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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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“This is true especially in light of the recent report suggesting adverse health outcomes with higher-dose, long-term vitamin E supplementation (16), a routine practice.”
BackgroundOxidized Forms of Glutathione in Peripheral Blood as Biomarkers of Oxidative Stress
Rossi, R., Dalle‐Donne, I., Milzani, A., & Giustarini, D. (2006) · Clinical Chemistry · doi:10.1373/clinchem.2006.067793 · Cited by 154
“Moreover, even if the alteration of one or more biomarkers of oxidative stress has been reported to occur virtually in all diseases, data on the outcome of preventive strategies based on an antioxidant therapy are still extremely scarce (36, 37).”
Advances in myocardial energy metabolism: metabolic remodelling in heart failure and beyond
Sun, Q., Karwi, Q. G., Wong, N. K. P., & Lopaschuk, G. D. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae231 · Cited by 164
Förstermann, U. (2006) · Biological Chemistry · doi:10.1515/bc.2006.190 · Cited by 155
Redox sensing: orthogonal control in cell cycle and apoptosis signalling
Jones, D. P. (2010) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02268.x · Cited by 159
Oxidative Stress and Antioxidants in Atherosclerosis Development and Treatment
Poznyak, A. V., Grechko, A. V., Orekhova, V. A., Chegodaev, Y. S., Wu, W., & Orekhov, A. N. (2020) · Biology · doi:10.3390/biology9030060 · Cited by 188
Nox5 and the Regulation of Cellular Function
Fulton, D. J. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2587 · Cited by 161
“However, much like cardiovascular disease, the ineffectiveness of antioxidants in vivo to prevent or treat cancer has been a major obstacle to the broad acceptance of this hypothesis (48, 63).”
Redox control in cancer development and progression
Helfinger, V., & Schröder, K. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.02.003 · Cited by 153
Targeting Oxidative Stress Involved in Endometriosis and Its Pain
Clower, L., Fleshman, T., Geldenhuys, W. J., & Santanam, N. (2022) · Biomolecules · doi:10.3390/biom12081055 · Cited by 145
Major, J. M., Yu, K. F., Wheeler, W., Zhang, H., Cornelis, M. C., Wright, M. E., Yeager, M., Snyder, K., Weinstein, S. J., Mondul, A. M., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr296 · Cited by 148
Mechanisms for the prevention of vitamin E excess
Traber, M. G. (2013) · Journal of Lipid Research · doi:10.1194/jlr.r032946 · Cited by 148
Cindrová‐Davies, T. (2009) · Placenta · doi:10.1016/j.placenta.2008.11.020 · Cited by 147
“Themost recent trial additionally showed that not only does long-term vitamin E supplementation fail to prevent cancer or major cardiovascular complications, it may increase the risk for heart failure [53].”
BackgroundDiabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future
Iacobini, C., Vitale, M., Pesce, C. M., Pugliese, G., & Menini, S. (2021) · Antioxidants · doi:10.3390/antiox10050727 · Cited by 161
“However, even long-term supplementation with vitamin E was unable to reduce major cardiovascular events in diabetic patients in a large phase III trial such as the Heart Outcomes Prevention Evaluation (HOPE) study [80].”
BackgroundMocchegiani, E., Costarelli, L., Giacconi, R., Malavolta, M., Basso, A., Piacenza, F., Ostan, R., Cevenini, E., Gonos, E. S., Franceschi, C., et al. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.01.001 · Cited by 149
Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study
Hajjar, I. M., Hayek, S. S., Goldstein, F. C., Martin, G. S., Jones, D. P., & Quyyumi, A. A. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-017-1026-z · Cited by 143
“Use of free radical-scavenging antioxidants such as vitamin E has failed to show a consistent benefit on cognitive preservation and has been linked to increased cardiovascular mortality [29, 30].”
BackgroundWard, N. C., Wu, J. H. Y., Clarke, M. W., Puddey, I. B., Burke, V., Croft, K. D., & Hodgson, J. M. (2006) · Journal of Hypertension · doi:10.1097/01.hjh.0000254373.96111.43 · Cited by 141
Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets
Ramachandra, C. J. A., Cong, S., Chan, X., Yap, E. P., Fan, Y., & Hausenloy, D. J. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.02.040 · Cited by 140
Zhu, H., Jia, Z., Misra, B. R., Zhang, L., Cao, Z., Yamamoto, M. P., Trush, M. A., Misra, H. P., & Li, Y. (2008) · Cardiovascular Toxicology · doi:10.1007/s12012-008-9016-0 · Cited by 139
Rodrigo, R., Hernán Prat, M., Walter Passalacqua, R., Julia Araya, A., & Bächler, J. P. (2008) · Clinical Science · doi:10.1042/cs20070343 · Cited by 140
Drugs for preventing lung cancer in healthy people
Cortés-Jofré, M., Rueda, J.-R., Lobos, C. A., Eva Madrid, A., & Bonfill, X. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd002141.pub3 · Cited by 141
Antioxidants vitamin C and vitamin E for the prevention and treatment of cancer
Coulter, I. D., Hardy, M. L., Morton, S. C., Hilton, L. G., Tu, W., Valentine, D., & Shekelle, P. (2006) · Journal of General Internal Medicine · doi:10.1111/j.1525-1497.2006.00483.x · Cited by 136
The Relationship of Redox With Hallmarks of Cancer: The Importance of Homeostasis and Context
Xing, F., Hu, Q., Qin, Y., Xu, J., Zhang, B., Yu, X., & Wang, W. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.862743 · Cited by 142
Preventing and Managing the Side Effects of Isotretinoin
Brelsford, M., & Beute, T. C. (2008) · Seminars in Cutaneous Medicine and Surgery · doi:10.1016/j.sder.2008.07.002 · Cited by 137
The role of oxidative stress in prostate cancer
Gupta‐Elera, G., Garrett, A. R., Robison, R. A., & O'Neill, K. L. (2011) · European Journal of Cancer Prevention · doi:10.1097/cej.0b013e32834a8002 · Cited by 139
“The treatment of these cells with vitamin E and selenium reverses the proliferation, thus suggesting a possible role of antioxidants in BPH prevention (Lonn et al., 2005).”
BackgroundGlynn, R. J., Ridker, P. M., Goldhaber, S. Z., Zee, R. Y. L., & Buring, J. E. (2007) · Circulation · doi:10.1161/circulationaha.107.716407 · Cited by 157
Almond Consumption and Cardiovascular Risk Factors in Adults with Prediabetes
Wien, M., Bleich, D., Raghuwanshi, M. P., Gould-Forgerite, S., Gomes, J., Couch, L. M., & Oda, K. (2010) · Journal of the American College of Nutrition · doi:10.1080/07315724.2010.10719833 · Cited by 129
“The Heart Outcomes Prevention Evaluation [29] featured a pharmacological dose of vitamin E (400 IU) and found a higher risk of heart failure among older patients with vascular disease or diabetes, which suggests that in specific cases, isolated vitamin components of naturally occurring foods do not recapitulate the be…”
BackgroundEvans, J. R. (2008) · Eye · doi:10.1038/eye.2008.100 · Cited by 132
Vitamin E: tocopherols and tocotrienols as potential radiation countermeasures
Singh, V. K., Beattie, L. A., & Seed, T. M. (2013) · Journal of Radiation Research · doi:10.1093/jrr/rrt048 · Cited by 131
“Similar negative results were reported earlier with vitamin E when its effect was examined on cardiovascular events and cancer in a randomized clinical trial [126].”
ResultOn the Clinical Pharmacology of Reactive Oxygen Species
Casas, A. I., Nogales, C., Mucke, H. A., Petraina, A., Cuadrado, A., Rojo, A. I., Ghezzi, P., Jaquet, V., Augsburger, F., Dufrasne, F., et al. (2020) · Pharmacological Reviews · doi:10.1124/pr.120.019422 · Cited by 131
“Vitamin E has been studied in the context of cardiovascular disease in the CHAOS (Stephens et al., 1996) and HOPE (Hegele, 2000; Lonn et al., 2005) trials, inwhich it failed to improve cardiovascular mortality.”
BackgroundInsulin resistance, glucose intolerance and diabetes mellitus in obstructive sleep apnoea.
Kent, B. D., McNicholas, W. T., & Ryan, S. (2015) · PubMed · doi:10.3978/j.issn.2072-1439.2015.08.11 · Cited by 131
“However, large studies have failed to show a beneficial effect of antioxidant therapy on cardiovascular diseases, and oxidative stress could potentially be a consequence rather than a cause of vascular inflammation and subsequent atherosclerosis (97).”
BackgroundKarim, N., Jia, Z., Zheng, X., Cui, S., & Chen, W. (2018) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2018.06.012 · Cited by 129
Fang, F., Kang, Z., & Wong, C. (2009) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200900119 · Cited by 126
Essential Nutrients: Food or Supplements?
Lichtenstein, A. H., & Russell, R. M. (2005) · JAMA · doi:10.1001/jama.294.3.351 · Cited by 129
Clinical pharmacology and therapeutic use of antioxidant vitamins
Rodrigo, R., Guichard, C., & Charles, R. (2007) · Fundamental & Clinical Pharmacology · doi:10.1111/j.1472-8206.2006.00466.x · Cited by 124
Werstuck, G. H., Khan, M. I., Femia, G., Kim, A. J., Tedesco, V. C., Trigatti, B. L., & Shi, Y. (2006) · Diabetes · doi:10.2337/diabetes.55.01.06.db05-0633 · Cited by 124
Oxidative stress and its downstream signaling in aging eyes
Pinazo-Duran, M. D., Gallego‐Pinazo, R., García‐Medina, J. J., Zanón‐Moreno, V., Nucci, C., Dolz‐Marco, R., Martínez-Castillo, S., Galbis, C. C., Díaz-Llopis, M., Marco, C., et al. (2014) · Clinical Interventions in Aging · doi:10.2147/cia.s52662 · Cited by 131
“Firstly, it has to be said that vitamin E supplementation has been associated with increased risk of heart failure.(128) In addition, β-carotene and vitamin A intake have been”
Background
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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