20th Anniversary Physicians’ Health Study Dear Doctor, The PHS Turns Twenty! This fall marks the 20th anniversary O of the Physicians’ n September 20,1982, a part in the Physician’s Health Study Health Study! computer-generated random to “improve the profession I love” or As we hope number assigned a Florida to “give something back to medicine.” you know, your physician to a daily combination of Those joining PHS-II have cited similar participation in this aspirin placebo and active beta-carotene. reasons. That brief event signaled the official Such responses are gratifying, and landmark study has start of the Physicians’ Health Study. important. If we want clear answers helped change the way This randomized trial (PHS-I), under to critical questions about how best to American physicians the direction of Charles H. Hennekens, prevent cardiovascular disease, cancer, and the public approach M.D., definitively evaluated the role and other chronic conditions, we need the prevention of of aspirin and beta-carotene in the people who are willing and committed cardiovascular disease, primary prevention of cardiovascular to join clinical trials. Having so many cancer, and a host of disease and cancer. A new trial (PHS- physicians answer the call sends a other chronic conditions. II), under the direction of J. Michael powerful message—that taking part Numerous results from the original study Gaziano, M.D., is now doing the same in such trials is the right thing to do. continue to appear in the New England for beta-carotene, vitamin E, vitamin C, It also sets a wonderful example for Journal of Medicine, JAMA, and other and a multivitamin. And thanks to your patients. leading medical journals. A new trial now ongoing commitment and support, the underway promises to have a similar Physicians’ Health Study has evolved Solid findings impact. into one of the largest and longest- When it comes to results, every trial running observational cohort studies in should be as blessed as the Physicians’ None of this would have been America. Health Study. The main findings on possible without your efforts. To thank The initial letter inviting physicians aspirin and beta-carotene have clearly you for your participation in and to join a randomized trial of aspirin and influenced both medical practice and commitment to the Physicians’ Health beta-carotene struck a nerve. Almost the direction of future research (see Key Study, we have enclosed a small token half of the 260,000 U.S. physicians who Findings). of appreciation. We hope you wear your received the invitation responded to The annual questionnaires you fill PHS tie with pride. it. A number of physicians who were out and the blood samples submitted This 20th anniversary newsletter older than the initial age limit argued by almost two thirds of the participants offers a snapshot of the study: a little so persuasively that the study shouldn’t are a treasure trove of information that history, some of the study’s achievements, be limited to younger men that the is advancing medical knowledge far where the PHS stands today, and what upper age limit was raised. Not only did beyond the focus of the randomized lies ahead, sprinkled with interesting facts physicians want to take part in the trial, trial. Data from these valuable resources about the participants and the study. but they stuck with it. The rates of pill are providing insights into associations We hope you enjoy the newsletter, taking and questionnaire return—both between lifestyle factors such as of which are crucial for the validity of alcohol use or physical activity and and we thank you for your participation in all trials—have been excellent. cardiovascular disease; into novel risk the Physicians’ Health Study. Why this interest and commitment? Physicians said they wanted to take continued on page 3 ▼ PHS Timeline 1978-80 1980 1981 1982 1984 1988 1995 1997 1997 2001 2007 Initial NIH funding First First Last Aspirin arm Beta- PHS-II First PHS-II Last PHS-II Expected planning invitation physician physician stopped carotene begun physician physician end of letters randomized randomized early arm ended randomized randomized PHS-II Key Findings of the PHS I f one of your reasons for joining produced neither benefit nor harm. Other endpoints the PHS was to make a difference These results demonstrated that beta- Although the in how physicians approach carotene alone wasn’t responsible for initial focus of the prevention, rest assured that you have the health benefits seen among people Physicians’ Health Address changes succeeded. Results from this trial have who ate plenty of fruits and vegetables. each year: 4,000 Study was squarely been translated into clinical practice. on cardiovascular You can’t ask for much more. Risk factors for cardiovascular disease and cancer, data you have supplied Selected highlights of the study’s disease and cancer have significantly broadened the study’s findings are listed below. A complete Another important avenue of scope. PHS investigators have looked at list of nearly 200 publications from the investigation in the PHS has been endpoints such as cataract, T-cell mediated PHS with links to Medline abstracts the evaluation of risk factors for immunity, and renal function. is available on the Physicians’ Health cardiovascular disease and cancer. These Exercise and the prevention of Study Web site (http://phs.bwh.harvard. range from dietary factors such as type 2 diabetes. Preventive measures edu). consumption of fish or dairy products are urgently needed to stem the rapid to biomarkers such as insulin-like increase in the incidence of type 2 Aspirin and Beta-carotene growth factor-1. diabetes. Data from the PHS pointed Perhaps the most important finding Alcohol consumption and to exercise. Study participants who from the PHS so mortality. Data from the PHS-I exercised almost every day were half as far emerged from Enrollment Cohort suggest that the likely to have developed type 2 diabetes the trial’s aspirin shape of the alcohol consumption/ than those who rarely exercised. The arm. As reported mortality curve is probably U-shaped, association was particularly pronounced in the July not J-shaped—men who reported among overweight men. JAMA 1992; 20, 1989 New moderate alcohol intake were less likely 268:63-67. England Journal to have died than nondrinkers or heavy Analgesic use and renal function. of Medicine, drinkers. This was largely driven by Data from the PHS may help answer a If laid end to end, aspirin reduced reductions in cardiovascular-related nagging clinical question: Does the use the forms completed the risk of first mortality. Journal of the American of aspirin and other nonsteroidal anti- by PHS participants myocardial College of Cardiology 2000; 35:96-105. inflammatory agents increase the risk of so far would stretch infarction Insulin-like growth factor-1 and chronic renal disease? Over 14 years of from Boston to New by 44% prostate cancer. Insulin-like growth follow-up, both mean creatinine levels York. (P <0.00001). factor-1 (IGF-1) is a and creatinine clearances were similar Pills sent: There were too mitogen for prostate 223,000,000 among PHS participants who did not few strokes or deaths upon which to epithelial cells. In a use analgesics and those who did, even base sound clinical judgment regarding nested case-control at total cumulative intakes of 2500 or aspirin and stroke or mortality. study, men in the highest more pills. JAMA 2001; 286:315-321. Results from the beta-carotene quartile of IGF-1 levels had a Smoking and macular arm were equally important. As 4-fold increased risk of prostate cancer degeneration. During seven years reported in the May 2, 1996 New compared with men in the lowest quartile, of follow-up, PHS participants who England Journal of Medicine, 13 years independent of baseline prostate-specific smoked a pack or more per day had of supplementation with beta-carotene antigen levels. Science 1998; 279:451-566. a 2.5-fold higher risk of macular Physicians’ Far-Flung Participants Health Study Rotorua, New Zealand Staff Moshi, Tanzania Choma, Zambia have had a myocardial infarction than those in the bottom 90%. JAMA 1992; 268:877-881 degeneration than never smokers; past Genetics of cholesteryl ester smokers had a slightly higher risk. transfer protein. Blood samples supplied JAMA 1996;276:1147-1151. by PHS participants are providing a unique database for genetic analysis. New and novel risk factors (As with all PHS studies approved New hypotheses constantly arise about by the Institutional Review Board, the factors that influence the onset participants are never identified and or progression of chronic disease. their information is held in the strictest Information collected over the course of confidence.) One recent genetic analysis the Physicians’ Health Study has been examined mutations in the gene coding used to test a number of these. for cholesteryl ester transfer protein, C-reactive protein and total such as the TaqIB polymorphism, cholesterol. Although C-reactive protein that are associated with higher plasma 20 YeARS—continued from page 1 (CRP) had been identified as a sensitive HDL. Although the marker of inflammation, and elevated B2B2 genotype was factors for cardiovascular disease and levels had been linked with future risk associated with higher Person-years cancer, particularly prostate cancer; and of follow-up: of myocardial infarction, little was HDL levels than into genetic markers for a range of 433,584 known about whether its measurement levels in men with chronic diseases. helped define, or refine, cardiovascular the B2B1 and B1B1 risk. In the PHS, the 5-fold relative risk genotypes, the risk of a myocardial Setting trends of future myocardial infarction among infarction wasn’t significantly different Most clinical trials are complex men with high levels of both CRP and across the genotypes. Atherosclerosis operations. The PHS has taken a total cholesterol were greater than the 2002; 161:469-74 different tack. It helped pioneer a new product of the individual risks associated kind of epidemiologic study—the with isolated elevations of either CRP Methodology large, simple clinical trial conducted or total cholesterol. This suggested that As mentioned in Setting Trends (to the entirely by mail. Physicians were a an individual’s CRP level adds to the right), the Physicians’ Health Study has perfect population for testing such predictive value of lipid parameters in helped pioneer the use of the large, simple a method by accurately reporting determining the risk of a first myocardial trial to efficiently answer pressing clinical medical conditions and other health infarction. Circulation 1998; 97:2007- questions. Dozens of publications about information on annual follow-up 2011. the study’s methodology offer “lessons questionnaires. Physicians have also Homocysteine and heart learned” that investigators have applied been excellent about sticking with disease. When Boston pathologist to the design and execution of other large, their assigned treatments. As a result, Kilmer McCully proposed in 1968 simple trials. the Physicians’ Health Study was, and that elevated levels of homocysteine As described in a 1990 report, the is, conducted at a fraction of the cost were associated with cardiovascular study’s factorial design, its use of a of most primary prevention trials. disease, his hypothesis was dismissed. pre-randomization run-in phase, and The National Institutes of Health Data from the PHS helped focus more the collection of blood samples before and investigators around the world attention on homocysteine, which is randomization were important strategies now look to the Physicians’ Health now being considered as a risk factor for ensuring long-term follow-up at a Study as a model for this kind of trial. for cardiovascular disease. Men with fraction of the usual cost of large-scale Thanks for helping “write the book” the highest 5% of serum homocysteine trials of primary prevention. Statistics in on conducting a large, simple clinical levels were 3.1 times more likely to Medicine 1990; 9:29-33. trial.