EAL

HTN: Vitamins (2007)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To assess whether 500mg per day of vitamin C or 20mg per day of atorvastatin improve endothelial function and blood pressure control in subjects with resistant essential hypertension and primary dyslipidemia.

Inclusion Criteria:

Essential hypertension treated with three blood pressure-lowering medications (one of them a diuretic) in maximal doses for at least six months
SBP over 140mm Hg or DBP over 90mm Hg, measured by 24-hour ambulatory BP monitoring
Hypercholesterolemia not treated with any lipid-lowering medication before study entry, with a fasting plasma LDL over 130mg per dL.

Exclusion Criteria:

Diabetes mellitus treated with medication, however persons with diabetes treated with diet alone were allowed to participate
Fasting hyperglycemia over 150mg per dL
Liver or kidney disease
Cancer
Acute myocardial infarction or unstable angina within six months
Heart failure
Smoking more than 10 cigarettes per day
Use of corticosteroids or other immunosuppressive therapy
Abnormal levels of plasma aldosterone, supine and standing plasma renin activity and 24-hour urinary catecholamines
Anomalies in the renal ultrasound scan or in renal arterial duplex indicating renal artery stenosis.

Description of Study Protocol:

Recruitment

Not discussed, other than being conducted at the WHO Collaborative Center for Prevention of Cardiovascular Disease.

Design

A four-week run-in period was followed by randomization of subjects in a single-blind manner to receive 20mg atorvastatin, 500mg ascorbic acid or placebo daily for eight weeks.

Blinding Used

Single-blinding for randomization to one of three intervention groups.

Intervention

All subjects continued on their antihypertensive medication, were monitored for BP and biochemical levels every four weeks, consumed a daily diet containing 120mmol sodium and 2,200kcal, 30% from fatty acids (10% from saturated fatty acids) and instructed to maintain the same diet throughout the study

The three treatment groups were:

20mg atorvastatin daily in addition to the above protocol
500mg vitamin C daily in addition to the above protocol
Placebo daily in addition to the above protocol.

Statistical Analysis

Paired T-test was used to compare difference between means
Two-way ANOVA with repeated measures was used to compare the effects of atorvastatin, vitamin C and placebo on brachial artery flow-mediated dilation
P<0.05 was considered significant.

Data Collection Summary:

Timing of Measurements

BP and endothelium-dependent and independent vasodilations of the brachial artery were measured at study entry and following eight weeks of intervention
Healthy controls were measured only on one occasion.

Dependent Variables

SBP and DBP measured by automatic 24-hour ambulatory BP measuring device
The 24-hour average BP value was determined from 66 measured values
Endothelium-dependent (flow-mediated) and independent (nitroglycerin-induced) vasodilation of brachial artery was measured using an ultrasonic phase-locked echotracking system after an eight-hour fast and abstenance from cigarette smoking
Plasma LDL.

Independent Variables

20mg per day of atorvastatin
500mg per day of vitamin C
Daily placebo.

Description of Actual Data Sample:

Initial N

52.

Attrition (Final N)

48 (25 males)
Three patients refused nitroglycerin-mediated dilation testing, two had FBG over 150mg per dL in later blood testing; all five did not return for follow-up and were not included in the data analysis
14 control subjects were enrolled for one-time measurements.

Age

Vitamin C group: 52.6±12.3 (mean±SD)
Atorvastatin group: 54.1±13.5
Placebo group: 51.4±12.8
Controls: 54.4±15.2.

Ethnicity

Not discussed.

Other Relevant Demographics

The number of subjects with a history of smoking per group was as follows

Vitamin C group: Seven
Atorvastatin group: Eight
Placebo group: Seven
Controls: Six.

Anthropometrics

BMI per group was as follows

Vitamin C group: 28.2±2.2 (mean±SD)
Atorvastatin group: 27.9±1.8
Placebo group: 27.7±2.1
Controls: 27.6±2.3.

BMI was not different across groups.

Location

Barzilai Hospital, Israel.

Summary of Results:

All groups were similar at baseline for gender, age, BMI, history of smoking, SBP, DBP, heart rate, blood glucose, LDL, brachial artery flow-mediated dilation, resting arterial diameter, reactive hyperemic blood flow and brachial artery nitroglycerin-mediated dilation, with the exception of the healthy, normotensive controls who did not have impaired brachial artery flow-mediated vasodilation.

Effect of Treatment On BP and Hemodynamic Parameters

	Vitamin C Baseline	Vitamin C Eight weeks	Atorvastatin Baseline	Atorvastatin Eight Weeks	Placebo Baseline	Placebo Eight Weeks
SBP	150.6±5.4	150.6 +5.4	153.1±4.8	136.9±6.1*	151.1±7.4	150.9±6.8
DBP	86.1±3.3	87.4±5.3	87.1±6.7	78.3±4.2*	84.7±5.9	83.2±5.7
Percentage change in flow-mediated dilation	8.9±6.4	8.5±7.9	8.5±5.6	11.5±5.1*	8.3±6.1	8.7±6.6

Mean±SD
*P<0.05

Other Findings

After eight weeks, when compared with vitamin C and placebo, atorvastatin significantly decresed SBP, DBP and LDL (P<0.001)
In the vitamin C and placebo groups, there were no significant changes in BP and LDL
Vitamin C and placebo treatment had no effect on brachial artery flow-mediated dilation (P=0.34) or nitroglycerin-mediated dialtion (P=0.48)
Vitamin C had no effect on baseline brachial artery diameter or hyperemic flow.

Author Conclusion:

In subjects with resistant hypertension and dyslipidemia, the BP reduction achieved by short-term treatment with atorvastatin was significant, while 500mg per day of vitamin C was ineffective.

Funding Source:

Government:

World Health Organization Collaborative Center for Prevention of CVD (Isreal)

Reviewer Comments:

The numbers lost to attrition do not add up with the final N to equal the original N.
The study took place in Israel, however ethnicity was not discussed
Other possible confounders such as change in weight, alcohol use and physical activity were not discussed, nor were measures of compliance with study protocol.
Limitation of results is that the study was short (eight weeks).

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?		???
	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?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
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.)	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?		???
	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?	No
	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?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	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.)	???
	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?		No
	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?	No
	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?		No
	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?	No
	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?	No
	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?		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)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	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?	???
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