Journal of the Neurological Sciences 252 (2007) 53 56

www.elsevier.com/locate/jns

Beta-blockers reduce the risk of early death in ischemic stroke

Tomasz Dziedzic , Agnieszka Slowik, Joanna Pera, Andrzej Szczudlik
Department of Neurology, Jagiellonian University, Botaniczna 3, 31-503 Krakow, Poland
Received 22 May 2006; received in revised form 4 October 2006; accepted 10 October 2006
Available online 28 November 2006

Abstract
Objectives: Beta-blockers reduce mortality in patients after myocardial infarction. Experimental studies suggest that beta-blockers have also
neuroprotective properties. The aim of this study was to assess if use of beta-blockers is associated with reduced risk of early death in
ischemic stroke patients.
Materials and methods: Retrospective data analysis of 841 consecutive patients with acute ischemic stroke admitted to the stroke unit within
24 h after stroke onset.
Results: 10.6% of patients received beta-blockers during hospitalization. Thirty-day case fatality was significantly lower in patients treated
with beta-blockers than in those not treated with beta-blockers (6.8% versus 19.0%, Pb0.01). After adjustment for other prognostic factors,
the use of beta-blockers was associated with reduced risk of early death (relative hazard 0.37, 95% confidence interval 0.160.84)
independently of age, stroke severity, fasting glucose, total cholesterol level and pneumonia. When patients who died of cardiovascular
causes were excluded from the analysis, the use of beta-blocker was no longer significantly associated with risk of death (P = 0.12).
Conclusion: In a retrospective series the use of beta-blockers was associated with reduced risk of early death in patients with ischemic stroke.
2006 Elsevier B.V. All rights reserved.
Keywords: Beta-blockers; Cerebral infarction; Mortality; Stroke

1. Introduction

2. Materials and methods

Many studies have demonstrated the cardioprotective

properties of beta-blockers in patients who survived an acute
myocardial infarction [1]. Beta-blockers are effective in
long-term secondary prevention after myocardial infarction
reducing mortality and morbidity [2]. Results of experimental studies suggest that older (propranolol) and newer
(carvedilol) beta-blockers could be neuroprotective against
glutamate-induced cell death and against focal cerebral
ischemia by inhibiting apoptosis and attenuating inflammatory reaction [37].
The aim of our study was to assess if use of beta-blockers
in acute phase of ischemic stroke is associated with reduced
the risk of early death.

We analyzed retrospectively our stroke database. Patients

to this study were recruited from 841 consecutive patients
with ischemic stroke admitted to our stroke unit within 24 h
after stroke onset in years 19941997. We choose that time
period, because in years 19941997 we have collected
information about beta-blockers use and 30-day case fatality
for all patients. For patients who died after discharge from
the hospital, the information about 30-day case fatality and
cause of death were taken from official registry of town. In
all cases the cause of death was established by physician.
Cerebral infarction was defined as a focal neurological
deficit of sudden onset that persisted beyond 24 h,
documented by a brain CT or an MRI indicating the
presence of infarction and the absence of hemorrhage. Stroke
was classified according to the system used by the Oxford
Community Stroke Project [8]. This describes patients as
having total anterior circulation infarction (TACI), partial

Corresponding author. Tel.: +48 12 424 86 00; fax: +48 12 424 86 26.
E-mail address: Dziedzic@cm-uj.krakow.pl (T. Dziedzic).
0022-510X/$ - see front matter 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2006.10.007

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T. Dziedzic et al. / Journal of the Neurological Sciences 252 (2007) 5356

anterior circulation infarction (PACI), posterior circulation

infarction (POCI), or lacunar infarction (LACI).
Arterial hypertension was diagnosed when its presence was
documented in medical records or when at least 2 readings of
blood pressure were 160 mm Hg (systolic) or 90 mm Hg
(diastolic) after the acute phase of stroke. Ischemic heart
disease was diagnosed when there was a history of angina
pectoris or myocardial infarction. Diabetes mellitus was diagnosed if its presence was documented in medical records or
patient was taking insulin or an oral hypoglycemic agents. A
patient was defined as a smoker if there was a history of
cigarette smoking during the last 5 years.
All patients underwent head CT within 24 h after stroke
onset. Stroke severity on admission was assessed using Scandinavian Stroke Scale (SSS) [9].
Glucose, total cholesterol and its fraction were measured
in blood samples taken from fasting patients on the morning
after admission.
No patient underwent thrombolysis because this form of
treatment was not registered in Poland during the study
period. No patient underwent carotid endarterectomy within
30 days after stroke onset.
The causes of death were classified into 4 groups: (1) deaths
resulting from first-ever stroke were due to the direct effects of
the brain lesion or complications of resulting immobility,
including deaths from bronchopneumonia; (2) deaths resulting
from recurrent stroke were due directly to the brain lesion or
complications of immobility; (3) deaths caused by cardiovascular events were those from myocardial infarction, heart
failure or sudden death; (4) deaths from other causes (cancer,
injuries etc.) or deaths of undetermined causes.
The 2 test was used to compare proportions and Student's
t test to compare continuous variables between groups.
Cumulative survival plots were calculated by the Kaplan
Meier statistics to evaluate survival in patients treated with
beta-blockers versus patients not treated with beta-blockers.
On univariate analysis the odds ratios of death were calculated
for the following variables: age, sex, vascular risk factors
(hypertension, diabetes mellitus, atrial fibrillation, ischemic
heart disease, history of myocardial infarction, smoking, history of transient ischemic attack), biochemical parameters
(fasting glucose, total cholesterol, triglycerides), stroke severity on admission (SSS score), systolic and diastolic blood
pressure on admission, stroke subtype (with LACI as
reference), pneumonia, drugs (beta-blockers, angiotensin converting enzyme-inhibitors, heparin). Logistic regression
analysis and Cox proportional hazards model was used to
assess the independent contribution of variables statistically
significant on univariate analysis in the prediction of death.
Before the logistic regression was applied, multicolinearity
among selected variables was assessed. Age, SSS score,
fasting glucose, total cholesterol were put into logistic
regression model as continuous variables. Age did not satisfy
the proportionality assumption and was entered into Cox
proportional hazards model as a dichotomous variable
(b 85 years versus 85 years); SSS score, fasting glucose

and total cholesterol were put into that model as continuous

variables. No colinearity was found between the selected
variables. Values of P b 0.05 were considered statistically significant. The calculations were performed using the commercial statistical package STATISTICA for Windows, v.6.0
(StatSoft, Inc).

Table 1
Characteristics of stroke patients treated with beta-blockers and those not
treated with beta-blockers

Age, mean (SD)

Men, n (%)
Hypertension, n (%)
Diabetes mellitus, n (%)
Ischemic heart disease,
n (%)
Myocardial infarction, n
(%)
Atrial fibrillation, n (%)
Smoking, n (%)
TIA, n (%)
Pneumonia, n (%)
Fasting glucose (mmol/
l), mean (SD)
TC (mmol/l), mean (SD)
TG (mmol/l), mean
(SD)
LDL (mmol/l), mean
(SD)
HDL (mmol/l), mean
(SD)
SSS score on admission,
median (quartile)
Systolic blood pressure
on admission (mm
Hg), mean (SD)
Diastolic blood pressure
on admission (mm
Hg), mean (SD)
Stroke subtype, n (%)
TACI
PACI
LACI
POCI
Undetermined
ACE inhibitors, n (%)
Heparin a, n (%)
30-day case fatality, n
(%)
Cause of death:
First-ever stroke, n
Recurrent stroke, n
Cardiovascular, n
Other, n

Patients treated
Patients not treated
with beta-blockers with beta-blockers
(N = 88)
(N = 745)

67.2 (12.1)
39 (44.3)
72 (81.8)
13 (14.8)
61 (69.3)

69.9 (12.7)
350 (47.0)
494 (66.3)
162 (21.7)
427 (57.3)

0.03
0.64
b0.01
0.12
0.03

22 (25.0)

87 (11.7)

b0.01

25 (28.4)
21 (23.9)
10 (11.4)
4 (4.5)
6.0 (2.5)

149 (20.0)
196 (26.3)
60 (8.0%)
85 (11.4)
6.4 (2.4)

0.08
0.62
0.30
0.05
0.06

5.4 (1.7)
1.5 (1.1)

5.4 (1.3)
1.5 (1.2)

0.85
0.67

3.4 (1.1)

3.4 (1.1)

0.92

1.3 (0.3)

1.4 (0.5)

0.52

36.0 (23.043.5)

34.0 (20.043.0)

0.32

162 (33)

161 (29)

0.64

95 (18)

94 (16)

0.39

17 (19.3)
47 (53.4)
15 (17.0)
9 (10.2)
0 (0)
53 (60.2)
17 (19.3)
6 (6.8)

108 (14.5)
394 (52.9)
145 (19.5)
94 (12.6)
4 (0.5)
255 (34.2)
56 (7.5)
141 (18.9)

4
0
2
0

56
2
82
1

0.68

b0.01
b0.01
b0.01

0.30
0.01

ACE: angiotensin converting enzyme; TIA: transient ischemic attack; TC: total
cholesterol; TG: triglycerides; LDL: low density lipoproteins cholesterol;
HDL: high density lipoproteins cholesterol; SSS: Scandinavian Stroke Scale;
TACI: total anterior circulation infarction; PACI: partial anterior circulation
infarction; POCI: posterior circulation infarction; LACI: lacunar infarction.
a
Unfractionated intravenous heparin and low-molecular-weight heparins.

T. Dziedzic et al. / Journal of the Neurological Sciences 252 (2007) 5356

3. Results
In years 19941997 we hospitalized 841 patients with
ischemic stroke admitted to our stroke unit within 24 h after
stroke onset. Eight patients had inadequate data for analysis
because of immediate death. Thus, complete data were
available for 833 patients (mean age: 69.6 12.6; 46.7% men).
Eighty eight from 833 (10.6%) patients received betablockers during hospitalization. 94.3% of them were treated
with beta-blocker before admission. These patients continued therapy with beta-blockers during acute phase of stroke.
The patients treated with beta-blockers were significantly
younger and more often suffered from hypertension and
ischemic heart disease and had history of myocardial
infarction than those who did not receive beta-blockers.
The characteristics of both group are shown in Table 1.
30-Day case fatality was significantly lower in patients
receiving beta-blockers than in those who did not receive
beta-blockers (6.8% versus 19.0%, P b 0.01). Fig. 1 shows
the KaplanMeier cumulative survival curves for patients
treated and those not treated with beta-blockers. The use of
beta-blockers was associated with reduced risk of death
caused by cardiovascular events (myocardial infarction,
heart failure, or sudden death) (2.3% of 88 patients versus
11.0% of 745 patients, P = 0.01).
On univariate analysis the following variables were
significantly associated with risk of early death: age (OR:
1.04 per 1 year increase, 95% CI: 1.021.06), ischemic heart
disease (OR: 1.97, 95% CI: 1.332.91), atrial fibrillation

55

(OR: 1.97, 95% CI: 1.322.94), smoking (OR: 0.44, 95%

CI: 0.270.72), SSS score on admission (OR: 0.92 per 1
point increase, 95% CI: 0.910.93), TACI (OR: 3.01, 95%
CI: 1.964.62), fasting glucose (OR: 1.21 per 1 mmol/
l increase, 95% CI: 1.131.30), total cholesterol level (OR:
0.76 per 1 mmol/l increase, 95% CI: 0.650.88), pneumonia
(OR: 5.72, 95% CI: 3.599.12) and therapy with betablockers (OR: 0.32, 95% CI: 0.130.74). In logistic
regression analysis greater age (OR: 1.02, 95% CI: 1.00
1.04), higher fasting glucose (OR: 1.12, 95% CI: 1.021.22)
and pneumonia (OR: 2.15, 95% CI: 1.173.95) remained
independently associated with increased risk of early death,
whereas greater SSS score on admission (OR: 0.93, 95% CI:
0.920.95), higher total cholesterol level (OR: 0.82, 95% CI:
0.680.98) and therapy with beta-blockers (OR: 0.31, 95%
CI: 0.100.96) were independently associated with decreased risk of early death. In the Cox proportional hazard
model, SSS score on admission (HR: 0.94, 95% CI: 0.93
0.95), fasting glucose (HR: 1.08, 95% CI: 1.031.14), total
cholesterol level (HR: 0.83, 95% CI: 0.730.95), pneumonia
(HR: 1.63, 95% CI: 1.132.37) and therapy with betablockers (HR: 0.37, 95% CI: 0.160.84) were independent
predictors of early death.
When patients who died of cardiovascular causes were
excluded from the analysis, the use of beta-blocker was no
longer significantly associated with risk of death (OR: 0.48,
95% CI: 0.191.23) and log-rank test did not show the
difference in survival between groups (P = 0.07). In patients
with cardiovascular death, the use of angiotensin converting
enzyme-inhibitors (HR: 0.56, 95% CI: 0.320.98) was the
only independent predictor of death in the Cox proportional
hazard model.
4. Discussion

Fig. 1. KaplanMeier cumulative survival curves for stroke patients treated

with beta-blockers and those not treated with beta-blockers.

We found that therapy with beta-blockers significantly

reduced 30-day case fatality in patients with ischemic stroke.
There is no established biological mechanism that explains
completely the beneficial effect of beta-blockers during
ischemic stroke. The results of our study suggest that betablockers decrease the risk of death in stroke patients by
reducing number of deaths due to cardiovascular events such
as myocardial infarction, heart failure or sudden death. When
we excluded from the analysis patients who died of
cardiovascular causes, the therapy with beta-blocker was no
longer significantly associated with risk of death, however, the
statistical trend towards lower mortality in patients using betablockers still remained (log-rank test: P = 0.07). Other
mechanisms explaining the effect of beta-blockers on risk of
death during stroke should also be taken into account. First
beta-blockers could attenuate sympathetic activation that is a
predictor of poor outcome in stroke patients [10]. Second
pneumonia in stroke patients is associated with a threefold
increased risk of 30-day mortality [11]. In a mouse model of
cerebral ischemia stroke induces immunodeficiency that
predisposes animals to septicemia and pneumonia by impaired

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T. Dziedzic et al. / Journal of the Neurological Sciences 252 (2007) 5356

synthesis of interferon gamma [12]. Administration of

propranolol which blocks the sympathetic nervous system,
drastically reduced mortality after stroke by preventing
immunodeficiency. In our study patients treated with betablockers less often developed pneumonia than those not
treated with beta-blockers (4.5% versus 11.4%, P = 0.05).
However, on multivariate analysis the therapy with betablockers and pneumonia independently from each other
predicted risk of death. Third beta-blockers may show
neuroprotective properties including anti-oxidative and antiinflammatory effects [37]. Fourth patients treated with
beta-blockers could have better control of hypertension,
however the systolic and diastolic blood pressure on admission
did not differ significantly between groups. Fifth patients
treated with beta-blockers more often took angiotensin
converting enzyme-inhibitors, drugs which could influence
stroke outcome [13]. In our study the use of angiotensin
converting enzyme-inhibitors did not influence case fatality
(P = 0.76 on univariate analysis).
The major limitation of our study is its retrospective
character. We did not collect information about use of
diuretics, calcium channel blockers or statins. Particularly,
statin use may improve stroke outcome [1416], albeit to
date no study has demonstrated that use of these drugs is an
independent predictor of early death in ischemic stroke
patients. The patients treated with beta-blockers more often
suffered from ischemic heart disease and myocardial
infarction. It is likely that these patients have been prescribed
statins what could influence our final results.
The possible limitations of our study are also related to
study period selected by us. The study data were evaluated
between 1994 and 1997. At that time thrombolysis was not
registered for in Poland as a treatment of acute stroke. Also
no patients with severe carotid stenosis underwent endarterectomy within 30 days after stroke onset, mainly due to
limited access to specialized vascular surgery units and due
to policy of surgeons to postpone that procedure beyond first
month of stroke.
Since the majority of our patients took beta-blockers
before stroke, it is unclear if beneficial effect of these drugs is
related to their use in acute phase of stroke or to pretreatment. Taking into results of cardiological studies
showing that short-term beta-blockade immediately after
myocardial infraction seems to be of little benefit unless
treatment is continued long term, it is more likely that pretreatment rather than treatment with beta-blockers in acute
phase of stroke exerts beneficial effect [2]. Our observations
need to be confirmed in prospective study investigating

short-and long-term prognosis in patients with stroke treated

with beta-blockers.
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