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Cardiovascular Disease and Dyslipidemia in Women
Francine K. Welty, MD, PhD
Arch Intern Med. 2001;161:514-522.
ABSTRACT
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Cardiovascular disease, primarily coronary heart disease (CHD), outnumbers
the next 16 causes of death in women combined. However, the long-held belief
that heart disease in women has a more benign prognosis than in men has resulted
in less aggressive diagnosis and management patterns. Appreciation of the
differences between men and women in CHD risk factors and presentation can
assist in treatment decisions. Although estrogen replacement offers substantial
beneficial effects on lipid levels in postmenopausal women, the first 2 randomized
trials of estrogen alone and estrogen plus progestin, the Heart and Estrogen/Progestin
Replacement Study and Estrogen Replacement and Atherosclerosis Study, observed
no benefit in reducing risk of CHD death and nonfatal myocardial infarction
and angiographic progression of CHD, respectively, in women with CHD. Available
data show that lipid-lowering therapy reduces women's CHD risk and mortality
but also indicate that a considerable proportion of women remains untreated
or undertreated. Randomized trials of statins for primary and secondary prevention
of coronary heart disease suggest that these agents are at least as effective
for lowering coronary disease risk in women as in men. Therefore, statin drugs
should be the drug of first choice for women with established CHD. Hypercholesterolemic
postmenopausal women who require estrogen for menopausal symptoms may derive
further reductions in low-density lipoprotein cholesterol and reductions in
trigyceride levels with the addition of a statin drug.
INTRODUCTION
Cardiovascular disease (CVD), particularly coronary heart disease (CHD),
is the leading cause of death among women aged 60 years and older.1, 2, 3, 4 Cardiovascular
disease deaths, primarily from CHD, outnumber the next 16 causes of death
in women combined, including all cancers.5
Indeed, women are 4 to 8 times more likely to die of CVD than of any other
disease.6 African American women have an even
poorer prognosis: for ages 35 to 74 years, the age-adjusted CHD mortality
rate is 69% higher than that of white women.5
Approximately 520 000 women die of CVD each year.5
Since 1980, death from CVD has declined dramatically in men, whereas it has
increased in women. Since 1984, annual CVD mortality in women has exceeded
that of men by about 50 000 a year.5
PRESENTATION OF CVD IN WOMEN
Despite this abundant evidence to the contrary, the perception persists
that CVD mainly affects men and is not a serious concern for women. This misconception
arose in part from sex differences in age at onset. In general, CHD begins
about a decade later in women than in men. The incidence of CHD in women is
significantly lower before menopause, a protection that has been attributed
to the effects of estrogen.3, 7
Women develop angina about 10 years later and a first myocardial infarction
(MI) about 20 years later than men do.1, 2, 8
An additional reason for this misconception is that chest pain is less
likely to be associated with substantial epicardial coronary artery disease
in women. As a result, sex differences in outcome after a diagnosis of angina
have been reported. In Framingham, although more women (47%) than men (29%)
had angina as their presenting symptom, it led to more serious disease in
only 19% of the women vs 44% of the men.9 Men
had 43% of the MIs vs 29% for women. In a 10-year follow-up of all Rochester,
Minn, residents diagnosed as having angina between 1960 and 1979, women with
angina had a lower risk of MI and a relative risk (RR) of 0.45 of dying compared
with men.10 In neither study was the diagnosis
of angina confirmed by objective measures.
Studies of patients presenting with acute chest pain have reported lower
rates of MI in women than in men. In the Myocardial Infarction Triage and
Intervention Registry (MITI) study, only 19% of women vs 26% of men admitted
to coronary care units for suspected MI developed MI.11
In another study, although equal numbers of men and women presented to emergency
departments complaining of chest pain, 19% of men compared with only 10% of
women were found to have MI.12
A possible explanation for these sex differences is that chest pain
syndromes in women are more likely than those in men to be accompanied by
angiographically normal coronary arteries. Overall, 50% of women examined
for chest pain in the Coronary Artery Surgery Study (CASS) had minimal or
no coronary arterial narrowing compared with only 17% of men.13
Reflecting this pattern, data from more than 80 000 hospital discharges
in 2 states indicate that women have higher rates of hospital admission for
ischemic symptoms without evidence of CHD; men who present with chest pain
are more likely to have severe coronary artery stenoses.14
These and similar findings led most physicians to conclude that most women
with chest pain did not have CHD or that their CHD prognosis was benign. Consequently,
women's participation in primary and secondary prevention trials has been
limited until recently.15
Compounding diagnostic problems, exercise treadmill testing has less
specificity in women than in men and, therefore, has less utility as a diagnostic
tool in women.16, 17, 18, 19, 20, 21
The addition of thallium to exercise treadmill testing improves sensitivity
and specificity in women; however, in a study of 390 consecutive patients
referred for exercise treadmill testing with thallium, of patients with a
positive test, 40% of men but only 4% of women were referred for catheterization.22 Of women with abnormal results of stress tests, 28%
were considered by their physicians to have a noncardiac cause for their chest
pain compared with 13% of men.22 Among patients
with an ejection fraction less than 0.40 after MI enrolled in the Survival
and Ventricular Enlargement (SAVE) study, men were twice as likely as women
to have undergone a cardiac procedure before the index infarction, even though
women reported greater functional disability from angina before the MI.23 Although coronary angiography and percutaneous transluminal
coronary angioplasty (PTCA) may be used less often in high-risk women than
in high-risk men, of those who do undergo coronary angiography, referral rates
for PTCA and coronary artery bypass grafting (CABG) are equivalent to those
for men.11, 23 These findings suggest
that, once an angiographic diagnosis of CHD is made in women, referral rates
for PTCA and CABG are similar.
Difficulties in diagnosing CHD in women on the basis of chest pain and
noninvasive testing may contribute to lower referral rates for catheterization
and revascularization. Newer noninvasive diagnostic modalities, such as electron
beam computed tomography, which can identify the presence or absence of coronary
artery disease, may assist in the diagnosis of coronary artery disease in
women. Unequivocal identification of coronary artery disease would allow for
early aggressive risk factor modification and medical management, including
dietary changes, exercise, and lipid-lowering therapy to prevent progression
of disease.
Early diagnosis in women is important, since two thirds of sudden deaths
occur in women with no CHD history.1 In addition,
women have a poorer prognosis and more severe outcome after MI, PTCA, and
CABG compared with men.1 Women are more likely
than men to die after a first MI, and, for survivors, there is a higher risk
of another infarction and death.1 In the Framingham
Heart Study, 44% of women who had an MI died within 1 year, compared with
27% of men.3 Some of the sex differences in
outcome may be related to the greater age of women at which they develop CHD.
Because age is a nonmodifiable risk factor, it is important to recognize risk
factors for CHD in women early and aggressively reduce them to prevent CHD.
CHD RISK FACTORS IN WOMEN
Menopause and Dyslipidemia
Natural menopause confers a 3-fold increase in CHD risk.3
In the Nurses' Health Study cohort, women undergoing bilateral oophorectomy
had up to an 8-fold increase in risk of CHD.24
After age 50 years, cholesterol levels plateau in men; however, levels of
low-density lipoprotein (LDL) cholesterol increase an average of 0.05 mmol/L
(2 mg/dL) per year between ages 40 and 60 years in women.25
At least part of this increase results from declining levels of estrogen,
which result in down-regulation of the LDL receptor on the liver.7, 26, 27 A high LDL cholesterol
level is a strong predictor of CHD risk in women younger than 65 years and
a somewhat weaker predictor in women aged 65 years and older.28
Increases in levels of total cholesterol, very-low-density lipoprotein (VLDL)
cholesterol, and triglycerides have also been observed after menopause.26, 27
In the cross-sectional National Health and Nutrition Examination Surveys
(NHANES), high-density lipoprotein (HDL) cholesterol levels were lower in
men than in women and did not change with age.25
However, in 2 smaller longitudinal studies, levels of HDL cholesterol decreased
in postmenopausal women.27, 29
A low HDL cholesterol level is a stronger predictor of CHD mortality in women
than in men and particularly so in women 65 years of age and older.2, 28, 30 Stevenson et al27 reported that the HDL2 cholesterol subfraction,
which is considered to be more cardioprotective than HDL1or HDL3, showed a marked drop after the onset of menopause. The risk of coronary
events increases with each increment in the ratio of total to HDL cholesterol.
In the Framingham Heart Study, the 8-year risk of heart disease was 7% for
women with a total/HDL cholesterol ratio less than 5, 12% for those with ratios
of 5 to 7, and 20% for those with ratios greater than 7.3
In a study of 2500 women aged 71 years and older, those with HDL cholesterol
levels less than 0.9 mmol/L (35 mg/dL) had a RR of CHD mortality twice that
of women with HDL cholesterol levels of 1.6 mmol/L (60 mg/dL) or more.30, 31
Elevated triglyceride concentrations are a particularly significant
risk factor in women, especially when the HDL cholesterol level falls below
1.03 mmol/L (40 mg/dL).32, 33 Average
or high HDL cholesterol levels appear to attenuate the triglyceride-associated
CHD risk. An increase in small, dense LDL particles also characterizes the
postmenopausal atherogenic shift34; these particles
are associated with a 3-fold increase in MI risk.35
Smoking
The leading preventable cause of CHD in women is cigarette smoking.4 More than 50% of MIs in middle-aged women can be attributed
to tobacco use.2 The risk in heavy smokers
( 20 cigarettes per day) is 2 to 4 times higher than in nonsmokers, and
even light smokers (1-4 cigarettes per day) have double the risk of nonsmokers.4, 36 Stopping smoking decreases the CHD
risk within months. Although the prevalence of smoking in recent years has
dropped in both men and women, women's rate of smoking cessation is still
lower than that of men. Almost one fourth of women still smoke cigarettes;
the greatest increase in the prevalence of smoking is in women aged 65 years
and older.1
Hypertension
Elevated systolic and diastolic blood pressure confers an increased
risk of CHD in both men and women. Women with hypertension have a 4-fold risk
of heart disease compared with normotensive women, whereas hypertension in
men is associated with a 3-fold increase.2, 37
Isolated systolic hypertension in older women, which has a 30% prevalence
in women older than 65 years, is of particular concern.2
The prevalence of hypertension increases with age, and, because of their
survival advantage, women with hypertension outnumber men with hypertension
in the older age groups.38 Its estimated prevalence
(identified as a blood pressure 140/90 mm Hg or use of antihypertensive
medication) in women older than 45 years is 60% for white women and 79% for
African American women.2
Diabetes Mellitus
Diabetes is a greater predictor of CHD for women than for men.4, 39 Diabetes also reduces women's life-expectancy
advantage.4, 40 Women with diabetes
have a CHD-related mortality rate 3 to 7 times higher than that of nondiabetic
women, whereas men's CHD mortality rate is 2 to 4 times higher than that of
nondiabetic men.41 The reasons for this sex
difference are not clear but may be related to differences in lipid levels.
A low HDL cholesterol level of 1.3 mmol/L (50 mg/dL) or less and a VLDL cholesterol
level of 0.5 mmol/L (20 mg/dL) or more confer a higher CHD risk in diabetic
women than in men with diabetes.39
Obesity and Physical Inactivity
Obesity has been increasing in both men and women in the United States
in the past few decades. Obesity and a sedentary lifestyle are interrelated.2, 42 About 25% of women report that they
have no regular, sustained physical activity.42
An increase in body mass index has been associated with an increase in the
RR of nonfatal MI and fatal CHD.42 Abdominal
obesity may be a particularly important CHD risk factor in women; the waist-hip
circumference appears to be a more important predictor of risk than the body
mass index.43
Although few studies of exercise and CHD risk have included women, available
data suggest that active women have a lower risk than their sedentary counterparts.2 Even brisk walking and other moderate-intensity activities
will substantially reduce CHD risk.44 Exercise
and dietary modifications resulting in weight loss have beneficial effects
on triglyceride levels even in persons with diabetes,45
and HDL cholesterol levels have shown a dose-response relationship in female
runners.
In summary, risk factors for CHD are similar in men and women,2, 3, 46 although sex differences
in LDL cholesterol and HDL cholesterol exist, and women with diabetes have
a worse outcome than men with diabetes. Some, such as hypertension, dyslipidemia,
and glucose intolerance, are metabolically linked and tend to cluster.3 Multiple factors have synergistic effects on CHD risk,
so that the presence of several risk factors is more than simply additive.
Similarly, modification of a single risk factor can have beneficial effects
on others. For example, weight loss may lower blood pressure and triglyceride
levels and improve glucose tolerance.46 Early
recognition and modification of these risk factors could potentially decrease
the rates of CHD in women.
POSTMENOPAUSAL HORMONE REPLACEMENT THERAPY
A meta-analysis of more than 30 observational studies showed a 56% reduction
in risk of a major coronary event or fatal CVD in healthy current estrogen
users compared with women who have never used estrogen replacement.47 Problems with observational studies include the fact
that healthier women, who already may have the lowest risk of developing heart
disease, may be more likely to be prescribed and to take hormone replacement.
These women may modify other risk factors and be in closer contact with the
medical system; thus, the lower risk in women taking estrogen in these observational
studies may be due to confounding factors.
Postmenopausal estrogen replacement therapy would be predicted to offer
cardioprotection via a number of potential mechanisms. These include lowering
levels of LDL cholesterol, lipoprotein(a), plasminogen activator inhibitor
1, and fibrinogen; raising levels of HDL cholesterol; improving endothelium-dependent
vasodilation; inhibiting proliferation and migration of smooth muscle cells;
decreasing inflammatory cell activation; and acting as an antioxidant.2, 7, 48, 49, 50, 51, 52, 53
The Lipid Research Clinics Program Follow-up Study suggested that estrogen's
cardioprotective effect is largely mediated through an increased HDL cholesterol
level.54
Despite these potential cardioprotective mechanisms, in the first large
randomized trial of hormone replacement therapy (HRT) in women with CHD, the
Heart and Estrogen/Progestin Replacement Study (HERS), women randomized to
estrogen and progestin (HRT group) had no significant differences in the combined
incidence of CHD death and nonfatal MI (RR, 0.99; 95% confidence interval
[CI], 0.80-1.22) or on CHD mortality (RR, 1.24; 95% CI, 0.87-1.75) compared
with women receiving placebo at 5-year follow-up (Table 1). 55 This lack of effect occurred
even though women receiving HRT had a mean reduction in LDL cholesterol level
of 11% and mean increase in HDL cholesterol level of 10%. Initial adverse
effects on coagulation and proischemic effects were postulated to account
for a significant increase in risk for primary coronary events in year 1,
and beneficial effects on lipid changes were thought to account for reduced
risk in years 4 and 5.
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Table 1. Deaths and Adverse Events in the Heart and Estrogen/Progestin
Replacement Study*
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A potential reason for the early adverse outcome in hormone-treated
women is an increase in C-reactive protein level, a marker of inflammation.
C-reactive protein level has been shown to be an independent predictor of
risk of CHD in the Women's Health Study.56
C-reactive protein levels are higher in women treated with estrogen and combined
HRT than in women taking placebo.57 Other possible
lipid-related adverse effects of estrogen include increases in the liver's
production of triglycerides and VLDL particles.1
Elevated triglyceride levels increase the risk of CHD in women, as noted above.
Whether the increase in triglyceride levels in hormone-treated women in HERS
was associated with lack of effect is unknown.
Hormone replacement therapy was associated with adverse events in HERS
(summarized in Table 1). Venous
thromboembolic events were 3 times as frequent in the hormone-treated women
(6.3/1000 woman-years) as in the placebo group (2.2/1000 woman-years).55 Hormone-treated women also had a significant increase
in risk of gallbladder disease. Estrogen replacement has other adverse effects.
Postmenopausal women with an intact uterus who take long-term unopposed estrogen
have a 3- to 8-fold increase in lifetime risk of developing endometrial cancer.7, 58, 59, 60, 61
In general, the potential risk of endometrial hyperplasia and endometrial
cancer from unopposed estrogen restricts its use to women whose uterus has
been surgically removed.7 Women with a uterus
must take estrogen with a progestin to prevent endometrial hyperplasia.
A second, large, randomized trial of HRT in women with CHD, the Estrogen
Replacement and Atherosclerosis (ERA) Study, also observed no benefit of HRT
with the use of quantitative coronary angiography.62
Women with previous MI or PTCA and a mean age of 65.8 years were randomized
to receive conjugated estrogens, conjugated estrogens plus medroxyprogesterone
acetate, or placebo. After 3 years of follow-up, the mean change in lumen
diameter was not significantly different in those receiving HRT compared with
placebo (Table 2). Although there
was no significant difference in clinical events among the 3 groups, estrogen-only
users had higher rates of deep vein thrombosis and pulmonary emboli compared
with users of estrogen plus progestin or placebo.
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Table 2. Estrogen Replacement and Atherosclerosis Study*
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On the basis of the HERS and ERA results, there appears to be no benefit
in initiating either an estrogen-only or an estrogen plus progestin regimen
for secondary prevention of CHD in women. In fact, it may be harmful during
the first year of use. The HERS authors suggested that women who have taken
estrogen plus progestin therapy for longer than 1 year are presumably beyond
the time frame for increased risk of prothrombotic events and should be able
to safely continue it. Although the ERA results suggest that there may be
no benefit in continuing HRT for prevention of angiographic progression of
atherosclerosis,55 women may wish to continue
HRT for menopausal symptoms or prevention of osteoporosis. The Women's Health
Initiative trial is hoped to better define the risks and benefits of HRT for
postmenopausal women without CHD.63
DYSLIPIDEMIA THERAPY
A Gender Gap in Treatment of Dyslipidemia
The US National Cholesterol Education Program (NCEP) guidelines recommend
an LDL cholesterol goal of less than 2.59 mmol/L (100 mg/dL) for men and women
with documented CHD.64 Clinical evidence has
shown that aggressive treatment effectively lowers elevated LDL cholesterol
levels. Although a study of 825 patients hospitalized for CHD at major US
and Canadian medical centers between 1993 and 1996 indicated a trend toward
increasing use of lipid-lowering therapy, significantly more men than women
received this therapy during each year of the study.65
The multicenter HERS study of postmenopausal women with CHD found that less
than half (47%) were taking lipid-lowering medication, and LDL cholesterol
levels in 91% of the study sample exceeded NCEP goals.66
Only one third of women with LDL cholesterol levels greater than 4.14 mmol/L
(160 mg/dL) were receiving a lipid-lowering agent.
Efficacy of Cholesterol-Lowering Therapy in Women
Data on cholesterol-lowering therapy in women are limited because most
studies have included only men or a small number of women. Studies including
women are summarized below.
Primary Prevention
Only 2 primary prevention trials have included a large number of women
without CVD. In the first, 1184 women were randomized to receive colestipol
or placebo. At an average follow-up of 2 years, treatment with colestipol
lowered cholesterol level an average of 10% but had no effect on CHD mortality
(RR, 0.93; 95% CI, 0.38-2.26).67 This study
may have lacked power to examine CHD mortality.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
was a primary prevention trial enrolling men and women with average total
and LDL cholesterol levels and below-average HDL cholesterol levels (mean,
1.03 mmol/L [40 mg/dL] for women). At the end of 1 year, treatment with lovastatin
reduced LDL cholesterol level by 25%, total cholesterol level by 18%, and
triglyceride levels by 15%, and increased HDL cholesterol level by 6% compared
with baseline.68 After an average 5.2 years
of follow-up, the risk of a first acute major coronary event (fatal or nonfatal
MI, unstable angina, or sudden cardiac death) was reduced by 37% in the total
group randomized to lovastatin compared with those taking placebo (P<.001). The reduction in RR was greater for women (46%) than men
(37%), but the difference was not significant because of a small number of
events among women (7 in the lovastatin group vs 13 in the placebo group).
The trial had insufficient power to examine CHD mortality or total mortality.
Secondary Prevention
In the Scandinavian Simvastatin Survival Study (4S), 3617 men and 827
women with angina or previous MI and mean LDL cholesterol level of 4.86 mmol/L
(188 mg/dL) (total cholesterol level ranging from 5.48 to 7.99 mmol/L [212
to 309 mg/dL]) were randomized to receive simvastatin, 20 mg/d (titrated to
40 mg/d if necessary to lower total cholesterol level to <5.17 mmol/L [<200
mg/dL]) vs placebo.69 At median follow-up of
5.4 years, simvastatin lowered LDL cholesterol levels by 37.4% in women and
significantly reduced the risk of the combined end point (all-cause mortality,
CHD death, nonfatal MI, or resuscitated cardiac arrest) by 34% in both women
and men. The need for CABG or PTCA was reduced by 49% in women (95% CI, 0.30-0.86).
Both CHD and total mortality were significantly reduced in men; however, there
was no significant reduction in CHD mortality and no benefit on total mortality
in women (RR, 1.16; 95% CI, 0.68-1.99), a finding related to the lower total
and CHD mortality of 6% and 4%, respectively, in women in the placebo group
compared with 13% and 8%, respectively, in men. One potential reason for the
lack of mortality differences is that women were more likely than men to be
enrolled for only angina (37% vs 17%). Since chest pain in women is less likely
to be associated with marked epicardial stenoses than in men, a majority of
women with only angina in the Scandinavian Simvastatin Survival Study may
not have had coronary artery disease as a cause of their chest pain. These
sex differences must be considered when results of clinical trials that enrolled
patients on the basis of a history of angina rather than MI or diagnostically
confirmed CHD are interpreted.
In the Cholesterol and Recurrent Events (CARE) trial, 3583 men and 576
postmenopausal women with a history of MI and mean LDL cholesterol level of
3.59 mmol/L (139 mg/dL) were randomized to receive pravastatin sodium, 40
mg, or placebo.70 At 5-year follow-up, the
reduction in risk of CHD death or nonfatal MI was about twice as great in
women randomized to receive pravastatin as in men (43% vs 21%). Although CHD
mortality was significantly reduced in men but not in women, women had a greater
reduction in nonfatal MI (51%) compared with men (15%). The need for PTCA
or CABG was decreased by 48% and 39%, respectively, in women compared with
17% and 24% in men. Women experienced a 56% reduction in stroke (P = .07). There was no reduction in total mortality for the total study
population.
The Long-term Intervention With Pravastatin in Ischemic Disease (LIPID)
trial, conducted in Australia and New Zealand, randomized 7498 men and 1516
women with previous MI or unstable angina to receive pravastatin sodium, 40
mg/d, or placebo.71 At an average follow-up
of 6.2 years, pravastatin was associated with a 26% reduction in CHD death
or nonfatal MI in men (95% CI, 17%-35%) but a nonsignificant 11% reduction
in women. For the total study population, total mortality was reduced by 22%;
CHD death, 24%; MI, 29%; CHD death or nonfatal MI, 24%; stroke, 19% (P = .048); and revascularization, 20%. Mortality data for
women were not reported.
A quantitative coronary angiographic trial also supports a benefit of
statin drugs in women. Women with diffuse coronary atherosclerosis, various
coronary risk factors, and total cholesterol levels between 5.69 and 7.76
mmol/L (220 and 300 mg/dL) enrolled in the Canadian Coronary Atherosclerosis
Intervention Trial (CCAIT) were examined with repeated coronary arteriography
2 years after randomization to either lovastatin or placebo.72
Lovastatin lowered LDL cholesterol level by 32% and total cholesterol level
by 24%. Women taking lovastatin had less progression of coronary atherosclerosis
and fewer new lesions than women receiving placebo.
The multicenter Women's Atorvastatin Trial on Cholesterol (WATCH) assessed
the effectiveness of atorvastatin calcium in achieving NCEP target levels
of LDL cholesterol in premenopausal and postmenopausal women with and without
CVD and with dyslipidemia.73 In this 16-week
trial, atorvastatin treatment enabled 87% of women with 2 or more CHD risk
factors and 80% of women with documented CHD to reach their LDL cholesterol
goals. The trial showed that lowering LDL cholesterol level to the NCEP goal
of 2.59 mmol/L (100 mg/dL) or less is feasible for the majority of women with
dyslipidemia and CVD.
In summary, statins in primary and secondary prevention trials have
demonstrated substantial effects in women: up to a 46% reduction in risk of
major coronary events, together with significant beneficial effects on lipoproteins.68, 69, 70, 71, 72
These randomized trials suggest that statins are at least as effective for
lowering cholesterol levels and reducing cardiovascular events in women as
in men with CHD; thus, statins should be first-line therapy in postmenopausal
women with CHD. In addition, it is reasonable to recommend statins as first-line
therapy for postmenopausal women with elevated LDL cholesterol levels; however,
it is also important to consider use of niacin for women who have low HDL
cholesterol levels in addition to elevated LDL cholesterol levels.
Combination Therapy
Estrogen is very beneficial in alleviating hot flashes and vaginal dryness
and atrophy; therefore, symptomatic menopausal women may require it for these
symptoms. For hypercholesterolemic postmenopausal women, it is important to
know the effects of HRT alone and in combination with various statins on lipid
levels. Four recent trials in postmenopausal women have compared the effectiveness
of HRT, a statin, or both.74, 75, 76, 77
In a 4-arm trial, 76 women with hypercholesterolemia were randomized to receive
treatment with 0.625 mg of conjugated equine estrogen alone; pravastatin sodium,
20 mg, alone; both combined; or placebo. Non-HDL cholesterol and LDL cholesterol
levels were significantly reduced in all active-treatment arms, least so by
estrogen monotherapy (Table 3).74 Both estrogen-treated groups saw a marked rise in
HDL cholesterol levels (22.5% and 21.2%), compared with only a 3.7% increase
in the group treated with pravastatin alone (Table 3). In sum, combination treatment more favorably affected
the lipid profile than either estrogen or pravastatin alone.74
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Table 3. Effects of Pravastatin Compared With HRT on Lipid Levels*
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A parallel design was used to compare atorvastatin calcium, 10 mg; estradiol,
1 mg; atorvastatin plus estradiol; or placebo in 83 postmenopausal women in
a 12-week trial. Lipid changes in the atorvastatin and atorvastatin plus estradiol
groups were of similar magnitude and significantly greater than in the estradiol
group (Table 4). Atorvastatin
reduced total cholesterol level by 31%, LDL cholesterol level by 43%, and
triglyceride levels by 7% and increased HDL cholesterol level by 4%. Combination
therapy increased HDL cholesterol level by 16%.75
Therefore, the advantage of combination therapy is a greater increase in HDL
cholesterol level. Since low levels of HDL cholesterol level may be a strong
risk factor for CHD in women, it is important to increase HDL levels as much
as possible.
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Table 4. Effect of Atorvastatin and Estradiol on Lipid Levels*
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The effects of estrogen and statin therapies on vascular function were
studied in 28 hypercholesterolemic postmenopausal women with a mean age of
57 years.76 The combination of conjugated equine
estrogen, 0.625 mg, and simvastatin, 10 mg, lowered LDL cholesterol level
more than did either alone (2.92 mmol/L [113 mg/dL] for combination vs 3.72
mmol/L [144 mg/dL] for estrogen alone and 3.13 mmol/L [121 mg/dL] for simvastatin
alone) and also lowered the ratio of LDL/HDL cholesterol to a greater degree.
Estrogen alone or in combination with statin therapy reduced levels of lipoprotein(a)
and plasminogen activator inhibitor 1, a marker of fibrinolytic activity.
Similarly, estrogen alone or in combination therapy significantly reduced
levels of markers of inflammation: E-selectin, intercellular adhesion molecule,
and vascular cell adhesion molecule. C-reactive protein, an inflammatory marker
increased by estrogen, was not examined. Only estrogen significantly improved
flow-mediated dilation of the brachial artery, and only statins significantly
reduced triglyceride levels. Although both treatments were beneficial, only
the inclusion of estrogen improved fibrinolysis and inflammation considered
to be important in atherogenesis. This study suggests that estrogen may provide
additional vasculoprotective benefit to hypercholesterolemic postmenopausal
women already receiving statin therapy; however, further research will be
necessary to determine the net effect of estrogen on all markers of inflammation,
including C-reactive protein.
In a randomized, crossover, placebo-controlled 8-week study of 16 postmenopausal
women with hypercholesterolemia and CHD, simvastatin alone (20 mg) and simvastatin
with 0.625 mg of estrogen and 2.5 mg of medroxyprogesterone acetate (HRT)
were similarly effective in significantly lowering total cholesterol level
(35% and 33%, respectively) and LDL cholesterol level (45% and 46%, respectively)
compared with placebo and significantly more effective than HRT alone, which
lowered LDL cholesterol level by 20%.77 Simvastatin
reduced triglyceride levels by 33% in contrast to HRT plus simvastatin, which
lowered triglyceride levels by 13.9%, and HRT, which had no effect. The HDL
cholesterol levels were not significantly altered by any treatment.
It is important that HRT will not lower LDL cholesterol levels to goal
(<2.59 mmol/L [<100 mg/dL]) in women with established CVD unless the
baseline LDL cholesterol level is 3.10 to 3.18 mmol/L (120-123 mg/dL), assuming
the average reduction of 14.5% to 17.5% observed with estrogen and/or progestin
over 3 years in the Postmenopausal Estrogen/Progestin Interventions (PEPI)
trial.78 Thus, women with CVD who require estrogen
for menopausal symptoms will almost always also require a statin or other
lipid-lowering drug to reach LDL cholesterol goal.
CURRENT AND FUTURE RESEARCH PROSPECTS
Since difficulties in diagnosing CHD in women on the basis of chest
pain and noninvasive testing may contribute to lower referral rates for catheterization
and revascularization, it is important to improve symptom evaluation and diagnosis
of ischemic heart disease in women. The Women's Ischemia Syndrome Evaluation
(WISE), sponsored by the National Heart, Lung, and Blood Institute, will address
this issue and is hoped to add to the limited information about the pathophysiology
of ischemia without substantial epicardial coronary artery stenoses, a syndrome
more common in women than men, as noted earlier.79
The Women's Health Initiative Study Group is conducting a long-term,
comprehensive clinical investigation of strategies to prevent and control
the most common causes of morbidity and mortality among postmenopausal women.63 These include cancer, CVD, and osteoporotic fractures.
A clinical trial will evaluate 3 interventions: a low-fat diet, HRT, and calcium
and vitamin D supplementation. An observational study is a separate component
of the overall investigation planned for completion in 2007.
A prospective, randomized, double-blind study, the Beyond Endorsed Lipid
Levels Evaluation Study (BELLES), which is currently recruiting postmenopausal
women, will compare the effects of 12 months' treatment with atorvastatin
or pravastatin on regression of coronary atherosclerosis. Efficacy will be
determined by the percentage change from baseline in total plaque volume as
measured by electron beam computed tomography.
CONCLUSIONS
Despite the abundant evidence that CVD is virtually epidemic in older
women, the belief that women have innate protection from coronary events still
prevails. In the face of considerable morbidity and mortality rates, prevention
and treatment strategies are still less aggressive for women than for men.
The control of CHD risk factors in women will require recognition of the differences
as well as the similarities between men and women in manifestation of risk
factors.
The rate of CHD can be reduced by aggressively lowering LDL cholesterol
to levels recommended by the NCEP guidelines, which recommend an LDL cholesterol
goal of 2.59 mmol/L (100 mg/dL) or less for men and women with documented
CHD. For those without CHD, NCEP guidelines recommend an LDL cholesterol goal
of less than 3.36 mmol/L (130 mg/dL) for those with 2 or more risk factors
for CHD and less than 4.14 mmol/L (160 mg/dL) for those with 1 or no risk
factors for CHD. Diet and exercise should be tried first. Although few primary
and secondary prevention trials have included women until recently, available
data suggest that women can substantially benefit from lipid-lowering drug
therapies if diet and exercise fail to lower LDL cholesterol level to goal.
Statins have proved particularly effective in lowering women's CHD risks and
mortality. Estrogen and HRTs to reduce CHD risk have been popular among postmenopausal
women, but in view of the recent HERS and ERA findings, results of future
trials will be required to define the true benefit in reducing cardiovascular
risk before it can be safely prescribed in this clinical context. On the basis
of the HERS and ERA results, statin drugs should be the drug of first choice
for women with established CHD. Hypercholesterolemic postmenopausal women
who require estrogen for menopausal symptoms may derive further lipid-lowering
benefits with the addition of a statin drug.
Finally, the population of older women can be expected to increase in
the coming decades. A major public health problem will doubtless ensue if
clinical issues fail to be addressed now.
AUTHOR INFORMATION
Accepted for publication September 18, 2000.
From the Cardiovascular Division, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, Mass. Dr Welty is a consultant to Pfizer Inc
and Merck & Co, Inc.
Corresponding author and reprints: Francine K. Welty, MD, PhD, 1
Autumn St, Fifth Floor, Boston, MA 02215 (e-mail: fwelty{at}caregroup.harvard.edu).
REFERENCES
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