EAL

HTN: Protein (2007)

Citation:

Kreijkamp-Kaspers S, Kok L, Bots ML, Grobbee DE, Lampe JW, van der Schouw Y. Randomized controlled trial of the effects of soy protein containing isoflavones on vascular function in postmenopausal women. Am J Clin Nutr. 2005; 81: 189-195.

PubMed ID: 15640479

Study Design:

Randomized Controlled Trial

Class:

A - Click here for explanation of classification scheme.

Quality Rating:

NEUTRAL: See Quality Criteria Checklist below.

Research Purpose:

To investigate whether soy protein containing isoflavones could improve endothelial function and blood pressure in post-menopausal women.

Inclusion Criteria:

Post-menopausal women.

Exclusion Criteria:

Women with conditions for which estrogens are contraindicated
Endometrial thickness off more than 4mm
Current and recent (within six months) estrogen users
Known allergy or hypersensitivity to soy or cow milk.

Description of Study Protocol:

Recruitment

Subjects were recruited from a database of a breast cancer screening program in Utrecht, Netherlands.

Design

Block-randomized, double-blinded controlled trial.

Blinding Used

Subjects and clinicians were blinded to the type of intervention.

Intervention

For the soy group, 25.6g of isoflavone-rich soy protein containing 52mg genistein, 41mg daidzein and 6mg glycitein in 36.5g soy protein powder was administered daily, mixed with food or beverages for 12 months
For the placebo group, total milk protein "identical looking and tasting" to the soy supplement was provided in the same manner
Both the soy supplement and the placebo supplement contained added vitamins B2, B6, B12 and D, folic acid and calcium.

Statistical Analysis

A power test was conducted determining that 200 subjects were needed with an alpha of 0.05 and beta of 0.20 to confirm an improvement of 32% in flow-mediated dilation (FMD)
All subjects completing a closeout or final (86% of those enrolled in the study) visit were included in the preliminary analysis on an intent-to-treat basis
A separate analysis was conducted on those who completed the whole treatment protocol (76%) with and without inclusion of those on anti-hypertensive medication
Linear regression analysis was used to check for differences from baseline between groups
Repeated-measures ANOVA tested for significance of the effects of soy, compared to placebo
Variables included in the ANOVA were number of years post-menopausal, equol producer status, smoking status and BMI under or at least 25.

Data Collection Summary:

Timing of Measurements

Measurements were taken at baseline prior to intervention, at randomization and at the final visit.

Dependent Variables

DBP and SBP were measured in the sitting position with a Dinamap on the right arm
Percentage flow-mediated dilation (FMD) was measured with B-mode ultrasound imaging of the brachial artery and assessing the increase in artery diameter during reactive hyperemia following hyperinflation of a BP cuff and deflation.

Independent Variables

Daily intake of soy protein for 12 months (intervention group)
Daily intake of milk protein for 12 months (placebo group)
Smoking
BMI under or at least 25
Use of anti-hypertensive medication
Use of cholesterol-lowering medication
Equol producer status.

Description of Actual Data Sample:

Initial N

202 began the study, however 14% did not complete one month of treatment or were unable or unwilling to complete a final visit
Data is presented for 175 subjects (all post-menopausal women) on an intent-to-treat basis.

Attrition (final N)

153 completed the treatment protocol; 24% did not complete the protocol for various reasons, with GI complaints and aversion to the taste of the supplement as the most commons reasons.

Age

66.8±4.7 (mean±SD) years for the placebo group
66.6±4.8 years for the soy group.

Anthropometrics

Weight: 69.5±10.1kg for the placebo group; 71.0±11.3kg for the soy group, P=0.33
BMI: 26.0±2.4 for the placebo group; 26.4±4.1 for the soy group, P=0.39.

Location

Utrecht, Netherlands.

Summary of Results:

Findings

Current smokers were greater in the soy group (19%) than in the placebo group (12.7%); use of anti-hypertensive medications was significantly lower in the soy group (5%) than in the placebo group (28.5%), P=0.02
No other differences between groups was detected as baseline or in those who did not complete the study
The only differences between groups (95% CI) in change from baseline as for SBP for intention to treat analysis (N=175) 4.34 (0.25, 8.42), P=0.04 and for SBP for those completing the protocol (N=153) 5.55 (1.07, 10.02), P=0.02
When those who were taking anti-hypertensives were excluded (N=138), there was no difference between groups on SBP
There were no significant differences in endothelial function between the groups, following intervention
There was a trend toward improvement in BP and endothelial function following treatment with soy in those who were equol producers; however, these changes did not reach statistical significance. P=0.48, P=0.09 and P=0.26 for changes from baseline in DBP, SBP and percentage FMD, respectively.

Author Conclusion:

There was no beneficial effect of a soy-protein supplement containing large ammounts of isoflavones on vascular function
Effects limited to women capable of equol production cannot be excluded.

Funding Source:

Government:

Netherlands Organization for Scientific Research and Development

Reviewer Comments:

Dietary intake was assessed by food-frequency questionnaire at baseline and at the final visit by a dietitian
Compliance was measured by blood genistein concentrations during the trial indicating good compliance in both groups
Change in weight from baseline, activity and alcohol intake were not reported
Differences in the groups at baseline could have affected the results; however, baseline SBP and DBP were included as covariates to adjust for baseline differences.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	???
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	No
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		???
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	???
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	???
	7.7.	Were the measurements conducted consistently across groups?	N/A
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes