High-dose B vitamin supplementation and progression of subclinical atherosclerosis: a randomized controlled trial

Stroke. 2009 Mar;40(3):730-6. doi: 10.1161/STROKEAHA.108.526798. Epub 2008 Dec 31.


Background and purpose: Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B vitamin supplementation reduces subclinical atherosclerosis progression.

Methods: In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial tHcy >8.5 micromol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B(12)+50 mg vitamin B(6)) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima media thickness (primary outcome) and multidetector spiral CT to measure aortic and coronary artery calcium (secondary outcome).

Results: Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found (P=0.31). However, among subjects with baseline tHcy >or=9.1 micromol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo (P=0.02); among subjects with a baseline tHcy <9.1 micromol/L, there was no significant treatment effect (probability value for treatment interaction=0.02). B vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups.

Conclusions: High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin "replete" individuals at low risk for cardiovascular disease with a fasting tHcy >or=9.1 micromol/L.

Trial registration: ClinicalTrials.gov NCT00114400.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aorta, Abdominal / diagnostic imaging
  • Atherosclerosis / diagnostic imaging
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / pathology
  • Calcium / metabolism
  • Carotid Arteries / diagnostic imaging
  • Coronary Vessels / diagnostic imaging
  • Coronary Vessels / pathology
  • Dietary Supplements*
  • Disease Progression
  • Double-Blind Method
  • Echocardiography
  • Female
  • Homocysteine / blood
  • Humans
  • Lipids / blood
  • Male
  • Middle Aged
  • Patient Compliance
  • Treatment Outcome
  • Vitamin B Complex / adverse effects
  • Vitamin B Complex / blood
  • Vitamin B Complex / therapeutic use*


  • Lipids
  • Homocysteine
  • Vitamin B Complex
  • Calcium

Associated data

  • ClinicalTrials.gov/NCT00114400