HTN: Vitamins (2015)


Witham MD, Price RJ, Struthers AD, Donnan PT, Messow CM, Ford I, McMurdo ME. Cholecalciferol treatment to reduce blood pressure in older patients with isolated systolic hypertension the vitDISH randomized controlled trial. JAMA Intern Med. 2013 Oct 14; 173(18): 1,672-1,679.

PubMed ID: 23939263
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
To test whether high-dose, intermittent cholecalciferol supplementation lowers blood pressure in older patients with isolated systolic hypertension (ISH).
Inclusion Criteria:
Patients 70 years and older with:
  • ISH (supine systolic blood pressure higher than 140mm Hg and supine diastolic blood pressure lower than 90mm Hg)
  • Baseline 25-hydroxyvitamin D (25OHD) levels less than 30ng per ml.
Exclusion Criteria:
Not specified.
Description of Study Protocol:


Patients were recruited via three routes:

  • Community via primary care practices
  • Article in the local newspaper about the research study
  • Secondary care clinics (cardiovascular and medicine for the elderly).


Parallel group, double-blind, placebo-controlled randomized trial.

Blinding Used

All outcome measures were performed by researchers who were masked to treatment allocations; participants were blind to treatment allocation.


A total of 100,000 IU of oral cholercalciferol or matching placebo every three months for one year.

Statistical Analysis

  • A two-sided P<0.05 was considered significant for all analyses
  • For each outcome measure, repeated measures, mixed effects analyses were conducted with estimation and testing of main effects of treatment allocation (T-test) and a group x time interaction (F-tests)
  • Analyses for outcome measures at individual time points, including the primary outcome measures, were based on analysis of covariance, adjusting for baseline values of the response variable and levels of the stratification variables
  • Analyses were based on a modified intent-to-treat population (all participants with baseline and follow-up values of the response variable being analyzed)
  • Unadjusted models and models adjusted for baseline values of the outcome measure under the study along with baseline 25OHD level, baseline blood pressure, the presence of diabetes and age were calculated
  • The use of thiazide diuretics were adjusted for, given the known effects of these medications on calcium metabolism and the use of statins and given their known interaction with vascular heath and vitamin D metabolism
  • Sensitivity analyses were conducted using multiple imputation to account for missing data and excluding patients with changes in antihypertensive medication type or dose for blood pressure analyses
  • On the basis of blood pressure data from a previous vitamin D intervention trial for hypertension, the study was powered to detect a 7mm Hg between group difference in systolic blood pressure change between baseline and three months, assuming an SD change of 18mm Hg
  • To detect this change with 80% power at alpha  level of 0.05 required 73 patients per groups
  • A dropout rate of 20% was anticipated, so 180 patients were needed to be recruited into the trial.
Data Collection Summary:

Timing of Measurements

  • The 24-hour blood pressure was measured at zero, three, six, nine and 12 months
  • Soluble markers and biochemical measurements were collected at baseline, three months and 12 months
  • Endothelial function and pulse wave velocity were assessed at zero, three and 12 months
  • Exercise capacity was determined at zero, six and 12 months.

Dependent Variables

  • Primary outcome measures: Between group treatment effects in office SBP and DBP
  • Secondary outcome measures: 
    • 24-hour blood pressure (systolic and diastolic)
    • Pulse wave velocity
    • Flow-mediated dilatation of brachial artery
    • Biochemical markers:
      • B-type natriuretic peptide (BNP)
      • High-sensitivity C-reactive protein (CRP)
      • Insulin
      • Glucose
      • Homeostasis model assessment of insulin resistance (HOMA-IR)
      • Total cholesterol
      • Low-density lipoprotein cholesterol (LDL)
      • High-density lipoprotein cholesterol (HDL)
      • Triglycerides
      • Serum albumin
      • Calcium
      • Creatinine
      • Parathyroid hormone (PTH)
      • Exercise capacity
      • Gall frequency.

Independent Variables

A total of 100,000 IU of oral cholecalciferol or matching placebo every three months for one year.

Control Variables

  • Age
  • Sex
  • Body mass index (BMI)
  • Myocardial infarction number
  • Angina
  • Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG)
  • Peripheral vascular disease
  • Diabetes mellititus
  • Stroke or transient ischemic attack (TIA)
  • Number of medications (median)
  • Number of antihypertensive medications (median)
  • Renin-angiotensin-aldosterone system (RAAS)
  • Blockers number (%), beta-blockers number
  • Calcium channel blockers
  • Diuretics
  • Statins.
Description of Actual Data Sample:
  • Initial N: 159
  • Attrition (final N): 142
  • Age: Mean age 76.8
  • Ethnicity: White.

Other Relevant Demographics

  Male Female
Vitamin D group 40 40
Placebo group 38 42


  BMI (SD)
Vitamin D group 28.5 (5.0)
Placebo group 27.9 (4.5)


Dundee, Scotland.


Summary of Results:

Key Findings

  • Effect of intervention on 25OHD levels:
    • Mean 25OHD levels increased from a baseline level of 18ng per ml to 28ng per ml at eight months in the intervention group before plateauing. A small (3ng per ml) increase was seen by six months in the placebo group; the overall effect estimate of the intervention during the 12-month study period was equivalent to a 7ng-per-ml increase 25OHD levels in the intervention group.
    • Adherence to study medication was high; 301 of 303 planned doses (99%) were ingested in the intervention group, and 285 of 294 planned doses (97%) were ingested in the placebo group
    • Missing doses were withheld because of elevated calcium level or suspected medication at any time point.
  • Primary outcome measure:
    • Office systolic blood pressure was not statistically different between treatment and placebo groups at three months
    • Office systolic blood pressure decreased by a mean standard deviation (SD) of 2.7mm Hg (12.5mm Hg) in the treatment group between baseline and three months compared with a smaller mean (SD) decrease of 1.4mm Hg (14.9mm Hg) in the placebo group
    • The between group treatment effect after adjusting for covariates was -0.7mm Hg (95% CI: -5.2mm Hg to 3.8mm Hg; P=076)
    • Season of recruitment (May to October vs. November to April, reflecting peak and through 25OHD levels in population studies) did not change the effect of treatment on blood pressure at three months; between-group difference in systolic blood pressure change was -.9mm Hg (95% CI: -5.3mm Hg to 3.5mm Hg) after adjustment for the season
    • No participants changed antihypertensive therapy between baseline and three months.
  • Secondary outcome measures:
    • No significant between group differences in blood pressure at any time point for either office blood pressure or daytime 24-hour blood pressure and no significant between group differences on repeated measure analysis were found
    • Further analysis that excluded participants with a change in their antihypertensive medications (one in the placebo group and three in the vitamin D group by 12 months) revealed no relevant change in these results
    • Daytime 24-hour blood pressure results were similar after excluding recordings that had fewer than 14-day time readings
    • No significant change in serum calcium levels was noted and PTH levels decreased by a small (3.8pg per ml) but significant amount in the intervention group.
  • Sub-group analysis:
    • No significant interaction was found between baseline 25OHD level, baseline systolic blood pressure, dietary calcium intake or PTH level (used as continuous variables) and the treatment effect of vitamin D on systolic blood pressure
    • A significant interaction was noted between angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use and treatment effect, with a greater treatment effect seen in those already taking ACE inhibitors or ARB medication (-4mm Hg vs. +8mm Hg, P=0.02)
    • No significant interaction was seen between the effect of treatment on diastolic blood pressure and baseline 25OHD level, ACE inhibitor or ARB use, baseline calcium intake or baseline PTH level.
  • Exercise capacity and falls:
    • Exercise capacity as measured by a six-minute walk did not increase by a clinically significant amount with vitamin D therapy; the between-group differences compared with baseline was 16m (95% CI: 2m to 31m; P=0.03) at six months and 12 minutes (95% CI: -4m to 28m; P=0.13) at 12 months
    • There were non-significantly fewer falls in the vitamin D group during the 12-month study period (36 vs. 46 falls; HR=0.77; 95% CI: 0.5 to 1.2; P=0.24); the time to first fall in each group was similar (P=0.94 by log-rank test) as was the number of participants in each group falling at least once (25 in the intervention group and 26 in the placebo group).
  • Safety:
    • Adverse events were similar in both trial arms, with no significant excess of adverse events in any sub-category of events
    • One participant in each group had an adjusted serum calcium level greater then 10.6mg per dL during the study; neither participant had symptoms or required treatment
    • Similarly, three of 80 participants (4%) in the vitamin D group and five of 79 participants (6%) in the placebo group had an increase in creatinine level greater then 20% compared with baseline during the study.
Author Conclusion:
  • Several explanations are possible for the lack of effect of vitamin D for this study:
    • Vitamin D may have no significant effect on blood pressure
    • Vitamin D may not reduce blood pressure in this specific patient group
    • The dose used was insufficient or incorrect
    • Other permissive factors, such as calcium intake, are required for vitamin D to produce a beneficial effect on blood pressure
  • Although the results of this study do not lend support to performing large randomized controlled trials aimed specifically at blood pressure reduction, at least in this patient group, it is still possible, however, that vitamin D supplementation could have beneficial effects. Ongoing large randomized trials are due to report on this in the next few years. In the meantime, the results do not support the use of high-dose, intermittent cholecalciferol to treat ISH in older, white patients.
Funding Source:
Government: Chief Scientist Office, Scottish Government
Reviewer Comments:
The authors note the following limitations:
  • Recruitment was only from a single health board area and patients were all of white ethnicity, which limits generalizability
  • Because of Vitamin D half life, more frequent doses would have been more effective at raising and maintaining serum 25OHD levels; this larger dose of Vitamin D could conceivably have had an effect.  However, in a another study, a four-month administration 100,000 IU of cholecalciferol was effective at increasing 25OHD levels and reducing fractures in a previous large osteoporosis trial, a finding that underpinned the choice of dose timing for this trial.
  • Ambulatory blood pressure was somewhat lower than expected, which may have limited the ability to demonstrate reductions in ambulatory blood pressure
  • The size of the trial means that a small beneficial effect on blood pressure still cannot be excluded, but the clinical relevance of such small improvements, at least at an individual patient level, is questionable. 
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? No
  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? ???
  2.2. Were criteria applied equally to all study groups? N/A
  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? No
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? 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? ???
  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? Yes
  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)? 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