Physicians' Health Study I
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) created the Physicians' Health Study 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? Several reasons. 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.
Under the direction of principal investigator Charles H. Hennekens, M.D., and with funding from the National Cancer Institute and the National Heart, Lung, and Blood Institute, the PHS was launched in 1980. It was the first large, randomized trial conducted entirely by mail. It employed another novel strategy, what's called a 2x2 factorial design. It assigned participants to get one of four possible combinations -- active aspirin and active beta-carotene, active aspirin and beta-carotene placebo, aspirin placebo and active beta-carotene, or aspirin placebo and beta-carotene placebo. The combination of a trial by mail and the 2x2 factorial design allowed the Physicians' Health Study to be conducted at a fraction of the cost of a standard primary prevention trial.
In 1981, the PHS team sent out invitation letters, consent forms, and enrollment questionnaires to all 261,248 male physicians between 40 and 84 years of age who lived in the United States and who were registered with the American Medical Association. Almost half responded to the invitation. Of the 59,285 who were willing to participate in the trial, 26,062 were told they could not because they reported a history of myocardial infarction, stroke, or transient ischemic attack; cancer (except non-melanoma skin cancer); current renal or liver disease; peptic ulcer; gout; or contraindication to or current use of either aspirin or beta-carotene.
Run-in and Randomization
The 33,223 willing and eligible physicians were enrolled in a run-in phase during which all received active aspirin and placebo beta-carotene. After 18 weeks, participants were sent a questionnaire asking about their health status, side effects, compliance, and willingness to continue in the trial. A total of 11,152 changed their minds, reported a reason for exclusion, or did not reliably take the study pills. The remaining 22,071 physicians were then randomly assigned to receive active aspirin and active beta-carotene (n=5,517), active aspirin and beta-carotene placebo (n=5,520), aspirin placebo and active beta-carotene (n=5,519), or aspirin placebo and beta-carotene placebo (n=5,515). A total of 11,037 physicians were randomized to aspirin and 11,034 to aspirin placebo; a total of 11,034 physicians were randomized to beta-carotene and 11,037 to beta-carotene placebo.
Active aspirin consisted of one 325 mg tablet (as Bufferin, supplied by Bristol-Myers Products) taken every other day. Active beta-carotene consisted of one 50 mg capsule (as Lurotin, supplied by BASF AG) taken every other day. The pills were supplied in foil-backed calendar packs.
During the four-month run-in period, participants were sent kits containing prepared Vacutainer tubes, cold packs for mailing, and prepaid shipping packs. They were asked to have their blood drawn into the Vacutainer tubes, to fractionate the blood by centrifugation, and to return the samples by overnight courier. Upon receipt in the PHS blood laboratory, samples were immediately frozen and stored in liquid nitrogen freezers. Almost 15,000 of the participants (68%) provided blood samples. After PHS-I ended, participants were asked to provide a second blood sample. More than 11,000 did.
The first follow-up questionnaires were sent at six and 12 months of treatment. After that, questionnaires were sent yearly. They included 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 trial's Data and Safety Monitoring Board stopped the aspirin arm of the PHS several years ahead of schedule because it was clear that aspirin had a significant effect on the risk of a first myocardial infarction. As reported in the July 20, 1989 New England Journal of Medicine, aspirin reduced the risk of first myocardial infarction by 44% (P less than 0.00001). There were too few strokes or deaths upon which to base sound clinical judgment regarding aspirin and stroke or mortality. Results from the beta-carotene arm were equally important. As reported in the May 2, 1996 New England Journal of Medicine, 13 years of supplementation with beta-carotene produced neither benefit nor harm. These results demonstrated that beta-carotene alone was not responsible for the health benefits seen among people who ate plenty of fruits and vegetables. More than 300 other findings have emerged from the trial so far.
The Physicians' Health Study-I was supported by four grants from the National Institutes of Health: CA-34944 and CA-40360 from the National Cancer Institute, and HL-26490 and HL-34595 from the National Heart, Lung, and Blood Institute.
PowerPoint overview of PHS
Click here for a 12-slide PowerPoint presentation that gives a brief synopsis of the methods and rationale of the PHS-I, an overview of its enrollment and randomization schemes, and baseline characteristics of the four treatment groups.