A 43 y/o male patient shows up at the pharmacy window asking for a recommendation regarding OTC antioxidants such as vitamin E, vitamin C, selenium, and beta carotene. He's in relatively good health but has a positive family history of MI in his father at age 55. He is on a low dose statin for mild hypercholesterolemia.

Do you recommend antioxidants or not? If so, what agent(s) and what dose(s)? If not, why not?

** THANKS to Dr Angela Allerman, CDR (Dr.) Denise Graham, and LCDR Robert Glasgow, PA for their help with this Pearl **

Would not recommend the use of antioxidants for prevention of coronary heart disease (CHD). Although it appears that antioxidants are not harmful (EXCEPT the use of beta carotene in smokers - increased coronary mortality and lung cancer), there is no conclusive evidence to support their use in CHD.

Several recent, large studies have NOT shown a benefit of using antioxidants in the treatment of hyperlipidemia or the prevention of coronary heart disease.

The working hypothesis before these recent studies was that antioxidants prevented or slowed the oxidation of LDL particles. This slowed or prevented them from being phagocytised by macrophages and becoming foam cells. Foam cells are the start of atherosclerotic plaques.

The most recent study of antioxidants for the prevention of coronary heart disease showed no benefit of adding antioxidants (Vitamins E, C, selenium, beta carotene) to a regimen of simvastatin and niacin. Additionally, the clinical and arterial benefits of simvastatin and niacin, when combined with these antioxidants, were attenuated, compared to simvastatin and niacin alone. The authors hypothesize these antioxidants substantially and specifically blunt the expected increase in the cardio-protective HDL-2 sub fraction. The authors caveat this suggestion stating the study's small size and that more specific, more potent, less HDL-2 adverse antioxidants may prove effective.

Below are some meta analyses of the trials evaluating Vitamin E, Vitamin C, and beta carotene.

EPSES (Established Populations for Epidemiologic Studies of the Elderly)

Finnish Cohort (A 14 year follow up of 5133 men and women in Finland)

HPS (Health Professional Follow Up Study)

Iowa Women's (The Iowa Women's Health Study)

Nurses Health (The Nurses Health Study)

Rotterdam (The Rotterdam Study)

Scottish Heart (Scottish Heart Health Study)

Vitamin E

Study                           Duration                RR (95% CI)             Dose/day               

EPESE                         9 years                  0.53  (0.34, 0.84)      assumed ³ 30 IU

Finnish Cohort            14 years                 0.35  (0.14, 0.88)      > 5 IU

Health Professionals   4 years                  0.63  (0.47, 0.84)      > 100 IU

Iowa Women's            7 years                  0.38  (0.18, 0.80)      > 10 IU

Nurses Health             8 years                   0.57  (0.41, 0.78)      > 100 IU

Rotterdam                  4 years                   1.05  (0.66, 1.69)      > 14.2 mg

Scottish Heart             8 years                   0.67  (0.38, 1.18)      2.74mg/4.18 MJ

Random effects                                          0.56 (0.41, 0.70)

References:

1.      Losonczy KG, Harris TB, Havlik RJ. Vitamin E and Vitamin C Supplement Use and Risk of All-cause and Coronary Heart Disease Mortality in Older Persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64:190-6

2.      Knekt P, Reunanen A, Järvinen R, Seppänen R, Heliövaara M, Aromaa A. Antioxidant Vitamin Intake and Coronary Mortality in a Longitudinal Population Study. Am J Epidemiol 1994;139:1180-9.

3.      Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E Consumption and the Risk of Coronary Heart Disease in Men. N Engl J Med 1993;328: 1450-6.

4.      Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM.  Dietary Antioxidant Vitamins and Death from Coronary Heart Disease in Postmenopausal Women. N Engl J Med 1996;334: 1156-62.

5.      Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E Consumption and the Risk of Coronary Heart Disease in Women. N Engl J Med 1993;328: 1444-9.

6.      Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, Boeing H, Hofman A, Grobbee DE, Witteman JCM. Dietary Antioxidants and Risk of Myocardial Infarction in the Elderly: The Rotterdam Study. Am J Clin Nutr 1999;69:261-6

7.      Todd S, Woodward M, Tunstall-pedoe H, Bolton-Smith C. Dietary Antioxidant Vitamins and Fiber in the Etiology of Cardiovascular Disease and All-Cause Mortality: Results from the Scottish Heart Health Study. Am J Epidemiol 1999;150:1073-80

ATBC (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study)

CHAOS (Cambridge Heart Antioxidant Study)

HOPE (Heart Outcomes Prevention Evaluation)

GISSI Prevenzione Trial (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarcto miocardico)

Vitamin E

Study                   Duration                RR (95% CI)                     Dose/day               

ATBC                    6 years                 0.90  (0.67, 1.22)              50 IU

CHAOS                 1.5 years               0.53  (0.34, 0.83)              400-800 IU

HOPE                    4.5 years               1.05  (0.90, 1.22)              400 IU

GISSI                    3.5 years               0.98  (0.87, 1.10)              300 IU

Random effects                                  0.88 (0.56, 1.20)

References:

1.      Rapola JM, Virtamo J, Ripatti S, Huttunen JK, Albanes D, Taylor PR, Heinonen OP. Randomized Trial of a-tocopherol and b-carotene Supplements on Incidence of Major Coronary Events in Men with Previous Myocardial Infarction. Lancet 1997;349:1715-20.

2.      Virtamo J, Rapola JM, Ripatti S, Heinonen OP, Taylor PR, Albanes D, Huttunen JK.  Effect of Vitamin E and Beta Carotene on the Incidence of Primary Nonfatal Myocardial Infarction and Fata Coronary Heart Disease. Arch Intern Med 1998;158:668-75.

3.      Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ, Brown BJ. Randomised Controlled Trial of Vitamin E in Patients with Coronary Disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-86.

4.      Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E Supplementation and Cardiovascular Events in High Risk Patients. N Engl J Med 2000;342:154-60.

5.      GISSI-Prevenzione Investigators. Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitamin E after Myocardial Infarction: Results of the GISSI-Prevenzione Trial. Lancet 1999;354:447-55.

Vitamin C

EPSES (Established Populations for Epidemiologic Studies of the Elderly)

Finnish Cohort (A 14 year follow up of 5133 men and women in Finland)

Gale, et al.  (A 20 year follow up study of a elderly cohort in Britain)

HPS (Health Professional Follow Up Study)

Iowa Women's (The Iowa Women's Health Study)

NHANES (National Health and Nutrition Examination Survey Epidemiologic Follow Up Study)

Rotterdam (The Rotterdam Study)

Scottish Heart (Scottish Heart Health Study)

Vitamin C

Study                           Duration        RR (95% CI)                     Dose (mg/day)          

EPESE                           6 years         1.00  (0.74, 1.34)              ~60

Finnish Cohort               14 years        0.49  (0.32, 0.98)              >90

Gale, et al                      20 years        0.50  (0.30, 0.80)              >45

Health Professionals      4 years          0.83  (0.64, 1.08)              >1100

Iowa Women's               7 years          1.22  (0.82, 1.82)              >196

NHANES Men                 10 years         0.58  (0.53, 0.82)              >50

NHANES Women            10 years        0.75  (0.55, 0.99)              >50

Rotterdam                      4 years          0.84  (0.54, 1.30)              >126

Scottish Heart                 8 years          0.42  (0.23, 0.75)              > 20 mg/4.18 MJ

Random effects model                         0.695 (0.533, .858)

References:

1.      Losonczy KG, Harris TB, Havlik RJ. Vitamin E and Vitamin C Supplement Use and Risk of All-cause and Coronary Heart Disease Mortality in Older Persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr 1996;64:190-6

2.      Knekt P, Reunanen A, Järvinen R, Seppänen R, Heliövaara M, Aromaa A. Antioxidant Vitamin Intake and Coronary Mortality in a Longitudinal Population Study. Am J Epidemiol 1994;139:1180-9.

3.      Gale CR, Martyn CN, Winter PD, Cooper C. Vitamin C and Risk of Death from Stroke and Coronary Heart Disease in Cohort of Elderly People. BMJ 1995;310:1563-6.

4.      Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E Consumption and the Risk of Coronary Heart Disease in Men. N Engl J Med 1993;328: 1450-6.

5.      Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM.  Dietary Antioxidant Vitamins and Death from Coronary Heart Disease in Postmenopausal Women. N Engl J Med 1996;334: 1156-62.

6.      Enstrom JE, Kanim LE, Klein MA. Vitamin C Intake and Mortality among a Sample of the United States Population. Epidemiology 1992;3:194-200.

7.      Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, Boeing H, Hofman A, Grobbee DE, Witteman JCM. Dietary Antioxidants and Risk of Myocardial Infarction in the Elderly: The Rotterdam Study. Am J Clin Nutr 1999;69:261-6

8.      Todd S, Woodward M, Tunstall-pedoe H, Bolton-Smith C. Dietary Antioxidant Vitamins and Fiber in the Etiology of Cardiovascular Disease and All-Cause Mortality: Results from the Scottish Heart Health Study. Am J Epidemiol 1999;150:1073-80

APPENDIX B:  Antioxidants and CAD

Betacarotene

Study                           Duration        RR (95% CI)                     Dose/day               

Health Professionals     4 years         0.30  (0.11, 0.72)              ³ 14,000 IU

Iowa Women's              7 years         0.92  (0.60, 1.41)              ³ 13,000 IU

Rotterdam                     4 years         0.55  (0.34, 0.86)              > 1.57 mg/day

Scottish Heart                8 years         0.54  (0.29, 0.99)              >1000 mg/4.18 MJ

Random effects model                       0.55 (0.18,.91)

References:

1.      Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E Consumption and the Risk of Coronary Heart Disease in Men. N Engl J Med 1993;328: 1450-6.

2.      Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM.  Dietary Antioxidant Vitamins and Death from Coronary Heart Disease in Postmenopausal Women. N Engl J Med 1996;334: 1156-62.

3.      Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, Boeing H, Hofman A, Grobbee DE, Witteman JCM. Dietary Antioxidants and Risk of Myocardial Infarction in the Elderly: The Rotterdam Study. Am J Clin Nutr 1999;69:261-6

4.      Todd S, Woodward M, Tunstall-pedoe H, Bolton-Smith C. Dietary Antioxidant Vitamins and Fiber in the Etiology of Cardiovascular Disease and All-Cause Mortality: Results from the Scottish Heart Health Study. Am J Epidemiol 1999;150:1073-80

Betacarotene

Study                           Duration        RR (95% CI)                     Dose/day               

ATBC                            6 years          1.16  (0.88, 1.52)              20 mg/day

CARET                          4 years          1.26  (0.99, 1.61)              30 mg (+ A)

Physician's Health        12 years        1.00  (0.91, 1.09)              50 mg (qod)

Random effects Model                       1.08 (0.30, 2.47)

References:

1.      ATBC (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study)

CARET (BetaiCarotene and Retinol Efficacy Trial)

Physician's Health (Physician's Health Study)

2.      Rapola JM, Virtamo J, Ripatti S, Huttunen JK, Albanes D, Taylor PR, Heinonen OP. Randomized Trial of a-tocopherol and b-carotene Supplements on Incidence of Major Coronary Events in Men with Previous Myocardial Infarction. Lancet 1997;349:1715-20.

3.      Virtamo J, Rapola JM, Ripatti S, Heinonen OP, Taylor PR, Albanes D, Huttunen JK.  Effect of Vitamin E and Beta Carotene on the Incidence of Primary Nonfatal Myocardial Infarction and Fata Coronary Heart Disease. Arch Intern Med 1998;158:668-75.

4.      Omenn GS, Goodman GE, Thornquist MD, Blames J, Cullen MR, Glass A, Keogh JP, Meyskens FL, Valanis B, Williams JH, Barnhart S, Hammar S. Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease. N Engl J Med 1996;334:1150-5.

5.      Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease. N Engl J Med 1996;334:1145-9.

Other references:

- Brown BG, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.

- HOPE Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154-60.

- Dagenais GR, et al. Effects of ramipril on coronary events in high-risk outcomes. Results of the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation 2001;104:522-6.