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 0.16–0.84)
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 experimen-
tal 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 inflamma-
tory reaction [3–7].
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.
⁎ 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
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 1994–1997. We choose that time
period, because in years 1994–1997 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
54 T. Dziedzic et al. / Journal of the Neurological Sciences 252 (2007) 53–56

anterior circulation infarction (PACI), posterior circulation and total cholesterol were put into that model as continuous
infarction (POCI), or lacunar infarction (LACI). variables. No colinearity was found between the selected
Arterial hypertension was diagnosed when its presence was variables. Values of P b 0.05 were considered statistically sig-
documented in medical records or when at least 2 readings of nificant. The calculations were performed using the com-
blood pressure were ≥160 mm Hg (systolic) or ≥90 mm Hg mercial statistical package STATISTICA for Windows, v.6.0
(diastolic) after the acute phase of stroke. Ischemic heart (StatSoft, Inc).
disease was diagnosed when there was a history of angina
pectoris or myocardial infarction. Diabetes mellitus was diag-
nosed if its presence was documented in medical records or Table 1
patient was taking insulin or an oral hypoglycemic agents. A Characteristics of stroke patients treated with beta-blockers and those not
patient was defined as a smoker if there was a history of treated with beta-blockers
cigarette smoking during the last 5 years. Patients treated Patients not treated P
All patients underwent head CT within 24 h after stroke with beta-blockers with beta-blockers
(N = 88) (N = 745)
onset. Stroke severity on admission was assessed using Scan-
dinavian Stroke Scale (SSS) [9]. Age, mean (SD) 67.2 (12.1) 69.9 (12.7) 0.03
Men, n (%) 39 (44.3) 350 (47.0) 0.64
Glucose, total cholesterol and its fraction were measured
Hypertension, n (%) 72 (81.8) 494 (66.3) b0.01
in blood samples taken from fasting patients on the morning Diabetes mellitus, n (%) 13 (14.8) 162 (21.7) 0.12
after admission. Ischemic heart disease, 61 (69.3) 427 (57.3) 0.03
No patient underwent thrombolysis because this form of n (%)
treatment was not registered in Poland during the study Myocardial infarction, n 22 (25.0) 87 (11.7) b0.01
(%)
period. No patient underwent carotid endarterectomy within
Atrial fibrillation, n (%) 25 (28.4) 149 (20.0) 0.08
30 days after stroke onset. Smoking, n (%) 21 (23.9) 196 (26.3) 0.62
The causes of death were classified into 4 groups: (1) deaths TIA, n (%) 10 (11.4) 60 (8.0%) 0.30
resulting from first-ever stroke were due to the direct effects of Pneumonia, n (%) 4 (4.5) 85 (11.4) 0.05
the brain lesion or complications of resulting immobility, Fasting glucose (mmol/ 6.0 (2.5) 6.4 (2.4) 0.06
l), mean (SD)
including deaths from bronchopneumonia; (2) deaths resulting
TC (mmol/l), mean (SD) 5.4 (1.7) 5.4 (1.3) 0.85
from recurrent stroke were due directly to the brain lesion or TG (mmol/l), mean 1.5 (1.1) 1.5 (1.2) 0.67
complications of immobility; (3) deaths caused by cardiovas- (SD)
cular events were those from myocardial infarction, heart LDL (mmol/l), mean 3.4 (1.1) 3.4 (1.1) 0.92
failure or sudden death; (4) deaths from other causes (cancer, (SD)
HDL (mmol/l), mean 1.3 (0.3) 1.4 (0.5) 0.52
injuries etc.) or deaths of undetermined causes.
(SD)
The χ2 test was used to compare proportions and Student's SSS score on admission, 36.0 (23.0–43.5) 34.0 (20.0–43.0) 0.32
t test to compare continuous variables between groups. median (quartile)
Cumulative survival plots were calculated by the Kaplan– Systolic blood pressure 162 (33) 161 (29) 0.64
Meier statistics to evaluate survival in patients treated with on admission (mm
Hg), mean (SD)
beta-blockers versus patients not treated with beta-blockers.
Diastolic blood pressure 95 (18) 94 (16) 0.39
On univariate analysis the odds ratios of death were calculated on admission (mm
for the following variables: age, sex, vascular risk factors Hg), mean (SD)
(hypertension, diabetes mellitus, atrial fibrillation, ischemic Stroke subtype, n (%) 0.68
heart disease, history of myocardial infarction, smoking, his- TACI 17 (19.3) 108 (14.5)
PACI 47 (53.4) 394 (52.9)
tory of transient ischemic attack), biochemical parameters
LACI 15 (17.0) 145 (19.5)
(fasting glucose, total cholesterol, triglycerides), stroke se- POCI 9 (10.2) 94 (12.6)
verity on admission (SSS score), systolic and diastolic blood Undetermined 0 (0) 4 (0.5)
pressure on admission, stroke subtype (with LACI as ACE inhibitors, n (%) 53 (60.2) 255 (34.2) b0.01
reference), pneumonia, drugs (beta-blockers, angiotensin con- Heparin a, n (%) 17 (19.3) 56 (7.5) b0.01
30-day case fatality, n 6 (6.8) 141 (18.9) b0.01
verting enzyme-inhibitors, heparin). Logistic regression
(%)
analysis and Cox proportional hazards model was used to Cause of death:
assess the independent contribution of variables statistically First-ever stroke, n 4 56 0.30
significant on univariate analysis in the prediction of death. Recurrent stroke, n 0 2
Before the logistic regression was applied, multicolinearity Cardiovascular, n 2 82 0.01
Other, n 0 1
among selected variables was assessed. Age, SSS score,
fasting glucose, total cholesterol were put into logistic ACE: angiotensin converting enzyme; TIA: transient ischemic attack; TC: total
regression model as continuous variables. Age did not satisfy cholesterol; TG: triglycerides; LDL: low density lipoproteins cholesterol;
HDL: high density lipoproteins cholesterol; SSS: Scandinavian Stroke Scale;
the proportionality assumption and was entered into Cox TACI: total anterior circulation infarction; PACI: partial anterior circulation
proportional hazards model as a dichotomous variable infarction; POCI: posterior circulation infarction; LACI: lacunar infarction.
(b 85 years versus ≥85 years); SSS score, fasting glucose a
Unfractionated intravenous heparin and low-molecular-weight heparins.
 T. Dziedzic et al. / Journal of the Neurological Sciences 252 (2007) 53–56
3. Results
In years 1994–1997 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 beta-
blockers during hospitalization. 94.3% of them were treated
with beta-blocker before admission. These patients contin-
ued 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 Kaplan–Meier 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: 1.02–1.06), ischemic heart
disease (OR: 1.97, 95% CI: 1.33–2.91), atrial fibrillation
Fig. 1. Kaplan–Meier cumulative survival curves for stroke patients treated
with beta-blockers and those not treated with beta-blockers.
55
(OR: 1.97, 95% CI: 1.32–2.94), smoking (OR: 0.44, 95%
CI: 0.27–0.72), SSS score on admission (OR: 0.92 per 1
point increase, 95% CI: 0.91–0.93), TACI (OR: 3.01, 95%
CI: 1.96–4.62), fasting glucose (OR: 1.21 per 1 mmol/
l increase, 95% CI: 1.13–1.30), total cholesterol level (OR:
0.76 per 1 mmol/l increase, 95% CI: 0.65–0.88), pneumonia
(OR: 5.72, 95% CI: 3.59–9.12) and therapy with beta-
blockers (OR: 0.32, 95% CI: 0.13–0.74). In logistic
regression analysis greater age (OR: 1.02, 95% CI: 1.00–
1.04), higher fasting glucose (OR: 1.12, 95% CI: 1.02–1.22)
and pneumonia (OR: 2.15, 95% CI: 1.17–3.95) remained
independently associated with increased risk of early death,
whereas greater SSS score on admission (OR: 0.93, 95% CI:
0.92–0.95), higher total cholesterol level (OR: 0.82, 95% CI:
0.68–0.98) and therapy with beta-blockers (OR: 0.31, 95%
CI: 0.10–0.96) were independently associated with de-
creased 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: 1.03–1.14), total
cholesterol level (HR: 0.83, 95% CI: 0.73–0.95), pneumonia
(HR: 1.63, 95% CI: 1.13–2.37) and therapy with beta-
blockers (HR: 0.37, 95% CI: 0.16–0.84) 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: 0.19–1.23) 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: 0.32–0.98) was the
only independent predictor of death in the Cox proportional
hazard model.
4. Discussion
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 beta-
blockers 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 beta-
blockers 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
56 T. Dziedzic et al. / Journal of the Neurological Sciences 252 (2007) 53–56
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 beta-
blockers 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 beta-
blockers and pneumonia independently from each other
predicted risk of death. Third — beta-blockers may show
neuroprotective properties including anti-oxidative and anti-
inflammatory effects [3–7]. 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 [14–16], 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 endarter-
ectomy 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 pre-
treatment. 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 pre-
treatment 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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