Two studies published recently in the Journal of the American Medical Association (The Physicians' Health Study II) reported that supplemental vitamin C (500 mg/day) or vitamin E (400 IU of synthetic vitamin E every other day) did not reduce the incidence of heart attacks and strokes; deaths from cardiovascular disease; the risk of prostate or total cancers; and cancer mortality in a group of 14,641 U.S. male physicians in a ten-year period.

All of the study subjects were at least 50 years old. Only about 5% had pre-existing heart disease, and about 9% had a history of cancer. They were randomized to receive vitamin C, vitamin E, both vitamin C and vitamin E, or placebo for the duration of the study. The investigators reported good adherence among participants (over 70%, with no differences between groups). There were no significant differences between groups at the beginning of the study—metrics included body mass index, history of cigarette smoking, frequency of exercise, alcohol consumption, aspirin use, and medical history of hypertension, diabetes, high cholesterol, or cardiovascular disease.

There were no statistically significant differences in cardiovascular outcomes, such as heart attacks, heart failure, or angina, between placebo groups and supplement groups, except for the incidence of hemorrhagic strokes. There were 39 such strokes in the vitamin E groups but only 23 in the groups not taking vitamin E, which represents an increased risk of about 75%. Bear in mind that the overall number of hemorrhagic strokes in these groups was small (62 among 14,641 subjects) and eclipsed by the number of ischemic strokes (387). Neither vitamin E nor vitamin C supplements had any significant effect on mortality from cardiovascular disease or total mortality.

The observed increased incidence of hemorrhagic stroke may be related to the known effects of vitamin E on blood clotting: the tolerable upper intake level of vitamin E set by the Food and Nutrition Board is based on its potential impairment of blood clotting. Over 77% of the physicians in the study reported taking aspirin. The combination of aspirin and supplemental vitamin E may have exacerbated the risk for hemorrhagic stroke.

There were no statistically significant differences between the supplement and placebo groups in the incidence of, or mortality from, total cancer or specific cancers, including prostate cancer, colorectal cancer, lung cancer, bladder cancer, pancreatic cancer, lymphoma, leukemia, and melanoma. The investigators noted that several factors, including supplement dose and duration and the good diets of the subjects, may have influenced the outcomes. They did not observe any significant adverse effects of supplemental vitamins C and E. They also noted that their results do not exclude the possibility that supplemental vitamins C and E may have cancer chemoprotective value in the context of other micronutrients, such as a multivitamin supplement.

These results of the Physicians' Health Study II contrast with results from some other large-scale studies. For example, a similar trial in women (The Women's Health Study; 39,900 women at least 45 years old followed for about ten years) who took 600 IU of natural vitamin E every other day for ten years reported a 25% reduction in cardiovascular mortality, as well as a 26% reduction in major cardiovascular events and a 49% reduction in cardiovascular mortality in those women 65 years and older. The Nurses' Health Study (85,000 women followed for 16 years), an observational study (studies that associate diet and supplement intake with disease outcome based on food-frequency questionnaires and other criteria), found that a daily intake of more than 350 mg of vitamin C was associated with over a 25% reduction in the risk for heart disease. Additionally, a meta-analysis of pooled studies (290,000 adults followed for about ten years) reported that the daily intake of at least 700 mg of vitamin C was associated with a 25% decreased risk for heart disease.

Many observational studies have found associations between the intake of vitamin C and reduced cancer incidence, especially of gastrointestinal and lung cancer and, in some subgroups, breast cancer. Generally, daily intakes of less than about 80 to 100 mg of vitamin C were associated with increased risk for cancer. Participants in the Physicians' Health Study II were described as well-nourished, suggesting that their dietary intake of vitamin C may have been sufficient for maximal cancer chemoprotection. Large-scale, long-term observational and randomized controlled studies have not generally found an association between supplemental vitamin E and reduced cancer risk, except for a 15-34% risk reduction for prostate cancer.

The Physicians' Health Study II did not measure blood levels of vitamin C or vitamin E, nor were levels of oxidative stress or C-reactive protein—a marker of inflammation—determined at baseline or at any time during the study. The distinct possibility remains that benefit may have been experienced among those participants with elevated levels of oxidative stress or inflammation at the beginning of the study, assuming that the intake of vitamin C or E was sufficient to attenuate these levels. However, this was not measured in the study and, therefore, is impossible to ascertain. Some other studies suggest that the amount of vitamin C for prophylaxis against heart disease may be greater than 500 mg/day and that very high doses of vitamin E are required to significantly attenuate oxidative stress, a presumptive causative factor for heart disease. It is also unknown if the study period of ten years was sufficient to observe long-term effects of supplemental vitamins C and E. One of the strengths of these studies is that they were not observational—specific doses of supplements were taken by the subjects over a long period of time. The studies were carefully executed by skilled investigators and contribute more evidence to the totality of accumulated studies of several different types, many of which have reported benefits for supplemental vitamins C or E in the prevention and treatment of heart disease or cancer.