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.
HOPE indicates Heart Outcomes Prevention Evaluation; HOPE-TOO, HOPE–The
Customize your JAMA Network experience by selecting one or more topics from the list below.
The HOPE and HOPE-TOO Trial Investigators. Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial. JAMA. 2005;293(11):1338–1347. doi:10.1001/jama.293.11.1338
EvaLonnMD, MSc, JackieBoschMSc, SalimYusufMBBS, DPhil, PatrickSheridanMSc, JanicePogueMSc (Population
Health Research Institute, Hamilton Health Sciences and McMaster University,
Hamilton, Ontario); J. Malcolm O.ArnoldMD (Department of Medicine, University
of Western Ontario, London, Ontario);
of Medicine and Medical Oncology, McMaster University, Hamilton, Ontario);
PeterSleightMD, DM (Department
of Cardiovascular Medicine, John Radcliffe Hospital, Oxford University, Oxford,
England); JeffreyProbstfieldMD (University of Washington, School of Medicine,
Seattle); and Gilles R.DagenaisMD (Institut Cardiologiede, University Laval, Ste-Foy,
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.
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.
α-Tocopherol, the predominant and most active form of vitamin
E in humans, is the major antioxidant in lipid phases.3 In
animal models, α-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, α-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 α-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]).
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 × 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.
The initial HOPE trial evaluated natural source vitamin E (RRR-α-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.
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.
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 α = .05; this calculation was made after
identifying the number of study participants willing to participate in the
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 κ=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.
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 α=.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).
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.
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.
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).
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 α=.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 α=.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.
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).
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).
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.
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
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 α-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.
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 α-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 λ-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
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.
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.
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
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,
Drafting of the manuscript: Yusuf, Lonn, Bosch,
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
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,
Substudies and Publications Committee: J. Probstfield
(chair), J. Bosch, R. Davies, E. Lonn, M. McQueen, J. Ostergren, J. Pogue,
Data and Safety Monitoring Board: D. Sackett
(chair), R. Collins, E. Davis, C. Furberg, C. Hennekens, B. Pitt, J. Pogue,
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