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

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Cardiovascular considerations of vitamin e why the controversy brian p jones m d april 23 2002 l.jpg
CARDIOVASCULAR CONSIDERATIONS OF VITAMIN E: WHY THE CONTROVERSY?BRIAN P. JONES, M.D.APRIL 23, 2002


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CLINICAL CASES CONTROVERSY?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.


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CASE #1 CONTINUED: CONTROVERSY?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 qhsThe physical exam and vital signs are without significant abnormalities.


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CASE #1 CONTINUED: CONTROVERSY?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?


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CASE #2 CONTROVERSY?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 qdThe physical exam and vital signs are unremarkable.


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CASE # 2 CONTINUED CONTROVERSY?: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?


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CLINICAL QUESTIONS CONTROVERSY?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?


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INTRODUCTION CONTROVERSY?* 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.


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* 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.


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HISTORY OF VITAMIN E approximately 970,000 hits if one types in “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.


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BIOCHEMISTRY OF VITAMIN E approximately 970,000 hits if one types in “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.


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* 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.


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* 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:


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* ability 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.


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* There are several defense mechanisms that the body employs against

free radical formation such as the superoxide dismutase, glutathionine

peroxidase 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.


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OTHER PROPOSED BENEFITS OF VITAMIN E against

* 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.


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CLINICAL TRIALS OF IMPORTANCE againstINVOLVING VITAMIN E IN CHRONOLOGICAL ORDER


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A against. 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.


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Stampfer et al. against

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.


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Stampfer et al. against

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 < 0.001) and the RR in the highest quintile of dietary vitamin E was 0.95 (0.72 - 1.23, p = 0.99).


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Stampfer et al. against

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.


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Stampfer et al. against

Relative Risks for Quintile Groups of Vitamin E Intake


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Stampfer et al. against

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.


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Stampfer et al. against

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?


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B. againstRimm 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.


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Rimm et al. against

Results:

* There were 667 cases of coronary disease (360 bypass

surgeries/angioplasties, 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).


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Rimm et al. against

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.


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Rimm et al. against

Relative Risks for Quintile Groups for Vitamin E Intake


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Rimm et al. against

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.


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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 Women’s 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.


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Kushi et al. from

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.


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Kushi et al. from

Relative Risks for Quintile Groups of Vitamin E Intake


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Kushi et al. from

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.


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Kushi et al. from

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.


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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.


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Stephens et al. Vitamin E

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.


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Stephens et al. Vitamin E

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.


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Stephens et al. Vitamin E

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.


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Stephens et al. Vitamin E

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.


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E. Marchioli et al. “Dietary Supplementation with n-3 Vitamin E

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 (< 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


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Marchioli et al. Vitamin E

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.


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Marchioli et al. Vitamin E

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).


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Marchioli et al. Vitamin E

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.


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Marchioli et al. Vitamin E

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.


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F. The Heart Outcomes Prevention Evaluation Study Vitamin E

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.


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HOPE Investigators Vitamin E

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.


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HOPE Investigators Vitamin E

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.


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HOPE Investigators Vitamin E

Relative Risks of Primary Outcomes on Vitamin E


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HOPE Investigators Vitamin E

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.


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G. Collaborative Group of the Primary Prevention Project. Vitamin E

“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 practitioner’s office.

* Inclusion criteria: old age, hypertension, hypercholesterolemia,

diabetes, obesity, and family history of MI,


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Primary Prevention Project Vitamin E

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.


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Primary Prevention Project Vitamin E

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)


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Primary Prevention Project Vitamin E

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.


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Primary Prevention Project Vitamin E

Relative Risks of Vitamin E and Aspirin


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Primary Prevention Project Vitamin E

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.


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Primary Prevention Project Vitamin E

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.


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SAFETY OF VITAMIN E 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.


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Safety of Vitamin E continued: Vitamin E

* 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.


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Safety of Vitamin E continued: Vitamin E

* 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.


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Safety of Vitamin E continued: Vitamin E

* 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.


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TRIALS OF VITAMIN E EITHER Vitamin E

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.


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Primary Prevention Trials continued: Vitamin E

Women’s 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.


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B. Secondary Prevention Trials Vitamin E

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.

Women’s 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.


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CONCLUSIONS Vitamin E

* 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 1990’s 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.


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Conclusions continued: Vitamin E

* 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.


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Conclusions continued: Vitamin E

* 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.


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THE END Vitamin E

Thanks to all


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