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

ROAD MAP

• Biological Mechanisms

• Animal Studies

• Human Observational Studies

• Randomized Clinical Trials

• Conclusions

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

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va

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41%

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 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.

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 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

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

* 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.

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

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 hypothesesslain by ugly facts.

Thomas Henry HuxleyCollected Essays, 1893-1894

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)

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

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)

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)

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.

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.

• 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)

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

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)

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

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)

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.

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)

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)

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)

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.

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

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)

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

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!"