Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer The Women’s Health Study: A Randomized Controlled Trial I-Min Lee, MBBS, ScD Nancy R. Cook, ScD J. Michael Gaziano, MD David Gordon, MA Paul M Ridker, MD JoAnn E. Manson, MD, DrPH Charles H. Hennekens, MD, DrPH Julie E. Buring, ScD

FREE RADICALS CAN CAUSE LIPIDperoxidation and DNA dam-age, contributing to the devel-opment of cardiovascular dis- ease (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 vita- min E concentrations and death rates from ischemic heart disease in men in several European countries.7 Addi- tionally, 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 rou- tine use of antioxidant supplements,

primarily vitamin E, compared with 42% who routinely used aspirin for the primary prevention of CVD.11See also pp 47 and 105.

Author Affiliations are listed at the end of this article. Corresponding Author: I-Min Lee, MBBS, ScD, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215 ([email protected]).

Context Basic research provides plausible mechanisms and observational studies sug- gest 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. Ran- domized trials do not generally support benefits of vitamin E, but there are few trials of long duration among initially healthy persons.

Objective To test whether vitamin E supplementation decreases risks of cardiovas- cular disease and cancer among healthy women.

Design, Setting, and Participants In the Women’s Health Study conducted be- tween 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 cardio- vascular death) and total invasive cancer.

Results During follow-up, there were 482 major cardiovascular events in the vita- min E group and 517 in the placebo group, a nonsignificant 7% risk reduction (rela- tive 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 inci- dences 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 mor- tality in healthy women. These data do not support recommending vitamin E supplementation for cardiovascular disease or cancer prevention among healthy women. JAMA. 2005;294:56-65 www.jama.com

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With regard to cancer, several obser- vational 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, how- ever, 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 reli- able study design strategy.13 Several trials were therefore initiated begin- ning 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 in- cidence of CVD or cancer and, in- deed, raised the question of possible ad- verse 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 ap- parently healthy persons, with most de- signed to examine ophthalmologic out- comes.30,33,37 Only one trial, testing a combination of antioxidant vitamins and minerals, has investigated CVD and cancer prevention among healthy per- sons not selected based on risk fac- tors.35 Additionally, the treatment du- ration in previous trials has generally been limited to 5 years or shorter, with 6 trials having a longer dura- tion.14-16,30,35,38 One possible explana- tion for the largely null results of ran- domized 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 can- cer in a large group of healthy women.

METHODS Study Design

The WHS was a randomized, double- blind, placebo-controlled, 2�2 facto- rial 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 ev- ery other day; Natural Source Vitamin E Association) in the primary preven- tion of CVD and cancer.46,47 Originally, a third component, beta carotene, was also included. However, this compo- nent was terminated early in January 1996 after a median treatment dura- tion of 2.1 years.48 Written informed consent was obtained from all partici- pating 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, be- tween September 1992 and May 1995, letters of invitation to participate in the trial and baseline health question- naires were mailed to more than 1.7 mil- lion 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. Eli- gibility criteria included the follow- ing: age 45 years or older; no previous history of coronary heart disease, cere- brovascular 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-inflamma- tory drugs (NSAIDs) more than once a week, or willingness to forgo their use; no use of anticoagulants or corticoste- roids; and no use of individual supple- ments of vitamin A, E, or beta caro- tene more than once a week. Eligible women were enrolled into a 3-month run-in period with placebo medica- tions to identify likely long-term com- pliers to pill taking. Following the run-in period, 39 876 women re- mained willing, eligible, and compli- ant, and they were randomized in blocks of 16 within 5-year age strata to vitamin E (n = 19 937) or placebo (n=19 939).

Study Treatment and Follow-up

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, po- tential adverse effects, occurrence of end points, and risk factors. Study medica- tions 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 mortal- ity 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 through- out the trial, it was 75.8% with no dif- ference between active and placebo groups (P=.64). Nontrial use of indi- vidual supplements of vitamin E for at least 4 days per month (“drop-ins”) was

Figure 1. Flow Diagram of the Vitamin E Component of the Women’s Health Study

65 169 Entered the Run-in Phase

453 787 Completed Baseline Questionnaire

1.7 Million Women Invited to Participate

19 937 Assigned to Receive Vitamin E

19 939 Assigned to Receive Placebo

25 293 Excluded After Run-in (Noncompliance, Unwillingness, or Ineligibility)

Status on March 31, 2004 19 124 Alive

681 Dead∗

132 Unknown Vital Status

Status on March 31, 2004 19 156 Alive

681 Dead∗

102 Unknown Vital Status

19 937 Included in Primary Analysis

19 939 Included in Primary Analysis

39 876 Randomized

*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 Com- mittee or by a death certificate.

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10.0% at 5 years and 10.9% at 10 years. Averaged throughout the trial, out- side use was somewhat lower in the ac- tive (8.6%) than in the placebo group (8.9%) (P=.07).

Confirmation of End Points

The primary end points were a compos- ite 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 cardio- vascular 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 re- vascularization procedures (bypass sur- gery or percutaneous coronary angio- plasty), transient ischemic attacks (TIAs), and total mortality.

Women reported the occurrence of relevant end points via follow-up ques- tionnaires, letters, or telephone calls. Deaths were usually reported by family members or postal authorities or ascer- tainedthroughtheNationalDeathIndex. After obtaining written consent, we acquired medical records from hospi- talsandphysicians,whichwerereviewed by the WHS Endpoints Committee of physicians blinded to randomized treat- ment assignment. The committee con- firmedadiagnosisofMI if symptomsmet World Health Organization criteria and the event was associated with abnor- mal levels of cardiac enzymes or diag- nostic electrocardiograms. The use of coronary revascularization procedures wasconfirmedbymedical recordreview. 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 reso- nance images were used to distinguish hemorrhagic from ischemic strokes.49 A confirmed TIA was defined as a neuro- logic 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 pathol- ogy or cytology reports. Rarely, the com- mittee confirmed a reported case of can- cer based on strong clinical and radiological or laboratory marker evi- dence (eg, elevated CA-125) when pathology or cytology review was not conducted. Total mortality was con- firmed by the committee or by obtain- ing a death certificate. Only confirmed end points are included in this report.

Statistical Analysis

All primary analyses were performed on an intention-to-treat basis (ie, based on all randomized persons, as random- ized), 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% confi- dence intervals (95% CIs), comparing event rates in the vitamin E and pla- cebo groups, after adjustment for age and randomized aspirin and beta carotene as- signments. Statistical significance was set at P�.05, using 2-sided tests. To test the proportionality assumption (ie, that of nonchanging RRs over time), we in- cluded an interaction term of vitamin E with the logarithm of time in the Cox models. The proportionality assump- tion was not violated for major cardio- vascular events (P=.16), total invasive cancer (P = .72), or total mortality (P=.81). We conducted subgroup analy- ses stratified by major risk factors for CVD and cancer, and assessed effect modification using interaction terms be- tween subgroup indicators and vita- min E assignment, testing for trend when subgroup categories were ordinal. To in- vestigate the effect of compliance, we carried out a sensitivity analysis that cen- sored follow-up for any participant at the time when she reported taking less than two thirds of study medications over the previous year.

RESULTS 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).

Cardiovascular Disease

By the end of the trial, 999 major car- diovascular events (253 per 100 000 per- son-years) had occurred: 482 in the vi- tamin 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 cardio- vascular 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 in- crease in hemorrhagic stroke rates. There was a significant 24% reduction in car- diovascular 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 as- signed to placebo) and fewer deaths from other cardiovascular disease (ie, deaths due to cardiovascular diseases other than ischemic heart disease and cerebrovas- cular disease, 20 vs 34, respectively). There was no significant effect of vita- min E on coronary revascularization pro- cedures (394 vs 369, respectively) or TIA (212 in each group).

FIGURE 2 shows the cumulative in- cidence rates of major cardiovascular events among women in the 2 groups by year of follow-up. An apparent ben- efit of vitamin E on major cardiovas- cular events, as well as on the indi- vidual 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 ap- peared to increase over time; how- ever, the change in RRs over time was not significant (P=.59). Because com-

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pliance diminishes over time, we ex- amined 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) fol- low-up time, there was no evidence that noncompliance influenced the find- ings (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 aspi- rin 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 cardiovascu- lar risk factors modified the relation be- tween vitamin E and major cardiovas- cular events (Table 3). In particular, we were interested in whether levels of oxi- dative 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 hyper- tension, hyperlipidemia, and diabetes are associated with increased produc- tion 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 oxida- tive stress. Additionally, no benefit was observed among both users and non- users of multivitamins, who would pre- sumably have lower and higher levels of oxidative stress, respectively.

There also was no statistically signifi- cant 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% reduc- tion 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 car- diovascular 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.

Cancer

During the trial, 2865 women devel- oped invasive cancer (741 events per

Table 1. Baseline Characteristics of Women by Group, Women’s Health Study

Characteristic

No. (%)*

P Value

Vitamin E (n = 19 937)

Placebo (n = 19 939)

Total (N = 39 876)

Age, y Mean (SD) 54.6 (7.0) 54.6 (7.0) 54.6 (7.0) .94

45-54 12 016 (60.3) 12 009 (60.2) 24 025 (60.2)

55-64 5878 (29.5) 5876 (29.5) 11 754 (29.5) .98

�65 2043 (10.3) 2054 (10.3) 4097 (10.3)

Smoking status Current 2590 (13.0) 2645 (13.3) 5235 (13.1)

.42 Past or never 17 328 (87.0) 17 277 (86.7) 34 605 (86.9)

Alcohol intake Never/rarely 9057 (45.4) 8925 (44.8) 17 982 (45.1)

.18 At least 1/mo 10 873 (54.6) 11 011 (55.2) 21 884 (54.9)

Multivitamin use 7807 (39.2) 7661 (38.4) 15 468 (38.8) .13

Body mass index† Mean (SD) 26.04 (5.07) 26.03 (5.06) 26.04 (5.06) .94

�25 9885 (50.7) 9964 (51.0) 19 849 (50.8)

25-29 6069 (31.1) 6012 (30.8) 12 081 (30.9) .75

�30 3557 (18.2) 3569 (18.3) 7126 (18.2)

Physical activity, kcal/wk �1000 13 030 (66.2) 12 964 (65.8) 25 994 (66.0)

.37 �1000 6645 (33.8) 6738 (34.2) 13 383 (34.0)

Menopausal status and hormone therapy use

Premenopausal 5458 (27.5) 5515 (27.7) 10 973 (27.6)

Uncertain 3568 (17.9) 3581 (18.0) 7149 (18.0)

Postmenopausal, current hormone therapy use

5981 (30.1) 5967 (30.0) 11 948 (30.0) .88

Postmenopausal, never or past hormone therapy use

4880 (24.5) 4824 (24.3) 9704 (24.4)

Hypertension‡ Yes 5103 (25.6) 5214 (26.2) 10 317 (25.9)

.20 No 14 832 (74.4) 14 718 (73.8) 29 550 (74.1)

Hyperlipidemia§ Yes 5842 (29.3) 5903 (29.6) 11 745 (29.5)

.50 No 14 089 (70.7) 14 026 (70.4) 28 115 (70.5)

Diabetes� Yes 517 (2.6) 510 (2.6) 1027 (2.6)

.83 No 19 411 (97.4) 19 414 (97.4) 38 825 (97.4)

Parental history of myocardial infarction before age 60 y

Yes 2321 (13.0) 2312 (12.9) 4633 (12.9) .83

No 15583 (87.0) 15 627 (87.1) 31 210 (87.1) *Numbers do not always sum to group totals due to missing information for some variables. †Body mass index was calculated as weight in kilograms divided by the square of height in meters. ‡Hypertension was defined as a self-reported systolic blood pressure �140 mm Hg, a diastolic blood pressure �90

mm Hg, or physician-diagnosed hypertension. §Hyperlipidemia was defined as a self-reported total cholesterol �240 mg/dL (6.2 mmol/L) or physician-diagnosed

high cholesterol. �Diabetes was defined by self-report.

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100 000 person-years): 1437 in the vi- tamin E group and 1428 in the placebo group (RR, 1.01; 95% CI, 0.94-1.08; P=.87; Table 2). Further analyses that ex- cluded the first 2 or 5 years of fol- low-up did not change the findings (data not shown). For the main site-specific cancers, there were no significant differ- ences between the vitamin E and pla- cebo 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 can- cer 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 stom- ach cancer among those randomized to a vitamin and mineral cocktail includ- ing vitamin E.14 We did not observe this in our healthy population (14 vs 6 cases of stomach cancer, respectively). Can- cer death rates also were not signifi- cantly 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 can- cers in the analysis led to virtually un- changed findings (1626 vs 1615 cases,

respectively; RR, 1.01; 95% CI, 0.94- 1.08; P=.84).

When we examined cumulative in- cidence rates of invasive cancer by year of follow-up, the curves were almost identical in the vitamin E and placebo groups (FIGURE 3). Additional analy- ses that censored noncompliant (tak- ing less than two thirds of study medi- cations) 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 second- ary cancer end points. Additionally, there was no significant effect modifi- cation by any of the cancer risk factors shown in Table 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, 1.04; 95% CI, 0.93-1.16; P=.53). The main causes of death, apart from car- diovascular and cancer deaths, were pulmonary diseases (32 vitamin E, 22

placebo); violent deaths, excluding sui- cide (31 vs 21); and suicide (9 vs 6). None of these causes of deaths was sig- nificantly related to vitamin E.

In analysis that censored noncom- pliant 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 assign- ment to either aspirin or beta carotene on the effect of vitamin E on total mor- tality. There also was no significant effect of any of the cardiovascular and cancer risk factors in Table 3 on the associa- tion of vitamin E with total mortality.

Adverse Effects

We examined whether vitamin E in- creased adverse effects due to bleed- ing (gastrointestinal bleeding, hema- turia, easy bruising, epistaxis) because of the potential for vitamin E to in- hibit platelet function,52 gastrointesti- nal symptoms (gastric upset, nausea, di- arrhea, constipation), or fatigue. There were no differences between reported adverse effects for any of these vari- ables among women in the 2 groups, apart from a small, but significant, in- crease in the risk of epistaxis (RR, 1.06; 95% CI, 1.01-1.11; P=.02).

COMMENT The WHS—the largest randomized trial of vitamin E supplementation to date with the longest duration of treat- ment—adds important information re- garding whether vitamin E plays any role in CVD and cancer prevention. In this trial, 600 IU of natural-source vi- tamin E every other day for 10 years did not provide any statistically signifi- cant benefits on the primary end points of major cardiovascular events or can- cer in almost 40 000 healthy women. There was, however, a significant 24% reduction in the secondary end point of cardiovascular deaths and a signifi- cant 26% reduction in major cardio- vascular events among the subgroup of women aged at least 65 years. We ob- served no significant effect of vitamin E on total mortality.

The finding of no overall effect of vi- tamin E on CVD is congruent with data

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

Outcome

No. of Events

Relative Risk (95% CI) P Value

Vitamin E (n = 19 937)

Placebo (n = 19 939)

Major cardiovascular event* 482 517 0.93 (0.82-1.05) .26

Myocardial infarction 196 195 1.01 (0.82-1.23) .96

Nonfatal 184 181 1.02 (0.83-1.25) .87

Fatal 12 14 0.86 (0.40-1.85) .70

Stroke 241 246 0.98 (0.82-1.17) .82

Nonfatal 220 222 0.99 (0.82-1.19) .93

Fatal 21 24 0.88 (0.49-1.57) .66

Ischemic† 194 197 0.99 (0.81-1.20) .88

Hemorrhagic† 44 48 0.92 (0.61-1.38) .68

Cardiovascular death 106 140 0.76 (0.59-0.98) .03

Total invasive cancer 1437 1428 1.01 (0.94-1.08) .87

Breast 616 614 1.00 (0.90-1.12) .95

Lung 107 98 1.09 (0.83-1.44) .52

Colon 107 107 1.00 (0.77-1.31) .99

Cancer death 308 275 1.12 (0.95-1.32) .17

Total mortality 636 615 1.04 (0.93-1.16) .53 Abbreviation: CI, confidence interval. *Defined as a composite end point comprising the first of any of these events: nonfatal myocardial infarction, nonfatal

stroke, or cardiovascular death. †Stroke type was not known for 3 women in the vitamin E group and 1 in the placebo group.

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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 analy- sis40 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 preex- isting disease. There are few data on populations comparable with the healthy women in the WHS. A re- cently published trial not included in either meta-analysis, the SU.VI.MAX study,35 like the WHS, enrolled primar- ily healthy persons. After 7.5 years, the SU.VI.MAX trial also reported no effect of randomized treatment using a com- bination of vitamins and minerals, in- cluding 30 mg/d of vitamin E, on CVD (RR, 0.97; 95% CI, 0.77-1.20).

With regard to the individual car- diovascular end points, we found a sig- nificant 24% reduction in cardiovascu- lar 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 pla- cebo group) to the latter and larger meta-analysis (2683 and 2689 cardio- vascular deaths, respectively) should not have an appreciable impact on the pooled RR. In the WHS, the single larg- est contribution to the reduction in car- diovascular deaths was fewer sudden deaths among women assigned to re- ceive vitamin E. One plausible expla- nation 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 ac- tive and placebo capsules were identi- cally formulated with soybean oil, the only difference being the addition of vi- tamin E to the active capsules. It is pos- sible that the observed reduction in car- diovascular deaths was due to chance, arising from multiple comparisons.

An interesting finding in subgroup analyses was the observation of a sig- nificant 26% reduction in major cardio- vascular events, primarily cardiovascu-

lar 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 par- ticipants 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 re- sults by age.26 Several large observa- tional studies that noted inverse asso- ciations 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 re- garding any age effects.

A recent trial, HOPE-TOO, noted a possible adverse effect of 400 IU/d of vi- tamin 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 fac- tors. First, was the dose of vitamin E sufficient? Previous observational stud- ies 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

Figure 2. Cumulative Incidence Rates of Cardiovascular Disease

0.01 Log-Rank P = .26

Log-Rank P = .96

0.02

0.03

0

C um

ul at

iv e

In ci

de nc

e

Major Cardiovascular Events Myocardial Infarction

0.03

0.01

0.02

0

C um

ul at

iv e

In ci

de nc

e

Stroke

No. at Risk Placebo Vitamin E

0

19 939 19 937

2

19 857 19 871

6

19 543 19 575

8

19 342 19 345

10

12 646 12 606

4

19 724 19 727

Years of Follow-up 0

19 939 19 937

2

19 896 19 894

6

19 668 19 668

8

19 501 19 483

10

12764 12731

4

19 808 19 793

Years of Follow-up

No. at Risk Placebo Vitamin E

0

19 939 19 937

2

19 822 19 840

6

19 446 19 493

8

19 218 19 230

10

12528 12491

4

19 661 19 675

Years of Follow-up 0

19 939 19 937

2

19 860 19 863

6

19 569 19 581

8

19 375 19 361

10

12 642 12 609

4

19 743 19 740

Years of Follow-up

Cardiovascular Death

Log-Rank P = .82

Log-Rank P = .03

Placebo Vitamin E

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.

VITAMIN E AND PREVENTION OF CVD AND CANCER

©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, July 6, 2005—Vol 294, No. 1 61

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

Group

Major Cardiovascular Event* Total Invasive Cancer

No. of Events

RR (95% CI) P Value

No. of Events

RR (95% CI) P ValueVitamin E Placebo Vitamin E Placebo

Age, y† 45-54 172 152 1.13 (0.91-1.41) .26 645 673 0.96 (0.86-1.07) .44

55-64 180 189 0.95 (0.77-1.16) .61 518 509 1.02 (0.90-1.15) .79

�65 130 176 0.74 (0.59-0.93) .009 274 246 1.12 (0.94-1.33) .20

Smoking status Current 139 145 0.99 (0.78-1.25) .91 238 228 1.07 (0.89-1.29) .45

Past or never 341 370 0.92 (0.79-1.06) .25 1199 1199 1.00 (0.92-1.08) .95

Alcohol intake Never/rarely 252 263 0.96 (0.80-1.14) .61 643 615 1.04 (0.93-1.16) .52

At least 1/mo 230 254 0.90 (0.76-1.08) .26 794 813 0.98 (0.89-1.09) .75

Multivitamin use Yes 201 194 1.02 (0.84-1.25) .81 577 531 1.07 (0.95-1.21) .24

No 281 323 0.88 (0.75-1.03) .10 860 897 0.97 (0.88-1.06) .48

Body mass index‡ �25 186 221 0.85 (0.70-1.03) .09 709 728 0.98 (0.89-1.09) .75

25-29 164 169 0.96 (0.77-1.19) .69 429 403 1.05 (0.92-1.21) .46

�30 113 114 1.00 (0.77-1.30) .99 269 272 0.99 (0.84-1.18) .95

Physical activity, kcal/wk �1000 328 357 0.92 (0.79-1.07) .28 949 967 0.98 (0.89-1.07) .64

�1000 147 153 0.95 (0.76-1.20) .68 473 445 1.08 (0.94-1.22) .27

Menopausal status and hormone therapy use

Premenopausal 59 59 1.01 (0.71-1.45) .94 294 300 1.00 (0.85-1.17) .96

Uncertain 75 67 1.13 (0.81-1.57) .46 173 211 0.82 (0.67-1.00) .06

Postmenopausal, current hormone therapy use

145 154 0.95 (0.76-1.20) .68 507 461 1.11 (0.98-1.26) .11

Postmenopausal, never or past hormone therapy use

201 234 0.84 (0.70-1.02) .08 460 453 1.00 (0.88-1.14) .97

Hypertension§ Yes 242 263 0.93 (0.78-1.11) .41 408 424 0.97 (0.85-1.11) .68

No 239 254 0.94 (0.78-1.12) .46 1028 1003 1.02 (0.94-1.11) .63

Hyperlipidemia � Yes 189 221 0.86 (0.71-1.05) .14 493 460 1.09 (0.96-1.23) .20

No 293 296 0.98 (0.83-1.15) .82 944 968 .97 (0.89-1.06) .50

Diabetes¶ Yes 62 58 1.05 (0.73-1.50) .79 48 35 1.39 (0.90-2.15) .14

No 420 458 0.92 (0.80-1.04) .19 1388 1393 1.00 (0.93-1.07) .93

Randomized to receive aspirin Yes 232 245 0.95 (0.79-1.13) .55 716 722 0.99 (0.89-1.10) .86

No 250 272 0.92 (0.77-1.09) .32 721 706 1.02 (0.92-1.13) .67

Parental history of MI before age 60 y

Yes 73 62 1.16 (0.82-1.62) .40

No 352 391 0.90 (0.78-1.04) .16

10-Year risk of CHD, %# �5.0 179 148 1.19 (0.96-1.48) .12

5.0-9.9 98 95 1.10 (0.83-1.46) .50

�10.0 53 68 0.81 (0.56-1.16) .24 Abbreviations: CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction; RR, relative risk. *Defined as a composite end point comprising the first of any of these events: nonfatal MI, nonfatal stroke, or cardiovascular death. †P value for interaction �.05 for major cardiovascular event. No other interactions are significant. ‡Calculated as weight in kilograms divided by the square of height in meters. §Hypertension was defined as a self-reported systolic blood pressure �140 mm Hg, a diastolic blood pressure �90 mm Hg, or physician-diagnosed hypertension. �Hyperlipidemia was defined as a self-reported total cholesterol �240 mg/dL (6.2 mmol/L) or physician-diagnosed high cholesterol. ¶Diabetes defined by self-report. #Calculated using the Framingham risk score among 28 345 women who provided a blood sample at baseline.

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effect was unlikely to be due to insuf- ficient treatment duration, since this av- eraged 10 years in the WHS, represent- ing 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 sec- ondary prevention that reported a ben- efit of vitamin E also used a natural source.21,27 On the other hand, a pre- vious trial of secondary prevention, which included high-risk primary pre- vention patients, used natural-source vi- tamin E and found no benefits on CVD,26 as did another secondary pre- vention trial testing natural-source vi- tamin E combined with other vita- mins and minerals.31

Fourth, declining compliance over time in the WHS may have diluted the findings. However, in sensitivity analy- ses in which follow-up time was cen- sored among women taking less than two thirds of their study pills, the find- ing 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 inter- act with simvastatin and niacin treat- ment.31 We did not systematically col- lect information on lipid-modifying therapy, but we did so for hyperlipid- emia. Among women who remained normolipemic throughout the trial and who were unlikely to have taken lipid- modifying drugs, we observed no sig- nificant effect of vitamin E on major car- diovascular events, providing little support for an influence of lipid therapy on the WHS findings.

Finally, the possibility exists that �-tocopherol, rather than vitamin E (or �-tocopherol), may be the relevant compound for CVD prevention.53 �-To- copherol appears to have similar or greater efficacy than �-tocopherol at in- hibiting lipid peroxidation under oxyradical systems and much more po- tency 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 inci- dence 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 statis- tical significance. We did not observe any effect of vitamin E on lung cancer in the WHS. The SU.VI.MAX study re- ported significantly lower cancer rates among men, but not women, random- ized to a combination of vitamins and minerals (including 30 mg/d of vita- min E).35 Among poorly nourished per- sons randomized to a vitamin and min-

eral cocktail (including 30 mg/d of vitamin E), lower rates of stomach can- cer occurred.14 This was not seen in the WHS, but the number of stomach can- cers was small. Taken as a whole, the available data do not provide strong evi- dence for a role of vitamin E in cancer prevention, particularly in well- nourished persons.

A recent meta-analysis raised con- cern for increased mortality with vita- min E, especially in doses of 400 IU/d or greater.42 In the WHS, using 600 IU every other day, there was no signifi- cant effect of vitamin E on total mor- tality. There was no excess of cardio- vascular (and, indeed, fewer such deaths) or cancer deaths, the main causes of mortality, in the vitamin E group. For the other main causes of

Figure 3. Cumulative Incidence Rates of Cancer

0.08

0.02

Log-Rank P = .86 Log-Rank P = .95

0.06

0.04

0

In ci

de nc

e R

at e

Total Cancer Breast Cancer

0.08

0.02

0.06

0.04

0

In ci

de nc

e R

at e

Lung Cancer

No. at Risk Placebo Vitamin E

0

19 939 19 937

2

19 677 19 669

6

18 978 18 956

8

18 543 18 550

10

12 002 11 994

4

19 336 19 339

Years of Follow-up 0

19 939 19 937

2

19 677 19 669

6

18 978 18 956

8

18 543 18 550

10

12 002 11 994

4

19 336 19 339

Years of Follow-up

No. at Risk Placebo Vitamin E

0

19 939 19 937

2

19 677 19 669

6

18 978 18 956

8

18 543 18 550

10

12 002 11 994

4

19 336 19 339

Years of Follow-up 0

19 939 19 937

2

19 677 19 669

6

18 978 18 956

8

18 543 18 550

10

12 002 11 994

4

19 336 19 339

Years of Follow-up

Colon Cancer

Log-Rank P = .53 Log-Rank P >.99

Placebo Vitamin E

VITAMIN E AND PREVENTION OF CVD AND CANCER

©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, July 6, 2005—Vol 294, No. 1 63

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death, there were more deaths (but not statistically significant) from pulmo- nary disease, violent deaths, and sui- cides in the vitamin E group.

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

CONCLUSIONS In conclusion, the WHS does not sup- port recommending vitamin E supple- mentation for CVD or cancer preven- tion among healthy women. This large trial supports current guidelines stat- ing that use of antioxidant vitamins is not justified for CVD risk reduc- tion.55,56 The WHS finding of a de- creased 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 ex- plored 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 pre- vention in men.57 At present, in the pri- mary prevention of CVD and cancer, therapeutic lifestyle changes includ- ing a healthy diet and control of major risk factors remain important clinical and public health strategies.

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), De- partment of Medicine, Brigham and Women’s Hos- pital, Harvard Medical School, Boston, Mass; Depart- ment 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 Pre- vention, Harvard Medical School, Boston (Dr Buring); and the Departments of Medicine and Epidemiology and Public Health, University of Miami School of Medi- cine, Miami, Fla, and Department of Biomedical Sci- ence, Center of Excellence, Florida Atlantic Univer- sity, Boca Raton (Dr Hennekens).

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, Hennekens, Buring. 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, Buring. 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 con- sultant to Bayer. Dr Gaziano has served as a consul- tant 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 re- ceived 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 In- stitute. Vitamin E and vitamin E placebo were pro- vided by the Natural Source Vitamin E Association. As- pirin and aspirin placebo (reported on pp 47-55) were provided by Bayer Healthcare. Role of the Sponsor: Neither the Natural Source Vi- tamin E Association nor Bayer Healthcare provided any input into the design and conduct of the study; col- lection, 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, Fre- derick 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 par- ticipants in the Women’s Health Study for their dedi- cated and conscientious collaboration; to the entire staff of the Women’s Health Study, under the lead- ership 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 assis- tance in the design and conduct of the trial; and es- pecially to James Taylor for chairing the Endpoints Committee.

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