Setting trends
Most clinical trials are complex operations. The PHS has taken a different tack. It helped pioneer a new kind of epidemiologic study--the large, simple clinical trial conducted entirely by mail. Physicians were a perfect population for testing such a method because they accurately reported their medical conditions and other health information on annual follow-up questionnaires. 
Physicians have also been excellent about sticking with their assigned treatments. As a result, the Physicians’ Health Study was, and is, conducted at a fraction of the cost of most primary prevention trials. The National Institutes of Health and investigators around the world now look to the Physicians’ Health Study as a model for this kind of trial. Thanks for helping "write the book" on conducting a large, simple clinical trial.
Key findings of the Physicians' Health Study
If one of your reasons for joining the PHS was to make a difference in how physicians approach prevention, rest assured that you have succeeded. Results from this trial have been translated into clinical practice. You can’t ask for much more.
Selected highlights of the study’s findings are listed below. A complete list of nearly 200 publications from the PHS with links to Medline abstracts is available elsewhere on this site.
Aspirin and beta-carotene
Perhaps the most important finding from the PHS so far emerged from the trial’s aspirin arm. As reported in the July 20, 1989 New England Journal of Medicine, aspirin reduced the risk of first myocardial infarction by 44% (P <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 wasn’t responsible for the health benefits seen among people who ate plenty of fruits and vegetables.
Risk factors for cardiovascular disease and cancer
Another important avenue of investigation in the PHS has been the evaluation
of risk factors for cardiovascular disease and 
cancer.
These range from dietary factors such as consumption of fish or dairy
products to biomarkers such as insulin-like growth factor-I.
Alcohol consumption and mortality. Data from the PHS-I Enrollment Cohort suggest that the shape of the alcohol consumption/mortality curve is probably U-shaped, not J-shaped. Men who reported moderate alcohol intake were less likely to have died than nondrinkers or heavy drinkers. This was largely driven by reductions in cardiovascular-related mortality. Journal of the American College of Cardiology 2000; 35:96-105.
Insulin-like growth factor-1 and prostate cancer. Insulin-like growth factor-1 (IGF-1) is a mitogen for prostate epithelial cells. In a nested case-control study, men in the highest quartile of IGF-1 levels had a 4-fold increased risk of prostate cancer compared with men in the lowest quartile, independent of baseline prostate-specific antigen levels. Science 1998; 279:563-566.
Other endpoints
Although the initial focus of the Physicians’ Health Study was squarely on cardiovascular disease and cancer, data you have supplied have significantly broadened the study’s scope. PHS investigators have looked at endpoints such as cataract, T-cell mediated immunity, and renal function.
Exercise and the prevention of type 2 diabetes. Preventive measures are urgently needed to stem the rapid increase in the incidence of type 2 diabetes. Data from the PHS pointed to exercise. Study participants who exercised almost every day were half as likely to have developed type 2 diabetes than those who rarely exercised. The association was particularly pronounced among overweight men. JAMA 1992; 268:63-67.
Analgesic use and renal function. Data from the PHS may help answer a nagging clinical question: Does the use of aspirin and other nonsteroidal antiinflammatory agents increase the risk of chronic renal disease? Over 14 years of follow-up, both mean creatinine levels and creatinine clearances were similar among PHS participants who did not use analgesics and those who did, even at total cumulative intakes of 2500 or more pills. JAMA 2001; 286:315-321.
Smoking and macular degeneration. During seven years of follow-up, PHS participants who smoked a pack or more per day had a 2.5-fold higher risk of macular degeneration than never smokers; past smokers had a slightly higher risk. JAMA 1996;276:1147-1151.
New and novel risk factors
New hypotheses constantly arise about the factors that influence the onset or progression of chronic disease. Information collected over the course of the Physicians’ Health Study has been used to test a number of these.
C-reactive protein and total cholesterol. Although C-reactive protein (CRP) had been identified as a sensitive marker of inflammation, and elevated
levels had been linked with future risk of myocardial infarction, little was known about whether its measurement helped define, or refine, cardiovascular risk. In the PHS, the 5- fold relative risk of future myocardial infarction among men with high levels of both CRP and total cholesterol were greater than the product of the individual risks associated with isolated elevations of either CRP or total cholesterol. This suggested that an individual’s CRP level adds to the predictive value of lipid parameters in determining the risk of a first myocardial infarction. Circulation 1998; 97:2007-2011.
Homocysteine and heart disease. When Boston pathologist Kilmer
McCully proposed in 1968 that elevated levels of homocysteine were associated
with cardiovascular disease, his hypothesis was dismissed. Data from
the PHS helped focus more attention on homocysteine, which is now being
considered as a risk factor for cardiovascular disease. Men with the
highest 5% of serum homocysteine levels were 3.1 times more likely to
have had a myocardial infarction than those in the bottom 90%. JAMA 1992;
268:877-881.
Genetics of cholesteryl ester transfer protein. Blood samples supplied by PHS participants are providing a unique database for genetic analysis. (As with all PHS studies approved by the Institutional Review Board, participants are never identified and their information is held in the strictest confidence.) One recent genetic analysis examined mutations in the gene coding for cholesteryl ester transfer protein, such as the TaqIB polymorphism, that are associated with higher plasma HDL. Men with the B2B2 genotype had higher HDL levels than men with the B2B1 and B1B1 genotypes. However, the risk of myocardial infarction wasn’t significantly different across the genotypes. Atherosclerosis 2002; 161:469-74.
Methodology
As mentioned in Setting Trends, the Physicians’ Health Study has helped pioneer the use of the large, simple trial to efficiently answer pressing clinical questions. Dozens of publications about the study’s methodology offer "lessons learned" that investigators have applied to the design and execution of other large, simple trials. As described in a 1990 report, the study’s factorial design, its use of a prerandomization run-in phase, and the collection of blood samples before randomization were important strategies for ensuring long-term follow-up at a fraction of the usual cost of large-scale trials of primary prevention. Statistics in Medicine 1990; 9:29-33.
