Intravenous tPA for Ischemic Stroke
Team Performance Over Time, Safety, and Efficacy in a
Single-Center, 2-Year Experience
Hans-Christian Koennecke, MD; Roland Nohr, MD; Stefanie Leistner, MD; Peter Marx, MD
Downloaded from http://stroke.ahajournals.org/ by guest on July 31, 2017
Background and Purpose—Safety and efficacy concerns toward thrombolysis for ischemic stroke prevail among many
neurologists because of the risks of hemorrhage and the small proportion of suitable patients. We therefore prospectively
assessed feasibility, safety, efficacy, and team performance in a single center to prove whether thrombolytic treatment
is practical in daily clinical routine.
Methods—Patients were prospectively recruited over a 2-year period. Major inclusion and exclusion criteria from large,
randomized controlled trials were combined. Prespecified outcome parameters were the modified Rankin scale (MRS)
and the Barthel Index (BI) at 3 months and symptomatic hemorrhagic complications. In addition, certain time intervals
during the diagnostic process preceding thrombolysis were prospectively recorded.
Results—Within 2 years a total of 75 patients underwent intravenous thrombolysis, corresponding to 9.4% of all admitted
patients with stroke and 14.9% of patients with ischemic stroke. Mean⫾SD age was 68⫾13 (range 34 to 90) years;
median baseline National Institutes of Health Stroke Scale score was 13⫾6 (range 2 to 34). Thrombolysis was started
at an average time of 144 minutes after symptom onset, and 13 patients (17.3%) were treated beyond 3 hours. Two
cerebral hemorrhages (2.7%) occurred. Outcome according to the MRS was good (MRS 0 to 1) in 40%, moderate (MRS
2 to 3) in 32%, and poor (MRS 4 to 5) in 13%; the corresponding results, as measured by the BI, were 61% (BI 95 to
100, good), 16% (BI 55 to 90, moderate), and 8% (BI 0 to 50, poor). The mortality rate was 15%. Over 2 years the
median door-to-CT time decreased from 30 to 22 minutes (27%), and the door-to-needle time was shortened from 96
to 73 minutes (14%). The mean number of patients treated per month increased from 2 to 4.
Conclusions—Thrombolytic therapy can be performed safely and efficaciously in daily clinical routine. More than a
minority of acute stroke patients might be eligible for intravenous thrombolysis. The performance of a stroke team can
be improved over time, subsequently increasing the proportion of eligible patients and thereby the efficiency of the
method. (Stroke. 2001;32:1074-1078.)
Key Words: outcome 䡲 stroke management 䡲 stroke, ischemic 䡲 thrombolytic therapy
T
aging results of another multicenter survey.8 Furthermore,
the small proportion of stroke patients suitable for
thrombolytic treatment is another major point of criticism
raised within the neurological community. Thus, time
constraints and the logistic efforts required to offer
thrombolysis to more than a minority of stroke patients
have further limited the acceptance and wider use of
thrombolysis in the daily routine of acute stroke care.
To prove whether the concept of systemic thrombolysis
with tPA for ischemic stroke can be transferred into
clinical practice, we prospectively assessed feasibility,
safety, and efficacy in an academic medical center serving
500 000 residents in the south of Berlin, Germany. We
further wanted to demonstrate that the performance of an
acute stroke team can be improved within a decent period
of time.
hrombolytic therapy with tissue plasminogen activator
(tPA) has been shown to improve outcome in ischemic
stroke patients treated within 3 hours from symptom
onset.1,2 However, while the persuasive results of this
study have launched some enthusiasm, safety concerns
prevail among many clinical neurologists because of the
risk of cerebral hemorrhage. Two large European studies
and 2 trials from the United States have clearly shown that
the time window for fibrinolytic therapy is rather narrow,1,3– 6 although the results of the second European
study4 suggest some benefit for patients who undergo
thrombolysis, even when treated within 3 to 6 hours from
symptom onset. Further concerns are nourished by a
report7 from the “real world,” in which the translation of
study results into daily clinical practice seemed to be less
easy and more harmful than expected, despite the encour-
Received December 27, 2000; final revision received January 19, 2001; accepted January 22, 2001.
From the Department of Neurology, Stroke Unit, Universitätsklinikum Benjamin Franklin, Berlin, Germany.
Correspondence to Hans-Christian Koennecke, MD, Department of Neurology, Evangelisches Krankenhaus Königin Elisabeth, Herzbergstrasse 79,
10362 Berlin, Germany. E-mail [email protected]
© 2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1074
Koennecke et al
Subjects and Methods
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In May 1998, despite the (by this time) pending approval of tissue
plasminogen activator (tPA) for the treatment of acute ischemic
stroke in our country, we decided to offer thrombolytic therapy to
patients with ischemic stroke. Programs to improve logistics and
organization of acute stroke care were initiated: rescue teams of the
Berlin Fire Department in the south of Berlin and staff at the
emergency room were systematically trained to recognize candidates
for thrombolytic therapy, and agreements were made with the
departments of radiology and clinical chemistry to treat these
patients with first priority. In addition, teaching courses were held at
primary care hospitals in the south of Berlin to encourage transfer of
patients suitable for thrombolytic therapy. The main criteria for
thrombolysis were adopted with some modification from the National Institute of Neurological Disorders and Stroke (NINDS) trial.1
Thus, alteplase (Actilyse; Boehringer Ingelheim) was administered
in a dose of 0.9 mg/kg body weight (maximum dose 90 mg), with
10% given as a bolus followed by delivery of the remaining 90% as
a constant infusion over a period of 60 minutes. Patients had to be
treated within 3 hours from symptom onset; however, infringements
of the 3-hour time window up to 4 hours in patients with a normal
baseline CT scan were left to the discretion of the attending
neurologists, who had to be present in all cases to finally decide and
direct the acute treatment. NINDS study criteria were combined with
the CT exclusion criteria of the European Cooperative Acute Stroke
Study (ECASS) trials, ie, exclusion of patients with major early
infarct signs in more than one third of the middle cerebral artery
(MCA) territory.1,3 Because we included patients with strokes of the
vertebrobasilar territory, patients with visible acute infarcts of the
cerebellum (irrespective of the size) or the brain stem were also
excluded. Pretreatment with aspirin or other antiplatelet agents was
not an exclusion criterion. Special attention was paid to the control
of elevated arterial blood pressure before, during, and for at least 24
hours after thrombolysis, according to the NINDS study criteria.
Major logistic parameters (time from symptom onset to arrival at the
emergency room [onset-to-ER time], door-to-CT time, door-toneedle time, onset-to-treatment time) were prospectively documented in all patients. The study was approved by the ethics
committee of our hospital.
Neurological deficit on admission was measured by the National
Institutes of Health Stroke Scale (NIHSS) and the modified Rankin
scale (MRS). Eligible patients had to have a disabling neurological
deficit independently from the NIHSS score at the time thrombolysis
was started. Patients with rapidly improving symptoms were excluded. No upper age limit was defined; however, an MRS score of
ⱖ3 before the acute event was an exclusion criterion. Informed
consent was obtained from all patients or their next of kin. A
follow-up CT scan was performed 24 hours after thrombolysis in all
patients. The performance of further CT or MRI studies, as well as
diagnostic studies to determine stroke etiology, were left to the
discretion of the treating neurologist. Neither heparin nor aspirin, or
other antiplatelet agents, were given for 24 hours after thrombolysis.
Prespecified outcome parameters were the MRS and Barthel index
(BI) at 3 months, and symptomatic hemorrhagic complications (ie,
any intracranial hemorrhage leading to decline in neurological
status,1 and any extracerebral hemorrhages requiring medical intervention like transfusion or surgery). A good outcome was defined as
an MRS score of 0 or 1 or a BI of 95 to 100, a moderate outcome as
an MRS score of 2 to 3 or a BI of 55 to 90, and a poor outcome as
an MRS of 4 to 5 or a BI of 0 to 50. Follow-up data were obtained
from structured telephone interviews 3 months after admission. Due
to similar inclusion and exclusion criteria, late outcome parameters
were adopted from and compared with those of the NINDS trial1 and
another study9 assessing intravenous thrombolysis in daily clinical
routine. In addition, outcome according to the MRS was compared
with the 3-hour intention-to-treat (IT) population of the ECASS I
trial.10
Results
Between May 1998 and April 2000, a total of 802 patients
with presumed stroke were admitted to our hospital, of whom
Intravenous tPA for Ischemic Stroke
1075
504 (62.8%) had suffered an ischemic cerebral infarction, as
confirmed by brain scan or duration of symptoms of ⬎24
hours. The remainder of diagnoses comprised 19% TIAs
(n⫽152), 8.7% cerebral hemorrhages (n⫽70), and 9.5% other
diagnoses such as migraine, syncope, hypoglycemia, or
seizure (n⫽76). Of the patients with cerebral infarct, 32%
(n⫽161) arrived ⬍3 hours after symptom onset, 8% (n⫽40)
were admitted after ⱖ3 but ⬍6 hours, and 20% (n⫽101) after
ⱖ6 hours; in 40% (n⫽202) the time of onset could not be
determined, mostly due to onset of symptoms during the night
or inconclusive statements about the time of onset.
Seventy-five patients were treated with intravenous tPA,
which corresponded to 9.4% of all patients admitted for
presumed stroke, 14.9% of patients with cerebral infarction,
and 47% of those potentially eligible for thrombolytic treatment (ie, admitted within 3 hours from symptom onset). Main
characteristics of tPA-treated patients are shown in Table 1.
Twenty-five patients (33%) were taking antiplatelet medication on admission. Median baseline NIHSS was 13, and thus
similar to the NINDS trial.1 Ten patients (13.4%) were
transferred from other hospitals. Thirteen patients (17.3%)
were treated beyond 3 hours from symptom onset (mean 23,
range 2 to 120 minutes). One aphasic patient was treated on
the basis of her relative’s first statement regarding the time of
onset, which was later markedly corrected backward; thus,
thrombolysis had actually been started 300 minutes after
onset. The infusion of tPA was prematurely stopped after 30
minutes in this patient.
To demonstrate the changes over time of major logistic
parameters, the entire 24-month period was trisected into
8-month intervals (Table 2). Median door-to-CT, door-toneedle, and onset-to-treatment time intervals were decreased
by 27%, 14%, and 13%, respectively, while the major
patient-dependent parameter (ie, time from symptom onset to
admittance) remained basically unchanged. During the 24
months of prospective data acquisition, the mean number of
tPA-treated patients per month increased from 1.9 during
months 1 to 8 to 4.1 during months 17 to 24, while the
numbers of admitted stroke patients per month remained
stable. Notably, door-to-CT and door-to-needle intervals
showed a tendency to slightly increase from the second to the
last 8-month interval (Table 2).
Parenchymal hemorrhage occurred in 2.7% of patients
(n⫽2) and was fatal in both cases. Neither of these patients
was treated beyond 3 hours from onset, had an abnormal CT
scan, or was pretreated with an antiplatelet agent. However,
protocol violations were evident in both cases: one patient
was treated despite the fact that adjusted partial thromboplastin time was still elevated because of heparin given during
cardiac catheterization; in the other patient, blood pressure
was poorly controlled for 12 hours after treatment. In another
patient, mild hemorrhagic transformation of an anterior cerebral artery infarct may have contributed to clinical worsening,
but a definite causal association could not be determined due
to the complexity of this case.11 Considering this case a
hemorrhagic complication would increase the proportion of
hemorrhages to 4%.
Early CT signs of acute cerebral infarction (hypoattenuation of cortical structures, sulcal effacement, insular ribbon
1076
Stroke
May 2001
TABLE 1.
Main Characteristics of Patients
NINDS rt-PA Trial,
Part II
(n⫽168)
Cologne
(n⫽100)
Berlin
(n⫽75)
69⫾12
63⫾11
68⫾13 (34–90)
60
60
56
Baseline NIHSS, median
14 (2–37)
12 (2–37)
13 (2–34)
Baseline MRS, median
NA
NA
4 (3–5)
Characteristic
Age, mean⫾SD, y
Gender, % male
Mean⫾SD time intervals, min
Onset to hospital admittance
NA
NA
66⫾42 (14–263)
Door to CT scan
NA
NA
27⫾12 (2–61)
Door to needle
NA
48⫾25 (20–130)
79⫾29 (25–150)
Onset to treatment
NA
124
144⫾41 (80–300)
51
26
9
Time interval from onset to treatment, %
ⱕ90 min
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91–180 min
49
74
74
⬎180 min
NA
NA
17
45
35
53
Stroke etiology, %*
Cardiac embolism
Artery-to-artery embolism
39
28
8
Microangiopathy
14
21
8
Other/Undetermined
2
16
31
Vascular territory, %
Carotid
NA
NA
86
Vertebrobasilar
NA
NA
11
Undetermined
NA
NA
3
Numbers in parenthesis denote range. NA indicates not available.
*According to TOAST criteria.22
sign, and dense media sign) were detected in 11 patients
(15%); in only 1 patient did baseline CT demonstrate signs of
a large MCA territory infarction (ie, approximately 30% of
the MCA territory). Neither of the patients treated after ⬎3
hours had signs of early infarction on baseline CT scan.
Asymptomatic hemorrhagic transformation was noted in 8%
(n⫽6) on follow-up imaging. No serious extracerebral bleeding complications occurred.
Assessment of outcome parameters after 3 months demonstrated that thrombolytic therapy was more efficacious than
standard treatment (NINDS study placebo cohort) and that
⬎70% of patients had a good or moderate outcome. Outcome
results of the entire cohort in comparison with the NINDS
trial, the ECASS I 3-hour IT population, and the results from
Cologne are shown in Figure 1. Compared with the patients
TABLE 2.
Evolution of Time Parameters Over 2 Years
Median Time Intervals, min
Parameter
May–
December
1998
January–
August
1999
September
1999 –April
2000
Onset to hospital admittance
54
67
52
Door to CT scan
30
20
22
Door to needle
96
70
73
150
153
131
Onset to treatment
treated with tPA in the ECASS I 3-hour IT cohort (n⫽49),10
in our study a greater proportion (61% versus 45%) of
patients achieved a good outcome, as assessed by the BI.
However, because of the relatively small number of patients,
the difference was not statistically significant (␹2 test,
P⫽0.07). When the 8-month intervals were compared with
regard to the proportion of patients with good functional
outcome, no significant changes over time were detected for
the MRS (␹2 test, P⫽0.29) or the BI (␹2 test, P⫽0.55).
Discussion
Among clinical neurologists, thrombolysis for acute ischemic
stroke remains a matter of debate despite quite encouraging
results of large clinical trials,1,3 as well as phase IV experiences from single or multiple centers.8,9 In particular, the
results from another phase IV study nourish concerns about
unacceptably high complication rates of systemic
thrombolysis when performed in the “real world.”7,12 However, the study from Cleveland is hardly comparable with our
study and other phase IV studies, because of its retrospective
design, the lack of documented stroke severity in the majority
of patients, and the small number of thrombolyzed patients in
most participating centers, indicating little experience with
thrombolytic treatment.7 The low rate of symptomatic hemorrhages in the present study concurs with the results of other
phase IV experiences8,9,13–15 and thereby confirms the as-
Koennecke et al
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Outcome of patients (percentages) at 3 months in comparison
with published data. *For the ECASS 3-h IT cohort, no detailed
BI data were available except number of patients with a score
of 100 –95.
sumption that intravenous thrombolysis can be performed
safely in daily clinical practice.
One other major point of criticism is the limited availability of thrombolysis for the vast majority of stroke victims. It
is thus necessary to demonstrate that thrombolytic treatment
can be implemented into the daily clinical routine of neurological stroke care by treating a decent proportion of acute
stroke patients. However, the results as reported from phase
IV evaluations are not always encouraging. In one study,8 it
took almost 2 years and 57 medical centers to gather
information about 389 consecutive patients treated with
intravenous thrombolysis. Another retrospective study collected data from 13 hospitals over a 2-year period with 189
patients thrombolyzed; however, the total number of stroke
patients and thus the proportion of treated subjects were not
determined.13 In another survey of 29 hospitals, almost 4000
patients admitted with “stroke” were screened, of whom only
70 (1.8%) finally underwent systemic thrombolysis.7 Somewhat better results have been reported from a smaller study,16
with a proportion of 6% of patients with ischemic stroke
(n⫽23) treated within 1 year. A proportion of 7% of ischemic
stroke patients (n⫽9) finally undergoing thrombolysis was
reported from 2 hospitals over a 12-month period after a
special stroke code system had been initiated.17 In a recent
single-center, phase IV experience, 46 patients treated within
45 months were reported, but data on the proportion of
thrombolyzed subjects among all stroke patients were not
provided.15 Another single center collected data on 68 patients treated within a period of almost 3 years, corresponding
to 4.4% of patients with stroke.18 Thus far, only 1 study9 from
a single center has been published that proves the yield of a
Intravenous tPA for Ischemic Stroke
1077
reorganization of the medical emergency system. In this
study, an extraordinary 22% of patients (n⫽100) admitted
with presumed stroke underwent thrombolysis within 3 hours
from symptom onset. Another single-center experience19
reported 100 patients treated with tPA within a time period of
34 months; however, the time window for thrombolytic
treatment was 7 hours and the proportion of thrombolyzed
stroke patients was not determined. In summary, there is little
evidence to prove that thrombolytic treatment is worth the
effort to become part of routine stroke care. However, the
results of the present study confirm the assumption that
intravenous thrombolysis may not remain a therapy for a tiny
minority of stroke patients.
Although the cost-effectiveness of tPA treatment has been
proved,20 a specific proportion of successfully treated stroke
patients is necessary to justify the technical, logistic, and
financial efforts required for this treatment. Our study confirms the assumption that this goal is achievable with only
moderate technical requirements and logistic efforts. We have
further demonstrated for the first time that the performance of
a stroke team and subsequently the proportion of thrombolyzed patients can be improved within a foreseeable period of
time (Table 2). To date, information about specific time
intervals in hyperacute stroke care are scarce. Reported
door-to-CT times in thrombolyzed patients range from 33 to
41 minutes14,16 and are similar to our overall mean doorto-CT time of 27 minutes (Table 1). Wider ranges have been
reported for the more important door-to-needle time. While 1
single center achieved an admirable mean of 48 minutes,9 the
reported 94 minutes from another university hospital16 was
similar to our 96 minutes during the first 8 months in our
study. Recent analyses from the NINDS trial have demonstrated that even within the 3-hour time window, patients
benefit most the earlier they are treated.5 Improving the
performance of a stroke team is thus crucial to increase
treatment efficacy. To the best of our knowledge, no data
have been reported with respect to the evolution of logistic
parameters over time in a stroke team. The increasing number
of thrombolyzed patients over time in the present study
indicates that improvement of hospital-dependent time parameters alone might additionally increase the proportion of
patients eligible for thrombolysis. Given the difficulties in
altering patient-related delays in stroke referrals,21 the implementation of an in-hospital fast track for acute stroke patients
is even more important. However, we were not able to
demonstrate changes in patient outcome with increasing
experience of the stroke team. Indeed, the number of patients
in our study is too small to reveal the presumably small
effects on functional outcome over time.
In conclusion, the present study, which is one of the largest
single-center experiences of thrombolysis for ischemic stroke
according to established criteria, has demonstrated that systemic thrombolytic therapy can be implemented safely and
efficaciously into daily clinical routine of stroke care. With
some effort, thrombolysis may be a treatment option for more
than a minority of patients with ischemic stroke. The performance of a stroke team can be improved over time, subsequently increasing the proportion of eligible patients.
1078
Stroke
May 2001
Acknowledgments
This solely investigator-driven study was supported by an unrestricted grant from Boehringer Ingelheim. The authors thank the
entire stroke unit staff of our department for their commitment. We
are also grateful to the rescue teams of the Berlin Fire Department in
the south of Berlin, the emergency room staff, and the personnel of
the departments of Radiology and Clinical Chemistry at the Universitätsklinikum Benjamin Franklin.
10.
11.
12.
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Intravenous tPA for Ischemic Stroke Team Performance Over Time, Safety, and Efficacy
in a Single-Center, 2-Year Experience
Hans-Christian Koennecke, Roland Nohr, Stefanie Leistner and Peter Marx
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Stroke. 2001;32:1074-1078
doi: 10.1161/01.STR.32.5.1074
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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