Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism

A Randomized Trial

5 June 2007 | Volume 146 Issue 11 | Pages 761-767

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.

Editors' Notes Context In observational studies, elevated plasma homocysteine levels were associated with venous thromboembolism. A multicenter trial of folic acid and B vitamins to reduce cardiovascular events investigated the effect of homocysteine lowering on venous thromboembolism. Contribution In this trial, 5522 adults were randomly assigned to receive placebo, or folic acid and vitamins B6 and B12 daily for 5 years. Vitamin therapy decreased homocysteine levels, but the incidence of venous thromboembolism was the same in both groups, even in participants with the highest levels of homocysteine. Caution Venous thromboembolism events were not centrally adjudicated. Implication Decreasing homocysteine levels with supplements containing folic acid and vitamins B6 and B12 does not reduce the incidence of venous thromboembolism. —The Editors

 

Author and Article Information

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.

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.

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