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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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Bittner, V. (2008) · Southern Medical Journal · doi:10.1097/smj.0b013e318167b13c · Cited by 1
Li, Y., He, G., Huang, J., & Hu, L. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1628032 · Cited by 1
“In addition, another study demonstrated that long-term consumption of 400 IU of vitamin E daily could lead to a 13% increase in the risk of heart failure and a 21% increase in the risk of hospitalization (33).”
The Role of Micronutrients in Atherosclerosis: Mechanisms and Clinical Application
Ouyang, Y., Jiang, W., Long, X., Mao, P., He, P., & Ouyang, X. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70920 · Cited by 2
Post-normal bioactives: Reframing food, health, and sustainability
Mason, P., Garcia‐Bennett, A. E., Lopes, C. V. A., Tang, D., Suresh, H., Wynn, L. L., McGregor, A., Downey, G., & Sunna, A. (2026) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2026.105685 · Cited by 1
Mitochondrial redox imbalance in triggering regulated cell death in kidney diseases
Zhu, W., Zou, R., Liu, R., Jia, Z., Zhang, Y., & Wu, M. (2026) · iScience · doi:10.1016/j.isci.2026.116405 · Cited by 2
“28 Therefore, achieving localized mtROS modulation while preserving physiological systemic mtROS signaling is critical for antioxidant-based therapeutic strategies. mtROS release results from the balance between ROS generation by the ETC and their subsequent elimination by mitochondrial antioxidant…”
Berger, M. M., Blaauw, R., D’Amelio, P., Ehrhart, N. P., Gombart, A. F., Gramlich, L. M., Kressig, R. W., & Calder, P. C. (2026) · GeroScience · doi:10.1007/s11357-026-02402-9 · Cited by 1
“…which tested very high doses of vitamin A and E in a population at higher risk for lung cancer, the SELECT trial which combined high doses of vitamin E and selenium [163], and the HOPE-TOO trial which also tested high doses of vitamin E [164]; doses used in these trials were often above the RDA.”
Kolotyeva, N. A., Novikova, S. V., Namiot, E., Zembatov, G. M., Tregub, P. P., Rozanova, N. A., Makarov, V., Komleva, Y. K., & Салмина, А. (2026) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-026-02132-x · Cited by 2
Matthews, B. R., & Miller, B. L. (2009) · Cambridge University Press eBooks · doi:10.1017/cbo9780511581410.005 · Cited by 1
Novel Synthetic Antioxidants and Nitrated Lipids: From Physiology to Therapeutic Implications
López, G. V., & Rubbo, H. (2010) · Humana Press eBooks · doi:10.1007/978-1-60761-600-9_25 · Cited by 1
Grossklaus, R., & Henning, K. (2008) · Der Ophthalmologe · doi:10.1007/s00347-008-1819-7 · Cited by 1
Shimosawa, T., Kaneko, T., Xu, Q., Miyamoto, Y., Shengyu, M., Wang, H., Ogura, S., Jimbo, R., Majtan, B., Uetake, Y., et al. (2012) · InTech eBooks · doi:10.5772/33448 · Cited by 1
“either alone or in combination with each other or with other antioxidant vitamins, does not appear to be efficacious for the treatment of cardiovascular disease (Lonn et al., 2005).”
BackgroundLifestyle Changes, CAM, and Kidney Stones: Heart Health = Kidney Health
Moyad, M. A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-8492-9_8 · Cited by 1
Atherogenesis: Diseases that May Affect the Natural History “Schistosomiasis and HIV Infection”
Teixeira, C., Godoi, E. T. A. M., Valenca, A., Mascena, G. V., & Godoi, J. T. A. M. (2013) · InTech eBooks · doi:10.5772/54018 · Cited by 1
Vitamins, intravenous solutions, and drugs and formulations used in nutrition
Aronson, J. K. (2012) · Side effects of drugs annual · doi:10.1016/b978-0-444-59499-0.00034-9 · Cited by 1
Moyad, M. A. (2014) · Springer eBooks · doi:10.1007/978-1-4939-0425-9_12 · Cited by 1
Trace Elements, Vitamins, and Lipids and Age-Related Macular Degeneration
Buitendijk, G. H. S., & Klaver, C. C. W. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-401717-7.00006-x · Cited by 1
Ghayour-Mobarhan, M., Sahebkar, A., Starkey, B. J., Livingston, C., Wang, T., Lamb, D., & Ferns, G. (2008) · Pakistan Journal of Nutrition · doi:10.3923/pjn.2008.561.565 · Cited by 1
“supplementation in high risk patients (Heart Protection Collaborative Study Group, 2002a; Lonn et al., 2005; Marchioli et al., 2002) it is still possible that the antioxidants are of benefit in the early phases of disease.”
BackgroundThe Role of Antioxidant Vitamins in Cardiovascular Disease
Seefeldt, T. M., & Bennett, L. L. (2011) · Journal of Pharmacy Technology · doi:10.1177/875512251102700105 · Cited by 1
The Role of Free Radicals and Antioxidant in Abortion
Suryawan, A., & Rahardjo, T. M. (2013) · The Indonesian Biomedical Journal · doi:10.18585/inabj.v5i1.47 · Cited by 1
Complementary and Alternative Medicine and Lifestyle Changes and Prostate Cancer
Moyad, M. A. (2013) · Springer eBooks · doi:10.1007/978-1-4614-8492-9_7 · Cited by 1
The expanding role of nutrition in endocrinology and metabolism
Apovian, C. M., & Kushner, R. F. (2006) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000244219.45539.58 · Cited by 1
Role of Oxidative Stress in Hypertension
Rodrigo, R., & González, J. (2014) · CRC Press eBooks · doi:10.1201/b16653-14 · Cited by 1
Cardiac Metabolism and Energetic Control
Rohrbach, S., & Niemann, B. (2016) · Springer eBooks · doi:10.1007/978-3-319-31251-4_4 · Cited by 1
Integrative Medicine in the Prevention of Cardiovascular Disease
Longhurst, J. C., & Costello, R. B. (2011) · Elsevier eBooks · doi:10.1016/b978-1-4377-1366-4.00017-2 · Cited by 1
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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