Interventional Trials of Antioxidants

  • Thomas S. Bowman
  • Shari S. Bassuk
  • J. Michael Gaziano

Prospective observational studies have found consistent associations between higher intakes of fruit and vegetables and reduced rates of coronary heart disease (CHD) and ischemic stroke. The exact mechanisms for these apparent protective effects are not entirely clear. It is possible that higher fruit and vegetable intake replaces fat and cholesterol intake, but alternatively, the observed beneficial effects may be due to micronutrients contained in the fruits and vegetables. Micronutrients with antioxidant properties might be responsible for the lower rates of cardiovascular disease (CVD) associated with fruit and vegetable consumption.


Heart Outcome Prevention Evaluation Primary Prevention Trial Heart Protection Study Secondary Prevention Trial Antioxidant Combination 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bazzano LA, He J, Ogden LG, et al. Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. Am J Clin Nutr 2002;76:93–99.PubMedGoogle Scholar
  2. 2.
    Joshipura KJ, Hu FB, Manson JE, et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med 2001;134:1106–1114.PubMedGoogle Scholar
  3. 3.
    Liu S, Manson J, Lee IM, et al. Fruit and vegetable intake and risk of cardiovascular disease: the Women’s Health Study. Am J Clin Nutr 2000;72:922–928.PubMedGoogle Scholar
  4. 4.
    Knekt A, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 1994;139:1180–1189.PubMedGoogle Scholar
  5. 5.
    Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA 1999;282:1233–1239.CrossRefPubMedGoogle Scholar
  6. 6.
    Gillman MW, Cupples LA, Gagnon D, et al. Protective effect of fruits and vegetables on development of stroke in men. JAMA 1995;273:1113–1117.CrossRefPubMedGoogle Scholar
  7. 7.
    Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915–924.PubMedCrossRefGoogle Scholar
  8. 8.
    Hessler JR, Morel DW, Lewis LJ, Chisolm GM. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis 1983;3:215–222.PubMedGoogle Scholar
  9. 9.
    Yagi K. Increased serum lipid peroxides initiate atherogenesis. Bioassays 1984;1:58–60.CrossRefGoogle Scholar
  10. 10.
    Gerrity RG. The role of the monocyte in atherogenesis: I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol 1981;103:181–190.PubMedGoogle Scholar
  11. 11.
    Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Endothelial cell-derived chemotactic activity for mouse peritoneal macrophages and the effects of modified forms of low density lipoprotein. Proc Natl Acad Sci 1985;82:5949–5953.CrossRefPubMedGoogle Scholar
  12. 12.
    Schaffner T, Taylor K, Bartucci EJ, et al. Arterial foam cells with distinctive immunomorphologic and histochemical features of macrophages. Am J Pathol 1980;100:57–80.PubMedGoogle Scholar
  13. 13.
    Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci 1979;76:333–337.CrossRefPubMedGoogle Scholar
  14. 14.
    Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci 1980;77:2214–2218.CrossRefPubMedGoogle Scholar
  15. 15.
    Salonen JT, Yla-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet 1992;339:883–887.CrossRefPubMedGoogle Scholar
  16. 16.
    Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci 1990;87:1620–1624.CrossRefPubMedGoogle Scholar
  17. 17.
    Marcus AJ, Silk ST, Safier LB, Ullman HL. Superoxide production and reducing activity in human platelets. J Clin Invest 1977;59:149–158.CrossRefPubMedGoogle Scholar
  18. 18.
    Saran M, Michel C, Bors W. Reaction of NO with O2 •− implications for the action of endothelium-derived relaxing factor (EDRF). Free Radic Res Commun 1990;10:221–226.CrossRefPubMedGoogle Scholar
  19. 19.
    Gaziano JM, Steinberg D. Natural Antioxidants. New York: Oxford University Press, 1996.Google Scholar
  20. 20.
    Albert CM, Manson JE. Aspirin, antioxidants, and alcohol. In: Charney P (ed). Coronary Artery Disease in Women. Philadelphia: American College of Physicians, 1999: pp. 236–63.Google Scholar
  21. 21.
    Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444–1449.CrossRefPubMedGoogle Scholar
  22. 22.
    Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450–1456.CrossRefPubMedGoogle Scholar
  23. 23.
    Kushi LH, Fee RM, Sellers TA, Zheng W, Folsom AR. Intake of vitamins A, C, and E and postmenopausal breast cancer. Am J Epidemiol 1996;144:165–174.PubMedGoogle Scholar
  24. 24.
    Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the established populations for epidemiologic studies of the elderly. Am J Clin Nutr 1996;64:190–196.PubMedGoogle Scholar
  25. 25.
    Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, et al. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam Study. Am J Clin Nutr 1999;69:261–266.PubMedGoogle Scholar
  26. 26.
    Evans RW, Shaten BJ, Day BW, Kuller LH. Prospective association between lipid soluble antioxidants and coronary heart disease in men. The multiple risk factor intervention trial. Am J Epidemiol 1998;147:180–186.PubMedGoogle Scholar
  27. 27.
    Steinberg D. Antioxidants in the prevention of human atherosclerosis. Summary of the proceedings of a National Heart, Lung, and Blood Institute Workshop: September 5–6, 1991, Bethesda, Maryland. Circulation 1992;85:2337–2344.Google Scholar
  28. 28.
    Esterbauer H, Gebicki J, Puhl H, Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med 1992;13:341–390.CrossRefPubMedGoogle Scholar
  29. 29.
    Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029–1035.CrossRefGoogle Scholar
  30. 30.
    Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA 1996;275:693–698.Google Scholar
  31. 31.
    ATBC study group. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 2003;290:476–485.CrossRefGoogle Scholar
  32. 32.
    Collaborative Group of the Primary Prevention Project. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet 2001;357:89–95.Google Scholar
  33. 33.
    Hodis HN, Mack WJ, LaBree L, et al. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E atherosclerosis prevention study (VEAPS). Circulation 2002;106(12):1453–1459.CrossRefPubMedGoogle Scholar
  34. 34.
    Buring JE, Hennekens CH. The Women’s health Study: summary of the study design. J Myocardial Ischemia 1992;4:27–29.Google Scholar
  35. 35.
    Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer. JAMA 2005;294:56–65.CrossRefPubMedGoogle Scholar
  36. 36.
    Christen WG, Gaziano JM, Hennekens CH. Design of Physicians’ health Study II–a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol 2000;10:125–134.CrossRefPubMedGoogle Scholar
  37. 37.
    DeMaio SJ, King SB, Lembo NJ, et al. Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). J Am Coll Nutr 1992;11:68–73.PubMedGoogle Scholar
  38. 38.
    Leng GC, Lee AJ, Fowkes FG, et al. Randomized controlled trial of antioxidants in intermittent claudication. Vasc Med 1997;2:279–285.PubMedGoogle Scholar
  39. 39.
    Tornwall M, Virtamo J, Haukka JK, et al. Effect of alpha-tocopherol (vitamin E) and beta-carotene supplementation on the incidence of intermittent claudication in male smokers. Vasc Biol 1997;17:3475–3480.Google Scholar
  40. 40.
    Anderson TW, Reid DB. A double-blind trial of vitamin E in angina pectoris. Am J Clin Nutr 1974;27:1174–1178.PubMedGoogle Scholar
  41. 41.
    Gillilan RE, Mondell B, Warbasse JR. Quantitative evaluation of vitamin E in the treatment of angina pectoris. Am Heart J 1977;93:444–449.CrossRefPubMedGoogle Scholar
  42. 42.
    Rapola JM, Virtamo J, Ripatti S, et al. Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris. Heart 1998;79:454–458.PubMedGoogle Scholar
  43. 43.
    Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781–786.CrossRefPubMedGoogle Scholar
  44. 44.
    GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–455.Google Scholar
  45. 45.
    Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154–160.CrossRefPubMedGoogle Scholar
  46. 46.
    HOPE and HOPE-TOO Trial investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA 2005;293:1338–1347.CrossRefGoogle Scholar
  47. 47.
    Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356:1213–1218.CrossRefPubMedGoogle Scholar
  48. 48.
    Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C, E and beta-carotene in the secondary prevention of cardiovascular events in women: results from the Women’s antioxidant cardiovascular study (WACS). American Heart Association Scientific Sessions 2006, Chicago, IL, 2006.Google Scholar
  49. 49.
    Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003;361:2017–2023.CrossRefPubMedGoogle Scholar
  50. 50.
    Halliwell B. The antioxidant paradox. Lancet 2000;355:1179–1180.CrossRefPubMedGoogle Scholar
  51. 51.
    Steinberg D. Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet 1995;346:36–38.CrossRefPubMedGoogle Scholar
  52. 52.
    Greenberg ER, Baron JA, Karagas MR, et al. Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation. JAMA 1996;275:699–703.CrossRefPubMedGoogle Scholar
  53. 53.
    Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–1149.CrossRefPubMedGoogle Scholar
  54. 54.
    Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s health Study. J Natl Cancer Inst 1999;91:2102–2106.CrossRefPubMedGoogle Scholar
  55. 55.
    Gaziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. Beta carotene therapy for chronic stable angina (abstract). Circulation 1990;82:III-202.Google Scholar
  56. 56.
    Manson JE, Gaziano JM, Spelsberg A, et al. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. The WACS Research Group. Ann Epidemiol 1995;5:261–269.Google Scholar
  57. 57.
    Gaziano JM, Manson J, Branch LG, Colditz GA, Willett WC, Buring JE. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann Epidemiol 1995;5:255–260.CrossRefPubMedGoogle Scholar
  58. 58.
    Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med 1996;334:1156–1162.CrossRefPubMedGoogle Scholar
  59. 59.
    Stocker R. The ambivalence of vitamin E in atherogenesis. Trends Biochem Sci 1999; 24:219–223.CrossRefPubMedGoogle Scholar
  60. 60.
    Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease- specific mortality in the general population. J Natl Cancer Inst 1993;85:1483–1492.CrossRefPubMedGoogle Scholar
  61. 61.
    Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–1155.CrossRefPubMedGoogle Scholar
  62. 62.
    Hercberg S, Preziosi P, Briancon S, et al. A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study–design, methods, and participant characteristics. SUpplementation en VItamines et Mineraux AntioXydants. Control Clin Trials 1998; 19:336–351.Google Scholar
  63. 63.
    Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med 2004;164:2335–2342.Google Scholar
  64. 64.
    Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583–1592.CrossRefPubMedGoogle Scholar
  65. 65.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.CrossRefGoogle Scholar
  66. 66.
    Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:23–33.CrossRefGoogle Scholar
  67. 67.
    Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA 2002;288:2432–2440.CrossRefPubMedGoogle Scholar
  68. 68.
    Salonen JT, Nyyssonen K, Salonen R, et al. Antioxidant Supplementation in atherosclerosis prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. J Intern Med 2000;248:377–386.CrossRefPubMedGoogle Scholar
  69. 69.
    Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression. Circulation 2003;107:947–953.CrossRefPubMedGoogle Scholar
  70. 70.
    Fang JC, Kinlay S, Beltrame J, et al. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet 2002;359:1108–1113.CrossRefPubMedGoogle Scholar
  71. 71.
    Tribble DL. AHA Science Advisory. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E, and beta-carotene: a statement for healthcare professionals from the American Heart Association. Circulation 1999;99:591–595.Google Scholar
  72. 72.
    Krauss RM, Eckel RH, Howard B, et al. AHA Dietary Guidelines: revision 2000: a statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation 2000;102:2284–2289.PubMedGoogle Scholar
  73. 73.
    Institute of Medicine. Evolution of Evidence for Selected Nutrient and Disease Relationships. Washington, DC: National Academy Press; 2002.Google Scholar
  74. 74.
    Morris CD, Carson S. Routine vitamin supplementation to prevent cardiovascular disease: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2003;139(1):56–71.Google Scholar
  75. 75.
    Kris-Etherton P, Lichtenstein AH, Howard BV, Steinberg D, Witzwum JL. Antioxidant vitamin supplements and cardiovascular disease. Circulation 2004;110:637–641.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Thomas S. Bowman
    • 1
  • Shari S. Bassuk
    • 2
  • J. Michael Gaziano
    • 1
  1. 1.Division of AgingBrigham and Women's HospitalBostonUSA
  2. 2.Division of Preventive MedicineBrigham and Women's HospitalBostonUSA

Personalised recommendations