Menopausal hormone therapy appears to exacerbate rather than reduce cardiovascular risk in menopausal women. While this evidence is important in recalculating the risk-to-benefit ratio of menopausal hormone therapy, it also provides an impetus to redirect greater attention to interventions and therapies that offer cardioprotection. Like men, women die in greater numbers from coronary heart disease (CHD) than from other any cause. Also like men, there is convincing evidence that control of modifiable coronary risk factors, such as smoking cessation, physical activity, heart-healthy diet, weight control, and control of elevated serum lipids and hypertension, yields large survival benefits.

The prospective evidence that menopausal hormone therapy, in particular estrogen and progestin, is not effective in reducing cardiovascular risk is compelling and undermines a predicted benefit based on observational data. Although the hypothesis that menopausal hormone therapy is cardioprotective was challenged by reanalysis of observational studies controlling for factors characteristic of its users, such as education, socioeconomic status, etc., the favorable effects of estrogen on some serum lipids had lent substantial support and credibility to the theory. However, the theory ignored several important adverse influences of menopausal hormone therapy on vascular health, including increases in triglyceride levels, stimulation of pro-inflammatory C-reactive protein, and inhibition of antithrombin III, an endogenous anticoagulation factor.

The most compelling evidence that HRT increases cardiovascular risk was generated by results of the prematurely halted estrogen/progestin arm of the Women's Health Initiative (WHI). In that primary prevention trial, the incidence of cardiovascular events was 22% greater in women randomized to HRT than in those randomized to placebo. These negative results were concordant with the earlier secondary prevention Heart Estrogen/Progestin Replacement Study (HERS), in which an increased risk for venous thromboembolism and cardiovascular events in the first year of the trial was not counterbalanced by a reduced risk in the latter years. The estrogen-only treatment arm of the WHI randomized hormone trial is continuing.

Both WHI and HERS were large, randomized, multicenter prospective trials with power sufficient to support evidence-based decision-making. The results of these trials refute the theoretical benefits of HRT in improving cardiovascular health. Although HRT was associated with a reduced incidence of colorectal cancer and bone fracture in WHI, it was also associated with an increased risk for breast cancer.

The hypothesis that there may be late benefit from HRT in secondary prevention was refuted by the open-label HERS II study, which followed the majority of surviving participants in the original HERS study for a mean of almost 3 additional years. During this follow-up, no cardiovascular benefit was detected in on-treatment or intention-to-treat analyses. In WHI, the increase in myocardial infarction and stroke among patients randomized to HRT was detected relatively early in the trial and continued until the trial was stopped prematurely due to excess risk for invasive breast cancer, and an unfavorable global benefit: risk score.

The increased risk for cardiovascular disease from HRT seen in the WHI trial was not great for an individual woman. It is estimated that there would be an excess of seven coronary events, eight strokes, and eight pulmonary emboli in 10,000 women treated for 1 year. Although these risks would be countered by six fewer cases of colorectal cancer and five fewer hip fractures during the same period, the anticipated eight excess cases of invasive breast cancer further establishes an unfavorable overall risk-to-benefit ratio.

Results of WHI do not nullify clinical benefits from HRT in selected patients. In particular, the ability of HRT to control hot flashes, sleep disturbances, or other acute symptoms of menopause may yield an improvement in quality of life that may well warrant potential modest risks over short-term treatment. Women with severe menopausal symptoms were unlikely to participate in the WHI or HERS, given a 50% likelihood of randomization to placebo; thus randomized trial data are not available for such women. In long-term prevention of osteoporosis, an approved indication for HRT, the benefits and risks of menopausal hormone therapy should be weighed against those of other options, such as bisphosphonates or selective estrogen receptor modulators (SERMs); however, it is important to recognize that long-term menopausal hormone therapy is required for protection against bone loss, making this strategy less attractive in women with known risk factors for cardiovascular disease or breast cancer.

Results of WHI and HERS encourage implementation of evidence-based strategies for cardioprotection. The absence of CHD risk reduction from menopausal hormone therapy in these large, data-driven trials can be compared with the information that the risk for CHD in women can be substantially and meaningfully reduced with other strategies, including lifestyle modifications, lipid-lowering pharmacologic interventions, and antihypertensive therapies. In trials such as the Heart Protection Study, a controlled trial with the HMG CoA reductase inhibitor simvastatin, the benefits of intervention have been at least as great in women as in men with similar risk.

The results of WHI and HERS should redirect attention to strategies with proven benefit in cardiovascular disease. There is substantial evidence that women with cardiovascular risk factors are less likely than men to receive appropriate therapy despite comparable likelihood of dying from CHD. The persistent misconception that CHD is primarily a disease of men has hindered effective preventive interventions; the female heart is vulnerable to CHD.

Intervention for modifiable risks should be implemented in women, as in men, as soon as they are detected. The risk for CHD events is known to increase with age, so menopausal women not only have a high prevalence of major risk factors, such as hyperlipidemia, hypertension, diabetes, and obesity, they also face a higher risk for CHD events. These characteristics provide a high yield when screening for CHD risk and an important opportunity for measurable and substantial improvements in survival.

In the United States, coronary heart disease (CHD) is by far the principal cause of death in both men and women; however, the persistent misperception that CHD is a disease predominantly affecting men contradicts an objective survey of its epidemiology. Although there is nearly a 10-year lag between the onset and peak incidence of cardiovascular events in women, the annual number of deaths due to CHD is greater in women than in men (see Figure 1).

Figure 1. Leading causes of death for all males and females, United States: 1998.

The delay in heart disease among women is commonly attributed to the protection derived from endogenous estrogen. There is a steady age-related increase in CHD in women with a slowing of rates in older men, suggesting that male hormones may contribute to this sex-specific difference. "CHD is a progressive disease process in women as in men. By intervening in modifiable risks, such as hyperlipidemia, hypertension, and diabetes, we can anticipate reductions in mortality and morbidity. There is a substantial opportunity for benefit in both men and women," stated Dr. Mosca.

"There is no jump in the risk for CHD after menopause. Although the risk is delayed in women, the pathological changes that lead to cardiovascular events, particularly atherosclerosis, begin decades earlier in both sexes," commented Dr. Mosca.

The major risk factors for cardiovascular disease are the same in women and men. These include elevated serum lipids, hypertension, obesity, sedentary lifestyle, and smoking. The prevalence of these risk factors increases with age and may worsen through menopause. For example, about 50% of women are hypertensive by 45 years of age and the rate progressively rises. Obesity and type II diabetes are common and growing problems in relatively young women. About 25% of adult women, regardless of age, report no regular sustained physical activity. While the prevalence of hyperlipidemia by 55 years of age is already 40%, abnormal serum lipids are often detected years before menopause.

"The absolute risk for events does not increase substantially in women until after 50 years of age, but the process of atherosclerosis begins much earlier. Our best opportunity to reduce cardiovascular risk in either women or men would be to identify risk factors early in life and intervene at initial stages in the disease process, especially because first events are often fatal in women," said Dr. Mosca.

Execution of effective intervention in women may be hampered by two important obstacles:

• Women are less likely than men to be evaluated for cardiovascular risk factors
• Women are less likely to receive adequate counseling and treatment about risk factor control even after modifiable risk factors have been identified, even in women with established cardiovascular disease

Additionally, after a myocardial infarction (MI) or other serious cardiovascular event, women are less likely than men to enroll in cardiac rehabilitation programs where aggressive risk factor interventions are offered. "The reasons that women are less likely to be screened for risk factors and then are less likely to receive counseling about risk management are complex," said Dr. Mosca. "But the fact that women share the same types of risk factors with men is undeniable. In some cases, adverse trends in risk factors are more ominous in women. For example, smoking rates are declining more slowly in women than in men."

Some risk factors, such as diabetes are riskier in women than in men. In women, diabetes increases cardiovascular risk by 3- to 7-fold compared with a 2- to 3-fold increase for men. Low levels of high density lipoproteins (HDL) and elevated levels of triglycerides also appear to be a stronger risk for cardiovascular events in women older than 65 years of age than in men of the same age group.

It is prudent to screen and treat risk factors early before disease progresses to more advanced stages. The American Heart Association/American College of Cardiology Guide to Preventive Cardiology for Women has identified pregnancy and the preconception period as an "optimal time to review a woman's risk factor status and health behaviors to reduce future cardiovascular disease." It is never too early to think about CVD risk reduction, and women are often motivated to adopt healthy lifestyle habits, such as stopping smoking during pregnancy.

Significant risk reductions can be achieved even after disease has progressed. Although menopause should not be considered a specific event with immediate implications for increased risk for cardiovascular disease, elevated risks are highly prevalent in the postmenopausal population. As a result, a high yield can be anticipated from screening for risk factors in this population. More important, due to an increased risk for events, there is a significant opportunity for substantial reductions in morbidity and mortality from intervention over a relatively short term.

The specific guidelines for intervention in women vary only slightly from those for men. In general, lifestyle modifications are recommended for patients with mild dyslipidemias or hypertension except in those with established cardiovascular disease (see Table 1).

Table 1. (click to enlarge) Guide to Cardiovascular Risk Reduction in Women

Drug therapy is appropriate with increasing severity of elevated lipids or blood pressure. In patients with diabetes or a prior cardiovascular event, such as MI or revascularization procedure, lipid-lowering therapy (statins) may be beneficial regardless of the presence or absence of hypercholesterolemia.

While menopause does not mark the beginning of cardiovascular risk, it does define a period in which screening for risk factors is likely to identify important opportunities for intervention. Health maintenance in postmenopausal women should include careful monitoring of modifiable risk factors and initiation of therapy when warranted.

"One of the most important health issues for the postmenopausal female is cardiovascular health. The recent evidence that HRT does not provide cardioprotection provides an opportunity to emphasize other strategies to improve cardiovascular health in this population," concluded Dr. Mosca.

Key Points

• CHD is a progressive pathological process that begins decades before it is clinically manifest.
• CHD is the primary cause of death in both women and men, but women tend to be treated less aggressively for elevated risk factors, even those women who have already had their first cardiovascular event.
• Treatment of modifiable risk factors provides an important opportunity to reduce the burden of cardiovascular disease in women.

The Women's Health Initiative (WHI) estrogen/progestin treatment arm was halted prematurely because the rate of invasive breast cancer exceeded the preset boundary of excess risk in the group of predominantly healthy menopausal women randomized to conjugated equine estrogen plus medroxyprogesterone acetate (HRT) compared with placebo; however, from a clinical perspective, equal harm may be the excess rates of coronary events, stroke, and pulmonary embolism in the HRT group.

"The Women's Health Initiative is the largest study of menopausal women ever undertaken. Women randomized to HRT were placed on the regimen most commonly used by women in the United States. The results clearly show that this hormone regimen is not cardioprotective but rather appears to increase the risk for adverse vascular events," reported Dr. Wenger. The estrogen-only arm of the trial in women with hysterectomy is ongoing.

Results of WHI were not dissimilar to those of the Heart and Estrogen/Progestin Replacement Study (HERS) completed several years earlier. Although WHI was largely a primary prevention trial because fewer than 8% of randomized women had a prior diagnosis of coronary heart disease (CHD), the failure of HRT to provide benefit in HERS, a secondary prevention trial, also suggested that HRT might adversely affect cardiovascular health. By the end of the 4-year HERS trial, there were no significant differences in cardiovascular events among menopausal women with CHD randomized to conjugated equine estrogen plus medroxyprogesterone acetate compared with placebo.

"The lack of cardiovascular benefit was concordant with a two-fold increase in the risk for venous thromboembolism, which predominated in the early years of the study," noted Dr. Wenger, as well as an increased risk of gall bladder disease requiring surgery.

In WHI, 16,608 patients were randomized to receive HRT (0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate in a once-daily tablet) or placebo. The trial was scheduled for completion in 2005, providing an average 8.5 years of follow-up; however, it was halted in July 2002 after a mean of 5.2 years of follow up when an interim analysis found that the preset boundary for excess invasive breast cancer risk was exceeded in the HRT group. An excess risk for cardiovascular events had been detected as early as 1999, but the preset boundary for this risk had not been reached when discontinuation was prompted by the 26% increase in invasive breast cancer.

"Earlier in the trial, participants were notified that an increased risk for myocardial infarction, stroke, and pulmonary embolism had been observed but that the study was being continued because the potential later benefits might still exceed the risks," recounted Dr. Wenger. "Notification was considered necessary because an increased risk for adverse cardiovascular events had not been anticipated and was not incorporated in the informed consent document."

Since WHI was designed before HERS was completed, cardiovascular risk was not anticipated. Both WHI and HERS were based on the hypothesis that HRT would be cardioprotective. Adverse cardiovascular effects had not been considered a significant risk; however, when results of HERS were published in 1998, the risk for HRT appeared to exceed the benefit in women with established CHD. Even though there was no significant difference in coronary death and non-fatal MI between the active treatment and placebo groups at the end of the trial, a higher rate of coronary death and non-fatal MI during the first year of the study raised questions about the safety of HRT.

At the time of publication, the results of HERS generated speculation about the potential for flaws in the trial design. The most common criticism was that the trial was not of adequate duration to capture potential late benefits of HRT; yet, the recently completed HERS II, which was initiated primarily to address this criticism, also failed to show cardiovascular benefits even over a longer term.

"More than 90% of the surviving HERS participants enrolled in HERS II, but the longer follow-up did not associate HRT with significant cardioprotection," observed Dr. Wenger.

In the initial HERS trial, 2763 postmenopausal women with established coronary heart disease were randomized to HRT or placebo. In HERS, as in WHI, the HRT regimen consisted of 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate once daily. Again, this regimen was chosen because it was the most commonly used HRT among women in the United States. The overall cancer rate in the HERS studies was 19% higher in the HRT group than in those randomized to placebo. Although this did not reach statistical significance, breast cancer, the most common of the cancers, occurred more frequently in the HRT group on a numerical basis.

While the first HERS trial also associated HRT with a trend to increased gallbladder disease leading to biliary tract surgery (P=.09), the difference between HRT and placebo became statistically significant (P<.05) in HERS II. At the end of this follow-up, the rate of biliary surgery was almost 50% higher in the HRT group. The increased risk was attributed to the association between estrogen use and increased cholesterol concentration in bile.

The failure of HRT to show protection from progression of existing coronary disease in HERS and HERS II, and failure of protection from cardiovascular disease in WHI reinforces the net adverse effect of HRT on vascular function. These results appear to conflict with previous observational data; however, a recently published meta-analysis of these observational trials that corrected for socioeconomic status, educational level, and coronary risk factors, failed to show cardiac protection.

"The results are now quite consistent and strongly indicate that a HRT regimen that combines estrogen and progestin should no longer be considered part of the strategy for reducing cardiovascular risk in menopausal women," stated Dr. Wenger. "The absence of cardioprotection contrasts markedly with the well established benefit of intervention for modifiable risk factors, such as smoking cessation, weight control, increased physical activity, heart-healthy diet, and control of elevated blood pressure and serum lipids."

Key Points

• The largest intervention trial ever undertaken in postmenopausal women has associated HRT with an increased risk for cardiovascular events, stroke, and pulmonary embolism. This risk, plus the increased risk for breast cancer, exceeds the benefit of protection afforded by HRT against fractures and colorectal cancer.
• The absence of primary prevention against cardiovascular disease by HRT, as documented in WHI, was anticipated by the absence of secondary prevention in HERS and further substantiated by a revised meta-analysis of observational studies.
• HRT is not effective in reducing cardiovascular risk in menopausal women and does not appear to have a favorable effect on overall health maintenance in this population. The US Preventive Services Task Force does not recommend HRT for the prevention of chronic illness.
• None of these studies addresses HRT use for amelioration of menopausal symptoms.

 

In the landmark Heart Protection Study (Lancet. 2002;360:7-22), an HMG CoA reductase inhibitor (statin) was shown to protect women from cardiovascular events. The magnitude of benefit in women closely paralleled that observed in men. "The benefit in women is not surprising based on what we know about the pathophysiology of disease, but this is the first clear evidence that women benefit to the same degree as men with a similar baseline risk," reported Dr. Collins.

Men and women as young as 40 years of age were eligible for this trial; however, due to the requirement for preexisting or elevated risk for coronary disease, the vast majority of women fell into the postmenopausal age group. "Our original upper age limit was 75, but due to the fact that women develop heart disease at an older age than men, we raised this limit in order to help recruit more women (and older individuals)," reported Dr. Collins. "In men and women, there was a fairly consistent relative risk reduction at any age, but the absolute benefit during the 5 years of the study was greatest in the older ages because they were at greatest risk for events over the course of the trial."

Patients were eligible for this study if they had coronary disease, another occlusive arterial disease, or diabetes. They were randomized to 40 mg/day of simvastatin [Zocor; Merck & Co., Inc.] R or matching placebo, and followed for an average of 5 years. Two-thirds compliance with allocated treatment produced an average reduction of low-density lipoprotein (LDL) cholesterol of 40 mg/dL during the trial. Of the 20,536 patients included in the study, 5082 were women, the largest number of women ever studied in a prospective intervention trial with lipid-lowering therapy. Other presenting features of the study population are outlined in Table 2.

Table 2.

"One of the most important points to make about this study was that the absolute benefit correlated to the degree of baseline risk, not the baseline lipid level. In women as in men, significant risk reductions could be achieved with statin therapy regardless of baseline lipid levels," reported Dr. Collins. "That emphasizes that the target of therapy is an individual's risk, not their lipid levels. Even those with a baseline pre-treatment LDL level below 100 mg/dL derived significant benefit."

In the Heart Protection Study, all-cause mortality was reduced by 12% with simvastatin allocation versus placebo (P<.001). Death from heart disease or related blood vessel disease was reduced by 17% (P=.0002). Simvastatin allocation was also associated with reductions of one quarter in major coronary events (P<.0001), in strokes (P<.0001), in revascularizations (P<.0001), and in all such major vascular events (P<.0001).

There was no significant difference in these proportional reductions in major vascular events when the results were stratified by sex. Relative benefits remained virtually unchanged when patients were compared by age, type of risk (such as prior myocardial infarction or diabetes), use of other cardiovascular drugs, or the presence of controlled hypertension. "There have been suggestions that some patients may be too old to benefit from lipid control, or that lipid control might not be as effective in women as in men, but this study shows remarkable consistency across every subgroup we evaluated," claimed Dr. Collins.

Approximately 3500 patients with a LDL level of about 100 mg/dL or less entered the trial. "These patients are already below the most extreme target recommended in any guidelines and yet their relative risk reduction from lipid lowering therapy was the same as those who started at high baseline levels," explained Dr. Collins. "This tells us that in patients with established risk for cardiovascular events, the benefit does not depend much on what the baseline lipids are."

Overall, a 40 mg/dL reduction in LDL provided about a 25% reduction in vascular disease risk over a 5-year period in the Heart Protection Study. According to Dr. Collins, the study shows that in high-risk patients, defined by a previous cardiovascular event or diabetes (which is now considered a cardiovascular event equivalent); no lipid level should be considered normal.

"LDL reductions are a means to an end, not the end itself. The target has to be reduction in risk, and therapies to reduce lipids (and other risk factors) should be more aggressive for people at higher absolute risk -- irrespective of their presenting lipid levels," explained Dr. Collins.

According to the experience with simvastatin in the Heart Protection Study, there appears to be little risk associated with aggressively treating lipids. The excess of myopathy with a 40 mg/day dosage of simvastatin was not significant, although it was compatible with an excess of just

0.01% per annum. Dr. Collins characterized simvastatin as "exceptionally well tolerated."

The results of the Heart Protection Study have relevance to all individuals at significant risk for a cardiovascular event, but the implications for women, who are less likely to be assessed for cardiovascular disease and less likely to be treated when evidence of disease is detected, deserve emphasis. While the onset of cardiovascular disease in women lags by about 10 years compared with men, similar protection from events can be achieved when risk factors are controlled. The presence of diabetes greatly lowers the age at which first events occur.

"The absolute benefit of simvastatin in women eligible for the Heart Protection Study was not different from that in men at similar risk. Women at high risk should be considered for lipid lowering therapy regardless of their cholesterol level. We know from the Heart Protection Study that this will produce substantial reductions in the risk for first and subsequent major vascular events among such women," said Dr. Collins.

Key Points

• Women at the same risk as men benefit to the same degree as men from lipid lowering therapy.
• In the Heart Protection Study, allocation of simvastatin was associated with a 12% reduction in all-cause mortality, a 17% reduction in cardiovascular mortality, and reductions of one quarter in major coronary events, strokes, and revascularizations (i.e. "major vascular events").
• The relative reduction in the risk for major vascular events was similar regardless of baseline cholesterol levels (including very low levels of LDL) demonstrating that risk rather than cholesterol level should determine when to initiate lipid-lowering therapy.
• Due to the increasing prevalence of risk with age, postmenopausal women at high risk for heart attacks and strokes are appropriate candidates for lipid-lowering therapy.

 

"Before WHI, there was a widespread belief that hormones were a panacea with respect to women's cardiovascular health. By placing women on a replacement regimen, it was thought that cardiovascular risk could be substantially reduced. The results of WHI tell us we need to go back to square one," according to Dr. Oparil, who believes that returning to the starting point will necessitate "evaluating women for established risk factors and providing effective intervention."

While lowering lipids in women at risk is very important, it is critical to recognize all cardiovascular disease risk factors and intervene accordingly. It is very important to treat all modifiable factors that increase the risk of cardiovascular disease progression and events. According to the AHA/ACC Consensus Panel Statement, Guide to Preventive Cardiology for Women, the modifiable lifestyle risk factors are cigarette smoking, inadequate physical activity, a high caloric and/or high fat diet, excess weight gain, excess stress, elevated blood pressure, elevated serum lipids, and diabetes.

Hyperlipidemia is an important target in the management of cardiovascular risk, but it should not be set apart from other risk factors such as hypertension or diabetes. "To say that hyperlipidemia is more important than hypertension fails to recognize the important interaction between risk factors. Both can play an important role," commented Dr. Oparil. "While menopause is not a cardiovascular risk factor, risk factors accumulate when women age and menopause is a milestone in the aging process. The guidelines, based on evidence, tell us that more aggressive therapy is needed for patients at greater risk."

Dyslipidemias and hypertension do not appear suddenly at menopause but represent ongoing processes that might not produce clinical consequences for decades. Therefore, screening for cardiovascular risk factors should not be withheld until menopause. Early detection of risk factors may permit the type of lifestyle interventions that circumvent the need for medication; however, hypertension risk is strongly age-related. By 65 years of age, more women are hypertensive than normotensive (see Figure 2). In some subgroups, such as African-American women, 75% have hypertension by 65 years of age. Remarkably, about 80% of elderly women (>75 years of age) in the US are hypertensive.

Figure 2. (click to enlarge) Estimated prevalence of cardiovascular diseases in Americans age 20 and older by age and sex, United States: 1988-1994.

"It is possible that the reduction in endogenous estrogen levels makes some contribution to the increase in hypertension that occurs with increasing age in women," suggested Dr. Oparil. "We know that there is a small reduction in blood pressure, as there is in total and LDL cholesterol, with hormone replacement therapy (HRT, estrogen with or without progestin), but the effect is modest. Results of WHI and other studies tell us that this effect of HRT does not produce a net benefit in terms of cardioprotection."

"Blood pressure should be measured annually in adult women as in adult men. Blood pressures tend to rise progressively with age, so spotting the problem early in life has important advantages," suggested Dr. Oparil. In particular, some of the risk factors that contribute to hypertension, such as excess weight and inadequate exercise, should be addressed early on, before bad habits become ingrained. The sedentary lifestyle that contributes to these problems often starts at a very young age.

"There are alarming data indicating that lack of exercise is becoming a terrible problem in girls. In some populations of teenage girls, physical activity is essentially zero," observed Dr. Oparil. "These girls are at very high risk for developing obesity, lipid problems, and hypertension. These are not issues just in older adults."

However, due to the low absolute rate of cardiovascular events in younger women, it is not uncommon for major cardiovascular risk factors to remain undetected and untreated in women until later in life. In postmenopausal women, it is not too late to substantially reduce risks with aggressive treatment of hypertension and other risk factors, but Dr. Oparil warned that many of these women can no longer be adequately managed with lifestyle changes alone. They usually require aggressive medical treatment including lipid-lowering agents and multiple antihypertensive drugs.

It is important to consider all cardiovascular risk factors because the treatment goals are different for those with multiple risk factors than for those with fewer, according to Dr. Oparil. In the case of hypertension, a goal of 140/90 mm Hg may be acceptable for women with a modest blood pressure elevation and no other risk factors. However, in women with a previous history of cardiovascular disease, renal disease, or diabetes mellitus, the target should be 130/80 mm Hg, a goal recommended by a member of expert consensus panels and reinforced by results of the Hypertension Optimal Treatment (HOT) trial.

"The goals of blood pressure treatment are not different by gender, but hypertension control tends to be more of a problem in the elderly. These individuals usually have systolic rather than diastolic hypertension, and it is important for physicians to recognize that control of systolic blood pressure to a goal of 140 mm Hg or lower is not going to be easy to achieve," warned Dr. Oparil. "Many patients will need a cocktail of drugs to get them to goal."

In postmenopausal women, the drug combination should include a diuretic. Diuretics have been shown to be particularly effective for control of systolic hypertension, and as Dr. Oparil pointed out, these drugs are particularly effective in older women who tend to be very salt sensitive. Another attractive drug class in this population is angiotensin II receptor blockers (ARBs). Both effective and well tolerated, ARBs appear to have other benefits important to cardiovascular risk, such as reduction of left ventricular hypertrophy (LVH). This was emphasized in a recent trial in which the ARB losartan [Cozaar; Merck & Co., Inc.] was compared with a beta blocker. According to Dr. Oparil, "losartan was very effective in regression of LVH, and in prevention of stroke and new-onset diabetes; the benefits seemed to be particularly pronounced in women."

The guidelines issued by the National Heart, Lung, and Blood Institute (JNC-6) include detailed information about strategies for blood pressure control, including treatment threshold and blood pressure goals stratified by risk. These guidelines -- or earlier versions -- existed long before results of WHI were disseminated, but the absence of cardiovascular benefits with HRT in WHI has emphasized the importance of adhering to strategies for risk reduction through traditional routes. The physicians who manage the health of postmenopausal women, including primary care physicians and gynecologists, should accept this responsibility.

"The individuals at the highest risk for cardiovascular disease, which is the number one cause of death regardless of gender, are aging women, and, in terms of hypertension, this is the group that is least well controlled," stated Dr. Oparil. "Results of the WHI were disappointing, but it is important to emphasize that there are effective therapies for managing cardiovascular risk factors and these have been shown to have an important impact on survival in women."

Key Points

• The failure of hormone replacement therapy to reduce cardiovascular risk in the WHI has renewed emphasis on the importance of controlling traditional risk factors, such as hypertension, smoking, excess weight, and lack of exercise.
• Hypertension is more common than normal blood pressure in women older than 65 years of age and is at least as important a target for intervention as hyperlipidemia in postmenopausal women.
• Hypertension and hyperlipidemia have additive effects on risk and more aggressive therapy of each is appropriate when they occur together.
• Systolic hypertension is the dominant form of elevated blood pressure in postmenopausal women, many of whom may require combination therapy regimens to achieve treatment goals.

The best opportunity for primary prevention of cardiovascular disease is early in the disease process; however, it is not uncommon for men and women to address modifiable risk factors -- if they address them at all -- only as they near or reach the age at which events take place. For women, this period of risk does not typically begin until after menopause. This initial relative protection from cardiovascular disease may be one reason that women are less likely to seek care or receive treatment for risk factors.

"The absolute event rate is very low in women under the age of 55. This does not mean that the relative benefit from intervention is any less. It just makes these benefits difficult to demonstrate in younger women," reported Dr. Blumenthal.

The failure to assess women for cardiovascular risk factors prior to menopause may reduce the proportion of women whose cardiovascular risk can be managed by lifestyle alone, but the benefits of modifying diet, increasing exercise, reducing weight, and eliminating smoking should not be underestimated.

"It is important to recognize that not everyone needs to be treated with medicine. Physicians have a responsibility to prescribe lifestyle modifications because of the opportunity for major health benefits," suggested Dr. Blumenthal. These benefits include substantial improvements in serum lipids and reductions in blood pressure. In compliant patients, even mild diabetes can be reversed with weight loss and increased exercise. Patients who require medication will benefit from an improved diet and increased exercise, which may reduce the drug requirement, thereby reducing the risk for side effects and lowering the cost of care.

In postmenopausal women, the initial goals of increased exercise must be weighed against risk for injury. In sedentary women, it is particularly important to gradually increase exercise to target levels. A healthy diet can be based on weight loss goals and degree of serum lipid abnormality. Blood pressure goals are relatively standard among men and women and are defined in guidelines from the JNC VI.

While there are small but important differences in target lipid levels among women compared with men, particularly in regard to triglyceride and high-density lipoprotein (HDL) levels, it is important to recognize that low-density lipoprotein (LDL) reductions are now tied to underlying risk. More aggressive LDL reductions are appropriate in women with multiple risk factors.

"Cardiovascular disease develops on a continuum. The question in primary prevention, especially for those in the older age group, is not whether cardiovascular disease is or is not present. Rather, it is to identify risk factors and provide interventions appropriate to the patient's level of risk," explained Dr. Blumenthal. "Risk factors are extremely prevalent in postmenopausal women, making this group an important target for intervention."

Key Points

• The optimal opportunity for primary prevention is at the earliest stages of cardiovascular disease, which may begin two or more decades before events.
• While many women may not be assessed for risk factors until the postmenopausal period, when the cardiovascular disease process is already advanced, lifestyle modifications may still be effective in reversing risks and avoiding pharmacologic therapy.
• In aging women, as well as in aging men, the atherosclerotic burden may already be advanced even in the absence of symptoms, complicating the concept of primary prevention. The goal is to ascertain the level of risk and intervene appropriately.

 

In women who have had a previous cardiovascular event or who have diabetes mellitus, the risk for a cardiovascular event during the 5 years following can reach or exceed 20% depending on the severity and total number of risk factors. A substantial proportion of these events is likely to be fatal.

In discussing cardiovascular disease mortality trends, Dr. Blumenthal noted, "the reason that initial cardiovascular events are more likely to be fatal in women than men is not completely understood." (See Figure 3)

Figure. Cardiovascular disease mortality trends for males and females, United States: 1979-1998.

"However, it is one reason to suggest that efforts to manage cardiovascular risk should be at least as aggressive in women as in men," he emphasized.

The most significant recent advance in secondary coronary heart disease (CHD) prevention for both sexes is the evidence of benefit from aggressive LDL lowering regardless of baseline LDL level. The substantial mortality reductions associated with reductions of LDL in high-risk patients, independent of age, sex, background cardiovascular therapy, or baseline serum lipid levels, were demonstrated with simvastatin in the Heart Protection Study. The results have generated a new orientation in risk management.

"The evidence that benefit is independent of lipids has changed our practice, and it is important to emphasize that the magnitude of the benefit from lipid lowering therapy in high-risk patients was nearly as good in women as in men," emphasized Dr. Blumenthal.

Secondary prevention should not be based solely on a pharmacologic protocol. Although pharmacologic therapy may be necessary to control concomitant hypertension, prevent hypertrophy, or inhibit neuroendocrine stimulation, rehabilitation should also involve lifestyle modifications. Smoking cessation, improved diet, and increased exercise have the potential to make significant contributions to risk reduction.

"High-risk patients should undergo a comprehensive management program that addresses multiple factors. Lipid lowering therapy may be the foundation for efforts to reduce risk for events, but patients need to participate in a strategy for improving overall health status," suggested Dr. Blumenthal.

Guidelines for specific risk modifications, such as hypertension control, are generally more aggressive in high-risk patients. Due to the additive contribution of risks, each degree of improved control may provide a meaningful reduction in projected risk. Unlike patients without established disease, patients who already have had a myocardial infarction face finite and well established risks.

"Women face an equivalent lifetime risk for heart disease relative to men. The evidence that women are treated less often and less aggressively than men is a significant public health problem that needs to be addressed. It is an even more serious problem in women with established cardiovascular disease. As in men, aggressive risk factor control in high-risk women provides a significant opportunity to save lives," claimed Dr. Blumenthal.

Key Points

• Aggressive lowering of LDL regardless of baseline LDL level is indicated as a secondary prevention strategy in all patients with established cardiovascular disease, as demonstrated by the highly significant cardiovascular benefits achieved with simvastatin in the Heart Protection Study.
• Women, because they have a higher risk for fatal cardiovascular events than men, can be expected to achieve at least the same degree of benefit from aggressive secondary interventions as men. These interventions provide an important opportunity to save lives regardless of sex.

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