Background and Aims: It is uncertain what impact increasing voluntary folate fortification may be having on the statistical power of randomized trials testing the homocysteine hypothesis of atherothrombosis. The objective of this study was to determine whether there has been a change in folate status between 1998 and 2002 in stroke patients randomized into the VITAmins TO Prevent Stroke (VITATOPS) Study at a single center in Perth, Australia, and what impact this may have had on the magnitude of the homocysteine-lowering effect achieved over time with folic acid-based multivitamin therapy. Methods: We conducted a randomized, double-blind, placebo-controlled study involving 285 patients with stroke or transient ischemic attack who were recruited between 1998 and 2002 and randomized to long-term folic acid 2.0 mg/day, pyridoxine 25 mg/day and cobalamin 0.5 mg/day (active VITATOPS medication) or placebo. Fasting plasma total homocysteine, red cell folate, serum cobalamin and serum pyridoxine levels were measured at baseline and 6 months, and the change in blood levels over 4 time quartiles and differences in levels between the two randomized treatments were examined. Results: Between 1998 and 2002, there was a significant rise in baseline mean red cell folate levels over 4 time quartiles among the entire stroke cohort (723.3, 780.1, 922.6 and 1,023.7 nmol/l in the first, second, third and fourth quartiles, respectively; p < 0.0001), but this was not associated with a spontaneous reduction in mean baseline total homocysteine levels during the same time period (12.7, 14.3, 12.1 and 12.8 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.55). The homocysteine-lowering effect of the active VITATOPS trial medication at 6 months after randomization also did not change significantly between 1998 and 2002 (difference between randomized groups: –4.1, –4.1, –3.1 and –3.6 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.56). Conclusions: The homocysteine-lowering effect of the active VITATOPS trial medication has not attenuated significantly in the past 5 years despite increasing voluntary fortification of foods with folic acid as reflected by a progressive rise in baseline folate status. These data suggest that in the continuing absence of a program of mandatory folate fortification of food in populations served by centers participating in the VITATOPS trial, the study will remain adequately powered to test the homocysteine-lowering hypothesis for which it was designed.

Keywords:
Randomized trial, Homocysteine, Folate, Pyridoxine, Cobalamin, Fortification
1.
Satchell FB, for the Food and Drug Administration, Health and Human Services: Food standards: Amendments of standards of identity for enriched grain products to require addition of folic acid. Federal Register 1996;61:8781–8797.
2.
Hankey GJ, Eikelboom JW: Homocysteine and vascular disease. Lancet 1999;354:407–413.
3.
Eikelboom JW, Lonn E, Genest J Jr, Hankey GJ, Yusuf S: Homocyst(e)ine and cardiovascular disease. A critical review of the epidemiological evidence. Ann Intern Med 1999;131:363–375.
4.
Spence JD, Howard VJ, Chambless LE, Malinow MR, Pettigrew LC, Stampfer M, Toole JF, for the VISP Investigators: Vitamin Intervention for Stroke Prevention (VISP) Trial: Rationale and design. Neuroepidemiology 2001;20:16–25.
5.
Bostom AG, Selhub J, Jacques PF, Rosenberg IH: Power shortage: Clinical trials testing the ‘homocysteine hypothesis’ against a background of folic acid-fortified cereal grain flour. Ann Intern Med 2001;135:1333–1137.
6.
Toole JF, Malinow R, Chambless L, Spence JD, Pettigrew LC, Howard VJ, Sides EG, Wang C-H, Stampfer M: Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death. The Vitamin Intervention for Stroke Prevention (VISP) randomised controlled trial. JAMA 2004;291:565–575.
7.
The VITATOPS Trial Study Group: The VITATOPS (VITAmins TO Prevent Stroke) trial: Rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis 2002;13:120–126.
8.
Hankey GJ, Eikelboom JW, Loh K, Yi Q, Pizzi J, Tang M, Hickling S, Le M, Klijn CJM, Dusitanond P, van Bockxmeer F, Gelavis A, Baker R, Jamrozik K: Is there really a power shortage in clinical trials testing the ‘homocysteine hypothesis’? Preliminary results from the VITAmins TO Prevent Stroke (VITATOPS) trial. Arterioscler Thromb Vasc Biol 2004;24:e147.
9.
Homocysteine Lowering Trialists’ Collaboration: Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. BMJ 1998;316:894–898.
10.
The Homocysteine Studies Collaboration: Homocysteine and risk of ischemic heart disease and stroke. A meta-analysis. JAMA 2002;288:2015–2022.
11.
Wald DS, Law M, Morris JK: Homocysteine and cardiovascular disease: Evidence on causality from a meta-analysis. BMJ 2002;325:1202–1208.
12.
Ubbink JB, Hayward Vermaak WJ, Bissbort S: Rapid high-performance liquid chromatographic assay for total homocysteine levels in human serum. J Chromatogr 1991;565:441–446.
13.
Davis RE, Smith BK, Curnow DH: An automated method for the microbiological assay of serum pyridoxal. J Clin Pathol 1973;23:232–242.
© 2005 S. Karger AG, Basel
2005
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