Homocysteine-lowering therapy and risk for venous thromboembolism - A randomized trial

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 mu mol/L in the vitamin therapy group and increased by 0.80 mu mol/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 2.281), or unprovoked venous thromboembolism (hazard ratio, 1.21 [CI, 0.66 to 2.231). 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 B-6 and B-12 did not reduce the risk for symptomatic venous thromboembolism.