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(Stroke. 2005;36:144.)
© 2005 American Heart Association, Inc.

Research Reports

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

P. Dusitanond, MD; J.W. Eikelboom, MBBS; G.J. Hankey, MD, FRACP; J. Thom, BSc; G. Gilmore, BSc; K. Loh, BEd; Q. Yi, PhD; C.J.M. Klijn, MD, PhD; P. Langton, FRACP; F.M. van Bockxmeer, PhD, FAHA; R. Baker, FRACP K. Jamrozik, DPhil, FAFPHM

From the Stroke Unit (P.D., G.J.H., K.L., C.J.M.K.), Royal Perth Hospital, Perth, Australia; the School of Medicine & Pharmacology (J.W.E., G.J.H., P.L.), and School of Surgery and Pathology (F.M.v.B.), University of Western Australia; the Department of Hematology (J.W.E., J.T., G.G., R.B.), Royal Perth Hospital, Perth, Australia; the Biostatistics Department (Q.Y.), Princess Margaret Hospital, Toronto, Canada; and the Department of Biochemistry (F.M.v.B.), Royal Perth Hospital, Perth, Australia; Imperial College (K.J.), London, United Kingdom.

Correspondence to Clinical Professor Graeme J. Hankey, Consultant Neurologist and Head of Stroke Unit, Department of Neurology, Royal Perth Hospital, 197 Wellington Street, Perth, Australia 6001. E-mail gjhankey{at}cyllene.uwa.edu.au

Background 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.

Key Words: cardiovascular diseases • homocyst(e)ine • inflammation

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