Published Online
on November 29, 2004

A more recent version of this article appeared on January 1, 2005

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Submitted on July 8, 2004
Revised on September 7, 2004
Accepted on September 10, 2004

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; and 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.

^* To whom correspondence should be addressed. 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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