Homocysteine-Lowering Therapy and Risk of Recurrent Stroke, Myocardial Infarction and Death: The Impact of Age in the VISP Trial

Background: Clinical trials have failed to show a benefit of B vitamin therapy in reducing composite outcomes of cardiovascular death, myocardial infarction, and stroke among stroke survivors with elevated total serum homocysteine (tHcy) levels. Recent post hoc analyses have shown that numerous factors including age, baseline tHcy levels, folic acid fortification of grains, B-12 status, renal function, comorbidities, and medications may modify the effect of B vitamin therapy on vascular risk in individuals with high tHcy. It remains possible that tHcy-lowering therapy may reduce cardiovascular risk in certain subgroups of stroke survivors. Post hoc subgroup analysis of the Heart Outcomes Prevention Evaluation-2 randomized controlled trial, which randomized participants with known cardiovascular disease to tHcy-lowering therapy or placebo, revealed larger treatment benefit for patients aged younger than 69 years; however, that analysis did not control for other factors. The aim of this study was to determine the effect of age on the impact of tHcy-lowering therapy for reducing vascular risk after stroke while controlling for other factors known to modify the effect of tHcy and tHcy-lowering therapy on vascular risk. Methods: In this post hoc analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial, a randomized controlled trial of tHcy lowering for secondary stroke prevention, we excluded individuals who had poor renal function (glomerular filtration rate <47; the 10th percentile) or were treated with vitamin B-12 injections. We assessed the effects of high-dose vitamin replacement on primary (stroke, myocardial infarction, or death) and secondary (stroke) outcomes, after stratifying by age (< vs. >= median age, 67 years) and adjusting for demographic and clinical factors. Results: This subgroup consisted of 2,993 individuals. Among individuals older than 67 years, high-dose vitamin therapy was associated with reduced risk of stroke, myocardial infarction or death (adjusted HR 0.76, 95% CI 0.58-0.99) and a trend towards reduced likelihood of stroke (adjusted HR 0.86, 95% CI 0.59-1.25). High-dose vitamin therapy did not impact outcomes among individuals younger than 67 years. Conclusions: In this post hoc subgroup analysis of the VISP trial, age modified the association between B vitamin therapy and recurrent vascular risk among stroke survivors with elevated serum tHcy levels. Older individuals with stroke were more likely to benefit from B vitamin therapy than younger individuals. These findings can help inform the future design of clinical trials of tHcy-lowering therapy for cardiovascular risk reduction after stroke. (C) 2014 S. Karger AG, Basel