Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism

A Randomized Trial

  1. Joel G. Ray, MD, MSc;
  2. Clive Kearon, MD, PhD;
  3. Qilong Yi, PhD;
  4. Patrick Sheridan, MSc;
  5. Eva Lonn, MD, MSc; and
  6. for the Heart Outcomes Prevention Evaluation 2 (HOPE-2) Investigators*
  1. From St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada, and the Population Health Research Institute, Hamilton General Hospital, McMaster University, Hamilton, Ontario, Canada.

    Abstract

    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 B6, and 1 mg of vitamin B12 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 µmol/L in the vitamin therapy group and increased by 0.80 µmol/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.

    *For a list of the HOPE-2 investigators, see the Appendix.

    ClinicalTrials.gov registration number: NCT00106886.

    Current Controlled Trials registration number: ISRCTN14017017.

    Article and Author Information

    • Grant Support: In part by a Canadian Institutes of Health Research grant (MT-15418) and by Jamieson Laboratories, Toronto, Ontario, Canada. Dr. Ray is supported by a Canadian Institutes for Health Research New Investigator Award.

    • Potential Financial Conflicts of Interest: None disclosed.

    • Requests for Single Reprints: Joel G. Ray, MD, MSc, Department of Medicine, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada; e-mail, rayj{at}smh.toronto.on.ca.

    • Current Author Addresses: Dr. Ray: Department of Medicine, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.

    • Dr. Kearon: 70 Wing, Room 39, Henderson General Hospital, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

    • Drs. Yi and Lonn and Mr. Sheridan: Population Health Research Institute, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

    • Author Contributions: Conception and design: J.G. Ray, E. Lonn.

    • Analysis and interpretation of the data: J.G. Ray, C. Kearon, Q. Yi, E. Lonn.

    • Drafting of the article: J.G. Ray, C. Kearon, E. Lonn.

    • Critical revision of the article for important intellectual content: J.G. Ray, C. Kearon, E. Lonn.

    • Final approval of the article: J.G. Ray, C. Kearon, E. Lonn.

    • Provision of study materials or patients: E. Lonn.

    • Statistical expertise: Q. Yi, P. Sheridan.

    • Obtaining of funding: E. Lonn.

    • Administrative, technical, or logistic support: J.G. Ray, P. Sheridan, E. Lonn.

    • Collection and assembly of data: P. Sheridan, E. Lonn.

    Responses to this article

    • In Response
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      Ann Intern Med published online October 26, 2009
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    1. Ann Intern Med June 5, 2007 vol. 146 no. 11 761-767
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