Research Article: Outcome Predictors in First-Ever Ischemic Stroke Patients: A Population-Based Study
Research Article: Outcome Predictors in First-Ever Ischemic Stroke Patients: A Population-Based Study
Research Article: Outcome Predictors in First-Ever Ischemic Stroke Patients: A Population-Based Study
Research Article
Outcome Predictors in First-Ever Ischemic Stroke Patients:
A Population-Based Study
Giovanni Corso,1 Edo Bottacchi,1 Piera Tosi,1 Laura Caligiana,1 Chiara Lia,1
Massimo Veronese Morosini,2 and Paola Dalmasso3
1
Department of Neurology, Stroke Unit Ospedale Regionale, Viale Ginevra, No., 11100 Aosta, Italy
Statistics Department, Ospedale Regionale, Viale Ginevra 3, 11100 Aosta, Italy
3
Department of Scienze della Sanit`a Pubblica, Universit`a degli Studi di Torino, Via Verdi 8, 10124 Torino, Italy
2
1. Introduction
Ischemic stroke has many causes, clinical presentations, risk
factors, courses, and outcomes [1]. Management and prognosis of patients with ischemic stroke is directly related to
specific mechanisms of the ischemic stroke. In the acute
phase of stroke, the most important predictors of outcome are
stroke severity [2, 3] and patient age [4]. Severe strokes seem
to be more frequently caused by cardiac emboli and less frequently by large-artery occlusive mechanisms [5]. Functional
status prior to stroke onset, presence of comorbid medical
conditions [2, 69], cognitive impairment, and reduced consciousness at onset may also predict a worse prognosis after
stroke, although with weaker evidence. Few studies have systematically evaluated multimodal factors in unselected consecutive ischemic stroke patients. The aim of this study is to
2. Methods
The Cerebrovascular Aosta Registry (CARe) is a populationbased registry recording first-ever strokes in all age groups
for a geographically defined area, the Aosta Valley, Italy. The
overall study design hasbeen published previously [10, 11]. We
prospectively checked all cases for diagnosis from overlapping sources. No selection of patients was performed with
2
regard to age, stroke severity, or comorbid medical conditions
before admission. Patients with recurrent stroke, intracerebral or subarachnoid hemorrhage, subdural hematoma, or
other causes mimicking stroke (trauma, infection or an intracranial malignant processes) were excluded. Hospital care is
free, and a very high proportion (92.5%) of stroke patients
were admitted to hospital.
The aims of this study were to determine the characteristics of patients who initially presented with ischemic stroke,
and to identify predictors of stroke severity and long-term (all
cause) mortality.
We retrieved medical history prior to the index stroke and
the CHADS2 score [12] was calculated for all patients. The following variables were analysed: gender, age (categorized as
<65, 6574, 7584, and 85), domestic arrangements (lives
with others, alone, or in a community), clinical history, and
medications. Vascular risk factors included history of hypertension, diabetes mellitus, ischemic heart disease (acute myocardial infarction, angina, or coronary revascularisation), low
ejection fraction, transient ischemic attack (TIA), current
or former smoking, hypercholesterolemia, and AF, either
as a history of AF and/or AF diagnosed during the index
admission with stroke by electrocardiography (ECG) and/or
24 hour ECG monitoring. At admission, patients were categorized as treated or nontreated with antithrombotic agents.
Patients with AF were considered as treated when they were
receiving the following treatments: antiplatelet drugs and had
CHADS2 score from 0 to 1; warfarin therapy with INR 2.0 to
3.0 at the time of stroke and had CHADS2 2. Comorbidity
conditions in patients admitted with acute ischemic stroke
were scored with the modified Charlson Index (CI) on the
basis of hospital discharge ICD-9CM codes [13] and patient
history obtained from standardized case report forms. A
weight was assigned to each indicated diagnosis and each
weight was added together to calculate the CI score. The
score varied according to the severity of the disease: myocardial infarction, congestive heart failure, peripheral vascular
disease, dementia, chronic pulmonary disease, connective
tissue disease, ulcer disease, mild liver disease, and diabetes
mellitus were weighted 1; diabetes with end-organ damage,
moderate to severe renal disease, nonmetastatic solid tumor,
leukaemia, lymphoma, and multiple myeloma were weighted
2; autoimmune deficiency syndrome and metastatic solid
tumor were weighted 6. The CI score was dichotomized (low
comorbidity 1 versus high 2). Prestroke disability was assessed by the modified Rankin scale (mRS) [14].
Stroke was defined according to the World Health Organisation (WHO) criteria [15]. Ischemic stroke was diagnosed
with a combination of clinical criteria and brain imaging.
All patients underwent brain CT scan without contrast upon
admission to exclude intracerebral hemorrhage.
Follow-up MRI examination or brain CT scan was repeated 2 to 5 days after the index event. Stroke severity was evaluated in the acute phase of the initial stroke by a neurologist
certified in the use of the National Institute of Health Stroke
Scale (NIHSS). Stroke severity by NIHSS was categorized
as mild (04), moderate (515), or severe (1642). Stroke
subtypes were defined using the Trial of ORG 10172 in
Acute Stroke Treatment (TOAST) criteria [16]. Metabolic,
3. Data Analysis
Differences in patient characteristics, premorbid risk factors,
and hospital investigations were assessed by 2 test (for
categorical variables) or analysis of variance (for continuous
variables).
The variables analysed were age, gender, body mass index
(BMI), life conditions, prestroke dependency, comorbidities,
NIHSS at admission, vascular risk factors, therapy prior to
stroke, pathophysiologic and metabolic factors.
Multivariate logistic regression models were used to estimate the impact of possible determinants of stroke severity at
admission. Differences between groups and effect of patient
characteristics on clinical outcome were assessed using Chisquare test. Cox regression model was used to estimate the
impact of possible determinants of survival.
Kaplan-Meier survival curves were generated to demonstrate the effect of determinants on long-term survival.
Statistical tests were considered significant when the
value was 0.05. Statistical analyses were performed using
STATA software version 10.
4. Results
The present analysis focused only on patients with first-ever
ischemic stroke, 1057 cases, registered between January 1,
2004, and December 31, 2008. Of these, 260 patients presented AF, of whom 235 (90%) were known to have AF and 25
(10%) were diagnosed with AF during admission. The mean
age of all patients was 75.7 (SD, 12.7) years. The mean age
in the AF group was 80.8 years (SD, 10.1), and 74 years (SD,
13.1) in the non-AF group ( < 0.001). At admission, only 27
(10.5%) patients with AF were adequately treated according
to the current guidelines. Nineteen patients had contraindication to oral anticoagulants because of frequent falls, severe
bleeding, and dementia.
Patient characteristics at time of initial stroke are presented in Table 1.
Table 1: Selected characteristics in the acute phase of 1057 patients with first-ever ischemic stroke.
Number of patients
Gender female
Mean body mass index
Median age (interquartile range)
Life conditions
Lives with other (family)
Lives alone
Lives in community
Missing
Vascular risk factors
Arterial hypertension
Diabetes mellitus
Hypercholesterolemia
Previous TIA
Current or former smoker
Ischaemic heart disease
Atrial fibrillation
Low ejection fraction (<35%)
CHADS2 score
0-1
2
Charlson Index score
0-1
2
Missing
Prestroke disability (measured with mRS)
02
35
Missing
Home therapy
Treated with antithrombotic agents
Nontreated with antithrombotic agents
Statins
Antihypertensive
Stroke onset during sleep
Metabolic values at admission
Glucose (mg/dL)
LDL cholesterol (mg/dL)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
TOAST classification of subtypes
Large-artery atherosclerosis
Cardioembolism
Small-vessel occlusion lacun
Stroke of undetermined etiology
NIH 04
426
199 (46.7%)
25.5 (25.4-25.5)
74.12 (64.680.4)
NIH 515
469
240 (51.2%)
25.22 (25.1-25.2)
79.3 (72.385.3)
NIH 16
162
105 (64.8%)
24.3 (24.2-24.3)
83.5 (74.289.9)
Total
1057
544 (51.5%)
25.2 (24.925.5)
77.5 (6984.4)
330 (77.4%)
86 (71.4%)
7 (5.7%)
3 (2.5%)
320 (68.2%)
118 (25.1%)
27 (5.7%)
4 (1%)
105 (64.8%)
38 (8.1%)
16 (3.4%)
3 (0.7%)
755 (71.4%)
242 (22.9%)
50 (4.7%)
10 (1%)
0.002
0.38
<0.0001
322 (75.6%)
74 (33.1%)
170 (39.9%)
25 (5.8%)
89 (20.9%)
50 (11.7%)
56 (13.1%)
21 (4.9%)
362 (77.2%)
103 (21.9%)
147 (31.3%)
27 (5.7%)
59 (12.6%)
63 (13.4%)
127 (27.1%)
45 (9.6%)
118 (72.8%)
23 (14.2%)
34 (21%)
9 (5.5%)
19 (11.7%)
21 (13%)
77 (47.5%)
20 (12.3%)
802 (75.9%)
200 (18.9%)
351 (33.2%)
61 (5.8%)
167 (15.8%)
134 (12.7%)
260 (24.6%)
86 (8.1%)
0.49
0.35
<0.0001
0.88
0.011
0.68
<0.0001
0.002
68 (16%)
358 (84%)
35 (7.5%)
434 (92.5%)
20 (12.4%)
142 (87.6%)
123 (11.6%)
934 (88.4%)
0.3
0.2
336 (78.8%)
58 (13.6%)
32 (7.6%)
345 (73.5%)
98 (20.9%)
26 (5.6%)
128 (79%)
24 (14.8%)
10 (6.2%)
809 (76.5%)
180 (17%)
68 (6.5%)
0.9
0.7
0.57
404 (94.8%)
18 (4.2%)
4 (1%)
369 (78.7%)
93 (19.8%)
7 (1.5%)
117 (72.3%)
42 (25.9%)
3 (1.8%)
890 (84.2%)
153 (14.6%)
14 (1.2%)
<0.0001
<0.0001
0.36
123 (28.8%)
303 (71.2%)
38 (8.9%)
242 (56.8%)
71 (16.6%)
135 (28.8%)
334 (71.2%)
20 (4.3%)
258 (55%)
109 (23.2%)
49 (30.2%)
113 (69.7%)
4 (2.5%)
85 (52.5%)
39 (24.1%)
307 (29%)
750 (71%)
62 (5.9%)
585 (55.4%)
219 (20.7%)
0.74
0.74
0.76
0.34
0.04
114.2 (40.1)
117.3 (37.6)
152.4 (24.3)
87.3 (12.1)
125 (54.7)
112.6 (36.2)
150.3 (24.1)
86 (11.6)
126.4 (50.4)
102.1 (41.8)
149.6 (24.6)
85.4 (12.4)
120.9 (48.9)
113.4 (37.7)
151 (24.5)
86.43 (11.9)
0.0012
<0.0001
0.11
0.044
66 (15.5%)
65 (15.2%)
109 (25.6%)
175 (41.1%)
73 (15.5%)
122 (26%)
97 (20.7%)
173 (36.9%)
14 (8.6%)
79 (48.8%)
4 (2.5%)
64 (39.5%)
153 (14.5%)
266 (25%)
210 (20%)
412 (39%)
0.032
<0.0001
<0.0001
0.7
0.0001
0.0004
<0.0001
Data are shown as number of patients (%) or mean (SD); TIA: transient ischaemic attack; mRS: modified Rankin scale; NIHSS: National Institute of Health
Stroke Scale. CHADS2: Congestive heart failure, hypertension, age, diabetes mellitus, TIA, or thromboembolism. statistical analysis was performed on the
NIHSS 04 and the NIHSS 16 groups. Variables included in the multivariate logistic regression analysis.
95% CI
1.212.40
1.755.06
1.724.44
1.134.32
1.362.93
0.0025
0.0001
<0.0001
0.0129
0.0004
5. Discussion
In this population-based study, on first-ever ischemic stroke
patients, we demonstrated that risk factors such as very old
age, AF, and cardioembolic stroke have an impact on neurologic impairment as evaluated in the acute phase and on
long-term mortality. The majority of these factors are associated with high risk cardioembolic conditions. In the present
study, very old age was found to be an independent predictor
of stroke severity at admission. There have not been many
community-based estimates of gender and older age as significant independent predictors of stroke severity, whereas very
old age per se was found to be a strong predictor of outcome
and mortality after stroke [18] and older age of patients with
AF has been postulated as a major contributing factor for
poor prognosis [5]. Female gender has been shown to have
more severe strokes than men, as already reported in a previous review [19]. Conversely, our previous results showed that
female patients were older and suffered more frequently from
AF [11]; hence, female patients generally had a more severe
stroke. We found cardioembolism to be the most common
etiology of stroke (25.1%) in our almost exclusively white
study population and cardioembolic stroke particularly dominated in the oldest age group. AF-related strokes are expected
to increase due to population aging, because it is known the
increase of AF with age [4, 6]. In our study, the mean age of
patients with AF was older than in other studies [2, 20]. The
well-documented impact of AF on the prognosis of first-ever
ischemic stroke [2, 2022] is confirmed in this investigation.
Previous studies have reported that stroke patients with AF
present more often large cortical infarcts, and less frequently
lacunar infarction compared with patients without AF [2, 3,
5]. This may be explained by the size of cardiac emboli as well
as by the lack of collateral vascularization, which may develop
and compensate for acute arterial occlusion in patients with
gradual occlusion of arteries, such as in atherosclerosis of
cervical or cerebral arteries.
In this population study, most patients admitted with a
stroke who had previously a diagnosis of AF were suboptimally anticoagulated before their stroke and only 10% of
patients with a history of AF were receiving an adequate
antithrombotic treatment prior to stroke. Other Italian studies on hospital admitted patients have reported underutilization of oral anticoagulant in patients with AF [23, 24]. Anticoagulation treatment is highly dependent on single patient
characteristics such as age, comorbidities, patients lifestyle,
and feasibility of adequate monitoring of therapy [25]. The
high percentage of nontreated patients is likely attributable
to the older age of our population, being anticoagulation
treatment difficult to control and to manage.
Several factors influenced long-term mortality among
which prestroke dependency and comorbidities, more common in the elderly population. Prestroke mRS score 35 and a
CI score >2 were found to be statistically significant independent factors of long-term mortality among first-ever stroke
ischemic patients.
Many of the identified predictors of long-term mortality
have been already reported in previous studies [3, 5, 18, 26
30] but hypertension, diabetes, or smoking. Hyperglycemia at
the time of the index stroke was not associated with a worse
outcome.
The strength of the present study is due to a communitybased design and due to the use of rigorous case ascertainment procedures to enroll all patients with first-ever ischemic
stroke. Complete case ascertainment allowed precise estimation of the prevalence of the risk factors among our patients.
However, the limitations of our study must also be recognized: the Aosta Valley population is predominantly Caucasian, which may limit the possibility to generalize our findings to other ethnic groups, in whom the risk of AF and
other risk factors may differ; the use of prestroke mRS is not
standardized, because the mRS was designed and validated
5
Sex
1.0
0.9
0.9
0.8
0.8
Cumulative survival
Cumulative survival
Age
1.0
0.7
0.6
0.5
0.4
0.3
0.7
0.6
0.5
0.4
0.3
0.2
0.2
P < 0.001
0.1
P = 0.076
0.1
0.0
0.0
0
3
4
5
Time to death (years)
064
6574
7584
85
(b)
Prestroke disability
Comorbidity
1.0
1.0
0.9
0.9
0.8
0.8
Cumulative survival
Cumulative survival
Men
Women
(a)
0.7
0.6
0.5
0.4
0.3
0.2
0.7
0.6
0.5
0.4
0.3
0.2
0.1
P < 0.0001
0.1
P < 0.0001
0.0
0.0
0
3
4
5
Time to death (years)
mRS 2
mRS 3
3
4
5
Time to death (years)
CI < 2
CI 2
(c)
(d)
Atrial fibrillation
1.0
1.0
0.9
0.9
0.8
0.8
Cumulative survival
Cumulative survival
3
4
5
Time to death (years)
0.7
0.6
0.5
0.4
0.3
0.2
0.6
0.5
0.4
0.3
0.2
P = 0.0289
0.1
0.7
P < 0.001
0.1
0.0
0.0
0
3
4
5
Time to death (years)
No
Yes
3
4
5
Time to death (years)
No
Yes
(e)
(f)
Figure 1: Continued.
1.0
1.0
0.9
0.9
0.8
0.8
Cumulative survival
Cumulative survival
Stroke severity
0.7
0.6
0.5
0.4
0.3
0.7
0.6
0.5
0.4
0.3
0.2
0.2
0.1
0.1
P < 0.0001
0.0
0
P < 0.0001
0.0
(g)
Lacunar
Undefined
(h)
Figure 1: Kaplan-Meier survival curves indicating the relationship of (a) age, (b) sex, (c) prestroke disability (evaluated by mRS), (d)
comorbidity (evaluated by Charlson Index, CI), (e) ischemic heart disease, (f) atrial fibrillation, (g) stroke severity, and (h) stroke subtypes
with all-cause mortality after ischemic stroke.
Age (year)
Risk factor
mRS before stroke
Charlson Index
Cardioembolism
Large-artery atherosclerosis
Small-vessel occlusion
Stroke of undetermined etiology
Male
Female
<65
6574
7584
85
Total
04
515
16
AF yes
AF no
0-1
2
0-1
2
Mortality at 28 days
48 (9.3%)
66 (12.1%)
7 (4.4%)
17 (6.4%)
44 (11.1%)
46 (19.6%)
114 (10.8%)
4 (0.9%)
41 (8.7%)
69 (42.6%)
48 (18.5%)
66 (8.3%)
84 (9.6%)
30 (16.6%)
84 (9.3%)
30 (19.6%)
50 (18.8%)
10 (6.5%)
2 (0.9%)
51 (12.4%)
Mortality at 1 year
145 (28.3%)
122 (22.4%)
16 (10%)
39 (14.5%)
108 (27.3%)
104 (44.4%)
267 (25.2%)
35 (8.2%)
118 (25.1%)
114 (70.4%)
115 (44.2%)
152 (19.1%)
196 (22.3%)
71 (39.4%)
185 (20.4%)
82 (53.6%)
113 (42.5%)
28 (18.3%)
13 (6.2%)
112 (27.2%)
Mortality at 5 years
236 (46%)
277 (50.9%)
35 (22%)
77 (28.8%)
209 (53%)
192 (81.6%)
513 (48.5%)
133 (31.2%)
245 (52.2%)
135 (83.3%)
183 (70.4%)
330 (41.4%)
388 (44.2%)
125 (69.4%)
392 (43.4%)
121 (79.1%)
175 (65.8%)
71 (46.4%)
73 (34.2%)
193 (46.8%)
Alive
277 (54%)
267 (49.1%)
125 (78%)
191 (71.2%)
186 (47%)
42 (18.4%)
544 (51.5%)
293 (68.8%)
224 (47.8%)
27 (16.7%)
77 (29.6%)
467 (58.6%)
489 (55.8%)
55 (30.6%)
512 (56.6%)
32 (20.9%)
91 (34.2%)
82 (53.6%)
137 (65.8%)
219 (53.2%)
0.076
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
Data are shown as number of patients (%); mRS: modified Rankin scale; NIHSS: National Institute of Health Stroke Scale.
Covariate
Age 85
Rankin before stroke 35
Charlson index 2
AF
NIHSS 16
Large-artery atherosclerosis
Cardioembolism
Small-vessel occlusion
Stroke of undetermined etiology
2.02
1.82
1.97
1.43
3.54
4.90
5.39
3.87
5.91
1.652.47
1.462.26
1.612.42
1.041.98
2.874.36
0.6835.10
0.7439.10
0.5427.76
0.8341.89
<0.0001
<0.0001
<0.0001
0.0302
<0.0001
0.1144
0.0966
0.1789
0.0764
Ethical Approval
The study was approved by the Ethics Committee of Aosta
Valley.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
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