Physicians' Health Study II - PHS II — Presented at AHA 2008


Although data from basic science and observational studies suggests a possible beneficial effect of antioxidants, especially vitamin C and E, in the primary prevention of cardiovascular events, there are no or conflicting data from randomized controlled trials on this topic. Accordingly, the PHS II trial was designed to assess the role of vitamin C and E supplementation in the prevention of cardiovascular events in low-risk male physicians.


Vitamin C and E supplementation would be individually associated with a reduction in cardiovascular events in male patients at a low risk for cardiovascular events.

Study Design

Study Design:

Patients Screened: 273,360
Patients Enrolled: 14,641
Mean Follow Up: 8 years
Mean Patient Age: 64.3 years
Female: 0

Patient Populations:

  • US male physicians
  • Age ≥50 years
  • Willing to forgo (during the course of PHS II) any current use of multivitamins or individual supplements containing more than 100% of the recommended daily allowance of vitamin E, vitamin C, beta carotene, or vitamin A


  • History of cirrhosis
  • Active liver disease
  • On anticoagulant medications

Primary Endpoints:

  • Composite of nonfatal MI, nonfatal stroke, and cardiovascular mortality

Secondary Endpoints:

  • Nonfatal MI
  • Nonfatal stroke
  • Cardiovascular mortality
  • Congestive heart failure
  • Angina pectoris
  • Revascularization

Drug/Procedures Used:

Patients were randomized in a 2 x 2 x 2 x 2 factorial trial to either vitamin E (400 IU synthetic α-tocopherol) or placebo every other day, vitamin C (500 mg synthetic ascorbic acid) or placebo daily, multivitamin (Centrum Silver) or placebo, and beta-carotene (50 mg of Lurotin) or placebo every other day.

Concomitant Medications:

Aspirin (77.4%)

Principal Findings:

A total of 14,641 healthy males were randomized, 3,656 to active vitamins E and C, 3,659 to active vitamin E and placebo vitamin C, 3,673 to placebo vitamin E and active vitamin C, and 3,653 to placebo vitamins C and E. Baseline characteristics were fairly similar between the four groups. About 61% exercised at least once every week, about 44% were past or current smokers, 77.4% were on aspirin, 42% had a history of hypertension, 36% had a history of hypercholesterolemia, 6% had a history of diabetes, and about 5% had a self-reported history of cardiovascular disease. Compliance was about 72% at 8 years.

Vitamin E: There was no difference between patients receiving vitamin E or placebo in the incidence of major cardiovascular events (8.5% vs. 8.5%, hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.90-1.13, p = 0.86). There was also no difference in the incidence of myocardial infarction (MI) (3.3% vs. 3.7%, p = 0.22), stroke (3.2% vs. 3.1%, p = 0.45), congestive heart failure (4.0% vs. 4.0%, p = 0.80), or all-cause mortality (11.5% vs. 11.2%, p = 0.15). However, there was a significant increase in the risk of hemorrhagic stroke in the vitamin E arm (0.53% vs. 0.31%, HR 1.74, 95% CI 1.04-2.91, p = 0.04). On stratifying patients based on baseline cardiovascular disease, there was still no difference between the two arms in any of the outcomes studied.

Vitamin C: There was no difference between patients receiving vitamin C or placebo in the incidence of major cardiovascular events (8.4% vs. 8.6%, HR 0.99, 95% CI 0.89-1.11, p = 0.91). There was also no difference in the incidence of MI (3.5% vs. 3.4%, p = 0.65), stroke (3.0% vs. 3.4%, p = 0.21), or all-cause mortality (11.7% vs. 11.0%, p = 0.16). There was no effect of vitamin C on hemorrhagic stroke (0.41% vs. 0.44%, p > 0.05). On stratifying patients based on baseline cardiovascular disease, there was still no difference between the two arms in any of the outcomes studied.

No significant increase in adverse events was noted with either vitamin C or E compared with placebo.


The results of the PHS II trial indicate that neither vitamin C nor vitamin E supplementation is associated with a reduction in major cardiovascular outcomes, as compared with placebo, although vitamin E may be associated with a slightly higher incidence of hemorrhagic stroke, compared with placebo.

Limitations of this trial include the fact that it included only male physicians in the United States, and, thus, these results may not generalizable to the general population. Exposure and some endpoint assessments were also assessed using a mailed questionnaire, and could thus be susceptible to bias. Although patients were followed for a mean duration of 8 years, it is possible that an even longer duration of follow-up, and possibly a different dose, may be necessary to demonstrate a difference between the groups.


Presented by Dr. J. Michael Gaziano at the American Heart Association Annual Scientific Sessions, New Orleans, November 2008.

Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men. The Physicians’ Health Study II randomized controlled trial. JAMA 2008;300:2123-33.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Homozygous Familial Hypercholesterolemia, Nonstatins, Acute Heart Failure, Diet, Hypertension

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Vitamin E, beta Carotene, Hypercholesterolemia, Primary Prevention, Vitamins, alpha-Tocopherol, Recommended Dietary Allowances, Dietary Supplements, Heart Failure, Vitamin A, Cardiovascular Diseases, Questionnaires, Confidence Intervals, Hypertension, Diabetes Mellitus

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