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Acta Neurologica Belgica ISSN 0300-9009 Acta Neurol BelgDOI 10.1007/s13760-013-0249-8
Quantitative and qualitative evaluationtool in planning stroke treatment strategies:the “Safe implementation of treatments instroke Monitoring Study (SITS MOST)”registryV. Bašić Kes, I. Zavoreo, V. Vargek-Solter, A. Aleksić Shihabi, B. Benčina,J. Božić, H. Budinčević, B. Malojčić,M. Mišir, et al.
1 23
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ORIGINAL ARTICLE
Quantitative and qualitative evaluation tool in planning stroketreatment strategies: the ‘‘Safe implementation of treatmentsin stroke Monitoring Study (SITS MOST)’’ registry
V. Basic Kes • I. Zavoreo • V. Vargek-Solter • A. Aleksic Shihabi •
B. Bencina • J. Bozic • H. Budincevic • B. Malojcic • M. Misir • I. Pavlicek •
S. Svalina • M. Vodopic • V. Vuletic • S. Basic • V. Demarin
Received: 25 June 2013 / Accepted: 30 August 2013
� Belgian Neurological Society 2013
Abstract A decade ago, stroke was the first leading cause
of morbidity and mortality in Croatia. Nowadays, we
record reduction in stroke incidence, as well as stroke
consequences—invalidity and mortality. These are due to
long-term planned actions in the field of public health as
well as actions performed by professional organizations.
Today, we can be satisfied with improvement in that field,
but there are still things we can improve, at the first place
improvement of the emergency medicine network due to
Croatian-specific topographical characteristics to reduce
onset-to-door time. In this paper, we evaluated results from
11 Croatian hospitals in the period 11/2005–11/2012. To
find out about the past and present state in applying
thrombolytic therapy in Croatia and to plan further actions
in light of new studies and efforts in Europe and in the
world, all with the aim of improvement in stroke preven-
tion and acute treatment resulting in reduction of stroke
morbidity, mortality and symptomatic intracerebral hem-
orrhage as well as better functional outcome. Our results
have shown that we improved stroke treatment in the last
decade, but further actions should be performed to raise
public stroke awareness and to improve emergency medi-
cine network as well as in hospital protocols.
Keywords Thrombolytic therapy � Croatia � SITS
MOST � Onset-to-door time � Door-to-needle time
Introduction
A decade ago, stroke was first leading cause of morbidity
and mortality in Croatia. Nowadays, we record reduction in
stroke incidence, as well as stroke consequences—inval-
idity and mortality. These are due to long-term planned
actions in the field of public health as well as actions
performed by professional organizations. In the field of
public health, we organized activities such as ‘‘Stroke
awareness day’’ where we presented to the population
V. Basic Kes � I. Zavoreo (&) � V. Vargek-Solter
University Hospital Center Sestre milosrdnice, Zagreb, Croatia
e-mail: [email protected]
A. Aleksic Shihabi
General Hospital Sibenik, Sibenik, Croatia
B. Bencina
General Hospital Virovitica, Virovitica, Croatia
J. Bozic
General Hospital Karlovac, Karlovac, Croatia
H. Budincevic
Clinical Hospital Sveti Duh, Zagreb, Croatia
B. Malojcic
University Hospital Center Zagreb, Zagreb, Croatia
M. Misir
University Hospital Center Osijek, Osijek, Croatia
I. Pavlicek
County Hospital Varazdin, Varazdin, Croatia
S. Svalina
General Hospital Vukovar, Vukovar, Croatia
M. Vodopic
General Hospital Dubrovnik, Dubrovnik, Croatia
V. Vuletic � S. Basic
Clinical Hospital Dubrava, Zagreb, Croatia
V. Demarin
Medical Center Aviva, Zagreb, Croatia
123
Acta Neurol Belg
DOI 10.1007/s13760-013-0249-8
Author's personal copy
mostly recognized stroke risk factors through the printed
materials, counseling, measuring risk factors such as blood
pressure, glucose serum levels, lipids in public, as well as
suggesting visits to our stroke prevention centers [1]. In the
professional field, we organize meetings to educate pro-
fessionals—neurology congresses, meetings with general
practitioners, meetings with emergency medicine doctors
and other medical professionals to raise knowledge about
recognition of stroke risk factors as well as early signs and
symptoms of stroke. We succeeded to introduce thrombo-
lytic therapy into the everyday practice as one of the rou-
tine stroke treatments. We spread information about
thrombolytic therapy not only to the medical professionals
and but also into the general population to reduce time to
needle time and to improve its efficacy. Today, we can be
satisfied with improvement in that field, but there are still
things we can improve, at the first place improvement of
the emergency medicine network due to Croatian-specific
topographical characteristics to reduce onset-to-door time.
Croatia is a part of SITS MOST (Safe implementation of
treatments in stroke Monitoring Study) from 2005. SITS
MOST has strictly defined treatment criteria. The study
aims to evaluate the proportions of symptomatic intrace-
rebral hemorrhage and death (primary endpoints) as well as
independence (secondary endpoint) for stroke patients
treated with rt-PA in clinical routine settings within 3 h
from stroke onset, and to compare these results with the
corresponding rt-PA treated patients in randomized con-
trolled trials [2, 3].
Results of the European Co-operative Acute Stroke
Study-I (ECASS I) and ECASS II support evidences that
alteplase improves functional outcome in selected patients
treated within 3 h of ischemic stroke symptoms onset [4].
ECASS III study has shown that treatment with intravenous
(IV) tissue plasminogen activator (rt-PA) initiated 3–4.5 h
after the onset of ischemic stroke improves 90-day out-
come and that the risk of symptomatic intracerebral hem-
orrhage is modest and acceptable relative to the derived
benefit. However, questions remain: do we only treat
patients fulfilling the enrollment criteria used in the study,
do we generalize the results to a more inclusive group of
stroke patients in the 3- to 4.5-time window, and are there
clinical and imaging-based subtypes of patients more or
less likely to benefit from this treatment? [5].
Some of the ongoing studies will probably answer these
questions. Studies are focused on reduction of the delay
between arriving at hospital and initiation of thrombolytic
therapy or on extension of time window up to 4.5 h on
routine clinical practice. The SITS-WATCH project aims
to reduce door-to-needle time from 65 min, which is the
median value in SITS, to median below 40 min, i.e., for at
least half of all patients. For some centers: 10–15 %
reduction. The SITS-UTMOST is a registry-based study
dedicated to the use of intravenous thrombolysis by rt-PA
in treatment of acute ischemic stroke patients. The purpose
of this study is to evaluate impact of the extended time
window up to 4.5 h on routine clinical practice. The study
is carried out upon request of the European Competent
Authorities that was issued together with approval of
extended time window in Europe [3].
It is not the question whether thrombolysis in acute
stroke is useful anymore; it is a question of well-trained
doctors and well-equipped centers offering this treatment
in a reliable and safe way.
In this paper, we evaluated results from 11 Croatian
hospitals in the period 11/2005–11/2012. To find out about
the past and present state in applying thrombolytic therapy
in Croatia and to plan further actions in light of new studies
and efforts in the Europe and in the world, all with the aim
of improvement stroke prevention and acute treatment
resulting in reduction of stroke morbidity, mortality and
symptomatic intracerebral hemorrhage as well as better
functional outcome.
Materials and methods
We retrospectively reviewed the medical data of thromb-
olysed patients from SITS registry in the period of 7 years
(11/2005–11/2012) in following hospitals: Clinical Hospi-
tal Dubrava, General Hospital Dubrovnik, General Hospital
Vukovar, Clinical Hospital Sveti Duh, General Hospital
Karlovac, Clinical Hospital Center Osijek, Clinical Hos-
pital Center Zagreb, Clinical Hospital Center Sestre mil-
osrdnice, General Hospital Sibenik, County Hospital
Varazdin, General Hospital Virovitica.
All patients were screened by a neurologist to determine
eligibility for intravenous thrombolytic therapy according
to strict European Stroke Organization (ESO) protocol, and
Croatian recommendations for stroke management [6, 7].
Data for each patient treated with rt-PA included: age,
gender, stroke risk factors, ‘‘time-do-door’’ (interval from
symptoms onset till admission to emergency room), ‘‘door-
to-needle’’ (interval from admission till administration of
rt-PA), door-to-image time (interval from admission till CT
scan), onset-to-treatment time (interval from symptoms
onset till application of thrombolytic therapy), blood
pressure at the admission and just before administration of
rt-PA, patient’s score on the National Institute of Health
Stroke Scale (NIHSS) at admission, NIHSS changes 0–2
and 2–24 h after rt-PA, global outcome at 24 h and 7 days
as well as Modified Rankin Scale (MRS) at the time of
admission, 2 h and 7th day after rt-PA treatment.
All patients had a computed tomography (CT) at the
admission time and another in the next 24 h after the rt-PA
administration.
Acta Neurol Belg
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Stroke subtypes were evaluated using TOAST classifi-
cation (Trial of Org 10172 in Acute Stroke Treatment) and
Oxford Community Stroke Project classification (OCSP,
also known as the Bamford or Oxford classification). The
TOAST classification denotes five subtypes of ischemic
stroke: (1) large-artery atherosclerosis, (2) cardioembolism,
(3) small-vessel occlusion, (4) stroke of other determined
etiology, and (5) stroke of undetermined etiology [8].
The OCSP classification relies primarily on the initial
symptoms. Based on these, stroke episode is classified as
total anterior circulation infarct (TACI), partial anterior
circulation infarct (PACI), lacunar infarct (LACI) or pos-
terior circulation infarct (POCI). These four entities predict
the extent of the stroke, the area of the brain affected, the
underlying cause, and the prognosis [9].
Data considering duration of hospital treatment and
complications during or after rt-PA treatment (death,
intracerebral hemorrhage, progressive ischemic stroke,
thromboembolic occlusions of the pulmonary blood ves-
sels) were analyzed as well. Symptomatic intracerebral
hemorrhage (SICH) was defined as any intracranial
bleeding during first 24 h after admission of thrombolytic
therapy, which caused clinical deterioration (defined by an
increase of four points or more in the NIHSS score) or
death.
The dose of administered rt-PA was 0.9 mg kg body
weight with a maximum of 90 mg. According to protocol,
1/10 of total dose of rt-PA was given intravenously in a
bolus and the remaining 9/10 during 1 h. Dose given per
patient as well as dose given per kg of body weight is
presented in tables for each center.
Clinical parameters and values were presented as means,
percentages as well as medians with ranges. Differences
were calculated using t test for paired samples. P values
\0.05 were considered significant.
Results
During the period of 7 years, 601 patient with signs and
symptoms of hemispheric stroke received thrombolytic
therapy. Mean age was 68 years, with the male predomi-
nance in CH Sveti Duh, GH Sibenik and UHC Sestre
milosrdnice, and female predominance in GH Dubrovnik
(Table 1).
Hypertension was the leading stroke risk factor in all
centers, hyperlipidemia, diabetes mellitus and atrial fibril-
lation are at the second place, while congestive heart fail-
ure, smoking and previous stroke are at the third place, the
same distribution we find in other SITS centers (Table 1).
Most of the patients before the stroke onset were in the
group with Rankin score 0 or 1 (as in all other centers in
SITS). Only in GH Karlovac and GH Sibenik most of the
patients were in the group Rankin 4 and 5. A Rankin 0–5
group of patients were equally represented in other Cro-
atian centers as well as in other SITS centers (Table 2).
Mean NIHSS at admission was 10–18 (lowest in UH
Dubrava and UHC Zagreb), in CH Varazdin was statisti-
cally significant higher than in other centers; p \ 0.05),
while in CH Sveti duh and GH Karlovac NIHSS at
admission was higher but not statistically significant
(p [ 0.05). In the group NIHSS 8–14 points were mostly
patients in CH Dubrava, GH Dubrovnik and GH Vukovar,
in the group NIHSS 15? were mostly patients in CH Sveti
Duh, GH Karlovac and CH Varazdin, while in UHC Sestre
milosrdnice, UHC Osijek and UHC Zagreb patients were
mostly in the NIHSS 8–14 and NIHSS 15? groups (equally
distributed), in other SITS centers, patients were equally
distributed in all three NIHSS groups (Table 2).
Systolic blood pressure was 152 mmHg, and diastolic
blood pressure was 85 mmHg at baseline, There are sta-
tistically significant higher values of systolic blood pressure
values (p \ 0.05) in GH Dubrovnik, and statistically sig-
nificant lower diastolic pressure values in (p \ 0.05) GH
Vukovar, higher diastolic blood pressure values are in UHC
Sestre milosrdnice and CH Varazdin (p [ 0.05), other
centers have similar values as other SITS centers (Table 2).
According to TOAST classification, most patients were
in the group with cerebral infarct due to large vessel dis-
ease with significant carotid stenosis ([50 % NASCET)
and other large vessel disease, cardiac emboli and small-
vessel disease were at the second place, while other groups
were in minority (in other SITS centers large vessel disease
and cardiac emboli were at the first place) (Table 3).
According to OCSP classification, most patients were in
the PACI group, LACI was at the second place while TACI
was at the third place, only one patient was in the group
with POCI (in other SITS centers PACI was at the first,
TACI at the second, LACI at the third and POCI at the
fourth place) (Table 3).
Mean onset-to-door time, door-to-image time, door-to-
treatment time, onset-to-treatment time were very similar
in Croatia and other SITS centers, there is in-group vari-
ation between different centers in Croatia according to the
territory area and organization of emergency room and
Neurology departments in hospitals—in GH Vukovar had
shortest onset-to-door and onset-to-image time, but door-
to-treatment time was longer as well as in GH Virovitica,
Karlovac and Sibenik, in GH Dubrovnik there was longer
onset-to-door time, while door-to-image time and door-to-
treatment time was same as in other GH (p \ 0.05). In
UHC, onset-to-door time was according to the territory
area covered, door-to-image time was similar to other SITS
centers in UHC Sestre milosrdnice and Zagreb, while in
Osijek was longer and door-to-treatment time was shorter
in UHC than GH and CH (p \ 0.05) (Table 4).
Acta Neurol Belg
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Acta Neurol Belg
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Evaluating NIHHS changes within first 24 h as well as
global outcome in first 24 h and 7 days, there was better
outcome in UHS and CH than GH. There was no statisti-
cally significant difference between Croatia and other SITS
centers (p [ 0.05) (Table 5).
Rankin after 3 months has shown no statistically sig-
nificant difference between Croatia and other SITS centers,
when evaluating different centers there was statistically
significant lower Rankin in GH than in CH and UHC
(p \ 0.05) (Table 6).
There was no statistically significant difference in pro-
portion of death within 3 months (p [ 0,05) between
Croatia and other SITS centers, there was higher total
number of hemorrhages in UHC Zagreb, as well as ische-
mic strokes in CH Dubrava, CH Sveti Duh and UHC
Zagreb, as well as pulmonary embolism in CH Dubrava
(Table 7).
In comparison with other clinical trials (SICH SITS
MOST, SICH ECASS II and SICH RCT), there was no
statistically significant difference (p \ 0,05) between
Croatia and other SITS centers (both about 10 % of
symptomatic hemorrhages as a cause of death), but still
there was a higher number of complications in GH Viro-
vitica, GH Vukovar and GH Dubrovnik and CH Sveti Duh,
while the number of complications was lower in UHC,
especially in UHC Sestre milosrdnice (p [ 0,05) (Table 7).
Discussion
Present state
During the last decade, stroke units (2001) and thrombol-
ysis (2004) are introduced in almost all Neurology
departments in Croatia (some of the small centers are
lacking stroke units). As we can see from Fig. 1, some of
the centers are giving thrombolytic therapy and treating
patients in stroke units as well, but they are still not active
in SITS MOST registry. This situation is due to well-
known fact that there are not enough medical professionals
as well as insufficient infrastructure and equipment.
According to our results, we can be satisfied with global
situation in Croatia, especially in University Hospital
Centers, but there is still problem with hospitals in smaller
cities and in the cities covering bigger areas. Delay in
arrival of acute stroke cases is influenced by many factors:
sex, age, stroke severity, mode of onset, stroke awareness,
recognition of signs and symptoms of stroke, distance from
the hospital and mode of transport, level of patient edu-
cation, marital status, etc. Therefore, it is of great impor-
tance to raise global knowledge about stroke signs and
symptoms, to educate medical professionals thru teaching
courses and lectures and to reorganize emergency service Ta
ble
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81
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55
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;
60
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;
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or-
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eti
me
(mea
n±
low
er
qu
arti
le;
up
per
qu
arti
le)
30
(25
;
43
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30
(30
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5)
50
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68
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24
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30
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29
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30
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30
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per
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le)
81
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;
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1)
90
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5)
95
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;
10
8)
92
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;
11
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9;
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2;
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Acta Neurol Belg
123
Author's personal copy
Ta
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Acta Neurol Belg
123
Author's personal copy
Ta
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Acta Neurol Belg
123
Author's personal copy
Ta
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7M
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;
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)
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2;
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)
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;
20
)
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10
20
12
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)5
57
10
04
00
60
20
56
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HR
CT
(%)
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14
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04
04
80
20
88
Acta Neurol Belg
123
Author's personal copy
to shorten onset-to-door time, according to our data there is
no statistically difference with other SITS centers [10].
Also we should work on improvement of the in hospital
services to shorten door-to-image time in smaller centers
(in smaller centers longer than in SITS) as well as to
decrease door-to-needle time introducing into everyday
practice protocols for rt-PA and introduce computer net-
work hospital systems enabling faster CT results and lab-
oratory parameters evaluation (\60 min should be the rule;
now in Croatia 75 min and more in smaller centers and in
other SITS centers 68 min) [11–15]. We should raise per-
ception that younger age and mild neurologic outcome
should not delay treatment (time is brain). Younger patients
(18–50 years) have lower morbidity and mortality than
older patients (51–80 years), but it should not be the reason
to delay or not to perform thrombolysis (International
Stroke Trial 3-IST 3 Trial) [16].
Our results have shown that higher NIHHS score (15?)
at admission and/or previous stroke ([3 months, Rankin 4
and 5) as well as multiple risk factors in anamnesis was the
negative predictive factor for stroke outcome (GH
Virovitica, GH Karlovac, GH Sibenik)—lower functional
outcome (NIHSS and Rankin) as well as symptomatic
bleeding. Referral systems for mRS in GH Karlovac and
GH Sibenik are the same as in other hospitals and this is
not the reason for higher mRS values in these centers.
What we have learned
Present state in Croatia is improving, in the last decade
teaching courses were organized in University centers,
especially UHC Sestre milosrdnice as a Referral Center of
the Ministry of Health for neurovascular disorders. As a
center of excellence in the field, UHC Sestre milosrdnice
organized teaching courses in intensive medicine, acute
stroke treatment, stroke units, thrombolysis, emergency
medicine. We were organizing public action to increase
global knowledge about the stroke signs and symptoms,
importance of recognizing them and fast transport to hos-
pitals, as well about the possibilities of thrombolysis as a
treatment. According to that actions as well as improve-
ment of emergency service and in hospital organization,
Fig. 1 Cities with neurology
departments (in Zagreb 4
centers, other 1)
Acta Neurol Belg
123
Author's personal copy
there is a decreasing trend in stroke morbidity (now at the
second place instead of the first) and mortality as well as
improvement in functional stroke outcome [17, 18]. SITS
MOST registry participation enabled transparent, inde-
pendent and organized monitoring of thrombolytic therapy
in Croatia and correlation of the results with other SITS
centers.
Future perspectives
Further actions should be performed to include all Croatian
Neurology departments in SITS registry, as well as intro-
duce Stroke units to enable thrombolytic therapy in all
parts of Croatia under same conditions. Further actions
should be performed reorganizing emergency services and
future global actions rising stroke awareness of population
in different areas of Croatia to improve door-to-needle
time.
Continuous teaching courses should be performed to
introduce new facts about stroke management and to dis-
cuss special demographic and geographic problems and try
to minimize them in co-operation with the Ministry of
Health. Croatia is now part of SITS-WATCH project which
aims to reduce door-to-needle time from 60 to 40 min, in
some countries for 10–15 %. In Croatia, mean door-to-
needle time is 75 min with interval 62–105 min depending
on the type of the hospital—as we previously mentioned
GH have longer times and UHC as a consequence of the
organization, human resources and technical equipment
possibilities.
Once again, we can conclude that rt-PA therapy is safe
and efficient, but in its application should be performed
according to the protocol and to the official European and
national stroke management recommendations. SITS
MOST registry as we mentioned enables monitoring of
such therapeutic actions and teaches us how to improve our
health care system.
Conflict of interest None.
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