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Effect of hormone therapy on the progression of carotid-artery atherosclerosis in postmenopausal women with and without established coronary artery disease
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Effect of hormone therapy on the progression of carotid-artery atherosclerosis in postmenopausal women with and without established coronary artery disease
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Content
EFFECT OF HORMONE THERAPY ON THE PROGRESSION OF CAROTID-
ARTERY ATHEROSCLEROSIS IN POSTMENOPAUSAL WOMEN WITH AND
WITHOUT ESTABLISHED CORONARY ARTERY DISEASE
by
Yan Shen
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(APPLIED BIOSTATISTICS/EPIDEMIOLOGY)
December 2005
Copyright 2005 Yan Shen
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UMI Number: 1435091
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Table of Contents
List of Tables iii
Abstract iv
Chapter 1: Introduction 1
Chapter 2: Methods 4
2.1 EPAT Study Design 4
2.2 WELL-HART Study Design 4
2.3 Carotid Artery Ultrasonography and Measurement of Carotid
Artery IMT 5
2.4 Pooled Trial Data 6
2.5 Statistical Analysis 7
Chapter 3: Results 10
3.1 Baseline Characteristics 10
Figure 1: Profile of the Pooled study on the Progression of
Atherosclerosis Trial 11
3.2 Analysis of Subclinical Atherosclerosis 15
Chapter 4: Discussion 23
4.1 Summary of Results 23
4.2 Clinical Significance of Findings 24
4.3 Comparisons with Other Clinical Studies 25
4.4 Strengths and Limitations 29
4.5 Conclusion 29
References 31
Alphabetized References 35
ii
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List of Tables
Table 1: Baseline Carotid Artery Intima-Media Thickness and Demographic and
Clinical Characteristics by Treatment Groups 13
Table 2: Baseline Carotid Artery Intima-Media Thickness and Demographic
and Clinical Characteristics by Coronary Artery Disease (CAD) Status 14
Table 3: Univariate And Multivariate Analyses of The Effects of Hormone
Therapy On The Progression of IMT 16
Table 4: Multivariate Subgroup Analyses of The Effect of Hormone Therapy
(HT) On Progression of IMT(um) Stratified by Lipid-Lowering
Medication Use 17
Table 5: Multivariate Analyses of the Effect of Hormone Therapy (HT) on
Progression of IMT (um) Among Women Who Were Not Taking Lipid-
lowering Medicines Stratified by Status of Coronary Heart Disease 19
Table 6: Multivariate Subgroup Analyses of the Effect of Hormone Therapy
(HT) On Progression of IMT (pm) Stratified by Status of Preexisting
Coronary Disease 20
Table 7. Multivariate Analysis of the Possible Mediating Effects of LDL- and
HDL-Cholesterol on Progression of IMT(pm) 21
iii
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Abstract
Objective: To determine the effect of hormone therapy on the progression of
subclinical atherosclerosis in postmenopausal women with and without preexisting
coronary artery disease. Design: Pooled study of two randomized, double-blind,
placebo-controlled clinical trials. Patients: 222 postmenopausal women without
preexisting cardiovascular and 226 postmenopausal women with at least one
coronary-artery lesion were included in the study. Intervention: Unopposed
micronized 17P-estradiol or 17p~estradiol plus medroxyprogesterone acetate versus
placebo. Measurement: High-resolution B-mode ultrasonography to measure
carotid artery IMT at baseline and follow up visits. Results: The average rate of
progression of subclinical atherosclerosis was lower in the hormone therapy (HT)
group than in the placebo group (p=0.05). Among women who didn’t take lipid-
lowering medications during the trial and had no coronary artery disease, the average
rate o f progression of subclinical atherosclerosis was lower in the HT group than in
the placebo group (p=0.002). Conclusion: 17 P-estradiol benefits atherosclerosis
progression in postmenopausal women. In particular, women without coronary artery
disease and are not taking lipid-lowering medications will derive an atherosclerosis
benefit from this hormone regimen.
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Chapter 1: Introduction
Postmenopausal hormone therapy (HT) is one of the most commonly prescribed drug
regimens in the United States. A large number of postmenopausal women choose to
take HT to treat symptoms of menopause (1). Cardiovascular disease (CVD),
primarily coronary artery disease (CAD), is the leading cause of death among
women in the United States. Observational studies in the past years have consistently
found a 30% to 35% decreased risk of coronary heart disease (CHD) among
postmenopausal women who use hormone therapy (2). More than 40 observational
studies have suggested that hormone therapy (HT) reduces cardiovascular morbidity
and mortality in postmenopausal women (3, 4). Several effects of estrogen on the
cardiovascular system suggest a potential for protection.
Until recently, only a few randomized clinical trials have been conducted to test the
effectiveness of hormone therapy, primarily using conjugated equine estrogen and
medroxyprogesteroe acetate in reducing CHD risk or in slowing the progression of
atherosclerosis. Many of the studies such as the WAVE , ERA and WELL-HART
trials (5, 6, 7) were conducted among women with coronary artery disease and
showed no benefit of HT in reducing the progression of coronary disease or reducing
CHD risk (secondary prevention, HERS trial) (8). The Women’s Health Initiative
(WHI) Trial (9), a primary prevention trial, showed an early increase in the risk of
cardiovascular events in women randomized to conjugated HT (CEE plus medroxy-
1
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progesteroe acetate). WHI results further suggest that reduction in CHD risk may
occur in women who are closer to menopause (5, 9, 10). Despite that, questions
remain regarding the effectiveness of 17p-estradiol (the endogenous estrogen
molecule) on the progression of atherosclerosis in postmenopausal women with and
without established coronary artery disease.
Two randomized, double-blind, placebo-controlled, carotid artery ultrasonography
trials using unopposed 17p-estradiol were conducted at the University of Southern
California Atherosclerosis Research Unit. One was the Estrogen in the Prevention of
Atherosclerosis Trial (EPAT), which aimed to test the efficacy o f unopposed 17P-
estradiol in reducing the progression of subclinical atherosclerosis in healthy
postmenopausal women without cardiovascular disease. (11). The other was the
Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression
Trial (WELL-HART), which tested the effects of unopposed 17p-estradiol alone or
with administration of medroxyprogesterone acetate in reducing the progression of
subclinical atherosclerosis in postmenopausal women with angiographically-
documented coronary artery disease. Since atherosclerosis is the underlying
pathophysiological process of CVD, intima-media thickness (IMT) of the carotid
arteries correlates with the presence, extent and severity of atherosclerosis in
coronary arteries (12-16) and is an established end point for testing the effect of an
intervention on atherosclerosis (17-18). Carotid artery IMT was used as the primary
2
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end point in the EPAT trial (13) and a secondary trial end point in the WELL-HART
study (14).
Results from the EPAT study indicated that 17(3-estradiol significantly slowed the
progression of subclinical atherosclerosis in healthy postmenopausal women
compared to placebo (13). However, results from the WELL-HART study indicated
that 17P-estradiol alone or with sequentially administered medroxyprogesterone
acetate had no significant effect on the progression of coronary artery atherosclerosis
(measured by coronary angiography) in postmenopausal women with established
coronary-artery atherosclerosis (7).
In this paper, we combine data from the EPAT and WELL-HART trials to
investigate whether 17P-estradiol reduces progression of subclinical atherosclerosis,
measured by carotid artery IMT, in postmenopausal women with and without
preexisting cardiovascular disease. Our primary hypothesis was that estrogen
significantly reduces the progression of atherosclerosis.
3
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Chapter 2: Methods
2.1 EPAT Study Design
EPAT was a randomized, double-blind, placebo-controlled carotid artery IMT trial
(13). In brief, women were eligible if they were postmenopausal, with serum
estradiol level <20pg/mL, 45 years of age or older, without preexisting
cardiovascular disease and had a low-density lipoprotein (LDL) cholesterol level of
130mg/dL or greater. Subjects who had breast or gynecologic cancer in the past 5
years, had previously used HT for more than 10 years or had used HT within 1
month of the first screening visit, had diastolic blood pressure greater than 110 mm
Hg; total triglyceride level of 400mg/dL or greater, high density lipoprotein
cholesterol level less than 30mg/dL or were currently smoking were excluded. All
participants gave written informed consent, and the study protocol was approved by
the University of Southern California Institutional Review Board. Participants were
randomly assigned to lm g estradiol or placebo groups and were followed every
month for the first 6 months and every other month thereafter for a total o f 2 years.
2.2 WELL-HART Study Design
WELL-HART was a randomized, double-blind, and placebo-controlled trial (7).
Postmenopausal women with at least one coronary-artery lesion, 75 years of age or
younger, with a low-density lipoprotein (LDL) cholesterol level of 100 to 250 mg/dL
were included in the study. Women were excluded if they currently smoked more
4
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than 15 cigarettes per day, had received a diagnosis of breast cancer or gynecologic
cancer within the five years before screening, had a life-threatening disease, had a
diastolic blood pressure >110 mm Hg, or had fasting serum glucose concentration
>200mg/dL. All participants gave written informed consent, and the study was
approved by the Institutional Review Board at the University of Southern California.
Eligible subjects were randomly assigned to one of three groups: 2 tablets of placebo,
lm g estradiol+1 tablet placebo, 1 mg estradiol+5mg sequential medroxypro
gesterone acetate (MPA). Participants had follow-up visits every month for the first 6
months and every other month for the remainder of the trial (36 months).
2.3 Carotid Artery Ultrasonography and Measurement of Carotid Artery IMT
High resolution B-mode ultrasound images for IMT measurement of the right
common carotid artery were obtained with a Toshiba SSH 140A/C ultrasound imager
using a linear array 7.5 MHz probe at two pre-randomization visits and every six
months during each trial (13). For each subject, the depth of field, gain, monitor
intensity setting and other instrumentation settings used at the baseline examination
were used at all follow-up examinations. An image analyst who was blinded to
treatment assignment measured the distal common carotid arterial far wall IMT by
automated computerized edge detection methods using in-house developed software.
The average IMT was measured over 70 to 100 points covering a one-centimeter
length just distal to the carotid artery bulb. This method standardized the location
and the distance over which intima-media thickness was measured, which ensured
5
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consistency and comparability of the measurement of the arterial wall within and
across all the participants (13).
2.4 Pooled Trial Data
To analyze the effect of HT on the progression of subclinical atherosclerosis
(carotid IMT) in either healthy postmenopausal women or women with at least one
coronary-artery lesion, data from the EPAT and WELL-HART studies were
combined into one dataset. Basic demographic variables and other clinical variables
potentially related to the progression of subclinical atherosclerosis (randomized
treatment group, heart disease history, diabetes status, use of lipid-lowering
medications and use of blood pressure lowering medications during the trial) were
obtained from each study dataset. In the WELL-HART study, participants were
assigned to either a placebo group or one of two estradiol groups (estradiol plus
placebo group “unopposed estrogen group”, or estradiol plus medroxyprogesterone
acetate “estrogen-progestin group”). Subjects with a baseline and at least one ontrial
carotid IMT measurement (n=199 for the EPAT study, n=204 for the WELL-HART
study) were included in the pooled study.
Based on the results from the WELL-HART study, there was no significant
difference in the baseline demographic characteristics as well as the progression of
coronary disease between the two hormone therapy (HT) groups. We also analyzed
the effect of the two treatments in the progression of IMT using the mixed effect
6
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between the estrogen group and estrogen-progestin group (p=0.65). . Therefore, in
the pooled dataset, the two groups were merged into one treatment group (hormone
therapy “HT” group). The combined data were coded and formatted uniformly and
the sample size for the pooled study is equivalent to the sum of the two separate
dataset sample sizes.
2.5 Statistical Analysis
Demographic characteristics and the baseline IMT values were compared between
HT and placebo groups using a t-test for independent samples for means or a chi-
square test for proportions. The primary end point of the study was the rate of change
in the common carotid artery intima-media thickness (IMT) for postmenopausal
women who were either healthy or had at least one coronary-artery lesion.
A linear, multivariate mixed-effects model (random coefficients corresponding to
participants) which included all available measures of IMT was used to test the
hypothesis of treatment difference in the average rates of change in IMT. In this
circumstance, IMT at a given follow-up time was regressed on the follow-time (years)
while adjusting for other available covariates (cardiovascular disease history,
diabetes mellitus, use of lipid-lowering medication etc.) and for the variables found
to be different across treatment groups at baseline. The regression coefficient
associated with follow-up time represents the average rate of change in IMT.
Random effects for the linear regression intercept and slope (follow-up time) were
7
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specified to allow for individual deviations from the sample average in the baseline
IMT and IMT rate of change. All variance and covariance terms were estimated, and
no assumption of homogeneity of variances between treatments groups was made.
Differences between treatment groups in the average rates of change in IMT were
tested for significance by including a treatment* follow-up time interaction term in
the mixed-effect model. The association between average IMT progression and other
covariates were tested for significance by including a covariate*follow-up time
interaction term in the mixed-effect model. Three-way interaction terms
(treatment*covariates*follow-up time) were included in the multivariate model to
test the significance of the modification effect of the covariates on the difference
between treatment groups in the average rates of IMT change. For example, the
three-way interaction term of treatment*CAD*follow-up years tested whether the
HT effect on IMT progression differed in women with versus without coronary
artery disease. All lower-order interaction terms and main effects were also included
in these models. Other covariates tested for possible treatment effect modification
were diabetes and lipid-lowering treatment. If the three-way interaction terms were
not significant, models without the interaction terms were refitted. If the three-way
interaction terms were significant, the subgroup analyses were performed stratified
by the effect modifiers.
We also performed a subgroup analysis of the benefit of HT on subclinical
atherosclerosis in participants who either had or had no preexisting coronary disease.
8
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In this subgroup analysis, we only controlled for the use of lipid-lowering and blood
pressure lowering medication since we were interested in testing the effect of HT on
IMT progression independent of the effects of lipid lowering and blood pressure
treatments. We used similar statistical methods as in the full cohort analysis.
Since previous studies have showed that HT had a significant beneficial effect on
HDL cholesterol and LDL cholesterol levels. We also performed a multivariate
analysis of the benefit of HT on subclinical atherosclerosis in the pooled sample after
controlling for preexisting coronary disease, diabetes as well as ontrial LDL and
HDL cholesterol levels. PROC MIXED procedure was used in this analysis.
All the statistical analyses were conducted with the use of SAS software (SAS 9.1,
SAS Institute, Cary, N.C.), and a P value of 0.05 was considered to indicate
statistical significance. The PROC MIXED procedure was used to estimate the
multivariable mixed-effect model.
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Chapter 3: Results
3.1 Baseline Characteristics
Of the 222 randomized women from the EPAT study, 199 completed the two-year
study or had at least one follow-up IMT measure (102 participants in the placebo
group and 97 participants in the HT group). O f the 226 randomized women from the
WELL-HART study, 204 completed the three-year study or had at lease one follow-
up IMT (70 participants in the placebo group and 134 in the HT group). For the
pooled study, 403 subjects had at least one follow-up IMT, 172 of them received
placebo and 231 received HT (Figure 1). The mean participant age was 62.4±6.8
years, and the mean IMT was 800±180 pm; 44% of the participants were non-
Hispanic White, 14% were non-Hispanic Black, 32.5% were Hispanic and 9% were
Asian and 0.5% were other race.
Table 1 summarizes the baseline characteristics of the 403 evaluable participants,
stratified by treatment assignment. Except for coronary disease history, the groups
did not differ significantly at baseline in carotid intima-media thickness,
demographic and clinical characteristics. Compared with the placebo group, HT
subjects were more likely to have coronary disease (at least one coronary-artery
lesion) than placebo subjects (p=0.0006). Since 2/3 of the WELL-HART subjects
were randomized to hormone therapy, the lower prevalence of CAD in the combined
placebo group is expected. A total of 217 (54%) evaluable participants, 96 in the
placebo group and 121 in the HT group, received lipid-lowering medication during
10
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the trial. The proportion of women receiving lipid-lowering medication was similar
between treatment groups (p=0.49). Compared to subjects in the placebo group,
women in HT group had higher
Figure 1: Profile of the Pooled study on the Progression of Atherosclerosis Trial
Placebo
group n=64
No follow-up
IMT (n=23)
No follow-up
IMT (n=22)
Placebo group
n=102
Estradiol Group
n=97
EPAT DATASET (n-222)
Pooled HT group n -2 3 1 Pooled placebo group n=172
WELL-HART STUDY (n=226)
Estradiol group n =134
(with and without
M PA*)
With at least one follow-up
intima-media thickness (n=204)
With at least one follow-up of
intima-media thickness (n=199)
Pooled study participants with at least one
follow-up IMT (n=403)
* MPA: medroxyprogesterone acetate
11
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levels of baseline HDL level (pO.OOOl) and higher ontrial LDL levels (p<00001).
We also analyzed the baseline characteristics of the 45 nonevaluable subjects (those
with no follow-up measurement of IMT). The results (data not shown) showed that
The nonevaluable subjects did not differ significantly at baseline on demographic
and clinical characteristics from the evaluable subjects (both treatment groups
combined).
Table 2 summarizes the demographic and clinical characteristics of the participants
stratified by the status of preexisting coronary artery disease. The results indicated
that except for marital status, participants without CAD were significantly different
from those participants with CAD on baseline demographic and clinical
characteristics. Women without CAD were more likely to be younger, more highly
educated, and employed. Their baseline IMT level was less than that of women with
CAD. Because of the different LDL-C inclusion criteria (EPAT required LDL-C
>130mg/dL, WELL-HART required LDL-C from 100 to 250 mg/dL), more women
without CAD used lipid-lowering medications during the trial than did women with
CAD. Compared to women with preexisting established coronary artery disease,
baseline HDL, baseline LDL, ontrial HDL and ontrial LDL levels were all
significantly higher for women without preexisting established CAD (p<0.0001
respectively, Table2).
12
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Table 1: Baseline Carotid Artery Intima-Media Thickness and Demographic and Clinical
Characteristics by Treatment Groups *
Variables
Evaluable Placebo group
(n= 172)
Evaluable HT group
(n= 231)
P
value*
Carotid artery intima-media
792±180 803±172 0.53
thickness, (pm)
Age, yr 62.7±6.9 62.0±6.9 0.31
Ethnic group-no.(%) 0.71
White 81 (47.1) 98 (42.4)
Black 20(11.6) 36(15.6)
Hispanic 57 (33.1) 74 (32.0)
Asian 13 (7.6) 22 (9.5)
Other 1 (0.6) 1 (0.5)
Marital status, n (%) 0.65
Single 11 (6.4) 18 (7.8)
Married 76 (44.2) 109 (47.2)
Seperated, divorced 85 (49.4) 104 (45)
Education, n (%) 0.84
<=high school 61 (35.5) 86 (37.2)
High school - college 68 (39.5) 93 (40.3)
>=bachelor 43 (25.0) 52 (22.5)
Employment, n (%) 0.08
Employed 68 (39.8) 72 (31.3)
Retired 66 (38.6) 88 (38.3)
Not employed, disability 37(21.6) 70 (30.4)
Income, n (%) 0.57
<=20k 89 (51.7) 120 (52.0)
20k-50k 50 (29.1) 75 (32.5)
>=50k 33(19.2) 36(15.5)
Diabetes, n (%) 41 (23.8) 68 (29.4) 0.21
Ontrial lip-lower medicine, n
96 (55.8) 121 (52.4) 0.49
(%)
Ontrial BP medicine, n (%) 93 (54.1) 154 (66.7) 0.01
Coronary disease, n (%) 70 (40.7) 134 (58) 0.0006
Baseline HDL-Cholesterol
52.1±10.5 50.2±10.7 <0.0001
(mg/dL)
Baseline LDL-Cholesterol
153.1±32.7 153.3±36.5 0.88
(mg/dL)
Ontrial HDL-Cholesterol
55.3±9.6 55.9±10.8 0.20
(mg/dL)
Ontrial LDL-Cholesterol
129.2±19.6 119.1±24.6 <0.0001
(mg/dL)
* Evaluable participants were wom en who had baseline and at least one follow-up measurement o f coratid artery
intima-media thickness. Plus-minus values are means ±SD.
& P values indicated the comparison between evaluable placebo group and evaluable estradiol group.
13
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Table 2: Baseline Carotid Artery Intima-Media Thickness and Demographic and Clinical
Characteristics by Coronary Artery Disease (CAD) Status
Variables
Participants without
preexisting coronary
artery disease (n=199)
Participants with
preexisting coronary
artery disease (n= 204)
P
value*
Carotid artery intima-media
thickness, (um )+
764±132 832±204 <0.0001
Age, yr~ 61.3±6.9 63.3±6.6 0.0036
Ethnic group-n.(%) <0.0001
White 118(59.3) 61 (29.9)
Black 22 (11.1) 34(16.7)
Hispanic 40 (20.1) 91 (44.6)
Asian 18(9.1) 17(8.3)
Other 1 (0.5) 1 (0.5)
Marital status, n (%) 0.97
Single 15 (7.5) 14 (6.9)
Married 91 (45.7) 94 (46.1)
Separated, divorced 93 (46.7) 96 (47.1)
Education, n (%) <0.0001
<=high school 30(15.1) 117(57.4)
High school - college 99 (50.0) 62 (30.4)
>=bachelor 70 (35.2) 25 (12.3)
Employment, n (%) <0.0001
Employed 102 (51.5) 38 (18.7)
Retired 69 (34.9) 85 (41.9)
Not employed, disability 27 (13.6) 80 (39.4)
Income, n (%) <0.0001
<=20k 70 (35.2) 139 (68.1)
20k-50k 75 (37.7) 50 (24.5)
>=5 Ok 54 (27.1) 15 (7.4)
Diabetes, n (%) 6(3.0) 103 (50.5) <0.0001
Lipid-lowering medicine, n
(%)
122 (61.3) 95 (46.6) 0.003
Baseline HDL-Cholesterol
(mg/dL)+
53.9±12.0 49.2±9.2 <0.0001
Baseline LDL-Cholesterol
(mg/dL)+
164.5±28.3 146.2±38.7 <0.0001
Ontrial HDL-Cholesterol
(mg/dL)+
59.1±11.2 53.6±9.1 <0.0001
Ontrial LDL -Cholesterol
(mg/dL)+
• j - ________________•
140.5±17.5 112.9±19.8 <0.0001
&P values indicated the comparison between participants without CAD and participants with CAD. P values
were derived by the chi-square test for categorical variables and by t-test for continuous variables.
+ Numbers indicated mean ± (SD).
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3.2 Analysis of Subclinical Atherosclerosis
Evaluable participants (172 in the placebo group and 231 in the HT group) had a
mean (±SD) measurement of IMT 792±180pm and 803±172pm (Table 1). Table 3
summarizes the unadjusted and adjusted effect of HT on IMT progression for women
in the pooled analysis sample. The unadjusted analysis showed that in the placebo
group, the IMT change rate predicted by the mixed-effects model was 0.995pm/year
(Model 1, Table 3). The HT group experienced regression of subclinical
atherosclerosis (negative average rate of change in IMT) at a rate of -2.995pm/year.
The difference in the average rates of IMT progression between the two treatment
groups was 3.99pm/year (p=0.014, Table 3). Thus carotid IMT progression was
significantly univariately inversely related to HT.
Since preexisting coronary disease, diabetes and use of lipid-lowering medications
potentially correlated with the progression of subclinical atherosclerosis, an adjusted
mixed-effects model controlling for these potential confounders was analyzed.
Three-way interaction terms were included in the model to test for HT modification
by these variables. In the multivariate regression analysis with two-way interaction
terms (Model 2, Table 3), the results indicate that overall (including women with and
without preexisting coronary disease), carotid IMT progression was independently
significantly related to HT (p=0.05) and preexisting coronary disease status
(p=0.007). The average rate of IMT progression for women who had HT was
3.2um/years lower than that for women in the placebo group. The average rate of
15
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Table 3: Univariate And Multivariate Analyses of the Effects of Hormone Therapy on the
Progression of IMT
Parameter Estimate P value
Model 1: Unadjusted effect of estradiol treatment on the IMT(um) progression
Intercept 792.13 <0.0001
Receipt ofH T 11.85 0.50
Years on study 0.995 0.42
Two-way interactions
Receipt of HT* Years -3.99 0.014
Model 2: Adjusted for related risk factors and their two- way interactions
Intercept 769.64 <0.0001
Receipt of HT 1.66 0.92
Years on study 4.0 0.02
Preexisting coronary disease 34.84 0.09
Lipid-lowering treatment -13.28 0.45
Diabetes 65.8 0.004
Two-way interactions
Receipt of HT*years -3.2 0.05
Coronary disease *years -5.26 0.007
Lipid-lowering treatment*years -2.32 0.15
Diabetes*years 1.95 0.36
Model 3: Adjusted for related risk factors and their two way and three way interactions
Intercept 769.64 <0.0001
Receipt of HT 1.65 0.92
Years on study 6.77 0.0009
Preexisting coronary disease 34.84 0.09
Lipid-lowering treatment -13.3 0.45
Diabetes 65.8 0.004
Two-way interactions
Receipt of HT*years -7.63 0.0013
Coronary disease *years -5.54 0.004
Lipid-lowering treatment*years -7.03 0.004
Diabetes*years 1.78 0.40
Three-way interactions
Years*receipt of HT*lipid-lowering treatment 8.17 0.01
16
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Table 4: Multivariate Subgroup Analyses of the Effect of Hormone Therapy (HT) on
Progression of IMT(um) Stratified by Lipid-Lowering Medication Use
Evaluable Participants Evaluable Participants Receiving
Receiving No Lipid-Lowering the Lipid-Lowering
Medications (N=186) Medications( N=217)
Parameter Estimate P value Estimate P value
Model 1: Adjusted for related risk factors and their two-way interaction
Intercept 758.6 <0.0001 764.5 <0.0001
Receipt of HT 7.9 0.80 -0.86 0.97
Years on study 9.6 0.0001 -1.7 0.29
Preexisting coronary
disease
26.2 0.45 47.1 0.05
Diabetes 114.1 0.004 23.0 0.37
Two-way interactions
Receipt of HT*years -7.44 0.004 -0.41 0.84
Coronary
disease*years
-9.52 0.0015 -2.0 0.41
Diabetes *years -0.44 0.89 3.1 0.24
Model 2: Adjusted for related risk factors and their two- way and three- way interactions
Intercept 758.4 <0.0001 764.5 <0.0001
Receipt of HT 8.08 0.79 -0.86 0.97
Years on study 14.2 <0.0001 -1.80 0.31
Preexisting coronary
disease
26.1 0.45 47.15 0.05
Diabetes 114.04 0.0036 23.04 0.37
Two-way interactions
Receipt of HT*years -16.04 <0.0001 -0.20 0.94
Coronary disease
*years
-18.15 <0.0001 -1.71 0.62
Diabetes *years 0.23 0.95 3.08 0.24
Three-way interactions
Years *receipt o f HT
*coronary disease
14.72 0.0038 -0.49 0.90
17
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IMT progression was 5.26 pm/year lower in women with CAD compared to women
without CAD (p=0.007). Thus HT and preexisting coronary artery lesions were the
significant predictors of the IMT progression after controlling for these other
variables.
In the model with the three-way interaction terms (Model 3, Table 3), the results
showed that the effect of HT on the IMT progression was significantly different
between women who took lipid-lowering treatment and those who did not use the
treatment (p=0.01). Subgroup analyses stratified by the ontrial use of lipid-lowering
treatment indicated that, after controlling for coronary-artery disease and diabetes,
HT had a significant effect on the progression of IMT in women who received no
lipid-lowering treatment (Model 1, Table 4). Among women who were not talking
lipid-lowering medication, the average rate o f IMT progression in the HT group was
7.44 pm/year lower than in the placebo group (p=0.0043). However, among women
who received lipid-lowering treatment, HT did not significantly alter the rate of IMT
progression (p=0.84).
Three-way interaction terms in the multivariate model indicated that among women
who were not taking lipid-lowering treatment, the HT effect on the progression of
IMT was significantly different for women who had established coronary disease
from those who did not have the disease (p=0.0038, Model 2, Table 4). The stratified
analyses based on
18
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the status of coronary disease among women who did not take lipid-lowering
medicines showed that HT significantly reduced the average rate of IMT progression
for women without coronary disease (p=0.0021, Table 5), but had no effect on IMT
progression in women with CAD.
Multivariate IMT progression analyses for the subgroups stratified by the status of
preexisting coronary artery disease (CAD) were performed (Table 6). Treatment
group, use of lipid-lowering medications and use of blood pressure-lowering
Table 5: Multivariate Analyses of the Effect of Hormone Therapy (HT) on Progression of IMT
(pm) Among Women Who Were Not Taking Lipid-lowering Medicines Stratified by Status of
Coronary Heart Disease
Evaluable Participants Evaluable Participants With
Without Coronary Heart Coronary Heart Disease
disease (CAD=0) N=77_____________(CAD=1)N=122____________
Parameter
Estimate P value Estimate P value
Intercept 796.6 <0.0001 750.24 <0.0001
Receipt ofH T -61.8 0.064 60.50 0.19
Years on study 13.43 0.0002 -3.52 0.18
Diabetes - - 117.78 0.009
Two-way interactions
Receipt o f HT*years -14.75 0.0021 -2.21 0.44
Diabetes *years - - 0.45 0.87
medications were included in the multivariate models. For women without coronary
artery lesions, carotid IMT progression was significantly independently correlated
with HT (p=0.02, Table 6) and use of lipid-lowering medications (p=0.004), but not
with BP-lowering medications (p=0.42). For women who had CAD, these three
19
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Table 6: Multivariate Subgroup Analyses of the Effect of Hormone Therapy (HT) on
Progression of IMT (pm) Stratified by Status of Preexisting Coronary Disease
Participants who had no
preexisting coronary disease
(CAD=0) N=199
Participants who had
preexisting coronary disease
(CAD=1) N=204
Parameter Estimate P value Estimate P value
Model 1: Adjusted for related risk factors and their two-way interactions
Intercept 767.0 <0.0001 733.1 <0.0001
Receipt of HT -23.4 0.21 26.6 0.38
Years on study 9.4 0.0005 -3.8 0.51
Lipid-lowering treatment -0.87 0.96 -15.2 0.6
Blood pressure lowering
treatment
Two-way interactions
25.3 0.24 91.8 0.28
Receipt of estradiol *years -5.93 0.02 -1.62 0.4
Lipid-lowering
treatment*years
-7.75 0.004 2.64 0.16
BP lowering
treatment*years
-2.42 0.42 0.12 0.98
Model 2: Adjusted for related risk factors and their two-way and three-way interactions
Intercept 770.0 <0.0001 733.1 <0.0001
Receipt of HT -23.4 0.21 26.6 0.38
Years on study 14.8 <0.0001 -3.8 0.71
Lipid-lowering treatment -0.9 0.96 -15.2 0.60
Blood pressure lowering
treatment
Two-way interactions
25.2 0.24 91.8 0.28
Receipt of HT *years -16.6 00002 -1.7 0.88
Lipid-lowering
-14.5 0.0001 2.4 0.43
treatment*years
BP lowering
t r + m < = > -n t * x r p ta r c
-6.4 0.12 0.2 0.98
Three-way interactions
Years *receipt of
HT*lipid- lowering
treatment
13.7 0.01 0.39 0.92
Years*receipt of HT*BP
lowering treatment
8.9 0.14 -0.10 0.99
20
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factors were not significant predictors for subclinical atherosclerosis progression
(p>0.05, Table 6). Among women who had no CAD, the effect of HT on the
progression of IMT significantly differed between women who used lipid-lowering
medication and those who did not (p=0.01, Table 6).
Table 7: Multivariate Analysis of the Possible Mediating Effects of LDL- and HDL-Cholesterol
on Progression of IMT(pm)
Parameter Estimate P value
Adjusted for related risk factors and their two-way interaction terms
Intercept 770.4 <0.0001
Receipt of HT 4.9 0.78
Preexisting coronary disease
42.5 0.06
Diabetes
62.4 0.008
Years on study 8.4 0.28
Ontrial HDL -1.1 0.22
Ontrial LDL 0.4 0.43
Two-way interactions
Receipt of HT* Years -2.6 0.12
Preexisting coronary disease *years -4.5 0.04
Diabetes*years 1.0 0.63
Ontrial HDL*years -0.2 0.02
Ontrial LDL*years 0.03 0.40
To ascertain the extent to which the significant effects of HT and CAD status on
IMT progression might be explained by ontrial levels of HDL-LDL-cholesterol, a
multivariate model including these lipid variables and their interaction with follow-
21
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up times was analyzed. For the pooled sample of postmenopausal women, HT did
not significantly reduce the progression of IMT after controlling for CAD, diabetes
and ontrial LDL and HDL-cholesterol levels (p=0.12, Table 7). Ontrial HDL level
was an inverse significant independent predictor for IMT progression (p=0.02, Table
7). This suggested that at least a portion of the HT benefit on IMT progression was
due to beneficial effects of HT on lipids. The significant reduction of IMT
progression in women who had CAD remained significant (p=0.04). However,
adjustment for lipids attenuated the CAD effect on IMT progression (unadjusted
coronary disease*years estimate=-5.26 pm/year, p=0.0007; and adjusted coronary
disease*years estimate=-4.5pm/year, p=0.04).
22
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Chapter 4: Discussion
4.1 Summary of Results
In this combined sample of postmenopausal women with and without coronary artery
disease, we found that overall, after controlling for lipid-lowering medicine use,
preexisting coronary disease status and diabetes status, progression of IMT in
postmenopausal women with or without established coronary disease who received
hormone therapy was significantly reduced compared to women who received
placebo.
In addition, the results indicated that the progression of IMT was lower in
postmenopausal women with angiographically documented coronary artery disease
than in healthy postmenopausal women (p= 0.007). After controlling for ontrial HDL
and LDL levels, hormone treatment had no significant effect in reduction of IMT
progression in the pooled sample. Ontrial HDL cholesterol level was a significant
independent predictor for the progression of IMT (p=0.02).
On stratification, the HT-related difference in IMT progression was significant in
women who did not receive lipid-lowering treatment (p=0.004) and no difference
was observed in women who took lipid-lowering medication (p=0.84). Among
women who did not receive lipid-lowering treatment, a significant effect of HT
treatment was observed in women who did not have established CAD (p=0.002) and
no significant effect was found in women with CAD (p= 0.44).
23
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Analyses stratified by the status of coronary artery disease indicated that HT and use
of lipid-lowering medication were independently significant inverse predictors for
the progression of IMT in women without coronary artery disease. The IMT
progression rate was not reduced by lipid-lowering treatment in women who had
coronary artery disease. In addition, blood pressure-lowering treatment was not
related to IMT progression and therefore could not explain why postmenopausal
women with established coronary artery disease had significantly lower rates of IMT
progression.
4.2 Clinical Significance of Findings
Coronary atherosclerosis is the underlying cause of most death and disability among
women. Effective measures to slow its progression in women are still urgently
needed. For many years, it was thought that hormone therapy in post-menopausal
women would reduce the risk of coronary artery disease. This belief was based on
three lines of evidence. First, the dramatic increase in a woman’s risk of developing
heart disease after menopause was thought to be at least in part caused by the large
drop in estrogen levels. Secondly, a large number of epidemiological studies
suggested that hormone replacement therapy reduces cardiovascular morbidity and
mortality in postmenopausal women (3, 4). Finally, treatment with estrogen increases
HDL-cholesterol levels and lowers the LDL-cholesterol levels (8, 9, 10, 19). Most of
the observational studies were conducted in healthy postmenopausal women who
used unopposed estrogen replacement therapy. Our results are consistent with these
24
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observational studies which indicated that postmenopausal women who use estrogen
have lower rates of coronary events than do postmenopausal women who do not take
estrogen (3, 4).
4.3 Comparisons with Other Clinical Studies
The benefit of estrogen treatment in reducing coronary atherosclerosis has also been
shown in cross-sectional studies using angiographic end points (20-23). Some
population-based studies have shown thinner carotid intima-media thickness in
estrogen users compared to nonusers (24-26). However, bias was a potential problem
in these observational studies because women who were prescribed hormone therapy
are often healthier than nonusers (selection bias), monitoring and treatment may be
more intensive for women taking HT (prevention bias), and adherence to taking a
medication on a regular basis is associated with a significant survival benefit
(compliance bias) (27).
Several randomized, placebo-controlled trials which can overcome many of these
types of bias were performed to investigate the effect of hormone therapy on
prevention of atherosclerosis in either healthy postmenopausal women or
postmenopausal women with established coronary artery disease (5, 6, 7, 9). Few
studies were conducted in general postmenopausal women regardless o f coronary
artery disease status. The results of our combined (EPAT+WELL-HART)
randomized, placebo-controlled study which indicated that hormone replacement
25
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did slow the progression of coronary atherosclerosis in postmenopausal women with
or without established coronary artery disease were consistent with EPAT which
indicated that estrogen treatment can slow the average rate of progression of
atherosclerosis in healthy postmenopausal women (13), but were inconsistent with
the primary WELL-HART results which indicated no effect o f estrogen on the
progression of coronary artery atherosclerosis in postmenopausal women with
coronary artery disease (11). However, results of our interaction and stratified
analyses are consistent with the separate EPAT and WELL-HART results. In
particular, the effect of HT on the progression of atherosclerosis was different
between women who took lipid-lowering medication and those who did not take the
medicine. HT reduced progression of atherosclerosis in women not receiving lipid-
lowering therapy but had no additional effect on progression in women receiving
lipid-lowering medicine. This finding was consistent with the result of EPAT study
which showed the treatment effect modification by lipid-lowering medication on the
progression of IMT (11). A possible explanation for this result is that the effect of
HT treatment on the progression of atherosclerosis was obtained in part by
increasing HDL-cholesterol and decreasing LDL-cholesterol. Thus, both lipid-
lowering treatment and HT treatment benefited cholesterol levels and HT may not
provide any additional benefit on progression of atherosclerosis beyond lipid-
lowering treatment.
Our study also indicated that among women who did not take lipid-lowering
26
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medicine, the effect of HT was only significant in women who had no preexisting
coronary artery disease but not in women who had coronary artery lesions. This is
consistent with the separate primary results of EPAT (IMT primary endpoint) and
WELL-HART (coronary angiographic primary endpoint). Further studies are needed
to investigate if the treatments or factors related to coronary artery disease can
explain why HT has no effect on women with coronary artery disease.
A few randomized clinical trials performed in postmenopausal women with
preexisting coronary disease showed that hormone therapy had no effect on
cardiovascular event risk. The Heart and Estrogen/progestin Replacement Study
(HERS) (28) indicated that during the average follow-up of 4.1 years, HT treatment
(conjugated equine estrogens plus medroxyprogesterone acetate) did not reduce the
overall rate of GHD events in postmenopausal women with established coronary
disease and increased the rate of thromboembolic events and gallbladder disease.
Despite the overall null results of HERS, the investigators reported a significant early
increase in risk for cardiovascular and thromboembolic event and a late time trend of
fewer myocardial infarctions in the HT groups than in the placebo group. The
Estrogen Replacement and Atherosclerosis (ERA) and Women’s Angiographic
Vitamin and Estrogen (WAVE) trials, which were similar in design to the
WELLHART trial, also failed to show a atherosclerosis benefit with HT (5,6). Our
combined clinical trial was not consistent with these results. The difference between
our study and those trials was that our study enrolled postmenopausal women either
27
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with or without coronary artery disease, while HERS, WAVE and ERA studies only
included postmenopausal women with established coronary artery disease. Our study
was consistent with the long-term results in the Women’s Health Initiative (WHI)
trial (11) showing a trend towards cardiovascular benefit. Results of our pooled
study were not consistent with the Postmenopausal HOrmone Replacement against
Atherosclerosis (PHOREA) trial (19). The lack of benefit of HT in PHOREA trial
may in part be due to the short treatment period (48 weeks) and inclusion of only
women with high IMT (>lmm).
In animal studies, an attenuated response to injury (28) and a diminished progression
of atherosclerosis in coronary arteries with hormone therapy (29) have been observed.
By contrast, recent studies in women have indicated a proinflammatory potential of
HT by increasing C-reactive protein levels, which in turn leads to atherosclerotic
complications (30). Therefore, the overall effect of HT on atherosclerosis may not be
significant, as found in our combined study. Controlled trials examining other
surrogate cardiovascular parameters demonstrated beneficial effects of HT on
endothelial function and systemic vascular compliance in healthy women (31-33)
and exercise capacity in women with CHD (34). Thus, the effect of estrogen
treatment on cardiovascular mortality observed in observational studies may well be
mediated by mechanisms other than inhibition of atherogenesis.
28
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4.4 Strengths and Limitations
As a double-blind, placebo-controlled randomized trial, our study ruled out the
potential bias evident in observational studies. The EPAT and WELLHART studies
were designed and conducted similarly. They also had large sample sizes to test the
difference between the HT and placebo groups. However, there were some
limitations for our pooled trial. Although EPAT and WELL-HART studies were
designed and conducted as sister studies, subjects from each of the two studies were
followed up for different time periods. They also had different enrollment standards
and different study populations.
4.5 Conclusion
The present pooled analysis showed that in a population of clinically healthy
postmenopausal women and women with angiographically established coronary
artery disease, using IMT as a measure of subclinical atherosclerotic disease and
increased risk for CHD and stroke, HT slowed the progression of atherosclerosis. In
subgroup analyses, this effect was only observed in women not receiving lipid-
lowering medication. Among women who were not taking lipid-lowering medication,
hormone therapy significantly reduced subclinical atherosclerosis progression in
women who had no coronary artery disease but not in women who had coronary
disease. No randomized clinical trials so far have examined the effect of HT on the
progression of atherosclerosis in a general sample of postmenopausal women
regardless of their preexisting coronary disease status. Additional randomized
29
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clinical trials are needed to elucidate the role of hormone treatment in primary
secondary prevention in postmenopausal women.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
References
1. Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement
therapy and the primary prevention of cardiovascular disease, Ann Intern
Med. 2002.; 137:273-284
2. Barrett Cnnor E, Grady D. Hormone replacement therapy, heart disease and
other considerations. Annu Rev Public Health. 1998;19:55-72.
3. Grodstein F, Stampfer M. The epidemiology of coronary heart disease and
estrogen replacement in postmenopausal women Prog Cardiovasc Dis.
1995;38:199-210.
4. Grodstein F, Stampfer M. Estrogen for women at varying risk of coronary
disease. Maturitas. 1998;30:19-26.
5. Waters DD, Alderman EL, Hsia J. et al. Effects of hormone replacement
therapy and antioxidant vitamin supplements on coronary atherosclerosis in
postmenopausal women: a randomized controlled trial. JAMA
2002;288:2432-40.
6. Herrington DM, Reboussin DM, Brosnihan DB, et al. Effects of estrogen
replacement on the progression o f coronary-artery atherosclerosis. The new
England Journal of Medicine. 2000;343:522-9.
7. Hodis HN, Mack WJ, Azen SP et al. Hormone therapy and the progression of
coronary-artery atherosclerosis in postmenopausal women. N Engl J Med
2003;349:535-45.
8. Shlipak MG, Simon JA, Vittinghoff E et al. Estrogen and progestin,
lipoprotein(a) and the risk of recurrent coronary heart disease events after
menopause. JAMA. 2000;283:1845-1852.
9. Rossouw JE, Anderson GL, Prentice RI, et al. Risks and benefits of estrogen
plus progestin in healthy postmenopausal women: principle results from the
Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-
33.
10. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin
for secondary prevention of coronary heart disease in postmenopausal women.
JAMA 1998;280:605-13.
31
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
11. Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of
atherosclerosis: a randomized, double blind, placebo-controlled trial. Ann
Intern Med 2001;135:939-53.
12. Craven TE, Ryu JE, Espeland MA et al. Evaluation of the associations
between carotid artery atherosclerosis and coronary artery stenosis: a case-
control study. Circulation. 1990;11:1786-1794.
13. Wofford JL, Kahl FR, Howard GR et al. Relation of extent of extracranial
carotid artery atherosclerosis as measured by B-mode ultrasound to the extent
of coronary atherosclerosis. Arterioscler Thromb. 1991;11:1786-1794.
14. Burke GL, Evans GW, Riley WA et al. Arterial wall thickness is associated
with prevalent cardiovascular disease in middle-aged adults. The
Atherosclerosis Risk In Communities (ARIC) Study. Stroke. 1995;26:386-91.
15. Adams MR, Nakagomi A, Keech A et al. Carotid intima-media thickness is
only weakly correlated with the extent and severity of coronary artery disease.
Circulation. 1995;92:2127-2134.
16. Crouse JR III, Craven TE, Hagaman AP et al. Association of coronary
disease with segment-specific intimal-medial thickening of the extracranial
carotid artery. Circulation. 1995;92:1141-1147.
17. Blankenhom DH, Selzer RH, Crawford DW et al. Beneficial effects of
cholestipol-niacin therapy on the common carotid artery. Circulation.
1993;88:20-28.
18. Hodis HN, Mack WJ, LaBree L et al. Reduction in carotid arterial wall
thickness using lovastatin and dietary therapy: a randomized controlled
clinical trial. Ann Intern Med. 1996;124:548-556.
19. Walk-de Roo GW, Stehouwer CD.A, Meijer P et al. Both raloxifene and
estrogen reduce major cardiovascular risk factors in healthy postmenopausal
women: a 2- year, placebo-controlled study. Arteriosclerosis, Thrombosis &
Vascular Biology. 1999;19:2993-3000.
20. McFarland KF, Boniface ME, Homung CA et al. Risk factors and
noncontradeptive estrogen use in women with and without coronary disease.
Am Heart J. 1989;117:1209-14.
21. Gruchow HW, Anderson AJ, Barboriak JJ et al. Postmenopausal use of
estrogen and occlusion of coronary arteries. Am Heart J. 1988; 115:954-63.
32
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
22. Sullivan JM, Vander ZR, Lemp GF et al. Postmenopausal estrogen use and
coronary atherosclerosis. Ann Intern aMed. 1988;108:358-63.
23. Hong MK, Romm PA, Reagan K et al. Effects of estrogen replacement
therapy on serum lipid values and angiographically defined coronary artery
disease in postmenopausal women. Am J Cardiol. 1992;69:176-8.
24. Manolio TA, /furberg CD, Shemanski L, et al. Asociations of
postmenopausal estrogen use with cardiovascular disease and its risk factors
in older women. The CHS Collaborative Research Group. Circulation.
1993;88:2163-71.
25. McGrath BP, Liang YL, Teede H. Shiel LM, et al. Age-related deterioration
in arterial structure and function in postmeopausal women: impact of
hormone placement therapy. Artherioscle Thromb Vase Biol.
1998;18:1149-56.
26. Westendorp IC, in’t Veld BA, Bots ML, et al. Hormone replacement therapy
and intima-media thickness of the common carotid artery: the Rotterdam
study. Stroke. 1999;30:2562-7.
27. Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann. Intern
M ed.l991;l 15:455-6.
28. Mendelsohn ME, Karas RH. The protective effects of estrogen on the
cardiovascular system. N Engl J Med. 999;340:1801-1811.
29. Clarkson TB, Anthony MS, Klein KP. Hormone replacement therapy and
coronary artery atherosclerosis: the monkey model. Br J Obstet Bynaecol.
1999;13:53-57.
30. Ridker PM, Hennekens CH, Rifai N, et al. Hormone replacement therapy
and increased plasma concentration of C-reactive protein. Circulation.
1999;100:713-716.
31. Lieberman EH, Gerhard MD, Uehata A, et al. Estrogen improves
endothelium-dependent flow-mediated vasodilation in postmenopausal
women. Ann Intern Med. 1994;121:936-941.
32. Gerhard M. Walsh BW, Tawakol A, Haley EA, et al. Estradiol therapy
combined with progesterone and endothelium-dependent vasodilation in
postmenopausal women. Circulation. 1998;98:1158-1163.
33
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
33. Rajkumar C, Kingwell BA, Cameron JD, et al. Homonal therapy increases
arterial compliance in postmenopausal women. J Am Coll Cardiol.
1997;30:350-356.
34. Rosano GM, Sarrel PM, Poole WP, et al. Beneficial effect of oestrogen on
exercise-induced myocardial ischaemia in women with coronary artery
disease. Lancet. 1993;342:133-136.
34
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Alphabetized References
Adams MR, Nakagomi A, Keech A et al. Carotid intima-media thickness is only
weakly correlated with the extent and severity of coronary artery disease. Circulation.
1995;92:2127-2134.
Barrett Connor E. Postmenopausal estrogen and prevention bias. Ann. Intern
Med. 1991 ;115:455-6.
Barrett Cnnor E, Grady D. Hormone replacement therapy, heart disease and other
considerations. Annu Rev Public Health. 1998;19:55-72.
Blankenhom DH, Selzer RH, Crawford DW et al. Beneficial effects of cholestipol-
niacin therapy on the common carotid artery. Circulation. 1993;88:20-28
Burke GL, Evans GW, Riley WA et al. Arterial wall thickness is associated with
prevalent cardiovascular disease in middle-aged adults. The Atherosclerosis Risk In
Communities (ARIC) Study. Stroke. 1995;26:386-91.
Clarkson TB, Anthony MS, Klein KP. Hormone replacement therapy and coronary
artery atherosclerosis: the monkey model. Br J Obstet Bynaecol. 1999;13:53-57.
Craven TE, Ryu JE, Espeland MA et al. Evaluation of the associations between
carotid artery atherosclerosis and coronary artery stenosis: a case-control study.
Circulation. 1990;11:1786-1794.
Crouse JR III, Craven TE, Hagaman AP et al. Association of coronary disease with
segment-specific intimal-medial thickening of the extracranial carotid artery.
Circulation. 1995;92:1141-1147.
Gerhard M. Walsh BW, Tawakol A, Haley EA, et al. Estradiol therapy combined
with progesterone and endothelium-dependent vasodilation in postmenopausal
women. Circulation. 1998;98:1158-1163.
Grodstein F, Stampfer M. Estrogen for women at varying risk of coronary disease.
Maturitas. 1998;30:19-26.
Grodstein F, Stampfer M. The epidemiology of coronary heart disease and estrogen
replacement in postmenopausal women Prog Cardiovasc Dis. 1995;38:199-210.
Gruchow HW, Anderson AJ, Barboriak JJ et al. Postmenopausal use of estrogen and
occlusion of coronary arteries. Am Heart J. 1988;115:954-63.
35
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Herrington DM, Reboussin DM, Brosnihan DB, et al. Effects of estrogen
replacement on the progression of coronary-artery atherosclerosis. The new
England Journal of Medicine. 2000;343:522-9.
Hodis HN, Mack WJ, Azen SP et al. Hormone therapy and the progression of
coronary-artery atherosclerosis in postmenopausal women. N Engl J Med.
2003;349:535-45.
Hodis HN, Mack WJ, LaBree L et al. Reduction in carotid arterial wall thickness
using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann
Intern Med. 1996;124:548-556.
Hodis HN, Mack WJ, Lobo RA, et al. Estrogen in the prevention of atherosclerosis:
a randomized, double blind, placebo-controlled trial. Ann Intern Med.2001;135:939-
53.
Hong MK, Romm PA, Reagan K et al. Effects of estrogen replacement therapy on
serum lipid values and angiographically defined coronary artery disease in
postmenopausal women. Am J Cardiol. 1992;69:176-8.
Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for
secondary prevention of coronary heart disease in postmenopausal women. JAMA
1998;280:605-13.
Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy
and the primary prevention of cardiovascular disease, Ann Intern Med.
2002.; 137:273-284
Lieberman EH, Gerhard MD, Uehata A, et al. Estrogen improves endothelium-
dependent flow-mediated vasodilation in postmenopausal women. Ann Intern Med.
1994;121:936-941.
McFarland KF, Boniface ME, Homung CA et al. Risk factors and noncontradeptive
estrogen use in women with and without coronary disease. Am Heart J.
1989;117:1209-14.
McGrath BP, Liang YL, Teede H. Shiel LM, et al. Age-related deterioration in
arterial structure and function in postmeopausal women: impact of hormone
placement therapy. Artherioscle Thromb Vase Biol. 1998;18:1149-56.
Manolio TA, /furberg CD, Shemanski L, et al. Asociations of postmenopausal
estrogen use with cardiovascular disease and its risk factors in older women. The
CHS Collaborative Research Group. Circulation. 1993;88:2163-71.
36
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular
system. N Engl J Med. 999;340:1801-1811.
Rajkumar C, Kingwell BA, Cameron JD, et al. Homonal therapy increases arterial
compliance in postmenopausal women. J Am Coll Cardiol. 1997;30:350-356.
Ridker PM, Hennekens CH, Rifai N, et al. Hormone replacement therapy and
increased plasma concentration of C-reactive protein. Circulation. 1999;100:713-716.
Rosano GM, Sarrel PM, Poole WP, et al. Beneficial effect of oestrogen on exercise-
induced myocardial ischaemia in women with coronary artery disease.
Lancet. 1993;342:133-136.
Rossouw JE, Anderson GL, Prentice RI, et al. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principle results from the Women’s
Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
Shlipak MG, Simon JA, Vittinghoff E et al. Estrogen and progestin, lipoprotein(a)
and the risk of recurrent coronary heart disease events after menopause. JAMA.
2000;283:1845-1852.
Sullivan JM, Vander ZR, Lemp GF et al. Postmenopausal estrogen use and coronary
atherosclerosis. Ann Intern aMed. 1988;108:358-63.
Walk-de Roo GW, Stehouwer CD.A, Meijer P et al. Both raloxifene and estrogen
reduce major cardiovascular risk factors in healthy postmenopausal women: a 2- year,
placebo-controlled study. Arteriosclerosis, Thrombosis & Vascular Biology.
1999;19:2993-3000.
Waters DD, Alderman EL, Hsia J. et al. Effects of hormone replacement therapy and
antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal
women: a randomized controlled trial. JAMA 2002;288:2432-40.
Westendorp IC, in’t Veld BA, Bots ML, et al. Hormone replacement therapy and
intima-media thickness of the common carotid artery: the Rotterdam study.
Stroke. 1999;30:2562-7.
Wofford JL, Kahl FR, Howard GR et al. Relation o f extent of extracranial carotid
artery atherosclerosis as measured by B-mode ultrasound to the extent of coronary
atherosclerosis. Arterioscler Thromb. 1991;11:1786-1794.
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Creator
Shen, Yan
(author)
Core Title
Effect of hormone therapy on the progression of carotid-artery atherosclerosis in postmenopausal women with and without established coronary artery disease
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Graduate School
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Master of Science
Degree Program
Applied Biostatistics and Epidemiology
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University of Southern California
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health sciences, medicine and surgery,health sciences, obstetrics and gynecology,OAI-PMH Harvest
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Shen, Yan
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