Atherosclerosis imaging methods: assessing cardiovascular disease and evaluating the role of estrogen in the prevention of atherosclerosis

Atherosclerosis Imaging Methods: Assessing Cardiovascular Disease and Evaluating the Role of Estrogen in the Prevention of Atherosclerosis Howard N. Hodis,

MD,

and Wendy J. Mack,

PhD

Various interventions for cardiovascular disease (CVD) slow or reverse the progression of atherosclerosis and reduce the risk of clinical coronary events. Although the cardiovascular benefits of hormone replacement therapy have been demonstrated in observational studies in predominantly healthy women, no benefit has been found in a randomized clinical trial conducted in older women with established CVD. It is possible that the benefit of hormone therapy occurs when it is used relatively early in the progression of atherosclerosis. Techniques are now available to monitor the various stages of atherosclerosis. Quantitative coronary angiography, a technique used to evaluate relatively late-stage atherosclerosis, has been shown to predict the risk of subsequent clinical coronary events. B-mode ultrasonography of the intima-media wall thickness (IMT) of the

carotid artery can assess the earlier stages of atherosclerosis and correlates with atherosclerosis risk factors, as well as with clinical cardiovascular and cerebrovascular outcome. This technique offers a relatively rapid and cost-effective method to test therapies for CVD and to screen for individuals who are at high risk for cardiovascular events. As an example of the use of atherosclerosis imaging to evaluate possible therapeutic interventions, measurements of IMT were performed in a randomized, controlled trial comparing oral 17␤-estradiol with placebo. The results demonstrated that 17␤estradiol significantly reduces the progression of subclinical atherosclerosis in healthy, postmenopausal women when compared with placebo. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;89(suppl):19E–27E

therosclerosis progresses through several welldefined stages, each of which can be measured by A different imaging techniques. Coronary angiography

niques is reviewed in this article. An example is the use of these imaging techniques to evaluate potential atherosclerosis interventions. Their role in evaluating different estrogens in reducing the progression of subclinical atherosclerosis is also reviewed.

is the current method of choice in clinical practice for diagnosing coronary artery disease (CAD). However, angiography visualizes only the later stages of atherosclerosis when stenosis of the lumen becomes apparent. At the earliest stage of this process, which is characterized by endothelial injury and the associated inflammatory response,1 atherosclerosis may be manifested as a change in vascular reactivity or stiffness. The subsequent thickening of the arterial wall can be detected in peripheral vessels by noninvasive imaging at a time when obstruction of the lumen is not yet present because of compensation of the vessel wall. These noninvasive imaging techniques allow researchers to investigate the effects of interventions on early atherosclerosis, when there may be more opportunity to prevent lesion development and subsequent clinical manifestations of cardiovascular disease (CVD). Noninvasive imaging of peripheral arteries also offers a rapid, low-cost technique for assessing preclinical CVD that allows clinicians to screen for emerging risk factors and to identify patients at risk for clinical CVD. The utility of these imaging techFrom the Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, California, USA. Supported in part by National Institutes of Health research grant No. R01 AG-18798 from the National Institute on Aging. Address for reprints: Howard N. Hodis, MD, University of Southern California, Atherosclerosis Research Unit, 2250 Alcazar Street, CSC 132, Los Angeles, California 90033. ©2002 by Excerpta Medica, Inc. All rights reserved.

IMAGING TECHNIQUES

Serial coronary angiography: Serial coronary angiography is the “gold standard” for assessing the progression of atherosclerosis; however, it is generally used only for symptomatic individuals. Angiography visualizes the vascular lumen, which is an indirect measure of change in the arterial wall.2 Several studies show that a change in luminal dimensions, as assessed by quantitative coronary angiography (QCA), is well correlated with clinical coronary events and thus can be used as a direct measure for studies of CAD progression.3–5 Using arteriographic change as an outcome measure allows trials to be conducted with smaller sample sizes and for a shorter duration than clinical trials analyzing cardiovascular events as an end point, thereby substantially reducing the costs involved when evaluating potential antiatherosclerosis therapies for clinical studies of coronary events.2 The Cholesterol Lowering Atherosclerosis Study (CLAS) was one of the first studies to show that change in coronary artery lumen dimensions, as measured by angiography, is predictive of clinical cardiac events.3 In this trial, 162 men with previous coronary artery bypass graft surgery were randomized to treatment with colestipol-niacin or placebo plus diet over 2 years. Atherosclerotic change was measured by the 0002-9149/02/$ – see front matter PII S0002-9149(02)02407-4

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FIGURE 1. The age-related mean surface area of atherosclerotic lesions in coronary and peripheral blood vessels, as determined from International Atherosclerosis Project autopsy data. The coronary values represent the average of the 3 coronary arteries, and the carotid values are the average of the common and internal carotid arteries. (Adapted from Arterioscler Thromb.2)

global change score, an overall expert panel– based assessment of all changes between baseline and the 2-year angiogram, and by QCA. QCA measures of luminal change are more common clinical trial outcomes. In the Cholesterol Lowering Atherosclerosis Study, QCA measures included the average change in the percent diameter stenosis of coronary artery stenosis and the minimum lumen diameter measured at the site of all coronary artery lesions. In CLAS, changes over 2 years in both global change score and QCA were found to be significantly predictive of clinical coronary events occurring in the average 8.8 years of follow-up study (p ⬍0.05).3 The Program on the Surgical Control of the Hyperlipidemias (POSCH) trial was designed to assess the relation between changes in sequential coronary angiograms and subsequent clinical coronary events.4 A total of 838 patients were randomized to receive instruction in dietary modification with either a partial ileal bypass or no treatment. Angiograms were obtained at baseline and at 3, 5, 7, and 10 years of follow-up study. Global change score was significantly associated with CAD mortality (p ⬍0.01).4 The POSCH trial therefore showed what had previously been assumed, namely that the difference between sequential coronary angiograms can be used as a surrogate end point for certain clinical coronary events.4 Imaging techniques to measure early coronary atherosclerosis: To assess the early progression of athero-

sclerosis, it is necessary to visualize the vessel wall itself. This is not possible using standard angiographic techniques. Assessment of the early stages of atherosclerosis allows early screening, particularly in asymptomatic individuals who are not in high-risk categories. Intravascular ultrasound readily delineates the arterial wall, but because the technique is invasive, it is limited to symptomatic patients. Magnetic resonance imaging, in contrast, is noninvasive but expensive, and it does not yet have the speed and resolution required to visualize coronary arteries. Newer techniques, such as ultrafast magnetic resonance imaging, may be refined for this purpose in the future.2 Ex20E THE AMERICAN JOURNAL OF CARDIOLOGY姞

trathorax ultrasonography is also limited because of the constant motion of coronary arteries and the interference of bony structures. Fast computerized tomography can be used to measure vascular calcium, but this technology does not have the resolution capability to directly measure the arterial wall. Measurement of changes in vascular calcium has not been validated as a clinical trial end point. In addition, the relation between vascular calcium (a late manifestation of atherosclerosis) and the progression of early atherosclerosis, although still limited to the arterial wall, is unknown. Whether the efficacy of therapeutic interventions can be determined through the measurement of changes in vascular calcium is also unknown. NONINVASIVE IMAGING OF PERIPHERAL VESSELS: The difficulties in imaging coronary arteries with noninvasive techniques have led to the use of peripheral blood vessels as vascular end points for assessing generalized atherosclerosis. Autopsy data from the International Atherosclerosis Project have shown that lesions across the major arterial beds parallel each other (Figure 1).2 The degree of atherosclerosis in the carotid artery correlates with that in the coronary arteries6 and the abdominal aorta.2 The carotid artery has the advantage of lying at a shallow tissue depth, allowing for high-resolution ultrasound imaging of the arterial wall. Precise measurement of the wall thickness of the carotid artery can be obtained through B-mode ultrasonography. More specifically, accurate measurements of the intima-media thickness (IMT) of the far wall of the common carotid artery can be obtained.7–10 Several studies show that carotid IMT correlates with cardiovascular risk factors, including age, systolic blood pressure, smoking, postmenopausal status, triglyceride-rich lipoproteins, total cholesterol, and low-density, intermediate-density, and high-density lipoprotein cholesterol.2,10 –13 These findings suggest that similar mechanisms underlie atherosclerosis progression in both coronary arteries and the common carotid artery. Carotid IMT is also positively linked to the presence and extent of CAD in both men and women.2,14 –16

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In addition to showing that coronary angiographic change correlates with the risk of subsequent coronary events, CLAS also included a substudy (n ⫽ 133) investigating the relation between common carotid artery IMT and CAD.17 Distal common carotid artery far-wall IMT was measured by automated computerized edge tracking, and QCA was used to measure the progression of CAD.7,8,17 Progression of common carotid artery IMT was significantly correlated with QCA-measured change when evaluated over all coronary lesions and in mild-to-moderate lesions, but not severe coronary lesions.17 Similarly, progression of mild-to-moderate but not severe coronary lesions was positively associated with clinical coronary events.3 The common carotid artery IMT rate of change also correlated with the average lipid levels measured during the trial, as were QCA-measured changes in coronary artery lesions.17 These findings further illustrate that although atherosclerosis in both arterial beds may be a result of similar risk factor exposure, the 2 imaging methods actually assess different stages of the disease, with IMT measuring earlier atherosclerosis and angiography evaluating the later, intrusivelesion stage of atherosclerosis.17 In a long-term (average, 8.8 years), follow-up study of a subgroup (n ⫽ 146) from CLAS, IMT was shown to correlate positively with clinical coronary events.18 The absolute thickness of the carotid wall was significantly related to the risk of clinical coronary events. The relative risk of nonfatal myocardial infarction or coronary death, as well as the risk of any coronary event (nonfatal myocardial infarction, coronary death, coronary arterial revascularization), increased significantly with each annual 0.03-mm increase in IMT.18 Both absolute thickness and progression of thickening of the carotid wall were more strongly related to the risk of coronary events than models that analyzed lipid levels or lesion changes in coronary angiograms.18 The results described above show that a reduced rate in the progression of carotid wall thickness is associated with a lower risk of CAD morbidity and mortality18 and suggest that IMT can be used for screening individuals at risk for cardiovascular events. The use of IMT as a direct measure of change in atherosclerosis and as a marker for clinical coronary events results in considerable reductions in the cost and duration of clinical trials for the study of antiatherosclerosis cardiovascular interventions. 18

REDUCING ATHEROSCLEROSIS PROGRESSION: USING IMAGING TECHNIQUES TO EVALUATE INTERVENTIONS Several studies have demonstrated that interventions to ameliorate various coronary risk factors (eg, elevated levels of low-density lipoprotein cholesterol) reduce cardiovascular morbidity and mortality in men. Studies in women, although fewer in number, have reported similar results. In the Cholesterol and Recurrent Events (CARE) trial, for example, it was found that treatment with pravastatin significantly reduced

the risk of subsequent coronary events in women who had previously had a myocardial infarction (p ⫽ 0.001).19 In fact, the reduction in risk was of even greater magnitude than that observed for men in the same study. Pravastatin had a similar effect on the lipid profile for men and women. In the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), decreasing levels of the lowdensity lipoprotein cholesterol (with lovastatin, in this case) was also shown to provide significant benefit in preventing a first myocardial infarction for both men and women (p ⫽ 0.002).20 The similarities in outcome between men and women because of a reduction in levels of low-density lipoprotein cholesterol suggest that this mechanism of altering atherosclerosis progression is similar for both sexes. Studies using vascular anatomic end points show that those interventions known to reduce coronary risk or clinical coronary events can slow or even reverse the progression of atherosclerosis. In CLAS, which included only men, lowering lipid levels with colestipol-niacin was associated with significant reductions in the number of coronary artery lesions that progressed, as well as in the formation of new lesions (p ⬍0.03).21 Furthermore, adherence to a low-fat diet versus a higher-fat diet resulted in the development of fewer new lesions in both the placebo group and the colestipol-niacin group in CLAS.22 Some angiographic studies have included small numbers of women. In 2 such studies (the Stanford Coronary Risk Intervention Project [SCRIP] and the Lifestyle Heart Trial), multifactorial lifestyle alterations were investigated (eg, diet, exercise, smoking cessation), and in SCRIP, the use of lipid-lowering medication was studied as well.23,24 In SCRIP (259 men, 41 women), these changes resulted in substantial improvements in lipid levels, less narrowing of coronary arteries, and a reduction in cardiac events that required hospitalization. There was also a significant reduction in new lesion formation in the lifestyle alteration group compared with subjects given usual clinical care (p ⫽ 0.05).24 In the Lifestyle Heart Trial (36 men, 5 women), lifestyle modification was associated with a regression in the degree of stenosis, even for severe lesions (⬎50% diameter stenosis), whereas usual clinical care was associated with the progression of stenosis.23 Further indication that lipid-lowering interventions can produce changes in atherosclerosis progression came from the Monitored Atherosclerosis Regression Study (MARS; 246 men, 24 women), which assessed the effect of treatment with lovastatin versus placebo, plus dietary intervention. In the lovastatin group, there were reductions in the average percent diameter stenosis overall and significant reductions in severe lesions (⬎50% diameter stenosis, p ⫽ 0.005), compared with the placebo group. The mean global change score also showed significantly less progression in lovastatin-treated subjects compared with placebo.25 These studies and others clearly show that there are a variety of risk modification interventions that can directly alter the progression of atherosclerosis, as evaluated

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by coronary angiography. Changes measured on coronary angiograms are directly related to the risk of clinical coronary events. Although these studies included only a few women, the evidence from risk factor–reduction trials suggests that women also can achieve the same benefit as men with the reduction of serum lipid levels.

EFFECT OF ESTROGEN ON PROGRESSION OF ATHEROSCLEROSIS Currently, there is confusion surrounding the role of estrogens and progestins in the prevention and treatment of CVD in postmenopausal women. Unfortunately, this confusion has been generated by an overzealous rush to judgment rather than by the tempered reflection and hypothesis testing that conflicting data typically bring to scientific investigation.26 This rush to judgment has been fueled by enormous overgeneralization and misinterpretation of recent clinical trial data by scientists and the lay press alike.27 The areas that have created the greatest confusion are discussed below. The Heart and Estrogen/progestin Replacement Study: The Heart and Estrogen/progestin Replacement

Study (HERS) was a randomized, double-blind, placebo-controlled trial in postmenopausal women with preexisting CVD that was designed to test whether treatment with a combination of oral daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg (Prempro; Wyeth-Ayerst, Philadelphia, PA) would lead to a reduction in the combined incidence of nonfatal myocardial infarction and CAD death (primary end point).28 The cohort consisted of 2,763 postmenopausal women who were 66.7 ⫾ 6.7 years of age and had a history of myocardial infarction, coronary artery revascularization, or angiographic evidence of CAD. When evaluated over the entire treatment period (average, 4.1 years of randomized treatment), there was no significant difference in the primary end point between the oral daily conjugated equine estrogen plus medroxyprogesterone acetate therapy arm and the placebo arm. There was a significant 52% increase in the primary end point in the first year of active oral daily conjugated equine estrogen plus medroxyprogesterone acetate therapy relative to placebo. After the first year of treatment, however, there was a statistically significant trend toward a reduction in the primary end point in years 4 and 5 in the oral daily conjugated equine estrogen plus medroxyprogesterone acetate therapy arm compared with the placebo arm (p ⫽ 0.009 for trend). A large body of literature amassed over the last 40 years, including ⬎20 observational studies and numerous in vitro, human, and animal studies, has resulted in consistent evidence that estrogen reduces the risk for CAD with strong mechanistic plausibility. Although HERS data appear to contradict these findings, closer inspection indicates otherwise. First, most observational studies were conducted in predominantly healthy women, which raises the issue of primary prevention of CAD in contrast to the treatment 22E THE AMERICAN JOURNAL OF CARDIOLOGY姞

of CAD as discussed below. Second, most observational studies examined the effects of unopposed estrogen replacement therapy. Observational studies examining the effects of progestin-opposed estrogen replacement therapy offer mixed results. Other human and animal studies indicate that progestins may in fact diminish the cardioprotective effects of estrogen replacement therapy. Third, observational studies indicate that long-term use (ⱖ10 years) of estrogen replacement may be required to detect a decrease in the incidence of CAD. In fact, in HERS, there was a trend toward a reduction in nonfatal myocardial infarction and CAD death in the fourth and fifth years of treatment. In short, what can be concluded from HERS is that within the specific cohort of postmenopausal women with established CVD who received oral daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg, the risk of nonfatal myocardial infarction and CAD death increased in the first year and then decreased in the subsequent years of treatment. These results have neither been verified nor validated by other trials. Estrogen Replacement and Atherosclerosis Trial: The Estrogen Replacement and Atherosclerosis (ERA) trial was a randomized serial coronary angiographic trial designed to test the effect of the combination of oral daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg (Prempro) and oral daily unopposed conjugated equine estrogen 0.625 mg (Premarin; Wyeth-Ayerst) on the progression of CAD.29 The cohort was composed of 309 postmenopausal women with an average age of 65.8 years and documented CAD of ⱖ1 stenoses of ⱖ30% luminal diameter on angiography. After a mean of 3.2 years of randomized treatment, there was no effect from either oral daily conjugated equine estrogen plus medroxyprogesterone acetate (n ⫽ 85) or oral daily unopposed conjugated equine estrogen therapy (n ⫽ 79) relative to placebo (n ⫽ 84) on the progression of coronary artery atherosclerosis as measured by serial QCA. The same issues of treatment regimen and duration of therapy that apply to HERS and the observational studies also apply to ERA and the angiographic crosssectional studies that have been published. Unfortunately, neither the power nor the duration of ERA was sufficient to determine whether the progression of coronary artery atherosclerosis differed between oral daily unopposed conjugated equine estrogen therapy and oral daily conjugated equine estrogen plus medroxyprogesterone acetate. It is important to note that HERS and ERA were conducted in older women with established CAD, and that the average time from menopause to randomization was 23 years. Neither HERS nor ERA addressed the question of whether the estrogen plus medroxyprogesterone acetate regimen alone confers cardiovascular benefit. In women with established CAD, this hormone therapy was added to a secondary prevention regimen that typically comprises lipid-lowering, angiotensin-converting enzyme inhibition, ␤-blockade,

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and aspirin, each of which has been independently demonstrated to reduce the risk of secondary cardiovascular events by 25% to 45%. Additionally, duration of hormone replacement therapy before randomization was considered not in the design of HERS and ERA. In summary, HERS and ERA data show that in women with established CAD who were, on average, 20 years past menopause and receiving secondary prevention therapies for CAD, there was no clear cardiovascular benefit when randomized to receive oral daily conjugated equine estrogen 0.625-mg plus medroxyprogesterone acetate 2.5-mg therapy. There is an unverified possibility of an increased risk for cardiovascular events within the first year of oral daily conjugated equine estrogen 0.625-mg plus medroxyprogesterone acetate 2.5-mg therapy and a possible longer-term cardiovascular benefit. Further clinical trials will be required to substantiate or refute these findings. In short, the HERS and ERA data support only the conclusion that postmenopausal women with known CAD who are ⱖ20 years past menopause should not have oral daily conjugated equine estrogen 0.625-mg plus medroxyprogesterone acetate 2.5-mg therapy added to other established therapies for the secondary prevention of CAD. Few clinicians would consider oral daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg as a treatment for CVD. As such, these results have little or no relevance to the management of CAD in either younger or older postmenopausal women.27 Secondary prevention of CAD in postmenopausal women includes emphasis on lipid lowering, lifestyle modification, and the use of aspirin, ␤-blockers, and angiotensin-converting enzyme inhibitors. Estrogen in the Prevention of Atherosclerosis Trial:

The Estrogen in the Prevention of Atherosclerosis Trial (EPAT) was a randomized, double-blind, placebo-controlled, carotid artery ultrasound trial designed to test whether unopposed oral micronized 17␤-estradiol (1 mg daily) versus placebo reduces progression of subclinical atherosclerosis (carotid IMT) in healthy postmenopausal women without preexisting CVD30 and baseline level of low-density lipoprotein cholesterol ⱖ130 mg/dL. Because EPAT was specifically designed to test the hypothesis that postmenopausal estrogen replacement therapy would reduce the progression of subclinical atherosclerosis, several important issues were taken into consideration in the design of EPAT. A cohort of women without CVD was chosen to avoid the major confounding effects of other atherosclerosis- and event-reducing medication ethically required in secondary prevention. In addition, during the design of EPAT, all observational data that had demonstrated a beneficial cardiovascular effect of estrogen replacement therapy had been in predominantly healthy women. Because 17␤-estradiol is the endogenously produced hormone, postmenopausal replacement with this preparation was chosen over other available estrogen compounds. Additionally, an unopposed regimen of 17␤-estradiol was chosen because various data indicate that progestins negate the bene-

FIGURE 2. At 2 years after randomization, common carotid intima-media thickness (IMT) was significantly reduced in women receiving unopposed estrogen replacement therapy versus placebo. This result was similar to that achieved in women receiving lipid-lowering therapy alone. Meds ⴝ medications. (Adapted from Ann Intern Med.30)

ficial cardiovascular effects of estrogen. Current smoking and previous use of estrogen replacement therapy for ⬎10 years were 2 important exclusion criteria that were used because of their potential for reducing the detectability of a cardiovascular benefit from estrogen replacement therapy under trial conditions. Active smoking increases metabolism of estradiol and reduces serum estradiol levels, and observational studies suggest that long-term use of estrogen replacement therapy is cardioprotective. The 222 subjects randomized to EPAT had a mean age of 61.1 years and an average time from menopause to randomization of 13 years; minorities comprised 42% of the cohort. Carotid artery ultrasonography was performed at baseline (2 visits) and every 6 months during the trial. The primary trial endpoint was the rate of change in the distal common carotid artery far wall IMT in computer image–processed B-mode ultrasonograms.7,8 After 2 years, there was a significant reduction in the progression of carotid IMT in women randomized to unopposed estrogen replacement therapy versus those randomized to placebo (Figure 2). This primary finding is consistent with many observational studies that indicate that postmenopausal women without CAD who use estrogen replacement therapy have lower rates of CAD than women who do not use estrogen replacement therapy. Because the subjects in EPAT who had a level of low-density lipoprotein cholesterol ⱖ160 mg/dL received lipid-lowering therapy, predominantly with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor (statin), preplanned subgroup analyses revealed 2 additional important findings (Figure 2): (1) unopposed 17␤-estradiol reduced the progression of subclinical atherosclerosis to the same degree as lipid-lowering therapy, and (2) lipidlowering therapy appeared not to add any additional

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benefit to unopposed 17␤-estradiol in reducing the progression of subclinical atherosclerosis. The findings from EPAT are consistent with earlier observational findings from the Asymptomatic Carotid Atherosclerosis Progression Study, a randomized, double-blind, placebo-controlled trial of lovastatin therapy. Subgroup analyses by self-selected estrogen replacement therapy use from this trial indicated that the effects on the progression of subclinical atherosclerosis were similar to those of EPAT, whereby estrogen replacement therapy reduced atherosclerosis progression in the women randomized to placebo without having any additional effect on carotid IMT progression in women randomized to lovastatin treatment.31 Postmenopausal Hormone Replacement Against Atherosclerosis trial: The Postmenopausal Hormone Re-

placement Against Atherosclerosis (PHOREA) trial was a randomized, single-blind, placebo-controlled study of 321 healthy postmenopausal women 40 to 70 years of age who were preselected for a carotid IMT ⬎1 mm.32 Women were randomized to 1 of the following 3 groups: (1) 17␤-estradiol 1 mg every day plus gestodene (a progestin) 0.025 mg on days 17 to 28 of each 4-week cycle, (2) 17␤-estradiol 1 mg every day plus gestodene 0.025 mg on days 17 to 28 of each third cycle only (every 3 months), or (3) placebo. After 48 weeks (or 12 cycles) of follow-up time, there was no difference in the progression of carotid IMT among the 3 treatment groups. Several important points need to be noted about PHOREA: (1) although the women randomized to this trial were “healthy” (no clinical evidence of CVD), defining the cohort with a carotid IMT ⬎1 mm preselects individuals with advanced atherosclerosis33; (2) there was no unopposed 17␤-estradiol arm in this trial; and (3) although on the surface, the results of PHOREA appear consistent with HERS and ERA, a treatment effect of any intervention on the progression of atherosclerosis with ⬍1 year of intervention is not likely. Statistically significant treatment effects on the progression of atherosclerosis after 1 year of intervention have been noted with aggressive lipid alteration in post-hoc analyses,34 but these are not consistent findings. Reduction in cardiovascular events with antiatherosclerosis therapies consistently shows a divergence between intervention and placebo after 2 years of therapy.2,20,35–38 Thus, based on the results of many atherosclerosis and cardiovascular event trials, a significant treatment effect on the progression of atherosclerosis with 48 weeks of hormone replacement therapy is highly unlikely. On the other hand, physiologic parameters, such as arterial blood flow, vasoreactivity, and arterial stiffness, improve over short intervals with hormone replacement therapy and established antiatherosclerosis interventions. Although arterial wall thickness was not significantly different between treatment arms in PHOREA after a 48-week treatment period, carotid arterial stiffness improved in the every-third-month, progestin-estrogen– opposed arm relative to placebo.39 This has important implications because aortic and carotid arterial stiffness are related to an increased risk 24E THE AMERICAN JOURNAL OF CARDIOLOGY姞

of cardiovascular and all-cause mortality, independently of established risk factors.40 These data also indicate that low-dose progestin administered every 3 months may not reduce the cardiovascular benefits of estrogen.

IMPLICATIONS OF THE RANDOMIZED, CONTROLLED TRIALS Overall, cumulative data suggest that hormone replacement therapy (specifically 17␤-estradiol) is most effective as preventive antiatherosclerosis therapy while the disease is in its early stages, but it is less effective once the atherosclerotic process has progressed. These results are consistent with the pathologic findings in younger premenopausal women in whom atherosclerosis tends to consist of more cellular fibrous tissue, found in earlier stages of development, and to consist less of dense fibrous tissue, found at later stages of development.41 Additionally, there is a greater degree of methylation of the estrogen receptor–␣ gene promoter with aging and atherosclerosis.42 Lack of expression of the estrogen receptor gene with atherosclerosis could result in a decreased ability of vascular tissue to respond to estrogen replacement therapy.43 Whether atherosclerosis is present for a shorter time before menopause or whether atherosclerosis develops rapidly as a woman enters menopause is unknown. Animal data suggest that lesions that develop quickly are predominantly composed of foam cells, whereas atherosclerosis that develops more slowly over time is composed primarily of fibrous tissue.44,45 If the loss of hormone and/or estrogen receptor activity is permissive for rapid development or progression of atherosclerosis, then early intervention, perhaps in the perimenopausal period, will be more effective than initiating hormone replacement therapy years after menopause. This concept is similar to that used for bone protection, whereby hormone replacement therapy is far more effective in early menopause when bone loss is most rapid. Therefore, the timing of initiation of hormone replacement therapy relative to menopause may be an important determinant as to whether this therapy is effective in reducing the progression of atherosclerosis. In the final analysis, current trial results indicate that there is no simple yes or no answer to the question of whether hormone replacement therapy can reduce the risk of CVD in postmenopausal women. In fact, current trial results raise many new questions about the role of hormone replacement therapy in CVD protection. It is clear that after menopause, mimicking biology to capture the CVD protection afforded women in premenopause is not a simple, straightforward proposition as once believed. Perhaps the failure of current trial results to fit neatly into currently held paradigms and to yield the expected simple yes or no answer has fueled the confusion that surrounds the interpretation of these trials. The complexity of issues related to hormone replacement therapy and CVD in postmenopausal women mandates clarity in the use of terminology and restraint in extrapolating, overgeneralizing, and interpreting single trials. For example, use

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of the term hormone replacement therapy causes confusion, misinterpretation, and inappropriate extrapolation. Whether all estrogen compounds, routes of delivery, and doses are equivalent needs to be determined. Whether the progestogen type, dose, or regimen negates the antiatherosclerosis effect of estrogen in humans remains unanswered. Also unanswered is the more complex question of whether other hormones that women lack after menopause need to be replaced before a maximal effect on reducing atherosclerosis progression will be realized. Because there are various forms of hormone replacement therapy, terminology specific to the therapy studied needs to be communicated at all times. Each specific form of hormone replacement therapy will need to be tested before generalized conclusions about hormone replacement therapy and CVD can be made. In the end, it may not be possible to make a general conclusion about hormone replacement therapy, and conclusions related to CVD will have to be specific to the hormone regimen. Promulgation of unpublished data, such as that from the Women’s Health Initiative (WHI), results in further confusion and misinformation.27 Concerns about the “early harm” in HERS prompted the National Heart, Lung, and Blood Institute (NHLBI) to release a statement on a trend toward an increase in mortality in WHI subjects in the first year after initiating hormone replacement therapy. Interestingly, the hormone replacement therapy regimen in WHI is the same as that used in HERS and ERA (oral daily conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg and oral daily unopposed conjugated equine estrogen 0.625 mg). Several investigators have used the NHLBI statement to conclude that hormone replacement therapy is ineffective and perhaps dangerous in healthy women without CVD. Yet, WHI was not terminated, no statistical analyses were released for review, no distinction in events between the treatment regimens of the trial were made, and the total events were ⬍0.5% in both the hormone replacement therapy group and the placebo group.46 Unfortunately, current ongoing randomized, controlled trials are predominantly testing oral conjugated equine estrogen and medroxyprogesterone acetate at the same dose and regimen as that used in HERS and ERA. As such, the many questions before us will remain unanswered. Until a more diverse set of randomized, controlled trials of hormone replacement therapy and CVD are completed, the results of the currently published trials need to be interpreted cautiously as well as precisely because clinical decisions, especially where prevention of CVD is concerned, should rarely be based on limited clinical trial results. Last, although it is true that CAD death is extremely rare in premenopausal women and that agematched premenopausal women are at lower risk for cardiovascular events than postmenopausal women, it is conceivable that the scientific community has overestimated the expected benefit of hormone replacement therapy on CVD (Figure 3). As can be seen in

FIGURE 3. The risk of death from coronary artery disease (CAD) is >200-fold greater in postmenopausal women >50 years of age than in premenopausal women <50 years.

Figure 4, although CVD and CAD death rates are lower for age-matched premenopausal women relative to postmenopausal women, CVD and CAD death rates still increase with increasing age. Furthermore, as age increases, the difference in CAD death rates between premenopausal and postmenopausal women of the same age decreases (Figure 4). In fact, the CAD death rate in premenopausal and postmenopausal women 50 to 54 years of age is nearly identical (Figure 4). It is a common misconception that endogenous hormones and hormone replacement therapy are completely cardioprotective. It is hard to dismiss the possibility that the myth of complete cardioprotection by hormones has resulted in unrealistic expectations of hormone replacement therapy.

CONCLUSION B-mode ultrasonography of IMT of the carotid artery offers a cost-effective way to screen for and monitor the progression of early atherosclerosis. This technique is low cost, portable, and easy to use. Early identification and treatment of high-risk asymptomatic individuals will result in a reduction in morbidity and mortality associated with CVD. Changes in carotid IMT have been shown to correlate well with other indicators of heart disease, including coronary angiographic change and clinical coronary events. Thus, IMT is a useful surrogate outcome for trials that evaluate interventions to modify CVD. Cardiovascular disease remains the number 1 cause of death in women. Recent trials indicate that the study of hormone replacement therapy for the reduction of atherosclerosis progression will be complicated by many factors, including the availability of a large array of different hormone preparations, regimens, doses, and delivery routes. To study the many questions before us will neither be simple nor inexpensive. Large morbidity/mortality trials, such as HERS and WHI, cannot appropriately address the many questions on the role of hormone replacement therapy in CVD prevention. These types of trials are prohibitively expensive, require thousands of subjects, and

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FIGURE 4. The number of deaths attributed to cardiovascular disease (CVD) and coronary artery disease (CAD) are lower for age-matched premenopausal women relative to postmenopausal women; however, with advancing age, this discrepancy becomes less apparent.

take ⱖ5 years to perform. Smaller, more cost-effective trials that are of shorter duration will be required if this area of investigation is to proceed at an appreciable rate.

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DISCUSSION Michael E. Mendelsohn, MD (Boston, Massachusetts): What is the mean age of the women you enrolled? Howard N. Hodis, MD (Los Angeles, California): That is a point that should be mentioned. In the Estrogen in the Prevention of Atherosclerosis Trial (EPAT),1 time from menopause to randomization was 10 years shorter than in the Estrogen Replacement and Atherosclerosis (ERA) study2 and in the Heart and Estrogen/progestin Replacement Study (HERS).3 It is another factor that we are looking at very carefully. We are beginning to believe that the time to start estrogen for prevention of atherosclerotic cardiovascular events is at menopause and, perhaps, during the perimenopausal period. I showed the graph of the lipid changes occurring as long as 12.4 months before a woman is considered postmenopausal, so we think the earlier the intervention, the better. Further, comparisons of postmenopausal women with premenopausal women show that premenopausal women have earlier histologic atherosclerosis changes. So, combining all the information that we have, it

appears that women either rapidly start developing atherosclerosis (which is hard to imagine, but we do not know because the normal progression of disease in women has not really been studied) or something happens with ovarian failure that permits the atherosclerotic process to take off. I think it is probably the latter. Something is missing, whether it is estrogen or estrogen and testosterone or all the other hormones that women lack in the menopausal/postmenopausal period, or estrogen receptor responsiveness. 1. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer

RH, Liu C-R, Liu C-H, Azen SP, for the Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135: 939 –953. 2. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu C-R, Liu C-H, Azen SP, for the Estrogen in the Prevention of Atherosclerosis Trial Research Group. Estrogen in the prevention of atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135: 939 –953. 3. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605– 613.

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