Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial

Ann Intern Med. 2007 Jun 5;146(11):761-7. doi: 10.7326/0003-4819-146-11-200706050-00157. Epub 2007 Apr 30.


Background: Elevated total homocysteine levels are associated with a higher risk for venous thromboembolism. Whether decreasing homocysteine levels with vitamin therapy reduces the risk for venous thromboembolism is not known.

Objective: To determine whether decreasing homocysteine levels alters the risk for symptomatic venous thromboembolism.

Design: Secondary analysis of data from the randomized, placebo-controlled Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial.

Setting: 145 clinical centers in 13 countries.

Participants: 5522 persons 55 years of age or older with known cardiovascular disease or diabetes mellitus and at least 1 other risk factor for vascular disease.

Intervention: A daily supplement of 2.5 mg of folic acid, 50 mg of vitamin B(6), and 1 mg of vitamin B(12) or matching placebo for 5 years.

Measurement: Prospectively diagnosed and confirmed symptomatic deep venous thrombosis or pulmonary embolism.

Results: The geometric mean homocysteine level decreased by 2.2 micromol/L in the vitamin therapy group and increased by 0.80 micromol/L in the placebo group. Venous thromboembolism occurred in 88 participants during a mean follow-up of 5 years. The incidence rate of venous thromboembolism was the same in the vitamin therapy group and the placebo group (0.35 per 100 person-years; hazard ratio, 1.01 [95% CI, 0.66 to 1.53]). Vitamin therapy did not reduce the risk for deep venous thrombosis (hazard ratio, 1.04 [CI, 0.63 to 1.72]), pulmonary embolism (hazard ratio, 1.14 [CI, 0.57 to 2.28]), or unprovoked venous thromboembolism (hazard ratio, 1.21 [CI, 0.66 to 2.23]).

Limitations: The proportion of patients with a previous episode of venous thromboembolism at enrollment was not known, and venous thromboembolism events were not centrally adjudicated.

Conclusion: Decreasing homocysteine levels with folic acid and vitamins B6 and B12 did not reduce the risk for symptomatic venous thromboembolism.

Trial registration: ClinicalTrials.gov NCT00106886.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Female
  • Folic Acid / therapeutic use*
  • Humans
  • Hyperhomocysteinemia / drug therapy*
  • Incidence
  • Male
  • Middle Aged
  • Prospective Studies
  • Pulmonary Embolism / epidemiology
  • Pulmonary Embolism / prevention & control*
  • Risk Factors
  • Thromboembolism
  • Venous Thrombosis / epidemiology
  • Venous Thrombosis / prevention & control*
  • Vitamin B 12 / therapeutic use*
  • Vitamin B 6 / therapeutic use*


  • Vitamin B 6
  • Folic Acid
  • Vitamin B 12

Associated data

  • ClinicalTrials.gov/NCT00106886
  • ISRCTN/ISRCTN14017017