Betacarotene Primary Prevention Trials

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Results from large-scale randomized trials of beta-carotene in the primary prevention of CVD have been disappointing. These trials are summarized in Table 3.4. In the previously described ATBC trial among Finnish male smokers, participants assigned to 20 mg/d of beta-carotene had an increased risk of ischemic heart disease mortality (RR = 1.12; 95% CI, 1.00-1.25) and no reduction in the risk of angina (RR = 1.06; 95% CI, 0.97-1.16). For the primary endpoint of lung cancer, an increased risk was noted after 4 years (RR = 1.18; 95% CI 1.03-1.36), but this association disappeared after 6 years of post-trial follow-up (RR = 1.06; 95% CI 0.94-1.20).31 There were no late preventive effects of beta-carotene.

The Skin Cancer Prevention Study randomized 1,805 men and women with a history of skin cancer to 50 mg of beta-carotene daily or placebo.52 After a median treatment period of 4.3 years and median follow-up of 8.2 years, there was no significant reduction in CVD mortality (RR = 1.15; 95% CI, 0.81-1.63), cancer mortality (RR = 0.86; 95% CI, 0.56-1.32), or total mortality (RR = 1.05; 95% CI, 0.83-1.32) associated with beta-carotene supplementation.

The Physicians' Health Study (PHS I) was a randomized, double-blind, placebo-controlled trial of beta-carotene (50 mg every other day) and low-dose aspirin among 22,071 U.S. male physicians aged 40-84 years, of whom 11% were current smokers and 39% were former smokers.53 After 12 years of follow-up, those assigned to beta-carotene experienced no benefit with respect to CVD mortality

Table 3.4 Completed and ongoing randomized clinical trials of beta-carotene alone in the primary prevention of cardiovascular disease (CVD)


Population; Country Agent(s)a

Duration of txb



Effect of beta-carotene supplementation, RR (95% CI)

Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) Skin Cancer

Prevention Study

Physicians' Health Study I (PHS I)

29,133 male smokers aged 50-69 years; Finland

1,805 men and women with history of skin cancer; United States

22,071 male physicians aged 40-84 years; United States

Beta-carotene (20mg/d), 6 vitamin E (50mg/d), or both

Beta-carotene (50 mg every other day), aspirin (325 mg every other day), or both

CVD mortality Fatal ischemic heart disease Fatal ischemic stroke Fatal hemorrhagic stroke CVD mortality

CVD mortality MI


CVD mortality + MI + stroke Nonsmokers: CVD mortality MI


CVD mortality + MI + stroke Fonner smokers: CVD mortality MI


CVD mortality + MI + stroke

  1. 12 (1.00-1.25) 1.12 (CI not available) 1.23 (CI not available) 1.17 (CI not available) 1.15 (0.81-1.63)
  2. 09 (0.93-1.27) 0.96 (0.84-1.09) 0.96 (0.83-1.11) 1.00 (0.91-1.09)
  3. 00 (0.78-1.29) 0.88 (0.72-1.07) 0.92 (0.73-1.16) 1.00 (0.91-1.09)
  4. 16 (0.92-1.48) 1.00 (0.82-1.22) 0.90 (0.72-1.12) 1.00 (0.87-1.15)

Women's Health Study (WHS)

Physicians' Health Study II (PHS II)

39,876 female health professionals aged >45 years; United States

15,000 male physicians aged >55 years; United States

Beta-carotene (50 mg every other day), vitamin E (600IU every other day), aspirin (lOOmg every other day), or a combination (2x2x2 factorial design) Beta-carotene (50 mg every other day), vitamin E (400 IU every other day), vitamin C (500 mg/ day), multivitamin (daily), or a combination (2x2x2x2 factorial design)

Current smokers:

CVD mortality









CVD mortality + MI + stroke



CVD mortality









CVD mortality + MI + stroke




CVD mortality + MI + stroke



CVD mortality MI


Ongoing aAll trials were placebo controlled.

bExcept as indicated, duration of treatment equals duration of follow-up.

cIn Skin Cancer Prevention Study, treatment was for 4.3 years and follow-up was for 8.2 years.

(RR = 1.09; 95% CI, 0.93-1.27), MI (RR = 0.96; 95% CI, 0.84-1.09), stroke (RR = 0.96; 95% CI, 0.83-1.11), or a composite of the three endpoints (RR = 1.00; 95% CI, 0.91-1.09). The beta-carotene group also did not have any significant change in rates of cancer mortality, malignant neoplasms, or lung cancer. In analyses limited to current or former smokers, there were no early or late effects of beta-carotene on any endpoint.

Due to the null results of other studies, the ongoing Physicians' Health Study II (PHS II)36 terminated its beta-carotene treatment arm (50 mg every other day) early (results not yet published). The Women's Health Study (WHS) also initially had a beta-carotene arm (50 mg every other day)54 that was stopped early after 2.1 years, at which time participants assigned to active beta-carotene had no benefit with respect to CVD mortality (RR = 1.17; 95% CI, 0.54-2.53), MI (RR = 1.08; 95% CI, 0.56-1.27), stroke (RR = 1.42; 95% CI, 0.96-2.10), or a composite of these endpoints (RR = 1.14; 95% CI 0.87-1.49), as compared with those assigned to placebo. In the WHS, there was no significant benefit or harm from beta-carotene during the shortened follow-up time.

The results of these primary prevention trials of beta-carotene provide strong evidence that this antioxidant taken alone does not have a protective effect on CVD.

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