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Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial
Open accessAbstract
CONTEXT: Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. OBJECTIVE: To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. INTERVENTION: Daily dose of natural source vitamin E (400 IU) or matching placebo. MAIN OUTCOME MEASURES: Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. RESULTS: Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P = .30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P = .24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P = .34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P = .03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P = .045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. CONCLUSION: In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.
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“However, despite this, vitamin E did not improve cardiovascular outcomes in a large multicenter trial and actually increased congestive heart failure (201).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [201]
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BackgroundNutrition impacts the prevalence of peripheral arterial disease in the United States
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“, [70] not only found that vitamin E supplementation (400 IU/day for a median of 7 years) failed to reduce the risk of cardiovascular incidence in affected individuals but also found that it increased the risk of heart failure by 13%.”
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Oxidant stress promotes disease by activating CaMKII
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“Program (CHEP) [56], Heart Outcomes Prevention Evaluation Study (HOPE) [23], HOPE-The Ongoing Outcomes [HOPE-TOO] [57], Iowa Women's Health Study (IWHS) [58],”
MethodImmunity, Inflammation, and Oxidative Stress in Heart Failure: Emerging Molecular Targets
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“This is particularly relevant since therapy with the non-specific anti-oxidant vitamin E or vitamin C preparations (which do not inhibit mtROS) did not show any benefit in previous trials [130].”
BackgroundMarchioli, R., Levantesi, G., Macchia, A., Marfisi, R. M., Nicolosi, G. L., Tavazzi, L., Tognoni, G., & Valagussa, F. (2006) · Journal of Cardiovascular Medicine · doi:10.2459/01.jcm.0000223257.09062.17 · Cited by 110
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BackgroundCeriello, A., Testa, R., & Genovese, S. (2016) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2016.01.006 · Cited by 106
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BackgroundSupplemental and Dietary Vitamin E Intakes and Risk of Prostate Cancer in a Large Prospective Study
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“…CVD, cancer or other disorders believed to result from oxidative stress (Heart Protection Study Collaborative Group, 2002; Genkinger et al. 2004; Lonn et al. 2005; Poston et al. 2006; for reviews, see Brigelius-Flohé et al. 2002a; Upston et al. 2003; Stocker & Keaney, 2004; Pham &…”
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Addressing nutritional gaps with multivitamin and mineral supplements
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“045) associated with vitamin E supplementation (400 IU/d) in high-risk people ≥55 years of age [67].”
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“1 years) on individual rates of breast cancer [409].”
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BackgroundLipoproteins: When size really matters
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Serum and Dietary Vitamin E in Relation to Prostate Cancer Risk
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“In addition, the lack of cardiovascular efficacy (and potential risk of increased incidence of heart failure) of high-dose synthetic α-tocopherol has raised questions about risk-benefit ratio [47].”
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Manor, D., & Morley, S. (2007) · Vitamins and hormones · doi:10.1016/s0083-6729(07)76003-x · Cited by 98
Micronutrients: dietary intake v. supplement use
Woodside, J. V., McCall, D. O., McGartland, C. P., & Young, I. S. (2005) · Proceedings of The Nutrition Society · doi:10.1079/pns2005464 · Cited by 93
“The Ongoing Outcomes extended follow-up of the Heart Outcomes Prevention Evaluation trial has even suggested an increased risk of heart failure in the vitamin E-supplemented group (Lonn et al. 2005).”
BackgroundComplementary and alternative medicine in urology
Dreikorn, K. (2005) · British Journal of Urology · doi:10.1111/j.1464-410x.2005.05931.x · Cited by 91
Peters, U., Littman, A. J., Kristal, A. R., Patterson, R. E., Potter, J. D., & White, E. (2007) · Cancer Causes & Control · doi:10.1007/s10552-007-9072-y · Cited by 91
“These sparse data on dose, and the fact that the HOPE Trial [18] observed no risk reduction for prostate cancer for daily supplementation with 400 IU vitamin E preclude a definitive statement about the range of possibly beneficial doses of vitamin E.”
BackgroundResultInfluentialPark, Y., Spiegelman, D. L., Hunter, D. J., Albanes, D., Bergkvist, L., Buring, J. E., Freudenheim, J. L., Giovannucci, E. L., Goldbohm, R. A., Harnack, L., et al. (2010) · Cancer Causes & Control · doi:10.1007/s10552-010-9549-y · Cited by 92
Paradoxical action of reactive oxygen species in creation and therapy of cancer
Kardeh, S., Ashkani‐Esfahani, S., & Alizadeh, A. M. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2014.04.023 · Cited by 93
Dietary Antioxidants and Prostate Cancer: A Review
Vance, T. M., Su, J., Fontham, E. T. H., Koo, S. I., & Chun, O. K. (2013) · Nutrition and Cancer · doi:10.1080/01635581.2013.806672 · Cited by 90
“A beneficial effect of vitamin E was also observed in 1 prospective study (20), in which the effect was limited to gamma-tocopherol, and 3 case control studies (22–24), whereas 4 intervention studies (12,13), 6 prospective studies (15–19,21), and 2 case control studies (25,26) found no effect.”
BackgroundChew, P., Yuen, D. Y. C., Koh, P., Stefanovic, N., Febbraio, M. A., Kola, I., Cooper, M. E., & de Haan, J. B. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.186619 · Cited by 90
Jiang, X. M., Bai, Y., Zhang, Z., Xin, Y., & Cai, L. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2014.06.009 · Cited by 90
Mitochondrial dysfunction and its impact on diabetic heart
Verma, S. K., Garikipati, V. N. S., & Kishore, R. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.08.021 · Cited by 94
Atherosclerosis and Oxidant Stress: The End of the Road for Antioxidant Vitamin Treatment?
Thomson, M. J. C. B., Püntmann, V. O., & Kaski, J. C. (2007) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-007-6027-1 · Cited by 91
Does reversal of oxidative stress and inflammation provide vascular protection?
Koh, K. K., Oh, P. C., & Quon, M. J. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn354 · Cited by 89
Choleva, T. G., Kappi, F. A., Giokas, D. L., & Vlessidis, A. G. (2014) · Analytica Chimica Acta · doi:10.1016/j.aca.2014.12.025 · Cited by 88
Oxidative Stress and the Aging Brain
Vila, J., Gemma, C., Bachstetter, A. D., & Bickford, P. C. (2007) · Frontiers in neuroscience · doi:10.1201/9781420005523.ch15 · Cited by 88
The Mitochondria in Diabetic Heart Failure: From Pathogenesis to Therapeutic Promise
Schilling, J. D. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6294 · Cited by 90
“However, when investigated in humans, these antioxidants either alone or in combination have not shown consistent beneficial effects on serum metabolic parameters or the incidence of cardiovascular disease (65, 108).”
Mechanisms Linking Metabolic-Associated Fatty Liver Disease (MAFLD) to Cardiovascular Disease
Badmus, O. O., Hinds, T. D., & Stec, D. E. (2023) · Current Hypertension Reports · doi:10.1007/s11906-023-01242-8 · Cited by 90
Chemopreventive Activity of Vitamin E in Breast Cancer: A Focus on γ- and δ-Tocopherol
Smolarek, A. K., & Suh, N. (2011) · Nutrients · doi:10.3390/nu3110962 · Cited by 86
Apigenin protects endothelium-dependent relaxation of rat aorta against oxidative stress
Jin, B., Qian, L.-B., Chen, S., Li, J., Wang, H., Bruce, I. C., Lin, J., & Xia, Q. (2009) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2009.06.020 · Cited by 92
“Unfortunately, the results of long-term epidemiological trials with oral delivery of acknowledged antioxidants such as vitamin C and vitamin E have been ambiguous and do not support the use of either to reduce the risk of cardiovascularmorbidity ormortality (Forstermann, 2008; Lonn et al., 2005).”
BackgroundThe Quest for Selective Nox Inhibitors and Therapeutics: Challenges, Triumphs and Pitfalls
Cifuentes-Pagano, E., Meijles, D. N., & Pagano, P. J. (2014) · Antioxidants & Redox Signaling · doi:10.1089/ars.2013.5620 · Cited by 84
“Two of the most notorious of these include reports of elevated heart failure rates in patients who took high dose of vitamin E (108) and an increased incidence of cancer in smokers supplemented with beta-carotene (68).”
BackgroundOxidative Stress in Patients with Rheumatoid Arthritis
Garcı́a-González, A., Gaxiola‐Robles, R., & Zenteno‐Savín, T. (2015) · Revista de investigaci�n Cl�nica · doi:10.1016/s0034-8376(25)00221-9 · Cited by 86
Nutraceuticals in Prostate Disease: The Urologist's Role.
Nickel, J. C., Shoskes, D. A., Roehrborn, C. G., & Moyad, M. A. (2008) · Europe PMC (PubMed Central) · Cited by 86
Are reactive oxygen species still the basis for diabetic complications?
Marco, E. D., Jha, J. C., Sharma, A., Wilkinson‐Berka, J. L., Jandeleit-Dahm, K. A. M., & de Haan, J. B. (2015) · Clinical Science · doi:10.1042/cs20150093 · Cited by 86
Bayesian model averaging in meta-analysis: vitamin E supplementation and mortality
Berry, D. A., Wathen, J. K., & Newell, M. (2009) · Clinical Trials · doi:10.1177/1740774508101279 · Cited by 82
Lee, J., Son, D., & Kwon, Y. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.1066159 · Cited by 86
Magnusson, M., Höglund, P., Johansson, K. I., Jönsson, C., Killander, F., Malmström, P., Weddig, A., & Kjellén, E. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2009.05.015 · Cited by 84
Management of complications of androgen deprivation therapy in the older man
Mohile, S. G., Mustian, K. M., Bylow, K. A., Hall, W. J., & Dale, W. (2008) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2008.09.004 · Cited by 84
“On the other hand, one dietary supplement that had een previously recommended for palliation of hot flashes, itamin E at 400 IU twice daily, has now been shown to be ssociated with increased all-cause mortality and may have egative effects on cardiovascular health [48,49].”
BackgroundThe Maximal Amount of Dietary α-Tocopherol Intake in U.S. Adults (NHANES 2001–2002)
Gao, X., Wilde, P., Lichtenstein, A. H., Bermúdez, O. I., & Tucker, K. L. (2006) · Journal of Nutrition · doi:10.1093/jn/136.4.1021 · Cited by 84
Xia, Z., Li, H., & Irwin, M. G. (2016) · British Journal of Anaesthesia · doi:10.1093/bja/aew267 · Cited by 88
Vitamin E: How much is enough, too much and why!
Traber, M. G., & Head, B. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.10.028 · Cited by 86
Stroke: roles of B vitamins, homocysteine and antioxidants
Sánchez‐Moreno, C., Jiménez‐Escrig, A., & Martin-Marco, A. (2009) · Nutrition Research Reviews · doi:10.1017/s0954422409990023 · Cited by 83
“Another study found that in patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure((135)).”
BackgroundInfluentialThe Role of Micronutrients in Heart Failure
McKeag, N. A., McKinley, M. C., Woodside, J. V., Harbinson, M., & McKeown, P. (2012) · Journal of the Academy of Nutrition and Dietetics · doi:10.1016/j.jand.2012.01.016 · Cited by 82
Xi, H., Akishita, M., Nagai, K., Yu, W., Hasegawa, H., Eto, M., Kozaki, K., & Toba, K. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.05.040 · Cited by 82
Roy, B. (2025) · Medical Sciences · doi:10.3390/medsci13030087 · Cited by 103
Dunn, B. K., Richmond, E. S., Minasian, L. M., Ryan, A. M., & Ford, L. G. (2010) · Nutrition and Cancer · doi:10.1080/01635581.2010.509833 · Cited by 82
“The 400 IU/day dose was chosen for reasons such as its inclusion in vitamin supplements as well as the potential benefit of this high dose for multiple disease endpoints as investigated in the HOPE trial ( 131 ), the Physicians’ Health Study II ( 132 ), and other studies ( 60 ).”
BackgroundModulation of oxidative stress-induced changes in hypertension and atherosclerosis by antioxidants.
Vasdev, S., Gill, V. D., & Singal, P. K. (2006) · PubMed Central · Cited by 78
Evans, J. R. (2006) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd000254.pub2 · Cited by 23
Therapeutic Strategies Targeting Oxidative Stress and Inflammation: A Narrative Review
Manful, C. F., Fordjour, E., Ikumoinein, E., Abbey, L., & Thomas, R. (2025) · BioChem · doi:10.3390/biochem5040035 · Cited by 96
Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression
Fulan, H., Changxing, J., Yi, B. W., Wencui, Z., Chunqing, L., Wang, F., Li, D., Sun, D., Tong, W., Pang, D., et al. (2011) · Cancer Causes & Control · doi:10.1007/s10552-011-9811-y · Cited by 79
Oxidative stress, antioxidants, and assessment of oxidative stress in dogs and cats
McMichael, M. A. (2007) · Journal of the American Veterinary Medical Association · doi:10.2460/javma.231.5.714 · Cited by 79
Fleshner, N. E., & Zlotta, A. R. (2007) · Cancer · doi:10.1002/cncr.23009 · Cited by 79
Stram, D. O., Hankin, J. H., Wilkens, L. R., Park, S., Henderson, B. E., Nomura, A. M. Y., Pike, M. C., & Kolonel, L. N. (2006) · Cancer Causes & Control · doi:10.1007/s10552-006-0064-0 · Cited by 79
“While some additional observations of protective relationships between vitamin E supplementation and prostate cancer risk have been reported [30–32], two other randomized trials of supplementation have found no relationship between either combined supplementation of vitamin C, betacarotene, and vitamin E [33] or vitam…”
Metadata
- Authors
- The HOPE and HOPE-TOO Trial Investigators
- Affiliations
- Population Health Research Institute (CA)
- Corresponding author
- The HOPE and HOPE-TOO Trial Investigators
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2005-03-16
- Volume
- 293
- Issue
- 11
- Pages
- 1338
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W1678920698
- Cited by
- 1,209
- References
- 20
- Citations by year
- 2026: 26 · 2025: 26 · 2024: 31 · 2023: 35 · 2022: 35 · 2021: 34 · 2020: 45 · 2019: 37 · 2018: 22 · 2017: 44 · 2016: 48 · 2015: 56 · 2014: 95 · 2013: 70 · 2012: 87
- FWCI
- 58.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Topics
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Vitamin D Research Studies
- Keywords
- vitamin E supplementation, long-term supplementation, cancer incidence, cancer mortality, cardiovascular events, myocardial infarction, stroke, cardiovascular mortality, heart failure, unstable angina, revascularization, older adults, vascular disease, diabetes mellitus
- MeSH terms
- Aged, Antioxidants, Cardiovascular Diseases, Diabetes Mellitus, Double-Blind Method, Female, Humans, Male, Middle Aged, Neoplasms, Risk, Vascular Diseases, Dietary Supplements, alpha-Tocopherol
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