From: Subject: JAMA -- Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer: The Women's Health Study: A Randomized Controlled Trial, July 6, 2005, Lee et al. 294 (1): 56 Date: Thu, 20 Jul 2006 17:06:24 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0062_01C6AC1E.D4C9A920" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.2869 This is a multi-part message in MIME format. ------=_NextPart_000_0062_01C6AC1E.D4C9A920 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://jama.ama-assn.org/cgi/content/full/294/1/56?ijkey=078b620874ba9a136fb9cf5860db6168e11ce7ba JAMA -- Vitamin E in the Primary Prevention of = Cardiovascular Disease and Cancer: The Women's Health Study: A = Randomized Controlled Trial, July 6, 2005, Lee et al. 294 (1): = 56

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JAMA-EXPRESS
Vitamin E in the Primary Prevention of = Cardiovascular=20 Disease and Cancer

The Women=92s Health Study: A Randomized = Controlled=20 Trial

I-Min=20 Lee, MBBS, ScD; Nancy R. Cook, ScD; = J.=20 Michael Gaziano, MD; David Gordon, MA;=20 Paul M Ridker, MD; JoAnn E. Manson, MD,=20 DrPH; Charles H. Hennekens, MD, DrPH;=20 Julie E. Buring, ScD

JAMA. 2005;294:56-65.

ABSTRACT
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Context  Basic research provides = plausible=20 mechanisms and observational studies suggest that = apparently healthy persons, who self-select for = high=20 intakes of vitamin E through diet or supplements, = have=20 decreased risks of cardiovascular disease and = cancer.=20 Randomized trials do not generally support benefits = of=20 vitamin E, but there are few trials of long duration = among=20 initially healthy persons.

Objective  To test whether vitamin E = supplementation=20 decreases risks of cardiovascular disease and = cancer=20 among healthy women.

Design, Setting, and Participants  In the=20 Women=92s Health Study conducted between 1992 and = 2004,=20 39 876 apparently healthy US women aged at = least 45=20 years were randomly assigned to receive vitamin E = or=20 placebo and aspirin or placebo, using a = 2 x 2 factorial design, and = were=20 followed up for an average of 10.1 years. =

Intervention  Administration of 600 IU of=20 natural-source vitamin E on alternate days. =

Main Outcome Measures  Primary outcomes were = a=20 composite end point of first major cardiovascular = event=20 (nonfatal myocardial infarction, nonfatal stroke, = or=20 cardiovascular death) and total invasive = cancer.=20

Results  During follow-up, there were 482 = major=20 cardiovascular events in the vitamin E group and = 517 in=20 the placebo group, a nonsignificant 7% risk = reduction=20 (relative risk [RR], 0.93; 95% confidence = interval=20 [CI], 0.82-1.05; P =3D .26). = There were no=20 significant effects on the incidences of myocardial=20 infarction (RR,  1.01; 95% CI, 0.82-1.23;=20 P =3D .96) or stroke = (RR, 0.98; 95%=20 CI, 0.82-1.17; P =3D .82), as = well as=20 ischemic or hemorrhagic stroke. For cardiovascular = death,=20 there was a significant 24% reduction (RR, 0.76; 95% = CI,=20 0.59-0.98; P =3D .03). There was no = significant=20 effect on the incidences of total cancer (1437 cases = in=20 the vitamin E group and 1428 in the placebo = group; RR,=20 1.01; 95% CI, 0.94-1.08; = P =3D .87) or=20 breast (RR, 1.00; 95% CI, 0.90-1.12;=20 P =3D .95), lung (RR, 1.09; 95% CI, = 0.83-1.44;=20 P =3D .52), or colon cancers (RR, = 1.00; 95% CI,=20 0.77-1.31; P =3D .99). Cancer = deaths also=20 did not differ significantly between groups. = There was no=20 significant effect of vitamin E on total = mortality (636=20 in the vitamin E group and 615 in the placebo = group; RR,=20 1.04; 95% CI, 0.93-1.16; P =3D .53). =

Conclusions  The data from this large trial = indicated=20 that 600 IU of natural-source vitamin E taken = every other=20 day provided no overall benefit for major = cardiovascular=20 events or cancer, did not affect total mortality, = and=20 decreased cardiovascular mortality in healthy=20 women. These data do not support recommending=20 vitamin E supplementation for cardiovascular disease = or=20 cancer prevention among healthy women. =



INTRODUCTION
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 =95 Top
 =95 Introduction
 =95 Methods
 =95 Results
 =95 Comment
 =95 Conclusions
 =95 Author=20 information
 =95 References
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Free=20 radicals can cause lipid peroxidation and DNA damage,=20 contributing to the development of cardiovascular = disease=20 (CVD) and cancer.1-5=20 Vitamin E has antioxidant properties, including = inhibition=20 of oxidation of low-density lipoprotein = cholesterol in=20 plasma, leading to the hypothesis that it can = prevent=20 these chronic diseases.5=20 In some, but not all, basic research reports, vitamin = E=20 supplementation retarded atherogenesis.6=20 In descriptive data, investigators noted a strong = inverse=20 relation between plasma vitamin E concentrations = and=20 death rates from ischemic heart disease in men in = several=20 European countries.7=20 Additionally, several large cohort studies = observed=20 decreased CVD rates among individuals who = self-selected=20 for higher intakes of vitamin E through diet = and/or=20 supplements.8-10=20 By 1997, despite a lack of randomized trials, 44% = of US=20 cardiologists reported routine use of antioxidant = supplements, primarily vitamin E, compared with = 42% who=20 routinely used aspirin for the primary prevention = of=20 CVD.11With=20 regard to cancer, several observational studies,=20 particularly case-control studies, also reported = reduced=20 rates of cancer among persons who self-selected = for high=20 antioxidant intakes.12=20

For small to moderate effects, however, the amount of=20 uncontrolled and uncontrollable confounding = inherent in=20 observational studies can be as large as the = postulated=20 benefit, so randomized clinical trials represent = the most=20 reliable study design strategy.13=20 Several trials were therefore initiated beginning in = the=20 late 1980s to directly test the vitamin E=20 hypothesis.14-38=20 To date, data from randomized trials have largely = demonstrated no significant benefit of vitamin E=20 supplementation on the incidence of CVD or cancer = and,=20 indeed, raised the question of possible adverse = effects=20 on total mortality with high doses.39-44=20 However, these trials have been conducted = primarily among=20 participants with cardiovascular risk factors = and/or CVD=20 or at high risk for cancer. Few trials have = recruited=20 apparently healthy persons, with most designed to = examine=20 ophthalmologic outcomes.30,=20 33,=20 37=20 Only one trial, testing a combination of = antioxidant=20 vitamins and minerals, has investigated CVD and = cancer=20 prevention among healthy persons not selected = based on=20 risk factors.35=20 Additionally, the treatment duration in previous = trials=20 has generally been limited to 5 years or shorter, = with 6=20 trials having a longer duration.14-16,30,=20 35,=20 38=20 One possible explanation for the largely null = results of=20 randomized trials is that the duration of = supplementation=20 has been insufficient for an effect.45=20

To provide further information, the Women=92s Health = Study=20 (WHS) tested whether vitamin E supplementation for 10=20 years decreased risks of CVD and cancer in a = large group=20 of healthy women.


METHODS
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 =95 Introduction
 =95 Methods
 =95 Results
 =95 Comment
 =95 Conclusions
 =95 Author=20 information
 =95 References
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Study=20 Design

The WHS was a randomized, double-blind, = placebo-controlled,=20 2 x 2 = factorial=20 trial evaluating the balance of risks and = benefits of=20 low-dose aspirin (100 mg every other day; Bayer=20 Healthcare) and vitamin E (600 IU of 3D{alpha}=20-tocopherol every other day; = Natural Source=20 Vitamin E Association) in the primary prevention = of CVD=20 and cancer.46-47=20 Originally, a third component, beta carotene, was = also=20 included. However, this component was terminated = early in=20 January 1996 after a median treatment duration of 2.1=20 years.48=20 Written informed consent was obtained from all = participating=20 women. The trial was approved by the institutional = review=20 board of Brigham and Women=92s Hospital and = monitored by an=20 external data and safety monitoring board. =

Detailed methods of the design have been described=20 previously.46-47=20 Briefly, between September 1992 and May 1995, letters = of=20 invitation to participate in the trial and = baseline=20 health questionnaires were mailed to more than = 1.7=20 million female health care professionals = throughout the=20 United States (Figure=20 1). A total of 453 787 women completed = the=20 questionnaires and 65 169 were willing and = eligible=20 to participate. Eligibility criteria included the=20 following: age 45 years or older; no previous history = of=20 coronary heart disease, cerebrovascular disease, = cancer=20 (except nonmelanoma skin cancer), or other major = chronic=20 illnesses; no history of adverse effects from = aspirin; no=20 use of aspirin or nonsteroidal anti-inflammatory = drugs=20 (NSAIDs) more than once a week, or willingness to = forgo=20 their use; no use of anticoagulants or corticosteroids; = and no use of individual supplements of vitamin A, E, = or=20 beta carotene more than once a week. Eligible = women were=20 enrolled into a 3-month run-in period with = placebo=20 medications to identify likely long-term = compliers to=20 pill taking. Following the run-in period, = 39 876=20 women remained willing, eligible, and compliant, = and they=20 were randomized in blocks of 16 within 5-year age = strata=20 to vitamin E (n =3D 19 937) or placebo=20 (n =3D 19 939).



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Figure 1. Flow Diagram of = the=20 Vitamin E Component of the Women=92s = Health Study

*The numbers of deaths are higher than = those in=20 Table 2 because this figure includes all = reported=20 deaths in the WHS, whereas the deaths in = Table 2=20 include only reported deaths confirmed by = the=20 Endpoints Committee or by a death = certificate. =


Study Treatment and = Follow-up

Each year, women received calendar packs that contained=20 amber capsules (vitamin E or placebo) and white = pills=20 (aspirin or placebo) on alternate days. Every 6 = months=20 for the first year and annually thereafter, they = also=20 received follow-up questionnaires inquiring about = compliance with pill-taking, potential adverse = effects,=20 occurrence of end points, and risk factors. Study = medications=20 and end point ascertainment were continued in blinded=20 fashion through the scheduled end of the trial = (March 31,=20 2004). Follow-up and validation of reported end = points=20 were completed in February 2005. Morbidity and = mortality=20 follow-up were 97.2% and 99.4% complete,=20 respectively.

Using the information provided on questionnaires,=20 compliance, defined as taking at least two thirds = of the=20 study capsules, was 78.9% at 5 years and 71.6% at = 10=20 years. Averaged throughout the trial, it was = 75.8% with=20 no difference between active and placebo groups=20 (P =3D .64). Nontrial use of = individual=20 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.=20 Averaged throughout the trial, outside use was = somewhat=20 lower in the active (8.6%) than in the placebo = group=20 (8.9%) (P =3D .07).

Confirmation of End Points

The primary end points were a composite of first major=20 cardiovascular event (nonfatal myocardial = infarction=20 [MI], nonfatal stroke, or cardiovascular death) = and total=20 invasive cancer (apart from nonmelanoma skin = cancer).=20 Secondary end points were the individual = cardiovascular=20 events=97total MI, total stroke, and cardiovascular=20 death=97and the main site-specific cancers in women:=20 breast, lung, and colon cancers. We also = collected=20 information on coronary revascularization = procedures=20 (bypass surgery or percutaneous coronary = angioplasty),=20 transient ischemic attacks (TIAs), and total=20 mortality.

Women reported the occurrence of relevant end points via=20 follow-up questionnaires, letters, or telephone = calls.=20 Deaths were usually reported by family members or = postal=20 authorities or ascertained through the National = Death=20 Index. After obtaining written consent, we = acquired=20 medical records from hospitals and physicians, which = were=20 reviewed by the WHS Endpoints Committee of physicians = blinded=20 to randomized treatment assignment. The committee=20 confirmed a diagnosis of MI if symptoms met World = Health=20 Organization criteria and the event was = associated with=20 abnormal levels of cardiac enzymes or diagnostic=20 electrocardiograms. The use of coronary = revascularization=20 procedures was confirmed by medical record = review. Stroke=20 was confirmed if the participant had a new = neurologic=20 deficit of sudden onset that persisted for more = than 24=20 hours or until death within 24 hours. Clinical = information=20 and computed tomographic scans or magnetic resonance=20 images were used to distinguish hemorrhagic from = ischemic=20 strokes.49=20 A confirmed TIA was defined as a neurologic deficit of = sudden onset lasting less than 24 hours. = Cardiovascular=20 deaths were confirmed by autopsy reports, death=20 certificates, medical records, and information = from next=20 of kin or family members. The vast majority = (96.8%) of=20 cancers were confirmed with pathology or cytology = reports. Rarely, the committee confirmed a reported = case=20 of cancer based on strong clinical and radiological or=20 laboratory marker evidence (eg, elevated CA-125) when=20 pathology or cytology review was not conducted. = Total=20 mortality was confirmed by the committee or by = obtaining=20 a death certificate. Only confirmed end points = are=20 included in this report.

Statistical Analysis

All primary analyses were performed on an = intention-to-treat=20 basis (ie, based on all randomized persons, as=20 randomized), using the SAS statistical software = package=20 (release 8.2; SAS Institute Inc, Cary, NC). We = used Cox=20 proportional hazards regression models to = calculate the=20 relative risks (RRs) and 95% confidence intervals = (95%=20 CIs), comparing event rates in the vitamin E and = placebo=20 groups, after adjustment for age and randomized = aspirin=20 and beta carotene assignments. Statistical significance = was set at P<.05, using 2-sided tests. To = test the=20 proportionality assumption (ie, that of = nonchanging RRs=20 over time), we included an interaction term of = vitamin E=20 with the logarithm of time in the Cox models. The = proportionality assumption was not violated for = major=20 cardiovascular events (P =3D .16), total=20 invasive cancer (P =3D .72), or = total=20 mortality (P =3D .81). We = conducted=20 subgroup analyses stratified by major risk factors = for=20 CVD and cancer, and assessed effect modification using=20 interaction terms between subgroup indicators and = vitamin=20 E assignment, testing for trend when subgroup = categories=20 were ordinal. To investigate the effect of = compliance, we=20 carried out a sensitivity analysis that censored=20 follow-up for any participant at the time when = she=20 reported taking less than two thirds of study = medications=20 over the previous year.


RESULTS
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 =95 Methods
 =95 Results
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 =95 Conclusions
 =95 Author=20 information
 =95 References
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The mean=20 (SD) age of participants at baseline was 54.6 (7.0)=20 years; other clinical characteristics are shown in Table=20 1. As expected in this very large sample,=20 randomization was effective in balancing the=20 characteristics of women in the vitamin E and = placebo=20 groups. The average duration of follow-up from = randomization=20 to the end of the trial was 10.1 years (range, = 8.2-10.9=20 years).


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Table 1. Baseline = Characteristics of=20 Women by Group, Women=92s Health Study =


Cardiovascular Disease

By the end of the trial, 999 major cardiovascular events=20 (253 per 100 000 person-years) had occurred: = 482 in=20 the vitamin E group and 517 in the placebo group = (Table=20 2). This corresponded to a nonsignificant 7% = risk=20 reduction with vitamin E (RR, 0.93; 95% CI, = 0.82-1.05;=20 P =3D .26). For the individual = cardiovascular=20 events, vitamin E had no effect on total MI (RR, 1.01; = 95%=20 CI, 0.82-1.23) or total stroke (RR, 0.98; 95% CI, = 0.82-1.17). For stroke subtypes, there was no = reduction=20 in ischemic or increase in hemorrhagic stroke = rates.=20 There was a significant 24% reduction in = cardiovascular=20 deaths among women in the vitamin E group (RR, = 0.76; 95%=20 CI, 0.59-0.98). This was largely attributable to = fewer=20 sudden deaths in the vitamin E group (38 vs 51 among=20 women assigned to placebo) and fewer deaths from other = cardiovascular disease (ie, deaths due to = cardiovascular=20 diseases other than ischemic heart disease and=20 cerebrovascular disease, 20 vs 34, respectively). = There=20 was no significant effect of vitamin E on = coronary=20 revascularization procedures (394 vs 369, respectively) = or TIA (212 in each group).


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Table 2. Relative Risks of = Cardiovascular Disease, Cancer, and Total=20 Mortality by Group, Women=92s Health Study =


Figure=20 2 shows the cumulative incidence rates of major=20 cardiovascular events among women in the 2 groups = by year=20 of follow-up. An apparent benefit of vitamin E on = major=20 cardiovascular events, as well as on the = individual end=20 points of MI, stroke, and cardiovascular death, = was=20 observed early in the trial. The effect on major=20 cardiovascular events diminished over time and = disappeared=20 for MI and stroke by the end of the trial. In = contrast,=20 the difference in cardiovascular death rates = between=20 active and placebo groups appeared to increase = over time;=20 however, the change in RRs over time was not = significant=20 (P =3D .59). Because compliance = diminishes=20 over time, we examined whether the observed trends = might=20 have been due to this tendency. In a sensitivity = analysis=20 that censored noncompliant (taking less than two = thirds of=20 study medications) follow-up time, there was no = evidence=20 that noncompliance influenced the findings (RR = for major=20 cardiovascular events, 0.96; 95% CI, 0.82-1.11;=20 P =3D .56).



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Figure 2. Cumulative = Incidence Rates=20 of Cardiovascular Disease

The composite cardiovascular end point = (the=20 first of any of the individual end points) = is=20 reported as well as the individual end = points of=20 myocardial infarction, stroke, and = cardiovascular=20 death. =


As reported previously, aspirin was associated with a=20 nonsignificant 9% reduction in major = cardiovascular=20 events.47=20 We therefore examined whether random assignment = to=20 aspirin modified the effect of vitamin E. There = was no=20 modification of the effect of vitamin E by random = assignment to aspirin (Table=20 3). Beta carotene also did not modify the = effect of=20 vitamin E on the primary or secondary end points = (data=20 not shown).


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Table 3. Relative Risks of = Cardiovascular Disease and Cancer = According to=20 Baseline Characteristics, Women=92s Health = Study =


We examined whether cardiovascular risk factors modified = the=20 relation between vitamin E and major cardiovascular = events (Table=20 3). In particular, we were interested in = whether=20 levels of oxidative stress may modify the effect = of=20 vitamin E.50=20 We did not have a direct measure of oxidative = stress;=20 however, smoking and diseases such as = hypertension,=20 hyperlipidemia, and diabetes are associated with=20 increased production of reactive oxygen species in the=20 vascular wall.51=20 Using these indirect markers (all self-reported), = we=20 found no evidence of benefit of vitamin E among persons = with=20 increased oxidative stress. Additionally, no benefit = was=20 observed among both users and nonusers of = multivitamins,=20 who would presumably have lower and higher levels = of=20 oxidative stress, respectively.

There also was no statistically significant effect=20 modification by any of the other factors = considered,=20 except age (P =3D .008). In = subgroup=20 analyses, women aged at least 65 years comprised = 10% of=20 study participants but contributed 31% of end points. = A=20 significant 26% reduction in major cardiovascular events = was=20 observed among women aged at least 65 years assigned = to=20 vitamin E (RR, 0.74; 95% CI, 0.59-0.93;=20 P =3D .009) due to a 34% = reduction in MI=20 (RR, 0.66; 95% CI, 0.45-0.98; = P =3D .04)=20 and 49% reduction in cardiovascular death (RR, 0.51; = 95%=20 CI, 0.33-0.77; P<.001) rates. However, = no=20 reduction in stroke rate was observed (RR, 0.88; = 95% CI,=20 0.64-1.21; P =3D .44). Among = women aged 45=20 through 54 and 55 through 64 years, the RRs for = major=20 cardiovascular events were 1.13 (95% CI, 0.91-1.41;=20 P =3D .26) and 0.95 (95% CI, = 0.77-1.16;=20 P =3D .61), respectively. =

Cancer

During the trial, 2865 women developed invasive cancer = (741=20 events per 100000 person-years): 1437 in the vitamin E = group and 1428 in the placebo group (RR, 1.01; = 95% CI,=20 0.94-1.08; P =3D .87; Table=20 2). Further analyses that excluded the first = 2 or 5=20 years of follow-up did not change the findings = (data not=20 shown). For the main site-specific cancers, there = were no=20 significant differences between the vitamin E and = placebo=20 groups (breast cancer: RR, 1.00; 95% CI, 0.90-1.12; = lung=20 cancer: RR, 1.09; 95% CI, 0.83-1.44; and colon = cancer:=20 RR, 1.00; 95% CI, 0.77-1.31). There also was no=20 significant difference in rectal cancer rates (22 = vs 33=20 cases in the vitamin E and placebo groups, = respectively).=20 A previous study in a poorly nourished population = reported lower rates of stomach cancer among those=20 randomized to a vitamin and mineral cocktail including = vitamin E.14=20 We did not observe this in our healthy population (14 = vs=20 6 cases of stomach cancer, respectively). Cancer death = rates also were not significantly influenced by = vitamin E=20 (308 vs 275 cancer deaths, respectively; RR, = 1.12; 95%=20 CI, 0.95-1.32; P =3D .17). =

Including in situ and invasive cancers in the analysis = led=20 to virtually unchanged findings (1626 vs 1615 = cases,=20 respectively; RR, 1.01; 95% CI, 0.94-1.08;=20 P =3D .84).

When we examined cumulative incidence rates of invasive=20 cancer by year of follow-up, the curves were = almost=20 identical in the vitamin E and placebo groups (Figure=20 3). Additional analyses that censored = noncompliant=20 (taking less than two thirds of study = medications)=20 follow-up time continued to show a lack of effect = of=20 vitamin E on total invasive cancer (RR, 1.01; 95% CI,=20 0.93-1.09; P =3D .88). =



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Figure 3. Cumulative = Incidence Rates=20 of Cancer =


As with major cardiovascular events, random assignment to = neither aspirin nor beta carotene modified the = effect of=20 vitamin E on the primary or secondary cancer end = points.=20 Additionally, there was no significant effect=20 modification by any of the cancer risk factors = shown in=20 Table=20 3.

Total Mortality

By the end of the trial, 636 women in the vitamin E group = had died, as had 615 women in the placebo group = (RR,=20 1.04; 95% CI, 0.93-1.16; = P =3D .53). The=20 main causes of death, apart from cardiovascular = and=20 cancer deaths, were pulmonary diseases (32 = vitamin E, 22=20 placebo); violent deaths, excluding suicide (31 = vs 21);=20 and suicide (9 vs 6). None of these causes of deaths = was=20 significantly related to vitamin E.

In analysis that censored noncompliant follow-up time, = there=20 also was no significant effect of vitamin E (RR, 1.08; = 95%=20 CI, 0.90-1.29; P =3D .42). =

There was no effect of random assignment to either = aspirin=20 or beta carotene on the effect of vitamin E on = total=20 mortality. There also was no significant effect = of any of=20 the cardiovascular and cancer risk factors in Table=20 3 on the association of vitamin E with total=20 mortality.

Adverse Effects

We examined whether vitamin E increased adverse effects = due=20 to bleeding (gastrointestinal bleeding, hematuria, = easy=20 bruising, epistaxis) because of the potential for = vitamin=20 E to inhibit platelet function,52=20 gastrointestinal symptoms (gastric upset, nausea, = diarrhea, constipation), or fatigue. There were no = differences=20 between reported adverse effects for any of these=20 variables among women in the 2 groups, apart from = a=20 small, but significant, increase in the risk of = epistaxis=20 (RR, 1.06; 95% CI, 1.01-1.11;=20 P =3D .02).


COMMENT
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 Jump to=20 Section
 =95 Top
 =95 Introduction
 =95 Methods
 =95 Results
 =95 Comment
 =95 Conclusions
 =95 Author=20 information
 =95 References
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The WHS=97the=20 largest randomized trial of vitamin E supplementation = to=20 date with the longest duration of treatment=97adds = important=20 information regarding whether vitamin E plays any role = in=20 CVD and cancer prevention. In this trial, 600 IU = of=20 natural-source vitamin E every other day for 10 = years did=20 not provide any statistically significant = benefits on the=20 primary end points of major cardiovascular events = or=20 cancer in almost 40 000 healthy women. There = was,=20 however, a significant 24% reduction in the secondary = end=20 point of cardiovascular deaths and a significant 26%=20 reduction in major cardiovascular events among = the=20 subgroup of women aged at least 65 years. We = observed no=20 significant effect of vitamin E on total = mortality.=20

The finding of no overall effect of vitamin E on CVD is=20 congruent with data from previous randomized = trials. In 2=20 recent meta-analyses, the pooled RR of CVD with = vitamin E=20 treatment was 1.0 (95% CI, 0.94-1.07) in a 2003=20 analysis40=20 and 0.98 (95% CI, 0.94-1.03) in a 2004 = analysis.41=20 These trials, however, recruited participants at = high=20 risk either because of CVD risk factors or preexisting=20 disease. There are few data on populations comparable = with=20 the healthy women in the WHS. A recently = published trial=20 not included in either meta-analysis, the = SU.VI.MAX=20 study,35=20 like the WHS, enrolled primarily healthy persons. = After=20 7.5 years, the SU.VI.MAX trial also reported no = effect of=20 randomized treatment using a combination of = vitamins and=20 minerals, including 30 mg/d of vitamin E, on CVD = (RR,=20 0.97; 95% CI, 0.77-1.20).

With regard to the individual cardiovascular end points, = we=20 found a significant 24% reduction in cardiovascular=20 deaths. This finding differs from the overall = data; in=20 the 2003 meta-analysis, the pooled RR for this = end point=20 was 1.0 (95% CI, 0.94-1.06)40=20 and 1.00 (95% CI, 0.94-1.05) in the 2004 = meta-analysis.41=20 The addition of the WHS data (106 cardiovascular = deaths=20 in the vitamin E group, 140 in the placebo group) = to the=20 latter and larger meta-analysis (2683 and 2689=20 cardiovascular deaths, respectively) should not = have an=20 appreciable impact on the pooled RR. In the WHS, = the=20 single largest contribution to the reduction in = cardiovascular=20 deaths was fewer sudden deaths among women assigned to = receive vitamin E. One plausible explanation that = we=20 considered was whether omega-3 fatty acids in the = treatment capsules may have played a role.24=20 This is unlikely, however, because both active = and=20 placebo capsules were identically formulated with = soybean=20 oil, the only difference being the addition of vitamin = E=20 to the active capsules. It is possible that the = observed=20 reduction in cardiovascular deaths was due to = chance,=20 arising from multiple comparisons.

An interesting finding in subgroup analyses was the=20 observation of a significant 26% reduction in = major=20 cardiovascular events, primarily cardiovascular = deaths,=20 among women aged at least 65 years. Few previous = trials=20 of vitamin E have reported findings by age. The = one that=20 did, the HOPE trial, enrolled participants aged = at least=20 55 years with CVD, or diabetes and one other risk = factor,=20 and reported no overall effect of vitamin E on CVD and = no=20 heterogeneity of results by age.26=20 Several large observational studies that noted = inverse=20 associations between vitamin E intake and CVD = rates did=20 not provide findings by age.8-10=20 Existing trials of vitamin E can help clarify = this by=20 providing findings regarding any age = effects.

A recent trial, HOPE-TOO, noted a possible adverse effect = of=20 400 IU/d of vitamin E on the risk of heart = failure.38=20 This was not a prespecified end point in the WHS; = however, we did collect self-reported = information, which=20 did not demonstrate any association between = random=20 assignment to vitamin E use and incidence of = heart=20 failure. These self-reports are currently being = validated=20 against medical records.

In view of the lack of overall benefit of vitamin E on=20 cardiovascular events in the WHS, we considered = several=20 factors. First, was the dose of vitamin E = sufficient?=20 Previous observational studies have reported = significant=20 benefits in women8=20 with a median intake of as little as 17 IU/d and = 25.2=20 IU/d in men.9=20 The WHS used a far higher dose of 600 IU every = other day.=20 Second, the lack of effect was unlikely to be due = to=20 insufficient treatment duration, since this = averaged 10=20 years in the WHS, representing the longest = duration of=20 any vitamin E trial. Third, we considered whether = the=20 source of vitamin E used, a natural source, influenced = the=20 findings. This was unlikely; 2 previous trials of=20 secondary prevention that reported a benefit of = vitamin E=20 also used a natural source.21,=20 27=20 On the other hand, a previous trial of secondary=20 prevention, which included high-risk primary prevention = patients, used natural-source vitamin E and found no=20 benefits on CVD,26=20 as did another secondary prevention trial testing=20 natural-source vitamin E combined with other vitamins = and=20 minerals.31=20

Fourth, declining compliance over time in the WHS may = have=20 diluted the findings. However, in sensitivity = analyses in=20 which follow-up time was censored among women = taking less=20 than two thirds of their study pills, the finding = for=20 cardiovascular events was little changed. = Additionally,=20 accounting for outside use of vitamin E also did = not make=20 a difference.

Fifth, the hypothesis has been raised that antioxidants = may=20 adversely interact with simvastatin and niacin=20 treatment.31=20 We did not systematically collect information on=20 lipid-modifying therapy, but we did so for=20 hyperlipidemia. Among women who remained = normolipemic=20 throughout the trial and who were unlikely to have = taken=20 lipid-modifying drugs, we observed no significant = effect=20 of vitamin E on major cardiovascular events, providing = little support for an influence of lipid therapy = on the=20 WHS findings.

Finally, the possibility exists that 3D{gamma}=20-tocopherol,=20 rather than vitamin E (or 3D{alpha}=20-tocopherol),=20 may be the relevant compound for CVD = prevention.53=20 3D{gamma}-Tocopherol appears to have similar or = greater=20 efficacy than 3D{alpha}=20-tocopherol=20 at inhibiting lipid peroxidation under oxyradical = systems=20 and much more potency using nitration systems.53=20

With regard to the cancer end points, there are few data=20 from randomized trials of vitamin E.43-44,54=20 The ATBC trial, conducted among men, observed a = lower=20 incidence of prostate cancer among men assigned = to=20 receive 50 mg/d of vitamin E, but no effect on = lung or=20 colon cancers.16-17=20 In the HOPE-TOO trial, there was no significant = effect of=20 400 IU/d of vitamin E on cancer incidence or = deaths, as=20 in the WHS.38=20 There was a lower incidence of lung cancer with = vitamin E=20 in HOPE-TOO, not reaching the predefined level of = statistical significance. We did not observe any = effect=20 of vitamin E on lung cancer in the WHS. The SU.VI.MAX=20 study reported significantly lower cancer rates among = men,=20 but not women, randomized to a combination of = vitamins=20 and minerals (including 30 mg/d of vitamin = E).35=20 Among poorly nourished persons randomized to a = vitamin=20 and mineral cocktail (including 30 mg/d of = vitamin E),=20 lower rates of stomach cancer occurred.14=20 This was not seen in the WHS, but the number of = stomach=20 cancers was small. Taken as a whole, the = available data=20 do not provide strong evidence for a role of = vitamin E in=20 cancer prevention, particularly in well-nourished = persons.

A recent meta-analysis raised concern for increased=20 mortality with vitamin E, especially in doses of = 400 IU/d=20 or greater.42=20 In the WHS, using 600 IU every other day, there was no = significant effect of vitamin E on total = mortality. There=20 was no excess of cardiovascular (and, indeed, = fewer such=20 deaths) or cancer deaths, the main causes of = mortality,=20 in the vitamin E group. For the other main causes = of=20 death, there were more deaths (but not = statistically=20 significant) from pulmonary disease, violent = deaths, and=20 suicides in the vitamin E group.

Vitamin E was well tolerated in the WHS with no = significant=20 differences in adverse effects between groups, except = for=20 epistaxis. This is likely to be a chance finding = because=20 there were no differences in other adverse = effects from=20 bleeding. Noteworthy was the observation of no = increase=20 in hemorrhagic strokes with vitamin E, in = contrast to the=20 ATBC trial with an excess of deaths from such=20 strokes.16=20


CONCLUSIONS
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In=20 conclusion, the WHS does not support recommending = vitamin=20 E supplementation for CVD or cancer prevention among=20 healthy women. This large trial supports current=20 guidelines stating that use of antioxidant = vitamins is=20 not justified for CVD risk reduction.55-56=20 The WHS finding of a decreased cardiovascular = death rate=20 with vitamin E, as well as decreased major = cardiovascular=20 events among women aged at least 65 years, differs = from=20 the totality of evidence and should be explored = further.=20 The WHS findings should be viewed in the context = of the=20 available randomized evidence, as well as data = that=20 should be available over the next several years = from=20 ongoing trials, including the Physicians=92 = Health Study,=20 which will provide data on primary prevention in=20 men.57=20 At present, in the primary prevention of CVD and = cancer,=20 therapeutic lifestyle changes including a healthy diet = and=20 control of major risk factors remain important = clinical=20 and public health strategies.


AUTHOR INFORMATION
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Corresponding Author: I-Min Lee, MBBS, = ScD,=20 Brigham and Women=92s Hospital, 900 Commonwealth = Ave E,=20 Boston, MA 02215 (ilee{at}rics.bwh.harvard.edu ).

Author Contributions: Dr Lee had full access to = all of the=20 data in the study and takes responsibility for = the=20 integrity of the data and the accuracy of the = data=20 analysis.

Study concept and design: Lee, Cook, Gaziano, = Gordon,=20 Ridker, Manson, Hennekens, Buring.

Acquisition of data: Lee, Gaziano, Gordon, = Hennekens,=20 Buring.

Analysis and interpretation of data: Lee, Cook, = Gaziano,=20 Ridker, Manson, Hennekens, Buring.

Drafting of the manuscript: Lee.

Critical revision of the manuscript for important=20 intellectual content: Lee, Cook, Gaziano, = Gordon,=20 Ridker, Manson, Hennekens, Buring.

Statistical analysis: Cook.

Obtained funding: Hennekens, Buring.

Administrative, technical, or material support: = Lee,=20 Gaziano, Gordon, Ridker, Manson, Hennekens, = Buring.=20

Study supervision: Lee, Gaziano, Gordon, Ridker, = Manson,=20 Hennekens, Buring.

Financial Disclosures: Dr Cook has served as a = consultant=20 to Bayer. Dr Gaziano has served as a consultant = to and=20 received grant support from Bayer, DSM = Nutritional=20 Products Inc, and McNeil. Dr Ridker has received = grant=20 support from Bayer. Dr Hennekens has served as a=20 consultant to Bayer and McNeil and received grant = support=20 from Bayer.

Funding/Support: This study was supported by = grants=20 HL-43851 and CA-47988 from the National Heart, = Lung, and=20 Blood Institute and the National Cancer = Institute.=20 Vitamin E and vitamin E placebo were provided by = the=20 Natural Source Vitamin E Association. Aspirin and = aspirin=20 placebo (reported on pp 47-55) were provided by = Bayer=20 Healthcare.

Role of the Sponsor: Neither the Natural Source = Vitamin E=20 Association nor Bayer Healthcare provided any = input into=20 the design and conduct of the study; collection,=20 management, analysis, and interpretation of the = data; or=20 preparation, review, or approval of the = manuscript.=20

Data and Safety Monitoring Board: Lawrence Cohen, = Rory=20 Collins, Theodore Colton, David DeMets, I. Craig=20 Henderson, Andrea La Croix, Ross Prentice, and = Nanette=20 Wenger (chair) and Mary Frances Cotch, Frederick = Ferris,=20 Lawrence Friedman, Peter Greenwald, Natalie = Kurinij,=20 Marjorie Perloff, Eleanor Schron, and Alan = Zonderman=20 (ex-officio members).

Acknowledgment: We are indebted to the 39 876 = participants in the Women=92s Health Study for = their=20 dedicated and conscientious collaboration; to the = entire=20 staff of the Women=92s Health Study, under the = leadership=20 of David Gordon, Maria Andrade, Susan Burt, Mary = Breen,=20 Marilyn Chown, Lisa Fields-Johnson, Georgina = Friedenberg,=20 Inge Judge, Jean MacFadyen, Geneva McNair, Laura = Pestana,=20 Philomena Quinn, Claire Ridge, Harriet Samuelson, = Fred=20 Schwerin and Marty Van Denburgh; to Christine Albert, = Michelle=20 Albert, Gavin Blake, Claudia Chae, Wendy Chen, Richard = Doll, Carlos Kase, Tobias Kurth, Richard Peto, = Aruna=20 Pradhan, Kathryn Rexrode, Bernard Rosner, = Jacqueline Suk,=20 and Shumin Zhang for their assistance in the = design and=20 conduct of the trial; and especially to James = Taylor for=20 chairing the Endpoints Committee.

Author=20 Affiliations: Divisions of Preventive Medicine (Drs Lee, = Cook,=20 Gaziano, Ridker, Manson, and Buring and Mr Gordon), = Cardiovascular=20 Medicine (Drs Gaziano and Ridker), and Aging (Drs Gaziano = and=20 Buring), Department of Medicine, Brigham and Women=92s = Hospital,=20 Harvard Medical School, Boston, Mass; Department of = Epidemiology,=20 Harvard School of Public Health, Boston (Drs Lee, Cook, = Ridker,=20 Manson, and Buring); Veterans Affairs Boston Healthcare = System (Dr=20 Gaziano); Department of Ambulatory Care and Prevention, = Harvard=20 Medical School, Boston (Dr Buring); and the Departments of = Medicine=20 and Epidemiology and Public Health, University of Miami = School of=20 Medicine, Miami, Fla, and Department of Biomedical Science, = Center=20 of Excellence, Florida Atlantic University, Boca Raton (Dr=20 Hennekens).


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 =95 Introduction
 =95 Methods
 =95 Results
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 =95 Author=20 information
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