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.
OBJECTIVE
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-micromol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy).


CONCLUSIONS
Lowering tHcy by 3.7 micromol/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.
Dusitanond
P
P
Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Australia.
Eikelboom
J W
JW
Hankey
G J
GJ
Thom
J
J
Gilmore
G
G
Loh
K
K
Yi
Q
Q
Klijn
C J M
CJ
Langton
P
P
van Bockxmeer
F M
FM
Baker
R
R
Jamrozik
K
K
D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D002318:Cardiovascular Diseases / Q000209:etiology; D004730:Endothelium, Vascular / Q000378:metabolism; D005492:Folic Acid / Q000627:therapeutic use; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000097:blood; D002546:Ischemic Attack, Transient / Q000097:blood* / Q000188:drug therapy; D011736:Pyridoxine / Q000627:therapeutic use; D012307:Risk Factors; D020521:Stroke / Q000097:blood* / Q000188:drug therapy; D014805:Vitamin B 12 / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use*
D015415:Biomarkers; D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid; D011736:Pyridoxine; D014805:Vitamin B 12