology.1999;52(suppl 2):455.Google Scholar