CARDIOVASCULAR DISEASE AND VITAMIN E
The American HeartAssociation estimated that nearly 2,400 Americans die of cardiovasculardiseases each day, which is an average of one death every 37 seconds (1).Cardiovascular diseases include coronary heart disease, hypertension,peripheral artery disease, congenital heart disease and heart failure. Heartattacks are mainly caused by plaque build up in blood vessels that supply theheart and brain (2). Plaque build up in blood vessels is due to a complex ofoxidized low density lipoproteins and macrophages that form a foam cell, whichcan rupture and deposit oxidized cholesterol into the arterial walls. Vitamin Eis thought to protect the cell membrane from oxidation by preventing lipid peroxidation(3). In 1993, Belcher(3) tested blood samples from five subjects who received800IU/day of DL-alpha tocopherol, for two weeks, and found a decrease in therate of LDL oxidation. There was also a significant increase inLDL-alpha-tocopherol content, 11+/-2 to 26+/-6 molecules per LDL particle. In1980, a large cohort study of more than 80,000 healthy nurses, found a 30%reduction of major coronary heart disease in the vitamin E group compared tothe placebo group (4). Subjects that received greater than 100 IU of vitamin Efor more than two years benefited the most, RR 0.59; 95% CI, 0.38-0.91. Observational studies may beable to show benefits for cardiovascular disease for a large cohort, but areunable to control for confounding variables or unknowns.
Although synthetic andnatural sources of alpha-tocopherol have been studied since the late 1900’s,the benefits of short-term (< 4 years) compared to long-term (>/= 4years) alpha-tocopherol supplementation, to reduce the risk of cardiovasculardisease is unclear. The purpose of this paper is to review ten randomized,placebo-controlled trials, that measured major cardiovascular events amonghealthy or at risk individuals, who received synthetic or natural alpha-tocopherolsupplements.The short term studies, Diabetes (5), Placebo (6), Myocardial (7),and Risk (8), measured the effect of 400-800 IU alpha-tocopherol oncardiovascular death, total myocardial infarction, and total stroke among496-11,324 healthy or at risk subjects, with a trial duration ranging from1.5-4 years. The long-term studies measured major cardiovascular events among8,171-39,876 healthy or at risk individuals, who received 75-800 IUalpha-tocopherol daily or every other day for a 4.5 to 10 year trial duration.A description of each trial is listed in table 1.
Short TermStudies
Diabetes (5) evaluated theeffect of vitamin E on 1434 males and females, age 55 or older, with type 2diabetes and hp 2-2 phenotype. Subjects were randomly allocated to either 400IU of natural d-alpha-tocopherol or placebo daily for 18 months. There was asignificant decrease in the vitamin E group compared to placebo for stroke,myocardial infarction, and cardiovascular death, RR 1.05; 95% CI, 0.90-1.22.
Placebo (6) randomized 196hemodialysis patients, aged 40-75 to receive 800 IU of natural alpha-tocopherolor placebo daily for two years. All of the patients had pre-existingcardiovascular disease. There was a significant difference in the vitamin Egroup compared to placebo for non-fatal myocardial infarction, RR 0.35; 95% CI0.35, 0.10-1.24. There was no significant difference at follow-up for stroke,RR 0.85; 95% CI, 0.30-2.70, or cardiovascular death, RR 0.61; 95% CI,0.28-1.30.
Myocardial (7) tested theeffects of vitamin E, n–3 PUFA, or both on 11,324 males and female patients whosurvived a myocardial infarction in the past three months. Syntheticalpha-tocopherol 450 IU was randomly assigned to 2,830 patients and 2,828patients received a placebo for 42 months. Age limits were not defined in this study.At follow-up there was an absence of significant effect for vitamin E onstroke, RR 0.87; 95% CI, 0.65-1.17, and combined cardiovascular death andmyocardial infarction, RR 1.00;95% CI, 0.88-1.14.
Risk (8) randomized controltrial to investigate aspirin and vitamin E among 4,495 male and females, and amean age of 64.4 years. Every participant had one or more risks forcardiovascular disease. Synthetic alpha-tocopherol 450 IU was administered to2,231 subjects and 2,264 received a placebo daily for a mean of four years.There was no significant difference at follow-up for the vitamin E and placebogroups for stroke, RR 0.67; 95% CI, 0.36-1.27, myocardial infarction, RR 0.69;95% CI 0.38-1.23, and cardiovascular deaths, RR 0.56; 95% 0.31-0.99. A significantlower incidence for peripheral-artery disease was seen among patients takingvitamin E compared to placebo, RR 0.60; 95% CI, 0.33-1.08.
Long Term Treatment
Trial (9) tested the effectsof vitamin E, ascorbic acid and beta-carotene on 8,171 females, age 40 orolder, with a history of CVD or three or more CVD risk factors. Women wererandomly selected to take 600 IU of natural alpha-tocopherol acetate or placeboevery other day for nine years. Vitamin E group was not significantly differentcompared to the placebo group for stroke, RR 0.84; 95% CI, 0.67-1.05,myocardial infarction, RR 0.91; 95% CI, 0.72-1.15, and cardiovascular death, RR0.94; 95% CI, 0.77-1.15. Subjects with prior CVD in the vitamin E groupexperienced a significant decrease in major cardiovascular events, RR 0.89; 95%CI, 0.79-1.00.
Prevention (10) tested thelong-term effect of vitamin E or vitamin C supplementation for majorcardiovascular events among 14,641 men age 50 or older. There were 754 men witha history of nonfatal MI and stroke at baseline. The men were randomly assignedto consume 400 IU of synthetic alpha-tocopherol or a placebo every other dayfor ten years. Vitamin E supplementation did not reduce myocardial infarction,HR 0.90; 95% CI, 0.75-1.07, stroke, HR 1.07; 95% CI, 0.89-1.29, andcardiovascular death, HR 1.07; 95% CI, 0.90-1.28.
Patients (11) examined theeffects of vitamin E among 9,541 patients, age 55 or older with a history ofcoronary or peripheral arterial disease. Patients were randomly selected toreceive 400 IU of natural RRR-alpha-tocopheryl acetate or placebo daily forseven years. Vitamin E had no significant effect on myocardial infarction, RR1.06; 95% 0.96-1.18, stroke, RR 1.10; 95% 0.93-1.31, and cardiovascular death,RR 1.02; 95% 0.91-1.10.
Disease (12) tested theeffect of vitamin E on 39,876 healthy women, age 54 +/- 7. Subjects wererandomly selected to take either 600 IU of natural alpha-tocopherol or aplacebo every other day. At ten year follow-up, vitamin E had no effect onfatal and non-fatal myocardial infarction, RR 1.01; 95% CI, 0.82-1.23 or totalstroke, RR 0.98; 95% CI, 0.82-1.17. Thevitamin E group had 106 cardiovascular deaths compared to 140 deaths in theplacebo group, which was a significant decrease, RR 0.76; 95% CI, 0.59-0.98.
Fatal (13) randomized 27,271male smokers, aged 50-69 years, to receive vitamin E, beta-carotene, both, orplacebo daily for a mean of six years. All of the participants had no historyof myocardial infarction. Alpha-tocopherol 75 UL was administered to 519subjects and 534 received a placebo. There was no significant differencebetween the vitamin E and placebo groups for non-fatal myocardial infarction,RR 0.99; 95% CI, 0.84-1.16.
High-Risk (14) enrolled2,545 women and 6,996 men, age 55 and older, who had cardiovascular disease ordiabetes, and one or more CVD risk factors. Patients were randomly assigned toreceive 400 IU of natural alpha-tocopherol or placebo daily for a mean of fourand a half years. There was no significant difference between the vitamin E andplacebo groups for stroke, RR 1.17; 95% CI, 0.95-1.43, myocardial infarction,RR 1.02; 95% CI, 0.90-1.15, and cardiovascular death, RR 1.05; 95% CI,0.90-1.22.
Discussion
The ten randomized studiesoffered little evidence that vitamin E supplementation from 75 to 800 IU hadany benefits for cardiovascular mortality, myocardial infarction, or stroke. Onlyone trial (9) for long term treatment showed a significant decrease for majorcardiovascular events, but only for individuals with prior CVD. Trials (5-6)had a significant decrease in myocardial infarction among hemodialysis patientsand diabetics. Vitamin E supplementation seems to be more effective forpatients at risk compared to healthy individuals, and the duration of thestudies is less important. There was awide distribution in sample sizes ranging from 179 to 39,876, which may put tolittle or to much emphasis on relative risks. Clinical trials should directtheir attention towards individuals at risk for CVD instead of healthy individuals.
Conclusion
The ten studies as a whole lack evidence thatsynthetic and natural alpha-tocopherol of different doses and duration of trialis beneficial for primary and secondary preventions of CVD for the generalpublic. A small benefit from vitamin E was shown among individuals at high riskfor CVD in three out of four short term trials and one out of six long termtrials. Hemodialysis patients or patients with high oxidative stress maybenefit more from high dose alpha-tocopherol compared to healthy individuals.Vitamin E supplementation is made mostly with tocopherols, and there is limitedresearch of the oxidative properties for tocotrienols. Researchers may want tofocus more on the different isomers of vitamin E, and rely less on tocopherolsand duration of treatment.
References
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4. Stamfer MJ,Hennekens CH, Manson AE, Colditz GA, Rosner B, Willet WC. Vitamin E consumptionand the risk of coronary disease in women. N Engl J Med 1993;328:1444-9.
6. Boaz M, SmetanaS, Weinstein T, Matas Z, Gafter U, Laina A, Knecht A, Weissgarten Y, Brunner D,Fainaru M, Green MS. Secondary prevention with antioxidants of cardiovasculardisease in endstage renal disease (SPACE): randomized placebo-controlled trial.The Lancet 2000;356:1213-18.
11. Hope investigators. Effects of long-termvitamin E supplementation on cardiovascular events and cancer. JAMA2005;293:1338-47.
14. The heart outcomes prevention evaluation studyinvestigators. Vitamin E supplementation and cardiovascular events in high-riskpatients. N Engl J Med 2000;342:154-60.
