Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy

Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)

Author Information <http://jama.ama-assn.org/issues/v288n1/ffull/#aainfo>
Deborah Grady, MD, MPH; David Herrington, MD, MHS; Vera Bittner, MD; Roger
Blumenthal, MD; Michael Davidson, MD; Mark Hlatky, MD; Judith Hsia, MD;
Stephen Hulley, MD, MPH; Alan Herd, MD; Steven Khan, MD; L. Kristin Newby,
MD; David Waters, MD; Eric Vittinghoff, PhD; Nanette Wenger, MD; for the
HERS Research Group
Context  The Heart and Estrogen/progestin Replacement Study (HERS) found no
overall reduction in risk of coronary heart disease (CHD) events among
postmenopausal women with CHD. However, in the hormone group, findings did
suggest a higher risk of CHD events during the first year, and a decreased
risk during years 3 to 5.
Objective  To determine if the risk reduction observed in the later years of
HERS persisted and resulted in an overall reduced risk of CHD events with
additional years of follow-up.
Design and Setting  Randomized, blinded, placebo-controlled trial of 4.1
years' duration (HERS) and subsequent unblinded follow-up for 2.7 years
(HERS II) conducted at outpatient and community settings at 20 US clinical
centers.
Participants  A total of 2763 postmenopausal women with CHD and average age
of 67 years at enrollment in HERS; 2321 women (93% of those surviving)
consented to follow-up in HERS II.
Intervention  Participants were randomly assigned to receive 0.625 mg/d of
conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380),
or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed
at personal physicians' discretion during HERS II. The proportions with at
least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6)
in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the
placebo group.
Main Outcome Measures  The primary outcome was nonfatal myocardial
infarction and CHD death. Secondary cardiovascular events were coronary
revascularization, hospitalization for unstable angina or congestive heart
failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient
ischemic attack, and peripheral arterial disease.
Results  There were no significant decreases in rates of primary CHD events
or secondary cardiovascular events among women assigned to the hormone group
compared with the placebo group in HERS, HERS II, or overall. The unadjusted
relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence
interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall,
0.99 (0.84-1.17). The overall RHs were similar after adjustment for
potential confounders and differential use of statins between treatment
groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women
who were adherent to randomized treatment assignment (RH, 0.96; 95% CI,
0.77-1.19).
Conclusions  Lower rates of CHD events among women in the hormone group in
the final years of HERS did not persist during additional years of
follow-up. After 6.8 years, hormone therapy did not reduce risk of
cardiovascular events in women with CHD. Postmenopausal hormone therapy
should not be used to reduce risk for CHD events in women with CHD.
JAMA. 2002;288:49-57
JOC20521
The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized,
blinded, placebo-controlled trial of the effect of 0.625 mg of conjugated
estrogens plus 2.5 mg of medroxyprogesterone acetate daily on coronary heart
disease (CHD) event risk among 2763 postmenopausal women with documented
CHD. 1 <http://jama.ama-assn.org/issues/v288n1/ffull/#r1>  Overall, during
4.1 years of follow-up, there were no significant differences between the
hormone and placebo groups in the primary outcome of CHD events (nonfatal
myocardial infarction [MI] plus CHD-related death) or in any secondary
cardiovascular outcomes. 2-5
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2>  However, post-hoc
analyses showed a statistically significant time trend, with more CHD events
in the hormone group than in the placebo group during the first year of
treatment, and fewer in years 3 to 5. 2
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2>  HERS investigators
speculated that early increased risk might be due to a prothrombotic,
proarrhythmic, or proischemic effect of treatment that is gradually
outweighed by a beneficial effect on the progression of underlying
atherosclerosis mediated by the observed favorable changes in low- and
high-density lipoprotein cholesterol. 2
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2>
The apparent pattern of early increase and later decrease in CHD events led
to the recommendation that women with CHD should not start treatment with
hormones for the purpose of preventing CHD events, but that those who were
already taking hormones could continue. Women enrolled in HERS tended to
follow this advice. Many of those randomized to hormones during the trial
continued with open-label treatment prescribed by their personal physicians
and most randomized to placebo elected not to start hormones. This provided
an opportunity to continue outcome surveillance for several years
(designated as HERS II) while many women remained on the regimen to which
they had been randomized.
This article presents cardiovascular outcomes during a total of 6.8 years of
observation to examine whether longer-duration postmenopausal hormone
therapy resulted in a reduced risk of CHD events among women with documented
CHD. A companion article 6
<http://jama.ama-assn.org/issues/v288n1/ffull/#r6>  examines the effects of
treatment on noncardiovascular outcomes.



METHODS



Study Participants

The design, methods, baseline findings, 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1>  and main outcomes 2
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2>  of HERS have been
published. Participants were postmenopausal women younger than 80 years with
no prior hysterectomy and a history of at least one of the following: MI,
coronary artery bypass graft surgery, percutaneous angioplasty, or more than
50% angiographic narrowing of a coronary artery. Women were randomly
assigned to 0.625 mg/d of conjugated estrogens plus 2.5 mg of
medroxyprogesterone acetate or to identical placebo.
At the end of the trial, in August 1998, participants were informed of their
treatment assignment and the main trial results. Participants assigned to
placebo were advised by HERS investigators not to start hormone therapy for
the purpose of preventing CHD events, given the observation of an early
increased risk and no overall cardiovascular benefit. Participants assigned
to hormone therapy were advised that it might be appropriate to continue
therapy because there was some evidence that CHD event risk was reduced
during years 3 to 5 of follow-up. HERS investigators recommended that all
participants make their decisions about postmenopausal hormone therapy with
their personal physician.
Clinical sites obtained institutional review board approval for continued
observation of the cohort. All surviving participants were asked to enroll
in follow-up, and those who agreed signed a new informed consent document.
Baseline and Follow-up

At baseline in HERS, we obtained information on demographics, reproductive
and health history, risk factors for CHD, quality of life, and medication
use. Participants underwent physical examination including breast and pelvic
examinations with Papanicolaou tests and endometrial evaluations, screening
mammography, standardized 12-lead electrocardiograms (ECGs), and measurement
of fasting lipoprotein cholesterol levels. 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1>
During HERS, participants visited the clinic every 4 months to receive study
medication and for ascertainment of cardiovascular and other events, adverse
effects, and study medication adherence. Annually and at the final HERS
visit, which took place an average of 4 months before enrollment in HERS II,
all baseline measures except demographics and health history were repeated.
During HERS II, participants were telephoned at 4-month intervals and asked
about cardiovascular and other outcomes using the same questions used during
HERS visits. They were also asked about use of hormones, selective
estrogen-receptor modulators, beta-blockers, aspirin, and lipid-lowering
medications.
Telephone contacts were comparable in the randomized groups. The proportion
of the 12-month telephone calls in HERS II that were completed, expressed as
a percentage of those alive, was 92% in women randomized to hormones and 92%
in those randomized to placebo. The proportion of telephone calls that took
place within a window of 2 weeks of the target date was 62% for the hormone
group and 61% for the placebo group and 99.2% and 98.9% of surviving women
were successfully contacted at the end of HERS II, respectively.
Outcomes

The primary outcomes of HERS and HERS II were CHD events (CHD death and
nonfatal MI). A CHD death included documented fatal MI, sudden death within
1 hour of onset of symptoms, unobserved death that occurred out of the
hospital in the absence of other known cause, and death due to coronary
revascularization or congestive heart failure. The diagnosis of nonfatal MI
was based on an algorithm that included ischemic symptoms, ECG
abnormalities, and elevated cardiac enzyme levels. 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1>  Other adjudication
criteria have been described. 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1> , 2
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2>  The only change in these
criteria for HERS II was that we discontinued routine ECGs that had been
collected at each annual visit in HERS. This meant that we were unable to
detect silent MIs in HERS II, a change unlikely to affect findings since
only 4% of the MIs in HERS were silent. 7
<http://jama.ama-assn.org/issues/v288n1/ffull/#r7>  Secondary cardiovascular
outcomes included coronary artery bypass graft surgery, percutaneous
coronary revascularization, hospitalization for unstable angina or
congestive heart failure, nonfatal ventricular arrhythmia, sudden death,
stroke or transient ischemic attack, and peripheral arterial disease. 1-4
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1>
Documentation of clinical events was identical to that required in HERS.
When potential cardiovascular events were reported, hospital and other
records (including admission and discharge summaries, ECGs, reports of
relevant diagnostic tests, and next-of-kin and physician descriptions for
out-of-hospital deaths) were requested and independently reviewed by 2
physicians at the HERS coordinating center, who were unaware of randomized
treatment assignment in HERS or open-label hormone use during HERS II.
Classification of CHD events was based on the same criteria used in HERS and
required consensus of the reviewers or a third physician to resolve
discordant classifications.
In addition to questioning women or their next of kin about possible outcome
events and deaths at the 4-month telephone contacts, we also searched the
Social Security Death Index for notification of death for HERS participants
who did not enroll in HERS II, and for those enrolled in HERS II who did not
complete the final telephone contact. When a participant was listed as dead
on the Social Security Death Index, we obtained the death certificate.
Hospital records and other information pertaining to each possible CHD event
were collected with similar completeness in the 2 randomized groups. Among
HERS II women with a first nonfatal MI, the proportion with complete
information available on the 3 criteria (ECG, enzymes, and symptoms) was 98%
in women originally randomized to hormones and 98% in those randomized to
placebo.
Study Termination

HERS II follow-up was planned to continue for 4 years. Data were kept
confidential and reviewed annually by a small data review committee. We
planned to stop follow-up and send participants the results if conditional
power to detect an overall benefit in the group originally randomized to
hormones (compared with the placebo group) became very low. The decision to
terminate HERS II follow-up was made at the second annual review, and the
HERS executive committee subsequently agreed that no useful information was
likely to result from continuing HERS II follow-up to the end of the fourth
year. By the time all closeout visits were completed, average follow-up in
HERS II was 2.7 years.
Statistical Analyses

All data were entered, edited, and analyzed at the HERS coordinating center
at the University of California, San Francisco. We included all CHD events
that occurred before January 1, 2001, and all have been fully adjudicated.
Duration of observation was computed among women who remained alive until
the end of HERS II. The primary analyses are intention-to-treat and compare
the risk of CHD events during HERS, HERS II, and overall (HERS and HERS II)
among women assigned to hormone therapy with corresponding risk among women
assigned to placebo. These intention-to-treat analyses use an unadjusted Cox
proportional hazards model for time to first CHD event and categorize women
according to treatment assignment without regard to subsequent use of
open-label hormone therapy. For analyses of nonfatal outcomes, participants
were censored at the time of death, loss to follow-up, or at their HERS
closeout visit if they did not enroll in HERS II. All HERS participants not
known to be dead were assumed to be alive.
We repeated the overall and annual analyses adjusting for potential
confounders. Predictor variables included in the models were treatment
assignment, baseline values of the variables in Table 1
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t1.html>  that
independently predicted primary CHD events at P<.20 in a backward stepwise
model, and use of statin drugs during follow-up.
The effect of treatment was also estimated in adjusted as-treated analyses
in which women were censored 30 days after they became nonadherent to their
originally assigned treatment. During HERS, nonadherence was defined as
nonuse of study medication or use of open-label hormone therapy among women
assigned to placebo (oral or transdermal estrogen or estrogen plus
progestin) for 30 days or more. During HERS II, among women originally
assigned to hormone therapy, nonadherence was defined as nonuse of
open-label hormone therapy for 30 days or more. Among those assigned to
placebo, nonadherence in HERS II was defined as use of any open-label
hormone therapy for 30 days or more.



RESULTS



Enrollment and Follow-up

Of the 2763 women enrolled in HERS, 2510 were alive at the time of
enrollment in HERS II (1260 in the placebo group and 1250 in the hormone
group). Of these, 2321 (93%) agreed to enroll in HERS II (1165 in the
placebo group and 1156 in the hormone group) ( Figure 1
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_f1.html> ). At the
end of HERS II, closeout telephone contacts were completed for 99% of
surviving women in both the placebo and hormone groups. Of the 10 surviving
women enrolled in HERS II without a closeout contact, 5 (all in the placebo
group) were known to be alive at the end of follow-up. Vital status for the
other 5 women was not known, but they were not listed as dead in the Social
Security Death Index. Average duration of follow-up was 2.7 years in HERS II
and 6.8 years overall.
Characteristics of the HERS and HERS II participants did not differ between
treatment groups at the time of randomization in HERS ( Table 1
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t1.html> ).
Use of Hormone Therapy

Among women randomly assigned to hormone treatment in HERS, the proportion
reporting 80% or more adherence to hormones was 81% during year 1 and
declined to 45% during year 6 of follow-up. Among women assigned to placebo,
none reported taking open-label hormones during year 1 and 8% during year 6
( Figure 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_f2.html> ). During
HERS II, the majority (89%) of women taking hormones reported taking oral
conjugated estrogens of 0.625 mg/d with 86% taking the HERS study medication
(0.625 mg of conjugated estrogens plus 2.5 mg of medroxyprogesterone
acetate). The proportion of women who reported taking either raloxifene or
tamoxifen was 0% in both treatment groups during HERS, and 3% in the hormone
group and 4% in the placebo group by the final year of HERS II.
CHD Outcomes

There were no differences between women originally assigned to the hormone
and placebo groups in the rates of CHD events during HERS (relative hazard
[RH], 0.99; 95% confidence interval [CI], 0.81-1.22), HERS II (RH, 1.00; 95%
CI, 0.77-1.29), or overall (RH, 0.99; 95% CI, 0.84-1.17; Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t2.html> ).
Similarly, there were no significant differences between the randomized
groups during HERS, HERS II, or overall for CHD death, nonfatal MI, or any
of the other secondary cardiovascular outcomes except nonfatal ventricular
arrhythmia. In HERS II and overall, women originally assigned to hormone
therapy had a higher rate of nonfatal ventricular arrhythmia compared with
those assigned to placebo (HERS II RH, 3.30; 95% CI, 1.08-10.1; overall RH,
1.97; 95% CI, 1.10-3.53). During 6.8 years of follow-up, there were 132 CHD
deaths in the hormone group and 122 in the placebo group (sudden death, 67
and 69; MI, 27 and 24; congestive heart failure, 23 and 22;
revascularization, 7 and 2; and other CHD death, 8 and 5). There were no
statistically significant differences between HERS and HERS II in the RHs
for the effects of hormone therapy on any CHD event ( Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t2.html> ).
Risk for CHD Events by Year of Use

During the fifth and sixth through eighth years of overall observation, RHs
for CHD events among women randomly assigned to hormone therapy were 1.09
(95% CI, 0.71-1.66) and 0.99 (95% CI, 0.73-1.35; Table 3
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t3.html> ).
Overall, there was no trend toward lower RHs with longer duration of hormone
therapy (continuous trend in log RH, P = .18). In data-driven post-hoc
comparisons, there was weak evidence for heterogeneity in the year-specific
RHs for treatment (P = .09). The RH for the first year (1.52; 95% CI,
1.01-2.29) differed from the RH for the subsequent years combined (0.92; 95%
CI, 0.77-1.09; interaction P = .03).
Survival curves for primary CHD events ( Figure 3
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_f3.html> )
correspond to the findings in Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t2.html>  and Table
3 <http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t3.html> . The
curves diverged during the early years of follow-up in HERS when the rate of
CHD events was higher in the hormone than in the placebo-treated group. In
the later years of HERS, the curves crossed as the rate of CHD events in the
hormone group became lower than in the placebo group. During HERS II, the
curves for each outcome were essentially parallel (overall log rank, P =
.97).
Adjusted and per Protocol Analyses

There were no significant differences between the treatment groups during
HERS in use of aspirin, beta-blockers, angiotensin-converting enzyme
inhibitors, or selective estrogen-receptor modulators. More women in the
placebo group began treatment with lipid-lowering drugs, primarily statins,
during follow-up. By enrollment in HERS II, 61% of women in the placebo
group vs 54% in the hormone group reported statin use (P<.001). By the end
of follow-up in HERS II, the proportion of statin use was 67% for the
hormone group and 63% for the placebo group (P = .01). In secondary
analyses, we adjusted for this difference by including statin use as a
time-dependent covariate, and also for 15 potential baseline confounders
listed in Table 4
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t4.html> . The
results of these adjusted analyses were similar to those obtained from the
unadjusted intention-to-treat analyses (primary CHD events for HERS II, RH,
0.98; 95% CI, 0.75-1.22; and overall RH, 0.97; 95% CI, 0.82-1.14; Table 4
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t4.html> ). There
were also no substantial differences in the unadjusted and adjusted RHs for
CHD events in annual analyses. The results of these analyses were not
changed when use of selective estrogen-receptor modulators was added to the
adjusted models as a time-dependent covariate.
In secondary analyses, we adjusted for potential confounders and also
limited the analyses to women who were 80% or more adherent to the regimen
to which they were randomly assigned. In these as-treated analyses, the
overall RH was 0.96 (95% CI, 0.77-1.19), closely resembling the unadjusted
intention-to-treat estimate ( Table 4
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20521_t4.html> ). The
as-treated RH for primary CHD events in HERS II was 0.82, somewhat lower
than the unadjusted estimate of 1.00, and with a wider confidence interval
(95% CI, 0.52-1.32) because there were fewer CHD events. The as-treated
annual RHs varied substantially with no clear temporal pattern (continuous
trend in log RH, P = .09). As-treated analyses should be viewed with caution
because the treatment groups were not randomly assigned and only 73% of HERS
and 37% of HERS II CHD events are included.
Effect of Hormone Therapy With Statin and Aspirin Use

We stratified our overall intention-to-treat analyses by statin or aspirin
use during follow-up. For the entire 6.8 years of follow-up, the RH for CHD
events comparing the hormone with the placebo group among women not taking
statins was 1.12 (95% CI, 0.89-1.42), compared with 0.86 (95% CI, 0.69-1.08)
for women taking statins. Among women taking aspirin, the RH was 1.01 (95%
CI, 0.83-1.22) compared with 0.96 (95% CI, 0.70-1.31) among women not taking
aspirin. None of the differences between the RHs for statin or aspirin use
was significantly different and the results were similar in adjusted and
as-treated analyses.



COMMENT



One of the most important questions at the end of the 4.1-year HERS trial
was whether the lower rate of CHD events in the hormone group observed
during the final years of the trial indicated that clear cardiovascular
benefit would emerge with additional years of treatment. Data from this
report do not support this hypothesis. Intention-to-treat analyses based on
original treatment assignment, analyses adjusted for differences in the 2
treatment groups that developed over time, and analyses restricted to women
who continued their randomized treatment did not demonstrate any
cardiovascular benefit during 6.8 years of observation.
In other trials of antiatherosclerotic interventions, including diet,
niacin, and statin use, benefits observed during the first years of
treatment persisted or increased over time, even in the absence of continued
treatment. 8-10 <http://jama.ama-assn.org/issues/v288n1/ffull/#r8>  In 2.7
years of additional follow-up after HERS, we observed no cardiovascular
benefit of randomized treatment with hormone therapy, despite the fact that
about half of the women continued to take the originally assigned therapy.
Given the absence of overall long-term benefit of hormone therapy, there
remain important questions about the pattern of CHD events over time in HERS
and HERS II. The RH for CHD events in the hormone group was higher in the
first year of treatment and lower in the fourth year, but based on the
entire 6.8 years of follow-up, there was no trend over time (continuous
trend over time, P = .18). These results raise the possibility that the
early increase in risk of CHD events observed in HERS, as well as the
decrease in risk during years 3 to 5, may have occurred by chance. However,
in this post-hoc analysis, the relative risk in the first year of hormone
therapy is statistically higher than the average relative risk over the
remainder of follow-up in the intention-to-treat analysis (P = .03). Other
randomized trials have also reported an early increase in risk of CHD events
related to postmenopausal hormone therapy. 11
<http://jama.ama-assn.org/issues/v288n1/ffull/#r11>  Preliminary results
from the Women's Health Initiative randomized trial of the effect of hormone
therapy among 27 347 women, few of whom had CHD at the start of the trial,
revealed an increased risk of cardiovascular events during the first years
of follow-up among women treated with either estrogen alone or estrogen plus
a progestin. 11-13 <http://jama.ama-assn.org/issues/v288n1/ffull/#r11>  The
Coronary Drug Project secondary prevention trial found a similar pattern of
early increase in nonfatal MI and CHD death in men randomized to a high dose
of conjugated estrogens. 14
<http://jama.ama-assn.org/issues/v288n1/ffull/#r14>  Data from recent
observational studies also suggest a possible early increase in risk of CHD
events related to postmenopausal hormone therapy. 15
<http://jama.ama-assn.org/issues/v288n1/ffull/#r15> , 16
<http://jama.ama-assn.org/issues/v288n1/ffull/#r16>
An early increased risk for CHD events might be due to prothrombotic,
proinflammatory, or proarrhythmic effects of hormones. 17
<http://jama.ama-assn.org/issues/v288n1/ffull/#r17> , 18
<http://jama.ama-assn.org/issues/v288n1/ffull/#r18>  This risk may be
limited to the first few years of therapy if tolerance to the risk develops,
or if susceptible individuals experience CHD events and are removed from the
at-risk cohort. We explored multiple subgroups in HERS to determine if
certain women classified by age, prior manifestations of CHD, CHD risk
factors, medication use, or other factors, might be particularly at risk for
an early harm associated with hormone use. Among 86 subgroups evaluated for
effect modification, there was no clear evidence that early risk was limited
to specific subgroups. 19
<http://jama.ama-assn.org/issues/v288n1/ffull/#r19>  HERS substudies that
are ongoing will attempt to address possible effect modification by
proinflammatory and genetic factors, such as the prothrombin mutation
associated with higher risk of CHD among hypertensive women taking estrogen.
20 <http://jama.ama-assn.org/issues/v288n1/ffull/#r20>
We found an increased risk of nonfatal ventricular arrhythmia among women
assigned to hormone therapy in HERS II and overall. Most of these events
were ventricular arrhythmias that required resuscitation. The significance
of this finding is unclear since there was no associated increased risk of
sudden death, which is commonly due to ventricular arrhythmia in persons
with CHD.
Our power to detect a persistent or increasing cardiovascular benefit was
eroded by the progressively greater proportion of study participants who
crossed over between the hormone and placebo groups. However, there was no
convincing evidence of overall risk reduction in women who remained adherent
to their randomized treatment assignment. The most appropriate measure of
our power to detect a difference in risk of primary CHD events between the
treatment groups after 6.8 years of follow-up is the precision of the
adjusted overall RH for treatment of 0.97 (95% CI, 0.82-1.14). The CI
demonstrates that it is highly unlikely that we missed a true reduction in
CHD risk of 18% or greater.
The follow-up phase of HERS was unblinded, creating an opportunity for
unintended interventions, biased outcome ascertainment, or biased outcome
adjudication that could favor the placebo group. To minimize advice
regarding behaviors that might reduce CHD risk, such as diet and exercise,
all HERS staff were instructed not to discuss CHD risk reduction during HERS
II telephone contacts. There is no evidence that staff had more contact with
either group, as telephone contacts occurred with similar frequency in the 2
treatment groups. Women in the placebo group were somewhat more likely to be
prescribed lipid-lowering medication by their physicians in both HERS and
HERS II, which we attribute to higher low-density lipoprotein cholesterol
levels in the absence of estrogen treatment. In intention-to-treat analyses,
adjustment for this difference had only a trivial effect on the findings.
Biased outcome ascertainment is unlikely as follow-up was equally complete
in the 2 treatment groups and documentation of outcome events was similar.
Finally, biased outcome adjudication is unlikely, as outcome measures were
objective and were adjudicated blindly using the same criteria in HERS and
HERS II.
Randomized therapy in HERS consisted of 0.625 mg of oral conjugated
estrogens plus 2.5 mg of medroxyprogesterone acetate daily. The impact on
CHD risk associated with other types and doses of estrogen, or with
unopposed estrogen, remains uncertain. It has been suggested that the
addition of medroxyprogesterone acetate to the conjugated estrogen used in
HERS may have negated any cardiovascular benefit of estrogen. However,
results of the Estrogen Replacement and Atherosclerosis trial suggest that
unopposed estrogen is no more effective than estrogen plus
medroxyprogesterone acetate. 21
<http://jama.ama-assn.org/issues/v288n1/ffull/#r21>  Findings in the Women's
Estrogen for Stroke Trial, 22
<http://jama.ama-assn.org/issues/v288n1/ffull/#r22>  which compared
unopposed oral estradiol with placebo, mirrored the HERS result of no
overall benefit in either stroke or CHD outcomes. 3
<http://jama.ama-assn.org/issues/v288n1/ffull/#r3>  Thus, it seems unlikely
that the addition of a progestin or the type of estrogen accounts for our
findings.
Conclusions

HERS II was undertaken primarily to determine if the apparent decrease in
risk of CHD observed in the later years of the HERS trial persisted or
became more marked resulting in overall benefit. Follow-up of the HERS
cohort was extended to a total of almost 7 years. Despite the fact that
almost half of the women originally assigned to hormone therapy were still
taking hormones at the end of follow-up, there was no evidence of overall
benefit for any cardiovascular outcome. Our findings lend additional support
to recent recommendations that postmenopausal hormone therapy should not be
used for the purpose of reducing risk for CHD events in women with CHD. 23
<http://jama.ama-assn.org/issues/v288n1/ffull/#r23>



Author/Article Information


Author Affiliations: Departments of Epidemiology and Biostatistics (Drs
Grady, Hulley, and Vittinghoff) and Medicine (Dr Waters), University of
California, San Francisco; Department of Internal Medicine/Cardiology, Wake
Forest University School of Medicine, Winston-Salem, NC (Dr Herrington);
Division of Cardiovascular Disease, Department of Medicine, University of
Alabama, Birmingham (Dr Bittner); Division of Cardiology, Johns Hopkins
University School of Medicine, Baltimore, Md (Dr Blumenthal);
Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Dr Davidson);
Departments of Health Research and Policy, and of Medicine, Stanford
University School of Medicine, Palo Alto, Calif (Dr Hlatky); Department of
Medicine, George Washington University, Washington, DC (Dr Hsia); Division
of Cardiology, Cedars Sinai and UCLA School of Medicine, Los Angeles, Calif
(Dr Khan); Department of Medicine, Baylor College of Medicine, Houston, Tex
(Dr Herd); Duke Clinical Research Institute, Duke University School of
Medicine, Durham, NC (Dr Newby); and Department of Medicine, Emory
University School of Medicine, Atlanta, Ga (Dr Wenger).

Corresponding Author and Reprints: Deborah Grady, MD, MPH, University of
California, San Francisco, 74 New Montgomery St, Suite 600, San Francisco,
CA 94105 (e-mail: [log in to unmask] <mailto:[log in to unmask]> ).
Author Contributions: Dr Grady, as coprincipal investigator of HERS and HERS
II, had full access to all of the data in the studies and takes
responsibility for the integrity of the data and the accuracy of the data
analyses.
Study concept and design: Grady, Hulley, Herrington, Herd, Newby,
Vittinghoff, Wenger.
Acquisition of data: Grady, Herrington, Bittner, Blumenthal, Davidson,
Hlatky, Hsia, Hulley, Herd, Khan, Newby, Waters, Vittinghoff, Wenger.
Analysis and interpretation of data: Grady, Hulley, Herrington, Bittner,
Blumenthal, Davidson, Hlatky, Hsia, Herd, Khan, Newby, Waters, Vittinghoff,
Wenger.
Drafting of the manuscript: Grady, Hulley, Vittinghoff.
Critical revision of the manuscript for important intellectual content:
Grady, Herrington, Bittner, Blumenthal, Davidson, Hlatky, Hsia, Hulley,
Herd, Khan, Newby, Waters, Vittinghoff, Wenger.
Statistical expertise: Vittinghoff.
Obtained funding: Grady, Hulley.
Administrative, technical, or material support: Grady, Herrington, Bittner,
Blumenthal, Davidson, Hlatky, Hsia, Hulley, Herd, Khan, Newby, Waters,
Vittinghoff, Wenger.
Study supervision: Grady, Hulley, Herd, Khan, Wenger.
Financial Disclosures: During the conduct of HERS, all authors were
supported by contracts from Wyeth-Ayerst. Dr Grady received research support
from Berlex and Eli Lilly. Dr Herrington receives research support from Eli
Lilly and Parke-Davis/Pfizer, and occasional honoraria from Wyeth-Ayerst and
Eli Lilly. Dr Bittner has grants from Wyeth-Ayerst (ancillary study to
HERS), Pfizer, and Merck (both cholesterol studies); and is also on the
speaker's bureau for Pfizer and Merck and has attended a consultant meeting
for Merck-Schering Plough. Dr Blumenthal has received clinical research
support and honoraria to speak at educational conferences from the following
companies that make lipid lowering drugs and/or antihypertensive drugs:
Merck, Pfizer, Kos Pharmaceuticals, and Bristol-Myers Squibb. Dr Wenger's
potential conflicts of interest are Eli Lilly Raloxifene Advisory Committee,
Heart Disease in Women, MED-ED, Pfizer Inc, Coalition for the Advancement of
Cardiovascular Health, Cardiology Consultants, Pfizer Inc.
Funding/Support: This study was funded by Wyeth-Ayerst Research.
Role of the Sponsor: Wyeth-Ayerst Research funded the study, contributed to
its design, oversaw quality control at the clinical centers including
periodic site visits, and edited the data collected by the clinical centers
(except for disease outcome data) before sending it to the coordinating
center at University of California, San Francisco. The sponsor did not have
access to the blinding code, and played no role in collecting or
adjudicating disease outcomes nor in data analysis. The sponsor had the
opportunity to review and comment on manuscripts that had been written by
the investigators, but our contract gave the investigators the final
decision as to content.




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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.