It is said that we are what we eat. It is advertised that

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1 Topical Reviews Vitamin Supplementation and Stroke Prevention Graeme J. Hankey, MD, FRCP, FRCP Edin, FRACP It is said that we are what we eat. It is advertised that vitamin supplements, of one kind or another, may invigorate us, our lives, and our health. Advertising has been so effective that in the year 2000, more than half of the adult population in the United States was taking dietary vitamin supplements. 1 This review examines the evidence linking vitamin supplementation with the incidence and prevention of stroke. Search Strategy and Selection Criteria References for this review were identified by searches of the PubMed database from 1970 until February 2012 using the following search terms: vitamins, antioxidants, folic acid, B-vitamins, vitamin C, vitamin D, vitamin E, diet, nutrition, stroke, prospective cohort study, randomized controlled trial (RCT), systematic review, and meta-analysis. Articles were also identified through searches of reference lists and my own files. Studies were selected for inclusion on the basis of a judgment about the quality of the evidence according to 4 key elements: study design, study quality, consistency, and directness, as proposed by the Grading of Recommendations Assessment, Development and Evaluating (GRADE) working group ( 2,3 For each vitamin, the studies with the highest level of evidence based on the GRADE criteria 2 were included. Only articles published in English were included. Antioxidant Vitamins The oxidative modification hypothesis of atherosclerosis is that oxidation of low-density lipoprotein cholesterol (lipid peroxidation) allows it to accumulate in artery walls and promote atherosclerosis. 4 This has prompted several studies of the effect of reducing oxidative stress by means of antioxidant vitamins (beta-carotene; vitamins A, C, and E) in preventing stroke. Vitamin A and Beta-Carotene Beta-carotene is a fat-soluble antioxidant and the biologically active metabolite of vitamin A. A meta-analysis of 3 randomized controlled trials (RCTs) of beta-carotene in a total of participants showed no effect of beta-carotene on the rate of stroke compared with control (OR, 1.0; 95% CI, ; P 0.92; Table 1). 5 Moreover, beta-carotene was associated with an increased risk of cardiovascular mortality (OR, 1.10; 95% CI, ; P 0.003) and all-cause mortality (OR, 1.07; 95% CI, ; P 0.003). 5 These data suggest that use of vitamin supplements containing beta-carotene and vitamin A should be actively discouraged because this family of agents is associated with a small but significant excess of cardiovascular and all-cause mortality. Vitamin C Vitamin C is a water-soluble antioxidant in plasma that helps regenerate oxidized vitamin E. Large observational epidemiological studies suggest that increasing plasma vitamin C concentrations are associated with a reduced risk of stroke. 6 8 A population-based prospective study of British men and women aged 40 to 79 years without prevalent stroke who were assessed during 1993 to 1997 and followed up for person-years (average 9.5 years) for the occurrence of 448 incident stroke showed that persons in the top quartiles of baseline plasma vitamin C concentration had a 42% lower risk (relative risk, 0.58; 95% CI, ) than did those in the bottom quartile independently of age, sex, smoking, body mass index, systolic blood pressure, cholesterol, physical activity, prevalence of diabetes and myocardial infarction, social class, alcohol consumption, and any supplement use. 7 More recent supportive evidence comes from a large observational study of Japanese men and women aged 40 to 79 years without a history of cardiovascular disease who were followed for a median period of 16.5 years for the occurrence of 1227 deaths from stroke. The multivariable hazard ratio for the highest versus lowest quintile of vitamin C intake was 0.70 (95% CI, ) for total stroke. 8 However, observational studies cannot eliminate bias and confounding (Table 2). 9,10 Three large RCTs, which minimize bias and confounding, have shown no effect of vitamin C on stroke risk The Heart Protection Study randomly assigned adults with prior stroke, coronary disease, other occlusive arterial disease, or diabetes to receive antioxidant vitamin supplementation (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) or matching placebo. 11 After 5 Received February 13, 2012; final revision received April 2, 2012; accepted April 3, From the Stroke Unit, Department of Neurology, Royal Perth Hospital, Perth, Western Australia; and the School of Medicine & Pharmacology, University of Western Australia, Australia. Correspondence to Graeme J. Hankey, MD, FRCP, FRCP Edin, FRACP, Consultant Neurologist and Head of Stroke Unit, Department of Neurology, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia, gjhankey@cyllene.uwa.edu.au (Stroke. 2012;43: ) 2012 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Hankey Vitamins and Stroke 2815 Table 1. Summary of the Effects of Vitamin Supplementation on Stroke Prevention Vitamin Evidence Effect on Stroke Rate Versus Control Beta-carotene A OR, 1.0; 95% CI, Vitamin C B RR, 0.86; 95% CI, B HR, 1.07; 95% CI, Vitamin E A RR, 1.01; 95% CI, Folic acid A RR, 0.96; 95% CI, Niacin A OR, 0.74; 95% CI, B HR, 1.61; 95% CI, Vitamin D A RR, % CI, A indicates meta-analysis of randomized controlled trials; B, single large randomized controlled trial; RR, rate ratio; HR, hazard ratio. years, the plasma concentration of vitamin C increased by one third among those assigned vitamins but there was no significant difference in stroke (5.0% vitamins versus 5.0% placebo) or any major vascular events (22.5% versus 22.5%; rate ratio, 1.00, 95% CI, ). 11 The Women s Antioxidant Cardiovascular Study randomly assigned 8171 female health professionals aged 40 years with a history of cardiovascular disease or 3 cardiovascular disease risk factors in a factorial design to ascorbic acid (500 mg/day), vitamin E (600 IU every other day), and beta-carotene (50 mg every other day) or placebo. 12 After 9.4 years (mean) follow-up, there was no effect of ascorbic acid (relative risk [RR], 0.86; 95% CI, ; Table 1), vitamin E (RR, 0.84; 95% CI, ), or beta-carotene (RR, 1.17; 95% CI, ) on the risk of stroke compared with placebo. 12 The Physicians Health Study II randomly assigned US male physicians aged 50 years in a 2 2 factorial trial to 400 IU of vitamin E every other day and/or 500 mg of vitamin C daily versus placebo. 13 After a mean follow-up of 8 years, Table 2. Limitations of Observational Epidemiological Studies in Unraveling the Relationship Between Vitamin D and Stroke Confounding Several factors are associated with both a low vitamin D and a high risk of stroke. For example, low socioeconomic status, cigarette smoking, physical inactivity, obesity. If these factors are not recorded, not measured, or measured inaccurately, statistical models will fail to appropriately adjust for their effect on the interaction between vitamin D and risk of stroke. Bias: Reverse causality The effects of a stroke may subsequently lead to a lower vitamin D concentration in the blood. For example, acute stroke may result in acute inflammation, which can reduce vitamin D. For example, stroke may cause a disability such as hemiparesis that restricts outdoor activity and therefore exposure to sunlight, which is a key determinant of vitamin D concentration. Bias: Publication and citation Studies with null or negative results are less likely to be published and cited than studies with positive results, particularly if there is an anticipation or perception of a positive association. there was no significant effect of vitamin C on the incidence of stroke (hazard ratio, 1.07; 95% CI, ; Table 1). 13 These data do not support the use of vitamin C supplements for the prevention of stroke in middle-aged and older women and men. Vitamin E Vitamin E is a lipid-soluble antioxidant which increases resistance of low-density lipoprotein cholesterol to oxidation, reduces smooth muscle cell proliferation, and reduces adhesiveness of platelets to collagen. It inhibits lipid peroxidation by scavenging reactive oxygen species and preserving cell membranes. 14 A systematic review of RCTs investigating the effect of vitamin E on stroke with 1 years of follow-up and published before January 2010 included 9 trials in which a total of participants were randomized to vitamin E (n ) or placebo (n ). Among the 7 trials that reported data for total stroke, vitamin E had no effect on the risk of incident total stroke compared with placebo (RR, 0.98; 95% CI, ). 15 However, among the 5 trials that reported hemorrhagic and ischemic stroke, vitamin E was associated with an increased risk of incident hemorrhagic stroke (0.44% vitamin E versus 0.36% placebo; RR, 1.22; 95% CI, ; P 0.045) and a reduced risk of ischemic stroke (1.94% vitamin E versus 2.16% placebo; RR, 0.90; 95% CI, ; P 0.02). 15 A subsequent meta-analysis of 13 RCTs of vitamin E in participants showed no significant benefit of vitamin E in the prevention of stroke of any type (RR, 1.01; 95% CI, ; Table 1), ischemic stroke (RR, % CI, ), or hemorrhagic stroke (RR, 1.12; 95% CI, ). 16 There was no significant heterogeneity among the trials (P for heterogeneity 0.37). The results were consistent irrespective of vitamin E source (natural versus synthetic), vitamin E dose ( or 200 IU/day), and baseline health status. 16 The discrepancy in findings for the effect of vitamin E on the pathological subtypes of stroke in both meta-analyses 15,16 may reflect the inclusion in the updated meta-analysis of 6 additional trials, longer follow-up data from one shared trial, and perhaps (although not stated) recurrent as well as incident strokes. 16 Overall, these data provide no support for the use of vitamin E supplements to prevent stroke. B Vitamins Folic Acid and Vitamin B 12 Randomized trials indicate that folic acid supplementation lowers plasma total homocysteine concentrations (thcy) by approximately 25% (95% CI, 23% 28%) and vitamin B 12 supplementation lowers thcy by approximately 7% (95% CI, 3% 10%). 17 Lowering thcy is associated with a lower risk of total stroke and lower risk of ischemic stroke due to large artery disease, small artery disease, and embolism from the heart, independent of other factors

3 2816 Stroke October 2012 However, a meta-analysis of RCTs of folic acid supplementation in patients showed a lack of effect of folic acid on all stroke (RR, 0.96; 95% CI, ; Table 1). 22 A subsequent meta-analysis of 237 genetic epidemiological studies, in which the dietary folate status, thcy, and the presence of the methylene tetrahydrofolate reductase C677T polymorphism of individuals were correlated with stroke events, predicted a lack of effect of lowering thcy in preventing stroke in regions with established or increasing folate intake, as observed in the RCTs. 23 However, the genetic studies also predicted that lowering thcy by 3.8 mol/l would reduce the rate of stroke by 22% (95% CI, 10% 32%) in regions of low folate intake (eg, Asia). 23 Because there have been no large RCTs of folic acid and vitamin B 12 supplementation in regions of low folate and B 12 intake such as Asia, it is uncertain whether supplementation or fortification of food with folic acid and vitamin B 12 in folate-deplete regions would prevent stroke. Among folate-replete individuals, vitamin B 12 is an important determinant of thcy. Subclinical metabolic vitamin B 12 deficiency, defined by elevation of plasma methylmalonic acid and reduction in serum vitamin B pmol/l, is not uncommon, particularly in the elderly. 24 Subgroup analyses from RCTs raise the hypothesis that higher doses of vitamin B 12 (such as 1 mg daily, as used successfully for stroke prevention in the Heart Outcomes Prevention Evaluation [HOPE] 2 trial 25 ) may substantially lower thcy and risk of stroke, particularly in people who are folate-replete but vitamin B 12 -deficient This hypothesis requires confirmation in clinical trials. Niacin (Vitamin B 3, Nicotinic Acid) Niacin increases high-density lipoprotein cholesterol by up to 20% and decreases low-density lipoprotein cholesterol and lipoprotein(a) plasma concentrations. A systematic review and meta-analysis of 11 RCTs of niacin alone, or in combination with other lipid-lowering drugs, published between January 1966 and August 2008 reported that among 2682 patients who were randomly allocated to niacin (1 3 g/day), there was a significantly reduced rate of stroke (OR, 0.74; 95% CI, ; Table 1), major coronary events (OR, 0.75; 95% CI, ), and any cardiovascular events (0.73; 95% CI, ) compared with 3934 assigned control subjects. 31 Many of these studies were conducted before statin therapy became standard care however. A more recent trial randomly assigned 3414 patients aged 45 years with established cardiovascular disease (including cerebrovascular and carotid disease) and low baseline levels of high-density lipoprotein cholesterol to receive extendedrelease niacin, 1500 to 2000 mg per day (n 1718), or placebo (n 1696). 32 All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an low-density lipoprotein cholesterol level of 40 to 80 mg/dl ( mmol/l). After a mean follow-up of 3 years, niacin therapy significantly increased high-density lipoprotein cholesterol, lowered triglycerides, and lowered low-density lipoprotein cholesterol concentrations in the blood but was associated with a trend toward an increase in ischemic stroke (1.7% niacin versus 1.1% placebo; hazard ratio, 1.61; 95% CI, ; P 0.11) and with no effect on the composite primary cardiovascular end point (16.4% niacin versus 16.2% placebo; hazard ratio, 1.02; 95% CI, ; P 0.79 by the log-rank test). 32 The results of an ongoing trial of niacin in patients with stable cardiovascular disease, the HPS2-THRIVE (Heart Protection Study-Treatment of High density lipoprotein to Reduce the Incidence of Vascular Events; NCT ), is awaited. Vitamin D Vitamin D deficiency has been associated with obesity, diabetes mellitus, dyslipidemia, endothelial dysfunction, hypertension, cardiovascular disease, and stroke in epidemiological studies A recent meta-analysis of 7 prospective studies that examined 25-hydroxyvitamin D levels in relation to the occurrence of stroke in 1214 individuals reported that low 25-hydroxyvitamin D levels were associated with an increased risk of stroke in comparison to high levels (pooled RR, 1.52; 95% CI, ). 36 However, epidemiological studies have limitations (Table 2), which can be minimized in RCTs. 9,10 Effect of Vitamin D Supplementation on Blood Pressure A meta-analysis of 10 RCTs of vitamin D ( IU/day) calcium on blood pressure in participants showed that random assignment to vitamin D was associated with no significant reduction in systolic blood pressure (weighted mean difference, 1.9; 95% CI, 4.2 to 0.4 mm Hg). 34 Effect of Vitamin D Supplementation on Markers of Vascular Health High-dose oral vitamin D supplementation produced shortterm improvement in endothelial function in one small RCT of 58 patients with stroke with baseline 25-hydroxyvitamin D levels 75 nmol/l (mean, 38 nmol/l). 37 Random allocation to receive U of oral vitamin D 2 or placebo realized higher flow-mediated dilatation in the intervention group at 8 weeks (6.9% versus 3.7%, adjusted P 0.007) but no significant difference at 16 weeks. 37 Effect of Vitamin D Supplementation on Cardiovascular Events A meta-analysis of 2 RCTs showed that vitamin D supplementation at moderate to high doses (approximately 1000 IU/day) was associated with no significant effect on cardiovascular events compared with placebo (RR, 0.90; 95% CI, ). 35 There was also no significant effect of supplementation with vitamin D plus calcium on cardiovascular events compared with placebo (RR, 1.04; 95% CI, ). 35 A broader systematic review involving 51 RCTs of low to moderate quality that were published before August 2010 reported that vitamin D supplementation was associated with no significant effect on stroke (RR, 1.05; 95% CI, ; P 0.59; Table 1), myocardial infarction (RR, 1.02; 95% CI, ; P 0.64), or death (RR, 0.96; CI, ; P 0.08). 38 Vitamin D was also associated with no significant changes in surrogate outcomes of lipid fractions, glucose, or systolic or diastolic blood pressure. 38

4 Hankey Vitamins and Stroke 2817 These data, from systematic reviews of earlier RCTs, are supported by the recently published Randomized Evaluation of Calcium Or vitamin D (RECORD) trial in which 5292 people (85% women) aged at least 70 years with previous low-trauma fracture were randomly assigned, in a 2 2 factorial trial, to daily vitamin D 3 (800 IU), calcium (1000 mg), both, or placebo for 24 to 62 months with a follow-up of 3 years after intervention. 39 Compared with participants who were not allocated vitamin D, those allocated to vitamin D had no significant difference in cerebrovascular disease mortality (4.3% with vitamin D 3 versus 3.97% without vitamin D 3 ), vascular mortality (hazard ratio, 0.91; 95% CI, ), or all-cause mortality (hazard ratio, 0.93; 95% CI, ). 39 Effect of Vitamin D Supplementation on Mortality A meta-analysis of 50 RCTs of supplemental vitamin D, administered for a median of 2 years, involving participants (predominantly elderly women who were mainly in institutions and dependent care) showed that vitamin D decreased mortality (11.1% vitamin D versus 11.4% control; RR, 0.97, 95% CI, ; I 2 0%). 40 When the different forms of vitamin D were assessed separately, only vitamin D 3 (cholecalciferol) decreased mortality significantly (9.8% versus 10.4%; RR, 0.94, 95% CI, ; I 2 0%; participants, 32 trials), whereas vitamin D 2 (ergocalciferol), alfacalcidol, or calcitriol did not. 40 Vitamin D 3 did not lower cardiovascular mortality (2.9% versus 3.0%; RR, 0.98; ). Vitamin D 3 combined with calcium increased the risk of nephrolithiasis (RR, 1.17; 95% CI, ; I 2 0%). 40 Effect of Vitamin D Supplementation on Stroke There is no reliable evidence from RCTs to support or refute a causal association between vitamin D status and stroke. The VITamin D and OmegA-3 trial (VITAL) is currently randomizing people to receive 2000 IU of vitamin D 3 (cholecalciferol) per day or placebo as well as 1 g of marine omega-3 fatty acids per day or placebo for 5 years. 41 The primary outcome of the study is total cancer and major cardiovascular events (a composite of myocardial infarction, stroke, and death due to cardiovascular events). 41 Conclusion Many studies have explored the association between exposure to one or more vitamin supplements and the risk of stroke. Few have minimized bias and confounding by random, double-blind allocation of the vitamin supplements, and few have been large enough and long enough to accumulate sufficient stroke outcome events to minimize random error. Among the relatively few studies that have been large RCTs with prolonged follow-up, most have reported stroke as a single outcome without distinguishing first-ever from recurrent stroke and without distinguishing pathological and etiologic subtypes of stroke. At present, there is sufficient evidence from meta-analyses of large RCTs to reliably conclude that dietary supplementation with the antioxidant vitamins beta-carotene, vitamin C, and vitamin E does not prevent stroke. There is also reliable evidence that supplementation with folic acid and vitamin B 12 does not prevent stroke in populations with established or increasing intake of folate and vitamin B 12. It remains uncertain, however, whether supplementation with folic acid and vitamin B 12 may prevent stroke in populations with low intake of folate or vitamin B 12. It is also uncertain whether stroke may be prevented by supplementation with vitamin B 3 (niacin) or vitamin D. Further research is needed to improve the quality of evidence relating the association of vitamins with the risk of stroke and its subtypes. At the time of awaiting the results of ongoing trials, the current evidence of possible health benefits of vitamin D and the safe and affordable manner by which it can be supplemented argue for the prevention and treatment of vitamin D deficiency. Disclosures Dr Hankey was the principal investigator of the VITAmins TO Prevent Stroke (VITATOPS) trial, which was funded by grants from the Australia National Health and Medical Research Council (project grants , , and ; program grants and ), the UK Medical Research Council, the Singapore Biomedical Research Council, the Singapore National Medical Research Council, the Australia National Heart Foundation (grants G 99P 0405, G 02P 0735, G 04P 1611), the Royal Perth Hospital Medical Research Foundation, and the Health Department of Western Australia. References 1. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, Am J Epidemiol. 2004;160: GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328: Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Yttter Y, Alonso-Coello P, et al; for the GRADE Working Group. 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