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

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 Ìg) 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. Copyright © 2002 S. Karger AG, Basel Introduction Stroke is looming as an increasing public health problem [1–3]. Potential strategies for reducing the burden of stroke include primary prevention, treatment of acute stroke, and continuing care for survivors of previous stroke or transient ischaemic attacks of the brain or eye (TIA). Despite the availability of proven strategies for prevention of recurrent stroke [4], its incidence remains high – 9% (95% confidence interval, CI: 5.4–12.1%) in the first 6 months after stroke, and 23% (95% CI: 16.8– 28.1%) over 5 years [5]. Reasons include inadequate application of effective strategies of stroke prevention, and failure to recognise and treat other, as yet unknown, causal risk factors for stroke. At present, only two thirds of all episodes of ischaemic stroke can be attributed to known genetic and environmental factors [6]. There is now a large body of evidence suggesting that an elevated plasma total homocysteine concentration (tHcy) is a common and causal risk factor for atherosclerotic ischaemic stroke [7–10]. Three recent systematic reviews of observational studies [7, 9, 10] reveal an independent relationship between higher concentrations of tHcy in individuals with cerebral, coronary, and peripheral arterial disease compared Peterson et al. [29] The VITATOPS Trial Cerebrovasc Dis 2002;13:120–126 121 Table 1. Summary of the randomised trials of homocysteine-lowering therapy with vitamins on surrogate outcome measures of vascular diseasea Study (year) Population n Intervention Design Surrogate outcome Results (1998) carotid atherosclerosis; tHcy 1 14 Ìmol/l 38 folic acid + vitamin B6 + vitamin B12 uncontrolled ‘before-after’ study rate of progression of carotid plaque area vitamin therapy associated with reduction in rate of progression of plaque area Woo et al. [30] (1999) healthy volunteers; tHcy 1 75th percentile 17 folic acid vs. placebo randomized double-blind crossover trial flow-mediated EDV of the brachial artery folic acid significantly increased endotheliumdependent flow Verhaar et al. [31] (1998) FH vs. healthy matched controls 20 5-MTHF controlled observational study EDV of forearm vessels 5-MTHF: restored impaired forearm flow in FH, no effect in controls Bellamy et al. [32] (1999) healthy volunteers, tHcy 1 13 Ìmol/l 18 folic acid vs. placebo randomized double-blind crossover trial EDV of forearm vessels folic acid significantly enhances endotheliumdependent vascular function Verhaar et al. [33] (1999) FH 20 folic acid vs. placebo randomized double-blind crossover trial EDV of forearm vessels folic acid: restored endothelium-dependent flow; placebo: no effect Wilmink et al. [34] (2000) healthy volunteers 20 folic acid vs. placebo randomized double-blind trial EDV of forearm vessels following an acute fat load folic acid pre-treatment prevented lipid-induced reduction in EDV Title et al. [35] (2000) angiographic coronary artery disease; tHcy 1 9 Ìmol/l 75 placebo vs. folic acid vs. folic acid + vitamin C/E randomized double-blind trial EDV of forearm vessels folic acid alone but not folic acid plus vitamin C/E significantly improved endothelium-dependent flow Hackam et al. [36] (2000) carotid atherosclerosis 101 folic acid + vitamin B6 + vitamin B12 uncontrolled ‘before-after’ study rate of progression of carotid plaque area vitamin therapy associated with reduction in rate of progression of plaque area Vermeulen et al. [37] (2000) healthy siblings of patients with premature atherothrombotic disease 167 folic acid + B6 vs. placebo randomized double-blind trial subclinical atherosclerosis measured by exercise ECG, ABI, carotid and femoral U/S folic acid + B6 reduced rate of abnormal exercise ECG ABI = Ankle-brachial index; EDV = endothelium-dependent vasodilation; FH = familial hypercholesterolemia; 5-MTHF = 5-methyltetrahydrofolate; NO = nitric oxide; U/S = ultrasound. a Does not include studies in patients with renal failure. b Folic acid alone prior to 1996. with individuals without vascular disease. Furthermore, high tHcy is associated specifically with ischaemic stroke caused by large-artery disease, and less so small-artery disease, but not with cardio-embolic or other non-atherosclerotic causes of stroke [11]. The association between elevated tHcy and atherosclerotic disease is also dose-related, strong, biologically plausible and supported by experimental studies [12–16]. However, the results obtained by different epidemiological methods are inconsistent. In addition, the temporal relationship between the onset of elevated tHcy and the onset of stroke is unclear; the finding of a stronger association in case-control studies than cohort studies suggests that elevated tHcy may be an acute-phase reactant that rises or falls after the stroke or other vascular events in response to tissue damage or tissue repair [10, 17–20]. Furthermore, the relationship between a polymorphism in methylenetetrahydrofolate reductase (MTHFR; C677T), which is associated with high tHcy in the plasma, and increased cardiovascular risk is not clear [21, 22]. The best evidence that the epidemiological and statistical association between plasma tHcy and arterial disease is causal would come from large randomised controlled trials showing unambiguously that lowering the level of plasma tHcy leads to a reduction in the incidence of major vascular events [23]. It is possible to lower plasma tHcy by 25% (95% CI: 23–28%) with folic acid 0.5–5 mg daily, and by a further 7% (95% CI: 3–10%) with vitamin B12 0.02–1 mg daily