Dr. Charles Hennekens
Interviewed by Richard A. Passwater, Ph.D.
Ambulatory Care and Prevention at Harvard Medical School, and Chief of
the Division of Preventive Medicine at Brigham and Women's Hospital. Dr.
Hennekens received his MD from Cornell University Medical College in New
York City, where he also trained in internal medicine at the New York Hospital.
He served for two years in the U. S. Public Health Service as an Epidemic
Intelligence Service (EIS) officer with the Center for Disease Control assigned
to the Dade County Health Department in Miami, Florida, and then received
an MPH, MS and DrPH in Epidemiology from the Harvard School of Public Health.
Dr. Hennekens is a diplomate of the National Board of Medical Examiners
and the American Board of Preventive Medicine, a Fellow of the American
College of Preventive Medicine (FACPM) and the American College of Epidemiology
(FACE), and is the immediate past president of the Society for Epidemiologic
Dr. Hennekens serves as editor-in-Chief of the American Journal of Preventive
Medicine, and Co-Editor-in-Chief of the Annals of Epidemiology.
He has been a member of the Editorial Board of Circulation, and the
Board of Overseers of the American Journal of Epidemiology. The breadth
and depth of Dr. Hennekens' contributions to public health are reflected
in part by the number and nature of his publications. He has over 320 publications,
including over 274 original papers, 44 reviews and two textbooks. His textbook,
Epidemiology in Medicine is in wide use in Medical and Public Health
During his career, Dr. Hennekens has elucidated much of what we know about
causal and preventive risk factors for cardiovascular disease. He had the
foresight to design and implement several epidemiologic studies over the
last 20 years that have provided a great deal of knowledge about medical,
behavioral, lifestyle and biochemical risk factors for the leading killer
in the U.S. and most developed countries.
In the previous column, Dr. Charles Hennekens shared with us the data his
group has gleaned from their epidemiological studies with respect to antioxidants
and heart disease. In this column, Dr. Hennekens will help us put the data
Passwater: Dr. Hennekens your research is fascinating. Thanks for
bringing us up to date. Where do you think research in this area should
Hennekens: As regards future avenues of research, I believe several
need to be pursued. First, basic research is needed to further define the
mechanisms of oxidation and the extent to which this occurs in vivo .
Better markers of oxidative stress may prove useful in identifying subjects
at increased risk who may benefit from antioxidants. Second, animal models
of increased oxidative stress may be helpful in determining if oxidative
damage can accelerate atherosclerosis and the degree to which this process
can be delayed or prevented by natural of synthetic antioxidants. Third,
the effects of antioxidants on vascular tone and thrombosis need further
investigation. Additional descriptive and observational study findings may
provide further support for a possible beneficial effect of dietary antioxidant
vitamins. However, the only way to determine reliably their possible role
is by randomized controlled trials in both primary and secondary prevention
of cardiovascular disease.
Over the next several years, data from trials of primary
prevention as well as treatment are necessary to fill a crucial and large
gap in existing knowledge about whether antioxidant vitamins do in fact
decrease risks of cardiovascular disease. Each will contribute importantly
relevant, reliable and complementary information to a totality of evidence
which will be crucial for both clinical decision-making as well as rational
public health policy.
From the standpoint of our research group specifically, we will be continuing
to evaluate these questions from a number of different directions. The Physicians'
Health Study will provide definitive data on the role of beta-carotene in
the primary prevention of cardiovascular disease in men. In addition,
our recently begun Women's Health Study is enrolling over 40,000 female
health professionals in a trial of low-dose aspirin (100 mg every other
day), beta-carotene (50 mg every other day), and vitamin E (600 IU of natural
source vitamin E, every other day). This trial will evaluate the risks and
benefits of beta-carotene and vitamin E on cardiovascular disease and cancer
in apparently healthy women. Finally, we have just been funded to conduct
the Women's Antioxidant - Cardiovascular Disease Study (WACS) which will
begin within the next few months and will evaluate the roles of beta-carotene,
vitamin E and vitamin C in secondary prevention among those women not eligible
to participate in the Women's Health Study due to prior cardiovascular disease.
Taken together, over the next several years, these trials will provide reliable
data concerning the role of antioxidant vitamins in the treatment and prevention
of cardiovascular disease.
Passwater: Looking at the totality of evidence in January 1994, what
recommendations do you think can be made to the U.S. public at this time
regarding antioxidant vitamins and cardiovascular disease?
Hennekens: At this time, I believe that any health claims or public
health recommendations concerning antioxidants in the prevention of cardiovascular
disease would be premature. Right now, what we have clearly shown in that
people who consume a high dietary intake of fruits and vegetables
rich in antioxidants have lower risks of cardiovascular disease (and cancer)
than people who do not - whether it is the antioxidants themselves, and
if so, which antioxidant and at what dose, is not yet clear. The currently
available data certainly raise the possibility that antioxidant vitamins
may decrease risks of cardiovascular disease, and basic research findings
have suggested possible mechanisms for a beneficial effect. At present,
however, I believe the message is not yet for the general public or even
for health care providers, but to researchers: namely, that antioxidant
vitamins represent a promising, but as yet unproven, means to reduce risks
of cardiovascular disease, which should be tested in large-scale randomized
trials of primary and secondary prevention. A number of these trials are
currently ongoing - in fact, the findings from the Finnish trial of beta-carotene
and vitamin E in male smokers will be released within the next few months.
We must await these randomized trial data to answer the question definitively.
Passwater: In the meanwhile, however, why shouldn't people just take
these antioxidant vitamins - after all, they appear to have few if any side-effects
and even if the evidence at this point is only that they might prevent
coronary heart disease, then why not take them?
Hennekens: My chief concern is analogous to that first raised by
our aspirin findings: that is, that a middle-age man who is a cigarette
smoker, overweight, has elevated cholesterol and a sedentary lifestyle might
take antioxidant vitamins rather than change his unhealthy lifestyle. In
the U.S. in 1994, most people prefer prescription of agents to reduce risks
of disease rather than proscription of harmful lifestyle practices. However,
even if antioxidant vitamins turn out to be as beneficial as we hope, the
risk reduction they confer will certainly not be as great as that which
can already be achieved from lifestyle changes on risk factors known to
be causal. For example, if that man were to stop cigarette smoking today,
his risk of coronary heart disease would begin to fall within a matter of
months and within two years his risk would have fallen to that of a never
smoker. And this is on top of the fact that smoking is not only a major
risk factor for cardiovascular disease, but is in fact the number one avoidable
cause of death in the U.S. today. Thus, if antioxidants are shown in randomized
trials to reduce cardiovascular disease risk, their use should always be
as an adjunct, not an alternative, to control or elimination of the known
modifiable coronary risk factors.
Another concern, though, relates to the fact that while I certainly do not
feel that access to these vitamins or supplements should be limited, I agree
strongly with Dr. David Kessler, the Commissioner of FDA, that a health
claim should not be made for any agent without solid scientific evidence
to back it up. Right now, vitamins are a billion dollar industry. In the
Nurses' Health Study, we found that even a decade ago 35% of middle-aged
nurses were taking multivitamin supplements, about 5-10% in the northeast,
over 50% on the west coast. During the last decade, even after adjusting
for inflation, there has been a several-fold increase in dollar sales of
vitamin supplements. Since the excess is largely excreted by the kidneys,
what we know for certain in 1994 is that the U.S. excretes the richest urine
in the world. What we don't yet know is whether there are health benefits
attributable to this already widespread practice. What we fear is that this
practice will continue even in the absence of controlled data from large-scale
randomized trials in humans. If in fact antioxidant vitamins are shown to
reduce risk of cardiovascular disease, then I would argue that too few people
are currently taking them - but if they are not, then too many people are
taking them, most likely in lieu of lifestyle changes that we know would
make a difference.
Finally, although it is commonly said that these vitamins have few, if any
side effects, we in fact have virtually no experience with long term consumption
at high doses. For healthy people taking these agents to reduce risk of
diseases that may or may not occur in their future, it is critical to clearly
demonstrate any risks that may exist, so that the benefits and risks can
be weighed for any individual. For example, vitamin E does have an antiplatelet
effect, similar to that of aspirin, and only a large scale trial at sufficient
dose and duration of treatment could detect any possible serious adverse
effects, such as cerebral hemorrhage. Only such a trial could tell us definitely
if the observational studies were correct, or whether they possibly overestimated
the benefits and underestimated the risks.
Passwater: You have mentioned a number of risk factors for coronary
heart disease that have been elucidated through your and others' work -
could you put antioxidants in the context of what you know currently about
how to prevent risk of a heart attack?
Hennekens: Over the past 25 years there has been a dramatic decline
in mortality from cardiovascular disease of about 2% per year, in men and
women, blacks and whites. Despite these improvements, however, coronary
heart disease remains the leading cause of death in this country as well
as in most of the developed world.
There are clear gender differences in death rates. Indeed, at every age,
women experience lower mortality rates than men, even among the oldest old.
My colleague Richard Doll has informed me that, based on a small sample
in the U.K., mortality rates in men and women do become equal, but only
by age 105, where the death rate is about 50% per year, regardless of gender.
While coronary heart disease is the leading cause of death in men by age
40, it only becomes so in women by age 60. According to data from the Framingham
Heart Study, by the age of 60, 1 out of every 5 men will have suffered a
significant coronary event, but only 1 out of 17 women. In fact, between
the ages of 40 and 59, lung cancer is the leading cause of death in women,
recently surpassing breast cancer.
Nonetheless, despite the sex difference in age-specific coronary mortality
rates, coronary heart disease is still responsible for 1 in 3 deaths in
U.S. women as well as men. Thus, despite the enormous advances in the reduction
of coronary heart disease mortality, this remains, far and away, the leading
cause of death in middle-aged men and older women.
Most primary prevention efforts have concentrated on the major modifiable
and well-established determinants of cardiovascular risk (Table 1). These
include the "big 3": cigarette smoking, elevated cholesterol,
and hypertension. In addition, obesity, lack of exercise, and inadequate
glycemic control from diabetes also contribute to increased coronary heart
disease risk. In the last decade, reliable data have emerged on a number
of newer agents which might decrease risk of myocardial infarction, including
postmenopausal hormone use and consumption of small to moderate amounts
of alcohol. Finally, the possible roles of low-dose aspirin as well as antioxidant
vitamins have generated a tremendous amount of research activity and interest
over the last decade.
At this time, low-dose aspirin has been demonstrated in randomized trials
to reduce risk of a first myocardial infarction in men, but the effects
on stroke and cardiovascular death have not yet been definitively evaluated.
The Women's Health Study will provide information on the risks and benefits
of low-dose aspirin in healthy women.
Although available data suggest that major benefits in public health can
be achieved by adopting these modifications of behavior and lifestyle, the
efficacy of current strategies to modify risk-factor status has been less
encouraging. Further research about the overall risk-benefit ratios of these
interventions and the development of effective strategies to help implement
risk-factor modifications are needed.
PRIMARY PREVENTION OF MYOCARDIAL INFARCTION