Spironolactone for hypertension
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
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To determine the effect of spironolactone as monotherapy on:
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Mortality
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Morbidity
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Systolic and diastolic blood pressure compared to placebo in adults (of varying age and race) with essential hypertension (with and without co‐morbidities).
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2. To determine whether spironolactone is associated with an increased incidence of adverse effects compared to placebo.
Background
Description of the condition
Hypertension is associated with structural changes in the heart and blood vessels which may lead to cardiovascular mortality and morbidity (i.e. cardiovascular disease, stroke, peripheral vascular disease, and renal disease). Hypertension is typically defined as having a systolic blood pressure (SBP) ≥ 140 mmHg and a diastolic blood pressure (DBP) ≥ 90 mmHg (CHEP 2008, Chobanian 2003). Worldwide, approximately 1 billion people are affected by hypertension (Chobanian 2003) and seven million deaths per year may be attributed to hypertension (WHO 2003). In addition, for every 20 mmHg increase in SBP and 10 mmHg increase in DBP (through the range from 115/75 to 185/115 mmHg) in people aged 40 to 70 years, the risk of cardiovascular disease (CVD) morbidity doubles (Chobanian 2003). This emphasizes the importance of finding safe and effective treatments for the prevention of the associated mortality and morbidity in hypertensive patients.
Description of the intervention
Spironolactone is an aldosterone antagonist that has been in use since the 1960's (Cranston 1962). Spironolactone has been used for hypertension, edema, and primary aldosteronism, and more recently its use in patients with moderate to severe heart failure has been justified (Brunton 2006, Pitt 1999). The British Hypertension Society guidelines suggest that spironolactone should be used as fourth line therapy in patients that have failed to be controlled on combination therapy with three other antihypertensives (Williams 2004).
How the intervention might work
Normally activation of mineralocorticoid receptors by aldosterone leads to an increase in sodium reabsorption from the lumen of the late distal tubule and collecting duct in exchange for an increase in potassium excretion (Brunton 2006). Spironolactone antagonizes the mineralocorticoid receptors resulting in fewer activated sodium channels at the luminal membrane, and fewer sodium‐potassium ATPase pumps at the interstitial space membrane. This leads to a greater loss of sodium and subsequent reduction in blood volume while potassium is retained (Brunton 2006).
Spironolactone also acts as an antagonist at the androgen receptor, and as an agonist at progesterone receptors leading to gynecomastia or loss of libido in male patients, and menstrual irregularities in women (Connell 2008, Brunton 2006). The rates of gynecomastia are dose dependent with only 6.9% of men receiving less than 50 mg experiencing the side effect compared to 52% in those receiving more than 150 mg (Jeunemaitre 1987). Spironolactone also increases serum potassium, and this effect has been implicated in higher rates of hospitalizations and deaths since its use with ACE inhibitors became more frequent in heart failure patients (Jurrlink 2004).
Why it is important to do this review
Hypertension can be difficult to manage; patients can be intolerant to other medications, and often require multiple medications to control their blood pressure within target values. Previous systematic reviews have not been done to evaluate the effect of spironolactone on cardiovascular morbidity, mortality, and magnitude of blood pressure lowering in patients with hypertension.
The purpose of this systematic review is to evaluate the relative effectiveness of spironolactone compared to placebo on blood pressure, morbidity, mortality, and withdrawals due to adverse effects.
Objectives
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To determine the effect of spironolactone as monotherapy on:
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Mortality
-
Morbidity
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Systolic and diastolic blood pressure compared to placebo in adults (of varying age and race) with essential hypertension (with and without co‐morbidities).
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2. To determine whether spironolactone is associated with an increased incidence of adverse effects compared to placebo.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials that compare spironolactone to placebo. The review will be limited to trials comparing oral antihypertensive treatments only.
Types of participants
Trials including participants of both sexes older than 18 years of age with primary hypertension defined by a systolic BP greater than 140 mmHg or a diastolic BP greater than 90 mmHg or both, and no secondary cause found for the high blood pressure. Trials including patients with and without co‐morbidity would be included.
Types of interventions
The intervention of interest is spironolactone monotherapy.
The comparative intervention will be placebo.
Types of outcome measures
Primary outcomes
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All cause mortality
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Cardiovascular mortality
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Non‐cardiovascular mortality
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Number of patients experiencing at least one serious adverse event
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Fatal and non‐fatal stroke
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Fatal and non‐fatal myocardial infarction
Secondary outcomes
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Number of patients who withdrew due to adverse effects
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Number of patients with at least one adverse event
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Differences in the mean change in systolic blood pressure
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Differences in the mean change in diastolic blood pressure
Search methods for identification of studies
Electronic searches
The Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews will be searched for related reviews.
The following electronic databases will be searched for primary studies:
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The Cochrane Central Register of Controlled Trials (CENTRAL)
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English language databases, including MEDLINE (2005‐), EMBASE (2007‐) and International Pharmaceutical Abstracts
Electronic databases will be searched using a strategy combining a variation of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision) with selected MeSH terms and free text terms relating to roselle and hypertension. No language restrictions will be used. The MEDLINE search strategy (Appendix 1) will be translated into the other databases using the appropriate controlled vocabulary as applicable.
Full strategies for all English language databases will be included in the Appendices of the review.
Searching other resources
Other sources:
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International Clinical Trials Registry Platform (WHO ICTRP)
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OpenSIGLE (System for Information on Grey Literature in Europe)
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Hand searching of those high‐yield journals and conference proceedings which have not already been hand searched on behalf of the Cochrane Collaboration.
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Reference lists of all papers and relevant reviews identified
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Authors of relevant papers will be contacted regarding any further published or unpublished work
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Authors of trials reporting incomplete information will be contacted to provide the missing information
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ISI Web of Science will be searched for papers which cite studies included in the review
Data collection and analysis
Selection of studies
All studies identified will be independently assessed by 2 reviewers for whether they meet the predefined inclusion criteria. All references that mention the use of spironolactone from articles identified in the search will be reviewed and will be included should they meet the criteria. Any reason for excluding a study will be documented. Any differences that arise on whether a trial should be included will be resolved through discussion with a third independent reviewer, if necessary.
Data extraction and management
Once all studies have been identified, those studies which have fulfilled the inclusion criteria will be examined in detail by the two original independent reviewers. A standardized data extraction form will be used by the 2 reviewers.
Assessment of risk of bias in included studies
The following parameters will be assessed:
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Method and/or security of randomization
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Whether or not the individuals involved in the study (including health care provider, assessor, and patient) were blinded to the treatment allocation
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Whether analysis by intention‐to‐treat was performed
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How many participants completed the study
Any differences in interpretation of the data will be resolved through consensus between the three reviewers. If additional information is required, the original authors of the study will be contacted and the reviewers will reassess the study once the missing information has been made available. Study characteristics and the outcome measures of interest will be collected independently by the two reviewers using a pre‐formed data extraction sheet. All data, regardless of compliance or completion of follow up will be collected in order to allow for analysis by intention to treat.
Measures of treatment effect
For evaluation of the primary outcomes (all cause mortality, cardiovascular events, and cerebrovascular events), the total number of patients with at least one event within each trial will be recorded. Proportions will be calculated for these dichotomous outcomes, and comparisons between groups will be presented as relative risk ratios (with corresponding 95% confidence intervals).
Data for blood pressure reduction will be combined using a weighted mean difference method. This combines a weight based on the number of individuals in the trial and the within study variance. If the trial does not report the within study variance for decrease in blood pressure, the standard deviation will be imputed from the average standard deviation from the other trials.
All analyses will be conducted using a fixed effects model unless there is significant heterogeneity in which case the random effects model will be used to test for statistical significance.
Unit of analysis issues
Data from all patients individually randomized to each intervention will be used in the analyses. Care will be taken to identify situations in which data has been censored/excluded or if data presented is the total number of events or the total number of patients with a first event. Authors will be contacted for clarification if necessary. Proportions will only be calculated for the first relevant event that occurred for each patient randomized to a particular intervention.
Dealing with missing data
In general if there is missing data, the authors of the study will be contacted for clarification. If standard deviation data is not provided for continuous outcomes (e.g. blood pressure), it will be imputed using standard deviation data from other similar trials.
Assessment of heterogeneity
Assessment for heterogeneity across the studies will be done using the I2 statistic test (a threshold of 30‐60% will be used to define important heterogeneity) and the chi‐squared statistic test (with statistical significance being set at p<0.10). If heterogeneity is detected for outcomes, a random effects model will be used to determine if the effects of spironolactone still are statistically significantly different from placebo. Clinical and methodological sources of heterogeneity will be explored and characteristics for consideration will include: baseline risk factors for the outcomes of interest, duration of studies, age, race, and sex distribution of patients across the studies.
Assessment of reporting biases
In the event that missing data is assumed to be a poor outcome or is imputed, sensitivity analyses will be performed to see if results are sensitive to the assumptions being made. The potential impact of missing data will be reviewed in the discussion section of the final report.
Data synthesis
Cochrane Review Manager software, RevMan 5, will be used for all data analyses. Quantitative analyses of outcomes will be based on intention‐to‐treat results. Relative risk ratios (RR) and the fixed effects model will be used to combine outcomes across trials. Absolute risk reduction (ARR) = risk difference x 100, and numbers needed to treat (NNT) = 1/risk difference, will be calculated for all dichotomous outcomes. Data for blood pressure reduction will be combined using a weighted mean difference method with standard deviations.
Subgroup analysis and investigation of heterogeneity
The following 3 subgroup analyses will be performed:
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Trials of less than 6 months duration, 6 to 12 months duration, and those more than 12 months duration
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Effect of race on blood pressure and adverse events
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Effect of age on blood pressure and adverse events
Sensitivity analysis
Sensitivity analysis will be carried out in order to test for the robustness of the results. Analysis of the following categories will be undertaken separately:
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Trials without proper randomization or concealment of allocation compared to those without these characteristics
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Trials preformed without intention‐to‐treat analysis compared to those with an intention‐to‐treat analysis
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Unblinded versus blinded trials
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The effects of spironolactone with the inclusion of trials where blood pressure standard deviations are imputed versus the exclusion of data from trials that did not report blood pressure standard deviations
