EAL

HTN: Vitamins (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To examine the effect of 500mg of vitamin C, compared with 50mg of vitamin C on blood pressure (BP) with the hypothesis that serum vitamin C might be inversely associated with BP.

Inclusion Criteria:

Japanese adults aged 40 to 69 years, living in a village within the Yokote Pulic Health Center district
Diagnosed with atrophic gastritis.

Exclusion Criteria:

Previous history of liver cancer, cirrhosis or other cancers within the past five years
Abnormal liver function
Use of diet supplements containing beta-carotene or vitamin C
Expectation of moving outside the study area within one year.

Description of Study Protocol:

Recruitment

Subjects (N=1,231) participating in annual screeing programs under the national Health and Welfare Services law for the Aged were screened to determine if they met the study criteria
The subject pool was limited further to those who provided serum to determine a diagnosis of atrophic gastritis (N=1,214)
Of these, 602 met study criteria.

Design

A double-blinded randomized control trial with subjects originally randomized to one of four treatment groups utilizing a 2x2 factorial design
Two of the treatment groups received beta-carotene supplements
Due to reports of potential risk associated in this population from beta-carotene this treatment was discontinued. These subjects were allowed to participate in one of the vitamin C treatment groups.
Treatment with vitamin C supplementation of 50mg or 500mg per day lasted for five years.

Blinding Used

Vitamin C was supplemented in a double-blind manner and all measurements were conducted by persons blinded to the intervention assignment.

Intervention

High-dose group: Received 500mg vitamin C as capsules each day for five years
Low-dose group: Received 50mg vitamin C as capsules each day for five years.

Statistical Analysis

Preliminary analysis used an intention-to-treat protocol (N=439) and analysis was repeated for those who completed the trial (N=378)
There were no significant differences in baseline characteristics or conclusions between the two sets of results
Descriptive statistics were used for baseline characteristics, nutrient intake and food consumption
Difference in the high- and low-dose groups were examined by T-test or one-way ANOVA for continuous variables
Differences between the high- and low-dose groups and the drop-out group were also examined by one-way ANOVA and a Duncan test.
ANCOVA was used to adjust for potentially confounding variables.

Data Collection Summary:

Timing of Measurements

BP measurements were taken at baseline and annually for five years. At recruitment and at the end of supplementation (five years after recruitment), the following data was collected:

Weight
Height
Marital and occupational status
Education
Smoking status
Alcohol consumption
Disease hx
BMI
Food frequency questionnaire
Fasting blood samples analyzed for serum vitamin C and lipids.

Dependent Variables

SBP and DBP measured with a sphygmomanometer after two minutes of rest in a sitting position.

Independent Variables

High-dose group ingested 500mg vitamin C as capsules daily
Low-dose group ingested 50mg vitamin C as capsules daily.

Control Variables

Age
BMI
Alcohol intake
Smokers.

Description of Actual Data Sample:

Initial N

602 subjects met study criteria, of which 439 consented to participate in the study.

Attrition (Final N)

134 subjects dropped out before and upon modification of the study protocol, when the groups originally assigned to take beta-carotene supplements were instructed to stop treatment and were randomized to one of the vitamin C treatment groups
This left 305 subjects and of these 244 completed the study
Final N=244 (80% dropout rate).

Age

High-dose group: 56.3±8.66 years
Low-dose group: 58.7±6.53 years
Dropout group: 57.2±7.83 years (mean±SD)
Age was different at baseline between the high- and low-dose groups, P=0.01.

Ethnicity

Japanese from a village in Akita Prefecture.

Other Relevant Demographics

	High-Dose Group (N=124)	Low-Dose Group (N=120)	P-Value	Dropout Group (N=134)	P-Value
Hypertensive	23	31	0.17	29	0.38
On Antihypertensives	19	25	0.28	20	0.50
Smoker	19	12	0.50	18	0.12

There were no differences between groups
First P-value represents analysis between high- and low-dose groups
Second P-value represents analysis between all groups.

Anthropometrics

	High-Dose Group (N=124)	Low-Dose Group (N=120)	P-Value	Dropout Group (N=134)	P-Value
Weight, kg	55.2±8.08	55.0±8.91	0.84	56.0±9.29	0.61
Height, cm	154.1±8.52	153.1±9.24	0.39	152.6±8.49	0.36
BMI	23.2±2.65	23.4±2.86	0.59	24.0±3.26	0.07

Mean±SD

There were no differences between groups
First P-value represents analysis between high- and low-dose groups
Second P-value represents analysis between all groups

Location

Akita Prefecture, Japan.

Summary of Results:

Baseline SBP and DBP were not different between the three groups in both sexes
After vitamin C supplementation, SBP increased in all three groups, compared with baseline regardless of vitamin C dose
SBP in the high-dose group increased 5.88mm Hg; 95% CI 3.11-8.65
SBP increased in the low-dose group 5.73mm Hg (95% CI 2.62-8.83)
The increase in the dropout group was 4.52mm Hg (95% CI 1.26-7.77)
These increases were significant in women, but not in men.
The significant changes in BP from baseline between groups are shown in the table below. There were no other significant differences between groups.

Mean Changes in BP with Five-Year Vitamin C Supplementation

High-Dose Group
Mean

Low-Dose Group
Mean

P-Value

Dropout Group
Mean

P-value

Male
DBP, mm Hg

0.93

-5.79

0.009

-2.73

0.03

Female
SBP, mm Hg

7.34

9.59

0.54

3.31

0.04

First P-value represents analysis between high- and low-dose groups
Second P-value represents analysis between all groups.

Other Findings

At baseline, serum vitamin C concentrations were not inversely associated with SBP or DBP
A subgroup analysis of those taking antihypertensive medication showed no difference in DBP change in any group regardless of taking or not taking antihypertensives
SBP nor DBP were significantly related with serum vitamin C concentration
There was no relationship of SBP nor DBP after adjusting for age, BMI, alcohol intake or smoking.

Author Conclusion:

There was no reduction in BP with five-year supplementation of vitamin C in this high-risk population for stomach cancer and stroke.

Funding Source:

Government:

Ministry of Health, Labor and Welfare (Japan)

University/Hospital:

National Cancer Center Research Institute East, Hiraka General Hospital (all Japan)

Not-for-profit

Foundation associated with industry:

Reviewer Comments:

Change in BMI over the five-year period was not presented nor was physical activity monitored
Dietary intake was measured by FFQ and compliance with supplementation was measured by pill count and serum vitamin C levels.
Discussion suggests that the increase in SBP that occured in all groups may be due to aging rather than an effect of vitamin C. Also, serum vitamin C is a marker of fruit and vegetable intake and healthy behavior which may have had an effect on BP.
The strengths of the present study are the adjustment for several confounders, it was a population-based study and the length (five years) of the study.
Limitations of the study are that it is inapplicable to the general population, because this population was at risk and the prevalence of atrophic gastritis increased with age.

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?	Yes
	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?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	No
	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?	Yes
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?	Yes
	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?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	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?		Yes
	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?	Yes
	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?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		???
	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?	No
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

	High-Dose Group Mean	Low-Dose Group Mean	P-Value	Dropout Group Mean	P-value
Male DBP, mm Hg	0.93	-5.79	0.009	-2.73	0.03
Female SBP, mm Hg	7.34	9.59	0.54	3.31	0.04