Factors Influencing In-Hospital Delay in Treatment With
Intravenous Thrombolysis
Robert Mikulík, MD, PhD; Pavla Kadlecová; Anna Czlonkowska, MD, PhD;
Adam Kobayashi, MD, PhD; Miroslav Brozman, MD, PhD; Viktor Švigelj, MD;
Laszlo Csiba, MD, PhD; Klara Fekete, MD; Janika Kõrv, MD, PhD; Vida Demarin, MD, PhD;
Aleksandras Vilionskis, MD; Dalius Jatuzis, MD, PhD; Yakup Krespi, MD; Niaz Ahmed, MD, PhD;
for the Safe Implementation of Treatments in Stroke-East Registry (SITS-EAST) Investigators
Downloaded from http://stroke.ahajournals.org/ by guest on October 2, 2016
Background and Purpose—Shortening door-to-needle time (DNT) for the thrombolytic treatment of stroke can improve
treatment efficacy by reducing onset-to-treatment time. The goal of our study was to explore the association between
DNT and outcome and to identify factors influencing DNT to better understand why some patients are treated late.
Methods—Prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST:
9 central and eastern European countries) on all patients treated with thrombolysis between February 2003 and February
2010 were analyzed. Multiple logistic regression analysis was used to identify predictors of DNT ⱕ60 minutes.
Results—Altogether, 5563 patients were treated with thrombolysis within 4.5 hours of symptom onset. Of these, 2097
(38%) had DNT ⱕ60 minutes. In different centers, the proportion of patients treated with DNT ⱕ60 minutes ranged
from 18% to 84% (P⬍0.0001). Patients with longer DNT (in 60-minute increments) had less chance of achieving a
modified Rankin Scale score of 0 to 1 at 3 months (adjusted OR, 0.86; 95% CI, 0.77– 0.97). DNT ⱕ60 minutes was
independently predicted by younger age (in 10-year increments; OR, 0.92; 95% CI, 0.87– 0.97), National Institutes of
Health Stroke Scale score 7 to 24 (OR, 1.44; 95% CI, 1.2–1.7), onset-to-door time (in 10-minute increments; OR, 1.19;
95% CI, 1.17–1.22), treatment center (P⬍0.001), and country (P⬍0.001).
Conclusions—Thrombolysis of patients with older age and mild or severe neurological deficit is delayed. The perception
that there is sufficient time before the end of the thrombolytic window also delays treatment. It is necessary to improve
adherence to guidelines and to treat patients sooner after arrival to hospital. (Stroke. 2012;43:00-00.)
Key Words: acute stroke 䡲 admission-to-treatment time 䡲 door-to-needle time 䡲 organized stroke care 䡲 stroke care
䡲 thrombolysis
T
he only proven effective pharmacological therapy of
acute ischemic stroke is the application of intravenous
tissue-type plasminogen activator (tPA) within 4.5 hours
from symptom onset.1,2 However, the efficacy of the treatment significantly diminishes with increasing onset-totreatment time; for example, the odds of achieving a modified
Rankin Scale score of 0 to 1 decreases from 2.6 in patients
treated 0 to 90 minutes after symptom onset to 1.2 in patients
treated 271 to 360 minutes after symptom onset.3
Therefore, if the time from symptom onset to admission
(onset-to-door-time [ODT]) or time from admission to treatment (door-to-needle time [DNT]) is shortened, it will improve the efficacy of thrombolysis because of shorter onsetto-treatment time. To better understand the factors
influencing physician decisions and other factors affecting
the timing of initiation of thrombolysis in different hospitals
and countries, we analyzed a large international data set of
patients treated with tPA.
Received November 6, 2011; final revision received December 30, 2011; accepted January 27, 2012.
From the Neurology Department (R.M.) and the International Clinical Research Center (R.M., P.K.), St Anne’s Hospital, Brno, Czech Republic; the
Second Department of Neurology (A.C., A.K.), Institute of Psychiatry and Neurology, Warsaw, Poland; the Department of Experimental and Clinical
Pharmacology (A.C.), Medical University of Warsaw, Poland; the Neurology Department (M.B.), University Hospital Nitra, Nitra, Slovakia; the
Department of Vascular Neurology and Neurological Intensive Care (V.S.), University Medical Centre Ljubljana and Zdravstveni Nasveti, Ljubljana,
Slovenia; the Department of Neurology (L.C., K.F.), Medical and Health Science Center, University of Debrecen, Debrecen, Hungary; the. Department
of Neurology and Neurosurgery (J.K.), University of Tartu, Tartu, Estonia; the Department of Neurology (V.D.), Sestre Milosrdnice University Hospital
Centre, Zagreb, Croatia; the Department of Neurology and Neurosurgery (A.V.), Vilnius University and Republican Vilnius University Hospital, Vilnius,
Lithuania; the Department of Neurology and Neurosurgery (D.J.), Vilnius University and Vilnius University Hospital Santariskiu Clinics, Vilnius,
Lithuania; the Neurology Department and Stroke Center (Y.K.), Istanbul Science University and Florence Nightingale Hospital, Istanbul, Turkey; and the
Department of Neurology (N.A.), Karolinska University Hospital, Solna, Sweden, and the Department of Clinical Neuroscience, Karolinska Institute,
Stockholm, Sweden.
Correspondence to Robert Mikulík, MD, PhD, Neurology Department, International Clinical Research Center, St Annes Hospital in Brno, Pekarska
53, Brno, Czech Republic 65691. E-mail mikulik@hotmail.com
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.644120
1
2
Stroke
June 2012
Methods
Downloaded from http://stroke.ahajournals.org/ by guest on October 2, 2016
This is an analysis of the subset of data from the Safe Implementation of Treatments in Stroke–International Stroke Thrombolysis
Registry (SITS-ISTR). SITS-ISTR is a prospective, multinational
Internet-based register for patients with acute ischemic stroke.
Today, SITS is present in Europe, Australia, Asia, and Central/Latin
America. More than 1000 departments in ⬎55 countries participate.4
Several projects have been accomplished on the basis of the SITS
registry.4 – 6 This study is based on an analysis of all data from
the SITS-EAST register. Nine countries participate in this registry:
Croatia (population 4.4 million), Czech Republic (population 10
million), Estonia (population 1.3 million), Hungary (population 10
million), Lithuania (population 3.3 million), Poland (population
38.2 million), Slovakia (population 5.4 million), Slovenia (population 1.9 million), and Turkey (population 77.8 million), representing the geopolitical region of eastern and central Europe (total
population 152.3 million). Data on patients receiving thrombolysis in
these countries were collected using the general SITS register
platform, but participating countries have ownership limited to the
SITS-EAST data. SITS-EAST has its own Steering Committee and
International Coordinator who also gave the approval for this article.
The methodology of the SITS-EAST register does not differ from the
general SITS register, which has already been described in detail.5,7
Our study is based on data of all consecutive patients collected in
the SITS-EAST registry between February 28, 2003, and February
28, 2010. All patients had acute ischemic stroke and were treated
with intravenous thrombolysis with 0.9 mg/kg alteplase. The initial
treatment window was 3 hours after system onset, but after the
publication of results of the European Cooperative Acute Stroke
Study (ECASS) 3 trial (September 2008) and the SITS-ISTR 3- to
4.5-hour study, the window was extended to 4.5 hours (treatment
before and after October 1, 2008, was explored as a predictor
variable).2,5 Indications and contraindications for treatment with
alteplase were fully compliant with European Summary of Product
Characteristics criteria in 66% of cases and were not compliant in
34%, mostly due to time-to-treatment ⬎3 hours (13.1%), treatment
with intravenous antihypertensive medications (8.3%), age ⬎80
years (7.3%), use of oral anticoagulant before admission (4.2%), a
combination of stroke history and concomitant diabetes (3.9%), and
history of previous stroke ⬍3 months before admission (2.7%).8
The following variables were documented and used for analysis:
age, sex, medical history (hypertension, diabetes, previous stroke,
atrial fibrillation, congestive heart failure, hyperlipidemia, smoking
status, use of antiplatelets), baseline characteristics (National Institutes of Health Stroke Scale [NIHSS] score, systolic blood pressure,
glucose, patient weight, dose of tPA, presence of early ischemic
changes on CT/MRI), ODT, DNT, treatment within working hours
(8 AM to 4 PM, Monday to Friday), treatment after October 1, 2008,
number of patients treated in each center, country of treatment,
modified Rankin Scale score at 3 months, and presence of symptomatic intracerebral hemorrhage according to National Institute of
Neurological Disorders and Stroke trial, ECASS II trial, and SITS
definition (SITS definition: local or remote parenchymal hemorrhage
Type 2 on CT/MRI at 22–36 hours after treatment combined with a
neurological deterioration ⱖ4 points on the NIHSS from baseline, or
from the lowest NIHSS score between baseline and 24 hours, or
leading to death).1,7,9
The need for ethical approval or patient consent for participation
in the registry varied among participating countries, but approvals
were obtained in countries where approval was required. The Ethics
Committee of the Karolinska Institute in Stockholm approved the
Safe Implementation of Thrombolysis in Stroke-MOnitoring
STudy (SITS-MOST).
Statistics
Intergroup differences (DNT ⱕ60 versus ⬎60 minutes) were analyzed with the Mann-Whitney test for ordinal parameters, MannWhitney U test, or t test for continuous parameters and ␹2 test for
categorical parameters. The relationship between each continuous/
ordinal variable and DNT ⱕ60 minutes was graphically analyzed. If
a nonlinear response was identified, variables were dichotomized.
The number of missing variables, relative to the total sample size,
was small (DNT, baseline NIHSS score, ODT, and modified Rankin
Scale score at 3 months; N⫽52, 89, 256, and 324, respectively), and
therefore a complete case analysis was performed.
A stepwise logistic regression model was used to identify independent predictors of DNT ⱕ60 minutes. All collected baseline
variables were used for univariate analysis, and those with discrimination power P⬍0.10 were used for the model where statistical
significance was set at P⬍0.05.
Logistic regression was also used to explore the relationship
between outcome and DNT (increment by 60 minutes) to document
the clinical benefit of shorter DNT. Outcome was measured as
modified Rankin Scale score 0 to 1 at 3 months after stroke and
symptomatic intracerebral hemorrhage according to SITS,7 National
Institute of Neurological Disorders and Stroke,1 and ECASS II9
definitions. For adjustment, the following variables were used: sex,
age, baseline NIHSS (score 7–24), weight, glucose level, systolic
blood pressure (130 –170 mm Hg), onset-to-treatment time, treatment after October 1, 2008, presence of hypertension, diabetes, atrial
fibrillation, previous stroke, early ischemic changes on CT/MRI,
current smoking, congestive heart failure, and use of antiplatelets.
Results
Altogether, 5563 patients were treated with thrombolysis
within 4.5 hours of symptom onset in 124 centers in 9
countries. Of these, 2097 (38%) were treated with DNT ⱕ60
minutes, 3414 (61%) with DNT ⬎60 minutes, and 52 (1%)
were excluded due to missing value of DNT. In different
centers, the proportion of patients treated with DNT ⱕ60
minutes ranged from 18% to 84% (P⬍0.0001). At the
country level, the proportion of patients treated with DNT
ⱕ60 minutes ranged from 19% to 60% (P⬍0.001). The
overall median DNT was 71 minutes (interquartile range,
52–95).
The patient and hospital characteristics are shown in Table
1. Patients treated with DNT ⱕ60 minutes and DNT ⬎60
minutes significantly differed in age, NIHSS, blood pressure,
glucose level, early ischemic changes on CT/MRI, history of
previous stroke, and treatment before October 1, 2008.
Analysis of the relationship between different variables
and DNT ⱕ60 minutes revealed that DNT ⱕ60 minutes was
achieved in a similar proportion of patients with middle
ranges of NIHSS (score 7–24) or systolic blood pressure
(130 –170 mm Hg) but differed for lower and higher values
(Figure). Therefore, for further analysis, NIHSS and systolic
blood pressure were divided into categories and middle
ranges were compared with higher and lower values of
NIHSS and systolic blood pressure.
Multivariate analysis (Table 2) showed that the following
variables were independently associated with DNT ⱕ60
minutes: younger age (10-year increments; OR, 0.92; 95%
CI, 0.87– 0.97), NIHSS score 7 to 24 (OR, 1.44; 95% CI,
1.2–1.7), ODT (10-minute increments; OR, 1.19; 95% CI,
1.17–1.22), center (P⬍0.001), and country (P⬍0.001). Sensitivity analysis revealed that results were similar if only
patients with ODT ⱕ120 minutes were analyzed.
The outcome of patients stratified according to DNT is
shown in Table 3. Patients with longer DNT had less chance
of achieving modified Rankin Scale score of 0 to 1 at 3
months and tended to have higher odds of symptomatic
intracranial hemorrhage (odds were significantly increased
Mikulik et al
Table 1.
In-Hospital Delays for Thrombolysis
3
Patient and Hospital Characteristics
DNT ⱕ60 Min (N⫽2097)
DNT ⬎60 Min (N⫽3414)
Characteristics
All (N⫽5563)
Sex, female, no, (%)
2304 (41%)
853 (41%)
1433 (42%)
0.34
Age, year, mean (SD)
66 (12)
66 (12)
67 (12)
⬍0.001
NIHSS, median (IQR)
12 (8–17)
12 (8–17)
12 (8–17)
NIHSS 7–24, no. (%)
4489 (81%)
1730 (83%)
2717 (80%)
0.009
153 (20)
153 (20)
153 (20)
0.89
3839 (69%)
1495 (71%)
2309 (68%)
0.005
Systolic BP, mm Hg, mean (SD)
Systolic BP, 130–170 mm Hg, no. (%)
P Value*
0.038
Glucose, mmol/L, median (IQR)
6.8 (5.9–8.1)
6.7 (5.8–8.0)
6.8 (5.9–8.2)
0.03
Patient weight, kg, mean (SD)
81 (15)
81 (14)
81 (15)
0.46
739 (13%)
348 (17%)
378 (11%)
⬍0.001
Early ischemic changes on CT or MRI, no. (%)
Dose of tPA, median (IQR)
70 (63–80)
70 (62–80)
70 (63–80)
0.94
Hypertension, no. (%)
3995 (72%)
1490 (71%)
2474 (73%)
0.12
Diabetes mellitus, no. (%)
1202 (22%)
460 (22%)
729 (21%)
0.68
679 (12%)
234 (11%)
444 (13%)
0.04
0.06
Previous stroke, no. (%)
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DM and previous stroke, no. (%)
Atrial fibrillation, no. (%)
Congestive heart failure, no. (%)
Hyperlipidemia, no. (%)
176 (3%)
55 (3%)
120 (4%)
1510 (27%)
540 (26%)
955 (28%)
0.11
712 (13%)
265 (13%)
441 (13%)
0.69
1786 (32%)
648 (31%)
1124 (33%)
0.37
0.198
Current smoker, no. (%)
1254 (23%)
492 (24%)
750 (22%)
Antiplatelets before stroke, no. (%)
1612 (29%)
592 (28%)
1008 (30%)
0.30
Patients treated after October 1, 2008, no. (%)
2375 (43%)
854 (41%)
1510 (44%)
0.01
Working hours, 8–16 h (Monday to Friday), no. (%)
2274 (41%)
883 (42%)
1372 (40%)
0.159
Onset-to-door-time, min, median (IQR)
70 (48–100)
90 (60–120)
60 (45–84)
⬍0.001
Door-to-imaging time, min, median (IQR)
20 (12–32)
15 (10–21)
27 (15–40)
⬍0.001
No. of patients treated in center, median (IQR)
84 (45–188)
101 (60–188)
84 (42–188)
Prestroke disability (mRS 3–5), no. (%)
374 (%)
133 (6%)
240 (7%)
Czech Republic, no. (%)
3054 (55%)
1255 (41%)
1766 (58%)
Poland, no. (%)
1015 (18%)
343 (34%)
670 (66%)
Slovak Republic, no. (%)
409 (7%)
79 (19%)
322 (79%)
Slovenia, no. (%)
305 (5%)
182 (60%)
115 (38%)
Hungary, no. (%)
301 (5%)
100 (33%)
201 (67%)
Estonia, no. (%)
192 (3%)
53 (28%)
138 (72%)
Croatia, no. (%)
148 (3%)
37 (25%)
111 (75%)
Lithuania, no. (%)
93 (2%)
37 (40%)
56 (60%)
Turkey, no. (%)
46 (1%)
11 (24%)
35 (76%)
0.001
0.21
⬍0.001
Difference between countries
DNT indicates door-to-needle time; NIHSS, National Institutes of Health Stroke Scale; IQR, interquartile range; BP, blood pressure; tPA, tissue plasminogen activator;
DM, diabetes mellitus; mRS, modified Rankin Scale.
*P value of (1) t test for age, systolic BP, patient weight; (2) Mann-Whitney test for NIHSS, glucose, dose of tPA, onset-to-door time, door-to-imaging time, and
no. of patients treated in center; and (3) ␹2 test for binary variables.
for symptomatic intracranial hemorrhage only according to
SITS definition).
Discussion
Our study confirms that “time is brain” because patients with
longer DNT had worse outcomes. Therefore, achieving DNT
ⱕ60 minutes for the majority of thrombolytic therapy candidates is a desirable goal. Our study improved our understanding of why this goal is not achieved, because our study
identified factors delaying physician decision to initiate
thrombolysis. These factors can fall into 3 categories: (1)
perception of urgency (ie, time remaining before the end of
the treatment window); (2) patient characteristics; and (3)
differences in stroke management within stroke centers and
countries.
First of all, our study shows that for every 10-minute
increment in time from symptom onset to admission, there are
19% higher odds that a patient will be treated with tPA within
60 minutes after admission to the hospital. The explanation is
that physician perception of having less time translates into
faster action to initiate treatment with tPA. Consequently,
although physicians manage to thrombolyze patients arriving
at the end of the treatment window, they simultaneously
waste the opportunity to offer highly effective treatment to
4
Stroke
June 2012
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Figure. shows the proportion of patients who were treated within 60 minutes after arrival to the hospital (y axis) stratified according to
baseline NIHSS (A), baseline systolic blood pressure (B), age (C), and year of treatment (D). The figure demonstrates a nonlinear relationship between door-to-needle time (DNT) ⱕ60 minutes and both baseline NIHSS and baseline blood pressure. NIHSS indicates
National Institutes of Health Stroke Scale.
patients arriving early. The same observation has been made
in Austria10 and in the United States, where for every
10-minute increase in ODT, there were very similar 23%
higher odds of being treated with DNT ⱕ60 minutes.11,12
In our previous study based on data from the whole SITS
registry, we reported that extending the treatment window for
thrombolysis from 0 to 3 hours to 0 to 4.5 hours did not
influence DNT.6 In our study, we further analyzed whether
the publication of the ECASS 3 trial in September 2008
changed the odds of being treated with DNT ⱕ60 minutes.
Truly, in univariate analysis, treatment after October 2008
decreased the odds of being treated with DNT ⱕ60 minutes,
but this association became nonsignificant in the final model.
The explanation is that in 8 centers, DNT was longer after the
extension of the time window for tPA treatment, but adding
“center” to the multivariate model took away the statistical
significance of variable “treatment after October 1, 2008.”
Therefore, the effect of the treatment window extension on
DNT needs to be closely watched and clarified. In the
meantime, all data strongly support the need for action: DNT
has to be monitored and established as 1 of the important
benchmarks of quality of care in stroke centers.
The other important finding of our study is that physicians
are delaying initiation of thrombolytic therapy in patients
who are older and have lower or higher NIHSS. The most
likely explanation is that in these subgroups of patients,
thrombolysis is perceived as less beneficial. This is important
to realize because delaying therapy in patients with poorer
prognoses at baseline due to higher age or NIHSS is further
promoting their unfavorable outcome. This happens despite
the fact that analysis of the National Institute of Neurological
Disorders and Stroke and ECASS 3 trials and recently the
Virtual International Stroke Trials Archive (VISTA) database
showed that age or baseline NIHSS does not modify the
efficacy of tPA treatment.13–15
Our study further showed that patients in some central and
eastern European countries had higher odds of being treated
ⱕ60 minutes after admission to the hospital than other
countries. The most likely explanation is that certain properties of different healthcare services (such as accessibility to
CT scanners, stroke units, emergency departments, etc) may
account for this finding. SITS data, however, do not contain
information on the specifics of healthcare services in each
country, and therefore our finding needs to be clarified in
other studies.
In contrast to a study from the United States,11 several
patients and hospital characteristics did not influence DNT in
our study, specifically the experience of stroke centers (measured both as tPA treatments per year and total tPA treatments), patient sex, or the time of day when patients were
treated. These positive findings can likely be explained by
differences between US and central/eastern European healthcare systems.
The limitation of our study is that the comparison between
countries may have been affected by the fact of differing
participating numbers of centers performing thrombolysis
Mikulik et al
Table 2.
In-Hospital Delays for Thrombolysis
5
Univariate and Multivariate Analysis for Door-to-Needle Time <60 Min
Univariate Analysis
Variable
OR (95% Cl)*
Multivariate Analysis
P Value†
OR (95% Cl)*
P Value†
Sex, female
0.95 (0.85–1.06)
0.34
Age, increment by 10 y
0.92 (0.88–0.96)
⬍0.001
0.92 (0.87–0.97)
0.004
Baseline NIHSS 7–24
1.21 (1.05–1.40)
0.009
1.44 (1.20–1.72)
⬍0.001
Systolic blood pressure,
130–170 mm Hg
1.19 (1.05–1.34)
0.005
1.10 (0.95–1.28)
0.20
Glucose, mmol/L
0.98 (0.96–1.004)
0.11
Patient weight
0.99 (0.995–1.002)
0.47
Early ischemic changes
on CT or MR
1.60 (1.37–1.87)
0.97 (0.77–1.22)
0.80
Dose of tPA
1.0 (0.996–1.005)
⬍0.001
0.87
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Hypertension
0.91 (0.80–1.02)
0.12
Diabetes mellitus
1.03 (0.90–1.17)
0.68
Previous stroke
0.84 (0.71–0.99)
0.042
1.02 (0.81–1.29)
0.86
Diabetes mellitus and
previous stroke
0.74 (0.53–1.02)
0.07
0.73 (0.47–1.12)
0.15
Atrial fibrillation
0.90 (0.80–1.02)
0.11
Congestive heart failure
0.96 (0.82–1.13)
0.66
Hyperlipidemia
0.95 (0.84–1.07)
0.37
Current smoker
1.09 (0.96–1.24)
0.20
Antiplatelets before stroke
0.94 (0.83–1.06)
0.31
Onset-to-door time,
increment by 10 min
1.18 (1.16–1.20)
⬍0.001
1.19 (1.17–1.22)
⬍0.001
Treatment after October 1,
2008
0.87 (0.78–0.97)
0.011
1.05 (0.90–1.23)
0.53
Working hours, 8–16 h
(Monday to Friday)
1.08 (0.97–1.21)
0.16
No. of patients treated in
centre
1.0 (1.0–1.001)
0.47
Prestroke disability (mRS
3–5 versus 0–2)
0.88 (0.71–1.10)
0.27
Centre
NA
⬍0.001
NA
⬍0.001
Country
NA
⬍0.001
NA
⬍0.001
SI versus CR
2.23 (1.74–2.84)
⬍0.001
1.51 (0.84–2.73)
0.17
LT versus CR
0.93 (0.61–1.42)
0.735
0.96 (0.52–1.79)
0.91
PL versus CR
0.72 (0.62–0.84)
⬍0.001
0.85 (0.49–1.46)
0.55
HU versus CR
0.70 (0.54–0.90)
0.005
0.56 (0.16 to 1.93)
0.36
EE versus CR
0.54 (0.39–0.75)
⬍0.001
0.064 (0.01–0.51)
0.009
HR versus CR
0.47 (0.32–0.69)
⬍0.001
0.36 (0.17–0.79)
0.011
TR versus CR
0.44 (0.22–0.87)
0.019
0.17 (0.05–0.50)
0.001
SK versus CR
0.35 (0.27–0.45)
⬍0.001
0.26 (0.17–0.41)
⬍0.001
For countries, percentage of all patients and percentage of patients in country are presented. For all other parameters, percentage
of patients in groups door-to-needle time ⱕ60 min and ⬎60 min are presented.
NIHSS indicates National Institutes of Health Stroke Scale; tPA, tissue plasminogen activator; mRS, modified Rankin Scale; SI,
Slovenia; CR, Czech Republic; LT, Lithuania; PL, Poland; HU, Hungary; EE, Estonia; HR, Croatia; TR, Turkey; SK, Slovakia; NA, not
applicable.
*OR for door-to-needle time (ⱕ60 min/⬎60 min) and its 95% Wald CIs.
†P value of Wald ␹2 test.
from each country; for example, many centers participated
from the Czech Republic (51) and Poland (27), but there were
only 2 from Lithuania. This can explain the rather large
difference in the proportion of patients treated with DNT ⱕ60
minutes in between different countries. Although our analysis
suggests that different healthcare systems may affect DNT,
this finding remains so far hypothetical. Another limitation is
that several variables that could potentially influence DNT
were not collected in the SITS register and therefore could not
be analyzed; for example, the existence of hospital prenoti-
6
Stroke
June 2012
Table 3.
Outcome Stratified According to DNT by 60 Min
Door-to-Needle Time, Min
ⱕ60 (N⫽2097)
mRS 0 –1
84%
61–180 (N⫽3339)
82%
⬎180 (N⫽75)
79%
OR (95% CI)*
Unadjusted
OR (95% CI)*
Adjusted
1.09 (0.97–1.22)
0.86 (0.77– 0.97)
sICH—SITS
1.5%
2.0%
6.7%
1.37 (1.12–1.67)
1.37 (1.05–1.79)
sICH—NINDS
6.9%
8.0%
10.7%
1.13 (0.99–1.30)
1.11 (0.93–1.34)
sICH—ECASS II
5.0%
6.0%
10.7%
1.20 (1.04–1.39)
1.17 (0.96–1.43)
DNT indicates door-to-needle time; mRS, modified Rankin Scale; sICH SITS, symptomatic intracerebral hemorrhage Safe
Implementation of Treatment in Stroke; sICH NINDS, symptomatic intracerebral hemorrhage National Institute of Neurological
Disorders and Stroke; sICH ECASS II, symptomatic intracerebral hemorrhage European Cooperative Acute Stroke Study.
*OR for door-to-needle time (ⱕ60 min/⬎60 min) and its 95% Wald CIs.
fication by ambulances, the distance from the site of stroke to
the hospital, and the use of secondary transfers or type of
transportation.
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Conclusions
Our study demonstrated that physicians delay thrombolysis if
they have more time before the end of the thrombolytic treatment window, if they perceive that thrombolysis would be less
beneficial, or likely due to poor management at the center or
country level. Therefore, it is necessary to improve adherence to
guidelines and to treat patients as soon as possible after arrival to
the hospital (in the majority within 60 minutes) regardless of the
amount of time left to the end of thrombolytic window and in all
patients for whom thrombolysis is indicated.
Sources of Funding
R.M. and P.K. have received research support from the European
Regional Development Fund Project FNUSA-ICRC (No. CZ.1.05/
1.1.00/02.0123), R.M., A.C., A.K., V.S., K.F., J.K., A.V., D.J., Y.K.,
and N.A. have received research support through a grant from the
European Union Public Health Executive Agency (EAHC). A.C. and
A.K. were supported until 2008 by Polish National Program for
Prevention and Treatment of Cardiovascular Diseases. The Safe
Implementation of Treatments in Stroke-EAST (SITS-EAST) is
funded by a grant from European Union Public Health Executive
Authority (PHEA), SITS-EAST is a part of the Safe Implementation
of Treatments in Stroke–International Stroke Thrombolysis Registry
(SITS-ISTR), which is funded by an unrestricted grant from Boehringer Ingelheim and Ferrer, and financial support was also provided
through the regional agreement on medical training and research
(ALF) between Stockholm County Council and the Karolinska
Institute.
Disclosures
R.M., A.C., A.K., A.V., and D.J. have received honoraria payments
and travel support from Boehringer-Ingelheim. L.C. has received
honoraria payment from Bayer, Boehringer Ingelheim, MSD,
Sanofi-Aventis, and Egis and was a member of advisory board in the
Management of Atherothrombosis With Clopidogrel in High-Risk
Patients (MATCH) trial, Rivaroxaban Once-daily oral Direct Factor
Xa Inhibition Compared with Vitamin K Antagonism for Prevention
of Stroke and Embolism Trial (ROCKET) trial, and in Bayer
Company, N.A. is a senior researcher in the Safe Implementation of
Treatments in Stroke International, which receives a grant from
Boehringer Ingelheim and Ferrer for the Safe Implementation of
Treatments in Stroke- the Monitoring study/International Stroke
Thrombolysis Registry.
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Factors Influencing In-Hospital Delay in Treatment With Intravenous Thrombolysis
Robert Mikulík, Pavla Kadlecová;, Anna Czlonkowska, Adam Kobayashi, Miroslav Brozman,
Viktor Svigelj, Laszlo Csiba, Klara Fekete, Janika Kõrv, Vida Demarin, Aleksandras Vilionskis,
Dalius Jatuzis, Yakup Krespi and Niaz Ahmed
for the Safe Implementation of Treatments in Stroke-East Registry (SITS-EAST) Investigators
Stroke. published online March 15, 2012;
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
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