Cited by 1,209Antioxidant Activity and Oxidative StressNutritional Studies and DietVitamin D Research Studies

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Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial

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The HOPE and HOPE-TOO Trial Investigators·2005·JAMA

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Abstract

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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Background
Role of Oxidative Stress in Remodeling of the Myocardial Microcirculation in Hypertension
Zhu, X.-Y., Daghini, E., Chade, A., Rodriguez-Porcel, M. G., Claudio Napoli, A., Lerman, A., & Lerman, L. O. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000227469.40826.01 · Cited by 44
Vitamin E Supplementation and the Risk of Heart Failure in Women
Chae, C. U., Albert, C. M., Moorthy, M. V., Lee, I.-M. M., & Buring, J. E. (2012) · Circulation Heart Failure · doi:10.1161/circheartfailure.111.963793 · Cited by 45
Glutathione and glutathione-linked enzymes in normal human aortic smooth muscle cells: chemical inducibility and protection against reactive oxygen and nitrogen species-induced injury
Zhu, H., Cao, Z., Zhang, L., Trush, M. A., & Li, Y. (2007) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-006-9396-z · Cited by 45
How to understand the dichotomy of antioxidants
Shen, L., Ji, H., & Zhang, H. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.07.125 · Cited by 45
Vitamin E Intake and Risk of Prostate Cancer: A Meta-Analysis
Loh, W. Q., Youn, J., & Seow, W. J. (2022) · Nutrients · doi:10.3390/nu15010014 · Cited by 44
Micro and nano-encapsulated natural products in yogurt: An emerging trend to achieve multifunctional benefits in product quality and human health.
Shishir, M. R. I., Saifullah, M., Hashim, S. B. H., Aalim, H., Bilal, M., Khan, S., Marappan, G., Tahir, H. E., Li, Z., Zhai, X., et al. (2024) · Food Hydrocolloids · doi:10.1016/j.foodhyd.2024.110124 · Cited by 44
Melanoma chemoprevention
Francis, S. O., Mahlberg, M. J., Johnson, K. R., Ming, M. E., & Dellavalle, R. P. (2006) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2006.04.014 · Cited by 45
Mild Cognitive Impairment — No Benefit from Vitamin E, Little from Donepezil
Blacker, D. (2005) · New England Journal of Medicine · doi:10.1056/nejme058086 · Cited by 44
Molecular Mechanisms Underlying the Therapeutic Role of Vitamin E in Age-Related Macular Degeneration
Edwards, G., Olson, C. G., Euritt, C. P., & Koulen, P. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.890021 · Cited by 49
Micronutrients in Chronic Heart Failure
Krim, S. R., Campbell, P. M. F., Lavie, C. J., & Ventura, H. O. (2012) · Current Heart Failure Reports · doi:10.1007/s11897-012-0118-4 · Cited by 45
Micronutrient Depletion in Heart Failure: Common, Clinically Relevant and Treatable
Cvetinovic, N., Loncar, G., Isakovic, A. M., von Haehling, S., Doehner, W., Lainščak, M., & Farkaš, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225627 · Cited by 44
“Moreover, there are indications that vitamin E treatment may contribute to HF development [54,55].”
Background
Chemoprevention of Prostate Cancer: Agents and Study Designs
Thompson, I. M. (2007) · The Journal of Urology · doi:10.1016/j.juro.2007.03.138 · Cited by 43
Effect of white wine consumption on oxidative stress markers and homocysteine levels
Rajdl, D., Racek, J., Trefil, L., & Siala, K. (2007) · Physiological Research · doi:10.33549/physiolres.930936 · Cited by 43
A randomized factorial study of the effects of long-term garlic and micronutrient supplementation and of 2-wk antibiotic treatment for Helicobacter pylori infection on serum cholesterol and lipoproteins
Zhang, L., Gail, M. H., Wang, Y.-Q., Brown, L. M., Pan, K., Ma, J., Amagase, H., You, W., & Moslehi, R. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/84.4.912 · Cited by 43
Influence of specific nutrients on progression of atherosclerosis, vascular function, haemostasis and inflammation in coronary heart disease patients: a systematic review
Hamer, M., & Steptoe, A. (2006) · British Journal Of Nutrition · doi:10.1079/bjn20061741 · Cited by 45
“…7 years’ supplementation with vitamin E (a-tocopherol; 400 IU/d) in patients with vascular disease or diabetes mellitus was not efficacious for the prevention of major cardiovascular events and was actually connected with a higher risk of heart failure (HOPE Trial Investigators; Lonn et al. 2005).”
Background
Treatment of Oxidative Stress with Exosomes in Myocardial Ischemia
Liu, Y., Wang, M., Liang, Y., Wang, C., Naruse, K., & Takahashi, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041729 · Cited by 42
“In the current research on exogenous anti-OS, the effects of OS damage were mot significantly reduced [6,7].”
Background
Targeting Key Inflammatory Mechanisms Underlying Heart Failure: A Comprehensive Review
Papamichail, A., Kourek, C., Briasoulis, Α., Xanthopoulos, A. V., Tsougos, E., Farmakis, D. T., & PARASKEVAIDIS, I. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010510 · Cited by 51
“Antioxidant agents [51,80–82] • A small double-blind randomized controlled trial investigating the use of vitamin E in HF patients did not demonstrate significant improvements.”
BackgroundMethod
The Role of Nutraceuticals in Male Fertility
Ko, E., & Sabanegh, E. S. (2013) · Urologic Clinics of North America · doi:10.1016/j.ucl.2013.08.003 · Cited by 43
Vitamin E supplementation and pneumonia risk in males who initiated smoking at an early age: effect modification by body weight and dietary vitamin C
Hemilä, H., & Kaprio, J. A. (2008) · Nutrition Journal · doi:10.1186/1475-2891-7-33 · Cited by 42
Prostate Cancer Screening
Dunn, M. W. (2017) · Seminars in Oncology Nursing · doi:10.1016/j.soncn.2017.02.003 · Cited by 42
“vitamins E and C) failed to demonstrate a reduction of prostate cancer with these supplements.(10,11) A huge dietary intake trial, The European Prospective Investigation into Cancer and Nutrition, has yet to find any association between total consumption of fruit and vegetables and risk for prostate cancer.”
Background
Micronutrients and their supplementation in chronic cardiac failure. An update beyond theoretical perspectives
Witte, K. K., & Clark, A. L. (2006) · Heart Failure Reviews · doi:10.1007/s10741-006-9194-4 · Cited by 42
The Role of Over‐the‐Counter Supplements for the Treatment of Male Infertility—Fact or Fiction?
Ko, E., & Sabanegh, E. S. (2012) · Journal of Andrology · doi:10.2164/jandrol.111.013730 · Cited by 42
Reducing the “Risk” of Chemoprevention: Defining and Targeting High Risk—2005 AACR Cancer Research and Prevention Foundation Award Lecture
Lippman, S. M., & Lee, J. J. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4573 · Cited by 42
Do antioxidants prevent colorectal cancer? A meta-analysis.
Pais, R., & Dumitraşcu, D. L. (2013) · PubMed · Cited by 41
Plasma Vitamin C, but Not Vitamin E, Is Associated With Reduced Risk of Heart Failure in Older Men
Wannamethee, S. G., Bruckdorfer, K. R., Shaper, A. G., Papacosta, O., LENNON, L. T., & Whincup, P. H. (2013) · Circulation Heart Failure · doi:10.1161/circheartfailure.112.000281 · Cited by 41
Progress in the development of new drugs in Alzheimer's disease
Piau, A., Nourhashémi, F., Hein, C., Caillaud, C., & Vellas, B. (2011) · The Journal of nutrition, health and aging · doi:10.1007/s12603-011-0012-x · Cited by 32
“However, recent meta-analysis and trial results suggest that vitamin E increases morbidity and mortality (107, 108) and the Cochrane review does not support the use of vitamin E to treat AD (109).”
Fatigue and illness in athletes
Nimmo, M. A., & Ekblom, B. T. (2007) · Journal of Sports Sciences · doi:10.1080/02640410701607379 · Cited by 49
“Although a recent meta-analysis (Moriera et al., 2007) supports the conclusion of vitamin C supplementation modulating the immunosuppression with exercise, there is no support for the administration of vitamin E supplementation in view of links to heart failure (Lonn et al., 2005).”
BackgroundResult
Redox homeostasis of breast cancer lineages contributes to differential cell death response to exogenous hydrogen peroxide
Hecht, F., Cazarin, J., Lima, C., de Faria, C. C., Leitão, Á. C., Ferreira, A. C. F., de Carvalho, D. P., & Fortunato, R. S. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.06.016 · Cited by 41
Salt Sensitivity of Blood Pressure in Blacks and Women: A Role of Inflammation, Oxidative Stress, and Epithelial Na + Channel
Sahinoz, M., Elijovich, F., Ertuğlu, L. A., Ishimwe, J., Pitzer, A. L., Saleem, M., Mwesigwa, N., Kleyman, T. R., Laffer, C. L., & Kirabo, A. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0212 · Cited by 41
Vitamin E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vitamin C intake
Hemilä, H., & Kaprio, J. A. (2008) · British Journal Of Nutrition · doi:10.1017/s0007114508923709 · Cited by 41
Ferroptosis and oxidative stress in endometriosis: A systematic review of the literature
Ni, C., & Li, D. (2024) · Medicine · doi:10.1097/md.0000000000037421 · Cited by 45
Vitamin E Supplementation and Mortality in Healthy People: A Meta-Analysis of Randomised Controlled Trials
Curtis, A. J., Bullen, M., Piccenna, L. G., & McNeil, J. J. (2014) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-014-6560-7 · Cited by 41
Nutrition and melanoma prevention
Jensen, J. D., Wing, G. J., & Dellavalle, R. P. (2010) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2010.03.026 · Cited by 41
Genetic deletion of Nox4 enhances cancerogen-induced formation of solid tumors
Helfinger, V., von Gall, F. F., Henke, N., Kunze, M. M., Schmid, T., Rezende, F., Heidler, J., Wittig, I., Radeke, H. H., Marschall, V., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2020152118 · Cited by 42
Clinical practice advice on lifestyle modification in the management of nonalcoholic fatty liver disease in Japan: an expert review
Kamada, Y., Takahashi, H., Shimizu, M., Kawaguchi, T., Sumida, Y., Fujii, H., Seko, Y., Fukunishi, S., Tokushige, K., Nakajima, A., et al. (2021) · Journal of Gastroenterology · doi:10.1007/s00535-021-01833-9 · Cited by 43
Serum concentrations of antioxidant vitamins and carotenoids are low in individuals with a history of attempted suicide
Li, Y., & Zhang, J. (2007) · Nutritional Neuroscience · doi:10.1080/10284150701250747 · Cited by 40
“It is well known that clinical trials with pharmacologic doses of singlecomponent supplements of antioxidants have had disappointing results (Omenn et al. 1996a,b; Rapola et al. 1997; Virtamo et al. 1998; Lee et al. 2005; Lonn et al. 2005).”
Background
Nutrition in pediatric cardiomyopathy
Miller, T. L., Neri, D. A., Extein, J., Somarriba, G. A., & Strickman-Stein, N. (2007) · Progress in Pediatric Cardiology · doi:10.1016/j.ppedcard.2007.08.007 · Cited by 40
“Vitamin E Vitamin E is an antioxidant that can be detected in lower concentrations in patients with congestive heart failure [49]; however there is little evidence that shows the benefits in improving myocardial function with exogenous supplementation [50–54].”
Background
Heart disease and single-vitamin supplementation
Traber, M. G. (2007) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/85.1.293s · Cited by 39
Non-alcoholic fatty liver disease and liver transplantation: Outcomes and advances
Said, A. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i48.9146 · Cited by 40
Molecular and Biochemical Analysis of the Estrogenic and Proliferative Properties of Vitamin E Compounds
Khallouki, F., de Médina, P., Caze-Subra, S., Bystricky, K., Balaguer, P., Poirot, M., & Silvente‐Poirot, S. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2015.00287 · Cited by 39
α-Tocopherol Is Ineffective in Preventing the Decomposition of Preformed Lipid Peroxides and May Promote the Accumulation of Toxic Aldehydes: A Potential Explanation for the Failure of Antioxidants to Affect Human Atherosclerosis
Raghavamenon, A. C., Garelnabi, M., Babu, S. A., Aldrich, A. M., Litvinov, D. Y., & Parthasarathy, S. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2248 · Cited by 41
Elevated Plasma γ-Tocopherol and Decreased α-Tocopherol in Men Are Associated With Inflammatory Markers and Decreased Plasma 25-OH Vitamin D
Cooney, R. V., Franke, A. A., Wilkens, L. R., Gill, J. K., & Kolonel, L. N. (2008) · Nutrition and Cancer · doi:10.1080/01635580802404162 · Cited by 39
The Role of Micronutrients in Managing Diabetes
Chehade, J. M., Sheikh‐Ali, M., & Mooradian, A. D. (2009) · Diabetes Spectrum · doi:10.2337/diaspect.22.4.214 · Cited by 38
Environmental Toxins and Oxidative Stress: The Link to Cardiovascular Diseases
Sule, R. O., Rivera, G. D. T., Vaidya, T., Gartrell, E., & Gomes, A. V. (2025) · Antioxidants · doi:10.3390/antiox14050604 · Cited by 41
Vitamin E intake and the lung cancer risk among female nonsmokers: A report from the S hanghai W omen's H ealth S tudy
Wu, Q., Xiang, Y., Yang, G., Li, H., Qing Lan, B., Gao, Y., Zheng, W., Shu, X., & Fowke, J. H. (2014) · International Journal of Cancer · doi:10.1002/ijc.29016 · Cited by 38
The response of γ vitamin E to varying dosages of α vitamin E plus vitamin C
Gutierrez, A., de Serna, D. G., Robinson, I., & Schade, D. S. (2009) · Metabolism · doi:10.1016/j.metabol.2008.11.003 · Cited by 37
Relation of Serum ^|^alpha;- and ^|^gamma;-Tocopherol Levels to Cardiovascular Disease-Related Mortality Among Japanese Men and Women
Nagao, M., Moriyama, Y., Yamagishi, K., Iso, H., & Tamakoshi, A. (2012) · Journal of Epidemiology · doi:10.2188/jea.je20120002 · Cited by 40
The Melbourne Atherosclerosis Vitamin E Trial (MAVET): a study of high dose vitamin E in smokers
Magliano, D. J., McNeil, J. J., Branley, P., Shiel, L. M., Demos, L., Wolfe, R. S., Kotsopoulos, D., & McGrath, B. P. (2006) · European Journal of Cardiovascular Prevention & Rehabilitation · doi:10.1097/01.hjr.0000219108.10167.46 · Cited by 39
Supplementation with mixed tocopherols increases serum and blood cell γ-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes
Clarke, M. W., Ward, N. C., Wu, J. H. Y., Hodgson, J. M., Puddey, I. B., & Croft, K. D. (2006) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/83.1.95 · Cited by 38
Walnuts Reduce Aortic ET-1 mRNA Levels in Hamsters Fed a High-Fat, Atherogenic Diet
Davis, P. A., Valacchi, G., Pagnin, E., Shao, Q., Gross, H. B., Calò, L. A., & YOKOYAMA, W. H. (2006) · Journal of Nutrition · doi:10.1093/jn/136.2.428 · Cited by 38

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
DOI: 10.1001/jama.293.11.1338
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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Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer: A Randomized Controlled Trial

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