To determine if supplements of vitamin C, vitamin E, beta-carotene, and B-vitamins (folic acid, vitamins B6 and B12) reduce risk of major cardiovascular events in high risk women with a prior history of atherosclerotic cardiovascular disease. The trial is a companion to the Women's Health Study (WHS), a primary prevention trial of vitamin E and aspirin in a low risk population of women.

BACKGROUND:

The antioxidant properties of vitamin C, vitamin E, and beta-carotene are well known and are postulated to prevent lipoprotein oxidation and thereby prevent or retard atherogenesis. Folic acid, vitamin B6, vitamin B12 are involved in homocysteine metabolism and are also postulated to have cardioprotective effects. Based on the successful experience with the Physicians' Health Study, the results of a pilot study conducted in nurses, and long-term experience following a large cohort of United States nurses, the study should provide either definitive positive or informative null results regarding the study hypotheses.

DESIGN NARRATIVE:

Subjects were randomized in a 2 x 2 x 2 factorial design to 500 mg of vitamin C or placebo daily, 600 mg of vitamin E or placebo on alternate days and/or 50 mg of beta-carotene or placebo on alternate days. There was a three month run-in phase in which eligible patients received placebo caplets. Subjects were randomized only if they reported good compliance, willingness to continue in the trial, had no history of cancer, active liver disease, or use of coumadin, and expressed continued willingness to forego the use of beta-carotene and vitamin A, C, or E supplements. In 1998, participants were further randomized to the B-vitamin intervention (folic acid, vitamin B6, vitamin B12).

Baseline dietary assessments were made using food frequency questionnaires and information was obtained on aspirin and postmenopausal hormone use at entry and during followup. Subjects were randomized with a stratification by age into eight five-year increments, one being 75+. Endpoints are followed by mail and include all major cardiovascular events such as non-fatal myocardial infarction, non-fatal stroke, coronary revascularization procedures, and cardiovascular mortality. The trial is conducted as a companion to the Women's Health Study (WHS), a large randomized trial assessing the efficacy of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among apparently healthy women.

The trial is currently in treatment and follow-up which will continue until February 2006.

• Cardiovascular Diseases
• Coronary Arteriosclerosis
• Coronary Disease
• Heart Diseases
• Myocardial Infarction
• Myocardial Ischemia

• Behavioral: dietary supplements
• Drug: vitamin C
• Drug: vitamin E
• Drug: beta-carotene
• Drug: folic acid/Vitamin B6/Vitamin B12

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• Mason PJ, Manson JE, Sesso HD, Albert CM, Chown MJ, Cook NR, Greenland P, Ridker PM, Glynn RJ. Blood pressure and risk of secondary cardiovascular events in women: the Women's Antioxidant Cardiovascular Study (WACS). Circulation. 2004 Apr 6;109(13):1623-9. Epub 2004 Mar 15.
• Bassuk SS, Albert CM, Cook NR, Zaharris E, MacFadyen JG, Danielson E, Van Denburgh M, Buring JE, Manson JE. The women's antioxidant cardiovascular study: design and baseline characteristics of participants. J Womens Health (Larchmt). 2004 Jan-Feb;13(1):99-117.
• Song Y, Cook NR, Albert CM, Van Denburgh M, Manson JE. Effects of vitamins C and E and beta-carotene on the risk of type 2 diabetes in women at high risk of cardiovascular disease: a randomized controlled trial. Am J Clin Nutr. 2009 Aug;90(2):429-37. Epub 2009 Jun 2.
• Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA. 2008 Nov 5;300(17):2012-21.
• Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008 May 7;299(17):2027-36.
• Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study. Arch Intern Med. 2007 Aug 13-27;167(15):1610-8.

Women, aged 40 and over, at high risk, with a history of coronary artery disease, carotid endarterectomy, peripheral artery surgery, or three or more coronary heart disease risk factors.