Multivitamin supplements are widely used in developed

Multivitamin Use and Risk of Stroke Mortality The Japan Collaborative Cohort Study Jia-Yi Dong, MMed; Hiroyasu Iso, MD, PhD; Akihiko Kitamura, MD, PhD; Akiko Tamakoshi, MD, PhD; Japan Collaborative Cohort Study Group* Background and Purpose An effect of multivitamin supplement on stroke risk is uncertain. We aimed to examine the association between multivitamin use and risk of death from stroke and its subtypes. Methods A total of 72 180 Japanese men and women free from cardiovascular diseases and cancers at baseline in 1988 to 1990 were followed up until December 31, 2009. Lifestyles including multivitamin use were collected using selfadministered questionnaires. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of total stroke and its subtypes in relation to multivitamin use. Results During a median follow-up of 19.1 years, we identified 2087 deaths from stroke, including 1148 ischemic strokes and 877 hemorrhagic strokes. After adjustment for potential confounders, multivitamin use was associated with lower but borderline significant risk of death from total stroke (HR, 0.87; 95% confidence interval, 0.76 1.01), primarily ischemic stroke (HR, 0.80; 95% confidence interval, 0.63 1.01), but not hemorrhagic stroke (HR, 0.96; 95% confidence interval, 0.78 1.18). In a subgroup analysis, there was a significant association between multivitamin use and lower risk of mortality from total stroke among people with fruit and vegetable intake <3 times/d (HR, 0.80; 95% confidence interval, 0.65 0.98). That association seemed to be more evident among regular users than casual users. Similar results were found for ischemic stroke. Conclusions Multivitamin use, particularly frequent use, was associated with reduced risk of total and ischemic stroke mortality among Japanese people with lower intake of fruits and vegetables. (Stroke. 2015;46:1167-1172. DOI: 10.1161/STROKEAHA.114.008270.) Multivitamin supplements are widely used in developed countries because of the popular belief that they can help promote health and prevent diseases. However, the results from researches examining the effects of multivitamin use on human health are controversial. Most published cohort studies have reported a lack of effect of multivitamin use on cardiovascular disease, cancer, or all-cause mortality. 1 4 One study found that multivitamin use was associated with decreased risk of cardiovascular mortality, 5 whereas several other studies suggested that it was associated with increased risk of cancer 6 and all-cause mortality. 6,7 On the contrary, previous prospective cohort studies showed that high consumption of fruit and vegetables, rich in antioxidants, vitamins, and minerals, was associated with reduced risk of stroke incidence. 8 Also, dietary intake of individual nutrients, including vitamin C, 9,10 folate, 11 13 magnesium, 14 and potassium 15,16 may have beneficial effects on stroke prevention. However, an effect of multivitamin supplement on stroke Key Words: cohort studies mortality stroke risk is uncertain. Only 2 prospective cohort studies 3,6 have evaluated the association between multivitamin use and risk of stroke incidence or mortality, and the results were negative. Furthermore, it is largely unknown whether the association varies by stroke subtypes and whether participant characteristics, for example, dietary intake of fruits and vegetables, modify the association. Therefore, the aim of this study was to examine the association between multivitamin use and risk of death from stroke and its subtypes. We also aimed to examine the association according to population characteristics. Materials and Methods Study Population The Japan Collaborative Cohort (JACC) study, established between 1988 and 1990, was designed to evaluate the effects of lifestyle factors on health of Japanese men and women. The detailed design of the JACC study was previously reported elsewhere. 17,18 Briefly, a total of Received November 24, 2014; final revision received March 9, 2015; accepted March 9, 2015. From Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (J.-Y.D., H.I., A.K.); and Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan (A.T.). *A list of all JACC Study Group participants is given in the Appendix in the online-only Data Supplement. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/strokeaha. 114.008270/-/DC1. Correspondence to Hiroyasu Iso, MD, PhD, Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565 0871, Japan. E-mail iso@pbhel.med.osaka-u.ac.jp 2015 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.008270 1167

1168 Stroke May 2015 110 585 men and women aged 40 to 79 years from 45 communities across Japan were enrolled in the investigation and completed selfadministered questionnaires, including information on demographics, medical history, lifestyle factors, and diet. All informed consents were obtained from participants except for several communities where consents were obtained from community leaders. The protocol of the investigation was approved by the ethics committees of Nagoya University and Osaka University. For this analysis, participants were excluded if they (1) had a history of myocardial infarction, stroke, or cancer; (2) did not report information on multivitamin use; (3) had a body mass index outside of the range between 16 and 40 kg/m 2 ; (4) had an implausible energy intake outside of the range between 800 and 4000 kcal/d. As a result, 72 180 participants were eligible for this analysis. Data Collection The baseline questionnaire included information on use of multivitamins (yes or no) and other single vitamin supplements. Participants were asked whether they used any of these supplements and the frequency of use (regular, casual, or never) during the last year. As for multivitamin user, regular user was defined as using multivitamins everyday and casual user was defined as using multivitamins occasionally. The baseline questionnaire also included information on age, sex, family history of diseases, history of hypertension, diabetes mellitus, cardiovascular diseases, and cancer, height, weight, education background, smoking status, alcohol use, physical activity, mental stress, and dietary habits. Body mass index was calculated by dividing the weight in kilograms by the square of height in meters. Dietary assessment was conducted using a food-frequency questionnaire with 33 items. The reproducibility and validity of the food-frequency questionnaire used in this study were previously reported elsewhere. 19 Ascertainment of Stroke Mortality Investigators conducted a systematic review of death certificates in each of the communities for mortality surveillance, all of which were forwarded to the public health centers, respectively. Mortality data were then centralized at the Ministry of Health and Welfare, and the underlying cause of death was coded according to the International Classification of Diseases. Deaths within the cohort were ascertained by death certificates from public health centers. Participants who died after they had moved from their original communities were treated as censored cases. The participants were followed up to determine mortality from stroke and other causes by the end of 2009, except for 4 areas in 1999, 4 areas in 2003, and 2 areas in 2008 where the follow-up had been terminated. The stroke mortality was determined based on the International Classification of Disease-Tenth Revision: I60 I69 for total stroke, I60 I62 and I69.0 I69.1 for hemorrhagic stroke, and I63 and I69.3 for ischemic stroke. Statistical Analysis Person-time of follow-up was calculated from the date of enrollment until the date of death from stroke, death from other causes, moving from the original community, or December 31, 2009, whichever came first. Age-adjusted means and proportions of the population baseline characteristics were calculated according to multivitamin use. The differences between users and nonusers were tested by ANOVA for continuous variables and χ 2 test for categorical variables. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of mortality from total, ischemic, and hemorrhagic strokes. We also examined the frequency of multivitamin use in relation to stroke mortality. All analyses were adjusted for age and study area. In multivariable models, we also adjusted for sex, body mass index (<18.5, 18.5 22.9, 23 24.9, 25 29.9, 30 39.9, and 40 kg/m 2 ), education (age at completed education of <13, 13 15, 16 18, or 19 years), history of hypertension (yes or no), history of diabetes mellitus (yes or no), family history of stroke (yes or no), alcohol use (never, former, and current drinker <23, 23 45.9, 46 68.9, and 69 g/d), smoking status (never, former, and current smoker 1 19 cigarettes/d or 20 cigarettes/d), sports (rarely, 1 2, 3 4, 5 hours/wk), walking (rarely, <30, 30 59, 60 minutes/d), mental stress (little or none, moderate, high, and extreme high), single use of vitamin C or vitamin E supplement (yes or no), and dietary intake of fresh fish, red meat, fruits, vegetables, and total energy (quintiles). To assess whether participant characteristics modifies the association, we next conducted a subgroup analysis. We examined the association according to age ( 65 and <65 years), sex, education level (age at completed education 16 and <16 years), and combined frequency of fruit and vegetable intake ( 3 and <3 times/d). All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). All statistical tests were 2 sided, and P values <0.05 were considered statistically significant. Results Baseline characteristics of the study population according to multivitamin use are summarized in Table 1. Among 72 180 participants under study, 13.1% of them (n=9483) used multivitamin supplement. Compared with nonusers, multivitamin users were more likely to have lower body mass index, higher level of education, and higher level of physical activity. They were also more likely to be men, current smoker, current drinker, and to have a history of diabetes mellitus and higher mental stress. In addition, multivitamin users were more likely to eat red meat and fruits and use vitamin C and vitamin E supplements. Among multivitamin users, regular users were more likely to be older, have a history of hypertension and diabetes mellitus, and have higher mental stress. During a median follow-up of 19.1 years among 72 180 participants, we identified 2087 deaths from stroke, including 1148 ischemic strokes, 877 hemorrhagic strokes, and 62 unspecified strokes. The associations between multivitamin use and death from total stroke and stroke subtypes are presented in Table 2. The results from the age- and area-adjusted model and the multivariable model differed little. After adjustment for potential confounders, multivitamin use (all users versus nonusers) was associated with reduced risk of death from total stroke (HR, 0.87; 95% CI, 0.76 1.01; P=0.07), primarily ischemic stroke (HR, 0.80; 95% CI, 0.63 1.01; P=0.06), but these associations were of borderline statistical significance. Multivitamin use was not related to death from hemorrhagic stroke (HR, 0.96; 95% CI, 0.78 1.18; P=0.70). Among multivitamin users, risk of death from total and ischemic stroke tended to be lower among regular users than among casual users, and the trends were of borderline statistical significance. We next conducted a subgroup analysis according to age, sex, education level, and dietary intake of fruits and vegetables (Table 3). For total stroke, no association was observed among participants grouped by age, sex, or education level. However, a significant inverse association between multivitamin use (all users versus nonusers) and risk of mortality from total stroke was observed among 49.2% of total subjects who had fruit and vegetable intake <3 times/d (HR, 0.80; 95% CI, 0.65 0.98). In that subgroup, the inverse association seemed to be more evident among regular users than among casual users (HR, 0.67; 95% CI, 0.45 0.99 versus HR, 0.86; 95% CI, 0.68 1.10). Yet such an association was not observed in those with fruit and vegetable intake 3 times/d. Similar as total stroke, multivitamin use was associated with a lower risk

Dong et al Multivitamin and Stroke Mortality 1169 Table 1. Baseline Characteristics of 72 180 Subjects According to Multivitamin Use Nonusers (n=62 697) All Users (n=9483) of ischemic stroke mortality in people with lower intake of fruits and vegetables (HR, 0.56 [0.39 0.79], 0.59 [0.39 0.89], and 0.48 [0.26 0.90] for all users, casual users, and regular P Value* Casual Users (n=6734) Regular Users (n=2609) P Value Age, y 57.2 (10.1) 57.3 (9.8) 0.10 56.2 (9.7) 60.0 (9.4) <0.001 Men, % 41.3 45.6 <0.001 46.5 43.6 0.03 BMI, kg/m 2 22.9 22.6 <0.001 22.7 22.5 0.004 Age at completed education 61.9 68.2 <0.001 67.3 71.0 0.003 16 y, % History of hypertension, % 20.4 21.1 0.13 20.4 23.0 0.02 History of diabetes mellitus, % 4.8 5.6 <0.001 4.9 7.7 <0.001 Family history of stroke, % 28.2 29.2 0.07 28.3 31.4 0.01 Current drinker, % 45.3 51.5 <0.001 51.4 51.8 0.53 Current smoker, % 26.3 29.1 <0.001 29.6 27.7 0.14 Sports 30 min/d, % 11.8 13.1 <0.001 13.6 12.1 0.06 Walking 1 h/d, % 51.0 50.8 0.76 51.5 48.9 0.08 High mental stress, % 20.1 27.1 <0.001 25.7 30.6 <0.001 Use of vitamin C supplement, % 5.1 6.5 <0.001 5.8 8.6 <0.001 Use of vitamin E supplement, % 5.6 7.2 <0.001 5.4 11.8 <0.001 Total energy, kcal/d 1579.5 1578.0 0.79 1589.1 1551.3 0.002 Fresh fish 1 time/d, % 27.1 26.7 0.41 26.3 27.8 0.16 Red meat 1 time/d, % 20.2 22.4 <0.001 22.7 21.9 0.59 Fruit intake 2 times/d % 20.6 22.3 <0.001 21.3 24.6 <0.001 Vegetable intake 3 times/d % 22.3 22.3 0.96 22.7 21.2 0.09 All values (except age) are standardized to the baseline age distribution of the study population. Values are means (SD) or percentages. BMI indicates body mass index. *P for difference between nonusers and all users. P for difference between casual users and regular users. users, respectively), whereas it was not related to hemorrhagic stroke mortality among any subgroups (Appendix Tables I and II in the online-only Data Supplement). Table 2. Age- and Area-Adjusted and Multivariable HRs of Mortality From Total Stroke and Its Subtypes According to Multivitamin Use Nonusers All Users P Value Difference Casual Users Regular Users P Value Trend No. at risk 62 697 9483 6734 2609 Person-year 1 028 535 146 641 106 518 38 067 Total stroke No. of deaths 1869 218 147 69 HR (95% CI)* 1.00 0.88 (0.76 1.01) 0.06 0.90 (0.76 1.07) 0.85 (0.67 1.08) 0.09 HR (95% CI) 1.00 0.87 (0.76 1.01) 0.07 0.91 (0.77 1.08) 0.84 (0.66 1.07) 0.08 Ischemic stroke No. of deaths 1043 105 69 35 HR (95% CI)* 1.00 0.78 (0.62 1.00) 0.05 0.80 (0.63 1.02) 0.77 (0.55 1.07) 0.08 HR (95% CI) 1.00 0.80 (0.63 1.01) 0.06 0.82 (0.64 1.05) 0.79 (0.56 1.11) 0.07 Hemorrhagic stroke No. of deaths 772 105 75 29 HR (95% CI)* 1.00 0.99 (0.81 1.21) 0.90 1.05 (0.83 1.33) 0.89 (0.61 1.29) 0.47 HR (95% CI) 1.00 0.96 (0.78 1.18) 0.70 1.03 (0.81 1.31) 0.86 (0.59 1.25) 0.34 CI indicates confidence interval; and HR, hazard ratio. *Adjusted for age and study area. Adjusted further for sex, body mass index, education level, history of hypertension, history of diabetes mellitus, family history of stroke, alcohol use, smoking, sports, walking, mental stress, use of vitamin C or vitamin E supplement, dietary intakes of fish, red meat, fruits, vegetables, and total energy.

1170 Stroke May 2015 Discussion In this large prospective cohort study among Japanese population, we observed an inverse association of borderline statistical significance between multivitamin use and risk of total stroke mortality, primarily ischemic stroke. In the subgroup analysis, multivitamin use, particularly frequent use, was associated with a significant lower risk of total and ischemic stroke mortality among people with lower intake of fruits and vegetables, which consisted of nearly half of the total population. Up to date, the impact of multivitamin use on stroke risk has been inconclusive. The Women s Health Initiative study, a cohort study of 161 808 postmenopausal women, found no association between multivitamin use and stroke incidence (HR, 0.99; 95% CI, 0.91 1.07). 3 The Cancer Prevention Study II study, a prospective study of 1 063 023 adult Americans, also showed no association between multivitamin use and stroke mortality (HR, 0.99; 95% CI, 0.89 1.10). 6 The Nutrition Intervention Trials in Linxian, China, conducted in 3318 adults with esophageal dysplasia suggested a nonsignificant lower risk of cerebrovascular disease in multivitamin treatment group (HR, 0.62; 95% CI, 0.37 1.06). 20 The Physicians Health Study II randomized controlled trial with a total sample of 14 641 men and a mean follow-up of 11.2 years found no benefits of multivitamin for the prevention of stroke (HR, 1.08; 95% CI, 0.76 1.53) or other cardiovascular events. 21 In the main analysis, we found an association of borderline statistical significance between multivitamin use and lower risk of stroke mortality. In our subgroup analysis, multivitamin use was significantly associated with a lower risk of total and ischemic stroke mortality in people with lower intake of fruits and vegetables (<3 times/d) but not those with higher intake ( 3 times/d). Fruits and vegetables, rich in antioxidants, vitamins, and minerals, have widely been reported to help protect against the development of stroke. 8 It is possible that people with lower intake of fruits and vegetables may be short in vitamins and minerals and could, therefore, benefit from multivitamin use. On the contrary, supplemental multivitamin intake may provide no benefit in those with high fruit and vegetable intake. Recently, the United States Preventive Services Task Force reviewed the evidence and concluded that the current evidence is insufficient to assess the balance of benefits or harms of the use of multivitamins for the prevention of cardiovascular diseases or cancer. 22 To be noted, this statement focused on healthy adults without special nutritional needs. Whether multivitamin use has beneficial effects on cardiovascular health in people with low nutrient intake remains unclear. Further cohort studies and clinical trials may take individual nutrient intakes into account when examining the health effects of multivitamin use. We observed a trend toward lower risk of ischemic stroke in relation to multivitamin use but not of hemorrhagic stroke. According to a meta-analysis of 9 randomized controlled trials, vitamin E supplement was associated with reduced risk of ischemic stroke (pooled HR, 0.90; 95% CI, 0.82 0.99) but with increased risk of hemorrhagic stroke (pooled HR, 1.22; 95% CI, 1.00 1.48), suggesting effects of individual vitamin/ mineral may vary by stroke subtypes. 23 Because few studies have examined multivitamin use in relation to risk of stroke subtypes, a potential differential effect needs to be clarified in further investigations. In our study, there was a trend toward a lower risk of total and ischemic stroke mortality among regular users, particularly those with lower fruit and vegetable intake. Finding from a previous cohort study showed that people who used multivitamins 6 to 7 times/week experienced lower risk of cardiovascular disease (HR, 0.84; 95% CI, 0.70 0.99) than those who used them 1 to 2 times/week (HR, 1.00; 95% CI, 0.81 1.24). 5 However, another cohort study showed no difference in risk of cardiovascular disease according to the frequency of multivitamin use. 4 A previous study of 1 063 023 American adults reported that the combined use of multivitamin and vitamin A, C, or E, but not the use of only multivitamin, was associated with reduced risk of stroke mortality (HR, 0.84; 95% CI, 0.74 0.95 for men and HR, 0.86; 95% CI, 0.76 0.98 for women), suggesting a combination of specific vitamin supplements may be necessary for risk reduction. 6 In our study, the combined use of multivitamin and vitamin C or E was not significantly associated with reduced risk of stroke mortality (HR, 0.77; 95% CI, 0.47 1.25). This nonsignificant association may be because of insufficient statistical power Table 3. Multivariable Hazard Ratios* (95% Confidence Interval) of Mortality From Total Stroke According to Multivitamin Use Stratified by Participant Characteristics Nonusers All Users Casual Users Regular Users Age <65 y 1.00 0.91 (0.73 1.14) 0.91 (0.71 1.17) 1.03 (0.70 1.53) Age 65 y 1.00 0.85 (0.70 1.02) 0.88 (0.70 1.10) 0.85 (0.62 1.15) Men 1.00 0.88 (0.72 1.06) 0.92 (0.73 1.15) 0.82 (0.59 1.16) Women 1.00 0.88 (0.71 1.08) 0.90 (0.70 1.17) 0.86 (0.61 1.22) Age at completed education <16 y 1.00 0.84 (0.67 1.06) 0.83 (0.63 1.10) 0.91 (0.62 1.32) Age at completed education 16 y 1.00 0.88 (0.71 1.07) 0.96 (0.76 1.22) 0.73 (0.51 1.05) Fruit and vegetable intake <3 times/d 1.00 0.80 (0.65 0.98) 0.86 (0.68 1.10) 0.67 (0.45 0.99) Fruit and vegetable intake 3 times/d 1.00 0.94 (0.76 1.14) 0.94 (0.74 1.21) 0.97 (0.70 1.34) *Adjusted for age, study area, sex, body mass index, education level, history of hypertension, history of diabetes mellitus, family history of stroke, alcohol use, smoking, sports, walking, mental stress, use of vitamin C or vitamin E supplementation, dietary intakes of fish, red meat, fruits, vegetables, and total energy.

Dong et al Multivitamin and Stroke Mortality 1171 because the number of participants who had the combined use (n=980) and the number of stroke death (n=16) were small in our study. Our study has several strengths. A population-based and prospective design eliminated recall bias and reduced selection bias. A median of 19.1 years follow-up allowed us to examine a long-term effect of multivitamin use on mortality from stroke and its subtypes. Also, we were able to examine the effect modifications of the associations by known risk factors of the population. Limitations of our study should be also noted. First, despite our efforts to adjust for possible confounding factors, we could not rule out the influences of unmeasured factors or residual confounding because of its observational nature. Second, we had the baseline data only for the analysis. Lack of repeated measurements during follow-up period may lead to nondifferential misclassification bias, resulting in attenuated risk estimates. Third, we had no data on multivitamin compositions, dose, or duration of multivitamin use, which made more detailed analysis impossible. However, previous studies found no evident difference in risk of cardiovascular disease by duration of multivitamin use. 3,4 In addition, measurement errors were inevitable because of the nature of selfadministrated questionnaire. In summary, from this prospective cohort study, we found that multivitamin use, particularly frequent use, was associated with reduced risk of total and ischemic stroke mortality among Japanese people with lower intake of fruits and vegetables. This finding supports a beneficial role of multivitamin use among people with insufficient nutrient intakes. Acknowledgments We thank all staff members involved in this study for their valuable help in conducting the baseline survey and follow-up. Sources of Funding This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (Monbusho), Grants-in-Aid for Scientific Research on Priority Areas of Cancer, Grants-in-Aid for Scientific Research on Priority Areas of Cancer Epidemiology from the Japanese Ministry of Education, Culture, Sports, Science and Technology (Monbu- Kagaku-sho; Nos. 61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, 11181101, 17015022, 18014011, 20014026, and 20390156), Grant-in-Aid from the Ministry of Health, Labour and Welfare, Health and Labor Sciences research grants, Japan (Research on Health Services: H17-Kenkou-007; Comprehensive Research on Cardiovascular Disease and Life-Related Disease: H18-Junkankitou [Seishuu]- Ippan-012; Comprehensive Research on Cardiovascular Disease and Life-Related Disease: H19-Junkankitou [Seishuu]-Ippan-012; Comprehensive Research on Cardiovascular and LifeStyle Related Diseases: H20-Junkankitou [Seishuu]-Ippan-013; Comprehensive Research on Cardiovascular and LifeStyle Related Diseases: H23- Junkankitou [Seishuu]-Ippan-005), and an Intramural Research Fund (22-4-5) for Cardiovascular Diseases of National Cerebral and Cardiovascular Center; and Comprehensive Research on Cardiovascular and LifeStyle Related Diseases: H26-Junkankitou [Seisaku]-Ippan-001. None. Disclosures References 1. Li K, Kaaks R, Linseisen J, Rohrmann S. Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg). Eur J Nutr. 2012;51:407 413. doi: 10.1007/s00394-011-0224-1. 2. Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch Intern Med. 2002;162:1472 1476. 3. Neuhouser ML, Wassertheil-Smoller S, Thomson C, Aragaki A, Anderson GL, Manson JE, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women s Health Initiative cohorts. Arch Intern Med. 2009;169:294 304. doi: 10.1001/archinternmed.2008.540. 4. Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study. Am J Epidemiol. 2011;173:906 914. doi: 10.1093/ aje/kwq447. 5. Pocobelli G, Peters U, Kristal AR, White E. Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality. Am J Epidemiol. 2009;170:472 483. doi: 10.1093/aje/kwp167. 6. Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath CW Jr. Multivitamin use and mortality in a large prospective study. Am J Epidemiol. 2000;152:149 162. 7. Mursu J, Robien K, Harnack LJ, Park K, Jacobs DR Jr. Dietary supplements and mortality rate in older women: the Iowa Women s Health Study. Arch Intern Med. 2011;171:1625 1633. doi: 10.1001/ archinternmed.2011.445. 8. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet. 2006;367:320 326. doi: 10.1016/S0140-6736(06)68069-0. 9. Kubota Y, Iso H, Date C, Kikuchi S, Watanabe Y, Wada Y, et al; JACC Study Group. Dietary intakes of antioxidant vitamins and mortality from cardiovascular disease: the Japan Collaborative Cohort Study (JACC) study. Stroke. 2011;42:1665 1672. doi: 10.1161/STROKEAHA.110.601526. 10. Vokó Z, Hollander M, Hofman A, Koudstaal PJ, Breteler MM. Dietary antioxidants and the risk of ischemic stroke: the Rotterdam Study. Neurology. 2003;61:1273 1275. 11. Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L, et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke. 2002;33:1183 1188. 12. Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A; Japan Collaborative Cohort Study Group. Dietary folate and vitamin b6 and B12 intake in relation to mortality from cardiovascular diseases: Japan collaborative cohort study. Stroke. 2010;41:1285 1289. doi: 10.1161/ STROKEAHA.110.578906. 13. He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, et al. Folate, vitamin B6, and B12 intakes in relation to risk of stroke among men. Stroke. 2004;35:169 174. doi: 10.1161/01. STR.0000106762.55994.86. 14. Larsson SC, Orsini N, Wolk A. Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies. Am J Clin Nutr. 2012;95:362 366. doi: 10.3945/ajcn.111.022376. 15. Aburto NJ, Hanson S, Gutierrez H, Hooper L, Elliott P, Cappuccio FP. Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analyses. BMJ. 2013;346:f1378. 16. Larsson SC, Orsini N, Wolk A. Dietary potassium intake and risk of stroke: a dose-response meta-analysis of prospective studies. Stroke. 2011;42:2746 2750. doi: 10.1161/STROKEAHA.111.622142. 17. Ohno Y, Tamakoshi A; JACC Study Group. Japan collaborative cohort study for evaluation of cancer risk sponsored by monbusho (JACC study). J Epidemiol. 2001;11:144 150. 18. Tamakoshi A, Yoshimura T, Inaba Y, Ito Y, Watanabe Y, Fukuda K, et al; JACC Study Group. Profile of the JACC study. J Epidemiol. 2005;15(suppl 1):S4 S8. 19. Date C, Fukui M, Yamamoto A, Wakai K, Ozeki A, Motohashi Y, et al; JACC Study Group. Reproducibility and validity of a self-administered food frequency questionnaire used in the JACC study. J Epidemiol. 2005;15(suppl 1):S9 23. 20. Li JY, Taylor PR, Li B, Dawsey S, Wang GQ, Ershow AG, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993;85:1492 1498.

1172 Stroke May 2015 21. Sesso HD, Christen WG, Bubes V, Smith JP, MacFadyen J, Schvartz M, et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians Health Study II randomized controlled trial. JAMA. 2012;308:1751 1760. doi: 10.1001/jama.2012.14805. 22. Moyer VA; U.S. Preventive Services Task Force. Vitamin, mineral, and multivitamin supplements for the primary prevention of cardiovascular disease and cancer: U.S. Preventive services Task Force recommendation statement. Ann Intern Med. 2014;160:558 564. doi: 10.7326/ M14-0198. 23. Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702.