Randomized Controlled Trial

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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.

• Caucasian
• 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
• 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.

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.

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.

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.

 

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).

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.

Government:	Research Foundation of Central Denmark Region
Industry:	Ferrosan A/S Pharmaceutical/Dietary Supplement Company:

• 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.