Physicians' Health Study I and Physicians' Health Study II (PHS I, II)
Lead Contacts and/or Principal Investigators (PIs):
- J. Michael Gaziano, M.D., M.P.H.
- Howard Sesso, Sc.D., M.P.H.
Brigham and Women’s Hospital and
Harvard Medical School
Funded Since: 1982
Funding Source: NCI Extramural Program (Division of Cancer Prevention (DCP)) and National Heart, Lung, and Blood Institute (NHLBI)
Year(s) of Enrollment: 1982-1983
Study Website: http://phs.bwh.harvard.edu/phs1.htm
In the late 1940s, Lawrence Craven, M.D., a California general practitioner, observed excessive bleeding among children who chewed aspirin gum to ease pain after a tonsillectomy. Craven assumed that aspirin somehow prevented blood from clotting and guessed that this drug might help prevent heart attacks caused by clots in coronary arteries. Over a span of ten years or so, he prescribed aspirin to several thousand patients and claimed that none had heart attacks. More rigorous studies in the 1960s and 1970s yielded conflicting results.
A team of investigators from Harvard Medical School and Brigham and Women's Hospital (a Harvard teaching hospital) initiated the PHS I as an effective way to test whether aspirin did, indeed, prevent myocardial infarction and other cardiovascular events. The investigators decided to also examine whether beta-carotene, which at the time was being touted as a wonder drug, prevented cancer. Why choose physicians as the study population? As a group, physicians would report their medical histories and health status more accurately than participants drawn from a general population. They would also be more likely to identify possible side effects of the study agents.
With funding from the National Cancer Institute (NCI) and the National Heart, Lung, and Blood Institute (NHLBI), the PHS I was launched in 1980. It was the first large, randomized trial conducted entirely by mail. It also employed another novel strategy called a 2x2 factorial design. Participants were assigned to receive one of four possible combinations: (1) active aspirin and active beta-carotene, (2) active aspirin and beta-carotene placebo, (3) aspirin placebo and active beta-carotene, (4) or aspirin placebo and beta-carotene placebo. The combination of a trial by mail and the 2x2 factorial design allowed the PHS I to be conducted at a fraction of the cost of a standard primary prevention trial.
Funded Since: 1997
Funding Source: NCI Extramural Program (DCP), NHLBI; and BASF Corporation (Florham Park, NJ) and other sources
Year(s) of Enrollment: 1997-2000
Study Website: http://phs.bwh.harvard.edu/phs2.htm
PHS I 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 American 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 of these diseases has never been adequately tested in a large randomized trial.
The PHS 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.
Beta-carotene (50 mg Lurotin or placebo on alternate days) was stopped as scheduled in March 2003. Vitamin E (400 IU synthetic alpha-tocopherol or placebo on alternate days) and vitamin C (500 mg synthetic ascorbic acid or placebo daily) treatment and follow-up continued in a blinded fashion through August 31, 2007, which was the scheduled end of the vitamin E and C components of PHS II. Results on cardiovascular disease and cancer have been published. The multivitamin component of the study remains ongoing.