- Email: [email protected]
Randomized clinical trials of hormone replacement therapy for treatment or prevention of cardiovascular disease: a review of the findings
Atherosclerosis 166 (2003) 203 /212 www.elsevier.com/locate/atherosclerosis
Review article
Randomized clinical trials of hormone replacement therapy for treatment or prevention of cardiovascular disease: a review of the findings David M. Herrington *, Karen Potvin Klein Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA Received 31 October 2001; received in revised form 17 May 2002; accepted 22 May 2002
Abstract Coronary heart disease (CHD) is the leading cause of death in women. Epidemiologic, mechanistic, and animal-model studies have produced convincing evidence that hormone replacement therapy (HRT) could substantially decrease rates of CHD in women. However, several randomized clinical trials of HRT in women with CHD have been unable to confirm the earlier suggestions of benefit, and there has even been a suggestion of increased CHD risk. This article will review the findings to date of these long-term randomized clinical trials of HRT for prevention or treatment of CHD. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Coronary heart disease; Hormone replacement therapy; Women; Risk factors
1. Introduction Coronary heart disease (CHD) is the leading cause of death in postmenopausal women; according to the American Heart Association’s most recent data, it accounted for 503 927 deaths in 1998 [1]. Contrary to what most women believe, the toll of cardiovascular disease (126.9 deaths per 100 000 women) far outstrips that of all types of cancer combined (105.5 deaths per 100 000 women) [1]. Furthermore, since 1990, the cardiovascular mortality trend for women has continued to increase, unlike that in men, which has decreased [1]. Because of the aging of the US population, the absolute number of women with or at risk for heart disease is also likely to increase. Currently, 38% of US women are 45 years of age and older; this percentage will increase to 45% by the year 2015 [2]. Thus, strategies are urgently needed for more effective treatment and prevention of CHD in women.
* Corresponding author. Fax: /1-336-716-9188 E-mail address: [email protected] (D.M. Herrington).
Until relatively recently, there was great enthusiasm for the use of postmenopausal hormone replacement for prevention of CHD in women [3,4]. Numerous observational studies and meta-analyses had strongly suggested that postmenopausal hormone replacement therapy (HRT), whether given alone or combined with a progestin, reduced the risk of symptomatic atherosclerotic CHD. This was reported in both primary [5,6] and secondary prevention settings [7 /11]. These observational studies were supported by numerous clinical studies demonstrating beneficial effects of estrogen on lipids and fibrinogen [12], endothelial function [13 /15], and other factors thought to be related to risk for coronary disease [16]. In addition, well-designed studies documented significant reductions in coronary atherosclerosis in surgically postmenopausal monkeys treated with estrogen [17,18]. Thus, it was unexpected when the Heart and Estrogen/progestin Replacement Study (HERS) showed no overall effect of 4.1 years of estrogen plus progestin therapy for secondary prevention of CHD in postmenopausal women [19]. Since then, five additional trials have been completed confirming the overall null effects observed in HERS.
0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 2 ) 0 0 2 0 2 - 2
204
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
The purpose of this review is to summarize the results of HERS and subsequent randomized clinical trials of the effects of HRT on anatomic or clinical manifestations of atherosclerosis.
2. The HERS results HERS was a multi-center, double-blind, randomized clinical trial to examine the effects of HRT on risk for CHD events in 2763 postmenopausal women with CHD. Participants (mean age 66.7 years) were randomized to either HRT (0.625 mg oral conjugated equine estrogen [CEE] and 2.5 mg medroxyprogesterone acetate [MPA] daily; n/1380) or placebo (n /1383). Because these women still had their uterus, annual gynecologic examinations were included in the protocol. The primary outcome was the occurrence of a nonfatal myocardial infarction (MI) or fatal CHD event. Secondary cardiovascular outcomes included coronary revascularization, resuscitated cardiac arrest, stroke or transient ischemic attacks, unstable angina, congestive heart failure, and peripheral arterial disease [20]. A total of 179 women in the HRT group and 182 women in the placebo group experienced a nonfatal MI or fatal CHD event during the 4.1 years of follow-up (relative hazard [RH] 0.99; 95% confidence interval [CI] 0.81 /1.22) (final data available at http://www.keeptrack.ucsf.edu/hers2/HERSfindat.htm). A nonsignificant difference was also seen between groups for all of the secondary cardiovascular outcomes. Within this overall null effect, a pattern of CHD risk reduction in Years 3/5 was offset by an unanticipated 50% increase in risk during Year 1. The overall null effect and the pattern of early risk observed in HERS raised many questions, both about the trial itself and about the validity of the hypothesis that HRT was effective for prevention of coronary disease. Many of these questions can now be answered in light of results from several subsequently completed randomized clinical trials, which are reviewed below.
3. Other recently completed trials of HRT for secondary prevention 3.1. The Estrogen Replacement and Atherosclerosis (ERA) trial The ERA trial was designed and begun while the HERS trial was ongoing. ERA was a 3-arm, randomized, double-blind trial (N /309) of unopposed oral CEE (0.625 mg conjugated estrogen), CEE plus MPA (2.5 mg daily), or a placebo. Postmenopausal women were recruited at five clinical sites using both hospital- and community-based methods [21]. Women
were eligible if they were postmenopausal, not currently taking HRT, and had at least one coronary stenosis of ]/30% confirmed by quantitative coronary angiography. Women with known or suspected breast or endometrial cancer, a history of deep-vein thrombosis or pulmonary embolism, or uncontrolled hypertension or diabetes were excluded. Once randomized to one of the three arms, participants (mean age 65.8 years) were followed for an average of 3.2 years. The primary endpoint was mean minimum coronary artery diameter, measured by quantitative coronary angiography at baseline and follow-up. Secondary endpoints included brachial artery vasodilator capacity, measured by ultrasound, and a series of known risk factors for atherosclerosis (e.g. blood pressure, lipids and lipoproteins, hemostatic and inflammatory factors, glucose metabolism). After adjustment for baseline coronary artery diameter and prespecified variables, no difference in mean minimum artery diameter was found among the three groups (CEE only, 1.879/0.02 mm; CEE plus MPA, 1.849/0.02 mm; and placebo, 1.879/0.02 mm) [22]. The lack of apparent benefit in the unopposed estrogen arm suggested that the HERS results could not simply be attributed to the concomitant treatment with MPA. Despite the failure to slow progression of atherosclerosis, some improvements in lipids and lipoproteins occurred in the treatment groups, as has been seen in multiple previous studies of HRT. HDL cholesterol was increased and LDL cholesterol was decreased relative to placebo in both active arms of the trial [22]. Triglycerides were also increased with treatment, a typical effect of HRT. Ongoing studies of the ERA cohort include examination of inflammatory markers and their association with HRT’s effects, as well as a series of genetic investigations (see Section 8.1 below for one example). 3.2. The PHASE trial Preliminary data are available for another clinical study of HRT, the Papworth HRT Atherosclerosis Study Enquiry (PHASE). In PHASE, 255 postmenopausal women with angiographically proven coronary artery disease were randomized to receive either transdermal 17b-estradiol 2 mg/day (plus 4 mg/day of cyclic norethindrone acetate in women with an intact uterus) or placebo. Women were followed for 4 years for the primary endpoints of hospitalization for unstable angina, MI, or death. In the intention-to-treat analysis, the average primary endpoint rate was 15.6/100 patientyears in the HRT group versus 12.6/100 patient-years in the control group (RR 1.23, 95% CI 0.82 /1.86; P / 0.30). Although event rates were higher in the HRT group in all 4 years, especially the first 2 years, the difference was not statistically significant [23]. In the wake of the HERS results, PHASE was stopped before
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
the recruitment goal was attained because of concerns about subjects’ safety. The PHASE findings suggest that the type of estrogen employed and route of administration do not explain the lack of a cardioprotective effect of oral CEE regimens reported elsewhere in postmenopausal women with CHD. 3.3. The PHOREA trial In the Postmenopausal Hormone Replacement against Atherosclerosis (PHOREA) trial, 321 postmenopausal women with subclinical carotid atherosclerosis (defined as /1 mm increase in intima-media thickness in ]/1 carotid artery segment, measured by ultrasound) were studied [24]. Subjects were allocated to one of two strata based on presence of cardiovascular risk factors (hypertension, smoking, diabetes, LDL /150 mg/dl) and then randomized within the stratum to prevent uneven distribution of these factors within treatment groups. There were three treatment arms: women received placebo, or 1 mg/day oral 17b-estradiol with one of two oral progestin regimens (cyclic 0.025 mg/day gestodene on days 17/28 of each 4-week cycle, or 0.025 mg/day gestodene for 12 days every third month). After 48 weeks of treatment, neither HRT regimen slowed progression of carotid atherosclerosis (measured as intima-media thickness [IMT]) compared with the placebo group [24]. This study has some limitations */ it was conducted at a single center, was relatively brief, and physicians and subjects were not blinded to treatment. However, the sonographer and reader of the carotid artery images were unaware of treatment assignments, so bias should not have entered into the ultrasound data acquisition.
205
women, and overall mortality rates were slightly higher in the 17b /estradiol group compared with the placebo group (18.4 vs. 16.3%) [25]. On balance, in this trial there was no evidence that 17b-estradiol was beneficial for secondary prevention of cerebrovascular disease. 3.5. Ongoing cardiovascular randomized clinical trials of HRT for secondary prevention Other ongoing secondary cardiovascular prevention trials of HRT include three examining angiographic endpoints (WELL-HART, WAVE, EAGAR) and one assessing clinical outcomes (ESPRIT). The Women’s Estrogen-progestin Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) is studying the progression of coronary stenosis in women (N :/ 450) receiving oral 17b-estradiol with or without cyclic MPA. Angiographic changes after 3 years of HRT and/ or vitamins C and E versus placebo are being evaluated in 400 postmenopausal women in the Women’s Angiographic Vitamin and Estrogen (WAVE) trial. Participants receive oral CEE with or without MPA, depending on their uterine status. Results of WAVE should be available late in 2002. Investigators of the Estrogen And Graft Atherosclerosis Research (EAGAR) study are studying the role of oral CEE in preventing the reocclusion of bypass grafts in approximately 100 postmenopausal women. In the U.K., the Estrogen in the Prevention of ReInfarction Trial (ESPRIT) is a study of 1017 postmenopausal women with a documented MI. They were randomized within 30 days of the MI to receive either placebo or 2 mg daily estradiol valerate. The primary endpoint of the trial is death or recurrent MI. Follow-up is scheduled to be completed in early 2002 [26].
3.4. HRT and stroke: the WEST data The Women’s Estrogen for Stroke Trial (WEST) was designed to evaluate whether 1 mg/day 17b-estradiol would affect the combined outcome of stroke or allcause mortality in 652 subjects (mean age 71 years) with a documented, non-disabling stroke or transient ischemic attack within 90 days of entry into the trial [25]. Randomization was stratified based on hospital site and baseline risk group (defined by a previously validated clinical index). Women who did not have a clinical event were followed for at least 12 months (mean 339/17 months). Treatment had no effect on the primary outcomes. Deaths occurred in 99 subjects in the estradiol group and in 93 in the placebo group (RR 1.1; 95% CI 0.8 /1.4). There were 51 non-fatal strokes in the estradiol group and 52 in the placebo group (RR 1.0; 95% CI 0.7 /1.4) [25]. While there were no increased rates of venous thromboembolic events or breast cancer in the 17b /estradiol group, vaginal bleeding and endometrial hyperplasia were more common in these
4. Questions and (some) answers concerning use of HRT for secondary prevention of CHD 4.1. Could the null result in HERS be due to the type of HRT regimen used? It is possible that the estrogen regimen used in HERS had no effect on CHD risk because of the type of estrogen (conjugated equine estrogen) or because the estrogen was opposed by a progestin. The progestin used in HERS, MPA, has been shown to attenuate beneficial effects of estrogen on atherosclerosis [18] and endothelial function [27] in animal models. In the Postmenopausal Estrogen-Progestin Intervention (PEPI) trial, women taking estrogen plus MPA had less favorable changes in HDL than women taking estrogen alone or estrogen plus micronized progesterone [12]. It has been suggested that unopposed estrogen, or estrogen combined with other progestins, might have
206
Table 1 Summary of results: long-term randomized clinical trials of hormone replacement therapy for treatment or prevention of cardiovascular disease Name of study
N
Hulley et al. [19] Herrington et al. [22] Clarke et al. [23] Angerer et al.c[24]
Heart and Estrogen/progestin Study (HERS) Estrogen Replacement and Atherosclerosis (ERA) Papworth HRT Atherosclerosis Enquiry (PHASE) Postmenopausal Hormone Replacement Against Atherosclerosis (PHOREA) Women’s Estrogen for Stroke Trial (WEST) Estrogen and Prevention of Atherosclerosis Trial (EPAT)
Viscoli et al. [25] Hodis et al. [55]
de Kleijn et al. None reported [56]
Treatment(s)a
Duration of follow-up
Primary endpoint(s)
Results (Outcome)
2763 0.625 mg/day CEE2.5 mg/day MPA
4.1 years
No difference in risk; improved lipids
309
0.625 mg/day CEE92.5 mg/day MPA
3.2 years
255
17b-E29cyclic norethisteroneb
3 years
321
1 year
652
1 mg/day 17b-E2; 1 mg/day 17-bE20.025 mg gestodene 12 d/mo; 17b-E20.025 mg gestodene 12 d/every 3 mo 1 mg/day 17b-E2
CHD death/nonfatal MI Mean minimum coronary artery diameter Unstable angina or MI Carotid IMT
222
1 mg/day 17b-E2; LLMs if indicated
2 years
121
1.5 mg/day 17b-E2cyclic 0.15 mg desogestrel; 0.625 mg CEE0.15 mg cyclic norgestrel
2 years
3 years
No difference; improved lipids No difference No difference in rate of progression
Combined stroke and No difference death Carotid IMT Significantly less progression with E2; no difference in progression in those taking LLMs Carotid IMT and end- No difference diastolic lumen diameter
a In these studies, a placebo arm is included and results are in comparison to placebo. 17b-E2 17b-estradiol; CEE conjugated equine estrogen; CHD coronary heart disease; IMT intimamedia thickness; LLMs lipid-lowering medications; MI myocardial infarction; MPA medroxyprogesterone acetate. b In this preliminary report, dosages were not provided. c In this study, results are in comparison to the no treatment arm.
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
1st author, reference #
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
been more effective. Similarly, some have argued that estradiol, given either orally or transdermally, would be a superior form of HRT for prevention of CHD. However, as is evident in Table 1, there are now four additional randomized clinical trials examining unopposed estrogen, oral or transdermal estradiol, or regimens using progestins other than MPA that also have shown no effect on progression of clinical or anatomic manifestations of atherosclerosis. Nonetheless, it is possible that newer estrogen agonists with different profiles of receptor or tissue specificity than current HRT regimens may be shown to be effective treatments in the future [28]. 4.2. Are HRT’s effects age-dependent? Some investigators have speculated that the beneficial cardiovascular effects of HRT may be nullified if subjects are older and atherosclerosis is too far advanced when HRT is begun [29]. There is some evidence in nonhuman primates to support this theory [30]. Further, in a recent report of brachial artery flow-mediated dilation from a large observational cohort, subjects over 80 years old and those with established CHD showed no benefit from HRT, unlike HRT users in the cohort without subclinical CHD or CHD risk factors [31]. However, a cross-sectional study of 217 postmenopausal women in Australia (mean age 60 years) reported that HRT protected subjects from age-related deleterious changes in carotid structure and function, compared with age-matched nonusers of HRT [32]. A recent analysis of women from the Nijmegen population study found that later age of menopause was associated with reduced risk of cardiovascular mortality [33], suggesting that longer duration of exposure to estrogen at an earlier stage of life might confer more benefit than starting HRT late in life. Unfortunately, no data on this issue are currently available from randomized clinical trials. 4.3. Could the overall null effect in HERS be due to early harm and late benefit? Secondary analysis of the HERS events over time suggest the possibility of early harm, which offsets a late benefit. A pattern of early harm and late benefit could explain the discordance between the null results described above and the earlier observational studies of HRT and CHD risk, since most observational studies are not designed to detect early adverse effects of treatment. A similar pattern is also suggested in the WEST results and in preliminary data from WHI, although the confidence intervals are too wide to make assertions with confidence about early harm. The other completed randomized trials are too small to address
207
this issue. Several observational cohorts have also been examined for evidence of early harm from HRT. In a recent retrospective analysis of 981 women in the Puget Sound Group Health Cooperative, risk for a first MI among women on HRT for 5/60 days was double that of similar women who had used HRT for ]/1 year (HRT use 5/60 days: RH 2.16, 95% CI 0.94 /4.95; HRT use ]/1 year: RH 0.76, 95% CI 0.42 /1.36). However, no increased risk was found among current HRT users versus non-users (RH 0.96; 95% CI 0.62 /1.50) [34]. Use of estrogen only and estrogen plus progestin (not further categorized, but described as most commonly oral esterified estrogen with or without MPA) was combined in this analysis. The RH ratios were adjusted for age, calendar year of the first MI, and diabetes; further adjustments for congestive heart failure and use of aspirin or beta-blockers did not substantially alter the finding [34]. Contrary to subjects in HERS, the Puget Sound women had not been diagnosed with heart disease before their first MI. Among women with established heart disease in another large cohort, the Nurses’ Health Study (N / 2489), a similar pattern was seen with respect to risk for MI recurrence or CHD death [35]. For women who had used HRT for B/1 year, the multivariateadjusted relative risk for a CHD event was 1.25 (95% CI 0.78 /2.00) compared with never-users. However, in women who had used HRT for ]/2 years, the relative risk dropped to 0.38 (95% CI 0.22 /0.66; P for trend /0.0002) [35]. No differences were seen between users of unopposed oral CEE or oral CEE plus MPA regimens. Analyses were limited to these two types of regimens because they are by far the most commonly used. Investigators have also reanalyzed data from the Coronary Drug Project, which examined use of oral conjugated estrogen (2.5 or 5.0 mg/day) versus placebo in 3800 men with electrocardiographically documented MI. They reported a previously unrecognized increased risk of CHD death or nonfatal MI within the first 4 months of treatment (RH 1.58; 95% CI 1.04 /2.40). This risk decreased substantially in men treated for 13/60 months (RH 0.9, 95% CI 0.80 /1.15). Over the course of the trial, the RH in the 2.5 mg/day group relative to placebo was 0.99 (95% CI 0.86 /1.15) [36]. The 5.0 mg/ day estrogen treatment arm was stopped after 1.5 years because of an excess rate of mortality and nonfatal MI [37]. Researchers in the ongoing Women’s Health Initiative (WHI), a clinical trial of oral CEE plus MPA in over 27 000 mostly healthy postmenopausal women, have reported similar patterns of early increased cardiovascular risk that decline over time (see a summary at http://www.nhlbi.nih.gov/whi/hrt-en.htm). However, details are not available until the WHI is completed in 2005.
208
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
Thus, there is evidence from several large, varied cohorts that supports the pattern of early increased risk associated with HRT use observed in HERS. The mechanisms responsible for this pattern remain undetermined.
4.4. Is there a susceptible cohort? The pattern of early risk that rapidly declined after Year 1 in HERS could have resulted from attrition of a small cohort who were uniquely susceptible to an adverse effect of HRT. During Year 1, as this highrisk group suffered primary events, they would not contribute cardiovascular events to the active treatment group, and apparent risk would be concomitantly reduced [38]. In fact, within the first year in HERS the risk was highest in the first 4 months, at an intermediate level in the second 4 months, and nearly back to unity during the final 4 months [39].
5. Potential mechanisms: early CHD risk associated with HRT Some of the many current areas of investigation into potential mechanisms of early risk of HRT include effects on the thrombosis/coagulation pathways, the role of thrombosis-related genes, and the possibility of a proinflammatory effect of estrogen.
5.1. Is a prothrombotic effect involved in early risk with HRT? The HERS trial also confirmed earlier reports [40 /44] of a 2-fold to 4-fold increase in risk for venous thromboembolic events (VTE) from estrogen plus progestin therapy [45]. However, unlike the earlier reports in healthy women with a low overall rate of VTE (around 0.02%), the annual rates in HERS were substantially higher (HRT /0.63% vs. placebo 0.22%; RH 2.9; 95% CI 1.5 /5.6, P /0.002). As was the case for cardiovascular events, the increased risk for VTE with HRT was greatest in the first year (RH 3.3, P B/0.05). Thus, an increased risk of VTE may be another important consideration in clinical decision-making about use of HRT in women with established heart disease. Furthermore, a prothrombotic effect of HRT could account for increased risk for both arterial and venous thrombotic events. More information is needed about the magnitude of the relative and absolute increases in VTE risk and how they may relate to risk of CHD events.
5.2. Is a proinflammatory effect involved in early risk with HRT? Increases in C-reactive protein (CRP) are independently associated with greater risk for cardiovascular events, even in postmenopausal women without CHD [46]. Significantly higher CRP levels were reported in several studies after treatment with either CEE or 17bestradiol [46 /49]. In the PEPI trial, significant increases in CRP were seen in all four groups (CEE alone or combined with cyclic MPA, continuous MPA, or micronized progesterone) (P /0.0001) after 3 years of treatment [47]. Subsequently, in a recent double-blind crossover trial, 6 weeks of oral CEE alone (0.625 mg/ day) significantly increased both CRP and interleukin-6 in healthy postmenopausal women [50]. Elevated CRP activation may be associated with CHD risk independent of a systemic pro-inflammatory effect. For example, CRP stimulates monocyte expression of tissue factor, which could potentiate a prothrombotic state [51]. On the other hand, estrogen appears to have favorable effects on other inflammatory proteins. In the same double-blind crossover trial noted above, oral CEE was associated with decreased levels of E-selectin and VCAM-1, consistent with an anti-inflammatory effect [52], possibly because of estrogen-related upregulation of endothelial nitric oxide synthase [53]. However, the clinical significance of changes in cytokines or adhesion molecules has yet to be established. Furthermore, the net effect of these seemingly contradictory actions of estrogen is still unknown. The need to weigh the complete physiological effects of HRT was illustrated by a pooled analysis of 22 clinical trials in 1997, which found an increased risk of cardiovascular events in women taking HRT [54]. Without doubt, the overall risk/benefit analysis for HRT must be taken into consideration for each individual. Results from long-term randomized clinical trials are needed to provide more data in this regard.
6. Effects of HRT for primary prevention Despite the negative or equivocal results described above, it is noteworthy that there is some evidence that HRT, taken earlier in the menopausal transition and thus earlier in the atherosclerotic process, may be efficacious in slowing progression of CHD in some women. Details of two studies providing such evidence are given below. 6.1. The EPAT data Results have now been reported from The Estrogen and Prevention of Atherosclerosis Trial (EPAT) [55].
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
EPAT was a randomized, double-blind clinical trial of estrogen in 199 postmenopausal women with elevated LDL cholesterol concentrations ( ]/130 mg/dl) but with no clinical evidence of CHD. Women with a history of smoking or uncontrolled diabetes mellitus were excluded. Participants were randomized to receive placebo or unopposed oral micronized 17b-estradiol (1 mg/day). Because most participants were not hysterectomized, all subjects underwent a yearly gynecologic examination (including a pelvic examination, Pap smear, mammogram, and uterine ultrasound if applicable). If their LDL concentrations exceeded 160 mg/dl, all participants also received lipid-lowering medication, regardless of treatment group. The primary endpoint was difference in carotid artery wall thickness, based on ultrasound measurements at baseline and after 2 years of treatment. When comparing only participants with normal LDL levels who were not taking lipid-lowering agents, the estradiol group showed a small decrease in carotid wall thickness compared with the placebo group (P /0.045, adjusted for oophorectomy status). But among subjects taking lipid-lowering agents, there was a greater difference in carotid wall thickness between the two arms (P /0.002), mostly because of greater increases in wall thickness among women in the placebo group [55]. Adjustment for oophorectomy status did not alter these results. Thus, in EPAT, unopposed 17b-estradiol was beneficial in slowing subclinical atherosclerosis only in subjects not taking lipid-lowering medications, suggesting that women using these drugs might not derive additional cardiovascular benefit from taking HRT. 6.2. Evidence in perimenopausal women Data regarding markers of change in carotid artery structure among women in the menopausal transition were reported by deKleijn et al. [56]. They studied a total of 121 healthy Dutch women without hysterectomies between 40 and 60 years of age who were undergoing menopause, defined as hot flushes or sweating episodes. Mean time since last menstruation was 3 months, and 13 women (11%) were postmenopausal (no menses for ]/12 months). Baseline measurement of circulating levels of estradiol was not reported. Exclusion criteria included use of sex steroids or lipidlowering agents, presence of cardiovascular or renal disease, or uncontrolled hypertension. Pap smears and mammograms were performed at baseline if test results were not available within the past 12 months (for Pap smears) or 24 months (for mammograms). Subjects were randomized to receive one of three regimens: (1) 0.625 mg/day oral conjugated equine estrogens and 0.15 mg/ day norgestrel (norgestrel taken on days 17/28 only); (2) 1.5 mg/day oral micronized 17b-estradiol and 0.15 mg/day desogestrel (desogestrel taken on days 13 /24 only) with four matched placebo pills (taken on days
209
25 /28 only); or (3) placebo only. The primary endpoints, common carotid IMT and end-diastolic lumen diameter, were measured at baseline and at the end of cycle 24. After 2 years, small reductions in carotid IMT and in lumen diameter were seen in the treatment groups compared with placebo, but the confidence intervals were wide and the authors concluded that a significant effect of treatment could not be demonstrated. However, data from only 52% of randomized subjects could be analyzed, because of a high drop-out rate and missing ultrasound data in all arms. Furthermore, the investigators broke the study blind after cycle six, and the placebo group was not subject to follow-up between cycles six and 24, but the reasons for these anomalies were not given. Despite these limitations, it is of interest that the changes seen were in a positive direction, and that there were no significant differences between the two treatment regimens in the endpoints of interest.
7. Ongoing cardiovascular randomized clinical trials of HRT for primary prevention The Women’s International Study of long Duration Oestrogen after the Menopause (WISDOM) and the WHI are two large primary prevention randomized clinical trials currently underway in primarily healthy postmenopausal women. WISDOM will examine a cohort of approximately 22 000 women recruited from general practices in the United Kingdom randomized to oral CEE (with or without MPA, depending on uterine status) versus placebo for a median of 10 years, with a planned 5-year follow-up (see http://www. mrc-gprf.ac.uk/maindocs/summaries/wisdom.htm). The HRT component of the WHI will study effects of the same treatments on risk of CHD in 27 348 women over an average of 8.5 years. Upon completion, these trials will provide valuable insight into effects of long-term HRT on clinically important chronic diseases such as osteoporosis and breast cancer, as well as primary prevention of cardiovascular disease in postmenopausal women.
8. New directions in studies of HRT and cardiovascular risk New studies are underway to attempt to explain the mechanisms involved in the clinical trial data described above. Of the many such studies underway, several of the most promising are summarized below.
210
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
8.1. Do genetic variants affect HRT response? Genetic polymorphisms are known to increase the risk of venous or arterial thrombotic events in users of oral contraceptives or HRT. How estrogen affects coagulation and thrombotic factors to potentiate a risk for thrombosis is not fully understood. Some genetic mutations, such as Factor V Leiden and prothrombin 20210A, appear to increase the risk of venous or arterial thrombotic events when estrogen levels are increased. In a recent case-control study, presence of the prothrombin 20210 G0/A mutation in women with hypertension was a significant risk factor for MI [57]. The mutation was discovered in 47% of MI cases and 54% of controls. Women with the mutant prothrombin allele who were using HRT had almost an 11-fold greater risk of a nonfatal MI, compared with current HRT users without the prothrombin variant [57]. In women who were / 80% compliant with their HRT, the risk was even higher. There is now evidence from the ERA trial that genetic polymorphisms of the estrogen receptor-a (ER-a) can alter lipid responses to HRT. Subjects in both activetreatment arms of ERA (oral CEE only and oral CEE plus MPA) and in the placebo group were characterized with respect to selected ER-a polymorphisms. After adjusting for potential confounders (age, alcohol intake, body mass index, diabetes, level of exercise, race, and smoking), women with the ER-a intervening sequence 1401 (IVS1-401) C/C genotype in the active-treatment arms showed increases in HDL cholesterol more than twice as high as C/C and T/T women (13.1 vs. 6.0 mg/dl; P value for treatment-by-genotype interaction /0.004) [58]. Importantly, women with the ER-a IVS1-401 C/C genotype comprised 18.9% of the subjects, and this augmented HDL response was shown in both activetreatment arms and across racial groups. It was even more robust in women classified as compliant to the study medications (]/80% of pills taken) (P/0.0004) [58]. In a subsequent report, women in the active treatment arms with the ER-a IVS1-401 C/C genotype showed greater reductions in E-selectin but not CRP, suggesting a selective drug-gene interaction [59]. Further examination into the relationship between the ER-a IVS1-401 C/C genotype (and other closely related polymorphisms) and clinical cardiovascular events might be of great value to better understanding how future use of HRT could be tailored to individual women.
HRT [60]. However, even after the most contemporary and careful attempts to adjust for possible confounders, HRT use continues to be associated with more favorable outcomes [61]. It is also true that participants in randomized clinical trials are not always representative of the general population. More work is required to understand how best to extrapolate the results from both observational studies and clinical trials to the general population.
9. Conclusions In light of the data reported in HERS and subsequent trials, the American Heart Association has published updated recommendations concerning HRT for prevention of heart disease [62]. In women with established heart disease, HRT is not recommended for secondary prevention. Other proven methods of treatment for heart disease should be the first line of defense, as has been pointed out in commentaries about the HERS results [29,38]. In women without objective evidence of CHD, there are currently inadequate data to make a firm recommendation for primary prevention. In either case, the emphasis should be on non-coronary indications for HRT use. Ongoing research is needed to help define the proper role for HRT in primary prevention of CHD and identify strategies to maximize its efficacy while minimizing risks. Results from the WHI and WISDOM trials will, it is hoped, shed more light on the overall effects of long-term HRT use. Newer estrogen agonists with more tissue-specific activities will also come into play as we continue to seek ways to reduce the burden of heart disease in all postmenopausal women.
Note added in proof The HERS follw-up study (HERS II) reported that after 6.8 years, hormone therapy did not reduce cardiovascular risk in the HERS cohort (JAMA 2002;288:49 /57). Furthermore, the WHI stopped the CEE+MPA arm of its HRT trial early because of excess risk of CHD events, invasive breast cancer, venous thromboembolism, and stroke in that group (JAMA 2002;288:321{333) The CEE-only arm continues as planned.
8.2. Other issues For many years, the results of observational studies of HRT use and cardiovascular disease were criticized because users of HRT tended to be healthier than non-users, potentially biasing the results in favor of
References [1] American Heart Association. 2001 Heart and stroke statistical update. Dallas: American Heart Association, 2000.
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212 [2] Wenger NK. Cardioprotection for the postmenopausal women: HERS results and their implications. Prevent Cardiol 1998;1:9 / 11. [3] NCEP, Adult Treatment Panel II. Second Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation 1994;89:1329-445. [4] Smith SC, Blair SN, Criqui MH, Fletcher GF, Fuster V, Gersh BJ, Gotto AM, Gould KL, Greenland P, Grundy SM, et al. Preventing heart attack and death in patients with coronary disease. The Secondary Prevention Panel. Circulation 1995;92:2 / 4. [5] Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses Health Study. New Engl J Med 1991;325:756 /62. [6] Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016 /37. [7] Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, Mirvis DM. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med 1990;150:2557 /62. [8] Sullivan JM, El-Zeky F, Vander Zwaag R, Ramanathan KB. Effect on survival of estrogen replacement therapy after coronary artery bypass grafting. Am J Cardiol 1997;79:847 /50. [9] O’Keefe JH, Jr., Kim SC, Hall RR, Cochran VC, Lawhorn SL, McCallister BD. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol 1997;29:1 /5. [10] O’Brien JE, Peterson ED, Keeler GP, Berdan LG, Ohman EM, Faxon DP, Jacobs AK, Topol EJ, Califf RM. Relation between estrogen replacement therapy and restenosis after percutaneous coronary interventions. J Am Coll Cardiol 1996;28:1111 /8. [11] Newton KM, LaCroix AZ, McKnight B, Knopp RH, Siscovick DS, Heckbert SR, Weiss NS. Estrogen replacement therapy and prognosis after first myocardial infarction. Am J Epidemiol 1997;145:269 /77. [12] The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Am Med Assoc 1995;273:199 /208. [13] Gerhard M, Walsh BW, Tawakol A, et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation 1998;98:1158 /63. [14] Sorensen KE, Dorup I, Hermann AP, Mosekilde L. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation 1998;97:1234 /8. [15] Herrington DM, Werbel BL, Riley WA, Pusser BE, Morgan TM. Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease. J Am Coll Cardiol 1999;33:2030 /7. [16] Herrington DM. Effects of estrogen on the anatomic and functional sequelae of coronary atherosclerosis. In: Forte TM, editor. Hormonal, metabolic, and cellular influences on cardiovascular disease in women. Armonk, NY: Futura Publishing Company, 1997:175 /92. [17] Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS, Wolfe MS, Clarkson TB. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051 /7. [18] Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:217 /21.
211
[19] Hulley S, Grady D, Bush T, Furberg C, Herrington DM, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 1998;280:605 /13. [20] Grady D, Applegate B, Bush T, Furberg C, Riggs B, Hulley S. The Heart and Estrogen/progestin Replacement Study: Design, methods and baseline characteristics. Controlled Clin Trials 1998;19:314 /35 (for the HERS Study Group). [21] Folmar S, Oates-Williams F, Sharp P, Reboussin DR, Smith J, Cheshire K, Klein KP, Herrington D. Recruitment of participants for the Estrogen Replacement and Atherosclerosis (ERA) trial: a comparison of costs, yields, and participant characteristics from community- and hospital-based recruitment strategies. Control Clin Trials 2001;22:13 /25. [22] Herrington DM, Reboussin DR, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. New Engl J Med 2000;343:522 /9. [23] Clarke S, Kelleher J, Lloyd-Jones H, Sharples L, Slack M, Schofield PM. Transdermal hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women (abstract). Eur Heart J 2000;21:212. [24] Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis. A randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262 /8. [25] Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. New Engl J Med 2001;345:1243 /9. [26] Khan MA, Heagerty AM, Kitchener H, McNamee R, Cherry NM, Hannaford PC. Oestrogen and women’s heart disease: ESPRIT-UK. Q J Med 2000;93:699 /702. [27] Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757 /61. [28] Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. Four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. J Am Med Assoc 2002;287:847 /57. [29] Mendelsohn ME, Karas RH. The time has come to stop letting the HERS tale wag the dogma. Circulation 2001;104:2256 /9. [30] Williams JK, Anthony MS, Honore EK, Herrington DM, Morgan TM, Register TC, Clarkson TB. Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol 1995;15:827 /36. [31] Herrington DM, Espeland MA, Crouse JR, Robertson J, Riley WA, McBurnie MA, Burke GL. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol 2001;21:1955 /61. [32] McGrath BP, Liang YL, Teede H, Shiel LM, Cameron JD, Dart A. Age-related deterioration in arterial structure and function in postmenopausal women. Impact of hormone replacement therapy. Arterioscler Thromb Vasc Biol 1998;18:1149 /56. [33] deKleijn MJJ, van der Schouw YT, Verbeek ALM, Peeters PHM, Banga JD, van der Graaf Y. Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. Am J Epidemiol 2002;155:339 /45. [34] Heckbert SR, Kaplan RC, Weiss NS, Psaty BM, Lin D, Furberg CD, Starr JR, Anderson GD, LaCroix AZ. Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Arch Intern Med 2001;161:1709 /13. [35] Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the
212
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212 Nurses’ Health Study. A prospective, observational study. Ann Intern Med 2001;135:1 /8. Wenger NK, Knatterud GL, Canner PL. Early risks of hormone therapy in patients with coronary heart disease (letter). J Am Med Assoc 2000;284:41 /3. Coronary Drug Project Research Group. The Coronary Drug Project: findings leading to discontinuation of the 2.5 mg/day estrogen group. J Am Med Assoc 1973;226:652 /7. Herrington DM. The HERS trial results: paradigms lost. Ann Intern Med 1999;131:463 /6. Hulley S, Grady D, Vittinghoff E, Bush T, Furberg C, Herrington D, Riggs B. Hormone replacement therapy for secondary prevention of coronary heart disease. J Am Med Assoc 1999;281:796 /7. Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. Br Med J 1997;314:796 /800. Varas-Lorenzo C, Garcia-Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez-Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol 1998;147:387 /90. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977 /80. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981 /3. Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983 /7. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000;132:689 /96 (for the HERS Study Group). Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New Engl J Med 2000;342:836 / 43. Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 1999;100:717 /22. Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999;19:893 /9. van Baal WM, Kenemans P, Emeis JJ, Schalkwijk CG, Miljatovic V, Van der Mooren MJ, Vischer UM, Stehouwer CDA. Longterm effects of combined hormone replacement therapy on
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60] [61]
[62]
markers of endothelial function and inflammatory activity in healthy postmenopausal women. Fertil Steril 1999;71:663 /70. Herrington DM, Pusser BE, Riley WA, Thuren TY, Brosnihan KB, Brinton EA, MacLean DB. Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women. Arterioscler Thromb Vasc Biol 2000;20:1606 /12. Cermak J, Key NS, Bach RR, Balla J, Jacobs HS. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513 /20. Herrington DM, Brosnihan KB, Pusser BE, Seely EW, Ridker PM, Rifai N, MacLean DB. Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001;86:4216 /22. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999;103:401 /6. Hemminki E, McPherson K. Impact of postmenopausal hormone therapy on cardiovascular events and cancer: Pooled data from clinical trials. Br Med J 1997;315:149 /53. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu CR, Liu CH, Azen SP. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939 /53. deKleijn MJJ, Bots ML, Bak AAA, Westendorp ICD, Planellas J, Bennink HJTC, Witteman JCM, Grobbee DE. Hormone replacement therapy in perimenopausal women and 2-year change of carotid intima-media thickness. Atherosclerosis 1999;32:195 /204. Psaty BM, Smith NL, Lemaitre RN, Vos HL, Heckbert SR, LaCroix AZ, Rosendaal FR. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. J Am Med Assoc 2001;285:906 /13. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker ER. Estrogen receptor polymorphisms and effects of estrogen replacement on HDL cholesterol in women with coronary disease. New Engl J Med 2002;346:967 /74. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA, Bleecker ER. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 2002;105:1879 /82. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. J Am Med Assoc 1991;265:1861 /7. Shlipak MG, Angeja BG, Go AS, Frederick PD, Canto JG, Grady D. Hormone therapy and in-hospital survival after myocardial infarction in postmenopausal women. Circulation 2001;104:2300 /4. Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC, Jr., Wenger NK. Hormone replacement therapy and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499 /503.
Review article
Randomized clinical trials of hormone replacement therapy for treatment or prevention of cardiovascular disease: a review of the findings David M. Herrington *, Karen Potvin Klein Department of Internal Medicine/Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA Received 31 October 2001; received in revised form 17 May 2002; accepted 22 May 2002
Abstract Coronary heart disease (CHD) is the leading cause of death in women. Epidemiologic, mechanistic, and animal-model studies have produced convincing evidence that hormone replacement therapy (HRT) could substantially decrease rates of CHD in women. However, several randomized clinical trials of HRT in women with CHD have been unable to confirm the earlier suggestions of benefit, and there has even been a suggestion of increased CHD risk. This article will review the findings to date of these long-term randomized clinical trials of HRT for prevention or treatment of CHD. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Coronary heart disease; Hormone replacement therapy; Women; Risk factors
1. Introduction Coronary heart disease (CHD) is the leading cause of death in postmenopausal women; according to the American Heart Association’s most recent data, it accounted for 503 927 deaths in 1998 [1]. Contrary to what most women believe, the toll of cardiovascular disease (126.9 deaths per 100 000 women) far outstrips that of all types of cancer combined (105.5 deaths per 100 000 women) [1]. Furthermore, since 1990, the cardiovascular mortality trend for women has continued to increase, unlike that in men, which has decreased [1]. Because of the aging of the US population, the absolute number of women with or at risk for heart disease is also likely to increase. Currently, 38% of US women are 45 years of age and older; this percentage will increase to 45% by the year 2015 [2]. Thus, strategies are urgently needed for more effective treatment and prevention of CHD in women.
* Corresponding author. Fax: /1-336-716-9188 E-mail address: [email protected] (D.M. Herrington).
Until relatively recently, there was great enthusiasm for the use of postmenopausal hormone replacement for prevention of CHD in women [3,4]. Numerous observational studies and meta-analyses had strongly suggested that postmenopausal hormone replacement therapy (HRT), whether given alone or combined with a progestin, reduced the risk of symptomatic atherosclerotic CHD. This was reported in both primary [5,6] and secondary prevention settings [7 /11]. These observational studies were supported by numerous clinical studies demonstrating beneficial effects of estrogen on lipids and fibrinogen [12], endothelial function [13 /15], and other factors thought to be related to risk for coronary disease [16]. In addition, well-designed studies documented significant reductions in coronary atherosclerosis in surgically postmenopausal monkeys treated with estrogen [17,18]. Thus, it was unexpected when the Heart and Estrogen/progestin Replacement Study (HERS) showed no overall effect of 4.1 years of estrogen plus progestin therapy for secondary prevention of CHD in postmenopausal women [19]. Since then, five additional trials have been completed confirming the overall null effects observed in HERS.
0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 0 2 ) 0 0 2 0 2 - 2
204
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
The purpose of this review is to summarize the results of HERS and subsequent randomized clinical trials of the effects of HRT on anatomic or clinical manifestations of atherosclerosis.
2. The HERS results HERS was a multi-center, double-blind, randomized clinical trial to examine the effects of HRT on risk for CHD events in 2763 postmenopausal women with CHD. Participants (mean age 66.7 years) were randomized to either HRT (0.625 mg oral conjugated equine estrogen [CEE] and 2.5 mg medroxyprogesterone acetate [MPA] daily; n/1380) or placebo (n /1383). Because these women still had their uterus, annual gynecologic examinations were included in the protocol. The primary outcome was the occurrence of a nonfatal myocardial infarction (MI) or fatal CHD event. Secondary cardiovascular outcomes included coronary revascularization, resuscitated cardiac arrest, stroke or transient ischemic attacks, unstable angina, congestive heart failure, and peripheral arterial disease [20]. A total of 179 women in the HRT group and 182 women in the placebo group experienced a nonfatal MI or fatal CHD event during the 4.1 years of follow-up (relative hazard [RH] 0.99; 95% confidence interval [CI] 0.81 /1.22) (final data available at http://www.keeptrack.ucsf.edu/hers2/HERSfindat.htm). A nonsignificant difference was also seen between groups for all of the secondary cardiovascular outcomes. Within this overall null effect, a pattern of CHD risk reduction in Years 3/5 was offset by an unanticipated 50% increase in risk during Year 1. The overall null effect and the pattern of early risk observed in HERS raised many questions, both about the trial itself and about the validity of the hypothesis that HRT was effective for prevention of coronary disease. Many of these questions can now be answered in light of results from several subsequently completed randomized clinical trials, which are reviewed below.
3. Other recently completed trials of HRT for secondary prevention 3.1. The Estrogen Replacement and Atherosclerosis (ERA) trial The ERA trial was designed and begun while the HERS trial was ongoing. ERA was a 3-arm, randomized, double-blind trial (N /309) of unopposed oral CEE (0.625 mg conjugated estrogen), CEE plus MPA (2.5 mg daily), or a placebo. Postmenopausal women were recruited at five clinical sites using both hospital- and community-based methods [21]. Women
were eligible if they were postmenopausal, not currently taking HRT, and had at least one coronary stenosis of ]/30% confirmed by quantitative coronary angiography. Women with known or suspected breast or endometrial cancer, a history of deep-vein thrombosis or pulmonary embolism, or uncontrolled hypertension or diabetes were excluded. Once randomized to one of the three arms, participants (mean age 65.8 years) were followed for an average of 3.2 years. The primary endpoint was mean minimum coronary artery diameter, measured by quantitative coronary angiography at baseline and follow-up. Secondary endpoints included brachial artery vasodilator capacity, measured by ultrasound, and a series of known risk factors for atherosclerosis (e.g. blood pressure, lipids and lipoproteins, hemostatic and inflammatory factors, glucose metabolism). After adjustment for baseline coronary artery diameter and prespecified variables, no difference in mean minimum artery diameter was found among the three groups (CEE only, 1.879/0.02 mm; CEE plus MPA, 1.849/0.02 mm; and placebo, 1.879/0.02 mm) [22]. The lack of apparent benefit in the unopposed estrogen arm suggested that the HERS results could not simply be attributed to the concomitant treatment with MPA. Despite the failure to slow progression of atherosclerosis, some improvements in lipids and lipoproteins occurred in the treatment groups, as has been seen in multiple previous studies of HRT. HDL cholesterol was increased and LDL cholesterol was decreased relative to placebo in both active arms of the trial [22]. Triglycerides were also increased with treatment, a typical effect of HRT. Ongoing studies of the ERA cohort include examination of inflammatory markers and their association with HRT’s effects, as well as a series of genetic investigations (see Section 8.1 below for one example). 3.2. The PHASE trial Preliminary data are available for another clinical study of HRT, the Papworth HRT Atherosclerosis Study Enquiry (PHASE). In PHASE, 255 postmenopausal women with angiographically proven coronary artery disease were randomized to receive either transdermal 17b-estradiol 2 mg/day (plus 4 mg/day of cyclic norethindrone acetate in women with an intact uterus) or placebo. Women were followed for 4 years for the primary endpoints of hospitalization for unstable angina, MI, or death. In the intention-to-treat analysis, the average primary endpoint rate was 15.6/100 patientyears in the HRT group versus 12.6/100 patient-years in the control group (RR 1.23, 95% CI 0.82 /1.86; P / 0.30). Although event rates were higher in the HRT group in all 4 years, especially the first 2 years, the difference was not statistically significant [23]. In the wake of the HERS results, PHASE was stopped before
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
the recruitment goal was attained because of concerns about subjects’ safety. The PHASE findings suggest that the type of estrogen employed and route of administration do not explain the lack of a cardioprotective effect of oral CEE regimens reported elsewhere in postmenopausal women with CHD. 3.3. The PHOREA trial In the Postmenopausal Hormone Replacement against Atherosclerosis (PHOREA) trial, 321 postmenopausal women with subclinical carotid atherosclerosis (defined as /1 mm increase in intima-media thickness in ]/1 carotid artery segment, measured by ultrasound) were studied [24]. Subjects were allocated to one of two strata based on presence of cardiovascular risk factors (hypertension, smoking, diabetes, LDL /150 mg/dl) and then randomized within the stratum to prevent uneven distribution of these factors within treatment groups. There were three treatment arms: women received placebo, or 1 mg/day oral 17b-estradiol with one of two oral progestin regimens (cyclic 0.025 mg/day gestodene on days 17/28 of each 4-week cycle, or 0.025 mg/day gestodene for 12 days every third month). After 48 weeks of treatment, neither HRT regimen slowed progression of carotid atherosclerosis (measured as intima-media thickness [IMT]) compared with the placebo group [24]. This study has some limitations */ it was conducted at a single center, was relatively brief, and physicians and subjects were not blinded to treatment. However, the sonographer and reader of the carotid artery images were unaware of treatment assignments, so bias should not have entered into the ultrasound data acquisition.
205
women, and overall mortality rates were slightly higher in the 17b /estradiol group compared with the placebo group (18.4 vs. 16.3%) [25]. On balance, in this trial there was no evidence that 17b-estradiol was beneficial for secondary prevention of cerebrovascular disease. 3.5. Ongoing cardiovascular randomized clinical trials of HRT for secondary prevention Other ongoing secondary cardiovascular prevention trials of HRT include three examining angiographic endpoints (WELL-HART, WAVE, EAGAR) and one assessing clinical outcomes (ESPRIT). The Women’s Estrogen-progestin Lipid Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) is studying the progression of coronary stenosis in women (N :/ 450) receiving oral 17b-estradiol with or without cyclic MPA. Angiographic changes after 3 years of HRT and/ or vitamins C and E versus placebo are being evaluated in 400 postmenopausal women in the Women’s Angiographic Vitamin and Estrogen (WAVE) trial. Participants receive oral CEE with or without MPA, depending on their uterine status. Results of WAVE should be available late in 2002. Investigators of the Estrogen And Graft Atherosclerosis Research (EAGAR) study are studying the role of oral CEE in preventing the reocclusion of bypass grafts in approximately 100 postmenopausal women. In the U.K., the Estrogen in the Prevention of ReInfarction Trial (ESPRIT) is a study of 1017 postmenopausal women with a documented MI. They were randomized within 30 days of the MI to receive either placebo or 2 mg daily estradiol valerate. The primary endpoint of the trial is death or recurrent MI. Follow-up is scheduled to be completed in early 2002 [26].
3.4. HRT and stroke: the WEST data The Women’s Estrogen for Stroke Trial (WEST) was designed to evaluate whether 1 mg/day 17b-estradiol would affect the combined outcome of stroke or allcause mortality in 652 subjects (mean age 71 years) with a documented, non-disabling stroke or transient ischemic attack within 90 days of entry into the trial [25]. Randomization was stratified based on hospital site and baseline risk group (defined by a previously validated clinical index). Women who did not have a clinical event were followed for at least 12 months (mean 339/17 months). Treatment had no effect on the primary outcomes. Deaths occurred in 99 subjects in the estradiol group and in 93 in the placebo group (RR 1.1; 95% CI 0.8 /1.4). There were 51 non-fatal strokes in the estradiol group and 52 in the placebo group (RR 1.0; 95% CI 0.7 /1.4) [25]. While there were no increased rates of venous thromboembolic events or breast cancer in the 17b /estradiol group, vaginal bleeding and endometrial hyperplasia were more common in these
4. Questions and (some) answers concerning use of HRT for secondary prevention of CHD 4.1. Could the null result in HERS be due to the type of HRT regimen used? It is possible that the estrogen regimen used in HERS had no effect on CHD risk because of the type of estrogen (conjugated equine estrogen) or because the estrogen was opposed by a progestin. The progestin used in HERS, MPA, has been shown to attenuate beneficial effects of estrogen on atherosclerosis [18] and endothelial function [27] in animal models. In the Postmenopausal Estrogen-Progestin Intervention (PEPI) trial, women taking estrogen plus MPA had less favorable changes in HDL than women taking estrogen alone or estrogen plus micronized progesterone [12]. It has been suggested that unopposed estrogen, or estrogen combined with other progestins, might have
206
Table 1 Summary of results: long-term randomized clinical trials of hormone replacement therapy for treatment or prevention of cardiovascular disease Name of study
N
Hulley et al. [19] Herrington et al. [22] Clarke et al. [23] Angerer et al.c[24]
Heart and Estrogen/progestin Study (HERS) Estrogen Replacement and Atherosclerosis (ERA) Papworth HRT Atherosclerosis Enquiry (PHASE) Postmenopausal Hormone Replacement Against Atherosclerosis (PHOREA) Women’s Estrogen for Stroke Trial (WEST) Estrogen and Prevention of Atherosclerosis Trial (EPAT)
Viscoli et al. [25] Hodis et al. [55]
de Kleijn et al. None reported [56]
Treatment(s)a
Duration of follow-up
Primary endpoint(s)
Results (Outcome)
2763 0.625 mg/day CEE2.5 mg/day MPA
4.1 years
No difference in risk; improved lipids
309
0.625 mg/day CEE92.5 mg/day MPA
3.2 years
255
17b-E29cyclic norethisteroneb
3 years
321
1 year
652
1 mg/day 17b-E2; 1 mg/day 17-bE20.025 mg gestodene 12 d/mo; 17b-E20.025 mg gestodene 12 d/every 3 mo 1 mg/day 17b-E2
CHD death/nonfatal MI Mean minimum coronary artery diameter Unstable angina or MI Carotid IMT
222
1 mg/day 17b-E2; LLMs if indicated
2 years
121
1.5 mg/day 17b-E2cyclic 0.15 mg desogestrel; 0.625 mg CEE0.15 mg cyclic norgestrel
2 years
3 years
No difference; improved lipids No difference No difference in rate of progression
Combined stroke and No difference death Carotid IMT Significantly less progression with E2; no difference in progression in those taking LLMs Carotid IMT and end- No difference diastolic lumen diameter
a In these studies, a placebo arm is included and results are in comparison to placebo. 17b-E2 17b-estradiol; CEE conjugated equine estrogen; CHD coronary heart disease; IMT intimamedia thickness; LLMs lipid-lowering medications; MI myocardial infarction; MPA medroxyprogesterone acetate. b In this preliminary report, dosages were not provided. c In this study, results are in comparison to the no treatment arm.
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
1st author, reference #
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
been more effective. Similarly, some have argued that estradiol, given either orally or transdermally, would be a superior form of HRT for prevention of CHD. However, as is evident in Table 1, there are now four additional randomized clinical trials examining unopposed estrogen, oral or transdermal estradiol, or regimens using progestins other than MPA that also have shown no effect on progression of clinical or anatomic manifestations of atherosclerosis. Nonetheless, it is possible that newer estrogen agonists with different profiles of receptor or tissue specificity than current HRT regimens may be shown to be effective treatments in the future [28]. 4.2. Are HRT’s effects age-dependent? Some investigators have speculated that the beneficial cardiovascular effects of HRT may be nullified if subjects are older and atherosclerosis is too far advanced when HRT is begun [29]. There is some evidence in nonhuman primates to support this theory [30]. Further, in a recent report of brachial artery flow-mediated dilation from a large observational cohort, subjects over 80 years old and those with established CHD showed no benefit from HRT, unlike HRT users in the cohort without subclinical CHD or CHD risk factors [31]. However, a cross-sectional study of 217 postmenopausal women in Australia (mean age 60 years) reported that HRT protected subjects from age-related deleterious changes in carotid structure and function, compared with age-matched nonusers of HRT [32]. A recent analysis of women from the Nijmegen population study found that later age of menopause was associated with reduced risk of cardiovascular mortality [33], suggesting that longer duration of exposure to estrogen at an earlier stage of life might confer more benefit than starting HRT late in life. Unfortunately, no data on this issue are currently available from randomized clinical trials. 4.3. Could the overall null effect in HERS be due to early harm and late benefit? Secondary analysis of the HERS events over time suggest the possibility of early harm, which offsets a late benefit. A pattern of early harm and late benefit could explain the discordance between the null results described above and the earlier observational studies of HRT and CHD risk, since most observational studies are not designed to detect early adverse effects of treatment. A similar pattern is also suggested in the WEST results and in preliminary data from WHI, although the confidence intervals are too wide to make assertions with confidence about early harm. The other completed randomized trials are too small to address
207
this issue. Several observational cohorts have also been examined for evidence of early harm from HRT. In a recent retrospective analysis of 981 women in the Puget Sound Group Health Cooperative, risk for a first MI among women on HRT for 5/60 days was double that of similar women who had used HRT for ]/1 year (HRT use 5/60 days: RH 2.16, 95% CI 0.94 /4.95; HRT use ]/1 year: RH 0.76, 95% CI 0.42 /1.36). However, no increased risk was found among current HRT users versus non-users (RH 0.96; 95% CI 0.62 /1.50) [34]. Use of estrogen only and estrogen plus progestin (not further categorized, but described as most commonly oral esterified estrogen with or without MPA) was combined in this analysis. The RH ratios were adjusted for age, calendar year of the first MI, and diabetes; further adjustments for congestive heart failure and use of aspirin or beta-blockers did not substantially alter the finding [34]. Contrary to subjects in HERS, the Puget Sound women had not been diagnosed with heart disease before their first MI. Among women with established heart disease in another large cohort, the Nurses’ Health Study (N / 2489), a similar pattern was seen with respect to risk for MI recurrence or CHD death [35]. For women who had used HRT for B/1 year, the multivariateadjusted relative risk for a CHD event was 1.25 (95% CI 0.78 /2.00) compared with never-users. However, in women who had used HRT for ]/2 years, the relative risk dropped to 0.38 (95% CI 0.22 /0.66; P for trend /0.0002) [35]. No differences were seen between users of unopposed oral CEE or oral CEE plus MPA regimens. Analyses were limited to these two types of regimens because they are by far the most commonly used. Investigators have also reanalyzed data from the Coronary Drug Project, which examined use of oral conjugated estrogen (2.5 or 5.0 mg/day) versus placebo in 3800 men with electrocardiographically documented MI. They reported a previously unrecognized increased risk of CHD death or nonfatal MI within the first 4 months of treatment (RH 1.58; 95% CI 1.04 /2.40). This risk decreased substantially in men treated for 13/60 months (RH 0.9, 95% CI 0.80 /1.15). Over the course of the trial, the RH in the 2.5 mg/day group relative to placebo was 0.99 (95% CI 0.86 /1.15) [36]. The 5.0 mg/ day estrogen treatment arm was stopped after 1.5 years because of an excess rate of mortality and nonfatal MI [37]. Researchers in the ongoing Women’s Health Initiative (WHI), a clinical trial of oral CEE plus MPA in over 27 000 mostly healthy postmenopausal women, have reported similar patterns of early increased cardiovascular risk that decline over time (see a summary at http://www.nhlbi.nih.gov/whi/hrt-en.htm). However, details are not available until the WHI is completed in 2005.
208
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
Thus, there is evidence from several large, varied cohorts that supports the pattern of early increased risk associated with HRT use observed in HERS. The mechanisms responsible for this pattern remain undetermined.
4.4. Is there a susceptible cohort? The pattern of early risk that rapidly declined after Year 1 in HERS could have resulted from attrition of a small cohort who were uniquely susceptible to an adverse effect of HRT. During Year 1, as this highrisk group suffered primary events, they would not contribute cardiovascular events to the active treatment group, and apparent risk would be concomitantly reduced [38]. In fact, within the first year in HERS the risk was highest in the first 4 months, at an intermediate level in the second 4 months, and nearly back to unity during the final 4 months [39].
5. Potential mechanisms: early CHD risk associated with HRT Some of the many current areas of investigation into potential mechanisms of early risk of HRT include effects on the thrombosis/coagulation pathways, the role of thrombosis-related genes, and the possibility of a proinflammatory effect of estrogen.
5.1. Is a prothrombotic effect involved in early risk with HRT? The HERS trial also confirmed earlier reports [40 /44] of a 2-fold to 4-fold increase in risk for venous thromboembolic events (VTE) from estrogen plus progestin therapy [45]. However, unlike the earlier reports in healthy women with a low overall rate of VTE (around 0.02%), the annual rates in HERS were substantially higher (HRT /0.63% vs. placebo 0.22%; RH 2.9; 95% CI 1.5 /5.6, P /0.002). As was the case for cardiovascular events, the increased risk for VTE with HRT was greatest in the first year (RH 3.3, P B/0.05). Thus, an increased risk of VTE may be another important consideration in clinical decision-making about use of HRT in women with established heart disease. Furthermore, a prothrombotic effect of HRT could account for increased risk for both arterial and venous thrombotic events. More information is needed about the magnitude of the relative and absolute increases in VTE risk and how they may relate to risk of CHD events.
5.2. Is a proinflammatory effect involved in early risk with HRT? Increases in C-reactive protein (CRP) are independently associated with greater risk for cardiovascular events, even in postmenopausal women without CHD [46]. Significantly higher CRP levels were reported in several studies after treatment with either CEE or 17bestradiol [46 /49]. In the PEPI trial, significant increases in CRP were seen in all four groups (CEE alone or combined with cyclic MPA, continuous MPA, or micronized progesterone) (P /0.0001) after 3 years of treatment [47]. Subsequently, in a recent double-blind crossover trial, 6 weeks of oral CEE alone (0.625 mg/ day) significantly increased both CRP and interleukin-6 in healthy postmenopausal women [50]. Elevated CRP activation may be associated with CHD risk independent of a systemic pro-inflammatory effect. For example, CRP stimulates monocyte expression of tissue factor, which could potentiate a prothrombotic state [51]. On the other hand, estrogen appears to have favorable effects on other inflammatory proteins. In the same double-blind crossover trial noted above, oral CEE was associated with decreased levels of E-selectin and VCAM-1, consistent with an anti-inflammatory effect [52], possibly because of estrogen-related upregulation of endothelial nitric oxide synthase [53]. However, the clinical significance of changes in cytokines or adhesion molecules has yet to be established. Furthermore, the net effect of these seemingly contradictory actions of estrogen is still unknown. The need to weigh the complete physiological effects of HRT was illustrated by a pooled analysis of 22 clinical trials in 1997, which found an increased risk of cardiovascular events in women taking HRT [54]. Without doubt, the overall risk/benefit analysis for HRT must be taken into consideration for each individual. Results from long-term randomized clinical trials are needed to provide more data in this regard.
6. Effects of HRT for primary prevention Despite the negative or equivocal results described above, it is noteworthy that there is some evidence that HRT, taken earlier in the menopausal transition and thus earlier in the atherosclerotic process, may be efficacious in slowing progression of CHD in some women. Details of two studies providing such evidence are given below. 6.1. The EPAT data Results have now been reported from The Estrogen and Prevention of Atherosclerosis Trial (EPAT) [55].
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
EPAT was a randomized, double-blind clinical trial of estrogen in 199 postmenopausal women with elevated LDL cholesterol concentrations ( ]/130 mg/dl) but with no clinical evidence of CHD. Women with a history of smoking or uncontrolled diabetes mellitus were excluded. Participants were randomized to receive placebo or unopposed oral micronized 17b-estradiol (1 mg/day). Because most participants were not hysterectomized, all subjects underwent a yearly gynecologic examination (including a pelvic examination, Pap smear, mammogram, and uterine ultrasound if applicable). If their LDL concentrations exceeded 160 mg/dl, all participants also received lipid-lowering medication, regardless of treatment group. The primary endpoint was difference in carotid artery wall thickness, based on ultrasound measurements at baseline and after 2 years of treatment. When comparing only participants with normal LDL levels who were not taking lipid-lowering agents, the estradiol group showed a small decrease in carotid wall thickness compared with the placebo group (P /0.045, adjusted for oophorectomy status). But among subjects taking lipid-lowering agents, there was a greater difference in carotid wall thickness between the two arms (P /0.002), mostly because of greater increases in wall thickness among women in the placebo group [55]. Adjustment for oophorectomy status did not alter these results. Thus, in EPAT, unopposed 17b-estradiol was beneficial in slowing subclinical atherosclerosis only in subjects not taking lipid-lowering medications, suggesting that women using these drugs might not derive additional cardiovascular benefit from taking HRT. 6.2. Evidence in perimenopausal women Data regarding markers of change in carotid artery structure among women in the menopausal transition were reported by deKleijn et al. [56]. They studied a total of 121 healthy Dutch women without hysterectomies between 40 and 60 years of age who were undergoing menopause, defined as hot flushes or sweating episodes. Mean time since last menstruation was 3 months, and 13 women (11%) were postmenopausal (no menses for ]/12 months). Baseline measurement of circulating levels of estradiol was not reported. Exclusion criteria included use of sex steroids or lipidlowering agents, presence of cardiovascular or renal disease, or uncontrolled hypertension. Pap smears and mammograms were performed at baseline if test results were not available within the past 12 months (for Pap smears) or 24 months (for mammograms). Subjects were randomized to receive one of three regimens: (1) 0.625 mg/day oral conjugated equine estrogens and 0.15 mg/ day norgestrel (norgestrel taken on days 17/28 only); (2) 1.5 mg/day oral micronized 17b-estradiol and 0.15 mg/day desogestrel (desogestrel taken on days 13 /24 only) with four matched placebo pills (taken on days
209
25 /28 only); or (3) placebo only. The primary endpoints, common carotid IMT and end-diastolic lumen diameter, were measured at baseline and at the end of cycle 24. After 2 years, small reductions in carotid IMT and in lumen diameter were seen in the treatment groups compared with placebo, but the confidence intervals were wide and the authors concluded that a significant effect of treatment could not be demonstrated. However, data from only 52% of randomized subjects could be analyzed, because of a high drop-out rate and missing ultrasound data in all arms. Furthermore, the investigators broke the study blind after cycle six, and the placebo group was not subject to follow-up between cycles six and 24, but the reasons for these anomalies were not given. Despite these limitations, it is of interest that the changes seen were in a positive direction, and that there were no significant differences between the two treatment regimens in the endpoints of interest.
7. Ongoing cardiovascular randomized clinical trials of HRT for primary prevention The Women’s International Study of long Duration Oestrogen after the Menopause (WISDOM) and the WHI are two large primary prevention randomized clinical trials currently underway in primarily healthy postmenopausal women. WISDOM will examine a cohort of approximately 22 000 women recruited from general practices in the United Kingdom randomized to oral CEE (with or without MPA, depending on uterine status) versus placebo for a median of 10 years, with a planned 5-year follow-up (see http://www. mrc-gprf.ac.uk/maindocs/summaries/wisdom.htm). The HRT component of the WHI will study effects of the same treatments on risk of CHD in 27 348 women over an average of 8.5 years. Upon completion, these trials will provide valuable insight into effects of long-term HRT on clinically important chronic diseases such as osteoporosis and breast cancer, as well as primary prevention of cardiovascular disease in postmenopausal women.
8. New directions in studies of HRT and cardiovascular risk New studies are underway to attempt to explain the mechanisms involved in the clinical trial data described above. Of the many such studies underway, several of the most promising are summarized below.
210
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212
8.1. Do genetic variants affect HRT response? Genetic polymorphisms are known to increase the risk of venous or arterial thrombotic events in users of oral contraceptives or HRT. How estrogen affects coagulation and thrombotic factors to potentiate a risk for thrombosis is not fully understood. Some genetic mutations, such as Factor V Leiden and prothrombin 20210A, appear to increase the risk of venous or arterial thrombotic events when estrogen levels are increased. In a recent case-control study, presence of the prothrombin 20210 G0/A mutation in women with hypertension was a significant risk factor for MI [57]. The mutation was discovered in 47% of MI cases and 54% of controls. Women with the mutant prothrombin allele who were using HRT had almost an 11-fold greater risk of a nonfatal MI, compared with current HRT users without the prothrombin variant [57]. In women who were / 80% compliant with their HRT, the risk was even higher. There is now evidence from the ERA trial that genetic polymorphisms of the estrogen receptor-a (ER-a) can alter lipid responses to HRT. Subjects in both activetreatment arms of ERA (oral CEE only and oral CEE plus MPA) and in the placebo group were characterized with respect to selected ER-a polymorphisms. After adjusting for potential confounders (age, alcohol intake, body mass index, diabetes, level of exercise, race, and smoking), women with the ER-a intervening sequence 1401 (IVS1-401) C/C genotype in the active-treatment arms showed increases in HDL cholesterol more than twice as high as C/C and T/T women (13.1 vs. 6.0 mg/dl; P value for treatment-by-genotype interaction /0.004) [58]. Importantly, women with the ER-a IVS1-401 C/C genotype comprised 18.9% of the subjects, and this augmented HDL response was shown in both activetreatment arms and across racial groups. It was even more robust in women classified as compliant to the study medications (]/80% of pills taken) (P/0.0004) [58]. In a subsequent report, women in the active treatment arms with the ER-a IVS1-401 C/C genotype showed greater reductions in E-selectin but not CRP, suggesting a selective drug-gene interaction [59]. Further examination into the relationship between the ER-a IVS1-401 C/C genotype (and other closely related polymorphisms) and clinical cardiovascular events might be of great value to better understanding how future use of HRT could be tailored to individual women.
HRT [60]. However, even after the most contemporary and careful attempts to adjust for possible confounders, HRT use continues to be associated with more favorable outcomes [61]. It is also true that participants in randomized clinical trials are not always representative of the general population. More work is required to understand how best to extrapolate the results from both observational studies and clinical trials to the general population.
9. Conclusions In light of the data reported in HERS and subsequent trials, the American Heart Association has published updated recommendations concerning HRT for prevention of heart disease [62]. In women with established heart disease, HRT is not recommended for secondary prevention. Other proven methods of treatment for heart disease should be the first line of defense, as has been pointed out in commentaries about the HERS results [29,38]. In women without objective evidence of CHD, there are currently inadequate data to make a firm recommendation for primary prevention. In either case, the emphasis should be on non-coronary indications for HRT use. Ongoing research is needed to help define the proper role for HRT in primary prevention of CHD and identify strategies to maximize its efficacy while minimizing risks. Results from the WHI and WISDOM trials will, it is hoped, shed more light on the overall effects of long-term HRT use. Newer estrogen agonists with more tissue-specific activities will also come into play as we continue to seek ways to reduce the burden of heart disease in all postmenopausal women.
Note added in proof The HERS follw-up study (HERS II) reported that after 6.8 years, hormone therapy did not reduce cardiovascular risk in the HERS cohort (JAMA 2002;288:49 /57). Furthermore, the WHI stopped the CEE+MPA arm of its HRT trial early because of excess risk of CHD events, invasive breast cancer, venous thromboembolism, and stroke in that group (JAMA 2002;288:321{333) The CEE-only arm continues as planned.
8.2. Other issues For many years, the results of observational studies of HRT use and cardiovascular disease were criticized because users of HRT tended to be healthier than non-users, potentially biasing the results in favor of
References [1] American Heart Association. 2001 Heart and stroke statistical update. Dallas: American Heart Association, 2000.
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212 [2] Wenger NK. Cardioprotection for the postmenopausal women: HERS results and their implications. Prevent Cardiol 1998;1:9 / 11. [3] NCEP, Adult Treatment Panel II. Second Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation 1994;89:1329-445. [4] Smith SC, Blair SN, Criqui MH, Fletcher GF, Fuster V, Gersh BJ, Gotto AM, Gould KL, Greenland P, Grundy SM, et al. Preventing heart attack and death in patients with coronary disease. The Secondary Prevention Panel. Circulation 1995;92:2 / 4. [5] Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the Nurses Health Study. New Engl J Med 1991;325:756 /62. [6] Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, Cummings SR. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016 /37. [7] Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, Mirvis DM. Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Arch Intern Med 1990;150:2557 /62. [8] Sullivan JM, El-Zeky F, Vander Zwaag R, Ramanathan KB. Effect on survival of estrogen replacement therapy after coronary artery bypass grafting. Am J Cardiol 1997;79:847 /50. [9] O’Keefe JH, Jr., Kim SC, Hall RR, Cochran VC, Lawhorn SL, McCallister BD. Estrogen replacement therapy after coronary angioplasty in women. J Am Coll Cardiol 1997;29:1 /5. [10] O’Brien JE, Peterson ED, Keeler GP, Berdan LG, Ohman EM, Faxon DP, Jacobs AK, Topol EJ, Califf RM. Relation between estrogen replacement therapy and restenosis after percutaneous coronary interventions. J Am Coll Cardiol 1996;28:1111 /8. [11] Newton KM, LaCroix AZ, McKnight B, Knopp RH, Siscovick DS, Heckbert SR, Weiss NS. Estrogen replacement therapy and prognosis after first myocardial infarction. Am J Epidemiol 1997;145:269 /77. [12] The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. J Am Med Assoc 1995;273:199 /208. [13] Gerhard M, Walsh BW, Tawakol A, et al. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation 1998;98:1158 /63. [14] Sorensen KE, Dorup I, Hermann AP, Mosekilde L. Combined hormone replacement therapy does not protect women against the age-related decline in endothelium-dependent vasomotor function. Circulation 1998;97:1234 /8. [15] Herrington DM, Werbel BL, Riley WA, Pusser BE, Morgan TM. Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease. J Am Coll Cardiol 1999;33:2030 /7. [16] Herrington DM. Effects of estrogen on the anatomic and functional sequelae of coronary atherosclerosis. In: Forte TM, editor. Hormonal, metabolic, and cellular influences on cardiovascular disease in women. Armonk, NY: Futura Publishing Company, 1997:175 /92. [17] Adams MR, Kaplan JR, Manuck SB, Koritnik DR, Parks JS, Wolfe MS, Clarkson TB. Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051 /7. [18] Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis. Arterioscler Thromb Vasc Biol 1997;17:217 /21.
211
[19] Hulley S, Grady D, Bush T, Furberg C, Herrington DM, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 1998;280:605 /13. [20] Grady D, Applegate B, Bush T, Furberg C, Riggs B, Hulley S. The Heart and Estrogen/progestin Replacement Study: Design, methods and baseline characteristics. Controlled Clin Trials 1998;19:314 /35 (for the HERS Study Group). [21] Folmar S, Oates-Williams F, Sharp P, Reboussin DR, Smith J, Cheshire K, Klein KP, Herrington D. Recruitment of participants for the Estrogen Replacement and Atherosclerosis (ERA) trial: a comparison of costs, yields, and participant characteristics from community- and hospital-based recruitment strategies. Control Clin Trials 2001;22:13 /25. [22] Herrington DM, Reboussin DR, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. New Engl J Med 2000;343:522 /9. [23] Clarke S, Kelleher J, Lloyd-Jones H, Sharples L, Slack M, Schofield PM. Transdermal hormone replacement therapy for secondary prevention of coronary artery disease in postmenopausal women (abstract). Eur Heart J 2000;21:212. [24] Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis. A randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262 /8. [25] Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. New Engl J Med 2001;345:1243 /9. [26] Khan MA, Heagerty AM, Kitchener H, McNamee R, Cherry NM, Hannaford PC. Oestrogen and women’s heart disease: ESPRIT-UK. Q J Med 2000;93:699 /702. [27] Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757 /61. [28] Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD. Raloxifene and cardiovascular events in osteoporotic postmenopausal women. Four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) trial. J Am Med Assoc 2002;287:847 /57. [29] Mendelsohn ME, Karas RH. The time has come to stop letting the HERS tale wag the dogma. Circulation 2001;104:2256 /9. [30] Williams JK, Anthony MS, Honore EK, Herrington DM, Morgan TM, Register TC, Clarkson TB. Regression of atherosclerosis in female monkeys. Arterioscler Thromb Vasc Biol 1995;15:827 /36. [31] Herrington DM, Espeland MA, Crouse JR, Robertson J, Riley WA, McBurnie MA, Burke GL. Estrogen replacement and brachial artery flow-mediated vasodilation in older women. Arterioscler Thromb Vasc Biol 2001;21:1955 /61. [32] McGrath BP, Liang YL, Teede H, Shiel LM, Cameron JD, Dart A. Age-related deterioration in arterial structure and function in postmenopausal women. Impact of hormone replacement therapy. Arterioscler Thromb Vasc Biol 1998;18:1149 /56. [33] deKleijn MJJ, van der Schouw YT, Verbeek ALM, Peeters PHM, Banga JD, van der Graaf Y. Endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. Am J Epidemiol 2002;155:339 /45. [34] Heckbert SR, Kaplan RC, Weiss NS, Psaty BM, Lin D, Furberg CD, Starr JR, Anderson GD, LaCroix AZ. Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy. Arch Intern Med 2001;161:1709 /13. [35] Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the
212
[36]
[37]
[38] [39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
D.M. Herrington, K.P. Klein / Atherosclerosis 166 (2003) 203 /212 Nurses’ Health Study. A prospective, observational study. Ann Intern Med 2001;135:1 /8. Wenger NK, Knatterud GL, Canner PL. Early risks of hormone therapy in patients with coronary heart disease (letter). J Am Med Assoc 2000;284:41 /3. Coronary Drug Project Research Group. The Coronary Drug Project: findings leading to discontinuation of the 2.5 mg/day estrogen group. J Am Med Assoc 1973;226:652 /7. Herrington DM. The HERS trial results: paradigms lost. Ann Intern Med 1999;131:463 /6. Hulley S, Grady D, Vittinghoff E, Bush T, Furberg C, Herrington D, Riggs B. Hormone replacement therapy for secondary prevention of coronary heart disease. J Am Med Assoc 1999;281:796 /7. Perez Gutthann S, Garcia Rodriguez LA, Castellsague J, Duque Oliart A. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. Br Med J 1997;314:796 /800. Varas-Lorenzo C, Garcia-Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez-Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol 1998;147:387 /90. Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977 /80. Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996;348:981 /3. Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996;348:983 /7. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunninghake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study. Ann Intern Med 2000;132:689 /96 (for the HERS Study Group). Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New Engl J Med 2000;342:836 / 43. Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL, Sakkinen PA, Tracy RP. Effect of postmenopausal hormones on inflammation-sensitive proteins. The Postmenopausal Estrogen/Progestin Interventions (PEPI) study. Circulation 1999;100:717 /22. Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999;19:893 /9. van Baal WM, Kenemans P, Emeis JJ, Schalkwijk CG, Miljatovic V, Van der Mooren MJ, Vischer UM, Stehouwer CDA. Longterm effects of combined hormone replacement therapy on
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60] [61]
[62]
markers of endothelial function and inflammatory activity in healthy postmenopausal women. Fertil Steril 1999;71:663 /70. Herrington DM, Pusser BE, Riley WA, Thuren TY, Brosnihan KB, Brinton EA, MacLean DB. Cardiovascular effects of droloxifene, a new selective estrogen receptor modulator, in healthy postmenopausal women. Arterioscler Thromb Vasc Biol 2000;20:1606 /12. Cermak J, Key NS, Bach RR, Balla J, Jacobs HS. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993;82:513 /20. Herrington DM, Brosnihan KB, Pusser BE, Seely EW, Ridker PM, Rifai N, MacLean DB. Differential effects of E and droloxifene on C-reactive protein and other markers of inflammation in healthy postmenopausal women. J Clin Endocrinol Metab 2001;86:4216 /22. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999;103:401 /6. Hemminki E, McPherson K. Impact of postmenopausal hormone therapy on cardiovascular events and cancer: Pooled data from clinical trials. Br Med J 1997;315:149 /53. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu CR, Liu CH, Azen SP. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135:939 /53. deKleijn MJJ, Bots ML, Bak AAA, Westendorp ICD, Planellas J, Bennink HJTC, Witteman JCM, Grobbee DE. Hormone replacement therapy in perimenopausal women and 2-year change of carotid intima-media thickness. Atherosclerosis 1999;32:195 /204. Psaty BM, Smith NL, Lemaitre RN, Vos HL, Heckbert SR, LaCroix AZ, Rosendaal FR. Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women. J Am Med Assoc 2001;285:906 /13. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker ER. Estrogen receptor polymorphisms and effects of estrogen replacement on HDL cholesterol in women with coronary disease. New Engl J Med 2002;346:967 /74. Herrington DM, Howard TD, Brosnihan KB, McDonnell DP, Li X, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Meyers DA, Bleecker ER. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 2002;105:1879 /82. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. J Am Med Assoc 1991;265:1861 /7. Shlipak MG, Angeja BG, Go AS, Frederick PD, Canto JG, Grady D. Hormone therapy and in-hospital survival after myocardial infarction in postmenopausal women. Circulation 2001;104:2300 /4. Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC, Jr., Wenger NK. Hormone replacement therapy and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 2001;104:499 /503.