Hyperacute Stroke Therapy With Tissue Plasminogen Activator

Hyperacute Stroke Therapy With Tissue Plasminogen Activator

Hyperacute Stroke Therapy With Tissue Plasminogen Activator Mark J. Alberts, MD The past year has seen tremendous progress in developing new therapi...

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Hyperacute Stroke Therapy With Tissue Plasminogen Activator Mark J. Alberts,

MD

The past year has seen tremendous progress in developing new therapies aimed at reversing the effects of acute stroke. Thrombolytic therapy with various agents has been extensively studied in stroke patients for the past 7 years. Tissue plasminogen activator (t-PA) received formal US Food and Drug Administration approval in June 1996 for use in patients within 3 hours of onset of an ischemic stroke. Treatment with t-PA improves neurologic outcome and functional disability to such a degree that, for every 100 stroke patients treated with t-PA, an additional 11–13 will be normal or nearly normal 3 months after their stroke. The downside of t-PA therapy is a 6% rate of symptomatic intracerebral hemorrhage (ICH) and a 3% rate of fatal ICH. Studies are under way to determine whether t-PA can be adminis-

tered with an acceptable margin of safety within 5 hours of stroke, to evaluate the therapeutic benefits of intraarterial pro-urokinase, and to assess the use of magnetic resonance spectroscopy to identify which patients are most likely to benefit from thrombolysis. Combination thrombolytic–neuroprotectant therapy is also being studied. In theory, patients could be given an initial dose of a neuroprotectant by paramedics and receive thrombolytic therapy in the hospital. We are now entering an era of proactive, not reactive, stroke therapies. These treatments may reverse some or all acute stroke symptoms and improve functional outcomes. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(4C):29D–34D

hrombolytic therapy has been extensively studied T for the past 7 years as a treatment for acute ischemic stroke. Data from the landmark National Insti-

lation status. They had to arrive at the study center in time to have all necessary diagnostic tests and begin t-PA treatment #3 hours after stroke onset. Patients or family members were required to sign an informed consent statement. Patients were excluded from the study if they had a recent history of major trauma, surgery, or a systemic bleed (Table I). They were also excluded if they had had a recent stroke or any type of central nervous system hemorrhage at any time in the past. They were barred from participation if they had a systolic blood pressure .185 mm Hg or a diastolic blood pressure .110 mm Hg before treatment that could not be reduced by modest medical intervention. A total of 624 patients were enrolled in the study, of whom 312 were treated with t-PA and 312 with placebo. At enrollment, 50% of the patients were treated #90 minutes after symptom onset. The fact that the investigators were able to enroll patients so quickly was a real triumph of the study. The other patients were treated in 91–180 minutes. Patients received t-PA at a dose of 0.9 mg/kg, with a maximum dose of 90 mg. Thus, the dose was much lower than the typical cardiac dose; 10% of the dose was given as an intravenous (IV) loading bolus, with the remainder given as a 1-hour intravenous infusion. The 4 outcome measures used in the study were chosen on the basis of their reliability, familiarity, adaptability for use in stroke patients, and comparability to endpoints used in other thrombolytic trials. The National Institutes of Health Stroke Scale is a serial measure of neurologic deficit. Both the Modified Rankin Scale and the Glasgow Outcome Scale are overall assessments of function. The Barthel Index measures the ability to perform the activities of daily living. Using these scales, neurologic deficits were evaluated at 24 hours, and functional and neurologic status and general disability were assessed 3 months after stroke.

tute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study confirmed the therapeutic benefit of tissue plasminogen activator (t-PA) when administered within 3 hours of stroke onset.1 This trial, which served as the basis for the US Food and Drug Administration’s (FDA) June 1996 approval of t-PA,2 ushered in a new era of proactive rather than reactive stroke therapy. This article discusses the NINDS rt-PA Stroke Study and summarizes the findings of other major stroke trials of thrombolytic therapy. Pretreatment and posttreatment t-PA protocols now in use are described. Finally, the article discusses some important new research directions in thrombolytic therapy.

STUDIES OF TISSUE PLASMINOGEN ACTIVATOR IN ACUTE STROKE The NINDS rt-PA Stroke Study was a randomized, double-blind, placebo-controlled clinical trial.1 Its results were published in the December 14, 1995, issue of The New England Journal of Medicine. Several previous investigations of thrombolytic therapy had been compromised by insufficiently stringent eligibility criteria or by failure to enforce these criteria carefully. As a result, the inclusion and exclusion criteria for the NINDS trial were very rigorous and were strictly enforced. Patients were eligible to participate in the study if they had an ischemic stroke in any part of the brain (Table I). They were required to have normal coaguFrom the Division of Neurology and the Stroke Acute Care Unit, Duke University Medical Center, Durham, North Carolina. Address for reprints: Mark J. Alberts, MD, Duke University Medical Center, P.O. Box 3392, Durham, North Carolina 27710. ©1997 by Excerpta Medica, Inc. All rights reserved.

0002-9149/97/$17.00 PII S002-9149(97)00582-1

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TABLE I Major Inclusion and Exclusion Criteria in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Criterion Type Inclusion

Exclusion

TABLE II Distribution of Stroke Subtypes at Baseline in the 624 Patients Enrolled in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study

Major Criteria ● ● ● ●

Number of Patients

Presence of ischemic stroke (any location) Normal coagulation status Can be treated #3 hours after symptom onset Informed consent obtainable

● Rapidly improving or minor symptoms ● Recent major trauma, surgery, or systemic bleed (,14 days) ● Stroke or serious head trauma within the preceding 3 months ● Gastrointestinal or urinary tract hemorrhage within the preceding 21 days ● History of any type of CNS hemorrhage ● Arterial puncture at a noncompressible site within the preceding 7 days ● Prothrombin times .15 seconds ● Elevated partial thromboplastin time ● Platelet counts ,100,000/mm3 ● Glucose concentrations ,50 mg/dL or .400 mg/dL ● Blood pressure .185/110 mm Hg

Warnings: Patients with early ischemic changes on head CT and patients with an NIH stroke scale score .20 may be at increased risk for ICH following t-PA therapy. Careful consideration is recommended before administering t-PA to such patients. BP 5 blood pressure; CNS 5 central nervous system; ICH 5 intracerebral hemorrhage; NIH 5 National Institutes of Health. Reproduced with permission from N Engl J Med.1

Compared with patients receiving placebo, there was an 11–13% absolute increase in the numbers of t-PA–treated patients with minimal or no disability compared with placebo (p 5 0.008). Minimal disability, as defined in this study, was so mild that a nonneurologist would not be able to detect it without performing a very detailed examination. The response was even more impressive in terms of relative increase. There was a 30 –55% relative increase in the number of t-PA–treated patients with favorable outcomes. There was a trend for decreased mortality in the t-PA versus the placebo group, with 17% mortality for t-PA and 21% for placebo (p 5 0.30). One surprising finding was the robust effect in terms of efficacy that was seen across the different types of stroke mechanisms (Table II). Patients with small-vessel (lacunar) strokes, large-vessel atherothrombotic/occlusive strokes (e.g., internal carotid artery occlusion), and cardioembolic strokes all showed a positive response to t-PA compared with placebo. This finding is reassuring because it indicates that it is not necessary to spend a great deal of time in the emergency department ascertaining the stroke mechanism before treating a patient with t-PA. Bleeding, a well-known complication of thrombolytic therapy, was expected and seen in the NINDS study (Table III). The rate of symptomatic intracerebral hemorrhage (ICH) in the t-PA group was 6.4%, which is an order of magnitude greater than the 0.64% observed in the placebo group. Clearly, this rate is much higher than that seen in cardiac studies. Approx30D

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Stroke Subtype*

t-PA

Placebo

Small-vessel occlusive (lacunar) Large-vessel atherothrombotic/occlusive Cardioembolic

51 117 136

30 135 137

*Eighteen patients with other stroke subtypes were excluded from this table. t-PA 5 tissue plasminogen activator. Reproduced with permission from N Engl J Med.1

TABLE III Intracerebral Hemorrhage, Within 36 Hours of Treatment, in 624 Patients in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Number of Patients Type of Hemorrhage

t-PA

Placebo

Symptomatic Fatal* Nonfatal Asymptomatic

20 9 11 14

2 1 1 9

*Values include all deaths attributed to hemorrhage. t-PA 5 tissue plasminogen activator. Reproduced with permission from N Engl J Med.1

imately half of the ICHs in this study were fatal. It is important to note that patients with symptomatic and fatal ICH were included in the study’s efficacy analysis. Thus, despite a significantly higher rate of ICH, the overall efficacy of t-PA compared with placebo was still demonstrated. Like any study, the NINDS study had several limitations. It was performed in a select group of patients who had been carefully screened to exclude conditions that would increase the risk of bleeding. The individual patients who improved did not necessarily do so across all outcome measures, although improvement was seen across all outcome measures for the overall t-PA versus placebo groups. The study was conducted at selected medical centers by an experienced team of vascular neurologists. How these results will translate to centers and hospitals without such experience is currently unknown. Furthermore, very few patients actually qualified for the study. The investigators screened about 17,000 patients to enroll the 624 persons who were actually treated. Not surprisingly, time was the factor that excluded most patients who were screened but not enrolled. It is important to add that the investigators at the centers that conducted the study—Cincinnati, San Diego, New York, Houston, Atlanta, Memphis, Charlottesville, and Detroit— did an excellent job of educating outlying hospitals, physicians, and the general public about the importance of a rapid response to stroke. Even with this maximal effort, the effect was relatively modest. Nevertheless, the investigators

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TABLE IV Summary of Major Randomized Clinical Trials of Intravenous Thrombolytic Therapy for Stroke That Have Been Completed

Study

Drug(s) Used

Dose

European Cooperative Stroke Study (ECASS)3

t-PA

1.1 mg/kg, to maximum of 100 mg

NINDS rt-PA Stroke Study1

t-PA

0.9 mg/kg, to maximum of 90 mg

Time Limit from Stroke Onset (h)

Number of Patients

6

620

17.4% of patients were enrolled despite major protocol violations. Analysis of all patients showed no benefit. Analysis of eligible patients (‘‘target population’’) revealed significant modified Rankin Scale improvement in favor of t-PA–treated patients (p 5 0.035); 20% rate of ICH.

1.5–3

624

Compared with placebo group, t-PA–treated patients were $30% more likely to have minimal or no disability at 3 months. Symptomatic ICH within 36 hours of stroke occurred in 6.4% of t-PA–treated patients and 0.6% of placebo-treated patients (p ,0.001).

Major Results

Multicenter Acute Stroke Trial–Europe (MAST-E)4–6

SK

1.5 MU*

6

310

Stopped early. There was a high frequency of hemorrhagic events and deaths in SK-treated patients. At 6 months, survivors in SK group had greater improvement in function and were less likely to be severely disabled than placebo-treated patients, but differences were not statistically significant.

Multicenter Acute Stroke Trial–Italy (MAST-I)7

SK6aspirin

1.5 MU SK; 300 mg/day aspirin

6

622

Stopped early. There was a nonsignificant reduction in likelihood of death/disability after treatment with SK. However, 10-day mortality and symptomatic ICH were significantly higher in patients treated with SK. Risk of early death or bleeding especially high when SK was combined with aspirin.

Australian Streptokinase Trial (ASK)8

SK

1.5 MU

4

340

Stopped early. Treatment with SK showed no significant benefit over placebo. There was a nonsignificant trend toward unfavorable outcomes in SK-treated patients.

*Other drugs could be administered at the discretion of the individual investigator. Some patients received heparin. ICH 5 intracerebral hemorrhage; SK 5 streptokinase; t-PA 5 tissue plasminogen activator.

should be congratulated for managing to complete this logistically difficult study. The most important result of the NINDS study was that, for every 100 stroke patients treated with t-PA, 11–13 additional patients had an excellent outcome with little or no neurologic or functional deficit. This is a fairly robust effect, even considering the risk of ICH. In interpreting the results of the NINDS study, it is helpful to consider the results of 4 other large, randomized trials of intravenous thrombolytic therapy for stroke whose results have been published (Table IV). One of these used t-PA; the others, streptokinase. The other major study of t-PA in stroke is the European Cooperative Acute Stroke Study (ECASS).3 This trial used a higher dose of t-PA, 1.1 mg/kg, and a time window of 6 hours from stroke onset. The investigators found no evidence of efficacy, and the rate of symptomatic ICH was almost 20%. Interpretation of the results was complicated by the fact that 17.4% of the patients enrolled in the study had major protocol violations, the most common of which was early infarct signs on the head computed tomography (CT) scan.

Studies of streptokinase: Streptokinase has been evaluated in 3 large, randomized stroke studies. Two Multicenter Acute Stroke Trials (MAST) were performed, one in France and the United Kingdom (MAST-E)4 – 6 and another in Italy (MAST-I).7 The third streptokinase study was the Australian Streptokinase (ASK) trial.8 Patients in all these studies received 1.5 MU of streptokinase. In MAST-E, patients could receive other acute stroke therapies at the discretion of the individual investigator, and approximately one third were given heparin within 12 hours of streptokinase treatment. In addition to streptokinase, one of the MAST-I treatment groups received aspirin at a dosage of 300 mg/day for 10 days. None of these studies showed that intravenous streptokinase was significantly more effective than placebo for the treatment of acute ischemic stroke. Furthermore, each was stopped early by the safety monitoring committee because of high rates of mortality and ICH in the streptokinase-treated patients. In MAST-E, 10-day mortality was 34% in the streptokinase group and 18.2% in the placebo group (p 5 0.002).6 In MAST-I, 10-day mortality in patients receiving both streptokinase and aspirin was 34%

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TABLE V Summary of the Tissue Plasminogen Activator (t-PA) Pretreatment and Posttreatment Protocols in Use at Duke University Medical Center Stage

Major Actions

Pretreatment

● ● ● ● ● ●

Posttreatment

● Avoid anticoagulants or antiplatelet agents for 24 hours after IV infusion ● Avoid arterial punctures, IM shots, or other invasive procedures for 24 hours after infusion ● Admit patient to a stroke unit or ICU for 24 hours ● Maintain blood pressure #185/110 mm Hg ● Repeat head CT scan in 24 hours to check for bleeding

Posttreatment (if bleeding occurs)

● ● ● ● ● ●

Take rapid history and perform physical examination Establish two IV lines and send off blood samples Send patient for head CT scan Obtain informed consent from family Review CT scan results on monitor Administer t-PA under close supervision in ED or in scanner

Apply direct pressure for peripheral bleeding Transfuse cryoprecipitate Transfuse platelets Transfuse fresh frozen plasma Transfuse packed red blood cells Fluid resuscitate

CT 5 computed tomography; ED 5 emergency department; ICU 5 intensive care unit; IM 5 intramuscular; IV 5 intravenous; t-PA 5 tissue plasminogen activator.

compared with 13% in the placebo group (p ,0.00001).7 In the ASK trial, there was a nonsignificant trend toward unfavorable outcomes for streptokinase-treated patients.8 Based on these results, it is highly unlikely that streptokinase will be approved as an alternative thrombolytic therapy for stroke in the foreseeable future.

REASONS FOR IMPROVED OUTCOMES IN THE NINDS t-PA STUDY There are several possible reasons why the other major trials of thrombolytic therapy had less favorable results than the NINDS t-PA study. Overall, patients enrolled in the NINDS study had less severe strokes than those enrolled in the other trials. Higher doses of t-PA were used in the ECASS trial compared with the NINDS study, which may explain the increased bleeding complications. The use of streptokinase rather than t-PA in MAST-E, MAST-I, and the ASK trial may also account for the increase in bleeding complications, because streptokinase is less clot selective than t-PA. In addition, 6-hour treatment windows were used in ECASS and the 2 MAST studies, and a 4-hour window was used in the ASK trial. The prolonged treatment windows, while offering the opportunity for treatment to more patients, may be another reason for the increased bleeding. Lastly, concurrent therapy with heparin in MAST-E and with aspirin in MAST-I may have contributed to the poor outcomes in those studies. A reasonable question is whether the NINDS t-PA study is the exception that proves the rule or the exception to the rule. In other words, the results of the NINDS study may signify that t-PA is effective and reasonably safe if given at a specific dose to a select group of stroke patients within a limited time after 32D

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stroke onset. On the other hand, that outcome might be the result of random chance (i.e., luck), meaning that the results of ECASS, the 2 MAST trials, and the ASK trial might be more indicative of the true outcomes. This reasoning could indicate that thrombolytics are simply not safe and effective in stroke patients. Clearly, it is impossible to make meaningful comparisons among the various studies because of important differences in study design. Even if the thrombolytic agent was the same, the dose was different. If the dose was the same, the timing was different. It is also important to consider that the NINDS study was really 2 studies in one, with both showing the same results. When it is further considered that efficacy and safety were seen in both the 0 –90-minute group and the 91–180-minute group, the results are more compelling. Based on these data, the FDA approved t-PA in June 1996 for administration within 3 hours, as the first and so far only acute therapy for ischemic stroke. Current t-PA protocols: The following section describes the pretreatment and posttreatment t-PA protocols that are currently in use at Duke University Medical Center (Table V). These resemble protocols used at other major stroke centers and are consistent with recent recommendations concerning the use of thrombolytic therapy in acute stroke prepared by the Stroke Council of the American Heart Association.9 Of course, individual protocols will vary depending on the institution and personal preferences. In fact, FDA approval was somewhat vague with respect to various inclusion/exclusion criteria, indicating some flexibility in certain areas. PRETREATMENT PROTOCOL: When a stroke patient arrives at the Duke University Medical Center emergency department, we take a rapid history and perform a physical examination. The inclusion and exclusion

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criteria (Table I) are reviewed. We immediately establish 2 intravenous lines and send off blood samples to assess prothrombin time, partial thromboplastin time, routine laboratory values, and a type and screen. While the blood tests are being conducted we send the patient for a head CT scan. While the patient is having the scan we obtain informed consent from the family, using a consent form that clearly explains that t-PA therapy is associated with an increased risk of bleeding. We review the CT scan results on the monitor so that no time is wasted printing and developing the images. We then administer t-PA in the emergency department or, if time is short, while the patient is in the scanner. During t-PA administration, the patient is closely monitored for changes in vital signs, neurologic status, and bleeding. POSTTREATMENT PROTOCOL: The posttreatment protocol differs markedly from t-PA protocols used in cardiology. We never give anticoagulants or antiplatelet agents for the first 24 hours after t-PA infusion because of the risk of increased bleeding complications. For the same reason, we do not perform invasive procedures or do arterial punctures or intramuscular injections for 24 hours, although some centers prohibit such procedures for only 6 – 8 hours after treatment. We recommend that the patient be admitted to a stroke unit or intensive care unit for close monitoring for at least 24 hours. During this period, we advise keeping the blood pressure #185 mm Hg systolic and 110 mm Hg diastolic. Even if the patient is asymptomatic, we repeat the head CT scan after 24 hours to determine whether there has been any hemorrhage into the brain. Findings of hemorrhage may affect our decision about how and when to begin treatment with heparin, warfarin, or antiplatelet agents. TREATMENT OF BLEEDING: The posttreatment protocol includes measures to treat bleeding. With peripheral bleeding, we try to apply direct pressure. If that is not effective or the patient has experienced internal bleeding, we give cryoprecipitate. This substance is rich in fibrinogen, and hypofibrinogenemia is a major cause of bleeding after lytic therapy. We typically infuse 5 U of cryoprecipitate. If that approach is not successful, we transfuse fresh frozen plasma or platelets. If bleeding continues, packed red blood cells can be transfused. We also recommend fluid resuscitation if necessary. The future of thrombolytic therapy: Investigators are now pursuing many promising avenues of research in an effort to improve the results of thrombolytic therapy for stroke and to make lytic therapy accessible to more patients. The Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) study is now under way to determine whether it is possible to expand the t-PA treatment window from 3 hours to 5 hours. Clearly, that would be desirable, because it would increase the pool of potential candidates for t-PA therapy. Another study of intravenous t-PA, ECASS 2, is under way in Europe. This study uses a protocol very similar to the NINDS t-PA study, but with a 6 hour treatment window. Results are due in early 1998.

INTRA-ARTERIAL PRO-UROKINASE: Research is also under way to evaluate intra-arterial pro-urokinase (Prolyse, Abbott Laboratories). Ideally, this approach may improve the efficacy and reduce the bleeding complications in at least some stroke patients. Patients selected to receive pro-urokinase undergo an angiogram. After the catheter has been inserted and positioned within the clot that is causing the stroke, prourokinase is infused to lyse the clot directly. Heparin is also administered to some patients. In light of promising results in the 40-patient Prolyse in Acute Cerebral Thrombolytic Trial (PROACT) pilot study,10 the larger PROACT II study is now in progress.11 MAGNETIC RESONANCE SPECTROSCOPY: An ongoing collaborative research effort is assessing the value of new neuroimaging techniques, such as magnetic resonance spectroscopy (MRS), to identify patients who might benefit from reperfusion. For example, if an MRS shows an area of infarcted brain without an ischemic penumbra, a physician might decide to withhold thrombolytics from that patient because it is unlikely that reperfusing infarcted brain will be efficacious. On the other hand, if the MRS shows a large area of brain that is ischemic but does not appear to be dead, that patient might benefit from therapy with a neuroprotectant or thrombolytics.12,13 Combination therapy: Preliminary research is now under way to test the safety and efficacy of combination therapy with a lytic and a neuroprotective agent. There are several potential advantages to what is sometimes called the “stroke cocktail” approach. The most important is improved efficacy. Theoretically, it may be possible to expand the treatment window by giving a neuroprotectant to prevent ischemic brain from being transformed into dead brain. The patient could then receive a lytic agent beyond the current 3-hour treatment window. However, this approach has not been proven in humans. Another advantage of this approach is that treatment can begin before the patient has had a head CT scan. Although such a scan is mandatory before thrombolytic therapy, patients are unlikely to require a scan before receiving one of the neuroprotective agents that are now at an advanced stage of clinical investigation because there is no evidence that these neuroprotectants increase the risk of ICH or are harmful in such patients. With combination therapy, it would be possible to begin administering a neuroprotectant in the field, obtain a head CT scan once the patient reaches the hospital, and then administer a lytic agent. Despite its theoretical appeal, there are several practical disadvantages to the stroke cocktail approach. Limited combined toxicology data are currently available,14 and there is always the potential for altered pharmacokinetics when 2 agents are combined. The agents may interact negatively, producing increased and unexpected adverse effects. The other area that may be problematic is that of dual exclusion criteria. With combination therapy, it is necessary to superimpose the exclusion criteria for thrombolytics on top of those for neuroprotectants. Although com-

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bination therapy may expand the therapeutic window, there may be a reduced pool of patients who qualify for this regimen.

DISCUSSION We are finally moving into an era when we can be proactive, rather than reactive, in the treatment of acute stroke patients. In the near future, we hope to be able to expand the therapeutic window for lytic agents and complement or duplicate the benefits of thrombolytic therapy by administering them alone or in conjunction with neuroprotectants. This is a very promising time to be treating stroke patients, because we may be able to reduce death and disability by reversing or limiting the effects of an acute stroke. However, for such therapies to become used in mainstream medical care, both patients and physicians must look upon stroke as a true medical emergency requiring very rapid diagnosis, care, and treatment. 1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587. 2. Anonymous. FDA committee clears Activase for stroke. Scrip 2137; June 14, 1996:24. 3. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen

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G, Bluhmki E, Hoxter G, Mahagne MH. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA 1995;274:1017–1025. 4. MAST Group. Protocol for the Multicenter Acute Stroke Trial–Thrombolysis study. Clin Trials Meta-Analys 1993;28:329 –344. 5. Hommel M, Boissel JP, Cornu C, Boutitie F, Lees KR, Besson G, Leys D, Amarenco P, Bogaert M. Termination of trial of streptokinase in severe acute ischaemic stroke. Lancet 1995;345:57. 6. Multicenter Acute Stroke Trial–Europe Study Group. Thrombolytic therapy with streptokinase in acute ischemic stroke. N Engl J Med 1996;335:145–150. 7. 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. 8. Donnan GA, Davis SM, Chambers BR, Gates PC, Hankey GJ, McNeil JJ, Rosen D, Stewart-Wynne EG, Tuck RR, for the Australian Streptokinase (ASK) Trial Study Group. Streptokinase for acute ischemic stroke with relationship to time of administration. JAMA 1996;276:961–966. 9. Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Stroke 1996;27:1711–1718. 10. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Gent M, Driscoll RM. The Prolyse in Acute Cerebral Thromboembolism Trial (PROACT): results of 6 mg dose tier. Stroke 1996;27:164. 11. Anonymous. Pro-urokinase beneficial in stroke. Scrip 2102;February 13, 1996:20. 12. Barker PB, Gillard JH, van Zijl PCM, Soher BJ, Hanley DF, Agildere AM, Oppenheimer SM, Bryan RN. Acute stroke: evaluation with serial proton MR spectroscopic imaging. Radiology 1994;192:723–732. 13. Fisher M, Prichard JW, Warach S. New magnetic resonance techniques for acute ischemic stroke. JAMA 1995;274:908 –911. 14. Grotta J. A glimpse to the future: multitherapy trials. Cerebrovasc Dis 1995;5(suppl 1):27–30.

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