In Acute Ischemic Stroke, Are Asymptomatic Intracranial
Hemorrhages Clinically Innocuous?
David M. Kent, MD, MS; Judith Hinchey, MD; Lori Lyn Price, MS;
Steven R. Levine, MD; Harry P. Selker, MD, MSPH
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Background—In patients with acute ischemic stroke, intracranial hemorrhages are categorized as symptomatic or
asymptomatic based on the presence or absence of a clinically detectable neurological deterioration. Asymptomatic
intracranial hemorrhages are believed by many to be clinically innocuous. We examined whether the occurrence of an
asymptomatic intracranial hemorrhage affects functional outcome in patients with acute ischemic stroke (AIS) treated
or not treated with recombinant tissue plasminogen activator (rt-PA).
Methods—We combined data from the NINDS rt-PA Stroke Trial and the ATLANTIS Trials, excluding patients with
symptomatic intracranial hemorrhage (n⫽1193). We used generalized estimating equations to test whether asymptomatic intracranial hemorrhage altered the likelihood of a normal or near-normal outcome at 90 days, as measured across
4 commonly used functional outcome scales, controlling for other variables that affect outcome. To look at additional
outcomes, including the likelihood of disability and death, we used logistic regression equations. Additionally, we
systematically reviewed previous studies that assessed the effect of intracranial hemorrhage in AIS.
Results—In the combined database, the rate of asymptomatic intracranial hemorrhage was higher in rt-PA treated than in
nontreated patients (9.9% versus 4.2%, P⬍0.0001). Controlling for other prognostic factors, the odds of a normal or
near-normal outcome was lower when a patient had an asymptomatic intracranial hemorrhage, but this effect did not
reach statistical significance (OR⫽0.69, 95% CI: 0.43 to 1.12, P⫽0.13). Similarly, the odds of not being moderately to
severely disabled (modified Rankin Score ⱕ2) was also lower for patients with asymptomatic intracranial hemorrhage
(OR⫽0.60, 95% CI: 0.33 to 1.08, P⫽0.09). Despite using a larger sample than any previously published study, the
power in our study to detect a 30% decrease in the odds of a good outcome was inadequate (⬇32%).
Conclusion—We could not confirm or exclude a clinically significant effect for asymptomatic intracranial hemorrhages
based either on our analysis or on any previously published trial. Analysis of substantially larger databases are needed
to assess the import of this common clinical event. (Stroke. 2004;35:1141-1146.)
Key Words: stroke, acute 䡲 stroke, ischemic 䡲 thrombolytic therapy 䡲 hemorrhage 䡲 intracranial hemorrhages 䡲
cerebrovascular accident 䡲 cerebral hemmorhage
I
n acute ischemic stroke, intracranial hemorrhages are
classified as symptomatic or asymptomatic based on
whether they are accompanied by clinically detectable neurological deterioration. Symptomatic intracranial hemorrhages are typically clinically catastrophic and occur more
frequently in the presence of thrombolytic therapy.1,2 In
contrast, whether asymptomatic intracranial hemorrhages
have any prognostic importance is not completely clear.
Many believe that so-called hemorrhagic transformations are
part of the natural history of acute ischemic stroke and are
clinically innocuous, a “CT scan event” without any adverse
sequela.3,4 Indeed, several studies have been unable to detect
any effect on overall prognosis once other factors associated
with a poor prognosis are accounted for.4 – 6
However, previous studies have had several important
limitations, including relatively small samples and the absence of any power calculations.4 – 6 We performed an analysis on a larger combined database that should have more
power to discern clinically important effects. We also performed a systematic review of previous studies that assessed
the functional significance of hemorrhagic transformation in
acute ischemic stroke.
Methods
We combined several randomized clinical trials that tested
thrombolytic therapy with recombinant tissue plasminogen activator
(rt-PA) against placebo: The National Institutes for Neurological
Disorders and Stroke (NINDS) rt-PA Study (n⫽624) (Parts 1 and
Received June 7, 2003; final revision received September 5, 2003; accepted December 23, 2003.
From Institute for Clinical Research and Health Policy Studies (D.M.K., J.H., L.L.P., H.P.S.), Tufts-New England Medical Center, Boston, Mass;
Department of Neurology (J.H.), Saint Elizabeth Medical Center, Boston, Mass; Department of Neurology (S.R.L.), Mount Sinai Medical Center, New
York, NY.
Correspondence to Dr David Kent, Division of Clinical Care Research, Department of Medicine, Tufts-New England Medical Center, 750 Washington
St, Box 63, Boston, MA 02111. E-mail [email protected]
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000125712.02090.6e
1141
1142
Stroke
May 2004
2),1 the ATLANTIS A Study7 (n⫽147), and the ATLANTIS B
Study2 (n⫽613).
Trials and Subjects
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The NINDS and ATLANTIS studies were randomized controlled
studies testing rt-PA therapy against placebo. The methods of these
trials, including inclusion and exclusion criteria, have been reported
in detail in the original articles. In all 4 trials, inclusion was based on
a clinical diagnosis of ischemic stroke determined by a focal
neurologic deficit measurable on the National Institutes of Health
Stroke Scale8 (NIHSS) with a clearly defined time of onset and a
baseline head CT scan that excluded hemorrhage. These trials had
similar exclusion criteria, excluding patients at high risk for bleeding
and patients with possible stroke mimics. All studies used the same
recombinant tissue plasminogen activator (rt-PA) dosage (0.9 mg/kg,
to a maximum dose of 90 mg, with the initial 10% given as a bolus)
and precluded the use of oral or intravenous anticoagulants or
antiplatelet agents for the first 24 hours after treatment. The studies
also measured similar outcomes at 3 months, although they did not
use the same primary outcome in their initial analysis.
An important difference in inclusion criteria between the studies
was the allowed time from stroke onset to treatment. In the NINDS
Trials, all patients were required to be randomized within 3 hours of
symptom onset. ATLANTIS A enrolled consecutive patients arriving
for therapy between 0 and 360 minutes without any stratification.
ATLANTIS B initially enrolled patients from 0 to 300 minutes.
However, soon after enrollment began, the results of the NINDS
Trial became known, and the therapeutic time window was narrowed
to 180 to 300 minutes from symptom onset.
Unlike the NINDS Trial, which had no upper or lower limits for
stroke severity and included patients regardless of CT scan findings
(provided hemorrhage was excluded), the ATLANTIS A Trial
excluded patients with minor stroke (NIHSS ⬍4), the ATLANTIS B
Trial excluded patients with extended early infarct signs on the
baseline CT scan (ie, diffuse swelling, parenchymal hypodensity,
and/or effacement of cerebral sulci in ⬎33% of the middle cerebral
artery territory). The ATLANTIS studies also excluded patients
younger than 18 and older than 80 years, whereas there was no age
cut-off in the NINDS Study.
Both the NINDS and ATLANTIS studies differentiated between
symptomatic and asymptomatic intracranial hemorrhage. Any patient with a deterioration of 2 points on the NIHSS who also had any
blood present on a CT scan, mandated by the protocol at 24 hours or
at the time of any deterioration, was considered to have had a
symptomatic intracranial hemorrhage. Neither study differentiated
between parenchymal hemorrhages nor hemorrhagic infarcts (HI) on
CT imaging.
Model Development
To assess the impact of asymptomatic intracranial hemorrhage on
patient outcome, we developed statistical models predicting 90-day
outcomes in patients receiving and not receiving thrombolytic
therapy in the combined database. There were 1197 patients in the
combined database after excluding patients with symptomatic intracranial hemorrhage (n⫽56) and any patients missing variables
necessary for modeling (n⫽131). These models could then be used
to test the effect of asymptomatic intracranial hemorrhage on
outcome after the effect of all other variables had been accounted for.
To select variables for inclusion in the model, we reviewed the
literature for published prognostic models.9 –13 In our model, we used
clinical variables that have previously been shown to be important
prognostic determinants of 90-day outcomes and also tested additional clinical variables available in our database, based on clinical
reasoning. Likewise, interactions between variables were explored
based on the existing literature and clinical reasoning. Because of
differences in the coding of CT scan variables between the databases,
we were unable to include radiologic variables in our model.
Our primary outcome was the global outcome, as described in the
original NINDS article.1,14 For this outcome, generalized estimating
equations are used to estimate the odds of a normal or near-normal
outcome across 4 different stroke scales simultaneously (the modi-
fied Rankin Score [mRS],16 the Barthel Index,17 the Glasgow
Outcome Score,18 and the NIHSS8). This outcome was chosen
because we reasoned that using all 4 scales should maximize the
power available for model development, provided the required
assumptions were met (ie, a common dose effect across all scales).
We performed similar analyses using logistic regression equations
and the 3 secondary outcomes: mRS ⱕ1 (normal or near-normal
outcome), mRS ⱕ2 (nondisabled), and death.
For all our models, we included all variables and interaction terms
that were independent predictors of the global outcome at the
P⫽0.05 level. Once the best models were determined, we tested
whether asymptomatic intracranial hemorrhage at the time of the first
posttreatment CT scan added significant prognostic information.
Power Calculations
In the event that we found an estimated effect size that was clinically
important but not statistically significant, we planned a post hoc
power analysis to calculate the size of the database that would be
needed to reliably detect an effect of the magnitude observed. To do
this, we performed analyses on samples of patients drawn with
replacement (ie, bootstrapped samples15) from our 1197-patient
database. To estimate the power of our overall database to detect an
effect of the magnitude observed, we drew 1000 bootstrapped
samples, with each sample containing 1197 observations. For each
sample, generalized estimating equations were used to determine if
the effect of asymptomatic intracranial hemorrhage on patient
outcome was significant, controlling for the same variables included
in our final model. We then calculated the proportion of the
bootstrapped samples in which a statistically significant effect for
asymptomatic hemorrhage was observed. We drew incrementally
larger samples until statistically significant effects were found in at
least 80% of these samples to estimate the sample size required for
adequate power to reliably detect an effect.
Systematic Review
To identify relevant articles comparing outcomes in patients with
hemorrhagic transformations to those in patients without, we
searched MEDLINE from the years 1966 to present using the
following strategies: (1) [cerebrovascular disease (exploded)] ⫹
[intracranial hemorrhage or parenchymal hematoma] ⫹ [prognosis];
(2) [cerebrovascular disease (exploded)] ⫹ [intracranial hemorrhage]⫹ [thrombolytic therapy]; and (3) [cerebrovascular disease
(exploded)] ⫹ [hemorrhagic transformation]. We also hand-searched
references in the identified articles for relevant studies. The research
team reviewed titles, abstracts, and articles from the literature
identified. Studies were excluded if they reported only on symptomatic intracranial hemorrhages, if they did not measure functional
outcomes, and if they did not include a control group without
intracranial hemorrhage. Only English-language studies were
included.
Results
In the combined database, asymptomatic intracranial hemorrhage was more frequent in rt-PA–treated compared with
untreated patients (9.9% versus 4.2%, P⬍0.0001).
The best predictive model for the global outcome (predicting a normal or near-normal outcome) is shown in Table 1,
with inclusion of asymptomatic intracranial hemorrhage. As
can be seen, although there was a trend for patients with
asymptomatic intracranial hemorrhage to fare worse after
accounting for the other prognostic variables (odds ratio
[OR]⫽0.69), this trend did not reach statistical significance
(P⫽0.13). The variables used in this model were similarly
predictive in logistic regression models using mRS ⱕ1 and
mRS ⱕ2 as the outcome. The ORs for the effect of asymptomatic intracranial hemorrhage on outcome for each of the
models are shown in Table 2.
Kent et al
Asymptomatic Intracranial Hemorrhages in AIS
1143
TABLE 1. Estimated Odds Ratio Based on Multivariate Model Predicting Normal
or Near-Normal Outcome Across 4 Functional Outcome Scales (“Global Outcome”)
Model With Hemorrhage Effect
Odds Ratio
(95% CI)
Parameter
Estimate
Baseline systolic blood pressure (mm Hg)
0.99 (0.989–0.997)
⫺0.006
0.04
History of diabetes
0.46 (0.34–0.61)
⫺0.78
⬍0.0001
Male
1.24 (0.98–1.56)
0.22
0.07
Asymptomatic intracranial hemorrhage
0.69 (0.42–1.12)
Parameter
P
Value
Main Effects
⫺0.37
0.13
Baseline NIHSS
0.12
0.04
Age (y)
0.04
Time-to-treatment (min)
rt-PA Therapy
0.0005
⫺0.0006
0.55
1.24
⬍0.0001
Interaction Terms
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rt-PA Therapy ⫻ time-to-treatment
⫺0.004
0.01
Baseline NIHSS ⫻ age
⫺0.005
⬍0.0001
When the interaction term between treatment with rt-PA
and asymptomatic intracranial hemorrhage was tested, there
was no apparent effect (P⫽0.73, in primary model), indicating that we could not detect any difference in the effects of
hemorrhage on outcome in patients with versus without rt-PA
treatment. There was also no evidence that there was any
interaction between asymptomatic intracranial hemorrhage
and study, indicating that any differences in the study
protocols or in case ascertainment between studies did not
have an appreciable effect on this analysis.
Ninety-day mortality was best predicted by baseline stroke
severity (NIHSS), age, serum glucose (log-transformed), and
systolic blood pressure. Asymptomatic intracranial hemorrhage did not add any substantial prognostic information to
this model (P⫽0.69).
Power Calculations
Our bootstrap simulations indicated that a sample of 1197 has
⬇32% power to detect a statistically significant effect if the
true population effect is of the observed magnitude
(OR⫽0.69) and if the true effect of the other included
variables are also the same as observed in our sample.
Simulations with larger bootstrapped samples indicated that
to reliably detect (ie, with ⬎80% power) the observed 30%
decrease in the odds of a favorable outcome with asymptomatic hemorrhage would require ⬎4000 patients (Table 3).
Systematic Review
Our review of the literature revealed 9 previous studies4 – 6,19 –24
that evaluated outcomes in patients with acute ischemic
stroke compared with those with and without intracranial
hemorrhages (Table 4). Studies varied in size from 32 to 790.
There were no previous studies that specifically examined the
impact of asymptomatic intracranial hemorrhages. Seven
studies5,6,19 –23 differentiated between parenchymal hemorrhages and HI (based on the CT scan appearance), but only 3
studies5,19,20 reported results separately for HI. Although 7
had results that were not statistically significant,4 – 6,20,21,23,24
none of these studies assessed whether, given a true effect of
hemorrhage on functional outcome, they had adequate statistical power to detect it. Uniformly, these studies interpreted
their results as indicating that the hemorrhagic event did not
effect prognosis (except for 1 study that inappropriately
concluded that HI worsened outcome24). One study found that
HI was associated with a more favorable outcome,19 whereas
1 study22 found that hemorrhage was associated with a less
favorable outcome.
Discussion
We did not detect a statistically significant effect for asymptomatic intracranial hemorrhage on our primary outcome (ie,
the global outcome). Despite this, these data offer no reassurance that asymptomatic intracranial hemorrhages are clin-
TABLE 2. Effect of Asymptomatic Intracranial Hemorrhages on Various Outcome
Measures, Controlling for Other Important Prognostic Factors
Outcome
Odds Ratio
95% CI
P Value
Probability of normal or near-normal outcome
(global outcome)
0.69
(0.43–1.12)
0.13
Probability of normal or near-normal outcome
(mRS ⬍1)
0.63
(0.33–1.20)
0.16
Probability of disability-free outcome (mRS ⬍2)
0.60
(0.33–1.08)
0.09
Probability of mortality
0.88
(0.46–1.67)
0.69
mRS indicates modified Rankin Score.
1144
Stroke
TABLE 3.
Power Calculations
Sample Size
May 2004
Estimated Power to Detect
an Odds Ratio of 0.69*
1197
0.32
3000
0.66
4000
0.78
5000
0.89
*Proportion of bootstrapped samples demonstrating a significant effect for
asymptomatic intracranial hemorrhage, when each bootstrapped sample is of
a given size.
Downloaded from http://stroke.ahajournals.org/ by guest on June 18, 2017
ically innocuous. Our model shows a point estimate for the
effect size of asymptomatic intracranial hemorrhage that, if
true, would be clinically significant, and this analysis does
not rule-out effect sizes considerably larger. For example,
according to the primary model, in the absence of a hemorrhage on follow-up CT scan, a representative patient (calculated for a “median” patient: a 68-year-old man without
diabetes with a systolic blood pressure of 154 mm Hg, a
baseline NIHSS score of 11, and receiving rt-PA at 3 hours)
has a 40% probability of a normal or near-normal outcome
(on the mRS), whereas this probability decreases to 32% in
the presence of an asymptomatic hemorrhage. The magnitude
of the estimated effect on outcome of an asymptomatic
intracranial hemorrhage is of a similar order to that of
thrombolytic therapy. Further, this model, which used the
global outcome, gave a slightly more conservative estimate of
the effect than did the models using mRS alone, for either
cut-off used.
Our study is intended to caution other investigators who
might too hastily conclude that asymptomatic intracranial
hemorrhages are clinically innocuous. A common error in
clinical epidemiology is to mistake the lack of a statistically
significant effect as evidence for the absence of an effect.25
Our review of the literature for asymptomatic intracranial
hemorrhage shows that this is common.4 – 6,19 –21 Although our
study found that even a sample size of almost 1200 would be
expected to have negative results ⬇70% of the time even if
hemorrhages in fact reduce the odds of a good outcome by
30%, other researchers have confidently asserted the lack of
an effect with far fewer subjects (as little as 3621 or 121
subjects4), and even when their studies found clinically
substantial but statistically nonsignificant effects. For example, in the ECASS 1 study,26 among patients treated with
rt-PA, the likelihood of 3-month disability was 43% among
those without any bleeding and 79% among those with HI2;
yet, based on the absence of sufficient power to detect a
statistically significant effect, the authors conclude that
3-month outcomes are not influenced by hemorrhagic infarcts.5 In these studies, the lack of statistical significance is
essentially predetermined by an inadequate sample size.
Because the main predictors of an intracranial hemorrhage
are also determinants of a poor outcome (notably baseline
stroke severity), estimating the prognostic significance of an
asymptomatic intracranial hemorrhage is difficult. The high
degree of collinearity between determinants of the hemorrhage and the outcome increases the imprecision of the
estimated effect of hemorrhage on the outcome and thus
decrease statistical power. To reliably detect the effect we
observed (a 30% reduction in the odds of a good outcome), a
sample size of between 4000 and 5000 patients would be
needed. The number of patients required to “prove” equivalence would be substantially greater and may not be feasible.
Our review revealed considerable heterogeneity in the
research design of studies that examine the clinical impact of
hemorrhagic transformation of acute ischemic stroke. Our
study was the only study that looked specifically at asymptomatic intracranial hemorrhages. ECASS 1 and 2, however,
classified hemorrhages radiographically, but not clinically.
These differences make combined analyses difficult. Additionally, although NINDS and ATLANTIS had similar rates
of hemorrhage and of asymptomatic hemorrhagic transformation, the ECASS studies showed substantially higher hemorrhage rates overall; in ECASS 1, 9.9% of placebo-treated
patients had hemorrhagic transformations (of all types combined), compared with 30.0% of patients who received rt-PA.
In ECASS 2, the corresponding proportions were 18.5% and
29.5%, respectively. The substantially higher rate of hemorrhage in the ECASS studies compared with that found in
NINDS and ATLANTIS suggests important differences in
case definition and/or ascertainment that is not apparent from
the published reports.
Not surprisingly, there was some heterogeneity in the
results of the reviewed studies. Although most studies did not
find statistically significant effects, one study found statistically significant worse outcomes in patients with hemorrhages.22 Another study claimed worse outcomes in patients
with hemorrhages, but their data did not fully support this
conclusion.24 More recently, a small but intriguing study
(n⫽32) found an enormous increase (OR⫽10.6, 95% CI: 1.7
to 69.9) in the likelihood of a good outcome among patients
receiving thrombolysis who manifest HI, which they found to
be associated with reperfusion as measured by transcranial
Doppler.19 It is unclear how the results of this small study
may be reconciled with the results of the other much larger
studies, including our own.
Whether asymptomatic hemorrhages, or a portion of such
hemorrhages, affect outcome (for good or ill) is particularly
important because they are so common in acute ischemic
stroke and their frequency is increased with the use of
antithrombotic therapy. Because their clinical impact is unknown, putative benefits of antithrombotic agents need to be
rigorously proven before routine adoption of such therapies,
even in patient subgroups.27
In addition to the insufficient power to detect clinically
meaningful effects, there are additional limitations to our
study. A fundamental limitation of this study is that in
developing our multivariable model, the estimation of effect
size is somewhat dependent on which additional variables are
controlled in the model. Only when the model was refined by
adding interaction terms did the effect of hemorrhage cease to
be statistically significant. Similarly, the effect of asymptomatic intracranial hemorrhage seen in our analysis might be
overestimated in our model if there are other variables
associated with the likelihood of asymptomatic intracranial
hemorrhage and with outcome, which are not included in the
model. Perhaps most important among these variables is a
Kent et al
TABLE 4.
Asymptomatic Intracranial Hemorrhages in AIS
1145
Results of Systematic Review
Author, Year
4
Bayramoglu,
2003
Molina,19
2002
Downloaded from http://stroke.ahajournals.org/ by guest on June 18, 2017
Berger,20
2001
Mayer,21
2000
Study Population
Method and Outcome
Differentiate
Between
Symptomatic
and
Asymptomatic
ICH
No
No
Not available
No
HT of an ischemic lesion
does not affect rehabilitation
outcome in stroke survivors
Not in analysis
of outcomes
Yes
OR in HI
patients⫽0.09
(0.01 to 0.59)†
Not
applicable
HI (HI1-HI2) represents a
surrogate marker of early
successful reperfusion and
good clinical outcome in
patients receiving rt-PA
No
Yes
For HI1:
OR⫽0.7
(0.4–1.2)
No
Heterogenous, petechial HI
关HI1 and HI2兴 are not
associated with worse early
or late outcome
N⫽121
t test and ␹
Retrospective study of
patients admitted to
rehabilitation facility
Outcomes: FIM & APECS
scores
N⫽32
Multivariate LR
MCA strokes treated
with rt-PA; excluded
those with early CT
signs in⬎33% MCA
territory at baseline
Outcome:
90-day mRS ⬎2
N⫽790
Multivariate LR
ECASS II trial, testing
t-PA against placebo.
Outcome:
MRS ⬎2 at 3 mo
N⫽36
Methods: ␹2 without
multivariable adjustment
2
Differentiate
Between HI
& PH
Estimated Effect
Size* (OR of
Poor Outcome)
(CI)
If
Negative,
Consider
Statistical
Power
For HI2:
OR⫽0.9
(0.4–1.9)
Conclusion
No
Yes
Not available
No
HT had no influence on
patient’s neurological status
No
Yes,
(categories
similar, but
not identical,
to HI & PH)
HT
No
Fears concerning an
undefined intraparenchymal
hemorrhagic transformation
could be dispelled
No
PH2 is the only type of
hemorrhagic transformation
that may alter the clinical
course of ischemic stroke
Not
applicable
Mass effect of the underlying
infarct rather than HI
contributes to deterioration
No
Apart form the infrequent
case of massive hematoma,
HT does not influence
prognosis
No
Clinical worsening or death
at discharge were more
common in HI patients
Outcome: change in
neurological deficit on
the Mathew scale
Motto,6 1999
Fiorelli,5 1999
N⫽554
Multivariate LR
MAST trial, testing SK
against placebo
MRS ⱖ3 (ie, unfavorable
outcome)
N⫽609
Multivariate LR
ECASS 1 trial, testing
t-PA against placebo
Outcome:
disability mRS ⱖ1)
No
Yes
Overall: OR⫽1.2
(0.7–2.2)
SK tx subgroup:
OR⫽1.4
(0.7–3.0)
HI
rt-PA: OR⫽1.05
(0.47–2.08)
Placebo:
OR⫽2.34
(0.62–8.81)
Davalos,22
1999
Toni,23 1996
Beghi,24 1989
N⫽615
Multivariate LR
ECASS 1 trial, testing
t-PA against placebo
Outcome: late
progressing stroke
N⫽150
Multivariate LR
Stroke registry of
patients admitted within
5 h of onset
Outcome: Barthel Index,
poor ⬍60
N⫽123
Case-control study
(age- and sex-matched)
Mantel Haenszel Student
t test No multivariate
adjustment
No
No
No
Yes, but
analyzed
together
OR⫽1.8
(1.1–3.0)
Yes, but
analyzed
together
OR⫽0.76
(0.25–2.37)
No
HT:
HT:
RR⫽2.36
(0.81–6.89)
Outcome: clinical
worsening or death
LR indicates logistic regression; OR, odds ratio; MCA, middle cerebral artery; HT, hemorrhagic transformation (includes PH and HI); PH, parenchymal hemorrhage:
homogeneous region of high attenuation with or without associated mass effect; HI, hemorrhagic infarct: patchy areas of high attenuation within an infarct, no mass
effect; mRS, modified Rankin Score; FIM, functional independence measure; APECS, adapted patient evaluation conference system; CT, head CAT scan; SK,
streptokinase.
*Expressed as likelihood of a bad outcome (ie, OR or RR ⬎1 indicates worsening of outcomes with hemorrhage).
†Original article reports results in terms of likelihood of a good outcome (ie, the reciprocal of the outcome report here).
1146
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May 2004
measurement of infarct size on baseline CT scan. However,
these measures were not available for all trials in our
database.
Conclusion
Our study did not find a statistically significant effect of
intracranial hemorrhage on 90-day functional outcome, although a consistent trend for poorer outcomes was seen
across several measures. Previous studies that conclude that
hemorrhagic transformation does not have an important
clinical effect have not been sufficiently powered to uncover
effects that would be clinically important. Careful analysis of
substantially larger databases, including detailed information
on other prognostic variables, is necessary to assess whether
asymptomatic intracranial hemorrhages are clinically
innocuous.
Acknowledgments
Downloaded from http://stroke.ahajournals.org/ by guest on June 18, 2017
Dr Kent is a Pfizer Scholar in Clinical Epidemiology and is
supported by a Career Development Award from the NINDS (K23
NS44929-01). Dr Hinchey is supported by a Career Development
Award from the NINDS (K23 NSO2163). Dr Levine is supported in
part by 1RO1-NS30896, 1K24-NS 23393, 3PO1-NS23393, and
(CDC) U50/CCU 520272.
The authors gratefully acknowledge the work of the NINDS rt-PA
Study and the ATLANTIS study investigators who made this
analysis possible.
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In Acute Ischemic Stroke, Are Asymptomatic Intracranial Hemorrhages Clinically
Innocuous?
David M. Kent, Judith Hinchey, Lori Lyn Price, Steven R. Levine and Harry P. Selker
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Stroke. 2004;35:1141-1146; originally published online April 15, 2004;
doi: 10.1161/01.STR.0000125712.02090.6e
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