State of the Art Lecture Antioxidant Vitamin Therapy: To 'E' or not to 'E' JoAnn E. Manson, MD, DrPH Chief, Division of Preventive Medicine Brigham and Women's Hospital Professor of Medicine Harvard Medical School ROAD MAP • Biological Mechanisms • Animal Studies • Human Observational Studies • Randomized Clinical Trials • Conclusions CAUSES OF DEATH IN THE UNITED STATES Cardiovascular Disease Heart Disease Other 27.5% 31.6% 41% Cerebrovascular Disease 9.4% Respiratory Diseases 8.1% Cancer 23.4% National Center for Health Statistics, 1998. HYPOTHESIZED ANTIATHEROGENIC MECHANISMS OF ANTIOXIDANT VITAMINS Antioxidant vitamins can inhibit the oxidation and/or uptake of LDL cholesterol. Oxidized LDL is the particularly atherogenic form of cholesterol. ROLE OF OXIDIZED-LDL IN ATHEROSCLEROSIS • Endothelial damage • Monocyte/macrophage recruitment • Increased uptake of LDL by foam cell • Alteration in vascular tone • Induction of growth factors • Formation of autoantibodies to oxidized LDL HYPOTHESIZED ANTICANCER MECHANISMS OF ANTIOXIDANT VITAMINS Antioxidant vitamins may prevent tissue damage by trapping organic free radicals and deactivating excited oxygen molecules, a by-product of many metabolic processes. DEFENSE MECHANISMS AGAINST FREE RADICAL OXIDATION • Compartmentalization of oxidative metabolism • Transition metal binding by transport and storage proteins • Intracellular enzymes Superoxide dismutase Glutathione peroxidase Catalase • Dietary antioxidants Vitamin E Vitamin C Carotenoids • DNA repair mechanisms STUDY OF PROBUCOL AND LOVASTATIN IN HYPERLIPIDEMIC RABBITS Extent of aortic lesions, % surface area involved Exp. group Total aorta Aortic arch Untreated (n = 6) 40.6 5.1 87.5 3.5 Lovastatin (n = 11) 27.5 4.6 65.0 4.9 Probucol (n = 11) 14.3 2.1 47.1 5.3 Source: Carew T, et al. Proc Natl Acad Sci 1987; 84:7725-29. ANIMAL STUDIES OF VITAMIN E AND PREVENTION OF ATHEROSCLEROSIS Species Dose Endpoint Restricted 1,000 mg/kg feed Decreased plasma an ovulatory hens peroxides and aortic intimal thickening Hypercholesterolemic 10 mg/kg body Decreased aortic mongrel rabbits weight thickening Monkeys fed 108 IU at entry or Decreased carotid atherogenic diet 12 months after ultrasound stenosis atherogenic diet PROSPECTIVE COHORT STUDIES OF ANTIOXIDANT VITAMINS AND CARDIOVASCULAR DISEASE • Nurses’ Health Study • Massachusetts Elderly Cohort • Health Professionals Follow-up Study • First National Health and Nutrition Examination Survey (NHANES I) • Iowa Women’s Health Study LIMITATIONS OF OBSERVATIONAL EVIDENCE • Observational epidemiologic studies are unable to control for the potential effects of confounding variables not collected or not known to the investigators. • When searching for small to moderate effects, the amount of uncontrolled confounding may be as large as the most likely effect. NURSES' HEALTH STUDY: Antioxidant Vitamin Intake and Risk of CHD Agent Relative Risk* P trend Beta-carotene 0.78 0.02 Vitamin E 0.66 <0.001 Vitamin C 0.80 0.15 * Highest vs. lowest intake quintile Source: Manson JE, et al. J Am Coll Nutr 1993; 12:400-11. HEALTH PROFESSIONALS FOLLOW-UP STUDY: Antioxidant Vitamins and Risk of CVD Agent Relative risk* P trend Beta carotene 0.71 0.03 Vitamin E 0.60 0.01 Vitamin C 1.25 0.98 * Highest vs. lowest quintile Source: Rimm E, et al. NEJM 1993; 328. ANTIOXIDANT VITAMINS AND CANCER PREVENTION Over 100 dietary and blood-based observational studies have suggested an inverse association between antioxidant vitamin intake or blood levels and risk of cancer. The great tragedy of science: Beautiful hypotheses slain by ugly facts. Thomas Henry Huxley Collected Essays, 1893-1894 META-ANALYSIS OF EFFECT OF VITAMIN E ON MI, STROKE, OR CVD DEATH Study Daily Dose Duration (yr) RR (95% CI) ATBC 50 5.0 0.96 (0.90-1.03) CHAOS >400 1.3 0.60 (0.40-0.89) GISSI 300 3.5 0.98 (0.87-1.10) HOPE 400 4.5 1.05 (0.95-1.16) Total 0.97 (0.92-1.02) Source: N Engl J Med 2000; 342:154-60 CHINESE CANCER PREVENTION TRIAL • Design: Double-blind, placebo-controlled trial of several vitamins and minerals • Subjects: 29,584 residents aged 40 to 69 in 1985 living in Linxian, a rural county in north- central China • Duration: 5 years CHINESE CANCER PREVENTION TRIAL Relative risk of death by cause for those receiving ß-carotene, vitamin E, and selenium vs. those not receiving this cocktail Cause of Death N RR (95% CI) All causes 2,127 0.91 (0.84 - 0.99) All cancer 792 0.87 (0.75 - 1.00) Esophageal 380 0.96 (0.78 - 1.18) Gastric 331 0.79 (0.64 - 0.99) Cerebrovascular 523 0.90 (0.76 - 1.07) Other 812 0.96 (0.84 - 1.11) Source: Blot WJ, et al. JNCI 1993; 85:1483-92. ALPHA-TOCOPHEROL BETA-CAROTENE STUDY • Randomized, double-blind, placebo-controlled trial among 29,333 male smokers, aged 50 to 69, living in southwestern Finland • Using a 2x2 factorial design, subjects were randomly assigned for ~ 6 years of treatment and follow-up to one of four treatment groups: alpha-tocopherol (50 mg/daily) beta-carotene (20 mg/daily) both active agents both placebos ATBC STUDY: SUMMARY Alpha-Tocopherol (Vitamin E) • No benefit on lung cancer, ischemic heart disease mortality, or total mortality • Hemorrhagic stroke deaths 50% • Prostate cancer incidence 34% Beta Carotene • No benefit on lung cancer, ischemic heart disease mortality, or total mortality • Lung cancer incidence 18% • Ischemic heart disease mortality 11% • Total mortality 8% Source: NEJM 1994; 330:1029-35. BETA-CAROTENE AND RETINOL EFFICACY TRIAL (CARET) (N=18,314 current or former smokers and asbestos-exposed workers randomized to ß-carotene plus vitamin A vs. placebo) Lung cancer 28% p = 0.02 CVD mortality 16% p = 0.06 Total mortality 17% p = 0.02 Source: Omenn GS, et al. NEJM 1996; 334:1150-55. PHYSICIANS’ HEALTH STUDY (N=22,071 U.S. male physicians, 40-84 yrs, ß-carotene 50 mg QOD vs. placebo, duration = 12 yrs) Beta-Carotene Findings Total malignant neoplasms 2% p = 0.65 (0.91-1.06) Cardiovascular disease p = 0.90 (MI, stroke, CV death) (0.91-1.09) Total mortality 2% p = 0.68 (0.93-1.11) Source: NEJM 1996; 334:1145-49. CAMBRIDGE HEART ANTIOXIDANT STUDY (CHAOS) • Design: Randomized, double-blind, placebo- controlled trial of daily vitamin E (400 or 800 IU) or placebo • Subjects: 2,002 men and women in the UK with angiographically proven coronary atherosclerosis. • Duration: median treatment and follow-up of 1.4 years CAMBRIDGE HEART ANTIOXIDANT STUDY (CHAOS) (N=2,002 U.K. M & F with atherosclerosis, vit E [400 or 800 IU] or placebo, duration = 1.4 yrs) Endpoint Relative risk (95% CI) P value Nonfatal MI + CVD death 0.53 (0.34-0.83) 0.005 Nonfatal MI 0.23 (0.11-0.47) <0.001 CVD death 1.18 (0.62-2.27) 0.61 Source: Stephens NG, et al. Lancet 1996; 347:781-6. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardio (GISSI Prevention Study) • Design: multicenter, open-label, 2x2 factorial trial of vitamin E (300 mg daily), fish oil supplement (n-3 PUFA,1 g daily), both, or neither • Subjects: 1,665 women and 9,659 men with prior myocardial infarction • Duration: mean, 3.5 years Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardio (GISSI Prevention Study) (N=9,659 M + 1,665 F with prior MI, vitamin E [300 mg/d] with or w/o fish oil, duration = 3.5 yrs) Results for Vitamin E Endpoint Relative risk (95% CI) MI + stroke + death 0.95 (0.86-1.05) MI + stroke + CV death 0.98 (0.87-1.10) All fatal events 0.92 (0.82-1.04) CV deaths 0.94 (0.81-1.10) Source: Lancet 1999; 354:447-55. HEART OUTCOMES PREVENTION EVALUATION (HOPE) STUDY • Design: multicenter, double-blind, placebo-controlled, 2x2 factorial trial of vitamin E (400 IU daily), ramipril, both, or neither • Subjects: 9,541 men and women at high risk of cardiovascular disease from 19 countries • Duration: mean, 4.5 years HEART OUTCOMES PREVENTION EVALUATION (HOPE) STUDY (N=9,541 M & F from 19 countries, high risk of CVD, vitamin E [400 IU/d] with or w/o Ramipril, duration = 4.5 yrs) Results for Vitamin E Endpoint Relative risk (95% CI) MI, stroke, or CV death 1.05 (0.95-1.16) CV death 1.05 (0.90-1.22) MI 1.02 (0.90-1.15) Death, any cause 1.00 (0.89-1.13) Source: N Engl J Med 2000; 342:154-60. HEART PROTECTION STUDY (HPS) • Preliminary results • Simvastatin (40 mg/d) 12% total mortality 17% vascular mortality 24% CHD events 27% strokes • Antioxidants No benefit or harm observed vitamin E (650 mg/d) vitamin C (250 mg/d) ß-carotene (20 mg/d) Source: Collins R, et al. International Journal of Clinical Practice 2002; 56:53-56. PHYSICIANS' HEALTH STUDY • Design: Randomized, double-blind, placebo- controlled, 2x2 factorial to low-dose aspirin (325 mg on alternate days) and beta-carotene (50 mg on alternate days) in the primary prevention of CVD and cancer • Subjects: 22,071 healthy male physicians, aged 40 to 84 at baseline in 1982, living in the US • Duration: 12 years PRIMARY PREVENTION PROJECT (PPP) • N=4,495 (M & F); 64.4 yrs (mean); 1+ CAD risk factor; F/U = 3.6 yrs • Randomized controlled 2x2 factorial trial of vitamin E (300 mg/d) and low-dose aspirin (100 mg/d) Vitamin E RR 95% CI CV death + nonfatal MI + stroke 1.07 (0.74-1.56) All cardiovascular disease 0.94 (0.77-1.16) Source: Collaborative Group of the Primary Prevention Project. Lancet 2001; 357:89-95 FIRST NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES I) Vitamin C Intake and Risk of CVD Death (N=11,348) Daily Intake SMR* (95% CI) 0 - 49 mg 1.03 (0.94 - 1.13) 50 mg; no regular supplement use 0.90 (0.82 - 0.99) 50 mg and regular supplement use 0.66 (0.53 - 0.82) *Compared with rates among U.S. whites HDL-ATHEROSCLEROSIS TREATMENT STUDY (HATS) (160 participants [89% men], with clinical CAD, low HDL-C, and normal LDL-C, F/U = 3 yrs) Mean change in Nonfatal MI, or Treatment Group % stenosis P-value revascularization,% P-value • Simvastatin and niacin* -0.4 <0.001 3 0.04 • Antioxidants† +1.8 0.16 21 ns‡ • Simvastatin and niacin, +0.7 0.004 14 ns plus antioxidants • Placebo +3.9 -- 24 ns * Doses were dependent on lipid levels † Vit E (800 IU) + vit C (1000 mg) + ß-carotene (25 mg) + selenium (100 µg) ‡ ns = nonsignificant Source: Brown BG, et al. NEJM 2001; 345:1583-92. SECONDARY PREVENTION WITH ANTIOXIDANTS OF CARDIOVASCULAR DISEASE IN ENDSTAGE RENAL DISEASE (SPACE) • N=196 (69% men); 40-75 yrs, hemodialysis patients with CVD, F/U = 1.4 yrs • Treatment: Vitamin E (800 IU/d) or placebo Outcome RR 95% CI CVD Excluding sudden death 0.46 (0.27-0.78) Including sudden death 0.54 (0.33-0.89) Source: Boaz M , et al. Lancet 2000; 356:1213-18. AGE-RELATED EYE DISEASE STUDY (AREDS) • N=3,640 (M & F), 55-80 yrs, with mild to moderate age-related macular degeneration (AMD), F/U = 6.3 yrs • Outcome: Progression to advanced AMD All Patients (mild/moderate AMD) Treatment Group OR 99% CI • Antioxidants only* 0.80 (0.59-1.09) • Zinc only 0.75 (0.55-1.03) • Antioxidants plus zinc 0.72 (0.52-0.98) • Placebo 1.00 (Referent) * Vit C (500 mg) + vit E (400 IU) + ß-carotene (15 mg) Source: Age-related Eye Disease Study Research Group. Arch Opthalmol 2001; 119:1417-36. ONGOING LARGE-SCALE TRIALS OF ANTIOXIDANTS Physician's Health Study II Vitamin E (400 IU QOD), vitamin C (PHS II) (500 mg/d), and a daily multivitamins in U.S. male physicians Women's Health Study Vitamin E (400 IU QOD) and low-dose (WHS) aspirin in healthy U.S. female health professionals Women's Antioxidant ß-carotene (50 mg QOD), vitamin E Cardiovascular Study (600 IU QOD), vitamin C (500 mg/d), (WACS) and folic acid/B6 and B12 in high-risk U.S. female health professionals CONCLUSIONS • Antioxidant vitamin supplements represent a promising, but unproven, means of reducing risk of CVD, cancer, and other chronic diseases • It would be premature to recommend routine use of antioxidants for disease prevention or treatment • Dietary intake of 5-7 servings/d of fruits and vegetables, and a daily multivitamin supplement, would be prudent • Additional large-scale randomized clinical trials of antioxidants, alone and in combination, are needed. We've decided that it's healthier to eat a vegetarian!"