Homocysteine Lowering by B Vitamins and the Secondary Prevention of Deep-Vein Thrombosis and Pulmonary Embolism. A First Randomised, Placebo-Controlled, Double-Blind Trial.

Hyperhomocysteinemia is a risk factor for venous thrombosis and arterial vascular disease. Supplementation with B-Vitamins (folic acid, vitamin B12 and vitamin B6) reduces homocysteine concentrations by 25–30% in healthy subjects and in patients with venous thrombosis. Until now, there are no results of clinical trials of the effect of homocysteine lowering by B-vitamins on the risk of venous thrombosis.

In the VITRO (Vitamins and Thrombosis) study, we investigated the effect of daily supplementation of 5 mg folic acid, 50 mg of pyridoxin and 0.4 mg hydroxycobalamin as secondary prevention of deep-vein thrombosis (DVT) and pulmonary embolism (PE). Patients with primary DVT or PE who were registered for out-patient treatment with an anticoagulation clinic, were asked to participate. Homocysteine was measured and information was retrieved about the diagnosis and circumstances in which patients developed their thrombosis. Patients between 20 to 80 years old with objectively confirmed proximal DVT or PE in the absence of other major risk factors for deep-vein thrombosis (surgery, pregnancy and child-bed, long-term immobility) and a homocysteine concentration in the top quartile entered the study. After informed consent they were randomised to high-dose multivitamin supplementation or placebo and were followed for 2.5 years. End-points were recurrent DVT or PE, as diagnosed by the physician of the patient. Parallel to this study a similar study was conducted in a random sample of patients in the lower three homocysteine quartiles.

Subjects were divided according to their homocysteine level in a hyperhomocysteinemic (with a homocysteine concentration in the top quartile, n=360) and a normohomocysteinemic group (a random sample of patients with a homocysteine concentration in the lower three homocysteine quartiles, n=325). The number of recurrent events of thrombosis were 43 out of 348 in the vitamin group (54/1000yr) and 50 out of 353 in the placebo group( 64/1000yr).

The relative risk associated with vitamin treatment in the hyperhomocysteinemic group was 1.14 (95%CI 0.65–1.98) and in the normohomocysteinemic group 0.58 (95%CI 0.31–1.07). The overall relative risk was 0.84 (95%CI 0.56–1.26). A baseline homocysteine above the 90th percentile was associated with an increased risk for recurrence of venous thrombosis (RR= 1.9 (95%CI 1.1 tot 3.3). This effect was independent of the treatment regimen. The results of our study does not provide evidence that homocysteine lowering by B-vitamin supplementation prevents recurrent venous thrombosis. The precision of our estimates does not allow to distinguish between ‘no effect’ or a 10 to 20% relative risk reduction. However such risk reduction would mean low absolute risk reduction and a number needed to treat of about 50. The fact that baseline homocysteine concentration is a risk factor for recurrence of thrombosis, independent of the treatment, does suggest that other factors - related to homocysteine but not folate - might be involved in the pathogenesis of recurrent thrombosis.