Does
hormone replacement therapy enhance or reduce cardiovascular
event rate?
Dr Nanette K. Wenger
Professor of Medicine (Cardiology), Division of Cardiology, Emory University
School
of Medicine, Atlanta, GA 30303, USA; Chief of Cardiology, Grady Memorial
Hospital; and Consultant, Emory Heart and Vascular Center, Atlanta, GA, USA
Epidemiologic data suggest the potential of postmenopausal
hormone replacement therapy (HRT) to confer cardioprotection.
These observations include the preponderance of coronary heart
disease (CHD) in postmenopausal women[1] and
the accelerated appearance of CHD in women with premature natural
menopause or bilateral oophorectomy. The almost doubled risk
of CHD in the latter is abolished by estrogen therapy.[2]
Population-based observational studies of both estrogen and estrogen/progestin
use in women not known to have CHD, and meta-analyses of these studies, almost
uniformly suggest a 35–50% reduction in CHD risk[3] (Figures
1 and 2).
Figure 1. Meta-analysis of studies investigating the
risk for CHD in estrogen users compared with non-users. (Reproduced
with permission from the Annual Review of Public Health, volume
19, ©1998 by Annual Reviews www.AnnualReviews.org).[3]
Figure 2. Meta-analysis of seven studies of estrogen
plus progestin in CHD. (Reproduced with permission from the
Annual Review of Public Health, volume 19, ©1998 by Annual
Reviews www.AnnualReviews.org ).[3]
However, observational data can be confounded
by selection bias, in that HRT is typically prescribed to healthy
women. An additional concern is compliance bias, such that women
compliant with HRT are likely to exhibit other favorable health-related
behaviors. In contrast, a recent meta-analysis of CHD adverse
events in 22 small trials of HRT suggests an increased relative
risk of 1.4 for hormone users.[4] An intermediate
outcomes, randomized, controlled clinical trial, the Postmenopausal
Estrogen/Progestin Interventions (PEPI) trial, documented an
overall favorable effect on coronary risk factors in healthy
postmenopausal women taking several estrogen and estrogen/progestin
regimens.[5] Whether HRT-related improvement
in coronary risk factors will translate into reduced coronary
event rates remains to be ascertained.
Observational data for women with documented CHD have also shown a decrease
in death or myocardial infarction in estrogen users compared with non-users
following PTCA.[6,7] Data regarding the estrogen effect on
restenosis following PTCA remain conflicting.[6,7] Also, among
a small cohort of women taking estrogen after CABG surgery (with only 3% of
estrogen users also receiving a progestin), survival was greater in estrogen
users than in non-users.[8]
The Heart and Estrogen/Progestin Replacement Study (HERS) significantly altered
the landscape of HRT information.[9] HERS is the sole randomized,
double-blind, placebo-controlled clinical trial of HRT in postmenopausal women
with established CHD reported to date. During an average follow-up of 4.1 years,
2763 such women aged <80 years with an intact uterus were randomized to
receive daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone
acetate in one tablet versus an identical placebo. Despite an average 11% decrease
in LDL cholesterol levels and a 10% increase in HDL cholesterol levels, there
was no overall reduction in the primary endpoint of coronary death and non-fatal
myocardial infarction (Figure 3);
 Figure
3. Kaplan-Meier estimates of the cumulative incidence of
primary CHD events (left) and its constituents: non-fatal myocardial
infarction (center) and CHD death (right). The number of women
observed at each year of follow-up and still free of an event
is given in parentheses, and the curves become fainter when
this number drops below half of the cohort. Log-rank P-values
are 0.91 for primary CHD events, 0.46 for non-fatal myocardial
infarction and 0.23 for CHD death. (Reproduced with permission
from the JAMA 1998; 280: 605–613, © 1998, American Medical
Association).
nor was there benefit for a variety of secondary
cardiovascular endpoints, including coronary revascularization,
hospitalization for unstable angina, hospitalization for heart
failure, resuscitated cardiac arrest, stroke or transient ischemic
attack, peripheral arterial disease and all-cause mortality.
Within this overall null effect was a puzzling trend: of concern
was a statistically significant time trend of an early increase
in the risk of coronary events in the first year of HRT (relative
hazard 1.52), but a favorable pattern of CHD events after several
years of therapy (relative hazard 0.67 in years 4 and 5). The
HERS recommendations are that women with established CHD should
not initiate this hormone regimen for cardioprotection, but that
it could be appropriate for women with CHD who are already taking
HRT to continue therapy for the potential of late protection.
The increased occurrence of venous thromboembolism (VTE) with
HRT is addressed below.
It is not appropriate to extrapolate HERS data to unopposed estrogen therapy
or other estrogen/progestin regimens, nor should they be extrapolated to healthy
women. Nonetheless, the HERS results highlight the need for clinical trial
data to ascertain whether HRT confers benefit or risk in other populations.
Among HRT trials currently underway in predominantly healthy women are the
US Women’s Health Initiative (WHI)[10,11] and the UK Women’s
International Study of Long Duration Oestrogen after Menopause (WISDOM) trial.[12] The
27,000 predominantly healthy postmenopausal women in the WHI randomized to
estrogen plus progestin, estrogen (for women with hysterectomy), or placebo
were notified in April 2000 of an early increase in cardiovascular events in
hormone-treated women involving about 1% of the women. Becauce the period of
risk had passed when these preliminary 2-year data were reviewed, the Data
Safety and Monitoring Board recommended continuation of the study to evaluate
potential late benefit. Secondary prevention trials in progress supported by
the US National Institutes of Health include WAVE (Women’s Angiographic Vitamin
and Estrogen trial), WELL-HART (Women’s Estrogen/Progestin and Lipid-Lowering
Hormone Atherosclerosis Regression Trial) ERA (Estrogen Replacement and Atherosclerosis
trial). Results were reported at the 2000 Scientific Sessions of the American
College of Cardiology. In this angiography trial, 30% of postmenopausal women
with documented CHD were randomized to estrogen, estrogen plus progestin, or
placebo. Comparing baseline and mean 3.2-year angiograms, there was no difference
in angiographic lesion changes between the hormone regimens and placebo.
Although the increased risk of VTE with oral contraceptive use has been well
documented,[13,14] only recently has there been evidence
that the far lower dose HRT is associated with an increased risk of VTE.
Data from recent observational studies suggest a two- to fourfold increase
in the risk of spontaneous deep vein thrombosis and pulmonary embolism.[15–19] In
HERS, randomized controlled trial data from older women with documented CHD
revealed a relative hazard of 2.7 (95% CI 1.4–5.0) for idiopathic and non-idiopathic
VTE in HRT-treated women.[20] Women with lower extremity
fractures had a relative hazard of 18.1, with cancer 3.9, in the first 90 days
after inpatient surgery 4.9, in the first 90 days after non-surgical hospitalization
5.7, and in the first 90 days after myocardial infarction 5.9 (even after adjustment
for hospitalization, with 80% of women taking daily aspirin). The increased
risk was similar with idiopathic (relative hazard 3.1) and non-idiopathic (relative
hazard 2.5) VTE, and the risks were similar for women with and without other
risk factors for VTE. This increased risk of VTE must be addressed when counseling
women about the risks and benefits of HRT.
Despite biologically plausible mechanisms for estrogen’s cardioprotective benefit[21]
and observational data suggesting such benefit, randomized controlled trial
data from HERS are contradictory. Of particular concern is the early increased
coronary risk in HERS as well as the increased risk of venous thromboembolism.
Given these uncertainties, clinical outcome randomized trial data are clearly
requisite using varied HRT regimens in healthy women and in women with CHD.
Until the results of such trials become available, the decision to initiate
HRT for cardioprotection must be individualized. Relevant variables include
the individual woman’s risk of CHD, as well as her risks for osteoporosis,
VTE and breast cancer, the severity of her menopausal symptoms and her individual
preferences.
REFERENCES
-
Comment in:
Coronary heart disease: an older woman's major health
risk.
Wenger NK.
Department of Medicine, Emory University School of Medicine, Atlanta, GA
30303, USA. nwenger@emory.edu
Publication Types:
PMID: 9366743 [PubMed - indexed for MEDLINE]
-
Menopause and the risk of coronary heart
disease in women.
Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer
FE, Hennekens CH.
To determine the relation of menopause to the risk of coronary heart disease,
we analyzed data on a prospective cohort of 121,700 U.S. women 30 to 55 years
old who were followed from 1976 to 1982. Information on menopausal status,
the type of menopause, and other risk factors was obtained in 1976 and updated
every two years by mailing questionnaires. Through 1982, the follow-up rate
was 98.3 percent for mortality and 95.4 percent for nonfatal events. After
we controlled for age and cigarette smoking, women who had had a natural
menopause and who had never taken replacement estrogen had no appreciable
increase in the risk of coronary heart disease, as compared with premenopausal
women (adjusted rate ratio, 1.2; 95 percent confidence limits, 0.8 and 1.8).
Again compared with premenopausal women, the occurrence of a natural menopause
together with the use of estrogens did not affect the risk (rate ratio, 0.8,
95 percent confidence limits, 0.4 and 1.3). Women who had undergone bilateral
oophorectomy and who had never taken estrogens after menopause had an increased
risk (rate ratio, 2.2; 95 percent confidence limits, 1.2 and 4.2). However,
the use of estrogens in the postmenopausal period appeared to eliminate this
increased risk among these women as compared with premenopausal women (rate
ratio, 0.9; 95 percent confidence limits, 0.6 and 1.6). These data suggest
that, in contrast to a natural menopause, bilateral oophorectomy increases
the risk of coronary heart disease. This increase appears to be prevented
by estrogen-replacement therapy.
PMID: 3574358 [PubMed - indexed for MEDLINE]
3. Barrett-Connor E, Grady D.
Hormone replacement therapy, heart disease, and other considerations.
Annu Rev Public Health 1998; 19: 55–72.
-
Comment in:
Impact of postmenopausal hormone therapy on cardiovascular
events and cancer: pooled data from clinical trials.
Hemminki E, McPherson K.
National Research and Development Centre for Welfare and Health, Health Services
Research Unit, Helsinki, Finland.
OBJECTIVE: To examine the incidence of cardiovascular diseases and cancer
from published clinical trials that studied other outcomes of postmenopausal
hormone therapy as some surveys have suggested that it may decrease the incidence
of cardiovascular diseases and increase the incidence of hormone dependent
cancers. DESIGN: Trials that compared hormone therapy with placebo, no therapy,
or vitamins and minerals in comparable groups of postmenopausal women and
reported cardiovascular or cancer outcomes were searched from the literature.
SUBJECTS: 22 trials with 4124 women were identified. In each group, the numbers
of women with cardiovascular and cancer events were summed and divided by
the numbers of women originally allocated to the groups. RESULTS: Data on
cardiovascular events and cancer were usually given incidentally, either
as a reason for dropping out of a study or in a list of adverse effects.
The calculated odds ratios for women taking hormones versus those not taking
hormones was 1.39 (95% confidence interval 0.48 to 3.95) for cardiovascular
events without pulmonary embolus and deep vein thrombosis and 1.64 (0.55
to 4.18) with them. It is unlikely that such results would have occurred
if the true odds ratio were 0.7 or less. For cancers, the numbers of reported
events were too low for a useful conclusion. CONCLUSIONS: The results of
these pooled data do not support the notion that postmenopausal hormone therapy
prevents cardiovascular events.
Publication Types:
PMID: 9251544 [PubMed - indexed for MEDLINE]
-
Erratum in:
- JAMA 1995 Dec 6;274(21):1676
Comment in:
Effects of estrogen or estrogen/progestin regimens on
heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin
Interventions (PEPI) Trial. The Writing Group for the PEPI Trial.
OBJECTIVE--To assess pairwise differences between placebo, unopposed estrogen,
and each of three estrogen/progestin regimens on selected heart disease risk
factors in healthy postmenopausal women. DESIGN--A 3-year, multicenter, randomized,
double-blind, placebo-controlled trial. PARTICIPANTS--A total of 875 healthy
postmenopausal women aged 45 to 64 years who had no known contraindication
to hormone therapy. INTERVENTION--Participants were randomly assigned in
equal numbers to the following groups: (1) placebo; (2) conjugated equine
estrogen (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone
acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive
MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone
(MP), 200 mg/d for 12 d/mo. PRIMARY ENDPOINTS--Four endpoints were chosen
to represent four biological systems related to the risk of cardiovascular
disease: (1) high-density lipoprotein cholesterol (HDL-C), (2) systolic blood
pressure, (3) serum insulin, and (4) fibrinogen. ANALYSIS--Analyses presented
are by intention to treat. P values for primary endpoints are adjusted for
multiple comparisons; 95% confidence intervals around estimated effects were
calculated without this adjustment. RESULTS--Mean changes in HDL-C segregated
treatment regimens into three statistically distinct groups: (1) placebo
(decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of 0.03
to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase
of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6 mg/dL]).
Active treatments decreased mean low-density lipoprotein cholesterol (0.37
to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean triglyceride (0.13
to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated
with a significantly greater increase in mean fibrinogen than any active
treatment (0.10 g/L compared with -0.02 to 0.06 g/L); differences among active
treatments were not significant. Systolic blood pressure increased and postchallenge
insulin levels decreased during the trial, but neither varied significantly
by treatment assignment. Compared with other active treatments, unopposed
estrogen was associated with a significantly increased risk of adenomatous
or atypical hyperplasia (34% vs 1%) and of hysterectomy (6% vs 1%). No other
adverse effect differed by treatment assignment or hysterectomy status. CONCLUSIONS--Estrogen
alone or in combination with a progestin improves lipoproteins and lowers
fibrinogen levels without detectable effects on postchallenge insulin or
blood pressure. Unopposed estrogen is the optimal regimen for elevation of
HDL-C, but the high rate of endometrial hyperplasia restricts use to women
without a uterus. In women with a uterus, CEE with cyclic MP has the most
favorable effect on HDL-C and no excess risk of endometrial hyperplasia.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 7807658 [PubMed - indexed for MEDLINE]
-
Comment in:
Estrogen replacement therapy and outcome of coronary
balloon angioplasty in postmenopausal women.
Abu-Halawa SA, Thompson K, Kirkeeide RL, Vaughn WK,
Rosales O, Fujisi K, Schroth G, Smalling R, Anderson HV.
University of Texas Health Science Center and Hermann Hospital, and the Texas
Heart Institute, Houston, USA.
Estrogen replacement therapy (ERT) in women after menopause is associated
with prevention of clinical coronary artery disease. However, few studies
have investigated possible benefits from ERT in postmenopausal women undergoing
treatment for established coronary disease. We therefore retrospectively
reviewed the clinical outcomes of 428 postmenopausal women undergoing percutaneous
transluminal coronary balloon angioplasty (PTCA) to test the hypothesis that
ERT has a beneficial effect in this setting. The women were divided into
2 groups based on ERT status at the time of the procedure. Estrogen users
were younger (60 +/- 10 vs 68 +/- 9 years, p <0.001), more commonly had
family histories of coronary heart disease (54% vs 41%, p = 0.04), had less
incidence of hypertension (63% vs 76%, p = 0.02), and had slightly fewer
diseased vessels per patient (1.3 +/- 0.5 vs 1.5 +/- 0.7, p = 0.03) compared
with nonusers. No in-hospital deaths occurred in estrogen users compared
with 5% hospital mortality in nonusers (p = 0.01). The combined outcome of
death or myocardial infarction (MI) also was lower in estrogen users (4%
vs 12%, p = 0.04). Of 348 women discharged after successful PTCA, 336 (97%)
were able to be contacted at an average follow-up interval of 22 +/- 17 months
(range 5 to 82). Estrogen users had superior event-free survival both for
death as well as for death or nonfatal MI. Repeat revascularizations were
similar in both groups (32% vs 24%, p = 0.15). In a Cox proportional-hazards
model, nonusers had 4 times the likelihood of death after angioplasty compared
with estrogen users (OR = 4.025, 95% CI = 1.3 to 13.4, p = 0.02). We conclude
that estrogen replacement may offer protection against clinical coronary
events in postmenopausal women who already have established coronary disease
and are undergoing balloon angioplasty. The benefit was independent of age,
smoking, presence of diabetes mellitus, or the number of diseased coronary
vessels. However, it did not include a reduction in repeat revascularization
procedures, suggesting no reduction in restenosis.
PMID: 9723624 [PubMed - indexed for MEDLINE]
-
-
Estrogen replacement therapy after coronary
angioplasty in women.
O'Keefe JH Jr, Kim SC, Hall RR, Cochran VC, Lawhorn
SL, McCallister BD.
Mid America Heart Institute, St. Luke's Hospital, Kansas City, Missouri,
USA.
OBJECTIVES: The purpose of this study was to assess the effects of estrogen
replacement therapy on long-term outcome, including restenosis, myocardial
infarction, stroke and death after a first percutaneous transluminal coronary
angioplasty (PTCA) procedure, in postmenopausal women. BACKGROUND: Observational
and epidemiologic studies, basic laboratory research and clinical trials
consistently suggest that estrogen replacement therapy is associated with
beneficial cardiovascular effects in women. These cardioprotective actions
may be particularly relevant to women with coronary artery disease, such
as those who have undergone PTCA. METHODS: This was a retrospective study
that included 337 women who underwent elective PTCA between 1982 and 1994.
The treatment group consisted of 137 consecutive women receiving long-term
estrogen therapy at the time of elective PTCA and during follow-up. The control
group comprised 200 women who were computer-matched with the estrogen group.
The mean follow-up period was 65 +/- 35 months. RESULTS: Actuarial survival
was superior in the estrogen group; the 7-year survival rate was 93% for
the estrogen group versus 75% for the control group (p = 0.001). The cardiovascular
event rate (death, nonfatal myocardial infarction or nonfatal stroke) was
significantly lower in the estrogen group at 7 years (12% vs. 35% in the
control group, p = 0.001). The need for subsequent revascularization during
follow-up was similar in the two groups. Multivariable analysis identified
diabetes, estrogen therapy (adjusted risk ratio 0.38, 95% confidence interval
0.19 to 0.79) and left ventricular ejection fraction < 40% as independent
correlates of cardiovascular death or myocardial infarction during follow-up.
CONCLUSIONS: Estrogen replacement therapy was associated with an improved
long-term outcome after PTCA in postmenopausal women.
PMID: 8996287 [PubMed - indexed for MEDLINE]
-
-
Effect on survival of estrogen replacement
therapy after coronary artery bypass grafting.
Sullivan JM, El-Zeky F, Vander Zwaag R, Ramanathan KB.
Division of Cardiovascular Diseases, The University of Tennessee, Memphis
38163, USA.
We examined the relation between postmenopausal estrogen placement therapy
(ERT) and survival in 1,098 women who underwent coronary artery bypass grafting
(CABG). Patients were selected for the study if their age was > or = 55
years at the time of preoperative coronary angiography or if they had previously
undergone bilateral oophorectomy. Life-table analysis was used to compare
survival after surgery in 92 women who received ERT and 1,006 women who did
not. Five-year survival was 98.8% in the estrogen users and 82.3% in the
non-users. Ten-year survival was 81.4% in the users and 65.1% in the nonusers
(p = 0.0001 by Lee Desu test). The women who did not take estrogen were significantly
older (p < 0.001), had more vessels with significant stenosis (p = 0.033),
lower ejection fractions (p = 0.051), and more prior myocardial infarctions
(p = 0.054). However, a Cox proportional-hazards model selected the number
of coronary arteries narrowed (RR 1.43, p < 0.0001), estrogen use (RR
0.38, p = 0.001), left main coronary stenosis (RR 1.83, p = 0.001), and diabetes
mellitus (RR 1.57, p = 0.003) as the significant independent predictors of
survival. These data suggest that ERT improves survival significantly after
CABG in postmenopausal women with coronary artery disease.
PMID: 9104892 [PubMed - indexed for MEDLINE]
-
Comment in:
Randomized trial of estrogen plus progestin for secondary
prevention of coronary heart disease in postmenopausal women. Heart and
Estrogen/progestin Replacement Study (HERS) Research Group.
Hulley S, Grady D, Bush T, Furberg C, Herrington D,
Riggs B, Vittinghoff E.
University of California, San Francisco 94143, USA.
CONTEXT: Observational studies have found lower rates of coronary heart disease
(CHD) in postmenopausal women who take estrogen than in women who do not,
but this potential benefit has not been confirmed in clinical trials. OBJECTIVE:
To determine if estrogen plus progestin therapy alters the risk for CHD events
in postmenopausal women with established coronary disease. DESIGN: Randomized,
blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient
and community settings at 20 US clinical centers. PARTICIPANTS: A total of
2763 women with coronary disease, younger than 80 years, and postmenopausal
with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625
mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate
in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383).
Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment
were taking it at the end of 1 year, and 75% at the end of 3 years. MAIN
OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal myocardial
infarction (MI) or CHD death. Secondary cardiovascular outcomes included
coronary revascularization, unstable angina, congestive heart failure, resuscitated
cardiac arrest, stroke or transient ischemic attack, and peripheral arterial
disease. All-cause mortality was also considered. RESULTS: Overall, there
were no significant differences between groups in the primary outcome or
in any of the secondary cardiovascular outcomes: 172 women in the hormone
group and 176 women in the placebo group had MI or CHD death (relative hazard
[RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall
effect occurred despite a net 11% lower low-density lipoprotein cholesterol
level and 10% higher high-density lipoprotein cholesterol level in the hormone
group compared with the placebo group (each P<.001). Within the overall
null effect, there was a statistically significant time trend, with more
CHD events in the hormone group than in the placebo group in year 1 and fewer
in years 4 and 5. More women in the hormone group than in the placebo group
experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58)
and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were
no significant differences in several other end points for which power was
limited, including fracture, cancer, and total mortality (131 vs 123 deaths;
RH, 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of
4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone
acetate did not reduce the overall rate of CHD events in postmenopausal women
with established coronary disease. The treatment did increase the rate of
thromboembolic events and gallbladder disease. Based on the finding of no
overall cardiovascular benefit and a pattern of early increase in risk of
CHD events, we do not recommend starting this treatment for the purpose of
secondary prevention of CHD. However, given the favorable pattern of CHD
events after several years of therapy, it could be appropriate for women
already receiving this treatment to continue.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 9718051 [PubMed - indexed for MEDLINE]
-
-
Design of the Women's Health Initiative
clinical trial and observational study. The Women's Health
Initiative Study Group.
The Women's Health Initiative (WHI) is a large and complex clinical investigation
of strategies for the prevention and control of some of the most common causes
of morbidity and mortality among postmenopausal women, including cancer,
cardiovascular disease, and osteoporotic fractures. The WHI was initiated
in 1992, with a planned completion date of 2007. Postmenopausal women ranging
in age from 50 to 79 are enrolled at one of 40 WHI clinical centers nationwide
into either a clinical trial (CT) that will include about 64,500 women or
an observational study (OS) that will include about 100,000 women. The CT
is designed to allow randomized controlled evaluation of three distinct interventions:
a low-fat eating pattern, hypothesized to prevent breast cancer and colorectal
cancer and, secondarily, coronary heart disease; hormone replacement therapy,
hypothesized to reduce the risk of coronary heart disease and other cardiovascular
diseases and, secondarily, to reduce the risk of hip and other fractures,
with increased breast cancer risk as a possible adverse outcome; and calcium
and vitamin D supplementation, hypothesized to prevent hip fractures and,
secondarily, other fractures and colorectal cancer. Overall benefit-versus-risk
assessment is a central focus in each of the three CT components. Women are
screened for participation in one or both of the components--dietary modification
(DM) or hormone replacement therapy (HRT)--of the CT, which will randomize
48,000 and 27,500 women, respectively. Women who prove to be ineligible for,
or who are unwilling to enroll in, these CT components are invited to enroll
in the OS. At their 1-year anniversary of randomization, CT women are invited
to be further randomized into the calcium and vitamin D (CaD) trial component,
which is projected to include 45,000 women. The average follow-up for women
in either CT or OS is approximately 9 years. Concerted efforts are made to
enroll women of racial and ethnic minority groups, with a target of 20% of
overall enrollment in both the CT and OS. This article gives a brief description
of the rationale for the interventions being studied in each of the CT components
and for the inclusion of the OS component. Some detail is provided on specific
study design choices, including eligibility criteria, recruitment strategy,
and sample size, with attention to the partial factorial design of the CT.
Some aspects of the CT monitoring approach are also outlined. The scientific
and logistic complexity of the WHI implies particular leadership and management
challenges. The WHI organization and committee structure employed to respond
to these challenges is also briefly described.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 9492970 [PubMed - indexed for MEDLINE.
-
The evolution of the Women's Health Initiative:
perspectives from the NIH.
Rossouw JE, Finnegan LP, Harlan WR, Pinn VW, Clifford
C, McGowan JA.
The Women's Health Initiative (WHI) addresses some of the major health concerns
of postmenopausal women. It is designed to test whether long-term preventive
measures will decrease the incidence of cardiovascular disease, certain cancers,
and fractures, and it seeks to find better predictors of future health and
disease in older women. This report traces the evolution of the clinical
trial and observational study (CT/OS) components of WHI from early planning
in the 1980s to the current status of the WHI CT/OS as an integrated, ongoing
clinical study. Particular attention is directed to the antecedent planning
meetings and feasibility studies that formed the underpinnings of the WHI.
The issues of hormone replacement therapy and of the optimal diet for postmenopausal
women were investigated for almost a decade prior to WHI. However, no studies
of sufficient size and duration to confidently test the value and risks of
these approaches were initiated because of the cost and insufficient political
commitment. The initiation of WHI in 1991 represents the confluence of scientific
need and capability with the social priorities to improve the health and
welfare of women.
PMID: 7722207 [PubMed - indexed for MEDLINE]
-
Hormone replacement therapy and cardiovascular
disease: the case for a randomized controlled trial.
Vickers MR, Meade TW, Wilkes HC.
MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine,
St Bartholomew's Hospital Medical College, London, UK.
The menopause is associated with an increased risk of developing cardiovascular
disease. Oestrogen may influence various metabolic pathways which contribute
to the pathogenesis of cardiovascular disease, and observational studies
suggest that in postmenopausal women oral oestrogen replacement therapy confers
some protection against coronary heart disease and to a lesser extent against
stroke. What is not clear is the magnitude of the cardioprotective effect
and the overall balance of long-term benefits and hazards. Research is also
required to establish the relative effects of oestrogen replacement therapy
and combined or opposed hormone replacement therapy (HRT) where progestogen
is added to counter the proliferative action of oestrogen on the endometrium.
A large randomized controlled trial is the only way to provide accurate estimates
of the cardioprotective effect of HRT and of other long-term benefits and
hazards. Feasibility studies undertaken through the UK Medical Research Council
(MRC) General Practice Research Framework show that such a trial is acceptable
to patients and their doctors. Recruitment and withdrawal rates indicate
that a trial of sufficient size to show a 25% reduction in cardiovascular
disease with 90% power at the 1% level would be feasible. The full trial
is costly and it is proposed that the UK collaborates with other countries
in a major international trial to complement the Women's Health Initiative
trial in the USA. Feasibility studies in Europe are underway, the design
and scientific rationale for the trial have been approved by the UK MRC and
it is hoped that recruitment to the full-scale trial can begin soon.
Publication Types:
PMID: 8582195 [PubMed - indexed for MEDLINE]
-
Comment in:
Venous thromboembolic disease and combined oral contraceptives:
results of international multicentre case-control study. World Health Organization
Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.
The composition and use of oral contraceptives (OCs) have changed since their
cardiovascular side-effects were established 20 years ago. This report describes
the risk of idiopathic venous thromboembolic (VTE) events (deep vein thrombosis
[DVT] and/or pulmonary embolism [PE]) in association with current use of
combined OCs among 1143 cases aged 20-44 and 2998 age-matched controls, as
evaluated in a hospital-based, case-control study in 21 centres in Africa,
Asia, Europe, and Latin America. OC use was associated with an increased
risk of VTE in Europe (odds ratio 4.15 [95% CI 3.09-5.57]) and in non-European
("developing") countries (3.25 [2.59-4.08]). Risk estimates were
generally higher for DVT than for PE but no consistent trend by certainty
of diagnosis (definite, probable, possible) was found. Increased risk was
apparent within 4 months of starting OCs, was unaffected by duration of current
episode of OC use, and had disappeared within 3 months of stopping OCs. Relative
risk estimates of VTE associated with OC use were unaffected by age of user,
by history of hypertension (excluding hypertension in pregnancy), or in any
consistent way by smoking. However, in both groups of countries increased
body mass index (BMI) was an independent risk factor for VTE, and OC-associated
odds ratios were higher among those with a BMI above 25 kg/m2 than among
those with smaller BMIs. OC-associated risk estimates were high among women
in Europe with a history of hypertension in pregnancy. Odds ratios associated
with the use of OCs containing a third-generation progestagen were higher
than those observed with progestagens of the first (norethindrone type) and
second (norgestrel group) generation. Odds ratios associated with first and
second generation progestagens tended to be lower, though not significantly,
when used in combination with low (< 50 micrograms oestrogen) rather than
higher oestrogen doses. This study confirms an association between OC use
and VTE in Europe and the developing countries, although overall risk estimates
associated with use were lower than demonstrated in most previous studies
of non-fatal idiopathic VTE.
Publication Types:
PMID: 7500748 [PubMed - indexed for MEDLINE]
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Estrogen and progestin components of oral
contraceptives: relationship to vascular disease.
Carr BR, Ory H.
UT Southwestern Medical Center at Dallas, Department of Obstetrics and Gynecology
75235-9032, USA.
Recently, new information has been published about: a) the relationship between
combination oral contraceptives (OCs), estrogen dose, cigarette smoking,
and the risk of myocardial infarction (MI) and stroke; and b) the effect
of different progestins on the risk of venous thromboembolism (VTE). We review
the epidemiologic data. Regardless of age, in the absence of smoking, use
of sub-50 micrograms OCs is not associated with any meaningful increase in
risk of MI or stroke. If the small, statistically nonsignificant elevations
in risk for these diseases are assumed (for the sake of argument) to be causal,
then the incidence of MI and stroke associated with use of OCs containing
less than 50 micrograms ethinyl estradiol (EE) would be approximately 2 per
100,000 per year. For women less than 35 years of age who do not smoke or
do not have a history of hypertension, the risk would be even lower. Any
woman over the age of 35 who smokes should be advised to use a non-estrogen
or nonhormonal contraceptive. There are now two reports, from jick et al.
and Lewis et al., that demonstrate that the relative risk of MI is certainly
no greater for users of OCs containing desogestrel or gestodene than for
users of OCs containing older progestins. In fact, both show reduced relative
risks for the newer progestins compared to the older ones. With respect to
progestins, four recent epidemiologic studies have indicated a twofold increased
risk of nonfatal VTE with use of OCs containing desogestrel or gestodene
compared with levonorgestrel. A fifth report, which showed an increased relative
risk for norgestimate, is based on use among only 19 cases and 31 controls
and is not statistically significant. As the authors themselves caution and
as subsequent follow-up analyses and editorials conclude, these studies do
not provide evidence for a cause-and-effect relationship between OCs containing
desogestrel or gestodene, and VTE. The recommendation with respect to desogestrel-
and gestodene-containing OCs is that no change in prescribing practices is
warranted for either current or new-start patients. There is a growing body
of evidence demonstrating that OCs containing 30 or 35 micrograms of EE have
lower risks of MI, stroke, and VTE than higher dose OCs. However, there is
no epidemiologic study that demonstrates a greater risk of vascular events
among women using OCs containing 30 or 35 micrograms EE compared with preparations
containing 20 micrograms EE. Users of sub-50 micrograms OCs of any age have
no clinically meaningful increase in incidence of MI or stroke compared with
non-OC users. This is also true for smokers under the age of 35 years who
use OCs. However, smokers over the age of 35 years who use OCs still have
an unacceptably high incidence rate of MI and stroke and should not use combination
OCs. Sub-50 micrograms OCs of all types are associated with a small excess
risk of VTE, about 15 per 100,000 events per year. Until there is biologic
explanation of the twofold greater risk of VTE in users of OCs containing
desogestrel or gestodene compared with users of those containing older progestins,
this association should not be accepted as one of cause and effect.
Publication Types:
PMID: 9220222 [PubMed - indexed for MEDLINE]
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Comment in:
Risk of venous thromboembolism in users of hormone replacement
therapy.
Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh
S.
University of Oxford, Department of Public Health and Primary Care, Radcliffe
Infirmary, UK.
BACKGROUND: The association between current use of oral contraceptives and
increased risk of venous thromboembolism (VTE) has been firmly established.
Although data-sheets for hormone replacement therapy (HRT) carry similar
warnings as regards VTE, evidence of an association is inconclusive. We carried
out a hospital-based case-control study to investigate whether current use
of HRT is associated with VTE. METHODS: We screened all women aged 45-64
years admitted to hospitals in the area of the Oxford Regional Health Authority
with a suspected diagnosis of VTE between February, 1993, and December, 1994.
We recruited 81 cases of idiopathic VTE and 146 hospital controls with disorders
of eyes, skin, ears, respiratory and alimentary tracts, kidneys, bones, and
joints, and trauma; controls were matched to cases for age-group and date
and district of admission. To increase the study power, an additional 22
cases of idiopathic VTE and 32 hospital controls admitted before February,
1993, were recruited retrospectively. Participants were questioned about
medical and gynaecological history, use of oral contraceptives and HRT, use
of other drugs within the previous 3 months, and lifestyle and socioeconomic
characteristics. Detailed diagnostic data were extracted from the notes of
eligible cases. Matched analyses, adjusted for body-mass Index, socioeconomic
group, and history of varicose veins, were undertaken by conditional logistic
regression. FINDINGS: 44 (42.7%) cases and 44 (24.7%) controls were current
users of HRT. The adjusted odds ratio for VTE in current users of HRT compared
with non-users (never-users and past users combined) was 3.5 (95% CI 1.8-7.0;
p < 0.001). No association was found with past use, and risk appeared
to be highest among short-term current users (adjusted likelihood ratio test
of trend in odds ratios across different durations of current use, p = 0.011).
INTERPRETATION: Current HRT use is associated with risk of VTE. The increased
risk may be concentrated in new users. The number of extra cases appears
to be only about one in 5000 users per year. These findings need to be weighed
against the probable benefits of long-term treatment, including reductions
in risks of osteoporotic fracture and coronary heart disease, and the probable
modest increase in risk of breast cancer.
PMID: 8855852 [PubMed - indexed for MEDLINE]
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Comment in:
Risk of hospital admission for idiopathic venous thromboembolism
among users of postmenopausal oestrogens.
Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM.
Boston Collaborative Drug Survelliance Program, Boston University Medical
Center, Lexington, MA 02173, USA.
BACKGROUND: At the request of researchers in the UK, we conducted a case-control
study to explore the relation between use of postmenopausal oestrogen hormone
replacement therapy (HRT) and idiopathic venous thromboembolism (VTE). METHODS:
The study was based on information derived from Group Health Cooperative
of Puget Sound for the period 1980 to 1994. Women aged 50-74 years admitted
to hospital for idiopathic VTE were identified from hospital records. The
diagnosis of idiopathic VTE was validated from the clinical record. Women
who had medical conditions predisposing to VTE (a history of VTE or cancer,
recent trauma, or surgery) were excluded as cases. Four control subjects
matched to each case by age, duration of Cooperative membership, and calendar
time were identified from the base population. Various potential risk factors
were recorded based on record review. FINDINGS: An initial analysis of 42
cases and 168 matched controls yielded a matched relative risk estimate of
3.6 (95% CI 1.6-7.8) for current users of oestrogens compared with non-users.
There was a substantial effect of daily oestrogen dose. The matched relative
risk estimates for oestrogen users of 0.325 mg, 0.625 mg, and 1.25 mg or
more daily were 2.1, 3.3, and 6.9, respectively. Body-mass index was independently
associated with the risk of VTE but did not materially confound the relation
of oestrogen and VTE. The absolute risk of idiopathic VTE is estimated to
be low (0.9 x 10(-4) woman-years) in non-users of oestrogen; the risk in
current users is estimated at 3.2 x 10(-4) woman-years. INTERPRETATION: The
risk of idiopathic VTE is about three times higher among current users of
replacement oestrogens than among non-users. However, the absolute risk is
low for both groups and accounts for only a modest increase in morbidity.
PMID: 8855853 [PubMed - indexed for MEDLINE]
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Comment in:
Prospective study of exogenous hormones and risk of
pulmonary embolism in women.
Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz
GA, Speizer FE, Willett WC, Hennekens CH.
Channing Laboratory, Boston, MA 02115, USA.
BACKGROUND: Current use of oral contraceptives (OCs) is a well-recognised
risk factor for venous thrombosis and consequent pulmonary embolism (PE).
Little is known about residual effects of past OC use. Furthermore, few epidemiological
studies have assessed the relation between postmenopausal use of hormones
and thrombotic disease. METHODS: In this prospective study information was
obtained through questionnaires sent every 2 years (1976-92) to 1125,93 women
aged 30-55 in 1976. We excluded women with previously diagnosed cardiovascular
disease or cancer in 1976 and at the beginning of each subsequent 2-year
follow-up period. FINDINGS: From self-reports and medical records, we documented
123 cases of primary PE (no identified antecedent cancer, trauma, surgery,
or immobilisation). Current users of postmenopausal hormones had an increased
risk of primary PE (relative risk adjusted for multiple risk factors 2.1
[95% CI 1.2-3.8]). However, past use showed no relation to PE (1.3 [0.7-2.4]).
In current users of OCs the risk of primary PE was about twice that in non-users
(2.2 [0.8-5.9]), but this finding was based on only five cases who were current
OC users. Users of OCs in the past had no increase in risk of PE (0.8 [0.5-1.2]).
These relations were consistent irrespective of cigarette-smoking status.
INTERPRETATION: Primary PE was uncommon in this cohort. The risk was increased
by current though not past use of postmenopausal hormones or OCs.
PMID: 8855854 [PubMed - indexed for MEDLINE]
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-
Hormone replacement therapy and risk of
venous thromboembolism: population based case-control study.
Perez Gutthann S, Garcia Rodriguez LA, Castellsague
J, Duque Oliart A.
Novartis Pharmaceuticals, Medical Department, Barcelona, Spain.
OBJECTIVE: To evaluate the association between use of hormone replacement
therapy and the risk of idiopathic venous thromboembolism. DESIGN: Population
based case-control study. SETTING: Population enrolled in the General Practice
Research Database, United Kingdom. SUBJECTS: A cohort of 347,253 women aged
50 to 79 without major risk factors for venous thromboembolism was identified.
Cases were 292 women admitted to hospital for a first episode of pulmonary
embolism or deep venous thrombosis; 10,000 controls were randomly selected
from the source cohort. MAIN OUTCOME MEASURES: Adjusted relative risks estimated
from unconditional logistic regression. RESULTS: The adjusted odds ratio
of venous thromboembolism for current use of hormone replacement therapy
compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This
increased risk was restricted to first year users, with odds ratios of 4.6
(2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months
after starting treatment. No major risk differences were observed between
users of low and high doses of oestrogens, unopposed and opposed treatment,
and oral and transdermal preparations. The risk of idiopathic venous thromboembolism
among non-users of replacement therapy was estimated to be 1.3 per 10,000
women per year. Among current users, idiopathic venous thromboembolism occurs
at two to three times the rate in non-users, resulting in one to two additional
cases per 10,000 women per year. CONCLUSIONS: Current use of hormone replacement
therapy was associated with a higher risk of venous thromboembolism, although
the risk seemed to be restricted to the first year of use.
PMID: 9081000 [PubMed - indexed for MEDLINE
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Comment in:
Hormone replacement therapy and the risk of hospitalization
for venous thromboembolism: a population-based study in southern Europe.
Varas-Lorenzo C, Garcia-Rodriguez LA, Cattaruzzi C,
Troncon MG, Agostinis L, Perez-Gutthann S.
Global Pharmacoepidemiology, Clinical Development and Regulatory Affairs,
Novartis Pharmaceuticals, Barcelona, Spain.
The authors evaluated the risk of venous thromboembolism associated with
hormone replacement therapy in a cohort of 265,431 women aged 45-79 years
who did not have major risk factors for venous thromboembolism. Through review
of hospital charts, 171 cases were confirmed (pulmonary embolism = 77; deep
venous thrombosis = 94). Ten thousand controls were randomly sampled. The
risk of venous thromboembolism among nonusers of hormone replacement therapy
was 1.3 per 10,000 women per year. Current users of hormone replacement therapy
had 2.3 times higher risk of venous thromboembolism (95 percent confidence
interval 1.0-5.3) compared with nonusers. The increased risk was restricted
to the first year of treatment.
PMID: 9508106 [PubMed - indexed for MEDLINE]
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Comment in:
Postmenopausal hormone therapy increases risk for venous
thromboembolic disease. The Heart and Estrogen/progestin Replacement Study.
Grady D, Wenger NK, Herrington D, Khan S, Furberg C,
Hunninghake D, Vittinghoff E, Hulley S.
University of California, San Francisco, 94105, USA.
BACKGROUND: Oral contraceptive use increases risk for venous thromboembolism,
but data on the effect of postmenopausal hormone therapy are limited. OBJECTIVE:
To determine the effect of therapy with estrogen plus progestin on risk for
venous thromboembolic events in postmenopausal women. DESIGN: Randomized,
double-blind, placebo-controlled trial. SETTING: 20 clinical centers in the
United States. PARTICIPANTS: 2763 postmenopausal women younger than 80 years
of age (mean age, 67 years) who had coronary heart disease but no previous
venous thromboembolism and had not had a hysterectomy. INTERVENTION: Conjugated
equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in
one tablet (n = 1380) or placebo that was identical in appearance (n = 1383).
MEASUREMENTS: Documented deep venous thrombosis or pulmonary embolism. RESULTS:
During an average of 4.1 years of follow-up, 34 women in the hormone therapy
group and 13 in the placebo group experienced venous thromboembolic events
(relative hazard, 2.7 [95% CI, 1.4 to 5.0] [P = 0.003]; excess risk, 3.9
per 1000 woman-years [CI, 1.4 to 6.4 per 1000 woman-years]; number needed
to treat for harm, 256 [CI, 157 to 692]). In multivariate analysis, the risk
for venous thromboembolism was increased among women who had lower-extremity
fractures (relative hazard, 18.1 [CI, 5.4 to 60.4]) or cancer (relative hazard,
3.9 [CI, 1.6 to 9.4]) and for 90 days after inpatient surgery (relative hazard,
4.9 [CI, 2.4 to 9.8]) or nonsurgical hospitalization (relative hazard, 5.7
[CI, 3.0 to 10.8]). Risk was decreased with aspirin (relative hazard, 0.5
[CI, 0.2 to 0.8]) or statin use (relative hazard, 0.5 [CI, 0.2 to 0.9]).
CONCLUSIONS: Postmenopausal therapy with estrogen plus progestin increases
risk for venous thromboembolism in women with coronary heart disease. This
risk should be considered when the risks and benefits of therapy are being
weighed.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 10787361 [PubMed - indexed for MEDLINE]
21. Wenger NK. Cardiovascular disease in menopausal women:
the benefits of HRT are not restricted to improving lipid profiles. Medicographica
1999; 21: 223–228.
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