Background Thrombolytic therapy for acute ischemic stroke hasbeen approached cautiously because there were high rates ofintracerebral hemorrhage in early clinical trials. We performeda randomized, double-blind trial of intravenous recombinanttissue plasminogen activator (t-PA) for ischemic stroke afterrecent pilot studies suggested that t-PA was beneficial whentreatment was begun within three hours of the onset of stroke.
Methods The trial had two parts. Part 1 (in which 291 patientswere enrolled) tested whether t-PA had clinical activity, asindicated by an improvement of 4 points over base-line valuesin the score of the National Institutes of Health stroke scale(NIHSS) or the resolution of the neurologic deficit within 24hours of the onset of stroke. Part 2 (in which 333 patientswere enrolled) used a global test statistic to assess clinicaloutcome at three months, according to scores on the Barthelindex, modified Rankin scale, Glasgow outcome scale, and NIHSS.
Results In part 1, there was no significant difference betweenthe group given t-PA and that given placebo in the percentagesof patients with neurologic improvement at 24 hours, althougha benefit was observed for the t-PA group at three months forall four outcome measures. In part 2, the long-term clinicalbenefit of t-PA predicted by the results of part 1 was confirmed(global odds ratio for a favorable outcome, 1.7; 95 percentconfidence interval, 1.2 to 2.6). As compared with patientsgiven placebo, patients treated with t-PA were at least 30 percentmore likely to have minimal or no disability at three monthson the assessment scales. Symptomatic intracerebral hemorrhagewithin 36 hours after the onset of stroke occurred in 6.4 percentof patients given t-PA but only 0.6 percent of patients givenplacebo (P<0.001). Mortality at three months was 17 percentin the t-PA group and 21 percent in the placebo group (P = 0.30).
Conclusions Despite an increased incidence of symptomatic intracerebralhemorrhage, treatment with intravenous t-PA within three hoursof the onset of ischemic stroke improved clinical outcome atthree months.
Ischemic stroke affects over 400,000 people in the United Statesannually,1 and there is no direct treatment to reduce the extentof neurologic injury. Cerebral angiography conducted soon afterthe onset of stroke demonstrates arterial occlusions in 80 percentof acute infarctions.2,3 Thrombolytic canalization of occludedarteries may reduce the degree of injury to the brain if itis done before the process of infarction has been completed.Since intracerebral hemorrhage was a frequent major complicationreported in early trials of thrombolytic therapy,4,5 the useof recombinant human tissue plasminogen activator (t-PA) forcerebral arterial thrombolysis requires a careful evaluationof both the risks and the potential benefits.
The safety of intravenous t-PA for the treatment of acute cerebralischemia was previously tested in two open-label, dose-escalationstudies,6,7 which emphasized very early treatment — within90 and 180 minutes of the onset of the stroke — to reducethe risk of hemorrhage and to maximize the potential for recovery.These studies suggested that doses of less than 0.95 mg of t-PAper kilogram of body weight were relatively safe and resultedin early neurologic improvement in a substantial proportionof patients. These results were enough to justify further investigationin the form of a larger, randomized, placebo-controlled trial.
Methods
The trial was carried out in two parts. Part 1 assessed changesin neurologic deficits 24 hours after the onset of stroke asa measure of the activity of t-PA. Part 2, the pivotal study,used four outcome measures representing different aspects ofrecovery from stroke to assess whether treatment with t-PA resultedin sustained clinical benefit at three months. To provide acomprehensive evaluation of t-PA as a treatment for acute ischemicstroke, the results of the two parts were combined and stratifiedaccording to the length of time from the onset of stroke tothe initiation of treatment.
Hypotheses and Design
Part 1 was designed to test whether t-PA had clinical activity— specifically, whether a greater proportion of patientstreated with t-PA, as compared with those given placebo, hadearly improvement. Early improvement was defined as completeresolution of the neurologic deficit or an improvement frombase line in the score on the National Institutes of Healthstroke scale (NIHSS) by 4 or more points 24 hours after theonset of stroke. Each group was assessed according to the timefrom the onset of stroke to the beginning of treatment: 0 to90 minutes, 91 to 180 minutes, and 0 to 180 minutes after theonset of stroke. The primary hypothesis for part 2 was thatthere would be a consistent and persuasive difference betweenthe t-PA and placebo groups in terms of the proportion of patientswho recovered with minimal or no deficit three months aftertreatment. Except for the difference in the primary hypotheses,the protocols for parts 1 and 2 were the same. To prevent prematureextrapolation of the results of part 1 to part 2, investigatorsremained unaware of the results of part 1 until the completionof part 2. The Data and Safety Monitoring Committee revieweddata from part 1 before approving the protocol for part 2 anddesignating the primary end point. Both protocols were approvedby the Human Research Committee at each site.
In part 1, with the inclusion of 70 patients per time stratum(0 to 90 minutes or 91 to 180 minutes) and treatment group (total,280 patients), the power was 0.90 to detect an absolute differenceof 24 percentage points in outcome given a rate of 16 percentin the placebo group (alpha level of 0.05 by a two-sided test).In part 2, with the inclusion of 160 patients per treatmentgroup, the power was 0.95 to detect a difference of 20 percentagepoints between groups in a single measure. The power of theglobal test is equal to or greater than that of a single measure.8
Selection of Patients
To be eligible for the study, patients had to have had an ischemicstroke with a clearly defined time of onset, a deficit measurableon the NIHSS, and a base-line computed tomographic (CT) scanof the brain that showed no evidence of intracranial hemorrhage.Patients did not undergo randomization if they had had anotherstroke or serious head trauma within the preceding 3 months;had undergone major surgery within 14 days; had a history ofintracranial hemorrhage; had a systolic blood pressure above185 mm Hg or diastolic blood pressure above 110 mm Hg; had rapidlyimproving or minor symptoms; had symptoms suggestive of subarachnoidhemorrhage; had gastrointestinal hemorrhage or urinary tracthemorrhage within the previous 21 days; had arterial punctureat a noncompressible site within the previous 7 days; or hada seizure at the onset of stroke. Patients who were taking anticoagulantsor who had received heparin within the 48 hours preceding theonset of stroke and had an elevated partial-thromboplastin timewere excluded, as were those with prothrombin times greaterthan 15 seconds, platelet counts below 100,000 per cubic millimeter,or glucose concentrations below 50 mg per deciliter (2.7 mmolper liter) or above 400 mg per deciliter (22.2 mmol per liter).Patients were also excluded if aggressive treatment was requiredto reduce their blood pressure to the specified limits. Informedconsent was obtained for all patients.
Randomization and Treatment
A permuted-block design with blocks of various sizes was usedfor randomization, with patients stratified according to clinicalcenter and time from the onset of stroke to the start of treatment(0 to 90 or 91 to 180 minutes). Patients received placebo oralteplase (Activase, Genentech, South San Francisco), a recombinantt-PA, in a dose of 0.9 mg per kilogram of body weight (maximum,90 mg), 10 percent of which was given as a bolus followed bydelivery of the remaining 90 percent as a constant infusionover a period of 60 minutes. Genentech supplied and distributedboth the t-PA and the placebo and monitored the clinical sites.
The protocol required that no anticoagulants or antiplateletagents be given for 24 hours after treatment and that bloodpressure be maintained within prespecified values. The medicalmonitor reviewed each patient's compliance with the protocolthroughout the trial.
Outcome Measures
Four outcome measures were selected on the basis of their reliability,familiarity to the neurologic community, adaptability for usein patients who have had a stroke, and comparability to endpoints used in other trials of thrombolytic therapy. The Barthelindex9 is a reliable and valid measure of the ability to performactivities of daily living such as eating, bathing, walking,and using the toilet. Patients able to perform all activitieswith complete independence are given a score of 100. The Barthelindex has been used to evaluate outcome in patients who havehad a stroke.10 The modified Rankin scale11 is a simplifiedoverall assessment of function in which a score of 0 indicatesthe absence of symptoms and a score of 5, severe disability.The Glasgow outcome scale12 is a global assessment of functionin which a score of 1 indicates a good recovery; a score of2, moderate disability; a score of 3, severe disability; a scoreof 4, survival but in a vegetative state; and a score of 5,death. It has been used in a trial of treatment for stroke causedby subarachnoid hemorrhage.13 The NIHSS,14 a serial measureof neurologic deficit, is a 42-point scale that quantifies neurologicdeficits in 11 categories. For example, a mild facial paralysisis given a score of 1, and complete right hemiplegia with aphasia,gaze deviation, visual-field deficit, dysarthria, and sensoryloss is given a score of 25. Normal function without neurologicdeficit is scored as zero. In part 1, the NIHSS was expectedto be sensitive to and reliably detect a change in neurologicdeficit in patients who had had a stroke. In part 2, the NIHSSwas dichotomized to identify clearly patients with minimal orno neurologic deficit. This use for the NIHSS is new but consistentwith its purpose and capability. Scores of 95 or 100 on theBarthel index, <1 on the NIHSS and the modified Rankin scale,and 1 on the Glasgow outcome scale were considered to indicatea favorable outcome.
Data Collection
According to the protocol, the outcome was determined at 24hours and three months by certified examiners who had not performedthe base-line examination and had not been present during theinitial treatment. The reliability and reproducibility of theBarthel index and the NIHSS certification process have beenreported.14,15,16 Classification of the subtypes of the strokeswas based only on information available before randomization.
CT Scans
During the study, third- or fourth-generation CT scanners hadto be available 24 hours a day. CT quality standards were establishedbefore the trial started. Each scan was reviewed centrally forcompliance by a radiologist blinded to all clinical information,including treatment group.
Statistical Analysis
All analyses were based on the intention to treat.17 The criticallevel for a two-sided test of each primary hypothesis was 0.05.Clinical center and, where appropriate, time from the onsetof the stroke were used to stratify the data.
Primary Outcome in Part 1
For each primary hypothesis, Mantel–Haenszel tests wereused to compare the proportion of patients with improvementin the NIHSS 24 hours after the onset of stroke. There was noadjustment for multiple comparisons, since the three hypotheseswere prespecified. Patients who for some reason were not assessedwith the NIHSS at 24 hours were considered to have had no improvement.
Primary Outcome in Part 2
The primary hypothesis was tested with a global statistic (theWald test) derived from a general linear model with logit-linkfunction, computed with the use of generalized estimating equations.18,19This global test statistic simultaneously tests for effect inall four outcome measures specified in the primary hypothesis.Patients who died before the three-month assessment were giventhe worst possible score for all outcomes. In cases of survivingpatients with missing outcome data, outcome data obtained afterthree months were used; if there were none, the data from themeasurement closest in time, but at least seven days after randomization,were used. Otherwise, the worst possible score was assigned.Mantel–Haenszel tests comparing the differences in eachof the four measures were planned only if the global-test resultswere significant at the 0.05 level. Each univariate test useda critical level of 0.05 as a guideline to interpretation. Anadditional global test was performed after adjustment for thestratifying variables and for covariates that differed significantlyat base line between the two groups (P<0.05).
Secondary Analyses
Intention-to-treat analysis was used for the secondary outcomesat three months in part 1 and for the NIHSS measurement at 24hours in part 2. These secondary analyses were considered descriptive.For binary outcomes, Mantel–Haenszel tests were used tocompare individual variables between groups, and global testswere used to compare sets of variables. Analysis of covariancewas used for post hoc comparisons of median NIHSS scores onthe ranked data.
Monitoring for Efficacy
Interim analyses with adjusted critical levels for the primaryoutcomes were performed once during part 1 and once during part2.20,21
Monitoring for Safety
Intracranial hemorrhage, serious systemic bleeding, death, andnew stroke were the primary adverse events monitored. To detectintracranial hemorrhage, CT scans were required at 24 hoursand 7 to 10 days after the onset of stroke and when any clinicalfinding suggested hemorrhage. A hemorrhage was considered symptomaticif it was not seen on a previous CT scan and there had subsequentlybeen either a suspicion of hemorrhage or any decline in neurologicstatus. All CT scans were made available to treating physicianswhile a patient was receiving care. Later, each CT scan wasexamined for evidence of hemorrhage by a neuroradiologist atthe CT-reading center who was blinded to clinical information.The medical monitor independently reviewed the clinical reportsto detect any unreported adverse events.
Interim analyses were required after every 3 symptomatic intracranialhemorrhages and after every 10 deaths. A lower boundary (z =-2.0) was set to allow the trial to be stopped if t-PA was foundto be harmful.22,23 For deaths, a direct comparison of the survivalcurves was made with a log-rank test. For symptomatic intracranialhemorrhage, the rate among patients treated with t-PA was comparedwith the rate of 8 percent estimated from pilot studies usingsimilar doses and times of treatment.
Results
From January 1991 through October 1994, 624 patients underwentrandomization. The treatment groups were well matched with respectto all base-line characteristics except weight in part 1 ofthe trial and age and aspirin use in part 2 (Table 1 and Table 2).
Table 2. Base-Line Characteristics of the Patients in the Two Parts of the Study, According to Treatment Group.
Compliance with the protocol was excellent in this trial. Inpart 1, 90 percent of the t-PA group and 92 percent of the placebogroup received the full dose (±5 percent) of the studymedication, whereas in part 2, 93 percent of both groups receivedthe full dose (±5 percent). Of the primary outcome measuresfor the 291 patients in part 1, data were missing for 1. Ofthe 1332 primary outcome measures in part 2 (333 patients),data were missing for 7 (4 patients). Twenty-four hours afterthe onset of stroke, only 2 percent of the patients given placebohad no neurologic deficit, as measured by the NIHSS.
In part 1 no statistically significant differences were detectedbetween groups in the primary outcome (improvement by 4 or morepoints in the NIHSS score or a complete resolution of the neurologicdeficit) (Table 3). However, post hoc comparisons of medianNIHSS scores showed improvement in the condition of patientstreated with t-PA as compared with those given placebo in mosttime strata in parts 1 and 2 and in the combined analysis.
Table 3. Scores on the NIHSS 24 Hours after the Onset of Stroke.
In part 2 the number of patients with favorable outcomes foreach of the four primary outcome measures three months afterstroke was higher in the t-PA group than in the placebo group(Table 4). As evaluated by the global test statistic, the oddsratio for a favorable outcome in the t-PA group was 1.7 (95percent confidence interval, 1.2 to 2.6; P = 0.008). As comparedwith the placebo group, there was a 12 percent absolute (32percent relative) increase in the number of patients with minimalor no disability (a score of 95 or 100 on the Barthel index)in the t-PA group. There was also an 11 percent absolute (55percent relative) increase in the number of patients with anNIHSS score of 0 or 1 in this group. A similar magnitude ofeffect was seen with respect to the absolute and relative improvementin the t-PA group with the use of the modified Rankin scaleand the Glasgow outcome scale. The inclusion of variables thatdiffered between the two groups at base line (aspirin use, weight,and age) as covariates in addition to the clinical center andtime to treatment after the onset of stroke in the global testincreased the odds ratio to 2.0 (95 percent confidence interval,1.3 to 3.1). Secondary outcomes for part 1 and data from thecombined analysis for both time strata are also shown in Table 4and indicate the same pattern of benefit for t-PA. There wereno significant differences in mortality between the groups (Figure 1).By 90 days after the onset of stroke, 54 of the 312 t-PA–treatedpatients had died (17 percent), as compared with 64 of the 312placebo-treated patients (21 percent) (P = 0.30).
Figure 1. Mean (±SE) Survival at Three Months According to Treatment.
The combined results of parts 1 and 2 are shown. There were 312 patients in each group, and no patient had missing data on mortality. Error bars represent the standard errors of the point estimates of survival at 30, 60, and 90 days. The number of patients surviving at each interval is shown.
Figure 2 shows the outcome at three months in part 2 of thestudy. The results of all four outcome measures favor the t-PAgroup. The greater proportion of patients left with minimalor no deficit three months after t-PA therapy, as compared withplacebo treatment, was not accompanied by an increase in severedisability or mortality. The results were similar in part 1.The positive effect of t-PA on all outcome measures at threemonths was seen consistently in subgroups categorized accordingto age, base-line classification of the stroke subtype (Table 5),severity of the stroke, and use of aspirin before the stroke.
Figure 2. Outcome at Three Months in Part 2 of the Study, According to Treatment.
Scores of 1 on the NIHSS, 95 or 100 on the Barthel index, 1 on the modified Rankin scale, and 1 on the Glasgow outcome scale were considered to indicate a favorable outcome. Values do not total 100 percent because of rounding.
Table 5. Outcome at Three Months According to the Classification of the Stroke Subtype at Base Line.
Symptomatic intracerebral hemorrhage during the first 36 hoursoccurred more commonly in t-PA–treated patients (P<0.001for the combined analysis) (Table 6). Patients with symptomaticintracranial hemorrhage had more severe deficits at base line(median NIHSS score, 20; range, 3 to 29) than the study populationas a whole (median NIHSS score, 14; range, 1 to 37). Nine percentof the patients with intracranial hemorrhage had CT evidenceof cerebral edema at base line, as compared with 4 percent ofthe study population as a whole. Another six patients had symptomaticintracranial bleeding (four given t-PA and two given placebo)between 36 hours and three months after the start of treatment.Eleven deaths were attributed to intracerebral hemorrhage. Atthree months, 17 of the 28 patients with symptomatic hemorrhage(61 percent) had died.
Table 6. Incidence of Intracranial Hemorrhage within 36 Hours of Treatment for Stroke.
The rate of asymptomatic intracerebral hemorrhage was similarin the two groups. The percentage of patients with serious systemicbleeding during the first 10 days was similar in part 1 (twopatients in the t-PA group and none in the placebo group) andpart 2 (three patients in the t-PA group and none in the placebogroup). Minor external bleeding during the first 10 days wasmore common with t-PA than placebo (23 percent vs. 3 percent).
In part 1 of the study, new ischemic strokes occurred in 8 percentof t-PA–treated patients and 7 percent of those givenplacebo. In part 2, new ischemic stroke occurred in 4 percentof t-PA–treated patients and 4 percent of those givenplacebo.
Discussion
This study found a benefit of intravenous t-PA therapy for patientswith ischemic stroke when treatment was initiated within threehours of the onset of symptoms. As compared with patients givenplacebo, patients treated with t-PA were at least 30 percentmore likely to have minimal or no disability at three months,as measured by the outcome scales (absolute increase in favorableoutcome, 11 to 13 percent). This benefit was not associatedwith any increase in mortality.
Treatment with t-PA resulted in a more favorable outcome thantreatment with placebo regardless of the subtype of stroke diagnosedat base line. Even though the diagnosis of these subtypes wasbased on the limited information obtained before treatment wasstarted, the distribution of the subtypes was similar in bothgroups. Because treatment was started so early, some patientswith transient ischemic attacks could have been enrolled despitethe exclusion of patients whose symptoms rapidly improved. Sinceso few patients given placebo (2 percent) were free of neurologicdeficits at 24 hours on the basis of the NIHSS scores, it isunlikely that the benefit seen with t-PA was due to the spontaneousresolution of stroke symptoms.
In part 2 of our study, our intent was to consider the balancebetween risk and benefit. To justify the serious risks of thrombolytictherapy, we required a meaningful increase in the number ofpatients who recovered with minimal or no disability after treatmentwith t-PA as compared with placebo. To increase our confidencein this outcome, we required that the results of all four outcomemeasures be similar. The modified Rankin scale, Barthel index,and Glasgow outcome scale represent the entire range of functionfrom death and severe disability to complete recovery. The NIHSSmeasures neurologic deficit and not functional outcome. As usedhere, it ensured that complete recovery also meant completeneurologic recovery regardless of function.
Two previous small, randomized studies of intravenous t-PA forstroke found no conclusive evidence of efficacy.24,25 In a recentlycompleted large, placebo-controlled European trial in which1.1 mg of t-PA per kilogram was given intravenously within sixhours of hemispheric ischemia, the investigators reported nobenefit in the population analyzed according to the intentionto treat.26 Two other large, randomized trials of intravenousstreptokinase were stopped early because of an unacceptablerate of symptomatic intracranial hemorrhage.27,28 These largetrials treated most patients more than three hours after theonset of stroke and used different drugs, dosing regimens, andmethods of outcome measurement from those used in our study.The most obvious difference between our study and the otherlarge trials is the extent to which we focused on minimizingthe time to treatment. For 302 patients, symptom recognition,transport to the hospital, triage, neurologic evaluation includingCT scanning, laboratory studies, informed consent, and randomizationwere accomplished within 90 minutes of the onset of stroke.Trials in patients with myocardial infarction have shown increasedbenefit with early treatment.29 Such a benefit from early treatmentis consistent with our understanding of the process of infarctionand the narrow window of opportunity for effective intervention.30
There were more intracranial hemorrhages in t-PA–treatedpatients than in those given placebo, but the proportion withhemorrhage was lower in our trial than in other randomized trialsof streptokinase27,28 and t-PA.26 These differences may be dueto the earlier initiation of treatment3 and lower doses usedin our study.26,31 Post-treatment elevation in blood pressuremay also increase the risk of hemorrhage.31 In our trial, treatingphysicians used an algorithm to manage blood pressure aftertreatment began. Accordingly, the safety of t-PA given laterthan three hours after the onset of stroke, in doses higherthan 0.9 mg per kilogram, and without careful blood-pressuremanagement is not clear.
In conclusion, despite an increased incidence of intracerebralhemorrhage, an improvement in clinical outcome at three monthswas found in patients treated with intravenous t-PA within threehours of the onset of acute ischemic stroke.
Supported by the National Institute of Neurological Disordersand Stroke (N01-NS-02382, N01-NS-02374, N01-NS-02377, N01-NS-02381,N01-NS-02379, N01-NS-02373, N01-NS-02378, N01-NS-02376, andN01-NS-02380).
* The persons and institutions who participated in this trialare listed in the Appendix.
Source Information
Dr. John Marler, as project officer for the study, assumes full responsibility for the overall content and integrity of the manuscript.
Address reprint requests to Dr. John R. Marler at the Division of Stroke and Trauma, National Institute of Neurological Disorders and Stroke, Federal Bldg., Rm. 800, 7550 Wisconsin Ave., Bethesda, MD 20892.
References
Division of Chronic Disease Control and Community Intervention. Cardiovascular disease surveillance: stroke, 1980-1989. Atlanta: Centers for Disease Control and Prevention, 1994.
Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci 1989;91:311-322. [CrossRef][Medline]
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. [CrossRef][Medline]
Fletcher AP, Alkjaersig N, Lewis M, et al. A pilot study of urokinase therapy in cerebral infarction. Stroke 1976;7:135-142. [Free Full Text]
Meyer JS, Gilroy J, Barnhart J. Therapeutic thrombolysis in cerebral thromboembolism: randomized evaluation of intravenous streptokinase. In: Siekert W, Whisnant JP, eds. Cerebral vascular diseases. New York: Grune & Stratton, 1965:200-13.
Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke. I. Pilot study of tissue plasminogen activator administered within 90 minutes. Stroke 1992;23:632-640. [Free Full Text]
Haley EC Jr, Levy DE, Brott TG, et al. Urgent therapy for stroke. II. Pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke 1992;23:641-645. [Free Full Text]
Pocock SJ, Geller NL, Tsiatis AA. The analysis of multiple endpoints in clinical trials. Biometrics 1987;43:487-498. [CrossRef][Medline]
Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Med J 1965;14:61-65. [Medline]
The American Nimodipine Study Group. Clinical trial of nimodipine in acute ischemic stroke. Stroke 1992;23:3-8. [Erratum, Stroke 1992;23:615.] [Free Full Text]
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. [Free Full Text]
Teasdale G, Knill-Jones R, van der Sande J. Observer variability in assessing impaired consciousness and coma. J Neurol Neurosurg Psychiatry 1978;41:603-610. [Free Full Text]
Haley EC Jr, Kassell NF, Torner JC, et al. A randomized controlled trial of high-dose nicardipine in aneurysmal subarachnoid hemorrhage. J Neurosurg 1993;78:537-547. [Medline]
Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. Stroke 1994;25:2220-2226. [Abstract]
Albanese MA, Clarke WR, Adams HP Jr, Woolson RF. Ensuring reliability of outcome measures in multicenter clinical trials of treatments for acute ischemic stroke: the program developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Stroke 1994;25:1746-1751. [Abstract]
Lyden PD, Broderick J, Mascha E. Reliability of the Barthel Index used for the NINDS t-PA Stroke Trial. In: Yamaguchi T, Mori E, Minematsuk K, del Zoppo GJ, eds. Thrombolytic therapy in acute stroke III. Tokyo, Japan: Springer-Verlag (in press).
Lefkopoulou M, Moore D, Ryan L. The analysis of multiple correlated binary outcomes: application to rodent teratology experiments. J Am Stat Assoc 1989;84:810-5.
Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:121-130. [CrossRef][Medline]
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659-663. [Free Full Text]
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549-556. [CrossRef][Medline]
DeMets DL, Ware JH. Group sequential methods for clinical trials with a one-sided hypothesis. Biometrika 1980;67:651-660. [Free Full Text]
DeMets DL, Ware JH. Asymmetric group sequential boundaries for monitoring clinical trials. Biometrika 1982;69:661-663. [Free Full Text]
Haley EC Jr, Brott TG, Sheppard GL, et al. Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke. Stroke 1993;24:1000-1004. [Free Full Text]
Mori E, Yoneda Y, Tabuchi M, et al. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology 1992;42:976-982. [Free Full Text]
Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;274:1017-1025. [Free Full Text]
Hommel M, Boissel JP, Cornu C, et al. Termination of trial of streptokinase in severe acute ischaemic stroke. Lancet 1995;345:57-57.
Donnan GA, Hommel M, Davis SM, McNeil JJ. Streptokinase in acute ischaemic stroke. Lancet 1995;346:56-56.
Fibrinolytic Therapists Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343:311-322. [Erratum, Lancet 1994;343:742.] [CrossRef][Medline]
Zivin JA, Fisher M, DeGirolami U, Hemenway CC, Stashak JA. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 1985;230:1289-1292. [Free Full Text]
Levy DE, Brott TG, Haley EC Jr, et al. Factors related to intracranial hematoma formation in patients receiving tissue-type plasminogen activator for acute ischemic stroke. Stroke 1994;25:291-297. [Abstract]
Appendix
The following persons and institutions participated in the NationalInstitute of Neurological Disorders and Stroke (NINDS) rt-PAStroke Trial: Clinical Centers — University of Cincinnati(150 patients): T. Brott, J. Broderick, R. Kothari, M. O'Donoghue,W. Barsan, T. Tomsick, J. Spilker, R. Miller, L. Sauerbeck;Affiliated sites: St. Elizabeth Hospital (South), J. Farrell,J. Kelly, T. Perkins, R. Miller; University Hospital, T. McDonald;Bethesda North Hospital, M. Rorick, C. Hickey; St. Luke Hospital(East), J. Armitage, C. Perry; Providence Hospital, K. Thalinger,R. Rhude; Christ Hospital, J. Armitage, J. Schill; St. LukeHospital (West), P.S. Becker, R.S. Heath, D. Adams; Good SamaritanHospital, R. Reed, M. Klei; St. Francis/St. George Hospital,A. Hughes, R. Rhude; Bethesda Oak Hospital, J. Anthony, D. Baudendistel;St. Elizabeth Hospital (North), C. Zadicoff, R. Miller; St.Luke Hospital — Kansas City, M. Rymer, I. Bettinger, P.Laubinger;Jewish Hospital, M. Schmerler, G. Meirose; Universityof California, San Diego (146): P. Lyden, K. Rapp, T. Babcock,P. Daum, D. Persona, M. Brody, C. Jackson, S. Lewis, J. Liss,Z. Mahdavi, J. Rothrock, T. Tom, R. Zweifler, J. Dunford, J.Zivin; Affiliated sites: Sharp Memorial Hospital, R. Kobayashi,J. Kunin, J. Licht, R. Rowen, D. Stein; Mercy Hospital, J. Grisolia,F. Martin; Scripps Memorial Hospital, E. Chaplin, N. Kaplitz,J. Nelson, A. Neuren, D. Silver; Tri-City Medical Center, T.Chippendale, E. Diamond, M. Lobatz, D. Murphy, D. Rosenberg,T. Ruel, M. Sadoff, J. Schim, J. Schleimer; Mercy General Hospital,Sacramento, R. Atkinson, D. Wentworth, R. Cummings, R. Frink,P. Heublein; University of Texas Medical School, Houston (104):J.C. Grotta, T. DeGraba, M. Fisher, A. Ramirez, S. Hanson, L.Morgenstern, C. Sills, W. Pasteur, F. Yatsu, K. Andrews, C.Villar-Cordova, P. Pepe, P. Bratina, L. Greenberg, S. Rozek,K. Simmons, Houston Fire Department Emergency Medical Services;Affiliated sites: Hermann Hospital, St. Luke's Episcopal Hospital,Lyndon Baines Johnson General Hospital, Memorial Northwest Hospital,Memorial Southwest Hospital, Heights Hospital, Park Plaza Hospital,Twelve Oaks Hospital; Long Island Jewish Medical Center (72):T.G. Kwiatkowski, S.H. Horowitz, R. Libman, R. Kanner, R. Silverman,J. LaMantia, C. Mealie, R. Duarte, R. Donnarumma, M. Okola,V. Cullin, E. Mitchell; Henry Ford Hospital (62): S.R. Levine,C.A. Lewandowski, G. Tokarski, N.M. Ramadan, P. Mitsias, M.Gorman, B. Zarowitz, J. Kokkinos, J. Dayno, P. Verro, C. Gymnopoulos,R. Dafer, L. D'Olhaberriague, K. Sawaya, S. Daley, M. Mitchell;Emory University School of Medicine (39): M. Frankel, B. Mackay,C. Barch, J. Braimah, B. Faherty, J. MacDonald, S. Sailor, A.Cook, H. Karp, B. Nguyen, J. Washington, J. Weissman, M. Williams,T. Williamson; Affiliated sites: Grady Memorial Hospital, CrawfordLong Hospital, Emory University Hospital, South Fulton Hospital,M. Kozinn, L. Hellwick; University of Virginia Health SciencesCenter (37): E.C. Haley, Jr., T.P. Bleck, W.S. Cail, G.H. Lindbeck,M.A. Granner, S.S. Wolf, M.W. Gwynn, R.W. Mettetal, Jr., C.W.J.Chang, N.J. Solenski, D.G. Brock, G.F. Ford, G.L. Kongable,K.N. Parks, S.S. Wilkinson, M.K. Davis; Affiliated site: WinchesterMedical Center, G.L. Sheppard, D.W. Zontine, K.H. Gustin, N.M.Crowe, S.L. Massey; University of Tennessee (14): M. Meyer,K. Gaines, A. Payne, C. Bales, J. Malcolm, R. Barlow, M. Wilson;Affiliated sites: Baptist Memorial Hospital, C. Cape; MethodistHospital Central, T. Bertorini; Jackson Madison County GeneralHospital, K. Misulis; University of Tennessee Medical Center,W. Paulsen, D. Shepard; Coordinating Center — Henry FordHealth Sciences Center: B.C. Tilley, K.M.A. Welch, S.C. Fagan,M. Lu, S. Patel, E. Masha, J. Verter, J. Boura, J. Main, L.Gordon, N. Maddy, T. Chociemski; CT Reading Centers: Part 1— Henry Ford Health Sciences Center, J. Windham, H. SoltanianZadeh; Part 2 — University of Virginia Medical Center,W. Alves, M.F. Keller, J.R. Wenzel; Central Laboratory:HenryFord Hospital, N. Raman, L. Cantwell; Drug Distribution Center:A. Warren, K. Smith, E. Bailey; Committees — Executive:K.M.A. Welch, B.C. Tilley, J.R. Marler; Steering: K.M.A. Welch,T. Brott, P. Lyden, J.C. Grotta, T.G. Kwiatkowski, S.R. Levine,M. Frankel, E.C. Haley, Jr., M. Meyer, B.C. Tilley, J.R. Marler;Genentech, Inc., Participants: J. Froehlich, J. Breed; Dataand Safety Monitoring Committee: J.D. Easton, J.F. Hallenbeck,G. Lan, J.D. Marsh, M.D. Walker; Project Office — NINDS:J.R. Marler.
Tissue Plasminogen Activator for Acute Ischemic Stroke
Friedman H. S., Koroshetz W. J., The Massachusetts General Hospital Stroke Service , Qureshi N., Marler J. R., The NINDS-PA Stroke Study Group , del Zoppo G. J.
Extract |
Full Text
N Engl J Med 1996;
334:1405-1406, May 23, 1996.
Correspondence
Lesley, W S, Rangaswamy, R, Smith, K H, Watkins, D M
(2009). Predicting acute ischemic stroke by measuring the degree of ocular gaze deviation (Prevost's sign) on CT. Journal of NeuroInterventional Surgery
0: jnis.2009.000281v1-jnis.2009.000281
[Abstract][Full Text]
Roussel, B. D., Macrez, R., Jullienne, A., Agin, V., Maubert, E., Dauphinot, L., Potier, M.-C., Plawinski, L., Castel, H., Hommet, Y., Munuera, J., Montaner, J., Yepes, M., Ali, C., Vivien, D.
(2009). Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact. Brain
0: awp162v1-awp162
[Abstract][Full Text]
Pedragosa, A., Alvarez-Sabin, J., Molina, C. A, Sanclemente, C., Martin, M C., Alonso, F., Ribo, M.
(2009). Impact of a telemedicine system on acute stroke care in a community hospital. J Telemed Telecare
15: 260-263
[Abstract][Full Text]
Hancock, M., Herbert, R. D., Maher, C. G.
(2009). A Guide to Interpretation of Studies Investigating Subgroups of Responders to Physical Therapy Interventions. ptjournal
89: 698-704
[Abstract][Full Text]
Anderson, B. E., Rafferty, A. P., Lyon-Callo, S., Fussman, C., Reeves, M. J.
(2009). Knowledge of Tissue Plasminogen Activator for Acute Stroke Among Michigan Adults. Stroke
40: 2564-2567
[Abstract][Full Text]
Rubiera, M., Ribo, M., Santamarina, E., Maisterra, O., Delgado-Mederos, R., Delgado, P., Ortega, G., Alvarez-Sabin, J., Molina, C. A.
(2009). Is it Time to Reassess the SITS-MOST Criteria for Thrombolysis?: A Comparison of Patients With and Without SITS-MOST Exclusion Criteria. Stroke
40: 2568-2571
[Abstract][Full Text]
Moonis, M.
(2009). Intraarterial Thrombolysis Within the First Three Hours After Acute Ischemic Stroke in Selected Patients. Stroke
40: 2611-2612
[Full Text]
Donnan, G. A., Davis, S. M.
(2009). IV and IA Thrombolytic Stroke Strategies Are Complementary. Stroke
40: 2615-2615
[Full Text]
Ahmed, N., Wahlgren, N., Brainin, M., Castillo, J., Ford, G. A., Kaste, M., Lees, K. R., Toni, D., for the SITS Investigators,
(2009). Relationship of Blood Pressure, Antihypertensive Therapy, and Outcome in Ischemic Stroke Treated With Intravenous Thrombolysis: Retrospective Analysis From Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR). Stroke
40: 2442-2449
[Abstract][Full Text]
Liu, W., Hendren, J., Qin, X.-J., Liu, K. J.
(2009). Normobaric Hyperoxia Reduces the Neurovascular Complications Associated With Delayed Tissue Plasminogen Activator Treatment in a Rat Model of Focal Cerebral Ischemia. Stroke
40: 2526-2531
[Abstract][Full Text]
Rafay, M. F., Cortez, M. A., de Veber, G. A., Tan-Dy, C., Al-Futaisi, A., Yoon, W., Fallah, S., Moore, A. M.
(2009). Predictive Value of Clinical and EEG Features in the Diagnosis of Stroke and Hypoxic Ischemic Encephalopathy in Neonates With Seizures. Stroke
40: 2402-2407
[Abstract][Full Text]
Lansberg, M. G., Bluhmki, E., Thijs, V. N.
(2009). Efficacy and Safety of Tissue Plasminogen Activator 3 to 4.5 Hours After Acute Ischemic Stroke: A Metaanalysis. Stroke
40: 2438-2441
[Abstract][Full Text]
Saver, J. L., Albers, G. W., Dunn, B., Johnston, K. C., Fisher, M., for the STAIR VI Consortium,
(2009). Stroke Therapy Academic Industry Roundtable (STAIR) Recommendations for Extended Window Acute Stroke Therapy Trials. Stroke
40: 2594-2600
[Abstract][Full Text]
Saver, J. L., Gornbein, J., Grotta, J., Liebeskind, D., Lutsep, H., Schwamm, L., Scott, P., Starkman, S.
(2009). Number Needed to Treat to Benefit and to Harm for Intravenous Tissue Plasminogen Activator Therapy in the 3- to 4.5-Hour Window: Joint Outcome Table Analysis of the ECASS 3 Trial. Stroke
40: 2433-2437
[Abstract][Full Text]
Kleindorfer, D., Khoury, J., Broderick, J. P., Rademacher, E., Woo, D., Flaherty, M. L., Alwell, K., Moomaw, C. J., Schneider, A., Pancioli, A., Miller, R., Kissela, B. M.
(2009). Temporal Trends in Public Awareness of Stroke: Warning Signs, Risk Factors, and Treatment. Stroke
40: 2502-2506
[Abstract][Full Text]
Tu, J. V., Nardi, L., Fang, J., Liu, J., Khalid, L., Johansen, H., for the Canadian Cardiovascular Outcomes Research,
(2009). National trends in rates of death and hospital admissions related to acute myocardial infarction, heart failure and stroke, 1994-2004. CMAJ
180: E118-E125
[Abstract][Full Text]
Grunwald, I. Q., Bose, A., Struffert, T., Romeike, B. F., Politi, M., Reith, W., Haass, A.
(2009). Liposuction in Mind. Arch Neurol
66: 800-801
[Full Text]
Brekenfeld, C., Tinguely, P., Schroth, G., Arnold, M., El-Koussy, M., Nedeltchev, K., Byrne, J.V., Gralla, J.
(2009). Percutaneous Transluminal Angioplasty and Stent Placement in Acute Vessel Occlusion: Evaluation of New Methods for Interventional Stroke Treatment. Am. J. Neuroradiol.
30: 1165-1172
[Abstract][Full Text]
Kaya, D., Dincer, A., Yildiz, M.E., Cizmeli, M.O., Erzen, C.
(2009). Acute Ischemic Infarction Defined by a Region of Multiple Hypointense Vessels on Gradient-Echo T2* MR Imaging at 3T. Am. J. Neuroradiol.
30: 1227-1232
[Abstract][Full Text]
Wintermark, M., Rowley, H. A., Lev, M. H.
(2009). Acute Stroke Triage to Intravenous Thrombolysis and Other Therapies with Advanced CT or MR Imaging: Pro CT. Radiology
251: 619-626
[Full Text]
Kohrmann, M., Schellinger, P. D.
(2009). Acute Stroke Triage to Intravenous Thrombolysis and Other Therapies with Advanced CT or MR Imaging: Pro MR Imaging. Radiology
251: 627-633
[Full Text]
Fisher, M., Feuerstein, G., Howells, D. W., Hurn, P. D., Kent, T. A., Savitz, S. I., Lo, E. H., for the STAIR Group,
(2009). Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations. Stroke
40: 2244-2250
[Abstract][Full Text]
Brunser, A. M., Lavados, P. M., Hoppe, A., Lopez, J., Valenzuela, M., Rivas, R.
(2009). Accuracy of Transcranial Doppler Compared With CT Angiography in Diagnosing Arterial Obstructions in Acute Ischemic Strokes. Stroke
40: 2037-2041
[Abstract][Full Text]
Putaala, J., Metso, T. M., Metso, A. J., Makela, E., Haapaniemi, E., Salonen, O., Kaste, M., Tatlisumak, T.
(2009). Thrombolysis in Young Adults With Ischemic Stroke. Stroke
40: 2085-2091
[Abstract][Full Text]
Meseguer, E., Mazighi, M., Labreuche, J., Arnaiz, C., Cabrejo, L., Slaoui, T., Guidoux, C., Olivot, J.-M., Abboud, H., Lapergue, B., Raphaeli, G., Klein, I. F., Lavallee, P. C., Amarenco, P.
(2009). Outcomes of Intravenous Recombinant Tissue Plasminogen Activator Therapy According to Gender: A Clinical Registry Study and Systematic Review. Stroke
40: 2104-2110
[Abstract][Full Text]
Fisher, M., Hachinski, V.
(2009). European Cooperative Acute Stroke Study III: Support for and Questions About a Truly Emerging Therapy. Stroke
40: 2262-2263
[Full Text]
Ingall, T. J.
(2009). Intravenous Thrombolysis for Acute Ischemic Stroke: Time Is Prime. Stroke
40: 2264-2265
[Full Text]
Davis, S. M., Donnan, G. A.
(2009). 4.5 Hours: The New Time Window for Tissue Plasminogen Activator in Stroke. Stroke
40: 2266-2267
[Full Text]
Easton, J. D., Saver, J. L., Albers, G. W., Alberts, M. J., Chaturvedi, S., Feldmann, E., Hatsukami, T. S., Higashida, R. T., Johnston, S. C., Kidwell, C. S., Lutsep, H. L., Miller, E., Sacco, R. L.
(2009). Definition and Evaluation of Transient Ischemic Attack: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease: The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists.. Stroke
40: 2276-2293
[Abstract][Full Text]
Wasiewski, W. W., Johnston, K. C.
(2009). Clinical Trials, Devices, Unproven Treatments, and Clinical Equipoise. Stroke
40: e441-e442
[Full Text]
Kasner, S. E., Del Giudice, A., Rosenberg, S., Sheen, M., Luciano, J. M., Cucchiara, B. L., Messe, S. R., Sansing, L. H., Baren, J. M.
(2009). Who will participate in acute stroke trials?. Neurology
72: 1682-1688
[Abstract][Full Text]
Copenhaver, B. R., Shin, J., Warach, S., Butman, J. A., Saver, J. L., Kidwell, C. S.
(2009). Gradient echo MRI: Implementation of a training tutorial for intracranial hemorrhage diagnosis. Neurology
72: 1576-1581
[Abstract][Full Text]
Nogueira, R.G., Yoo, A.J., Buonanno, F.S., Hirsch, J.A.
(2009). Endovascular Approaches to Acute Stroke, Part 2: A Comprehensive Review of Studies and Trials. Am. J. Neuroradiol.
30: 859-875
[Abstract][Full Text]
Janjua, N., El-Gengaihy, A., Pile-Spellman, J., Qureshi, A.I.
(2009). Late Endovascular Revascularization in Acute Ischemic Stroke Based on Clinical-Diffusion Mismatch. Am. J. Neuroradiol.
30: 1024-1027
[Abstract][Full Text]
Reeves, M., Bhatt, A., Jajou, P., Brown, M., Lisabeth, L.
(2009). Sex Differences in the Use of Intravenous rt-PA Thrombolysis Treatment for Acute Ischemic Stroke: A Meta-Analysis. Stroke
40: 1743-1749
[Abstract][Full Text]
Schumacher, H. C., Meyers, P. M., Higashida, R. T., Derdeyn, C. P., Lavine, S. D., Nesbit, G. M., Sacks, D., Rasmussen, P., Wechsler, L. R.
(2009). Reporting Standards for Angioplasty and Stent-Assisted Angioplasty for Intracranial Atherosclerosis. Stroke
40: e348-e365
[Abstract][Full Text]
Foerch, C., Sitzer, M., Steinmetz, H., Neumann-Haefelin, T., for the Arbeitsgruppe Schlaganfall Hessen (ASH),
(2009). Future Demographic Trends Decrease the Proportion of Ischemic Stroke Patients Receiving Thrombolytic Therapy: A Call to Set-Up Therapeutic Studies in the Very Old. Stroke
40: 1900-1902
[Abstract][Full Text]
Kohrmann, M., Sauer, R., Huttner, H. B., Engelhorn, T., Doerfler, A., Schellinger, P. D.
(2009). MRI Mismatch-Based Intravenous Thrombolysis for Isolated Cerebellar Infarction. Stroke
40: 1897-1899
[Abstract][Full Text]
Mandava, P., Kent, T. A.
(2009). A Method to Determine Stroke Trial Success Using Multidimensional Pooled Control Functions. Stroke
40: 1803-1810
[Abstract][Full Text]
Wasiewski, W. W.
(2009). To Phase 3 or Not to Phase 3?. Stroke
40: 1553-1554
[Full Text]
Mayer, S. A., Schwab, S.
(2009). Advances in Critical Care and Emergency Medicine. Stroke
40: e298-e300
[Full Text]
Meyers, P. M., Schumacher, H. C., Higashida, R. T., Barnwell, S. L., Creager, M. A., Gupta, R., McDougall, C. G., Pandey, D. K., Sacks, D., Wechsler, L. R.
(2009). Indications for the Performance of Intracranial Endovascular Neurointerventional Procedures: A Scientific Statement From the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation
119: 2235-2249
[Full Text]
Arsava, E. M., Rahman, R., Rosand, J., Lu, J., Smith, E. E., Rost, N. S., Singhal, A. B., Lev, M. H., Furie, K. L., Koroshetz, W. J., Sorensen, A. G., Ay, H.
(2009). Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke. Neurology
72: 1403-1410
[Abstract][Full Text]
Saver, J. L., Gornbein, J.
(2009). Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology
72: 1310-1315
[Abstract][Full Text]
Hommel, M, Trabucco-Miguel, S, Joray, S, Naegele, B, Gonnet, N, Jaillard, A
(2009). Social dysfunctioning after mild to moderate first-ever stroke at vocational age. J. Neurol. Neurosurg. Psychiatry
80: 371-375
[Abstract][Full Text]
Konstas, A.A., Goldmakher, G.V., Lee, T.-Y., Lev, M.H.
(2009). Theoretic Basis and Technical Implementations of CT Perfusion in Acute Ischemic Stroke, Part 1: Theoretic Basis. Am. J. Neuroradiol.
30: 662-668
[Abstract][Full Text]
Nogueira, R.G., Schwamm, L.H., Hirsch, J.A.
(2009). Endovascular Approaches to Acute Stroke, Part 1: Drugs, Devices, and Data. Am. J. Neuroradiol.
30: 649-661
[Abstract][Full Text]
Lansberg, M. G., Schwartz, N. E.
(2009). Tissue Plasminogen Activator Does Not Benefit Most Eligible Patients With Stroke. Arch Neurol
66: 540-541
[Full Text]
Mateen, F. J., Nasser, M., Spencer, B. R., Freeman, W. D., Shuaib, A., Demaerschalk, B. M., Wijdicks, E. F. M.
(2009). Outcomes of Intravenous Tissue Plasminogen Activator for Acute Ischemic Stroke in Patients Aged 90 Years or Older. Mayo Clin Proc.
84: 334-338
[Abstract][Full Text]
Ford, A. L., Connor, L. T., Tan, D. K., Williams, J. A., Lee, J.-M., Nassief, A. M.
(2009). Resident-Based Acute Stroke Protocol Is Expeditious and Safe. Stroke
40: 1512-1514
[Abstract][Full Text]
Zivin, J. A., Albers, G. W., Bornstein, N., Chippendale, T., Dahlof, B., Devlin, T., Fisher, M., Hacke, W., Holt, W., Ilic, S., Kasner, S., Lew, R., Nash, M., Perez, J., Rymer, M., Schellinger, P., Schneider, D., Schwab, S., Veltkamp, R., Walker, M., Streeter, J., for the NEST-2 Investigators,
(2009). Effectiveness and Safety of Transcranial Laser Therapy for Acute Ischemic Stroke. Stroke
40: 1359-1364
[Abstract][Full Text]
Whitehead, J., Bolland, K., Valdes-Marquez, E., Lihic, A., Ali, M., Lees, K., for the VISTA Collaborators,
(2009). Using Historical Lesion Volume Data in the Design of a New Phase II Clinical Trial in Acute Stroke. Stroke
40: 1347-1352
[Abstract][Full Text]
Ebinger, M., Christensen, S., De Silva, D. A., Parsons, M. W., Levi, C. R., Butcher, K. S., Bladin, C. F., Barber, P. A., Donnan, G. A., Davis, S. M., for the EPITHET Investigators,
(2009). Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End Point. Stroke
40: 1353-1358
[Abstract][Full Text]
Parsons, M. W., Miteff, F., Bateman, G. A., Spratt, N., Loiselle, A., Attia, J., Levi, C. R.
(2009). Acute ischemic stroke: Imaging-guided tenecteplase treatment in an extended time window. Neurology
72: 915-921
[Abstract][Full Text]
Shuaib, A.
(2009). Disappearance of the hyperdense MCA sign after thrombolysis: is it a predictor of better prognosis in patients with acute ischaemic stroke?. J. Neurol. Neurosurg. Psychiatry
80: 248-248
[Full Text]
Cloft, H.J., Rabinstein, A., Lanzino, G., Kallmes, D.F.
(2009). Intra-Arterial Stroke Therapy: An Assessment of Demand and Available Work Force. Am. J. Neuroradiol.
30: 453-458
[Abstract][Full Text]
Ozdemir, O., Beletsky, V., Chan, R., Hachinski, V.
(2009). Thrombolysis, Fluctuations, and Protocol Expansions--Reply. Arch Neurol
66: 418-419
[Full Text]
Aviv, R. I., d'Esterre, C. D., Murphy, B. D., Hopyan, J. J., Buck, B., Mallia, G., Li, V., Zhang, L., Symons, S. P., Lee, T.-Y.
(2009). Hemorrhagic Transformation of Ischemic Stroke: Prediction with CT Perfusion. Radiology
250: 867-877
[Abstract][Full Text]
Arnold, M., Steinlin, M., Baumann, A., Nedeltchev, K., Remonda, L., Moser, S. J., Mono, M.-L., Schroth, G., Mattle, H. P., Baumgartner, R. W.
(2009). Thrombolysis in Childhood Stroke: Report of 2 Cases and Review of the Literature. Stroke
40: 801-807
[Abstract][Full Text]
Barreto, A. D., Martin-Schild, S., Hallevi, H., Morales, M. M., Abraham, A. T., Gonzales, N. R., Illoh, K., Grotta, J. C., Savitz, S. I.
(2009). Thrombolytic Therapy for Patients Who Wake-Up With Stroke. Stroke
40: 827-832
[Abstract][Full Text]
Mikulik, R., Goldemund, D., Reif, M., Aulicky, P., Krupa, P.
(2009). Outcome of Patients With Negative CT Angiography Results for Arterial Occlusion Treated With Intravenous Thrombolysis. Stroke
40: 868-872
[Abstract][Full Text]
The Optimising the Analysis of Stroke Trials (OAST,
(2009). Should Stroke Trials Adjust Functional Outcome for Baseline Prognostic Factors?. Stroke
40: 888-894
[Abstract][Full Text]
Brekenfeld, C., Schroth, G., Mattle, H. P., Do, D.-D., Remonda, L., Mordasini, P., Arnold, M., Nedeltchev, K., Meier, N., Gralla, J.
(2009). Stent Placement in Acute Cerebral Artery Occlusion: Use of a Self-Expandable Intracranial Stent for Acute Stroke Treatment. Stroke
40: 847-852
[Abstract][Full Text]
Copen, W. A., Rezai Gharai, L., Barak, E. R., Schwamm, L. H., Wu, O., Kamalian, S., Gonzalez, R. G., Schaefer, P. W.
(2009). Existence of the Diffusion-Perfusion Mismatch within 24 Hours after Onset of Acute Stroke: Dependence on Proximal Arterial Occlusion. Radiology
250: 878-886
[Abstract][Full Text]
Alexandrov, A. V.
(2009). Ultrasound Enhancement of Fibrinolysis. Stroke
40: S107-S110
[Abstract][Full Text]
(2009). Thrombolytic therapy with alteplase for ischaemic stroke. DTB
47: 14-18
[Abstract][Full Text]
Yagi, K., Kitazato, K. T., Uno, M., Tada, Y., Kinouchi, T., Shimada, K., Nagahiro, S.
(2009). Edaravone, a Free Radical Scavenger, Inhibits MMP-9-Related Brain Hemorrhage in Rats Treated With Tissue Plasminogen Activator. Stroke
40: 626-631
[Abstract][Full Text]
Nogueira, R. G., Smith, W. S., on Behalf of the MERCI and Multi MERCI Writing Com,
(2009). Safety and Efficacy of Endovascular Thrombectomy in Patients With Abnormal Hemostasis: Pooled Analysis of the MERCI and Multi MERCI Trials. Stroke
40: 516-522
[Abstract][Full Text]
Zhang, C., An, J., Strickland, D. K., Yepes, M.
(2009). The Low-Density Lipoprotein Receptor-Related Protein 1 Mediates Tissue-Type Plasminogen Activator-Induced Microglial Activation in the Ischemic Brain. Am. J. Pathol.
174: 586-594
[Abstract][Full Text]
Rafay, M. F., Pontigon, A.-M., Chiang, J., Adams, M., Jarvis, D. A., Silver, F., MacGregor, D., deVeber, G. A.
(2009). Delay to Diagnosis in Acute Pediatric Arterial Ischemic Stroke. Stroke
40: 58-64
[Abstract][Full Text]
Ali, M., Atula, S., Bath, P. M.W., Grotta, J., Hacke, W., Lyden, P., Marler, J. R., Sacco, R. L., Lees, K. R., for the VISTA Investigators,
(2009). Stroke Outcome in Clinical Trial Patients Deriving From Different Countries. Stroke
40: 35-40
[Abstract][Full Text]
Sato, S., Uehara, T., Toyoda, K., Yasui, N., Hata, T., Ueda, T., Okada, Y., Toyota, A., Hasegawa, Y., Naritomi, H., Minematsu, K., the Stroke Unit Multicenter Observational (SUMO) S,
(2009). Impact of the Approval of Intravenous Recombinant Tissue Plasminogen Activator Therapy on the Processes of Acute Stroke Management in Japan: The Stroke Unit Multicenter Observational (SUMO) Study. Stroke
40: 30-34
[Abstract][Full Text]
Kimura, K., Iguchi, Y., Shibazaki, K., Terasawa, Y., Aoki, J., Matsumoto, N.
(2009). The Presence of a Right-to-Left Shunt Is Associated With Dramatic Improvement After Thrombolytic Therapy in Patients With Acute Ischemic Stroke. Stroke
40: 303-305
[Abstract][Full Text]
Cai, W., Guzman, R., Hsu, A. R., Wang, H., Chen, K., Sun, G., Gera, A., Choi, R., Bliss, T., He, L., Li, Z.-B., Maag, A.-L. D., Hori, N., Zhao, H., Moseley, M., Steinberg, G. K., Chen, X.
(2009). Positron Emission Tomography Imaging of Poststroke Angiogenesis. Stroke
40: 270-277
[Abstract][Full Text]
Torbey, M. T., Jauch, E., Liebeskind, D. S., the Acute Stroke Advisory Board of the National St, , Fitzpatrick, A. E., Noone, I., O'Shea, D. D., Schwamm, L. H., Fonarow, G. C., Morris, D. C., Hacke, W., Kaste, M., Toni, D.
(2008). Thrombolysis 3 to 4.5 Hours after Acute Ischemic Stroke. NEJM
359: 2839-2841
[Full Text]
Alberts, M. J., Felberg, R. A., Guterman, L. R., Levine, S. R., for Writing Group 4,
(2008). Atherosclerotic Peripheral Vascular Disease Symposium II: Stroke Intervention: State of the Art. Circulation
118: 2845-2851
[Full Text]
Castellanos, M., Sobrino, T., Pedraza, S., Moldes, O., Pumar, J. M., Silva, Y., Serena, J., Garcia-Gil, M., Castillo, J., Davalos, A.
(2008). High plasma glutamate concentrations are associated with infarct growth in acute ischemic stroke. Neurology
71: 1862-1868
[Abstract][Full Text]
Rose, K. M., Rosamond, W. D., Huston, S. L., Murphy, C. V., Tegeler, C. H.
(2008). Predictors of Time From Hospital Arrival to Initial Brain-Imaging Among Suspected Stroke Patients: The North Carolina Collaborative Stroke Registry. Stroke
39: 3262-3267
[Abstract][Full Text]
Henning, E. C., Latour, L. L., Hallenbeck, J. M., Warach, S.
(2008). Reperfusion-Associated Hemorrhagic Transformation in SHR Rats: Evidence of Symptomatic Parenchymal Hematoma. Stroke
39: 3405-3410
[Abstract][Full Text]
Cho, A-H., Kim, J. S., Kim, S.-J., Yun, S.-C., Choi, C.-G., Kim, H.-R., Kwon, S. U., Lee, D.-H., Kim, E.-K., Suh, D.-C., Kang, D.-W.
(2008). Focal Fluid-Attenuated Inversion Recovery Hyperintensity Within Acute Diffusion-Weighted Imaging Lesions Is Associated With Symptomatic Intracerebral Hemorrhage After Thrombolysis. Stroke
39: 3424-3426
[Abstract][Full Text]
Pancioli, A. M., Broderick, J., Brott, T., Tomsick, T., Khoury, J., Bean, J., del Zoppo, G., Kleindorfer, D., Woo, D., Khatri, P., Castaldo, J., Frey, J., Gebel, J. Jr, Kasner, S., Kidwell, C., Kwiatkowski, T., Libman, R., Mackenzie, R., Scott, P., Starkman, S., Thurman, R. J., for the CLEAR Trial Investigators,
(2008). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke: The CLEAR Stroke Trial. Stroke
39: 3268-3276
[Abstract][Full Text]
Johnston, S. C.
(2008). The 2008 William M. Feinberg Lecture: Prioritizing Stroke Research. Stroke
39: 3431-3436
[Abstract][Full Text]
Saleem, S., Zhuang, H., Biswal, S., Christen, Y., Dore, S.
(2008). Ginkgo Biloba Extract Neuroprotective Action Is Dependent on Heme Oxygenase 1 in Ischemic Reperfusion Brain Injury. Stroke
39: 3389-3396
[Abstract][Full Text]
Wahlgren, N., Ahmed, N., Eriksson, N., Aichner, F., Bluhmki, E., Davalos, A., Erila, T., Ford, G. A., Grond, M., Hacke, W., Hennerici, M. G., Kaste, M., Kohrmann, M., Larrue, V., Lees, K. R., Machnig, T., Roine, R. O., Toni, D., Vanhooren, G., for the SITS-MOST Investigators,
(2008). Multivariable Analysis of Outcome Predictors and Adjustment of Main Outcome Results to Baseline Data Profile in Randomized Controlled Trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke
39: 3316-3322
[Abstract][Full Text]
Murata, Y., Rosell, A., Scannevin, R. H., Rhodes, K. J., Wang, X., Lo, E. H.
(2008). Extension of the Thrombolytic Time Window With Minocycline in Experimental Stroke. Stroke
39: 3372-3377
[Abstract][Full Text]
Thiyagarajan, M., Fernandez, J. A., Lane, S. M., Griffin, J. H., Zlokovic, B. V.
(2008). Activated Protein C Promotes Neovascularization and Neurogenesis in Postischemic Brain via Protease-Activated Receptor 1. J. Neurosci.
28: 12788-12797
[Abstract][Full Text]
Flaherty, M. L., Karlawish, J., Khoury, J. C., Kleindorfer, D., Woo, D., Broderick, J. P.
(2008). How important is surrogate consent for stroke research?. Neurology
71: 1566-1571
[Abstract][Full Text]
Hermann, D. M.
(2008). Review: Future perspectives for brain pharmacotherapies: implications of drug transport processes at the blood--brain barrier. Therapeutic Advances in Neurological Disorders
1: 167-179
[Abstract]
Wippold, F.J. II, for the Expert Panel on Neurologic Imaging,
(2008). Focal Neurologic Deficit. Am. J. Neuroradiol.
29: 1998-2000
[Full Text]
Burns, T.C., Rodriguez, G.J., Patel, S., Hussein, H.M., Georgiadis, A.L., Lakshminarayan, K., Qureshi, A.I.
(2008). Endovascular Interventions following Intravenous Thrombolysis May Improve Survival and Recovery in Patients with Acute Ischemic Stroke: A Case-Control Study. Am. J. Neuroradiol.
29: 1918-1924
[Abstract][Full Text]
Liang, B. A., Lew, R., Zivin, J. A.
(2008). Review of Tissue Plasminogen Activator, Ischemic Stroke, and Potential Legal Issues. Arch Neurol
65: 1429-1433
[Abstract][Full Text]
Marks, M. P., Olivot, J.-M., Kemp, S., Lansberg, M. G., Bammer, R., Wechsler, L. R., Albers, G. W., Thijs, V.
(2008). Patients with Acute Stroke Treated with Intravenous tPA 3-6 Hours after Stroke Onset: Correlations between MR Angiography Findings and Perfusion- and Diffusion-weighted Imaging in the DEFUSE Study. Radiology
249: 614-623
[Abstract][Full Text]
Lees, K.R., Ford, G.A., Muir, K.W., Ahmed, N., Dyker, A.G., Atula, S., Kalra, L., Warburton, E.A., Baron, J.-C., Jenkinson, D.F., Wahlgren, N.G., Walters, M.R., for the SITS-UK Group,
(2008). Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register. QJM
101: 863-869
[Abstract][Full Text]
Stoll, G., Kleinschnitz, C., Nieswandt, B.
(2008). Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood
112: 3555-3562
[Abstract][Full Text]
Lou, M., Safdar, A., Mehdiratta, M., Kumar, S., Schlaug, G., Caplan, L., Searls, D., Selim, M.
(2008). The HAT Score: A simple grading scale for predicting hemorrhage after thrombolysis. Neurology
71: 1417-1423
[Abstract][Full Text]
Tanne, D., Levine, S. R.
(2008). Safer thrombolysis for acute ischemic stroke: Is early recanalization the key?. Neurology
71: 1300-1301
[Full Text]
1 on the NIHSS, 95 or 100 on the Barthel index,