HRT, Women, and Heart Disease: What We Need to Know
Apparently women are still under the impression that cancer, not cardiovascular disease (CVD), poses the greatest risk to their health. According to a survey commissioned by the Society for Women's Health Research, over 60% of the 1019 women aged 18 years and older polled indicated cancer as the greatest threat to their health. By contrast, only 6% identified CVD or stroke. Such a drastic disparity may be one of the reasons why the incidence of CVD-related deaths among women is on the rise and continues to be the number 1 killer of women, accounting for half a million deaths each year. This total is nearly twice the number of cancer deaths in women and more than 10 times the mortality rate from breast cancer. Whereas only 1 in 30 women's deaths are attributable to breast cancer, the rate of CVD-related deaths is exponentially higher, accounting for 1 in every 2.4 deaths. This is particularly striking considering that deaths due to heart disease have declined quite substantially in the general population over the past 30 years. In addition, the disease is not limited to only an older population, but also affects younger women. Research from the US Centers for Disease Control and Prevention report that the number of sudden cardiac deaths caused by heart disease jumped by more than 31% among young women (15-36 years of age) from 1989 to 1996, and the recently published Women's Pooling Project identified high cholesterol levels as a risk factor for stroke death. Unfortunately, without greater awareness, the high rate of cardiovascular-related deaths across all generations of women will continue to prevail.
Undoubtedly, hormone replacement therapy (HRT) -- estrogen with or without progestin - is on the top of everyone's list of concerns with respect to the risk of heart disease in the postmenopausal population. While concern over the effects of HRT continues to loom, other factors such as obesity and smoking also continue to adversely affect incidence and outcome. Currently, prevention is key, certainly as emphasized by the American Heart Association's new public health initiative "Simple Solutions," which promotes relatively easy steps to reduce risk, particularly as it relates to diet.
The debate as to whether or not hormone replacement therapy (HRT) is associated with cardioprotective properties in postmenopausal women has been ongoing for several years -- but information from several recent clinical trials has been so seemingly unambiguous that it has brought the issue onto the front pages of the popular press, including the July 22 covers of Newsweek and Time, leading some to wonder whether the issue has been resolved, once and for all.
Publication of the results of the Heart and Estrogen/progestin Replacement Study (HERS II) and the arrest of the HRT arm of the Women's Health Initiative (WHI), coupled with the appearance of 2 recent meta-analyses, all point to the same conclusion: HRT is not associated with any benefit in preventing heart disease or stroke and should not be used in postmenopausal women for the sole purpose of heart disease prevention -- a position officially endorsed by last year's scientific statement from the American Heart Association (AHA).
HERS and WHI. The original HERS trial found that women with existing cardiovascular disease (CVD) who were treated with HRT were at increased risk of CVD at 1 year. However, over the course of the next 3.1 years of follow-up, this increased risk reduced somewhat. HERS II then followed the original HERS enrollees for an additional 2.7 years to determine whether the risk reduction associated with HRT was maintained or augmented with additional years of follow-up. Results indicated that after a total of 6.8 years of follow-up, there was no trend toward increased risk of CVD in women treated with HRT (P = .18) (Figure).
(Enlarge Image)
Kaplan-Meier estimates of the cumulative incidence of CHD events.
CHD events are death and nonfatal MI. The curves are truncated at year 7 when less than half of the cohort remains in follow-up.
Shortly after the first HERS trial was designed, the WHI study was initiated to test a large group of women on combination HRT (estrogen, 0.625 mg/d plus progestin, 2.5 mg/d) vs a matched group on placebo. However, at about the same time that HERS I and II reported no increased risk of CVD-related events for women on HRT, the HRT arm of the WHI was halted after 5.2 years of follow-up, because of the increased incidence of CVD (22%) and breast cancer (26%) in women treated with combination HRT (n = 8506) compared with placebo (n = 8102). The risk of stroke was also significantly higher in the HRT group, accounting for a 41% increase.
Thus, both the HERS and the WHI trials reported that there is no benefit to the use of HRT as a means of primary or secondary prevention against future CVD events. It is important to note, however, that neither trial answered, nor were they designed to answer, what the potential health benefits of HRT may be (especially with regard to the use of estrogen therapy alone, as opposed to the combination therapy used in the WHI). Other benefits associated with HRT (such as relief of symptoms associated with menopause) and the optimal duration of HRT in postmenopausal women remain in question and continue to occupy the attention of many women and the medical profession.
USPSTF Systemic Evidence Review. Developed for the US Preventive Services Task Force (USPSTF) as a background for new recommendations on the use of HRT, researchers from the Oregon Health and Sciences University (Portland) conducted a meta-analysis of trials that evaluated HRT for the primary prevention of chronic conditions, including CVD, osteoporosis, cancer, and dementia. Appearing in the August 21 issue of JAMA, the evidence-based review found that the summary relative risk (RR) associated with CVD outcomes (RR, 0.80) and the RR for mortality (RR, 0.64) were decreased in current users of estrogen therapy when compared with "ever, past, or all user" groups. However, when examining only those trials that controlled for socioeconomic status, the summary RR became nonsignificantly different from unity (RR, 0.97) -- a finding the investigators attributed to the wide variance of the results.
As seen in Table 1 , researchers also found that the risk of nonfatal stroke among all users of estrogen therapy was significantly higher, particularly during the first year of use. In addition, current HRT use was associated with an increased risk of breast cancer, and the risk was found to increase with duration of use. While the meta-analysis found that the increased risks associated with HRT correlated with 5 or more years of use, researchers also found that the use of HRT protected against osteoporosis and decreased the risk of colorectal cancer.
Whereas the aforementioned JAMA study looked at HRT with respect to all chronic conditions, a second review published in the August 20 issue of the Annals of Internal Medicine solely focused on the primary prevention of CVD. To determine a more specific breakdown of the relationship between heart disease and HRT, investigators examined CVD and coronary artery disease (CAD) outcomes separately. Findings from the review, which also serve as background for USPSTF recommendations, were similar to those cited in the JAMA study, in that there was no significant association linking past, ever, or any use of HRT to total CVD (RR, 0.75) or CAD death (RR, 0.74) ( Table 2 ). In addition, the use of HRT did not reduce the incidence of total CVD (RR, 1.28) or CAD (RR, 0.87).
Now What? The rise and fall of risks on a per-year basis indicate a great need to determine what form of HRT to prescribe (unopposed vs combination therapy) and for how long. Following the negative results of the WHI with combination therapy, it would appear that this may leave unopposed estrogen as the solution. However, some women taking unopposed estrogen may be at reduced risk for some outcomes but increased risk for others. Additional research is needed to determine the roles of progestins and varying doses of estrogen. For now, determining whether or not to prescribe HRT will have to be done on an individual basis -- particularly for those seeking symptom relief.
It has been generally accepted for some time that estrogen appears to confer some protective effect against CVD in premenopausal women, and when estrogen secretion decreases with menopause, a woman's risk of CVD greatly increases. Yet the results of the recent clinical trials now leave clinicians faced with a conundrum: replacing the estrogen lost at menopause with HRT either exacerbates or has no impact on CVD risk, how, then, should clinicians treat their postmenopausal patients at risk for CVD?
The answer may be that primary or secondary prevention against future CVD events in the postmenopausal woman is basically the same as in men -- ie, it is predicated on identification and management of associated risk factors. This emphasizes the need for increased prevention efforts include lifestyle changes, diet, exercise, and appropriate medical therapy.
The continued prevalence of obesity has been identified as a national epidemic and is undeniably attributable to increased cardiovascular risk. The inactivity associated with obesity leads to the onset of additional risk factors such as hypertension, hypercholesterolemia, diabetes, and CAD. Now, however, new data show that obesity itself, and not just its associated medical conditions, is a predictor of risk.
It is apparently not how much one weighs, but where the majority of the weight resides, such that "apple-shaped" women with excess abdominal fat face a higher risk for CVD and, according to the ongoing Manhattan Stroke Study, these women are 2.5 times more likely to suffer a stroke. The same can be said for men. According to the same study, men with expanding waistlines have a 4.4 times greater risk for stroke (See "HeartBytes: Can We Avoid Losing Patients to Stroke?"). Such findings may be indicative of the fact that abdominal fat is associated with higher blood levels of low-density lipoprotein (LDL) cholesterol.
The Nurses' Health Study identified that increased body mass index (BMI) correlated to an increased risk of CVD in diabetic women (see "HeartBytes: Greater Risk Identified Between Diabetes and Heart Disease: Awareness Is Key"). A recent study indicates that BMI may also be independently associated with an increased risk of heart failure. A subset of the Framingham Heart Study that evaluated 496 patients who developed heart failure over the course of the study's 14-year follow-up period revealed that increasing BMI is a significant independent predictor of heart failure. Published in the August 1 issue of The New England Journal of Medicine, after adjusting for other risk factors, researchers reported that for each increment of 1 in BMI, the risk of heart failure increased 5% in men and 7% in women. The findings were not limited to those only with extreme obesity -- investigators discovered that the risk of developing heart failure among people who were merely overweight was 34% greater than in non-overweight individuals, and for those who were obese, the risk increased by 104%.
Weight may have greater implications in women, as the study found that overweight men had a nonsignificant 20% increase in heart-failure risk compared with a highly significant 50% increase in risk among women of comparable weight. When considering those who were obese, the risk climbed to double in women and 90% in obese men. The study estimated that obesity accounted for approximately 11% of cases of heart failure among men and 14% of women. In an accompanying editorial, the emergence of BMI as an independent predictor of risk "suggests that obesity itself or some intermediary mechanisms are responsible for heart failure."
According to a meta-analysis published in the Archives of Internal Medicine, diabetic women face an increased risk of coronary heart disease (CHD)-related mortality, nonfatal myocardial infarction (MI), and overall cardiovascular mortality compared with men. However, when adjusting for classic CHD risk factors, the differences between men and women were not statistically significant. The meta-analysis was conducted to determine the independent association between diabetes and CHD outcomes in both men and women. From the 8 prospective studies pooled for CHD mortality due to diabetes, the summary odds ratio (OR) was 2.3 for men and 2.9 for women. When pooling for nonfatal MI due to diabetes, the summary OR was 1.6 for men and 1.7 for women and the summary OR for cardiovascular mortality was 3.2 in men and 4.1 in women. Researchers attribute the findings to the fact that diabetic women may have a more severe degree of risk factor abnormalities than men do, and these risk factors may have a bigger impact on women than on men. They also add that the risk factors in women may be managed less aggressively than in men.
The American Cancer Society reports that more than 22 million adult women and at least 1.5 million adolescent girls in the United States currently smoke cigarettes. Smoking-related diseases claim the lives of 165,000 women a year, and since the Surgeon General's office released its first report on the issue in 1980, 3 million women have died prematurely as a consequence of smoking. Research shows that women who smoke are not only 2 to 6 times more likely to suffer a heart attack than a nonsmoker, but smokers also tend to have their first heart attack an average of 19 years earlier than nonsmokers.
Another analysis of the data from the Nurses' Health Study, published in the Archives of Internal Medicine, examined the association between smoking and CVD risk among diabetic women during 20 years of follow-up. Whereas women with type 2 diabetes are already at an increased risk of MI, when adding smoking to the mix, risk is substantially exacerbated and is dose-responsive. Compared with never smokers, diabetic women who smoke 1 to 14 cigarettes per day had an RR of 1.66 for CHD, and the RR climbed to 2.68 for diabetic women who smoke ≥ 15 cigarettes per day. Researchers also reported that diabetic women who smoke ≥ 15 cigarettes per day had an 84% higher risk of developing stroke compared with nonsmokers. The combined impact of smoking and diabetes on the development of CHD was substantial. Compared with nondiabetic persons who had never smoked, the RR for diabetic women who smoked ≥ 15 cigarettes a day was 7.67. Experts believe that in addition to other long- and short-term effects that increase CHD risk for diabetics, smoking also increases insulin resistance and aggravates metabolic disturbances among diabetic patients. Researchers advocate the increased need to encourage smoking cessation, as the results from the study indicate that the risk of CHD among diabetic women who smoke could have been reduced by about 54% had they not smoked.
It has long been suspected that women may be more susceptible than men to smoking-induced lung cancer, and it appears that women are more prone to early severe chronic obstructive pulmonary disease as well. Now, follow-up data from the Copenhagen City Heart Study indicate that women who smoke face more of an increased risk of heart attack and death than male smokers do. The follow-up cohort, which examined the risk of MI and all-cause mortality associated with light smoking and inhalation in 12,149 male and female participants, may have put an end to the existing naive impression that one can reduce their risk by using low-tar, low-nicotine cigarettes and by not inhaling. Researchers found that compared to the risk of nonsmokers (RR, 0.83), women inhalers who smoked 3 to 5 grams of tobacco a day (1 gram of tobacco is equivalent to 1 cigarette) doubled their risk of a heart attack (RR, 2.14), and smoking 6 to 9 grams a day without inhaling increased the risk by almost 60% (RR, 1.58). Overall, there was a significant interaction between smoking and gender, in which the RR for MI and death was approximately 50% higher in female vs male smokers. Researchers postulate that the "anti-estrogenic" effect on women may be one biological explanation, whereby smoking causes additional negative effects that leave women more susceptible to ischemic heart disease.
Two recent studies examined the relationship between high levels of stress in women and heart disease. One study, presented at the annual meeting of the American Psychological Association, attributes traditional gender roles and the accompanying expectations to the fact that women diagnosed with heart disease report a poorer quality of life (QOL) than men with the disease. In addition, researchers speculate that such factors may leave a woman "ill-prepared" to cope with the effects of the disease, leading to a decline in QOL. Through a survey that assessed 410 men and women with heart disease for changes in sadness, stress, and physical activity, as well as the perception of emotional support from others, researchers from Ohio State University (Columbus) report that women tested lower than men in both mental and physical QOL scores. The results also identified a link between declines in QOL and lower levels of perceived support in women, but not in men. Researchers conclude that increasing the levels of emotional support may increase QOL, which could result in lessening the high rates of morbidity and mortality among women with heart disease.
A second study, evaluating the direct relationship between stress and cardiovascular risk among Japanese women and men, found that women who report high levels of stress are at double the risk of total stroke-related (RR, 2.24) and CHD-related deaths (RR, 2.28) and a 1.5 times higher risk for total CVD (RR, 1.64) compared with those reporting lower levels. Likewise, after adjusting for other risk factors, men reporting medium or high levels of stress faced a 1.74 RR for total CVD. The findings were based on health screening and lifestyle questionnaires administered to the 73,424 healthy people enrolled in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC).
The Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that the addition of an angiotensin-converting enzyme (ACE) inhibitor (ramipril) reduced the risk of stroke-, MI-, and CV-related death in high-risk patients with a history of CVD or diabetes and at least 1 other cardiovascular risk factor. Prior to the release of HOPE, there was insufficient data to fully determine the therapeutic effects of ACE inhibitor therapy in women, particularly those at high risk. Published in the August 21 issue of the Journal of the American College of Cardiology, researchers found that the therapeutic benefits of high-risk patients treated with an ACE inhibitor were similar in women and men. Researchers found that among the 2480 women enrolled in HOPE, women treated with ramipril had a reduced primary composite end point of MI-, stroke-, or cardiovascular-related death compared with placebo (11.3% vs 14.9%, respectively [P = .029]). In addition, the individual rates of stroke and CV death were also significantly reduced (P = .029 and P = .0068), and there were trends toward reduced rates of MI, heart failure, and all-cause mortality among those treated with ramipril.
Beyond pharmaceutical approaches, diet definitely comes into play with respect to prevention, and evidence is steadily mounting that fish and fish oil supplements (omega-3 fatty acids) have an independent effect on heart disease risk. To date, however, the majority of data available has only examined the cardiac benefits of omega-3 acids in men. To determine the association between fish and omega-3 fatty acid intake among women, researchers from the Harvard School of Public Health (Boston, Massachusetts) analyzed the dietary patterns of the 84,688 participants enrolled in the Nurses' Health Study. The study's findings were based on 5 food-frequency questionnaires administered over the course of the 16-year follow-up period. Overall, independent of other established risk factors and dietary predictors of heart disease, investigators found an inverse relationship between fish intake and risk of heart disease, where the more frequent the intake, the greater the risk reduction (21% for those consuming fish 1-3 times/month, climbing to 34% for those with intakes > 5 times/week). In addition, the inverse association was stronger for reducing the risk of CHD-related deaths (RR, 0.55) compared with nonfatal MIs (RR, 0.73). The same inverse relationship was identified when examining the intake of dietary omega-3 fatty acids.
The cardiac benefits of omega-3 fatty acids may be attributable to multiple mechanisms, including the reduction of serum triglycerides, platelet aggregability, and antiarrhythmic effects. To further understand the benefits, a study published in the American Journal of Clinical Nutrition assessed the impact of omega-3 fatty acids on systolic and pulse pressure and vascular resistance among 38 middle-aged adults at high risk for ischemic heart disease and sudden death. The study found that while there was no change in the placebo group, systemic arterial compliance increased in individuals taking omega-3 fatty acid supplements (eicosapentaenoic acid [EPA; 36%] and docosahexaenoic acid [DHA; 27%]). In addition, there was a positive trend toward reduced systolic and pulse pressure in the 2 treated groups.
A recent study also indicates that soy intake lowers the risk of CVD and atherosclerosis in women by lessening arterial pressure. The study noted that the greatest benefit was found in women who had been postmenopausal the longest. The positive effects are attributed to phytoestrogens, plant-based estrogen-like compounds found in soy. However, researchers indicate that these findings may be, in part, due to the fact that of the 400 women in the study, those who consumed higher levels of soy may also have had healthier lifestyles.
Among all of the other studies assessing the utility of vitamins, an article published in the American Journal of Clinical Nutrition found a direct link between the development of atherosclerosis and vitamin E intake in women. The study indicated that women at higher risk for atherosclerosis had lower intakes of the vitamin, and those with higher intakes were shown to be less likely to exhibit early signs of atherosclerosis. In addition, the ratio of blood levels of the vitamin to cholesterol was also linked to early CAD. The majority of the vitamin E intake among the 310 Southern Italian women enrolled in the study was derived from diets rich in legumes, vegetables, and olive oil.
Continued research efforts on the exact utility of particular diets are required to determine the candidates who would best benefit from such measures. Increasing patient awareness through enhanced communication and encouraging patient compliance with respect to lifestyle is imperative. However, greater awareness on the part of the physician is also necessary in order to properly identify patients at high risk, particularly with respect to gender differences.
Two meta-analyses confirm no cardiac benefit to HRT
Studies reveal that risk associated with obesity depends upon location of added weight
Positive trend indicates diabetic women are at greater risk for heart disease than diabetic men
Studies confirm that female smokers face increased risk of heart disease, heart failure, stroke, and cardiac-related deaths
Studies identify "gender gap" when correlating heart disease and stress
ACE inhibitors for cardiovascular disease prevention are equally effective in men and women
Dietary approaches to risk reduction include greater intake of omega-3 fatty acids, soy, and vitamin E
Apparently women are still under the impression that cancer, not cardiovascular disease (CVD), poses the greatest risk to their health. According to a survey commissioned by the Society for Women's Health Research, over 60% of the 1019 women aged 18 years and older polled indicated cancer as the greatest threat to their health. By contrast, only 6% identified CVD or stroke. Such a drastic disparity may be one of the reasons why the incidence of CVD-related deaths among women is on the rise and continues to be the number 1 killer of women, accounting for half a million deaths each year. This total is nearly twice the number of cancer deaths in women and more than 10 times the mortality rate from breast cancer. Whereas only 1 in 30 women's deaths are attributable to breast cancer, the rate of CVD-related deaths is exponentially higher, accounting for 1 in every 2.4 deaths. This is particularly striking considering that deaths due to heart disease have declined quite substantially in the general population over the past 30 years. In addition, the disease is not limited to only an older population, but also affects younger women. Research from the US Centers for Disease Control and Prevention report that the number of sudden cardiac deaths caused by heart disease jumped by more than 31% among young women (15-36 years of age) from 1989 to 1996, and the recently published Women's Pooling Project identified high cholesterol levels as a risk factor for stroke death. Unfortunately, without greater awareness, the high rate of cardiovascular-related deaths across all generations of women will continue to prevail.
Undoubtedly, hormone replacement therapy (HRT) -- estrogen with or without progestin - is on the top of everyone's list of concerns with respect to the risk of heart disease in the postmenopausal population. While concern over the effects of HRT continues to loom, other factors such as obesity and smoking also continue to adversely affect incidence and outcome. Currently, prevention is key, certainly as emphasized by the American Heart Association's new public health initiative "Simple Solutions," which promotes relatively easy steps to reduce risk, particularly as it relates to diet.
The debate as to whether or not hormone replacement therapy (HRT) is associated with cardioprotective properties in postmenopausal women has been ongoing for several years -- but information from several recent clinical trials has been so seemingly unambiguous that it has brought the issue onto the front pages of the popular press, including the July 22 covers of Newsweek and Time, leading some to wonder whether the issue has been resolved, once and for all.
Publication of the results of the Heart and Estrogen/progestin Replacement Study (HERS II) and the arrest of the HRT arm of the Women's Health Initiative (WHI), coupled with the appearance of 2 recent meta-analyses, all point to the same conclusion: HRT is not associated with any benefit in preventing heart disease or stroke and should not be used in postmenopausal women for the sole purpose of heart disease prevention -- a position officially endorsed by last year's scientific statement from the American Heart Association (AHA).
HERS and WHI. The original HERS trial found that women with existing cardiovascular disease (CVD) who were treated with HRT were at increased risk of CVD at 1 year. However, over the course of the next 3.1 years of follow-up, this increased risk reduced somewhat. HERS II then followed the original HERS enrollees for an additional 2.7 years to determine whether the risk reduction associated with HRT was maintained or augmented with additional years of follow-up. Results indicated that after a total of 6.8 years of follow-up, there was no trend toward increased risk of CVD in women treated with HRT (P = .18) (Figure).
(Enlarge Image)
Kaplan-Meier estimates of the cumulative incidence of CHD events.
CHD events are death and nonfatal MI. The curves are truncated at year 7 when less than half of the cohort remains in follow-up.
Shortly after the first HERS trial was designed, the WHI study was initiated to test a large group of women on combination HRT (estrogen, 0.625 mg/d plus progestin, 2.5 mg/d) vs a matched group on placebo. However, at about the same time that HERS I and II reported no increased risk of CVD-related events for women on HRT, the HRT arm of the WHI was halted after 5.2 years of follow-up, because of the increased incidence of CVD (22%) and breast cancer (26%) in women treated with combination HRT (n = 8506) compared with placebo (n = 8102). The risk of stroke was also significantly higher in the HRT group, accounting for a 41% increase.
Thus, both the HERS and the WHI trials reported that there is no benefit to the use of HRT as a means of primary or secondary prevention against future CVD events. It is important to note, however, that neither trial answered, nor were they designed to answer, what the potential health benefits of HRT may be (especially with regard to the use of estrogen therapy alone, as opposed to the combination therapy used in the WHI). Other benefits associated with HRT (such as relief of symptoms associated with menopause) and the optimal duration of HRT in postmenopausal women remain in question and continue to occupy the attention of many women and the medical profession.
USPSTF Systemic Evidence Review. Developed for the US Preventive Services Task Force (USPSTF) as a background for new recommendations on the use of HRT, researchers from the Oregon Health and Sciences University (Portland) conducted a meta-analysis of trials that evaluated HRT for the primary prevention of chronic conditions, including CVD, osteoporosis, cancer, and dementia. Appearing in the August 21 issue of JAMA, the evidence-based review found that the summary relative risk (RR) associated with CVD outcomes (RR, 0.80) and the RR for mortality (RR, 0.64) were decreased in current users of estrogen therapy when compared with "ever, past, or all user" groups. However, when examining only those trials that controlled for socioeconomic status, the summary RR became nonsignificantly different from unity (RR, 0.97) -- a finding the investigators attributed to the wide variance of the results.
As seen in Table 1 , researchers also found that the risk of nonfatal stroke among all users of estrogen therapy was significantly higher, particularly during the first year of use. In addition, current HRT use was associated with an increased risk of breast cancer, and the risk was found to increase with duration of use. While the meta-analysis found that the increased risks associated with HRT correlated with 5 or more years of use, researchers also found that the use of HRT protected against osteoporosis and decreased the risk of colorectal cancer.
Whereas the aforementioned JAMA study looked at HRT with respect to all chronic conditions, a second review published in the August 20 issue of the Annals of Internal Medicine solely focused on the primary prevention of CVD. To determine a more specific breakdown of the relationship between heart disease and HRT, investigators examined CVD and coronary artery disease (CAD) outcomes separately. Findings from the review, which also serve as background for USPSTF recommendations, were similar to those cited in the JAMA study, in that there was no significant association linking past, ever, or any use of HRT to total CVD (RR, 0.75) or CAD death (RR, 0.74) ( Table 2 ). In addition, the use of HRT did not reduce the incidence of total CVD (RR, 1.28) or CAD (RR, 0.87).
Now What? The rise and fall of risks on a per-year basis indicate a great need to determine what form of HRT to prescribe (unopposed vs combination therapy) and for how long. Following the negative results of the WHI with combination therapy, it would appear that this may leave unopposed estrogen as the solution. However, some women taking unopposed estrogen may be at reduced risk for some outcomes but increased risk for others. Additional research is needed to determine the roles of progestins and varying doses of estrogen. For now, determining whether or not to prescribe HRT will have to be done on an individual basis -- particularly for those seeking symptom relief.
It has been generally accepted for some time that estrogen appears to confer some protective effect against CVD in premenopausal women, and when estrogen secretion decreases with menopause, a woman's risk of CVD greatly increases. Yet the results of the recent clinical trials now leave clinicians faced with a conundrum: replacing the estrogen lost at menopause with HRT either exacerbates or has no impact on CVD risk, how, then, should clinicians treat their postmenopausal patients at risk for CVD?
The answer may be that primary or secondary prevention against future CVD events in the postmenopausal woman is basically the same as in men -- ie, it is predicated on identification and management of associated risk factors. This emphasizes the need for increased prevention efforts include lifestyle changes, diet, exercise, and appropriate medical therapy.
The continued prevalence of obesity has been identified as a national epidemic and is undeniably attributable to increased cardiovascular risk. The inactivity associated with obesity leads to the onset of additional risk factors such as hypertension, hypercholesterolemia, diabetes, and CAD. Now, however, new data show that obesity itself, and not just its associated medical conditions, is a predictor of risk.
It is apparently not how much one weighs, but where the majority of the weight resides, such that "apple-shaped" women with excess abdominal fat face a higher risk for CVD and, according to the ongoing Manhattan Stroke Study, these women are 2.5 times more likely to suffer a stroke. The same can be said for men. According to the same study, men with expanding waistlines have a 4.4 times greater risk for stroke (See "HeartBytes: Can We Avoid Losing Patients to Stroke?"). Such findings may be indicative of the fact that abdominal fat is associated with higher blood levels of low-density lipoprotein (LDL) cholesterol.
The Nurses' Health Study identified that increased body mass index (BMI) correlated to an increased risk of CVD in diabetic women (see "HeartBytes: Greater Risk Identified Between Diabetes and Heart Disease: Awareness Is Key"). A recent study indicates that BMI may also be independently associated with an increased risk of heart failure. A subset of the Framingham Heart Study that evaluated 496 patients who developed heart failure over the course of the study's 14-year follow-up period revealed that increasing BMI is a significant independent predictor of heart failure. Published in the August 1 issue of The New England Journal of Medicine, after adjusting for other risk factors, researchers reported that for each increment of 1 in BMI, the risk of heart failure increased 5% in men and 7% in women. The findings were not limited to those only with extreme obesity -- investigators discovered that the risk of developing heart failure among people who were merely overweight was 34% greater than in non-overweight individuals, and for those who were obese, the risk increased by 104%.
Weight may have greater implications in women, as the study found that overweight men had a nonsignificant 20% increase in heart-failure risk compared with a highly significant 50% increase in risk among women of comparable weight. When considering those who were obese, the risk climbed to double in women and 90% in obese men. The study estimated that obesity accounted for approximately 11% of cases of heart failure among men and 14% of women. In an accompanying editorial, the emergence of BMI as an independent predictor of risk "suggests that obesity itself or some intermediary mechanisms are responsible for heart failure."
According to a meta-analysis published in the Archives of Internal Medicine, diabetic women face an increased risk of coronary heart disease (CHD)-related mortality, nonfatal myocardial infarction (MI), and overall cardiovascular mortality compared with men. However, when adjusting for classic CHD risk factors, the differences between men and women were not statistically significant. The meta-analysis was conducted to determine the independent association between diabetes and CHD outcomes in both men and women. From the 8 prospective studies pooled for CHD mortality due to diabetes, the summary odds ratio (OR) was 2.3 for men and 2.9 for women. When pooling for nonfatal MI due to diabetes, the summary OR was 1.6 for men and 1.7 for women and the summary OR for cardiovascular mortality was 3.2 in men and 4.1 in women. Researchers attribute the findings to the fact that diabetic women may have a more severe degree of risk factor abnormalities than men do, and these risk factors may have a bigger impact on women than on men. They also add that the risk factors in women may be managed less aggressively than in men.
The American Cancer Society reports that more than 22 million adult women and at least 1.5 million adolescent girls in the United States currently smoke cigarettes. Smoking-related diseases claim the lives of 165,000 women a year, and since the Surgeon General's office released its first report on the issue in 1980, 3 million women have died prematurely as a consequence of smoking. Research shows that women who smoke are not only 2 to 6 times more likely to suffer a heart attack than a nonsmoker, but smokers also tend to have their first heart attack an average of 19 years earlier than nonsmokers.
Another analysis of the data from the Nurses' Health Study, published in the Archives of Internal Medicine, examined the association between smoking and CVD risk among diabetic women during 20 years of follow-up. Whereas women with type 2 diabetes are already at an increased risk of MI, when adding smoking to the mix, risk is substantially exacerbated and is dose-responsive. Compared with never smokers, diabetic women who smoke 1 to 14 cigarettes per day had an RR of 1.66 for CHD, and the RR climbed to 2.68 for diabetic women who smoke ≥ 15 cigarettes per day. Researchers also reported that diabetic women who smoke ≥ 15 cigarettes per day had an 84% higher risk of developing stroke compared with nonsmokers. The combined impact of smoking and diabetes on the development of CHD was substantial. Compared with nondiabetic persons who had never smoked, the RR for diabetic women who smoked ≥ 15 cigarettes a day was 7.67. Experts believe that in addition to other long- and short-term effects that increase CHD risk for diabetics, smoking also increases insulin resistance and aggravates metabolic disturbances among diabetic patients. Researchers advocate the increased need to encourage smoking cessation, as the results from the study indicate that the risk of CHD among diabetic women who smoke could have been reduced by about 54% had they not smoked.
It has long been suspected that women may be more susceptible than men to smoking-induced lung cancer, and it appears that women are more prone to early severe chronic obstructive pulmonary disease as well. Now, follow-up data from the Copenhagen City Heart Study indicate that women who smoke face more of an increased risk of heart attack and death than male smokers do. The follow-up cohort, which examined the risk of MI and all-cause mortality associated with light smoking and inhalation in 12,149 male and female participants, may have put an end to the existing naive impression that one can reduce their risk by using low-tar, low-nicotine cigarettes and by not inhaling. Researchers found that compared to the risk of nonsmokers (RR, 0.83), women inhalers who smoked 3 to 5 grams of tobacco a day (1 gram of tobacco is equivalent to 1 cigarette) doubled their risk of a heart attack (RR, 2.14), and smoking 6 to 9 grams a day without inhaling increased the risk by almost 60% (RR, 1.58). Overall, there was a significant interaction between smoking and gender, in which the RR for MI and death was approximately 50% higher in female vs male smokers. Researchers postulate that the "anti-estrogenic" effect on women may be one biological explanation, whereby smoking causes additional negative effects that leave women more susceptible to ischemic heart disease.
Two recent studies examined the relationship between high levels of stress in women and heart disease. One study, presented at the annual meeting of the American Psychological Association, attributes traditional gender roles and the accompanying expectations to the fact that women diagnosed with heart disease report a poorer quality of life (QOL) than men with the disease. In addition, researchers speculate that such factors may leave a woman "ill-prepared" to cope with the effects of the disease, leading to a decline in QOL. Through a survey that assessed 410 men and women with heart disease for changes in sadness, stress, and physical activity, as well as the perception of emotional support from others, researchers from Ohio State University (Columbus) report that women tested lower than men in both mental and physical QOL scores. The results also identified a link between declines in QOL and lower levels of perceived support in women, but not in men. Researchers conclude that increasing the levels of emotional support may increase QOL, which could result in lessening the high rates of morbidity and mortality among women with heart disease.
A second study, evaluating the direct relationship between stress and cardiovascular risk among Japanese women and men, found that women who report high levels of stress are at double the risk of total stroke-related (RR, 2.24) and CHD-related deaths (RR, 2.28) and a 1.5 times higher risk for total CVD (RR, 1.64) compared with those reporting lower levels. Likewise, after adjusting for other risk factors, men reporting medium or high levels of stress faced a 1.74 RR for total CVD. The findings were based on health screening and lifestyle questionnaires administered to the 73,424 healthy people enrolled in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC).
The Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that the addition of an angiotensin-converting enzyme (ACE) inhibitor (ramipril) reduced the risk of stroke-, MI-, and CV-related death in high-risk patients with a history of CVD or diabetes and at least 1 other cardiovascular risk factor. Prior to the release of HOPE, there was insufficient data to fully determine the therapeutic effects of ACE inhibitor therapy in women, particularly those at high risk. Published in the August 21 issue of the Journal of the American College of Cardiology, researchers found that the therapeutic benefits of high-risk patients treated with an ACE inhibitor were similar in women and men. Researchers found that among the 2480 women enrolled in HOPE, women treated with ramipril had a reduced primary composite end point of MI-, stroke-, or cardiovascular-related death compared with placebo (11.3% vs 14.9%, respectively [P = .029]). In addition, the individual rates of stroke and CV death were also significantly reduced (P = .029 and P = .0068), and there were trends toward reduced rates of MI, heart failure, and all-cause mortality among those treated with ramipril.
Beyond pharmaceutical approaches, diet definitely comes into play with respect to prevention, and evidence is steadily mounting that fish and fish oil supplements (omega-3 fatty acids) have an independent effect on heart disease risk. To date, however, the majority of data available has only examined the cardiac benefits of omega-3 acids in men. To determine the association between fish and omega-3 fatty acid intake among women, researchers from the Harvard School of Public Health (Boston, Massachusetts) analyzed the dietary patterns of the 84,688 participants enrolled in the Nurses' Health Study. The study's findings were based on 5 food-frequency questionnaires administered over the course of the 16-year follow-up period. Overall, independent of other established risk factors and dietary predictors of heart disease, investigators found an inverse relationship between fish intake and risk of heart disease, where the more frequent the intake, the greater the risk reduction (21% for those consuming fish 1-3 times/month, climbing to 34% for those with intakes > 5 times/week). In addition, the inverse association was stronger for reducing the risk of CHD-related deaths (RR, 0.55) compared with nonfatal MIs (RR, 0.73). The same inverse relationship was identified when examining the intake of dietary omega-3 fatty acids.
The cardiac benefits of omega-3 fatty acids may be attributable to multiple mechanisms, including the reduction of serum triglycerides, platelet aggregability, and antiarrhythmic effects. To further understand the benefits, a study published in the American Journal of Clinical Nutrition assessed the impact of omega-3 fatty acids on systolic and pulse pressure and vascular resistance among 38 middle-aged adults at high risk for ischemic heart disease and sudden death. The study found that while there was no change in the placebo group, systemic arterial compliance increased in individuals taking omega-3 fatty acid supplements (eicosapentaenoic acid [EPA; 36%] and docosahexaenoic acid [DHA; 27%]). In addition, there was a positive trend toward reduced systolic and pulse pressure in the 2 treated groups.
A recent study also indicates that soy intake lowers the risk of CVD and atherosclerosis in women by lessening arterial pressure. The study noted that the greatest benefit was found in women who had been postmenopausal the longest. The positive effects are attributed to phytoestrogens, plant-based estrogen-like compounds found in soy. However, researchers indicate that these findings may be, in part, due to the fact that of the 400 women in the study, those who consumed higher levels of soy may also have had healthier lifestyles.
Among all of the other studies assessing the utility of vitamins, an article published in the American Journal of Clinical Nutrition found a direct link between the development of atherosclerosis and vitamin E intake in women. The study indicated that women at higher risk for atherosclerosis had lower intakes of the vitamin, and those with higher intakes were shown to be less likely to exhibit early signs of atherosclerosis. In addition, the ratio of blood levels of the vitamin to cholesterol was also linked to early CAD. The majority of the vitamin E intake among the 310 Southern Italian women enrolled in the study was derived from diets rich in legumes, vegetables, and olive oil.
Continued research efforts on the exact utility of particular diets are required to determine the candidates who would best benefit from such measures. Increasing patient awareness through enhanced communication and encouraging patient compliance with respect to lifestyle is imperative. However, greater awareness on the part of the physician is also necessary in order to properly identify patients at high risk, particularly with respect to gender differences.
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