Fermented milk for hypertension
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to examine whether fermented milk or similar products produced by lactobacilli fermentation of milk proteins has any blood pressure lowering effect in humans when compared to no treatment or placebo.
Background
Description of the condition
Hypertension is a common condition and a strong risk factor for cardiovascular morbidity and mortality. Target organ damage is quite often present; especially sensitive are blood vessels, heart, kidneys and brain. World Health Organisation estimated in 1999 that hypertension causes 7.1 million deaths per year, which is 13% of total deaths worldwide (WHO 1999). In a meta‐analysis of 61 prospective studies of blood pressure (BP) and mortality a 2 mmHg decrease of systolic blood pressure (SBP) reduced cardiovascular mortality by 7% and stroke mortality by 10%. The correlation between reduced mortality and BP reduction was still evident for individuals usually considered normotensive, with BP as low as 115/75 (Lewington 2002). Pre‐hypertension, SBP = 130–139 and/or diastolic blood pressure (DBP) = 80–89, is also related to an enhanced risk of cardiovascular disease, and 50% of individuals with pre‐hypertension develop hypertension within 4 years (Julius 2006). Lifestyle modifications alone or in combination with medical treatment of hypertension are recommended to reduce BP and the risk of cardiovascular disease (ESH 2003).
Description of the intervention
Different lifestyle modifications, i.e. exercise, weight reduction, dietary changes and salt restriction, have been shown to lower BP (Dickinson 2006). Fermented milk has been suggested to reduce BP in humans and therefore, as a lifestyle modification, the antihypertensive effect of fermented milk deserves careful consideration. Fermented milk is currently on the market as a functional food with putative antihypertensive properties in the USA, Spain, UK, Finland, Switzerland, Italy, South Korea, Japan, Iceland and Portugal (Boelsma 2009).
How the intervention might work
During fermentation lactic acid bacteria cell wall proteinases hydrolyses milk proteins, hereby increasing the amount of peptides in the fermented product. The concentration of different peptides is highly dependent of the bacteria strain used for fermentation (Chantal 2003). The research on fermented milk and BP has mainly focused on peptides with in vitro ACE‐inhibitor effects. However, fermented milk products contain several proteins, peptides and minerals, all with possible different antihypertensive modes of actions. In addition to the presumed ACE‐inhibitor effect, reduced sympathetic activity and an opioid agonist effect have been suggested. Studies on spontaneously hypertensive rats are persuasive, repeatedly finding reductions of SBP (Fuglsang 2002, Sipola 2002).
Why it is important to do this review
In contrast to the evidence from animal studies, interventional human studies of the antihypertensive effect of fermented milk are diverging, with SBP changes ranging from 0 to 12 mmHg (Usinger 2009). The bioavailability and in vivo actions in humans of the peptides in fermented milk are widely unknown. As outlined, the putative antihypertensive effect in humans is not unambiguous and gathering the evidence accumulated to date will hopefully help determine if fermented milk has a role in the treatment of hypertension.
Objectives
The aim of this review is to examine whether fermented milk or similar products produced by lactobacilli fermentation of milk proteins has any blood pressure lowering effect in humans when compared to no treatment or placebo.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials.
Types of participants
Male or female adults age 18 or above.
Types of interventions
Products produced by fermentation of milk proteins by lactic acid bacteria.
Oral administration at any dose or any frequency.
Minimum 4 weeks duration.
Control: placebo or no treatment.
Types of outcome measures
Primary outcomes
Change of SBP or DBP from baseline compared to no treatment or placebo.
If different measurements of BP have been made, results are used in the following order of priority:
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office BP
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24 hour ambulatory BP (average of all measurements)
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home measurements
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sitting
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supine
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standing
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Secondary outcomes
None.
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:
The Cochrane Central Register of Controlled Trials (CENTRAL), English language databases, including MEDLINE (1966—2009), EMBASE (1974—2009), Cochrane Complementary Medicine Trials Register, Allied and Complementary Medicine (AMED) (1985—2009), Food science and technology abstracts (1969—2009).
MEDLINE will be searched using a standard Cochrane search strategy (Appendix 1). This search strategy will be adapted to the other databases.
Searching other resources
The following other resources will be searched:
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International Clinical Trials Registry Platform (WHO ICTRP)
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Reference lists of all eligible studies 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
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OpenSIGLE (System for Information on Grey Literature in Europe)
Data collection and analysis
Selection of studies
Studies which are clearly irrelevant will be excluded from the titles alone. Titles and abstracts will be searched for studies meeting the inclusion criteria above independently by two authors (LU, CR). Full text manuscripts will be retrieved for papers of all potentially eligible studies and read independently by the two authors; LU with knowledge of the area and CR, who is not a content expert. All manuscripts will be independently reviewed following an established trial selection form (Appendix 2). Where disagreement occurs the inclusion of the study will be discussed. All studies where agreement on inclusion is reached will be included. If doubt of the eligibility of a study arises, the study investigators will be contacted for further information. If disagreement between the two authors persists after all information is available, a third author (HI) will decide whether the actual study should be included or not. The authors will have full study reports without concealment of any information when assessing eligibility.
Data extraction and management
Two authors (LU, CR) will extract data independently filling a predefined data extraction table. The extracted data will be compared and where disagreement occurs it will be solved through discussion. When disagreement persists, a third author (HI) will decide which data to extract. In the case of missing data the principal investigators of the study will be contacted. Extracted data will include:
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Number of participants screened, randomised and completing the study.
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Number of intervention groups.
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Patients characteristics: age, gender, BP, antihypertensive medication (yes/no).
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Description of placebo product.
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Description of intervention; strain and species of lactic acid bacteria used, carrier, dose, frequency and length of intervention.
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Baseline SBP/DBP and SBP/DBP at the end of intervention.
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Methods used to measure BP.
Data on study methodology, results and assessment of bias will be shown in the included or excluded studies table in the review.
Assessment of risk of bias in included studies
The risk of bias in each study will be estimated independently by two authors and a table for assessing risk of bias will be made for each study. The risk of bias table will evaluate sequence generation, allocation concealment, blinding, subjects lost to follow up, selective outcome reporting and incomplete outcome data for each study as recommended in the Cochrane Handbook (Higgins 2008). After agreement between the authors, data will be analysed using the Cochrane Review Manager software, RevMan 5. A graph summarizing the risk of bias of all studies will be generated and included in the review. Assesment of publication bias in the included studies will be determined by a funnel plot.
Measures of treatment effect
Treatment effect will be determined as change in SBP/DBP from baseline in the fermented milk group minus the placebo or no treatment group at the end of intervention. If several doses are given the data from the group receiving the highest dose will be used.
When BP is measured with several measures in the same study, data will be extracted according to the following priority: office BP, 24‐hour ambulatory BP (average of all measurements), home BP measurements (1. sitting, 2. supine, 3. standing).
Unit of analysis issues
Cross over trials will be included. Because the presumed antihypertensive effect of fermented milk in humans is widely unknown, a carry‐over effect cannot be excluded. Therefore only data from the first period of cross over trials will be analysed in this review.
Dealing with missing data
Standard deviation for each group will be found in the manuscripts or calculated from available data whenever possible. When standard deviation for each group is impossible to calculate, study investigators will be contacted (by email, letter or fax). If the standard deviation is impossible to obtain or calculate, the average standard deviation from the other studies will be used.
In case of insufficient data the study will be excluded.
Assessment of heterogeneity
Standard chi‐square statistics will be used to test for heterogeneity between studies. The fixed effect model will be used to analyse pooled data unless the test for heterogeneity is statistically significant P<0.01. In this case the random effect model will be applied.
Data synthesis
Data synthesis and analysis will be done using the Cochrane Review Manager Software, RevMan 5.
Weighted mean difference and 95% confidence interval between treatment and placebo or no treatment will be calculated.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis will be done according to:
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Inclusion BP: normotensive (office SBP<140 and DBP<90) versus hypertensive (office SBP≥140 or DBP≥90). The studies including participants from both groups will be classified according to the mean of minimum and maximum inclusion SBP and DBP (inclusions criteria described in the manuscript of the study).
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Lenght of intervention period: 4—8 weeks versus above 8 weeks.
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Subjects taking antihypertensive medication excluded versus subjects taking antihypertensive medication included.
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According to the method used to measure BP: 24 hour ambulatory BP versus home measurements versus office BP.
Sensitivity analysis
Sensitivity analysis will be done according to:
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High quality versus low quality studies as estimated from the Cochrane risk of bias tool (Higgins 2008).
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Industrial sponsored versus non industrial sponsored
