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 Research.

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 Schools.

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 into perspective.

Passwater: Dr. Hennekens your research is fascinating. Thanks for bringing us up to date. Where do you think research in this area should go next?

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.