Prediction of Functional Outcome and In-Hospital Mortality

After Admission With Oral AnticoagulantRelated

Intracerebral Hemorrhage
Joris Berwaerts, MB, ChB; Roelf S. Dijkhuizen, MD, FRCP (Edin);
Olive J. Robb, FRCR; John Webster, MD, FRCP (Edin)
Background and PurposeEarly survival of patients with intracerebral hemorrhage in general is known to be most
strongly dependent on the Glasgow Coma Scale score on admission. The aim of this study was to examine the factors
determining functional outcome and in-hospital mortality of patients admitted with an intracerebral hemorrhage related
to oral anticoagulant (OAC) use.
MethodsCorrelation studies and multiple logistic regression analyses were performed on data from a retrospective series of 42
patients admitted with OAC-related intracerebral hemorrhages over a 6-year period to a tertiary care center in the north of
Scotland.
ResultsThe functional outcome after an OAC-related intracerebral hemorrhage was dependent on maximum diameter of
hematoma on CT scan (R0.72, P0.001) and international normalized ratio (INR) (R0.35, P0.024). Hematoma
diameter and INR were not themselves strongly correlated (R0.31, P0.099). In-hospital mortality can be predicted by the
Glasgow Coma Scale score alone (R20.36, overall predictive accuracy 68%) but more accurately by a logistic regression
model including hematoma diameter and CT signs of cerebrovascular disease (R20.70, predictive accuracy 83%).
ConclusionsNeither functional outcome nor in-hospital mortality appears to be strongly dependent on INR measured on
admission. CT scan, however, provides essential information and allows accurate predictions about the short-term outcome
of OAC-related intracerebral hemorrhages. (Stroke. 2000;31:2558-2562.)
Key Words: hemorrhage mortality prognosis tomography, x-ray computed warfarin

or intracerebral hemorrhage in general, short-term mortality is strongly related to decreased levels of consciousness on presentation (odds ratio [OR] 4.8 to 11.8).13 Thirtyday (or in-hospital) mortality is also strongly dependent on
the volume of hematomas measured on CT scan (eg, OR of
up to 28.5 for volumes 60 cm3).1,3 Location of the hemorrhage in the posterior fossa2 and extension of the hemorrhage
into the ventricular system1,2,4 are bad prognostic factors.
Displacement of the midline structures is less clearly related
to short-term mortality (OR 2.7).1,4 One reason that the above
factors are not equally important in predicting early survival
is the strong colinearity of the factors considered in multivariate analysis. Hence, the introduction of a combined
variable mass effect in one of the studies mentioned.4
Mortality at 6 months, but not short-term mortality after an
intracerebral hemorrhage, has been shown to be strongly
dependent on age (OR 11.8 for each increase in age by 10
years).4
The present study of oral anticoagulant (OAC)-related intracerebral hemorrhages explores the possible correlations between

the diameter of hematomas on CT scan and the intensity of OAC

therapy measured on admission (international normalized ratio
[INR]) and the relationships between outcome and hematoma
diameter on one hand and outcome and INR on the other.
Another objective of the present study was to identify clinical
and/or radiological features that may accurately predict early
mortality. This has never before been attempted in a systematic
way for intracerebral hemorrhages related to OAC use.

Subjects and Methods

From January 1993 until March 1999, a total of 1512 patients had
been admitted to Aberdeen Royal Infirmary (ARI) with intracranial
hemorrhages. For most patients, we have been able to determine
whether an intracerebral hemorrhage may have been associated with
OAC use or not. For such cases, the following patient-related
information was collected by a retrospective review of patient notes:
sex, age, presence of hypertension, diabetes mellitus, hypercholesterolemia, cardiovascular disease (ie, atrial fibrillation, ischemic
heart disease, or congestive heart failure), cerebrovascular disease,
venous thromboembolism, alcohol abuse, liver and renal disease,
cancer, and previous OAC-related hemorrhages. Furthermore, we
recorded the following treatment characteristics: duration of OAC

Received February 7, 2000; final revision received May 24, 2000; accepted August 9, 2000.
From the Acute Stroke Unit (J.B., R.S.D., J.W.) and the Department of Radiology (O.J.R.), Aberdeen Royal Infirmary, Aberdeen, UK.
This study was conducted as part of a project leading to a master of science degree in clinical pharmacology (J. Berwaerts) at the University of Aberdeen.
Correspondence to Joris Berwaerts, University of Aberdeen, Department of Medicine and Therapeutics, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD.
E-mail j.berwaerts@abdn.ac.uk
2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

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Berwaerts et al

Prognosis of OAC-Related Intracerebral Hemorrhage

2559

TABLE 1. Prevalence of Different Features in 42 Patients With

OAC-Related Intracerebral Hemorrhages
Prevalence, % (n42)
Male sex

57

Age
65 y

24

6579 y

59

79 y

17

Hypertension

50

Diabetes

14

Hypercholesterolemia

14

Ischemic heart disease

50

Prosthetic heart valve

14

Atrial fibrillation

57

Congestive heart failure

31

Cerebrovascular disease

40

Venous thromboembolism

24

Alcohol abuse

Liver disease

10

Renal disease

Cancer

12

Previous hemorrhage

10

Duration
12 mo

50

1395 mo

43

96 mo

Concomitant drugs (3)

31

Aspirin use

12

INR
2.0

17

2.04.5

63

4.5

20

Last INR check 42 d previously

22

Lack of concordance with SIGN

guidelines

10

SIGN indicates Scottish Intercollegiate Guidelines Network.

therapy, number of concomitant drugs, aspirin use, INR as measured

on admission, most recently checked INR value, time interval
between the latter 2 INR measurements, and concordance with the
Scottish Intercollegiate Guidelines Network guidelines.5 When reviewing the notes of patients known to have been discharged from
ARI with a diagnosis of OAC-related intracerebral hemorrhage
between January 1993 and March 1999, we also recorded the
following data for every patient: means of diagnosis, preceding head
trauma, duration of symptoms before admission, Glasgow Coma
Scale (GCS) score on admission, maximum diameter of the hematoma on CT scan (if performed), displacement of the midline
(possibly associated intraventricular blood), location in the posterior
fossa, signs of cerebral ischemia on CT scan, need for surgical
intervention, short-term outcome (death or no, partial, or full
recovery on discharge from ARI), and length of in-hospital stay.
The diameter of intracerebral hemorrhages and the corresponding
INR values were nonnormally distributed; therefore, the nonparametric
Spearman rank test was applied to confirm a possible correlation
between both variables. In the same way, possible correlations were
checked for outcome (death or no, partial, or full recovery) of intracerebral hemorrhages and hematoma diameter and for outcome and INR.

Figure 1. Frequency distribution of INR values on admission of

patients with intracerebral hemorrhages.

The 5% significance level was adopted for hypothesis testing, and

scatterplots were produced as illustrations. Multiple logistic regression
analysis was used to investigate which of the patient and treatment
characteristics and which of the clinical and radiological features of
intracerebral hemorrhages are important for the prediction of in-hospital
mortality (forward method) and to determine how much weight each of
these factors carries (enter method). Where applicable, 95% CIs were
calculated for the estimated ORs. Sensitivity, specificity, and positive
and negative predictive values have been determined to assess the
constructed predictive models. All statistical analyses were performed
by use of SPSS 8.0.

Results
Between January 1993 and March 1999, 1512 patients had
been admitted to ARI because of a confirmed intracranial
hemorrhage. From this total, 68 patients were found to have
been treated with OACs at the time of sustaining their
intracranial hemorrhage. Out of this total of 68 hemorrhages,
42 (62%) had been diagnosed as intracerebral. Data were
missing with regard to the duration of OAC therapy for 1
patient, the INR value as checked on admission for 1 patient,
and the time interval between the preceding and the most
recent check for 11 patients. These 3 variables were, together
with age and number of concomitant drugs, the only clinical
variables under consideration that were continuous. The mean
age of all 42 patients admitted with an OAC-related intracerebral hemorrhage was 7110 years. The mean duration of
OAC therapy was 2943 months. The mean number of
concomitant drugs was 3.01.9. The mean INR value on
admission to hospital was 3.62.1 (Figure 1). The INR
values had, on average, been checked 2625 days before
hospital admission.
The above continuous variables have been further broken
down into categorical variables: age categories (65, 65 to 79,
and 79 years), duration of OAC therapy (12, 13 to 95, and
96 months), use of 3 or 3 concomitant drugs other than
warfarin, INR on admission (2, 2 to 4.5, and 4.5), and most
recently checked INR value (42 or 42 days ago). The
frequencies for these respective variables, as well as for the
previously mentioned dichotomous variables (eg, sex, presence
of hypertension), are shown in Table 1.
Among the 42 patients with OAC-related intracerebral hemorrhages, the diagnosis was made by means of CT scan in 36
patients, MRI in 1 patient, and autopsy in 2 patients. Size

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Figure 2. Frequency distribution of GCS scores on admission

of patients with OAC-related intracerebral hemorrhages.

estimates based on CT scan were available for 30 patients (6

patients had been scanned elsewhere before referral to ARI).
There were no missing data for any outcome variable other than
those checked on the basis of CT scan.
Minor head trauma had preceded OAC-related intracerebral
hemorrhages in 14% of cases. The mean duration of symptoms
before admission to the hospital because of OAC-related intracerebral hemorrhages was 3959 hours. The mean GCS score
on admission was 11.94.4 (Figure 2). On CT scan, 40% of all
OAC-related intracerebral hemorrhages were associated with
signs of cerebral ischemia. The mean maximum diameter of the
hematomas was 4021 mm. The distribution of diameters was
clearly nonnormal (Figure 3). Intraventricular blood was present
on 45% of CT scans, the midline was displaced in 21% of cases,
and 21% of the hematomas were located in the posterior fossa.
One patient demonstrated the characteristics of a hemorrhagic
infarct on CT scan. Surgical management was undertaken in
12% of the patients. At the time of discharge from the hospital,
the distribution of clinical outcomes was as follows: 43% death,
9% no recovery, 41% partial recovery, and 7% full recovery.
The mean duration of in-hospital stay was 1413 days.
The relationship between hematoma diameter and the
corresponding INR value found on admission is shown in
Figure 4. The diameter of OAC-related intracerebral hemor-

Figure 3. Frequency distribution of hematoma diameters on CT

scan (maximum diameter, in millimeters) on admission of
patients with OAC-related intracerebral hemorrhages.

Figure 4. Scatterplot of size (maximum diameter, in millimeters)

against corresponding INR values for OAC-related intracerebral
hemorrhages (R0.31, P0.099).

rhages was clearly correlated with clinical outcome (Figure

5). The relationship between INR value and clinical outcome
is shown in Figure 6.
Although clinical outcome, as defined by the 4 abovementioned categories, was not strongly correlated with INR at
the time of admission, this would not preclude a strong relationship between in-hospital mortality and INR. To further investigate this, logistic regression was used to identify prognostic
factors for in-hospital mortality. When all intracranial hemorrhages were considered together (n68), short-term mortality
appeared to be largely predictable on the basis of 3 variables:
type of hemorrhage, admission within 12 hours of onset of
symptoms, and level of consciousness on admission (GCS score
14) (R20.66, 74% sensitivity, and 100% specificity). Although included in the analysis, there was no place for any of the
above-mentioned patient- or treatment-related characteristics in
the model (eg, hypertension or INR). On the contrary, short-term
mortality for all OAC-related intracranial hemorrhages could be
predicted from the clinical characteristics of the hemorrhage
alone.
When OAC-related intracerebral hemorrhages were considered separately, the GCS score on its own was found to predict

Figure 5. Scatterplot of size (maximum diameter, in millimeters)

against outcome for patients admitted with OAC-related intracerebral hemorrhages. There were 4 outcome categories: 1, death;
2, no recovery; 3, partial recovery; and 4, full recovery
(R0.74, P0.001).

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Berwaerts et al
TABLE 2.

Prognosis of OAC-Related Intracerebral Hemorrhage

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Details of Logistic Regression Analysis for Prediction of In-Hospital Mortality

Variable

Parameter Estimate

2.78

0.039

0.10

0.021

3.87

0.043

R 0.702
2

Ischemia
Diameter (continuous variable)
Constant

Univariate
Dead, % (n18)

Alive, % (n24)

OR

95% CI

Multivariate
OR

95% CI

0.053

0.0030.979

Ischemia

17

58

0.14

0.030.63

Intraventricular blood

50

42

1.40

0.414.79

10.21

Displacement

39

7.00

1.2439.49

2.89

0.04212.98

Location in fossa posterior

28

17

1.92

0.438.52

1.71

0.0645.39

0.49211.81

Diameter increments
30 mm

63

0.06

0.010.56

3050 mm

27

32

0.81

0.164.20

50 mm

64

31.50

2.98333.22

10 mm

1.93

0.705.33

in-hospital mortality most accurately (R20.36, sensitivity 46%,

and specificity 83%). Other patient-related (eg, hypertension) or
treatment-related (eg, INR) characteristics did not add to the
predictive value of GCS alone. When the radiological (ie, CT
scan) features were considered, a best predictive model was
found on the basis of hematoma diameter and the presence of
associated signs of cerebral ischemia. Details of this model are
listed in Table 2. It demonstrates a sensitivity of 73%, a
specificity of 89%, a positive predictive value of 80%, and a
negative predictive value of 85%. The most striking finding
about this model is the negative sign of the parameter estimate
for cerebral ischemia; ie, evidence of ischemia on CT scan
appears protective against short-term mortality. This conclusion
is reinforced when considering the multivariate ORs of inhospital mortality for the different possible radiological features
of OAC-related intracerebral hemorrhages (Table 2).

Discussion
The present study is the first to apply logistic regression to the
short-term prognosis of patients admitted with OAC-related

Figure 6. Scatterplot of INR values against outcome for

patients admitted with OAC-related intracerebral hemorrhages
(R0.35, P0.024).

intracerebral hemorrhages. Because of the relative lack of

patients with complete data, we have performed regression
analysis twice, once for all clinical (ie, patient-, treatment-,
and bleeding-related) characteristics and once for the radiological features. We have thereby been able to identify GCS
score and hematoma diameter as the 2 most important
independent prognostic factors for short-term mortality. This
is in keeping with the previous findings for intracerebral
hemorrhages in general and for those related to OAC use.
Diminished consciousness on admission was an important
prognostic factor of mortality according to 2 studies,6,7 in
accordance with the conclusions reached for the short-term
prognosis of intracerebral hemorrhages in general.13
Five reports have commented on the effect of hematoma size
on mortality. Three clearly showed the average size of hematomas to be larger in deceased patients than in survivors.8 10
Another report merely claimed that mortality increased with
hematoma size,11 whereas the last report contradicted this
finding.7 Hematoma size has, of course, also been found to be an
important prognostic factor for the short-term survival of patients admitted with an intracerebral hemorrhage in general.1,3
For intracerebral hemorrhages in general (ie, without associated OAC use), there is some evidence to suggest that functional
outcome, and not just mortality, is related to hematoma size.2
Two previous reports claimed that there was no such (strong)
correlation between size and outcome for OAC-related hemorrhages,6,7 although neither provided any details to substantiate
this claim. Our data suggest a strong correlation between
functional outcome and the diameter of intracerebral hematomas. However, this correlation may be dominated by the effect
of hematoma diameter on (short-term) mortality. Volumetric
measurement of hematoma size is widely accepted as a reliable
measurement but would have been available to us in only a
proportion of patients who were examined in the most recent
version of our CT scanner. However, to maximize the number of
patients on whom some measure of hematoma size was available, we chose to use maximum diameter instead, in the

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knowledge that this measurement is readily available to clinicians in routine clinical practice even in the absence of sophisticated software.
Unexpectedly, radiological signs of cerebral ischemia appeared to have a significant protective influence. This finding
cannot easily be explained, especially because we have previously found a past medical history of cerebrovascular disease to
be a significant risk factor for intracerebral bleeding on warfarin
(J.B. and J.W., unpublished data, 1999). One possibility is that
gliosis resulting from previous major stroke may have permitted
the accommodation of acute intracranial bleeding better than in
patients without previous cerebral damage. Our classification of
cerebral ischemia included gliosis, lacunae, and periventricular
ischemia in single, multiple, or diffuse distributions. Further
explanation of such appearances would be of interest. The few
previous studies reporting the occurrence of OAC-related intracerebral hemorrhages in patients with old cerebral infarcts on CT
scan have not provided any separate information on the casefatality rate for those patients.1,6,10,12 In the above studies of
prognostic factors for the short-term survival of patients with
intracerebral hemorrhages in general, radiological or clinical
evidence of existing cerebrovascular disease has not emerged as
a risk factor.1 4 In previous reports, midline displacement,9
posterior fossa location,2,11 and intraventricular hemorrhage1,2,4
were associated with a high mortality. We found similar trends
in univariate analysis, although they did not contribute significantly in the logistic regression model. It should be emphasized
that our prognostic model deals with the chance of dying in the
short term of an OAC-related intracerebral hemorrhage and not
with the chance of sustaining such a hemorrhage in the first
place.
Few reports have commented on a possible relation between
clinical outcome and the intensity of OAC therapy measured on
admission. Graphical data (without statistical analysis) provided
in one report suggest that there is no such correlation for
intracerebral hemorrhages.8 In the present study, we have found
this correlation to be statistically significant for intracerebral
hemorrhage, although not for intracranial hemorrhages in general (n68).
Previously, studies reported on a possible correlation between
the size of intracerebral hemorrhages and the corresponding
intensity of OAC therapy measured on admission. One report
claimed such a correlation, which was based on rather simple
data (mean sizes were 91 cm3 for INR 3.6, 65 cm3 for INR 2.0
to 3.6, and 59 cm3 for INR 2.0) and no statistical analysis.1
Other reports found no strong correlation between hematoma
size and intensity values, but there was no formal analysis.6,8
Only one report has appropriately provided the results of a
statistical analysis (n27, R0.14, P0.5).9 The results of the
present study confirm the absence of a significant correlation
between hematoma hemorrhage and anticoagulant intensity.

Two logistic regression models had previously been reported

to predict the short-term mortality of patients with intracerebral
hemorrhages in general.3,11 The present study was limited by
incomplete data in a number of patients, but we still believe that
our model(s) may be clinically relevant and merit validation in
an independent patient sample, eg, for clinical decision making
or advising patients and family about prognosis. Another important application is that future experimental studies of OACinduced intracerebral hemorrhage (eg, into reversal of OAC
therapy) may now be controlled for the factors identified in our
analyses (particularly GCS score and hematoma diameter).
Finally, our data also confirm the importance of early clinical
assessment and radiological confirmation of a suspected intracranial hemorrhage on warfarin.1215 First of all, urgent CT
scanning confirms the diagnosis and allows a rational decision to
be made about reversal of anticoagulation. Second, it helps in the
prediction of eventual outcome.

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Prediction of Functional Outcome and In-Hospital Mortality After Admission With Oral
AnticoagulantRelated Intracerebral Hemorrhage
Joris Berwaerts, Roelf S. Dijkhuizen, Olive J. Robb and John Webster
Stroke. 2000;31:2558-2562
doi: 10.1161/01.STR.31.11.2558
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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Print ISSN: 0039-2499. Online ISSN: 1524-4628

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