Physicians' Health Study II
The first Physicians' Health Study was an extremely successful test for hypotheses about aspirin and beta-carotene in the prevention of cardiovascular disease, and cancer. By the time the trial had ended, a host of new questions had emerged in the area of primary prevention--some of them generated by preliminary data from PHS I.
One pressing unresolved issue involved the use of vitamins for the prevention of cardiovascular disease, cancer, and other conditions ranging from aging-related eye disease to memory loss. The impact of these chronic conditions is enormous. One or another affects, or will affect, most U.S. adults. At least half of Americans take vitamin supplements because they believe these agents can help ward off chronic disease. In reality, the true benefit of vitamins in the primary prevention these diseases has never been adequately tested in a large randomized trial.
The Physicians' Health Study II aims to do just that. It is testing
four of the most popular and promising agents--vitamin C, vitamin E,
beta-carotene, and a multivitamin--for the primary prevention of cardiovascular
disease, total cancer, and prostate cancer. It will also evaluate the
effect of these agents on colon polyps and colon cancer, cataract, macular
degeneration, and early cognitive decline. A detailed description of
the rationale and design of PHS II has been published: "Design of Physicians'
Health Study II -- A Randomized Trial of Beta-Carotene, Vitamins E and
C, and Multivitamins, in Prevention of Cancer, Cardiovascular Disease,
and Eye Disease, and Review of Results of Completed Trials" by William
Christen and colleagues in the February 2000 Annals
Physicians were invited to join PHS II in two phases. In the first phase, beginning in July 1997, physicians who had participated in PHS I were sent a letter explaining the background and rationale for PHS-II along with an informed consent form and a questionnaire asking about the occurrence of relevant medical conditions and the use of various vitamin supplements over the preceding year. To take part in PHS II, men who were taking individual supplements containing more than 100% of the RDA of vitamin E, vitamin C, beta-carotene, or a multivitamin had to forego the use of such supplements for the course of the trial. A total of 7,641 of the participants of PHS I signed on for another hitch.
In phase two, invitation packets were mailed to 254,597 U.S. male physicians aged 50 years and older who were registered with the American Medical Association and who had not taken part in PHS I. Of these, 16,743 said they were willing to participate in PHS-II and 11,128 were eligible for the trial.
Run-in and Randomization
As was done in PHS I, these "new" physicians were sent calendar packs containing placebos of all four of the study drugs. A total of 7,001 took the pills regularly and said they wanted to continue with the study.
Since August 1997, 14,642 men have been randomized into PHS II. Each man was assigned to one of 16 possible combinations of vitamin C (500 mg synthetic ascorbic acid), vitamin E (400 IU of synthetic alpha-tocopherol), beta-carotene (50 mg Lurotin), a multivitamin (Centrum Silver), or their placebos. Vitamin C and the multivitamin or their placebos are taken daily, while beta-carotene and vitamin E or its placebo are taken every other day. The pills are supplied in foil-backed calendar packs.
As in PHS-I, the participants PHS-II were asked to provide a blood sample before randomization. More than 11,100 (76%) did so. These samples were immediately frozen and are stored in liquid nitrogen freezers in the PHS blood laboratory.
Once a year, PHS-II participants get a 12-month supply of study pills in calendar packs. This shipment also contains an annual follow-up questionnaire. It includes questions about compliance with the study treatments, use of non-study medications, occurrence of major illnesses or adverse effects, and other risk factor information.
The Physicians' Health Study-II is scheduled to continue until December 2007. By that time, the average length of treatment and follow-up will be more than eight years. This should be long enough to yield definitive answers about the impacts of vitamin C, vitamin E, beta-carotene, and a multivitamin on the primary prevention of cardiovascular disease; total, prostate, and colon cancer; aging-related eye disease; and early cognitive decline.
PHS-II is funded by the National Institutes of Health and several industry