1. 3/98medslides.com1 Antioxidants and Coronary Artery Disease Jason M. Lazar, MD George Yiachos, MD Winthrop-University Hospital

2. 3/98medslides.com2 Coronary ArteryDisease In 1997, the direct and indirect cost for CAD was $90.9 billion in the U.S. only 50% of CAD can be attributed to conventional risk factors: smokinghypertension diabeteshyperlipidemia family history

3. 3/98medslides.com3 Is the use of vitamins justified Although observational studies support a cardio-protective effects of antioxidants, clinical trials are disappointing In the mean time, Americans spend an estimate $700 million on vitamin supplements

4. 3/98medslides.com4 Epidemiologic Evidence In Europe, those living in the south consume greater amounts of fruits and vegetables containing the antioxidants beta-carotene, vitamin E and vitamin C, have lower rates of CAD than those living in the north NEJM 1997;337:408-416

5. 3/98medslides.com5 Lipid Oxidation Hypothesis Lipid uptake across the cell wall is greatly enhanced by oxidized LDL-C. Antioxidants may therefore be beneficial in reducing the risk of coronary artery disease NEJM 1989;320:915-924

6. 3/98medslides.com6 Antioxidants vitaminsherbs estrogensflavonoids amino acidsbeta-carotene lipid-lowering agents monounsaturated fats

7. 3/98medslides.com7 Vitamin E A family of fat-soluble compounds, the tocopherols. Alpha-tocopherol is the most common and most active. Best sources of vitamin E –vegetable, seeds, nut oils recommended daily allowance is 15 IU

8. 3/98medslides.com8 Vitamin E laboratory and animal studies Vitamin E  the oxidation of LDL-C inhibit smooth-muscle cell growth inhibit platelet adhesion improves endothelial function reduced the number and severity of atherosclerotic lesions in rabbits fed high- fat diets Clin Cardiol 1993;16:I16-18

9. 3/98medslides.com9 Vitamin E human studies Nurse’s Health Study –87,245 women, ages 34-59, with no prior heart disease –those taking  100 IU/d of vitamin E for  2 years, had 40% lower risk of developing CAD after 8 years NEJM 1993;328(20):1444-1449

10. 3/98medslides.com10 Vitamin E human studies Health Professional’s Follow-up to the Physician’s Health Study –39,910 men, ages 40-70 –subjects with the highest vitamin E intake (> 60 IU / day) had a 36% lower risk of coronary disease after 4 years NEJM 1993;328(20):1450-1466

11. 3/98medslides.com11 Vitamin E human studies Iowa Women’s Health –a prospective cohort study of 34,000 postmenopausal women –subjects with the highest vitamin E intake from diet (but no vitamin supplements) had a lower risk for CAD NEJM 1996;334(18):1156-1162

12. 3/98medslides.com12 Vitamin E randomized trials CHAOS Study (Cambridge Heart Antioxidant Study) –a prospective randomized trial of 2,002 patients with prior coronary disease –treated with vitamin E (400-800 IU / day) for 3 years –77% reduction in nonfatal MI –no change in total mortality Lancet 1996;347(9004):781-786

13. 3/98medslides.com13 Vitamin E randomized trials ABC Prevention Trial (Alpha-tocopherol Beta-carotene Cancer Prevention Trial) –a lung cancer prevention trial –50 mg/d of vitamin E had no effect on the rate of MI or death –50 mg/d vit E + 20 mg/d beta-carotene resulted in greater coronary death NEJM 1994;330(15):1029-1035

14. 3/98medslides.com14 Vitamin C a water-soluble vitamin found in many fruits and vegetables a less potent antioxidant than vit E associated with lower LDL-C, higher HDL- C, and lower BP inhibits platelet aggregation recommended daily allowance 60 mg

15. 3/98medslides.com15 Vitamin C human studies The benefit of vitamin C in CAD is inconsistent and inconclusive only 3 of 8 observational studies found an inverse relationship between vitamin C intake and CAD

16. 3/98medslides.com16 Vitamin C human studies First National Health and Nutritional Examination Survey –11,349 subjects received vitamin C supplements –subjects taking vitamin C had a lower relative risk of cardiovascular death of.58 Epidemiology 1992;3(3):194-202

17. 3/98medslides.com17 Vitamin C human studies The Nurse’s Health and the Health Professional’s Follow-Up Study –subjects in the highest quintile of vitamin C intake had relative risk of cardiovascular disease of.8

18. 3/98medslides.com18 Beta-carotene A plant-derived nutrient contained in yellow and orange vegetables and fruits, and leafy green vegetables provides up to half of dietary vit A recommended daily allowance is 5,000 IU

19. 3/98medslides.com19 Beta-carotene human studies The antioxidant effects of beta-carotene and vitamin A have been well established The clinical studies are disappointing Only 3 of 6 observational studies found a decreased coronary risk associated with beta-carotene

20. 3/98medslides.com20 Beta-carotene human studies The Physician Health Study –over 22,000 male physicians –randomized to 50 mg of beta-carotene every other day –after 12 years, there was no difference in cardiovascular, cancer, and all-cause mortality NEJM 1993;328(20):1450-1466

21. 3/98medslides.com21 Beta-carotene human studies The Physician Health Study –in a subset of 333 subjects with preexisting coronary disease –beta-carotene was associated with a 44% reduction of coronary events (p=0.046) –the analysis was limited by its borderline p- value and post hoc nature Circ 1990;82s:202

22. 3/98medslides.com22 Beta-carotene human studies The CARET Study (Carotene and Retinol Efficacy Trial) –a randomized placebo-controlled trial of 18,000 male smokers with history of asbestos exposure –randomized to beta-carotene and vit A –the trial was terminated 21 months early N Engl J Med 1996;334(18):11150-1155

23. 3/98medslides.com23 Beta-carotene human studies The CARET Study subjects treated with 30 mg /d of beta- carotene had –28%  in mortality from lung cancer –17%  in all-cause mortality –29%  in cardiovascular mortality N Engl J Med 1996;334(18):11150-1155

24. 3/98medslides.com24 Flavonoids human studies The Zutphen Elderly Study –the consumption of flavonoid was inversely related to the occurrence of coronary heart disease Lancet 1993;342:1007-1011

25. 2/99medslides.com25 Antioxidants at a glance NutrientRDIDietary SourcesEvidence Vitamin E30 IUVegetable oils (soy, corn, olive,100-800 IU may lower cotton-seed, safflower, sunflower),heart disease risk by nuts, sunflower seed, wheat germ30%-40% Vitamin C60 mgCitrus fruits, strawberries, tomatoes,no evidence that RDI in cantaloupe, broccoli, asparagus,supplement form can peppers, spinach, potatoesprevent CHD or cancer ß-caroteneNADark green, yellow, and orangemay protect against vegetables: spinach, collard greenCHD and macular broccoli, carrots, peppers, sweetdegeneration potatoes; yellow fruits: peaches Selenium  70 ugEgg yolks, tuna, seafood, chicken,150-200 ug may lower  55 ugliver, whole grains, plant grown inprostate cancer risk selenium-rich soil ( west of Mississippi)

26. 3/98medslides.com26 Summary Current data do not support a large role for the use of antioxidant supplements in the prevention of CAD Nonetheless, many Americans rather consume vitamin supplements and neglect modification of known coronary risk factors

27. 3/98medslides.com27 Summary “Until further studies are completed, it is reasonable to recommend a diet rich in vegetable products, combined with exercise, risk modification behaviors, and appropriate medications”

28. 3/98medslides.com28 References Antioxidants and atherosclerotic heart disease. Diaz MN, Frei B, Vita JA, et al. NEJM 1997;337:408-416 Beyond cholesterol:modifications of low-density lipoprotein that increase its atherogenicity. Steinberg D, ParthasarathyS, et al. NEJM 1989;320:915-924 Vitamin E: more than an antioxidant. Steiner M. Clin Cardiol 1993;16 (4 Suppl 1):I16-18 Vitamin E consumption and the risk of coronary disease in women. Stampfer MJ, Hennekens CH, et al. NEJM 1993;328(20):1444-1449 Vitamin E consumption and the risk of coronary disease in men. Rimm EB, Stampfer MJ, et al. NEJM 1993;328(20):1450-1466 Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. Kushi LH, et al. NEJM 1996;334:1156-1162

29. 3/98medslides.com29 References Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Stephens NG, Parson A, et al. Lancet 1996;347(9004):781-786 The Alpha-tocopherol Beta-carotene Cancer Prevention Sutdy Group: the effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. NEJM 1994;330(15):1029-1035 Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascuar disease. Omenn GS, et al. N Engl J Med 1996;334(18):11150-1155