The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis.
BACKGROUND
Experimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown.


METHODS
We conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD.


RESULTS
After a mean treatment period of 3.9 +/- 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 micromol/L, 95% CI 7.5 to 8.4 versus 11.8 micromol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 +/- 0.17 mm vitamins versus 0.83 +/- 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials.


CONCLUSIONS
Although short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.
Potter
Kathleen
K
School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. pottek04@cyllene.uwa.edu.au
Hankey
Graeme J
GJ
Green
Daniel J
DJ
Eikelboom
John
J
Jamrozik
Konrad
K
Arnolda
Leonard F
LF
D000368:Aged; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D019587:Dietary Supplements; D004311:Double-Blind Method; D015536:Down-Regulation; D004338:Drug Combinations; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012039:Regional Blood Flow; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D017540:Tunica Media / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects*; D014805:Vitamin B 12 / Q000627:therapeutic use; D025101:Vitamin B 6 / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use*
D004338:Drug Combinations; D006710:Homocysteine; D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12