From the Klinik für Neurologie der Universität zu Köln
(M.G., C.S., S. Schmülling, J.R., M.N., S. Schneweis, W.-D.H.), Germany,
and the Institut für Nofallmedizin der Berufsfeuerwehr Köln (A.L.).
Correspondence to Prof Dr W.-D. Heiss, Klinik für Neurologie der Universität zu Köln, Joseph-Stelzmann-Str 9, D-50924 Köln, Germany.
Methods—We offered rtPA treatment to stroke patients in a
prospective open-label monocenter study applying inclusion criteria
similar to those of the National Institute of Neurological Disorders,
and Stroke study. In order to treat patients within 3 hours of symptom
onset, a referral system was used by which eligible patients from all
over the city of Cologne, Federal Republic of Germany, were rushed to
the Department of Neurology of the University Hospital. We present
data on the effectiveness of the referral system and the outcome
results of the first 100 consecutive patients treated within an
18-month period.
Results—Of 453 consecutive patients with a presumed diagnosis of
acute stroke referred to our department between March 1996 and August
1997, 100 patients (22%) were treated with intravenous
thrombolysis, 26% of them within 90 minutes of symptom
onset. The average time from stroke onset to arrival at our department
was 78 minutes, and from arrival to treatment 48 minutes. After 3
months, 53 patients recovered to fully independent function. The rates
of total, symptomatic, and fatal
intracerebral hemorrhage were 11%, 5%, and
1%, respectively. Overall mortality was 12%.
Conclusions—Thrombolysis with rtPA was effectively
applied in routine management of stroke patients in a community-based
approach with acceptable efforts and without additional costs. Under
these circumstances, outcome and complication rates were comparable to
those of multicenter trials.
As there were no reliable data available about stroke management in
Germany, between March 1997 and May 1997 (3-month period) all patients
with presumed acute stroke being referred to any of the 16 Cologne
hospitals were assessed prospectively within 24 hours after admission
and will be followed until 1 year after discharge by members of our
stroke group. Among other variables, we evaluated patient arrival
times to the hospitals and final diagnosis at discharge. Definitions of
time intervals were established before data collection. The time of
stroke onset was defined as the time when symptoms of stroke first
occurred. If no accurate information was available, the stroke was
considered to start when the patient was last known to be
asymptomatic. In cases where no reliable information could
be given, this variable was labeled "unknown." From the data
collected during this 3-months, estimates were made for an 18-month
period by multiplying the respective numbers with the factor 6.
Inclusion Criteria, Clinical Assessment, and Treatment
After informed consent had been obtained from the patient or next of
kin, 0.9 mg/kg rtPA (alteplase [Actilyse], Thomae) was administered
intravenously over 60 minutes (10% bolus, 90%
continuously). In contrast to former studies, immediate anticoagulation
with heparin was routinely performed. This was done for early secondary
prophylaxis and analogous to coronary
thrombolysis. After completion of rtPA infusion,
heparin was administered by continuous infusion, aiming to increase
aPTT to 1 1/2 to 2 times standard normal values. Initial dosage
of heparin infusion was 1000 U/h. aPTT was repeatedly controlled, and
dosage was adjusted for the duration of heparin therapy (approximately
10 days). All patients received osmodiuretic drugs (mannitol
10%, in rare cases glycerol 10%, 500 mL per day, in 5 doses of 100 mL
each) during the first day to prevent brain edema. Osmotherapy was
continued only if brain edema was detected in the following CT
examination.
Outcome Assessment
Statistical Analysis
CT Scans
Etiologic Data
Treatment Group
Effect of Thrombolysis
Twelve patients died during the 90-day observation period, 8 of them
during the first week. One patient died from parenchymal
hemorrhage, 7 from malignant brain edema, and 1 with
infratentorial stroke from brain stem dysfunction and additional
supratentorial hemorrhage. One patient died
during carotid artery surgery on day 43, 1 patient died from septic
pneumonia on day 74, and 1 from sudden cardiac arrest on day 44. The
latter 3 deaths were considered to be unrelated to the treatment of
acute stroke.
Early infarct signs on CT defined as hypodensity covering less than one
third of the MCA territory were present in 31 patients (35% of the
supratentorial ischemias).
Hemorrhagic Complications
Patient Referral System
Within an 18-month period 149 patients who met these criteria perfectly
were referred to us; of these, 100 were treated with
thrombolysis. This fact underlines the effectiveness of
the system on the one hand and the effectiveness of our center on the
other hand. Whereas arrival times are somewhat longer, especially for
those patients referred from a community hospital, than in the recently
published first American feasibility study, this difference was
compensated for by our extremely short door-to-needle time (average of
48 minutes compared with 100 minutes in the American
study).21 This gives evidence of a successful
optimization of in-hospital management that would be hard to achieve in
all centers in the alternative multicenter approach. Despite additional
exclusion criteria, we were able to treat the largest series of
patients in a single center ever reported. Our aim for the future is to
optimize preselection (eg, by stressing the importance of the exact
time of symptom onset) and to increase the number of patients eligible
for thrombolysis. Because late arrival still is a major
limiting factor for early thrombolysis, a public
educational program was started by which potential patients, their
relatives, and the general medical community are informed about signs
and symptoms of ischemic events and the chances and potential
benefits of emergency management of stroke. In 2 studies in which
public awareness and education were stimulated by intensive campaigns,
intervals between onset of symptoms and arrival in specialized
institutions were significantly shortened by increased use of emergency
services.22 23
Safety
Other protocol violations were also rare: Only at the beginning of our
study, 2 patients were treated even though they were ineligible for
thrombolysis because of an elapsed time window. They
both died from malignant brain edema following unsuccessful
thrombolysis. This observation is in accordance with
the finding that patients with protocol violations have higher
complication rates2 28 and stresses the
importance of careful patient selection, especially the exact
definition of the time of onset of symptoms. Mistaking the moment of
symptom recognition for the moment of symptom onset was a major pitfall
for the first contacting doctors.
Incidence of symptomatic hemorrhage was not
excessively high after combined treatment with rtPA and high-dose
heparin, and independent of aPTT values after 24 hours. The finding
that prior myocardial infarction was associated with a higher risk of
intracerebral hemorrhage goes in line with the
results of the univariate analysis of the NINDS
data.29 Surprisingly, a relationship between
baseline stroke severity and intracerebral
hemorrhage could not be established in our patients, whereas a
significant relationship between ASA pretreatment and
intracerebral hemorrhage was detected. This
might indicate that the combination of ASA, rtPA, and high-dose heparin
should be avoided. Whether the devastating parenchymal
hemorrhage seen during rtPA infusion in 1 patient can be
attributed to his ticlopidine pretreatment cannot be answered, because
he was the only patient pretreated with ticlopidine.
Outcome Results
Besides differences in the study populations, other factors could have
also had a positive influence on our results: the use of
intravenous heparin and the concomitant use of
osmodiuretics. The same factors were suggested by Trouillas et
al14 to be responsible for the excellent results
in their open rtPA study. A definite assessment of the effectiveness of
immediate heparin cannot be given because of the lack of a control
group in our study. Even though heparin treatment was recently shown
not to be effective in stroke with therapy onset within the first 48
hours,30 it could play a role as adjunctive
therapy in thrombolysis of stroke, as it does in
myocardial infarction.31 Our data could therefore
encourage a controlled trial to assess the potential benefit of
combined therapy of rtPA and heparin.
In conclusion, in a community-based approach early
intravenous thrombolysis was offered to a
considerable number of stroke patients without additional cost (except
for drug costs) and without expiring the limited capacity of a single
stroke center. However, the number of potential candidates for
thrombolysis is substantially higher. Therefore,
further optimization of the referral system is necessary.
Received March 5, 1998;
revision received April 29, 1998;
accepted April 29, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Early Intravenous Thrombolysis for Acute Ischemic Stroke in a Community-Based Approach
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Controlled
multicenter studies have demonstrated the efficacy of systemic
recombinant tissue-type plasminogen activator
(rtPA) treatment in selected cases of acute ischemic
stroke. The feasibility of this therapeutic option in clinical practice
was assessed in a community-based approach.
Key Words: stroke management • stroke, acute • thrombolytic therapy
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Controlled
multicenter studies with rtPA demonstrated for the first time an
effective treatment for selected cases of acute
stroke.1 2 3 The next necessary step is to
introduce the experiences from the positive trials into clinical
routine and to carefully monitor the results.4
However, this therapeutic option bears a potential risk of
intracerebral hemorrhage, and its major
shortcoming for routine application is the short therapeutic window of
<3 hours. In addition, it is recommended that the application of
thrombolysis should be restricted to neurologists or
other disciplines with expertise in neurological emergency and CT
reading.5 6 In Cologne, only our department met
the criteria described above at that time. With these limitations, we
offered rtPA treatment in a community-based approach to stroke patients
in a prospective open-label study applying inclusion criteria similar
to those of the NINDS study. A referral system was used by which
eligible patients from all over Cologne were rushed to our department.
The feasibility of early thrombolysis for patients with
acute ischemic stroke in this setting was assessed. In
addition, outcome and complication rates were analyzed and
compared with those of the NINDS and ECASS-I trials.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Patients and Recruitment
With a city area of 156 square miles and 1 004 928
inhabitants, Cologne is the third largest city in Germany in terms of
area and the fourth largest in terms of population. There are 14
community hospitals without a neurology department, 7 of them with a CT
scanner but only 2 of them with 24-hour-service. One teaching hospital
with a neurology department and CT scanner with 24-hour service had
decided not to offer thrombolysis at that time. Thus,
our neurology department at the University Hospital was the only place
where patients could receive thrombolytic therapy. In
case of stroke, patients are usually referred by the emergency services
to the community hospitals nearest to their homes. A cooperation
between the community hospitals and our department was established
several years ago in order to optimize acute stroke management. With
systemic thrombolysis introduced in our department in
March 1996 as a promising therapeutic strategy, this referral system
was activated, and its effectiveness was significantly improved
by inclusion of the municipal emergency services. The cooperative
strategy was to offer rtPA therapy to as many suitable patients as
possible. Preselective criteria to refer patients to our department
were restricted to the following: onset of symptoms suspicious of
stroke within less than 3 hours, patient age under 80 years, and
absence of severe impairment of consciousness. If referred patients
were not eligible for thrombolytic treatment, they were
sent to their community hospitals after diagnosis with recommendations
for further therapy. Patients receiving rtPA treatment were usually
transferred to their primary care hospitals after the first week. By
this cooperative practice, the number of patients referred to our
department was limited in order not to exhaust the capacity of a single
center, and, on the other hand, competition for patients with the
community hospitals was avoided.
Inclusion and exclusion criteria for systemic rtPA treatment
were adopted from the NINDS1 study, with the
following additional exclusion criteria taken from the ECASS
study2 : Age over 80 years, hypodensity of more
than 33% of the middle cerebral artery territory on initial CT scan,
severely impaired consciousness (except for vertebrobasilar stroke), or
forced head and eye deviation. On admission, neurological deficit was
assessed using the NIHSS (0 to 42 points).7
Clinical assessment was repeated with NIHSS after 24 hours and
after 90 days. In addition, activities of daily living were measured
using the Barthel Index (0 to 100 points),8 and
overall function was assessed using the modified Rankin scale (grade 0
to 5)9 after 90 days. The outcome at 3 months was
determined by 2 trained examiners (S. Schmülling and S.
Schneweis) who had not performed the baseline examination and had not
been present during the initial treatment. Early clinical
improvement was defined according to the NINDS criteria as 4-point
improvement in the NIHSS score from baseline values or complete
resolution of neurological deficit. Classification of late outcome was
also adopted from the NINDS study. Late outcome data were compared with
those of the NINDS study. Rankin score at day 90 was also compared with
the 3-hour cohort of the intention-to-treat population of the ECASS
trial.10
Data were analyzed using SAS procedures (SAS Institute
Inc). The values were expressed as mean±SD, and comparisons of
baseline characteristics among groups were performed with
Wilcoxon's signed rank test. Potential predictors of
intracerebral hemorrhage were analyzed
by Fisher's exact test for dichotomous variables.
Unenhanced head CT scanning with a Siemens Somatom Plus 32
scanner was routinely performed on admission, at 24 hours, and after 1
week and whenever neurological deterioration occurred. Initial CT scans
were scrutinized for early signs of infarction defined as a hypodensity
and for indications of hemorrhage, and follow-up scans for
demarcation of infarction, extent of brain edema, and hemorrhagic
conversion. This was done independently by a neurologist (C.S.) who had
participated in the ECASS CT training but who had no knowledge of the
clinical data of the patients and follow-up CTs. Hemorrhage was
classified as hemorrhagic infarction or parenchymal
hemorrhage according to the criteria described by Pessin et
al.11 The latter were then subdivided into
symptomatic hemorrhages and
asymptomatic
hemorrhages.1
Classification of stroke was based on the information available
at discharge after thorough examination that included Doppler
ultrasonography of extra- and intracranial vessels and both
echocardiography and Holter-ECG in cases of
suspected cardiac embolism. Patients were classified into the
diagnostic subgroups of large-vessel atherothrombosis,
small-vessel lacunae, and cardiogenic embolism. Failure to define
etiology was classified as undetermined
cause.12
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Epidemiological Background
Between March 1997 and May 1997 (3 months), 672 patients with
presumed acute stroke were admitted to the Cologne hospitals. In 325
patients (48.4%) the final diagnosis was acute ischemic
stroke, in 136 (20.2%) patients transient ischemic attack, and
in 35 (5.2%) patients hemorrhage; in 93 (13.8%) patients
final diagnosis was not established because no CT scan was performed.
In 69 (10.5%) patients final diagnosis was something other than stroke
(eg, metabolic disease or infection); in 14 (2%) patients
final diagnosis was missing. In 64 (20%) of 325 patients with the
final diagnosis of acute ischemic stroke, no reliable
information about symptom onset was available. Ninety-six (29.5%)
patients with the final diagnosis of acute ischemic stroke were
admitted to a Cologne hospital within 3 hours after symptom onset, 67
of them were under age 80 years. From these data the following
estimates can be made for an 18-month period (Figure 1
).
View larger version (30K):
[in a new window]
Figure 1. Diagram detailing the number of patients referred
within 18 months.
Between March 1996 and August 1997, 453 consecutive patients were
referred to our department with presumed acute stroke. Of those,
230 (50.8%) patients were referred by the emergency services,
196 (43.3%) patients from a community hospital, and 27 (5.9%)
patients from a general practitioner. Forty-eight (10.6%)
patients were initially misdiagnosed, 29 of them with neurological
disease (eg, epileptic seizures with Todd's paresis,
meningoencephalitis, or psychiatric disorders), 19 of them with
nonneurological disease (eg, intoxication, syncope, or
metabolic disorder). In 84 (18.5%) patients, CT scanning
revealed intracerebral brain hemorrhage.
Seventy-six (16.8%) patients showed rapid improvement or full
resolution of clinical symptoms. In 245 (54%) patients, the diagnosis
of acute ischemic stroke was established. In 96 of these
patients, however, the time of onset was longer than 3 hours before
admission or could not be defined reliably. Therefore, only 149
(32.9%) patients matched our preselective criteria. Of these 149
patients, 47 patients had to be excluded because of the presence of
predefined exclusion criteria (eg, excessive hypertension, pretreatment
with anticoagulants, early major infarct signs on CT, or recent major
surgery), 2 patients refused consent. Finally, 100 patients (22% of
the patients referred) were treated with systemic rtPA (Figure 1
). In 2 of them, the protocol was violated (cases 1 and
9), because they were treated even though contradicting the information
available on admission, severe symptoms had been present on
awakening from sleep so that symptom onset could not clearly be defined
and probably was longer than 3 hours previous. They both died from
transtentorial herniation due to severe space-occupying edema within
the first week after treatment. Sixty-one treated patients were
transported directly from their homes to our hospital by the emergency
medical services with a mean arrival interval of 68 minutes. Thirty-one
patients were transferred from another hospital and mean arrival
interval was 100 minutes. Eight patients were seen by their general
practitioners first and then transferred to our hospital
and mean arrival interval was 81 minutes. The difference in arrival
interval between these groups was statistically significant
(P<0.0001). Mean time from arrival at our department to
initiation of treatment ("door-to-needle time") was 48 minutes (SD,
25 minutes; range, 20 to 130 minutes). Thirty-four patients were
treated 30 minutes or less after arrival.
The baseline characteristics of the 100 patients treated with
thrombolysis are given in the Table in
comparison to the NINDS I and II subpopulations. The frequency of
cardiovascular risk factors was comparable between the
NINDS study and our cohort. Eighty-eight patients suffered from
supratentorial stroke, and 12 patients from
infratentorial stroke. Early improvement (within the first 24 hours)
was found in 53 patients, 17 of them had normalized after 24 hours.
Late outcome for the whole population (all data in percent of the
respective population) in comparison with NINDS and ECASS 3-hour
intent-to-treat population cohort results is shown in Figure 2.
View this table:
[in a new window]
Table 1. Baseline Characteristics of the
Patients
View larger version (18K):
[in a new window]
Figure 2. Outcome at 3 months in comparison with the NINDS
and ECASS 3-hour intention-to-treat group.
Hemorrhagic infarction occurred in 7 patients, in 1 of them
hemorrhagic infarction was associated with neurological deterioration.
Asymptomatic parenchymal hemorrhage occurred in 6
patients and symptomatic parenchymal hemorrhage in
5 patients. Incidence of hemorrhagic conversion was neither
significantly related to baseline NIHSS nor to aPTT values after 24
hours. After 24 hours, 31 patients were undercoagulated, in 36 patients
aPTT values were within the target range and 33 patients were
over-anticoagulated. Compared with the group of patients without
hemorrhagic conversion, incidence of ASA pretreatment (9/30
versus 9/70, P=0.01), history of myocardial infarction
(6/15 versus 12/85, P=0.002), and incidence of early
infarct signs on CT (9/31 versus 8/57, P=0.02) were
significantly higher in the hemorrhagic conversion group. In the 1
patient pretreated with ticlopidine, devastating
symptomatic parenchymal hematoma occurred during rtPA
infusion and before initiation of heparin treatment.
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
This report presents data from an open therapeutic trial in
which early systemic thrombolysis with rtPA was offered
in the setting of a community-based monocenter approach. The trial
followed a strict protocol and was prospective, but was not blinded,
and did not include a parallel control group. Therefore, this study
cannot provide evidence for the efficacy of treatment, but it supports
the feasibility of intravenous thrombolysis
for patients with acute ischemic stroke in clinical practice.
The main point addressed in this study is the power of a cooperative
system to refer patients potentially suitable for
thrombolysis to a single center within the short
therapeutic window. In addition, outcome and safety results of systemic
thrombolysis in this setting are compared with those of
multicenter trials.
Thrombolysis is an effective but potentially harmful
treatment, and there is only limited experience from 2 large
placebo-controlled trials and a few open
trials.1 2 13 14 15 16 17 18 19 20 Therefore, it is presently
recommended that thrombolysis should be restricted to
neurologists and other specialties with expertise in neurological
emergency and CT reading. Since these criteria cannot be met in any of
our community hospitals, there are 2 possible cooperative strategies
for putting thrombolysis into clinical practice: One is
to establish communication systems between the hospitals and stroke
teams examining the patients on-site before the decision to initiate
thrombolysis. This would mean additional manpower and
consequently additional costs. On the other hand, the reliable
selection of suitable patients would be performed in a clinical
setting, and there would be no unnecessary further time-consuming
transportation of the patient. Furthermore, competition between
hospitals would be avoided. The second strategy is a monocenter
approach using a referral system. The advantage of this strategy is
that the whole staff of one center can be trained and in-hospital
management can be optimized. Because the capacity regarding the number
of patients that can adequately be managed in a single center is
limited, an effective referral system is needed to preselect patients
without losing too much time. To achieve that goal, the emergency
services and the community hospitals were provided with preselective
criteria that are easy to handle on the one hand and effective on the
other hand.
Clinical and radiological assessment and therapeutic decision were
made by the neurologists in charge of the intensive care unit. They had
been made familiar with the protocol and the CT exclusion criteria and
were trained in the use of the NIHSS. When we started the study in
March 1996 we based our protocol on the experiences of the NINDS and
ECASS studies. At that time, subgroup analysis of the ECASS
study was already available indicating that patients with very severe
strokes and major early infarct signs would not benefit from
thrombolysis. In addition, except for the NINDS study,
all studies had an upper age limit of 80 years. Therefore, these
additional exclusion criteria were used. These modifications had an
effect on our study population. As compared with the NINDS study
population (median NIHSS of 14 and mean age of 67 and 69 years,
respectively), our patients were less severely affected (median NIHSS
of 12, mean NIHSS of 13) and younger (mean age of 63 years), but were
comparable to the ECASS 3-hour intention-to-treat population (mean
NIHSS of 13). Whether our additional exclusion criteria are still
justified if the recently published subgroup analysis of the
NINDS trial is taken into account should be a matter of discussion.
Whereas age and deficit severity did not alter the likelihood of
responding favorably to rtPA, the relevance of early infarct signs was
not adequately analyzed because no differentiation between
minor and major early infarct signs was made.24
The post hoc analysis of the ECASS data yielded convincing
evidence that for patients treated within a 6-hour time window the
response to rtPA can be predicted on the basis of initial CT findings
of the extent of parenchymal hypoattenuation.25
Whether this also is true for patients treated within 3 hours after
symptom onset needs further elucidation. The finding is important that
in 35% of the patients treated who had
supratentorial stroke, minor early infarct signs
were detected on initial CT. These are the patients with an extended
volume of critically hypoperfused tissue who are at risk to develop
extended infarctions that can potentially be prevented by early
reperfusion.26 27 Patients with major early
infarct signs on CT were reliably excluded in our study: Not a single
protocol violation could be detected at reevaluation of admission CT
scans.
Early and late results in our patients are slightly better than
those of the NINDS trial and comparable to those of the ECASS 3-hour
cohort.10 This might be due to the differences in
stroke severity and age on admission. Age-by-deficit severity
interaction has been shown to relate significantly to 3-month
outcome.24
Selected Abbreviations and Acronyms
aPTT
=
activated partial thromboplastin time
ASA
=
acetylsalicylic acid
ECASS-I
=
European Cooperative Acute Stroke Study I
NIHSS
=
National Institutes of Health Stroke Scale
NINDS
=
National Institute of Neurological Disorders and Stroke
rtPA
=
recombinant tissue-type plasminogen
activator
Acknowledgments
The authors thank the emergency services and the medical
personnel at each participating hospital, without whose efforts this
work would not have been possible: St Hildegardis-Krankenhaus
(Priv.-Doz. Dr M. von Eiff), St Franziskus-Hospital (Dr F.-J.
Schneider), Krankenhaus Porz am Rhein (Prof Dr V. Hossmann), St Agatha
Krankenhaus (Dr H. Huber), Ev. Krankenhaus Köln-Weyertal (Prof Dr
R. Eckhardt), St Antonius-Krankenhaus (Prof Dr R. Mies), St
Vinzenz-Hospital (Priv.-Doz. Dr W. Fehske), Eduardus-Krankenhaus (Dr C.
Witthöft), St Marien-Hospital (Prof Dr P. von Smekal),
Heilig-Geist-Krankenhaus (Priv.-Doz. Dr W. Geisthövel), Ev.
Krankenhaus Köln-Kalk (Prof Dr W. Kruis), Krankenhaus der
Augustinerinnen (Dr D. Mitrenga and Prof Dr R. Thoma), St
Elisabeth-Krankenhaus (Prof Dr J. Schönemann), Städt.
Krankenhaus Köln-Holweide (Prof Dr F. Saborowski), Städt.
Krankenhaus Köln-Merheim (Prof Dr H. Bewermeyer). We also
thank Birgit Kühlmorgen, Stefan Blümmers, and Marc Wegener
for assessment of stroke patients in the Cologne hospitals.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
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T. Yamaguchi, E. Mori, K. Minematsu, J. Nakagawara, K. Hashi, I. Saito, Y. Shinohara, and for the Japan Alteplase Clinical Trial (J-ACT) Gro Alteplase at 0.6 mg/kg for Acute Ischemic Stroke Within 3 Hours of Onset: Japan Alteplase Clinical Trial (J-ACT) * Supplemental Appendix 2 Stroke, July 1, 2006; 37(7): 1810 - 1815. [Abstract] [Full Text] [PDF]
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 R.G. Gonzalez Imaging-guided acute ischemic stroke therapy: From "time is brain" to "physiology is brain". AJNR Am. J. Neuroradiol., April 1, 2006; 27(4): 728 - 735. [Abstract] [Full Text] [PDF]
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 R J van Oostenbrugge, R M M Hupperts, and J Lodder Thrombolysis for acute stroke with special emphasis on the very old: experience from a single Dutch centre. J. Neurol. Neurosurg. Psychiatry, March 1, 2006; 77(3): 375 - 377. [Abstract] [Full Text] [PDF]
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A. W. Wojner-Alexandrov, A. V. Alexandrov, D. Rodriguez, D. Persse, and J. C. Grotta Houston Paramedic and Emergency Stroke Treatment and Outcomes Study (HoPSTO) Stroke, July 1, 2005; 36(7): 1512 - 1518. [Abstract] [Full Text] [PDF]
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A. I. Qureshi, J. F. Kirmani, M. A. Sayed, A. Safdar, S. Ahmed, R. Ferguson, L. A. Hershey, K. J. Qazi, and for the Buffalo Metropolitan Area and Erie County Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in ischemic stroke Neurology, June 28, 2005; 64(12): 2115 - 2120. [Abstract] [Full Text] [PDF]
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B. S. Jacobs, P. L. Baker, C. Roychoudhury, R. H. Mehta, and S. R. Levine Improved Quality of Stroke Care for Hospitalized Medicare Beneficiaries in Michigan Stroke, June 1, 2005; 36(6): 1227 - 1231. [Abstract] [Full Text] [PDF]
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 M. D. Hill, A. M. Buchan, and for The Canadian Alteplase for Stroke Effectivenes Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study Can. Med. Assoc. J., May 10, 2005; 172(10): 1307 - 1312. [Abstract] [Full Text] [PDF]
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H. J. Audebert, C. Kukla, S. Clarmann von Claranau, J. Kuhn, B. Vatankhah, J. Schenkel, G. W. Ickenstein, R. L. Haberl, M. Horn, and on behalf of the TEMPiS Group Telemedicine for Safe and Extended Use of Thrombolysis in Stroke: The Telemedic Pilot Project for Integrative Stroke Care (TEMPiS) in Bavaria Stroke, February 1, 2005; 36(2): 287 - 291. [Abstract] [Full Text] [PDF]
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T. J. Ingall, W. M. O'Fallon, K. Asplund, L. R. Goldfrank, V. S. Hertzberg, T. A. Louis, and T. J. H. Christianson Findings From the Reanalysis of the NINDS Tissue Plasminogen Activator for Acute Ischemic Stroke Treatment Trial Stroke, October 1, 2004; 35(10): 2418 - 2424. [Abstract] [Full Text] [PDF]
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 G. W. Albers, P. Amarenco, J. D. Easton, R. L. Sacco, and P. Teal Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 483S - 512S. [Abstract] [Full Text] [PDF]
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W.-D. Heiss, J. Sobesky, U. v. Smekal, L. W. Kracht, F.-G. Lehnhardt, A. Thiel, A. H. Jacobs, and K. Lackner Probability of Cortical Infarction Predicted by Flumazenil Binding and Diffusion-Weighted Imaging Signal Intensity: A Comparative Positron Emission Tomography/Magnetic Resonance Imaging Study in Early Ischemic Stroke Stroke, August 1, 2004; 35(8): 1892 - 1898. [Abstract] [Full Text] [PDF]
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P. J. Lindsberg, L. Soinne, R. O. Roine, O. Salonen, T. Tatlisumak, M. Kallela, O. Happola, M. Tiainen, E. Haapaniemi, M. Kuisma, et al. Community-Based Thrombolytic Therapy of Acute Ischemic Stroke in Helsinki Stroke, June 1, 2003; 34(6): 1443 - 1449. [Abstract] [Full Text] [PDF]
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P. U. Heuschmann, K. Berger, B. Misselwitz, P. Hermanek, C. Leffmann, M. Adelmann, H.-J. Buecker-Nott, J. Rother, B. Neundoerfer, and P. L. Kolominsky-Rabas Frequency of Thrombolytic Therapy in Patients With Acute Ischemic Stroke and the Risk of In-Hospital Mortality: The German Stroke Registers Study Group Stroke, May 1, 2003; 34(5): 1106 - 1112. [Abstract] [Full Text] [PDF]
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K. Nedeltchev, M. Arnold, C. Brekenfeld, J. Isenegger, L. Remonda, G. Schroth, and H. P. Mattle Pre- and In-Hospital Delays From Stroke Onset to Intra-arterial Thrombolysis Stroke, May 1, 2003; 34(5): 1230 - 1234. [Abstract] [Full Text] [PDF]
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