antioxidant vitamin therapy: to 'e' or not to 'e' joann e. manson, md, drph...
TRANSCRIPT
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Antioxidant Vitamin Therapy:To 'E' or not to 'E'
JoAnn E. Manson, MD, DrPHChief, Division of Preventive Medicine
Brigham and Women's HospitalProfessor of Medicine
Harvard Medical School
State of the Art Lecture
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ROAD MAP
• Biological Mechanisms
• Animal Studies
• Human Observational Studies
• Randomized Clinical Trials
• Conclusions
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CAUSES OF DEATH IN THE UNITED STATES
National Center for Health Statistics, 1998.
Heart Disease31.6%
Cerebrovascular Disease 9.4%
Other 27.5%
Cancer 23.4%
Respiratory Diseases 8.1%
Ca
rdio
va
scu
lar Dis
eas
e
41%
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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.
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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
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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.
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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
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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.
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ANIMAL STUDIES OF VITAMIN E AND PREVENTION
OF ATHEROSCLEROSIS
Species Dose Endpoint
Restricted 1,000 mg/kg feed Decreased plasmaan ovulatory hens peroxides and aortic
intimal thickening
Hypercholesterolemic 10 mg/kg body Decreased aorticmongrel rabbits weight thickening
Monkeys fed 108 IU at entry or Decreased carotidatherogenic diet 12 months after ultrasound stenosis
atherogenic diet
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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
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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.
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NURSES' HEALTH STUDY:Antioxidant Vitamin Intake and Risk of CHD
* Highest vs. lowest intake quintile
Agent Relative Risk* P trend
Beta-carotene 0.78 0.02
Vitamin E 0.66 <0.001
Vitamin C 0.80 0.15
Source: Manson JE, et al. J Am Coll Nutr 1993; 12:400-11.
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Source: Rimm E, et al. NEJM 1993; 328.
HEALTH PROFESSIONALS FOLLOW-UP STUDY:Antioxidant Vitamins and Risk of CVD
* Highest vs. lowest quintile
Agent Relative risk* P trend
Beta carotene 0.71 0.03
Vitamin E 0.60 0.01
Vitamin C 1.25 0.98
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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.
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The great tragedy of science:
Beautiful hypothesesslain by ugly facts.
Thomas Henry HuxleyCollected Essays, 1893-1894
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META-ANALYSIS OF EFFECT OF VITAMIN EON MI, STROKE, OR CVD DEATH
Source: N Engl J Med 2000; 342:154-60
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)
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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
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Relative risk of death by cause for those receiving ß-carotene, vitamin E, and selenium vs. those not receiving this cocktail
CHINESE CANCER PREVENTION TRIAL
Source: Blot WJ, et al. JNCI 1993; 85:1483-92.
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)
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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
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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.
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BETA-CAROTENE AND RETINOL EFFICACY TRIAL (CARET)
Lung cancer 28% p = 0.02
CVD mortality 16% p = 0.06
Total mortality 17% p = 0.02
(N=18,314 current or former smokers and asbestos-exposed workers randomized to ß-carotene plus vitamin A vs. placebo)
Source: Omenn GS, et al. NEJM 1996; 334:1150-55.
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PHYSICIANS’ HEALTH STUDY
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)
(N=22,071 U.S. male physicians, 40-84 yrs, ß-carotene 50 mg QOD vs. placebo, duration = 12 yrs)
Source: NEJM 1996; 334:1145-49.
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• 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)
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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.
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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
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Source: Lancet 1999; 354:447-55.
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)
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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
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Source: N Engl J Med 2000; 342:154-60.
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)
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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.
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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
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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)
Source: Collaborative Group of the Primary Prevention Project. Lancet 2001; 357:89-95
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)
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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
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HDL-ATHEROSCLEROSIS TREATMENT STUDY (HATS)
(160 participants [89% men], with clinical CAD, low HDL-C, and normal LDL-C, F/U = 3 yrs)
Meanchange 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.
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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.
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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
Source: Age-related Eye Disease Study Research Group. Arch Opthalmol 2001; 119:1417-36.
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)
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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
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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.
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We've decided that it's healthier to eat a vegetarian!"