ANTIOXIDANTS FOR PREVENTION OF CAD

Observational studies have shown, though not unanimously, lower risk for CAD with both men and women who have high intake of antioxidant vitamins, either through diet or supplements; inc. beta-carotene and vit. E

I. Vitamin E

  1. In a study in pts w/CAD randomized to vit. E 400IU/d, 800IU/d, or placebo, vit. E was ass'd with sig. reduction in incidence of nonfatal MI, but sl. (& nonsig.) higher incidence of CV death and all-cause mortality; median duration of tx 510d ("Cambridge Heart Antioxidant Study"; Lancet 347:781, 1996--UW Pharm Letter & Med. Lett.)
  2. In a study of 1,862 male smokers with previous h/o MI randomized to vit. E 50mg QD, beta-carotene 20mg QD, both, or neither, Vit. E ass'd with RR 0.62 (sig.) of non-fatal MI but nonsig. increase in risk (RR 1.33) of death from ischemic heart disease ("Alpha-Tocopherol, Beta Carotene Prevention Study"; Lancet 349: 1715, 1997--UW Pharm Letter)
  3. Alpha-tocopherol 50IU/d vs. placebo ass'd with no sig. diff. in CV risk but lower incidence of prostate Ca and prostate Ca-mortality (Arch. Int. Med. 158:668, 1998 & J. Nat. Ca. Inst. 90:440, 1998--Med. Lett.)
  4. In a study of 11,324 pts with MI in previous 3mos randomized to 1g/d of fish-oil (n-3-polyunsaturated fatty acids), 300IU/d of vit. E, both, or neither, over avg. 3.5y f/u, those randomized to vit. E had no diff. in overall mortality than those on placebo [see Fish and Fish Oil for Prevention of CAD for results re: fish oil] (Lancet 354:447, 1999--JW, AFP)
  5. In a study in 9,297 pts > 55yo with (h/o CAD, CVA, PVD, or DM) and (HTN, high tot. chol., high LDL, smoking, or microalbuminuria) randomized to vit. E 400IU QD vs. placebo ("HOPE" trial)
    1. Over mean 4.5y f/u, incidence of primary endpoint (MI, CVA, or CV death) was not sig. different; ditto for all-cause mortality (NEJM 342:144, 2000--JW)
    2. In a follow-up study looking at 6,786 members of the original cohort who agreed to continue on vit. E vs. placebo, over mean 7.1y total f/u,  vitamin E pts had sig. greater incidence of heart failure (RR 1.13) and the incidence of heart failure "events" and hospitalization for heart failure were sig. higher among vit. E recipients (14.7% and 5.8% vs. 12.6% and 4.2%, respectively); there was no sig. diff. in incidence of cancer, cancer mortality, or major cardiovascular events ("HOPE-TOO" Trial; JAMA 293:1338, 2005--abst)
  6. Click Here to see data on Vitamin E from the Primary Prevention Study
  7. In a randomized trial of 423 postmenopausal women with angiographically-proven CAD of at least one vessel randomized to (vit. E 400IU + vit. C 500mg both BID) vs. placebo, over mean 2.8y f/u, incidence of angiographic progression was not sig. different in the two groups, bot total mortality was sig. higher in vitamin group (HR 2.8) ("WAVE" trial; JAMA 288:2432, 2002--abst)
  8. In a meta-analysis 7 randomized trials of vitamin E vs. placebo, there was no sig. difference in all-cause mortality, CVA's, or cardiovascular death (Lancet 361:2017, 2003--JW)
  9. In a meta-analysis of 6 randomized trial of vitamin E vs. placebo, there was no sig. diff. in overall or cardiovascular mortality, either for primary or secondary prevention (J. Gen. Int. Med. 19:380, 2004--AFP)
  10. In the Women's Health Study (click on link for details), over mean 10y f/u, there was no sig. diff. between vitamin E vs. placebo recipients in incidence of MI, ischemic CVA, or hemorrhagic CVA, though there were sig. fewer cardiovascular deaths (RR 0.76), mostly because of fewer sudden cardiac deaths (JAMA 294:56, 2005--JW)

II. Beta-carotene--Primary sources are dark-colored fruits & vegetables

  1. Harvard study randomized 22,000 male physicians to 50mg of beta-carotene QOD vs. placebo for avg. 12y; at 12y, rates of Ca, CVA, MI, and death were nearly equal in both groups (NEJM 334:1145, 1996-JW)
  2. Finnish Alpha-Tocopherol, Beta Carotene Cancer Prevention Study reported no change in incidence of CAD among middle-aged smokers assigned to daily beta-carotene, vit. E (50mg QD, a very low dose), or both. There was sig. incr. of lung Ca in pts on beta carotene, and apparent incr. of hemorrhagic stroke in men on vit. E (NEJM 330:1029, 1994; cited in NEJM 332:1758, 1995)
  3. 18,000 pts randomized to 30mg beta-carotene QD plus 25,000 IU vit. A QD vs. placebo-all were current or former smokers or workers exposed to asbestos. Study stopped prematurely after mean f/u 4y b/c of incr. risk of lung Ca (RR 1.28) and death (RR 1.17) in pts on supplements (both significant) (NEJM 334:1150, 1996-JW)
  4. Physicians' Health Study had a subgroup of 333 men with h/o chronic stable angina or coronary revascularization assigned to 50mg beta-carotene QOD vs. placebo; tx group had RR 0.5 for major coronary events (Circ 82: Supple III, 1990; cited in NEJM 332:1758, 1995)
  5. 34,000 postmenopausal women without known CAD given detailed prospective dietary assessments of intake of carotenoids and vitamins A, C, D, and E. No association between intake of vit. A, D, or carotenoids and death from CHD. Vit. C intake associated with increased CHD mortality. Vit. E intake from supplements not ass'd with change in CHD mortality but progressively greater intake of vit. E from food was associated with sig. decrease in CHD mortality in dose-response fashion (RR 0.38 for CHD death comparing highest and lowest quintile of vit. E intake) (NEJM 223:1156, 1996-JW)
  6. "Alpha-Tocopherol, Beta Carotene Prevention Study" (see above)--Beta-carotene ass'd with increased risk of death from ischemic heart disease (RR = 1.75, sig.)
  7. In a meta-analysis 8 randomized trials of beta-carotene vs. placebo, beta-carotene was ass'd with slight but statistically significantly increased risks of all-cause mortality and cardiovascular mortality (Lancet 361:2017, 2003--JW)

III. Vitamin A--Primary sources are meats, fish oil, fish and dairy products; 1000IU = 0.6mg; see studies above

IV. Flavonoids

  1. Have anti-oxidant, antithrombotic, and anti-inflammatory properties
  2. Present in high amounts in tea; some indirect evidence of benefit
    1. In a prospective observational study of 4807 people (mean age 67), over mean 5.6y f/u, consumption of > 2 cups/day of tea ass'd with sig. lower risk of MI (RR 0.57) or fatal MI (RR 0.3)
    2. In a prospective observational study of 1900 pts (mean age 61) with MI, all-cause mortality over 3.8y of f/u was sig. lower (RR 0.72) in pts drinking 1-14 cups/wk and even lower (RR 0.56) in pts drinking > 14 cups/wk, compared with pts who drank no tea (Circ. 105:2476, 2002--JW)
    3. Lowered total cholesterol and LDL in one randomized study (click link for details)

V. Combinations of antioxidants

  1. In a study in 1,276 pts > 40yo with diabetes mellitus and asymptomatic peripheral arterial disease (ankle-brachial index < 1) randomized to (aspirin 100mg/d + antioxidant tablet containing alpha-tocopherol 200mg, vitamin C 100mg, pyridoxine 25mg, zinc sulfate 10mg, nicotinamide 10mg, lecithin 9.4mg, and sodium selenite 0.8mg), (aspirin + placebo), (antioxidants + placebo), or (double placebo), over median 6.7y f/u, there was no sig. diff. among the groups in incidence of (death from coronary or cerebrovascular disease, MI, CVA, or LE extremity amputation for ischemia). ("Prevention of Progression of Arterial Disease and Diabetes" ("POPADAD") trial; BMJ 337:a1840, 2008-AFP)