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Antioxidant Vitamin Therapy

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					     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!"

				
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