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. 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 multivitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. Purpose: To determine whether vitamin supplements (folic acid 2 mg, B6 25 mg, B12 500 µg) reduce the risk of stroke, and other serious vascular events, in patients with recent stroke or transient ischaemic attacks of the brain or eye (TIA). Methods: An international, multi-centre, randomised, double-blind, placebo-controlled clinical trial. Results: As of November 2001, more than 1,400 patients have been randomised from 10 countries in four continents. Conclusion: VITATOPS aims to recruit and follow up 8,000 patients between 2000 and 2004, and provide a reliable estimate of the safety and effectiveness of dietary supplementation with folic acid, vitamin B12, and vitamin B6 in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke.

Keywords:
Homocysteine, Multivitamins, Stroke, Transient ischaemic attack, VITATOPS Trial
1.
Murray CJL, Lopez AD: Mortality by cause for eight regions of the world. Global Burden of Disease Study. Lancet 1997;349:1269–1276.
2.
Murray CJL, Lopez AD: Global mortality, disability and the contribution of risk factors. Global Burden of Disease Study. Lancet 1997;349:1436–1442.
3.
Hankey GJ: Stroke: How large a public health problem and how can the neurologist help? Arch Neurol 1999;56:748–754.
4.
Hankey GJ, Warlow CP: Treatment and secondary prevention of stroke: Evidence, costs, and effects on individuals and populations. Lancet 1999;354:1457–1463.
5.
Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, Stewart-Wynne EG: Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998;29:2491–2500.
6.
Whisnant JP: Modeling of risk factors for ischemic stroke. The Willis Lecture. Stroke 1997;28:1839–1843.
7.
Danesh J, Lewington S: Plasma homocysteine and coronary heart disease: Systematic review of published epidemiological studies. J Cardiovasc Risk 1998;5:229–232.
8.
Hankey GJ, Eikelboom JW: Homocysteine and vascular disease. Lancet 1999;354:407–413.
9.
Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S: Homocyst(e)ine and cardiovascular disease: A critical review of the epidemiologic evidence. Ann Intern Med 1999;131:363–375.
10.
Christen WG, Ajani UA, Glynn RJ, Hennekens CH: Blood levels of homocysteine and increased risks of cardiovascular disease: Causal or casual? Arch Intern Med 2000;160:422–434.
11.
Eikelboom JW, Hankey GJ, Anand SS, Lofthouse E, Staples N, Baker RI: Association between high homocyst(e)ine and ischaemic stroke due to large- and small-artery disease but not other etiological subtypes of ischaemic stroke. Stroke 2000;31:1069–1075.
12.
Boger RH, Bode-Boger SM, Sydow K, Heistad DD, Lentz SR: Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia. Arterioscler Thromb Vasc Biol 2000;20:1557–1564.
13.
Outinen PA, Sood SK, Pfeifer SI, et al: Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 1999;94:959–967.
14.
Khajuria A, Houston DS: Induction of monocyte tissue factor expression by homocysteine: A possible mechanism for thrombosis. Blood 2000;96:966–972.
15.
Harpel PC, Chang VT, Borth W: Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: A potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci USA 1992;89:10193–10197.
16.
Bostom AG, Culleton BF: Hyperhomocysteinemia in chronic renal disease. J Am Soc Nephrol 1999;10:891–900.
17.
Dudman NP: An alternative view of homocysteine. Lancet 1999;354:2072–2074.
18.
Meiklejohn DJ, Vickers MA, Dijkhuisen R, Greaves M: Plasma homocysteine concentrations in the acute and convalescent periods of atherothrombotic stroke. Stroke 2001;32:57–62.
19.
Lindgren A, Brattstron L, Norrving B, Hultberg B, Andersson A, Johansson BB: Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 1995;26:795–800.
20.
Egerton W, Silberberg J, Crooks R, Ray C, Xie L, Dudman N: Serial measures of plasma homocyst(e)ine after acute myocardial infarction. Am J Cardiol 1996;77:759–761.
21.
Van Bockxmeer F, Mamotte CD, Vasikaran SD, Taylor RR: Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation 1997;95:21–23.
22.
Brattstrom L, Wilcken DE, Ohrvik J, Brudin L: Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not vascular disease: The results of a meta-analysis. Circulation 1998;98:2520–2526.
23.
Hill AB: The environment and disease: Association or causation. Proc R Soc Med 1965;58:295–300.
24.
Homocysteine Lowering Trialist’s Collaboration: Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. BMJ 1998;316:894–898.
25.
Bostom AG, Gohh RY, Beaulieu AJ, Nadeau MR, Hume AL, Jacques PF, Selhub J, Rosenberg IH: Treatment of hyperhomocysteinaemia in renal transplant recipients. Ann Intern Med 1997;127:1089–1092.
26.
Franken DG, Boers GHJ, Blom HJ, Trijbels FJ, Kloppenborg PW: Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb 1994;14:465–470.
27.
van den Berg M, Franken DG, Boers GHJ: Combined vitamin B6 plus folate therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vasc Surg 1994;20:933–940.
28.
Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ: Vitamin B-12, vitamin B-6 and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993;57:47–53.
29.
Peterson JC, Spence JD: Vitamins and progression of atherosclerosis in hyper-homocyst(e)- inaemia (letter). Lancet 1998;351:263.
30.
Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS: Folic acid improves arterial endothelial function in adults with hyperhomocysteinemia. J Am Coll Cardiol 1999;34:2002–2006.
31.
Verhaar MC, Wever RMF, Kastelein JJP, van Dam T, Koomans HA, Rabelink TJ: 5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 1998;97:237–241.
32.
Bellamy MF, McDowell IFW, Ramsey MW, Brownlee M, Newcombe RG, Lewis MJ: Oral folate enhances endothelial function in hyperhomocysteinaemic subjects. Eur J Clin Invest 1999;29:659–662.
33.
Verhaar MC, Wever RMF, Kastelein JJP, et al: Effects of oral folic acid supplementation on endothelial function in familial hypercholesterolemia. A randomized placebo-controlled trial. Circulation 1999;100:335–338.
34.
Wilmink HW, Stroes ES, Erkelens WD, et al: Influence of folic acid on postprandial endothelial dysfunction. Arterioscler Thromb Vasc Biol 2000;20:185–188.
35.
Title LM, Cummings PM, Giddens K, Genest JJ, Nassar BA: Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000;36:758–765.
36.
Hackam DG, Peterson JC, Spence JD: What levels of plasma homocyst(e)ine should be treated? Effect of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/l. Am J Hypertens 2000;13:105–110.
37.
Vermeulen EGJ, Stehouwer CDA, Twisk JWR, et al: Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: A randomised, placebo-controlled trial. Lancet 2000;355:517–522.
38.
Spence JD, Howard VJ, Chambless LE, Malinow MR, Pettigrew LC, Stampfer M, Toole JF: Vitamin Intervention for Stroke Prevention (VISP) trial: rationale and design. Neuroepidemiology 2001;20:16–25.
39.
VITAmins TO Prevent Stroke (VITATOPS): Major Ongoing Stroke Trials. Stroke 2000;31:561–562.
40.
Warlow CP, Dennis MS, van Gijn J, Hankey GJ, Sandercock PAG, Bamford J, Wardlaw J: Stroke. A Practical Guide to Management, ed 2. Oxford, Blackwell Scientific, 2000.
41.
Dagnan D, Chadwick P, Trower P: Psychometric properties of the Hospital Anxiety and Depression Scale with a population of members of a depression self-help group. Br J Med Psychol 2000;73:129–137.
42.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-Mental State’: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–198.
43.
CAPRIE Steering Committee: A randomised blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339.
44.
Fassbender K, Mielke O, Bertsch T, Nafe B, Fröschen S, Hennerici M: Homocysteine in cerebral macroangiopathy and microangiopathy. Lancet 1999;353:1586–1587.
45.
Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung H-P: MRI white matter hyperintensities. Three-year follow-up of the Austrian Stroke Prevention Study. Neurology 1999;53:132–139.
46.
Genest JJ, Audelin MC, Lonn E: Homocysteine: To screen and treat or to wait and see? CMAJ 2000;163:37–38.
47.
Malinow MR, Bostom AG, Krauss RM: Homocyst(e)ine, diet, and cardiovascular diseases. A statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178–182.
© 2002 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.