Homocystine-lowering therapy and risks for venous thromboembolism: A randomized trial

Abstract

Conclusion: The risk of symptomatic venous thromboembolism (VTE) is not decreased by lowering homocystine levels with folic acid and vitamins B6 and B12. Summary: Elevated homocystine levels are a risk factor for VTE. It is, however, unknown whether decreasing homocystine levels with vitamin therapy will lower the risk of VTE. The authors sought to determine whether lowering homocystine levels will lower the risk of symptomatic VTE. This was a secondary analysis of data obtained as part of the Heart Outcomes Prevention Evaluation 2 (HOPE-2) trial. Data were derived from 145 centers in 13 countries. Included in the study were 5522 persons aged 55 or older who had diabetes or known cardiovascular disease with at least one risk factor for vascular disease. Patients were randomized to receive vitamin therapy consisting of 2.5 mg of folic acid, 1 mg of vitamin B12, and 50 mg of vitamin B6, or to receive placebo. Medications were administered for 5 years. End points included symptomatic deep venous thrombosis or pulmonary embolism. In patients treated with vitamin therapy, the mean homocystine level decreased 2.2 μmol/L. In the placebo group, mean homocystine levels increased 0.80 μmol/L. There were 88 instances VTE with a mean follow-up of 5 years. VTE rate was the same in the vitamin therapy group and the placebo group (0.35/100 person-years; hazard ratio, 1.01; 95% confidence interval [CI], 0.66 to 1.53). The risk for deep venous thrombosis was not reduced by vitamin therapy (hazard ratio, 1.04; 95% CI, 0.63 to 1.72), nor was the risk of pulmonary embolism (hazard ratio, 1.14; 95% CI, 0.57 to 2.28) or unprovoked VTE (hazard ratio, 1.21; 95% CI, 0.66 to 2.23). Comment: The HOPE-2 trial evaluated the effect of homocystine-lowering therapy on major arterial vascular disease. This article represents a secondary analysis of the HOPE 2 trial. The trial did not include patients specifically at high risk for VTE. Elevated homocystine is a relatively minor risk factor for VTE, and therefore, it is not surprising that the minor decrease in homocystine levels associated with vitamin therapy in the HOPE 2 participants did not result in a detectable rate of decrease of VTE. The data cannot be applied to patients at high risk for VTE or those with markedly elevated levels of homocystine. Nevertheless, this is another of a number of studies that indicate that although elevated homocystine may be a risk factor or marker for venous or arterial disease, vitamin therapy to lower the homocystine levels does not appear to clinically affect vascular events.