HTN: Vitamins (2015)
Citation:
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: 22854639Study Design:
Randomized Controlled Trial
Class:
A - Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To determine the effect of vitamin D supplementation during the winter months on blood pressure in adults with hypertension who live at a northern latitude.
Inclusion Criteria:
- Caucasian
- Arterial hypertension
- Living in Denmark
- Informed consent.
Exclusion Criteria:
- 24-hour ambulatory blood pressure (24-hour BP) systolic BP higher than 150mm Hg and diastolic BP higher than 95mm Hg
- Cancer
- Atrial flutter or fibrillation
- Hypercalcemia
- 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.
Description of Study Protocol:
Recruitment
- Newspaper advertisements
- Pamphlets in physician office
- Recruitment and follow-up occurred between October 2010 and March 2011.
Design
- 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.
Blinding Used
- Placebo identical in size, color, shape, consistency, taste and ingredients except for cholecalciferol
- Participants, investigators and study personnel were blinded to treatment assignment.
Intervention
A total of 75mcg cholecalciferol (25mcg x three tablets) vs. placebo for 20 weeks.Statistical Analysis
- 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.
Data Collection Summary:
Timing of Measurements
Baseline | Week Five | Week 10 | Week 15 | Week 20 | |
Clinical exam | x | x | x | x | x |
Urine sample | x | x | x | x | x |
Applanation tonometry | x | x | x | x | x |
Safety assessment labs (plasma calcium, phosphate, 25OH-D) | x | x | x | x | x |
Ambulatory BP | x | x | x | x | x |
Plasma 25OH D2+D3 | x | x | x | x | x |
Brain natriuretic peptide | x | x | x | x | x |
Plasma renin | x | x | x | x | x |
Angiotensin II | x | x | x | x | x |
Aldosterone | x | x | x | x | x |
Intact plasma fibroblast growth factor 23 | x | x | x | x | x |
Dependent Variables
- Primary: 24-hour systolic blood pressure
- Secondary:
- 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 Variables
75mcg cholecalciferol vs placebo.Description of Actual Data Sample:
Initial N
N=130:
- 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.
Age
Years (Mean age±SD):
- Placebo: 61.9±9 years
- Cholecalciferol: 60±1.2 years.
Ethnicity
Caucasian.
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
- Medications:
- Multivitamins
- Bisphosphonates
- Statins
- Diuretics
- 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.
Anthropometrics
BMI, kg/m2 (mean±SD):- Placebo: 28.3±3.7
- Cholecalciferol: 27.7±4.2.
Location
Holstebro, Denmark.
Summary of Results:
Key Findings
- 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.
Other Findings
- 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).
Author Conclusion:
Cholecalciferol supplementation in adults with hypertension living in a northern latitude during the winter months did not produce significant reductions in 24-hour systolic BP. A borderline reduction in both 24-hour systolic and diastolic BP was observed in participants with low levels of plasma 25OH-D (less than 32ng per ml) at baseline. Cholecalciferol supplementation produced a significant reduction on central BP.
Funding Source:
Government: | Research Foundation of Central Denmark Region | ||
Industry: |
|
Reviewer Comments:
- 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
|
|||
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.) | 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 | |