Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous transient ischemic attack or stroke: A randomized substudy of the VITATOPS trial

Published online before print November 29, 2004Background and Purpose— Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine (total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. Methods— We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B12 0.5 mg, and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. Results— At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P=0.32]; soluble CD40L [P=0.33]; IL-6 [P=0.77]), endothelial dysfunction (vascular cell adhesion molecule-1 [P=0.27]; intercellular adhesion molecule-1 [P=0.08]; von Willebrand factor [P=0.92]), and hypercoagulability (P-selectin [P=0.33]; prothrombin fragment 1 and 2 [P=0.81]; D-dimer [P=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-µmol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). Conclusions— Lowering tHcy by 3.7 µmol/L with folic acid-based multivitamin therapy does not significantly reduce blood concentrations of the biomarkers of inflammation, endothelial dysfunction, or hypercoagulability measured in our study. The possible explanations for our findings are: (1) these biomarkers are not sensitive to the effects of lowering tHcy (eg, multiple risk factor interventions may be required); (2) elevated tHcy causes cardiovascular disease by mechanisms other than the biomarkers measured; or (3) elevated tHcy is a noncausal marker of increased vascular risk.P. Dusitanond, J.W. Eikelboom, G.J. Hankey, J. Thom, G. Gilmore, K. Loh, Q. Yi, C.J.M. Klijn, P. Langton, F.M. van Bockxmeer, R. Baker and K. Jamrozi

Is there really a power shortage in clinical trials testing the "homocysteine hypothesis?".

G.J. Hankey, J.W. Eikelboom, K. Loh, Q. Yi, J. Pizzi, M. Tang, S. Hickling, M. Le, C.J. M. Klijn, P. Dusitanond, F. van Bockxmeer, A. Gelavis, R. Baker and K. Jamrozi

VITATOPS, the VITAmins TO Prevent Stroke Trial: Rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444)

Background Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B12 and vitamin B6, it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. Aim To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B6 25 mg, B12 500 μg) to best medical and surgical management will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. Design A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial. Setting One hundred and four medical centres in 20 countries on five continents. Subjects Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye). Randomisation Randomisation and data collection are performed by means of a central telephone service or secure internet site. Intervention One tablet daily of either placebo or B vitamins (folic acid 2mg, B6 25 mg, B12 500 μg). Primary outcome The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. Secondary outcomes TIA, unstable angina, revascularisation procedures, dementia, depression. Statistical power With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6·8%/year), applying a two-tailed level of significance of 5%. Conclusion VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008, and provide a reliable estimate of the safety and effectiveness of folic acid, vitamin B12, and vitamin B6 supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world. The VITATOPS Trial Study Grou