cardiovascular considerations of vitamin e why the controversy brian p jones m d april 23 2002 n.
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  2. CLINICAL CASESCASE #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 qhsThe 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 #2A 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.

  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 QUESTIONSIs 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. * 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:

  14. * 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.

  15. * 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.

  16. 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. 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.

  19. 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.

  20. 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 < 0.001) and the RR in the highest quintile of dietary vitamin E was 0.95 (0.72 - 1.23, p = 0.99).

  21. 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.

  22. Stampfer et al. Relative Risks for Quintile Groups of Vitamin E Intake

  23. 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.

  24. 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?

  25. 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.

  26. Rimm et al. 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).

  27. 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.

  28. Rimm et al. Relative Risks for Quintile Groups for Vitamin E Intake

  29. 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.

  30. 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.

  31. 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.

  32. Kushi et al. Relative Risks for Quintile Groups of Vitamin E Intake

  33. 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.

  34. 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.

  35. 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.

  36. 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.

  37. 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.

  38. 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.

  39. 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.

  40. 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 (< 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

  41. 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.

  42. 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).

  43. 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.

  44. 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.

  45. 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.

  46. 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.

  47. 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.

  48. HOPE Investigators Relative Risks of Primary Outcomes on Vitamin E

  49. 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.