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					                                                                                             20th Anniversary

Physicians’ Health Study
                                                                                             Dear Doctor,
The PHS Turns Twenty!                                                                         This fall marks the
                                                                                              20th anniversary

                                                                                              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
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

     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
     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;
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
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.