Time course for blood pressure lowering of thiazides
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To analyze the temporal (hourly and 24‐hour) blood pressure lowering efficacy of thiazide and thiazide‐like drugs.
Background
Description of the condition
Elevated blood pressure is a prevalent condition that is associated with an increased risk of adverse cardiovascular events including stroke, heart failure and myocardial infarction. Drug treatment has been shown to significantly reduce the risk of these cardiovascular events. There is evidence that different drug classes have different effects in terms of reduction of cardiovascular events. For example in the ALLHAT trial outcomes with the alpha blocker were significantly worse than with the thiazide‐like drug chlorthalidone. [ALLHAT 2000] Furthermore Wiysonge and colleagues have demonstrated that first‐line beta blockers probably do not reduce cardiovascular events as much as other first‐line drug classes [Wiysonge 2007]. At the present time it is not known what is the cause of these different effects.
Most reviews have focused on the blood pressure lowering effect of different classes of drugs at a single time e.g. trough effects 22 to 26 hours after the last dose of drug. There are no systematic reviews assessing the temporal effects of classes of drugs on blood pressure.
Description of the intervention
In terms of benefit, thiazides are the class of antihypertensive drug that has the most mortality and morbidity evidence when used as a first‐line drug [Wright 1999, Psaty 2003]. Therefore it is important to better understand the time course of antihypertensive effect of this class of drugs. We are combining thiazides and thiazide‐like drugs because they have the same pharmacologic action on the kidney.
How the intervention might work
The mechanism of how thiazides reduce blood pressure in humans is not known for certain, but it probably is related to the action to increase salt and water excretion in the distal convuluted tubule of the kidney. If that is true one would expect the blood pressure lowering effect to have a long duration of action and for the effect to be reasonably constant over time.
Why it is important to do this review
Thiazides are one of the most commonly prescribed classes of drugs for hypertension and the benefits of antihypertensive drug therapy may be partly dependent on the time course of blood pressure lowering. It is, therefore, very important for physicians and patients to know the time course of the blood pressure lowering effect of thiazides.
Objectives
To analyze the temporal (hourly and 24‐hour) blood pressure lowering efficacy of thiazide and thiazide‐like drugs.
Methods
Criteria for considering studies for this review
Types of studies
Studies must conform with either of the following designs:
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Random allocation to a standard dose* of thiazide or thiazide‐like drug and to a parallel control group
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Base‐line controlled trials^
However, they must meet the following criteria:
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Duration of follow‐up of at least three weeks
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Blood pressure must be measured, using a 24‐hour ambulatory monitoring, at base‐line (following washout) and at one or more time points after week 3
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Blinding intervention to investigators, patients or both is not required
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Cross‐over trials could be included if data is available before crossing over
* Standard doses are defined as those recommended for current clinical practice
^ The reason that baseline controlled trials are eligible is because using 24 hour ambulatory blood pressure there is negligible or no placebo effect.
Types of participants
Individuals suffering from primary hypertension who are over 18 years of age will be included. Participants must have a baseline systolic blood pressure of at least 140 mmHg and/or diastolic blood pressure of at least 90 mmHg.
It is assumed that age does not impact the temporal blood pressure lowering effect of this class of drugs.
Types of interventions
Thiazides, including hydrochlorothiazide, chlorothiazide, buthiazide, bendroflumethiazide, hydroflumethiazide, trichlormethiazide, methylclothiazide, polythiazide, cyclothiazide, cyclopenthiazide.
Thiazides‐like drugs, including chlorthalidone, metolazone, quinethazone, fenquizone, clorexolone, clopamide, indapamide, diapamide, isodapamide, mefruside and xipamide.
Types of outcome measures
Primary outcomes
End‐point hourly blood pressures using a 24 hour ambulatory blood pressure device or other technique.
Secondary outcomes
Hourly pulse rate.
Search methods for identification of studies
Electronic searches
PubMed, EMBASE, Cochrane Clinical Trial Database.
Searching other resources
Additional resources will be searched, including the references of the published studies and review articles.
Data collection and analysis
Selection of studies
Selection of studies will be done primarily based on abstracts and titles, with studies that do not meet the inclusion criteria or that fulfil exclusion criteria being rejected. For those studies selected, full texts will be reviewed for their overall applicability based on the inclusion criteria. The references of these reviews will also be examined for their relevance. The selected reviews will be assessed for inclusion by two authors independently.
Data extraction and management
Data will be entered into a data extraction form and data extraction will be cross‐checked by two authors independently. All interpolations and calculations done will be double checked by a second author. The investigators of the specific trials will be directly contacted to obtain any missing data.
Assessment of risk of bias in included studies
The risk of bias will be assessed following the methodology described in the Cochrane Handbook Chapter 8, under the subheadings: sequence generation, allocation sequence concealment, blinding of participants, incomplete outcome data and selective outcome reporting.
Measures of treatment effect
The treatment effect is the average change in systolic and diastolic blood pressure in mmHg (a continuous variable) for each hour over a 24 hour period. For example, if a trial used 24‐h ambulatory BP monitoring at different points in time after week 3, the average of all measurements will be used.
Dealing with missing data
Missing data will be dealt with through an attempt to contact the authors of selected articles via email or telephone. The attempt to get the information and the authors' reply or lack thereof will be included in the review.
Standard deviation data at end point is often not included in published reports. In the event that this information cannot be obtained from the authors standard deviations will be imputed according to the following hierarchy:
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Standard deviation of the change in blood pressure obtained from the same trial
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Weighted mean standard deviation of blood pressure at end point calculated from at least 3 other trials using the same drug and dose regimen
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Weighted mean standard deviation of blood pressure at end point calculated from other trials using the same drug
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Weighted mean standard deviation of blood pressure at end point calculated from all other trials (any drug and dose)
Assessment of heterogeneity
The test for heterogeneity of treatment effect will be made using the standard chi‐square statistic for heterogeneity provided in Review Manager 5. If meaningful heterogeneity is present between studies, the random effects model will be used to assess the statistical significance of summary statistics of pooled trials. Otherwise, the fixed effects model will be used.
Assessment of reporting biases
Publication bias will be assessed using funnel plots, as outlined in Cochrane Handbook Chapter 10.
Data synthesis
Mean change from control or baseline plus the standard error of the mean will be entered for each trial and pooled as generic inverse variance data.
Subgroup analysis and investigation of heterogeneity
Thiazide and thiazide‐like drugs will be divided according to dose as done in other reviews (see low dose and high dose subgroups in [Wright 1999]. Placebo or no treatment controls and baseline control trials will also be analyzed as subgroups.
Sensitivity analysis
Sensitivity analyses will be done if possible according to patient characteristics, gender, or baseline BP.
