Homocysteine, B-vitamin supplementation, and stroke prevention: from observational to interventional trials

Homocysteine is an amino acid, the metabolism of which is linked to that of several vitamins-especially folic acid, B6, and B12. A high concentration of homocysteine in the plasma is linked to vascular disease, including stroke. Concentrations of homocysteine can be inexpensively and safely lowered by treatment with a combination of folate, vitamin B12, and vitamin B6. However, whether the association between high plasma concentrations of homocysteine and vascular disease is causal is unclear.

Two studies have assessed the relation between dietary or supplementary B vitamin intake on the risk of stroke. In a prospective observational study of 43?732 healthy men, there was an inverse relation between dietary folate intake and the risk of ischaemic stroke. The Vitamin Intervention for Stroke Prevention study (VISP) was the first large-scale randomised interventional study that investigated the lowering of homocysteine concentrations with B vitamins in patients with ischaemic stroke. There was an association between baseline homocysteine concentrations and vascular risk in this trial. Plasma concentrations of homocysteine were only modestly reduced by high-dose versus low-dose formulation, and there was no treatment effect on recurrent stroke, coronary events, or deaths. Limitations of VISP included that only patients with mild increases in baseline homocysteine concentrations were studied, only modest reductions of homocysteine concentrations were achieved, and follow up was short. In addition, fortification of food with folate and treatment of low vitamin-B12 concentrations may have masked the effect of treatment on stroke risk. WHAT NEXT?: When exposure can be safely assigned at random, as in the case of B-vitamin therapy, randomised trials should be the standard proof to determine the effect of therapy. The results of the first randomised clinical trial of B vitamins for secondary prevention of stroke were neutral. Larger trials with longer follow-up, selection of patients with higher plasma concentrations of homocysteine, and systematic assessment of cognitive functions and dementia are needed. In the meantime, homocysteine-lowering treatment that is cheap and well-tolerated should be considered a rational approach in patients at high risk of stroke and high concentrations of homocysteine.