HTN: Vitamins (2015)
Larsen T, Mose FH, Bech JN, Hansen AB, Pedersen EB. Effect of cholecalciferol supplementation during winter months in patients with hypertension: A randomized, placebo-controlled trial. Am J Hypertens. 2012; 25: 1,215-1,222.PubMed ID: 22854639
- Arterial hypertension
- Living in Denmark
- Informed consent.
- 24-hour ambulatory blood pressure (24-hour BP) systolic BP higher than 150mm Hg and diastolic BP higher than 95mm Hg
- Atrial flutter or fibrillation
- Pregnant or nursing
- Alcohol abuse (higher than 36g for men, higher than 24g for women)
- Routine use of non-steroidal anti-inflammatory drugs or glucocorticoids
- Daily vitamin D intake greater than 10mcg of cholecalciferol or ergocalciferol
- Use of tanning beds
- Change in anti-hypertensive medications during the study.
- Newspaper advertisements
- Pamphlets in physician office
- Recruitment and follow-up occurred between October 2010 and March 2011.
- Assigned to placebo or vitamin D by hospital pharmacy via permutated block randomization generated by computer. Assignment was received after baseline exam but before ambulatory BP monitoring
- Study duration: A total of 20 weeks
- Data collected included:
- Blood pressure
- Arterial stiffness
- Blood sampling for calcium metabolism and vasoactive hormones.
- Placebo identical in size, color, shape, consistency, taste and ingredients except for cholecalciferol
- Participants, investigators and study personnel were blinded to treatment assignment.
InterventionA total of 75mcg cholecalciferol (25mcg x three tablets) vs. placebo for 20 weeks.
- Sample size calculation suggested that 54 participants were needed in each group
- Independent T-test or Mann Whitney U-test assessed differences between groups
- General linear model: Differences in plasma 25OH-D were assessed during the study
- Significance: P<0.05.
Timing of Measurements
|Baseline||Week Five||Week 10||Week 15||Week 20|
|Safety assessment labs (plasma calcium, phosphate, 25OH-D)||x||x||x||x||x|
|Plasma 25OH D2+D3||x||x||x||x||x|
|Brain natriuretic peptide||x||x||x||x||x|
|Intact plasma fibroblast growth factor 23||x||x||x||x||x|
- Primary: 24-hour systolic blood pressure
- 24-hour diastolic blood pressure
- Heart rate
- Central BP
- Central augmentation index
- Carotid-femoral pulse wave velocity (PWV): Surrogate for arterial stiffness and measured with applanation tonometry
- Urinary calcium to creatinine ratio
- Plasma renin, angiotensin II, aldosterone
- Brain natriuretic peptide
- Plasma 25OH-D (chemilumescence immunoassay)
- Plasma intact parathyroid hormone, ionized calcium, phosphate
- Plasma fibroblast growth factor 23 (FGF23).
Independent Variables75mcg cholecalciferol vs placebo.
- Placebo: N=65
- Cholecalciferol: N=65.
Attrition (Final N)
N=112 (35 males and 77 females):
- Placebo: N=57 (18 males and 39 females):
- Did not complete the initial 24-hour BP measurement: N=2
- Mean systolic 24-hour BP higher than 150mm Hg: N=3
- Withdrew consent: N=2
- Medication change: N=1.
- Cholecalciferol: N=55 (17 males and 38 females):
- Mean systolic 24-hour BP higher than 150mm Hg: N=2
- Withdrew consent: N=4
- Medication change: N=1
- Initial NSAID therapy: N=1
- Breast cancer diagnosis: N=1
- Major surgery: N=1.
Years (Mean age±SD):
- Placebo: 61.9±9 years
- Cholecalciferol: 60±1.2 years.
Other relevant demographics:
- Initial 24-hour BP (mm Hg):
- Placebo: 131/77±9/6
- Cholecalciferol: 132/77±10/6.
- Plasma 25OH-D (ng per ml):
- Placebo: 23±12
- Cholecalciferol: 23±9
- Levels less than 32ng per ml: N=92
- Levels less than 20ng per ml: N=47.
- No difference between groups at baseline for the following:
- Smoking status
- Type 2 diabetes
- Calcium channel or beta blockers
- Angiotensin-converting enzyme inhibitors.
- Chemistries except for higher ionized calcium (P=0.003) and plasma alkaline phosphatase (P=0.01) in the placebo group.
AnthropometricsBMI, kg/m2 (mean±SD):
- Placebo: 28.3±3.7
- Cholecalciferol: 27.7±4.2.
- Blood pressure:
- 24-hour systolic BP (primary): No significant differences were observed between the cholecalciferol or placebo groups at the end of the study
- In post-hoc analysis comparing response to vitamin D supplementation in participants with low plasma 25OH-D (less than 32ng per ml) at baseline, both 24-hour systolic and diastolic BP were significantly reduced in the cholecalciferol group (N=46) compared to the placebo group (N=46) by 4/3mm Hg (P=0.05/0.01)
- Central BP decreased by 7/2mm Hg in the cholecalciferol group (N=52) compared to the placebo group (N=55), P=0.007.
- Arterial stiffness: At study end, no significant differences were noted between the cholecalciferol and placebo groups for central augmentation index or carotid-femoral pulse wave velocity. An increase in PWV was observed within both groups throughout the study (placebo, P=0.06; cholecalciferol, P=0.004)
- Calcium metabolism:
- A mean reduction in plasma 25OH-D was observed within the placebo group (3±6ng per ml, P<0.001) at the end of 20 weeks. The cholecalciferol group showed a mean increase of 21±10ng per ml, P<0.001
- Compared to placebo at study end, the cholecalciferol group experienced an increase in ionized calcium (0.06±0.11mg per dL, P<0.05) and a reduction in PTH (–9.2±8.8pg per ml, P<0.01)
- Pearson correlation showed a negative relationship between changes in plasma 25OH-D and changes in plasma PTH (N=112, R=–0.48, P<0.001)
- A positive correlation was suggested between changes in plasma PTH and changes in systolic 24-hour BP (N=112, r = 0.28, P=0.04)
- Compared to placebo, no significant differences were observed relative to plasma phosphate, plasma FGF23 or the urinary calcium to creatinin ratio at study end.
- Vasoactive hormones: At study end, no significant changes were observed between the placebo and cholecalciferol groups for brain natriuretic peptide, plasma renin, angiotensin II and aldosterone.
- Using pill count, mean adherence was 99% in both groups
- Adverse event: Raised, pruritic rash on trunk (N=6, three in each group)
- Nine traveled to latitudes or altitudes that could result in cutaneous vitamin D synthesis:
- Placebo: Smaller decrease in plasma 25OH-D compared to others in placebo group (N=5)
- Cholecalciferol: Experienced similar increase in plasma 25OH-D as others in the treatment group (N=4).
|Government:||Research Foundation of Central Denmark Region|
- Including participants with adequate vitamin D levels reduced the effect of cholecalciferol supplementation. Post-hoc analysis was underpowered when they were removed.
- May have missed an effect of cholecalciferol supplementation on BP, by including those with well-controlled hypertension
- Dietary intake was not addressed
- Due to the two-month half-life of cholecalciferol, future studies should aim to maintain a high plasma 25OH-D level for an extended period of time to evaluate effects on the cardiovascular system.
- No intention to treat.
Quality Criteria Checklist: Primary Research
|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|
|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.)||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?||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?||N/A|
|7.3.||Was the period of follow-up long enough for important outcome(s) to occur?||???|
|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?||???|
|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)?||No|
|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?||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|