(Stroke. 2001;32:1074.)
© 2001 American Heart Association, Inc.
Original Contributions |
Intravenous tPA for Ischemic Stroke Team Performance Over Time, Safety, and Efficacy in a Single-Center, 2-Year Experience
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 h.koennecke{at}keh-berlin.de
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Abstract |
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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.
Key Words: outcome • stroke management • stroke, ischemic • thrombolytic therapy
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thrombolytic 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 4 5 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 encouraging 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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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-to-needle 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 
3 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
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Between May 1998 and April 2000, a total of 802 patients with presumed stroke were admitted to our hospital, of whom 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
3 but <6 hours, and 20% (n=101) after 6
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.
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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-to-needle, 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).
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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 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 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).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 14 15 and thereby confirms the assumption 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 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 door-to-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.
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Acknowledgments |
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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.
Received December 27, 2000; revision received January 19, 2001; accepted January 22, 2001.
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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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P. D. Mitsias, J. R. Ewing, M. Lu, M. M. Khalighi, M. Pasnoor, H. B. Ebadian, Q. Zhao, S. Santhakumar, M. A. Jacobs, N. Papamitsakis, et al. Multiparametric Iterative Self-Organizing MR Imaging Data Analysis Technique for Assessment of Tissue Viability in Acute Cerebral Ischemia AJNR Am. J. Neuroradiol., October 1, 2004; 25(9): 1499 - 1508. [Abstract] [Full Text] [PDF]
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M. K. Kapral, A. Laupacis, S. J. Phillips, F. L. Silver, M. D. Hill, J. Fang, J. Richards, J. V. Tu, and for the Investigators of the Registry of the Canad Stroke Care Delivery in Institutions Participating in the Registry of the Canadian Stroke Network Stroke, July 1, 2004; 35(7): 1756 - 1762. [Abstract] [Full Text] [PDF]
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G. D. Graham Tissue Plasminogen Activator for Acute Ischemic Stroke in Clinical Practice: A Meta-Analysis of Safety Data Stroke, December 1, 2003; 34(12): 2847 - 2850. [Abstract] [Full Text] [PDF]
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R. T. Higashida and A. J. Furlan Trial Design and Reporting Standards for Intra-Arterial Cerebral Thrombolysis for Acute Ischemic Stroke Stroke, August 1, 2003; 34 (8): e109 - e137. [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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M. Fisher and T. G. Brott Emerging Therapies for Acute Ischemic Stroke: New Therapies on Trial Stroke, February 1, 2003; 34(2): 359 - 361. [Full Text] [PDF]
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