Download Impact of the Extended Thrombolysis Time Window on the

Impact of the Extended Thrombolysis Time Window on the
Proportion of Recombinant Tissue-Type Plasminogen
Activator-Treated Stroke Patients and on
Door-to-Needle Time
Jens Minnerup, MD*; Heike Wersching, MD, MSc*; E. Bernd Ringelstein, MD; Matthias Schilling, MD;
Wolf-Rüdiger Schäbitz, MD; Jürgen Wellmann, PhD; Klaus Berger, MD, MPH, MSc
Downloaded from http://stroke.ahajournals.org/ by guest on June 15, 2017
Background and Purpose—The European Cooperative Acute Stroke Study (ECASS) III extended the thrombolysis time
window for patients with stroke from 3 to 4.5 hours after symptom onset. We investigated the effect of the extended
thrombolysis time window on the proportion of recombinant tissue-type plasminogen activator-treated stroke patients
and on the time of treatment initiation after hospital arrival.
Methods—The present study was based on a prospective database of 93 hospitals of the Stroke Register of Northwestern
Germany, which included 91 805 patients with ischemic stroke admitted between January 2007 and December 2009.
Main outcome measures were the use of recombinant tissue-type plasminogen activator among patients with stroke and
the door-to-needle time before and after the publication of ECASS III in September 2008 and subsequent changes of
the German guidelines in May 2009.
Results—Overall, 9262 patients (10.1%) were treated with recombinant tissue-type plasminogen activator. The proportion
of thrombolyzed patients increased from 8.6% in 2007 to 11.7% in 2009. This increase was pronounced for patients
admitted between 3 and 6 hours after symptom onset after the third quarter of 2008 (OR, 1.88; 95% CI, 1.24 to 2.85)
and after the second and third quarters of 2009 (OR, 2.50; 95% CI, 1.69 to 3.69 and OR, 3.02; 95% CI, 2.07 to 4.41)
compared with the first half year 2007. The proportion of patients with stroke with a door-to-needle time ⬍60 minutes
increased after publication of ECASS III (OR, 1.49; 95% CI, 1.37 to 1.63).
Received February 10, 2011; final revision received May 2, 2011; accepted May 6, 2011.
Jeffrey L. Saver, MD, was the Consulting Editor for this paper.
From the Department of Neurology (J.M., E.B.R., M.S.), University of Münster, Albert-Schweitzer-Straße 33, 48149 Münster, Germany; the Institute
of Epidemiology and Social Medicine (H.W., J.W., K.B.), University of Münster, Münster, Germany; and the Department of Neurology (W.-R.S.), EVK
Bielefeld, Bielefeld, Germany.
*J.M. and H.W. contributed equally to this work.
Stroke Register of Northwestern Germany: For the present study we used data from the neurological departments of Johannes Wesling Klinikum
Minden; Klinikum Herford; St Josef-Hospital, Bochum; Knappschaftskrankenhaus, Bochum-Langendreer; BG Universitätsklinikum Bergmannsheil
GmbH, Bochum; Evangelisches Krankenhaus, Hattingen; Evangelisches Krankenhaus GmbH, Gelsenkirchen; Evangelisches Krankenhaus, Herne;
Universität Münster; Herz-Jesu-Krankenhaus, Münster-Hiltrup; Klinikum Ibbenbüren; LWL-Klinik; St Marien-Hospital, Hamm; St Johannes Hospital,
Hagen; Klinikum Lüdenscheid; Kreisklinikum Siegen, Klinikum Lippe-Lemgo; Ev Krankenhaus Bielefeld gGmbH; St Vincenz Krankenhaus
Landeshospital, Paderborn; Ev Krankenhaus Bielefeld Johannesstift; Städtische Kliniken, Dortmund; Knappschaftskrankenhaus, Dortmund;
Christophorus-Kliniken GmbH, Dülmen; St Marien-Hospital, Borken; Evangelisches Krankenhaus, Castrop-Rauxel; Elisabeth-Krankenhaus, Recklinghausen; Knappschaftskrankenhaus, Bottrop; St Barbara Hospital, Gladbeck; Universitätsklinikum Carl Gustav Carus Dresden; Klinikum Bernburg
gGmbH, Bernburg; Sächsisches Krankenhaus Altscherbitz, Schkeuditz; Harz-Klinikum Wernigerode-Blankenburg, Martin-Luther-Universität HalleWittenberg, Halle (Saale); Universität Leipzig; Städtisches Krankenhaus Martha-Maria, Halle-Dölau; Klinikum Chemnitz gGmbH; Kreiskrankenhaus
Freiberg gGmbH; Sächsisches Krankenhaus Arnsdorf; Hanse-Klinikum Stralsund; Hanse-Klinikum Wismar GmbH; Ernst-Moritz-Arndt-Universität
Greifswald; Helios Kliniken Schwerin; Asklepios Fachklinikum Teupitz; Asklepios Fachklinikum Brandenburg; Dietrich-Bonhoeffer-Klinikum,
Neubrandenburg; Carl-Thiem-Klinikum, Cottbus; Asklepios Klinikum Uckermark, Schwedt; Klinikum Frankfurt (Oder) GmbH, Frankfurt (Oder);
Klinikum Meiningen GmbH; Südharz-Krankenhaus Nordhausen GmbH; Kreiskrankenhaus Altenburg; Universitätsklinikum Jena; SRH Waldklinikum
Gera; Ökumenisches Hainich Klinikum GmbH, Mühlhausen; Helios Kliniken Aue; Fachkrankenhaus Hubertusburg gGmbH, Wermsdorf; ChristianAlbrechts-Universität, Kiel; Elbe-Klinikum Stade; Klinikum Bremen-Mitte, Bremen; Diakoniekrankenhaus Rotenburg (Wümme); Städtisches Klinikum,
Lüneburg; Klinikum Uelzen; KRH Klinikum Nordstadt, Hannover; Universitätsklinikum Göttingen; Neurologische Klinik, Hessisch Oldendorf;
Agnes-Karll-Krankenhaus Laatzen; Asklepios-Kliniken Schildautal, Seesen; St Bernward Krankenhaus, Hildesheim; Medizinische Hochschule,
Hannover; Krankenhaus St Elisabeth-Stift, Damme; Klinikum Osnabrück; Hans-Susemihl-Krankenhaus, Emden; Ev Bathildiskrankenhaus Bad Pyrmont
gGmbH; Diakoniekrankenhaus Friederikenstift GmbH, Hannover; Christliches Krankenhaus, Quakenbrück; Allgemeines Krankenhaus Celle; Ammerland
Klinik GmbH, Westerstede; Medizinisches Zentrum Kreis Aachen, Würselen; Universitätsklinikum Aachen; Klinikum Saarbrücken gGmbH; Wedau
Kliniken, Duisburg; Kliniken Maria Hilf, Mönchengladbach; Kreiskrankenhaus Gummersbach; Helios Klinikum Wuppertal-Barmen; Centre Hospitalier
de Luxembourg, Luxembourg; Centre Hospitalier Emile Mayrisch, Esch-Sur-Alzette, Luxembourg; Hôpital St-Louis–Neurology, Ettelbruck, Luxembourg, and from the Departments of Internal Medicine of St Barbara Klinik Heesen, Hamm; Evangelisches Krankenhaus, Hamm; St Elisabeth-Hospital,
Gütersloh; Hüttenhospital, Dortmund; Katholisches Krankenhaus Dortmund-West; and DRK Krankenhaus Saarlouis.
Correspondence to Klaus Berger, MD, MPH, MSc, Institute of Epidemiology and Social Medicine, University of Münster, Domagkstrasse 3, Münster,
Germany. E-mail [email protected]
© 2011 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.616565
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Stroke
October 2011
Conclusions—Results of ECASS III were rapidly implemented in routine stroke care. Concerns of a delay in recombinant
tissue-type plasminogen activator treatment initiation after the extension of the thrombolysis time window were not
confirmed. (Stroke. 2011;42:00-00.)
Key Words: ECASS III 䡲 guidelines 䡲 stroke 䡲 thrombolysis
T
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hrombolysis with recombinant tissue-type plasminogen
activator (rtPA) for the treatment of acute ischemic
stroke was approved by the Food and Drug Administration in
1996 and by the European Medicines Agency in 2002.1 The
European Medicines Agency approval was subject to 2
requests. First, an observational safety study had to be
initiated. Subsequently, the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was conducted showing a similar safety profile of rtPA in routine
clinical practice compared with that shown in clinical trials.2
Second, a randomized controlled trial was requested in which
the therapeutic time window should be extended beyond the
so far proven 3 hours. The European Cooperative Acute
Stroke Study (ECASS) III trial enrolled 821 patients who
were randomized to receive either rtPA or placebo within 3 to
4.5 hours after the onset of symptoms.3 Thrombolysis was
associated with a significant improvement in the clinical outcome in this study that was published in September 2008.
Subsequently, in May 2009, the recommendation of rtPA use in
patients with stroke within 4.5 hours of symptom onset was
included into the German guidelines.4 Because the majority of
patients with stroke arrive at the hospital later than 3 hours after
symptom onset and because the narrow therapeutic time window
is a main reason for the overall small proportion of patients with
stroke receiving thrombolysis, the results of ECASS III raised
hope that considerably more patients will be treated with
rtPA.5–7 Recently, the Safe Implementation of Treatment in
Stroke-International Stroke Thrombolysis Registry (SITS-ISTR)
observational study reported a rapid increase of rtPA-treated
stroke patients after publication of ECASS III.8 However, the
interpretation of this finding is limited because the overall
number of patients with ischemic stroke was not surveyed but
only stroke patients treated with thrombolysis were included.
There is a general trend of a rising number of patients with
stroke, which was even increased in the SITS-ISTR study due to
the successive participation of additional hospitals during the
study period.8 Thus, the important information regarding the
proportion of patients treated with thrombolysis could not be
obtained in this trial. Moreover, the SITS-ISTR analysis only
considered the subgroup of rtPA-treated patients who were
compliant with the European Summary of Product Characteristics criteria, thus not reflecting the stroke population routinely
accessible for thrombolysis.
The beneficial effects of thrombolysis in patients with
stroke are strongly time-dependent with the highest therapeutic yield after early treatment initiation.9 Therefore, the
door-to-needle (DTN) time, which indicates the time between
hospital arrival and treatment initiation, is required to be as
short as possible. Despite the well-known importance of rapid
rtPA administration, an inverse relation between time from
symptom onset to hospital arrival and DTN time was reported.10,11 The DTN time was shorter in patients arriving late
after symptom onset compared with patients arriving early,
raising concerns about a “loss of time” if the interval until the
end of the 3 hours window is still large. Because ECASS III
extended the therapeutic time window to 4.5 hours, there
were concerns whether this would cause a further delay in
treatment initiation of early-arriving patients.
The aim of this analysis was to study changes in the
proportion of patients with stroke treated with rtPA after the
publication of ECASS III and the subsequent guideline modification as well as the rapidity with which these changes were
implemented in routine stroke care. We further investigated the
effects of the extended time window on the DTN time. Data of a
large German stroke register for the years 2007 to 2009 were used.
Methods
All data were collected within the regional Stroke Register of
Northwestern Germany.12,13 This registration is part of a legal act
implemented in Germany through which hospitals participate in
programs for quality assurance of acute clinical stroke care. The
registry is not population-based and participation is open to all
hospitals that treat patients with acute stroke. Although registration is
optional, for reasons of quality assurance, hospitals with a stroke unit
need to prove participation in a registry to be certified by the German
Stroke Society. Participation in the registry is subject to a fee for data
management and benchmarking reports. Participating hospitals cover
the whole variation of hospitals that provide acute stroke care in
Germany, including hospitals in urban and rural regions as well as
departments of neurology and internal medicine from academic and
community hospitals. Of 149 participating hospitals, we considered
those 93 hospitals that continuously documented their patients with
stroke during the study period between January 1, 2007, and December
31, 2009. All patients with ischemic stroke admitted to the participating
hospitals during the study period were considered in the present
analysis; sampling of cases was not allowed. Data were collected
prospectively by the treating hospital physician. Information gathered
for each patient included sociodemographic characteristics, comorbidities, neurological deficits, stroke type, complications, diagnostic procedures, admission procedures, and treatment strategies during the inhospital period. In addition, details concerning the treating institution
were documented. Data collection was standardized and the documented forms were sent to the coordinating center of the Stroke Register
of Northwestern Germany at the University of Muenster. Forms were
scanned and checked for completeness and plausibility.
The following definitions were used.
Hypertension was defined as systolic blood pressure of
ⱖ160 mm Hg, diastolic blood pressure of ⱖ95 mm Hg, or patient
self-report of treated arterial hypertension. Diabetes mellitus was defined as elevated fasting blood glucose level, patients’ self-report of a
physician’s diagnosis of diabetes, or use of antidiabetic drugs. Atrial
fibrillation was documented by electrocardiogram. Previous stroke was
defined as a neurological deficit ⬎24 hours before the current event.
Stroke was defined according to the World Health Organization
criteria.14 The stroke subtype (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack, undefined) was diagnosed from the results of CT or MRI scan. Stroke
severity was assessed using an ordinal score reflecting the number of
major stroke-related symptoms, that is, presence or absence of upper
and/or lower limb paresis, presence or absence of diminished
vigilance, presence or absence of dysarthria, and presence or absence
of aphasia. Treatment with rtPA intravenously, intra-arterial
Minnerup et al
Table. Baseline Characteristics of the Study Population (nⴝ91 805)
Characteristics
Patients With Ischemic Stroke
Age, mean (SD), y
Women, no. (%)
Comorbidities, no. (%)
Hypertension
Diabetes mellitus
Atrial fibrillation
Prior stroke
Onset-to-door time,* no. (%), h
⬍2
2–3
3–6
⬎6
Unknown
71.6 (13.0)
42 820 (46.6)
58 125 (63.3)
26 210 (28.5)
24 098 (26.2)
23 670 (25.8)
15 391 (16.8)
10 564 (11.5)
17 349 (18.9)
39 275 (42.8)
9226 (10.0)
*Time from symptom onset to hospital admission.
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thrombolysis, or no thrombolysis was recorded. The onset-to-door
(OTD) time was categorized into ⬍2 hours, 2 to 3 hours, 3 to 6
hours, and ⬎6 hours. Because the stroke register was designed
before the publication of ECASS III, the OTD times did not include
a separate category of a 3- to 4.5-hour time window. The DTN time
was categorized into ⬍30 minutes, 30 to 60 minutes, 60 to 120
minutes, 120 to 180 minutes, and ⬎180 minutes. Following prior
analyses, we defined the total number of patients with stroke treated in
an individual hospital per year as the hospital expertise with acute stroke
treatment.15 To investigate whether the hospital expertise influences the
time until the extended thrombolysis time window was implemented in
clinical practice, hospitals were categorized according to the number of
patients that were treated on average per year during the study period:
(1) ⬍500; (2) 500 to 749; and (3) ⱖ750 patients.
Statistical Analysis
Means were compared using Student t test; for medians, Wilcoxon rank
sum test was used. For comparison of frequencies, we used Fisher exact
test and for trend analyses Maentel-Haenszel ␹2 test. Multivariable
logistic regression was applied to identify the impact of the publication
of ECASS III in September 2008 and the German guideline changes in
May 2009 on thrombolysis frequency for the different OTD time
categories.3,4 All models were adjusted for age, sex, Rankin Scale,
stroke severity, and history of diabetes mellitus. We included 2 time
variables in the regression models: (1) 3-month periods from January
2007 to December 2009 with the first 2 quarters combined to a 6-month
period being the reference category for the overall time trend; and (2) a
3-categorical time variable categorized into time period before publica-
Impact of ECASS III on Routine Stroke Care
3
tion of ECASS III (before guideline changes if appropriate), time span
between publication of ECASS III (reference), and guideline changes
and time period after guideline changes. Statistical significance was
determined as an ␣ error ⬍0.05. Statistical analyses were carried out
using SAS 9.2 (SAS Institute Inc, Cary, NC).
Ethics
The design of the study was approved by the ethics committee of the
Westphalian Board of Physicians and the University of Muenster,
Muenster, Germany. The identity of the individual patients was
completely anonymous. Therefore, no specific informed consent was
obtained from patients. The investigators who performed the data
analysis were blinded to hospital identities.
Results
During the 3-year observation period, a total of 93 245
patients with ischemic stroke were registered within the 93
included hospitals of the Stroke Register of Northwestern
Germany. Of those, 1440 were excluded from further analysis
because of missing values for thrombolysis-related variables.
Mean age of the remaining 91 805 patients was 71.6 years;
46.6% were women. Comorbid conditions of patients with
ischemic stroke and OTD times are given in the Table. There
was no significant difference in the prevalence of arterial
hypertension, atrial fibrillation, and prior stroke across the
time period under study. However, there was a significant
decrease in the presence of diabetes in patients with stroke
across quarters (P for trend⫽0.002). In-hospital mortality of
all patients with ischemic stroke was 5.13% before and 5.25%
after publication of ECASS III (P⫽0.41).
Overall, 9262 patients (10.1%) were treated with rtPA
intravenously for acute ischemic stroke during the 3 years:
41.5% of patients admitted within 2 hours, 19.2% of patients
admitted within 2 to 3 hours, 2.7% of patients admitted within
3 to 6 hours, and 0.6% of patients admitted ⬎6 hours after
symptom onset received intravenous thrombolysis. The proportion of patients treated with rtPA intravenously significantly increased over time from 8.6% in 2007 to 11.7% in
2009 (P⬍0.0001). Figure 1 shows the increase in the overall
proportion of intravenous rtPA-treated patients and the increases in proportions of patients who received thrombolysis
with OTD times ⬍3 and between 3 and 6 hours according to
quarters. The total number of patients treated with rtPA
Figure 1. The proportion of rtPA-treated
patients of all patients with stroke, the
proportion of rtPA-treated patients of
those who arrived at hospital within 3
hours, and the proportion of rtPA-treated
patients of those who arrived between 3
and 6 hours after symptom onset. rtPA
indicates recombinant tissue-type plasminogen activator; OTD, onset-to-door.
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Stroke
October 2011
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Figure 2. Stacked column chart showing the proportion of rtPA-treated patients for different onset-to-door times. The total number of rtPAtreated patients per quarter is given below the x-axis. rtPA indicates recombinant tissue-type plasminogen activator.
intravenously increased from 451 in the first 3 months of
2007 to 1033 in the last 3 months of 2009 (Figure 2).
When analyzing the increase in the proportion of intravenous rtPA-treated patients (Figure 2), the strongest effect was
observed for patients admitted between 3 and 6 hours after
symptom onset between the third and the fourth quarters of
2008 (88.9% relative increase in IV 2008 compared with the
first half year 2007, OR, 1.88; 95% CI, 1.24 to 2.85) and after
the second and third quarters of 2009 (144.4% relative
increase in III 2009 and 194.4% relative increase in IV 2009
compared with the first half year of 2007, OR, 2.50; 95% CI,
1.69 to 3.69 and OR, 3.02; 95% CI, 2.07 to 4.41). After
adjustment for important confounders (age, gender, diabetes,
number of neurological symptoms, Rankin Scale), this increase
in the proportions of intravenous rtPA-treated patients after the
third quarter of 2008 and after the second quarter of 2009
remained significant (P⬍0.0001 and P⫽0.004, respectively).
The increase in the proportion of rtPA-treated patients with an
OTD time between 3 and 6 hours was independent from the
hospital expertise with acute stroke treatment (data not shown).
Among the patients with stroke treated with intravenous
rtPA, the largest proportion received thrombolysis within 30
to 60 minutes after hospital admission (48.9%; Figure 3). The
proportion of stroke patients with a DTN time ⬍60 minutes
increased after publication of ECASS III (OR, 1.49; 95% CI,
1.37 to 1.63), whereas the proportion of patients with a DTN
time of 60 to 180 minutes decreased after publication of
ECASS III (OR, 0.74; 95% CI, 0.67 to 0.81). Within the
fourth quarter of 2008, the proportion of patients treated with
rtPA intravenously within 30 minutes exceeded the proportion of patients who received thrombolysis within 60 to 120
minutes after hospital admission (Figure 3). When analyzing
the DTN time separately for different OTD times, the trend of
a decreased time to rtPA treatment after admission was
pronounced within the group of patients with an OTD time
between 3 and 6 hours (data not shown).
Figure 3. Door-to-needle time of rtPAtreated patients with stroke. Due to the
small number of patients with a DTN time
of ⬎180 minutes, these data are not
shown. rtPA indicates recombinant
tissue-type plasminogen activator; DTN,
door-to-needle.
Minnerup et al
We additionally investigated the proportion of patients
treated with intra-arterial thrombolysis. During the study
period, 929 patients (1.02%) received rtPA intra-arterially
(0.71% in 2007, 0.97% in 2008, and 1.29% in 2009, P for
trend ⬍0.0001). Of all patients admitted within 2 hours,
2.66% were treated with intra-arterial rtPA while the proportions were 1.80% between 2 and 3 hours, 0.86% between 3
and 6 hours, and 0.29% of the patients admitted ⬎6 hours.
There was no significant effect of ECASS III or guideline
publication on the proportion of intra-arterially treated patients when analyzed for the overall study population and
stratified for OTD times.
Discussion
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In this large stroke register, we examined if the publication of
ECASS III and the subsequent new guideline recommendation to extend the thrombolysis time window from 3 to 4.5
hours increased the number of patients with acute ischemic
stroke receiving rtPA and how fast this increase occurred.
The time period chosen sufficiently covered the period before
trial publication and after guideline changes. The overall
proportion of patients with ischemic stroke treated with
intravenous thrombolysis increased from 8% to 11% during
the study period. The increase was particularly evident in the
3-month period after the publication of the ECASS III trial in
September 2008 among patients admitted between 3 and 6 hours
after symptom onset and in the 3-month period after the
publication of the new German guidelines. This rapid implementation into clinical practice was independent from the hospital
expertise with acute stroke treatment as indicated by the number
of patients with stroke admitted to an individual hospital per
year. In-hospital mortality did not change during the implementation period. Extension of the time window for intravenous
thrombolysis had no significant effect on intra-arterial
thrombolysis rates. There was no increase in the DTN time after
the publication of ECASS III and the subsequent guideline
changes indicating that the extension of the thrombolysis time
window did not result in a “laissez-faire” approach for those
patients admitted early. In contrast, the proportion of patients
who received rtPA early after admission was even increased,
whereas the proportion of patients treated later after admission
decreased after the publication of ECASS III.
Previous studies reported an increasing use of rtPA in
patients with stroke over time.16 –18 However, the impact of
the extension of the thrombolysis time window to 4.5 hours
on routine clinical practice was not reported so far. Factors
previously reported to be associated with the proportion of
patients with ischemic stroke receiving thrombolysis were the
number of beds per hospital, admission to a stroke unit
compared with admission to general wards, the population
density of the area served by the hospital, and the education
of the emergency department staff.16,19 –21
The adoption of results from landmark clinical trials into
clinical practice and the adherence to new guidelines was
extensively investigated for cardiovascular diseases.22–25 In
contrast, only 1 recent study evaluated the transferral of
clinical trial results into routine stroke care.8 However, the
impact of guideline changes was not included. It has been
shown that the speed of this transferral into clinical practice
Impact of ECASS III on Routine Stroke Care
5
varies in studies evaluating different drug effects in cardiovascular diseases. Comparable to our finding, an immediate
adoption of positive results from clinical trials was reported
for the use of spironolactone in heart failure.26 However,
other therapies shown to be effective in large clinical trials
such as angiotensin-converting enzyme inhibitors in heart
failure were incorporated only slowly in clinical routine.27,28
No temporal impact of guideline publication on clinical
management was reported for early mechanical revascularization after myocardial infarction.25 Overall, the factors that
determine the promptness with which evidence-based therapies influence clinical practice are not well understood so far.
The SITS-ISTR study found an overall similar DTN time
before and after September 2008, the date of ECASS III
publication.8 However, after the publication of ECASS III, it
reported an increased DTN time for patients arriving ⬎60
minutes.8 In our study, the proportion of early treated patients
was increased after September 2008. This effect was present
also when we stratified the analysis for different OTD times.
Several factors were reported to be associated with the DTN
time. Larger experience with thrombolysis, the use of a
prehospital notification system, and a protocol-driven assessment of patients with stroke led to a decreased DTN
time.10,29,30 In contrast, delays in neuroimaging and its interpretation, processing of laboratory results, and stabilization of
blood pressure were identified to extend the DTN time.31 We
cannot rule out that changes in these factors might account for
the increased proportion of early treated patients in our study.
However, the rapid increase of early treated patients within
the last quarter of 2008 in our study suggests that the results
of ECASS III strengthened the overall confidence in
thrombolysis as a stroke therapy and thus contributed to
achieve faster treatment consensus in individual patients.
Our study has strengths and limitations. Information was
collected in a uniform, prospective way over a study period of 3
years in 93 hospitals across Germany, thus enabling the analysis
of temporal trends. In contrast to one prior study, our analysis
was restricted to hospitals that participated during the entire
study period because changes in treatment patterns can only be
evaluated in this group. Due to the large number of patients,
subgroup analyses among rtPA-treated patients could be performed with sufficient power. However, it is possible that
changes in rtPA use reflect several influences including the
overall trend of an increased proportion of patients receiving
thrombolysis or unobserved variations in patient characteristics.
Thus, a definitive causal relationship between ECASS III and
guideline publications with the frequency of thrombolysis as
well as with the DTN times cannot be made. However, statistical
analyses were adjusted for relevant factors such as demographic
characteristics, stroke severity, and comorbid conditions. Moreover, the sudden changes in rtPA use in the last quarter of 2008
and the first quarter of 2009 clearly suggest an impact of ECASS
III. Although our analysis includes a large number of hospitals of
northwestern Germany, the Northwestern Germany Stroke Registry is not population-based, thus limiting the generalizability of
our findings.
The findings of ECASS III extended the thrombolysis time
window from 3 to 4.5 hours. Because the data of our stroke
register were collected prospectively and the register was
6
Stroke
October 2011
designed before the publication of ECASS III, the OTD times
were categorized into 3 to 6 hours and not recorded separately
as a 3- to 4.5- and a 4.5- to 6-hour time window. However, on
the basis of the recently completed 2010 data, we demonstrated that the largest proportion of rtPA-treated patients
with OTD times between 3 and 6 hours were within the
subgroup with OTD times of 3 to 4 hours (data not shown).
Our observational study did not aim to show a benefit of
the extended thrombolysis time window on patient outcome.
The significantly improved clinical outcome of patients with
stroke treated with rtPA between 3 and 4.5 hours after the
onset of symptoms has been demonstrated by the ECASS III
publication.3
Conclusions
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In our study, we observed a rapid implementation of the results
of the ECASS III study and the following guideline changes into
routine stroke care. Within 3 months after publication of ECASS
III, the proportion of patients who received thrombolysis among
patients with ischemic stroke who arrived at the hospital within
3 to 6 hours after symptom onset was significantly increased.
Previous concerns that the DTN time would increase after the
extension of the thrombolysis time window were not confirmed.
The proportion of early treated patients was even increased after
publication of ECASS III.
Acknowledgments
We thank Dr Marianne Kalic for her efforts in data management and
her technical support.
Disclosures
None.
References
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Jens Minnerup, Heike Wersching, E. Bernd Ringelstein, Matthias Schilling, Wolf-Rüdiger
Schäbitz, Jürgen Wellmann and Klaus Berger
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