title: Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study : A Randomized Clinical Trial.
abstract: Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D.
  
  
  
  To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population.
  
  
  
  The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis.
  
  
  
  Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years).
  
  
  
  The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis.
  
  
  
  Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes.
  
  
  
  Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study.
  
  
  
  clinicaltrials.gov Identifier: ACTRN12611000402943.
authors.affiliation: School of Population Health, The University of Auckland, Auckland, New Zealand.
authors.forename: Robert
authors.initials: R
authors.lastname: Scragg
authors.affiliation: School of Population Health, The University of Auckland, Auckland, New Zealand.
authors.forename: Alistair W
authors.initials: AW
authors.lastname: Stewart
authors.affiliation: School of Population Health, The University of Auckland, Auckland, New Zealand.
authors.forename: Debbie
authors.initials: D
authors.lastname: Waayer
authors.affiliation: School of Population Health, The University of Auckland, Auckland, New Zealand.
authors.forename: Carlene M M
authors.initials: CMM
authors.lastname: Lawes
authors.affiliation: Department of Public Health & General Practice, The University of Otago, Christchurch, New Zealand.
authors.forename: Les
authors.initials: L
authors.lastname: Toop
authors.affiliation: School of Population Health, The University of Auckland, Auckland, New Zealand.
authors.forename: John
authors.initials: J
authors.lastname: Sluyter
authors.affiliation: School of Population Health, The University of Auckland, Auckland, New Zealand.
authors.forename: Judy
authors.initials: J
authors.lastname: Murphy
authors.affiliation: Department of Public Health, University of Cambridge, Cambridge, England.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Camargo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000453:epidemiology / Q000517:prevention & control; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000517:prevention & control; D001161:Arteriosclerosis / Q000453:epidemiology / Q000517:prevention & control; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control*; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000627:therapeutic use; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000453:epidemiology / Q000517:prevention & control; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000517:prevention & control; D009520:New Zealand; D016016:Proportional Hazards Models; D020521:Stroke / Q000453:epidemiology / Q000517:prevention & control; D020246:Venous Thrombosis / Q000453:epidemiology / Q000517:prevention & control; D014808:Vitamin D Deficiency / Q000188:drug therapy* / Q000453:epidemiology; D014815:Vitamins / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D014815:Vitamins; D002762:Cholecalciferol