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Beta-blockers for preventing stroke recurrence

  1. Luiz Gustavo De Lima1,
  2. Bernardo GO Soares1,
  3. Humberto Saconato2,
  4. Álvaro N Atallah3,
  5. Edina MK da Silva4,*

Editorial Group: Cochrane Stroke Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 3 NOV 2011

DOI: 10.1002/14651858.CD007890.pub2

How to Cite

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.

Author Information

  1. 1

    Universidade Federal de São Paulo, Brazilian Cochrane Centre, São Paulo, São Paulo, Brazil

  2. 2

    Santa Casa de Campo Mourão, Department of Medicine, Campo Mourão, Campo Mourão, Brazil

  3. 3

    Centro de Estudos de Medicina Baseada em Evidências e Avaliação Tecnológica em Saúde, Brazilian Cochrane Centre, São Paulo, São Paulo, Brazil

  4. 4

    Universidade Federal de São Paulo, Emergency Medicine and Evidence Based Medicine, São Paulo, São Paulo, Brazil

*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.

Publication History

  1. Publication Status: New
  2. Published Online: 31 MAY 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms

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-related disease 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) significantly 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 hypertension and have also been used as the reference drug in randomised controlled trials (RCTs), compared with other agents, to treat hypertension. However, since the end of the last decade, systematic 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 hypertension, 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 Collaboration overview found that treatment with any commonly used regimen reduces the risk of cardiovascular events, but with some differences between regimens. Regimens based on beta-blockers showed a trend toward greater risk reduction compared with regimens 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-blockers (BPLTTC 2003). A Cochrane review evaluating the efficacy of beta-blockers for treating hypertension concluded that available 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 reduction in hypertension study (LIFE), losartan prevented cardiovascular 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 values 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 independent of blood pressure lowering. In the Valsartan Antihypertensive 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 cardiovascular 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, alprenolol, atenolol, betaxolol, bisoprolol, bucindolol, bufuralol, bupranolol, butoxamine, carteolol, carvedilol, celiprolol, epanolol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, sotalol, and timolol.

 

How the intervention might work

Beta-blockers might work by reducing arterial pressure and cardiovascular 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.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms

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 TIA, and to determine their safety, particularly with regard to the development of diabetes mellitus.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

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 thrombosis 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.

 

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 cardiovascular 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/) (December 2011), MEDLINE (1966 to December 2011) (Appendix 1), EMBASE (1980 to December 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):

 

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 participants, methods, interventions, outcomes, and results. We collected 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 described 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.

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 review, we will do best- and worst-case-scenario analyses for incomplete 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 undertake 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 participants (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 undertake 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.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

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 reference lists of these studies but found no additional studies. Upon verification of all whole articles that appeared to meet our inclusion criteria, only two articles fulfilled all the inclusion criteria of this review (DUTCH TIA TRIAL 1993; Eriksson 1995) (Figure 1).

 FigureFigure 1. Study flow diagram.

 

Included studies

 

Trial design

Both included studies were multicentre, double-blind, randomised, 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 (symptoms 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 modified 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 contraindication 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 atenolol group (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 condition 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 occurrence of death from vascular causes, non-fatal stroke, or non-fatal 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 design. 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 medication 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 intervention 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 intervention and 1089 to placebo. There were no statistical differences 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 differences 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 medication 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).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

Summary of main results

This review showed no evidence of reduction of recurrent stroke, total mortality, vascular disease, and cardiovascular events in people with previous stroke treated with beta-blockers. Some pathophysiological considerations may in part explain these findings. Atherothrombotic vascular disease manifests, as a rule, as a cerebrovascular event (stroke or TIA), myocardial infarction, or peripheral 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 established (Sacco 1997). The theory of divergent pathophysiological mechanisms for stroke and coronary heart disease has been reinforced 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 cerebrovascular 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 therapy, requiring significantly larger samples, because the effects of a preventive intervention tend to be smaller than therapeutic effects. 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 statistical 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-blockers have a beneficial effect in secondary prevention of stroke, because 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 diabetes mellitus in people receiving beta-blockers. However, the studies included in this review did not provide data on the development 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 effectiveness. 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 measure. In 1997, a meta-analysis concluded that pharmacological interventions 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 diuretic) 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 note that in PROGRESS 2001, the difference between intervention and placebo was seen only in those participants 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 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 intervention 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 borderline 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 restrictions, 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 pressure, investigators observed different outcomes in people treated with beta-blockers, diuretics, or newer drugs such as calcium channel blockers, ACE inhibitors, and angiotensin II receptor antagonists (Dahlöf 2002; Dahlöf 2005; Hansson 1999a; Hansson 2000; MacMahon 1990). Discussion of differences between different classes of antihypertensive drugs with regard to reduction of mortality, 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 prevention (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 practice (Chalmers 2003).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms

 

Implications for practice

Beta-blockers have not demonstrated superiority over placebo for the secondary prevention of stroke. We did not find any statistically significant differences in outcomes analysed between the beta-blocker atenolol and placebo. Included studies did not analyse the potential association between beta-blockers and increased risk of developing diabetes mellitus. Therefore, no evidence supports 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 prevention of stroke, according to the findings of this systematic review.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms

We thank the Cochrane Stroke Group, especially Hazel Fraser and Brenda Thomas, for their support.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms
Download statistical data

 
Comparison 1. Atenolol 50 mg versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatal and non-fatal stroke recurrence22193Risk Ratio (M-H, Random, 95% CI)0.95 [0.76, 1.18]

 2 Death from all causes22193Risk Ratio (M-H, Random, 95% CI)0.94 [0.68, 1.32]

 3 Cardiac death and non-fatal myocardial infarction22193Risk Ratio (M-H, Random, 95% CI)0.94 [0.63, 1.41]

 4 Major vascular events22193Risk Ratio (M-H, Random, 95% CI)1.01 [0.84, 1.21]

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

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$).tw.
8. (acebutalol or alprenolol or atenolol or betaxolol or bisoprolol or bupranolol or bucindolol or butoxamine or bufuralol or carteolol or carvedilol or celiprolol or esmolol or epanolol or labetalol or labetolol or metoprolol or nadolol or oxprenolol or pindolol or propranolol or sotalol or timolol).tw.
9. 6 or 7 or 8
10. 5 and 9
11. limit 10 to humans
12. Randomized Controlled Trials as Topic/
13. random allocation/
14. Controlled Clinical Trials as Topic/
15. control groups/
16. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/
17. double-blind method/
18. single-blind method/
19. Placebos/
20. placebo effect/
21. cross-over studies/
22. Therapies, Investigational/
23. Drug Evaluation/
24. Research Design/
25. randomized controlled trial.pt.
26. controlled clinical trial.pt.
27. (clinical trial).pt.
28. random$.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$).tw.
#8 (acebutalol or alprenolol or atenolol or betaxolol or bisoprolol or bupranolol or bucindolol or butoxamine or bufuralol or carteolol or carvedilol or celiprolol or esmolol or epanolol or labetalol or labetolol or metoprolol or nadolol or oxprenolol or pindolol or propranolol or sotalol or timolol).tw.
#9 6 or 7 or 8
#10 5 and 9
#11 limit 10 to human
#12 Controlled study/
#13 Randomization/
#14 Double blind procedure/
#15 Single blind procedure/
#16 Clinical trial/
#17 (clinical adj5 trial$).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
#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 CONTROLLED 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

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms

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.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Index terms
 

Internal sources

  • Brazilian Cochrane Centre, Brazil.

 

External sources

  • CAPES, Brazil.
    Comissão de Aperfeiçoamento de Pessoal de Ensino Superior

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Characteristics of studies
  16. References to studies included in this review
  17. References to studies excluded from this review
  18. Additional references
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}

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Characteristics of studies
  16. References to studies included in this review
  17. References to studies excluded from this review
  18. Additional references
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 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 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, Fitzsimons T, 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

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Characteristics of studies
  16. References to studies included in this review
  17. References to studies excluded from this review
  18. 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
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 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
Lindholm 2005
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
Wiysonge 2007