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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“rial (SELECT) reported that the daily supplementation of vitamin (400 IU for a mean follow-up of 7 years) in healthy elderly men or t high CVD risk, respectively, had no clear impact on fatal and nonatal cancers, or deaths [16] or against prostate cancer incidence 17].”
BackgroundInfluential
Vitamin and mineral use and risk of prostate cancer: the case–control surveillance study
Zhang, Y., Coogan, P. F., Palmer, J. R., Strom, B. L., & Rosenberg, L. A. (2008) · Cancer Causes & Control · doi:10.1007/s10552-008-9282-y · Cited by 63
“One clinical trial [9] and two observational studies [10, 22] found that the use of vitamin E supplements was inversely associated with the risk of prostate cancer but other studies showed no association [11, 13-16, 27].”
Background
High-Dose Supplements of Vitamins C and E, Low-Dose Multivitamins, and the Risk of Age-related Cataract: A Population-based Prospective Cohort Study of Men
Selin, J. Z., Rautiainen, S., Lindblad, B. E., Morgenstern, R., & Wolk, A. (2013) · American Journal of Epidemiology · doi:10.1093/aje/kws279 · Cited by 64
“On the contrary, studies have reported potential harmful effects of high-dose antioxidant supplements, such as increased risk of mortality (3, 4), heart failure (5), and some cancer types (6–8).”
Background
Trace Elements, Heavy Metals and Vitamin Levels in Patients with Coronary Artery Disease
Çebi, A., Kaya, Y., Güngör, H., Demir, H., Yoruk, I. H., Söylemez, N., Güneş, Y., & Tuncer, M. (2011) · International Journal of Medical Sciences · doi:10.7150/ijms.8.456 · Cited by 63
“Levels of tocopherol were reported to be decreased in coronary artery disease (23).”
Background
Oral Tocotrienols Are Transported to Human Tissues and Delay the Progression of the Model for End-Stage Liver Disease Score in Patients4
Patel, V., Rink, C. L., Gordillo, G. M., Khanna, S., Gnyawali, U. S., Roy, S., Shneker, B. F., Ganesh, K., Phillips, G. S., More, J. L., et al. (2012) · Journal of Nutrition · doi:10.3945/jn.111.151902 · Cited by 63
Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure
Sag, C. M., Schnelle, M., Zhang, J., Murdoch, C. E., Kossmann, S., Protti, A., Santos, C. X. C., Sawyer, G. J., Zhang, X., Mongue‐Din, H., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.023877 · Cited by 62
Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age‐related macular degeneration: a review of current practice
van Wijngaarden, P., & Qureshi, S. H. (2008) · Clinical and Experimental Optometry · doi:10.1111/j.1444-0938.2008.00305.x · Cited by 63
Adverse effects of vitamin E by induction of drug metabolism
Brigelius‐Flohé, R. (2007) · Genes & Nutrition · doi:10.1007/s12263-007-0055-0 · Cited by 62
Vitamin Status and Needs for People with Stages 3-5 Chronic Kidney Disease
Steiber, A. L., & Kopple, J. D. (2011) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2010.12.004 · Cited by 62
“This increased risk was associated with vitamin E intakes as low as 150 IU/day (136 mg/day).(61,62) These studies, taken together, suggest that among people at high risk for cardiovascular events, supplemental vitamin E may not be indicated in the general population or in nondialysis CKD patients.”
Background
Blood Pressure in Acute Stroke
Bath, P. M., Appleton, J. P., Krishnan, K., & Sprigg, N. (2018) · Stroke · doi:10.1161/strokeaha.118.021254 · Cited by 62
Suppression of prostate cancer in a transgenic rat model via γ‐tocopherol activation of caspase signaling
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Chemoprevention of Lung Cancer
Szabo, E. M., Mao, J. T., Lam, S. C., Reid, M. E., & Keith, R. L. (2013) · CHEST Journal · doi:10.1378/chest.12-2348 · Cited by 65
Dietary Supplementation With Vitamin E Ameliorates Cardiac Failure in Type I Diabetic Cardiomyopathy by Suppressing Myocardial Generation of 8-iso-Prostaglandin F2α and Oxidized Glutathione
Hamblin, M., Smith, H., & Hill, M. F. (2007) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2007.07.002 · Cited by 61
Evolution of medical treatment for endometriosis: back to the roots?
Wieser, F., Cohen, M., Gaeddert, A., Yu, J., Burks-Wicks, C., Berga, S. L., & Taylor, R. N. (2007) · Human Reproduction Update · doi:10.1093/humupd/dmm015 · Cited by 76
“Data from the HOPE and HOPE-TOO trials showed that vitamin E did not decrease fatal or non-fatal cancer (Lonn et al., 2005).”
Vitamin E supplement use and the incidence of cardiovascular disease and all-cause mortality in the Framingham Heart Study: Does the underlying health status play a role?
Dietrich, M., Jacques, P. F., Pencina, M. J., Lanier, K. J., Keyes, M. J., Jasuja, G. K., Wolf, P. A., D’Agostino, R. B., & Vasan, R. S. (2008) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2008.12.019 · Cited by 60
Unleashing the untold and misunderstood observations on vitamin E
Gee, P. T. (2010) · Genes & Nutrition · doi:10.1007/s12263-010-0180-z · Cited by 60
Evaluation and Management of the Elderly Patient Presenting with Cognitive Complaints
Hildreth, K. L., & Church, S. D. (2014) · Medical Clinics of North America · doi:10.1016/j.mcna.2014.11.006 · Cited by 66
Targeting NOS as a therapeutic approach for heart failure
Tang, L., Wang, H., & Ziolo, M. T. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.013 · Cited by 60
Vitaminas e minerais com propriedades antioxidantes e risco cardiometabólico: controvérsias e perspectivas
Catania, A. S., de Barros, C. R., & Ferreira, S. R. G. (2009) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302009000500008 · Cited by 60
The effects of high-dose vitamin E supplementation on biomarkers of kidney injury, inflammation, and oxidative stress in patients with diabetic nephropathy: A randomized, double-blind, placebo-controlled trial
Khatami, P. G., Soleimani, A., Sharifi, N., Aghadavod, E., & Asemi, Z. (2016) · Journal of clinical lipidology · doi:10.1016/j.jacl.2016.02.021 · Cited by 62
“0 years did not 219 prevent cancer or major cardiovascular events while increased the risk of heart failure [24].”
Background
Vitamin E Supplementation in Cardiovascular Disease and Cancer Prevention: Part 1
Pham, D. Q., & Plakogiannis, R. (2005) · Annals of Pharmacotherapy · doi:10.1345/aph.1g211 · Cited by 59
Mitochondrial Dysfunction and Mitophagy in Type 2 Diabetes: Pathophysiology and Therapeutic Targets
Apostolova, N., Vezza, T., Muntané, J., Rocha, M., & Víctor, V. M. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2022.0016 · Cited by 60
Aged Garlic Extract Improves Homocysteine-Induced Endothelial Dysfunction in Macro- and Microcirculation
Weiss, N., Ide, N., Abahji, T. N., Nill, L., Keller, C., & Hoffmann, U. (2006) · Journal of Nutrition · doi:10.1093/jn/136.3.750s · Cited by 59
Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl‐2 ratio
Reagan‐Shaw, S., Nihal, M., Ahsan, H., Mukhtar, H., & Ahmad, N. (2008) · The Prostate · doi:10.1002/pros.20824 · Cited by 60
Betulinic acid ameliorates endothelium-dependent relaxation in l-NAME-induced hypertensive rats by reducing oxidative stress
Fu, J.-Y., Qian, L.-B., Zhu, L.-G., Liang, H.-T., Tan, Y., Lu, H., Lü, J., Wang, H., & Xia, Q. (2011) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2011.08.025 · Cited by 61
Early decrease of oxidative stress by atorvastatin in hypercholesterolaemic patients: effect on circulating vitamin E
Cangemi, R., Loffredo, L., Carnevale, R., Perri, L., Patrizi, M. P., Sanguigni, V., Pignatelli, P., & Violi, F. (2007) · European Heart Journal · doi:10.1093/eurheartj/ehm565 · Cited by 59
A High Intake of trans Fatty Acids Has Little Effect on Markers of Inflammation and Oxidative Stress in Humans
Smit, L. A., Katan, M., Wanders, A. J., & Basu, S. (2011) · Journal of Nutrition · doi:10.3945/jn.110.134668 · Cited by 59
The Impact of Nutrition on Cognition in the Elderly
Dyk, K. V., & Sano, M. C. (2007) · Neurochemical Research · doi:10.1007/s11064-006-9241-5 · Cited by 63
Vitamins C and E attenuate apoptosis, β-adrenergic receptor desensitization, and sarcoplasmic reticular Ca2+ ATPase downregulation after myocardial infarction
Qin, F., Chen, Y., Patel, R., Liu, W., & Dong, E. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.01.019 · Cited by 60
The angiotensin AT 4 receptor subtype as a target for the treatment of memory dysfunction associated with Alzheimer's disease
Wright, J. W., & Harding, J. W. (2008) · Journal of the Renin-Angiotensin-Aldosterone System · doi:10.1177/1470320308099084 · Cited by 62
Antioxidants for prostate cancer chemoprevention: Challenges and opportunities
Thapa, D., & Ghosh, R. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.12.027 · Cited by 58
“Several studies have indicated that large doses of antioxidants can increase the risk of cancer and other diseases [63,81,84,92].”
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Vitamin E and Non-Communicable Diseases: A Review
Ciarcià, G., Bianchi, S., Tomasello, B., Acquaviva, R., Malfa, G. A., Николаевна, Н. И., Mantia, A. L., & Giacomo, C. D. (2022) · Biomedicines · doi:10.3390/biomedicines10102473 · Cited by 58
Vitamin E and memantine in Alzheimer's disease: Clinical trial methods and baseline data
Dysken, M. W., Guarino, P., Vertrees, J. E., Asthana, S., Sano, M. C., Llorente, M. D., Pallaki, M., Love, S. B., Schellenberg, G. D., McCarten, J. R., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.01.014 · Cited by 62
“Caregivers and patients were queried in general about adverse experiences at each contact, and were queried specifically about patient falls, syncope, and congestive heart failure diagnoses resulting from concerns from previous studies that these events could be related to high-dose alpha-tocopherol treatment [5,19].”
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Diet in dermatology
Murzaku, E. C., Bronsnick, T., & Rao, B. K. (2014) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2014.06.016 · Cited by 60
Use of pentoxifylline and tocopherol in radiation-induced fibrosis and fibroatrophy
Patel, V., & McGurk, M. (2016) · British Journal of Oral and Maxillofacial Surgery · doi:10.1016/j.bjoms.2016.11.323 · Cited by 60
Dietary Antioxidants: Potential Anticancer Agents
Wu, X., Cheng, J., & Wang, X. (2017) · Nutrition and Cancer · doi:10.1080/01635581.2017.1299872 · Cited by 58
“deaths between individuals randomly assigned to take 400 IU/day vitamin E or a placebo (35).”
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Effects of dietary RRR α-tocopherol vs all-racemic α-tocopherol on health outcomes
Ranard, K. M., & Erdman, J. W. (2017) · Nutrition Reviews · doi:10.1093/nutrit/nux067 · Cited by 60
Redox Systems Biology of Nutrition and Oxidative Stress
Dennis, K. K., Go, Y., & Jones, D. P. (2018) · Journal of Nutrition · doi:10.1093/jn/nxy306 · Cited by 60
Risk of Mortality with Vitamin E Supplements: The Cache County Study
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Pinocembrin ameliorates post-infarct heart failure through activation of Nrf2/HO-1 signaling pathway
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Diabetes and Vascular Disease: Basic Concepts of Nitric Oxide Physiology, Endothelial Dysfunction, Oxidative Stress and Therapeutic Possibilities
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Supplemental Vitamins and Minerals for Cardiovascular Disease Prevention and Treatment
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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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