Risk Factors for Intracranial Hemorrhage in Acute Ischemic
Stroke Patients Treated With Recombinant Tissue
Plasminogen Activator
A Systematic Review and ­Meta-­Analysis of 55 Studies
William N. Whiteley, PhD; Karsten B
­ ruins Slot, MD; Peter Fernandes, BM, BCh;
Peter Sandercock, MD; Joanna Wardlaw, MD
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Background and Purpose—Recombinant tissue plasminogen activator (rtPA) is an effective treatment for acute ischemic
stroke but is associated with an increased risk of intracranial hemorrhage (ICH). We sought to identify the risk factors for
ICH with a systematic review of the published literature.
Methods—We searched for studies of r­ tPA-­treated stroke patients that reported an association between a variable measured
before rtPA infusion and clinically important ICH (parenchymal ICH or ICH associated with clinical deterioration). We
calculated associations between baseline variables and ICH with ­random-­effect ­meta-­analyses.
Results—We identified 55 studies that measured 43 baseline variables in 65 264 acute ischemic stroke patients. ­Post-­rtPA
ICH was associated with higher age (odds ratio, 1.03 per year; 95% confidence interval, 1.01–1.04), higher stroke severity
(odds ratio, 1.08 per National Institutes of Health Stroke Scale point; 95% confidence interval, 1.06–1.11), and higher
glucose (odds ratio, 1.10 per mmol/L; 95% confidence interval, 1.05–1.14). There was approximately a doubling of
the odds of ICH with the presence of atrial fibrillation, congestive heart failure, renal impairment, previous antiplatelet
agents, leukoaraiosis, and a visible acute cerebral ischemic lesion on pretreatment brain imaging. Little of the variation
in the sizes of the associations among different studies was explained by the source of the cohort, definition of ICH, or
degree of adjustment for confounding variables.
Conclusions—Individual baseline variables were modestly associated with p­ ost-­rtPA ICH. Prediction of p­ ost-­rtPA ICH
therefore is likely to be difficult if based on single clinical or imaging factors alone. These observational data do not provide
a reliable method for the individualization of treatment according to predicted ICH risk. (Stroke. 2012;43:2904-2909.)
Key Words: acute ­stroke ◼ meta-­analysis ◼ systematic review ◼ thrombolysis
T
mmHg because of concerns that the risk of ICH is higher in
patients outside these criteria. However, there is no convincing
evidence that those at highest risk for p­ ost-­rtPA ICH do not
benefit from treatment.
The risk factors for ­post-­rtPA ICH and the strength of any
association therefore are of great relevance, particularly to
the currently defined thresholds for the use of rtPA defined
in acute stroke guidelines.5,6 We therefore aimed to review
systematically the published literature reporting the associations between variables available before treatment with
­post-­rtPA ICH, to quantify the direction and magnitude of the
effects, and to determine whether any important ­study-­level
variables modified the size of the associations and so provide
best evidence to predict ICH after rtPA.
hrombolytic treatment with intravenous recombinant tissue plasminogen activator (rtPA) is an effective treatment
for acute ischemic stroke. However, it increases the risk of
intracranial hemorrhage (ICH), which is otherwise uncommon in ischemic stroke.1 Thrombolysis with rtPA increases
the odds of ICH by ≈4-fold; ≈27 extra fatal ICH occur for
every 1000 patients treated.2 Large or symptomatic ICH that
are not immediately fatal are associated with an increased risk
of subsequent death or disability.3
Clinicians may overestimate the risk of ICH when they treat
patients with rtPA, and so they inappropriately avoid treatment.4 The current European license restricts the use of rtPA
to stroke patients younger than age 80 years, patients without
severe strokes, and those with systolic blood pressure <180
Received May 21, 2012; accepted August 20, 2012.
From the Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK (W.N.W., P.F., P.S., J.W.); Oslo University Hospital-Ullevål,
Oslo, Norway (K.B.S.); Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Edinburgh, UK (J.W.).
Bo Norrving, MD, PhD, was the guest editor for this article.
The ­online-­only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.
665331/-/DC1.
Correspondence to Dr William Whiteley, Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU.
E-mail [email protected]
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI:10.1161/STROKEAHA.112.665331
2904
Whiteley et al Risk Factors for Intracranial Hemorrhage After rtPA 2905
Materials and Methods
We systematically searched for published cohort studies of patients
with acute ischemic stroke treated with intravenous rtPA that reported
the associations between pretreatment variables with posttreatment
ICH. We applied the methods recommended in the M
­ eta-­analysis of
Observational Studies in Epidemiology (MOOSE) guidelines.7 The
study protocol is available on the web site of the Division of Clinical
Neurosciences, University of Edinburgh (tinyurl.com/7czs5oe).
Study Inclusion Criteria
Studies were eligible if they: (1) enrolled ischemic stroke patients
treated with intravenous rtPA, (either into observational cohorts or the
treatment arms of trials of rtPA); (2) measured variables available to a
clinician before the infusion of rtPA; (3) were primary studies rather
than pooling projects (to prevent double counting of the individual
cohorts); and (4) recorded at least 10 ICH within the first 10 days after treatment, because this is the minimum number needed to measure
an association reliably.8
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Search Strategy
We searched Medline and EMBASE from inception to August 2011
(Supplementary Materials I), and we supplemented this by searching
our personal files and citations of relevant studies. We did not limit
our search by language.
Data Extraction
Three authors (W.W., K.B.S., and P.F.) read the abstracts of retrieved
studies and reviewed the full text of those that appeared relevant. Two
authors read each abstract and resolved differences by discussion with a
third author if necessary. We extracted data into an electronic database.
We recorded ­study-­level characteristics that might bias the estimates
of associations within each study: the nature of the study (randomized
controlled trial or observational cohort); losses to f­ ollow-­up; and statistical methods. We then recorded (or calculated from figure presented)
the odds ratios (OR) and 95% confidence intervals (CI) between baseline variables and ICH. For each OR, we recorded the degree of adjustment for confounding (for age, stroke severity, or other factors), the
method of measurement of the baseline variables, the number of ICH,
the number of patients with the baseline variables measured, and the
definition of ICH used by the investigators. When a study gave both
unadjusted and adjusted OR, we recorded the adjusted OR. Where a
continuous variable was not examined continuously but was dichotomized or a dichotomy could be calculated, we recorded the c­ut-­off
point; when a variable had more divisions and a dichotomy could not
be calculated, we recorded the comparison of the extreme thirds. When
a study defined ICH in several ways we used the definition of symptomatic ICH, which gave the greatest number of ICH, unless it was clear
that the focus of the study was to record a particular hemorrhage definition. Data were extracted twice for each study to reduce transcription
errors. We tried to avoid double counting of cohorts, which would have
artificially increased the precision of the effect sizes.
Definition of ICH
We defined clinically important p­ ost-­rtPA ICH as “any visible hemorrhage associated with any neurological deterioration,”9 “any visible
hemorrhage with significant neurological deterioration,”10,11 “parenchymal hemorrhage with or without neurological deterioration,”12
and “parenchymal hemorrhage with significant neurological deterioration”13 (Supplementary Materials II).
Analysis
We calculated a weighted estimate of the proportions of patients
with each definition of ICH by m
­ eta-­analyzing the inverse v­ ariance-­
weighted proportions from each study. For each association, we
­calculated the natural log of the OR and the standard error of the log
ratio. We used ­random-­effects ­meta-­analysis, which assumes that the
true underlying effect size varies between studies, to calculate summary
OR and 95% CI. We used r­andom-­effects m
­ eta-­regression to explore
the extent to which study design, degree of adjustment for confounding
factors, and definition of ICH explained b­ etween-­study heterogeneity
for those associations with >10 studies. We assessed heterogeneity between study estimates using the I2 statistic,14 with thresholds for low,
moderate, and high degrees of heterogeneity and very high heterogeneity at 25%, 50%, and 75%, respectively. We inspected funnel plots and
used Egger test to examine for evidence of publication bias15 for those
associations described in >10 studies. We used Stata 11 for the analysis.
Results
Included Studies
We identified 55 studies that met our inclusion criteria (Figure 1)
that measured associations between baseline variables and
­post-­rtPA ICH (median 2 associations per study; interquartile
range, 1–6), a total of 3953 ICH in 65 264 acute ischemic stroke
patients. Studies were based in Europe (24), North America
(14), or East Asia (4), or they were multiregional (13). Almost
all studies used rtPA at the currently recommended dose of 0.9
mg/kg; 54 papers were written in English and 1 was w
­ ritten
in Japanese. Eleven studies were of ­
rtPA-­
treated patients
from randomized controlled trials of rtPA and other acute
stroke treatments, and 44 were prospective cohort studies. No
study reported losses to ­follow-­up before the occurrence of
­post-­rtPA ICH. The analysis examined 43 baseline variables,
each of which was examined in between 1 and 22 studies.
For each variable there were a median of 136 hemorrhages
(interquartile range, 33–347) and a median of 3215 stroke
patients treated with rtPA (interquartile range, 640–10 707).
The characteristics of the included studies are summarized in
Supplementary Tables III and IV.
Definition of ­Post-­rtPA ICH
Most studies used a definition of “any visible hemorrhage with
any neurological deterioration” (26/55), fewer used the definition
“any visible hemorrhage with significant neurological deterioration” (12/55) and “parenchymal hemorrhage with or without
neurological deterioration” (9/55), and fewest used the definition
“parenchymal hemorrhage with significant neurological deterioration” (8/55). There was variation in the timing of the measurement of hemorrhage for each hemorrhage definition. (Table)
There was ≈3-fold difference in the proportion of patients with
a reported post-rtPA ICH between studies that reported hemorrhage as “parenchymal hemorrhage with significant neurological deterioration” (4.1%) and those that reported hemorrhage as
“parenchymal hemorrhage with or without neurological deterioration” (12.2%; Table). The definition “any hemorrhage with
significant deterioration” was the only definition for which the
proportion of patients with ­post-­rtPA ICH varied little between
studies (ie, low statistical heterogeneity; I2=0%).
Associations Between Baseline Variables With ­
Post-­rtPA Hemorrhage
Figure 2 shows the results of a m
­ eta-­analysis for each of
the 43 baseline variables. Older age was associated with
a significantly increased risk of ­
post-­
rtPA ICH across all
studies with moderate to low heterogeneity in the size of
estimates, when modeled as a continuous variable (OR, 1.03
2906 Stroke November 2012
Figure 1. PRISMA diagram and study identification.
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per year), or when dichotomized at 65 years (1 study; OR,
2.63; 95% CI, 1.16–6.90), 70 years (1 study; OR, 4.12; 95%
CI, 1.10–15.4), 80 years (5 studies; pooled OR, 1.25; 95% CI,
0.82–1.90; P=0.31; I2=0%), or 90 years (1 study; OR, 1.78;
95% CI, 0.39–8.59). The associations between ­post-­rtPA ICH
with the following variables were all statistically significant:
renal impairment (OR, 2.79), congestive heart failure (OR,
1.96), atrial fibrillation (OR, 1.86), a previous diagnosis of
hypertension (OR, 1.50), ischemic heart disease (OR, 1.54),
and prescription of a statin before stroke (OR, 1.72). Smoking
was associated with a lower risk of ­post-rtPA ICH (OR, 0.70).
Furthermore, for each of these estimates there was no significant
Table. Definitions of Intracranial Hemorrhage in the Included Studies
Components of Hemorrhage Definition
Any hemorrhage with any neurological
deterioration
Any hemorrhage with significant
neurological deterioration
Any parenchymal hemorrhage, with or
without neurological deterioration
Parenchymal hemorrhage with
significant neurological deterioration
Clinical Deterioration
(N of Studies)
Radiological Change
(N of Studies)
­Follow-­Up Scan
(N of Studies)
N of Studies (%)
% Hemorrhage (CI)
Any (23)
Any hemorrhage (25)
<36 h (21)
26 (47)
5.3% (4.6%–6.0%)
NIHSS score >1 (3)
Parenchymal (1)
NIHSS score >4 (12)
Any hemorrhage (12)
<48 h (22)
<7 d (23)
Not recorded (3)
<36 h (3)
NA
NIHSS score >4 (8)
Any parenchymal
hemorrhage (9)
Any parenchymal
hemorrhage (3)
Type 2 parenchymal
hemorrhage (5)
<72 h (5)
<7 d (9)
Not recorded (3)
<36 h (3)
<48 h (4)
<72 h (5)
<7 d (6)
<30 d (7)
Not recorded (2)
<36 h (7)
<10 d (8)
CI indicates 95% confidence interval; NA, not available; NIHSS, National Institutes of Health Stroke Scale.
The proportion of patients with each hemorrhage definition was calculated by a r­ andom-­effects ­meta-­analysis.
I2=82%
12 (23)
6.5% (5.8%–7.2%)
I2=0%
9 (18)
12.2% (8.6–15.7%)
I2=79%
8 (16)
4.1% (2.7%–5.5%)
I2=88%
Whiteley et al Risk Factors for Intracranial Hemorrhage After rtPA 2907
Variable
OR (95% CI)
Number of studies
p
I2
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Figure 2. Summary odds ratios for the associations between baseline variables measured in
stroke patients treated with recombinant tissue
plasminogen activator (rtPA) and subsequent
intracranial hemorrhage. The size of each
square is proportional to the number of contributing studies and the horizontal line indicates
the 95% CI. aPTT, activated partial throm­
boplastin time; ASPECTS, Alberta Stroke Program Early CT Score; cFn, cellular fibronectin;
MCA, middle cerebral artery; MMP-9, matrix
metalloproteinase 9; NIHSS, National Institutes
of Health Stroke Scale score; VAP-1/SSAO,
vascular adhesion protein-1/­semicarbazide-­
sensitive amine oxidase.
haemorrhage
OR (95% CI)
haemorrhage
b­ etween-­studyvariationinthesizeoftheestimates(Supplementary
Materials and Supplementary Figures I–XI). Higher stroke
severity, measured by the National Institutes of Health Stroke
Scale score, was associated with a higher risk of p­ ost-­rtPA ICH
with low heterogeneity, when modeled as a continuous variable
(OR, 1.08 per point increase), or as a dichotomized measure
(3 studies, National Institutes of Health Stroke Scale score
thresholds 5, 15, and 20, 1 study each) or trichotomized measure (2 studies at 5 and 20 and at 18 and 7).
Patients using antiplatelet agents at the time of treatment
with rtPA had a higher risk of ICH (OR, 2.08; 95% CI, 1.46–
2.97), although this summary estimate had high heterogeneity (I2=74%) that was not explained by the number or type of
antiplatelets prescribed (when reported).
Higher blood glucose levels were associated with a significantly higher risk of ­post-­rtPA ICH, with a moderate degree
of heterogeneity (I2=26%) when modeled as a continuous
variable (OR, 1.10 per mmol/L), and when divided at 8 or
10 mmol/L (I2=39%). We found surprisingly few associations between systolic blood pressure with p­ ost-­rtPA ICH (6
studies) with a high degree of heterogeneity in the size of the
estimates from different studies, whether examined as a continuous variable (I2=67%) or dichotomous variable (I2=35%).
The overall estimate was consistent with a small decrease and
a larger increase in the risk of ICH with higher blood pressure.
Later timing of thrombolysis did not increase the risk of ICH
significantly, although the studies reported time as a dichotomous rather than continuous variable.
The presence of a visible brain imaging lesion was associated with a higher risk of ICH, whether recorded as the “presence of any lesion” vs “no visible lesion” (OR, 2.39; I2=49%;
14 studies) or by larger vs smaller lesion extent as a dichotomized ASPECTS score (OR, 3.46; I2=14% split at 5 [2 studies],
7 [3 studies], or 8 [1 study]). A ­random-­effects m
­ eta-­regression
analysis showed no significant effect of the definition of the
lesion size on the strength of the association (>33% of middle
cerebral artery territory vs any visible lesion: OR, 2.07; 95%
CI, 0.81–5.27; P=0·12). The presence vs absence of leukoaraiosis on baseline imaging was associated with an increased risk
of p­ ost-­rtPA hemorrhage (OR, 2·45) with low heterogeneity.
Assessment of Heterogeneity
We were unable to demonstrate that the definition of ICH,
study design (randomized trial vs observational cohort), or
degree of adjustment for confounding factors in the original
studies explained a statistically significant proportion of
2908 Stroke November 2012
b­ etween-­study heterogeneity in the strength of the association
between ­post-­rtPA ICH with any of: age; smoking; any computed tomography low density; National Institutes of Health
Stroke Scale score; gender; diabetes; previous hypertension;
glucose; visible brain lesion; use of previous antiplatelets; and
atrial fibrillation (baseline variables with >10 measured associations). Two studies16,17 compared the association between
baseline variables with different ways of defining p­ ost-­rtPA
ICH within the study population; there was no evidence in
these studies that hemorrhage definition explained heterogeneity in the strength of the associations between p­ ost-­rtPA ICH
with antiplatelet agents, National Institutes of Health Stroke
Scale, age, systolic blood pressure, or glucose level.
Assessment of Publication Bias
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We found no evidence for publication bias for any of the associations of p­ ost-­rtPA ICH with age, smoking, any computed
tomography low density, National Institutes of Health Stroke
Scale score, gender, diabetes, previous hypertension, glucose,
visible brain lesion, and atrial fibrillation. There was, however,
evidence of significant small study bias for the association
between ­post-­rtPA ICH with the prescription of antiplatelets
(P<0.001; Egger bias coefficient 1.92; 95% CI, 1.15–2.69),
although 1 study had a significant influence on this statistic.
Discussion
We found moderate and positive associations between
­post-­rtPA ICH with older age, higher neurological impairment,
higher plasma glucose, antiplatelets, statins, computed tomography changes of acute ischemic stroke, leukoarioisis, and the
presence of atrial fibrillation, diabetes, previous ischemic heart
or cerebral vascular diseases, and congestive cardiac failure.
The associations of these factors with p­ ost-­rtPA hemorrhage
were modest and they are unlikely–at least when measured
individually–to predict whether an individual patient will
experience a ­post-­rtPA ICH. The presence or absence of any of
these variables does not appear to be a reliable way to decide
whether to treat an acute stroke patient with intravenous rtPA.
The definition of ICH used by each study had an effect on
the prevalence of ICH but did not materially alter the relative
measures of association of baseline variables with the occurrence of ICH.
The apparently protective effect of smoking on ­post-­rtPA
ICH is probably analogous to the “smoker’s paradox” first
observed in large trials of thrombolysis for myocardial infarction. There is a similar apparent improvement in survival of
smokers after ischemic stroke.18 The improved survival compared with that of nonsmokers after myocardial infarction is
largely accounted for by the younger age and less advanced
atherosclerosis at the time of presentation. Because we only
had access to group data, we have not been able to examine
whether this association in stroke patients attenuated after
adjusting for age and degree of neurological impairment.
Antiplatelet agents were associated with an increased risk
of p­ost-­rtPA ICH. We did not observe a significant dose–
response with the number of antiplatelet agents prescribed
across studies. The recent ARTIS trial tested the addition of
aspirin to rtPA, and demonstrated an increased risk of postrtPA ICH in patients treated with aspirin (risk ratio 2.78, 95%
CI:1.01 to 7.63). This is similar to the association we observed
in our systematic review (OR 2.08 95% CI: 1.46 to 2.97), and
strongly suggests a causal relationship between antiplatelets
and the risk of intracranial haemorrhage.19
Most of the clinical risk factors for ICH after rtPA also have
been associated with poor prognosis after stroke.20 The extent
to which confounding by other risk factors explains each
association is difficult to judge from this systematic review,
because even though we could not demonstrate a significant
attenuation in the size of the associations with increasing
adjustment for age, stroke severity, or other factors, these
analyses lacked statistical power because the comparisons
were made between studies rather than within study.
Systematic reviews of prognostic variables are methodologically challenging, and methods for such reviews are developing and improving. We did not search the gray literature, and
so we may have missed some studies, although we did not find
much evidence of publication or other small study biases in the
associations we measured (other than for antiplatelet medication). Despite our efforts to prevent it, it is possible that some
cohorts were d­ ouble-­counted, which may have led to inappropriately overstated precision of the reported effect sizes.
We did not find a sufficient number of studies that examined either systolic blood pressure or timing of thrombolysis
as continuous variables to draw strong conclusions. Where we
were able to examine time to treatment, it was simply dichotomized into later vs earlier treatment, and the pooled estimate
for association between later time of treatment and ICH was
not statistically significant. This was consistent with the results
of an analysis of pooled data from the ATLANTIS, ECASS,
and NINDS trials, which did not show any clear gradient in
the risk of ICH with increasing delay to treatment.21 This may
reflect confounding by the degree of neurological impairment
(because patients with more severe strokes tend to arrive in
hospital earlier).
ICH after treatment of acute stroke patients with rtPA might
be avoided by not treating patients at high predicted risk for
ICH. At least 7 multivariate models have been constructed to
predict the risk of ICH after treatments with rtPA.22–28 Each
model had modest predictive power in validation datasets,
although none of these studies reported the raw associations
between factors and p­ ost-­rtPA ICH. However, none of these
studies establishes whether treatment with rtPA was of less
benefit to those with a higher predicted risk of ­post-­rtPA ICH.
There are 2 potentially modifiable baseline clinical variables
associated with p­ ost-­rtPA hemorrhage, increased blood glucose, and increased blood pressure. Neither the lowering of
blood glucose29 nor the lowering of blood pressure30 is associated with less death or disability after acute stroke in completed randomized trials, but it is possible that correction
of increased blood pressure or glucose might mitigate the
increased risk of ICH with rtPA treatment.
The findings of this review may help clinicians to make
modest predictions about the risk of ICH in individual patients.
ICH after rtPA is more likely to be seen in patients who are
older, with substantial comorbidities and more severe strokes,
and in those using antiplatelet agents and with visible abnormalities on baseline computed tomography imaging. This
might aid communication with patients and their relatives,
Whiteley et al Risk Factors for Intracranial Hemorrhage After rtPA 2909
although this probably should not influence the decision
whether to administer rtPA, because no variable measured at
baseline–other than time to treatment–has shown a significant
interaction with the net benefit of treatment on subsequent
death or disability.
Conclusions
Factors that predict ICH after treatment with rtPA are similar to the factors that predict poor outcome after stroke. The
modest association between these factors and p­ ost-­rtPA ICH
means accurate identification of those patients most likely to
experience an ICH with treatment is difficult. Without clear
evidence that ischemic stroke patients with higher predicted
risk of ­post-­rtPA ICH experience net harm or have no worthwhile benefit from treatment, these data do not provide a reliable means to select the patients least likely to be harmed and
most likely to gain net benefit from intravenous rtPA.
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Disclosures
Dr Whiteley is supported by a Clinician Scientist Fellowship from
the UK Medical Research Council (G0902303). Dr ­Bruins Slot is a
member of the European Medicine Agency Committee for Medicinal
Products for Human Use and Cardiovascular Working Party. The
views expressed in this article are the personal views of the author
and may not be understood or quoted as being made on behalf of
or reflecting the position of the European Medicines Agency or
one of its committees or working parties. Professor Wardlaw is
Imaging Principal Investigator, and Professor Sandercock is a Chief
Investigator of IST-3. Professor Wardlaw was supported by the SFC
through the Scottish Imaging Network, a Platform for Scientific
Excellence Collaboration.
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21. Lees KR, Bluhmki E, von Kummer R+, Brott TG, Toni D, Grotta JC,
et al. Time to treatment with intravenous alteplase and outcome in
stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and
EPITHET trials. Lancet. 2010;375:1695–1703.
22. 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.
23. Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke. 2007;38:2279–2283.
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. Mazya M, Egido JA, Ford GA, Lees KR, Mikulik R, Toni D, et al.
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. Stroke. 2012;43:1524–1531.
26. Saposnik G, Fang J, Kapral MK, Tu JV, Mamdani M, Austin P, et al. The
iScore predicts effectiveness of thrombolytic therapy for acute ischemic
stroke. Stroke. 2012;43:1315–1322.
27. Strbian D, Engelter S, Michel P, Meretoja A, Sekoranja L, Ahlhelm FJ,
et al. Symptomatic intracranial hemorrhage after stroke thrombolysis:
the SEDAN score. Ann Neurol. 2012;71:634–641.
28. Menon BK, Saver JL, Prabhakaran S, Reeves M, Liang L, Olson DM,
et al. Risk score for intracranial hemorrhage in patients with acute ischemic stroke treated with intravenous ­tissue-­type plasminogen activator.
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Risk Factors for Intracranial Hemorrhage in Acute Ischemic Stroke Patients Treated
With Recombinant Tissue Plasminogen Activator: A Systematic Review and
Meta-Analysis of 55 Studies
William N. Whiteley, Karsten Bruins Slot, Peter Fernandes, Peter Sandercock and Joanna
Wardlaw
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doi: 10.1161/STROKEAHA.112.665331
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SUPPLEMENTAL MATERIAL
Webtable 1 Electronic search strategy (Medline)
1 Cerebrovascular disorders/
2 exp Brain ischemia/
3 Carotid artery diseases/ or Carotid artery thrombosis/
4 stroke/ or exp brain infarction/
5 exp Hypoxia-ischemia, brain/
6 Cerebral arterial diseases/ or Intracranial arterial diseases/
7 exp "Intracranial embolism and thrombosis"/
8 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or transient isch?emic attack$ or tia$).tw.
9 (brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or
supratentorial or middle cerebr$ or mca$ or anterior circulation).tw.
10 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$).tw.
11 9 and 10
12 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 11
13 Thrombolytic therapy/
14 Fibrinolysis/
15 exp plasminogen activators/
16 Fibrinolytic agents/ or Plasmin/ or Plasminogen/
17 (thromboly$ or fibrinoly$ or clot lysis).tw.
18 (plasminogen or plasmin or tPA or t-PA or rtPA or rt-PA).tw.
19 (alteplase).tw.
20 exp "intracranial embolism and thrombosis"/dt or Thromboembolism/dt
21 Thrombosis/dt [Drug Therapy]
22 or/13-21
23 12 and 22
24 randomized controlled trial.pt.
25 randomized controlled trials/
26 controlled clinical trial.pt.
27 controlled clinical trials/
28 random allocation/
29 double-blind method/
30 single-blind method/
31 single-blind method/
32 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).tw.
33 placebos/
34 placebo$.tw.
35 random$.tw.
36 research design/
37 clinical trial phase ii.pt.
38 clinical trial phase iii.pt.
39 clinical trial phase iv.pt.
40 multicenter study.pt.
41 intervention studies/
42 control$.tw.
43 latin square.tw.
44 "comparative study"/
45 exp evaluation studies/
46 Follow-up studies/
47 Prospective studies/
48 prospective.tw.
49 (versus or allocat$).tw.
50 experimental group$.tw.
51 or/24-50
52 23 and 51
53 limit 52 to human
Web table 2 Post rtPA haemorrhage as defined in important clinical trials of rtPA in
stroke and the SITS-MOST register.
ECASS 1 hemorrhagic events were classified as HI types I and II and PH types I and II. HI I is defined as small
petechiae along the margins of the infarct, while HI II represents more confluent petechiae within the infracted
area, but without space-occupying effect. PH I is defined as blood clot not exceeding 30% ofthe infarcted area
with some mild space-occupying effect, and PH II represents dense blood clot(s) exceeding 30% of the infarct
volume with significant space-occupying effect. CT at 24 hrs and 6-8 days and discretion of investigator.(16)
NINDS symptomatic: Symptomatic ICH was defined as a CT-documented hemorrhage that was temporally
related to deterioration in the patient's clinical condition in the judgment of the clinical investigator.
Symptomatic ICH attributable to study medication was defined, before completion of the randomized study, as
symptomatic hemorrhage that occurred within 36 hours from treatment onset. Scans at 24h 7-10 days and
discretion of investigator. (13)
NINDS asymptomatic: Asymptomatic ICH was defined as CT-documented hemorrhage that was not associated
with deterioration in the patient's neurological condition in the judgment of the clinical investigator. Scans at
24h 7-10 days and discretion of investigator.(13)
ECASS 2: symptomatic: Symptomatic intracranial haemorrhage was defined as blood at any site in the brain on
the CT scan (as assessed by the CT reading panel, independently of the assessment by the investigator),
documentation by the investigator of clinical deterioration, or adverse events indicating clinical worsening (eg,
drowsiness, increase of hemiparesis) or causing a decrease in the NIHSS score of 4 or more points. Scans at 2236 hr and day 7. (14)
ECASS 3: symptomatic intracranial hemorrhage was defined as any apparently extravascular blood in the brain
or within the cranium that was associated with clinical deterioration, as defined by an increase of 4 points or
more in the score on the NIHSS, or that led to death and that was identified as the predominant cause of the
neurologic deterioration. Scans at 22-36 hr and at discretion of investigator. (15)
SIST MOST: symptomatic intracerebral haemorrhage and death within 3 months. Symptomatic intracerebral
haemorrhage, per the SITS-MOST protocol, was defined as local or remote parenchymal haemorrhage type 2 on
the 22–36 h post-treatment imaging scan, combined with a neurological deterioration of 4 points or more on the
NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 h, or leading to death. Scan at
22-36 Hr. (17)
Webtable 3 Characteristics of included studies
First author
Year
NINDS (1)
1997
Larrue (2)
Number of
haemorrhages
Number
of patients
Randomised
trial
Study definition of
haemorrhage
22
311
Yes
NINDS
1997
62
307
No
ECASS-2 PH
Demchuk (3)
1999
13
138
Yes
Barber (4)
2000
10
156
Patel (5)
2001
20
Larrue (6)
2001
Bruno (7)
Imaging
definition of
haemorrhage
Timing of
haemorrhage
measurement
(hours/days)
Clinical definition
of haemorrhage
Number of
associations
Any
36 hrs
Any
3
PH1/2
7 days
Not necessary
2
NINDS
Any
36 hrs
Any
6
No
NINDS
Any
24 hrs
Any
4
312
Yes
NINDS
Any
36 hrs
Any
1
26
407
Yes
ECASS-2
Any
7 days
>4
4
2002
.
.
Yes
NINDS
Any
36 hrs
Any
1
Tanne (8)
2002
.
826
No
NINDS
Any
36 hrs
Any
13
Schmulling (9)
2003
13
206
No
NINDS
PH1/2
7 days
NR
2
Trouillas (10)
2004
11
157
No
ECASS-2 PH
PH1/2
24 hrs
Not necessary
9
Hill (11)
2005
52
1100
No
NINDS
Any
24 hrs
Any
2
Chen (12)
2005
12
183
No
ECASS-2
Any
7 days
>4
1
Kakuda (13)
2005
12
70
Yes
ECASS-2 PH
PH1/2
30 days
Not necessary
1
Engelter (14)
2005
29
325
No
NINDS
Any
36 hrs
Any
1
Demchuk (15)
2005
16
300
Yes
NINDS
Any
36 hrs
Any
1
Berrouschot (16)
2005
14
228
No
ECASS-2 PH
PH1/2
NR
Not necessary
1
Sylaja (17)
2006
52
1135
No
NINDS
Any
24 hrs
Any
1
Kohrmann (18)
2006
24
382
No
NINDS
Any
36 hrs
Any
2
Neumann-Haefelin (19)
2006
14
363
No
NINDS
Any
36 hrs
Any
1
Meseguer (20)
2007
11
129
No
ECASS-2
Any
24 hrs
>4
1
Thomalla (21)
2007
15
152
No
ECASS-2 PH
PH1/2
NR
Not necessary
6
First author
Year
Palumbo (22)
2007
Castellanos (23)
Number of
haemorrhages
Number
of patients
Randomised
trial
Study definition of
haemorrhage
28
820
No
NINDS
2007
12
134
No
ECASS-2 PH
Tsivgoulis (24)
2007
12
192
No
Schellinger (25)
2007
54
1210
Fiehler (26)
2007
18
Uyttenboogaart (27)
2008
Singer (28)
Imaging
definition of
haemorrhage
Timing of
haemorrhage
measurement
(hours/days)
Clinical definition
of haemorrhage
Number of
associations
Any
24 hrs
Any
2
PH1/2
36 hrs
Not necessary
4
ECASS-2
Any
72 hrs
>4
1
No
NINDS
Any
36 hrs
Any
2
570
No
SITS-MOST
PH2
10 days
>4
1
13
252
No
NINDS
Any
48 hrs
Any
17
2008
28
536
No
NINDS
Any
36 hrs
>1
1
Bravo (29)
2008
26
605
No
SITS-MOST
PH1/2
36 hrs
>4
15
Saqqur (30)
2008
26
349
Yes
ECASS-2
Any
72 hrs
>4
5
Lyrer (31)
2008
12
196
No
NINDS
Any
36v
Any
1
Wahlgren (32)
2008
107
6483
No
SITS-MOST
PH2
36 hrs
>4
17
Uyttenboogaart (33)
2008
11
301
No
SITS-MOST
PH1/2
36 hrs
>4
3
Demchuk (34)
2008
16
299
Yes
NINDS
Any
24 hrs
Any
1
Butcher (35)
2009
11
49
Yes
ECASS-2 PH
PH1/2
72 hrs
Not necessary
1
Diedler (36)
2009
832
11736
No
NINDS
Any
NR
Any
6
Bluhmki (37)
2009
33
418
No
ECASS-3
Any
NR
>4
10
Tsivgoulis (38)
2009
31
510
No
ECASS-2
Any
36 hrs
>4
10
Poppe (39)
2009
49
1098
No
NINDS
Any
24 hrs
Any
1
Cucchiara (40)
2009
54
965
Yes
ECASS-2
Any
36v
>4
18
Aries (41)
2009
24
384
No
SITS-MOST
PH2
36 hrs
>4
1
Nezu (42)
2010
15
477
No
SITS-MOST
PH1/2
36 hrs
>4
1
Mateen (43)
2010
12
270
No
NINDS
Any
NR
Any
1
Miedema (44)
2010
29
476
No
SITS-MOST
PH2
36
>4
1
First author
Year
Meretoja (45)
2010
Hernandez-Guillamon (46)
Number of
haemorrhages
Number
of patients
Randomised
trial
Study definition of
haemorrhage
69
985
No
ECASS-2
2010
16
140
No
ECASS-2 PH
Chao (47)
2010
13
241
No
Ahmed (48)
2010
1686
23942
Dorado (49)
2010
33
Aries (50)
2010
Makihara (51)
Imaging
definition of
haemorrhage
Timing of
haemorrhage
measurement
(hours/days)
Clinical definition
of haemorrhage
Number of
associations
Any
7 days
>4
9
PH1/2
48 hrs
Not necessary
7
ECASS-2
Any
7 days
>4
3
No
NINDS
Any
NR
Any
1
235
No
ECASS-2 PH
PH1/2
36 hrs
Not necessary
10
24
400
No
SITS-MOST
PH2
36 hrs
>4
4
2010
23
600
No
NINDS
Any
36 hrs
>1
3
Seet (52)
2011
16
212
No
ECASS-2
Any
NR
>4
1
Kellert (53)
2011
10
427
No
ECASS-2
Any
36 hrs
>4
11
Naganuma (54)
2011
25
578
No
NINDS
Any
36 hrs
>1
5
Vergouwen (55)
2011
102
1739
No
NINDS
Any
36 hrs
Any
1
Webtable 4 Included studies
(1) NINDS rt-PA Stroke Study Group. Intracerebral Hemorrhage After Intravenous t-PA Therapy for
Ischemic Stroke. Stroke 1997;28:2109-18.
(2) Larrue V, von KR, del ZG, Bluhmki E. Hemorrhagic transformation in acute ischemic stroke. Potential
contributing factors in the European Cooperative Acute Stroke Study. Stroke 1997;28:957-60.
(3) Demchuk AM, Morgenstern LB, Krieger DW, Linda CT, Hu W, Wein TH et al. Serum glucose level
and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic
stroke. Stroke 1999;30:34-9.
(4) Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability of a quantitative computed
tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS
Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000;355:1674.
(5) Patel SC, Levine SR, Tilley BC, Grotta JC, Lu M, Frankel M et al. Lack of Clinical Significance of
Early Ischemic Changes on Computed Tomography in Acute Stroke. Journal of the American Medical
Association 2001;286:2830-8.
(6) Larrue V, von Kummer RR, ller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in
ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of
the European-Australasian Acute Stroke Study (ECASS II). Stroke 2001;32:438-41.
(7) Bruno A, Levine SR, Frankel MR, Brott TG, Lin Y, Tilley BC et al. Admission glucose level and
clinical outcomes in the NINDS rt-PA Stroke Trial. Neurology 2002;59:669-74.
(8) Tanne D, Kasner SE, Demchuk AM, Koren-Morag N, Hanson S, Grond M et al. Markers of increased
risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for
acute ischemic stroke in clinical practice: the Multicenter rt-PA Stroke Survey. Circulation
2002;105:1679-85.
(9) Schmulling S, Rudolf J, Strotmann-Tack T, Grond M, Schneweis S, Sobesky J et al. Acetylsalicylic
Acid Pretreatment, Concomitant Heparin Therapy and the Risk of Early Intracranial Hemorrhage
following Systemic Thrombolysis for Acute Ischemic Stroke. Cerebrovascular Diseases 2003;16:18390.
(10) Trouillas P, Derex L, Philippeau F, Nighoghossian N, Honnorat J, Hanss M et al. Early Fibrinogen
Degradation Coagulopathy Is Predictive of Parenchymal Hematomas in Cerebral rt-PA Thrombolysis:
A Study of 157 Cases. Stroke 2004;35:1323-8.
(11) 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. Canadian Medical Association Journal 2005;172:1307-12.
(12) Chen CI, Iguchi Y, Grotta JC, Garami Z, Uchino K, Shaltoni H et al. Intravenous tPA for very old
stroke patients. European Neurology 2005;54:140-4.
(13) Kakuda W, Thijs VN, Lansberg MG, Bammer R, Wechsler L, Kemp S et al. Clinical importance of
microbleeds in patients receiving IV thrombolysis. Neurology 2005;65:1175-8.
(14) Engelter ST, Bonati LH, Lyrer PA. Intravenous thrombolysis in stroke patients of > or = 80 versus < 80
years of age--a systematic review across cohort studies. Age & Ageing 2006;35:572-80.
(15) Demchuk AM, Hill MD, Barber PA, Silver B, Patel SC, Levine SR et al. Importance of Early Ischemic
Computed Tomography Changes Using ASPECTS in NINDS rtPA Stroke Study. Stroke
2005;36:2110-5.
(16) Berrouschot J, Rother J, Glahn J, Kucinski T, Fiehler J, Thomalla G. Outcome and severe hemorrhagic
complications of intravenous thrombolysis with tissue plasminogen activator in very old stroke
patients. Stroke 2005;36:2421.
(17) Sylaja PN, Cote R, Buchan AM, Hill MD. Thrombolysis in patients older than 80 years with acute
ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. Journal of Neurology,
Neurosurgery & Psychiatry 2006;77:826-9.
(18) Kohrmann M, Juttler E, Fiebach JB, Huttner HB, Siebert S, Schwark C et al. MRI versus CT-based
thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study.
Lancet Neurology 2006;5:661-7.
(19) Neumann-Haefelin T, Hoelig S, Berkefeld J, Fiehler J, Gass A, Humpich M et al. Leukoaraiosis is a
risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke
2006;37:2463-6.
(20) Meseguer E, Labreuche J, Olivot JM, Abboud H, Lavallee PC, Simon O et al. Determinants of
outcome and safety of intravenous rt-PA therapy in the very old: a clinical registry study and
systematic review. Age & Ageing 2008;37:107-11.
(21) Thomalla G, Sobesky J, Kohrmann M, Fiebach JB, Fiehler J, Zaro WO et al. Two tales: hemorrhagic
transformation but not parenchymal hemorrhage after thrombolysis is related to severity and duration
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
(40)
of ischemia: MRI study of acute stroke patients treated with intravenous tissue plasminogen activator
within 6 hours. Stroke 2007;38:313-8.
Palumbo V, Boulanger JM, Hill MD, Inzitari D, Buchan AM, CASES Investigators. Leukoaraiosis and
intracerebral hemorrhage after thrombolysis in acute stroke. Neurology 2007;68:1020-4.
Castellanos M, Sobrino T, Millan M, Garcia M, Arenillas J, Nombela F et al. Serum cellular
fibronectin and matrix metalloproteinase-9 as screening biomarkers for the prediction of parenchymal
hematoma after thrombolytic therapy in acute ischemic stroke: a multicenter confirmatory
study.[Erratum appears in Stroke. 2007 Aug;38(8):e76.]. Stroke 2007;38:1855-9.
Tsivgoulis G, Saqqur M, Sharma VK, Lao AY, Hoover SL, Alexandrov AV et al. Association of
pretreatment ASPECTS scores with tPA-induced arterial recanalization in acute middle cerebral artery
occlusion. Journal of Neuroimaging 18(1):56-61, 2008;18:56-61.
Schellinger PD, Thomalla G, Fiehler J, hrmann M, Molina CA, Neumann-Haefelin T et al. MRI-based
and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an
analysis of 1210 patients. Stroke 2007;38:2640-5.
Fiehler J, Albers GW, Boulanger JM, Derex L, Gass A, Hjort N et al. Bleeding risk analysis in stroke
imaging before thrombolysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging
data from 570 patients. Stroke 2007;38:2738-44.
Uyttenboogaart M, Koch MW, Koopman K, Vroomen PC, Luijckx GJ, De KJ. Lipid profile, statin use,
and outcome after intravenous thrombolysis for acute ischaemic stroke. Journal of Neurology
255(6):875-80, 2008;255:875-80.
Singer OC, Humpich MC, Fiehler J, Albers GW, Lansberg MG, Kastrup A et al. Risk for symptomatic
intracerebral hemorrhage after thrombolysis assessed by diffusion-weighted magnetic resonance
imaging. Ann Neurol 2008;63:52-60.
Bravo Y, Marti-Fabregas J, Cocho D, Rodriguez-Yanez M, Castellanos M, de la Ossa NP et al.
Influence of antiplatelet pre-treatment on the risk of symptomatic intracranial haemorrhage after
intravenous thrombolysis. Cerebrovascular Diseases 2008;26:126-33.
Saqqur M, Tsivgoulis G, Molina CA, Demchuk AM, Siddiqui M, Alvarez S et al. Symptomatic
intracerebral hemorrhage and recanalization after IV rt-PA: a multicenter study. Neurology
2008;71:1304-12.
Lyrer PA, Fluri F, Gisler D, Papa S, Hatz F, Engelter ST. Renal function and outcome among stroke
patients treated with IV thrombolysis. Neurology 2008;71:1548-50.
Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Davalos A et al. 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;39:3316-22.
Uyttenboogaart M, Koch MW, Koopman K, Vroomen PC, De KJ, Luijckx GJ. Safety of antiplatelet
therapy prior to intravenous thrombolysis in acute ischemic stroke. Arch Neurol 2008;65:607-11.
Demchuk AM, Khan F, Hill MD, Barber PA, Silver B, Patel S et al. Importance of leukoaraiosis on CT
for tissue plasminogen activator decision making: evaluation of the NINDS rt-PA Stroke Study.
Cerebrovascular Diseases 2008;26:120-5.
Butcher K, Christensen S, Parsons M, De Silva DA, Ebinger M, Levi C et al. Postthrombolysis blood
pressure elevation is associated with hemorrhagic transformation. Stroke 2010;41:72-7.
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;41:288-94.
Bluhmki E, Chamorro A, valos A, Machnig T, Sauce C, Wahlgren N et al. Stroke treatment with
alteplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS III): additional outcomes and
subgroup analysis of a randomised controlled trial. Lancet Neurology 2009;8:1095-102.
Tsivgoulis G, Frey JL, Flaster M, Sharma VK, Lao AY, Hoover SL et al. Pre-tissue plasminogen
activator blood pressure levels and risk of symptomatic intracerebral hemorrhage. Stroke2009;40:36314.
Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD et al. Admission
hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis.
Diabetes Care 2009;32:617-22.
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;40:3067-72.
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Supplementary figure 1: A meta-analysis of 13 studies of the associations between age (per year) and post-rtPA
intracranial haemorrhage. ES=odds ratio per year increase in age. I 2 (a measure of between study
heterogeneity)=28%. Ordered by strength of association.
%
Study
Year
ES (95% CI)
Weight
Castellanos
2007
0.94 (0.88, 1.00)
3.06
Saqqur
2008
0.98 (0.93, 1.03)
4.29
Naganuma
2011
1.00 (0.96, 1.04)
6.70
Demchuk
1999
1.01 (0.97, 1.06)
6.09
Larrue
1997
1.03 (1.00, 1.05)
11.74
Tanne
2002
1.03 (1.00, 1.05)
12.70
Uyttenboogaart
2008
1.03 (0.96, 1.10)
2.74
Schellinger
2007
1.03 (1.01, 1.06)
13.05
Cucchiara
2009
1.04 (1.01, 1.07)
10.60
Larrue
2001
1.04 (1.01, 1.08)
8.69
Thomalla
2007
1.04 (0.99, 1.10)
4.64
Wahlgreen
2008
1.05 (1.02, 1.08)
10.61
Kohrmann
2006
1.05 (1.00, 1.10)
5.08
1.03 (1.01, 1.04)
100.00
Overall
.8
1
older lower risk of ICH
1.2
older higher risk of ICH
Supplementary figure 2: A meta-analysis of 13 studies of the associations between smokers (versus nonsmokers) and post-rtPA intracranial haemorrhage. ES=odds ratio smokers versus non-smokers. I2 (a measure of
between study heterogeneity)=0.4%. Ordered by strength of association.
%
Study
Year
ES (95% CI)
Weight
NINDS
1997
0.25 (0.08, 0.78)
4.63
Cucchiara
2009
0.36 (0.14, 0.92)
6.78
Demchuk
1999
0.40 (0.09, 1.84)
2.56
Bluhmki
2009
0.47 (0.19, 1.17)
7.12
Kellert
2011
0.52 (0.03, 10.26)
0.67
Tanne
2002
0.58 (0.31, 1.09)
14.95
Tsivgoulis
2009
0.59 (0.17, 2.03)
3.88
Uyttenboogaart
2008
0.64 (0.17, 2.40)
3.39
Wahlgreen
2008
0.82 (0.50, 1.35)
23.51
Bluhmki
2009
0.82 (0.40, 1.69)
11.31
Dorado
2010
1.04 (0.50, 2.15)
11.30
Bravo
2008
1.41 (0.57, 3.46)
7.37
Trouillas
2004
1.62 (0.35, 7.51)
2.53
0.70 (0.55, 0.89)
100.00
Overall
.1
smokers less ICH
1
10
smokers more ICH
Supplementary figure 3: A meta-analysis of 13 studies of the associations between CT low density with postrtPA intracranial haemorrhage. ES=odds ratio presence versus absence of visible CT lesion. Ordered by strength
of association.
%
Study
Year
ES (95% CI)
Weight
Hernandez-Guillamon
2010
0.29 (0.04, 2.11)
3.40
Uyttenboogaart
2008
0.81 (0.14, 4.67)
4.13
Wahlgreen
2008
1.28 (0.82, 2.01)
14.63
Meretoja
2010
2.00 (1.06, 3.78)
12.39
Larrue
2001
2.03 (1.18, 3.51)
13.48
Patel
2001
2.19 (0.78, 6.15)
8.29
Kellert
2011
3.84 (0.84, 17.65)
5.08
NINDS
1997
7.80 (2.22, 27.38)
6.60
1.88 (1.22, 2.90)
67.99
Any CT low density
Subtotal
>33% of MCA territory low density
Trouillas
2004
0.30 (0.02, 4.52)
1.99
Bravo
2008
2.52 (1.04, 6.09)
9.68
Demchuk
1999
3.22 (0.78, 13.30)
5.62
Tanne
2002
6.70 (2.14, 20.99)
7.40
Dorado
2010
6.79 (1.19, 38.58)
4.19
Barber
2000
14.00 (1.74, 112.87)
3.13
Subtotal
3.89 (1.91, 7.91)
32.01
Overall
2.39 (1.59, 3.58)
100.00
.1
CT low density reduces ICH
1
10
CT low density increases ICH
Supplementary figure 4: A meta-analysis of 11 studies of the associations between NIHSS (a 1 point increase)
and post-rtPA intracranial haemorrhage. ES=odds ratio per unit increase in NIHSS. Ordered by strength of
association.
%
Study
Year
ES (95% CI)
Weight
Thomalla
2007
1.02 (0.93, 1.12)
6.06
Demchuk
1999
1.04 (0.93, 1.16)
4.29
Saqqur
2008
1.06 (0.96, 1.17)
5.10
Schellinger
2007
1.06 (1.01, 1.11)
23.48
Kohrmann
2006
1.08 (0.99, 1.17)
7.50
Aries
2010
1.09 (1.02, 1.17)
11.12
Cucchiara
2009
1.09 (1.03, 1.15)
17.23
Tsivgoulis
2009
1.11 (1.05, 1.18)
15.36
Castellanos
2007
1.12 (0.95, 1.33)
1.82
Uyttenboogaart
2008
1.12 (1.02, 1.22)
6.53
Uyttenboogaart
2008
1.23 (1.02, 1.48)
1.51
1.08 (1.06, 1.11)
100.00
Overall
.8
high NIHSS less ICH
1
1.2
high NIHSS more ICH
Supplementary figure 5: A meta-analysis of 14 studies of the associations between gender and post-rtPA
intracranial haemorrhage. ES=odds ratio women versus men. Ordered by strength of association.
%
Study
Year
ES (95% CI)
Weight
Bravo
2008
0.44 (0.15, 1.26)
3.81
Naganuma
2011
0.50 (0.17, 1.45)
3.72
Trouillas
2004
0.52 (0.10, 2.65)
1.59
Bluhmki
2009
0.52 (0.21, 1.29)
5.13
Makihara
2010
0.59 (0.20, 1.71)
3.75
Uyttenboogaart
2008
0.64 (0.21, 1.99)
3.27
Tanne
2002
0.74 (0.45, 1.22)
17.01
Saqqur
2008
0.74 (0.29, 1.86)
4.97
Cucchiara
2009
1.04 (0.60, 1.81)
13.74
Tsivgoulis
2009
1.05 (0.47, 2.33)
6.67
Thomalla
2007
1.06 (0.36, 3.13)
3.61
Wahlgreen
2008
1.10 (0.75, 1.62)
28.53
Hernandez-Guillamon
2010
1.85 (0.57, 5.95)
3.10
Kellert
2011
3.87 (0.55, 27.26)
1.11
0.88 (0.72, 1.08)
100.00
Overall
.1
Men higher risk of ICH
1
10
Women higher risk of ICH
Supplementary figure 6: A meta-analysis of 12 studies of the associations between diabetes and post-rtPA
intracranial haemorrhage. ES=odds ratio patients with diabetes versus patient without diabetes. Ordered by
strength of association.
%
Study
Year
ES (95% CI)
Weight
Hernandez-Guillamon
2010
0.25 (0.02, 3.35)
1.07
Uyttenboogaart
2008
0.37 (0.05, 2.74)
1.78
Cucchiara
2009
1.00 (0.49, 2.04)
12.41
Bluhmki
2009
1.03 (0.46, 2.30)
10.03
Kellert
2011
1.40 (0.27, 7.30)
2.59
Dorado
2010
1.42 (0.58, 3.49)
8.19
Wahlgreen
2008
1.54 (0.96, 2.47)
24.04
Tsivgoulis
2009
1.61 (0.56, 4.59)
6.17
Trouillas
2004
1.89 (0.35, 10.24)
2.48
Tanne
2002
2.03 (1.21, 3.41)
20.72
Bravo
2008
2.81 (1.15, 6.85)
8.32
Demchuk
1999
7.46 (1.24, 44.74)
2.21
1.54 (1.18, 2.02)
100.00
Overall
.1
Diabetes lower risk of ICH
1
10
Diabetes higher risk of ICH
Supplementary figure 7: A meta-analysis of 11 studies of the associations between blood glucose and post-rtPA
intracranial haemorrhage. ES=odds ratio per mmol/L increase in glucose. Ordered by strength of association.
%
Study
Year
ES (95% CI)
Weight
Saqqur
2008
0.96 (0.88, 1.06)
11.16
Cucchiara
2009
1.04 (0.93, 1.15)
9.49
Wahlgreen
2008
1.09 (1.02, 1.17)
16.81
Hill
2005
1.10 (1.03, 1.17)
18.39
Bruno
2002
1.11 (1.02, 1.20)
13.44
Naganuma
2011
1.11 (0.97, 1.27)
6.41
Meretoja
2010
1.13 (1.02, 1.25)
10.11
Demchuk
1999
1.16 (1.01, 1.33)
6.28
Aries
2010
1.19 (0.99, 1.44)
3.67
Uyttenboogaart
2008
1.25 (1.02, 1.54)
3.09
Uyttenboogaart
2008
1.41 (1.00, 1.99)
1.15
1.10 (1.05, 1.14)
100.00
Overall
.5
1
high glucose less ICH
2
high glucose more ICH
Supplementary figure 8: A meta-analysis of 11 studies of the associations between prior hypertension and postrtPA intracranial haemorrhage. ES=odds ratio prior hypertension versus no prior hypertension. Ordered by
strength of association.
%
Study
Year
ES (95% CI)
Weight
Uyttenboogaart
2008
0.44 (0.00, 1866.47)
0.08
Cucchiara
2009
0.95 (0.52, 1.74)
14.81
Bluhmki
2009
1.06 (0.51, 2.21)
10.05
Dorado
2010
1.08 (0.47, 2.47)
7.90
Trouillas
2004
1.40 (0.35, 5.58)
2.83
Bravo
2008
1.49 (0.59, 3.74)
6.38
Hernandez-Guillamon
2010
1.51 (0.44, 5.16)
3.57
Tanne
2002
1.61 (0.95, 2.72)
19.53
Tsivgoulis
2009
1.72 (0.75, 3.94)
7.88
Wahlgreen
2008
2.22 (1.41, 3.49)
26.31
Kellert
2011
2.75 (0.16, 48.24)
0.66
1.50 (1.19, 1.89)
100.00
Overall
.1
Prior hypertension less ICH
1
10
Prior higher more ICH
Supplementary figure 9: A meta-analysis of 11 studies of the associations between atrial fibrillation (AF) and
post-rtPA intracranial haemorrhage. ES=odds ratio presence versus absence of AF. Ordered by strength of
association.
%
Study
Year
ES (95% CI)
Weight
Kellert
2011
0.89 (0.17, 4.58)
1.75
Uyttenboogaart
2008
1.33 (0.39, 4.50)
3.17
Cucchiara
2009
1.57 (0.88, 2.80)
14.14
Larrue
1997
1.60 (0.91, 2.82)
14.61
Trouillas
2004
1.78 (0.33, 9.66)
1.64
Wahlgreen
2008
1.84 (1.23, 2.75)
29.35
Tanne
2002
1.92 (1.14, 3.23)
17.36
Bravo
2008
1.97 (0.82, 4.72)
6.16
Tsivgoulis
2009
2.39 (0.88, 6.51)
4.69
Bluhmki
2009
2.90 (1.16, 7.27)
5.58
Butcher
2009
10.13 (1.77, 57.94)
1.55
1.86 (1.49, 2.31)
100.00
Overall
.1
AF lower risk of ICH
1
10
AF higher risk of ICH
Supplementary figure 10: A meta-analysis of 15 studies of the associations between the prescription of any
antiplatelet and post-rtPA intracranial haemorrhage. ES=odds ratio antiplatelet versus no antiplatelet. Ordered
by strength of association.
%
Study
Year
ES (95% CI)
Weight
Diedler
2009
1.05 (0.96, 1.14)
11.61
Bluhmki
2009
1.12 (0.52, 2.40)
7.60
Larrue
2001
1.26 (0.55, 2.90)
7.09
Kellert
2011
1.29 (0.29, 5.72)
3.81
Tsivgoulis
2009
1.35 (0.59, 3.11)
7.09
Tanne
2002
1.69 (1.03, 2.78)
9.48
Wahlgreen
2008
1.72 (0.92, 3.23)
8.54
Dorado
2010
1.90 (0.65, 5.52)
5.68
Schmulling
2003
2.15 (0.48, 9.59)
3.79
Bravo
2008
2.28 (0.90, 5.76)
6.50
Cucchiara
2009
2.69 (1.54, 4.70)
9.06
Aries
2010
3.98 (1.64, 9.65)
6.75
Uyttenboogaart
2008
5.96 (2.04, 17.39)
5.65
Uyttenboogaart
2008
8.92 (1.63, 48.91)
3.16
Chao
2010
12.56 (3.13, 50.39)
4.18
2.09 (1.46, 2.97)
100.00
Overall
.1
1
10
Antiplatelets lower risk of ICHAntiplatelets higher risk of ICH
Supplementary figure 11: A meta-analysis of 4 studies of the associations between systolic blood pressure (per
mmHg) and post-rtPA intracranial haemorrhage. ES=odds ratio antiplatelet versus no antiplatelet. Ordered by
strength of association.
%
Study
Year
ES (95% CI)
Weight
Saqqur
2008
0.99 (0.98, 1.01)
21.89
Cucchiara
2009
1.01 (1.00, 1.02)
27.34
Wahlgreen
2008
1.01 (1.00, 1.03)
27.70
Tsivgoulis
2009
1.02 (1.01, 1.03)
23.08
1.01 (1.00, 1.02)
100.00
Overall
.9
higher BP less ICH
1
1.2
higher BP more ICH