*The numbers of deaths are higher than those in Table 2 because this
figure includes all reported deaths in the WHS, whereas the deaths in Table
2 include only reported deaths confirmed by the Endpoints Committee or by
a death certificate.
The composite cardiovascular end point (the first of any of the individual
end points) is reported as well as the individual end points of myocardial
infarction, stroke, and cardiovascular death.
Lee I, Cook NR, Gaziano JM, Gordon D, Ridker PM, Manson JE, Hennekens CH, Buring JE. Vitamin E in the Primary Prevention of Cardiovascular Disease and CancerThe Women’s Health Study: A Randomized Controlled Trial. JAMA. 2005;294(1):56–65. doi:10.1001/jama.294.1.56
Author Affiliations: Divisions of Preventive
Medicine (Drs Lee, Cook, Gaziano, Ridker, Manson, and Buring and Mr Gordon),
Cardiovascular Medicine (Drs Gaziano and Ridker), and Aging (Drs Gaziano and
Buring), Department of Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Mass; Department of Epidemiology, Harvard School of
Public Health, Boston (Drs Lee, Cook, Ridker, Manson, and Buring); Veterans
Affairs Boston Healthcare System (Dr Gaziano); Department of Ambulatory Care
and Prevention, Harvard Medical School, Boston (Dr Buring); and the Departments
of Medicine and Epidemiology and Public Health, University of Miami School
of Medicine, Miami, Fla, and Department of Biomedical Science, Center of Excellence,
Florida Atlantic University, Boca Raton (Dr Hennekens).
Context Basic research provides plausible mechanisms and observational studies
suggest that apparently healthy persons, who self-select for high intakes
of vitamin E through diet or supplements, have decreased risks of cardiovascular
disease and cancer. Randomized trials do not generally support benefits of
vitamin E, but there are few trials of long duration among initially healthy
Objective To test whether vitamin E supplementation decreases risks of cardiovascular
disease and cancer among healthy women.
Design, Setting, and Participants In the Women’s Health Study conducted between 1992 and 2004, 39 876
apparently healthy US women aged at least 45 years were randomly assigned
to receive vitamin E or placebo and aspirin or placebo, using a 2 × 2
factorial design, and were followed up for an average of 10.1 years.
Intervention Administration of 600 IU of natural-source vitamin E on alternate days.
Main Outcome Measures Primary outcomes were a composite end point of first major cardiovascular
event (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular
death) and total invasive cancer.
Results During follow-up, there were 482 major cardiovascular events in the
vitamin E group and 517 in the placebo group, a nonsignificant 7% risk reduction
(relative risk [RR], 0.93; 95% confidence interval [CI], 0.82-1.05; P = .26). There were no significant effects on
the incidences of myocardial infarction (RR, 1.01; 95% CI, 0.82-1.23; P = .96) or stroke (RR, 0.98; 95% CI, 0.82-1.17; P = .82), as well as ischemic or hemorrhagic
stroke. For cardiovascular death, there was a significant 24% reduction (RR,
0.76; 95% CI, 0.59-0.98; P = .03). There
was no significant effect on the incidences of total cancer (1437 cases in
the vitamin E group and 1428 in the placebo group; RR, 1.01; 95% CI, 0.94-1.08; P = .87) or breast (RR, 1.00; 95% CI, 0.90-1.12; P = .95), lung (RR, 1.09; 95% CI, 0.83-1.44; P = .52), or colon cancers (RR, 1.00; 95% CI,
0.77-1.31; P = .99). Cancer deaths also
did not differ significantly between groups. There was no significant effect
of vitamin E on total mortality (636 in the vitamin E group and 615 in the
placebo group; RR, 1.04; 95% CI, 0.93-1.16; P = .53).
Conclusions The data from this large trial indicated that 600 IU of natural-source
vitamin E taken every other day provided no overall benefit for major cardiovascular
events or cancer, did not affect total mortality, and decreased cardiovascular
mortality in healthy women. These data do not support recommending vitamin
E supplementation for cardiovascular disease or cancer prevention among healthy
Free radicals can cause lipid peroxidation and DNA damage, contributing
to the development of cardiovascular disease (CVD) and cancer.1- 5 Vitamin
E has antioxidant properties, including inhibition of oxidation of low-density
lipoprotein cholesterol in plasma, leading to the hypothesis that it can prevent
these chronic diseases.5 In some, but not all,
basic research reports, vitamin E supplementation retarded atherogenesis.6 In descriptive data, investigators noted a strong
inverse relation between plasma vitamin E concentrations and death rates from
ischemic heart disease in men in several European countries.7 Additionally,
several large cohort studies observed decreased CVD rates among individuals
who self-selected for higher intakes of vitamin E through diet and/or supplements.8- 10 By 1997, despite a
lack of randomized trials, 44% of US cardiologists reported routine use of
antioxidant supplements, primarily vitamin E, compared with 42% who routinely
used aspirin for the primary prevention of CVD.11With
regard to cancer, several observational studies, particularly case-control
studies, also reported reduced rates of cancer among persons who self-selected
for high antioxidant intakes.12
For small to moderate effects, however, the amount of uncontrolled and
uncontrollable confounding inherent in observational studies can be as large
as the postulated benefit, so randomized clinical trials represent the most
reliable study design strategy.13 Several trials
were therefore initiated beginning in the late 1980s to directly test the
vitamin E hypothesis.14- 38 To
date, data from randomized trials have largely demonstrated no significant
benefit of vitamin E supplementation on the incidence of CVD or cancer and,
indeed, raised the question of possible adverse effects on total mortality
with high doses.39- 44 However,
these trials have been conducted primarily among participants with cardiovascular
risk factors and/or CVD or at high risk for cancer. Few trials have recruited
apparently healthy persons, with most designed to examine ophthalmologic outcomes.30,33,37 Only one trial, testing
a combination of antioxidant vitamins and minerals, has investigated CVD and
cancer prevention among healthy persons not selected based on risk factors.35 Additionally, the treatment duration in previous
trials has generally been limited to 5 years or shorter, with 6 trials having
a longer duration.14- 16,30,35,38 One
possible explanation for the largely null results of randomized trials is
that the duration of supplementation has been insufficient for an effect.45
To provide further information, the Women’s Health Study (WHS)
tested whether vitamin E supplementation for 10 years decreased risks of CVD
and cancer in a large group of healthy women.
The WHS was a randomized, double-blind, placebo-controlled, 2 × 2
factorial trial evaluating the balance of risks and benefits of low-dose aspirin
(100 mg every other day; Bayer Healthcare) and vitamin E (600 IU of α-tocopherol every other day; Natural Source Vitamin
E Association) in the primary prevention of CVD and cancer.46,47 Originally,
a third component, beta carotene, was also included. However, this component
was terminated early in January 1996 after a median treatment duration of
2.1 years.48 Written informed consent was obtained
from all participating women. The trial was approved by the institutional
review board of Brigham and Women’s Hospital and monitored by an external
data and safety monitoring board.
Detailed methods of the design have been described previously.46,47 Briefly, between September 1992 and
May 1995, letters of invitation to participate in the trial and baseline health
questionnaires were mailed to more than 1.7 million female health care professionals
throughout the United States (Figure 1).
A total of 453 787 women completed the questionnaires and 65 169
were willing and eligible to participate. Eligibility criteria included the
following: age 45 years or older; no previous history of coronary heart disease,
cerebrovascular disease, cancer (except nonmelanoma skin cancer), or other
major chronic illnesses; no history of adverse effects from aspirin; no use
of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) more than once
a week, or willingness to forgo their use; no use of anticoagulants or corticosteroids;
and no use of individual supplements of vitamin A, E, or beta carotene more
than once a week. Eligible women were enrolled into a 3-month run-in period
with placebo medications to identify likely long-term compliers to pill taking.
Following the run-in period, 39 876 women remained willing, eligible,
and compliant, and they were randomized in blocks of 16 within 5-year age
strata to vitamin E (n = 19 937) or placebo (n = 19 939).
Each year, women received calendar packs that contained amber capsules
(vitamin E or placebo) and white pills (aspirin or placebo) on alternate days.
Every 6 months for the first year and annually thereafter, they also received
follow-up questionnaires inquiring about compliance with pill-taking, potential
adverse effects, occurrence of end points, and risk factors. Study medications
and end point ascertainment were continued in blinded fashion through the
scheduled end of the trial (March 31, 2004). Follow-up and validation of reported
end points were completed in February 2005. Morbidity and mortality follow-up
were 97.2% and 99.4% complete, respectively.
Using the information provided on questionnaires, compliance, defined
as taking at least two thirds of the study capsules, was 78.9% at 5 years
and 71.6% at 10 years. Averaged throughout the trial, it was 75.8% with no
difference between active and placebo groups (P = .64).
Nontrial use of individual supplements of vitamin E for at least 4 days per
month (“drop-ins”) was 10.0% at 5 years and 10.9% at 10 years.
Averaged throughout the trial, outside use was somewhat lower in the active
(8.6%) than in the placebo group (8.9%) (P = .07).
The primary end points were a composite of first major cardiovascular
event (nonfatal myocardial infarction [MI], nonfatal stroke, or cardiovascular
death) and total invasive cancer (apart from nonmelanoma skin cancer). Secondary
end points were the individual cardiovascular events—total MI, total
stroke, and cardiovascular death—and the main site-specific cancers
in women: breast, lung, and colon cancers. We also collected information on
coronary revascularization procedures (bypass surgery or percutaneous coronary
angioplasty), transient ischemic attacks (TIAs), and total mortality.
Women reported the occurrence of relevant end points via follow-up questionnaires,
letters, or telephone calls. Deaths were usually reported by family members
or postal authorities or ascertained through the National Death Index. After
obtaining written consent, we acquired medical records from hospitals and
physicians, which were reviewed by the WHS Endpoints Committee of physicians
blinded to randomized treatment assignment. The committee confirmed a diagnosis
of MI if symptoms met World Health Organization criteria and the event was
associated with abnormal levels of cardiac enzymes or diagnostic electrocardiograms.
The use of coronary revascularization procedures was confirmed by medical
record review. Stroke was confirmed if the participant had a new neurologic
deficit of sudden onset that persisted for more than 24 hours or until death
within 24 hours. Clinical information and computed tomographic scans or magnetic
resonance images were used to distinguish hemorrhagic from ischemic strokes.49 A confirmed TIA was defined as a neurologic deficit
of sudden onset lasting less than 24 hours. Cardiovascular deaths were confirmed
by autopsy reports, death certificates, medical records, and information from
next of kin or family members. The vast majority (96.8%) of cancers were confirmed
with pathology or cytology reports. Rarely, the committee confirmed a reported
case of cancer based on strong clinical and radiological or laboratory marker
evidence (eg, elevated CA-125) when pathology or cytology review was not conducted.
Total mortality was confirmed by the committee or by obtaining a death certificate.
Only confirmed end points are included in this report.
All primary analyses were performed on an intention-to-treat basis (ie,
based on all randomized persons, as randomized), using the SAS statistical
software package (release 8.2; SAS Institute Inc, Cary, NC). We used Cox proportional
hazards regression models to calculate the relative risks (RRs) and 95% confidence
intervals (95% CIs), comparing event rates in the vitamin E and placebo groups,
after adjustment for age and randomized aspirin and beta carotene assignments.
Statistical significance was set at P<.05, using
2-sided tests. To test the proportionality assumption (ie, that of nonchanging
RRs over time), we included an interaction term of vitamin E with the logarithm
of time in the Cox models. The proportionality assumption was not violated
for major cardiovascular events (P = .16),
total invasive cancer (P = .72), or total
mortality (P = .81). We conducted subgroup
analyses stratified by major risk factors for CVD and cancer, and assessed
effect modification using interaction terms between subgroup indicators and
vitamin E assignment, testing for trend when subgroup categories were ordinal.
To investigate the effect of compliance, we carried out a sensitivity analysis
that censored follow-up for any participant at the time when she reported
taking less than two thirds of study medications over the previous year.
The mean (SD) age of participants at baseline was 54.6 (7.0) years;
other clinical characteristics are shown in Table
1. As expected in this very large sample, randomization was effective
in balancing the characteristics of women in the vitamin E and placebo groups.
The average duration of follow-up from randomization to the end of the trial
was 10.1 years (range, 8.2-10.9 years).
By the end of the trial, 999 major cardiovascular events (253 per 100 000
person-years) had occurred: 482 in the vitamin E group and 517 in the placebo
group (Table 2). This corresponded to
a nonsignificant 7% risk reduction with vitamin E (RR, 0.93; 95% CI, 0.82-1.05; P = .26). For the individual cardiovascular events,
vitamin E had no effect on total MI (RR, 1.01; 95% CI, 0.82-1.23) or total
stroke (RR, 0.98; 95% CI, 0.82-1.17). For stroke subtypes, there was no reduction
in ischemic or increase in hemorrhagic stroke rates. There was a significant
24% reduction in cardiovascular deaths among women in the vitamin E group
(RR, 0.76; 95% CI, 0.59-0.98). This was largely attributable to fewer sudden
deaths in the vitamin E group (38 vs 51 among women assigned to placebo) and
fewer deaths from other cardiovascular disease (ie, deaths due to cardiovascular
diseases other than ischemic heart disease and cerebrovascular disease, 20
vs 34, respectively). There was no significant effect of vitamin E on coronary
revascularization procedures (394 vs 369, respectively) or TIA (212 in each
Figure 2 shows the cumulative
incidence rates of major cardiovascular events among women in the 2 groups
by year of follow-up. An apparent benefit of vitamin E on major cardiovascular
events, as well as on the individual end points of MI, stroke, and cardiovascular
death, was observed early in the trial. The effect on major cardiovascular
events diminished over time and disappeared for MI and stroke by the end of
the trial. In contrast, the difference in cardiovascular death rates between
active and placebo groups appeared to increase over time; however, the change
in RRs over time was not significant (P = .59).
Because compliance diminishes over time, we examined whether the observed
trends might have been due to this tendency. In a sensitivity analysis that
censored noncompliant (taking less than two thirds of study medications) follow-up
time, there was no evidence that noncompliance influenced the findings (RR
for major cardiovascular events, 0.96; 95% CI, 0.82-1.11; P = .56).
As reported previously, aspirin was associated with a nonsignificant
9% reduction in major cardiovascular events.47 We
therefore examined whether random assignment to aspirin modified the effect
of vitamin E. There was no modification of the effect of vitamin E by random
assignment to aspirin (Table 3). Beta
carotene also did not modify the effect of vitamin E on the primary or secondary
end points (data not shown).
We examined whether cardiovascular risk factors modified the relation
between vitamin E and major cardiovascular events (Table 3). In particular, we were interested in whether levels of
oxidative stress may modify the effect of vitamin E.50 We
did not have a direct measure of oxidative stress; however, smoking and diseases
such as hypertension, hyperlipidemia, and diabetes are associated with increased
production of reactive oxygen species in the vascular wall.51 Using
these indirect markers (all self-reported), we found no evidence of benefit
of vitamin E among persons with increased oxidative stress. Additionally,
no benefit was observed among both users and nonusers of multivitamins, who
would presumably have lower and higher levels of oxidative stress, respectively.
There also was no statistically significant effect modification by any
of the other factors considered, except age (P = .008).
In subgroup analyses, women aged at least 65 years comprised 10% of study
participants but contributed 31% of end points. A significant 26% reduction
in major cardiovascular events was observed among women aged at least 65 years
assigned to vitamin E (RR, 0.74; 95% CI, 0.59-0.93; P = .009)
due to a 34% reduction in MI (RR, 0.66; 95% CI, 0.45-0.98; P = .04) and 49% reduction in cardiovascular death (RR, 0.51;
95% CI, 0.33-0.77; P<.001) rates. However, no
reduction in stroke rate was observed (RR, 0.88; 95% CI, 0.64-1.21; P = .44). Among women aged 45 through 54 and
55 through 64 years, the RRs for major cardiovascular events were 1.13 (95%
CI, 0.91-1.41; P = .26) and 0.95 (95% CI,
0.77-1.16; P = .61), respectively.
During the trial, 2865 women developed invasive cancer (741 events per
100000 person-years): 1437 in the vitamin E group and 1428 in the placebo
group (RR, 1.01; 95% CI, 0.94-1.08; P = .87; Table 2). Further analyses that excluded the
first 2 or 5 years of follow-up did not change the findings (data not shown).
For the main site-specific cancers, there were no significant differences
between the vitamin E and placebo groups (breast cancer: RR, 1.00; 95% CI,
0.90-1.12; lung cancer: RR, 1.09; 95% CI, 0.83-1.44; and colon cancer: RR,
1.00; 95% CI, 0.77-1.31). There also was no significant difference in rectal
cancer rates (22 vs 33 cases in the vitamin E and placebo groups, respectively).
A previous study in a poorly nourished population reported lower rates of
stomach cancer among those randomized to a vitamin and mineral cocktail including
vitamin E.14 We did not observe this in our
healthy population (14 vs 6 cases of stomach cancer, respectively). Cancer
death rates also were not significantly influenced by vitamin E (308 vs 275
cancer deaths, respectively; RR, 1.12; 95% CI, 0.95-1.32; P = .17).
Including in situ and invasive cancers in the analysis led to virtually
unchanged findings (1626 vs 1615 cases, respectively; RR, 1.01; 95% CI, 0.94-1.08; P = .84).
When we examined cumulative incidence rates of invasive cancer by year
of follow-up, the curves were almost identical in the vitamin E and placebo
groups (Figure 3). Additional analyses
that censored noncompliant (taking less than two thirds of study medications)
follow-up time continued to show a lack of effect of vitamin E on total invasive
cancer (RR, 1.01; 95% CI, 0.93-1.09; P = .88).
As with major cardiovascular events, random assignment to neither aspirin
nor beta carotene modified the effect of vitamin E on the primary or secondary
cancer end points. Additionally, there was no significant effect modification
by any of the cancer risk factors shown in Table
By the end of the trial, 636 women in the vitamin E group had died,
as had 615 women in the placebo group (RR, 1.04; 95% CI, 0.93-1.16; P = .53). The main causes of death, apart from
cardiovascular and cancer deaths, were pulmonary diseases (32 vitamin E, 22
placebo); violent deaths, excluding suicide (31 vs 21); and suicide (9 vs
6). None of these causes of deaths was significantly related to vitamin E.
In analysis that censored noncompliant follow-up time, there also was
no significant effect of vitamin E (RR, 1.08; 95% CI, 0.90-1.29; P = .42).
There was no effect of random assignment to either aspirin or beta carotene
on the effect of vitamin E on total mortality. There also was no significant
effect of any of the cardiovascular and cancer risk factors in Table 3 on the association of vitamin E with total mortality.
We examined whether vitamin E increased adverse effects due to bleeding
(gastrointestinal bleeding, hematuria, easy bruising, epistaxis) because of
the potential for vitamin E to inhibit platelet function,52 gastrointestinal
symptoms (gastric upset, nausea, diarrhea, constipation), or fatigue. There
were no differences between reported adverse effects for any of these variables
among women in the 2 groups, apart from a small, but significant, increase
in the risk of epistaxis (RR, 1.06; 95% CI, 1.01-1.11; P = .02).
The WHS—the largest randomized trial of vitamin E supplementation
to date with the longest duration of treatment—adds important information
regarding whether vitamin E plays any role in CVD and cancer prevention. In
this trial, 600 IU of natural-source vitamin E every other day for 10 years
did not provide any statistically significant benefits on the primary end
points of major cardiovascular events or cancer in almost 40 000 healthy
women. There was, however, a significant 24% reduction in the secondary end
point of cardiovascular deaths and a significant 26% reduction in major cardiovascular
events among the subgroup of women aged at least 65 years. We observed no
significant effect of vitamin E on total mortality.
The finding of no overall effect of vitamin E on CVD is congruent with
data from previous randomized trials. In 2 recent meta-analyses, the pooled
RR of CVD with vitamin E treatment was 1.0 (95% CI, 0.94-1.07) in a 2003 analysis40 and 0.98 (95% CI, 0.94-1.03) in a 2004 analysis.41 These trials, however, recruited participants at
high risk either because of CVD risk factors or preexisting disease. There
are few data on populations comparable with the healthy women in the WHS.
A recently published trial not included in either meta-analysis, the SU.VI.MAX
study,35 like the WHS, enrolled primarily healthy
persons. After 7.5 years, the SU.VI.MAX trial also reported no effect of randomized
treatment using a combination of vitamins and minerals, including 30 mg/d
of vitamin E, on CVD (RR, 0.97; 95% CI, 0.77-1.20).
With regard to the individual cardiovascular end points, we found a
significant 24% reduction in cardiovascular deaths. This finding differs from
the overall data; in the 2003 meta-analysis, the pooled RR for this end point
was 1.0 (95% CI, 0.94-1.06)40 and 1.00 (95%
CI, 0.94-1.05) in the 2004 meta-analysis.41 The
addition of the WHS data (106 cardiovascular deaths in the vitamin E group,
140 in the placebo group) to the latter and larger meta-analysis (2683 and
2689 cardiovascular deaths, respectively) should not have an appreciable impact
on the pooled RR. In the WHS, the single largest contribution to the reduction
in cardiovascular deaths was fewer sudden deaths among women assigned to receive
vitamin E. One plausible explanation that we considered was whether omega-3
fatty acids in the treatment capsules may have played a role.24 This
is unlikely, however, because both active and placebo capsules were identically
formulated with soybean oil, the only difference being the addition of vitamin
E to the active capsules. It is possible that the observed reduction in cardiovascular
deaths was due to chance, arising from multiple comparisons.
An interesting finding in subgroup analyses was the observation of a
significant 26% reduction in major cardiovascular events, primarily cardiovascular
deaths, among women aged at least 65 years. Few previous trials of vitamin
E have reported findings by age. The one that did, the HOPE trial, enrolled
participants aged at least 55 years with CVD, or diabetes and one other risk
factor, and reported no overall effect of vitamin E on CVD and no heterogeneity
of results by age.26 Several large observational
studies that noted inverse associations between vitamin E intake and CVD rates
did not provide findings by age.8- 10 Existing
trials of vitamin E can help clarify this by providing findings regarding
any age effects.
A recent trial, HOPE-TOO, noted a possible adverse effect of 400 IU/d
of vitamin E on the risk of heart failure.38 This
was not a prespecified end point in the WHS; however, we did collect self-reported
information, which did not demonstrate any association between random assignment
to vitamin E use and incidence of heart failure. These self-reports are currently
being validated against medical records.
In view of the lack of overall benefit of vitamin E on cardiovascular
events in the WHS, we considered several factors. First, was the dose of vitamin
E sufficient? Previous observational studies have reported significant benefits
in women8 with a median intake of as little
as 17 IU/d and 25.2 IU/d in men.9 The WHS used
a far higher dose of 600 IU every other day. Second, the lack of effect was
unlikely to be due to insufficient treatment duration, since this averaged
10 years in the WHS, representing the longest duration of any vitamin E trial.
Third, we considered whether the source of vitamin E used, a natural source,
influenced the findings. This was unlikely; 2 previous trials of secondary
prevention that reported a benefit of vitamin E also used a natural source.21,27 On the other hand, a previous trial
of secondary prevention, which included high-risk primary prevention patients,
used natural-source vitamin E and found no benefits on CVD,26 as
did another secondary prevention trial testing natural-source vitamin E combined
with other vitamins and minerals.31
Fourth, declining compliance over time in the WHS may have diluted the
findings. However, in sensitivity analyses in which follow-up time was censored
among women taking less than two thirds of their study pills, the finding
for cardiovascular events was little changed. Additionally, accounting for
outside use of vitamin E also did not make a difference.
Fifth, the hypothesis has been raised that antioxidants may adversely
interact with simvastatin and niacin treatment.31 We
did not systematically collect information on lipid-modifying therapy, but
we did so for hyperlipidemia. Among women who remained normolipemic throughout
the trial and who were unlikely to have taken lipid-modifying drugs, we observed
no significant effect of vitamin E on major cardiovascular events, providing
little support for an influence of lipid therapy on the WHS findings.
Finally, the possibility exists that γ-tocopherol, rather than
vitamin E (or α-tocopherol), may be the relevant compound for CVD prevention.53 γ-Tocopherol appears to have similar or greater
efficacy than α-tocopherol at inhibiting lipid peroxidation under oxyradical
systems and much more potency using nitration systems.53
With regard to the cancer end points, there are few data from randomized
trials of vitamin E.43,44,54 The
ATBC trial, conducted among men, observed a lower incidence of prostate cancer
among men assigned to receive 50 mg/d of vitamin E, but no effect on lung
or colon cancers.16,17 In the
HOPE-TOO trial, there was no significant effect of 400 IU/d of vitamin E on
cancer incidence or deaths, as in the WHS.38 There
was a lower incidence of lung cancer with vitamin E in HOPE-TOO, not reaching
the predefined level of statistical significance. We did not observe any effect
of vitamin E on lung cancer in the WHS. The SU.VI.MAX study reported significantly
lower cancer rates among men, but not women, randomized to a combination of
vitamins and minerals (including 30 mg/d of vitamin E).35 Among
poorly nourished persons randomized to a vitamin and mineral cocktail (including
30 mg/d of vitamin E), lower rates of stomach cancer occurred.14 This
was not seen in the WHS, but the number of stomach cancers was small. Taken
as a whole, the available data do not provide strong evidence for a role of
vitamin E in cancer prevention, particularly in well-nourished persons.
A recent meta-analysis raised concern for increased mortality with vitamin
E, especially in doses of 400 IU/d or greater.42 In
the WHS, using 600 IU every other day, there was no significant effect of
vitamin E on total mortality. There was no excess of cardiovascular (and,
indeed, fewer such deaths) or cancer deaths, the main causes of mortality,
in the vitamin E group. For the other main causes of death, there were more
deaths (but not statistically significant) from pulmonary disease, violent
deaths, and suicides in the vitamin E group.
Vitamin E was well tolerated in the WHS with no significant differences
in adverse effects between groups, except for epistaxis. This is likely to
be a chance finding because there were no differences in other adverse effects
from bleeding. Noteworthy was the observation of no increase in hemorrhagic
strokes with vitamin E, in contrast to the ATBC trial with an excess of deaths
from such strokes.16
In conclusion, the WHS does not support recommending vitamin E supplementation
for CVD or cancer prevention among healthy women. This large trial supports
current guidelines stating that use of antioxidant vitamins is not justified
for CVD risk reduction.55,56 The
WHS finding of a decreased cardiovascular death rate with vitamin E, as well
as decreased major cardiovascular events among women aged at least 65 years,
differs from the totality of evidence and should be explored further. The
WHS findings should be viewed in the context of the available randomized evidence,
as well as data that should be available over the next several years from
ongoing trials, including the Physicians’ Health Study, which will provide
data on primary prevention in men.57 At present,
in the primary prevention of CVD and cancer, therapeutic lifestyle changes
including a healthy diet and control of major risk factors remain important
clinical and public health strategies.
Corresponding Author: I-Min Lee, MBBS, ScD,
Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215
Author Contributions: Dr Lee had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Lee, Cook, Gaziano,
Gordon, Ridker, Manson, Hennekens, Buring.
Acquisition of data: Lee, Gaziano, Gordon,
Analysis and interpretation of data: Lee, Cook,
Gaziano, Ridker, Manson, Hennekens, Buring.
Drafting of the manuscript: Lee.
Critical revision of the manuscript for important
intellectual content: Lee, Cook, Gaziano, Gordon, Ridker, Manson, Hennekens,
Statistical analysis: Cook.
Obtained funding: Hennekens, Buring.
Administrative, technical, or material support:
Lee, Gaziano, Gordon, Ridker, Manson, Hennekens, Buring.
Study supervision: Lee, Gaziano, Gordon, Ridker,
Manson, Hennekens, Buring.
Financial Disclosures: Dr Cook has served as
a consultant to Bayer. Dr Gaziano has served as a consultant to and received
grant support from Bayer, DSM Nutritional Products Inc, and McNeil. Dr Ridker
has received grant support from Bayer. Dr Hennekens has served as a consultant
to Bayer and McNeil and received grant support from Bayer.
Funding/Support: This study was supported by
grants HL-43851 and CA-47988 from the National Heart, Lung, and Blood Institute
and the National Cancer Institute. Vitamin E and vitamin E placebo were provided
by the Natural Source Vitamin E Association. Aspirin and aspirin placebo (reported
on pp 47-55) were provided by Bayer Healthcare.
Role of the Sponsor: Neither the Natural Source
Vitamin E Association nor Bayer Healthcare provided any input into the design
and conduct of the study; collection, management, analysis, and interpretation
of the data; or preparation, review, or approval of the manuscript.
Data and Safety Monitoring Board: Lawrence
Cohen, Rory Collins, Theodore Colton, David DeMets, I. Craig Henderson, Andrea
La Croix, Ross Prentice, and Nanette Wenger (chair) and Mary Frances Cotch,
Frederick Ferris, Lawrence Friedman, Peter Greenwald, Natalie Kurinij, Marjorie
Perloff, Eleanor Schron, and Alan Zonderman (ex-officio members).
Acknowledgment: We are indebted to the 39 876
participants in the Women’s Health Study for their dedicated and conscientious
collaboration; to the entire staff of the Women’s Health Study, under
the leadership of David Gordon, Maria Andrade, Susan Burt, Mary Breen, Marilyn
Chown, Lisa Fields-Johnson, Georgina Friedenberg, Inge Judge, Jean MacFadyen,
Geneva McNair, Laura Pestana, Philomena Quinn, Claire Ridge, Harriet Samuelson,
Fred Schwerin and Marty Van Denburgh; to Christine Albert, Michelle Albert,
Gavin Blake, Claudia Chae, Wendy Chen, Richard Doll, Carlos Kase, Tobias Kurth,
Richard Peto, Aruna Pradhan, Kathryn Rexrode, Bernard Rosner, Jacqueline Suk,
and Shumin Zhang for their assistance in the design and conduct of the trial;
and especially to James Taylor for chairing the Endpoints Committee.