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Grady D, Herrington D, Bittner V, et al. Cardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy: Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II). JAMA. 2002;288(1):49–57. doi:10.1001/jama.288.1.49
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
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.
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 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
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
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
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 article6 examines the effects
of treatment on noncardiovascular outcomes.
The design, methods, baseline findings,1
and main outcomes2 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
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
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.
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
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, β-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.
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 Other adjudication
criteria have been described.1,2
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
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
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
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.
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 that independently predicted primary CHD events at P<.20 in a backward stepwise model, and use of statin drugs during
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.
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).
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).
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). 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.
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). 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).
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). 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) correspond to the findings in Table 2 and Table 3.
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).
There were no significant differences between the treatment groups during
HERS in use of aspirin, β-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.
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). 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). 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.
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
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 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
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
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 Data from recent
observational studies also suggest a possible early increase in risk of CHD
events related to postmenopausal hormone therapy.15,16
An early increased risk for CHD events might be due to prothrombotic,
proinflammatory, or proarrhythmic effects of hormones.17,18
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 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
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
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 Findings in
the Women's Estrogen for Stroke Trial,22 which
compared unopposed oral estradiol with placebo, mirrored the HERS result of
no overall benefit in either stroke or CHD outcomes.3
Thus, it seems unlikely that the addition of a progestin or the type of estrogen
accounts for our findings.
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
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