Early Intravenous Thrombolysis for Acute Ischemic Stroke

in a Community-Based Approach
Martin Grond, MD; Christoph Stenzel, MD; Susanne Schmülling, MD; Jobst Rudolf, MD;
Michael Neveling, MD; Alex Lechleuthner, MD; Susanne Schneweis, MD; Wolf-Dieter Heiss, MD

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.
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.
Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018

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. (Stroke. 1998;29:1544-1549.)
Key Words: stroke management n stroke, acute n thrombolytic therapy

C ontrolled multicenter studies with rtPA demonstrated for

the first time an effective treatment for selected cases of
acute stroke.1–3 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 recom-
mended that the application of thrombolysis should be re-
stricted 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
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 acti-
vated, 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 re-
stricted 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 commu-

Received March 5, 1998; final revision received April 29, 1998; accepted April 29, 1998.
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.
© 1998 American Heart Association, Inc.

1544

Selected Abbreviations and Acronyms
aPTT 5 activated partial thromboplastin time
ASA 5 acetylsalicylic acid
ECASS-I 5 European Cooperative Acute Stroke Study I
NIHSS 5 National Institutes of Health Stroke Scale
NINDS 5 National Institute of Neurological Disorders and
Stroke
rtPA 5 recombinant tissue-type plasminogen activator
nity 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 hospi-
tals was avoided.
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
Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018
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
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
After informed consent had been obtained from the patient or next
of kin, 0.9 mg/kg rtPA (alteplase [Actilyse], Thomae) was adminis-
tered 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 prophy-
laxis 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 repeat-
edly 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
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
Grond et al August 1998 1545
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
Statistical Analysis
Data were analyzed using SAS procedures (SAS Institute Inc). The
values were expressed as mean6SD, 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.
CT Scans
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 hemor-
rhagic 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 parenchy-
mal hemorrhage according to the criteria described by Pessin et al.11
The latter were then subdivided into symptomatic hemorrhages and
asymptomatic hemorrhages.1
Etiologic Data
Classification of stroke was based on the information available at
discharge after thorough examination that included Doppler ultra-
sonography of extra- and intracranial vessels and both echocardiog-
raphy 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
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).
Treatment Group
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.
 1546 Early Intravenous Thrombolysis

(22% of the patients referred) were treated with systemic rtPA

Figure 1. Diagram detailing the number of patients referred
within 18 months.
Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018
(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 trans-
ferred 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

Forty-eight (10.6%) patients were initially misdiagnosed, 29
of them with neurological disease (eg, epileptic seizures with
Todd’s paresis, meningoencephalitis, or psychiatric disor-
ders), 19 of them with nonneurological disease (eg, intoxica-
tion, 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 preselec-
tive criteria. Of these 149 patients, 47 patients had to be
excluded because of the presence of predefined exclusion
criteria (eg, excessive hypertension, pretreatment with anti-
coagulants, early major infarct signs on CT, or recent major
surgery), 2 patients refused consent. Finally, 100 patients
(“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.
Effect of Thrombolysis
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 cardiovas-
cular risk factors was comparable between the NINDS study
and our cohort. Eighty-eight patients suffered from supraten-
torial 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.

Baseline Characteristics of the Patients

Trial

NINDS rt-PA, Part I NINDS rt-PA, Part II Cologne

Characteristics (n5144) (n5168) (n5100)
Age, mean6SD 67610 69612 63611
Time to treatment, minimum and mean 48% within 90 min 124 min
26% within 90 min
Sex, % female 42 40 40
Weight, kg 76615 76616 75615
NIHSS score, median (range) 14 (1–37) 14 (2–37) 12 (2–37)
Small-vessel, % 19 14 21
Large-vessel, % 35 39 28
Cardioembolic, % 42 45 35
Other/Undetermined, % 3 2 16
SBP, mm Hg 155622 153622 161623
DBP, mm Hg 85612 85614 93613
Fibrinogen, g/L 332694 3116102 303698
Glucose, mg/dL 149676 149666 141668
SBP indicates systolic blood pressure; DBP, diastolic blood pressure.

Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018
Figure 2. Outcome at 3 months in comparison with the NINDS
and ECASS 3-hour intention-to-treat group.
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).
Grond et al August 1998 1547
Hemorrhagic Complications
Hemorrhagic infarction occurred in 7 patients, in 1 of them
hemorrhagic infarction was associated with neurological
deterioration. Asymptomatic parenchymal hemorrhage oc-
curred in 6 patients and symptomatic parenchymal hemor-
rhage 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. Com-
pared with the group of patients without hemorrhagic con-
version, incidence of ASA pretreatment (9/30 versus 9/70,
P50.01), history of myocardial infarction (6/15 versus 12/85,
P50.002), and incidence of early infarct signs on CT (9/31
versus 8/57, P50.02) were significantly higher in the hem-
orrhagic conversion group. In the 1 patient pretreated with
ticlopidine, devastating symptomatic parenchymal hematoma
occurred during rtPA infusion and before initiation of heparin
treatment.
Discussion
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.
Patient Referral System
Thrombolysis is an effective but potentially harmful treat-
ment, and there is only limited experience from 2 large
placebo-controlled trials and a few open trials.1,2,13–20 There-
fore, 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 com-
munication 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, com-
petition 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
 1548 Early Intravenous Thrombolysis
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.
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 effective-
ness 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 addi-
Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018
tional 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
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.
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 devastat-
ing 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
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
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 intra-
venous 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 opti-
mization of the referral system is necessary.
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
Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018
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 assess-
ment of stroke patients in the Cologne hospitals.
References
1. The National Institute of Neurological Disorders and Stroke r-tPA Stroke
Study Group. Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995;333:1581–1587.
2. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, Von Kummer R,
Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M, for the
ECASS Study Group. Intravenous thrombolysis with recombinant tissue
plasminogen activator for acute hemispheric stroke. JAMA. 1995;274:
1017–1025.
3. del Zoppo GJ. Acute stroke: on the threshold of a therapy? N Engl J Med.
1995;333:1632–1633.
4. Grotta J. t-PA: the best current option for most patients. N Engl J Med.
1997;337:1310 –1312.
5. Adams HP, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason C,
Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg
M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a
supplement to the guidelines for the management of patients with acute
ischemic stroke: a statement for healthcare professionals from a special
writing group of the Stroke Council, American Heart Association. Cir-
culation. 1996;94:1167–1174.
6. Lyden P, Grotta J, Levine SR, Marler JR, Frankel MR, Brott TG. Intra-
venous thrombolysis for acute stroke. Neurology. 1997;49:14 –20.
7. Lyden P, Brott T, Tilley B, Welch KMA, Mascha EJ, Levine S, Haley
EC, Grotta J, and the NINDS TPA Stroke Study Group. Improved
reliability of the NIH stroke scale using video training. Stroke. 1994;25:
2220 –2226.
8. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md
Med J. 1965;14:61– 65.
9. 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.
10. Hacke W, Toni D, Steiner T, Kaste M, von Kummer R, Fieschi C,
Bluhmki E, for the ECASS Study Group. rt-PA in acute ischemic stroke-
results from the ECASS three hour cohort. Stroke. 1997;28:272. Abstract.
11. Pessin MS, Del Zoppo GJ, Estol CJ. Thrombolytic agents in the treatment
of strokes. Clin Neuropharmacol. 1990;13:271–289.
Grond et al August 1998 1549
12. Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR,
Wolf PA. Infarcts of undetermined cause: the NINCDS Stroke Data
Bank. Ann Neurol. 1989;25:382–390.
13. von Kummer R, Hacke W. Safety and efficacy of intravenous tissue
plasminogen activator and heparin in acute middle cerebral artery stroke.
Stroke. 1992;23:646 – 652.
14. Trouillas P, Nighoghossian N, Getenet JC, Riche G, Neuschwander P,
Froment JC, Turjman F, Jin JX, Malicier D, Fournier G, Gabry AL,
Ledoux X, Derex L, Berthezène Y, Adeleine P, Xie J, Ffrench P,
Dechavanne M. Open trial of intravenous tissue plasminogen activator in
acute carotid territory stroke. Stroke. 1996;27:882– 890.
15. Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K,
Tsutsumi A, Yamadori A. Intravenous recombinant tissue plasminogen ac-
tivator in acute carotid artery territory stroke. Neurology. 1992;42:976–982.
16. Yamaguchi T, Hayakawa T, Kiuchi H, for the Japanese Thrombolysis Study
Group. Intravenous tissue plasminogen activator ameliorates the outcome of
hyperacute embolic stroke. Cerebrovasc Dis. 1993;3:269–272.
17. Brott TG, Haley EC Jr, Levy DE, Barsan W, Broderick J, Sheppard GL,
Spilker J, Kongable GL, Massey S, Reed R, Marler JR. Urgent therapy for
stroke, part I: pilot study of tissue plasminogen activator administered
within 90 minutes. Stroke. 1992;23:632– 640.
18. Haley EC, Levy DE, Brott TG, Sheppard GL, Wong MCW, Kongable
GL, Torner JC, Marler JR. Urgent therapy for stroke, part II: pilot study
of tissue plasminogen activator administered 91–180 minutes from onset.
Stroke. 1992;23:641– 645.
19. Haley EC Jr, Brott TG, Sheppard GL, Barsan W, Broderick J, Marler JR,
Kongable GL, Spilker J, Massey S, Hansen CA, Torner JC, for the TPA
Bridging Study Group. Pilot randomized trial of tissue plasminogen
activator in acute ischemic stroke. Stroke. 1993;24:1000 –1004.
20. Del Zoppo GJ, Poeck K, Pessin MS, Wopert SM, Furlan AJ, Ferbert A,
Alberts MJ, Zivin JA, Wechsler L, Busse O, Greenlee R Jr, Brass L, Mohr
JP, Feldmann E, Hacke W, Kase CS, Biller J, Gress D, Otis SM. Recom-
binant tissue plasminogen activator in acute thrombotic and embolic
stroke. Ann Neurol. 1992;32:78 – 86.
21. Chiu D, Krieger D, Villar-Cordova C, Kasner SE, Morgenstern LB,
Bratina PL, Yatsu FM, Grotta JC. Intravenous tissue plasminogen acti-
vator for acute ischemic stroke: feasibility, safety and efficacy in the first
year of clinical practice. Stroke. 1998;29:18 –22.
22. Alberts MJ, Perry A, Dawson DV, Bertels C. Effects of public and
professional education on reducing the delay in presentation and referral
of stroke patients. Stroke. 1992;23:352–356.
23. Barsan WG, Brott TG, Broderick JP, Haley EC, Levy DE, Marler JR.
Urgent therapy for acute stroke: effects of a stroke trial on untreated
patients. Stroke. 1994;25:2132–2137.
24. The NINDS rt-PA Stroke Study Group. Generalized efficacy of t-PA for
acute stroke: subgroup analysis of the NINDS t-PA Stroke Trial. Stroke.
1997;28:2119 –2125.
25. Von Kummer R, Allen KL, Holle R, Bozzao L, Bastianello S, Manelfe C,
Bluhmki E, Ringleb P, Meier DH, Hacke W. Acute stroke: usefulness of
early CT findings before thrombolytic therapy. Radiology. 1997;205:
327–333.
26. Grond M, von Kummer R, Sobesky J, Schmülling S, Heiss WD. Early
computed-tomography abnormalities in acute stroke. Lancet. 1997;350:
1595–1596.
27. Heiss WD, Grond M, Thiel A, Stockhausen HM, Rudolf J. Ischemic brain
tissue salvaged from infarction with alteplase. Lancet. 1997;349:
1599 –1600.
28. Tanne D, Mansbach HH, Verro P, Binder JR, Karanjia PN, Dayno J, Dulli
D, Book D, Levine SR, and the rt-PA in Clinical Practice Stroke Survey
Group. Intravenous rt-PA therapy for stroke in clinical practice: a mul-
ticenter evaluation of outcome. Stroke. 1998;29:288. Abstract.
29. The NINDS rt-PA Stroke Study Group. Intracerebral hemorrhage after
intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28:
2109 –2118.
30. International Stroke Trial Collaborative Group. The International Stroke
Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or
neither among 19 435 patients with acute ischemic stroke. Lancet. 1997;
349:1569 –1581.
31. Gunnar RM, Passamani ER, Bourdillon PDV, Dixon DW, Fuster V, Karp
RB, Kennedy JW, Klocke FJ, Pitt B, Rapaport E, Reeves TJ, Russel RO
Jr, Sobel BE, Winter WL Jr. Guidelines for the early management of
patients with acute myocardial infarction: a report of the American
College of Cardiology/American Heart Association task force on
assessment of diagnostic and therapeutic cardiovascular procedures. J Am
Coll Cardiol. 1990;16:249 –292.
 Early Intravenous Thrombolysis for Acute Ischemic Stroke in a Community-Based
Approach
Martin Grond, Christoph Stenzel, Susanne Schmülling, Jobst Rudolf, Michael Neveling, Alex
Lechleuthner, Susanne Schneweis and Wolf-Dieter Heiss
Downloaded from http://stroke.ahajournals.org/ by guest on April 13, 2018

Stroke. 1998;29:1544-1549
doi: 10.1161/01.STR.29.8.1544
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1998 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://stroke.ahajournals.org/content/29/8/1544

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.
Once the online version of the published article for which permission is being requested is located, click
Request Permissions in the middle column of the Web page under Services. Further information about this
process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Stroke is online at:

http://stroke.ahajournals.org//subscriptions/