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Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer
A Randomized Controlled Trial
The HOPE and HOPE-TOO Trial Investigators*
JAMA. 2005;293:1338-1347.
ABSTRACT
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Context Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration.
Objective To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events.
Design, Setting, and Patients A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE–The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years.
Intervention Daily dose of natural source vitamin E (400 IU) or matching placebo.
Main Outcome Measures Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations.
Results Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure.
Conclusion In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.
INTRODUCTION
Oxidative injury has been implicated in atherosclerotic cardiovascular disease and in cancer, the 2 leading causes of death. Low-density lipoprotein cholesterol is rendered more atherogenic by oxidative modification1 and many carcinogens create free oxygen radicals that damage DNA and other cellular structures, initiating and promoting tumor development.2 Therefore, antioxidant vitamins have been extensively evaluated in the prevention of cardiovascular diseases and cancer.
 -Tocopherol, the predominant and most active form of vitamin E in humans, is the major antioxidant in lipid phases.3 In animal models, -tocopherol has been shown to reduce atherosclerotic lesions,4 smooth muscle cell proliferation,5 platelet adherence and aggregation,6 and protein kinase C activation.7 In humans, it can improve endothelial function.8 Epidemiological data indicate an inverse association between cardiovascular risk and vitamin E intake from dietary sources and/or supplements.9 Vitamin E appears similarly attractive in cancer chemoprevention. Antioxidants can neutralize free radicals, thereby preventing cell damage and subsequent malignant transformation.2 In addition, -tocopherol may prevent cancer by inhibiting cell proliferation and angiogenesis,10 inducing apoptosis,11 and enhancing immune function.12 In observational studies, diets high in fresh fruits and vegetables were associated with reduced incidence of cancers,13 and inverse associations between -tocopherol levels or vitamin E intake and risk of lung,14 prostate,15 oral and pharyngeal,16 and colorectal cancer17 have been reported in some but not other studies.18-20
Despite these promising experimental and epidemiological data, most randomized controlled trials have failed to confirm a role for vitamin E supplementation in cardiovascular prevention.21 With few exceptions,22-23 trials of cancer chemoprevention have also been disappointing.24-25 It has been suggested that this may be related to the relatively short period of treatment and observation (generally 3-5 years) of these trials and that longer studies are needed.26-27
The Heart Outcomes Prevention Evaluation (HOPE) trial conducted between December 21, 1993, and April 15, 1999, reported a neutral effect of vitamin E on cardiovascular outcomes after an average 4.5 years of treatment.28 To assess whether longer duration of treatment would prevent cancer and/or cardiovascular disease, the HOPE study was extended (HOPE–The Ongoing Outcomes [HOPE-TOO]).
METHODS
Study Design and Participants
The design and organization of the main HOPE trial have been previously reported.28-29 In summary, HOPE was an international, multicenter, double-blind, randomized, 2 x 2 factorial design trial that evaluated ramipril (10 mg/d) vs placebo and vitamin E (400 IU/d) vs placebo in 9541 patients at high risk for cardiovascular events. Patients were eligible if they were at least 55 years old, had a history of coronary or peripheral arterial disease, prior stroke, or diabetes mellitus plus at least 1 other cardiovascular risk factor and did not have heart failure, known low ejection fraction (<40%), uncontrolled hypertension or overt nephropathy, had not sustained myocardial infarction or stroke within 4 weeks before the study began, were not planned to undergo revascularization, and were not taking an angiotensin-converting enzyme inhibitor or vitamin E.
The initial HOPE study was conducted between December 21, 1993, and April 15, 1999. At the conclusion of the trial, all study centers were invited to participate in a trial extension (HOPE-TOO), which was conducted between April 16, 1999, and May 26, 2003. Of the initial 267 centers, 174 agreed to participate in the HOPE-TOO trial. These 174 centers had originally randomized 7030 patients. Of these, 916 were deceased at the beginning of the trial extension, 1382 (22.6% of those still alive) refused participation, 4732 agreed to extended observation and were evaluated every 6 months, 3994 of which (65.3% of those still alive) agreed to continuation of study intervention—vitamin E or matching placebo (Figure 1). To maximize the study power and duration of follow-up, the steering committee of the trial decided that the main study analyses will incorporate all randomized HOPE trial patients, including those who did and those who did not participate in the trial extension, with each patient contributing all available data for his/her duration of follow-up within the trial. All patients enrolled at the centers continuing in the trial extension were included in a sensitivity analysis. The HOPE trial and HOPE-TOO trial were approved by the ethics boards of all participating institutions, and all patients provided separate written informed consent for each stage. Most study participants were white (8580 [89.9%]), followed by Hispanic (533 [5.6%]), Asian (155 [1.6%]), black (141 [1.5%]), native American (43 [0.5%]), and other (89 [0.9%]) ethnic groups. This information was based on self-declared race/ethnicity.
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Figure 1. Flow Diagram of the Main HOPE Trial and the HOPE-TOO Trial Extension
The initial Heart Outcomes Prevention Evaluation (HOPE) trial included 267 centers and randomized 9541 study participants between December 21, 1993, and June 15, 1995. Mean follow-up was 4.5 years. Details regarding all stages of the initial HOPE trial have been previously published.28-29 The trial extension, HOPE–The Ongoing Outcomes (HOPE-TOO), began on April 16, 1999, and extended for an average of 2.6 years. A total of 93 HOPE study centers that had randomized 2511 study participants refused participation in the HOPE-TOO trial. The primary analysis of the HOPE-TOO trial includes all available data from all HOPE study participants. The sensitivity analysis includes all available data from all patients at the centers continuing in the trial extension. Clinic visits occurred at 1 month postrandomization, at 6 months, and every 6 months thereafter during the initial HOPE trial and the HOPE-TOO trial. All patients lost to follow-up and/or those who refused follow-up completed at least 2 clinic visits and are included in the final analysis censored for duration of observation.
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Interventions
The initial HOPE trial evaluated natural source vitamin E (RRR--tocopheryl acetate) (400 IU/d) vs placebo and ramipril (10 mg/d) vs placebo. During the HOPE-TOO trial, 3994 study participants continued to take daily vitamin E (400 IU) or matching placebo. Treatment allocation for the vitamin E group of the trial remained blinded for all study participants, including those who did not participate in the trial extension. Due to clear benefit of ramipril in the initial HOPE trial, at its completion, the ramipril group of the study was unblinded and angiotensin-converting enzyme inhibitor therapy was recommended for all patients.
Plasma vitamin E levels were measured by liquid chromatography (Waters 625 LC system; Millipore, Milford, Mass) at baseline and at 2 years postrandomization in 163 randomly selected patients in the vitamin E group and in 34 randomly selected patients in the placebo group.
Randomization and Allocation Concealment
The study used central telephone randomization. The randomization code was generated using a fixed block size of 4, stratified by center. The information about block size and whether it was random or fixed was kept confidential for all study investigators. The kit numbers were not sequential and were received by calling the central randomization number. The randomization sequence was concealed and all study personnel and study participants were blinded to treatment allocation for both study interventions during the initial HOPE trial and for vitamin E during the HOPE-TOO trial. The vitamin E and placebo pill formulations were manufactured (Banner Pharmacaps, High Point, NC) to be indistinguishable by size, color, weight, taste, or dissolution in water. There were no adverse events or changes in any physiological parameters that could be attributed to vitamin E or have unmasked blinding. No request was made to stop the blinding for vitamin E.
Study Objective and Main Outcome Measures
The main objective of the HOPE trial extension was to evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular outcomes.
For the initial HOPE trial, the primary outcome was the composite of myocardial infarction, stroke, and death from cardiovascular causes. For the HOPE-TOO trial extension, the primary outcome included the same composite cardiovascular outcome in addition to cancer incidence and cancer death.
The duration of the HOPE-TOO trial was calculated to allow for an average follow-up of 7 years, considering the fixed number of possible participants, and to allow the detection of a 15% to 20% reduction in incident cancers with vitamin E with more than 80% power, assuming a 1.5% to 2% yearly placebo incident cancer rate (2-sided = .05; this calculation was made after identifying the number of study participants willing to participate in the trial extension).
All cancer events from the beginning of the initial HOPE trial and those occurring during the trial extension were adjudicated and classified during the HOPE-TOO trial by an adjudication committee, with specific expertise in cancer. Classification was performed according to the International Classification of Diseases, Ninth Revision (ICD-9). Source documentation, including pathology (or cytology) reports, discharge and other clinical summaries, and results of imaging, serum markers, and other diagnostic procedures were obtained. Clinical summaries were available for all reported cancers. In addition, microscopic confirmation was available for 70.1%, direct tumor visualization for 0.8%, and imaging reports, tumor markers, or other laboratory investigations for 10.7%. The final adjudication was based on clinical summaries alone for 18.5% of all cancers.
To further evaluate the validity of the cancer ascertainment, we compared the adjudication of cancers in the trial with the Cancer Care Ontario Registry (CCOR) in the subset of 2492 HOPE study participants from Ontario, Canada. A total of 2127 study participants (85.4%) did not have incident cancer, both in the trial and in the CCOR; 283 participants (11.4%) had cancer both in the trial and in the CCOR, all classified as involving the same major organ system in both databases. Only 52 study participants (2.1%) had an incident cancer identified in the trial but not in the CCOR, and for only 30 participants (1.2%), cancer was reported in the CCOR but not in the trial. The overall coefficient of agreement was  =0.85. Coefficients of agreement for the most common cancers, including lung, prostate, breast, colorectal, oral/pharyngeal cancers, and melanoma, were 0.92, 0.88, 0.84, 0.90, 0.86, and 0.95, respectively.
Cardiovascular outcomes were the same as in the initial HOPE trial and continued to be adjudicated by an adjudication committee with cardiovascular expertise and according to the definitions used in the initial HOPE trial.28 The main cardiovascular outcome remained the composite of myocardial infarction, stroke, and death from cardiovascular causes. Each component of this composite was also evaluated. Secondary and other cardiovascular outcomes were all-cause death, hospitalization for unstable angina, revascularization or limb amputation, hospitalization for heart failure with clinical and radiological signs of congestion, and the development of heart failure regardless of the need for hospitalization.
Statistical Analysis
All analyses were by intention-to-treat (all randomized participants were analyzed in the treatment groups to which they were assigned at randomization) and stratified for assignment to ramipril or placebo, to account for the factorial study design; there was no interaction between ramipril and vitamin E for any outcomes analyzed. The predefined primary analysis in the HOPE-TOO trial used all available data on all 9541 HOPE trial participants, with each patient censored for his/her duration of observation. For this analysis, the median duration of follow-up was 7.0 years. A sensitivity analysis was conducted considering only patients at the centers continuing in the trial extension. This analysis included data from all 7030 patients at the centers continuing in the trial extension, with each patient censored for his/her duration of observation. The median duration of follow-up for the sensitivity analysis was 7.2 years. The decision to incorporate in the sensitivity analyses all patients at these centers, including those who declined further participation at the completion of the initial HOPE trial, was taken to minimize bias. Survival curves were estimated according to the Kaplan-Meier method and treatments were compared using the log-rank test. Subgroup analyses were conducted using tests for interaction in the Cox proportional hazards regression model; the Cox proportional hazards regression assumption was confirmed. For all predefined cancer and cardiovascular outcomes, the level of significance was predefined for 2-sided =.05. All analyses were performed at the Population Health Research Institute, McMaster University, Hamilton, Ontario, by using SAS version 8.2 (SAS Institute, Cary, NC) and graphs were generated using S-Plus version 6 (Insightful, Seattle, Wash).
RESULTS
Patient Characteristics and Adherence
The baseline characteristics of the 9541 patients who participated in the initial HOPE trial were similar across the vitamin E and placebo groups and the baseline characteristics of the 7030 patients at the centers continuing in the trial extension were similar to those of the entire HOPE study population and were also well balanced (Table 1). Compliance was high throughout the initial HOPE trial, as previously reported.28 In the subset of patients who had vitamin E levels measured, mean (SD) plasma vitamin E levels were similar at baseline (28.1 [9.7] mmol/L in the vitamin E group and 29.8 [15.2] mmol/L in the placebo group). At 2 years, mean (SD) plasma vitamin E levels increased to 48.7 (17.6) mmol/L in the vitamin E group (P < .001) and remained unchanged in the placebo group (30.4 [21.1] mmol/L). Among the 3994 patients who agreed to continue to take study intervention at the beginning of the trial extension, compliance as measured by pill count at 1 year, 1.5 years, and at study end was 96.7%, 95.7%, and 90.7%, respectively, in the vitamin E group, and 96.0%, 95.5%, and 90.9%, respectively, in the placebo group. Vitamin E was well tolerated and there were no serious adverse events related to its use.
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Table 1. Baseline Characteristics of All HOPE Study Patients and of the Patients at Centers Continuing in the Trial Extension (HOPE-TOO)*
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At the end of the initial HOPE trial, vital status was ascertained for 9535 (99.9%) of 9541 randomized patients. At the end of the HOPE-TOO trial, vital status was ascertained for 4724 (99.8%) of 4732 patients who participated in the extension trial.
Effect of Vitamin E on Cancer
There were no significant differences in incident cancers and cancer deaths, both in the primary analysis of all HOPE study patients and in the sensitivity analysis, which included all patients in the centers continuing in the trial extension (Table 2 and Figure 2).
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Table 2. Incidence and Relative Risks of Cancers and Deaths Due to Cancer*
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Figure 2. Kaplan-Meier Analysis of the Effects of Vitamin E on Incident Cancer and Major Cardiovascular Events for All 9541 Study Patients
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Additional exploratory analyses evaluated the effect of vitamin E on site-specific cancers by major organ systems (using ICD-9 groupings) and for selected cancers with previous promising vitamin E data (Table 3). Due to the exploratory nature of these analyses and the large number of cancer groupings evaluated, the level of significance for these analyses was set for 2-sided =.01. There was a reduction in lung cancers with vitamin E (relative risk [RR], 0.72; 95% confidence interval [CI], 0.53-0.98; P = .04) in the analysis that considered all HOPE study patients; however, this did not reach the predefined level of statistical significance (2-sided =.01) and was not confirmed in the sensitivity analysis (RR, 0.78; 95% CI, 0.55-1.10; P = .16). No other differences were observed.
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Table 3. Incidence and Relative Risks of Site-Specific Cancers*
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Effects of Vitamin E on Cardiovascular Outcomes
Among all HOPE study patients as well as among patients in the centers participating in HOPE-TOO trial extension, there were no differences in the main composite cardiovascular outcome (Figure 2), or its components, in deaths, hospitalizations for unstable angina, and revascularizations (Table 4). Heart failure overall and hospital admissions for heart failure were more common in the vitamin E group (Table 4 and Figure 3). The increased risk for heart failure was consistent among subgroups defined by ramipril use, sex, baseline history of coronary artery disease, diabetes mellitus and hypertension, systolic blood pressure, heart rate, and use of other drugs. A regression model, which considered all HOPE study patients and included all major baseline variables, identified treatment assignment to vitamin E as an independent predictor for heart failure (hazard ratio, 1.13; 95% CI, 1.01-1.26; P = .04).
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Table 4. Incidence and Relative Risks of Major Vascular Events, Deaths, and Secondary Cardiovascular Outcomes
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Figure 3. Kaplan-Meier Analysis of the Effects of Vitamin E on All Heart Failure Events and Hospital Admissions for Heart Failure in All 9541 HOPE Study Patients and in the 7030 Patients at Centers Continuing in the Study Extension (HOPE-TOO)
HOPE indicates Heart Outcomes Prevention Evaluation; HOPE-TOO, HOPE–The Ongoing Outcomes.
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An echocardiographic substudy evaluated the effects of ramipril and vitamin E on left ventricular mass, volumes, and function in 506 HOPE study patients.30 Baseline left ventricular ejection fraction was similar (58% both in the vitamin E and placebo groups). During the period of 4 years, there was a mean (SD) decrease in left ventricular ejection fraction of 1.86% (0.58%) in the vitamin E group and 0.58% (0.61%) in the placebo group. The adjusted mean (SD) difference in left ventricular ejection fraction loss between the 2 groups was 1.66% (0.69%) (P = .02).
COMMENT
The major finding of the HOPE trial, including the initial trial and the trial extension, is the lack of benefit for vitamin E in preventing cancer or major cardiovascular events after a prolonged period of treatment and observation. Furthermore, our study raises concern about an increased risk of heart failure related to vitamin E.
No Clear Evidence of Benefit in Cancer Chemoprevention
After a median 7.0 years of follow-up for the entire study population and a median 7.2 years for patients at centers continuing in the trial extension, we observed no overall effect of vitamin E on the incidence of fatal and nonfatal cancers. There was also no apparent benefit for vitamin E in preventing most site-specific cancers, including selected cancers, for which some previous epidemiological studies or clinical trials had suggested particular promise.14-17,22-23 Thus, there were no reductions in incident prostate, colorectal, oral/pharyngeal, and gastrointestinal cancers.
We did observe a lower incidence of lung cancer among patients receiving vitamin E vs those receiving placebo (69 [1.4%] vs 96 [2.0%]; P = .04). However, when applying more stringent statistical rules, which account for multiple comparisons when assessing the effect of vitamin E on site-specific cancers and which consider the exploratory post hoc nature of these analyses, the difference in lung cancer rates did not reach the predefined level of significance, and in the sensitivity analyses in patients at the centers continuing in the study extension (ie, those with longer duration of treatment and observation), the difference observed was not statistically significant (P = .16). As expected, most lung cancers (94.1%) occurred in current or previous smokers. Moreover, these findings need to be interpreted with caution, in light of the lack of benefit for vitamin E in preventing lung cancer in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study24 and the Heart Protection Study,25 which were larger and had more lung cancer events. Combined data from these large randomized vitamin E trials do not show benefit for vitamin E in the prevention of lung cancer and suggest that the differences observed in our study are likely a chance finding (Table 5). Furthermore, 2 large randomized trials24, 31 using the antioxidant vitamin beta carotene reported increased rates of lung cancer, and a recent meta-analysis32 found no benefit for antioxidant vitamin supplementation (including vitamin E) in the prevention of gastrointestinal cancers and raised concerns about an increase in total mortality.
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Table 5. Lung Cancer in Large Randomized Trials of Vitamin E*
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The lack of benefit for prostate cancer is especially noteworthy, as the only prior evidence from randomized clinical trials supporting a potential benefit of vitamin E in cancer chemoprevention in a western population was provided by the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study,24 which found a 34% lower rate of prostate cancer in middle-aged male Finnish smokers who were administered 50 mg of -tocopherol daily for 6.1 years. However, similar to our study, the Heart Protection Study,25 which involved more than 15 000 men, reported no significant impact of vitamin E on prostate cancer; this trial used a combination of vitamin E (600 mg), vitamin C (250 mg), and beta carotene (20 mg) administered daily for 5 years. The ongoing Selenium and Vitamin E Cancer Prevention Trial33 evaluates up to 12 years of supplementation with selenium and vitamin E in the prevention of prostate cancer among 32 400 men in North America, and will provide further information.
No Benefit on Cardiovascular Events and Potential for Excess HF
Vitamin E had no significant effect on myocardial infarction, stroke, cardiovascular death, unstable angina, revascularization, and total mortality. The long duration of treatment and observation and the large number of cardiovascular outcomes conclusively exclude any benefit for vitamin E in our study. Our results are also consistent with most previous large randomized controlled trials and a recent meta-analysis.21, 24-25,34-36
We observed an unexpected and disturbing increase in heart failure rates in patients assigned to vitamin E. Although this finding could be due to chance, several factors persuade us to believe that it may be real. Heart failure was a predefined secondary study outcome and the excess in heart failure events in the vitamin E group was a robust and consistent finding in our study, present in all prespecified analyses. This finding was observed for all heart failure events and for heart failure needing hospital admission (an adjudicated event of greater seriousness); it was present both at the end of the initial HOPE trial (RR increased 17%, P = .02)28 and after the extended follow-up (RR increased 13%, P = .03); it was observed in the primary analysis including all study participants and was more pronounced in the sensitivity analysis, which included patients randomized at the centers that continued in the trial extension. In the latter analysis of the study patients with longest duration of treatment and observation, the increase in risk was particularly striking (19% increase in the risk of all heart failure events [P = .007] and 40% increase in the risk of hospital admission for heart failure [P = .002]). These analyses are based on a large number of events, more than 1200 heart failure events and more than 400 hospitalizations for heart failure. A regression analysis identified vitamin E as an independent predictor of heart failure and supportive mechanistic evidence from an echocardiographic substudy of the HOPE trial found that vitamin E decreased left ventricular ejection fraction.
We did not identify any previous articles of an adverse effect of vitamin E on heart failure, and none of the previous large randomized trials of vitamin E published information about heart failure. A review of heart failure events in these trials is strongly recommended.
The mechanism for the observed harmful effect of vitamin E on heart failure is not clear but may relate to the potential for -tocopherol to become a pro-oxidant in an oxidative milieu, thereby depressing myocardial function.37 Other potential mechanisms of harm associated with vitamin E supplements in doses much higher than those provided by balanced diets may relate to displacement of other fat-soluble antioxidants, such as  -tocopherol, disrupting the natural balance of antioxidant systems and a reduction in high-density lipoprotein (HDL2)cholesterol.38 Moreover, although the precise explanation for a possible harmful effect of vitamin E is not entirely clear, a recent meta-analysis reported increased mortality in trials using high-dose vitamin E ( 400 IU/d).39
Study Limitations
In the initial HOPE trial, data on cancers were collected prospectively, but reported cancers were not adjudicated. Adjudication of all cancer events (including those that occurred during the initial trial) was performed during the HOPE-TOO trial, when cancer was identified as a primary study outcome. Nevertheless, we believe that the ascertainment of cancer outcomes is accurate, as all events were adjudicated by an expert committee blinded to treatment assignment and using predefined criteria; histological confirmation was available for 70.1% of cardiovascular events and there was a high degree of agreement with an independent cancer registry.
Not all eligible centers and patients continued in the study extension, but this is unlikely to have biased the results, as the patient characteristics were similar among patients at centers continuing in the extension and those withdrawing. Moreover, our primary analyses considered all available data on all study participants, and sensitivity analyses in patients at the centers participating in the study extension provided similar results.
CONCLUSIONS
In the HOPE and HOPE-TOO trials, the daily administration of 400 IU of natural source vitamin E for a median of 7.0 years had no clear impact on fatal and nonfatal cancers, major cardiovascular events, or deaths. We observed an increase in the risk of heart failure, which is of concern. Although this adverse effect of vitamin E was unexpected and cannot be confirmed at this time by other trials, our data are internally consistent. Therefore, a meta-analysis of heart failure events including all completed large vitamin E trials is strongly recommended.
In conjunction with its lack of efficacy, the potential for harm suggested by our findings strongly supports the view that vitamin E supplements should not be used in patients with vascular disease or diabetes mellitus.
Our study also has wider implications. There is a tendency to accept "natural products" (eg, vitamins) as being safe, even if they have not been proven to be effective. However, our findings emphasize the need to thoroughly evaluate all vitamins, other natural products, and complementary medicines in appropriately designed trials before they are widely used for presumed health benefits.
AUTHOR INFORMATION
Corresponding Author: Eva Lonn, MD, Population Health Research Institute and McMaster University, Hamilton Health Sciences Corporation, General Site, 237 Barton St E, Hamilton, Ontario, Canada L8L 2X2 (lonnem{at}mcmaster.ca).
Author Contributions: Dr Lonn 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: Yusuf, Lonn, Bosch, Pogue, Sleight, Dagenais.
Acquisition of data: Lonn, Bosch, Sheridan, Pogue, J.M.O. Arnold, Ross, A. Arnold, Probstfield.
Analysis and interpretation of data: Yusuf, Lonn, Bosch, Sheridan, Pogue, J.M.O. Arnold, Ross, A. Arnold, Sleight, Probstfield, Dagenais.
Drafting of the manuscript: Yusuf, Lonn, Bosch, Sheridan, Pogue.
Critical revision of the manuscript for important intellectual content: Sleight, Probstfield, Dagenais, J.M.O. Arnold, Ross, A. Arnold.
Statistical expertise: Sheridan, Pogue.
Obtained funding: Yusuf, Lonn, Bosch.
Administrative, technical, or material support: Yusuf, Lonn, Bosch.
Study supervision: Yusuf, Lonn, Bosch.
Financial Disclosures: Dr Sleight receives grant support for ISIS 1-4, HPS, SEARCH, HOPE, ONTARGET/ TRANSCEND trials from British Heart Foundation, UK Medical Research of Canada, Ontario Heart and Stroke Foundation, AstraZeneca, Aventis, Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Monarch, Merck Sharpe & Dohme, Natural Source Vitamin E Association, and Roche; and receives speaker/data and safety monitoring board fees from Abbott, AstraZeneca, Aventis, Bayer, Boehringer-Ingelheim, Boehringer Mannheim, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Knoll, Menarini, Merck, Monarch, Merck Sharpe & Dohme, Novartis, Organon, Pfizer, Pharmacia, Sanofi, Schering, and Servier. No other authors reported financial disclosures.
Funding/Support: The HOPE trial was funded by the Medical Research Council of Canada, Hoechst-Marion Roussel, AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association and Negma, and the Heart and Stroke Foundation of Ontario. The HOPE trial extension (HOPE-TOO) was funded by Aventis Pharmaceuticals, King Pharmaceuticals, and the Natural Source Vitamin E Association.
Role of the Sponsor: The study sponsors had no role in the study design, data analysis, data interpretation, or writing of this article.
List of Centers and HOPE Investigators: The list of HOPE Investigators has been published previously.29 The following persons participated in the trial extension (HOPE-TOO):
International Steering Committee: S. Yusuf (co-chair), P. Sleight (co-chair), G. Dagenais (co-chair), J. Bosch, E. Lonn, M. Micks, J. Pogue. Canada: M. Arnold, M. Bourassa, J. Choy, R. Davies, G. Fodor, J. Genest, R. Hoeschen, R. Kuritzky, B. Mitchell, R. Starra, B. Sussex, K. Teo, L. Title, R. Tsuyuki. United States: J. Probstfield. Europe: T. Hamalainen, G. Heyndrickx, W. Klein, J. Mann, J. Ostergren, P. Peci, G. Spinas, B. Wolffenbuttel. Brazil: A. Avezum.
Canadian Regional Coordinators: D. Bedard, J. Cossett, J. Donaldson, L. Frenette, L. Harris, M. Krupa, D. LaForge, A. M. Luther, A. Magi, R. Miles, D. Paterson, J. Skanes, K. Stevens.
Study Coordination: S. Avery, A. Avezum, J. Bosch, M. Fuentes, E. Lonn, M. McQueen, M. Micks, L. Richardson, J. Riley, L. Sardo, P. Spriggs, A. Stranaghan, S. Yuki Miyakoshi, M. Villamarin Zamana.
Events Adjudication Committee: J.M.O. Arnold (chair), A. Arnold, P. Auger, A. Avezum, I. Bata, V. Bernstein, M. Bourassa, G. Dagenais, M. Fisher, G. Fodor, J. Grover, C. Held, R. Hoeschen, J. Mann, J. Mathew, D. Meldrum, C. Pilon, R. Roccaforte, C. Ross, R. Starra, B. Sussex, K. Teo.
Substudies and Publications Committee: J. Probstfield (chair), J. Bosch, R. Davies, E. Lonn, M. McQueen, J. Ostergren, J. Pogue, S. Yusuf.
Data and Safety Monitoring Board: D. Sackett (chair), R. Collins, E. Davis, C. Furberg, C. Hennekens, B. Pitt, J. Pogue, W. Taylor.
HOPE-TOO Investigators: Austria: H. Fohler, M. Grisold, W. Klein; Belgium: A. Bodson, J. Cano, J-M. Chaudron, J-P. Degaute, H. Dhont, G. Heyndrickx, G. Krzentowski, J. Mockel, J. C. Wautrecht; Brazil: E. Alexander, C. Amodeo, D. Armaganijan, J. Ayub, H. Barbatto, M. Barros, M. Bertolami, L. C. Bodanese, F. Borelli, S. M. Grespan Carvalhaes, A. C. C. Carvalho, G. Dioguardi, J. M. Esteves, M. Z. S. Fichino, B. Garbelini, N. Ghorayeb, G. Greque, N. C. B. Lima, F. Malheiros, L. P. Marafon, F. Neto, W. Nogueira, C. Ogawa, O. Passarelli, C. Pedrngiras Jaeger, A. Seixas Silva, P. Smith, A. G. Sousa, L. F. Tanajura, J. Tavares, A. P. Turola, V. Vaz, H. Zatz; Canada: Alberta: P. Beresford, J. Choy, B. Cujec, A. Edwards, P. Giannoccaro, J. P. Giannoccaro, P. Greenwood, M. Grose, M. Heule, A. Irving, Z. Lakhani, R. Lesoway, D. Lewis, P. Ma, S. Majumdar, D. Meldrum, L. B. Mitchell, T. Muzyka, J. Paradis, D. Paterson, A. Plesko, A. Prosser, M. Schaumberger, J. Stone, T. Talibi, D. Taylor, R. Tsuyuki, W. Tymchak, B. Woloschuk; British Columbia: T. Ashton, E. Asirvatham, J. Askew, V. Bernstein, W. Bishop, G. Bloomberg, M. Dahl, K. G. Dawson, R. Dong, J. Dufton, R. Geddis, S. Ghosh, V. A. Heath, J. Heath, J. Imrie, D. Kinch, J. Kornder, R. Kuritzky, W. Leong, J. Lewis, K. MacDonald, D. MacRitchie, L. McGee, A. S. Pearce, S. Rabkin, M. Reilly, K. Roberts, G. Simkus, K. Stevens, R. Sweeney, P. Tan, M. Terwiel, S. Vederah, K. Wagner, K. Wedding, K. Woo; Manitoba: L. Briol, P. Mehta, A. Miller, G. Ong, A. Ong, M. L. Wilson; New Brunswick: R. Bessoudo, J. Milton, L. O'Brien; Newfoundland: D. Gibbons, C. Joyce, J. Knight, A. Luther, D. O'Keefe, M. Ravalia, G. Sherman, J. Skanes, R. Smith, B. Sussex; Nova Scotia: I. Bata, N. Campbell, J. Cossett, J. Cox, R. Hatheway, D. Johnstone, T. Machel, J. Morash, W. Sheridan, M. Shirley, L. Title, M. Wheatley; Ontario: M. Arnold, M. Baird, T. Baitz, D. Boksa, B. Bozek, N. W. Cameron, M. Cann, N. Chan, Y. Chan, C. Charlebois, J. Charles, A. Chouinard, L. Cleghorn, M. Crowther, G. Curnew, R. F. Davies, R. A. Davies, D. Day, D. DeCurtis, G. DeRose, P. DeYoung, R. Dhaliwal, M. Drobac, E. Fallen, D. Fell, L. Finkelstein, T. Forbes, R. Fowlis, L. Frenette, J. Fulop, H. Gerstein, A. Glanz, E. Goode, S. Hagar, A. Hanna, K. Harris, L. Higginson, R. Houlden, I. M. Hramiak, D. Hutton, I. Janzen, A. Kenshole, W. J. Kostuk, M. Krupa, G. Kumar, G. Kuruvilla, K. Kwok, C. Lai, A. Langer, T. LaVallee, M. Lee, J. Lemenchick, B. Lent, H. Lochnan, M. Lovell, D. Lowe, T. Mabb, S. MacLean, A. Magi, E. MacPhee, D. Massel, M. Mayer, M. A. McLean, J. McQueen, J. McSherry, S. Milencoff, F. Miller, J. Misterski, G. Moe, S. Nawaz, C. Noseworthy, M. Parkovnick, R. Paterson, P. Pflugfelder, A. M. Powell, S. Powers, T. Rebane, A. Redda, J. Ricci, A. Selby, N. Singh, R. Southern, D. Spence, P. Squires, L. Sternberg, H. Sullivan, B. Sullivan, M. Sullivan, J. Swan, P. Tanser, T. Vakani, R. Vexler, C. Vilag, A. Weeks, S. Weeks, S. Wetmore, J. Willing, G. Wisenberg, M. Wolfe, D. Zaniol, B. Zinman; Prince Edward Island: E. MacMillan, D. Steeves; Quebec: N. Aris-Jilwan, P. Auger, A. Belanger, L. Beliveau, J. Bergeron, P. Bogaty, M. Boulianne, J. Campeau, S. Carrier, J-L Chiasson, G. Dagenais, S. Dallaire, G. D'Amours, F. Delage, D. Dion, F. Dumont, R. Dupuis, B. Forest, S. Gauthier, J. Genest, P. Gervais, R. Giroux, D. Gossard, G. Gosselin, G. Goulet, F. Grondin, J. Halle, N. Kandalaft, M. Lamy, H. Langelier, C. Lauzon, G. LeBlanc, M. LeBlanc, C. Lemay, R. Loisel, K. MacLellan, A. Morissette, F. Ouimet, J. Piche, C. Pilon, P. Plourde, C. Poirier, M. Poulin, L. Primeau, G. Pruneau, B. Roberge, D. C. Riel, M. Ruel, D. Saulnier, D. Savard, F. Sestier, R. St-Hilaire, A. Toupin-Halle, P. Wilson; Saskatchewan: S. Ahmed, N. Habib, M. Hart, M. Sayeed, G. Thomasse, J. Walker, M. Walker, L. Zaychkowski; Denmark: H. Juhl, P. Ronsted; Finland: T. Hamalainen, R. Lehtonen; Germany: S. Cilaci, J. Friederichs, A. Gordalla, A. Guth, R. Hampel, J. Mann, S. Miedlich, S. Muehldorfer, H. P. Nast, B. Prehn, R. Paschke, R. Riel; Ireland: P. Crean, D. Hughes; Italy: P. Centofante, A. Cotogni, L. A. De Giorgio, P. Giani, D. Giorgi-Pierfranceschi, C. Imparato, U. Joannon, E. Manicardi, M. Marini, E. Paciaroni, P. Peci, F. Perazoli, S. Provasoli, S. Repetto, G. Rigatelli, R. Roccaforte, E. Romano, E. Rossi, G. Saccomanno, P. Vincenzi, D. Zavaroni; the Netherlands: N. Hopmans, J. P. Sels, L.G. van Doorn, B. H. R. Wolffenbuttel; Spain: X. Albert, F. G. Cosio, I. Garcia, P. Gonzalez, R. Masia; Sweden: T. Almgren, K. Andersson, O. Andersson, L. Astrom, M. Bennermo, L. Bergsten, H. Bjorkman, C. Dahlgren, L. Ekholm, U-B. Ericsson, P. Gillberg, A. Hagg, A. Hallberg, B. G. Hansson, C. Held, C. Jagren, T. Jonasson, P. Katzman, B. Leijd, P. Lennerhagen, L. Ljungdahl, F. Nystrom, P. Olofsson, P-O. Olsson, J. Ostergren, U. Rosenqvist, B. Ryden, G. Sartor, P. Sjostedt, L. Smith, A. Svensson, K. A. Svensson, I. Svenstam, T. Thulin, P. Weber, M. Wysocki; Switzerland: P. Gerber, W. Kiowski, T. Moccetti, E. Safwan, B. Schwarz, G. Spinas; United Kingdom: L. Cumming, M. Cunningham, D. Currie, S. Heller, J. Hinnie, C. Kesson, J. Manns, M. Small, S. Struthers; United States: California: Y. Szlachcic, F. Yee; Colorado: L. Clegg, L. Horwitz, R. Zolty; Connecticut: J. Anderson, A. Cooper Nolan, A. Rashkow, K. Schwartz; Georgia: M. E. Gunby, P. Orander, V. Sridharan; Illinois: S. Berger, M. Davidson, C. Forchetti, J. Geohas, N. Islam, S. Khadra, R. Rajanahally, A. Susmano, J. Wong; Iowa: S. Advani, R. Rough, W. Wickemeyer, N. Young; Minnesota: A. Basu, P. Helgemoe, G. Pierpont, J. Weigenant; New Mexico: J. Abrams, R. Donohoe, D. Robbins; New York: M. Bonora, G. Cohen, A. Dimova, L. Gage, S. Graham, R. Kohn, E. Lader, M. Meyer, D. Parikh, P. Reiter, A. Sass; Ohio: S. Gupta, B. Hoogwerf, S. Stein, A. Suryaprasad, D. Williams; Oklahoma: K. Danisa, M. Lowery; Washington: J. Gorham, R. Letterer, G. Lorch, R. Mack, J. Nemanich, R. K. Primm, J. Probstfield, R. Utley, L. Vaughn.
Acknowledgment: We thank the numerous patients who volunteered to participate in this trial, Cheryl Weir, for expert secretarial assistance, and Mary Micks, Mario Fuentes, MD, and Amy Stranaghan, for organizational assistance.
Authors/Writing Committee: Eva Lonn, MD, MSc, Jackie Bosch, MSc, Salim Yusuf, MBBS, DPhil, Patrick Sheridan, MSc, Janice Pogue, MSc (Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario); J. Malcolm O. Arnold, MD (Department of Medicine, University of Western Ontario, London, Ontario); Catherine Ross, MD, Andrew Arnold, MBBS (Department of Medicine and Medical Oncology, McMaster University, Hamilton, Ontario); Peter Sleight, MD, DM (Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford University, Oxford, England); Jeffrey Probstfield, MD (University of Washington, School of Medicine, Seattle); and Gilles R. Dagenais, MD (Institut Cardiologiede, University Laval, Ste-Foy, Quebec).
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JAMA 2007;297:842-857.
ABSTRACT
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Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling
Takimoto and Kass
Hypertension 2007;49:241-248.
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Heart disease and single-vitamin supplementation
Traber
Am. J. Clin. Nutr. 2007;85:293S-299S.
ABSTRACT
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The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease)
Dzau et al.
Circulation 2006;114:2850-2870.
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Rethinking Primary Prevention of Atherosclerosis-Related Diseases
Napoli et al.
Circulation 2006;114:2517-2527.
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Dietary flavonoids with a catechol structure increase {alpha}-tocopherol in rats and protect the vitamin from oxidation in vitro
Frank et al.
J. Lipid Res. 2006;47:2718-2725.
ABSTRACT
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Heart outcomes prevention evaluation-the ongoing outcomes study, vitamin e, and age-related macular degeneration.
Pulido
Arch Ophthalmol 2006;124:1665-1665.
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Heart Outcomes Prevention Evaluation-The Ongoing Outcomes Study, Vitamin E, and Age-Related Macular Degeneration--Reply
Chew and Clemons
Arch Ophthalmol 2006;124:1665-1666.
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A randomized factorial study of the effects of long-term garlic and micronutrient supplementation and of 2-wk antibiotic treatment for Helicobacter pylori infection on serum cholesterol and lipoproteins.
Zhang et al.
Am. J. Clin. Nutr. 2006;84:912-919.
ABSTRACT
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Summary of American Heart Association Diet and Lifestyle Recommendations Revision 2006
Lichtenstein et al.
Arterioscler. Thromb. Vasc. Bio. 2006;26:2186-2191.
FULL TEXT
American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: Reducing the Risk of Cancer With Healthy Food Choices and Physical Activity
Kushi et al.
CA Cancer J Clin 2006;56:254-281.
ABSTRACT
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Nutrition and Stroke Prevention
Fisher et al.
Stroke 2006;37:2430-2435.
ABSTRACT
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EUK-8, a Superoxide Dismutase and Catalase Mimetic, Reduces Cardiac Oxidative Stress and Ameliorates Pressure Overload-Induced Heart Failure in the Harlequin Mouse Mutant
van Empel et al.
J Am Coll Cardiol 2006;48:824-832.
ABSTRACT
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Role of Oxidative Stress in Remodeling of the Myocardial Microcirculation in Hypertension
Zhu et al.
Arterioscler. Thromb. Vasc. Bio. 2006;26:1746-1752.
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Diet and Lifestyle Recommendations Revision 2006: A Scientific Statement From the American Heart Association Nutrition Committee
Lichtenstein et al.
Circulation 2006;114:82-96.
ABSTRACT
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The rust on the magic bullet
Katz
Br. J. Ophthalmol. 2006;90:811-811.
FULL TEXT
Oxidized Forms of Glutathione in Peripheral Blood as Biomarkers of Oxidative Stress
Rossi et al.
Clin. Chem. 2006;52:1406-1414.
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Assessment of Tocopherol Metabolism and Oxidative Stress in Familial Hypobetalipoproteinemia
Clarke et al.
Clin. Chem. 2006;52:1339-1345.
ABSTRACT
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A 76-year-old man with macular degeneration.
Arroyo
JAMA 2006;295:2394-2406.
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The Maximal Amount of Dietary {alpha}-Tocopherol Intake in U.S. Adults (NHANES 2001-2002)
Gao et al.
J. Nutr. 2006;136:1021-1026.
ABSTRACT
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Biomarkers of Oxidative Damage in Human Disease
Dalle-Donne et al.
Clin. Chem. 2006;52:601-623.
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Reducing the "Risk" of Chemoprevention: Defining and Targeting High Risk--2005 AACR Cancer Research and Prevention Foundation Award Lecture.
Lippman and Lee
Cancer Res. 2006;66:2893-2903.
ABSTRACT
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Optimizing the ongoing search for new treatments for Parkinson disease: Using futility designs
Tilley et al.
Neurology 2006;66:628-633.
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Aged Garlic Extract Improves Homocysteine-Induced Endothelial Dysfunction in Macro- and Microcirculation
Weiss et al.
J. Nutr. 2006;136:750S-754S.
ABSTRACT
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Vitamin E in the prevention of prostate cancer: where are we today?
Lee et al.
JNCI J Natl Cancer Inst 2006;98:225-227.
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Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk.
Kirsh et al.
JNCI J Natl Cancer Inst 2006;98:245-254.
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Neither vitamin E nor donepezil delays progression from amnestic mild cognitive impairment to Alzheimer's disease in the long term
Blacker
Evid. Based Ment. Health 2006;9:20-20.
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Walnuts Reduce Aortic ET-1 mRNA Levels in Hamsters Fed a High-Fat, Atherogenic Diet
Davis et al.
J. Nutr. 2006;136:428-432.
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Supplementation with mixed tocopherols increases serum and blood cell {gamma}-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes
Clarke et al.
Am. J. Clin. Nutr. 2006;83:95-102.
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Clinical Cancer Advances 2005: Major Research Advances in Cancer Treatment, Prevention, and Screening--A Report From the American Society of Clinical Oncology
Herbst et al.
JCO 2006;24:190-205.
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Glucosamine-Induced Endoplasmic Reticulum Dysfunction Is Associated With Accelerated Atherosclerosis in a Hyperglycemic Mouse Model
Werstuck et al.
Diabetes 2006;55:93-101.
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Kinetics of Response to Long-Term Treatment Combining Pentoxifylline and Tocopherol in Patients With Superficial Radiation-Induced Fibrosis
Delanian et al.
JCO 2005;23:8570-8579.
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Vitamin C and Vitamin E for Alzheimer's Disease
Boothby and Doering
The Annals of Pharmacotherapy 2005;39:2073-2079.
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Role of Diet in Prostate Cancer Development and Progression
Chan et al.
JCO 2005;23:8152-8160.
ABSTRACT
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Potential harm of vitamin E supplementation
Hemila
Am. J. Clin. Nutr. 2005;82:1141-1142.
FULL TEXT
Vitamin E Supplementation in Cardiovascular Disease and Cancer Prevention: Part 1
Pham and Plakogiannis
The Annals of Pharmacotherapy 2005;39:1870-1878.
ABSTRACT
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Use of Antioxidants During Chemotherapy and Radiotherapy Should Be Avoided
D'Andrea
CA Cancer J Clin 2005;55:319-321.
ABSTRACT
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Clinical trials update from the American College of Cardiology meeting: CARE-HF and the Remission of Heart Failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER
Cleland et al.
Eur J Heart Fail 2005;7:931-936.
ABSTRACT
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Vitamin E Supplementation, Cardiovascular Events, and Cancer
Richey
JAMA 2005;294:425-425.
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Vitamin E Supplementation, Cardiovascular Events, and Cancer
Gaby
JAMA 2005;294:425-425.
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Vitamin E Supplementation, Cardiovascular Events, and Cancer
Jarski et al.
JAMA 2005;294:425-426.
FULL TEXT
Essential Nutrients: Food or Supplements?: Where Should the Emphasis Be?
Lichtenstein and Russell
JAMA 2005;294:351-358.
ABSTRACT
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Brief Communication: The Prevalence of High Intake of Vitamin E from the Use of Supplements among U.S. Adults
Ford et al.
ANN INTERN MED 2005;143:116-120.
ABSTRACT
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An Editorial Update: Annus horribilis for Vitamin E
Guallar et al.
ANN INTERN MED 2005;143:143-145.
FULL TEXT
Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer: The Women's Health Study: A Randomized Controlled Trial
Lee et al.
JAMA 2005;294:56-65.
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Low-Dose Aspirin and Vitamin E: Challenges and Opportunities in Cancer Prevention
Jacobs and Thun
JAMA 2005;294:105-106.
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Some Dietary and Adipose Tissue Carotenoids Are Associated with the Risk of Nonfatal Acute Myocardial Infarction in Costa Rica
Kabagambe et al.
J. Nutr. 2005;135:1763-1769.
ABSTRACT
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From the Library
Br. J. Ophthalmol. 2005;89:930-930.
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Vitamin E Not Helpful Against Heart Disease and Cancer
JWatch Emergency Med. 2005;2005:4-4.
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Cardiovascular Risk Associated with Celecoxib
Brophy et al.
NEJM 2005;352:2648-2650.
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