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Antioxidant Vitamin Therapy: To 'E' or not to 'E'

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

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Antioxidant Vitamin Therapy: To 'E' or not to 'E'

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  1. State of the Art Lecture Antioxidant Vitamin Therapy:To 'E' or not to 'E' JoAnn E. Manson, MD, DrPHChief, Division of Preventive MedicineBrigham and Women's HospitalProfessor of MedicineHarvard Medical School

  2. ROAD MAP • Biological Mechanisms • Animal Studies • Human Observational Studies • Randomized Clinical Trials • Conclusions

  3. Heart Disease31.6% Other 27.5% 41% Cardiovascular Disease Cerebrovascular Disease 9.4% Respiratory Diseases 8.1% Cancer 23.4% CAUSES OF DEATH IN THE UNITED STATES National Center for Health Statistics, 1998.

  4. 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.

  5. 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

  6. HYPOTHESIZED ANTICANCER MECHANISMSOF 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.

  7. 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

  8. Extent of aortic lesions, % surface area involvedExp. 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 STUDY OF PROBUCOL AND LOVASTATIN IN HYPERLIPIDEMIC RABBITS Source: Carew T, et al. Proc Natl Acad Sci 1987; 84:7725-29.

  9. 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 ANIMAL STUDIES OF VITAMIN E AND PREVENTION OF ATHEROSCLEROSIS

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. The great tragedy of science: Beautiful hypothesesslain by ugly facts. Thomas Henry HuxleyCollected Essays, 1893-1894

  16. META-ANALYSIS OF EFFECT OF VITAMIN EON 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

  17. 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

  18. 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.

  19. 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

  20. 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.

  21. 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.

  22. 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.

  23. 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

  24. 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.

  25. 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

  26. 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) 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) Source: Lancet 1999; 354:447-55.

  27. 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

  28. 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) 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) Source: N Engl J Med 2000; 342:154-60.

  29. 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 observedvitamin 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.

  30. 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

  31. 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 ERR 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

  32. 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) FIRST NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES I) Vitamin C Intake and Risk of CVD Death (N=11,348) *Compared with rates among U.S. whites

  33. 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, orTreatment 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.

  34. Outcome RR 95% CI CVD Excluding sudden death 0.46 (0.27-0.78) Including sudden death 0.54 (0.33-0.89) 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 Source: Boaz M , et al. Lancet 2000; 356:1213-18.

  35. 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) 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 * 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.

  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 ECardiovascular Study (600 IU QOD), vitamin C (500 mg/d),(WACS) and folic acid/B6 and B12 in high-risk U.S. female health professionals

  37. 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.

  38. We've decided that it's healthier to eat a vegetarian!"

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