Blood pressure lowering efficacy of dual alpha and beta blockers for primary hypertension
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary objective
To quantify the dose‐related effects of various doses and types of dual alpha and beta adrenergic receptor blockers on systolic and diastolic blood pressure versus placebo in patients with primary hypertension.
Secondary objectives
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To determine the effects of dual alpha and beta adrenergic receptor blockers on variability of blood pressure.
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To determine the effects of dual alpha and beta adrenergic receptor blockers on pulse pressure.
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To quantify the dose‐related effects of dual alpha and beta adrenergic receptor blockers on heart rate.
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To quantify the effects of dual alpha and beta adrenergic receptor blockers in different doses on withdrawals due to adverse events.
Background
Description of the condition
Elevated blood pressure is a highly prevalent condition that is associated with an increased risk of adverse cardiovascular events including stroke, myocardial infarction, congestive heart failure and renal failure. Antihypertensive drug treatment has been shown to reduce the incidence of these adverse events. There are a number of classes of antihypertensive drugs used to treat elevated blood pressure. Beta adrenergic receptor blockers (beta‐blockers) are one of those classes of drugs.
Description of the intervention
Beta‐blockers were originally marketed and used to treat angina. During their use in angina patients it was discovered that they also lower blood pressure. Since then they have received clinical attention because of their proven effectiveness for certain arrhythmias and to prevent recurrence in patients who have had a myocardial infarction.
Five previous systematic reviews are relevant to this proposed review. Wright 2000 assessed the mortality and morbidity associated with different types of beta blockers. They found that patients treated with non‐selective beta blockers post myocardial infarction have statistically significant reduction in total mortality as compared to placebo whereas those treated with beta1‐selective beta blockers or partial agonist beta‐blockers did not. A recent review assessed the effects of beta adrenergic blocking agents on morbidity and mortality in adults with hypertension (Wisonge 2007). This review concluded that beta blockers are not the best class of drugs to use as first‐line antihypertensive therapy. However, it is possible that this relates to beta‐1‐selective beta blockers as atenolol was the beta‐blocker used in 75% of the trials.
Two systematic reviews have assessed the effects of beta‐blockers on blood pressure. A Cochrane systematic review on beta blockers in hypertension during pregnancy (Magee 2003) showed that oral beta‐blockers decrease the incidence of severe hypertension and the need for additional antihypertensive therapy. A systematic review of the dose‐response blood pressure lowering effect of beta blocker drugs and other antihypertensive drugs (Law 2005) did not differentiate between the different classes of beta‐blockers. Finally a systematic review of the blood pressure lowering efficacy of beta‐blockers a second‐line drug was not able to differentiate between the different classes of beta‐blockers (Chen 2010).
How the intervention might work
Beta adrenergic receptors are present in many body systems including the heart, blood vessels, kidneys, nervous system and etc. At the present time it is not known the mechanism whereby beta‐blockers lower blood pressure though many hypothetical mechanisms have been proposed. Beta blockers could lower blood pressure by decreasing cardiac output, reducing renin production, modulating the sympathetic nervous system or other mechanisms. It is likely to be a combination of mechanisms that lead to the blood pressure lowering effect.
Alpha adrenergic receptors are another group of receptors that participate in regulation of blood flow in the body. Alpha receptors are present in smooth muscle throughout the body. Activation of alpha adrenergic receptors cause vasoconstriction and therefore raise blood pressure. This effect could counter the blood pressure lowering effect of beta adrenergic antagonism.
Dual alpha and beta‐blocking drugs were designed to competitively inhibit both alpha and beta‐receptors. There are 2 main classes of alpha receptors, alpha‐1 and alpha‐2. There are 3 main classes of beta‐receptors, beta‐1, beta‐2 and beta‐3. Currently there are no known selective antagonist for beta‐3 receptors. Dual alpha and beta blockers have both alpha and beta blocking property but no partial agonist activity. The drugs may be non‐selective or beta‐1 selective and/or alpha‐1 or alpha‐2 selective.
Why it is important to do this review
Since it is probable that beta‐blockers with different mechanisms of action have different effects to reduce morbidity and mortality it is crucial to determine whether they have different abilities to lower blood pressure. No published review has compared the blood pressure lowering effect of beta blockers based on their mechanism of action. If beta‐blockers with different beta receptor selectivity lower blood pressure differently it will provide useful information towards understanding the mechanism by which they lower blood pressure in man.
Furthermore since blood pressure is used on a daily basis by physicians managing patients with high blood pressure, it is important to know accurately the magnitude of blood pressure lowering of beta blockers both individually and as sub‐classes. The results of this review will be compared to the other reviews of non‐selective, beta‐1 selective and partial agonist reviews. The information found in this review will be useful for clinicians, researchers designing future drug trials and authors of other systematic reviews.
Objectives
Primary objective
To quantify the dose‐related effects of various doses and types of dual alpha and beta adrenergic receptor blockers on systolic and diastolic blood pressure versus placebo in patients with primary hypertension.
Secondary objectives
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To determine the effects of dual alpha and beta adrenergic receptor blockers on variability of blood pressure.
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To determine the effects of dual alpha and beta adrenergic receptor blockers on pulse pressure.
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To quantify the dose‐related effects of dual alpha and beta adrenergic receptor blockers on heart rate.
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To quantify the effects of dual alpha and beta adrenergic receptor blockers in different doses on withdrawals due to adverse events.
Methods
Criteria for considering studies for this review
Types of studies
Study design must meet the following criteria:
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placebo‐controlled;
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random allocation to beta adrenergic receptor blocker group and placebo group;
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parallel or crossover design;
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double blinded;
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duration of follow‐up of at least three weeks;
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blood pressure measurements at baseline (following washout) and at one or more time points between 3 to 12 weeks after starting treatment.
Types of participants
Participants must have a baseline blood pressure of at least 140 mmHg systolic and/or a diastolic blood pressure of at least 90 mmHg, measured in a standard way. Patients must not have creatinine levels greater than 1.5 times the normal level. Participants will not be restricted by age, gender, baseline risk or any other co‐morbid conditions.
Types of interventions
Monotherapy with any dual alpha and beta adrenergic receptor blocker, including carvedilol, dilevalol and labetalol.
Data from trials in which titration to a higher dose is based on blood pressure response are not eligible.
Types of outcome measures
Primary outcomes
Change in trough (13 to 26 hours after the dose) and/or peak (1 to 12 hours after the dose) systolic and diastolic blood pressure compared to placebo. If blood pressure measurements are available at more than one time within the acceptable window, the weighted means of blood pressures taken in the 3‐12 week range will be used.
Secondary outcomes
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Change in standard deviation compared to placebo.
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Change in pulse pressure compared to placebo.
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Change in heart rate compared to placebo.
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Number of patients who withdraw due to adverse events compared to placebo.
Search methods for identification of studies
To identify randomized placebo‐controlled trials of beta adrenergic receptor blockers, Medline (Jan. 1966‐May 2010), EMBASE (Jan. 1988‐May 2010), the Cochrane clinical trial register and bibliographic citations will be searched. Previously published meta‐analyses on dose‐response of beta adrenergic receptor blockers will be used to help identify references to trials.
No language restrictions will be applied.
A modified, expanded version of the standard search strategy of the Hypertension Group with additional terms related to beta adrenergic receptor blockers in general and all the specific drugs listed above will be used to identify the relevant articles.
The initial search of all the databases will be performed to identify citations with potential relevance. The initial screen of these abstracts will exclude articles whose titles and/or abstracts are clearly irrelevant. The full text of remaining articles will then be retrieved (and translated into English where required). The bibliographies of pertinent articles, reviews and texts will be searched for additional citations. Two independent reviewers will assess the eligibility of the trials using a trial selection form. A third reviewer will resolve discrepancies.
Data collection and analysis
Selection of studies
References and abstracts of search results will be imported to Reference Manager 11 software. Selection of studies will be based on the criteria listed above.
Data extraction and management
Data will be extracted independently by two reviewers using a standard form, and then cross‐checked. All numeric calculations and graphic interpolations will be confirmed by a second person.
Assessment of risk of bias in included studies
Standard quality measures are not useful to distinguish between trials meeting the strict entry criteria of this review (Jadad 1996). Risk of bias will be assessed using the Risk of Bias Tables for each trial.
Measures of treatment effect
The position of the patient during blood pressure measurement may affect the blood pressure lowering effect. However, in order to not lose valuable data if only one position is reported data from that position will be collected. When blood pressure measurement data is available in more than one position, sitting blood pressure is the first preference. If both standing and supine are available, standing blood pressure will be used.
Dealing with missing data
In case of missing information in the included studies, investigators will be contacted (using email, letter and/or fax) to obtain the missing information.
In the case of missing standard deviation of the change in blood pressure, the standard deviation will be imputed based on the information in the same trial or from other trials using the same drug. The following hierarchy (listed from high to low preference) will be used to impute standard deviation values:
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standard deviation of change in blood pressure taken in a different position than that of the blood pressure data used
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standard deviation of blood pressure at the end of treatment
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standard deviation of blood pressure at the end of treatment measured in a different position than that of the blood pressure data used
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standard deviation of blood pressure at baseline (except if this measure is used for entry criteria)
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mean standard deviation of change in blood pressure from other trials using the same drug
Assessment of heterogeneity
Test for heterogeneity of treatment effect between the trials will be made using a standard chi‐square statistic for heterogeneity. The fixed effects model will be applied to obtain summary statistics of pooled trials, unless significant between‐study heterogeneity is present, in which case the random effects model will be used.
Data synthesis
Data synthesis and analyses will be done using the Cochrane Review Manager software, RevMan 5.
Data for changes in blood pressure and heart rate will be combined using a weighted mean difference method. The drop‐outs due to side effects will be analyzed using relative risk, risk difference, and number needed to harm.
Subgroup analysis and investigation of heterogeneity
If possible, subgroup analyses will include:
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Different regimens of the same active chemical entity.
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Gender, Age and Race.
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Co‐morbid conditions: ischemic heart disease, peripheral vascular disease, diabetes.
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Baseline severity of hypertension: mild, moderate, severe.
Sensitivity analysis
The robustness of the results will be tested using several sensitivity analyses, including:
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Trials that are industry‐sponsored versus non‐industry sponsored
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Trials with blood pressure data measured in the sitting position vs. other measurement positions
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Trials with reported standard deviations of blood pressure change vs. imputed standard deviations
