Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism: A Randomized Trial
Ray JG, Kearon C, Yi Q, Sheridan P, Lonn E, for the Heart Outcomes Prevention Evaluation 2 (HOPE-2) Investigators. Homocysteine-lowering therapy and risk for venous thromboembolism: A randomized trial. Ann Intern Med 2007;146:761-767.
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.
Homocysteine-Lowering Therapy and Risk for Venous Thromboembolism: A Randomized Trial
Review by Ranjith Shetty, MD
Does decreasing homocysteine levels reduce the occurrence of symptomatic venous thromboembolism (VTE)? This study was a randomized, placebo controlled clinical trial in which participants were randomly assigned to receive once daily supplement containing 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or matching placebo. Patients were evaluated for VTE 18 months after randomization. Thereafter, VTE, was assessed routinely every 6 months to an average follow-up of 5 years. The primary outcome was symptomatic VTE, and an intention to treat analysis was used.
Of the 5,522 patients, 2,758 were randomly assigned to receive homocysteine-lowering therapy, and 2,764 were assigned to receive placebo. 3,306 (60%) patients had baseline homocysteine levels. 3,982 (72%) were from areas with universal food fortification with folic acid. Mean age of participants was 69 years. Twenty eight percent were women. Mean homocysteine level was 11.5 μmol/L in both groups. At the end of the study, the mean homocysteine level was 9.3 μmol/L in the treatment group and 12.3 μmol/L in the placebo group.
Eighty-eight episodes of VTE were documented. Two thirds of the VTE were DVT, and 47% were unprovoked. Forty-four episodes of VTE occurred in each group, with an incidence rate of 0.35 per 100 person years in each group. Among 821 participants whose baseline homocysteine level was in the highest quartile (> 13.8 μmol/L), vitamin therapy did not reduce the risk for VTE (hazard ratio, 1.71 [CI, 0.48 to 6.06])
Though VTE history and baseline risk for VTE were not known for the majority of the patients, the most striking feature of the study was that even the patients in the highest quartile of baseline homocysteine levels (> 13.8 μmol) who would qualify as having hyperhomocysteinemia, a previously accepted risk factor for VTE, showed no reduction in incidence of VTE with homocysteine-lowering therapy. In summary, it appears that there is no role for homocysteine-lowering therapy for decreasing the incidence of symptomatic VTE.About Ranjith Shetty, MD: Dr. Shetty completed his internship and residency in internal medicine at Georgetown University. Having recently completed a 1-year Fellowship with the Venous Thromboembolism Research Group, Dr. Shetty is currently a Cardiology Fellow at the Medical College of Virginia in Richmond, VA.