Homocysteine lowering for stroke prevention: Unravelling the complexity of the evidence

Elevated levels of total homocysteine impair endothelial dysfunction and increase thrombosis. Homocysteine is causal in animal models, and in human studies, elevated total homocysteine is significantly associated with carotid atherosclerosis, lacunar infarction, and markedly increased risk of stroke in atrial fibrillation. Because two of the early large trials of B vitamin therapy (Vitamin Intervention for Stroke Prevention and the Norwegian Vitamin Study) did not show any reduction of stroke, and the Heart Outcomes Prevention Evaluation 2 trial was mistakenly interpreted as not showing a reduction of stroke (because the authors could not think of a biological difference between stroke and myocardial infarction), there has been widespread pessimism regarding treatment to lower total homocysteine for stroke prevention. However, the Heart Outcomes Prevention Evaluation 2 trial, the French trial of folic acid and omega three oils, the Vitamins to Prevent Stroke subgroup excluding antiplatelet therapy all showed a significant reduction of stroke. Reasons why the Vitamin Intervention for Stroke Prevention trial were negative included folate fortification in North America, provision of injections of B12 to patients with low baseline serum B12, and as it turns out, harm from cyanide in cyanocobalamin among participants with impaired renal function. In the Diabetic Intervention with Vitamins in Nephropathy trial, B vitamins including cyanocobalamin were harmful, and in a Vitamin Intervention for Stroke Prevention subgroup excluding participants who received B12 injections and those with impaired renal function, there was a statistically significant reduction of stroke/myocardial infarction/vascular death. In 2015, the China Stroke Primary Prevention Trial (CSPPT), in over 20,000 participants followed for 5 years, showed a significant reduction of stroke with folic acid in a setting where folate fortification has not been implemented. In the setting of folate fortification, the main causes of elevated total homocysteine are renal failure and metabolic B12 deficiency; the latter is very common among stroke patients (30% over age 71), and frequently missed. Serum B12 and total homocysteine should be checked routinely in stroke patients and elevated total homocysteine should be treated.