Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: A randomized, placebo-controlled, double-blind trial.

Randomized, double-blind, placebo-controlled multicenter trial. Participants were adults aged 20–80 years with a first objectively confirmed venous thrombosis (DVT or PE) and without major risk factors; participants were stratified by baseline homocysteine into hyperhomocysteinemic (top quartile) and normohomocysteinemic groups; recruited via anticoagulation clinics in The Netherlands, with additional Milan and Vienna centers; follow-up duration 2.5 years; primary endpoint: recurrent proximal DVT or PE.

Daily high-dose multivitamin containing 5 mg folic acid, 0.4 mg cyanocobalamin, and 50 mg pyridoxine; taken orally for 2.5 years.

Lowering homocysteine with B vitamins reduced plasma homocysteine (about 46% in hyperhomocysteinemic and 33% in normohomocysteinemic groups by 3 months) but did not reduce recurrent venous thrombosis. Intention-to-treat hazard ratio for recurrence with vitamins vs placebo was 0.84 (95% CI 0.56–1.26) overall; hyperhomocysteinemic HR 1.14 (0.65–1.98); normohomocysteinemic HR 0.58 (0.31–1.07). The authors conclude that homocysteine lowering by B vitamins lowers homocysteine but does not reduce risk of recurrent DVT/PE; effects were not statistically significant, suggesting no clear clinical benefit in this setting.

No central adjudication of recurrent DVT/PE; some recurrences occurred during anticoagulation, complicating endpoint assessment; limited power to detect modest risk reductions; post-hoc subgroup analyses; generalizability may be limited to populations without folate fortification.