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Title: CARDIOVASCULAR CONSIDERATIONS OF VITAMIN E: WHY THE CONTROVERSY BRIAN P' JONES, M'D' APRIL 23, 2002


1
CARDIOVASCULAR CONSIDERATIONS OF VITAMIN E WHY
THE CONTROVERSY? BRIAN P. JONES, M.D. APRIL
23, 2002
2
CLINICAL CASES CASE 1 56 year old
male with past medical history significant for
cardiovascular disease, diabetes, hypertension,
DVT, hyperlipidemia, and tobacco abuse presents
to clinic for a new patient visit. Patient
reports he had a myocardial infarction
approximately 5 years ago with successful
angioplasty and since then has had no further
chest pain.
3
CASE 1 CONTINUED Medicines Toprol XL 25 mg
po qd Lotensin 20 mg po qd Aspirin 325 mg po
qd Niacin 1 gram po qd Zocor 10 mg po
qhs Vitamin E 400 IU po qd Glucotrol XL 10 mg
po qd Coumadin 5 mg po qhs The physical exam
and vital signs are without significant
abnormalities.
4
CASE 1 CONTINUED The patient expresses
concern over his medications and specifically
whether he should continue to take the vitamin E.
His cardiologist told him several years ago that
it would help prevent future heart attacks and
that he should take it for the long term.
However, he was reading on the internet and found
out that this may not be the case and wants to
know your opinion if he should remain on it.
What do you advise the patient?
5
CASE 2 A 34 year old resident at an anonymous
training hospital somewhere in central North
Carolina presents to clinic for a new patient
evaluation. Upon further questioning, the rather
difficult patient states he has no medical
problems and just wants a routine check
up. Medicines Vitamin E 200 IU po
qd Multivitamin po qd The physical exam and
vital signs are unremarkable.
6
CASE 2 CONTINUED The patient states that
he began taking anywhere from 200 - 400 IU a day
of vitamin E in 1994 when he heard on the news
that vitamin E was supposed to make him live
longer and prevent future heart attacks. He has
remained on it fairly consistently for the last 8
years even through medical school when he
survived on just coffee, beer and vitamin E. He
seeks your advice on whether he should continue
to take the vitamin E every day and whether it is
safe to take. What advice do you provide to this
patient?
7
CLINICAL QUESTIONS Is there any evidence to
suggest that vitamin E consumption, whether from
dietary sources or by supplementation, is
beneficial in primary prevention or secondary
prevention of cardiovascular disease?
8
INTRODUCTION Cardiovascular disease is the
leading cause of morbidity and mortality in the
Western World despite great advances in
pharmaceutical research and interventional
procedures. There has been great interest over
the past decade in alternative medical therapies
as well as an explosion of information on the
internet. Vitamin E is a great example of how
a nontraditional medical therapy came to the
forefront of medicine by early promising
observational studies only to have these results
called into question by subsequent randomized
controlled trials. The publicity and growing
consumer use of vitamin E was aided by the timing
of the internet coming into mainstream use in the
mid-1990s.
9
The search engine GOOGLE for example provides
approximately 970,000 hits if one types in
Vitamin E. The growing popularity of vitamin
E is not restricted to the general public for it
was estimated that one-half of all American
cardiologists took supplemental vitamin E in the
year 2000. It is the hope of this presentation
to provide some basic biochemistry of vitamin E
and highlight some of the best known studies over
the last decade and allow the audience to see the
evolution of evidence on vitamin E and
cardiovascular prevention.
10
HISTORY OF VITAMIN E First discovered in 1922
as a substance essential for rat pregnancy and
officially named alpha-tocopherol in 1924. In
Greek, tocos means to bear a child and phero
means to provide a person with
power. Research 1938 -- chemical structure
determined 1950 -- research on frostbite 1956
-- Free Radical Theory of Aging by
Harmann 1972 -- RDA set at 30 IU per day in the
U.S.
11
BIOCHEMISTRY OF VITAMIN E Vitamin E is widely
distributed in nature and exists in such foods as
grains, green plants, vegetables, vegetable oils,
fish and meat. There are eight type of
homologues of vitamin E and the difference
between synthetic and natural vitamin E is in
optical isomers. Synthetic has a mixture of d
and l form isomers and natural vitamin E exists
only in the d-form. The dosage of vitamin E is
expressed in International Units (IU) which is
the amount of biological activity expressed.
Synthetic vitamin E is approximately one-half as
active as natural vitamin E.
12
Vitamin E has high biological activity in the
human body and it is thought that only the
alpha-tocopherol homologue is incorporated into
the lipoprotein VLDL. Vitamin E has a very
specific liver transfer protein called
alpha-tocopherol transfer protein (alpha-TTP).
Below is a schematic illustrating the route of
which vitamin E is incorporated into VLDL and
ultimately into LDL where it is proposed to have
antioxidant effects that help reduce
cardiovascular events.
13
(No Transcript)
14
The proposed mechanisms of vitamin E center
around its ability modify the course of oxidized
LDL and the development of an atherosclerotic
plaque. Atherosclerosis is a complex event
that has been shown to develop at a young age
with development of fatty streak lesions that may
ultimately progress to more complicated plaques
composed of a core of lipid and necrotic cell
debris covered by a fibrous cap. This
complicated plaque may obstruct blood flow and
precipitate clinical events. The diagram below
helps illustrate the proposed mechanisms
of injury of oxidized LDL and its contribution to
plaque formation
15
LDL crosses the endothelium and becomes trapped
in the extra-cellular matrix. The subendothelium
is an oxidizing environment. Oxidized LDL
affects gene expression in endothelial cells
which leads to an increase in monocyte binding
molecules (X-CAM), monocyte chemoattractant
protein (MCP) and macrophage colony stimulating
factors (CSFs). These recruit monocytes and
helps drive their phenotypic differentiation to
macrophages. Oxidized LDL is internalized by
macrophages and forms lipid-laden foam cells.
Oxidized LDL is also cytotoxic leading to further
endothelial injury and promoting further entry of
LDL thus leading to a continuation of the disease
process.
16
There are several defense mechanisms that the
body employs against free radical formation such
as the superoxide dismutase, glutathionine peroxid
ase and catalase. As previously noted, vitamin
E is incorporated into LDL. Each LDL contains
about 5 - 9 molecules of vitamin E and
approximately 2700 fatty acid molecules.
Approximately one-half of these fatty acids
are polyunsaturated that are particularly
susceptible to oxidation. Vitamin E helps
terminate lipid peroxidation by donating a
hydrogen atom to the fatty acid free radical
which forms a nonreactive alpha-tocopherol
radical. This radical may actually be
regenerated by vitamin C and this explains the
interest in combination antioxidant therapy.
17
OTHER PROPOSED BENEFITS OF VITAMIN E
Decreased platelet adhesion and
aggregation. Preservation of vascular tone by
protecting nitric oxide and endothelial
derived relaxing factor. Inhibition of vitamin
K-dependent clotting factors.
18
CLINICAL TRIALS OF IMPORTANCE INVOLVING VITAMIN E
IN CHRONOLOGICAL ORDER
19
A. Stampfer et al. Vitamin E Consumption and
the Risk of Coronary Disease in Women.
1993 Design Prospective cohort
study Subjects 87,245 female nurses, ages 34 -
59 years of age, who were free of diagnosed
cardiovascular disease and cancer. Methods
The Nurses Health Study actually began in 1976
when 121,700 nurses completed questionnaires
every two years about their lifestyle and medical
history. A cohort was formed in 1980 when
87,245 nurses were mailed questionnaires
that assessed their consumption of a wide variety
of nutrients including vitamin E.
20
Stampfer et al.
Methods continued
Primary endpoints were nonfatal MI and death
due to CV disease as well as other CV events such
as cardiac intervention and strokes.
21
Stampfer et al.
Results During the 8 year follow-up there
were 552 cases of major coronary disease (437
cases of nonfatal MI and 115 deaths due to
coronary disease). In the vitamin E group
there were 49 cases of coronary disease versus
503 cases in the nonusers. Those nurses with
the highest intake of vitamin E had the most
reduction in risk of major coronary disease
(nonfatal MI) and this was specifically with
supplementation and not diet. The RR in the
highest quintile vitamin E group after adjustment
for age and smoking was 0.66 (0.50 - 0.87, p lt
0.001) and the RR in the highest quintile of
dietary vitamin E was 0.95 (0.72 - 1.23, p
0.99).
22
Stampfer et al.
Results continued Users of vitamin E for less
than 2 years had no significant reductions in
risk whereas greater than 2 years was with a
significant reduction. After excluding those
on vitamin E for less than 2 years, they found no
benefit on less than 100 IU/day. No trend
could be developed for greater reduction with
higher doses of vitamin E in a period of greater
than 2 years. Those who consumed vitamins
tended to be nonsmokers, exercise more, have
lower blood pressure, and be postmenopausal
hormone users.
23
Stampfer et al.
Relative Risks for Quintile Groups of Vitamin E
Intake
24
Stampfer et al.
Conclusions In this prospective cohort
study of 34 - 59 year old nurses, vitamin E was
shown to be beneficial in reducing the risk of
major coronary disease in supplemental amounts of
at least 100 IU/day and a duration of greater
than 2 years. Although not statistically
significant there was a trend towards a reduction
in risk of mortality from CV causes, ischemic
stroke, coronary surgery and overall mortality.
25
Stampfer et al.
Limitations Observational study and not a
randomized controlled trial. ? Unknown
confounding variables. As noted in this study,
healthy people tend to consume vitamins and is
this risk reduction truly secondary to vitamin
supplementation and not lifestyle?
26
B. Rimm et al. Vitamin E Consumption and the
Risk of Coronary Heart Disease in Men.
1993 Design Prospective cohort
study. Subjects 39,910 U.S. male health
professionals, ages 40 - 75, who were free of
diagnosed coronary heart disease, diabetes and
hyper- cholesterolemia. Methods The Health
Professionals Follow-up Study began in 1986 and
involved a detailed questionnaire about dietary
habits and vitamin E use every 2 years. The
primary endpoints were fatal coronary disease,
nonfatal MI, coronary surgery and angioplasty.
27
Rimm et al. Results There were 667 cases
of coronary disease (360 bypass surgeries/angiopla
sties, 201 nonfatal myocardial infarctions and
106 fatal coronary events) during the 4 years of
follow-up. The men in the highest quintile
group of vitamin E had the greatest risk
reduction with a RR of 0.59 (p 0.001). The
maximal reduction in risk was observed at a
supplemental dose of 100 - 249 IU/day without a
further decrease at higher doses. Men
reporting usage of greater than 10 years had a RR
of 0.65 (p 0.10).
28
Rimm et al.
Results continued
Overall mortality showed a RR of 0.78 (p
0.06) when comparing the individuals in the
highest quintile group of vitamin E to the
lowest quintile group. It was also noted that
those with the highest consumption of vitamin E
tended to smoke less, have less hypertension, use
more aspirin and exercise more than those in the
lower quintile groups.
29
Rimm et al.
Relative Risks for Quintile Groups for Vitamin E
Intake
30
Rimm et al.
Conclusions In males ages 40 - 75 without
cardiovascular disease, diabetes or
hypercholesterolemia, vitamin E supplementation
at higher doses than can be achieved by diet
alone significantly decreased the risk of
cardiovascular events. This risk reduction was
particularly noted at doses of 100 - 249
IU/day. Limitations While the results are
remarkably similar to the Nurses Study, it is
still an observational study that may not account
for uncontrolled confounding variables.
Those on higher doses of vitamin E had healthier
baseline profiles than those individuals on
lower doses.
31
C. Kushi et al. Dietary Antioxidant Vitamins
and Death from Coronary Heart Disease in
Postmenopausal Women. 1996 Design
Prospective cohort study. Subjects 34,486
postmenopausal females ages 55 - 69 with no
cardiovascular disease. Methods The Iowa
Womens Health Study began in 1986 and
participants were recruited from a random sample
of women who had a valid Iowa drivers license.
The study involved a questionnaire about dietary
habits and vitamin use and follow-up
questionnaires were mailed in 1988, 1990 and
1992. The endpoint of the study was death
from cardiovascular disease.
32
Kushi et al.
Results During 7 years of follow-up, 242
women died of coronary heart disease. After
adjusting for age and dietary intake, there was a
significant reduction in cardiovascular risk with
vitamin E however, this was noted with dietary
consumption and not by supplementation. The RR
with only dietary intake in the highest quintile
was 0.42 (p 0.008). In contrast, vitamin E
supplementation had a RR of 0.82 (p 0.78) in
the highest quintile group. This study also
noted healthier lifestyles in those with higher
consumption of vitamin E.
33
Kushi et al.
Relative Risks for Quintile Groups of Vitamin E
Intake
34
Kushi et al.
Conclusions In postmenopausal women without
cardiovascular disease at entry, a high vitamin E
diet was statistically significant in reducing
cardiovascular death. Supplementation showed
no significant benefit. This study is in
contrast with prior studies showing no
significant benefit with dietary intake and
significant benefit with supplementation.
35
Kushi et al.
Limitations Observational study and not a
randomized controlled trial. There may be
unknown variables that were not accounted for as
well as the reliability of studies involving
questionnaires. This study had no information
on the length of time of vitamin
E supplementation and few participants were on
high doses of vitamin E.
36
D. Stephens et al. Randomised Controlled
Trial of Vitamin E in Patients with Coronary
Disease Cambridge Heart Antioxidant Study
(CHAOS). 1996 Design Randomized
placebo-controlled blinded trial. Subjects
2,002 patients with proven ( angiogram) coronary
disease of which 90 were symptomatic with
angina and/or evidence of reversible
ischemia. Methods Patients were recruited
on day of admission after elective angiography.
1,035 patients were given vitamin E of which
546 patients received 800 IU/day and the
remaining individuals received 400 IU/day. 967
patients received identical placebo.
37
Stephens et al.
Methods continued
Exclusion criteria was prior vitamin E use and
the patients were followed for a median of 510
days with no planned clinic follow-up. Primary
endpoints were a combination of cardiovascular
death and nonfatal MI as well as nonfatal MI
alone.
38
Stephens et al.
Results In the study period there were a
total of 50 cardiovascular deaths and 55 nonfatal
MIs. In the placebo group, 41 patients had
nonfatal MIs and 23 died of cardiovascular
disease. In the vitamin E group, there were 14
patients who had a nonfatal MI and 27 patients
with cardiovascular death. The vitamin E group
had a decreased risk of cardiovascular death and
nonfatal MI with a RR of 0.53 (p 0.005). This
risk reduction was most evident in the nonfatal
MI category with a RR of 0.23 (p 0.005). There
was a nonsignificant increase in cardiovascular
death noted in the vitamin E group with a RR of
1.18 (p 0.61). Baseline characteristics
were notable for a higher percentage of vitamin E
users on beta blocker therapy.
39
Stephens et al.
Conclusions This study provides evidence
that high doses of vitamin E may be beneficial in
reducing the risk of nonfatal MI in patients with
proven coronary atherosclerosis. It also
showed a nonsignificant increase in
cardiovascular death in the vitamin E group in
the first 200 days.
40
Stephens et al.
Limitations The main concerning finding is
of the increased number of cardiovascular deaths
in the vitamin E group however, the
authors later published an analysis that
suggested that the deaths were mainly in those
deemed noncompliant with vitamin E. There
also was concern over whether randomization led
to truly comparable study groups since there were
unequal baseline characteristics such as the
higher numbers of beta blocker usage in the
vitamin E group. The study was also of short
duration and it is difficult to form solid
conclusions on a therapy that many have suggested
the predominate benefit is likely over many years.
41
E. Marchioli et al. Dietary Supplementation
with n-3 Polyunsaturated Fatty Acids and Vitamin
E after Myocardial Infarction Results of the
GISSI-Prevenzione Trial. 1999 Design
Randomized controlled trial with open-label
design. Subjects 11,324 patients with recent
MI (lt 3 months). Methods Patients
randomized to one of four groups 1.) n-3
polyunsaturated fatty acid supplement 2.) 300 mg
synthetic vitamin E/day 3.) both 4.) no
supplement
42
Marchioli et al.
Methods continued All patients were kept on
their appropriate cardiovascular medicines
throughout the study. Patients were followed
for 3.5 years by clinic visits. The primary
combined endpoints were the cumulative rate
of all-cause death, nonfatal MI and nonfatal
stroke and the cumulative rate of cardiovascular
death, nonfatal MI and nonfatal stroke.
43
Marchioli et al.
Results There was no significant reduction in
the endpoints with vitamin E. The vitamin E group
had a RR of 0.95 (0.86 - 1.05) in the
all-cause death, nonfatal MI and nonfatal stroke
category. The RR was 0.98 (0.87 - 1.10) in the
cardiovascular death, nonfatal MI and
nonfatal stroke category. In a four-way analysis
there was still no significant reduction.
Treatment with the polyunsaturated fatty acid
supplement had a significant reduction in risk
with a RR of 0.90 (0.82 - 0.99, p 0.048) in the
all-cause death, nonfatal MI and nonfatal stroke
category. It was not significant in the
cardiovascular death, nonfatal MI and nonfatal
stroke category with a RR of 0.89 (p 0.053)
however, in a four-way analysis there was a
significant reduction noted with a RR of 0.80 (p
0.008).
44
Marchioli et al.
Conclusions In a 3.5 year study,
supplementation of synthetic vitamin E at doses
of 300 mg/day had no significant benefit on risk
reduction of deaths, nonfatal MI or nonfatal
stroke in patients with a recent MI. n-3 PUFA
was associated with a significant decrease in
these cardiovascular events.
45
Marchioli et al.
Limitations The study was of short duration
(3.5 years) and may not have been long enough to
show a significant trend in cardiovascular risk
reduction. Patients were aware of which drug
they were taking raising the possibility of bias
involving not only the physicians but
the participants themselves (i.e. changing
dietary habits or other lifestyles). The
study involved a Mediterranean population that
has a diet higher in vitamin E which poses
questions on how much more benefit they would
receive from supplementation as well as possible
genetic differences.
46
F. The Heart Outcomes Prevention Evaluation
Study Investigators. Vitamin E Supplementation
and Cardiovascular Events in High-Risk
Patients. 2000 Design Randomized double
blind placebo-controlled trial. Subjects 9,541
patients, ages 55 and older, at high-risk
for cardiovascular events (patients either had
cardiovascular disease or diabetes in addition to
one other risk factor for cardiovascular
disease). Methods Patients were randomized
to either natural vitamin E (400 IU/day) or
placebo and either ramipril (10 mg/day) or
placebo. Patients were followed for 4.5 years.
47
HOPE Investigators Methods continued The
primary outcome measured was a composite of
myocardial infarction, stroke, and death from
cardiovascular disease. The secondary outcomes
measured included unstable angina, congestive
heart failure, revascularization or amputation,
complications of diabetes, cancer and death from
any cause.
48
HOPE Investigators Results 772 of 4,761
patients assigned to vitamin E had a primary
outcome event compared to 739 of the 4,780
patients assigned to placebo. The RR for
vitamin E for primary outcomes was 1.05 (0.95 -
1.16, p 0.33) and there was no significant
reduction with any of the secondary outcomes with
vitamin E. Ramipril was found to have a
significant benefit. The study was terminated
early because of the benefits of ramipril and the
lack of benefit of vitamin E.
49
HOPE Investigators
Relative Risks of Primary Outcomes on Vitamin E
50
HOPE Investigators Conclusions In a study that
was well-designed and executed with a high
number of participants and high number of primary
outcomes and high statistical power, vitamin E
had no significant benefit on the primary and
secondary outcomes in patients that were at
high-risk for future cardiovascular events.
Ramipril had a substantial benefit. Limitations
The length of the trial was only 4.5 years and
the study group itself was high-risk patients.
Researchers and former studies have suggested
more of a long-term benefit and possibly more of
a primary risk reduction than secondary prevention
in high-risk patients.
51
G. Collaborative Group of the Primary Prevention
Project. Low-dose Aspirin and Vitamin E in
People at Cardiovascular Risk a Randomized
Trial in General Practice. 2001 Design
Randomized controlled open-label
design. Subjects 4,496 people (2,583 females),
mean age of 64.4 years, with significant risk
factors for future cardiovascular events but
no known cardiovascular disease. Methods
Patients were randomly recruited from their
general practitioners office. Inclusion
criteria old age, hypertension,
hypercholesterolemia, diabetes, obesity, and
family history of MI,
52
Primary Prevention Project Methods continued
Exclusion criteria treatment with anti-platelet
drugs, chronic use of ant-inflammatory agents or
anti-coagulants, contraindications to aspirin,
diseases with predictable poor short-term
prognosis and psychological difficulties with
complying with the study. Patients were
randomly assigned to receive either an aspirin a
day (100 mg/day) or no aspirin per day and
synthetic vitamin E (300mg/ day) or no vitamin E
per day. Patients were followed for 3.6 years
in clinic. Primary endpoints were cumulative
rate of cardiovascular death, nonfatal MI and
nonfatal stroke.
53
Primary Prevention Project Results Vitamin E
had no significant reduction on the defined
primary endpoints of cardiovascular death,
nonfatal MI and nonfatal stroke with a RR of 1.07
(0.74 - 1.56). Vitamin E did show a
significant decrease in the incidence
of peripheral artery disease with a RR of 0.54
and p 0.043. Aspirin showed a nonsignificant
decrease in the combined primary endpoints with a
RR of 0.71 (0.48 - 1.04) however, it did show a
significant benefit in the incidence of
cardiovascular death with a RR of 0.56 (0.31 -
0.99, p 0.049) and total number of
cardiovascular events/diseases with a RR of 0.77
(0.62 - 0.95, p 0.014)
54
Primary Prevention Project Results continued
There was a higher incidence of severe bleedings
in the aspirin group. The vitamin E group had
a similar number of bleeding events compared to
those not on vitamin E. The trial was stopped
early on ethical grounds when results of
other trials showed a benefit of aspirin on
cardiovascular disease and when there was no
significant benefit noted of vitamin E plus
financial considerations.
55
Primary Prevention Project
Relative Risks of Vitamin E and Aspirin
56
Primary Prevention Project Conclusions In
this primary prevention trial in patients with
significant risk factors for cardiovascular
disease, vitamin E had no significant benefit on
the primary outcome of cardiovascular death,
nonfatal MI and nonfatal stroke. Vitamin E
did have a significant benefit on peripheral
artery disease. Aspirin was found to have a
significant benefit on total cardiovascular
events and cardiovascular death but also with a
higher incidence of bleeding.
57
Primary Prevention Project Limitations The
study was not a true blinded study and the
participants were aware of the study medicines
which may raise the question of bias and
participants altering their behavior. The
study was also of a short duration and many have
proposed that the benefits of vitamin E in a
primary prevention role are realized over a long
course of time. The study population was also
older with a mean age of 64.4 years.
58
SAFETY OF VITAMIN E
Vitamin E is generally regarded as safe to
administer but concerns have been raised over a
possible increase in hemorrhagic strokes and its
effects on the anticoagulation system. The
most common adverse reactions cited are blurred
vision, contact dermatitis, diarrhea, fatigue,
gonadal dysfunction, headache, intestinal cramps,
nausea and weakness (all less than 1). Other
reported adverse effects from various studies or
anecdotal reports lowering of serum thyroid
hormone levels, increased triglyceride levels,
thrombophlebitis, breast soreness,
increased creatine metabolism and emotional
disturbances.
59
Safety of Vitamin E continued The safety of
vitamin E has also been questioned in individuals
on anticoagulation such as warfarin or who have
malabsorption. Vitamin E has the ability to
inhibit vitamin K-dependent clotting factors by
blocking the oxidation of vitamin K which
increases the levels of inactive vitamin K.
Cases have been reported of worsening coagulation
parameters in patients on warfarin and vitamin E
these parameters usually resolved after
discontinuation of vitamin E. The issue of a
possible increase in hemorrhagic strokes came to
the attention of the investigators of the ATBC
Trial (The Alpha- Tocopherol, Beta-Carotene
Cancer Prevention Study Group) in 1994.
60
Safety of Vitamin E continued In the ATBC
Trial, which looked at whether vitamin E
and beta-carotene decreased the risk of lung
cancer, a higher rate of death from hemorrhagic
stroke was observed in the vitamin E group.
The vitamin E group (50 mg/day for 5 - 8 years)
had 66 cases of deaths from hemorrhagic stroke
compared to 44 cases in those not on vitamin
E. The incidence of death from ischemic stroke
showed the opposite with 56 deaths in the vitamin
E group and 67 cases in the group not on vitamin
E. There has been considerable debate over
this finding and many have refuted it by
referring to the small number of cases and that
it could have easily been explained by chance.
61
Safety of Vitamin E continued The evidence
from other trials that include observational
and randomized controlled trials do seem to
indicate that vitamin E is indeed a safe drug to
administer. CHAOS used much higher doses of
vitamin E and was without a significant increase
in hemorrhagic stroke. The Nurses Health Study,
Health Professional Study, GISSI and HOPE also
showed no significant increase in hemorrhagic
stroke. Further studies will be needed to
ultimately answer this question but at the
present time the consensus is that vitamin E is
safe. The exception may be those individuals
who are at increased risk of bleeding such as
those on warfarin or who are malnourished.
62
TRIALS OF VITAMIN E EITHER RECENTLY COMPLETED OR
ONGOING
A. PRIMARY PREVENTION TRIALS Physicians Health
Study II 15,000 US physicians Vitamin E 400
IU/day and beta-carotene 50 mg/day on alternate
days. Vitamin C 500 mg/day and MVI on daily
basis. Primary Endpoints MI, stroke,
cardiovascular death.
63
Primary Prevention Trials continued Womens
Health Study 40,000 US women Vitamin E 600
IU/day and aspirin 100 mg/day on alternate
days. Primary endpoints MI, stroke and
cardiovascular death. Supplementation en
Vitamines et Mineraux Antioxidants Trial
15,000 French men and women Vitamin E 15
IU/day, selenium 0.1 mg/day, zinc 20
mg/day, beta-carotene 6 mg/day and vitamin C 120
mg/day. Primary endpoints MI, stroke and
cardiovascular death.
64
B. Secondary Prevention Trials Heart Protection
Study 20,000 UK men and women with
cardiovascular disease or diabetes. Vitamin E
600 IU/day, beta-carotene 20 mg/day, vitamin C
250 mg/day and simvastatin. Primary endpoints
MI, stroke and cardiovascular death. Womens
Antioxidant Cardiovascular Study 8,000 US
women with cardiovascular disease or at least 3
risk factors. Vitamin E 600 IU/day and
beta-carotene 50 mg/day on alternate days.
Vitamin C 500 mg/day, folic acid 2.5 mg/day,
vitamin B6 50 mg/day, and vitamin B12 1 mg/day
every day. Primary endpoints MI, stroke,
revascularization and cardiovascular death.
65
CONCLUSIONS
The debate on whether vitamin E supplementation
actually reduces the risk of cardiovascular
disease will likely go on for several more years
until trials currently ongoing release their
results. What we do know is that the highly
encouraging results seen in the early 1990s from
observational studies has not held up to
the standards of the most recently published
randomized controlled trials in primary and
secondary prevention. It may be that what is
proposed on a biochemical level does not hold
true in clinical practice or that we do not have
as of yet a sufficient number of randomized
controlled trials of a long duration to see
the benefit of vitamin E.
66
Conclusions continued At present time there
is not enough compelling evidence to advocate
widespread vitamin E supplementation to prevent
cardiovascular events. It does appear that
vitamin E is safe for supplementation in the
majority of the population exceptions may be
those on warfarin or who are malnourished. In
reference to the cases presented at the beginning
of this presentation, I would advise the
gentleman with the proven coronary disease that
the most recent studies have suggested that he
would not benefit from remaining on vitamin E.
This patient is also on warfarin which may
increase his risk of bleeding. There is also
recent evidence to suggest that his vitamin E may
deleteriously interact with his niacin and Zocor.
67
Conclusions continued In case number two for
primary prevention, I would advise the patient
that earlier studies of an observational nature
showed a significant decrease in cardiovascular
events in individuals who maintained a healthy
lifestyle. I would also advise the patient
that the most recent randomized controlled trial
in primary prevention did not support this
former evidence although it was a group of
individuals with significant risk factors for
cardiovascular disease as well as an older
age. In regards to the safety of vitamin E, I
would advise the patient that the evidence
suggests that vitamin E at 200 IU/day is safe
and that he may benefit from long-term vitamin E
supplementation to prevent cardiovascular disease
since his profile is consistent with the
observational study cohort in maintaining a
healthy lifestyle.
68
THE END
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