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Beta-blockers for hypertension
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DOI: 10.1002/14651858.CD002003.pub5
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Cochrane Database of Systematic Reviews
Beta-blockers for hypertension (Review)
Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH
Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH.

Beta-blockers for hypertension.
Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD002003.
DOI: 10.1002/14651858.CD002003.pub5.
www.cochranelibrary.com

Copyright © 2017 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane
Collaboration.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Analysis 1.1. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 1 Mortality. . . . . . . . 59
Analysis 1.2. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 2 Total stroke. . . . . . . . 60
Analysis 1.3. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 3 Total coronary heart disease. . 61
Analysis 1.4. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 4 Cardiovascular death. . . . 62
Analysis 1.5. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 5 Total cardiovascular disease. . 63
Analysis 1.6. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 6 Withdrawal due to adverse effects. 64
Analysis 2.1. Comparison 2 Beta-blocker versus diuretic, Outcome 1 Mortality. . . . . . . . . . . . . . 65
Analysis 2.2. Comparison 2 Beta-blocker versus diuretic, Outcome 2 Total stroke. . . . . . . . . . . . . 66
Analysis 2.3. Comparison 2 Beta-blocker versus diuretic, Outcome 3 Total coronary heart disease. . . . . . . . 67
Analysis 2.4. Comparison 2 Beta-blocker versus diuretic, Outcome 4 Cardiovascular death. . . . . . . . . . 68
Analysis 2.5. Comparison 2 Beta-blocker versus diuretic, Outcome 5 Total cardiovascular disease. . . . . . . . 69
Analysis 2.6. Comparison 2 Beta-blocker versus diuretic, Outcome 6 Withdrawal due to adverse effects. . . . . . 70
Analysis 3.1. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 1 Mortality. . . . . . 71
Analysis 3.2. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 2 Total stroke. . . . . 72
Analysis 3.3. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 3 Total coronary heart
disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Analysis 3.4. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 4 Cardiovascular death. . 74
Analysis 3.5. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 5 Total cardiovascular disease. 75
Analysis 3.6. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 6 Withdrawal due to adverse
effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Analysis 4.1. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 1 Mortality. . . 76
Analysis 4.2. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 2 Total stroke. . 77
Analysis 4.3. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 3 Total coronary heart
disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Analysis 4.4. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 4 Cardiovascular
death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Analysis 4.5. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 5 Total cardiovascular
disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Analysis 4.6. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 6 Withdrawal due to
adverse effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Beta-blockers for hypertension (Review) i
Copyright © 2017 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The
Cochrane Collaboration.
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 92
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Beta-blockers for hypertension (Review) ii

[Intervention Review]
Charles S Wiysonge1,2 , Hazel A Bradley3 , Jimmy Volmink1 ,2 , Bongani M Mayosi4 , Lionel H Opie5
1 Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa. 2 Centre for Evidence-based Health Care,
Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. 3 School of Public Health, University of
the Western Cape, Cape Town, South Africa. 4 Department of Medicine, J Floor, Old Groote Schuur Hospital, Cape Town, South
Africa. 5 Hatter Cardiovascular Research Institute, Medical School, Cape Town, South Africa
Contact address: Charles S Wiysonge, Cochrane South Africa, South African Medical Research Council, Francie van Zijl Drive, Parow
Valley, Cape Town, Western Cape, 7505, South Africa. [email protected], [email protected].
Editorial group: Cochrane Hypertension Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2017.
Review content assessed as up-to-date: 13 December 2016.
Citation: Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. Cochrane Database of Systematic
Reviews 2017, Issue 1. Art. No.: CD002003. DOI: 10.1002/14651858.CD002003.pub5.
Copyright © 2017 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of
The Cochrane Collaboration. This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial
Licence, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used
for commercial purposes.
ABSTRACT
Background
Beta-blockers refer to a mixed group of drugs with diverse pharmacodynamic and pharmacokinetic properties. They have shown long-
term beneficial effects on mortality and cardiovascular disease (CVD) when used in people with heart failure or acute myocardial
infarction. Beta-blockers were thought to have similar beneficial effects when used as first-line therapy for hypertension. However, the
benefit of beta-blockers as first-line therapy for hypertension without compelling indications is controversial. This review is an update
of a Cochrane Review initially published in 2007 and updated in 2012.
Objectives
To assess the effects of beta-blockers on morbidity and mortality endpoints in adults with hypertension.
Search methods
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to June 2016:
the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 6),
MEDLINE (from 1946), Embase (from 1974), and ClinicalTrials.gov. We checked reference lists of relevant reviews, and reference lists
of studies potentially eligible for inclusion in this review, and also searched the the World Health Organization International Clinical
Trials Registry Platform on 06 July 2015.
Selection criteria
Randomised controlled trials (RCTs) of at least one year of duration, which assessed the effects of beta-blockers compared to placebo
or other drugs, as first-line therapy for hypertension, on mortality and morbidity in adults.
Beta-blockers for hypertension (Review) 1
Data collection and analysis
We selected studies and extracted data in duplicate, resolving discrepancies by consensus. We expressed study results as risk ratios (RR)
with 95% confidence intervals (CI) and conducted fixed-effect or random-effects meta-analyses, as appropriate. We also used GRADE
to assess the certainty of the evidence. GRADE classifies the certainty of evidence as high (if we are confident that the true effect lies
close to that of the estimate of effect), moderate (if the true effect is likely to be close to the estimate of effect), low (if the true effect
may be substantially different from the estimate of effect), and very low (if we are very uncertain about the estimate of effect).
Main results
Thirteen RCTs met inclusion criteria. They compared beta-blockers to placebo (4 RCTs, 23,613 participants), diuretics (5 RCTs,
18,241 participants), calcium-channel blockers (CCBs: 4 RCTs, 44,825 participants), and renin-angiotensin system (RAS) inhibitors
(3 RCTs, 10,828 participants). These RCTs were conducted between the 1970s and 2000s and most of them had a high risk of bias
resulting from limitations in study design, conduct, and data analysis. There were 40,245 participants taking beta-blockers, three-
quarters of them taking atenolol. We found no outcome trials involving the newer vasodilating beta-blockers (e.g. nebivolol).
There was no difference in all-cause mortality between beta-blockers and placebo (RR 0.99, 95% CI 0.88 to 1.11), diuretics or RAS
inhibitors, but it was higher for beta-blockers compared to CCBs (RR 1.07, 95% CI 1.00 to 1.14). The evidence on mortality was of
moderate-certainty for all comparisons.
Total CVD was lower for beta-blockers compared to placebo (RR 0.88, 95% CI 0.79 to 0.97; low-certainty evidence), a reflection of
the decrease in stroke (RR 0.80, 95% CI 0.66 to 0.96; low-certainty evidence) since there was no difference in coronary heart disease
(CHD: RR 0.93, 95% CI 0.81 to 1.07; moderate-certainty evidence). The effect of beta-blockers on CVD was worse than that of CCBs
(RR 1.18, 95% CI 1.08 to 1.29; moderate-certainty evidence), but was not different from that of diuretics (moderate-certainty) or RAS
inhibitors (low-certainty). In addition, there was an increase in stroke in beta-blockers compared to CCBs (RR 1.24, 95% CI 1.11 to
1.40; moderate-certainty evidence) and RAS inhibitors (RR 1.30, 95% CI 1.11 to 1.53; moderate-certainty evidence). However, there
was little or no difference in CHD between beta-blockers and diuretics (low-certainty evidence), CCBs (moderate-certainty evidence)
or RAS inhibitors (low-certainty evidence). In the single trial involving participants aged 65 years and older, atenolol was associated
with an increased CHD incidence compared to diuretics (RR 1.63, 95% CI 1.15 to 2.32). Participants taking beta-blockers were
more likely to discontinue treatment due to adverse events than participants taking RAS inhibitors (RR 1.41, 95% CI 1.29 to 1.54;
moderate-certainty evidence), but there was little or no difference with placebo, diuretics or CCBs (low-certainty evidence).
Authors’ conclusions
Most outcome RCTs on beta-blockers as initial therapy for hypertension have high risk of bias. Atenolol was the beta-blocker most
used. Current evidence suggests that initiating treatment of hypertension with beta-blockers leads to modest CVD reductions and little
or no effects on mortality. These beta-blocker effects are inferior to those of other antihypertensive drugs. Further research should be
of high quality and should explore whether there are differences between different subtypes of beta-blockers or whether beta-blockers
have differential effects on younger and older people.
PLAIN LANGUAGE SUMMARY
What is the aim of this review?
The aim of this Cochrane Review was to assess whether beta-blockers decrease the number of deaths, strokes, and heart attacks associated
with high blood pressure in adults. We collected and analysed all relevant studies to answer this question and found 13 relevant studies.
Are beta-blockers as good as other medicines when used for treatment of adults with high blood pressure?
Beta-blockers were not as good at preventing the number of deaths, strokes, and heart attacks as other classes of medicines such as
diuretics, calcium-channel blockers, and renin-angiotensin system inhibitors. Most of these findings come from one type of beta-blocker
called atenolol. However, beta-blockers are a diverse group of medicines with different properties, and we need more well-conducted
research in this area.
What was studied in the review?

Millions of people with high blood pressure have strokes, heart attacks, and other diseases, and many of them die. This situation could
be prevented with appropriate treatment. Researchers have tried different medicines for treating high blood pressure.
What are the main results of the review?
We found 13 studies from high-income countries, mainly Western Europe and North America. In the studies, the people receiving
beta-blockers were compared to people who received no treatment or other medicines. The studies showed the following.
Beta-blockers probably make little or no difference in the number of deaths among people on treatment for high blood pressure. This
effect appears to be similar to that of diuretics and renin-angiotensin system inhibitors, but beta-blockers are probably not as good at
preventing deaths from high blood pressure as calcium-channel blockers.
Beta-blockers may reduce the number of strokes, an effect which appears to be similar to that of diuretics. However, beta-blockers may
not be as good at preventing strokes as renin-angiotensin system inhibitors or calcium-channel blockers.
Beta-blockers may make little or no difference to the number of heart attacks among people with high blood pressure. The evidence
suggests that this effect may not be different from that of diuretics, renin-angiotensin system inhibitors, or calcium-channel blockers.
However, among people aged 65 years and older, the evidence suggests that beta-blockers may not be as good at reducing heart attacks
as diuretics.
People given beta-blockers are more likely to have side effects and stop treatment than people taking renin-angiotensin system inhibitors,
but there may be little or no difference in side effects between beta-blockers and diuretics or calcium-channel blockers.
How up-to-date is this review?
The review authors searched for studies that had been published up to June 2016.

Beta-blockers for hypertension (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Beta- blockers versus placebo as first- line therapy for hypertension
Participants: people with hypertension

Settings: high-incom e countries, m ainly Western Europe and North Am erica
Intervention: beta-blockers
Comparison: placebo
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of participants Certainty of the evidence
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Placebo Beta- blockers
Total mortality 52 per 1000 51 per 1000 RR 0.99 23613 ⊕⊕⊕

(46 to 57) (0.88 to 1.11) (4 studies) M oderate 1
Total cardiovascular dis- 64 per 1000 57 per 1000 RR 0.88 23613 ⊕⊕

ease (51 to 63) (0.79 to 0.97) (4 studies) Low1,2
Total stroke 23 per 1000 18 per 1000 RR 0.80 23613 ⊕⊕

(15 to 22) (0.66 to 0.96) (4 studies) Low1,2
Total coronary heart dis- 37 per 1000 34 per 1000 RR 0.93 23613 ⊕⊕⊕
ease (30 to 40) (0.81 to 1.07) (4 studies) M oderate 1
Withdrawal due to adverse 74 per 1000 249 per 1000 RR 3.38 22729 ⊕⊕
effect (60 to 1000) (0.82 to 13.95) (3 studies) Low3
* The basis f or the assumed risk (e.g. the m edian control group risk across studies) is provided in f ootnotes. The corresponding risk (and its 95% conf idence interval) is
based on the assum ed risk in the com parison group and the relative effect of the intervention (and its 95% CI).
CI: conf idence interval; RR: risk ratio.
4
GRADE Working Group grades of evidence

High certainty: Further research is very unlikely to change our conf idence in the estim ate of ef f ect.
M oderate certainty: Further research is likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and m ay change the estim ate.
Low certainty: Further research is very likely to have an im portant im pact on our conf idence in the estim ate of ef f ect and is likely to change the estim ate.
Very low certainty: We are very uncertain about the estim ate.
1 The two studies that contribute to the m ost weight of the pooled RR have high risk of bias (especially incom plete outcom e
reporting due to attrition bias): downgraded by 1 point.
2
The RR is too close to 1 and could easily include 1 if m ore trials are added: downgraded by 1 point.
3 Inconsistent results across studies (I 2 = 100%): downgraded by 2 points.
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5
BACKGROUND outcomes versus the various other classes of drugs. For instance,
several studies have claimed that CCBs are better than other an-
tihypertensive agents in preventing stroke but less good at pre-
Description of the condition venting coronary heart disease (CHD; Angeli 2004; Opie 2002;
Verdecchia 2005). Thus, it is important to know to what extent the
Hypertension is one of the leading causes of disability and pre-
comparisons made by Lindholm and colleagues (Carlberg 2004;
mature deaths worldwide (GBD 2015). The rationale for treat-
Lindhom 2005) and Khan and co-authors (Khan 2006; Kuyper
ing hypertension achieved great impetus with the finding that
2014) relate to beta-blockers versus specific classes of antihyper-
even small reductions in blood pressure can significantly reduce
tensive drugs such as diuretics, CCBs, or RAS inhibitors. RAS in-
associated morbidity and mortality risks (Collins 1990; Staessen
hibitors refer to angiotensin-converting enzyme (ACE) inhibitors,
2003; Thomopoulos 2015). The major classes of drugs for treat-
angiotensin receptor blockers (ARBs), and direct renin inhibitors
ing hypertension include beta-blockers, calcium-channel blockers
(DRI). In general, beta-blockers might be better or worse than
(CCBs), diuretics, and renin-angiotensin system (RAS) inhibitors
one specific class of drugs for specific endpoints so that comparing
(Wiysonge 2013).
beta-blockers with all other classes could be misleading (Carlberg
2004; Lindhom 2005; Khan 2006). In addition, the safety of a
medication is as important to the clinician and the person as is
Description of the intervention the effectiveness; but neither Lindholm and colleagues (Carlberg
Beta-blockers refer to a diverse group of drugs which block the ac- 2004; Lindhom 2005) nor Khan and co-authors (Khan 2006;
tion of endogenous catecholamines on beta-adrenergic receptors, Kuyper 2014) provided data on this aspect when comparing beta-
part of the autonomic (or sympathetic) nervous system (Wiysonge blockers to other antihypertensive agents (see also Table 1).
2007a). The autonomic nervous system has been known to play
a role in blood pressure control since 1949 (Smithwick 1949).
The principal adrenergic receptors present in the human cardio-
vascular system are the β1, β2, and α1 receptors (Fergus 2015; Why it is important to do this review
Pucci 2016). Beta-blockers vary in their β1/β2-adrenergic recep- Proper understanding of the evidence for beta-blocker therapy
tor selectivity and vasodilatory properties, and this diversity has in hypertension requires a regularly updated systematic, compre-
given rise to their classification into first, second, and third gener- hensive, and appropriate analysis of all currently available data.
ation. First-generation beta-blockers exercise identical affinity for In 2007, we published a Cochrane Review which re-assessed the
β1 and β2 receptors and are thus classified as non-selective beta- place of beta-blockers as first-line therapy for hypertension relative
blockers (e.g. propranolol). Second-generation beta-blockers are to each of the other major classes of antihypertensive drugs. An
more attracted to β1 than β2 receptors, and are thus termed se- update of the review was published in 2012. The current review
lective beta-blockers (e.g. atenolol). The third-generation of beta- is an update of the 2012 review.
blockers are known for their intrinsic vasodilatory properties (e.g.
nebivolol) (Weber 2005).
How the intervention might work OBJECTIVES

Beta-blockers have been used as first-line therapy for hypertension To assess the effects of beta-blockers on morbidity and mortality
since the late 1960s, apparently because activation of the sympa- endpoints in adults with hypertension.
thetic nervous system is important in the aetiology and mainte-
nance of hypertension (Berglund 1981; JNC-6 1997; Larochelle
2014; Philipp 1997; Psaty 1997; Ramsay 1999; Wiysonge 2013);
but the robustness of the evidence for use of beta-blockers as METHODS
first-line therapy for hypertension without compelling indica-
tions is controversial (Carlberg 2004; Khan 2006; Lindhom 2005;
Messerli 2003; Opie 1997; Opie 2014; Wiysonge 2007a; Wright Criteria for considering studies for this review
2000). From 2004 to 2006, three meta-analyses were published
which found that beta-blockers were less effective in reducing the
incidence of stroke (Lindhom 2005), and the composite of major
cardiovascular outcomes including stroke, myocardial infarction, Types of studies
and death (Khan 2006), compared to all drugs for treating hyper- Randomised controlled trials (RCTs) with a duration of one year
tension. However, beta-blockers might have different comparative or more.

Types of participants • MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid
Men and non-pregnant women, aged 18 years and over, with hy- Epub Ahead of Print, and MEDLINE Ovid In-Process & Other
pertension as defined by cut-off points operating at the time of Non-Indexed Citations (searched 14 June 2016);
the study under consideration. • Embase Ovid (searched 14 June 2016);
• ClinicalTrials.gov (www.clinicaltrials.gov) searched 14 June
2016);
Types of interventions
The Information Specialist modelled subject strategies for
The treatment group must have received a beta-blocker drug either
databases on the search strategy designed for MEDLINE. Where
as monotherapy or as a first-line drug in a stepped-care approach.
appropriate, they were combined with subject strategy adaptations
The control group could have been a placebo, no treatment, or
of the highly sensitive search strategy designed by Cochrane for
another antihypertensive drug (including a different beta-blocker
identifying randomised controlled (as described in the Cochrane
or the same beta-blocker at a different dose).
Handbook for Systematic Reviews of Interventions Version 5.1.0,
Box 6.4.b. (Handbook 2011)). Search strategies from 19 January
Types of outcome measures 2015 are found in Appendix 1. Search strategies for all major
databases are provided in Appendix 2.
Searches for previous versions of the review were conducted in June
Primary outcomes 2006, May 2011, December 2011, and November 2012 (Bradley
2006; Wiysonge 2007b; Wiysonge 2012; Wiysonge 2013). In the
• Mortality.
previous search conducted in June 2006 (Bradley 2006; Wiysonge
2007b), we searched PubMed, Embase, Cochrane Database of
Secondary outcomes Systematic Reviews, and the York Database of Abstracts of Re-
views of Effectiveness for previous reviews and meta-analyses of
• Total (i.e. fatal and non-fatal) stroke.
antihypertensive treatments that included beta-blockers. Reports
• Total coronary heart disease (myocardial infarction, sudden
of relevant trials referred to in these reviews were obtained. We
death).
then carried out an exhaustive search for eligible RCTs in MED-
• Total cardiovascular disease (CVD: i.e. fatal and non-fatal
LINE (for the period 1966 to June 2006) using the terms “adren-
CHD, stroke, congestive heart failure, and transient ischaemic
ergic beta-antagonists” [MESH], “beta (blockers)” and exp “hy-
attacks).
pertension” [MESH] combined with the optimally sensitive strat-
• Adverse events leading to discontinuation of allocated
egy for identifying RCTs recommended by Cochrane (Higgins
treatment.
2011); Embase (for the period 1980 to June 2006) using a search
• Degree of reduction in systolic and diastolic blood pressure
strategy similar to that used for MEDLINE; and CENTRAL (the
achieved by beta-blocker therapy in relation to each comparator
Cochrane Library, 2016, Issue 2). Finally, experts in the field of
treatment.
hypertension and drug companies manufacturing beta-blockers
We used the definitions employed by the investigators of the study were contacted for unpublished trials. After reaching consensus on
under consideration. the search strategy for each electronic database, the information
specialist of the South African Cochrane Centre conducted the
respective electronic searches.
Search methods for identification of studies

Searching other resources
The Cochrane Hypertension Information Specialist searched
Electronic searches the Hypertension Specialised Register segment (which includes
The Cochrane Hypertension Information Specialist conducted searches of MEDLINE for systematic reviews) to retrieve existing
systematic searches in the following databases for randomised con- systematic reviews relevant to this systematic review, so that we
trolled trials without language, publication year or publication sta- could scan their reference lists for additional trials.
tus restrictions: Where necessary, we contacted authors of key papers and abstracts
• the Cochrane Hypertension Specialised Register via the to request additional information about their trials.
Cochrane Register of Studies (CRS-Web) (searched 14 June We did not perform a separate search for adverse effects of inter-
2016); ventions used for the treatment of hypertension. We considered
• the Cochrane Central Register of Controlled Trials adverse effects described in included studies only.
(CENTRAL; 2016, Issue 6) via the Cochrane Register of Studies We also screened the reference lists of 41 potentially eligible
(CRS-Web) (searched 14 June 2016); studies and 25 relevant reviews and guidelines (Balamuthusamy

2009; Bangalore 2007; Bangalore 2008; Bath 2014; Carlberg blocker and other medications used; outcome measures, including
2004; Chen 2010; Dahlöf 2007; ESH-ESC 2013; Gradman morbidity and mortality endpoints, and adverse events.
2010; Howlett 2014; James 2014; Jennings 2013; Khan 2006; We conducted quantitative analyses according to standard
Kuyper 2014; Larochelle 2014; NICE 2006; Poirier 2014; Pucci Cochrane guidelines (Higgins 2011). We analysed trial partici-
2016; Ripley 2014; Sander 2011; Sciarretta 2011; Thomopoulos pants in groups to which they were randomised, regardless of which
2015; Wong 2014a; Wong 2014b; Wright 2009). In addition, or how much treatment they actually received, and expressed study
we searched the World Health Organization International Clin- results as risk ratios (RR) with 95% confidence intervals (CI). We
ical Trials Registry Platform (www.who.int/trialsearch) using the assessed heterogeneity between studies by graphical inspection of
terms (beta-blocker OR beta-blockers) AND hypertension on 06 results and, more formally followed by, the Chi2 test of homogene-
July 2015. ity. In the absence of significant statistical heterogeneity between
studies (P > 0.1), we performed meta-analysis using a fixed-effect
method (Breslow 1980; Mantel 1959). When there was significant
heterogeneity between study results, we used the random-effects
method (DerSimonian 1986), and investigated the cause of het-
Data collection and analysis
erogeneity by stratified analysis with reference to the characteris-
For the current update, two review authors (CSW and HB) in- tics of the studies included in the meta-analysis. The study char-
dependently examined the eligibility of all titles and abstracts of acteristics considered in the subgroup analyses were age (less than
studies identified by electronic or bibliographic scanning. The two 65 years versus 65 years and older), type of beta-blockade (cardios-
review authors then independently assessed the risk of bias within elective versus non-selective), control group (placebo versus no
included studies and extracted data. At each stage, the they re- treatment), and risk of bias (high versus low risk of bias). In addi-
solved differences by discussion and consensus. If any discrepan- tion, we used the I2 statistic to describe the percentage of between-
cies had persisted, JV would have arbitrated. study variability in effect estimates (for each outcome) attributable
We assessed the risk of bias by addressing seven specific domains, to true heterogeneity rather than chance (Higgins 2003).
as described in Chapter 8 of the Cochrane Handbook for Systematic Various related reviews differ from ours in their inclusion or exclu-
Reviews of Interventions (Higgins 2011). The seven domains were sion of various studies (Carlberg 2004; Dahlöf 2007; Khan 2006;
random sequence generation, allocation concealment, blinding of Lindhom 2005; Wright 2009). We conducted sensitivity analyses
participants and personnel, blinding of outcome assessment, in- to confirm that those different decisions did not lead to different
complete outcome data, selective outcome reporting, and other conclusions.
bias’. For each included study, we described what the study au-
thors reported that they did for each domain and then made a
decision relating to the risk of bias for that domain; by assigning a
judgement of ’low risk’ of bias, ’high risk’ of bias, or ’unclear risk’ RESULTS
of bias.
The data extracted for each study were: methods, including means
of assigning participants to trial interventions, blinding of those
receiving and providing care and outcome assessors, losses to fol-
Description of studies
low-up and how they were handled, and length of trial follow-up; Figure 1 shows the search and selection of studies for this review, in
participant characteristics, including gender, ethnicity and comor- line with the statement of preferred reporting items for systematic
bid conditions; interventions, including type and dose of beta- reviews and meta-analyses (Moher 2009).
Figure 1. PRISMA flow diagram showing the search and selection of studies.

Results of the search 1992), a diuretic (Berglund 1981; HAPPHY 1987; MRC 1985;
We obtained 4453 records from the search conducted in January MRCOA 1992; VA COOP 1982), a CCB (AASK 2002; ASCOT
2015; including 696 duplicates. Of the remaining 3757 records, 2005; ELSA 2002; INVEST 2003), an ACE inhibitor (AASK
1263 were new records. We screened these and found no poten- 2002; UKPDS-39-1998), or an ARB (LIFE 2002).
tially eligible studies. The search conducted on 6 July 2015 found Unlike two related reviews (Dahlöf 2007; Wright 2009), we did
450 studies in Clinicaltrials.gov and 283 records of 257 studies in not consider the UKPDS-39-1998 as a placebo-controlled trial
the WHO International Clinical Trials Registry Platform. None of because participants in the ’less tight control group’ (which these
these ’ongoing’ studies was potentially eligible. Finally, the search reviews consider as placebo) took antihypertensive treatment for
conducted in June 2016 yielded 2716 records, with 596 being du- 57% of total person-years.
plicates. We screened the remaining 2120 records (of which 1551 Ten RCTs recruited participants of both sexes (AASK 2002;
were new records) and found no potentially eligible studies. ASCOT 2005; Coope 1986; ELSA 2002; INVEST 2003; IPPPSH
From the search conducted in June 2006, we identified 21 po- 1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS-39-
tentially eligible RCTs (AASK 2002; ASCOT 2005; Berglund 1998). Six RCTs included participants up to the age of 65 years
1981; Coope 1986; ELSA 2002; HAPPHY 1987; INVEST (Berglund 1981; HAPPHY 1987; IPPPSH 1985; MRC 1985;
2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS-39-1998; VA COOP 1982), and the rest included partic-
UKPDS-39-1998; VA COOP 1982; CAPP 1999; CONVINCE ipants aged 18 to 70 years (AASK 2002), 40 to 79 years (ASCOT
1998; Dutch TIA 1993; MAPHY 1988; NORDIL 2000; STOP 2005), 45 to 75 years (ELSA 2002), more than 50 years (INVEST
1991; STOP-2 1999; TEST 1995), from which we excluded eight. 2003), 55 to 80 years (LIFE 2002), 60 to 79 years (Coope 1986),
In five of the six RCTs, participants in the ’beta-blocker’ group were and 65 to 74 years (MRCOA 1992).
not randomly allocated to a beta-blocker at baseline but to conven- All 13 studies were conducted in industrialised countries, mainly
tional therapy, which referred to either a beta-blocker or a diuretic Western Europe and North America. Nine RCTs provided infor-
(CAPP 1999; CONVINCE 1998; NORDIL 2000; STOP 1991; mation on race or ethnicity: AASK 2002 (0% white), INVEST
STOP-2 1999). None of the five RCTs reported data separately 2003 (44% white), VA COOP 1982 (48% white), UKPDS-39-
for the participants taking beta-blockers and participants taking 1998 (86% white), IPPPSH 1985 (92% white), LIFE 2002 (92%
diuretics. We excluded two studies because not all participants had white), ASCOT 2005 (95.0% white), ELSA 2002 (98.2% white),
hypertension at baseline (Dutch TIA 1993; TEST 1995). We ex- and HAPPHY 1987 (more than 99% white).
cluded the eighth RCT (MAPHY 1988), because it was a subset We have described the 13 RCTs included in this review in detail
of an included RCT (HAPPHY 1987). in the Characteristics of included studies table, and summarised
The remaining 13 RCTs with 91,561 participants meet our inclu- their main features below:
sion criteria (AASK 2002; ASCOT 2005; Berglund 1981; Coope • AASK 2002. This RCT compared the effects of an ACE
1986; ELSA 2002; HAPPHY 1987; INVEST 2003; IPPPSH inhibitor (ramipril), a CCB (amlodipine), and a beta-blocker
1985; LIFE 2002; MRC 1985; MRCOA 1992; UKPDS-39-1998; (metoprolol) on hypertensive renal disease progression in African
VA COOP 1982), and we included them in the previous review American people aged 18 to 70 years. Additional
(Bradley 2006; Wiysonge 2007b). antihypertensive agents were added sequentially to achieve blood
The May 2011 search yielded 1566 records from the electronic pressure goals. Cardiovascular events, cardiovascular mortality.
databases (after removing duplicates), which we screened and iden- and all-cause mortality were reported. The trial followed 1094
tified 19 potentially eligible studies (ACCORD 2010; ADaPT participants for a mean duration of 4.1 years.
2008; APSIS 2006; CAPRICORN 2001; CARDHIAC 2008;
• ASCOT 2005. The participants were randomised to a CCB
CHHIPS 2009; CIBIS-II 1999; COMET 2003; COPE 2005;
(amlodipine) adding an ACE inhibitor (perindopril) as required
COPERNICUS 2004; COSMOS 2010; Dietz 2008; GEMINI
to reach blood pressure targets or a beta-blocker (atenolol)
2008; IMPACT-HF 2004; MERIT-HF 2002; Nilsson 2007;
adding a diuretic (bendroflumethiazide) as required. The
REASON 2009; RESOLVD 2000; SENIORS 2005). Following
participants were men and women with hypertension aged 40 to
review of the full-text articles of the 19 studies, we found that none
79 years. The main outcome measure was combined non-fatal
of them met our inclusion criteria.
myocardial infarction and fatal CHD, and secondary endpoints
Finally, we obtained 508 abstracts from the December 2011 search;
included all-cause mortality, cardiovascular mortality, and total
with one potentially eligible study (Marazzi 2011). This study did
stroke. At the end of the trial, 78% of participants were taking at
not met our inclusion criteria and was excluded.
least two antihypertensive medications and only 15% were
taking amlodipine and 9% were taking atenolol monotherapy.
The study enrolled 19,257 participants and followed them for a
Included studies
median duration of 5.5 years.
The 13 included RCTs compared a beta-blocker to a placebo or
no treatment (Coope 1986; IPPPSH 1985; MRC 1985; MRCOA

• Berglund 1981. This RCT evaluated the long-term effects • INVEST 2003. The trial was designed to compare the
of a thiazide diuretic (bendroflumethiazide) compared to a beta- effect of a CCB (verapamil sustained release, SR), and a beta-
blocker (propranolol) in men with hypertension aged 47 to 54 blocker (atenolol) in hypertensive participants with documented
years. Hydralazine and other antihypertensive medications were coronary artery disease, on all-cause and cardiovascular death,
added to achieve blood pressure goals. The investigators reported and various non-fatal cardiovascular events. Other drugs, mainly
total mortality. At the end of the trial, 70% of participants taking trandolapril (to the verapamil SR group) and
diuretic and 74% taking beta-blockers were on assigned hydrochlorothiazide (to the atenolol group), were added to
treatment and 40% of participants taking diuretic and 42% achieve blood pressure control as required. At two years, 77.5%
taking beta-blocker were on monotherapy. The study enrolled of participants in the beta-blocker group and 81.5% in the CCB
106 participants and the study lasted 10 years. group were on the assigned treatment (18.1% taking beta-
blocker and 17.4% taking CCB monotherapy). The trial
• Coope 1986. The trial was designed to determine whether followed up 22,576 participants aged 50 years and older for a
the treatment of hypertension using beta-blocker therapy mean duration of 2.7 years.
(atenolol) in a stepped-care approach compared to no treatment
reduced the incidence of stroke, CHD, cardiovascular death, or • IPPPSH 1985. The trial was designed to evaluate the effect
all-cause mortality. Step one was monotherapy with atenolol, of antihypertensive therapy with a beta-blocker (oxprenolol) on
step two added a thiazide diuretic (bendrofluazide), and steps the incidence of cardiac events (myocardial infarction and
three and four added other antihypertensive agents. At the end of sudden death) and cerebrovascular accidents. Trial medication
the trial, 70% of participants in the beta-blocker group were could be increased or other non-beta-blocker antihypertensive
taking assigned treatment, 17% were taking atenolol alone, and drugs added according to predefined recommendations, as
53% were taking atenolol plus bendrofluazide. The trial followed necessary, to reduce blood pressure. During the trial, 30% of
up 884 participants aged 60 to 79 years for a mean duration of participants remained on beta-blocker monotherapy while 15%
4.4 years. remained on placebo only. The trial followed up 6357
participants aged 40 to 64 years for three to five years.
• ELSA 2002. The trial was designed to compare the effects
of a beta-blocker (atenolol) and a CCB (lacidipine) on the • LIFE 2002. The trial was designed to evaluate the effects of
change in mean maximum intima-media thickness and plaque an ARB (losartan) compared to a beta-blocker (atenolol) in
number in men and women with hypertension. The people with hypertension with documented left ventricular
investigators also reported data on fatal and non-fatal hypertrophy on the combined incidence of cardiovascular
cardiovascular events and total mortality. If satisfactory blood mortality and morbidity. Other drugs were added to reduce
pressure control was not achieved, trial medication could be blood pressure as necessary. At the end of the trial, 63% of
increased, and when necessary open-label hydrochlorothiazide participants in the beta-blocker group and 67% in the ARB
was added. At the end of the trial, 85% of participants in the group were on assigned treatment; 11% of participants were on
beta-blocker group and 78% in the CCB group were known to monotherapy in each group. The trial followed up 9193
be on assigned treatment. The participants on monotherapy at participants aged 55 to 80 years for a mean duration of 4.8 years.
the end of the trial were 43% in the beta-blocker group and 42%
in the CCB group. The trial followed up 2334 participants aged • MRC 1985. The trial was designed to determine whether
45 to 75 years for a mean duration of 3.75 years. drug treatment of mild hypertension reduced the rates of fatal
and non-fatal stroke and of coronary events. Participants were
• HAPPHY 1987. The trial was designed to compare the randomised to active treatment (propranolol or bendrofluazide)
effects of beta-blockers (mainly atenolol, 1599 participants or or placebo. At the end of the study, the proportion of
metoprolol, 1631 participants) and thiazide diuretics participants on assigned treatment in the beta-blocker group was
(bendroflumethiazide or hydrochlorothiazide) on the incidence 59%, in the diuretic group was 62%, and placebo group was
of non-fatal myocardial infarction, CHD mortality, and total 56%. The trial followed up 17,354 participants aged 35 to 64
mortality in men with mild to moderate hypertension. Other years for a mean duration of 4.9 years.
drugs were added to reduce blood pressure as necessary. At the
end of the trial, 86% of participants in the beta-blocker group • MRCOA 1992. The trial was designed to establish whether
and 83% in the diuretic group were on assigned treatment. More treatment of hypertension in older adults reduced the risk of
participants in the beta-blocker group (68%) than in the diuretic stroke, CHD, and death from all causes. Participants were
group (62%) were on monotherapy. The trial followed up 6569 randomised to a beta-blocker (atenolol), a diuretic (amiloride
participants aged 40 to 64 years for a mean duration of 45.1 and hydrochlorothiazide), or placebo. Other drugs were added as
months. necessary. At five years, 52% of participants assigned to beta-
blockers required supplementary drugs compared to 38% in the
diuretic group. At the end of the study, 37% of participants in

the beta-blocker group, 52% in the diuretic group, and 47% in We excluded 28 potentially eligible studies because of the very
the placebo group were on the assigned treatment. The trial short duration of relevant interventions (CHHIPS 2009; Dietz
followed up 4396 participants aged 65 to 74 years for 5.8 years. 2008), a beta-blocker was not given as monotherapy or first-line
therapy (ACCORD 2010; CAPP 1999; CAPRICORN 2001;
• UKPDS-39-1998. The trial was designed to determine CARDHIAC 2008; CIBIS-II 1999; CONVINCE 1998; COPE
whether tight control of blood pressure with either a beta- 2005; GEMINI 2008; Marazzi 2011; NORDIL 2000; STOP
blocker (atenolol) or an ACE inhibitor (captopril) prevents 1991; STOP-2 1999), the study was not an RCT (ADaPT 2008),
macrovascular and microvascular complications in participants the study was a subset of an included RCT (MAPHY 1988),
with type 2 diabetes. Participants were randomised to study the study has not reported data on mortality or hard cardio-
drugs, with other drugs added as required. At the end of the trial, vascular endpoints (COSMOS 2010; Nilsson 2007), or not all
65% of participants in the beta-blocker group and 78% in the enrolled participants had hypertension (APSIS 2006; CIBIS-II
ACE inhibitor group were on assigned treatment. The trial 1999; CAPRICORN 2001; COMET 2003; COPERNICUS
followed up 758 participants aged 25 to 65 years for 8.4 years. 2004; Dutch TIA 1993; IMPACT-HF 2004; MERIT-HF
2002; RESOLVD 2000; SENIORS 2005; TEST 1995).The tri-
• VA COOP 1982. This trial compared a beta-blocker
als where not all enrolled participants had hypertension were
(propranolol) and a diuretic (hydrochlorothiazide) for the initial
of beta-blockers in people with heart failure (CIBIS-II 1999;
treatment of hypertension in men aged 21 to 65 years. During
COMET 2003; COPERNICUS 2004; IMPACT-HF 2004;
treatment, fewer participants receiving hydrochlorothiazide
Marazzi 2011; MERIT-HF 2002; RESOLVD 2000; SENIORS
required termination as compared with men receiving
2005), angina pectoris (APSIS 2006), post-myocardial infarction
propranolol. A total of 683 men were recruited. During the
(CAPRICORN 2001), or transient ischaemic attack or stroke
initial 10 weeks (i.e. dose-finding period), the clinic staff titrated
(Dutch TIA 1993; TEST 1995).
the blinded drug upward until the target blood pressure was
We have described each of the 28 excluded studies in greater detail
reached. Participants were withdrawn from the study if, on any
in the Characteristics of excluded studies table.
follow-up visit, diastolic blood pressure was 120 mmHg or more.
The trial lasted one year.
Risk of bias in included studies
The risk of bias in included studies is summarised in Figure 2 and
Excluded studies Figure 3.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

Allocation
study protocols of the remaining studies (Berglund 1981; Coope
Seven trials reported the method used to generate the randomi- 1986; VA COOP 1982).
sation sequence adequately (ASCOT 2005; Coope 1986; ELSA
2002; INVEST 2003; IPPPSH 1985; LIFE 2002; UKPDS-39-
1998). It was unclear in the remaining six (AASK 2002; Berglund Other potential sources of bias
1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA COOP All the studies added other antihypertensive drugs to the first-line
1982). treatment to help achieve the blood pressure goals. The observed
Five trials had adequate allocation concealment (ASCOT 2005; effects may equally have resulted from the additional drugs used.
Coope 1986; INVEST 2003; IPPPSH 1985; UKPDS-39-1998), In addition, two studies were stopped early for data-dependent
while in the remaining eight, the information provided was insuf- reasons (AASK 2002; ASCOT 2005).
ficient to assess this aspect of risk of bias (AASK 2002; Berglund The high risk of bias in most of the included studies limits our
1981; ELSA 2002; HAPPHY 1987; LIFE 2002; MRC 1985; confidence in the effect estimates for beta-blockers as first-line
MRCOA 1992; VA COOP 1982). therapy for hypertension (Balshem 2011; Guyatt 2011), as shown
in the ’Summary of findings’ tables (Summary of findings for the
main comparison; Summary of findings 2; Summary of findings
Blinding
3; Summary of findings 4).
Outcome assessors were blinded in 11 studies (AASK 2002;
ASCOT 2005; Coope 1986; ELSA 2002; HAPPHY 1987;
Effects of interventions
INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA
1992; VA COOP 1982), and two trials were completely unblinded See: Summary of findings for the main comparison Beta-
(Berglund 1981; UKPDS-39-1998). However, in the Berglund blockers versus placebo as first-line therapy for hypertension;
1981 study, the outcome assessed (i.e. death) is unlikely to be in- Summary of findings 2 Beta-blockers compared to diuretics
fluenced by lack of blinding. as first-line therapy for hypertension; Summary of findings 3
Participants were also blinded in seven trials (AASK 2002; ELSA Beta-blockers compared to calcium-channel blockers as first-line
2002; IPPPSH 1985; LIFE 2002; MRC 1985; MRCOA 1992; therapy for hypertension; Summary of findings 4 Beta-blockers
VA COOP 1982), but healthcare workers were only blinded in compared to renin-angiotensin system inhibitors as first-line
five trials (AASK 2002; ELSA 2002; IPPPSH 1985; LIFE 2002; therapy for hypertension
VA COOP 1982) . Due to the small number of participants in trials with ACE in-
hibitors (2 trials with 1635 participants (AASK 2002; UKPDS-
39-1998)) and ARBs (1 trial with 9193 participants (LIFE 2002)),
Incomplete outcome data we combined data for the two classes of RAS inhibitors. We ex-
Loss to follow-up was negligible in AASK 2002 (0%), ASCOT cluded the trial that compared the effects of atenolol and aliskiren,
2005 (0.3%), IPPPSH 1985 (0.6%), HAPPHY 1987 (1%), LIFE the first DRI to be approved for the treatment of hypertension
2002 (2%), INVEST 2003 (2.5%), ELSA 2002 (4%), UKPDS- (Dietz 2008), because of the very short duration (12 weeks) of
39-1998 (4%), Berglund 1981 (7%), and VA COOP 1982 (8%), relevant interventions.
but high in MRC 1985 (19%) and MRCOA 1992 (25%) trials.
Coope 1986 did not report loss to follow-up.
The following trials stated the proportions of participants taking Mortality
assigned beta-blocker treatment at the end of the trial: HAPPHY The effect of beta-blocker therapy on total mortality was not sig-
1987 (86%), ELSA 2002 (85%), Berglund 1981 (74%), Coope nificantly different from that of placebo (4 trials, 23,613 partici-
1986 (70%), UKPDS-39-1998 (65%), LIFE 2002 (63%), MRC pants: RR 0.99, 95% CI 0.88 to 1.11; I2 = 0%; moderate certainty
1985 (59%), VA COOP 1982 (39%), MRCOA 1992 (37%), and evidence).
IPPPSH 1985 (30%). Apart from the four studies included in our placebo comparison,
previous related reviews included four other studies (Dutch TIA
1993; STOP 1991; TEST 1995; UKPDS-39-1998). When we
Selective reporting added these studies in a sensitivity analysis, there was still no evi-
Ten studies reported outcomes as stated in the respective study dence of a significant effect of beta-blockers on mortality (8 trials,
protocols (AASK 2002; ASCOT 2005; ELSA 2002; HAPPHY 28,181 participants: RR 0.93, 95% CI 0.85 to 1.02, I2 = 39%).
1987; INVEST 2003; IPPPSH 1985; LIFE 2002; MRC 1985; In addition, total mortality was not significantly different between
MRCOA 1992; UKPDS-39-1998). We did not have access to the beta-blockers and diuretics (5 trials, 18,241 participants: RR 1.04,

95% CI 0.91 to 1.19, I2 = 0%; moderate certainty evidence), and 1.54, I2 = 66%; low certainty evidence), a CCB (3 trials, 44,167
beta-blockers and RAS inhibitors (3 trials, 10,828 participants: RR participants: RR 1.05, 95% CI 0.96 to 1.15, I2 = 32%; moderate
1.10, 95% CI 0.98 to 1.24, I2 = 54%; moderate certainty evidence). certainty evidence), or a RAS inhibitor (2 trials, 9951 participants:
Total mortality was significantly higher for beta-blockers com- RR 0.90, 95% CI 0.76 to 1.06, I2 = 42%; low certainty evidence).
pared to CCBs (4 trials, 44,825 participants: RR 1.07, 95% CI There was significant statistical heterogeneity between trials com-
1.00 to 1.14, I2 = 2%; moderate certainty evidence) corresponding paring beta-blockers to diuretics (I2 = 66%, P = 0.03), which may
to an absolute risk increase (ARI) of 0.5% and number of partici- be explained by differences in age. The pooled RR in the trials
pants needed to treat for an additional harmful outcome (NNTH) whose participants were less than 65 years of age was 0.97 (95%
with a beta-blocker rather than a CCB treated for five years of 200. CI 0.81 to 1.17, I2 = 5%, P = 0.35), while in the single trial in-
volving participants aged 65 years and older atenolol was associ-
ated with an increased CHD incidence (RR 1.63, 95% CI 1.15
Total stroke
to 2.32) (MRCOA 1992). The difference between the subgroups
Participants treated with a beta-blocker had a significantly lower was statistically significant (test for subgroup differences: Chi2 =
risk of developing a stroke than participants taking placebo (4 6.70, degrees of freedom (df ) = 1, P = 0.01, I2 = 85.1%).
trials, 23,613 participants: RR 0.80, 95% CI 0.66 to 0.96, I2 =
0%; low certainty evidence). A sensitivity analysis adding the four
studies included in related reviews yielded similar results (8 trials, Total cardiovascular disease
28,181 participants: RR 0.79, 95% CI 0.70 to 0.90, I2 = 31%).
Compared to participants taking placebo, participants taking beta-
Expressed as absolute risk reduction (ARR), beta-blockers reduced
blockers had a significantly reduced risk of having a cardiovascular
the risk of stroke by 0.5% (compared to placebo). The correspond-
event (4 trials, 23,613 participants: RR 0.88, 95% CI 0.79 to
ing number of participants needed to treat for an additional ben-
0.97, I2 = 21%; ARR 0.7%, NNTB 140 for 5 years; low certainty
eficial outcome (NNTB) with a beta-blocker for approximately
evidence). A sensitivity analysis adding studies included in related
five years to prevent one stroke was 200.
reviews yielded similar results.
We found no statistically significant difference in stroke events
The effect of beta-blockers on total cardiovascular events was not
between participants treated with a beta-blocker and participants
significantly different from that of diuretics (4 trials, 18,135 par-
treated with a diuretic (4 trials, 18,135 participants: RR (ran-
ticipants: RR 1.13, 95% CI 0.99 to 1.28, I2 = 45%; moderate cer-
dom effects) 1.17, 95% CI 0.65 to 2.09, I2 = 73%; moderate cer-
tainty evidence) and RAS inhibitors (3 trials, 10,828 participants:
tainty evidence). However, participants treated with a beta-blocker
RR (random effects) 1.00, 95% CI 0.72 to 1.38, I2 = 74%; low cer-
(atenolol) had more stroke events than participants treated with a
tainty evidence). Beta-blockers increased total cardiovascular dis-
CCB (3 trials, 44,167 participants: RR 1.24, 95% CI 1.11 to 1.40,
ease as compared to CCBs (2 trials, 19,915 participants: RR 1.18,
I2 = 0%; ARI = 0.6%, NNTH 180; moderate certainty evidence)
95% CI 1.08 to 1.29, I2 = 0%; ARI = 1.3%, NNTH 80; moderate
or an RAS inhibitor (2 trials, 9951 participants: RR 1.30, 95%
certainty evidence).
CI 1.11 to 1.53, I2 = 29%; ARI = 1.5%, NNTH 65; moderate
The significant heterogeneity of effect on total cardiovascular dis-
certainty evidence).
ease between beta-blockers and RAS inhibitors (I2 = 74%, P =
The heterogeneity among trials comparing beta-blockers to di-
0.02) was explained by the effect of beta-blockers being similar to
uretics may be related to the type of beta-blockade (I2 = 73%, P
that of ACE inhibitors (2 trials, 635 participants: RR 0.82, 95%
= 0.01). There was an increase in the risk of stroke with the non-
CI 0.64 to 1.05, I2 = 0%) but worse than that of an ARB (1 trial,
selective beta-blocker, propranolol, in the MRC 1985 trial (RR
9193 participants: RR 1.16, 95% CI 1.04 to 1.30) with an ARI
2.28, 95% CI 1.31 to 3.95) with an ARI of 0.5% and NNTH
of 1.8% and NNTH of 56.
with a beta-blocker for approximately five years of 200; but no dif-
ference with the cardio-selective beta-blockers, atenolol or meto-
prolol (RR 1.00, 95% CI 0.74 to 1.33, I2 = 60).
Adverse events leading to discontinuation of
allocated treatment
Total coronary heart disease We analysed data on the rate of withdrawal from randomly as-
The effect of beta-blocker therapy on CHD was not significantly signed treatment due to any adverse events, and also report on the
different from that of a placebo (4 trials, 23,613 participants: RR frequency of specific adverse events including depression, fatigue,
0.93, 95% CI 0.81 to 1.07, I2 = 0%; moderate certainty evidence). and sexual dysfunction.
A sensitivity analysis adding the four studies included in related Trial participants on a beta-blocker were no more likely than par-
reviews yielded similar results (8 trials, 28,181 participants: RR ticipants receiving a placebo to discontinue treatment due to ad-
0.91, 95% CI 0.81 to 1.02, I2 = 0%). verse events (3 trials, 22,729 participants: RR (random effects)
The beta-blocker effect was similar to that of a diuretic (4 trials, 3.38, 95% CI 0.82 to 13.95; low certainty evidence). However,
18,135 participants: RR (random effects) 1.12, 95% CI 0.82 to there was significant heterogeneity of effect between the trials (I

2 = 100%, P < 0.00001); with no difference in the likelihood of fatigue than participants taking a diuretic (1 trial, 8700 partici-
discontinuing treatment with oxprenolol (1 trial, 6357 participants: RR 2.48, 95% CI 1.73 to 3.54), a CCB (1 trial, 19,257
pants: RR 0.95, 95% CI 0.87 to 1.04) and an increased likelihood participants: RR 1.99, 95% CI 1.84 to 2.16), or a RAS inhibitor
with propranolol or atenolol (2 trials, 16,372; RR (random effects) (2 trials, 9951 participants: RR 1.17, 95% CI 1.06 to 1.28, I2 =
6.35, 95% CI 3.94 to 10.22, I2 = 91%). A sensitivity analysis 0%).
adding studies included in related reviews also revealed significant The risk of sexual dysfunction was not different between beta-
heterogeneity of effect (I2 = 99%, P < 0.00001). blockers and placebo (2 trials, 19,414 participants: RR (random
Participants taking a beta-blocker were more likely to discontinue effects) 1.95, 95% CI 0.33 to 11.59, I2 = 97.5%). However, beta-
treatment due to adverse events than participants taking a RAS blockers decreased the risk of sexual dysfunction when compared
inhibitor (2 trials, 9951 participants: RR 1.41, 95% CI 1.29 to to diuretics (1 trial, 8700 participants: RR 0.50, 95% CI 0.36
1.54, I2 = 12%; ARI 5.5%, NNTH 18; low certainty evidence), to 0.70); but increased the risk relative to CCBs (1 trial, 19,257
but there was no significant difference with a diuretic (3 trials, participants: RR 1.27, 95% CI 1.14 to 1.42) and RAS inhibitors
11,566 participants: RR (random effects) 1.69, 95% CI 0.95 to (2 trials, 9951 participants: RR 1.34, 95% CI 1.10 to 1.63, I2 =
3.00, I2 = 95%; low certainty evidence) or a CCB (2 trials, 21,591 56.2%).
participants: RR (random effects) 1.20, 95% CI 0.71 to 2.04, I2
= 93%; low certainty evidence).
Degree of reduction in systolic and diastolic blood
There was no significant difference in the incidence of depressive
pressure achieved by beta-blocker therapy in relation
symptoms between beta-blockers and placebo (2 trials, 7082 par-
to each comparator treatment
ticipants: RR (random effects) 1.03, 95% CI 0.65 to 1.63, I2 =
83.0) or RAS inhibitors (1 trial, 758 participants: RR 1.12, 95% Compared to placebo, first-line beta-blockers plus supplementary
CI 0.07 to 17.80). antihypertensive drugs reduced systolic blood pressure by about
Beta-blockers did not increase the risk of fatigue compared to 11 mmHg and diastolic blood pressures by about 6 mmHg (Table
placebo or no treatment (2 trials, 13,782 participants: RR (ran- 2). However, compared to diuretics, CCBs, or RAS inhibitors, the
dom effects) 4.35, 95% CI 0.17 to 108.74, I2 = 99.0%). However, mean systolic and diastolic blood pressures at the end of the trials
trial participants taking a beta-blocker were more likely to develop were 0 to 2 mmHg higher in the beta-blocker group (Table 2).

Beta-blockers for hypertension (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Beta- blockers compared to diuretics as first- line therapy for hypertension

Comparison: diuretics
Diuretics Beta- blockers

Total cardiovascular dis- 45 per 1000 51 per 1000 RR 1.13 18135 ⊕⊕⊕
Total stroke 12 per 1000 14 per 1000 RR 1.17 18135 ⊕⊕

(8 to 25) (0.65 to 2.09) (4 studies) Low1,2
Total coronary heart dis- 33 per 1000 37 per 1000 RR 1.12 18135 ⊕⊕
effect (104 to 327) (0.95 to 3.00) (3 studies) Low1,2
16

1 The two studies that contribute to the m ost weight of the pooled RR have high risk of bias (especially incom plete outcom e
reporting due to attrition bias): downgraded by 1 point.
2
Inconsistent results across studies (I 2 = 73% f or stroke, 66% f or coronary heart disease, and 95% f or adverse ef f ects):
downgraded by 1 point.
17
Beta- blockers compared to calcium- channel blockers as first- line therapy for hypertension

Comparison: calcium -channel blockers
Calcium- channel blockers Beta- blockers

Total cardiovascular dis- 81 per 1000 96 per 1000 RR 1.18 19915 ⊕⊕⊕
Total stroke 23 per 1000 29 per 1000 RR 1.24 44167 ⊕⊕⊕

Total coronary heart dis- 39 per 1000 41 per 1000 RR 1.05 44167 ⊕⊕⊕

effect (23 to 67) (0.71 to 2.04) (2 studies) Low2,4
18

1 The RR is too close to 1 and could easily include 1 if m ore trials are added: downgraded by 1 point.
2
Only 2 hypertension trials com paring beta-blockers to calcium -channel blockers have reported data on this outcom e:
3 Only 3 hypertension trials com paring beta-blockers to calcium -channel blockers have reported data on this outcom e:
4 Inconsistent results across studies (I 2 = 93%): downgraded by 1 point.
19
Beta- blockers compared to renin- angiotensin system inhibitors as first- line therapy for hypertension

Comparison: renin-angiotensin system inhibitors
Renin- angiotensin system Beta- blockers

inhibitors

Total cardiovascular dis- 115 per 1000 115 per 1000 RR 1.0 10828 ⊕⊕
Total stroke 51 per 1000 66 per 1000 RR 1.30 9951 ⊕⊕⊕

Total coronary heart dis- 54 per 1000 49 per 1000 RR 0.90 9951 ⊕⊕
Withdrawal due to adverse 137 per 1000 194 per 1000 RR 1.41 9951 ⊕⊕⊕
effect (177 to 211) (1.29 to 1.54) (2 studies) M oderate 3
20

1 Only 3 hypertension trials com paring beta-blockers to RAS inhibitors have reported data on this outcom e: downgraded by 1
point.
2
Inconsistent results across studies (I 2 = 74%): downgraded by 1.
3 Only 2 hypertension trials com paring beta-blockers to RAS inhibitors have reported data on this outcom e: downgraded by 1
point.
4 Im precise results, as the ef f ect ranges f rom a clinically im portant benef it to a sm all increase in harm : downgraded by 1
point.
21
DISCUSSION treatment of hypertension (Poirier 2014). Of the 40,245 partic-
ipants using beta-blockers in this review, atenolol was used by
30,150 participants (75%). Due to the paucity of data using beta-
blockers other than atenolol, it is not possible to say whether the
Summary of main results
(lack of ) effectiveness and (in)tolerability of beta-blockers seen in
We included 13 eligible RCTs, which compared beta-blockers to this review is a property of atenolol or is a class effect of beta-block-
placebo, diuretics, CCBs, and RAS inhibitors. These RCTs gen- ers. From this review, we cannot support the claim by Lindhom
erally had a high risk of bias resulting from limitations in study and colleagues that cardioselective beta-blockers may be inferior
design, conduct, and data analysis. to non-selective beta-blockers in the treatment of hypertension
We found little or no difference in all-cause mortality between (Carlberg 2004).
beta-blockers and placebo, diuretics or RAS inhibitors, but all- A limitation of both previous reviews and ours is the absence of
cause mortality was higher for beta-blockers compared to CCBs. trials assessing the effects of the new vasodilating beta-blockers
The evidence on mortality was of moderate-certainty for all com- (e.g. carvedilol, bucindolol, and nebivolol) on mortality and hard
parisons. Total cardiovascular disease was lower for beta-blockers cardiovascular outcomes. Possible mechanisms to explain the poor
compared to placebo, which is a reflection of the significant de- ability of beta-blockers to reduce stroke include a propensity to
crease in stroke, since there was little or no difference in CHD because diabetes (Opie 2004), a failure to decrease central aortic
tween beta-blockers and placebo. There were no significant differ- pressure as much as brachial pressure, and others. Diabetes likely
ences between beta-blockers and placebo in adverse events leading requires years to develop cardiovascular complications (Verdecchia
to withdrawal from assigned treatment (low-certainty evidence). 2004), so we favour the mechanism involving lesser reduction of
The effect of beta-blockers on cardiovascular disease was worse central aortic pressure by beta-blockers. Vasodilating beta-blockers
than that of CCBs (moderate-certainty evidence), but was not (Broeders 2000; Kalinowski 2003; Pucci 2016) have been shown
different from that of diuretics (moderate-certainty evidence) or to reduce central pressures better than conventional beta-block-
RAS inhibitors (low-certainty evidence). In addition, there was an ers (Kamp 2010; Polónia 2010); most probably because vasodi-
increase in stroke with beta-blockers compared to CCBs (mod- latation favourably alters the pattern of the pressure wave reflect-
erate-certainty evidence) and RAS inhibitors (moderate-certainty ing back from the periphery, thereby lowering the central pres-
evidence). However, there was little or no difference in CHD be- sure. Nonetheless, carvedilol and nebivolol also cause bradycardia,
tween beta-blockers and diuretics (low-certainty evidence), CCBs which is thought to be the principal mechanism whereby atenolol
(moderate-certainty evidence), or RAS inhibitors (low-certainty with or without thiazide may be less able to lower the central
evidence). Participants taking beta-blockers were more likely to pressure than amlodipine with or without perindopril (Williams
discontinue treatment due to adverse events than participants tak- 2006). At any rate, high-quality outcome studies are required to
ing RAS inhibitors (moderate-certainty evidence), but there was show that hard cardiovascular endpoints such as stroke and CHD
no significant difference with diuretics (low-certainty evidence) or are significantly reduced by beta-blockers not studied in this re-
CCBs (low certainty evidence). view.
We demonstrated a high degree of homogeneity of effect for the Information reported in the trials considered in this review was
comparisons of beta-blockers versus CCBs for all-cause mortality insufficient to explore the effect of race or ethnicity, as most trial
(I2 = 2%), stroke (I2 = 0%), and total cardiovascular events (I2 participants were white (Park 2007). However, the finding that
= 0%) but with less homogeneity for CHD (I2 = 32%). For the beta-blockers are less effective than diuretics in older people, is
comparison of beta-blockers versus RAS inhibitors, the I2 values most likely to be applicable to older black people as well (Materson
for stroke and withdrawal rates also demonstrate a high degree of 1993).
consistency across the studies making our conclusions more secure
(Higgins 2003; Higgins 2011). For the comparison with diuretics,
there were no statistically significant differences in any morbidity Quality of the evidence
or mortality outcome.
The certainty of the evidence on the effects of beta-blockers was
generally moderate to low (Balshem 2011). In the GRADE system,
RCTs without important limitations constitute high-certainty ev-
Overall completeness and applicability of idence. However, the system considers five factors that can lower
evidence the certainty of the evidence: study limitations, heterogeneity, indi-
Though beta-blockers are a heterogeneous group of pharmacolog- rectness, imprecision, and publication bias. Overall, the GRADE
ical agents, differing in beta-adrenergic receptor selectivity, intrin- system classifies research evidence into high-, moderate-, low-, or
sic sympathomimetic activity, and vasodilatory capabilities (Kamp very low-certainty. Low-certainty evidence implies that the “true
2010; Pedersen 2007; Polónia 2010), we found no outcome tri- effect is likely to be different from the estimate of effect” found in
als with head-to-head comparisons between beta-blockers for the the review.

Our major concern with the evidence related to inherent short- inhibition for stroke. By comparing beta-blockers with all other
comings in the included primary studies. The emphasis was often therapies, Lindholm and colleagues were only able to show an
on the results with the first drug used, whereas most studies used inferiority of beta-blockade on stroke reduction (Carlberg 2004;
stepped-up therapy to help achieve the blood pressure goals. Thus Lindhom 2005). In a similar meta-analysis, Khan and McAlister
poorer outcomes with first-line beta-blockers may equally have re- found beta-blockers to be inferior to all other therapies in effects
sulted from the use of other drugs; explaining why other authors on a composite outcome of major cardiovascular events (stroke,
restricted their systematic reviews of beta-blocker therapy to tri- myocardial infarction, and death) and stroke for older people with
als where confounding supplementary drug classes were adminis- hypertension but found no difference in effects for younger people
tered to less than half of participants (Wright 1999; Wright 2000; (Khan 2006). The claim by Khan 2006 that the defects of beta-
Wright 2009). Although we were less restrictive than Wright and blockade are limited to older people relies heavily on the Medical
colleagues (Wright 1999; Wright 2000), we included only trials in Research Council trial in older people with hypertension in which
which all the participants in one group received a beta-blocker at the beta-blocker was atenolol and where the dropout rate was 25%
baseline, whether or not other antihypertensive drug classes were (MRCOA 1992). In addition, Khan 2006 classified trials which
later added to achieve blood pressure targets. This requirement enrolled participants as young as 40 (ASCOT 2005), 45 (ELSA
was in contrast to other systematic reviews (Carlberg 2004; Dahlöf 2002), and 50 (INVEST 2003) years as trials of older people with
2007; Khan 2006; Lindhom 2005). The dropout rates were high hypertension. At present, there are insufficient data to make a valid
in two of the studies of diuretics, potentially introducing attrition comparison of beta-blocker effects on younger versus older people,
bias (MRC 1985; MRCOA 1992). although this is an important hypothesis.
It may be that only people with complicated hypertension or ad- We used the I2 statistic to evaluate the consistency in study results
vanced disease are included in most studies, thereby ignoring the (Higgins 2003; Higgins 2011). In our meta-analyses, heterogene-
possible differing benefits of different antihypertensive medica- ity was very low for the outcomes of beta-blockers versus placebo or
tions on different organs and on different stages of disease devel- no treatment. We found a modest 20% relative reduction in stroke
opment (Zanchetti 2005). A further problem is that in the two by beta-blockers compared to placebo with six studies, which is
groups of the studies we analysed, and especially in the case of similar to the relative reduction reported by Lindholm and col-
the comparison with diuretics, there were discrepancies between leagues using seven studies (Lindhom 2005). With their wider
the achieved blood pressure levels (Table 2), and even small blood inclusion criteria, Lindholm and colleagues included three stud-
pressure differences may be linked to significant differences in out- ies not considered by us (Dutch TIA 1993; STOP 1991; TEST
comes (Collins 1990; Staessen 2003). However, there were no con- 1995), which resulted in significant heterogeneity of effect in their
sistent differences in the blood pressure reduction between beta- findings. By contrast, there was excellent homogeneity of effect
blockers and the other agents used to explain the outcome differ- with the four studies included in our comparison of beta-blockers
ences we found (Table 2). Yet another limitation is that (due to to placebo as shown by an I2 value of 0% (Coope 1986; IPPPSH
the scarcity of relevant trials) we combined the potentially differ- 1985; MRC 1985; MRCOA 1992). Thus, we were able to give
ent classes of RAS inhibitors (i.e. ACE inhibitors (captopril and additional validation to one of the crucial findings of Lindholm
lisinopril) and ARB (losartan). However, we believe that the sim- and colleagues (Lindhom 2005), namely that stroke reduction by
ilarities between these agents as antihypertensive drugs outweigh beta-blockade is suboptimal.
any potential differences. Two other reviews also differed from ours in their inclusion or ex-
clusion of various studies (Dahlöf 2007; Wright 2009). Both con-
sidered the UKPDS-39-1998 as a placebo-controlled trial and ex-
Potential biases in the review process cluded IPPPSH 1985. In addition, Wright 2009 excluded Coope
1986 because of high use of diuretics in the beta-blocker group
We minimised potential biases in the review process by adhering while Dahlöf 2007 included STOP 1991 because more than 85%
to the Cochrane guidelines (Higgins 2011). We conducted a com- of participants on active treatment received beta-blocker as first-
prehensive search for eligible studies, without limiting the search line or second-line therapy. Both reviews considered the “less tight
to a specific language. Two review authors independently assessed control group” in UKPDS-39-1998 as “placebo” because the tar-
study eligibility, extracted data, and assessed the risk of bias in each get for blood pressure reduction in this group was not as low as
included study. in the beta-blocker group. However, participants in this control
group took antihypertensive treatment for 57% of their total per-
son-years in the UKPDS-39-1998 trial.
Agreements and disagreements with other We combined trials of low-dose and high-dose thiazide diuretics
studies or reviews because of the paucity of trials comparing beta-blockers to diuretics
(Berglund 1981; HAPPHY 1987; MRC 1985; MRCOA 1992; VA
We showed that beta-blockers are inferior to various CCBs for all-
COOP 1982). This may be the reason for the lack of a statistical
cause mortality, stroke, and total cardiovascular events, and to RAS

difference between beta-blockers and diuretics in our review, since previous meta-analyses suggesting that beta-blockers are inferior
Wright and Musini have shown that first-line low-dose thiazides first-line choices when compared to diuretics, renin-angiotensin
reduce stroke, CHD, and mortality outcomes while first-line high- system inhibitors, and calcium-channel blockers.
dose thiazides have no significant effects on mortality and CHD
(Wright 2009). Implications for research
We conducted sensitivity analyses and found our results to be
More randomised controlled trials studying the use of beta-block-
consistent with those of the related reviews, despite differences in
ers for elevated blood pressure are required. Such hypertension
inclusion and exclusion criteria (Effects of interventions). Overall,
trials must measure clearly defined morbidity and mortality end-
despite a variation in the studies included in other beta-blocker
points, including coronary heart disease, heart failure, and stroke.
reviews arising from different interpretations of inclusion criteria,
These trials should be used to define differences between beta-
all the reviews arrived at similar conclusions that the available
blockers and other classes of antihypertensive drugs and between
evidence does not support the use of beta-blockers as first-line
the different subclasses of beta-blockers. In addition, the possible
drugs in the treatment of hypertension.
differential effect of beta-blockers on younger and older people
needs to be assessed in future hypertension trials.
AUTHORS’ CONCLUSIONS
ACKNOWLEDGEMENTS
Implications for practice We thank the staff of the Cochrane Hypertension Group for as-
sistance during the update of this systematic review. We acknowl-
First-line beta-blockers in people with hypertension lead to modest
edge the significant contributions of Professor Anthony Mbewu
reductions in stroke and have no significant effects on total mor-
and Dr Roy Maroney to the protocol and previous versions of the
tality and coronary heart disease. In addition, beta-blockers are in-
review. Professor Mbewu and Dr Maroney did not contribute to
ferior to calcium-channel blockers and renin-angiotensin system
and have neither read nor approved the current review.
inhibitors for various important outcomes. Most of this evidence
is considered to be of low quality according to the GRADE system, Professor CS Wiysonge’s work is partly supported by the South
implying that further research is likely to change our confidence in African Medical Research Council, the National Research Foun-
the estimate of these effects. However, the evidence comes mainly dation of South Africa, and the Effective Health Care Research
from trials that used atenolol. Our findings extend the results of Consortium (Grant: 5242).
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
AASK 2002
Methods Multicentre study

Randomisation: described as randomised controlled trial, but method of allocating par-
ticipants to treatment was not described
Blinding: participants, providers, and outcome assessors blinded
Loss to follow-up: 0%
Mean duration of follow-up: 4.1 years
Analyses: by intention-to-treat
Participants Geographic location: USA

Study setting: hospital
Number of participants: 1094 (61.2% men)
Age range: 18 to 70 years (mean: 54 years)
Entry criteria: DBP ≥ 95 mmHg (mean BP 150/96 mmHg) and glomerular filtration
rate 20 mL/minute/1.73 m2 to 65 mL/minute/1.73 m2 and no other identified causes
of renal insufficiency
Race: all African Americans
Exclusion criteria: DBP < 95 mmHg, known history of diabetes mellitus, urinary protein
to creatinine ratio > 2.5, accelerated or malignant hypertension within 6 months, sec-
ondary hypertension, non-BP-related causes of kidney disease, serious systemic disease,
clinical CHF, or specific (contra)indication for a study drug or procedure
Interventions Beta-blocker group:

Metoprolol 50 mg/day to 200 mg/day
ACE inhibitor group:
Ramipril 2.5 mg/day to 10 mg/day
Calcium-channel blocker group:
Amlodipine 5 mg/day to 10 mg/day
If the BP goal could not be achieved by the randomly allocated drug, additional open-
labelled antihypertensive drugs were added sequentially
Outcomes Cardiovascular events

Cardiovascular mortality
All-cause mortality
Notes A formal stopping rule was constructed based on the primary renal function analysis
with separate O’Brien-Fleming boundaries for the chronic and total mean slopes for
each of the 3 primary treatment group comparisons. The stopping rule stipulated that
a treatment group should be discontinued at 1 of the study’s annual interim analyses if
the stopping boundaries indicating faster progression were crossed in the same direction
for both the chronic and total mean slopes
Risk of bias
Bias Authors’ judgement Support for judgement

AASK 2002 (Continued)
Random sequence generation (selection Unclear risk Not described

bias)
Allocation concealment (selection bias) Unclear risk Described as “randomly allocated”
Blinding of participants and personnel Low risk Participants and personnel blinded
(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Blind outcome assessment

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Loss to follow-up: 0%

All outcomes Participants withdrawing from the study
were accounted for in an intention-to-treat
analysis
Selective reporting (reporting bias) Low risk Reported all outcomes as stated in protocol
Other bias Unclear risk Amlodipine group terminated early at rec-

ommendation of Data and Safety Moni-
toring Board, according to predetermined
stopping rules
Other antihypertensive drugs added to ran-
domly allocated treatment to control BP.
The observed effects may equally have re-
sulted from the different additional drugs
ASCOT 2005

Randomisation: computer-generated, using separate lists for each co-ordinating centre.
Participating physicians called the co-ordinating centre to obtain the treatment allocation
for each participant. Open treatment and blinded endpoint evaluation (PROBE) design
Loss to follow-up: 0.3% withdrew consent and 0.3% lost to follow-up
Median duration of follow-up: 5.5 years
Analyses: by intension-to-treat
Participants Geographic location: UK, Ireland, Denmark, Finland, Iceland, Norway, and Sweden
Study setting: hospital and primary care
Number of participants: 19,257 (76.6% men)
Entry criteria: sitting SBP ≥ 160 with or without DBP 100 mmHg (for people with
untreated hypertension) OR SBP ≥ 140 with or without DBP ≥ 90 mmHg (for people
taking antihypertensive treatment), and 3 CHD risk factors
Race: 95% white
Exclusion criteria: previous MI, current angina, cerebrovascular event in previous 3

ASCOT 2005 (Continued)
months, fasting triglycerides > 4.5 mmol/L, heart failure, uncontrolled arrhythmias, or
any clinically important haematological or biochemical abnormality on routine screening
Comorbid conditions: current smoking (33%), LVH (22%), type 2 diabetes (27%)
; peripheral arterial disease (6%), previous stroke or TIA (11%), microalbuminuria,
obesity, hyperlipidaemia

Step 1: atenolol 50 mg
Step 2: atenolol 100 mg
Step 3: atenolol 100 mg + bendroflumethiazide 1.25 mg + potassium
Step 4: atenolol 100 mg + bendroflumethiazide 2.5 mg + potassium
Step 5: atenolol 100 mg + bendroflumethiazide 2.5 mg + potassium + doxazosin gas-
trointestinal transport system 4 mg
Step 6: atenolol 100 mg + bendroflumethiazide 2.5 mg + potassium + doxazosin gas-
trointestinal transport system 8 mg
Further treatment to achieve BP goal added, as required
Step 1: amlodipine 5 mg
Step 2: amlodipine 10 mg
Step 3: amlodipine 10 mg + perindopril 4 mg
Step 4: amlodipine 10 mg + perindopril 8 mg (2 × 4 mg)
Step 5: amlodipine 10 mg + perindopril 8 mg (2 × 4 mg) + doxazosin gastrointestinal
transport system 4 mg
Step 6: amlodipine 10 mg + perindopril 8 mg (2 × 4 mg) + doxazosin gastrointestinal
transport system 8 mg
Further treatment to BP goal added, as required.
On average, of total time, 79% were taking atenolol and 83% were taking amlodipine. At
the end of the study, 9% were taking atenolol monotherapy and 15% taking amlodipine
monotherapy
Outcomes Primary outcome: combined endpoint of non-fatal MI (including silent MI) and fatal
CHD
Secondary outcomes: all-cause mortality, total stroke, primary endpoint minus silent MI,
all coronary events, total cardiovascular events and procedures, cardiovascular mortality,
and non-fatal and fatal heart failure
Tertiary outcomes: silent MI, unstable angina, chronic stable angina, peripheral arterial
disease, life-threatening arrhythmias, development of diabetes, development of renal
impairment, and the effects on the primary endpoint and on total cardiovascular events
and procedures among prespecified subgroups
Notes
Risk of bias
Random sequence generation (selection Low risk Computer-generated

bias)

ASCOT 2005 (Continued)
Allocation concealment (selection bias) Low risk Central randomisation
Blinding of participants and personnel High risk Open treatment

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Blinded outcome assessment

bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk 0.3% withdrew consent and 0.3% were lost
All outcomes to follow-up. Not indicated whether rea-
sons for missing outcome data were similar
across treatment groups
Selective reporting (reporting bias) Low risk Reported all outcomes as stated in protocol
Other bias Unclear risk Other antihypertensive drugs added to ran-

Berglund 1981
Methods Single-centre study

ticipants to treatment was not described
Blinding: not known if participants, providers, or assessors blinded
Mean duration of follow-up: 10 years
Participants Geographic region: Sweden

Number of participants: 106 (all men)
Age range: 47 to 54 years (mean: 50.8 years)
Race: not reported
BP at entry: > 170/105 mmHg
Comorbid conditions: not mentioned

Step 1: propranolol 80 mg twice daily
Step 2: propranolol 160 mg twice daily
Step 3: propranolol 160 mg twice daily + hydralazine 25 mg to 50 mg twice daily
Step 4: propranolol 160 mg twice daily + hydralazine 25 mg to 50 mg twice daily + other
antihypertensive drugs
Diuretic group:
Step 1: bendroflumethiazide 2.5 mg once daily

Berglund 1981 (Continued)
Step 2: bendroflumethiazide 5 mg once daily

Step 3: bendroflumethiazide 5 mg once daily + hydralazine 25 mg to 50 mg twice daily
Step 4: bendroflumethiazide 5 mg once daily + hydralazine 25 mg to 50 mg twice daily
+ other antihypertensive drugs
At the end of trial, 74% were taking propranolol and 70% were taking bendroflumethi-
azide; with 42% taking propranolol and 40% taking bendroflumethiazide monotherapy
Outcomes Total mortality
Notes
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk Described as randomised controlled trial,
but method of allocating participants to
treatment was not described
Blinding of participants and personnel High risk Completely unblinded

(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk There was no blinding of outcome assess-
bias) ment, but the outcome assessed (i.e. death)
All outcomes is unlikely to be influenced by lack of blind-
ing
Incomplete outcome data (attrition bias) Unclear risk Loss to follow-up: 7%. Not indicated
All outcomes whether reasons for missing outcome data
were similar across treatment groups
Selective reporting (reporting bias) Unclear risk No access to the protocol.


Coope 1986

Randomisation: participants were randomised on a 50:50 basis without stratification
using random number tables. Opaque envelopes were supplied in sequence from the
trial administrative centre that gave instructions for allocation to treatment or control
group
Loss to follow-up: not stated
Participants Geographic region: England and Wales

Study setting: primary care
Number of participants: 884 (31% men)
Race: not stated
Exclusion criteria: atrial fibrillation, A-V heart block, ventricular failure, bronchial
asthma, diabetes mellitus (needing pharmacological treatment) or any serious concomi-
tant disease, and untreated hypertension with levels persistently > 280 mmHg for SBP or
120 mmHg for DBP or people already being treated for hypertension (within 3 months)
Mean BP at entry: 196.4/98.8 mmHg
BP entry criteria: not stated
Comorbid conditions: smoking 215 (24%)

Step 1: atenolol 100 mg/day
Step 2: bendrofluazide 5 mg/day
Step 3: methyldopa 500 mg/day
Step 4: any other recognised therapy such as nifedipine retard 20 mg twice daily
Control group:
No treatment
Proportion on assigned treatment at end of study: beta-blocker group: 70%

CHD mortality: fatal MI, sudden death
CHD morbidity: non-fatal MI
Cerebrovascular mortality: fatal stroke
Cerebrovascular morbidity: non-fatal stroke
Cardiovascular mortality: fatal stroke, MI, sudden death, ventricular failure, ruptured
aneurysm, hypertensive nephropathy
Cardiovascular morbidity: non-fatal stroke, MI, non-fatal ventricular failure
Notes
Risk of bias
Random sequence generation (selection Low risk Used random number table
bias)

Coope 1986 (Continued)
Allocation concealment (selection bias) Low risk Used opaque sequentially numbered en-
velopes supplied by the trial administrative
centre
Blinding of participants and personnel Unclear risk Not stated

(performance bias)
All outcomes

bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk Not indicated whether reasons for missing
All outcomes outcome data were similar across treatment
groups
Selective reporting (reporting bias) Unclear risk No access to protocol

ELSA 2002

Randomisation: computer-generated, using separate lists for each centre with a block size
of 4. Participants and study personnel, excluding the Safety Committee, were blinded
to treatment assignment for study duration
Loss to follow-up: 3.9%
Participants Geographic location: France, Germany, Greece, Italy, Spain, Sweden, UK

Study setting: 410 clinical units
Entry criteria: sitting SBP 150 mmHg to 210 mmHg and DBP 95 mmHg to 115 mmHg,
fasting serum total cholesterol concentration ≤ 320 mg/dL, fasting serum triglyceride
concentration ≤ 300 mg/dL, and serum creatinine concentration ≤ 1.7 mg/dL
Race: 98.2% white
Main exclusion criteria: recent MI or stroke and insulin-dependent diabetes mellitus
Mean BP at entry: 163.5/101.3 mmHg
Comorbid conditions: current smoking (20.5%), ≥ 1 plaque (64%), previous antihy-
pertensive therapy (63%), diabetes, hyperlipidaemia

ELSA 2002 (Continued)

Atenolol 50 mg once daily
Lacidipine 4 mg once daily
If satisfactory BP control was not achieved, lacidipine could be increased to 6 mg and
atenolol to 100 mg (month 1), with open-label hydrochlorothiazide added (12.5 mg/
day (month 3) and 25 mg/day (month 6))
Outcomes Change in mean maximum intima-media thickness

Plaque number
Fatal and non-fatal cardiovascular events
Total mortality
Notes
Risk of bias
Random sequence generation (selection Low risk Randomisation sequence computer-gener-

bias) ated
Allocation concealment (selection bias) Unclear risk Not adequately described
(performance bias)
All outcomes

bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk Loss to follow-up: 3.9%. Not indicated
Selective reporting (reporting bias) Low risk All outcomes reported as stated in protocol.


HAPPHY 1987

Randomisation: participants were divided into 3 groups according to predicted CHD
risk based on a serum cholesterol, smoking habits, and SBP. Each risk group was divided
into 3 age strata and participants in the 9 groups were allocated to treatment at random.
Allocation method not described
Blinding: participants and providers not blinded, assessors blinded
Mean duration of follow-up: 45.1 months
Participants Geographic region (% participant-years): Belgium (0.8%), Canada (4.8%), Czechoslo-

vakia (1.9%), Denmark (0.6%), Finland (14.0%), France (1.0%), Germany (3.3%),
Greece (0.3%), Iceland (3.6%), Italy (2.7%), the Netherlands (1.6%), Norway (1.8%),
Sweden (39.4%), UK (15.6%), USA (8.4%)
Race: > 99% white
Exclusion criteria: history of MI, angina pectoris, stroke, malignant or secondary hyper-
tension, malignant disease, liver cirrhosis, alcoholism or other serious diseases; people
with absolute or relative contraindications to beta-blockers (chronic obstructive lung
disease) or thiazide diuretics (diabetes mellitus or gout); and people with other non-
hypertensive conditions requiring treatment with beta-blockers or diuretics
Mean BP at entry: 166/107 mmHg
BP entry criteria: diastolic BP 100 mmHg to 130 mmHg
Comorbid conditions: smoking 2266 (34.5%)

Step 1: atenolol 100 mg/day or metoprolol 200 mg/day; (until 1981) - atenolol 200 mg/
day or metoprolol 400 mg/day. Propranolol 160 mg/day given to 46 participants in 1
centre
Diuretic group:
Step 1: bendroflumethiazide 5 mg/day or hydrochlorothiazide 50 mg/day; (until 1981)
- bendroflumethiazide 10 mg/day or hydrochlorothiazide 100 mg/day
Additional treatment for both groups:
Step 2: hydralazine 75 mg/day
Step 3: hydralazine 150 mg/day
Step 4: step 3 + spironolactone 75 mg/day
Step 5: step 3 + spironolactone 150 mg/day
Step 6: step 5 + optional drug
Percentage on assigned treatment at end of study: beta-blocker group: 85.9% (68% as
monotherapy); diuretic group: 83.4% (62% as monotherapy)
Outcomes Total mortality - death from any cause

CHD mortality - fatal MI, sudden death
CHD morbidity - non-fatal MI
Cerebrovascular mortality - fatal stroke
Cerebrovascular morbidity - non-fatal stroke
Cardiovascular mortality - fatal stroke, MI
Cardiovascular morbidity - non-fatal stroke, non-fatal MI
HAPPHY 1987 (Continued)
Notes
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk Not described
Blinding of participants and personnel High risk Participants and personnel not blinded
(performance bias)
All outcomes

bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk Loss to follow-up: 1%. Not indicated

INVEST 2003

Randomisation: Internet-based management system automatically randomised each par-
ticipant to a treatment strategy. Randomisation scheme used a standard C routine and
blocked by site using randomly permuted block sizes of 4 and 6. Randomisation result
was automatically stored in the central database as part of the participant’s record and
was also returned to the site investigator for electronic signature of strategy drugs in
accordance with the protocol
Blinding: not clear whether participants were blinded; provider not blinded; assessor
blinded
Participants Geographic location: Australia, Canada, Cuba, Dominican Republic, El Salvador, Ger-
many, Guatemala, Hungary, Italy, Mexico, New Zealand, Panama, Turkey, US

INVEST 2003 (Continued)
Number of participants: 22,576 (47.9% men)

Age: ≥ 50 years (mean 66.1 years)
Entry criteria: sitting BP > 140/90 mmHg and documented coronary artery disease;
mean entry BP 149.5/86.3 mmHg (SD 19.7/12.0)
Race: 48.4% white, 13.4% black, 35.6% Hispanic, 0.7% Asian
Exclusion criteria: people taking beta-blockers within 2 weeks of randomisation or taking
beta-blockers for an MI that occurred in the previous 12 months
Comorbid conditions: current smokers (12.4%), hypercholesterolaemia (55.8%), dia-
betes (28.3%), prior MI or abnormal angiogram (53.0%), previous stroke (5.1%), LVH
(21.9%)

(added trandolapril 2 mg/day for participants with diabetes, renal impairment, or heart
failure)
Step 2: atenolol 50 mg/day + hydrochlorothiazide 25 mg/day
Step 3: atenolol 50 mg twice day + hydrochlorothiazide 25 mg twice daily
Step 4: atenolol 50 mg twice day + hydrochlorothiazide 25 mg twice daily + trandolapril
2 mg/day
Step 5: maximum tolerated or add non-study antihypertensive medication, or both.
Titration ranges: atenolol 25 mg/day to 200 mg/day, hydrochlorothiazide 12.5 mg/day
to 100 mg/day, trandolapril 1 mg/day to 8 mg/day, verapamil SR 120 mg/day to 480
mg/day
Step 1: verapamil SR 240 mg/day
(added trandolapril 2 mg/day for participants with diabetes, renal impairment, or heart
failure)
Step 2: verapamil SR 240 mg/day + trandolapril 2 mg/day
Step 3: verapamil SR 180 mg twice daily + trandolapril 2 mg twice daily
Step 4: verapamil SR 180 mg twice daily + trandolapril 2 mg twice daily + hydrochloroth-
iazide 25 mg/day
Step 5: maximum tolerated or add non-study antihypertensive medication, or both.
Titration ranges: atenolol 25 mg/day to 200 mg/day, hydrochlorothiazide 12.5 mg/day
to 100 mg/day, trandolapril 1 mg/day to 8 mg/day, verapamil SR 120 mg/day to 480
mg/day
Percentage on assigned treatment at end of study: beta-blocker group: 77.5% (18.1% as
monotherapy); calcium-channel blocker group: 81.5% (17.4% as monotherapy)
Outcomes Primary: first occurrence of death from any cause, non-fatal MI, or non-fatal stroke
Secondary: all-cause death, non-fatal MI, non-fatal stroke, cardiovascular death, angina,
cardiovascular hospitalisations, BP control, cancer, Alzheimer’s disease, Parkinson’s dis-
ease, gastrointestinal bleeding
Notes
Risk of bias

INVEST 2003 (Continued)
Random sequence generation (selection Low risk Computer-generated (assumed to be com-

bias) puter-generated, because it is a blocked ran-
domisation with varying block sizes)
Allocation concealment (selection bias) Low risk Central allocation (web-based randomisa-
tion: an Internet-based management sys-
tem automatically randomised each partic-
ipant to a treatment strategy)
Blinding of participants and personnel Unclear risk Not clear whether participants were
(performance bias) blinded; provider not blinded
All outcomes

bias)
All outcomes
groups

IPPPSH 1985

Randomisation: random allocation of participants was achieved by providing to the in-
vestigating centres participant numbers randomised into balanced blocks each having 6
numbers. Sealed envelopes containing the treatment code were provided to each inves-
tigator
Loss to follow-up: 0.6%
Duration of follow-up: 3 to 5 years (mean 4 years)
Participants Geographic region: UK (36.4%), Canada (12.0%), the Netherlands (3.6%), Israel (20.
9%), Italy (11.7%), Federal Republic of Germany (15.4%)
Age range: 40 to 64 years (mean age: 52.2 years)
Entry BP criteria: diastolic BP of 100 mmHg to 125 mmHg (Korotkoff Phase V)
measured in seated position using standard mercury sphygmomanometer;
mean SBP at entry 173 mmHg (SD 18.4)
Race:
Exclusion criteria: past or present history of angina pectoris or MI; heart failure; relevant
cardiac valvular disease; atrio-ventricular blocks grades II and III or sick sinus syndrome;

IPPPSH 1985 (Continued)
bradycardia (< 50 beats per minute); intermittent claudication; previous cerebrovascular

accident; insulin-dependent diabetes; pregnancy; obstructive airways disease or history
of bronchial asthma; renal, hepatic, gastrointestinal or any other severe disease
Comorbid conditions: current smokers (29.1%)

Step 1: oxprenolol slow release 160 mg/day
Control group:
Step 1: film-coated placebo of identical appearance
Step 2: diuretic or sympatholytic or vasodilator
Step 3: diuretic + sympatholytic, or diuretic + vasodilator, or sympatholytic + vasodilator
Step 4: diuretic + sympatholytic + vasodilator
During study, 30% of participants remained on beta-blocker only while 15% remained
placebo only. Total diuretic use was 67% in the beta-blocker group and 82% in the
placebo group
Outcomes CHD mortality: fatal MI, sudden death

Cardiovascular mortality
Cardiovascular morbidity
Total mortality
Adverse effects
Notes
Risk of bias
Random sequence generation (selection Low risk Block randomisation used so assumed to be
bias) computer-generated
Allocation concealment (selection bias) Low risk Random allocation of participants was
achieved by providing to the investigating
centres participant numbers randomised
into balanced blocks each having 6 num-
bers. Sealed envelopes containing the treat-
ment code were provided to each investiga-
tor
(performance bias)
All outcomes

bias)

IPPPSH 1985 (Continued)
All outcomes
groups

LIFE 2002
Methods Multicentre study. 2-week run-in placebo period

Randomisation: allocation numbers assigned with treatment groups using a computer-
generated allocation schedule; participants were classed as assigned to a group when they
had received an allocation number. All participants received masked losartan and masked
atenolol, 1 active and 1 placebo tablet
Blinding: participants, providers, and outcome assessors blinded
Mean duration of follow-up: 4.8 years (SD 0.9)
Participants Geographic region: Scandinavia, UK and USA

Study setting: 945 clinical centres, mostly primary care except in Denmark where most
participants were referred to hospital-based centres.
9222 randomised but 29 participants at 1 centre excluded for irregularities. 9193 (46%
men): Denmark (15%), Finland (16%), Iceland (1%), Norway (15%), Sweden (24%),
UK (9%), USA (19%)
Age range: 55 to 80 years
BP entry criteria: DBP 95 mmHg to 115 mmHg or SBP 160 mmHg to 200 mmHg
Race: 92% white, 6% black
Exclusion criteria: secondary hypertension, MI or stroke within the previous 6 months;
angina pectoris requiring treatment with beta-blockers or calcium-channel blockers;
heart failure or left ventricular ejection fraction of ≤ 40%; a disorder requiring treatment
with angiotensin-II antagonist, beta-blocker, hydrochlorothiazide, or ACE inhibitor
Comorbid conditions: LVH (100%), smoking (16%), diabetes (13%), previous MI
(16%), previous stroke (8%), atrial fibrillation (4%), peripheral vascular disease (6%)

Step 1: atenolol 50 mg/day and losartan placebo daily
Angiotensin-II antagonist group:
Step 2: losartan 50 mg/day and atenolol placebo daily
Step 2: add hydrochlorothiazide 12.5 mg/day
Step 3: double dose of Step 1 therapy, atenolol 100 mg/day or losartan 100 mg/day +
hydrochlorothiazide 12.5 mg/day

LIFE 2002 (Continued)
Step 4: add other antihypertensive drugs excluding ACE inhibitors, angiotensin-II an-
tagonists and beta-blockers
Participants on assigned treatment at end of follow-up: losartan group: 84%, atenolol
group: 80%
Outcomes Primary: CVD mortality and mortality (composite endpoint of cardiovascular death,
MI, and stroke)
Secondary: total mortality, angina pectoris, or CHF requiring hospital admission
Notes
Risk of bias
Random sequence generation (selection Low risk Computer-generated allocation sequence

bias)
Allocation concealment (selection bias) Unclear risk Method not adequately described
(performance bias)
All outcomes

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Minimal loss to follow-up
All outcomes
Other bias Unclear risk Other antihypertensive drugs were added

to randomly allocated treatment to control
BP. The observed effects may equally have
resulted from the different additional drugs
MRC 1985

Randomisation: stratified blocks of 8 within each sex, 10-year age group and clinic
Blinding: participants and outcome assessors blinded, providers not blinded

MRC 1985 (Continued)
Participants Geographic region: England, Scotland, and Wales

Number of participants: 17,354 (52% men)
Race: not stated
Exclusion criteria: secondary hypertension; taking antihypertensive treatment; normally
accepted indications for antihypertensive treatment (such as congestive cardiac failure)
present; MI or stroke within the previous 3 months; presence of angina, intermittent
claudication, diabetes, gout, bronchial asthma, serious intercurrent disease, or pregnancy
BP entry criteria: SBP < 200 mmHg and DBP 90 to 109 mmHg
Comorbid conditions: smoking 29%
Interventions Control:
Matching placebo
Beta-blocker group:
Propranolol up to 240 mg
Supplementary drug: methyldopa (guanethidine used initially)
Diuretic group:
Bendrofluazide 10 mg/day
Supplementary drug: methyldopa
Percentage on assigned therapy at study end: beta-blocker group: 59%, diuretic group:
61.8%, placebo group: 56.3%
Outcomes Total mortality: death from any cause

Cardiovascular mortality - fatal stroke, MI, sudden death
Cardiovascular morbidity - non-fatal stroke, MI, ruptured aneurysms, and others
Notes
Risk of bias

bias)
Blinding of participants and personnel Unclear risk Participants blinded, but providers not
(performance bias) blinded
All outcomes

MRC 1985 (Continued)

bias)
All outcomes
Incomplete outcome data (attrition bias) High risk Loss to follow-up (19%)
All outcomes

MRCOA 1992

Randomisation: stratified blocks of 8 within each sex and clinic
Blinding: participants and outcome assessors blinded, providers not blinded
Participants Geographic region: England, Scotland, and Wales

Race: not reported
Exclusion criteria: known or suspected secondary hypertension; taking antihypertensive
drugs; cardiac failure or any other accepted indication for antihypertensive treatment;
receiving treatment for angina pectoris; history of MI or stroke within the preceding 3
months; impaired renal function; diabetic asthma; serious intercurrent disease, including
malignancy known to be present at time of examination; serum potassium concentration
≤ 3.4 mmol/L or > 5.0 mmol/L
BP entry criteria: SBP 160 mmHg to 209 mmHg and DBP < 115 mmHg
Comorbid conditions: smoking: 17.5%
Interventions Control group:

Matching placebo
Beta-blocker group:
Step 1: atenolol 50 mg/day, may be increased to 100 mg/day
Step 2: amiloride 2.5 mg/day + hydrochlorothiazide 25 mg/day or amiloride 5 mg/day
+ hydrochlorothiazide 50 mg/day
Step 3: nifedipine up to 20 mg/day
Step 4: other drugs
Diuretic group:
Step 1: amiloride 2.5 mg/day + hydrochlorothiazide 25 mg/day or amiloride 5 mg/day

MRCOA 1992 (Continued)
+ hydrochlorothiazide 50 mg/day
Step 3: nifedipine up to 20 mg/day
Step 4: other drugs
Percentage on assigned treatment at end of study: beta-blocker group: 37%; diuretic
group: 52%; placebo group: 47%

Cardiovascular morbidity - non-fatal stroke, MI, CHF, TIAs
Notes
Risk of bias

bias)
Blinding of participants and personnel Unclear risk Participants blinded, but providers not
(performance bias) blinded
All outcomes

bias)
All outcomes
Incomplete outcome data (attrition bias) High risk High loss to follow-up (25%)
All outcomes


UKPDS-39-1998

Randomisation: included participants were part of the UKPDS involving allocation at
random to 1 of 3 therapeutic groups: less tight control (avoid beta-blockers and ACE
inhibitors) 33%; tight control (ACE inhibitor) 33%; tight control (beta-blocker) 33%.
Allocation concealment was done with opaque, sealed envelopes with a check maintained
on numerical sequence, dates of opening and results
Blinding: participants, providers, and assessors not blinded
Median duration of follow-up: 8.4 years
Participants Geographic region: England, Scotland, and Northern Ireland

Race: white 651 (86%); black 62 (8%); Asian-Indian 39 (5%); other 6 (1%)
Exclusion criteria: ketonuria > 3 mmol/L; history of MI in the previous year; current
angina or heart failure; > 1 vascular episode; serum creatinine concentration > 175 µmol/
L; retinopathy requiring laser treatment; malignant hypertension; uncorrected endocrine
abnormality; occupation which would preclude insulin treatment (such as heavy goods
vehicle driver); a severe concurrent illness likely to limit life or require extensive treatment;
or inadequate understanding or unwillingness to enter the study
BP entry criteria: SBP ≥ 160 mmHg or DBP ≥ 90 mmHg, or both; or SBP ≥ 150
mmHg or DBP ≥ 85 mmHg in participants receiving antihypertensive medication
Comorbid conditions: smoking: 171 (23%)

Step 1: atenolol 50 mg/day, increasing to 100 mg/day
ACE inhibitor group:
Step 1: captopril 25 mg twice daily, increasing to 50 mg twice daily
Step 2: frusemide 20 mg/day (maximum 40 mg twice daily)
Step 3: nifedipine slow release 10 mg (maximum 40 mg) twice daily
Step 4: methyldopa 250 mg (maximum 500 mg) twice daily; prazosin 1 mg (maximum
5 mg) 3 times daily
Participants remaining on assigned therapy at study end: beta-blocker group: 65%, ACE
inhibitor group: 78%

Cardiovascular morbidity - non-fatal stroke, MI, heart failure
Notes

UKPDS-39-1998 (Continued)
Risk of bias
Random sequence generation (selection Low risk Computer-generated random sequence

bias)
Allocation concealment (selection bias) Low risk Allocation concealment with opaque,
sealed envelopes with a check maintained
on numerical sequence, until dates of open-
ing and results
Blinding of participants and personnel High risk Participants and providers not blinded
(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk No blinding of outcome assessment, but
bias) the outcome assessed (i.e. death) is unlikely
All outcomes to be influenced by lack of blinding
groups

VA COOP 1982

ticipants to treatment not described
Blinding: participants, providers, and assessors blinded
Mean duration of follow-up: 12 months
Participants withdrawn from the study for uncontrolled BP not included in the analysis
Participants Geographic region: USA

Number of participants: 683 (all men)
Race: 43% white and 57% black
BP at entry: DBP 95 to 104 mmHg
Comorbid conditions: not described
VA COOP 1982 (Continued)

Propranolol 40 mg twice daily, increasing to 640 mg/day
Diuretic group:
Hydrochlorothiazide 25 mg twice daily, increasing to 200 mg/day
Participants still on assigned baseline therapy at study end: beta-blocker group, 39%,
diuretic group: 52%

Cerebrovascular disease
CHD
Notes Participants were withdrawn from the study if, on any follow-up visit, DBP ≥ 120
mmHg
Risk of bias

bias)
Allocation concealment (selection bias) Unclear risk Not described
Blinding of participants and personnel Low risk Participants and providers blinded
(performance bias)
All outcomes
Blinding of outcome assessment (detection Low risk Outcome assessors blinded

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk “A total of 73 (10.7%) of the patients were
All outcomes dropped from the study after randomiza-
tion. Of these, 42 (57.5%) were in the
propranolol group and 31 were taking hy-
drochlorothiazide. The difference was not
significant”
Analyses by intention-to-treat
Selective reporting (reporting bias) Unclear risk No access to study protocol.


ACE: angiotensin-converting enzyme; BP: blood pressure; CHD: coronary heart disease; CHF: congestive heart failure; CVD: cardio-
vascular disease; DBP: diastolic blood pressure; LVH: left ventricular hypertrophy; MI: myocardial infarction; SBP: systolic blood
pressure; SD: standard deviation; SR: sustained release; TIA: transient ischaemic attack.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
ACCORD 2010 Study designed to test the effect of BP lowering in addition to glycaemic control in people with diabetes.
Participants were assigned to 2 BP treatment goals - intensive (SBP < 120 mmHg) or standard (SBP < 140
mmHg). Various classes of antihypertensive drugs used but recommended start with combination of diuretic
and ACE inhibitor or beta-blocker. Beta-blockers not first-line or monotherapy
ADaPT 2008 Observational study conducted in primary care compared ACE inhibitor-based treatment (ramipril) with a
treatment based on diuretics or beta-blockers. Not randomised
APSIS 2006 Study compared verapamil or metoprolol in people with stable angina pectoris. Not all participants had
hypertension (27%). Mean baseline BP not given
CAPP 1999 This study compared the effects of ACE inhibitors and conventional therapy (diuretics and beta-blockers) on
cardiovascular morbidity and mortality in people with hypertension. Findings were not reported separately
for beta-blockers
CAPRICORN 2001 Trial evaluated the effects of carvedilol with placebo on survival in post-MI participants with left ventricular
dysfunction with or without symptomatic heart failure. All participants given ACE inhibitors for at least 48
hours before randomisation. Not all participants had hypertension (54%) and beta-blockers not first-line
or monotherapy
CARDHIAC 2008 Study examined effects of doxazosin GITS and atenolol on 3 measures of target organ damage in people
with type 2 diabetes and hypertension. Participants received ACE inhibitors or ARB and diuretic initially
before receiving doxazosin GITS and atenolol. Beta-blockers not first-line or monotherapy
CHHIPS 2009 This RCT, which was conducted in 6 centres in the UK, evaluated the effects of active treatment with the
ACE inhibitor, lisinopril, or beta-blocker, labetalol, compared to placebo in people aged > 18 years with a
clinical diagnosis of suspected stroke (with symptom onset < 36 hours) and hypertension (defined as SBP >
160 mmHg). After 2 weeks of treatment, study participants were routinely started on an ACE inhibitor with
or without a diuretic irrespective of whether they had normal BP or hypertension, unless they were deemed
to be unsuitable for such therapy. Decisions with regard to future antihypertensive therapy were delayed until
the end of the trial intervention (2 weeks). The proportion of participants on assigned treatment at the end
of the study was 71% in the beta-blocker group, 68% in the ACE inhibitor group, and 80% in the placebo
group. 172 participants, with mean age 74 years, were enrolled and the study reported mortality data at 3
months. We excluded this study because of the short duration (i.e. only 2 weeks) of relevant interventions
CIBIS-II 1999 Trial compared bisoprolol and placebo in people with heart failure receiving standard therapy with an ACE
inhibitor and diuretic. Not all participants had hypertension (mean baseline BP 139/80 mmHg) and beta-
blocker not first-line or monotherapy

(Continued)
COMET 2003 Trial compared carvedilol and metoprolol in people with chronic heart failure. Not all had hypertension
(36%). Mean baseline BP 126/77 mmHg
CONVINCE 1998 The Controlled ONset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial is a
randomised, prospective, double-blind, parallel-group, 2-arm, multicentre, international trial. The study
recruited 15,000 people with hypertension, aged > 55 years, with an established second risk factor for
cardiovascular disease and followed them for 5 years to compare the effects of controlled onset-extended
release verapamil 180 mg/day and hydrochlorothiazide 12.5 mg/day or atenolol 50 mg/day. Data has not
been reported separately for hydrochlorothiazide and atenolol
COPE 2005 Study compared a combination of ARB, beta-blocker, or thiazide diuretic in addition to a calcium-channel
blocker, benidipine hydrochloride, in Japanese people with hypertension. Beta-blockers not first-line treat-
ment or monotherapy.
COPERNICUS 2004 Study compared carvedilol vs placebo in people with chronic heart failure and receiving spironolactone or
not at baseline. Not all participants had hypertension (mean baseline BP 123/76 mmHg)
COSMOS 2010 People with stage 1 or 2 hypertension were randomised evenly to 1 of 15 groups for 6 weeks: extended-release
carvedilol (carvedilol CR) monotherapy 20 mg/day, 40 mg/day, or 80 mg/day; lisinopril monotherapy 10 mg/
day, 20 mg/day, or 40 mg/day; or 1 of 9 combinations of carvedilol CR + lisinopril initiated simultaneously.
The study has not reported effects on mortality or cardiovascular endpoints
Dietz 2008 This RCT was conducted in 85 centres in China, Germany, India, South Africa, Spain, and Turkey. People
with hypertension (defined as mean sitting DBP 95 mmHg to 110 mmHg) were randomised to once-daily
aliskiren 150 mg (231 participants), atenolol 50 mg (231 participants), or the combination (150/50 mg;
232 participants) for 6 weeks, followed by a further 6 weeks on double the initial doses of aliskiren and
atenolol. Aliskiren is the first direct renin inhibitor to be approved for the treatment of hypertension. The
proportion of participants on assigned treatment at the end of the study was 92.2% in the beta-blocker
group, 91.3% in the direct renin inhibitor group, and 88.4% in the combination group. The trial followed
up 694 participants (mean age 55.2 years, 23% aged ≥ 65 years) for 12 weeks. We excluded this study
because of the short duration (i.e. only 12 weeks) of relevant interventions
Dutch TIA 1993 The trial evaluated the effects of a beta-blocker (atenolol) in people after a transient ischaemic attack or non-
disabling ischaemic stroke in 56 collaborative centres in the Netherlands. Participants were randomised to
atenolol or a matching placebo. The proportion of participants on assigned treatment in the beta-blocker
group was 71% at 2 years (and 64% at 3 years) and in the placebo group was 75% at 2 years (and 68% at 3
years). The trial followed up 1473 participants (52% aged > 65 years) for a mean duration of 2.7 years. We
excluded the trial because only 29% of participants had hypertension at baseline
GEMINI 2008 Trial compared effects of carvedilol with metoprolol on glycaemic control in people with hypertension and
type-2 diabetes. BP was stabilised using ACE inhibitors or ARB antihypertensive regimens (or both) prior
to randomisation. Beta-blockers not first-line or monotherapy
IMPACT-HF 2004 Study assessed the use of carvedilol therapy initiated before discharge in people hospitalised with heart
failure compared with ’usual care’. Not all participants had hypertension (64%). Baseline mean BP 124/69.
5 mmHg)

(Continued)
MAPHY 1988 This multicentre study was a subset of the HAPPHY trial. Analysis take into consideration only 1 of the 2
beta-blockers (metoprolol). Including this trial alongside the HAPPHY trial would count those participants
twice
Marazzi 2011 This trial compared the effects of long-term treatment with nebivolol vs carvedilol on left ventricular ejection
fraction in people with hypertensive chronic heart failure. We excluded this study because the majority of
participants were already taking other antihypertensives at baseline, mainly ACE inhibitors
MERIT-HF 2002 Trial evaluated metoprolol compared to placebo added to standard therapy in people with heart failure. Not
all participants had hypertension (44%). Mean baseline BP not given
Nilsson 2007 This trial compared 2 first-line antihypertensive therapies for initiating treatment in hypertension, i.e. the
ACE inhibitor zofenopril and the beta-blocker atenolol. The study has not reported effects on mortality or
cardiovascular endpoints
NORDIL 2000 The Nordic Diltiazem (NORDIL) study enrolled 10,881 people with hypertension aged 50 to 74 years at
health centres in Norway and Sweden and randomly assigned them to either diltiazem, or diuretics with/
without beta-blockers. Morbidity and mortality were not reported separately for participants assigned to
beta-blocker therapy
REASON 2009 Trial compared the effects of atenolol and perindopril/indapamide on BP and carotid-femoral pulse wave
velocity, which is a marker for aortic stiffness and arterial wall alterations. No morbidity or mortality data
reported
RESOLVD 2000 Trial compared metoprolol or placebo in people with heart failure who had received treatment with either
an ACE inhibitor (enalapril) or ARB (candesartan) or both for 5 months prior to trial commencement (+ a
diuretic in 84% of participants). Beta-blocker not first-line or monotherapy
SENIORS 2005 Study compared the effects of nebivolol with placebo, in addition to standard therapy, in elderly people with
chronic heart failure. Not all participants had hypertension (62%). Mean baseline BP 139/81 mmHg
STOP 1991 This study compared the effects of active hypertensive treatment (1 of 3 beta-blockers or a diuretic) and
placebo in elderly people with hypertension. Morbidity and mortality were not reported separately for
participants assigned to beta-blocker therapy
STOP-2 1999 Conventional antihypertensive drugs (1 of 3 beta-blockers or a diuretic) were compared with newer agents,
ACE inhibitors and calcium-channel blockers. Findings were not reported separately for participants taking
beta-blockers
TEST 1995 The trial was conducted in 21 centres in Sweden between July 1988 and June 1992. The study evaluated
the effects of a beta-blocker (atenolol) in people aged > 40 years enrolled within 3 weeks of a stroke or
transient ischaemic attack. Participants were randomised to atenolol or a matching placebo. The proportion
of participants on assigned treatment at the end of the study not stated. The trial followed up 720 participants
(mean age 70.4 years) for a mean duration of 2.5 years. We excluded this study because not all participants
had hypertension at baseline

ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; BP: blood pressure; DBP: diastolic blood pressure; MI:
myocardial infarction; RCT: randomised controlled trial; SBP: systolic blood pressure.

DATA AND ANALYSES
Comparison 1. Beta-blocker versus placebo or no treatment
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Mortality 4 23613 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.88, 1.11]
2 Total stroke 4 23613 Risk Ratio (M-H, Fixed, 95% CI) 0.80 [0.66, 0.96]
3 Total coronary heart disease 4 23613 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.81, 1.07]
4 Cardiovascular death 4 23613 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.80, 1.09]
5 Total cardiovascular disease 4 23613 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.79, 0.97]
6 Withdrawal due to adverse 3 Risk Ratio (M-H, Random, 95% CI) Totals not selected
effects
6.1 Oxprenolol 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
6.2 Propranolol 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
6.3 Atenolol 1 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
Comparison 2. Beta-blocker versus diuretic
No. of No. of
2 Total stroke 4 18135 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.65, 2.09]
2.1 Cardio-selective 3 9435 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.55, 1.54]
beta-blocker
2.2 Non-selective beta-blocker 1 8700 Risk Ratio (M-H, Random, 95% CI) 2.28 [1.31, 3.95]
3 Total coronary heart disease 4 18135 Risk Ratio (M-H, Random, 95% CI) 1.12 [0.82, 1.54]
3.1 Aged < 65 years 3 15952 Risk Ratio (M-H, Random, 95% CI) 0.97 [0.81, 1.17]
3.2 Aged > 65 years 1 2183 Risk Ratio (M-H, Random, 95% CI) 1.63 [1.15, 2.32]
6 Withdrawal due to adverse 3 11566 Risk Ratio (M-H, Random, 95% CI) 1.69 [0.95, 3.00]
effects

Comparison 3. Beta-blocker versus calcium-channel blocker (CCB)
No. of No. of
4 Cardiovascular death 4 44825 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.92, 1.46]
6 Withdrawal due to adverse 2 21591 Risk Ratio (M-H, Random, 95% CI) 1.20 [0.71, 2.04]
effects
Comparison 4. Beta-blocker versus renin-angiotensin system (RAS) inhibitor
No. of No. of
5 Total cardiovascular disease 3 10828 Risk Ratio (M-H, Random, 95% CI) 1.00 [0.72, 1.38]
5.1 Angiotensin-converting 2 1635 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.63, 1.04]
enzyme inhibitors
5.2 Angiotensin receptor 1 9193 Risk Ratio (M-H, Random, 95% CI) 1.16 [1.04, 1.30]
blockers
6 Withdrawal due to adverse 2 9951 Risk Ratio (M-H, Fixed, 95% CI) 1.41 [1.29, 1.54]
effects

Analysis 1.1. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 1 Mortality.
Review: Beta-blockers for hypertension
Comparison: 1 Beta-blocker versus placebo or no treatment
Outcome: 1 Mortality
Study or subgroup Beta-blocker Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
IPPPSH 1985 108/3185 114/3172 20.4 % 0.94 [ 0.73, 1.22 ]
MRC 1985 120/4403 253/8654 30.5 % 0.93 [ 0.75, 1.15 ]
Coope 1986 60/419 69/465 11.7 % 0.97 [ 0.70, 1.33 ]
MRCOA 1992 167/1102 315/2213 37.4 % 1.06 [ 0.90, 1.27 ]
Total (95% CI) 9109 14504 100.0 % 0.99 [ 0.88, 1.11 ]

Total events: 455 (Beta-blocker), 751 (Placebo)
Heterogeneity: Chi2 = 1.14, df = 3 (P = 0.77); I2 =0.0%
Test for overall effect: Z = 0.21 (P = 0.83)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10

Favours beta-blocker Favours placebo

Analysis 1.2. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 2 Total stroke.
Outcome: 2 Total stroke
Study or subgroup Beta-blocker Pacebo Risk Ratio Weight Risk Ratio

IPPPSH 1985 45/3185 46/3172 18.4 % 0.97 [ 0.65, 1.47 ]
MRC 1985 42/4403 109/8654 29.4 % 0.76 [ 0.53, 1.08 ]
Coope 1986 23/419 44/465 16.7 % 0.58 [ 0.36, 0.94 ]
MRCOA 1992 56/1102 134/2213 35.6 % 0.84 [ 0.62, 1.14 ]
Total (95% CI) 9109 14504 100.0 % 0.80 [ 0.66, 0.96 ]

Total events: 166 (Beta-blocker), 333 (Pacebo)
0.1 0.2 0.5 1 2 5 10


Analysis 1.3. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 3 Total coronary heart
disease.
Outcome: 3 Total coronary heart disease

IPPPSH 1985 98/3185 107/3172 26.4 % 0.91 [ 0.70, 1.19 ]
MRC 1985 103/4403 234/8654 38.8 % 0.87 [ 0.69, 1.09 ]
Coope 1986 35/419 38/465 8.9 % 1.02 [ 0.66, 1.59 ]
MRCOA 1992 80/1102 159/2213 26.0 % 1.01 [ 0.78, 1.31 ]
Total (95% CI) 9109 14504 100.0 % 0.93 [ 0.81, 1.07 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.4. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 4 Cardiovascular death.
Outcome: 4 Cardiovascular death

IPPPSH 1985 45/3185 56/3172 17.7 % 0.80 [ 0.54, 1.18 ]
MRC 1985 65/4403 139/8654 29.6 % 0.92 [ 0.69, 1.23 ]
Coope 1986 35/419 50/465 15.0 % 0.78 [ 0.51, 1.17 ]
MRCOA 1992 95/1102 180/2213 37.8 % 1.06 [ 0.84, 1.34 ]
Total (95% CI) 9109 14504 100.0 % 0.93 [ 0.80, 1.09 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.5. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 5 Total cardiovascular
disease.
Outcome: 5 Total cardiovascular disease

IPPPSH 1985 143/3185 153/3172 21.6 % 0.93 [ 0.75, 1.16 ]
MRC 1985 146/4403 352/8654 33.4 % 0.82 [ 0.67, 0.99 ]
Coope 1986 82/419 121/465 16.1 % 0.75 [ 0.59, 0.96 ]
MRCOA 1992 151/1102 309/2213 28.9 % 0.98 [ 0.82, 1.18 ]
Total (95% CI) 9109 14504 100.0 % 0.88 [ 0.79, 0.97 ]

Heterogeneity: Chi2 = 3.81, df = 3 (P = 0.28); I2 =21%
0.1 0.2 0.5 1 2 5 10


Analysis 1.6. Comparison 1 Beta-blocker versus placebo or no treatment, Outcome 6 Withdrawal due to
adverse effects.
Outcome: 6 Withdrawal due to adverse effects
Study or subgroup Beta-blocker Placebo Risk Ratio Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
1 Oxprenolol
IPPPSH 1985 719/3185 750/3172 0.95 [ 0.87, 1.04 ]
2 Propranolol
MRC 1985 518/4403 203/8654 5.02 [ 4.28, 5.87 ]
3 Atenolol
MRCOA 1992 333/1102 82/2213 8.16 [ 6.48, 10.27 ]
0.1 0.2 0.5 1 2 5 10


Analysis 2.1. Comparison 2 Beta-blocker versus diuretic, Outcome 1 Mortality.
Comparison: 2 Beta-blocker versus diuretic
Study or subgroup Beta-blocker Diuretic Risk Ratio Weight Risk Ratio

Berglund 1981 5/53 4/53 1.1 % 1.25 [ 0.36, 4.40 ]
MRC 1985 120/4403 128/4297 34.9 % 0.91 [ 0.72, 1.17 ]
HAPPHY 1987 96/3297 101/3272 27.3 % 0.94 [ 0.72, 1.24 ]
MRCOA 1992 167/1102 134/1081 36.4 % 1.22 [ 0.99, 1.51 ]
VA COOP 1982 1/340 1/343 0.3 % 1.01 [ 0.06, 16.06 ]
Total (95% CI) 9195 9046 100.0 % 1.04 [ 0.91, 1.19 ]

Total events: 389 (Beta-blocker), 368 (Diuretic)
0.1 0.2 0.5 1 2 5 10

Favours beta-blocker Favours diuretic

Analysis 2.2. Comparison 2 Beta-blocker versus diuretic, Outcome 2 Total stroke.

M- M-
n/N n/N CI CI
1 Cardio-selective beta-blocker
VA COOP 1982 0/340 3/343 3.5 % 0.14 [ 0.01, 2.78 ]
HAPPHY 1987 32/3297 42/3272 32.4 % 0.76 [ 0.48, 1.19 ]
MRCOA 1992 56/1102 45/1081 34.4 % 1.22 [ 0.83, 1.79 ]
Subtotal (95% CI) 4739 4696 70.3 % 0.92 [ 0.55, 1.54 ]

Heterogeneity: Tau2 = 0.10; Chi2 = 4.12, df = 2 (P = 0.13); I2 =52%
2 Non-selective beta-blocker
MRC 1985 42/4403 18/4297 29.7 % 2.28 [ 1.31, 3.95 ]
Subtotal (95% CI) 4403 4297 29.7 % 2.28 [ 1.31, 3.95 ]

Heterogeneity: not applicable
Total (95% CI) 9142 8993 100.0 % 1.17 [ 0.65, 2.09 ]
Test for subgroup differences: Chi2 = 5.54, df = 1 (P = 0.02), I2 =82%
0.1 0.2 0.5 1 2 5 10


Analysis 2.3. Comparison 2 Beta-blocker versus diuretic, Outcome 3 Total coronary heart disease.

M- M-
n/N n/N CI CI
1 Aged < 65 years

VA COOP 1982 2/340 2/343 2.4 % 1.01 [ 0.14, 7.12 ]
MRC 1985 103/4403 119/4297 33.8 % 0.84 [ 0.65, 1.10 ]
HAPPHY 1987 138/3297 125/3272 35.2 % 1.10 [ 0.86, 1.39 ]
Subtotal (95% CI) 8040 7912 71.4 % 0.97 [ 0.81, 1.17 ]

2 Aged > 65 years
MRCOA 1992 80/1102 48/1081 28.6 % 1.63 [ 1.15, 2.32 ]
Subtotal (95% CI) 1102 1081 28.6 % 1.63 [ 1.15, 2.32 ]

Total (95% CI) 9142 8993 100.0 % 1.12 [ 0.82, 1.54 ]
0.1 0.2 0.5 1 2 5 10


Analysis 2.4. Comparison 2 Beta-blocker versus diuretic, Outcome 4 Cardiovascular death.

MRC 1985 65/4403 69/4297 35.5 % 0.92 [ 0.66, 1.29 ]
HAPPHY 1987 57/3297 60/3272 30.6 % 0.94 [ 0.66, 1.35 ]
MRCOA 1992 95/1102 66/1081 33.9 % 1.41 [ 1.04, 1.91 ]
Total (95% CI) 8802 8650 100.0 % 1.09 [ 0.90, 1.32 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.5. Comparison 2 Beta-blocker versus diuretic, Outcome 5 Total cardiovascular disease.

VA COOP 1982 2/340 5/343 1.2 % 0.40 [ 0.08, 2.07 ]
MRC 1985 146/4403 140/4297 34.4 % 1.02 [ 0.81, 1.28 ]
HAPPHY 1987 170/3297 157/3272 38.2 % 1.07 [ 0.87, 1.33 ]
MRCOA 1992 151/1102 107/1081 26.2 % 1.38 [ 1.10, 1.75 ]
Total (95% CI) 9142 8993 100.0 % 1.13 [ 0.99, 1.28 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.6. Comparison 2 Beta-blocker versus diuretic, Outcome 6 Withdrawal due to adverse effects.

M- M-
n/N n/N CI CI
MRC 1985 518/4403 462/4297 43.4 % 1.09 [ 0.97, 1.23 ]
MRCOA 1992 333/1102 160/1081 42.6 % 2.04 [ 1.72, 2.42 ]
VA COOP 1982 11/340 3/343 14.0 % 3.70 [ 1.04, 13.14 ]
Total (95% CI) 5845 5721 100.0 % 1.69 [ 0.95, 3.00 ]

Heterogeneity: Tau2 = 0.19; Chi2 = 37.62, df = 2 (P<0.00001); I2 =95%
0.1 0.2 0.5 1 2 5 10


Analysis 3.1. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 1 Mortality.
Comparison: 3 Beta-blocker versus calcium-channel blocker (CCB)
Study or subgroup Beta-blocker CCB Risk Ratio Weight Risk Ratio

AASK 2002 38/441 13/217 1.1 % 1.44 [ 0.78, 2.64 ]
ELSA 2002 17/1157 13/1177 0.8 % 1.33 [ 0.65, 2.73 ]
INVEST 2003 893/11309 873/11267 53.3 % 1.02 [ 0.93, 1.11 ]
ASCOT 2005 820/9618 738/9639 44.9 % 1.11 [ 1.01, 1.22 ]
Total (95% CI) 22525 22300 100.0 % 1.07 [ 1.00, 1.14 ]

Total events: 1768 (Beta-blocker), 1637 (CCB)
0.1 0.2 0.5 1 2 5 10

Favours betablocker Favours CCB

Analysis 3.2. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 2 Total stroke.

ELSA 2002 14/1157 9/1177 1.7 % 1.58 [ 0.69, 3.64 ]
INVEST 2003 201/11309 176/11267 34.4 % 1.14 [ 0.93, 1.39 ]
ASCOT 2005 422/9618 327/9639 63.8 % 1.29 [ 1.12, 1.49 ]
Total (95% CI) 22084 22083 100.0 % 1.24 [ 1.11, 1.40 ]

0.1 0.2 0.5 1 2 5 10

Favours beta-blocker Favours CCB

Analysis 3.3. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 3 Total coronary
heart disease.

ELSA 2002 17/1157 18/1177 2.1 % 0.96 [ 0.50, 1.85 ]
INVEST 2003 441/11309 452/11267 52.6 % 0.97 [ 0.85, 1.11 ]
ASCOT 2005 444/9618 390/9639 45.3 % 1.14 [ 1.00, 1.30 ]
Total (95% CI) 22084 22083 100.0 % 1.05 [ 0.96, 1.15 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.4. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 4 Cardiovascular
death.

M- M-
n/N n/N CI CI
AASK 2002 4/441 2/217 1.8 % 0.98 [ 0.18, 5.33 ]
ELSA 2002 8/1157 4/1177 3.5 % 2.03 [ 0.61, 6.74 ]
INVEST 2003 431/11309 431/11267 49.0 % 1.00 [ 0.87, 1.14 ]
ASCOT 2005 342/9618 263/9639 45.7 % 1.30 [ 1.11, 1.53 ]
Total (95% CI) 22525 22300 100.0 % 1.15 [ 0.92, 1.46 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.5. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 5 Total
cardiovascular disease.

AASK 2002 13/441 4/217 0.7 % 1.60 [ 0.53, 4.85 ]
ASCOT 2005 937/9618 796/9639 99.3 % 1.18 [ 1.08, 1.29 ]
Total (95% CI) 10059 9856 100.0 % 1.18 [ 1.08, 1.29 ]

0.1 0.2 0.5 1 2 5 10

Analysis 3.6. Comparison 3 Beta-blocker versus calcium-channel blocker (CCB), Outcome 6 Withdrawal
due to adverse effects.

M- M-
n/N n/N CI CI
ASCOT 2005 254/9618 162/9639 49.9 % 1.57 [ 1.29, 1.91 ]
ELSA 2002 173/1157 192/1177 50.1 % 0.92 [ 0.76, 1.11 ]
Total (95% CI) 10775 10816 100.0 % 1.20 [ 0.71, 2.04 ]

0.1 0.2 0.5 1 2 5 10

Favours Beta-blocker Favours CCB

Analysis 4.1. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 1
Mortality.
Comparison: 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor
Study or subgroup Beta-blocker RAS inhibitor Risk Ratio Weight Risk Ratio
UKPDS-39-1998 27/358 43/400 9.0 % 0.70 [ 0.44, 1.11 ]
AASK 2002 38/441 29/436 6.5 % 1.30 [ 0.81, 2.06 ]
LIFE 2002 431/4588 383/4605 84.6 % 1.13 [ 0.99, 1.29 ]
Total (95% CI) 5387 5441 100.0 % 1.10 [ 0.98, 1.24 ]

Total events: 496 (Beta-blocker), 455 (RAS inhibitor)
0.1 0.2 0.5 1 2 5 10

Favours beta-blocker Favours RAS inhibitor

Analysis 4.2. Comparison 4 Beta-blocker versus renin-angiotensin system (RAS) inhibitor, Outcome 2 Total
stroke.
UKPDS-39-1998 17/358 21/400 7.9 % 0.90 [ 0.48, 1.69 ]
LIFE 2002 309/4588 232/4605 92.1 % 1.34 [ 1.13, 1.58 ]
Total (95% CI) 4946 5005 100.0 % 1.30 [ 1.11, 1.53 ]

0.1 0.2 0.5 1 2 5 10

coronary heart disease.
UKPDS-39-1998 48/358 73/400 25.9 % 0.73 [ 0.53, 1.03 ]
LIFE 2002 188/4588 198/4605 74.1 % 0.95 [ 0.78, 1.16 ]
Total (95% CI) 4946 5005 100.0 % 0.90 [ 0.76, 1.06 ]

0.1 0.2 0.5 1 2 5 10


Cardiovascular death.
UKPDS-39-1998 32/358 47/400 17.8 % 0.76 [ 0.50, 1.16 ]
AASK 2002 4/441 2/436 0.8 % 1.98 [ 0.36, 10.74 ]
LIFE 2002 234/4588 204/4605 81.4 % 1.15 [ 0.96, 1.38 ]
Total (95% CI) 5387 5441 100.0 % 1.09 [ 0.92, 1.29 ]

0.1 0.2 0.5 1 2 5 10


cardiovascular disease.
M- M-
n/N n/N CI CI
1 Angiotensin-converting enzyme inhibitors

UKPDS-39-1998 74/358 106/400 38.7 % 0.78 [ 0.60, 1.01 ]
AASK 2002 13/441 11/436 12.7 % 1.17 [ 0.53, 2.58 ]
Subtotal (95% CI) 799 836 51.4 % 0.81 [ 0.63, 1.04 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.91, df = 1 (P = 0.34); I2 =0.0%
2 Angiotensin receptor blockers
LIFE 2002 588/4588 508/4605 48.6 % 1.16 [ 1.04, 1.30 ]
Subtotal (95% CI) 4588 4605 48.6 % 1.16 [ 1.04, 1.30 ]

Total (95% CI) 5387 5441 100.0 % 1.00 [ 0.72, 1.38 ]
0.1 0.2 0.5 1 2 5 10


Withdrawal due to adverse effects.
UKPDS-39-1998 125/358 88/400 12.2 % 1.59 [ 1.26, 2.00 ]
LIFE 2002 826/4588 599/4605 87.8 % 1.38 [ 1.26, 1.52 ]
Total (95% CI) 4946 5005 100.0 % 1.41 [ 1.29, 1.54 ]

Test for overall effect: Z = 7.50 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10

ADDITIONAL TABLES
Table 1. Previous systematic reviews of beta-blockers as first-line hypertension therapy
Identification Comparison Trials included Comments
Psaty 1997 Beta-blocker vs placebo MRC 1985; MRCOA 1992; Coope STOP 1991 classified as beta-
1986; STOP 1991 trials blocker trial as 68% in active group
were taking a beta-blocker
Messerli 1998 Beta-blocker vs placebo in older peo- Coope 1986; MRCOA 1992 The review concluded that beta-
ple blockers should not be used in el-
derly people with hypertension
Wright 1999 Beta-blocker vs diuretic Berglund 1981; HAPPHY 1987; IPPPSH not included because 67%
MRC 1985; MRCOA 1992; VA of participants taking beta-blocker
COOP 1982 were taking a diuretic
Wright 2000 Beta-blocker vs placebo MRC 1985; MRCOA 1992 Coope 1986 and STOP excluded be-
cause of high use of diuretic
Carlberg 2004 Atenolol vs placebo, and atenolol vs Placebo: Coope 1986; MRCOA Included trials in which only a pro-
other antihypertensive drugs 1992; Dutch TIA 1993; TEST portion (> 50%) of participants
1995) were assigned to start treatment with

Table 1. Previous systematic reviews of beta-blockers as first-line hypertension therapy (Continued)
Other antihypertensive drugs: HAP- atenolol

PHY
1987; MRCOA 1992; UKPDS-39-
1998; LIFE 2002; ELSA 2002
NICE 2004 Beta-blockers vs placebo, thiazide Placebo: IPPPSH 1985; MRC 1985; Included MAPPHY which is a subset
diuretics, calcium-channel blockers, Coope 1986; MRCOA 1992; Dutch of HAPPHY study. Included some
ACE inhibitors, and angiotensin re- TIA 1993; TEST 1995; STOP-2 studies in which only a proportion
ceptor blockers 1999 of participants were assigned to start
Thiazide diuretics: MRC 1985; treatment on a beta-blocker
HAPPHY 1987; MAPHY 1988;
MRCOA 1992
Calcium-channel blockers:
CONVINCE 1998; STOP-2 1999;
NORDIL 2000; ELSA 2002; IN-
VEST 2003
ACE inhibitors: CAPP 1999;
STOP-2 1999
Angiotensin receptor blockers: LIFE
2002
Lindhom 2005 Beta-blocker vs placebo, and beta- Placebo: IPPPSH 1985; MRC 1985; Included trials in which only a pro-
blocker vs other antihypertensive Coope 1986; MRCOA 1992; Dutch portion (> 50%) of participants were
drugs TIA 1993; TEST 1995 assigned to start treatment with a
Other antihypertensive beta-blocker
drugs: Berglund 1981; MRC 1985;
HAPPHY 1987; STOP 1991; MR-
COA 1992; Yurenev 1992; UKPDS-
39-1998; STOP-2 1999; NORDIL
2000; LIFE 2002; ELSA 2002;
CONVINCE 2003; ASCOT 2005
Bradley 2006 Beta-blocker vs placebo, diuret- Placebo: IPPPSH 1985; MRC 1985; Excluded Dutch TIA 1993 and
ics, calcium-channel blockers, and Coope 1986; MRCOA 1992 TEST 1995 because not all partici-
renin-angiotensin system inhibitors Diuretics: Berglund pants in these 2 trials were had hy-
1981; VA COOP 1982; MRC 1985; pertension
HAPPHY 1987; MRCOA 1992
Calcium-channel blockers: AASK
2002; ELSA 2002; INVEST 2003;
ASCOT 2005
Renin-angiotensin system
inhibitors: UKPDS-39-1998; AASK
2002; LIFE 2002
Khan 2006 Beta-blocker vs placebo, and beta- Placebo: IPPPSH 1985; MRC 1985; Included trials in which only a pro-
blocker vs other antihypertensive Coope 1986; MRCOA 1992; Dutch portion (> 50%) of participants were
drugs TIA 1993; TEST 1995 assigned to start treatment with a
Other antihypertensive drugs: beta-blocker
Berglund 1981; MRC 1985; HAP-
PHY 1987; STOP 1991; MRCOA
1992; Yurenev 1992; UKPDS-39-

1998; STOP-2 1999; CAPP 1999;
NORDIL 2000; LIFE 2002; ELSA
2002; CONVINCE 2003; ASCOT
2005
NICE 2006 Beta-blockers vs thiazide diuretics, Thiazide diuretics: MRC 1985; Updated NICE 2004 review by eval-
calcium-channel blockers, ACE in- HAPPHY 1987; MRCOA 1992 uating head-to-head trials only. AS-
hibitors, and angiotensin receptor Calcium-channel blockers: ASCOT COT new study added and ex-
blockers 2005; ELSA 1992; INVEST 2003 cluded CONVINCE; NORDIL;
ACE inhibitors: no studies meeting and CAPP due to confounded use
criteria
Angiotensin receptor blockers: LIFE
2002
Dahlöf 2007 Beta-blockers with or without di- Coope 1986; MRC 1985; MRCOA IPPPSH 1985 not included. STOP
uretics vs placebo or no treatment 1992; STOP 1991; UKPDS-39 1991 included because > 85% of
participants on active treatment re-
ceived beta-blocker as first-line or
second-line therapy. Regarded the
’control group’ in the UKPDS-39
as placebo, even though the group
permitted antihypertensive therapy
(other than
ACE inhibitors and beta-blockers),
because the target for blood pressure
reduction was not as low as in the
beta-blocker group
Wright 2009 Beta-blocker vs placebo MRC 1985; MRCOA 1992; Dutch IPPPSH 1985 and Coope 1986 ex-
TIA 1993; TEST 1995; UKPDS-39 cluded because of high use of diuret-
1998 ics in beta-blocker group. UKPDS-
39 included using ’less tight control
group’ as placebo, but participants
took antihypertensive treatments for
57% of total person-years
Wiysonge 2012 Beta-blocker vs placebo, diuret- Placebo: IPPPSH 1985; MRC 1985; Previously published version of this
ics, calcium-channel blockers, and Coope 1986; MRCOA 1992 systematic review
renin-angiotensin system inhibitors Diuretics (Berglund
1981; VA COOP 1982; MRC 1985;
2002; ELSA 2002; INVEST 2003;
ASCOT 2005
2002; LIFE 2002

Kuyper 2014 Beta-blocker vs placebo, and beta- Placebo: IPPPSH 1985; MRC 1985; Compared the efficacy of atenolol vs
blocker vs other antihypertensive Coope 1986; STOP 1991; MRCOA non-atenolol beta-blockers in clini-
drugs 1992; Dutch TIA 1993; TEST 1995 cal trials enrolling young (aged < 60
Other antihypertensive drugs: years) and older people with hyper-
Berglund 1981; MRC 1985; HAP- tension
PHY 1987; STOP 1991; MRCOA The review concluded that atenolol
1992; Yurenev 1992; UKPDS-39- should not be used in
1998; STOP-2 1999; CAPP 1999; older people with hypertension but
NORDIL 2000; LIFE 2002; ELSA class effect uncertain, and beta-
2002; CONVINCE 2003; ASCOT blockers reasonable option for the
2005 young
Wiysonge 2017 Beta-blocker vs placebo, diuret- Placebo: IPPPSH 1985; MRC 1985; Current systematic review
ics, calcium-channel blockers, and Coope 1986; MRCOA 1992
renin-angiotensin system inhibitors Diuretics: Berglund
1981; VA COOP 1982; MRC 1985;
2002; ELSA 2002; INVEST 2003;
ASCOT 2005
2002; LIFE 2002
ACE: angiotensin-converting enzyme.
Table 2. Effect of beta-blockers on lowering of blood pressure
Trial identification Beta-blocker Comparison drug Baseline BP (SBP/DBP; Mean BP difference

mmHg) (SBP/DBP)*
Beta-blocker vs placebo/no treatment
Coope 1986 Atenolol No treatment 196.7/99.7 -18.0/-11.0
MRCOA 1992 Atenolol Placebo 184.0/91.0 -13.0/-7.0
MRC 1985 Propranolol Placebo 162.0/98.5 -9.5/-5.0
IPPPSH 1985 Oxprenolol Placebo 173.2/107.9 -4.1/-1.5
Beta-blocker vs diuretic
MRCOA 1992 Atenolol Diuretic 184.0/91.0 +1.0/-0.5
HAPPHY 1987 Atenolol or metoprolol or Diuretic 166.0/107.9 0.0/-1.0

propranolol

Table 2. Effect of beta-blockers on lowering of blood pressure (Continued)
Berglund 1981 Propranolol Diuretic 174.0/105.5 -4.0/+2.0
VA COOP 1982 Propranolol Diuretic 146.3/101.5 +7.0/+1.6
MRC 1985 Propranolol Diuretic 162.0/98.5 +3.5/+1.0
Beta-blocker vs calcium-channel blocker
ELSA 2002 Atenolol Calcium-channel blocker 163.1/101.3 +0.2/-0.1
INVEST 2003 Atenolol Calcium-channel blocker 150.8/87.2 +0.3/+0.2
ASCOT 2005 Atenolol Calcium-channel blocker 164.0/94.7 +1.6/+1.8
AASK 2002 Metoprolol Calcium-channel blocker 150.0/96.0 +2.0/0.0
Beta-blocker vs renin-angiotensin system inhibitor
UKPDS-39-1998 Atenolol Renin-angiotensin 159.0/93.0 -1.0/-1.0

system inhibitor (ACE in-
hibitor)
LIFE 2002 Atenolol Renin-angiotensin 174.5/97.7 +1.1/-0.2

system inhibitor (ARB)
AASK 2002 Metoprolol Renin-angiotensin 150.0/96.0 0.0/-1.0

system inhibitor (ACE in-
hibitor)
* ’Minus sign’ means beta-blocker group had lower BP, and ’plus sign’ means beta-blocker group had higher BP than control group.
ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; BP: blood pressure; DBP: diastolic blood pressure; SBP:
systolic blood pressure.

APPENDICES
Appendix 1. 2015 search strategy

Ovid MEDLINE(R) 1946 to Present with Daily Update
Search Date: 19 January 2015
--------------------------------------------------------------------------------
1 exp adrenergic beta-antagonists/ (76928)
2 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or
bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or
bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or
cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or
exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or
iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol
or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol
or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or
primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol
or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).mp.
(73611)
3 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw. (86331)
4 or/1-3 (139776)
5 hypertension/ (192862)
6 hypertens$.tw. (304808)
7 exp blood pressure/ (247717)
8 (blood pressure or blood pressure).mp. (350302)
9 or/5-8 (589677)
10 randomized controlled trial.pt. (381216)
11 controlled clinical trial.pt. (88387)
12 randomi?ed.ab. (334664)
13 placebo.ab. (147683)
14 drug therapy.fs. (1727364)
15 randomly.ab. (198880)
16 trial.ab. (288170)
17 groups.ab. (1274045)
18 or/10-17 (3261120)
19 animals/ not (humans/ and animals/) (3879559)
20 18 not 19 (2775676)
21 4 and 9 and 20 (19415)
22 21 and (2013$ or 2014$ or 2015$).ed. (674)
23 remove duplicates from 22 (663)
Embase <1974 to 2015 January 16>
--------------------------------------------------------------------------------
1 exp beta adrenergic receptor blocking agent/ (243970)
(178474)
4 or/1-3 (294052)
5 exp hypertension/ (510805)
8 blood pressure o bloodpressure.mp. (0)
9 or/5-8 (911302)
10 randomized controlled trial/ (358482)
11 crossover procedure/ (41032)
12 double-blind procedure/ (119385)
13 (randomi?ed or randomly).tw. (749012)
14 (crossover$ or cross-over$).tw. (73500)
15 placebo$.ab. (204404)
16 (doubl$ adj blind$).tw. (152473)
17 assign$.ab. (245912)
18 allocat$.ab. (86645)
19 or/10-18 (1145599)
20 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5518138)
21 19 not 20 (995733)
22 4 and 9 and 21 (11880)
23 22 and (2013$ or 2014$ or 2015$).em. (1164)
Cochrane Central Register of Controlled Trials on Wiley <Issue 1, 2015> via Cochrane Register of Studies Online
--------------------------------------------------------------------------------
#1:(adrenergic beta-antagonist*) - 3953
#2: (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or
primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or
spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol) - 14056
#3: beta near2 (adrenergic* or antagonist* or block* or receptor*) - 11011
#4: #1 OR #2 OR #3 - 18403
#5: antihypertens* or hypertens* - 35486
#6: (“blood pressure” or bloodpressure) - 46400
#7: #5 OR #6 - 63228
#8: #4 AND #7 - 9332
#9: 01/10/2013 TO 19/01/2015:CD - 123974
#10: #8 AND #9 - 793
***************************
Hypertension Group Specialised Register
--------------------------------------------------------------------------------
1 (adrenergic beta-antagonist*)
2 (beta blocker*)
3 (beta adrenergic block*)
4 (adrenergic beta receptor block*)
5 (beta adrenergic receptor block*)
6 #1 OR #2 OR #3 OR #4 OR #5
7 (hypertens*)
8 #6 AND #7
9 #8 AND (RCT OR Review OR Meta-Analysis) (1782)
***************************
ClinicalTrials.gov (via Cochrane Register of Studies)
--------------------------------------------------------------------------------
Search terms: randomized
Study type: Interventional
Conditions: hypertension
Interventions: “adrenergic beta-antagonist” OR “adrenergic beta-antagonists” OR “beta blocker” OR “beta blockers”
Outcome Measures: blood pressure
First received: 1/10/2013 to 19/1/2015 (9)
***************************
Appendix 2. 2016 Search strategy

Ovid MEDLINE(R) 1946 to Present with Daily Update
Search Date: 14 June 2016
--------------------------------------------------------------------------------
1 exp adrenergic beta-antagonists/ (79179)
(75673)
4 or/1-3 (145660)
5 hypertension/ (210798)
8 (blood pressure or blood pressure).mp. (373969)

9 or/5-8 (633729)
10 randomized controlled trial.pt. (420851)
11 controlled clinical trial.pt. (91010)
12 randomi?ed.ab. (379711)
13 placebo.ab. (159968)
14 drug therapy.fs. (1873762)
15 randomly.ab. (223574)
16 trial.ab. (328035)
17 groups.ab. (1409370)
18 or/10-17 (3572728)
19 animals/ not (humans/ and animals/) (4231241)
20 18 not 19 (3046252)
21 4 and 9 and 20 (20003)
22 21 and (2015$ or 2016$).ed. (528)
***************************
Cochrane Central Register of Controlled Trials on Wiley <2016, Issue 6> via Cochrane Register of Studies Online
--------------------------------------------------------------------------------
#1MESH DESCRIPTOR Adrenergic beta-Antagonists EXPLODE ALL TREES9429
#2adrenergic beta-antagonist*4072
#3(acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or
primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or
spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol)14950
#4beta near2 (adrenergic* or antagonist* or block* or receptor*)12693
#5#1 OR #2 OR #3 OR #420606
#6antihypertens* or hypertens*40964
#7blood pressure or bloodpressure52553
#8#6 OR #772648
#9#5 AND #810268
#1001/01/2015 TO 14/06/2016:CD AND 01/01/2015 TO 14/06/2016:CD107219
#11#9 AND #10558
***************************
Embase <1974 to 2016 June 13>
--------------------------------------------------------------------------------
1 exp beta adrenergic receptor blocking agent/ (257952)
(186549)
4 or/1-3 (312536)
5 exp hypertension/ (577705)
8 blood pressure o bloodpressure.mp. (0)
9 or/5-8 (1027859)
10 randomized controlled trial/ (408424)
11 crossover procedure/ (47399)
12 double-blind procedure/ (131405)
13 (randomi?ed or randomly).tw. (880104)
14 (crossover$ or cross-over$).tw. (82444)
15 placebo$.ab. (231893)
16 (doubl$ adj blind$).tw. (169466)
17 assign$.ab. (283020)
18 allocat$.ab. (102246)

19 or/10-18 (1321527)
20 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (5874427)
21 19 not 20 (1153534)
22 4 and 9 and 21 (12623)
23 22 and (2015$ or 2016$).em. (818)
***************************
Cochrane Hypertension Specialised Register
Search Date: Search Date: 14 June 2016
--------------------------------------------------------------------------------
#1 (adrenergic beta-antagonist*) (1506)
#2 (beta blocker*) (2211)
#3 (beta adrenergic block*) (247)
#4 (adrenergic beta receptor block*) (13)
#5 (beta adrenergic receptor block*) (1141)
#6 #1 OR #2 OR #3 OR #4 OR #5 (3838)
#7 RCT:DE (22671)
#8 (Review or Meta-Analysis):MISC2 (1147)
#9 #6 AND (#7 OR #8) (2176)
#10 (#9) AND (1/1/2015 TO 14/6/2016:CRSMODIFIED) (398)
***************************
ClinicalTrials.gov
--------------------------------------------------------------------------------
Search terms: randomized
Study type: Interventional
Conditions: hypertension
Interventions: “adrenergic beta-antagonist” OR “adrenergic beta-antagonists” OR “beta blocker” OR “beta blockers”
Outcome Measures: blood pressure (95)
***************************
WHAT’S NEW
Last assessed as up-to-date: 13 December 2016.
Date Event Description
12 January 2017 New search has been performed Up to date search. No new studies met the inclusion
criteria

(Continued)
12 January 2017 New citation required but conclusions have not changed Conclusions have been reworded and there is a change
in authorship and author affiliations
HISTORY
Protocol first published: Issue 3, 1998
Review first published: Issue 1, 2007
Date Event Description
16 November 2012 Amended New search from December 2011 to November 2012.
27 August 2012 Amended updated author affiliations
9 July 2012 New search has been performed New search from June 2006 to December 2011. No
new studies met the inclusion criteria. The Risk of
Bias table has been updated for all included studies
and 4 Summary of findings tables have been added
to the updated review. In the 2007 version there were
unintended errors in the data entered for withdrawals
due to side effects for the two UK Medical Research
Council trials (MRC 1985, MRCOA 1992), which
led to the erroneous conclusion that patients on beta-
blockers were more likely to discontinue treatment due
to side effects than those on diuretics. The corrected
data, in this update, show no significant differences in
withdrawals due to side effects between beta-blockers
and diuretics. The overall message in the conclusions
has not changed
9 July 2012 New citation required but conclusions have not New citation due to update
changed
13 August 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
CSW and HB screened the search output, selected studies, assessed the risk of bias, and extracted data. At each stage, the two review
authors resolved differences by discussion and consensus; with arbitration by JV.
CW conducted the analyses.
All review authors read and approved the final version before submission.
CSW and HB contributed equally to this review and share first authorship.
DECLARATIONS OF INTEREST
We have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of this
systematic review.
SOURCES OF SUPPORT
Internal sources
• South African Medical Research Council (CSW), South Africa.
• Stellenbosch University (CSW, JV), South Africa.
• University of the Western Cape (HB), South Africa.
• University of Cape Town (BMM, LHO), South Africa.
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

We have decided to have clearly defined strict eligibility criteria regarding duration of treatment, which we have now set at one year or
more on trial medications. In the protocol and initial version of the review published in 2007, duration of treatment was not included
as a criterion for eligibility. We have now used the ’Risk of bias’ tool as described in Chapter 8 of the Cochrane Handbook for Systematic
Reviews of Interventions (Higgins 2011). This tool was not yet developed when the protocol was written.
INDEX TERMS
Medical Subject Headings (MeSH)

Adrenergic beta-Antagonists [adverse effects; ∗ therapeutic use]; Angiotensin Receptor Antagonists [therapeutic use]; Antihypertensive
Agents [adverse effects; ∗ therapeutic use]; Atenolol [therapeutic use]; Calcium Channel Blockers [therapeutic use]; Coronary Disease
[prevention & control]; Diuretics [therapeutic use]; Heart Arrest [prevention & control]; Hypertension [∗ drug therapy; mortality];
Randomized Controlled Trials as Topic; Stroke [prevention & control]

MeSH check words
Adult; Aged; Humans; Middle Aged

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Beta-blockers for hypertension

Article in Cochrane database of systematic reviews · January 2017

Charles Shey Wiysonge Hazel A Bradley

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Bongani M Mayosi Lionel H Opie

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Beta-blockers for hypertension (Review)

Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH

Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH.

Beta-blockers for hypertension (Review)

Beta-blockers for hypertension (Review) ii

Beta-blockers for hypertension

Editorial group: Cochrane Hypertension Group.

PLAIN LANGUAGE SUMMARY

Beta-blockers for hypertension

What is the aim of this review?

What was studied in the review?

Beta-blockers for hypertension (Review) 3

Beta- blockers versus placebo as first- line therapy for hypertension

Participants: people with hypertension

Assumed risk Corresponding risk

Placebo Beta- blockers

Total mortality 52 per 1000 51 per 1000 RR 0.99 23613 ⊕⊕⊕

Total cardiovascular dis- 64 per 1000 57 per 1000 RR 0.88 23613 ⊕⊕

Total stroke 23 per 1000 18 per 1000 RR 0.80 23613 ⊕⊕

GRADE Working Group grades of evidence

How the intervention might work OBJECTIVES

Beta-blockers for hypertension (Review) 6

Search methods for identification of studies

Beta-blockers for hypertension (Review) 7

Beta-blockers for hypertension (Review) 8

Beta-blockers for hypertension (Review) 9

Beta-blockers for hypertension (Review) 10

Beta-blockers for hypertension (Review) 11

Beta-blockers for hypertension (Review) 12

Beta-blockers for hypertension (Review) 13

Beta-blockers for hypertension (Review) 14

Beta-blockers for hypertension (Review) 15

Beta- blockers compared to diuretics as first- line therapy for hypertension

Participants: people with hypertension

Assumed risk Corresponding risk

Diuretics Beta- blockers

Total mortality 41 per 1000 43 per 1000 RR 1.04 18241 ⊕⊕⊕

Total stroke 12 per 1000 14 per 1000 RR 1.17 18135 ⊕⊕

GRADE Working Group grades of evidence

Participants: people with hypertension

Assumed risk Corresponding risk

Calcium- channel blockers Beta- blockers

Total mortality 73 per 1000 78 per 1000 RR 1.07 44825 ⊕⊕⊕

Total stroke 23 per 1000 29 per 1000 RR 1.24 44167 ⊕⊕⊕

Withdrawal due to adverse 33 per 1000 40 per 1000 RR 1.20 21591 ⊕⊕

GRADE Working Group grades of evidence

Participants: people with hypertension

Assumed risk Corresponding risk

Renin- angiotensin system Beta- blockers

Total mortality 84 per 1000 92 per 1000 RR 1.10 10828 ⊕⊕⊕

Total stroke 51 per 1000 66 per 1000 RR 1.30 9951 ⊕⊕⊕