Beta-bloqueadores para prevenção de AVC

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Beta-blockers for preventing stroke recurrence (Review)
De Lima LG, Soares BGO, Saconato H, Atallah ÁN, da Silva EMK
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 5
http://www.thecochranelibrary.com
Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com
T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
8DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Atenolol 50 mg versus placebo, Outcome 1 Fatal and non-fatal stroke recurrence. . . . 15
Analysis 1.2. Comparison 1 Atenolol 50 mg versus placebo, Outcome 2 Death from all causes. . . . . . . . . 16
Analysis 1.3. Comparison 1 Atenolol 50 mg versus placebo, Outcome 3 Cardiac death and non-fatal myocardial
infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Analysis 1.4. Comparison 1 Atenolol 50 mg versus placebo, Outcome 4 Major vascular events. . . . . . . . . 17
17APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iBeta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]
Beta-blockers for preventing stroke recurrence
Luiz Gustavo De Lima1 , Bernardo GO Soares1, Humberto Saconato2 , Álvaro N Atallah3, Edina MK da Silva4
1Brazilian Cochrane Centre, Universidade Federal de São Paulo, São Paulo, Brazil. 2Department of Medicine, Santa Casa de Campo
Mourão, Campo Mourão, Brazil. 3Brazilian Cochrane Centre, Centro de Estudos de Medicina Baseada em Evidências e Avaliação
Tecnológica em Saúde, São Paulo, Brazil. 4Emergency Medicine and Evidence Based Medicine, Universidade Federal de São Paulo,
São Paulo, Brazil
Contact address: Edina MK da Silva, Emergency Medicine and Evidence Based Medicine, Universidade Federal de São Paulo, Rua
Pedro de Toledo 598, São Paulo, São Paulo, 04039-001, Brazil. edinaksilva@terra.com.br.
Editorial group: Cochrane Stroke Group.
Publication status and date: New, published in Issue 5, 2013.
Review content assessed as up-to-date: 3 November 2011.
Citation: De Lima LG, Soares BGO, Saconato H, Atallah ÁN, da Silva EMK. Beta-blockers for preventing stroke recurrence. Cochrane
Database of Systematic Reviews 2013, Issue 5. Art. No.: CD007890. DOI: 10.1002/14651858.CD007890.pub2.
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very
important. Stroke has a high rate of recurrence; therefore secondary prevention is also important. Many clinical approaches to control
risk factors have been proposed. One of these approaches is the prescription of beta-blockers that have effects beyond the reduction of
blood pressure, which can reduce the recurrence of stroke.
Objectives
To evaluate the efficacy of beta-blockers for preventing stroke recurrence and for reducing death and major vascular events in people
with a previous stroke or transient ischaemic attack (TIA), and to determine their safety, particularly with regard to the development
of diabetes mellitus.
Search methods
We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CEN-
TRAL) and the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library 2011, Issue 12), the Database of Abstracts of
Reviews of Effects (DARE) (December 2011), MEDLINE (1966 to December 2011), EMBASE (1980 to December 2011), and Latin
American and Caribbean Health Sciences Literature (LILACS) (1982 to December 2011). We also searched ongoing trials registers
and reference lists.
Selection criteria
Randomised controlled trials (RCTs) that included participants with previous stroke or TIA due to arterial thrombosis or embolism.The
intervention was any beta-blocker versus control, or beta-blocker plus other treatment versus other treatment.
Data collection and analysis
Two review authors independently screened the trials identified, appraised quality, and extracted data.
1Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
mailto:edinaksilva@terra.com.br
Main results
We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol
5 mg) or placebo. No statistical differences were noted among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94,
95% confidence interval (CI) 0.75 to 1.17). For all other outcomes analysed (death from all causes, cardiac death, non-fatal myocardial
infarction, major vascular events), we observed no significant differences between the groups.
Authors’ conclusions
To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies
with larger samples are needed.
P L A I N L A N G U A G E S U M M A R Y
Beta-blockers for preventing stroke recurrence
People who have had a stroke or a transient ischaemic attack (TIA) are at risk of having further strokes or heart attacks, or other serious
circulatory problems. Beta-blockers are drugs that reduce heart rate and blood pressure, and have other effects that might also reduce
the risks of stroke and heart attack. We found two trials involving 2193 participants that tested beta-blockers after stroke in people with
a recent stroke or TIA. No clear evidence indicated that beta-blockers reduced the risk of stroke, heart attack, or death from vascular
disease. More studies with larger samples are needed.
B A C K G R O U N D
Stroke is one of the main causes of death worldwide. It is also a
leading cause of disability and dependence, especially in the elderly.
Among the survivors, many become functionally dependent, thus
imposing a great burden on the family and community. Stroke
caused an estimated 5.7 million deaths in 2005, and 87% of these
deaths were reported in low-income and middle-income countries.
Estimates suggest that by the year 2020, stroke will be the second
leading cause of death worldwide (Strong 2007).
Systemic hypertension is an important and well-established risk
factor for cardiovascular disease. In a study of the global burden
of blood pressure-relateddisease in 2001, approximately 54% of
strokes worldwide were attributable to high blood pressure (Lawes
2008). Evidence suggests that treating hypertension can reduce
cardiovascular risk in people with a prior stroke (Gueyffier 1997).
Similarly, other studies have found that stroke survivors actually
benefited from blood pressure-lowering treatment even if they did
not have hypertension at baseline: PROGRESS 2001 found that
treatment with perindopril (adding indapamide as required) sig-
nificantly reduced the risk of subsequent stroke.
Stroke and transient ischaemic attack (TIA) increase the risk of a
subsequent stroke. Without preventive treatment, there is a 7% to
12% annual risk of death from vascular causes, non-fatal stroke,
or non-fatal myocardial infarction in people suffering a TIA or a
non-disabling ischaemic stroke (Hankey 1998). In a prospective
observational study, the risk of stroke after TIA or minor stroke
was as high as 18.5% at three months (Coull 2004). Treating
modifiable risk factors, such as hypertension, diabetes, and tobacco
use, may reduce such risk. Also, antiaggregant agents have proven
efficacy in preventing stroke recurrence (Shah 2000).
Beta-blockers have long been used as first-line agents to treat hy-
pertension and have also been used as the reference drug in ran-
domised controlled trials (RCTs), compared with other agents, to
treat hypertension. However, since the end of the last decade, sys-
tematic reviews, meta-analyses, and RCTs have put in doubt the
efficacy of these drugs in preventing outcomes such as death and
vascular events in hypertensive patients. In a recent meta-analysis,
Messerli and colleagues concluded that, in uncomplicated hyper-
tension, neither diuretics nor beta-blockers are acceptable as first-
line treatment (Messerli 2008). Another meta-analysis has shown
that, in comparison with other antihypertensive drugs, the effect
of beta-blockers is less than optimal, with a raised risk of stroke.
The authors concluded that beta-blockers should not remain as the
first choice of drug in the treatment of hypertension and should
not be used as reference drugs in RCTs of hypertension (Lindholm
2005). The Blood Pressure Lowering Treatment Trialists Collab-
oration overview found that treatment with any commonly used
regimen reduces the risk of cardiovascular events, but with some
2Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
differences between regimens. Regimens based on beta-blockers
showed a trend toward greater risk reduction compared with regi-
mens based on angiotensin-converting enzyme (ACE) inhibitors,
and regimens based on calcium antagonists showed a trend toward
greater risk reduction compared with those based on beta-block-
ers (BPLTTC 2003). A Cochrane review evaluating the efficacy
of beta-blockers for treating hypertension concluded that avail-
able evidence does not support the use of beta-blockers as first-
line drugs (Wiysonge 2007). Moreover, RCTs comparing beta-
blockers with other drugs in hypertensive patients have shown
negative results. In the Losartan Intervention For Endpoint re-
duction in hypertension study (LIFE), losartan prevented cardio-
vascular morbidity and death more frequently than atenolol for
similar reductions in blood pressure (Dahlöf 2002). Furthermore,
in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), an
amlodipine-based regimen prevented major cardiovascular events
more often and induced diabetes less frequently than an atenolol-
based regimen (Dahlöf 2005). Nevertheless, diagnostic criteria for
hypertension and blood pressure targets have evolved to lower val-
ues over the years; the efficacy of beta-blockers was established in
populations with higher levels of blood pressure. Hence, a meta-
analysis including trials from different decades may underestimate
the efficacy of beta-blockers.
Studies showing better outcomes with specific antihypertensive
therapy, such as ACE inhibitors or angiotensin receptor blockers
(ARBs), compared with beta-blockers or diuretics were unable to
address whether there is a mechanism for risk reduction that is in-
dependent of blood pressure lowering. In the Valsartan Antihyper-
tensive Long-term Use Evaluation (VALUE) study (Julius 2004),
blood pressure lowering was more intense in people who received
amlodipine than in those who received valsartan. The cardiovas-
cular endpoint, however, was similar in both groups.
The ’beyond-blood pressure effect’ may be related to differences
between pulse pressure and central blood pressure. A recent study
found that, despite similar results for peripheral blood pressure,
atenolol had less impact than eprosartan on central systolic blood
pressure , which could explain differences in outcomes, especially
stroke (Dhakam 2006).
However, relatively few studies have tested the impact of beta-
blockers in people with or without hypertension who have had a
TIA or stroke (DUTCH TIA TRIAL 1993). This approach may
be effective in preventing stroke recurrence.
Description of the condition
Previous stroke of any severity or TIA due to arterial thrombosis
or embolism (symptoms persisting for less than 24 hours).
Description of the intervention
Adrenergic beta-antagonist drugs or beta-blockers: acebutolol, al-
prenolol, atenolol, betaxolol, bisoprolol, bucindolol, bufuralol,
bupranolol, butoxamine, carteolol, carvedilol, celiprolol, epanolol,
esmolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, pro-
pranolol, sotalol, and timolol.
How the intervention might work
Beta-blockers might work by reducing arterial pressure and car-
diovascular events. They have been used for decades as first-line
agents to treat hypertension. Clinical evidence suggests that they
reduce hypertension and cardiovascular events (BPLTTC 2003).
Why it is important to do this review
No previous review has focused on beta-blockers for the secondary
prevention of stroke. Secondary prevention is very important,
given the high rate of stroke recurrence.
O B J E C T I V E S
To evaluate the efficacy of beta-blockers for preventing stroke re-
currence and for reducing death and major vascular events in peo-
ple with a previous stroke or TIA, and to determine their safety,
particularly with regard to the development of diabetes mellitus.
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included RCTs of unconfounded comparisons of beta-blocker
versus control, or beta-blocker plus other treatment, versus other
treatment in people with previous stroke or TIA.
Types of participants
Adults with a prior history of stroke or TIA due to arterial throm-
bosis or embolism, with and without hypertension. We excluded
trials that included participants without a previous stroke or TIA
unless we could identify a subgroup of stroke patients for whom
separate results were available.
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Types of interventions
Beta-blocker versus control, or beta-blocker plus other treatment
versus other treatment.
Types of outcome measures
Primary outcomes
Fatal and non-fatal stroke.
Secondary outcomes
Major vascular events, death from all causes, death from cardio-
vascular causes, change in blood pressure (mean blood pressure as
a continuous outcome), development of diabetes, adverse events,
quality of life.
Search methods for identification of studies
See the ’Specialized register’ section in the Cochrane Stroke Group
module. We searched for trials in all languages.
Electronic searches
We searched the Cochrane Stroke Group Trials Register (last
searched December 2011), the Cochrane Central Register of
Controlled Trials (CENTRAL) and the Cochrane Database of
Systematic Reviews (CDSR) (The Cochrane Library 2011, Issue
12), the Database of Abstracts of Reviews of Effects (DARE)
(www.crd.york.ac.uk/crdweb/) (December2011), MEDLINE
(1966 to December 2011) (Appendix 1), EMBASE (1980 to De-
cember 2011) (Appendix 2), and Latin American and Caribbean
Health Sciences Literature (LILACS) (1982 to December 2011)
(Appendix 3). We developed the MEDLINE search strategy with
the help of the Cochrane Stroke Group Trials Search Co-ordinator
and adapted it for the other databases.
We also searched the following ongoing trials and research registers
(December 2011):
• MetaRegister of Controlled Trials (www.controlled-
trials.com);
• US National Institutes of Health Ongoing Trials Register (
www.clinicaltrials.gov); and
• EU Clinical Trials Register (www.clinicaltrialsregister.eu/).
Searching other resources
In an effort to identify additional published, unpublished, and
ongoing trials, we searched reference lists of relevant articles and
contacted authors, trialists, and experts in the field.
Data collection and analysis
Selection of studies
Two review authors (LGL and HS) independently scanned the
titles and abstracts of records identified by the electronic searches
and excluded those articles that clearly were not randomised trials
or did not address the effects of beta-blockers in stroke patients.
We obtained the full text of the remaining articles, and the same
two authors selected those studies that met the predetermined
inclusion criteria stated. These two review authors resolved any
disagreements by discussion and consultation with a third review
author if necessary.
Data extraction and management
Two authors (LGL and BS) independently extracted data on par-
ticipants, methods, interventions, outcomes, and results. We col-
lected the following information:
• general information: published/unpublished, title, authors,
reference, contact address, country, language of publication, year
of publication, duplicate publications, sponsor, setting;
• trial characteristics: design, duration of follow-up, method
of randomisation, allocation concealment, blinding (participants
and outcome assessors);
• interventions: interventions (dose, route, timing),
comparison interventions (dose, route, timing), co-medications
(dose, route, timing);
• participants: total number and numbers in comparison
groups, age, baseline characteristics, diagnostic criteria, similarity
of groups at baseline, assessment of compliance, losses to follow-
up (reasons/description), subgroups; and
• outcomes: outcomes specified above, any other outcomes
assessed, other events, length of follow-up, quality of reporting of
outcomes.
Assessment of risk of bias in included studies
To assess the risk of bias, we independently assessed the quality
of the studies included in the review according to the criteria de-
scribed by Higgins (Higgins 2011).
We assessed the following domains for each trial and rated them
at low, unclear, or high risk of bias.
• Random sequence generation.
• Allocation concealment.
• Blinding of participants and personnel.
• Blinding of outcome assessment.
• Incomplete outcome data.
• Selective outcome reporting.
• Other bias.
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http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.html
http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.html
http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.html
http://www.crd.york.ac.uk/crdweb/
http://www.crd.york.ac.uk/crdweb/
http://www.controlled-trials.com/
http://www.controlled-trials.com/
http://www.clinicaltrials.gov/
http://www.clinicaltrialsregister.eu/
We reported these assessments for each individual study in the
’Risk of bias’ tables located in the Characteristics of included
studies table.
The review authors resolved disagreements arising at any stage of
the process through discussion until consensus was reached.
Measures of treatment effect
As the nature of outcome data was dichotomous, we used the
risk ratio (RR) and 95% confidence interval (CI) to measure the
intervention effect.
Unit of analysis issues
We did not find any cluster-randomised or cross-over trials. In
future updates of this review, we will exclude cluster-randomised
trials. We will include only the first period of cross-over trials,
and we will assess trials with multiple observations for the same
outcome (e.g. recurring events) if randomised. We will exclude
recurring events.
Dealing with missing data
We only analysed the available data. In future updates of this re-
view, we will do best- and worst-case-scenario analyses for incom-
plete outcome data.
Assessment of heterogeneity
We used I² to assess the likelihood of heterogeneity.
Assessment of reporting biases
Given the limited number of included studies, we did not create
funnel plots to assess reporting biases. In future updates of this
review, we will interpret any funnel plot asymmetry with caution.
Data synthesis
We used the Cochrane Review Manager software (RevMan 5.1)
to carry out a quantitative analysis, based on the intention-to-treat
principle (RevMan 2011). We performed meta-analyses using a
fixed-effect model if no substantial heterogeneity existed and if
pooling of results was clinically appropriate.
Subgroup analysis and investigation of heterogeneity
Given the limited number of included studies, we did not under-
take subgroup analyses. In future updates of this review, we will
explore differences in the results by creating subgroups according
to type and dose of beta-blocker (based on data), age of partici-
pants (younger than 65 years old versus 65 years of age and older),
and ethnicity of participants (white and non-white) for each trial.
Sensitivity analysis
Given the limited number of included studies, we did not under-
take sensitivity analyses. In future updates of this review, we will
assess the robustness of results by performing sensitivity analyses to
fixed-effect versus random-effects assumptions and will consider
the inclusion or exclusion of studies of poor quality and those that
were not placebo controlled or blinded.
R E S U L T S
Description of studies
Results of the search
We identified a total of 3078 records from the electronic searches.
After examination of the titles and abstracts, we excluded 3062
records and obtained full text copies of the remaining 16, which
we then subjected to further assessment. We also checked the ref-
erence lists of these studies but found no additional studies. Upon
verification of all whole articles that appeared to meet our inclu-
sion criteria, only two articles fulfilled all the inclusion criteria of
this review (DUTCH TIA TRIAL 1993; Eriksson 1995) (Figure
1).
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Figure 1. Study flow diagram.
6Beta-blockers for preventing stroke recurrence (Review)
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Included studies
Trial design
Both included studies were multicentre, double-blind, ran-
domised, placebo-controlled trials. The mean duration of follow-
up was 32 months in one study (DUTCH TIA TRIAL 1993),
and 28 months in the other (Eriksson 1995).
Participants
One trial included 1473 participants who had had a TIA (symp-
toms persisting for less than 24 hours) or a non-disabling ischaemic
stroke (symptoms persisting for longer than 24 hours) less than
three months before randomisation. Patients with a stroke had to
be independent in most of their daily activities (score on the modi-
fied Rankin Scale of grade 3 or less). Excluded from the study were
patients with cerebral ischaemia from identifiable causes other than
arterial thrombosis or arterial embolism, and patients with a con-
traindication against or a strict indication for a beta-blocker. One-
third of participants were women, and there was a slight excess of
males and of patients older than 65 years of age in the atenololgroup (DUTCH TIA TRIAL 1993). The other study included
720 participants recruited within three weeks of an index event
of a minor or major stroke or TIA. Patients with subarachnoid
haemorrhage, systolic blood pressure < 140 mm Hg and diastolic
blood pressure < 80 mm Hg, bradycardia < 50 beats per minute,
or manifest heart failure, and those who had atrioventricular block
I to III were excluded from the study. Patients in poor general con-
dition or dependent on help for daily activities were not admitted
to the trial. Men made up 61% of included participants; mean age
of participants was around 70 years (Eriksson 1995).
Interventions
The two included studies compared atenolol 50 mg once a day
with placebo.
Outcome
The primary outcome event in one study was the combined occur-
rence of death from vascular causes, non-fatal stroke, or non-fa-
tal myocardial infarction, whichever occurred first (DUTCH TIA
TRIAL 1993), and in the other study, death from any cause, non-
fatal myocardial infarction, and non-fatal stroke (Eriksson 1995).
Excluded studies
We excluded most of the 14 excluded studies because they were
RCTs of primary prevention in hypertensive patients. Some studies
performed subgroup analyses in participants with prior stroke, but
these data were not provided in detail in the results, even after we
contacted the authors. For further information, please refer to the
Characteristics of excluded studies table.
Risk of bias in included studies
The two included studies had high overall methodological quality.
Allocation
The two included studies used a random permuted blocks de-
sign. In one blinded randomisation (DUTCH TIA TRIAL 1993),
codes were distributed by telephone, and in the other, no reference
was made to allocation concealment (Eriksson 1995).
Blinding
Both included studies were double-blinded.
Incomplete outcome data
In one study, 36% of participants had discontinued trial medi-
cation in the intervention group and 32% in the placebo group
after three years of follow-up (DUTCH TIA TRIAL 1993). In
the other study, treatment was discontinued in 17% in the inter-
vention group and in 10% in the placebo group (Eriksson 1995).
In both studies, the authors performed analysis by intention-to-
treat.
Selective reporting
There was no concern about selective reporting.
Other potential sources of bias
We believe that the included studies were free of other sources of
bias.
Effects of interventions
Primary outcomes
The two included studies randomised 1104 participants to inter-
vention and 1089 to placebo. There were no statistical differences
7Beta-blockers for preventing stroke recurrence (Review)
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between the groups for risks of fatal and non-fatal stroke (RR 0.95,
95% CI 0.76 to 1.18) (Analysis 1.1).
Secondary outcomes
For all other outcomes analysed, there were no significant differ-
ences between the atenolol group and the placebo group: death
from all causes: RR 0.94 (95% CI 0.68 to 1.32) (Analysis 1.2);
cardiac death and non-fatal myocardial infarction: RR 0.94 (95%
CI 0.63 to 1.41) (Analysis 1.3); and major vascular events: RR
1.01 (95% CI 0.84 to1.21) (Analysis 1.4). Neither of the studies
included in this review reported the occurrence of diabetes among
their outcomes.
In one study, adverse reactions of any kind were significantly
more frequent in participants taking atenolol than in those given
placebo: RR 1.50 (95% CI 1.20 to 1.89). Adverse effects were
the most common reason given for stopping the trial medica-
tion early, and twice as many participants taking atenolol as were
given placebo stopped because of an adverse effect (DUTCH TIA
TRIAL 1993). In the other included study, 10% of participants
in the placebo group and 17% in the atenolol group discontinued
treatment because of side effects (Eriksson 1995).
D I S C U S S I O N
Summary of main results
This review showed no evidence of reduction of recurrent stroke,
total mortality, vascular disease, and cardiovascular events in peo-
ple with previous stroke treated with beta-blockers. Some patho-
physiological considerations may in part explain these findings.
Atherothrombotic vascular disease manifests, as a rule, as a cere-
brovascular event (stroke or TIA), myocardial infarction, or pe-
ripheral vascular disease. The predominant risk factors for all
these events are quite similar and include hypertension, diabetes
mellitus, obesity, dyslipidaemia, and cigarette smoking (Sacco
2006; Smith 2001). This similarity reflects the systemic nature of
atherothrombotic vascular disease. However, differences observed
between the risk factors specific for vascular disease suggest some
degree of specificity in pathophysiological processes. For example,
dyslipidaemia is a well-established risk factor for coronary artery
disease, but its role in cerebrovascular disease is not well estab-
lished (Sacco 1997). The theory of divergent pathophysiological
mechanisms for stroke and coronary heart disease has been rein-
forced by data from epidemiological studies and RCTs. Thus, the
specificity between different forms of vascular disease may explain
the fact that the beneficial effects of beta-blockers demonstrated
in ischaemic heart disease may not be valid with respect to cere-
brovascular disease.
Overall completeness and applicability of
evidence
It should be emphasised that this review was based on studies of
prevention, which usually are more complex than studies of ther-
apy, requiring significantly larger samples, because the effects of
a preventive intervention tend to be smaller than therapeutic ef-
fects. Systematic reviews are particularly important in studies on
prevention, with the function to minimize the potential for error
type 2 (i.e. lack of effect of insufficient sample size). Therefore, the
results of this systematic review did not exclude the possibility that
the observed absence of effect of beta-blockers in the secondary
prevention of stroke and TIA may be due to lack of further statis-
tical power.
Authors of the most recent study included in this review (Eriksson
1995) commented that more studies with greater statistical power,
or meta-analyses, would be needed to confirm whether beta-block-
ers have a beneficial effect in secondary prevention of stroke, be-
cause the study did not reach the desired sample size planned and
included fewer than half the participants required. The other study,
published in 1993, despite including twice as many participants,
was also smaller than planned, and neither study was able to find
statistically significant differences between atenolol and placebo
in any outcome measured.
Previous studies have shown an increased risk of developing di-
abetes mellitus in people receiving beta-blockers. However, the
studies included in this review did not provide data on the devel-
opment of diabetes mellitus.
Quality of the evidence
Secondary prevention of stroke is of fundamental importance, and
researchers need to explore all potentially beneficial interventions.
Antiplatelet agents, particularly aspirin, have shown their effec-
tiveness. It remains for investigators to define other prevention
strategies and to answer the question, still uncertain, whether there
are differences between different classes of antihypertensive drugs
with regard to prevention of clinical outcomes. Reduction of blood
pressure, even in normotensive patients, can be an effective mea-
sure. In 1997, a meta-analysis concluded that pharmacological in-
terventions for blood pressure reduction reduce the risk of new
stroke in people with previous cerebrovascular events (Gueyffier
1997). Similarly, the RCT PROGRESS 2001, which compared
perindopril and indapamide (respectively, ACE inhibitor and di-
uretic) with placebo in participants with prior stroke, showed a
reduction of stroke recurrence directly proportionate to arterial
pressure reduction in participants who received active treatment.
It is interesting to notethat in PROGRESS 2001, the difference
between intervention and placebo was seen only in those partici-
pants who received combination therapy with diuretics and ACE
inhibitors, which produced a mean reduction in systolic blood
pressure of 12 mm Hg and in diastolic blood pressure of 5 mm
8Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hg. In participants who received only perindopril, investigators
described no benefit over placebo, and participants had an average
reduction of blood pressure of 5/3 mm Hg.
We included only two studies in this review; despite their high
methodological quality, blood pressure reduction in the interven-
tion group was 4/3 mm Hg in one study (Eriksson 1995), and
the difference in blood pressure between intervention and placebo
groups was 5.8/2.9 mm Hg in the other study (DUTCH TIA
TRIAL 1993). It is possible that one explanation for the positive
effects not observed in studies with beta-blockers is the relatively
minor reduction in blood pressure detected, although this was not
the goal of the treatment. Although the inclusion criteria were
similar in the two studies, which had sought to select not people
with a diagnosis of hypertension but people with prior stroke, in
fact one study included people with hypertension or with border-
line hypertension, because one of the exclusion criteria was blood
pressure less than or equal to 140/80 mm Hg (Eriksson 1995).
Potential biases in the review process
We conducted an extensive literature search without language re-
strictions, so we believe it is unlikely that we missed any potentially
relevant studies. Therefore, we believe that there is no significant
bias in the review process.
Agreements and disagreements with other
studies or reviews
Recent clinical trials have questioned the efficacy of beta-blockers
even in primary prevention. For similar reductions in blood pres-
sure, investigators observed different outcomes in people treated
with beta-blockers, diuretics, or newer drugs such as calcium chan-
nel blockers, ACE inhibitors, and angiotensin II receptor antago-
nists (Dahlöf 2002; Dahlöf 2005; Hansson 1999a; Hansson 2000;
MacMahon 1990). Discussion of differences between different
classes of antihypertensive drugs with regard to reduction of mor-
tality, stroke, and other vascular events has raised suspicion that
beta-blockers may produce a smaller benefit in clinical outcomes,
despite similar reductions in blood pressure. This question is still
controversial and has been restricted to studies on primary pre-
vention (Collins 1990; Lindholm 2005; Messerli 2008; Wiysonge
2007). The latest consensus on the treatment of hypertension still
put beta-blockers as first-line drugs, and their easy availability and
relatively low cost continue to be important factors in clinical prac-
tice (Chalmers 2003).
A U T H O R S ’ C O N C L U S I O N S
Implications for practice
Beta-blockers have not demonstrated superiority over placebo for
the secondary prevention of stroke. We did not find any statis-
tically significant differences in outcomes analysed between the
beta-blocker atenolol and placebo. Included studies did not anal-
yse the potential association between beta-blockers and increased
risk of developing diabetes mellitus. Therefore, no evidence sup-
ports the routine use of beta-blockers for secondary prevention
after stroke or TIA.
Implications for research
Studies of secondary prevention of stroke assessing recurrence,
mortality, and other cardiovascular outcomes are very important.
However, they are scarce, and additional studies are needed. Also
needed are further studies of beta-blockers for secondary preven-
tion of stroke, according to the findings of this systematic review.
A C K N O W L E D G E M E N T S
We thank the Cochrane Stroke Group, especially Hazel Fraser and
Brenda Thomas, for their support.
R E F E R E N C E S
References to studies included in this review
DUTCH TIA TRIAL 1993 {published data only}
The DUTCH TIA Trial Study Group. Trial of secondary
prevention with atenolol after transient ischemic attack or
nondisabling ischemic stroke. Stroke 1993;24:543–8.
Eriksson 1995 {published data only}
Eriksson S, Olofsson B, Wester P. Atenolol in secondary
prevention after stroke. Cerebrovascular Diseases 1995;5:
21–2.
References to studies excluded from this review
Azuma 1997 {published data only}
Azuma T, Matsubara T, Nagai Y, Funauchi M, Fujimoto T,
Saito T, et al.Effects of antihypertensive agents on circadian
blood pressure in hypertensive patients with previous
brain infarction. Journal of Human Hypertension 1997;11:
637–40.
Black 2003 {published data only}
Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T,
White WB, et al.Principal results of the Controlled ONset
9Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Verapamil INvestigation of Cardiovascular End points
(CONVINCE) trial. JAMA 2003;289:2073–82.
Coope 1986 {published data only}
Coope J, Warrender TS. Randomized trial of treatment of
hypertension in elderly patients in primary care. BMJ 1986;
293:1145–51.
Dahlöf 1991 {published data only}
Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom
T, Wester PO. Morbidity and mortality in the Swedish Trial
in Old Patients with Hypertension (STOP-Hypertension).
Lancet 1991;338:1281–5.
Dahlöf 2002 {published data only}
Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G,
de Faire U, et al.Cardiovascular morbidity and mortality
in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): a randomized trial against
atenolol. Lancet 2002;359:995–1003.
Dahlöf 2005 {published data only}
Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers
DG, Caulfield M, et al.Prevention of cardiovascular
events with an antihypertensive regimen of amlodipine
adding perindopril as required versus atenolol adding
bendroflumethiazide as required, in the Anglo-Scandinavian
Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA): a multicentre randomized controlled trial.
Lancet 2005;366:895–906.
Hansson 1999a {published data only}
Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner
T, Niklason A, et al.Effect of angiotensin-converting-
enzyme inhibition compared with conventional therapy on
cardiovascular morbidity and mortality in hypertension: the
Captopril Prevention Project (CAPPP) randomized trial.
Lancet 1999;353:611–6.
Hansson 1999b {published data only}
Hansson L, Lindholm LH, Ekborn T, Dahlöf B, Lanke
J, Schersten B, et al.Randomized trial of old and new
antihypertensive drugs in elderly patients: cardiovascular
mortality and morbidity: the Swedish Trial in Old Patients
with Hypertension-2 study. Lancet 1999;354:1751–6.
Hansson 2000 {published data only}
Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE,
Lindholm LH, Syvertsen JO, et al.Randomized trial of
effects of calcium antagonists compared with diuretics and
β-blockers on cardiovascular morbidity and mortality in
hypertension: the Nordic Diltiazem (NORDIL) study.
Lancet 2000;356:359–65.
Kinnander 1987 {published data only}
Kinnander G, Viitanen M, Asplund K. Beta-adrenergic
blockade after stroke: a preliminary closed cohort study.
Stroke 1987;18:240–3.
MRC 1985 {published data only}
Medical Research Council Working Party. MRC trial of
treatment of mild hypertension: principal results. BMJ
1985;291:97–104.
MRC 1992 {published data only}
MRC Working Party. Medical Research Council trial of
treatment of hypertension in older adults: principal results.
BMJ 1982;304:405–12.
SHEP 1991 {published data only}
SHEP Cooperative Research Group. Prevention of stroke
by antihypertensive drug treatment in older persons with
isolated systolic hypertension: final results of the Systolic
Hypertension in the Elderly Program (SHEP). JAMA 1991;
265:3255–64.
Wilhelmsen 1987 {published data only}
Wilhelmsen L, Berglund G, Elmfeldt D, FitzsimonsT,
Holzgreve H, Hosie J, et al.Beta-blockers versus diuretics in
hypertensive men: main results from the HAPPHY trial.
Journal of Hypertension 1987;5:561–72.
Additional references
BPLTTC 2003
Blood Pressure Lowering Treatment Trialists Collaboration.
Effects of different blood-pressure-lowering regimens
on major cardiovascular events: results of prospectively-
designed overviews of randomized trials. Lancet 2003;362:
1527–35.
Chalmers 2003
Chalmers J, Todd A, Chapman N, Beilin L, Davis S,
Donnan G, et al.International Society of Hypertension
(ISH): statement on blood pressure lowering and stroke
prevention. Journal of Hypertension 2003;21:651–63.
Collins 1990
Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH,
Eberlein KA, et al.Blood pressure, stroke, and coronary heart
disease. Part 2, short-term reductions in blood pressure:
overview of randomized drug trials in their epidemiological
context. Lancet 1990;335:827–38.
Coull 2004
Coull AJ, Rothwell PM. Underestimation of the early risk
of recurrent stroke - evidence of the need for a standard
definition. Stroke 2004;35:1925–9.
Dhakam 2006
Dhakam Z, McEniery CM, Yasmin C, Cockcroft JR, Brown
MJ, Wilkinson IB. Atenolol and eprosartan: differential
effects on central blood pressure and aortic pulse wave
velocity. American Journal of Hypertension 2006;19(2):
214–9.
Gueyffier 1997
Gueyffier F, Boissel JP, Boutitie F, Pocock S, Coope J,
Cutler J, et al.Effect of antihypertensive treatment in
patients having already suffered from stroke. Gathering the
evidence. The INDANA (INdividual Data ANalysis of
Antihypertensive intervention trials) Project Collaborators.
Stroke 1997;12:2557–62.
Hankey 1998
Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill
PW, Anderson CS, et al.Long-term risk of first recurrent
10Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
stroke in the Perth Community Stroke Study. Stroke 1998;
29(12):2491–500.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1.0 [updated
March 2011]. The Cochrane Collaboration. Available from
www.cochrane-handbook.org.
Julius 2004
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S,
Hansson L, et al.Outcomes in hypertensive patients at high
cardiovascular risk treated with regimens based on valsartan
or amlodipine: the VALUE randomised trial. Lancet 2004;
363(9426):2022–31.
Lawes 2008
Lawes CMM, Hoorn SV, Rodgers A. Global burden of
blood-pressure-related disease, 2001. Lancet 2008;371:
1513–8.
Lindholm 2005
Lindholm LH, Carlberg B, Samuelsson O. Should beta
blockers remain first choice in the treatment of primary
hypertension? A meta-analysis. Lancet 2005;366:1545–53.
MacMahon 1990
MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton
J, et al.Blood pressure, stroke and coronary heart disease.
Part 1, prolonged differences in blood pressure: prospective
observational studies corrected for the regression dilution
bias. Lancet 1990;335:765–74.
Messerli 2008
Messerli FH, Bangalore S, Julius S. Risk/benefit assessment
of beta-blockers and diuretics precludes their use for first-
line therapy in hypertension. Circulation 2008;117(20):
2706–15.
PROGRESS 2001
PROGRESS Collaborative Group. Randomised trial
of a perindopril-based blood-pressure lowering regimen
among 6,105 individuals with previous stroke or transient
ischaemic attack. Lancet 2001;358(9287):1033–41.
RevMan 2011
The Nordic Cochrane Centre. The Cochrane Collaboration.
Review Manager (RevMan). 5.1. Copenhagen: The Nordic
Cochrane Centre. The Cochrane Collaboration, 2011.
Sacco 1997
Sacco RL, Benjamin EJ, Broderick JP, Dyken M, Easton JD,
Feinberg WM, et al.American Heart Association Prevention
Conference: IV: prevention and rehabilitation of stroke:
risk factors. Stroke 1997;28:1507–17.
Sacco 2006
Sacco RL, Adams R, Albers G, Alberts MJ, Benavente
O, Furie K, et al.Guidelines for prevention of stroke in
patients with ischemic stroke or transient ischemic attack: a
statement for healthcare professionals from the American
Heart Association/American Stroke Association Council
on Stroke: cosponsored by the Council on Cardiovascular
Radiology and Intervention: the American Academy of
Neurology affirms the value of this guideline. Stroke 2006;
37:577–617.
Shah 2000
Shah H, Gondek K. Aspirin plus extended-release
dipyridamole or clopidogrel compared with aspirin
monotherapy for the prevention of recurrent ischemic
stroke: a cost effectiveness analysis. Clinical Therapy 2000;
22:363–70.
Smith 2001
Smith SC Jr, Blair SN, Bonow RO, Brass LM, Cerqueira
MD, Dracup K, et al.American Heart Association/American
College of Cardiology guidelines for preventing heart attack
and death in patients with atherosclerotic cardiovascular
disease: 2001 update: a statement for healthcare
professionals from the American Heart Association and the
American College of Cardiology. Circulation 2001;104:
1577–9.
Strong 2007
Strong K, Mathers C, Bonita R. Preventing stroke: saving
lives around the world. Lancet Neurology 2007;6:182–7.
Wiysonge 2007
Wiysonge CS, Bradley H, Mayosi BM, Maroney R, Mbewu
A, Opie LH, et al.Beta-blockers for hypertension. Cochrane
Database of Systematic Reviews 2007, Issue 1. [DOI:
10.1002/14651858.CD002003.pub2]
∗ Indicates the major publication for the study
11Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
DUTCH TIA TRIAL 1993
Methods Multicentre, double-blind, randomised, placebo-controlled
Participants 1473 participants who had had a TIA or a non-disabling ischaemic stroke < 3 months
before
Interventions Atenolol 50 mg once a day versus placebo
Outcomes Death from vascular causes, non-fatal stroke, or non-fatal myocardial infarction,
whichever occurred first
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Randomisation was performed by random
permuted blocks
Allocation concealment (selection bias) Low risk Blinded randomisation codes were dis-
tributed by telephone
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Placebo tablets had an identical appearance
and taste; double-blinded
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk All outcome events were independently
classified by at least 3 members without
knowledge of treatment allocation
Incomplete outcome data (attrition bias)
All outcomes
Low risk 34% of participants discontinued, and
analysis was performed by intention-to-
treat; no participants were lost to follow-up
Selective reporting (reporting bias) Low risk All relevant outcomes were described
Other bias Low risk None
12Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Eriksson 1995
Methods Multicentre, double-blind, randomised, placebo-controlled
Participants 720 participants recruited within 3 weeks of an index event of a minor or major stroke
or TIA
Interventions Atenolol 50 mg once a day versus placebo
Outcomes Death by any cause, non-fatal myocardial infarction, and non-fatal stroke
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection
bias)
Low risk Randomisation by random permuted
blocks
Allocation concealment (selection bias) Unclear risk Not related
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Double-blinded
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Blinded assessment
Incomplete outcome data (attrition bias)
All outcomes
Low risk 13.5% of treatment discontinued, analysis
by intention-to-treat; no losses described
Selective reporting (reporting bias) Low risk All relevant outcomes describedOther bias Low risk None
TIA: transient ischaemic attack
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Azuma 1997 Observational study
Black 2003 RCT of primary prevention
13Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)
Coope 1986 RCT of primary prevention
Dahlöf 1991 RCT of primary prevention
Dahlöf 2002 RCT of primary prevention
Dahlöf 2005 RCT of primary prevention
Hansson 1999a RCT of primary prevention
Hansson 1999b RCT of primary prevention
Hansson 2000 RCT of primary prevention
Kinnander 1987 Observational study
MRC 1985 RCT of primary prevention
MRC 1992 RCT of primary prevention
SHEP 1991 RCT of primary prevention
Wilhelmsen 1987 RCT of primary prevention
RCT: randomised controlled trial
14Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
D A T A A N D A N A L Y S E S
Comparison 1. Atenolol 50 mg versus placebo
Outcome or subgroup title
No. of
studies
No. of
participants Statistical method Effect size
1 Fatal and non-fatal stroke
recurrence
2 2193 Risk Ratio (M-H, Random, 95% CI) 0.95 [0.76, 1.18]
2 Death from all causes 2 2193 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.68, 1.32]
3 Cardiac death and non-fatal
myocardial infarction
2 2193 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.63, 1.41]
4 Major vascular events 2 2193 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.84, 1.21]
Analysis 1.1. Comparison 1 Atenolol 50 mg versus placebo, Outcome 1 Fatal and non-fatal stroke
recurrence.
Review: Beta-blockers for preventing stroke recurrence
Comparison: 1 Atenolol 50 mg versus placebo
Outcome: 1 Fatal and non-fatal stroke recurrence
Study or subgroup Atenolol Placebo Risk Ratio Weight Risk Ratio
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
DUTCH TIA TRIAL 1993 52/732 62/741 38.1 % 0.85 [ 0.60, 1.21 ]
Eriksson 1995 81/372 75/348 61.9 % 1.01 [ 0.77, 1.33 ]
Total (95% CI) 1104 1089 100.0 % 0.95 [ 0.76, 1.18 ]
Total events: 133 (Atenolol), 137 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.58, df = 1 (P = 0.45); I2 =0.0%
Test for overall effect: Z = 0.50 (P = 0.62)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
15Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.2. Comparison 1 Atenolol 50 mg versus placebo, Outcome 2 Death from all causes.
Review: Beta-blockers for preventing stroke recurrence
Comparison: 1 Atenolol 50 mg versus placebo
Outcome: 2 Death from all causes
Study or subgroup Atenolol Placebo Risk Ratio Weight Risk Ratio
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
DUTCH TIA TRIAL 1993 64/732 58/741 50.2 % 1.12 [ 0.79, 1.57 ]
Eriksson 1995 51/372 60/348 49.8 % 0.80 [ 0.56, 1.12 ]
Total (95% CI) 1104 1089 100.0 % 0.94 [ 0.68, 1.32 ]
Total events: 115 (Atenolol), 118 (Placebo)
Heterogeneity: Tau2 = 0.03; Chi2 = 1.90, df = 1 (P = 0.17); I2 =47%
Test for overall effect: Z = 0.34 (P = 0.73)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
Analysis 1.3. Comparison 1 Atenolol 50 mg versus placebo, Outcome 3 Cardiac death and non-fatal
myocardial infarction.
Review: Beta-blockers for preventing stroke recurrence
Comparison: 1 Atenolol 50 mg versus placebo
Outcome: 3 Cardiac death and non-fatal myocardial infarction
Study or subgroup Atenolol Placebo Risk Ratio Weight Risk Ratio
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
DUTCH TIA TRIAL 1993 45/732 40/741 53.6 % 1.14 [ 0.75, 1.72 ]
Eriksson 1995 29/372 36/348 46.4 % 0.75 [ 0.47, 1.20 ]
Total (95% CI) 1104 1089 100.0 % 0.94 [ 0.63, 1.41 ]
Total events: 74 (Atenolol), 76 (Placebo)
Heterogeneity: Tau2 = 0.03; Chi2 = 1.69, df = 1 (P = 0.19); I2 =41%
Test for overall effect: Z = 0.30 (P = 0.76)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
16Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.4. Comparison 1 Atenolol 50 mg versus placebo, Outcome 4 Major vascular events.
Review: Beta-blockers for preventing stroke recurrence
Comparison: 1 Atenolol 50 mg versus placebo
Outcome: 4 Major vascular events
Study or subgroup Atenolol Placebo Risk Ratio Weight Risk Ratio
n/N n/N
M-
H,Random,95%
CI
M-
H,Random,95%
CI
DUTCH TIA TRIAL 1993 97/732 95/741 46.3 % 1.03 [ 0.79, 1.35 ]
Eriksson 1995 97/372 92/348 53.7 % 0.99 [ 0.77, 1.26 ]
Total (95% CI) 1104 1089 100.0 % 1.01 [ 0.84, 1.21 ]
Total events: 194 (Atenolol), 187 (Placebo)
Heterogeneity: Tau2 = 0.0; Chi2 = 0.07, df = 1 (P = 0.80); I2 =0.0%
Test for overall effect: Z = 0.09 (P = 0.93)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10
Favours experimental Favours control
A P P E N D I C E S
Appendix 1. MEDLINE search strategy
1. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp
intracranial arterial diseases/ or exp “intracranial embolism and thrombosis”/ or exp intracranial hemorrhages/ or stroke/ or exp brain
infarction/ or vasospasm, intracranial/ or vertebral artery dissection/
2. (stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or isch?emi$ attack$ or tia$1).tw.
3. ((brain$ or cerebr$ or cerebell$ or vertebrobasilar or intracran$ or intracerebral or infratentorial or supratentorial or MCA) adj10
(isch?emi$ or infarct$ or thrombo$ or emboli$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or subarachnoid) adj10 (haemorrhage$ or hemorrhage$ or haematoma$
or hematoma$ or bleed$)).tw.
5. 1 or 2 or 3 or 4
6. exp Adrenergic beta-Antagonists/
7. (beta$ adj5 block$).tw.
17Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
8. (acebutalol or alprenolol or atenolol or betaxolol or bisoprolol or bupranolol or bucindolol or butoxamine or bufuralol or carteolol or
carvedilol or celiprolol or esmolol or epanolol or labetalol or labetolol or metoprolol or nadolol or oxprenolol or pindolol or propranolol
or sotalol or timolol).tw.
9. 6 or 7 or 8
10. 5 and 9
11. limit 10 to humans
12. Randomized Controlled Trials as Topic/
13. random allocation/
14. Controlled Clinical Trials as Topic/
15. control groups/
16. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or
clinical trials, phase iv as topic/
17. double-blind method/
18. single-blind method/
19. Placebos/
20. placebo effect/
21. cross-over studies/
22. Therapies, Investigational/
23. Drug Evaluation/
24. Research Design/
25. randomized controlled trial.pt.
26. controlled clinical trial.pt.
27. (clinical trial).pt.
28. random$.tw.
29. (controlled adj5 (trial$ or stud$)).tw.
30. (clinical$ adj5 trial$).tw.
31. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
32. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
33. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
34. (coin adj5 (flip or flipped or toss$)).tw.
35. latin square.tw.
36. versus.tw.
37. (cross-over or cross over or crossover).tw.
38. placebo$.tw.
39. (assign$ or alternate or allocat$).tw.
40. controls.tw.
41. or/12-40
42. 11 and 41
Appendix 2. EMBASE search strategy
#1. cerebrovascular disease/ or basal ganglion hemorrhage/ or exp brain hematoma/ or exp brain hemorrhage/ or exp brain infarction/
or exp brain ischemia/ or exp carotid artery disease/ or cerebral artery disease/ or cerebrovascular accident/ or exp intracranial aneurysm/
or exp occlusive cerebrovascular disease/ or stroke/or stroke unit/ or stroke patient/
#2 (stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or isch?emi$ attack$ or tia$1).tw.
#3 ((brain$ or cerebr$ or cerebell$ or vertebrobasilar or intracran$ or intracerebral or infratentorial or supratentorial or MCA) adj10
(isch?emi$ or infarct$ or thrombo$ or emboli$)).tw.
#4 ((brain$ or cerebr$ or cerebell$ or intracerebral or intracran$ or subarachnoid) adj10 (haemorrhage$ or hemorrhage$ or haematoma$
or hematoma$ or bleed$)).tw.
#5 1 or 2 or 3 or 4
#6 exp beta adrenergic receptor blocking agent/
#7 (beta$ adj5 block$).tw.
18Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
#8 (acebutalol or alprenolol or atenolol or betaxolol or bisoprolol or bupranolol or bucindolol or butoxamine or bufuralol or carteolol or
carvedilol or celiprolol or esmolol or epanolol or labetalol or labetolol or metoprolol or nadolol or oxprenolol or pindolol or propranolol
or sotalol or timolol).tw.
#9 6 or 7 or 8
#10 5 and 9
#11 limit 10 to human
#12 Controlled study/
#13 Randomization/
#14 Double blind procedure/
#15 Single blind procedure/
#16 Clinical trial/
#17 (clinical adj5 trial$).ti,ab,hw.
#18 ((doubl$ or singl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).ti,ab,hw.
#19 Placebo/
#20 Placebo$.ti,ab,hw.
#21 Random$.ti,ab,hw.
#22 Methodology.sh.
#23 latin square.ti,ab,hw.
#24 crossover.ti,ab,hw.
#25 cross-over.ti,ab,hw.
#26 Crossover Procedure/
#27 Drug comparison/
#28 Comparative study/
#29 (comparative adj5 trial$).ti,ab,hw.
#30 (control$ or prospectiv$ or volunteer$).ti,ab,hw.
#31 exp “Evaluation and Follow Up”/
#32 Prospective study/
#33 or/12-32
#34 11 and 33
Appendix 3. LILACS search strategy
#1 Acidente Cerebral Vascular
#2 Derrame Cerebral
#3 AVC
#4 Apoplexia
#5 Acidente Cerebrovascular
#6 Apoplexia Cerebral
#7 Apoplexia Cerebrovascular
#8 Icto Cerebral
#9 Acidente Vascular Encefálico
#10 AVE
#11 Acidente Vascular do Cérebro
#12 Acidente Cerebral Vascular
#13 Acidentes Cerebrais Vasculares
#14 Acidentes Cerebrovasculares
#15 Acidentes Vasculares Cerebrais
#16 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15
#17 Antagonistas de Receptores Adrenérgicos beta 1
#18 Antagonistas de Receptores beta-1 Adrenérgicos
#19 Antagonistas de Receptores Adrenérgicos beta-1
#20 Antagonistas dos Receptores beta-1 Adrenérgicos
19Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
#21 (acebutalol or alprenolol or atenolol or betaxolol or bisoprolol or bupranolol or bucindolol or butoxamine or bufuralol or carteolol or
carvedilol or celiprolol or esmolol or epanolol or labetalol or labetolol or metoprolol or nadolol or oxprenolol or pindolol or propranolol
or sotalol or timolol)
#22 #17 OR #18 OR #19 OR #20 OR #21
#23 ((Pt RANDOMIZED CONTROLLED TRIAL OR Pt CONTROLLED CLINICAL TRIAL OR Mh RANDOMIZED CON-
TROLLED TRIALS OR Mh RANDOM ALLOCATION OR Mh DOUBLE-BLIND METHOD OR Mh SINGLE-BLIND
METHOD OR Pt MULTICENTER STUDY) OR ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw acaso or tw placebo or
tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego) or (tw doble and tw ciego) or (tw double and tw blind)) and tw
clinic$)) AND NOT ((CT ANIMALS OR MH ANIMALS OR CT RABBITS OR CT MICE OR MH RATS OR MH PRIMATES
OR MH DOGS OR MH RABBITS OR MH SWINE) AND NOT (CT HUMAN AND CT ANIMALS)) [Palavras]
#24 #16 AND #22 AND #23
C O N T R I B U T I O N S O F A U T H O R S
Luiz Gustavo Lima (LGL) and Humberto Saconato (HS) were responsible for the conception of this review. LGL, HS, Álvaro Nagib
Atallah (ANA), Edina MK da Silva (EMKS), and Bernardo Soares (BS) were responsible for developing the search strategy, screening
search results, obtaining papers, screening retrieved papers against the inclusion criteria, appraising the quality of papers, and extracting
data. LGL and EMKS were responsible for writing the review.
D E C L A R A T I O N S O F I N T E R E S T
None known.
S O U R C E S O F S U P P O R T
Internal sources
• Brazilian Cochrane Centre, Brazil.
External sources
• CAPES, Brazil.
Comissão de Aperfeiçoamento de Pessoal de Ensino Superior
I N D E X T E R M S
Medical Subject Headings (MeSH)
Adrenergic beta-1 Receptor Antagonists [∗therapeutic use]; Atenolol [∗therapeutic use]; Cause of Death; Ischemic Attack, Transient
[complications]; Myocardial Infarction [mortality]; Recurrence [prevention & control]; Secondary Prevention [∗methods]; Stroke
[∗prevention & control]
20Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
MeSH check words
Humans
21Beta-blockers for preventing stroke recurrence (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.