Abstract
Background
Beta‐blockers are commonly used in the treatment of hypertension. We do not know whether the blood pressure (BP) lowering efficacy of beta‐blockers varies across the day. This review focuses on the subclass of beta‐blockers with partial agonist activity (BBPAA).
Objectives
To assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24‐hour period in adults with essential hypertension.
Search methods
The Cochrane Hypertension Information Specialist searched the following databases for relevant studies up to June 2020: the Cochrane Hypertension Specialised Register; CENTRAL; 2020, Issue 5; MEDLINE Ovid; Embase Ovid; the World Health Organization International Clinical Trials Registry Platform; and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions.
Selection criteria
We sought to include all randomised and non‐randomised trials that assessed the hourly effect of BBPAA by ambulatory monitoring, with a minimum follow‐up of three weeks.
Data collection and analysis
Two review authors independently selected the included trials and extracted the data. We assessed the certainty of the evidence using the GRADE approach. Outcomes included in the review were end‐point hourly systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR), measured using a 24‐hour ambulatory BP monitoring (ABPM) device.
Main results
Fourteen non‐randomised baseline controlled trials of BBPAA met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta‐analysis. Beta‐blockers studied included acebutalol, pindolol and bopindolol. We judged most studies at high or unclear risk of bias for selection bias, attrition bias, and reporting bias. We judged the overall certainty of the evidence to be very low for all outcomes.
We analysed and presented data by each hour post‐dose. Very low‐certainty evidence showed that hourly mean reduction in BP and HR visually showed an attenuation over time. Over the 24‐hour period, the magnitude of SBP lowering at each hour ranged from ‐3.68 mmHg to ‐17.74 mmHg (7 studies, 121 participants), DBP lowering at each hour ranged from ‐2.27 mmHg to ‐9.34 mmHg (7 studies, 121 participants), and HR lowering at each hour ranged from ‐0.29 beats/min to ‐10.29 beats/min (4 studies, 71 participants). When comparing between three 8‐hourly time intervals that correspond to day, evening, and night time hours, BBPAA was less effective at lowering BP and HR at night, than during the day and evening. However, because we judged that these outcomes were supported by very low‐certainty evidence, further research is likely to have an important impact on the estimate of effect and may change the conclusion.
Authors' conclusions
There is insufficient evidence to draw general conclusions about the degree of variation in hourly BP‐lowering efficacy of BBPAA over a 24‐hour period, in adults with essential hypertension. Very low‐certainty evidence showed that BBPAA acebutalol, pindolol, and bopindolol lowered BP more during the day and evening than at night. However, the number of studies and participants included in this review was very small, further limiting the certainty of the evidence. We need further and larger trials, with accurate recording of time of drug intake, and with reporting of standard deviation of BP and HR at each hour.
Plain language summary
Is the blood pressure‐lowering effect of beta‐blockers with partial agonist activity consistent or variable throughout the day?
Review question
This review explores whether the blood pressure‐lowering effect of beta‐blockers with partial agonist activity is consistent or variable throughout the day in adults with high blood pressure (upper blood pressure reading of at least 140 mmHg, or lower blood pressure reading of at least 90 mmHg, or both).
Background
High blood pressure, also known as hypertension, is very common in the general population, and if not treated, can increase the risk of stroke and heart disease. In an individual, blood pressure naturally varies throughout the day. It is at its lowest at night, rises before awakening, and then falls progressively during the day. Changes to this pattern of variation have been found to be a risk factor for heart disease, independent of the degree of rise in blood pressure.
Beta‐blockers are commonly used in the treatment of high blood pressure. Currently, we do not know whether beta‐blockers lower blood pressure to different degrees at different times of the day, and how this differs when compared to other classes of drugs used to treat high blood pressure. This review focused on a particular class of beta‐blockers – those with partial agonist activity (molecules that both activate and inhibit its receptor).
Search date
We searched the available scientific literature, and included relevant studies up to June 2020.
Study characteristics
We sought studies that examined the blood pressure‐lowering effects of treatment with six beta‐blockers with partial agonist activity at different times throughout a 24‐hour period, measured by a device that automatically measures blood pressure at regular intervals (ambulatory monitoring).
Key results
We identified seven studies, involving 121 participants, that studied three of the six beta‐blockers with partial agonist activity (acebutolol, pindolol, and bopindolol). We found that these beta‐blockers lowered blood pressure and heart rate more during the day and evening than at night. Currently, we do not know the benefits and harms of this pattern of blood pressure lowering, such as its impact on reducing stroke and heart disease.
Certainty of the evidence
Only a small number of eligible studies were identified, involving relatively few participants. We judged the majority of studies at high or unclear risk of bias. We judged the overall certainty of the evidence to be very low for all outcomes. Further research is likely to have important impact on the estimate of effect and may change the conclusion.
Summary of findings
Summary of findings 1. Beta‐blockers with partial agonist activity compared to no treatment for hypertension.
| Beta‐blockers with partial agonist activity compared to no treatment for hypertension | |||
| Patient or population: adults with essential hypertension Setting: outpatient Intervention: beta‐blockers with partial agonist activity Comparison: baseline or pre‐treatment | |||
| Outcomes | № of participants (studies) | Certainty of the evidence (GRADE) | Comments |
|
Variation in the decrease in 24‐hour ambulatory hourly SBP (at 3 to 12 weeks) |
121 (7 baseline controlled studies) | ⊕⊝⊝⊝ Very lowa,b,c | The magnitude of SBP lowering at each hour ranged from ‐3.68 mmHg to ‐17.74 mmHg over the 24‐hour period. Comparing across three 8‐hourly time intervals (day, evening, night), the SBP‐lowering effects were lower at night than during the day and evening: day (MD ‐12.04 mmHg, 95% CI ‐13.12 to ‐11.07); evening (MD ‐12.17 mmHg, 95% CI ‐13.43 to ‐10.90); night (MD ‐6.65 mmHg, 95% CI ‐7.90 to ‐5.36). |
|
Variation in the decrease in 24‐hour ambulatory hourly DBP (at 3 to 12 weeks) |
121 (7 baseline controlled studies) | ⊕⊝⊝⊝ Very lowa,b,c |
The magnitude of DBP lowering at each hour ranged from ‐2.27 mmHg to ‐9.34 mmHg over the 24‐hour period. Comparing across three 8‐hourly time intervals (day, evening, night), the DBP‐lowering effects were lower at night than during the day and evening: day (MD ‐7.87 mmHg, 95% CI ‐8.33 to ‐7.41), evening (MD ‐7.53, 95% CI ‐8.13 to ‐6.93), night (MD ‐5.16 mmHg, 95% CI ‐5.60 to ‐4.73). |
|
Variation in the decrease in 24‐hour ambulatory hourly HR (at 3 to 12 weeks) |
71 (4 baseline controlled studies) | ⊕⊝⊝⊝ Very lowa,b,c | The magnitude of HR lowering at each hour ranged from ‐0.29 beats/min to ‐10.29 beats/min over the 24‐hour period. Comparing across three 8‐hourly time intervals (day, evening, night), the HR‐lowering effects were lower at night than during the day and evening: day (MD ‐6.76 beats/min, 95% CI ‐7.49 to ‐6.00), evening (MD ‐5.28 beats/min, 95% CI ‐6.03 to ‐4.52), night (MD ‐3.30 beats/min, 95% CI ‐4.00 to ‐2.61). |
| SBP – systolic blood pressure; DBP – diastolic blood pressure; HR – heart rate; MD – mean difference; CI – confidence interval; SD – standard deviation | |||
| GRADE Working Group grades of evidence High certainty. We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty. We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty. Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect Very low certainty. We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect | |||
| Downgraded due to: aInconsistency: high I² values at the majority of individual hourly time points for all outcomes bImprecision: small number of participants per study, and small number of studies eligible for inclusion in meta‐analysis, resulting in wide confidence intervals around effect estimate. Uncertain SD estimates, as variable SD data reported in the included studies, so imputations applied to estimate SD as per hierarchy described in methods cAttrition bias across included studies, as incomplete outcome data reporting: 7 eligible studies did not report data that could be used in meta‐analysis | |||
Background
Description of the condition
Elevated blood pressure (BP), defined as systolic blood pressure (SBP) ≥ 140 mmHg, or diastolic blood pressure (DBP) ≥ 90 mmHg, or both, is highly prevalent in the population (Egan 2010). It is associated with numerous serious adverse events, including an increased risk of coronary heart disease, heart failure, stroke, and chronic kidney disease. The likelihood of developing these complications is related to the degree of BP elevation (Lewington 2002; Hsu 2005). Pharmacological therapy to reduce BP has been shown to significantly reduce the risk of these adverse events (Wright 2009). Several classes of antihypertensive agents are currently in use to treat elevated BP; beta‐adrenergic receptor blockers (beta‐blockers) are one of these classes.
BP displays a diurnal variation, characterised by substantial reductions during sleep (nocturnal dip) and a rapid rise before awakening (morning surge). The original study that used continuous intra‐arterial monitoring showed that BP is lowest at night, rises before awakening, and then falls progressively throughout the day (Millar‐Craig 1978a). Numerous studies have shown that the pattern of circadian BP variation has prognostic significance. The lack of nocturnal BP reduction (non‐dipping) is a risk factor for the development of cardiovascular complications, independent of the degree of hypertension (Fan 2010). A marked decrease in BP at night (extreme dippers), and a morning surge in BP are also associated with increased cardiovascular risk (Elliott 1999; Kario 2004).
Description of the intervention
Beta‐blockers are a heterogeneous group of pharmacological agents, with varying beta‐adrenergic receptor selectivity, intrinsic sympathomimetic activity, and vasodilatory properties. Beta‐blockers with partial agonist activity (BBPAA) not only block the effect of endogenous catecholamines by acting as a competitive antagonist, they also provide a degree of receptor stimulation that is less than that of a full agonist (Westfall 2011). The potential clinical advantage of this, although unproven, is that whilst substantial sympathomimetic activity would be counterproductive to the effect desired from an antagonist, slight receptor stimulation may prevent profound bradycardia or negative inotropy in a resting heart.
Previous Cochrane Reviews have given us a precise measure of the office BP lowering efficacy of beta‐blockers as a class of antihypertensives (Wiysonge 2007; Wright 2009). Wright and colleagues found that first‐line beta‐blocker treatment reduced BP by 10/6 mmHg compared to placebo or no treatment. This is comparable to the degree of BP lowering by low‐dose thiazides (13/5 mmHg), high‐dose thiazides (14/7 mmHg), and calcium channel blockers (9/5 mmHg), but is lower than that of angiotensin converting enzyme (ACE) inhibitors (21/10 mmHg; Wright 2009). When added as a second drug to diuretics or calcium channel blockers, a beta‐blocker was found to reduce BP by 6/4 mmHg at one time the starting dose, and 8/6 mmHg at twice the starting dose (Chen 2010).
A growing body of evidence shows that beta‐blockers are less effective at reducing hypertensive complications than other classes of antihypertensives. Two recent Cochrane Reviews on beta‐blockers as first‐line agents in adults with hypertension, found that they have no conclusive effect on all‐cause mortality, or the rik of coronary heart disease, and only slightly reduce the risk of stroke (Wiysonge 2007; Wright 2009). Wiysonge 2007 found that beta‐blockers are inferior to calcium channel blockers and renin‐angiotensin system inhibitors in stroke reduction, and are associated with a higher all‐cause mortality than calcium channel blockers. However, 75% of study participants in the analysis used atenolol, making it unclear whether the findings were representative of beta‐blockers as a class, or apply only to atenolol.
How the intervention might work
The antihypertensive effect of beta‐blockers was discovered fortuitously, when it was found to lower BP in people with hypertension with angina. Despite their widespread use, the mechanisms underlying this important clinical effect are not well understood, although a number of possible mechanisms have been put forward.
Generally, beta‐blockers do not lower BP in people with normal BP, but do lower BP in those with hypertension. Antagonism of beta‐adrenergic receptors reduces myocardial contractility and heart rate (HR), which hence, lowers cardiac output. This results in an initial compensatory proportional rise in peripheral vascular resistance, and generally, no net change in arterial pressure. However, long‐term administration of beta‐blockers leads to a delayed fall in peripheral vascular resistance to initial level or below by an unknown mechanism, which in the face of a persistent reduction in cardiac output, appears to account for much of the antihypertensive effect of beta‐blockers (Man 1988; Michel 2011). Beta‐blockers may also lower BP by reducing sympathetic stimulation of renin release by the juxtaglomerular apparatus. Some beta‐blockers have additional effects that may contribute to their capacity to lower BP (Michel 2011). As beta‐blockers are sympatholytic, their effect is most pronounced when the sympathetic nervous system is activated, such as during exercise or stress.
Why it is important to do this review
Studies have shown that different classes of antihypertensive agents differ in their ability to reduce mortality and cardiovascular events, which is not entirely related to their efficacy in BP lowering (Wright 2009). However, it remains unclear what underlies these differential effects. As BP varies throughout the day, and the circadian pattern has been shown to have prognostic significance, it is not inconceivable that the temporal effect of BP lowering by antihypertensive agents may affect clinical outcome. A recent systematic review, evaluating the administration time‐related effects of evening versus morning dosing of antihypertensive agents, found that evening dosing significantly reduced 24‐hour BP, but none of the trials reported relevant clinical outcomes, such as all‐cause mortality and cardiovascular events (Zhao 2011). Since then, a large prospective study of 2156 hypertensive subjects, with a median follow‐up of 5.6 years, using ambulatory BP monitoring, showed that bedtime treatment with one or more hypertensive medications, resulted in a significantly lower sleep‐time BP, reduced prevalence of non‐dipping, and a significant reduction in cardiovascular morbidity and mortality compared to conventional upon‐waking treatment (Hermida 2010). However, this study did not report on the effect of time of treatment on circadian BP pattern, other than a reduction in mean asleep BP.
Given the differing pharmacokinetics and pharmacodynamics of the various classes of antihypertensive agents, differences in their efficacy around the clock might be expected. Indeed, the Gould 1991 study on circadian BP control by a variety of antihypertensive agents using intra‐arterial BP monitoring, found that beta‐blockers appear to have less effect on nocturnal BP and surge in BP after arousal. Since non‐invasive ambulatory BP monitoring devices became available, the 24‐hour BP lowering efficacy of many antihypertensive agents has been studied. However, most systematic reviews to date have focused on the BP lowering efficacy of different classes of antihypertensive agents at a single time point. An exception is a review that examined the effect of beta‐blockers, ACE inhibitors, and calcium channel blockers on day and night BP, using ambulatory BP monitoring (Voogel 1996). It found that all three classes of antihypertensive agents tend to preserve the circadian BP profile with only negligible attenuation. However, this review has several important limitations. First, the robustness and generalisability of the review's conclusions are unclear, because they did not assess the quality of the included studies, and reported a limited attempt to identify all relevant primary studies. Second, they presented only average changes in day and night, rather than hourly BP, and excluded early morning and late evening hours. Third, due to the small number of studies identified, the authors made no attempt to analyse the circadian effect of different beta‐blockers.
This review is part of a series of reviews on the time course of BP lowering by the major classes of antihypertensive agents, currently undertaken by the Cochrane Hypertension Group. Our methodology follows that of Sekhon 2008, which is planning to assess the time course for BP lowering of thiazides, and Ghamami 2014, which assessed the time course for BP lowering of dihydropyridine calcium channel blockers, the later a completed review. Ghamami 2014 found that dihydropyridine calcium channel blockers lowered BP by a relatively similar amount each hour over the course of 24 hours. Interpreting the findings of our review alongside those from other reviews in this series may contribute to our understanding of their relative effects on mortality and cardiovascular events.
Most reviews have focused on beta‐blockers as a class of antihypertensive agents, and have not taken into account the heterogeneity in their properties. Gavin Wong and colleagues, of the Cochrane Hypertension Group, published a series of reviews on the office BP lowering efficacy of different groups of beta‐blockers: beta1‐selective (Wong 2016), non‐selective (Wong 2014a), dual alpha‐ and beta‐blockers (Wong 2015), and partial agonist (Wong 2014b). They found that partial agonist beta‐blockers lowered BP to a smaller degree than beta‐1 selective and non‐selective blockers, but by a similar magnitude to dual alpha‐ and beta‐blockers (Wong 2016). Findings from this series of reviews on ambulatory BP lowering efficacy by the same groups of beta‐blockers will supplement findings from their work.
Objectives
To assess the degree of variation in hourly BP lowering efficacy of beta‐blockers with partial agonist activity over a 24‐hour period in adults with essential hypertension.
Methods
Criteria for considering studies for this review
Types of studies
For inclusion, studies must conform to either of the following designs:
Randomised controlled trial comparing the blood pressure (BP)‐lowering effect of a standard dose* of a beta‐blocker of interest (see Types of interventions), against a parallel control group (placebo or no intervention)
Baseline controlled trial measuring BP before and after treatment with a beta‐blocker of interest, in a single group of subjects
We included baseline controlled trials because there is negligible, or no placebo effect, with 24‐hour ambulatory BP measurement (Gould 1981; Dupont 1987).
The following criteria must also be met for a study to be included:
Minimum of three weeks of follow‐up
Baseline measurements must be taken after an appropriate washout period
Cross‐over trials reporting combined data from before and after cross over can be included as baseline controlled trial, if BP is also measured prior to commencing treatment. Cross‐over trials can be included as randomised controlled trials (placebo or no intervention) only if data before the cross over are available.
Study participants must be ambulatory during BP measurementǂ
Blinding of intervention to investigators, participants, or both is not required
*Standard doses are those recommended for current clinical practice.
ǂWe excluded studies where BP was measured by an invasive technique, which requires people to be on strict bed rest. As the effects of beta‐blockers are particularly pronounced during exercise, its efficacy in blood pressure reduction in an ambulatory person would be more informative of its clinical usage.
Types of participants
Individuals over 18 years of age, with essential hypertension, with a baseline systolic blood pressure (SBP) of at least 140 mmHg, or diastolic blood pressure (DBP) of at least 90 mmHg, or both, were included.
Types of interventions
We included monotherapy with any beta‐blockers with partial agonist activity (BBPAA), including acebutolol, celiprolol, oxprenolol, pindolol, alprenolol, and bopindolol. Medication should be given at a standard dose, and may be administered at any frequency (for example, once daily or twice daily).
Types of outcome measures
Primary outcomes
End point hourly systolic and diastolic BP, measured using a 24‐hour ambulatory BP monitoring device.
Secondary outcomes
End point hourly heart rate (HR), measured using a 24‐hour ambulatory BP monitoring device.
As the primary goal of this review was to assess the degree of variation in hourly BP lowering efficacy of BBPAA over a 24‐hour period (as an insight into how this may influence hypertensive complications), rather than their overall efficacy in BP lowering (a measure of benefit), we chose not to assess their adverse effects in this review.
Search methods for identification of studies
Electronic searches
The Cochrane Hypertension Information Specialist searched the following databases, without language, publication year, or publication status restrictions:
the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web; searched 10 June 2020);
the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, issue 5) via the Cochrane Register of Studies (CRS‐Web; searched 10 June 2020);
MEDLINE Ovid, MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 10 June 2020);
Embase Ovid (searched 10 June 2020);
ClinicalTrials.gov (www.clinicaltrials.gov; searched 11 June 2020);
World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch; searched 11 June 2020).
The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane to identify randomised controlled, as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 6 (Lefebvre 2019). We present search strategies for major databases in Appendix 1.
Searching other resources
The Cochrane Hypertension Information Specialist searched the Hypertension Specialised Register segment of CRS‐Web (which includes searches of MEDLINE, Embase, and Epistemonikos for systematic reviews) to retrieve existing reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. The Specialised Register also includes searches of CAB Abstracts & Global Health, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ProQuest Dissertations & Theses, and Web of Science for controlled trials.
We checked the bibliographies of included studies, and any relevant systematic reviews identified for further references to relevant trials.
Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials.
Data collection and analysis
Selection of studies
Two review authors (XYZ and SS) independently screened studies identified through database searches for relevance, based on titles and abstracts. Studies that failed to meet the inclusion criteria, or that fulfilled the exclusion criteria, were rejected. The same two review authors independently reviewed and assessed full texts of selected studies from the initial screening, to establish whether they were suitable to include in this review. A third review author (VM) resolved any discrepancies.
Data extraction and management
Two reviewers (XYZ and SS) independently extracted and cross‐checked all data from included studies. Hourly BP and HR data were often presented in graphical format. We extracted the data either manually, or by using a suitable data extraction software. After resolving any significant discrepancies (defined as greater than 1 mmHg or 1 beat/min), we calculated an average of the two values obtained by the review authors, and used this in the meta‐analysis. A third review author (VM) cross‐checked data extraction and imputation of standard deviation from all included studies.
In studies where the same cohort of people was treated with either different doses of the same drug, or with the same drug but for different lengths of time, we used data from the highest dose and longest treatment period in the meta‐analysis. The logic behind this is that a higher dosage and longer treatment are likely to produce the greatest change in BP and HR.
Where ambulatory BP and HR were measured and reported at less than a one‐hourly interval (for example, every 30 or 15 minutes), we calculated the hourly average, and used this in the meta‐analysis.
Beta‐blockers are commonly prescribed to be taken once or twice daily, with the first or only dose taken in the morning. In analysing ambulatory BP data, the time at which the morning dose was taken was considered 'hour 0'. Where the time the drug was taken was not specified in the study, 9 a.m. was assigned 'hour 0'. When taken as twice daily dosing, the time at which the afternoon dose was taken was assigned 'hour x', where x was the number of hours since the morning dose, not 'hour 0'. The reason behind this is that while we anticipated beta‐blockers would have differential effect on BP, depending both on the time of day and the time since the drug was taken, the emphasis of this review was on their circadian effect, not their duration of effect after a dose.
We contacted the authors of Neutel 1990; Stephan 1993; Schmieder 1985; and Schmieder 1989 for missing data. Neutel informed us that the original data were no longer available. We did not receive any reply from the other three authors. We were unable to contact other authors for missing data due to lack of contact details.
Assessment of risk of bias in included studies
We assessed the risk of bias in included studies by following Cochrane methodology, detailed in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8 (Higgins 2011). Features of included studies assessed included sequence generation (selection bias), allocation sequence concealment (selection bias), blinding of participants, investigators, and outcome assessors, incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other potential sources of bias.
Measures of treatment effect
The treatment effect was measured as the mean difference with 95% confidence interval (CI) in systolic and diastolic BP (in mmHg) between baseline and after treatment, or between placebo and treatment group, at each hour over a 24‐hour period. However, only baseline controlled trials met the inclusion criteria in this review.
Unit of analysis issues
Where studies measured ambulatory BP at multiple points during treatment, we extracted data for one treatment period only, to avoid collecting multiple observations from each participant. Where a randomised cross‐over design was employed, we extracted data pre‐cross‐over, when available. Where only combined data for each intervention (pre‐ and post‐cross‐over) was available, we extracted data from a single intervention group only, to avoid unit of analysis error.
See Characteristics of included studies for further details.
Dealing with missing data
Standard deviation (SD) of change in BP at each hour was often not included in the published reports. When we could not obtain this information from trial authors, we imputed standard deviations according to the hierarchy below, which is a modified version of the strategy described by Sekhon 2008.
Standard deviation of the change in average daily BP from the same trial
Standard deviation of the average BP at each hour at the end of treatment from the same trial
Standard deviation of the average daily BP at the end of treatment from the same trial
Weighted mean standard deviation of the change in average daily BP from at least three other trials using the same drug and dose regimen
Weighted mean standard deviation of average daily BP at the end of treatment from at least three other trials using the same drug and dose regimen
Weighted mean standard deviation of change in average daily BP from other trials using the same drug
Weighted mean standard deviation of average daily BP at the end of treatment from other trials using the same drug
Weighted mean standard deviation of change in average daily BP from all included trials (any drug and dose)
Weighted mean standard deviation of average daily BP at the end of treatment from all included trials (any drug and dose)
We imputed the standard deviation according to steps one, and three to nine of the hierarchy at each hour.
For steps four to nine, weighting was by the number of participants in the included trials.
Assessment of heterogeneity
We used Review Manager 5 software's built‐in test for heterogeneity of treatment effects to determine the degree of heterogeneity at each hourly time point (Review Manager 2014).
Assessment of reporting biases
If ten or more studies met the inclusion criteria, we wanted to assess reporting bias using funnel plots, as outlined in the Handbook, Chapter 10 (Sterne 2011). However, since only seven studies met the criteria, we did not create funnel plots.
Data synthesis
All eligible studies identified for inclusion in this review were non‐randomised baseline controlled trials. We entered the mean difference from baseline measurement in BP or HR plus its standard error, and pooled them as generic inverse variance data to obtain a mean difference with 95% CI. We could not use RevMan 5.4 for the analyses of total effects across time points because of correlated errors introduced by repeated observations on the same people. We used the following process instead.
We defined each hourly time point as a categorical variable, with 24 categories corresponding to a 24‐hour day, and numbered 0 through 23. We retrieved the standard deviation for each hourly mean difference (MD) in each study by multiplying the standard error of the MD for that hour by the square root of the study sample size.
In order to simulate random variability of individual subjects around each hourly MD, we randomly drew a sample of individual differences, where the sample size was equal to the study sample size, from a normal distribution centred on the MD, and corresponding standard deviation for that study and hour. Within‐patient correlation across hours in these simulated patients was ignored and assumed to be independent. After simulating a sample of individuals across hours for each study, we calculated an overall MD for each hour, by averaging the differences across all simulated subjects and studies.
We repeated this process 1001 times, and ranked the overall MDs in ascending order. After ranking, we took the 501st observation from the ranked set of overall MDs to be the final estimated MD for that hour. We took the 26th and 976th observations to be the 95% confidence limits. Finally, we completed the process for each hour and in 8‐hour time categories, to summarize the day, evening, and night time differences in BP or HR.
We used SAS and SAS/STAT software, Version 9.4 of the SAS System for Windows to generate the data analysis for this paper (SAS 2012). In particular, we used the RAND function to generate individual subjects to simulate within‐study variation between participants.
Subgroup analysis and investigation of heterogeneity
Due to the limited number of eligible studies identified, we did not carry out subgroup analysis.
Sensitivity analysis
Due to the limited number of eligible studies identified, we did not carry out sensitivity analysis.
Summary of findings and assessment of the certainty of the evidence
We used the GRADE approach to assess the certainty of the evidence for each outcome (Schünemann 2019a; Schünemann 2019b). We presented key findings of the review, including a summary of the data, the magnitude of the effect size, and the overall certainty of the evidence, in Table 1. We determined GRADE assessments of certainty by considering five domains: study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias. We categorised the certainty in a body of evidence for each outcome as high, moderate, low, or very low.
We presented evidence for the following key outcomes: variation in the decrease in 24‐hour ambulatory hourly SBP, DBP, and HR.
Results
Description of studies
Results of the search
Our search, until June 2020, identified 1137 reports in total. After removing duplicates, we screened 642 unique reports by title and abstract. Of these, we retrieved 85 full‐text articles, from which we identified 14 studies that met the inclusion criteria. Seven of these studies provided hourly BP data that we included in the meta‐analysis.
Figure 1 summarises the PRISMA flow diagram for the screening process.
1.
Study flow diagram
Included studies
See Characteristics of included studies.
There were no randomised controlled trials comparing against a placebo or no intervention that fulfilled the inclusion criteria. Fourteen studies of beta‐blockers with partial agonist activity (BBPAA) met our inclusion criteria, but only seven studies, involving 121 participants, reported hourly ambulatory BP data that could be included in the meta‐analysis. Beta‐blockers studied included acebutalol, pindolol, and bopindolol, with mean duration of treatment ranging from 4 weeks to 12 weeks. In all seven studies, ambulatory blood pressure monitoring (ABPM) was measured at baseline, before treatment; from this point onwards, we treated all of them as non‐randomised baseline controlled trials of the beta‐blocker of interest for the purpose of the meta‐analysis.
We included seven studies with 121 participants in the meta‐analysis. The total number of data points varied at some hours, as some studies provided bi‐hourly data (Neutel 1990), or provided less than 24 hours of data (Abetel 1986; Abetel 1988). Four of the seven included studies were randomised trials comparing different beta‐blockers (Abetel 1986; Neutel 1990; Kotake 1992; Kanematsu 1993). Two studies were randomised cross‐over trials, comparing two different dosages of bopindolol (Favre 1986c), or two different formula of acebutalol (Sadowski 2002). Abetel 1988 had a baseline controlled design.
Sample sizes were low in all seven included studies, ranging from 11 to 77. All studies included men and women, with an average age of 40 years to 50 years.
Three BBPAA were studied in the seven studies: bopindolol (Abetel 1986; Favre 1986c; Abetel 1988), acebutalol (Neutel 1990; Kotake 1992; Sadowski 2002), and pindolol (Kanematsu 1993). We found no eligible studies on the other three beta‐blockers of interest: oxprenolol, celiprolol, and alprenolol. Bopindolol was given once daily (Abetel 1986; Favre 1986c; Abetel 1988; Neutel 1990), acebutalol once or twice daily (Kotake 1992; Sadowski 2002), and pindolol was given twice daily (Kanematsu 1993). The most common time the drug was taken at was 9 a.m. (Abetel 1986; Favre 1986c; Abetel 1988; Neutel 1990). Pindolol was taken at 8 a.m. and 8 p.m. in Kanematsu 1993. Time of taking the drug was not specified in Kotake 1992 and Sadowski 2002. Titrated doses were used in five studies (Abetel 1986; Favre 1986c; Abetel 1988; Neutel 1990; Kotake 1992), and a single fixed dose in one (Kanematsu 1993). The last study compared two formulations of acebutalol, at the same total daily dosage (Sadowski 2002). Five studies began with a one‐ to six‐week washout of previous antihypertensive medication or placebo run‐in; Kanematsu 1993 did not specify).
The treatment duration ranged from two to four weeks to 12 weeks in the seven included studies. The most common treatment duration was four weeks in four studies (Abetel 1986; Favre 1986c; Kanematsu 1993; Sadowski 2002). We included Kotake 1992 in the meta‐analysis despite some participants receiving only two weeks of treatment, as the average treatment duration was considered to be three weeks, which met the inclusion criteria for this review. The treatment period was six weeks in Neutel 1990, and 12 weeks in Abetel 1988.
The studies provided variable standard deviation or standard error data. One study provided standard error of the decrease in average daily BP (Neutel 1990). One study provided individual hourly standard deviation after treatment (Kotake 1992). Two studies included the standard deviation of average daily BP after treatment (Abetel 1986; Kotake 1992), and two studies included the standard deviation of the decrease in average daily BP after treatment (Favre 1986c; Abetel 1988). Two studies did not provide any standard deviation or standard error data (Kanematsu 1993; Sadowski 2002). We imputed standard error data according to the hierarchy specified in Dealing with missing data.
Four of the seven included studies (71 participants) included data on hourly HR (secondary outcome; Favre 1986c; Kotake 1992; Kanematsu 1993; Sadowski 2002). The total number of data points varied at some hours as Favre 1986c provided bi‐hourly data only; Kotake 1992 provided hourly standard deviation after treatment; and Favre 1986c provided standard deviation of decrease in average daily HR after treatment. Kanematsu 1993 and Sadowski 2002 did not provide any standard deviation or standard error data. We applied the standard error data from Favre 1986c for these two studies, as specified in the hierarchy in Dealing with missing data.
Four of the seven studies were published in languages other than English. We translated these studies with the help of Cochrane. None of the studies reported their funding source.
We could not include data from seven small studies (sample size range = 10 to 30; total participants = 112) that met the inclusion criteria in the meta‐analysis, as hourly BP data were measured, but either not reported at all, or not reported in a usable format. These included three studies on acebutalol (Favre 1986; Favre 1986a; Stephan 1993), three studies on celiprolol (Halabi 1989; Wambach 1994; Podzolkov 2002), and one study on pindolol (Garrett 1982).
Excluded studies
See Characteristics of excluded studies
We excluded 539 reports at the initial title and abstract screening stage. We excluded a study at this stage if it was clear from the title or abstract that the study did not:
Assess the effect of beta‐blockers on BP;
Study one of the six BBPAA specified in the methods;
Monitor ambulatory BP, i.e. if only office BP was measured, or if BP was measured by an intra‐arterial method.
After the initial title and abstract screening stage, we retrieved 85 full‐text articles. Of these, we excluded 18 studies because they did not measure ambulatory BP; five studies because BP was measured by an intra‐arterial method; two cross‐over studies because they did not report BP data pre‐cross‐over or at baseline; five studies because they did not measure or report baseline BP; two studies used combined treatment with other antihypertensive agents; and one study because the treatment duration was only two weeks long. There were also twelve review articles.
The reasons for exclusion of each study are provided in the table Characteristics of excluded studies.
Risk of bias in included studies
The overall risk of bias judgements and reasons can be found in Figure 2, Figure 3, and Characteristics of included studies.
2.
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
3.
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
Allocation
Even though six of the seven included studies were of randomised parallel design, all were treated as non‐randomised baseline controlled trials for the purpose of the meta‐analysis. Hence we judged all studies to be at high risk for selection bias.
As BP and HR measurements at baseline and at the end of each hour post‐treatment were compared in the same participant, there was no bias in terms of distribution of baseline characteristics.
Blinding
As all included studies were non‐randomised, blinding was unclear. However, ambulatory BP monitoring is objective, and not subject to performance and detection bias. We judged all studies to have an unclear risk for performance and detection bias.
Incomplete outcome data
We judged six of the seven studies to have an unclear risk of attrition bias due to lack of reporting on the number of participants lost to follow‐up, and number of failed ABPM measurements. Abetel 1988 noted that missing values (participant forgot, technical failure) were replaced with the average of the previous and next measurements, but did not report on the frequency of such occurrence. We judged Sadowski 2002 to have a high risk of attrition bias, as they excluded data from 9/41 participants (> 20%), either because the subjects were considered poor responders to treatment (8/41), or the subject did not take the study drug (1/41).
Selective reporting
We judged three of the seven studies to have low risk of reporting bias, as they each reported ABPM and HR measurement at baseline and after treatment, as described in their methods. The remaining four studies included in the meta‐analysis were judged to have unclear or high risk of reporting bias, as they did not report ABPM at every hour over the 24‐hour period, and only one study reported HR data.
Other potential sources of bias
A factor considered as another potential source of bias was the source of funding for each included study. None of the seven included studies disclosed their source of funding. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. Since seven additional studies met the inclusion criteria but did not provide data, attrition bias across included studies is evident.
Effects of interventions
See: Table 1
Primary outcome
Blood pressure
Only seven of the 14 published studies meeting the inclusion criteria in 121 participants contributed data. We could not include data from seven studies (112 participants in total) that met the inclusion criteria in the meta‐analysis, as hourly BP data were measured but not reported at all, or not reported in a usable way. These included three studies on acebutalol (Favre 1986; Favre 1986a; Stephan 1993), three studies on celiprolol (Halabi 1989; Wambach 1994; Podzolkov 2002), and one study on pindolol (Garrett 1982).
At each hour throughout the 24‐hour dosing interval, beta‐blockers with partial agonist activity (BBPAA) significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP, compared to baseline or placebo (P < 0.05), with the exception of hour 21 for SBP.
The estimated mean hourly differences ranged between 3.68 mmHg and 17.74 mmHg for SBP (7 studies, 121 participants; Analysis 1.1), and ranged between 2.27 mmHg and 9.34 mmHg for diastolic blood pressure (DBP; 7 studies, 121 participants; Analysis 1.2,). There was there was significant heterogeneity (I² ≥ 50%), except for DBP — hour 17; and SBP — hours 3, 9, 13, 14, 16, 22, and 23, due to a small number of small studies, and use of different BBPAAs.
1.1. Analysis.
Comparison 1: Beta‐blocker vs control, Outcome 1: SBP
1.2. Analysis.
Comparison 1: Beta‐blocker vs control, Outcome 2: DBP
Whilst hourly difference defied precise estimation, visually, the hourly mean differences showed a reduction in the amount of SBP, DBP, and HR lowering over the course of the 24‐hour period Figure 4; Figure 5; Figure 6). To assess for the presence of this 'pattern' statistically, we compared the change in mean BP and HR across three eight‐hour time intervals: (i) day (the first eight hours after the morning dose, 9:00 to 17:00 hours), (ii) evening (the second eight hours after the morning dose, 17:00 to 1:00 hours), and (iii) night (the third eight hours after the morning dose, 1:00 to 9:00 hours).
4.
Change in systolic blood pressure (SBP) from baseline, at each hour post dose (0 to 23 hour period)
5.
Change in diastolic blood pressure (DBP) from baseline, at each hour post dose (0 to 23 hour period)
6.
Change in heart rate (HR) from baseline, at each hour post dose (0 to 23 hour period)
We found that change in mean SBP was approximately ‐12.11 mmHg in the first 16 hours after the morning dose, and then the change reduced; day mean difference (MD) ‐12.04 mmHg, 95% confidence interval (CI) ‐13.12 to ‐11.07; evening MD ‐12.17 mmHg, 95% CI ‐13.43 to ‐10.90; and night MD ‐6.65 mmHg, 95% CI 95% CI ‐7.90 to ‐5.36 Figure 7.
7.
Mean change in systolic blood pressure (SBP) [day 9:00‐17:00, evening 17:00‐1:00, night 1:00‐9:00]
Change in mean DBP followed a similar pattern: day MD ‐7.87 mmHg, 95% CI ‐8.33 to ‐7.41; evening MD ‐7.53, 95% CI ‐8.13 to ‐6.93; and night ‐5.16 mmHg, 95% CI ‐5.60 to ‐4.73 Figure 8.
8.
Mean change in diastolic blood pressure (DBP) [day 9:00‐17:00, evening 17:00‐1:00, night 1:00‐9:00]
We did not calculate the overall BP‐lowering effect, the reason for which is two‐fold. First, we were only interested in the variation of BP‐lowering over the 24‐hour period. Second, the magnitude of BP lowering would not have been meaningful in this review, as the very few eligible studies included used different beta‐blockers with partial agonist activity (BBPAA), or the same beta‐blockers at different doses and titration regimen.
Secondary outcome
Heart rate
Only four (Favre 1986; Kanematsu 1993; Kotake 1992; Sadowski 2002) of the 14 published studies meeting the inclusion criteria involving 71 participants contributed data. We could not include data from 10 studies (162 participants in total) that met the inclusion criteria in the meta‐analysis, as hourly HR data were measured but not reported at all, or not reported in a usable way.
The HR‐lowering effects of BBPAA were more variable across the 24‐hour period, and results were inconsistent between groups at hours 14, 16, 18, 20, or 22, i.e. towards the end of the 24‐hour dosing interval. The estimated mean hourly difference ranged between 0.29 beats/min and 10.29 beats/min (4 studies, 71 participants; Analysis 1.3).
1.3. Analysis.
Comparison 1: Beta‐blocker vs control, Outcome 3: HR
There was significant heterogeneity (I² ≥ 50%) for HR at hours 3, 4, 6, 12, 16, 18, and 23, of a small number of small studies, which used different BBPAA.
Change in mean HR also decreased as time progressed: day MD ‐6.76 beats/min, 95% CI ‐7.49 to ‐6.00; evening MD ‐5.28 beats/min, 95% CI ‐6.03 to ‐4.52, and night MD ‐3.30 beats/min, 95% CI ‐4.00 to ‐2.61 Figure 9.
9.
Mean change in heart rate (HR) [day 9:00‐17:00, evening 17:00‐1:00, night 1:00‐9:00]
These results support a pattern of more BP and HR lowering by BBPAA during the day and evening, compared to at night.
See Table 1.
Discussion
Summary of main results
We included seven non‐randomised baseline controlled studies, with 121 participants, in this meta‐analysis. We analysed and presented data on blood pressure (BP)‐ and hear rate (HR)‐ lowering by hour post dose. Hourly mean reduction in BP and HR visually showed an attenuation over the course of the 24‐hour period. When we compared across three 8‐hourly time intervals (day, evening, night), the systolic blood pressure (SBP)‐, diastolic blood pressure (DBP)‐ and HR‐lowering effects were significantly lower at night than during the day and evening. This suggests that the BBPAA studied in this review was less effective at lowering BP and HR at night, than during the day and evening.
Overall completeness and applicability of evidence
A major limitation of this review is the small number of studies identified that met our inclusion criteria and the resulting small total number of participants. Seven eligible studies involving 112 participants did not report hourly BP data that could be included in the meta‐analysis. Selective reporting bias is evident here, given data from nearly 50% of eligible study participants (including ones taking the BBPAA celiprolol, currently not featured in our analysis) could not be included in the meta‐analysis. This is likely to have a significant impact on the magnitude of our estimate of the hourly BP and HR reduction, and may affect the pattern of BP and HR lowering efficacy observed over the 24‐hour period.
Only three beta‐blockers with partial agonist activity were studied in the seven included studies: bopindolol, acebutalol, and pindolol. We found no eligible studies on the other three beta‐blockers of interest: oxprenolol, celiprolol, and alprenolol. This limits the generalisability of our conclusion, as it may be restricted to the beta‐blockers studied, rather than reflecting a class effect.
There was significant heterogeneity in the beta‐blocker studied and the dosage. However, we believe our review is as comprehensive as it is currently feasible, based on available scientific literature, as we identified all eligible studies, without language restriction. In fact, four of the seven included studies were published in languages other than English.
Only one of the seven included studies reported standard deviation for each hourly time point. We used imputed standard deviations for the remaining studies. This represents another significant limitation that should be addressed in future studies.
Quality of the evidence
We treated all included studies as non‐randomised baseline controlled trials, although the majority were of randomised parallel design, with or without cross‐over. We did consider the risk of bias tools for non‐randomised studies, but since it was not specified in the protocol, we used the Cochrane risk of bias tool for randomised controlled trials (Higgins 2011). As a result, we rated the risk of bias due to randomisation and allocation concealment as high in this review.
Six of the seven included studies were judged to have unclear risk of attrition bias due to lack of reporting on the number of participants lost to follow‐up and number of failed ABPM measurements.
Three of the seven included studies were judged to have low risk of reporting bias as they each reported ABPM and HR measurement at baseline and after treatment. However, the remaining four studies were judged to have unclear or high risk of reporting bias as they did not report ABPM at every hour over the 24 hour period and all except one study reported no HR data. Selective reporting bias across included studies was high as seven out of 14 eligible studies identified did not report hourly BP data that can be used in the meta‐analysis, even though these were measured as part of the studies.
A factor considered as another potential source of bias was the source of funding for each included study. None of the seven included studies disclosed their source of funding. However, given ambulatory blood pressure and heart rate are objective outcomes, bias from this source can be considered negligible.
While publication bias is thought to be high, there was insufficient number of eligible studies included to generate a funnel plot to provide a good measure of the likelihood of publication bias.
All the included studies included a washout period followed by treatment with a beta‐blocker. Ambulatory BP was measured at the end of the washout, and treatment period. Because the order of no treatment and treatment was not randomised, BP measurement at these two time points may be confounded by other factors that changed over time, e.g. decreasing anxiety as ambulatory BP monitoring became more familiar.
This review is limited to only three BBPAA that were studied in the seven included studies: bopindolol, acebutalol and pindolol. We could not include the other seven studies (112 participants) that met the inclusion criteria in the meta‐analysis as hourly BP data was not reported at all or not reported in a usable way. This is likely to have a significant impact on the magnitude of our estimate of the hourly BP and HR reduction, and may affect the pattern of BP/HR lowering efficacy observed over the 24‐hour period. There were no eligible studies found on the other three BBPAA of interest ‐ oxprenolol, celiprolol and alprenolol. This limits the generalisability of our conclusion, as it may be restricted to the BBPAA studied, rather than reflecting a class effect.
One limitation is that the time of drug administration was not reported for two of the seven studies, so that 'Hour 0' was set as 9 am to maintain consistency across all included studies.
We judge the overall certainty of the evidence to be very low for all outcomes (downgraded due to inconsistency, imprecision, and selective reporting bias across included studies ‐ see Table 1). Further research is likely to have important impact on our estimate of effect and may change the conclusion.
Potential biases in the review process
We used the Cochrane 'Risk of bias' tool for randomised controlled trials, as stated in the protocol, instead of 'Risk of bias' tools for non‐randomised studies. We will use the ROBINS‐I or Newcastle‐Ottawa scale to assess risk of bias in a future update of this review. However, it is not likely to impact conclusions, given the uncertainty of evidence identified (outcomes rated as very low certainty).
Agreements and disagreements with other studies or reviews
We are not aware of any other review studying the time course of blood pressure lowering by BBPAA.
A Cochrane Review of similar methodology, studying the BP‐lowering efficacy of dihydropyridine calcium channel blockers, was published in 2014 (Ghamami 2014). The reviewers concluded that dihydropyridine calcium channel blockers reduce BP and HR by a consistent magnitude over the course of the day. In contrast, this present review found a significant difference in BP‐ and HR‐lowering effect when comparing day and evening results to night time results. Ghamami 2014 identified many more eligible studies, such that they included 16 randomised controlled trials of dihydropyridine calcium channel blockers with 2768 participants. They judged the overall certainty of the evidence to be moderate.
The difference in the findings of these two reviews is potentially clinically relevant, as it is widely known that 'non‐dipping' in nocturnal BP is an independent risk factor for cardiovascular complications. A large prospective study showed that bedtime administration of antihypertensives significantly lowered nocturnal BP, reduced prevalence of non‐dipping, and significantly reduced cardiovascular morbidity and mortality compared to conventional morning treatment (Hermida 2010). Beta‐blockers are less effective at reducing hypertensive complications than other classes of antihypertensives, with no effect on all‐cause mortality or the risk of coronary heart disease (Wiysonge 2007; Wright 2009). Compared to calcium channel blockers, beta‐blockers are inferior in stroke reduction and are associated with a higher all‐cause mortality (Wiysonge 2007). We hypothesise that the reason behind the lower clinical efficacy of beta‐blockers compared to calcium channel blockers is the difference in their ability to lower nocturnal BP. One reason for their reduced efficacy at night may be that, as beta‐blockers are sympatholytic, their effect is most pronounced when the sympathetic nervous system is activated, during exercise or stress in the awake hours. Alternatively, this may be due to their pharmacokinetics and pharmacodynamics, such that there is less drug effect remaining towards the end of the dosing period (which occurs at night with the traditional morning, once daily administration).
Our findings in this review are also in contrast with those from Voogel 1996, who examined the effect of beta‐blockers, ACE inhibitors, and calcium channel blockers on day and night BP, using ambulatory BP monitoring. They found that all three classes of antihypertensive agents tended to preserve the circadian BP profile, with only negligible attenuation. Our review overcame some of the limitations of Voogel 1996 by following Cochrane methodology, assessing the risk of bias of the included studies, attempting to identify all relevant primary studies, and assessing BP‐lowering at hourly interval. However, the small number of eligible studies identified, and the overall very low‐certainty evidence, limited the certainty of our conclusions.
With the limited data available, it remains unclear how individual classes of antihypertensives differ in their pattern of BP lowering, and how this correlates with their effectiveness in reducing morbidity and mortality. We await further systematic reviews that study the BP‐lowering profile of other classes of antihypertensives that have been studied in long‐term mortality and morbidity outcome trials.
A series of similar time course reviews, focusing on other antihypertensive drug classes, including other subclasses of beta‐blockers, thiazide diuretics, angiotensin‐converting enzyme (ACE) inhibitors, angiotensin‐receptor blockers and alpha‐blockers, have been proposed, and are at the protocol stage awaiting results. Interpreting the findings of our review alongside these will help us to hypothesise how the diurnal pattern of blood pressure‐lowering by antihypertensive agents may be related to their effect on reducing hypertensive complications.
Authors' conclusions
Implications for practice.
The three beta‐blockers with partial agonist activity studied in this review (bopindolol, acebutolol and pindolol) lowered blood pressure (BP) more during the day and evening hours compared to overnight. The number of studies and participants included in this review was very small, limiting the certainty of our conclusions. We currently do not know the benefits and harms of this pattern of BP lowering.
Implications for research.
In order to improve the quality of this type of review, trials investigating BP‐lowering effects of drugs over 24‐hours should report standard deviations for each hourly measurement. The time of drug intake should also be recorded accurately. Overall, more trials are needed for all BBPAA for a more robust assessment of their temporal BP lowering effect.
Systematic reviews studying the BP lowering profile of other classes of antihypertensive drugs will be informative in our understanding of the impact of the pattern of BP lowering on reducing hypertensive complications.
History
Protocol first published: Issue 8, 2012 Review first published: Issue 9, 2020
Acknowledgements
The authors would like to acknowledge the help provided by editors of the Cochrane Hypertension Group. We would like to thank Marcie Reinhart, Yuri Vilin, Ciprian Jauca, and Gavin Wong for their assistance with translating non‐English articles. We would also like to thank Stephen Adams for help with retrieving full‐text articles for review.
Appendices
Appendix 1. Search strategies
Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) <1946 to June 09, 2020> Search Date: 10 June 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 exp adrenergic beta‐antagonists/ (83981) 2 (partial adj5 agonist$).tw,kf. (11190) 3 intrinsic sympathomimetic activit$.tw,kf. (717) 4 ISA.tw. (2463) 5 1 and (2 or 3 or 4) (1383) 6 acebutolol.mp. (1121) 7 alprenolol.mp. (1582) 8 bopindolol.mp. (137) 9 celiprolol.mp. (511) 10 oxprenolol.mp. (1328) 11 pindolol.mp. (4687) 12 or/6‐11 (8351) 13 5 or 12 (9069) 14 blood pressure monitoring, ambulatory/ (9774) 15 ((blood pressure or bp or dbp or sbp) adj10 (ambulatory or monitor$)).tw,kf. (24900) 16 ((24 hour? or 24h or 24hr or 24 hr or 24‐h or hourly) adj10 (ambulatory or blood pressure or bp or dbp or monitor$ or sbp)).tw,kf. (24802) 17 (abp or abpm).tw,kf. (6717) 18 time factors/ (1182650) 19 time course?.tw,kf. (81185) 20 circadian.mp. (89859) 21 or/14‐20 (1362502) 22 hypertension/ (233217) 23 essential hypertension/ (2248) 24 (antihypertens$ or hypertens$).tw,kf. (452482) 25 exp blood pressure/ (289227) 26 (blood pressur$ or bloodpressur$).mp. (446971) 27 or/22‐26 (791673) 28 randomized controlled trial.pt. (507211) 29 controlled clinical trial.pt. (93710) 30 randomized.ab. (482299) 31 placebo.ab. (208444) 32 dt.fs. (2209757) 33 randomly.ab. (334924) 34 trial.ab. (508549) 35 groups.ab. (2056012) 36 (after or baseline$ or before).tw,kf. (5628216) 37 or/28‐36 (8714546) 38 animals/ not (humans/ and animals/) (4672771) 39 37 not 38 (7182545) 40 13 and 21 and 27 and 39 (345) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies (CRS‐Web) Search Date: 10 June 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ #1 ("Adrenergic beta‐Antagonist" OR "Adrenergic beta‐Antagonist" OR "partial agonist" OR "partial agonists" OR intrinsic sympathomimetic activit* OR ISA OR acebutolol OR alprenolol OR bopindolol OR celiprolol OR oxprenolol OR pindolol) AND INSEGMENT #2 (time OR circadian OR 24 hour* OR 24hr OR 24 hr OR 24‐h OR hourly OR ambulatory) AND INSEGMENT #3 (RCT OR CCT):DE AND INSEGMENT #4 Review:ODE AND INSEGMENT #5 #3 OR #4 AND INSEGMENT #6 #1 AND #2 AND #5 AND INSEGMENT ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Database: Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 5) via Cochrane Register of Studies (CRS‐Web) Search Date: 10 June 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ #1 MESH DESCRIPTOR Adrenergic beta‐Antagonists EXPLODE ALL AND CENTRAL:TARGET #2 partial NEAR5 agonist* AND CENTRAL:TARGET #3 "intrinsic sympathomimetic" NEXT activit* AND CENTRAL:TARGET #4 ISA AND CENTRAL:TARGET #5 #1 AND (#2 OR #3 OR #4) AND CENTRAL:TARGET #6 (acebutolol OR alprenolol OR bopindolol OR celiprolol OR oxprenolol OR pindolol) AND CENTRAL:TARGET #7 #5 OR #6 AND CENTRAL:TARGET #8 MESH DESCRIPTOR Blood Pressure Monitoring, Ambulatory EXPLODE ALL AND CENTRAL:TARGET #9 (blood pressur* OR bp OR dbp OR sbp) NEAR10 (ambulatory OR monitor*) AND CENTRAL:TARGET #10 (24 hour* OR 24h OR 24hr OR 24 hr OR 24‐h OR hourly) NEAR10 (ambulatory OR blood pressur* OR bp OR dbp OR monitor* OR sbp) AND CENTRAL:TARGET #11 (abp OR abpm) AND CENTRAL:TARGET #12 MESH DESCRIPTOR Time Factors AND CENTRAL:TARGET #13 time NEXT course AND CENTRAL:TARGET #14 circadian AND CENTRAL:TARGET #15 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 AND CENTRAL:TARGET #16 MESH DESCRIPTOR Hypertension AND CENTRAL:TARGET #17 MESH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET #18 (antihypertens* OR hypertens*) AND CENTRAL:TARGET #19 MESH DESCRIPTOR Blood Pressure EXPLODE ALL AND CENTRAL:TARGET #20 (blood pressur* OR bloodpressur*) AND CENTRAL:TARGET #21 (#16 OR #17 OR #18 OR #19 OR #20) AND CENTRAL:TARGET #22 #7 AND #15 AND #21 AND CENTRAL:TARGET ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Database: Embase <1974 to 2020 June 09> Search Date: 10 June 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 exp beta adrenergic receptor blocking agent/ (292318) 2 (partial adj5 agonist$).tw. (14040) 3 intrinsic sympathomimetic activity/ (672) 4 intrinsic sympathomimetic activit$.tw. (827) 5 ISA.tw. (4582) 6 1 and (2 or 3 or 4 or 5) (2335) 7 acebutolol.mp. (5176) 8 alprenolol.mp. (4935) 9 bopindolol.mp. (302) 10 celiprolol.mp. (1580) 11 oxprenolol.mp. (5330) 12 pindolol.mp. (10441) 13 or/7‐12 (20127) 14 6 or 13 (21307) 15 blood pressure monitoring/ (46896) 16 ((blood pressur$ or bp or dbp or sbp) adj10 (ambulatory or monitor$)).tw. (40256) 17 ((24 hour? or 24h or 24hr or 24 hr or 24‐h or hourly) adj10 (ambulatory or blood pressur$ or bp or dbp or monitor$ or sbp)).tw. (40496) 18 (abp or abpm).tw. (12242) 19 time/ (319911) 20 time course?.tw. (95726) 21 circadian.mp. (101828) 22 or/15‐21 (597028) 23 exp hypertension/ (726566) 24 (antihypertens$ or hypertens$).tw. (664996) 25 exp blood pressure/ (556162) 26 (blood pressur$ or bloodpressur$).tw. (425630) 27 or/23‐26 (1341597) 28 randomized controlled trial/ (607453) 29 crossover procedure/ (63474) 30 double‐blind procedure/ (173535) 31 (randomi?ed or randomly).tw. (1244974) 32 (crossover$ or cross‐over$).tw. (106980) 33 placebo.ab. (298985) 34 (doubl$ adj blind$).tw. (210218) 35 assign$.ab. (388781) 36 allocat$.ab. (149892) 37 (after or baseline$ or before).ab. (7314478) 38 or/28‐37 (8259693) 39 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6407131) 40 38 not 39 (6550103) 41 14 and 22 and 27 and 40 (202) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Database: ClinicalTrials.gov Search Date: 11 June 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Condition or disease: Hypertension Other terms: (24 hour* OR 24h OR 24hr OR “24 hr” OR “24‐h” OR ABPM OR chronotherap* OR circadian OR hourly OR “time course” OR "time factors" OR “time response”) Study type: Interventional Studies (Clinical Trials) Intervention/treatment: "Adrenergic beta‐Antagonist" OR "Adrenergic beta‐Antagonist" OR "partial agonist" OR "partial agonists" OR intrinsic sympathomimetic activit* OR ISA OR acebutolol OR alprenolol OR bopindolol OR celiprolol OR oxprenolol OR pindolol Outcome Measure: "blood pressure" ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ Database: WHO International Clinical Trials Registry Platform (ICTRP) Search Date: 11 June 2020 ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ hypertension AND adrenergic beta antagonists AND 24h hypertension AND adrenergic beta antagonists AND 24hr hypertension AND adrenergic beta antagonists AND 24 hr hypertension AND adrenergic beta antagonists AND ABPM hypertension AND adrenergic beta antagonists AND ambulatory hypertension AND adrenergic beta antagonists AND chronotherapy hypertension AND adrenergic beta antagonists AND time course hypertension AND beta blocker* AND 24h hypertension AND beta blocker* AND 24hr hypertension AND beta blocker* AND 24 hr hypertension AND beta blocker* AND ABPM hypertension AND beta blocker* AND ambulatory hypertension AND beta blocker* AND chronotherapy hypertension AND beta blocker* AND time course hypertension AND acebutolol AND 24h hypertension AND acebutolol AND 24hr hypertension AND acebutolol AND 24 hr hypertension AND acebutolol AND ABPM hypertension AND acebutolol AND ambulatory hypertension AND acebutolol AND chronotherapy hypertension AND acebutolol AND time course hypertension AND alprenolol AND 24h hypertension AND alprenolol AND 24hr hypertension AND alprenolol AND 24 hr hypertension AND alprenolol AND ABPM hypertension AND alprenolol AND ambulatory hypertension AND alprenolol AND chronotherapy hypertension AND alprenolol AND time course hypertension AND bopindolol AND 24h hypertension AND bopindolol AND 24hr hypertension AND bopindolol AND 24 hr hypertension AND bopindolol AND ABPM hypertension AND bopindolol AND ambulatory hypertension AND bopindolol AND chronotherapy hypertension AND bopindolol AND time course hypertension AND celiprolol AND 24h hypertension AND celiprolol AND 24hr hypertension AND celiprolol AND 24 hr hypertension AND celiprolol AND ABPM hypertension AND celiprolol AND ambulatory hypertension AND celiprolol AND chronotherapy hypertension AND celiprolol AND time course hypertension AND oxprenolol AND 24h hypertension AND oxprenolol AND 24hr hypertension AND oxprenolol AND 24 hr hypertension AND oxprenolol AND ABPM hypertension AND oxprenolol AND ambulatory hypertension AND oxprenolol AND chronotherapy hypertension AND oxprenolol AND time course hypertension AND pindolol AND 24h hypertension AND pindolol AND 24hr hypertension AND pindolol AND 24 hr hypertension AND pindolol AND ABPM hypertension AND pindolol AND ambulatory hypertension AND pindolol AND chronotherapy hypertension AND pindolol AND time course
Data and analyses
Comparison 1. Beta‐blocker vs control.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 SBP | 7 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Hour 0 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐10.91 [‐12.74, ‐9.09] |
| 1.1.2 Hour 1 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐11.49 [‐13.52, ‐9.46] |
| 1.1.3 Hour 2 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐10.32 [‐12.15, ‐8.48] |
| 1.1.4 Hour 3 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐12.91 [‐14.98, ‐10.83] |
| 1.1.5 Hour 4 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐15.97 [‐17.80, ‐14.13] |
| 1.1.6 Hour 5 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐16.55 [‐18.61, ‐14.48] |
| 1.1.7 Hour 6 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐17.74 [‐19.57, ‐15.91] |
| 1.1.8 Hour 7 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐15.51 [‐17.59, ‐13.42] |
| 1.1.9 Hour 8 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐14.56 [‐16.40, ‐12.72] |
| 1.1.10 Hour 9 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐13.83 [‐15.91, ‐11.75] |
| 1.1.11 Hour 10 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐13.38 [‐15.99, ‐10.76] |
| 1.1.12 Hour 11 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐13.22 [‐16.82, ‐9.63] |
| 1.1.13 Hour 12 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐14.09 [‐16.77, ‐11.41] |
| 1.1.14 Hour 13 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐11.23 [‐14.89, ‐7.57] |
| 1.1.15 Hour 14 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐12.59 [‐15.25, ‐9.92] |
| 1.1.16 Hour 15 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐11.02 [‐14.63, ‐7.41] |
| 1.1.17 Hour 16 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐8.19 [‐10.83, ‐5.56] |
| 1.1.18 Hour 17 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐6.94 [‐10.48, ‐3.40] |
| 1.1.19 Hour 18 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐8.85 [‐11.52, ‐6.18] |
| 1.1.20 Hour 19 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐6.46 [‐10.07, ‐2.85] |
| 1.1.21 Hour 20 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐9.38 [‐12.01, ‐6.75] |
| 1.1.22 Hour 21 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐3.68 [‐7.82, 0.47] |
| 1.1.23 Hour 22 | 5 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐9.90 [‐12.78, ‐7.02] |
| 1.1.24 Hour 23 | 5 | 89 | Mean Difference (IV, Fixed, 95% CI) | ‐8.02 [‐10.20, ‐5.84] |
| 1.2 DBP | 7 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Hour 0 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐4.44 [‐5.25, ‐3.62] |
| 1.2.2 Hour 1 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐6.23 [‐7.13, ‐5.33] |
| 1.2.3 Hour 2 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐7.63 [‐8.44, ‐6.81] |
| 1.2.4 Hour 3 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐7.15 [‐8.05, ‐6.25] |
| 1.2.5 Hour 4 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐5.27 [‐6.09, ‐4.45] |
| 1.2.6 Hour 5 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐8.39 [‐9.29, ‐7.50] |
| 1.2.7 Hour 6 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐9.34 [‐10.16, ‐8.53] |
| 1.2.8 Hour 7 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐8.65 [‐9.55, ‐7.75] |
| 1.2.9 Hour 8 | 7 | 121 | Mean Difference (IV, Fixed, 95% CI) | ‐5.85 [‐6.67, ‐5.03] |
| 1.2.10 Hour 9 | 6 | 102 | Mean Difference (IV, Fixed, 95% CI) | ‐7.45 [‐8.34, ‐6.55] |
| 1.2.11 Hour 10 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐9.00 [‐9.90, ‐8.10] |
| 1.2.12 Hour 11 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐8.59 [‐9.60, ‐7.57] |
| 1.2.13 Hour 12 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐7.61 [‐8.52, ‐6.71] |
| 1.2.14 Hour 13 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐8.91 [‐9.93, ‐7.90] |
| 1.2.15 Hour 14 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐7.60 [‐8.50, ‐6.70] |
| 1.2.16 Hour 15 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐4.98 [‐5.99, ‐3.97] |
| 1.2.17 Hour 16 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐4.50 [‐5.39, ‐3.61] |
| 1.2.18 Hour 17 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐3.49 [‐4.50, ‐2.49] |
| 1.2.19 Hour 18 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐4.80 [‐5.70, ‐3.91] |
| 1.2.20 Hour 19 | 5 | 84 | Mean Difference (IV, Fixed, 95% CI) | ‐2.72 [‐3.73, ‐1.72] |
| 1.2.21 Hour 20 | 6 | 103 | Mean Difference (IV, Fixed, 95% CI) | ‐6.00 [‐6.89, ‐5.10] |
| 1.2.22 Hour 21 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐2.27 [‐3.32, ‐1.22] |
| 1.2.23 Hour 22 | 5 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐6.85 [‐7.78, ‐5.92] |
| 1.2.24 Hour 23 | 5 | 89 | Mean Difference (IV, Fixed, 95% CI) | ‐5.48 [‐6.41, ‐4.55] |
| 1.3 HR | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 Hour 0 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐8.48 [‐10.06, ‐6.90] |
| 1.3.2 Hour 1 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐6.87 [‐8.43, ‐5.32] |
| 1.3.3 Hour 2 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐2.05 [‐4.05, ‐0.05] |
| 1.3.4 Hour 3 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐9.55 [‐11.21, ‐7.90] |
| 1.3.5 Hour 4 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐6.38 [‐8.35, ‐4.41] |
| 1.3.6 Hour 5 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐6.42 [‐8.09, ‐4.76] |
| 1.3.7 Hour 6 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐6.52 [‐8.51, ‐4.52] |
| 1.3.8 Hour 7 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐10.29 [‐11.94, ‐8.63] |
| 1.3.9 Hour 8 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐4.24 [‐6.22, ‐2.27] |
| 1.3.10 Hour 9 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐7.42 [‐9.06, ‐5.78] |
| 1.3.11 Hour 10 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐6.42 [‐8.44, ‐4.41] |
| 1.3.12 Hour 11 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐6.78 [‐8.42, ‐5.13] |
| 1.3.13 Hour 12 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐6.89 [‐8.89, ‐4.88] |
| 1.3.14 Hour 13 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐7.18 [‐8.84, ‐5.53] |
| 1.3.15 Hour 14 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐1.92 [‐3.92, 0.09] |
| 1.3.16 Hour 15 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐5.14 [‐6.77, ‐3.50] |
| 1.3.17 Hour 16 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.46 [‐2.30, 1.38] |
| 1.3.18 Hour 17 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐3.48 [‐5.04, ‐1.92] |
| 1.3.19 Hour 18 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.89 [‐2.77, 1.00] |
| 1.3.20 Hour 19 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐2.71 [‐4.36, ‐1.06] |
| 1.3.21 Hour 20 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐0.29 [‐2.28, 1.69] |
| 1.3.22 Hour 21 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐4.42 [‐6.03, ‐2.82] |
| 1.3.23 Hour 22 | 3 | 60 | Mean Difference (IV, Fixed, 95% CI) | ‐7.89 [‐9.87, ‐5.90] |
| 1.3.24 Hour 23 | 4 | 71 | Mean Difference (IV, Fixed, 95% CI) | ‐7.43 [‐9.07, ‐5.79] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Abetel 1986.
| Study characteristics | ||
| Methods | Randomised parallel design, but included in the review as a non‐randomised baseline controlled study Double‐blinded for the first 10 weeks and open‐labelled thereafter (method of blinding was not described). |
|
| Participants | N = 33 (21 men, 12 women) Average age 49.6 years (range 33 to 66) Inclusion criteria: people of both sexes, aged 18 to 70 years, with mild or moderate hypertension (DBP 100 mmHg to 120 mmHg) and no contraindications for beta‐blockers or diuretics (e.g. uncontrolled heart failure, unstable diabetes, asthma) |
|
| Interventions | Bopindolol 1 mg or 2 mg once daily vs atenolol 50 mg or 100 mg once daily Drug received at 9 a.m. If after 4 weeks' treatment DBP was > 90 mmHg, the dosage was doubled, and if after a further 4 weeks' treatment DBP was still > 90 mmHg, a diuretic was added Treatment duration = 4 and 8 weeks, 6, 9, and 12 months Washout period = 2 weeks |
|
| Outcomes | Half hourly BP measured by ABPM between 8 a.m. and 6 p.m., after 2 weeks washout, after 4 and 8 weeks post‐treatment, and after 6, 9, and 12 months of treatment | |
| Notes | This study was treated as a baseline‐controlled trial with N = 18 ABPM data from the bopindolol arms after 4 weeks' treatment were extracted for meta‐analysis, as from 8 weeks post initiation of treatment, 55% participants were on a combination of a beta‐blocker and a diuretic |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Due to lack of reporting on the number of participants lost to follow‐up and number of failed ABPM measurements |
| Selective reporting (reporting bias) | High risk | ABPM data at baseline and after treatment were reported between 8 a.m. and 6 p.m. as per study method. Data were available until hour 9 and no data were reported from hour 10 until hour 23. HR data were not available at any time point. |
| Other bias | Low risk | Source of funding was not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Abetel 1988.
| Study characteristics | ||
| Methods | Baseline controlled trial | |
| Participants | N = 13 (8 men, 5 women) Average age 42 ± 11 years (17 to 59) Average weight 72 ± 11 kg, average height 168 ± 10 cm Office DBP ≥ 100 mmHg Previously untreated or after a washout period of at least 6 weeks |
|
| Interventions | Bopindolol 0.5 mg to 1 mg once daily (start at 0.5 mg once daily, after 3 weeks of placebo increase to 1 mg once daily if DBP ≥ 90 mmHg after 6 weeks' treatment) Drug given at 9 a.m. Treatment duration = 12 weeks Washout period = at least 9 weeks (6 weeks pre‐inclusion in study and 3 weeks placebo at start of study) |
|
| Outcomes | Half‐hourly BP measured by ABPM before and after 6 and 12 weeks' treatment | |
| Notes | ABPM data after 12 weeks' treatment were extracted for meta‐analysis Study published in French |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This study is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This study is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. The authors noted that missing values (participant forgot, technical failure) were replaced with the average of the previous and next measurements. |
| Selective reporting (reporting bias) | Unclear risk | ABPM data at baseline and after treatment available from hour 0 until hour 20, reported as per‐study method. Data for hour 21 until 23 were not reported. HR data were not available at any time point. |
| Other bias | Low risk | Source of funding was not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Favre 1986.
| Study characteristics | ||
| Methods | Baseline controlled trial This study was not suitable for inclusion into meta‐analysis as the required data were not provided. |
|
| Participants | N = 10 (5 male, 5 female) Mean age 36.4 ± 15.5 years (range 20 to 51) Untreated SBP > 160 mmHg, or DBP > 95 mmHg, or combination Five previously untreated; five stopped existing treatment 10 days before start |
|
| Interventions | Acebutalol 400 mg once daily Drug taken mid‐ or late‐morning (differed between subjects) Treatment period = 3 weeks Washout period = 10 to 15 days |
|
| Outcomes | BP and HR measured every 15 minutes by ABPM after washout period, and after 3 weeks of treatment | |
| Notes | To take into account individual variations in daily routine and activities, BP and HR recordings were divided into three phases (day, night, awakening). Each phase included a fixed and arbitrary number of intervals, corresponding to a variable period of time, and each interval included 1 to 4 measurements of BP. ABPM data presented as average BP of the ten subjects at each of these time intervals over the course of the day (rather than fixed point in time), and therefore, was not suitable to include in meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Authors noted that of the expected measurements, only 84% were effectively registered because of technical problems, and 75% of the measurements were valuable and analysed. |
| Selective reporting (reporting bias) | High risk | ABPM data at baseline and after treatment reported as per‐study method. However, data provided were not suitable to include in meta‐analyses. HR data were not available at any time point. |
| Other bias | Low risk | Source of funding was not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Favre 1986a.
| Study characteristics | ||
| Methods | Baseline controlled trial This study was not suitable for inclusion into meta‐analysis, as the required data were not provided. |
|
| Participants | N = 11 (5 male, 6 female) Average age 41 ± 12 years Four previously untreated, seven stopped existing treatment 10 days before start of study Essential hypertension with untreated BP > 160/95 mmHg |
|
| Interventions | Acebutalol 400 mg once daily, increasing to 600 mg once daily if BP > 160/95 mmHg after 3 weeks treatment Time of drug administration not specified Treatment duration = 3 and 6 weeks Washout period = 10 to 15 days |
|
| Outcomes | BP measured every 15 minutes by ABPM at the end of washout period, and after 3 weeks of treatment | |
| Notes | To take into account individual variations in daily routine and activities, BP and HR recordings were divided into three phases (day, night, awakening). Each phase included a fixed and arbitrary number of intervals, corresponding to a variable period of time, and each interval included 1 to 4 measurements of BP. ABPM data presented as average BP of the ten subjects at each of these time intervals over the course of the day (rather than fixed point in time). Only ABPM data post‐treatment (not at baseline) were presented. For reasons above, this study was not suitable for inclusion into the meta‐analysis. Study published in French. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement |
| Selective reporting (reporting bias) | High risk | ABPM data at baseline and after treatment reported as per‐study method. ABPM data presented as average BP of the ten subjects at each arbitrarily defined time intervals that corresponded to a variable period of time over the course of the day (rather than fixed point in time). Only ABPM data post‐treatment (not at baseline) were presented. Therefore, this study was not suitable for inclusion into meta‐analyses. HR data were not available at any time point. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Favre 1986c.
| Study characteristics | ||
| Methods | Randomised cross‐over design but included in the review as a non‐randomised baseline controlled study Double‐blinded (method of blinding not described) |
|
| Participants | N = 11 (10 men, 1 woman) Age 20 to 60 years Mild to moderate hypertension Inclusion criteria: essential hypertension with SBP > 160 mmHg and DBP > 95 mmHg, normal BP values restored during previous treatment with a beta‐blocker, no contraindications to beta‐blocker |
|
| Interventions | Bopindolol 0.5 mg and 1 mg once daily Drug given at 9 a.m. Treatment duration = 4 weeks Washout period = at least 15 days |
|
| Outcomes | BP and HR measured every 15 minutes (presented as hourly data) before and after 4 and 8 weeks' treatment, from hour 0 to hour 23 | |
| Notes | Study subjects were randomised to two groups. Group A received 0.5 mg bopindolol once daily, group B received 1 mg bopindolol once daily for 4 weeks before crossing over to receive the other drug dose. Combined data for study subjects in groups A and B after treatment with 0.5 mg or 1 mg bopindolol presented. ABPM data after treatment with 1 mg bopindolol were extracted for meta‐analysis (N =11), and this study was treated as baseline controlled trial. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | Low risk | Low risk for ABPM data as they were reported at baseline and after treatment as per‐study method, from hour 0 to hour 23. High risk of bias for HR data, as they were reported only at hour 0, hour 1, and every 2 hours until hour 23. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Garrett 1982.
| Study characteristics | ||
| Methods | Parallel design (unclear whether randomised). This study was included in the review as a non‐randomised baseline controlled study, but it was not suitable to include in meta‐analysis as the required data were not provided. Double‐blinded (method of blinding not described) |
|
| Participants | N = 16 | |
| Interventions | Pindolol 15 mg vs hydrochlorothiazide 50 mg vs pindolol 15 mg + hydrochlorothiazide 50 mg Time of drug administered not reported Treatment period = 8 weeks Washout period = 3 weeks |
|
| Outcomes | BP measured by ABPM at the end of washout period, and after 8 weeks of treatment | |
| Notes | Only abstract available. ABPM data not reported. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | High risk | ABPM and HR data at baseline and after treatment not reported in abstract. This study was not included in the meta analysis. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Halabi 1989.
| Study characteristics | ||
| Methods | Baseline controlled trial This study was not suitable to include in meta‐analysis as the required data were not provided. |
|
| Participants | N = 12 (8 male, 4 female) Average age 55 ± 9 years Arterial hypertension with DBP > 95 mmHg |
|
| Interventions | Celiprolol 200 mg once daily Time of drug administration not reported Treatment period = 4 weeks Washout period = 3 to 4 weeks |
|
| Outcomes | BP measured by ABPM after washout period, and after 4 weeks of treatment | |
| Notes | Only abstract published. Hourly BP data not reported. Unable to contact author. Therefore, not included in meta‐analysis. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This study is a non‐randomised baseline controlled trial. |
| Allocation concealment (selection bias) | High risk | This study is a non‐randomised baseline controlled trial. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | High risk | Hourly BP and HR data not reported. This study was not included in the meta‐analysis. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP is an objective outcome, bias from this source can be considered negligible. |
Kanematsu 1993.
| Study characteristics | ||
| Methods | Randomised parallel design, but included in the review as a non‐randomised baseline controlled study Unblinded |
|
| Participants | N = 77 (49 men, 29 women) in study Age 56 ± 16 years Inclusion criteria: essential hypertension, DBP 90 mmHg to 114 mmHg Pindolol arm N = 16 (10 men, 6 women), age 53 ± 13 years |
|
| Interventions | Pindolol 10 mg twice daily Atenolol 50 mg twice daily Nipradilol 6 mg twice daily Metoprolol 80 mg twice daily Drug given at 8 a.m. and 8 p.m. Treatment duration = 4 weeks |
|
| Outcomes | Hourly BP and HR measured by ABPM before and after 4 weeks' treatment | |
| Notes | This study was treated as a baseline controlled trial with N = 16 Only data from the pindolol arm of the study were used in the meta‐analysis Even though pindolol was administered at 8 a.m. in this study, 9 a.m. was taken as 'hour 0', as an exception of what was specified in our protocol and methodology. This was to maintain consistency across the 7 included studies; in four studies, drug was given at 9 a.m. (thus taken as 'hour 0'), and in the remaining two studies, time of drug administration was not specified, and 9 a.m. was taken as 'hour 0' by default. Published in Japanese |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | Low risk | ABPM data at baseline and after treatment reported as per‐study method, from hour 0 to hour 23. HR data provided from hour 0 to hour 23. |
| Other bias | Low risk | Source of funding was not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Kotake 1992.
| Study characteristics | ||
| Methods | Randomised parallel design, but included in the review as a non‐randomised baseline controlled study Blinded (method not described) |
|
| Participants | N = 23 (12 men, 11 women), acebutalol group N = 12 (5 men, 7 women) Mean age 54.3 ± 11.8 years Inclusion criteria: essential hypertension (WHO grade I), SBP > 160 mmHg, DBP > 95 mmHg |
|
| Interventions | Acebutalol 200 mg to 400 mg twice daily vs Metoprolol 80 mg to 160 mg twice daily Time of drug administration not specified Treatment duration = 2 to 4 weeks Washout period = 4 weeks |
|
| Outcomes | Hourly (23:00 to 8:00), or half hourly (8:00 to 23:00) BP and HR, as measured by ABPM before and after 2to 4 weeks' treatment | |
| Notes | This study was treated as a baseline controlled trial with N = 12 Only data from the acebutalol arm of the study were used in the meta‐analysis Study published in Japanese |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | Low risk | ABPM data at baseline and after treatment reported as per‐study method from hour 0 to hour 23. HR data provided from hour 0 to hour 23. |
| Other bias | Low risk | Source of funding was not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Neutel 1990.
| Study characteristics | ||
| Methods | Study performed at two centres Randomised parallel design, but included in the review as a non‐randomised baseline controlled study Double blinded (method of blinding not described) |
|
| Participants | N = 39 (29 men, 10 women) Mean age 52 years (range 24 to 70) Mild to moderate essential hypertension (DBP 90 mmHg to 115 mmHg) Previously untreated, or had been free of treatment for at least 3 weeks |
|
| Interventions | Acebutalol 400 mg to 800 mg once daily vs atenolol 50 mg to 100 mg once daily If after 3 weeks treatment, DBP was > 90 mmHg, the dosages were doubled during a further 3‐week period Drug taken at 9 a.m. Treatment duration = 6 weeks Washout period = 3 weeks |
|
| Outcomes | Half hourly BP, measured by ABPM before and after 6 weeks' treatment | |
| Notes | This study was treated as a baseline controlled trial with N = 19 Only data from the acebutalol arm of the study were used in the meta‐analysis. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | High risk | ABPM data at baseline and after treatment reported as per‐study method. Data were provided from hour 0, and every 2 hours thereafter, until hour 22 HR data were not provided at any time point. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Podzolkov 2002.
| Study characteristics | ||
| Methods | Baseline controlled trial This study was not suitable to include in the meta‐analysis, as the required data were not provided |
|
| Participants | N = 30 (13 male, 17 female) Average age 51.9 ± 6.6 years History of WHO stage I to II hypertension, for 3 to 17 years, with no other comorbidities or previous antihypertensive treatment |
|
| Interventions | Celiprolol 200 mg once daily Time of drug administration not specified Treatment duration = 8 weeks Washout period = 2 weeks |
|
| Outcomes | BP measured every 15 minutes (day) or 30 minutes (night) by ABPM, before and after 8 weeks of treatment | |
| Notes | Hourly BP data not reported, and therefore, not included in meta‐analysis. Unable to contact author. Study published in Russian. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | High risk | Hourly BP and HR data not reported. This study was not included in the meta‐analysis. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Sadowski 2002.
| Study characteristics | ||
| Methods | Study performed at two centres between February and July 2001 Randomised cross‐over design, but included in the review as non‐randomised baseline controlled study Double‐blinded (method of blinding not described) Data from 9 out of 41 study subjects were excluded ‐ 8 study subjects were considered poor responders to treatment, with SBP 160 mmHg to 179 mmHg and DBP 95 mmHg to 110 mmHg after treatment ‐ 1 study subject did not take the study drug in the last 3 days of treatment period |
|
| Participants | N = 41 (23 men, 18 women) Mean age 48.5 ± 10.7 years 31 study subjects had been previously treated Inclusion criteria: essential hypertension (WHO grade I to II), SBP 140 mmHg to 179 mmHg and DBP 90 mmHg to 109 mmHg; HR above 60/min Exclusion criteria: malignant hypertension, secondary hypertension, exacerbation of ischaemic heart disease, myocardial infarction (within 6 months prior to study), stroke (within 12 months prior to study), severe cardiac arrhythmia, junctional arrhythmias, heart failure, other severe peripheral arterial diseases, type I diabetes, renal, or liver failure |
|
| Interventions | Acebutalol slow‐release 400 mg once daily vs standard formula 200 mg twice daily Time of drug administration not specified Treatment duration = 4 weeks Washout period = 7 days |
|
| Outcomes | Hourly BP and HR, measured by ABPM before and after 4 weeks' treatment | |
| Notes | Study subjects were randomised to two groups. Group I received 400 mg once daily acebutalol slow‐release, group II received 200 mg twice daily acebutalol standard formula for 4 weeks before crossing over to receive the other study formula. Combined data for participants in groups I and II after treatment, with acebutalol 200 mg twice daily or 400 mg once daily, presented. ABPM data after treatment with 400 mg once daily were extracted for meta‐analysis (N = 32), and this study was treated as a baseline controlled trial. Study published in Polish. |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Data from 9 out of 41 study subjects excluded from analysis |
| Selective reporting (reporting bias) | Low risk | ABPM data at baseline and after treatment, with both study formula, reported as per‐study method from hour 0 to hour 23. HR data reported from hour 0 to hour 23. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
Stephan 1993.
| Study characteristics | ||
| Methods | Randomised, parallel design but included in the review as a non‐randomised baseline controlled study Double‐blinded (method of blinding not described) This study was not suitable to include in meta‐analysis, as the required data were not provided |
|
| Participants | N = 17 (5 male, 12 female) Average age 47 ± 2 years (23 to 60) Previous history of hypertension for 8 ± 2 years (0.7 to 20), DBP > 95 mmHg |
|
| Interventions | Acebutalol 400 mg once daily or enalapril 20 mg once daily Time of drug administration not specified Treatment duration = up to 3 months Washout period = 2 weeks |
|
| Outcomes | BP measured by ABPM after washout period, and after 1 and 3 months of treatment | |
| Notes | Hourly BP data not reported. Not included in meta‐analysis | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | High risk | Hourly BP and HR data not reported. This study was not included in the meta‐analysis. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP is an objective outcome, bias from this source can be considered negligible. |
Wambach 1994.
| Study characteristics | ||
| Methods | Randomised, parallel design but included in the review as baseline controlled study Double‐blinded (method of blinding not described) This study was not suitable to include in the meta‐analysis, as the required data were not provided |
|
| Participants | N = 16 (10 male, 6 female) Age 40 to 75 years Essential hypertension and left ventricular hypertrophy, DBP 95 mmHg to 109 mmHg |
|
| Interventions | Celiprolol 200 mg once daily or atenolol 50 mg once daily Time of drug administration not specified Treatment duration = 6 months Washout period = 4 weeks |
|
| Outcomes | BP measured by ABPM at baseline and after 6 months treatment | |
| Notes | Hourly BP data not reported. Not included in meta‐analysis. Study published in German |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Allocation concealment (selection bias) | High risk | This is a non‐randomised baseline controlled study. |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to performance bias. |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | Blinding in this non‐randomised study is unclear. However, ABPM is objective and not subject to detection bias. |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Unclear whether there was any loss to follow‐up or failed ABPM measurement. |
| Selective reporting (reporting bias) | High risk | ABPM and HR data at baseline, and after treatment not reported at any time point. This study was not included in the meta‐analysis. |
| Other bias | Low risk | Source of funding is not reported. However, given ambulatory BP and HR are objective outcomes, bias from this source can be considered negligible. |
ABPM: ambulatory blood pressure monitoring; BP: blood pressure; DBP: diastolic blood pressure; HR: heart rate; SBP: systolic blood pressure; WHO: World Health Organisation
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Capone 1986 | Ambulatory BP not measured |
| Cleophas 1999 | Randomised cross‐over trial of treatment with celiprolol 200 mg daily vs enalapril 10 mg daily for 4 weeks before crossing over. ABPM measured after 4 and 8 weeks of treatment, but not at baseline |
| Eguchi 2015 | Studied effect of celiprolol as an add‐on treatment to existing antihypertensives |
| Floras 1982 | Intra‐arterial BP measurement |
| Guanghua 1997 | Treatment duration of 2 weeks only |
| Marquand 1994 | A diuretic was added after 8 weeks if DBP > 95 mmHg with celiprolol treatment alone. Ambulatory BP not measured at 8 weeks before addition of diuretics |
| Millar‐Craig 1978 | Intra‐arterial BP measurement |
| Millar‐Craig 1979 | Intra‐arterial BP measurement |
| Parati 1988 | Randomised, double‐blind cross‐over trial comparing celiprolol 400 mg daily to placebo, with cross‐over after 1 month of treatment. No pre‐cross‐over or baseline (pre‐treatment data) ambulatory BP data available for meta‐analysis |
| Planes 1999 | Study selected participants with sleep apnoea. Hourly BP data not reported |
| Raftery 1981 | Intra‐arterial BP measurement |
| Raftery 1982 | Intra‐arterial BP measurement |
| Ruddel 1984 | No baseline ambulatory BP measurement. ABPM between 8 a.m. and 5 p.m. only |
| Schmieder 1985 | No baseline ambulatory BP measurement. ABPM between 8 a.m. and 5 p.m. only |
| Schmieder 1989 | No baseline ambulatory BP measurement, and hourly BP data not reported |
| Sheps 1985 | Evaluated effect of pindolol on ABPM. No baseline ambulatory BP measurement |
| Widimsky 1994 | No baseline ambulatory BP measurement. |
ABPM: ambulatory blood pressure monitoring; BP: blood pressure; DBP: diastolic blood pressure; OD: once daily
Differences between protocol and review
Colin Dormuth joined the team of reviewers after the publication of the initial version of the review protocol in August 2012.
During the completion of this review, it transpired that the linear regression models originally proposed in the review protocol in August 2012 were not suitable for identifying any pattern of change in the efficacy of BP‐ or HR‐lowering by BBPAA over the 24‐hour period. An alternative method was used, as described under Data synthesis.
Contributions of authors
Vijaya Musini and Xiao‐Yin Zhang developed the basis for the protocol of this review.
Xiao‐Yin Zhang took the lead role in screening, identifying, and assessing studies; in data extraction and analyses; and in writing up the review.
Sam Soufi aided in identifying and assessing studies, and in data extraction.
Vijaya Musini cross‐checked data extraction and imputation of standard deviation from all included studies.
Colin Dormuth performed data synthesis using SAS versions 9.4.
All authors contributed to writing up the review.
Sources of support
Internal sources
-
University of British Columbia, Canada
infrastructure support
External sources
No sources of support supplied
Declarations of interest
Xiao‐Yin Zhang: None known
Sam Soufi: None known
Colin Dormuth: None known
Vijaya M Musini: None known
New
References
References to studies included in this review
Abetel 1986 {published data only}
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