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 self-
administered 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.)
Key Words: cohort studies ◼ mortality ◼ stroke
Downloaded from http://ahajournals.org by on October 24, 2023

M ultivitamin supplements are widely used in devel-

oped countries because of the popular belief that they
can help promote health and prevent diseases. However, the
results from researches examining the effects of multivita-
min 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 cancer6 and all-cause mortality.6,7
On the contrary, previous prospective cohort studies showed
that high consumption of fruit and vegetables, rich in anti-
oxidants, 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
potassium15,16 may have beneficial effects on stroke preven-
tion. However, an effect of multivitamin supplement on stroke
risk is uncertain. Only 2 prospective cohort studies3,6 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 character-
istics, for example, dietary intake of fruits and vegetables,
modify the association.
Therefore, the aim of this study was to examine the associa-
tion 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 fac-
tors 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 self-
administered questionnaires, including information on demograph-
ics, 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 his-
tory 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/m2; (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 multivita-
mins (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 multivita-
mins 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, dia-
betes mellitus, cardiovascular diseases, and cancer, height, weight,
education background, smoking status, alcohol use, physical activ-
ity, mental stress, and dietary habits. Body mass index was calcu-
lated 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 re-
ported elsewhere.19
Ascertainment of Stroke Mortality
Downloaded from http://ahajournals.org by on October 24, 2023
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 χ2 test for categorical variables.
We used Cox proportional hazards regression models to estimate
hazard ratios (HRs) with 95% confidence intervals (CIs) of mortal-
ity 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 mod-
els, 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/m2), education (age at com-
pleted education of <13, 13–15, 16–18, or ≥19 years), history of hy-
pertension (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 ex-
treme 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 associa-
tion, we next conducted a subgroup analysis. We examined the as-
sociation according to age (≥65 and <65 years), sex, education level
(age at completed education ≥16 and <16 years), and combined fre-
quency 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 mul-
tivitamin supplement. Compared with nonusers, multivita-
min 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, includ-
ing 1148 ischemic strokes, 877 hemorrhagic strokes, and 62
unspecified strokes. The associations between multivitamin
use and death from total stroke and stroke subtypes are pre-
sented in Table 2. The results from the age- and area-adjusted
model and the multivariable model differed little. After adjust-
ment 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 isch-
emic stroke tended to be lower among regular users than
among casual users, and the trends were of borderline statisti-
cal significance.
We next conducted a subgroup analysis according to age,
sex, education level, and dietary intake of fruits and vegeta-
bles (Table 3). For total stroke, no association was observed
among participants grouped by age, sex, or education level.
However, a significant inverse association between multivita-
min 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 All Users Casual Users Regular Users
(n=62 697) (n=9483) P Value* (n=6734) (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.
Downloaded from http://ahajournals.org by on October 24, 2023

of ischemic stroke mortality in people with lower intake of users, respectively), whereas it was not related to hemorrhagic
fruits and vegetables (HR, 0.56 [0.39–0.79], 0.59 [0.39–0.89], stroke mortality among any subgroups (Appendix Tables I and
and 0.48 [0.26–0.90] for all users, casual users, and regular 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 pop-
ulation, 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 dyspla-
sia 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 border-
line statistical significance between multivitamin use and
Downloaded from http://ahajournals.org by on October 24, 2023
lower risk of stroke mortality. In our subgroup analysis, mul-
tivitamin 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 veg-
etables 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
Table 3. Multivariable Hazard Ratios* (95% Confidence Interval) of Mortality From Total Stroke According
to Multivitamin Use Stratified by Participant Characteristics
Nonusers
Age <65 y 1.00
Age ≥65 y 1.00
Men 1.00
Women 1.00
Age at completed education <16 y 1.00
Age at completed education ≥16 y 1.00
Fruit and vegetable intake <3 times/d 1.00
Fruit and vegetable intake ≥3 times/d 1.00
*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.
evidence and concluded that the current evidence is insuf-
ficient 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 multivi-
tamin 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 tri-
als, 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, particu-
larly those with lower fruit and vegetable intake. Finding from
a previous cohort study showed that people who used multivi-
tamins 6 to 7 times/week experienced lower risk of cardiovas-
cular 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 mul-
tivitamin 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 sup-
plements 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 mor-
tality (HR, 0.77; 95% CI, 0.47–1.25). This nonsignificant
association may be because of insufficient statistical power
All Users Casual Users Regular Users
0.91 (0.73–1.14) 0.91 (0.71–1.17) 1.03 (0.70–1.53)
0.85 (0.70–1.02) 0.88 (0.70–1.10) 0.85 (0.62–1.15)
0.88 (0.72–1.06) 0.92 (0.73–1.15) 0.82 (0.59–1.16)
0.88 (0.71–1.08) 0.90 (0.70–1.17) 0.86 (0.61–1.22)
0.84 (0.67–1.06) 0.83 (0.63–1.10) 0.91 (0.62–1.32)
0.88 (0.71–1.07) 0.96 (0.76–1.22) 0.73 (0.51–1.05)
0.80 (0.65–0.98) 0.86 (0.68–1.10) 0.67 (0.45–0.99)
0.94 (0.76–1.14) 0.94 (0.74–1.21) 0.97 (0.70–1.34)
 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 selec-
tion 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 fac-
tors 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 attenu-
ated 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, mea-
surement errors were inevitable because of the nature of self-
administrated questionnaire.
In summary, from this prospective cohort study, we found
that multivitamin use, particularly frequent use, was associ-
ated with reduced risk of total and ischemic stroke mortality
among Japanese people with lower intake of fruits and veg-
etables. This finding supports a beneficial role of multivitamin
Downloaded from http://ahajournals.org by on October 24, 2023
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.
Disclosures
None.
References
1. Li K, Kaaks R, Linseisen J, Rohrmann S. Vitamin/mineral supplementa-
tion and cancer, cardiovascular, and all-cause mortality in a German pro-
spective 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 phy-
sicians 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 mul-
tiethnic 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 sup-
plements 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 car-
diovascular 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 col-
laborative 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 supple-
mentation, 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
Downloaded from http://ahajournals.org by on October 24, 2023
disease and cancer: U.S. Preventive services Task Force recommen-
dation 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.