Cardiovascular Disease Outcomes During 6.8 Years of Hormone
Therapy
Heart and Estrogen/Progestin Replacement
Study Follow-up (HERS II)
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
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
cholesterol.2
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.
Study Participants
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 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
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, -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 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 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
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.
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).
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).
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).
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).
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).
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).
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).
Adjusted and per Protocol
Analyses
There were no significant differences between the treatment groups during HERS
in use of aspirin, -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.
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.
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 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 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.
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
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]).
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.
1.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.