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Risk Factors, Outcome, and Treatment in Subtypes of Ischemic Stroke: The German

Stroke Data Bank


Armin J. Grau, Christian Weimar, Florian Buggle, Alexander Heinrich, Michael Goertler, Stefan
Neumaier, Joerg Glahn, Tobias Brandt, Werner Hacke and Hans-Christoph Diener
Stroke. 2001;32:2559-2566
doi: 10.1161/hs1101.098524
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2001 American Heart Association, Inc. All rights reserved.
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Risk Factors, Outcome, and Treatment in Subtypes of


Ischemic Stroke
The German Stroke Data Bank
Armin J. Grau, MD; Christian Weimar, MD; Florian Buggle, MD; Alexander Heinrich, MD;
Michael Goertler, MD; Stefan Neumaier, MD; Joerg Glahn, MD; Tobias Brandt, MD;
Werner Hacke, MD; Hans-Christoph Diener, MD; on behalf of the German Stroke
Data Bank Collaborators
Background and PurposeData on risk factors for etiologic subtypes of ischemic stroke are still scant. The aim of this
study was to characterize stroke subtypes regarding risk factor profile, outcome, and current treatment strategies.
MethodsWe analyzed data from 5017 patients with acute ischemic stroke (42.4% women, aged 65.914.1 years) who
were enrolled in a large multicenter hospital based stroke data bank. Standardized data assessment and stroke subtype
classification were used by all centers.
ResultsSex and age distribution, major risk factors and comorbidities, recurrent stroke, treatment strategies, and outcome
were all unevenly distributed among stroke subtypes (P0.001, respectively). Cardioembolism, the most frequent
etiology of stroke (25.6%), was particularly common in the elderly (those aged 70 years) and associated with an
adverse outcome, a low rate of early stroke recurrence, and frequent use of thrombolytic therapy and intravenous
anticoagulation. Large-artery atherosclerosis (20.9%), the most common cause of stroke in middle-aged patients (those
aged 45 to 70 years), showed the highest male preponderance, highest rate of early stroke recurrence, and highest
prevalence of previous transient ischemic attack, current smoking, and daily alcohol consumption among all subtypes.
The highest prevalence of hypertension, diabetes mellitus, hypercholesterolemia, and obesity was found in small-vessel
disease (20.5%), which, in turn, was associated with the lowest stroke severity and mortality.
ConclusionsOur results foster the concept of ischemic stroke as a polyetiologic disease with marked differences between
subtypes regarding risk factors and outcome. Therefore, studies involving risk factors of ischemic stroke should
differentiate between etiologic stroke subtypes. (Stroke. 2001;32:2559-2566.)
Key Words: outcome risk factors stroke classification stroke, ischemic

t is unanimously accepted that different diseases can cause


ischemic stroke. The most important etiologies of ischemic
stroke include large-artery atherosclerosis (macroangiopathy), cardioembolism, and cerebral small-vessel disease (microangiopathy). Less common causes of stroke are cervical
artery dissection, cerebral vasculitis, coagulopathies, hematologic disorders, and others. A considerable minority of
ischemic stroke cases remains etiologically undefined even
after complete diagnostic workup. It is presently an important
challenge to tailor acute therapy and secondary prevention
according to the cause of stroke in individual patients.
However, there is still scant information on the role of risk
factors and the clinical course in etiologic stroke subtypes.1,2
The Stroke Data Bank of the German Stroke Foundation
(Stiftung Deutsche Schlaganfall-Hilfe) is a multicenter hos-

pital based stroke registry that was initiated in 1997 to obtain


data on stroke etiology, management, and outcome, as well as
on the quality of clinical stroke care in Germany. It was one
of the prespecified aims of this data bank to collect a patient
sample that would be large enough to allow for proper
characterization of different stroke subtypes regarding associated risk factors and comorbidities, stroke severity, mortality, clinical complications, early stroke recurrence, and current treatment strategies.
Based on previous studies and observations during the
treatment of stroke patients, the following hypotheses were
developed that guided the data analysis in the present study:
(1) Stroke due to large-artery atherosclerosis and stroke due
to small-vessel disease show the highest prevalence of hypertension and diabetes mellitus. (2) Macroangiopathic stroke

Received June 19, 2001; final revision received August 15, 2001; accepted August 15, 2001.
From the Department of Neurology, University of Heidelberg (A.J.G., F.B., T.B., W.H.), Heidelberg; the Department of Neurology, University of Essen
(C.W., H.-C.D.), Essen; the Department of Neurology, University of Greifswald (A.H.), Greifswald; the Department of Neurology, University of
Magdeburg (M.G.), Magdeburg; the Department of Neurology, University of Homburg (S.N.), Homburg; and the Department of Neurology, Klinikum
Minden (J.G.), Minden, Germany.
Correspondence to Armin J. Grau, MD, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg,
Germany. E-mail armin_grau@med.uni-heidelberg.de
2001 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

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is characterized by a strong prevalence of current smoking,


coronary heart disease, and peripheral arterial disease.
(3) Cardioembolic stroke is associated with the highest stroke
severity and stroke due to small-vessel disease with the
lowest stroke severity. (4) The diagnosis of different stroke
etiologies guides decisions regarding early- and long-term
secondary prevention in current practice.

Subjects and Methods


Twenty-three neurology departments from all geographic parts of
Germany participated in data acquisition for the German Stroke Data
Bank, which took part between January 1998 and December 1999.
All hospitals are equipped with an acute-stroke unit and, in most
cases, also with a neurological intensive care unit. They serve
catchment areas of 100 000 to 1 million inhabitants and are the main
care providers for stroke patients in these regions. Almost all stroke
patients with acute stroke in these centers received a cranial CT or
MRI, extracranial and transcranial Doppler sonography and/or an
angiographic evaluation of brain-supplying arteries (including CT or
magnetic resonance angiography), an ECG and/or ECG monitoring,
basic blood tests, and additional laboratory investigations as required. The majority of patients were examined by transthoracic or
transesophageal echocardiography. The protocol of the Stroke Registry was approved by the responsible Institutional Review Boards.
All patients gave informed consent if their personal data (name,
address, and telephone number) were to be transferred to the data
management center. If no informed consent could be obtained from
the patient, only the anonymous medical data were transferred to the
data management center.
Prospective data collection was performed by using a standardized
questionnaire based on an extensive manual. It included age, sex,
time of ischemia and admission to hospital, vascular risk factors and
prior diseases, previous medication, results from technical examinations (eg, Doppler ultrasound), infarct localization, acute-stroke
therapy, complications, medication for secondary prevention, and
severity of the clinical deficit; the National Institutes of Health
Stroke Scale (NIH-SS), the Barthel index, and the modified Rankin
Scale (mRS) were used at admission and discharge. Assessment of
the NIH-SS was based on video training. Information on risk factors,
previous diseases, and medication was primarily obtained from the
patient, and additional information was collected from relatives and
general practitioners. The definitions of risk factors follow.

Risk Factors
Arterial Hypertension
Arterial hypertension was defined as history of elevated blood
pressure 160/90 mm Hg at 2 independent readings before stroke or
on antihypertensive medication.

Diabetes Mellitus
Diabetes mellitus was defined as history of elevated blood glucose at
2 independent readings before stroke or elevated hemoglobin A1c at
admission or on antidiabetic medication.

Hypercholesterolemia
Hypercholesterolemia was defined as history of elevated total
cholesterol 220 mg/dL at 2 independent readings before stroke or
lipid-lowering medication.
Complications were assessed until the day of discharge from the
documenting hospital, but for this analysis, only such complications
that occurred within the first week after admission were considered.
Follow-up evaluations after 3 months assessed recurrent stroke
and functional dependency by Barthel index and mRS. If the patient
did not consent in submission of his personal data, the participating
center performed the follow-up interview at site. Otherwise, the
follow-up was performed by trained telephone interviewers at the
University of Essen or the Stiftung Deutsche Schlaganfall-Hilfe. If a
patient could not be reached by telephone or via his general
practitioner, a follow-up letter was sent. If still no information on the

patients outcome could be obtained, a query at the citizen registry


was made to check for current address or death.
The data bank included patients with transient ischemic attacks
(TIAs) and all types of acute stroke admitted within 7 days after the
event. In this analysis, only patients with ischemic stroke, defined as
a clinical deficit lasting 24 hours, were included. Patients with TIA
or cerebral hemorrhage were excluded. For assessment of etiologic
stroke subtypes, we used the classification of the Trial of Org 10172
in Acute Stroke Treatment (TOAST) investigators.3 We included, as
a slight modification, an additional category for patients with 2
possible etiologies (concurrent etiology, see below). The diagnoses
are based on clinical features and ancillary tests, such as brain
imaging, Doppler ultrasound studies, cardiological examinations,
and laboratory investigations. The classification in the present study
was performed by the local neurologists after completion of ancillary
studies and was based on the criteria that follow.

Stroke Criteria
Macroangiopathy (Large-Artery Atherosclerosis)
Macroangiopathy is defined as the presence of an occlusion or a
stenosis with 50% diameter reduction of a brain-supplying artery
corresponding to clinical symptoms and with location and morphology typical of atherosclerosis on Doppler ultrasound or angiography.
Diagnostic studies had to exclude potential sources of cardiogenic
embolism.

Cardioembolism
Cardioembolism is defined as the presence of a high- or medium-risk
source of cardiac embolism.3 Potential large-artery atherosclerotic
sources of thrombosis or embolism had to be absent.

Microangiopathy (Small-Vessel Disease)


Microangiopathy is defined as the presence of one of the traditional
lacunar syndromes (eg, pure motor stroke, pure sensory stroke,
sensorimotor stroke, ataxic hemiparesis, and dysarthria-clumsy hand
syndrome), infarction(s) 1.5 cm of diameter or normal CT/MRI
examination, and absence of acute cerebral cortical dysfunction.
Potential cardiac sources for embolism should be absent, and
evaluation of the large extracranial arteries should not demonstrate a
stenosis of 50% in an ipsilateral artery.

Other Determined Etiologies


The questionnaire specifically mentioned spontaneous dissection,
traumatic dissection, vasculitis, hematologic disorders, coagulopathies, or other not-further-specified diseases. These diagnoses had to
be revealed by diagnostic studies, such as angiography or blood tests.
Cardiac sources of embolism and large-artery atherosclerosis had to
be excluded by other studies.

Undetermined Etiology
This category included patients in whom a likely etiology could not
be determined despite an extensive evaluation or in whom the
treating physician felt that not all necessary investigations had been
performed.

Concurrent Etiology
This category was included as an independent entity for the frequent
situation in which a patient had 2 probable stroke etiologies, and it
could not be determined which of them was causative.
In the present analysis, we only included patients from those
centers who registered 75% (range 76% to 98%) of all acute-stroke
patients hospitalized during the period in which the respective center
participated. Thus, we included data from 14 centers who participated for 10 to 24 months during the biannual registration period and
registered a total of 5105 patients with acute ischemic stroke. The
centers, 8 university hospitals and 6 municipal and local hospitals,
are situated in North (Bielefeld, Minden, and Rostock), East
(Leipzig, Berlin, Magdeburg, and Jena), West (Essen, Frechen, and
Hamburg), and South (Stuttgart, Ulm, Mnchen-Harlaching, and
Salzhausen) Germany. Of these centers, 6 centers with a registration
rate 95% and a total of 2797 patients were compared with the other

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Grau et al
TABLE 1.

Risk Factors in Subtypes of Ischemic Stroke

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Demographic Data in Etiologic Subgroups of Ischemic Stroke


Etiologic Subgroups of Ischemic Stroke

Parameter
Total group, n (%)

Macroangiopathy

Cardioembolism

Microangiopathy

Other
Etiologies

Concurrent
Etiologies

Unknown
Etiology

175 (3.5)

Total Group

1047 (20.9)

1286 (25.6)

1028 (20.5)

344 (6.9)

1137 (22.7)

5017 (100)

Females, n (%)

354 (33.8)

644 (50.1)

411 (40.0)

77 (44.0)

125 (36.3)

516 (45.4)

2127 (42.4)

Males, n (%)

693 (66.2)

642 (49.9)

617 (60.0)

98 (56.0)

219 (63.7)

621 (54.6)

2890 (57.6)

0.001

65.711.5

69.612.3

68.710.7

50.015.6

69.411.2

66.214.3

65.914.1

0.001

Women, y

67.712.7

72.012.3

72.410.5

49.717.0

71.511.3

69.014.7

69.813.5

0.001

Men, y

64.710.8

67.111.9

66.310.1

50.314.5

68.210.9

63.313.1

65.112.0

0.001

47 (4.5)

58 (4.5)

18 (1.8)

61 (34.9)

12 (3.5)

89 (7.8)

285 (5.7)

Age, y

Age 45 y, n (%)
Age 4570 y, n (%)

618 (59.0)

551 (42.8)

541 (52.6)

95 (54.3)

142 (41.3)

588 (51.8)

2535 (50.5)

Age 70 y, n (%)

382 (36.5)

677 (52.6)

469 (45.6)

19 (10.9)

190 (55.2)

459 (40.4)

2196 (43.8)

0.001

The data depict numbers of patients in each group. Numbers in parentheses give percentages that add to 100 in each subgroup. Age is given as meanSD.

centers with a lower registration rate to test for a potential selection


bias.

Data Evaluation and Statistics


After a final consistency check with the source data at the site,
questionnaires were sent to the data management centers at the
University of Essen and the German Stroke Foundation. They were
rechecked by 2 physicians for completeness and plausibility and
were entered in duplicate into the database by trained personnel.
Missing or implausible data (in particular, contradictions between
clinical and ancillary test results and subtype classification) were
referred to the treating clinician. Data quality was furthermore
ensured by monthly reports and clinical site visits. The final
decisions of the local centers on subtype diagnosis were accepted,
and patients were not excluded from our analyses for possible
misclassification. Missing data were not considered in the analyses.
Twenty-six patients had to be excluded because of missing information on stroke subtypes, and 62 patients were excluded because they
had no documented cerebral imaging. Thus, 5017 patients were
finally included in the present study.
Continuous variables are presented as meanSD or as median and
first and third quartile and were compared by ANOVA between
groups of stroke subtypes. Categorical variables are presented as
percentages. Comparisons of categorical variables between all subtypes were performed with the 2 test according to Pearson with 5 df.
Therefore, significance levels refer to differences between all groups.
Separate comparisons between single groups were limited to those
etiologic subgroups and parameters for which separate hypotheses
had been formulated to avoid multiple testing. We used binary
logistic regression analysis with forward selection and adjustment for
age (as a linear variable) and sex to test for significant differences in
risk factor distribution and treatment strategies between stroke
subtypes with macroangiopathy as the reference category. Statistical
analyses were performed by using the program package SPSS
version 9.0.

Results
A total of 5017 patients with ischemic stroke, 2127 women
and 2890 men aged 65.914.1 (meanSD) years, were
included in the present study. Cardioembolism was the most
common cause of stroke (n1286, 25.6%), followed by
large-artery atherosclerosis (n1047, 20.9%) and microangiopathy (n1028, 20.5%) (Table 1). Patients with stroke from
large-artery atherosclerosis had territorial (n936) or extraterritorial infarcts of presumed hemodynamic origin (n111).
Combined other etiologies (n175, 3.5%) involved patients
with spontaneous (n68, 1.3%) or traumatic (n12, 0.2%)

cervical artery dissection, vasculitis (n13, 0.3%), coagulation disorders (n35, 0.7%), other hematologic diseases
(n10, 0.2%), or nonspecified etiologies (n37, 0.7%). In
1137 patients (22.7%), the etiology remained undefined
because of incomplete investigations (n255, 5.1%) or despite complete workup (n882, 17.5%), and in 344 patients
(6.9%), 1 potential cause of stroke could be found.
The diagnosis of etiologic subgroups was based on frequently used ancillary tests. All patients received cerebral
imaging, either cranial CT scan (4859 patients, 96.9%) or
cranial MRI (1460 patients, 29.1%); 4177 patients (83.3%)
were examined by extracranial Doppler sonography; 3846
(76.7%), by duplex sonography; 4517 (90.0%), by transcranial Doppler; 1022 (20.4%), by CT, magnetic resonance, or
digital subtraction angiography; and 3170 (63.2%), by transthoracic or transesophageal echocardiography.

Risk Factors
Sex distribution differed significantly between etiologic subtypes; the highest male preponderance was in the macroangiopathic stroke category (66.2%), and the lowest proportion
of men was in the cardioembolic stroke category (49.9%).
Cardioembolism, concurrent etiologies, and microangiopathy
were associated with the highest mean age, and combined
other etiologies were associated with the lowest mean age.
The relative contribution of various etiologies differed among
age strata. Combined other etiologies clearly dominated
among young patients (aged 45 years), macroangiopathy
was the most common cause in the middle-age stratum (aged
45 to 70 years), and cardioembolism was the most common
cause among the elderly (aged 70 years) (Table 1).
The prevalence of modifiable risk factors and associated
diseases was significantly different among various stroke
subgroups (Table 2). A history of previous stroke was most
common in patients with concurrent etiologies (29.1%), least
frequently encountered in patients with combined other etiologies (10.5%), and of similar prevalence in patients with
macroangiopathy (22.8%), cardioembolism (22.3%), and microangiopathy (25.1%). In contrast, a history of previous TIA
was most prevalent in large-artery atherosclerosis (20.0%)
and least frequent in cardioembolism (8.1%). Arterial hypertension was highly prevalent in all groups except combined

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TABLE 2.

Risk Factors in Patients With Various Etiologies of Ischemic Stroke


Etiologic Subgroups of Ischemic Stroke

Macroangiopathy,
n (%)

Cardioembolism,
n (%)

Microangiopathy,
n (%)

Other
Etiologies,
n (%)

Concurrent
Etiologies,
n (%)

Unknown
Etiology,
n (%)

Total Group
n (%)

P*

Previous stroke

234 (22.8)

281 (22.3)

254 (25.1)

18 (10.5)

99 (29.1)

241 (21.4)

1127 (22.8)

0.023

Previous TIA

200 (20.0)

99 (8.1)

128 (13.0)

20 (11.5)

45 (13.5)

120 (10.8)

612 (12.7)

0.001

Hypertension

716 (70.0)

794 (62.5)

806 (79.4)

60 (35.1)

258 (75.7)

653 (58.5)

3287 (66.6)

0.001

Diabetes mellitus

298 (29.0)

356 (28.1)

359 (35.5)

16 (9.4)

109 (31.9)

274 (24.4)

1412 (28.5)

0.001

Hypercholesterolemia

401 (41.4)

331 (27.8)

418 (44.0)

35 (21.9)

112 (34.0)

356 (33.0)

1653 (35.3)

0.001

Current smoking

370 (37.6)

212 (17.6)

261 (25.9)

59 (34.7)

88 (26.7)

337 (31.1)

1327 (27.8)

0.001

No alcohol consumed

384 (40.6)

629 (53.8)

431 (44.4)

75 (45.7)

141 (43.7)

566 (53.3)

2226 (48.0)

0.001

Daily alcohol consumed

139 (14.7)

83 (7.1)

111 (11.4)

15 (9.1)

35 (10.8)

95 (9.0)

478 (10.3)

0.001

BMI 25

359 (40.1)

442 (42.3)

333 (36.5)

79 (50.3)

103 (36.7)

388 (39.6)

1704 (39.9)

0.002

BMI 30

134 (15.0)

143 (13.7)

162 (17.7)

17 (10.8)

42 (14.9)

157 (16.0)

655 (15.3)

0.006

19 (1.8)

20 (1.5)

12 (1.2)

15 (8.7)

7 (2.1)

32 (2.9)

105 (2.1)

0.53

CHD

234 (23.3)

363 (29.5)

212 (21.5)

15 (8.7)

122 (36.4)

218 (19.6)

1164 (24.0)

0.001

Cardiac arrhythmia

102 (10.0)

769 (61.1)

106 (10.7)

7 (4.0)

133 (39.1)

158 (14.2)

1275 (26.1)

0.001

21 (2.1)

126 (10.2)

21 (2.1)

1 (0.6)

20 (6.0)

22 (2.0)

211 (4.3)

0.001

104 (10.3)

77 (6.1)

77 (7.7)

7 (4.0)

42 (12.4)

70 (6.3)

377 (7.7)

0.001

Parameter

Oral contraception

Cardiac valve disease


PAD

BMI indicates body mass index; CHD, coronary heart disease; and PAD, peripheral arterial disease.
*Adjusted for age and sex.

other etiologies (35.1%). Despite a generally high level,


hypertension was significantly more common in microangiopathy (79.4%) than in macroangiopathy (70.0%, P0.001)
and also more common in macroangiopathic than in cardioembolic stroke (62.5%, P0.001). Diabetes mellitus was
more prevalent in microangiopathy (35.5%) than in stroke
due to large-artery atherosclerosis (29.0%, P0.002) or
cardioembolism (28.1%, P0.001) and relatively uncommon
in patients with combined other etiologies (9.4%). Hypercholesterolemia was particularly common in both microangiopathic stroke (44.0%) and macroangiopathic stroke (41.4%)
and least frequent in cardioembolism (27.8%) and combined
other etiologies (21.9%). Patients with stroke due to largeartery atherosclerosis most often affirmed current smoking
(37.6%) and smoked more often than did patients with
microangiopathy (25.9%, P0.001). Current smoking was
also common in combined other stroke etiologies (34.7%) but
infrequent in cardioembolism (17.6%) (Table 2).
Patients with large-artery atherosclerosis most often reported daily alcohol consumption (14.7%) and least often
reported complete alcohol abstinence (40.6%), whereas a
reverse pattern was found in patients with cardioembolism. A
normal body mass index (25) was most often present in
patients with combined other etiologies (50.3%) and least
frequent in patients with cerebral microangiopathy (36.5%).
Instead, stroke due to microangiopathy was most often
associated with severe obesity (body mass index 30,
17.7%). Coronary heart disease was particularly prevalent in
patients with concurrent etiologies (36.4%), whereas the rate
was similar in macroangiopathic (23.3%), cardioembolic
(29.5%), and microangiopathic (21.5%) stroke. Patients with
concurrent etiologies (12.4%) and those with large-artery

atherosclerosis (10.3%) most often had a concomitant diagnosis of peripheral arterial disease.

Stroke Severity, Complications, Mortality, and


Treatment Strategies
The neurological deficit on admission was most severe in
cardioembolism, least pronounced in microangiopathic
stroke, and of medium severity and similar distribution in the
other etiologies. Within the first week, recurrent cerebral
ischemic events occurred in 216 (4.3%) patients. Recurrent
ischemic stroke or TIA was most common in patients with
large-artery atherosclerosis (8.1%) and also occurred frequently in patients with concurrent etiologies (5.2%) and least
often in patients with cardioembolic stroke (2.8%). Secondary parenchymal hemorrhage was most prevalent in stroke of
unknown origin (2.6%) and in cardioembolic stroke (2.7%).
A similar proportion of patients with concurrent etiologies,
cardioembolism, and large-artery atherosclerosis required
treatment for severe hypertension (200/110 mm Hg). Epileptic seizures were uncommon in all subgroups and least
common in microangiopathic stroke (Table 3).
Mortality within 90 days amounted to 14.7% of all patients
with available follow-up assessment (n3529, 70.3% of all
patients). Mortality was highest in cardioembolic stroke
(22.6%) and lowest in microangiopathy (3.3%) and combined
other etiologies (9.3%). Similarly, good outcome (mRS 0 to
2) was most frequently reached by patients with microangiopathic stroke and stroke due to other etiologies, whereas a
poor outcome (mRS 4 to 5) was most common in patients
with cardioembolism, followed by those with macroangiopathy and concurrent mechanisms (Table 3).
Almost the same proportions of patients with cardioembolic stroke (31.1%), macroangiopathic stroke (29.3%), and

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Grau et al
TABLE 3.

Risk Factors in Subtypes of Ischemic Stroke

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Stroke Severity, Length of Hospitalization, Complications, and Outcome in Stroke Subtypes


Etiologic Subgroups of Ischemic Stroke

Macroangiopathy

Cardioembolism

Microangiopathy

Other
Etiologies

Concurrent
Etiologies

Unknown
Etiology

Total Group

NIH-SS on admission (median;


1st, 3rd quartile)

5; 3, 12

8; 4, 16

3; 2, 5

5; 2, 11

5; 3, 11

5; 2, 10

5; 3, 10

0.001

Length of stay (median; 1st,


3rd quartile), d

12; 7, 18

12; 7, 17

9; 5, 13

15; 9, 21

12; 7, 17

9; 5, 15

11; 6, 16

0.001

Recurrent ischemia

85 (8.1)

36 (2.8)

31 (3.0)

6 (3.4)

18 (5.2)

40 (3.5)

216 (4.3)

0.001

Parenchymal hemorrhage

11 (1.1)

35 (2.7)

1 (0.1)

4 (2.3)

6 (1.7)

30 (2.6)

87 (1.7)

0.001

Severe hypertension

84 (8.0)

96 (7.5)

62 (6.0)

7 (4.0)

28 (8.1)

66 (5.8)

343 (6.8)

Epileptic seizure

10 (1.0)

20 (1.6)

5 (0.5)

2 (1.1)

8 (2.3)

24 (2.1)

69 (1.4)

0.012

Intracranial pressure 1

85 (8.1)

114 (8.9)

1 (0.1)

13 (7.4)

21 (6.1)

84 (7.4)

318 (6.3)

0.001

720

910

732

118

232

817

3529

Parameter

Complications within 7 d, n (%)

Follow-up after 90 d, n
Deceased, n (%)

113 (15.7)

206 (22.6)

24 (3.3)

11 (9.3)

34 (14.7)

131 (16.0)

519 (14.7)

mRS 02, n (%)

379 (52.6)

427 (46.9)

536 (73.2)

83 (70.3)

127 (54.7)

467 (57.2)

2019 (57.2)

mRS 3, n (%)
mRS 45, n (%)

68 (9.4)

71 (7.8)

84 (11.5)

10 (8.5)

23 (9.9)

77 (9.4)

333 (9.4)

160 (22.2)

206 (22.6)

88 (12.0)

14 (11.9)

48 (20.7)

142 (17.4)

658 (18.6)

microangiopathic stroke (29.0%) and a slightly higher


proportion of patients with concurrent etiologies (36.0%)
had been treated with aspirin before ictus. Previous anticoagulation was particularly common in patients with
cardioembolism (8.0%) and in those with 1 probable
etiology (7.0%). Systemic thrombolysis was most often
used in cardioembolic stroke (6.5%) and only rarely in
patients with a final diagnosis of microangiopathy. Intravenous anticoagulation with heparin was most frequently
administered in patients with combined other etiologies
(36.0%) and in patients with cardioembolism (55.7%) but
only rarely in microangiopathy (18.8%). Similarly, oral
anticoagulants for long-term secondary prevention were
most often administered in patients with combined other
TABLE 4.

0.1

0.001
0.001

etiologies (50.6%) and in patients with cardioembolism


(44.8%). In contrast, almost all patients with microangiopathy (96.2%) and the vast majority of patients with
macroangiopathic stroke (73.7%) were treated with platelet inhibitors for secondary prevention (Table 4). A separate analysis including only the 6 centers with 95%
registration completeness did not show any relevant differences regarding stroke subtypes, age, sex, risk factors,
previous treatment, and stroke severity among subtypes
compared with the above analyses.

Discussion
The present study from a large multicenter hospital based
stroke data bank investigates the distribution of risk factors,

Treatment, Neurological Deficit, and Complications in Stroke Subtypes


Etiologic Subgroups of Ischemic Stroke

Parameter

Macroangiopathy

Cardioembolism

Microangiopathy

Other
Etiologies

Concurrent
Etiologies

Unknown
Etiology

Total Group

P*

306 (29.3)

399 (31.1)

298 (29.0)

17 (9.7)

124 (36.0)

274 (24.1)

1418 (28.3)

0.001

19 (1.8)

103 (8.0)

18 (1.8)

3 (1.7)

24 (7.0)

14 (1.2)

181 (3.6)

0.001

Previous treatment, n (%)


Aspirin
Anticoagulation
Acute treatment, n (%)
Local thrombolysis

16 (1.5)

9 (0.7)

1 (0.3)

8 (0.7)

34 (0.7)

0.34

Systemic thrombolysis

29 (2.8)

83 (6.5)

3 (0.3)

7 (4.0)

13 (3.8)

45 (4.0)

180 (3.6)

0.001

468 (44.7)

716 (55.7)

193 (18.8)

111 (63.4)

124 (36.0)

267 (23.5)

1879 (37.5)

0.001

Full-dose heparin

Secondary prevention on discharge, n (%)


Oral anticoagulation

111 (11.9)

500 (44.8)

23 (2.3)

79 (50.6)

73 (23.7)

40 (3.9)

826 (18.3)

0.001

Platelet inhibitors

693 (73.7)

408 (36.6)

950 (96.2)

51 (32.7)

201 (65.3)

876 (87.2)

3179 (70.5)

0.001

Full-dose heparin

85 (9.0)

133 (11.9)

5 (0.5)

10 (6.4)

21 (6.8)

30 (3.0)

284 (6.3)

0.001

None/others

51 (5.4)

74 (6.6)

10 (1.0)

16 (10.3)

13 (4.2)

59 (5.9)

223 (5.0)

0.001

*Adjusted for age and sex.


Because of missing data (n505), this analysis is based on only 4512 patients.

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2564

Stroke

November 2001

in-hospital complications, outcome, and treatment strategies


in different subtypes of ischemic stroke. Despite including
patients from both university and municipal hospitals in all
parts of Germany, the present study is not population-based;
therefore, certain limitations apply when interpreting its
results. However, precise and unselected clinical data of an
equally high number of patients can be obtained neither from
a population-based register nor from a clinical study.
According to an ongoing population-based stroke registry
in the city of Erlangen (Germany), almost 95% of all stroke
patients in Germany are admitted to the hospital for acute
treatment, and even in the elderly (aged 75 years), the
admission rate is 90%.4 Mean age in the present study was
69.8 years for women and 65.1 years for men and was thus
somewhat lower than in the Erlangen study (mean age 75.3
years for women and 69.7 years for men).4 Thus, our patients
are probably representative of all stroke patients except for
the oldest age groups. It is a shortcoming of the present study
that participating centers did not include all consecutive
patients into the data bank. Reasons given for not including a
patient were forgetfulness or lack of time of the treating
physicians, loss of questionnaires, early referrals, or misdiagnoses. Because 6 centers with a near complete inclusion
rate (95%) showed only minor differences regarding stroke
subtypes, age, sex, and risk factor distribution, the patients
included in the present study most likely represent a random
sample of all patients hospitalized in German neurology
departments with acute-stroke units. There is no reason to
believe that the ascertainment of risk factors differed between
stroke subtypes; therefore, the data bank lends itself to
investigate the association of risk factors with different stroke
subtypes, which was a main focus of the present study.
Despite many advantages, population-based stroke registries
have often lacked the power to detect differences between
stroke subtypes because of small sample size,1,2 a problem
that is overcome by the large number of patients in our
hospital-based data bank.
The TOAST criteria are a reliable tool to determine
etiologic subtypes of ischemic stroke.3 Using the TOAST
criteria, interphysician agreement was shown to be high for
stroke caused by cardioembolism and large-artery atherosclerosis but lower for stroke due to microangiopathy or stroke of
undefined etiology.5 Therefore, interrater variability and misclassification cannot be excluded in the present study. Among
the most difficult problems is the differentiation between
lacunar stroke and small subcortical infarcts due to embolism
or intracranial branch atheromatous occlusion.6 However,
ancillary tests were more frequently used in our patients than
in recent studies,2 a fact that strengthens the reliability of our
subtype classification.
Similar to a recently published population-based study in a
mainly white population2 but in contrast to several older
studies712 that used different stroke classifications and included different ethnical groups, the present study found
cardioembolism to be the most common etiology of stroke
(25.6%) in our almost exclusively white study population.
Cardioembolic stroke particularly dominated in the oldest age
group. This is most likely caused by the increase of atrial
fibrillation parallel to aging.1315 In contrast, large-artery

atherosclerosis was the most prevalent etiology in middleaged patients (aged 45 to 70 years). Despite the frequent use
of ancillary tests, the rate of unclassified stroke was still 23%,
a proportion that is smaller than in some studies2,16,17 but
comparable to many other studies.7,11,18
The present study shows a strong male preponderance in
stroke due to large-artery atherosclerosis and a less pronounced dominance of men in the other stroke subtypes, with
the striking exception of cardioembolic stroke, for which
slightly 50% of the patients were women, which can be
explained by the higher age in this subgroup. Unlike a
previous study2 but similar to the National Institute of
Neurological and Communicative Disorders and Stroke
(NINCDS) Stroke Data Bank,19 we found strong differences
in prior TIA rates among stroke subtypes, with macroangiopathic stroke being most often and cardioembolic stroke
being least frequently preceded by TIA. In contrast, the rate
of previous stroke was similar in macroangiopathic and
cardioembolic stroke. This is compatible with the hypothesis
that cardiac emboli particularly often lead to persistent vessel
occlusion and definite infarction.
Arterial hypertension, the single most frequent stroke risk
factor, showed a high prevalence in all stroke subtypes,
except for combined other etiologies. The results confirm the
hypothesis that hypertension and diabetes mellitus are more
common in microangiopathic stroke than in cardioembolism.
Our hypothesis that their prevalence is also higher in stroke
due to large-artery atherosclerosis is confirmed only for
hypertension but not for diabetes mellitus. In the NINCDS
Stroke Data Bank, hypertension and diabetes mellitus were
more common in lacunar and atherothrombotic stroke than in
cardioembolic stroke.19 In the Rochester Study,2 the prevalence of hypertension was not different among stroke subtypes, and diabetes mellitus was less common in atherothrombotic than in lacunar and cardioembolic stroke. The
Oxfordshire Community Stroke Project found no differences
between lacunar and cardioembolic stroke regarding hypertension or diabetes mellitus.1 Fisher20 originally suggested
that lacunar stroke was almost exclusively caused by smallvessel disease related to hypertension. Our results, based on
the largest sample size so far, support this concept by
indicating that hypertension and diabetes mellitus are more
closely associated with microangiopathic stroke than with
other stroke subtypes, although causality between risk factors
and stroke subtype cannot be inferred from our data. We
cannot exclude that the simultaneous presence of hypertension and diabetes mellitus may have influenced physicians
toward a diagnosis of cerebral microangiopathy in some
patients with doubtful etiology. However, with the TOAST
criteria applied, it appears unlikely that such ascertainment
bias could account for the whole effect detected.
Results for hypercholesterolemia as a stroke risk factor are
contradictory,21 and previous studies on stroke subtypes did
not include this risk factor. Our results indicate that hypercholesterolemia plays a role in some but not in other stroke
etiologies. The high prevalence in atherothrombotic stroke is
in line with a previous study that identified hypercholesterolemia as a risk factor for stroke due to large-artery atherosclerosis.21 Furthermore, our results allow us to generate the

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Grau et al
hypothesis that hypercholesterolemia is associated with
stroke due to cerebral microangiopathy. To the best of our
knowledge, such an association has not been reported so far,
and further studies are required to specifically investigate this
issue. In accordance with a recent Japanese study that
identified obesity as a risk factor for lacunar infarction in
women,22 we found a particularly high prevalence of obesity
in patients with microangiopathy.
The prevalence of current smoking was rather low among
our patients but comparable to that found in previous studies
in Germany.18,23 Our finding that smoking is mainly associated with stroke due to large-artery atherosclerosis is in
accordance with our own hypothesis and with previous
results.2,24,25 Smoking may furthermore contribute to uncommon etiologies in younger patients (eg, coagulopathy in
female smokers taking oral contraceptives) but appears to be
less important in other stroke subtypes. Smoking was not
unanimously identified as a risk factor for stroke by large
prospective studies.26,27 The different impact of smoking on
various subtypes of stroke may partly account for these
varying results. Several studies indicated a J- or U-shaped
association between alcohol consumption and carotid atherosclerosis, with light drinkers facing a lower risk than either
heavy drinkers or abstainers.28,29 In the present study, daily
alcohol consumption was most often reported by patients
with atherothrombotic stroke, supporting the hypothesis that
high intake of alcohol may be associated with atherogenesis.
Daily alcohol consumption was relatively infrequent in cardioembolic stroke, which may partly be explained by the
higher age of this subgroup.
Similar to studies that focused on atrial fibrillation,15,30,31
we found that cardioembolic stroke was associated with the
highest mortality and worst functional outcome after 90 days
and the most severe acute neurological deficit. Consequently,
thrombolytic therapy was most often administered in cardioembolism. The poor prognosis in cardioembolic stroke was
mainly caused by the index stroke, whereas early stroke
recurrence was low in these patients. In line with previous
studies, early stroke recurrence was most common in macroangiopathic stroke.2,17,32 The reason for this difference is
poorly understood. It could be argued that the frequent use of
anticoagulants may prevent further cardioembolic events,
whereas rapidly effective measures may not be available for
arterial embolism. However, results from recent studies do
not support this hypothesis.17 Instead, stroke due to largeartery atherosclerosis is particularly prone to procedurerelated cerebral ischemia, which may partly account for the
higher risk of recurrent ischemia in this subtype. As expected,
patients with lacunar stroke had the mildest deficits and the
best prognosis among all subtypes.33,34
One aim of modern stroke therapy is to tailor treatment and
secondary prevention to stroke etiology and individual conditions of the patient to optimize the risk-benefit ratio. The
results support our initial hypothesis that early and permanent
secondary prevention are adjusted to stroke etiology; eg, only
a few patients with a final diagnosis of microangiopathy
received intravenous and oral anticoagulants, whereas such
therapy was frequently used in patients with cardioembolism
or combined other etiologies. Despite the frequent use of

Risk Factors in Subtypes of Ischemic Stroke

2565

heparin early after stroke, the rate of secondary parenchymal


hemorrhage was rather low (1.7%), suggesting that physicians take into account contraindications and associated risks
of this therapy.
In conclusion, our results foster the concept of ischemic
stroke as a polyetiologic disease with profound differences
between subtypes regarding age and sex distribution, risk
factors, outcome, and current treatment strategies. Our findings support the hypotheses that both smoking and high
alcohol intake are associated mainly with stroke due to
large-artery atherosclerosis and suggest a particular link
between stroke from small-vessel disease, obesity, and hypercholesterolemia. However, to confirm any causality, our
findings require investigation in prospective studies. Therefore, future studies on risk factors of ischemic stroke should
differentiate between stroke etiologies to unmask the role of
particular risk factors (eg, smoking and hypercholesterolemia) for single subtypes.

Appendix
Participating Centers and Investigators of the
German Stroke Data Bank
Department of Neurology Klinikum Minden (J. Glahn, MD); Department of Neurology, Krankenhaus Mnchen-Harlaching (M.
Wimmer, MD); Department of Neurology, University of Essen (C.
Weimar, MD); Department of Neurology, University of Hamburg (S.
Neumaier, MD); Department of Neurology, University of Heidelberg
(P. Ringleb, MD); Department of Neurology, University of Leipzig
(D.S. Schneider, MD); Department of Neurology, Benjamin Franklin
University of Berlin (C. Koennecke, MD); Department of Neurology, Rheinische Landesklinik Bonn (C. Kley, MD); Department of
Neurology, Asklepiosklinik Bad Salzhausen (G.M. von Reutern,
MD); Department of Neurology, Klinikum Nrnberg Sd (G. Krzocek, MD); Department of Neurology, Klinikum Grohadern (G.F.
Hamann, MD); Department of Neurology, University of Regensburg
(T. Hlscher, MD); Department of Neurology, University of Rostock
(A. Kloth, MD); Department of Neurology, St. Katharinen-Hospital
Frechen (R. Adams, MD); Department of Neurology, University of
Greifswald (J. Machetanz, MD); Department of Neurology, Klinikum Charit Berlin (L. Harms, MD); Department of Neurology,
University of Magdeburg (M. Goertler, MD); Department of Neurology, University of Jena (J. Roether, MD); Department of Neurology, University of Tbingen (M. Fetter, MD); Department of
Neurology, University of Ulm (M. Riepe, MD); Department of
Neurology, Brgerhospital Stuttgart (O. Schwarz, MD); Department
of Neurology, Kliniken Gilead Bielefeld (A. Schacker, MD); and
Department of Neurology, University of Mnster (H. Henningsen,
MD).

Acknowledgments
We thank the Stiftung Deutsche Schlaganfall-Hilfe as well as the
following sponsors: Bayer, Bristol-Myers-Squib, Boehringer Ingelheim, Glaxo-Wellcome, Heinz-Nixdorf-Stiftung, Janssen-Cilag,
Knoll, Sanofi-Synthelabo, and Schering. This sponsorship was not
performed to identify patients for randomized trials.

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