Heart Disease What is heart disease? Heart disease mortality data and critique, USA. Heart disease mortality graph, USA: medical vs health perspective. First randomized trial, HERS, shows no benefit. Hormones and Heart Disease: Medical Bias Disregards Best Evidence What is heart disease? You can just skim this part if you wish. A brief summary at the end may be all the information you want. Some people, however, like more detail. Heart disease, as the name implies, includes all diseases associated with the heart, including congenital heart disease, a defect present at birth. Most of the research, however, on the medically constructed menopause-heart disease link has been on a particular type of heart disease, ischemic heart disease (IHD). The word "ischemia" means lack of blood to an organ, in this case, the heart. Ischemia most often results from atherosclerosis and/or blood clotting. Atherosclerosis refers to a narrowing of the coronary arteries with plaque (deposits of cholesterol mixed with other substances). Blood clotting often occurs when a piece of plaque breaks off the inner lining of the artery, which then bleeds, and the blood clots. An angina episode or a heart attack is a manifestation of ischemic heart disease. Angina simply means a person has insufficient blood supply to the heart for a very short period of time, most often on exertion. (Sometimes angina occurs because of a spasm of the coronary artery rather than a narrowing) If all or almost all blood is blocked to the heart, a person has a heart attack, medically referred to as a myocardial infarction (MI). This may cause damage to the heart; if the damage is extensive, it can result in death. Coronary artery disease (CAD) refers to the condition of the arteries. A person who has atherosclerosis (arteries partially blocked with plaque) or arteriosclerosis (arteries that are less elastic and harder than healthy arteries) is said to have CAD. Some people may have 50% or more of their coronary arteries blocked yet have no symptoms. If they do have symptoms such as angina or a heart attack, they are said to have ischemic heart disease (IHD). IHD and coronary heart disease (CHD) are used interchangably. Summary: Ischemic heart disease (IHD) and coronary heart disease (CHD) are the same. They refer to insufficient blood to the heart muscle which can result in an angina episode or a heart attack. These are most often caused by a combination of blocked arteries and blood clotting. Heart disease mortality data and a critique Below is a chart with heart disease mortality rates for both women and men along with the sex ratios according to age for the United States. Deaths are per 100,000 from ischemic heart disease (ICD-9 410-414). Source: National Center for Health Statistics, Vital Statistics of the United States, 1992, Vol II, Mortality, part A. Washington: Public Health Service, 1996. Age Range Male Female Ratio M/F 40-44 40.3 10.3 3.9 45-49 84.9 21.0 4.0 50-54 153.4 45.0 3.4 55-59 264.9 91.2 2.9 60-64 427.5 161.7 2.6 65-69 673.0 284.3 2.4 70-74 1039.3 506.0 2.1 75-79 1602.8 871.2 1.8 80-84 2589.2 1637.9 1.6 >85 4878.2 4056.4 1.2 Many people think they can't understand this type of medical data. If you are one of them, I'll prove you wrong. Just pay attention to the ratio column. In this column, the rate of heart disease in men is compared with that in women. One can see that the ratio of men's death rates to women's peaks in the 45-49 age range. At that age, it is 4.0 and then begins to decline. This means that men die of heart disease at a rate 4 times greater than women. At age 50-54 it is 3.4 (almost 3 1/2 times greater) and at age 55-59, it is 2.9 (almost 3 times greater). Even at the greatest age for which we have data, 85 and older, the death rate for men still exceeds that for women by 20%. Menopause is not linked to an increased risk of heart disease. Yet, proponents of the medically constructed menopause-heart disease link typically begin articles with statements such as these: In premenopausal women, heart disease is rare. The risk of dying from heart disease increases greatly for postmenopausal women. After menopause, the death rate for women begins to catch up with that for men. While these statements are true, they are, in fact, very misleading. As you yourself can see in the rate column for women, we do have higher rates of death from heart disease after menopause than before. There is no acceleration of risk, however, around or after menopause. But by defining women by their hormonal status, the reader might reasonably assume that menopause has something to do with the increase in heart disease risk. Why else would these statements be made? As a way of illustrating the effect of using the "post-menopausal" modifier, supposing I said that the leading cause of death in left-handed people was heart disease. This is perfectly true, and it would be reasonable for you to assume that left-handedness had something to do with the increased risk. Otherwise, why would I say it? In actuality, heart disease is the leading cause of death among all groups who live in Western countries, whether we're women or men, left-handed or right. The risk of heart disease increases with age: younger people are at much lower risk than older people. Again, menopause is not a marker for an increased risk of heart disease. The death rate for men exceeds that for women in  all age groups studied. Medical perspective vs a health perspective: CHD mortality statistics, US, 1992. Note: y axis is log(deaths per 100,000)

Medical perspective	Health perspective
In premenopausal women, heart disease is rare. This is because they are protected by high levels of estrogen.	Younger women have significantly lower risk of heart disease than younger men. There is no evidence that this is due to high levels of estrogen.
The risk of dying from heart disease increases greatly for postmenopausal women.	Heart disease for both women and men increases with age. At midlife, the rate of increase slows for both; the slowdown is greater for men.
The increased risk for postmenopausal women has resulted in a decrease in the gap between women and men.	The decreased gap after midlife is due to the greater slowdown for men than for women.
The primary heart disease prevention strategy for low risk men should be lifestyle change; for women it should be exogenous estrogen.	The primary heart disease prevention strategy for both low risk women and men should be lifestyle change.

First randomized trial, HERS, shows no benefit

This article below was published in the Network News (Nov/Dec 1998), a publication from the National Women's Health Network. (With permission)

The women in the HERS trial had established heart disease. This is the group of women who had been expected to derive the greatest benefit from hormone use after menopause.

Hormones and Heart Disease: Latest evidence shows no benefit

by Vicki Meyer

The results of the long awaited, first ever, large scale randomized clinical trial on postmenopausal hormones and heart disease are in. This trial, the Heart and Estrogen/progestin Replacement Study (HERS) compared women who took Prempro, the combined estrogen-progestin pill, with women who took a look-alike placebo. 1

In the first year of the study, women who took Prempro actually had a greater number of heart attacks and more deaths from heart disease than women who took the placebo. At the end of the study, 4.1 years later, there was no overall difference in either heart attacks or deaths between these two groups. The hormone users, however, had three times more venous thromboembolic events (blood clots and pulmonary emboli) than non users, and had more gallbladder disease.

This study stands in sharp contrast to more than thirty observational studies showing a beneficial effect of estrogen for heart disease. 2 Based on the analyses of these studies, it was estimated that women who take hormones would have about one-half the rate of heart disease and live 1-3 years longer than women who do not. 3

How are women to interpret these findings? Are the results from the HERS trial just a fluke? Shouldn't the more than thirty studies showing beneficial effects for hormone use outweigh one study that doesn't? How can the different findings be explained? In order to answer these questions, it's important to understand how observational studies differ from randomized clinical trials.

Observational studies simply means that researchers observe differences between existing groups. In the observational studies on hormones and heart disease, researchers simply observed that groups of hormone users had less heart disease than groups of non users. These types of studies cannot show, however, that hormone use caused a reduction in heart disease. This difference may seem trivial but it is not. The better health found in hormone users may be simply due to the reasons why women took hormones in the first place. You may be surprised to know that up until about 1990, with few exceptions, physicians were advised not to prescribe hormones for women at risk for heart disease or breast cancer, nor for women with poor general health. 4,5 Moreover, women who chose to take hormones because of the purported health benefits were more likely to engage in other behaviors to improve their health, like eating low fat foods, taking vitamins, and exercising. 6 Now, if physicians were more likely to prescribe hormones to women with little risk of heart disease and who were in good general health, and women who took hormones were more likely to act in ways to improve their health, it is not surprising that women who took hormones had a reduced risk of heart disease and a longer life than women who did not. It certainly cannot be concluded that hormone use caused women's better health. The only way to find out if hormone use is beneficial or harmful is by a large scale randomized clinical trial such as the HERS trial.

In the HERS trial, neither the physicians nor the women themselves decided who would take Prempro and who would take a placebo. The decision was made randomly by a computer. After random assignment, the two groups were analyzed to ensure that there were no differences between them before the study began. Therefore, at the end of the study, if hormone use actually caused a reduction in heart disease, women assigned to the hormone group would have less heart disease. As noted above, there was no difference in heart disease nor in death rates between the groups.

It is the random assignment of women to hormone use or placebo that makes HERS so powerful. Before publication of HERS, researchers had cautioned that the beneficial effects found in observational studies may simply be because physicians have discouraged women at risk for heart disease from taking hormones. Wulf Utian, the co-founder of the North American Menopause Society has stated, 7 "we are now doing the exact opposite." He goes so far as to suggest that since women with a high risk of heart disease are now being advised to take hormones, we may begin seeing a "...huge increase in heart disease among women on estrogen replacement therapy."

Women have not been made aware of this. They have been led to believe that it is a scientific fact that estrogen causes a reduction in heart disease and have been urged to take hormones to reduce their risk. How are women to make informed decisions when the facts are kept from them?

Now that the results of HERS are in, will midlife and older women no longer be urged to take hormones to reduce their risk of heart disease? This is very unlikely. The belief that midlife and older women benefit from additional estrogen is, by now, so embedded in the medical community, it will be hard for that community to accept a finding contrary to this belief.

A related example of this resistance to change is provided by the belief, beginning in the 1940's, that giving pregnant women additional estrogen was beneficial. It was thought that diethylstilbestrol (DES), a synthetic estrogen, reduced the risk of miscarriage, and it became widely prescribed. In the early 1950s, a large scale randomized clinical trial was published showing no beneficial effect of DES on pregnancy outcomes. 8 Yet physicians continued to prescribe it until 1971 when published studies reported that DES caused a rare vaginal cancer in the daughters of women who took this drug during their pregnancies. In this instance there was a lag of 18 years between the discovery of "no benefit" and the cessation of prescription of DES. 9 Moreover, it was not the discovery of "no benefit" that stopped the use of DES but the adverse effects.

In fact, although the authors of the HERS report state that women with heart disease should not be advised to begin taking hormones, they recommend that women already taking hormones should continue taking them. An accompanying editorial agrees, 10 and calls for more randomized clinical trials on hormones and heart disease.

But more trials on hormones cannot answer the questions women want answered most; that is, how can we best maintain our health, reduce our risk of disease, and improve our overall quality of life? It is well-known that many factors influence health. Men are generally told that genetic or lifestyle factors put them at risk, but we are told that our "failed ovaries" put us at risk.

What needs to change before real progress can be made in medical research is that menopause be accepted as a normal physiological process rather than a deficiency condition. Only then would hormone use no longer be emphasized to reduce disease, but rather a wide variety of strategies would be promoted, as is done for men. Women need to understand the medical studies that affect them and be aware of the biases in medical research so that they are better able to make health decision compatible with their own interests and beliefs.

References

1. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Hulley S, Grady D, Bush T, et. al. JAMA 1998; 280: 605-613.

2. Stampfer M, Colditz G. Estrogen replacement therapy and coronary heart disease: A quantitative assessment of the epidemiologic evidene. Prev Med 1991; 20: 47-63

3. Col NF, Eckman MH, Karas RH, Pauker SG, Goldberg RJ, Ross EM, Orr RK, Wong JB. Patient-specific decisions about hormone replacement therapy in postmenopausal women. JAMA 1997; 277: 1140-1147.

4. Notelovitz M. Estrogen replacement therapy: Indications, contraindications, and agent selection. Am J Obstet Gynecol 1989; 161: 1832-1841.

5. Hemminki E, Sihvo S. A review of postmenopausal hormone therapy recommendations: Potential for selection bias. Obstet Gynecol 1993; 82: 1021-1028.

6. Matthews KA, Kuller LH, Wing RR, Neilahn EN, Plantinga P. Prior to use of estrogen replacment therapy,: are users healthier than nonusers. Am J Epidemio 1996; 143: 971-82.

7. Skolnick A. At third meeting, menopause experts make the most of insufficient data. JAMA 1992; 268: 2483-2485.

8. Ferguson, JH Effects of stilbestrol on pregnancy compared to placebo. Am J Obstet Gynecol 1953; 65: 592-601

9. Herbst AL, Ulfelder J, Poskanzer, DC. Adenocarcinoma of the vagina: Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 1971; 284: 878-881.

10. Petitti, DB. Hormone replacement therapy and heart disease prevention: Experimentation trumps observation. JAMA 1998; 280: 650-652.




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In the recent past, it had become almost dogma that estrogen use after menopause decreases a woman's risk of heart disease. Both healthy women and women with heart disease were urged to take long term hormones to reduce their risk. The final results of two high quality studies and the preliminary results from a third, however, provide the best available evidence to date that exogenous hormones do not reduce a woman's risk of heart disease.

The first such study was the Heart and Estrogen/progestin Replacement Study (HERS) published in 1998 (1). This was the first large-scale randomized clinical trial comparing women who took hormones with women who took a look-alike placebo. The women in this study had established heart disease, the very group who were expected to benefit the most (2). At the trial's end, however, women who took hormones did not have lower rates of additional heart attacks and deaths than the women who took placebos (3).

Responses from the medical and health community to HERS were mixed. Some researchers stated that hormones should no longer be advocated for heart disease prevention (4). The American Heart Association and the American College of Cardiology felt the results sufficiently compelling that they issued a new joint position statement (5). They are now advising the use of a statin, a group of cholesterol lowering drugs, rather than hormones as they did previously, for high risk women with abnormal lipid levels. In randomized clinical trials, statins have been shown to save women's lives (6). As stated above, exogenous hormones have not.

The majority of clinicians, however, continued to promote the use of hormones to reduce risk in healthy women (7). They argued that since the HERS trial only provided information on women with established heart disease, there is no reason not to urge women without heart disease to take hormones to reduce their risk.

Finally, there are those who discount the HERS trial altogether and encourage women both with and without heart disease to take hormones to reduce their risk. Unfortunately, this is the position given in a 1999 textbook for medical students studying to be gynecologists (8).

The results of the second major randomized clinical trial on hormones and heart disease, the Estrogen Replacement and Atherosclerosis (ERA) trial, were released in March 2000 (9). This study measured changes in the degree of atherosclerosis. At the trial's end, the women who took hormones had the same amount of atherosclerosis as the women who took placebos. Sponsored by the National Institutes of Health, this trial included only women who already had heart disease, as did the HERS trial. The results confirmed HERS: exogenous hormones do not benefit women with established heart disease.

Again, some argue that these studies may not be relevant for healthy women without heart disease. Dr. Sidney Smith, a spokesperson for the American Heart Association, noted that neither trial could show whether hormone use would reduce the risk in women before they developed heart disease (9). That answer should come from the Hormone Replacement Therapy trial of the Women's Health Initiative. This is the very first large-scale randomized trial on women without heart disease to determine whether hormone use would reduce their risk. Although the final results of this federally sponsored study are not expected until 2005, the preliminary results were released on April 4th, 2000 (10).

Surprisingly, these preliminary results showed that women who took hormones experienced a small but significant increased risk of heart disease. Dr. Jacques Rossouw, the acting director of the trial, felt morally obliged to send letters to the women in the study to inform them of this. Before agreeing to be a participant, women were warned of the many known risks of hormone use. An increased risk of heart disease, however, was not one of them. Rossouw cogently stated, "Doctors who have prescribed [hormones] do so without evidence to back up their bias that it will help." (11)

This bias continues. Some medical professionals are saying that these latest findings should not change the current clinical practice of urging women to take hormones, suggesting a "wait and see" attitude. The New York Times of April 6, 2000, quotes Dr. Wulf Utian, a Cleveland ob/gyn and director of the North American Menopause Society, as saying the new findings "don't change my stance at all" (12). Cardiologist Elizabeth Ross of the American Heart Association, while agreeing that hormones may not help all women, maintains that exogenous hormones might help a subgroup of women to reduce their risk and advocates more research to learn just who belongs in that subgroup (13). Others are suggesting that the trials should be longer or that different combinations of hormones should be studied to see if they could reduce heart disease (14). Still others suggest that perhaps one of the new SERMs, such as Nolvadex or Evista, might be beneficial for women's hearts (15). These new drugs act as an estrogen in some of our body parts and as an anti-estrogen in others.

Given the fact that the best available scientific evidence to date shows that exogenous hormones do not protect women from heart disease, why do so many medical professionals continue to insist on finding a hormonal prevention strategy? Although men have a higher rate of heart disease than women well into old age, they are discouraged from taking any drugs unless they are at high risk, and only after a lifestyle strategy is tried. How can we make sense of this different and unequal approach to heart disease prevention? What might be the origin of the bias to which Rossouw refers?

A brief historical sketch of medical approaches to women's health concerns sheds light on the origins of these biases. There is a long legacy of attributing ill health and even characteristics considered undesirable for women to our reproductive organs and hormones. The term “hysterical” comes from the erroneous belief that behaviors considered inappropriate for women were somehow due to the uterus, and many women in the 19th century had unnecessary hysterectomies. Other medical professionals felt that the ovaries were the source of ill health in women and advocated their removal (16).

Today, it is the lower amount of ovarian hormones, universal for women after menopause, that is the stipulated cause for any current or future ill health women might experience. This hypothesis makes it appear reasonable to urge healthy women to take hormones (which, of course, are drugs) with many documented adverse effects, including increased breast cancer (17), in the hope that it will reduce the risk of heart disease, even though randomized clinical trials show no benefit. It would be unthinkable to urge healthy men to take any drug with such adverse effects without proof of benefit.

Women need to be aware of the debate surrounding hormones and heart disease so that the health decisions they make for themselves are truly informed.

1. Hulley S, Grady D, Bush T, et. al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-613.

2. Wenger NK. Postmenopausal hormone therapy. Is it useful for coronary prevention? Cardiol Clin. 1998; 16: 17-25. Sullivan JM, Vander Zwaag R, Hughes JP, et al. Estrogen replacement and coronary artery disease - effect of survival in postmenopausal women. Arch Intern Med 1990; 150; 2557-62. Villablanca AC. Coronary heart disease in women: Gender differences and effects of menopause. Postgraduate Med 1996; 100: 191-96.

3. See Network News Nov/Dec 1998 for ways in which this study differed from most previous studies which had led people to believe that hormones reduced the risk of heart disease.

4. Herrington EM, Furberg CD. Hormone therapy: time for replacement? JAMA 1999; 20: 1285-6. Barrett-Connor E, Stuenkel C. Hormones and heart disease in women: Heart and Estrogen/progestin Replacement Study in perspective. J Clin Endo Metab. 1999; 84: 1848-53. Newham RR, Silberberg J. Does estrogen therapy have a role in cardiovascular prevention? Amercian Family Physician 1999; 59: 1125-26, 1131.

5. Mosca L, Grundy SM, Judelson D, et al. Guide to preventive cardiology for women. AHA/ACC Scientific Statement: Consensus Panel. Circulation 1999; 99: 2480-84.

6. LaRosa JC, He J, Vupputuri S. Effects of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282: 2340-6.

7. Ong P, et al. Hormone replacement thrapy for secondary prevention of coronary heart diseaes. JAMA 1999; 281: 794-5. Col NF, Pauker SG, Goldberg RJ et al. Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women. Arch Intern Med 1999; 159: 1458-1466. Also see: A decision tree for the use of estrogen replacement therapy in post-menopausal women: Consensus opinion of The North America Menopause Society. Menopause 2000; 7: 76-86.

8. Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 6th Edition. Lippincott Williams & Wilkins. 1999 p725.

9. Another study disputes estrogen heart benefits. New York Times 3/14/00, 4D. Herrington DM e al. Effects of estrogen replacement on the progression of coronary artery atherosclerosis. New England J Med. 2000; 343: 522-29. Details on how the study was done can be found in Control Clinical Trials. 2000; 21: 257-85.

10. Estrogen use tied to slight increase in risks to heart: Data is not conclusive.
New York Times, 4/5/2000, A1. These results have not yet been published in a medical journal. Details on how the study was done can be found in Control Clinical Trials. 1998; 19: 61-109.

11. Ups and downs for HRT and heart disease. Lancet 2000: 355: 1338.

12. Estrogen question gets tougher. New York Times 4/6/2000 A22.

13. Nagel EG. Coronary heart disease in women - An ounce of prevention. New England J Med 2000; 343: 572-574. Ong PJ, Sorensen MB, Hayward CS. Hormone replacement therapy for secondary prevention of coronary heart disease. JAMA 1999; 281: 794-5; discussion 796-7.

14. Nabel EG. Valk-de Roo GW, Stehouwer CD, Meijer P, et al. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: A 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol 1999 Dec;19(12):2993-3000.

16. For these and other biases in women's health see: Ehrenreich B, English DFor Her Own Good: 150 Years of the Experts' Advice to women. New York: Anchor, 1978 and Barker-Benfield GJ, The horrors of the half-known life. New York: Harper Colophon books, 1976.

17. Daly E, Vessey MP, Hawins MM, et al. Risk of venous thromboembolism in users of hormone replacment therapy. Lancet 1996; 348: 977-80. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000; 132: 689-96. Beresford SAA, Weiss NS, Voigt LF, McKnight. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet; 1997: 349: 458-61. Petitti DB, Sidney S, Perlman JA. Increased risk of cholecystectomy in users of supplemental estrogen. Gastroenterology 1988; 94: 91-5. Colditz G. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst 1998; 90: 814-823. Schairer C, Lubin J, Troisi R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 383: 485-491.

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