Predicting the Risk of Symptomatic Intracerebral
Hemorrhage in Ischemic Stroke Treated With
Intravenous Alteplase
Safe Implementation of Treatments in Stroke (SITS) Symptomatic
Intracerebral Hemorrhage Risk Score
Michael Mazya, MD; José A. Egido, MD, PhD; Gary A. Ford, MD, FRCP;
Kennedy R. Lees, MD, FRCP; Robert Mikulik, MD, PhD; Danilo Toni, MD, PhD;
Nils Wahlgren, MD, PhD; Niaz Ahmed, MD, PhD; for the SITS Investigators
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Background and Purpose—Symptomatic intracerebral hemorrhage (SICH) is a serious complication in patients with acute
ischemic stroke treated with intravenous thrombolysis. We aimed to develop a clinical score that can easily be applied to
predict the risk of SICH.
Methods—We analyzed data from 31 627 patients treated with intravenous alteplase enrolled in the Safe Implementation of
Treatments in Stroke (SITS) International Stroke Thrombolysis Register. The outcome measure was SICH per the Safe
Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition: a Type 2 parenchymal hemorrhage
with deterioration in National Institutes of Health Stroke Scale score of ⱖ4 points or death. Univariate risk factors associated
with the outcome were entered into a logistic regression model after stratification of continuous variables. Adjusted ORs for
the independent risk factors were converted into points, which were summated to produce a risk score.
Results—We identified 9 independent risk factors for SICH: baseline National Institutes of Health Stroke Scale, serum
glucose, systolic blood pressure, age, body weight, stroke onset to treatment time, aspirin or combined aspirin and
clopidogrel, and history of hypertension. The overall rate of SICH was 1.8%. The risk score ranged from 0 to 12 points
and showed a ⬎70-fold graded increase in the rate of SICH for patients with a score ⱖ10 points (14.3%) compared with
a score of 0 point (0.2%). The prognostic discriminating capability by C statistic was 0.70.
Conclusions—The SITS SICH risk score predicts large cerebral parenchymal hemorrhages associated with severe
clinical deterioration. The score could aid clinicians to identify patients at high as well as low risk of SICH after
intravenous alteplase. (Stroke. 2012;43:1524-1531.)
Key Words: cerebral infarct 䡲 database 䡲 intracerebral hemorrhage 䡲 prognosis 䡲 stroke management
䡲 thrombolysis
I
patients who benefit from thrombolysis by at least 1 point on the
modified Rankin Scale has been calculated to 32%,15 whereas
3% sustaine worsened outcome by any degree of the modified
Rankin Scale compared with placebo.16 However, alteplase has
the potential to cause life-threatening intracerebral hemorrhage.
Several clinical, radiological, and pharmacological factors have
ntravenous thrombolysis with alteplase improves functional
neurological outcome and reduces mortality in acute ischemic
stroke.1 After numerous randomized controlled trials2– 8 and
safety monitoring studies,9 –12 alteplase is now approved within 3
hours and recommended by major professional organizations
within 4.5 hours of symptom onset.13,14 The proportion of
Received November 11, 2011; final revision received January 29, 2012; accepted February 21, 2012.
Jeffrey L. Saver, MD, was the Guest Editor for this paper.
From the Department of Neurology (M.M., N.A., N.W.), Karolinska University Hospital, and Department of Clinical Neuroscience, Karolinska
Institutet, Stockholm, Sweden; the Stroke Unit (J.A.E.), Hospital Clínico San Carlos, Universidad Complutense Madrid, Spain; the Stroke Research Group
(G.A.F.), Institute for Ageing and Health, Newcastle University, Newcastle, UK; the Acute Stroke Unit & Cerebrovascular Clinic (K.R.L.), Institute of
Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK; the International Clinical Research Center (R.M.), Neurology Department,
St Anne’s Hospital, Brno, Czech Republic; and the Department of Neurology and Psychiatry (D.T.), Sapienza University of Rome, Rome, Italy.
N.W. and N.A. coordinated the study. M.M. performed the statistical analyses under the supervision by N.A., M.M., N.W., and N.A. wrote the initial
draft of the article. N.W., G.A.F., K.R.L., R.M., and D.T. were members of the SITS Scientific Committee. G.A.F., K.R.L., R.M., and D.T. were national
coordinators of leading recruiting countries. J.E. was the coordinator for a leading recruiting center. All authors have read and commented on the first
draft with regard to interpretation of the data and editing of the article and have seen and approved the final version. M.M., N.W., and N.A. have direct
access to the original data and vouch for the accuracy and completeness of this report.
The views expressed are those of the authors. M.M., N.W., and N.A. had full access to all data in this study and had the final responsibility for the
preparation of this article and its submission for publication.
Correspondence to Michael Mazya, MD, SITS International Coordination Office, Karolinska Stroke Research, Department of Neurology, Karolinska
University Hospital–Solna, Stockholm, Sweden. E-mail [email protected]
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.111.644815
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Mazya et al
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been implicated in raising the risk for different varieties of
thrombolysis-related cerebral hemorrhage.17,18 Not all types and
amounts of cerebral blood extravasation have been found to
cause symptoms superimposed on those caused by the acute
ischemia itself or by edema or to worsen long-term functional
outcome.19 –22 Truly symptomatic intracerebral hemorrhage
(SICH) caused by thrombolysis can be conceptualized as a
homogenous blood clot large enough to exert a mass effect on
brain tissue outside the infarct. Furthermore, it must be associated with distinct deterioration in neurological status occurring
within a timeframe when an effect of alteplase is pharmacologically plausible. Previously published models of risk stratification in thrombolysis were designed for a less specific outcome
definition, that is, any type and size of hemorrhage plus any level
of neurological decline within a variable timeframe.23,24 There is
currently a lack of risk scores that predict true SICH.
To be clinically practical, a risk score should be easy to apply
at the bedside using information available in the emergency
situation. To perform accurately, it should use variables that
confer independent prognostic information and must take into
account the complex profile of patients with multiple risk
factors. Such a score could be useful in adjusting for baseline
risk and patient selection in future trials of reperfusion therapy
and could be combined with future radiological methods and
biomarkers predicting thrombolytic complications.
In the present study, we aimed to develop a risk score for
SICH derived from a comprehensive multivariate analysis in
a large prospectively collected cohort of patients treated with
intravenous alteplase for acute ischemic stroke enrolled into
the Safe Implementation of Treatments in Stroke–International Stroke Thrombolysis Register (SITS-ISTR).
Methods
Study Population
All patients recorded in the SITS-ISTR between December 25, 2002,
and March 1, 2010, were included in this study. Patients were included
if they presented with stroke symptoms and were treated with intravenous alteplase (Actilyse; Boehringer-Ingelheim, Ingelheim, Germany)
within as well as outside license criteria. The need for ethical approval
or patient consent for participation in the SITS-ISTR varied among
participating countries, but ethics approval and patient consent were
obtained in countries that required this; other countries approved the
register for conduct as an anonymized audit. The SITS-MOnitoring
STudy (MOST) data (n⫽6483)10 are embedded within the SITS-ISTR.
The SITS-MOST was approved by the Ethics Committee of the
Karolinska Institutet in Stockholm, Sweden, as well as by the Swedish
Medical Products Agency. The SITS International Coordination Office
did regular online monitoring of the SITS-ISTR data and checked
individual patient data monthly to identify errors or inconsistencies. For
a sample of patients included in SITS-MOST, source data were verified
on-site by monitors under the supervision of the national coordinator.
Procedures
The SITS-ISTR is an ongoing, prospective, Internet-based,
academic-driven, multinational, observational monitoring register
for clinical centers using thrombolysis for the treatment of acute
ischemic stroke. The methodology of the SITS-ISTR, including the
procedure for data collection and management, patient identification,
and verification of source data, has been described previously.10
We collected baseline and demographic characteristics, stroke
severity per the National Institutes of Health Stroke Scale (NIHSS),
risk factors, onset-to-treatment time, medication history, and imaging data on admission and follow-up.
Predicting Risk of SICH
1525
The main outcome measure of this study was SICH per the
SITS-MOST definition: a local or remote Type 2 parenchymal
hemorrhage on imaging 22 to 36 hours after treatment or earlier if the
imaging scan was performed due to clinical deterioration combined
with a neurological deterioration of ⱖ4 NIHSS points from baseline
or from the lowest NIHSS score between baseline and 24 hours or
leading to death within 24 hours. A grading of Type 2 parenchymal
hemorrhage for intracranial hemorrhage indicates a coagulum exceeding 30% of the infarct with substantial space occupation.
In addition to the SITS-MOST definition, we used 2 other
definitions of SICH to enable comparison with previously published
data: (1) SICH per the European Cooperative Acute Stroke Study
(ECASS) II definition: any type of intracerebral hemorrhage on any
posttreatment imaging after the start of thrombolysis and increase of
ⱖ4 NIHSS points from baseline, or from the lowest value within 7
days, or leading to death; and (2) SICH per the National Institute of
Neurological Disorders and Stroke (NINDS) definition: any deterioration in NIHSS score or death within 7 days combined with
intracerebral hemorrhage of any type (including petechial) on any
posttreatment imaging after the start of thrombolysis.
All assessments of imaging studies and neurological status were done
according to clinical routine at centers participating in the SITS-ISTR. A
follow-up CT or MR scan at 22 to 36 hours after intravenous tissue-type
plasminogen activator treatment was required for all patients. All SICH
events (per SITS-MOST, ECASS II, and NINDS definitions) were
adjudicated centrally by the SITS International Coordination Office
based on submitted imaging and clinical data.
Statistical Analysis
We performed descriptive statistics for baseline, imaging, and demographic data, comparing patients with and without SICH per SITSMOST definition. All baseline variables available in the SITS-ISTR
were analyzed. For continuous variables, median and interquartile range
values were calculated. For categorical variables, we calculated percentage proportions by dividing the number of events by the total number of
patients, excluding missing or unknown cases, as done in previous SITS
publications.10 –12 For calculation of significance of difference between
medians and proportions, we used the Mann-Whitney U test and the
Pearson ␹2 method, respectively. To avoid variable selection caused by
spurious correlations, only variables showing an association with SICH
at the Pⱕ0.10 level in the univariate analysis were included as potential
predictors into the multivariate logistic regression model. In this analysis, variables significant at P⬍0.05 were regarded as independent risk
factors for SICH. Stratification of continuous variables was necessary
for bedside practicality. In an exploratory manner, we obtained the
cutoff value for each variable, which resulted in the highest univariate
odds ratio for SICH per SITS-MOST in a dichotomization. If several
adjacent values showed the same OR at dichotomization, the lowest
value was chosen to include all levels of the variable with the highest
odds for SICH. Stroke severity by NIHSS was stratified in an explorative manner into 3 levels optimizing the difference between the
univariate ORs for SICH of the respective strata. Stratification of the
NIHSS into more groups did not result in an improved predictive ability
of the score. A new multivariate logistic regression analysis was
performed, including the stratified continuous risk factors and the
categorical risk factors, obtaining the final adjusted ORs for SICH per
SITS-MOST. Point values were assigned to the risk factors based on
their adjusted ORs: 1 point for OR ⬎1.0 and ⱕ1.7, 2 points for OR
⬎1.7 and ⬍2.7, and 3 points for OR ⱖ2.7.
For each patient, the SITS SICH risk score was calculated as the
sum of point values assigned to their risk factors with possible total
individual scores ranging between 0 and 12. Rates of SICH by all 3
definitions were calculated among patients in each score category.
Score categories were collapsed when the prevalence of a given
score was ⬍1%, that is, for ⱖ9 points. For clinical practicality, we
also performed a stratification of the total risk scores for SICH per
SITS-MOST into 4 tiers: low, average, moderate, and high risk. The
discriminating capacity of the risk score in the derivation cohort was
assessed using the area under the receiver operating characteristic
curve (C statistic) as an index of model performance. All analyses
were performed using STATISTICA 10.0.
1526
Stroke
Table 1.
June 2012
Univariate Analysis of Baseline Variables
SICH SITS-MOST
No SICH SITS-MOST
No./Total
Median (IQR) or
Proportion (%)
No./Total
Median (IQR) or
Proportion (%)
Onset to treatment time, min
558
150 (120 –176)
30 072
145 (117–170)
Age, y
568
74 (66–78)
30 349
69 (60–76)
⬍0.001
Glucose, mg/dL
546
127 (106–162
29 018
118 (103–142)
⬍0.001
rtPA dose, mg
560
70 (60–80)
30 171
68 (60–77)
Weight, kg
559
79 (70–90)
30 163
75 (67–85)
NIHSS at baseline
558
14 (9–19
30 009
12 (7–17)
Systolic BP, mm Hg
557
160 (145–170)
29 728
150 (137–167)
Diastolic BP, mm Hg
555
82 (75–91)
29 708
81 (74–90)
Sex, female
224/558
40%
12 782/30 352
42%
0.201
Hypertension
430/555
77%
18 684/29 772
63%
⬍0.001
⬍0.001
P Value
0.005
0.002
0.002
⬍0.001
⬍0.001
0.561
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Diabetes mellitus type 2
142/555
26%
5105/29 918
17%
Hyperlipidemia
207/493
42%
9501/27 001
35%
0.002
Smoking–never
300/471
64%
16 466/28 111
59%
⬍0.001
Smoking–current
79/471
17%
6528/28 111
23%
⬍0.001
Smoking–previous
93/471
20%
5117/28 111
18%
0.912
Previous stroke
111/525
21%
3951/29 929
13%
⬍0.001
Atrial fibrillation
188/553
34%
7466/29 602
25%
⬍0.001
69/547
13%
2548/29 701
9%
⬍0.001
⬍0.001
Heart failure
Aspirin
276/554
50%
9392/30 035
31%
Dipyridamole
19/560
3%
701/30 144
2%
0.098
Clopidogrel
30/560
5%
1087/30 166
4%
0.028
6/566
1%
299/30 222
1%
0.862
Oral anticoagulant, INR N/A
Oral anticoagulant, INR ⱕ1.7
10/566
2%
473/30 222
2%
0.700
Oral antihypertensive
332/556
60%
14 018/30 097
47%
⬍0.001
Signs of infarct on CT/MRI
138/373
27%
6181/28 230
22%
⬍0.001
Continuous variables: median with interquartile range (IQR) and P values per the Mann-Whitney U test. Categorical variables: proportions (%) and
P values per the Pearson ␹2 test.
SICH indicates symptomatic intracerebral hemorrhage; SITS-MOST, Safe Implementation of Thrombolysis in Stroke-Monitoring Study; rtPA,
recombinant tissue-type plasminogen activator; NIHSS, National Institutes of Health Stroke Scale; BP, blood pressure; INR, international normalized
ratio, N/A, not available or unreported.
Internal Validation
The model was developed on a population of 15 814 patients with odd
database entry numbers, a random pick, avoiding potential chronological and geographical confounding factors. All statistical methods described were performed at this stage. Having obtained the score model,
it was internally validated on the remaining 15 813 patients with even
database entry numbers. In both populations, only patients with complete data for all score variables and outcomes were included in the
analysis. Validation was performed by evaluating the discriminating
capability of the model by receiver operating characteristic analysis as
well as calibration using the Hosmer-Lemeshow goodness-of-fit
method. Both methods were subsequently also applied to the entire
database population with complete data for score variables and
outcomes.
Results
In total, 31 627 patients with ischemic stroke treated with
intravenous thrombolysis were recorded in SITS-ISTR at 669
centers from 34 countries, of whom 93.3% (29 508 of 31 627)
were from Europe. Data were complete for all score variables
and the main outcome in 13 908 (87,9%) patients in the
model derivation cohort, in 13 896 (87.9%) patients in the
internal validation cohort, and in 27 804 patients (87.9%), in
the entire database. Follow-up imaging results at 22 to 36
hours were available in 96.4% of cases.
The time from symptom onset to tissue-type plasminogen
activator treatment ranged between 3 and 4.5 hours in 10.3%
(3257 of 31 627 patients), whereas 1.5% (459 of 31 627 patients)
were recorded as treated ⬎270 minutes after stroke onset.
In the entire population, the rate of SICH per SITS-MOST
was 1.8%, the rate of SICH per ECASS II was 5.1%, and the
rate of SICH per NINDS was 7.4%.
Table 1 shows the baseline characteristics of patients with
SICH per the SITS-MOST definition compared with those
without SICH. Multivariate logistic regression analysis resulted in 9 risk factors independently associated with SICH
per SITS-MOST. These are reported in Table 2 together with
the attributed score points for each risk factor.
The SITS SICH Risk Score
The SITS SICH risk score showed a strong association with
SICH per the SITS-MOST definition with a ⬎70-fold increase
Mazya et al
Table 2. Final Multivariate Scoring Model Using Risk Factors for
SICH per SITS-MOST After Stratification of Continuous Variables
Predicting Risk of SICH
1527
In the entire material, the C statistic for the predictive
capability of the score for SICH per ECASS II was 0.67 and
0.66 for SICH per NINDS. The Hosmer-Lemeshow test
statistic was 8.0 (P⫽0.09) in the validation cohort and 7.5
(P⫽0.19) in the entire population.
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Risk Factor
OR (95% CI)
P Value
Points
Aspirin⫹clopidogrel
3.2 (1.9 –5.2)
⬍0.001
3
Aspirin monotherapy
1.8 (1.5–2.1)
⬍0.001
2
NIHSS ⱖ13
2.2 (1.7–3.0)
⬍0.001
2
Discussion
NIHSS 7–12
1.6 (1.1–2.1)
0.006
1
B–Glucose ⱖ180 mg/dL
2.1 (1.7–2.6)
⬍0.001
2
Age ⱖ72 y
1.7 (1.4–2.0)
⬍0.001
1
Systolic BP ⱖ146 mm Hg
1.6 (1.3–2.0)
⬍0.001
1
Weight ⱖ95 kg
1.6 (1.2–2.0)
⬍0.001
1
Onset-to-treatment time ⱖ180 min
1.5 (1.2–2.0)
0.002
1
History of hypertension
1.4 (1.1–1.7)
0.004
1
We have designed a clinical risk score with good discriminatory
ability to identify patients with acute stroke at high risk of SICH
when treated with IV alteplase. Previous studies of other
hemorrhage risk scores have been performed on smaller data
sets of a few hundred patients.23,24 The present study is based on
31 627 patients. We have identified and incorporated several
independent risk factors for SICH into a risk score, which
demonstrates a strong association between the risk for SICH and
an accumulating burden of risk factors. The rate of SICH
increases ⬎70-fold in patients with a score ⱖ10 points (14.3%)
compared with those with a score of 0 (0.2%). The predictive
ability of the score is acceptable with a C statistic of 0.70 in the
entire population. Internal validation depicted nearly identical
performance among the model derivation, validation, and total
study cohorts. The Hosmer-Lemeshow goodness-of-fit test comparing predicted and observed rates of SICH showed good
calibration of the score model in the validation cohort.
Identifying patients at low risk of SICH may facilitate
treatment by nonspecialists. In a survey of American
emergency physicians, 26% of 1105 respondents were
reluctant to use thrombolysis in acute ischemic stroke for
fear of SICH.25 Among this physician population, the
highest acceptable rate of SICH was 3.4%, which is
approximately double the average rate of SICH per SITSMOST (1.8%) in the SITS-ISTR registry. Our risk score
shows that 11% of thrombolyzed patients have a risk for
SICH of this magnitude or higher (ⱖ3.7% with ⱖ7 points).
Still, any decision whether to withhold thrombolysis because of an increased risk of SICH needs to weigh this
against the potential benefit to the patient.
The SITS SICH risk score may be relevant and useful in 3
different contexts: (1) the score may aid clinicians as well as
patients and families in the process of decision-making when
faced with acute ischemic stroke eligible for thrombolytic
treatment; (2) as neuroimaging modalities and biomarkers
evolve in their ability to predict SICH, they could be used in
conjunction with the SITS SICH risk score; and (3) the risk
score may be useful in clinical trials for patient selection and
balancing the risk of SICH between randomized groups.
Overall Risk Level
Total Score
SICH Rate (95% CI)
0.4% (0.2%–0.6%)
Low
0–2 points
Average
3–5 points
1.5% (1.3%–1.7%)
Moderate
6–8 points
3.6% (3.1%–4.1%)
High
ⱖ9 points
9.2% (5.9%–12.5%)
Multivariate ORs with CIs. For clinical practicality, the total score is tiered into 4
levels according to risk severity. Points are attributed strictly either for “aspirin
combined with clopidogrel” or “aspirin as antiplatelet monotherapy.” Absence of
aspirin treatment and history of hypertension, NIHSS 0 – 6, and values of continuous
parameters below the stated cut points are scored as zero points.
SICH indicates symptomatic intracerebral hemorrhage; SITS-MOST, Safe
Implementation of Thrombolysis in Stroke-Monitoring Study; NIHSS, National
Institutes of Health Stroke Scale; BP, blood pressure.
in SICH between patients with a score of 0 and those with a
score ⱖ10 (Figure 1). The overall rate of SICH was 1.8% for the
entire population. The median total score was 4 points. Eleven
percent of patients scored ⱖ7 points, showing a rate of SICH of
ⱖ3.7%, that is, at least double the population average. With a
score ⱖ10 points (0.2% of all patients), the rate of SICH
increased 8-fold from the average to 14.3%. In Figures 1 to 3,
due to the low prevalence, patients with ⱖ10 points have been
pooled together with those scoring 9 points. Conversely, among
the 500 patients with a score of 0 points, there was only a single
case of SICH per SITS-MOST. In addition to presenting the
SICH rates for all score levels in Figure 1, we have also shown
the total risk score levels as 4 tiers: low, average, moderate, and
high risk (Table 2).
For purposes of comparability with published results, the
ability of the score to predict SICH per ECASS II and NINDS
definitions was also assessed (Figures 2 and 3). The association
between rising score and increasing SICH rates was evident here
as well. A doubled rate of both SICH per ECASS II and NINDS
was seen in patients with a score ⱖ7 who comprise 11% of the
population. Compared with the average rates, a score ⱖ10 was
associated with a 6-fold increase in SICH per ECASS II to 31%
and a 4-fold increase in SICH per NINDS to 29%.
The index of predictive capability of the score for SICH per
SITS-MOST in the model derivation cohort, internal validation cohort, and entire database population was calculated
using the area under the receiver operating characteristic
curve (C statistic). The C statistic in the derivation cohort was
0.71. The C statistic in the internal validation cohort was
0.69. The C statistic in the pooled total population was 0.70.
Risk Factors for SICH per SITS-MOST
We have identified 9 clinical and anamnestic parameters that
have been included in the risk score. They are presented in this
section by order of decreasing multivariate ORs for SICH, as
shown in Table 2. The strongest predictor of SICH in our
material is current dual antiplatelet therapy with aspirin and
clopidogrel. This has been previously suggested by Diedler et
al26 as well as in a pooled analysis of the Stroke-Acute Ischemic
NXY Treatment (SAINT) I and II trials.27 Single antiplatelet
treatment with aspirin is also an independent risk factor, which,
however, is not the case for monotherapy with clopidogrel.
Stroke severity has been shown in several studies to be associ-
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Stroke
June 2012
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Figure 1. The Safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage (SICH) risk score, SICH per
the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition. Bars show the rate of SICH for each
score category in the design, validation, and all patient populations. Percentages indicate rates per score category in the all patient
cohort. At risk: proportion of all thrombolyzed patients with the respective risk score.
ated with various definitions of SICH after thrombolysis.17,18
Multivariate analysis of outcomes in the SITS-MOST study has
previously shown NIHSS score ⱖ8 to be associated with
increased risk for SICH per SITS-MOST.11 In our study,
explorative stratification of the NIHSS, aiming to maximize the
difference in OR for SICH between groups, resulted in 3 levels:
NIHSS 0 to 6, 7 to 12, and ⱖ13. Further stratification did not
improve model performance. An elevated baseline serum glucose level ⱖ10 mmol/L is also independently associated with
SICH, a finding consistent with previously published results.28 It
is noteworthy that this association was not seen in patients with
known diabetes mellitus and baseline glucose levels
⬍10 mmol/L. Current guidelines recommend treatment with
insulin titration in patients with stroke and serum glucose
⬎10 mmol/L,13,14 although it is unclear whether reducing blood
glucose reduces the risk of hemorrhage. Age is another wellknown predictor of SICH. In our population, the sharpest
increase in risk for SICH occurs in the beginning of the eighth
decade of life with 72 years being the optimal cutoff level
between lower and higher risk groups. A detailed analysis of
age-related SICH risk in the SITS material was recently published by Ford et al.29 Elevated baseline blood pressure is
another independent risk factor for SICH in our register, previously reported by Ahmed et al.30 Meanwhile, it remains an open
question whether acute antihypertensive therapy attenuates
SICH risk. Dichotomizing baseline systolic blood pressure, we
aimed for a maximum risk difference between groups above and
below the cut point. Here, a level of 146 mm Hg was found
optimal. Adding more strata did not improve overall score
performance. Stratifying the next risk factor, body weight, we
found the level of ⱖ95 kg to have the strongest association with
an increased risk for SICH. It is intriguing that neither the net
dose of alteplase nor the dose in mg/kg of body weight elevated
the risk for SICH. A recent analysis by Diedler et al31 has
demonstrated a higher incidence of symptomatic intracerebral
hemorrhage in patients ⬎100 kg despite the lower per-kilogram
dose of alteplase. Furthermore, in agreement with findings in the
ECASS III trial7 as well as previous results from the SITSISTR,12 we found a small but significant increase in the risk for
SICH in patients treated between 3 and 4.5 hours after symptom
onset. Lastly, the independent risk factor with the lowest but
statistically significant impact is a known history of hypertension. This is, to our knowledge, previously unreported; however,
results from the SITS-ISTR have shown that patients with a
history of untreated hypertension have increased rates of SICH
per SITS-MOST.30
Comparison With Previous SICH Scores
Major differences exist between the present study and the 2
previously published risk scores for intracerebral hemorrhage
Mazya et al
Predicting Risk of SICH
1529
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Figure 2. The Safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage (SICH) risk score, SICH per
the European Cooperative Acute Stroke Study (ECASS) II definition. Bars show the rate of SICH for each score category. Percentages
indicate rates per score category in the all patient cohort. At risk: proportion of all thrombolyzed patients with the respective risk score.
after stroke thrombolysis. The SITS SICH score predicts
large parenchymal hemorrhages associated with severe clinical deterioration. It is designed using data from ⬎30 000
patients using weighted risk factors. The Hemorrhage After
Thrombolysis (HAT) score was designed through a literature
review and tested on 400 patients.23 The Multicenter Recombinant Tissue-Type Plasminogen Activator Stroke Survey
Group score was constructed with unweighted parameters
using data from 1205 patients; however, of these, only 481
had complete data for relevant variables.24 Importantly, both
scores were designed to assess the risk for any amount of
blood extravasation on CT related to any clinical deterioration, that is, the NINDS definition of SICH. This definition is
confounded by clinical deterioration due to infarct edema,
new infarction, and intra- and interrater variability in assessment of NIHSS deterioration of 1 point, required for labeling
as “symptomatic” in the NINDS studies. These confounders
may be present concomitantly with small amounts of blood in
the infarct core on follow-up imaging. Thus, it can be argued
that the 2 previous scores predict any clinical deterioration,
which only in part may depend on cerebral hemorrhage.
In the HAT score study, the C statistic was 0.74, whereas
the score by Cucchiara et al32 had a C statistic of 0.68 in the
original population. Both scores have recently been subjected
to external validation using the pooled SAINT I and II
cohorts. This resulted in lower predictive capability with C
statistic values of 0.59 for both algorithms.
The SITS SICH risk score does not require waiting for a
measurement of a blood platelet count (required by the Stroke
Survey Group score) nor a volumetric measurement of the
manifest infarct size on initial imaging (used in the HAT
score). It can thus readily be calculated immediately on
presentation or even in the prehospital setting en route to the
hospital. Under these circumstances, the stroke center’s
average door-to-needle time could be used to calculate a
probable onset-to-treatment time required by our score.
Study Limitations
Despite our belief that the patient data in the SITS-ISTR are
representative for clinical practice across a variety of demographics and stroke center types, for the risk score to be suitable
for routine clinical practice, an external validation is warranted.33
Like with other register-based studies, the presented results are
based on retrospective, explorative analysis of observational
material. Data for the relevant variables and outcomes were
missing in 12.1% of our patients, which may have had an
influence on the outcome. Furthermore, stratification of continuous variables as well as conversion of risk factor ORs to score
point values, although necessary for clinical practicality, can be
assumed to have resulted in a loss of information and decreased
1530
Stroke
June 2012
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Figure 3. The Safe Implementation of Treatments in Stroke (SITS) symptomatic intracerebral hemorrhage (SICH) risk score, SICH per the
National Institute of Neurological Disorders and Stroke (NINDS) definition. Bars show the rate of SICH for each score category. Percentages
indicate rates per score category in the all patient cohort. At risk: proportion of all thrombolyzed patients with the respective risk score.
model accuracy. We cannot exclude that some patients in the
intravenous thrombolysis register were given additional intra-arterial therapy, although this is likely to be marginal. The present
study is based on patients treated between the end of 2002 and
beginning of 2010. During this period, intra-arterial therapy was
not widely available across Europe, where 93.3% of our patients
were treated.
Conclusions
The SITS SICH risk score shows good predictive ability for the
risk of SICH in patients with ischemic stroke treated with
intravenous thrombolysis. Our score may aid clinicians to
identify patients with the highest as well as the lowest risk of
SICH. However, we cannot propose withholding treatment with
alteplase in patients otherwise eligible according to current
guidelines. An external validation of our score is warranted.
Furthermore, a study of the clinical effect of recombinant
tissue-type plasminogen activator across risk score categories is
needed to assess whether some patients at high risk of SICH may
still have a favorable risk-to-benefit ratio with treatment.
Appendix
Scientific Committee of SITS International
Nils Wahlgren (chair), Antoni Dávalos, Gary A. Ford, Martin Grond,
Werner Hacke, Michael Hennerici, Markku Kaste, Kennedy R. Lees, R.
Mikulik, Risto Roine, Turgut Tatlisumak, Danilo Toni, and K.S. Wang.
Scientific Committee of Fighting Stroke (Uppdrag
Besegra Stroke)
Nils Wahlgren (chair), Niaz Ahmed, Maaret Castrén, Ulf Eriksson,
Jonas Frisén, Ulf Hedin, Staffan Holmin, Åke Sjöholm, Mikael
Svensson, and Mia von Euler.
Acknowledgments
We thank all SITS-ISTR investigators and their centers for their
participation. We also pass on our thanks to all patients who participated
in SITS-ISTR. Uppsala Clinical Research (UCR) center, Uppsala,
Sweden, developed, maintained, and upgraded the software for the SITS
register in close collaboration with SITS until September 2010. The
current SITS registry is developed, maintained, and upgraded by
Zitelab, Copenhagen, Denmark, in close collaboration with SITS.
Sources of Funding
SITS-ISTR is funded by an unrestricted grant from Boehringer Ingelheim, Ferrer, and by a grant from European Union Public Health
Executive Authority (PHEA). Financial support was also provided
through the regional agreement on medical training and research (ALF)
between Stockholm County Council and the Karolinska Institute. This
study is a part of the Fighting Stroke Project (Uppdrag Besegra Stroke),
supported by the Swedish Heart and Lung Foundation and Karolinska
Institutet, Friends of Karolinska Institutet, USA, and Johanniterorden.
Disclosures
J.A.E. has received fees from Boehringer Ingelheim as a member of
an Advisors’ Committee and for educational activities. He has also
received fees for the ECASS II and ECASS III trials. He has also
received fees from Novo Nordisk as an investigator for the Factor
Mazya et al
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Seven for Acute Hemorrhagic Stroke (FAST) trials. G.A.F. has
received fees and expenses from Boehringer Ingelheim for educational activities. He has also received fees and expenses from
Lundbeck for educational activities. His institution has received
grant assistance from Boehringer Ingelheim toward administrative
expenses for coordination of SITS in the United Kingdom, fees for
consultancy work, and study payments. K.R.L. has received fees and
expenses from Boehringer Ingelheim for his role as chairman of the
independent data safety monitoring board of the ECASS III trial with
alteplase and related lectures. He has also received fees from Paion,
Forest and Lundbeck for the Desmoteplase in Acute Ischemic Stroke
Trial (DIAS) trials with desmoteplase. His institution has received
grant assistance toward administrative expenses for coordination of
SITS in the United Kingdom. R.M. has received research support
from European Regional Development Fund Project FNUSA-ICRC
(No. CZ.1.05/1.1.00/02.0123). D.T. has served as a consultant for
Boehringer Ingelheim and has been paid lecture fees for attending
and speaking at workshops held by Boehringer Ingelheim, SanofiAventis and Novo Nordisk. N.W. has received expenses from
Boehringer Ingelheim for his role as member of the Steering
Committee in relation to the ECASS III trial with alteplase and
served as a consultant to Thrombogenics as chairman of the Data
Safety Monitoring Board. SITS International (chaired by N. Wahlgren) received a grant from Boehringer Ingelheim and Ferrer for the
SITS-MOST/SITS-ISTR. His institution has also received grant
support toward administrative expenses for coordination of the
ECASS III trial. N.W. has also received lecture fees from Boehringer
Ingelheim and Ferrer. N.A. is a senior researcher in SITS International, which receives a grant from Boehringer Ingelheim and Ferrer
for the SITS-MOST/SITS-ISTR.
References
1. Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute
ischaemic stroke. Cochrane Database Syst Rev. 2009;4:CD000213.
2. The National Institute of Neurological Disorders and Stroke rtPA Stroke
Study Group. Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995;333:1581–1587.
3. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, et al.
Intravenous thrombolysis with recombinant tissue plasminogen activator
for acute hemispheric stroke: the European Cooperative Acute Stroke
Study (ECASS). JAMA. 1995;274:1017–1025.
4. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, et
al. Randomised double-blind placebo-controlled trial of thrombolytic
therapy with intravenous alteplase in acute ischaemic stroke (ECASS II).
Lancet. 1998;352:1245–1251.
5. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP,
Hamilton S. Recombinant tissue-type plasminogen activator (alteplase)
for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS
study. JAMA. 1999;282:2019 –2026.
6. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0to 6-hour acute stroke trial, part A (A0276G): results of a double-blind,
placebo-controlled, multicenter study. Stroke. 2000;31:811– 816.
7. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, et
al, for the ECASS Investigators. Thrombolysis with alteplase 3 to 45
hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329.
8. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et
al, for the EPITHET investigators. Effects of alteplase beyond 3 h after
stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial
(EPITHET). Lancet Neurol. 2008;7:299 –309.
9. Hill MD, Buchan AM. Canadian Alteplase for Stroke Effectiveness Study
(CASES) Investigators. Thrombolysis for acute ischemic stroke: results
of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ. 2005;
172:1307–1312.
10. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al.
Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST):
an observational study. Lancet. 2007;369:275–282.
11. Wahlgren N, Ahmed A, Eriksson N, Aichner F, Bluhmki E, Dávalos A, et al,
for the SITS-MOST investigators. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in
randomized controlled trials; Safe Implementation of Thrombolysis in Stroke
Monitoring Study (SITS-MOST). Stroke. 2008;39:3316–3322.
Predicting Risk of SICH
1531
12. Wahlgren N, Ahmed N, Davalos A, Hacke W, Millán M, Muir K, et al.
Thrombolysis with alteplase 3– 4.5 h after acute ischaemic stroke (SITSISTR): an observational study. Lancet. 2008;372:1303–1309.
13. Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr, American Heart
Association Stroke Council. Expansion of the time window for treatment
of acute ischemic stroke with intravenous tissue plasminogen activator: a
science advisory from the American Heart Association/American Stroke
Association. Stroke. 2009;40:2945–2948.
14. The European Stroke Organization (ESO) Executive Committee; ESO
Writing Committee. Guidelines for management of ischaemic stroke and
transient ischaemic attack 2008. Cerebrovasc Dis. 2008;25:457–507.
15. Saver JL. Number needed to treat estimates incorporating effects over the
entire range of clinical outcomes: novel derivation method and application to
thrombolytic therapy for acute stroke. Arch Neurol. 2004;61:1066–1070.
16. Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically
relevant number needed to harm. Stroke. 2007;38:2279 –2283.
17. Lansberg MG, Albers GW, Wijman CA. Symptomatic intracerebral hemorrhage following thrombolytic therapy for acute ischemic stroke: a
review of the risk factors. Cerebrovasc Dis. 2007;24:1–10.
18. Derex L, Nighoghossian N. Intracerebral haemorrhage after thrombolysis
for acute ischaemic stroke: an update. J Neurol Neurosurg Psychiatry.
2008;79:1093–1099.
19. Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V,
Lesaffre E, et al. Hemorrhagic transformation within 36 hours of a
cerebral infarct: relationships with early clinical deterioration and
3-month outcome in the European Cooperative Acute Stroke Study I
(ECASS I) cohort. Stroke. 1999;30:2280 –2284.
20. Larrue V, von Kummer R, Müller A, Bluhmki E. Risk factors for severe
hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the EuropeanAustralasian Acute Stroke Study (ECASS II). Stroke. 2001;32:438–441.
21. Berger C, Fiorelli M, Steiner T, Schäbitz WR, Bozzao L, Bluhmki E, et
al. Hemorrhagic transformation of ischemic brain tissue: asymptomatic or
symptomatic? Stroke. 2001;32:1330 –1335.
22. Trouillas P, von Kummer R. Classification and pathogenesis of cerebral
hemorrhages after thrombolysis in ischemic stroke. Stroke. 2006;37:
556 –561.
23. Lou M, Safdar A, Mehdiratta M, Kumar S, Schlaug G, Caplan L, et al.
The HAT Score: a simple grading scale for predicting hemorrhage after
thrombolysis. Neurology. 2008;71:1417–1423.
24. Cucchiara B, Tanne D, Levine SR, Demchuk AM, Kasner S. A risk score to
predict intracranial hemorrhage after recombinant tissue plasminogen activator for acute ischemic stroke. J Stroke Cerebrovasc Dis. 2008;17:331–333.
25. Brown DL, Barsan WG, Lisabeth LD, Gallery ME, Morgenstern LB.
Survey of emergency physicians about recombinant tissue plasminogen
activator for acute ischemic stroke. Ann Emerg Med. 2005;46:56 – 60.
26. Diedler J, Ahmed N, Sykora M, Uyttenboogaart M, Overgaard K, Luijckx GJ
et al. Safety of intravenous thrombolysis for acute ischemic stroke in patients
receiving antiplatelet therapy at stroke onset. Stroke. 2010;41:288–294.
27. Cucchiara B, Kasner SE, Tanne D, Levine SR, Demchuk A, Messe SR,
et al. Factors associated with intracerebral hemorrhage after thrombolytic
therapy for ischemic stroke: pooled analysis of placebo data from the
Stroke-Acute Ischemic NXY Treatment (SAINT) I and SAINT II Trials.
Stroke. 2009;40:3067–3072.
28. Ahmed N, Dávalos A, Eriksson N, Ford GA, Glahn J, Hennerici M, et al.
Association of admission blood glucose and outcome in patients treated
with intravenous thrombolysis: results from the Safe Implementation of
Treatments in Stroke International Stroke Thrombolysis Register (SITSISTR). Arch Neurol. 2010;67:1123–1130.
29. Ford GA, Ahmed N, Azevedo E, Grond M, Larrue V, Lindsberg PJ, et al.
Intravenous alteplase for stroke in those older than 80 years old. Stroke.
2010;41:2568 –2574.
30. Ahmed N, Wahlgren N, Brainin M, Castillo J, Ford GA, Kaste M, et al.
Relationship of blood pressure, antihypertensive therapy, and outcome in
ischemic stroke treated with intravenous thrombolysis: retrospective analysis from Safe Implementation of Thrombolysis in Stroke–International
Stroke Thrombolysis Register (SITS-ISTR). Stroke. 2009;40:2442–2449.
31. Diedler J, Ahmed N, Glahn J, Grond M, Lorenzano S, Brozman M, et al.
Is the maximum dose of 90 mg alteplase sufficient for patients with
ischemic stroke weighing ⬎100 kg? Stroke. 2011;42:1615–1620.
32. Cucchiara B, Kasner S, Tanne D, Levine S, Demchuk A, Messe S, et al.
Validation assessment of risk scores to predict postthrombolysis intracerebral haemorrhage. Int J Stroke. 2011;6:109 –111.
33. Altman DG, Vergouwe Y, Royston P, Moons KG. Prognosis and prognostic research: validating a prognostic model. BMJ. 2009;338;b605.
Downloaded from http://stroke.ahajournals.org/ by guest on July 12, 2017
Predicting the Risk of Symptomatic Intracerebral Hemorrhage in Ischemic Stroke
Treated With Intravenous Alteplase: Safe Implementation of Treatments in Stroke (SITS)
Symptomatic Intracerebral Hemorrhage Risk Score
Michael Mazya, José A. Egido, Gary A. Ford, Kennedy R. Lees, Robert Mikulik, Danilo Toni,
Nils Wahlgren and Niaz Ahmed
for the SITS Investigators
Stroke. 2012;43:1524-1531; originally published online March 22, 2012;
doi: 10.1161/STROKEAHA.111.644815
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
Print ISSN: 0039-2499. Online ISSN: 1524-4628
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Data Supplement (unedited) at:
http://stroke.ahajournals.org/content/suppl/2013/10/02/STROKEAHA.111.644815.DC1
http://stroke.ahajournals.org/content/suppl/2013/10/08/STROKEAHA.111.644815.DC2
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Abstract
25
Abstract
アルテプラーゼ静注で治療した虚血性脳卒中における症候性
脳内出血のリスクの予測
— Safe Implementation of Treatments in Stroke
（ SITS）
症候性脳内出血のリスク
スコア
Predicting the Risk of Symptomatic Intracerebral Hemorrhage in Ischemic Stroke Treated With
Intravenous Alteplase
― Safe Implementation of Treatments in Stroke (SITS) Symptomatic Intracerebral Hemorrhage Risk Score
Michael Mazya, MD1; José A. Egido, MD, PhD2; Gary A. Ford, MD, FRCP3; Kennedy R. Lees, MD, FRCP4;
Robert Mikulik, MD, PhD5; Danilo Toni, MD, PhD6; Nils Wahlgren, MD, PhD1; Niaz Ahmed, MD, PhD1;
PhD; for the SITS Investigators
1 Department of Neurology, Karolinska University Hospital, and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm,
Sweden; 2 Stroke Unit, Hospital Clínico San Carlos, Universidad Complutense Madrid, Spain; 3 Stroke Research Group, Institute for Ageing and
Health, Newcastle University, Newcastle, UK; 4 Acute Stroke Unit & Cerebrovascular Clinic, Institute of Cardiovascular & Medical Sciences,
University of Glasgow, Glasgow, UK; 5 International Clinical Research Center, Neurology Department, St Anne’s Hospital, Brno, Czech Republic;
6 Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.
背景および目的：症候性脳内出血（ SICH ）
は静脈内血栓溶
コアとした。
解療法で治療した急性期虚血性脳卒中患者の重篤な合併症
結果：9 つの SICH の独立危険因子が同定された：ベー
である。本研究は，SICH のリスクを予測するために容易
スラインの NIHSS スコア，血清グルコース値，収縮期血
に適用することができる臨床的スコアの作成を目的とした。 圧，年齢，体重，脳卒中発症から治療までの時間，アスピ
方法：Safe Implementation of Treatments in Stroke（ SITS ） リンまたはアスピリンとクロピドグレルの併用，および高
International Stroke Thrombolysis Register に登録されて
血圧の既往。SICH の全体の発生率は 1.8％であった。リ
いる，アルテプラーゼ静注による治療を受けた患者 31,627
スクスコアは 0 ～ 12 ポイントの範囲であり，スコア 10
例のデータを解析した。転帰の尺度は Implementation of
ポイント以上の患者（ 14.3％）はスコア 0 ポイントの患者
Thrombolysis in Stroke-Monitoring Study（ SITS-MOST ） （ 0.2％）と比べて，SICH の発現率が 70 倍超に段階的に上
の定義による SICH であった（ NIHSS スコアの 4 ポイン
昇した。C 統計量で示した予後識別能は，0.70 であった。
ト以上の悪化を伴う 2 型実質性出血または死亡 ）
。連続変
結論：STS SICH リスクスコアは，重度の臨床的悪化を
数で層別化後，転帰に関連する単変量危険因子をロジス
伴う脳実質の大量出血を予測する。このスコアは，臨床医
ティック回帰モデルにあてはめた。独立危険因子に関する
がアルテプラーゼ静注後に SICH をきたすリスクが高い患
補正 OR をポイントに変換し，それらを合計してリスクス
者や低い患者を同定するために役立つと考えられる。
Stroke 2012; 43: 1524-1531
表 2 連続変数について層別化後の SITS-MOST による SICH の危険因子の最終的な多変量スコア化モデル
OR（95％ CI）
p値
ポイント
アスピリン＋クロピドグレル
3.2（1.9 〜 5.2）
＜ 0.001
3
低度
0 ～ 2 ポイント
0.4%（ 0.2 〜 0.6% ）
アスピリン単独療法
1.8（1.5 〜 2.1）
＜ 0.001
2
平均的
3 ～ 5 ポイント
1.5%（ 1.3 〜 1.7% ）
NIHSS ≧ 13
2.2（1.7 〜 3.0）
＜ 0.001
2
中等度
6 ～ 8 ポイント
NIHSS 7 ～ 12
1.6（1.1 〜 2.1）
0.006
1
高度
血清グルコース≧ 180 mg/dL
2.1（1.7 〜 2.6）
＜ 0.001
2
年齢≧ 72 歳
1.7（1.4 〜 2.0）
＜ 0.001
1
収縮期 BP ≧ 146 mmHg
1.6（1.3 〜 2.0）
＜ 0.001
1
体重≧ 95 kg
1.6（1.2 〜 2.0）
＜ 0.001
1
発症から治療開始までの時間≧ 180 分
1.5（1.2 〜 2.0）
0.002
1
高血圧の既往
1.4（1.1 〜 1.7）
0.004
1
危険因子
全体のリスクレベル
総スコア
≧ 9 ポイント
SICH 発生率（ 95％ CI ）
3.6%（ 3.1 〜 4.1% ）
9.2%（ 5.9 〜 12.5% ）
多変量 OR と CI。臨床での実用性を考慮し，総スコアをリスクの程度に従って 4 つのレベルに分類した。ポイントには「アスピリンとクロピドグレルの併用」
か「アスピリン単独による抗血小板療法」のいずれかのポイントが必ず含まれる。アスピリン療法なし，高血圧の既往なし，NIHSS 0 ～ 6 および連続パラメー
タが上述のカットオフ値未満である場合は，0 ポイントとして評価した。
STCH：症候性脳内出血，SITS-MOST：Safe Implementation of Thrombolysis in Stroke-Monitoring Study，NIHSS：米国国立衛生研究所脳卒中スケール，
BP：血圧。
36 Stroke 한국어판 Vol. 5, No. 3
Abstract 14
정맥혈전용해제 치료를 받은 허혈뇌졸중 환자에서
증상성 뇌내출혈의 위험도에 대한 연구
Safe Implementation of Treatments in Stroke (SITS) 증상성 뇌내출혈 위험도 점수
Predicting the Risk of Symptomatic Intracerebral Hemorrhage in Ischemic Stroke
Treated With Intravenous Alteplase
Safe Implementation of Treatments in Stroke (SITS) Symptomatic Intracerebral Hemorrhage Risk Score
Michael Mazya, MD; José A. Egido, MD, PhD; Gary A. Ford, MD, FRCP; Kennedy R. Lees, MD, FRCP;
Robert Mikulik, MD, PhD; Danilo Toni, MD, PhD; Nils Wahlgren, MD, PhD; Niaz Ahmed, MD, PhD; for the SITS Investigators
(Stroke. 2012;43:1524-1531.)
Key Words: cerebral infarct ■ database ■ intracerebral hemorrhage ■ prognosis ■ stroke management ■ thrombolysis
배경과 목적
증상성 뇌내출혈은 정맥내 혈전용해제 치료를 받은 급성기 허
혈뇌졸중 환자에서 발생할 수 있는 심각한 합병증의 하나이다.
저자들은 증상성 뇌내출혈의 위험도를 예측하기 위해 쉽게 적
용될 수 있는 임상적인 점수를 개발하는 연구를 진행하였다.
방법
저자들은 Safe Implementation of Treatments in Stroke
(SITS) International Stroke Thrombolysis Register에 등
록된 31,627명의 자료를 분석하였다. 결과측정은 the Safe
Implementation of Treatments in Stroke-Monitoring
Study (SITS-MOST) 정의를 이용하여, NIHSS 4점 이상의
악화 혹은 사망을 보인 2형 뇌실질혈종으로 정의하였다. 결과
와 연관된 단변수 위험인자들은 연속변수를 계층화한 이후 로
지스틱 회귀분석에 포함되었다. 독립적인 위험인자들에 대한
보정위험도가 점수로 전환되어 위험도 점수를 산출하기 위해
합산되었다.
결과
저자들은 증상성 뇌내출혈에 대한 9개의 위험인자로 초기
NIHSS 점수, 혈당, 수축기 혈압, 연령, 체중, 뇌졸중 발생에서
치료까지의 시간, 아스피린 혹은 아스피린/클로피도그렐 병용
및 고혈압의 병력을 확인하였다. 뇌내출혈의 전체발생률은 1.8%
였다. 위험도 점수는 0점에서 12점으로 조사되었는데, 0점의
위험도 점수를 가진 환자들의 뇌내출혈 발생률은 0.2%였고,
10점 이상의 점수를 가진 환자들의 경우 뇌내출혈의 발생률이
14.3%로 70배 이상 위험도가 증가하는 것으로 나타났다. C
statistic에 의한 예후분별능력은 0.70으로 나타났다.
결론
SITS 증상성 뇌내출혈 위험도는 심각한 임상적 악화완 연관된
큰 뇌내실질혈종을 예측할 수 있다. 이 점수는 임상의가 정맥
혈전 치료 이후의 증상성 뇌내출혈 발생의 위험도를 예측하는
데 도움을 줄 수 있을 것이다.