Noncardiovascular Disease Outcomes During 6.8 Years of
Hormone Therapy
Heart and Estrogen/Progestin Replacement
Study Follow-up (HERS II)
Stephen Hulley, MD, MPH; Curt Furberg, MD, PhD; Elizabeth
Barrett-Connor, MD; Jane Cauley, PhD; Deborah Grady, MD, MPH; William Haskell, PhD;
Robert Knopp, MD; Maureen Lowery, MD; Suzanne Satterfield, MD; Helmut Schrott,
MD; Eric Vittinghoff, PhD; Donald Hunninghake, MD; for the HERS Research Group
Context The Heart and Estrogen/progestin Replacement Study (HERS) was a
randomized trial of estrogen plus progestin therapy after menopause.
Objective To examine the effect of long-term postmenopausal hormone therapy
on common noncardiovascular disease outcomes.
Design and Setting Randomized, blinded, placebo-controlled trial of 4.1 years'
duration (HERS) and subsequent open-label observational follow-up for 2.7 years
(HERS II), carried out between 1993 and 2000 in outpatient and community
settings at 20 US clinical centers.
Participants A total of 2763 postmenopausal women with coronary disease 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 plus 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 Thromboembolic events,
biliary tract surgery, cancer, fracture, and total mortality.
Results Comparing women assigned to hormone therapy with those assigned to
placebo, the unadjusted intention-to-treat relative hazard (RH) for venous
thromboembolism declined from 2.66 (95% confidence interval [CI], 1.41-5.04)
during HERS to 1.40 (95% CI, 0.64-3.05) during HERS II (P for time trend = .08); it was 2.08
overall for the 6.8 years (95% CI, 1.28-3.40), and 3 of the 73 women with
thromboembolism died within 30 days due to pulmonary embolism. The overall RH
for biliary tract surgery was 1.48 (95% CI, 1.12-1.95); for any cancer, 1.19
(95% CI, 0.95-1.50); and for any fracture, 1.04 (95% CI, 0.87-1.25). There were
261 deaths among those assigned to hormone therapy and 239 among those assigned
to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjusted and as-treated analyses did
not alter our conclusions.
Conclusions Treatment for 6.8 years with estrogen plus progestin in older
women with coronary disease increased the rates of venous thromboembolism and
biliary tract surgery. Trends in other disease outcomes were not favorable and
should be assessed in larger trials and in broader populations.
JAMA. 2002;288:58-66
The Heart and Estrogen/progestin Replacement
Study (HERS) was a randomized, blinded trial to determine the effects of
estrogen plus progestin compared with placebo in older postmenopausal women
with coronary disease. Disease surveillance continued in HERS II for an
additional 2.7 years, during which many of the women randomized to hormones
took open-label estrogen prescribed by their personal physicians but only a few
of those assigned to placebo did.1 During the 6.8 years
of observation in HERS and HERS II combined, we detected no overall effect of
hormone therapy on cardiovascular disease (CVD) event rates.1
Hormone therapy after menopause can have effects
on a variety of disease outcomes. We present data on non-CVD events over this
extended period of hormone therapy. We examine whether the increase in risk of
thromboembolic events observed in hormone-treated women in HERS2 diminishes over time,
as observational studies have suggested,3, 4 and whether the
increased rate of biliary tract surgery that appeared to be present in
hormone-treated women in HERS5 is confirmed as
additional events occur. More generally, we present data on the effect of
hormone therapy on other disease outcomes thought to be associated with hormone
therapy, including fractures, cancer, and total mortality.
Study Participants and Baseline
Measurements
The design and methods of HERS and HERS II have been described.1, 6, 7 Briefly, participants
were postmenopausal women younger than 80 years at baseline with coronary
artery disease and no prior hysterectomy. Among the reasons for exclusion were
a history of deep vein thrombosis or pulmonary embolism, history of breast
cancer, endometrial hyperplasia or cancer, abnormal Papanicolaou (Pap) result,
any hormone use within the past 3 months, and disease judged likely to be fatal
within 4 years.
During the baseline period of HERS we obtained
information by questionnaire and interview, and participants underwent physical
examination, including pelvic examination with Pap smear and endometrial
evaluation and screening mammography. All baseline measures except demographics
and health history were repeated at the final HERS visit, an average of 4
months before enrollment in HERS II.
Treatment, Follow-up, and
Outcomes
During the HERS trial, women were randomly allocated to receive either 0.625
mg/d of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate or an
identical placebo. After stopping blinded medications at the end of the HERS
trial, decisions about whether to undertake open-label hormone therapy were
left to the women and their personal physicians. During HERS II participants
were called at 4-month intervals and asked about hormone therapy and about
symptoms or clinical encounters for possible disease events1; assessment of
lipid-lowering drugs (but not bisphosphonates) was also continued during HERS
II.
Disease events were ascertained and documented
using the methods from the HERS trial.7 For in-hospital
nonfatal events and deaths, we required the hospital discharge summary and the
following information: for pulmonary embolism, clinical signs or symptoms and a
positive ventilation/perfusion scan or imaging result; for deep vein
thrombosis, documentation by venography, impedance plethysmography, or Doppler
ultrasound; for biliary tract surgery, an operative report; for clinical
fracture, symptoms and a definite fracture on radiography; and for cancer,
report of a tissue diagnosis. For all deaths in which clinical documentation
was insufficient, we obtained a death certificate. For out-of-hospital deaths
we interviewed the physician and/or next of kin for a description of the
terminal event. Data pertaining to suspected outcome events were independently
reviewed and classified according to the prespecified criteria used in the HERS
trial by 2 physicians at the University of California, San Francisco
Coordinating Center who were blinded to original treatment assignment and to
open-label hormone therapy.1, 6, 7
Both the telephone contacts and the
documentation of outcomes were carried out with similar efficiency and
completeness in the 2 HERS randomized groups.1 The proportions of all
HERS II deaths for which we obtained clinical documentation beyond a death
certificate were 81% among women originally randomized to hormone therapy and
82% among those randomized to placebo.
Statistical Analyses
As described,1 the primary
analyses (using SAS version 8.2, SAS Inc, Cary, NC) compared the risk of events
among women assigned to hormone therapy with the risk among women assigned to
placebo using unadjusted, intention-to-treat Cox proportional hazards models
for time to first event. We censored women at the last contact or at loss to
follow-up. In the analyses of biliary tract surgery, we excluded those with a
cholecystectomy prior to enrollment in HERS.
Mortality was assessed in all HERS participants
throughout the 6.8 years of follow-up, but morbidity surveillance during HERS
II was limited to the 93% of surviving women who enrolled. To control for
confounding, we estimated the effects of hormone therapy in adjusted Cox models
that included all predictors significant at P<.20
in multivariate analysis. The 1993-1994 baseline values were used for all
variables except statin use, which was included as a time-dependent covariate.
In as-treated adjusted analyses, women were censored 30 days after they become
nonadherent to randomly assigned treatment, defined as taking less than 80% of
their HERS medication or its equivalent during HERS II.1
The number of women randomized in HERS was 1380
in the hormone therapy group and 1383 in the placebo group. Of these, 1156 and
1165 enrolled in HERS II, representing 93% of the 2485 surviving women. Vital
status was known for 99.8% of these women at the end of HERS II, with final
telephone contacts completed in 99.5% of known survivors (see Figure 1
on page 53 of the printed journal). The mean duration of disease event
surveillance was 6.8 years for women who survived, which included 2.7 years in
HERS II.
Risk Factors and Other
Characteristics
Table 1
presents risk factors for non-CVD outcomes using measurements made at the
outset of HERS in 1993-1994. All the variables were equitably distributed
between randomized groups for both the HERS and HERS II cohorts.
Treatment With Hormones
Among women randomized to estrogen plus progestin, the proportions reporting at
least 80% adherence to hormone therapy during years 1 through 6 were 81%, 78%,
74%, 67%, 50%, and 45%; comparable proportions for women randomized to placebo
were 0%, 2%, 3%, 3%, 4%, and 8%.
Thromboembolism
There was a 2- to 3-fold increase in incidence of both deep vein thrombosis and
pulmonary embolism in the hormone group during HERS (Table 2).
The relative hazard (RH) for deep vein thrombosis was considerably smaller
(1.23) and no longer statistically significant during HERS II. There was no
comparable reduction in RH for pulmonary embolism, although the number of
events available to detect such a time trend was small. When risk for venous
thromboembolism was examined by year of observation (Table 3),
the RH declined after the first 2 years, but the time trend was not
statistically significant (P =
.08).
The RH for any venous thromboembolic event over
the entire 6.8 years was 2.08 (95% confidence interval [CI], 1.28-3.40). Event
rates were 5.9 per 1000 person-years in the hormone group and 2.8 per 1000
person-years in the placebo group, an excess of 3.1 per 1000 person-years (P = .003). The number needed to treat
(NNT) for 5 years per excess thromboembolic event is 65 when estimated by
intention-to-treat and 50 in the as-treated analysis. Seven of the 73 women
with thromboembolism died within 30 days of the event, and 3 of these deaths
were judged due to the event (all were pulmonary embolisms in women randomized
to hormone therapy). Stratifying the overall findings by baseline aspirin use,
the data are weakly consistent with the hypothesis that aspirin attenuates the
adverse effect of hormone therapy on risk of thromboembolism (RH, 1.68; 95% CI,
0.96-2.92 for aspirin users; RH, 4.23; 95% CI, 1.41-12.7 for nonusers;
interaction P = .14).
Biliary Tract Surgery
The RH for biliary tract surgery in the hormone group compared with placebo was
1.39 during HERS, 1.70 during HERS II, and 1.48 overall (95% CI, 1.12-1.95) (Table 2).
The overall RH after adjustment for statin use, a statistically significant
predictor of lower rates of biliary tract surgery in our study, was 1.44 (95%
CI, 1.10-1.90; P = .01).
The rate of surgery was 19.1 per 1000
person-years in the hormone group, an excess of 6.2 per 1000 person-years over
the placebo group (P = .002). The
estimated NNT for 5 years per excess surgery was 32 (intention-to-treat) and 31
(as-treated). Six of the 211 women who had biliary tract surgery died within 30
days, and 1 of these deaths was judged a consequence of the surgery.
Cancer
None of the differences between groups in cancer incidence was statistically
significant (Table 2).
The overall RH comparing the hormone and placebo groups was 1.27 (95% CI,
0.84-1.94) for the 88 breast cancer cases, 1.39 (95% CI, 0.84-2.28) for the 64
lung cancer cases, and 0.81 (95% CI, 0.46-1.45) for the 47 colon cancer cases.
Death due to these cancers during the period of observation occurred in 3% of
women with breast cancer, 61% of women with lung cancer, and 17% of women with
colon cancer.
Other cancers that occurred in at least 5 women
included endometrial cancer (2 women in the hormone group and 8 in placebo);
malignant melanoma (3 hormone and 5 placebo); lymphoma (7 hormone and 1
placebo); and ovarian cancer (5 hormone and 2 placebo). The total number of
women with any cancer was 159 in the hormone group vs 135 in the placebo group
(RH, 1.19; 95% CI, 0.95-1.50).
Fractures
Women randomized to hormone therapy had more hip fractures than women
randomized to placebo; the overall RH during 6.8 years of observation was 1.61
(95% CI, 0.98-2.66; P = .06) (Table 2).
The RH was 1.16 in HERS and 2.11 in HERS II, a difference that is not
statistically significant.
The RH estimates for vertebral, wrist, and other
fractures were close to unity. Based on the total of 452 clinical fractures
during 6.8 years of observation, the RH for any fracture was 1.04 (95% CI,
0.87-1.25). Prevalence of bisphosphonate use was 2.6% at HERS closeout (in
1998) among women randomized to hormone therapy and 2.5% among those randomized
to placebo.
Mortality
Death rates were high and increasing in this population of older women with
coronary disease. Total mortality in the placebo group was 22 per 1000
person-years during HERS and 38 per 1000 person-years during HERS II (Table 4).
The RH for total mortality in the hormone vs placebo group was 1.06 during
HERS, 1.14 during HERS II, and 1.10 overall (95% CI, 0.92-1.31).
During the entire 6.8 years of observation,
there were 261 deaths in the hormone group and 239 in the placebo group.
Overall, 61% of the deaths were classified as due to CVD, 19% due to cancer,
and 20% due to other cause. Among the CVD deaths, 132 women in the hormone
group and 122 in the placebo group died of CHD and the remainder died of stroke
(23 and 20) and peripheral arterial disease (4 and 2). Among the cancer deaths,
3 were due to breast cancer (all in women randomized to hormone therapy). For
lung cancer deaths 20 occurred in women randomized to hormone therapy and 19 in
those randomized to placebo; for colon cancer deaths, 2 and 6; and for all
other cancer deaths, 26 and 19. Among the non-CVD noncancer deaths, the numbers
in the hormone and placebo groups were 24 and 14 for infectious diseases
(including pneumonia and all forms of sepsis); 15 and 13 for respiratory
failure (primarily chronic obstructive pulmonary disease, excluding pneumonia);
2 and 9 for traumatic causes, and 10 and 15 for all other causes.
Adjusted and As-Treated
Analyses
In addition to the unadjusted intention-to-treat findings described above, we
also estimated the effects of hormone therapy in Cox regression analyses that
adjusted for covariates that were predictors of the outcome. The purpose was to
adjust for imbalances that could have developed because some women declined to
enroll in HERS II. None of the RH estimates was appreciably altered by the
multivariate adjustment (Table 5).
We also carried out analyses restricted to women
who remained adherent to randomly assigned treatment (Table 5).
These as-treated RH estimates had wider CIs than the intention-to-treat
estimates due to the smaller numbers of events (40%-73% of the total in the
various models). The as-treated RH for venous thromboembolism was higher than
the unadjusted intention-to-treat value (3.04 vs 2.08 for the overall study);
the as-treated RH was 5.83 during HERS (95% CI, 2.23-15.3) and 0.70 during HERS
II (95% CI, 0.14-3.64). Other as-treated RH estimates in Table 5
differed somewhat from those estimated by intention-to-treat, but the CIs
largely overlapped.
This report examines non-CVD outcomes over a
total of 6.8 years of observation during and following the HERS randomized
trial of hormone therapy in postmenopausal women with coronary disease. We
found an increased risk of venous thromboembolism and biliary tract surgery
among women randomized to hormone therapy; rates of other important disease
outcomes were not favorably affected.
Deep Vein Thrombosis and
Pulmonary Embolism
HERS2, 7 confirmed reports from
observational studies3, 8, 9 that hormone therapy
after menopause increases risk of venous thromboembolism. The estrogen
component of HERS treatment is the likely cause because estrogen without
progestin is associated with venous thromboembolism3, 4 and selective estrogen
receptor modulators also increase the risk.10, 11 Risk factors for
thromboembolism in HERS participants included lower extremity fracture, cancer,
surgery, and nonsurgical hospitalization; use of aspirin or statins appeared to
be protective.2
HERS participants represent a population at
relatively high absolute risk of deep vein thrombosis or pulmonary embolism.
The overall rate in the placebo group, 2.8 per 1000 person-years, is far higher
than that observed in healthy young postmenopausal women but resembles rates in
other populations of elderly women.3, 12 Therefore our
estimated NNT, 1 excess thromboembolic event among every 50 to 65 women taking
hormones for 5 years, is probably much smaller than it would be for younger and
healthier women.
The longer follow-up available in HERS II
suggests that the relative risk for venous thromboembolic events may decrease
after the second year of hormone therapy (P
= .08). Similar decreases over time have been reported in observational studies
of postmenopausal hormone3, 4 and oral contraceptive13 use, although there
is generally some residual excess risk. A decreasing risk is plausible, either
through attrition of a susceptible subgroup14 or by developing
tolerance, and the as-treated analysis suggests that it is not just due to
decreased compliance with hormone therapy during HERS II. However, the decrease
might partly reflect our decision in 1997 (after noting that venous
thromboembolism was more common in hormone-treated women) to emphasize to study
participants the need to stop HERS treatment in the event of fracture,
immobilization, surgery, or cancer.15
Biliary Tract Surgery
Several decades ago the Coronary Drug Project randomized trial found that
high-dose estrogen therapy caused gallbladder disease in men,16 probably due to
alteration of the concentration of cholesterol in the bile,17 and observational
studies of women receiving postmenopausal estrogen have had similar findings.5 We previously reported
a 38% higher adjusted rate of biliary tract surgery in hormone-treated women (P = .09).5 The longer period of
observation reported here has revealed the increased risk to be statistically
significant. Gallbladder disease was 3 times more common than venous
thromboembolism in HERS women, and the NNT for 5 years to cause 1 excess
surgery was 31.
Cancer
Cancer was 19% more common in the hormone therapy group, but the finding was
not statistically significant, nor were there statistically significant
differences in the rates of any specific cancer. The most common of these,
breast cancer, occurred slightly more frequently in the hormone group; the
second most common, lung cancer, also occurred slightly more frequently in the
hormone group; and the third most common, colon cancer, occurred slightly less
often in the hormone group. For each of these 3 cancers, statistically
significant associations in the same direction have been found in observational
studies and biological plausibility has been discussed.18-23 However, the wide
CIs and limited duration of follow-up do not permit clear inferences from these
observations of cancer occurrence.
Risk of endometrial cancer was 75% lower among
women randomized to hormone therapy than among those assigned to placebo, but
the difference was not statistically significant. The fact that risk is not
increased provides assurance that the progestin component of HERS treatment
prevents the endometrial hyperplasia and cancer resulting from prolonged use of
estrogen.24, 25
Fracture
Estrogen is widely believed to prevent osteoporotic fractures. Observational
studies reveal 50% lower fracture rates among women taking hormones than in
women who are not,26, 27 and there is strong
clinical trial evidence for a favorable effect of postmenopausal estrogen
treatment, with or without progestin, on bone mineral density in various
populations, including older women.28, 29 However, the clinical
trial evidence for an effect on fractures has been limited.30, 31 Our earlier report
from the HERS main trial revealed little difference between the hormone and
placebo groups in risk of any type of fracture.32 Surprisingly, the
additional follow-up experience from HERS II suggests a risk of hip fracture among
women in the hormone therapy group that is higher than that in the placebo
group. Chance may explain the finding, which does not meet the criteria for
statistical significance, is considerably smaller in the as-treated analysis,
and lacks biological plausibility.
Chance also could play a role in the larger
question as to why we did not observe any reduction in risk of all fractures in
the hormone group, although the confidence interval makes it unlikely that we
missed a large benefit. The absence of routine spine radiographs limited our
ability to detect vertebral fractures. Women studied in HERS were not selected
for osteoporosis and are therefore not well suited to revealing the effects of
fracture-prevention treatments. Clinical trials of bisphosphonates have found
an effect on the risk of fracture in women with osteoporosis, but not in women
with normal bone density.33, 34
Mortality
We recorded 261 deaths in the hormone group and 239 in the placebo group. The
absence of mortality benefit contrasts with the finding in observational
studies of lower mortality rates among women who use postmenopausal hormones compared
with nonusers.35, 36 Population
differences could underlie this disparity, but we believe that the lower mortality
rate among hormone users in observational studies is primarily due to
confounding; women who seek hormone therapy and remain compliant tend to be
healthier and wealthier than those who do not.37-39 Because these
characteristics cannot be measured precisely, their influence cannot be
adequately addressed by statistical adjustment in observational studies.40
Strengths and Limitations
Clinical trials have shown that short-term hormone therapy after menopause has
favorable effects on surrogate markers for disease, such as blood lipid levels
and bone mineral density, and that it relieves menopausal symptoms such as hot
flushes and insomnia,41, 42 but the effects of
prolonged hormone therapy in preventing clinical events have not been
established. HERS is the first randomized trial to provide substantial
information on the common disease outcomes that hormones may influence.
HERS II increases the precision of the estimated
RHs by adding events that reflect carryover effects from the randomized
treatment phase as well as the effects of continuation of the originally
assigned treatment. About 50% of the hormone group used open-label treatment
during HERS II compared with less than 10% of the placebo group. Those women
who did not continue their randomly assigned treatment (crossovers) diminish
the power to observe effects of the randomized treatment but do not alter the
fundamental value of randomization. To take advantage of this value, our
primary analytic approach was an intention-to-treat comparison of outcomes
measured over the entire 6.8 years. However, we also examined the findings with
as-treated analyses to compensate for the effects of crossing over and with
adjusted analyses to compensate for baseline differences resulting from the 7%
of women who did not enroll in HERS II. The as-treated and adjusted findings
differ somewhat from those of intention-to-treat, but the overall conclusions
are not altered.
Inferences about the effects of randomized
treatments are also contingent on avoiding unintended interventions applied
disproportionately to one randomized group. Randomized assignment was no longer
blinded in HERS II, so at the HERS closeout visit and in subsequent telephone
calls we provided a neutral message to all women and left advice on hormone use
and other preventive treatments to their personal physicians. We also took
steps to prevent bias in the ascertainment of outcomes by choosing disease
events that were objective and by maintaining the HERS systems for obtaining
records and for blinded adjudication. The success of efforts to avoid
between-group bias is supported by the comparability in the timing and
completeness with which the telephone contacts were made and clinical event
data collected.1
Important limitations of HERS stem from the
older age of HERS participants, who averaged 67 years at baseline and 74 years
at the end of HERS II, the presence of coronary disease on entry, and the
particular estrogen and progestin that we chose to study. These characteristics
limit generalizability, and the effects of other hormones in younger, healthier
postmenopausal women may be different. Further information on the effects of
hormone therapy on disease outcomes in healthy postmenopausal women will be
available at the conclusion of the Women's Health Initiative randomized trial.43
Treatment with estrogen plus progestin in older
women with coronary disease increased the rates of venous thromboembolism and
biliary tract surgery and did not produce favorable trends in overall rates of
CVD,1 fracture, or
death. Postmenopausal hormone therapy should be limited to indications that are
supported by randomized trial evidence that beneficial clinical outcomes
outweigh harmful ones.
Author/Article Information
Author Affiliations: Department of
Epidemiology and Biostatistics, School of Medicine, University of California,
San Francisco (Drs Hulley, Grady, and Vittinghoff); Department of Public Health
Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (Dr
Furberg); Division of Epidemiology, Department of Family and Preventive
Medicine, University of California, San Diego (Dr Barrett-Connor); Department
of Epidemiology, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, Pa (Dr Cauley); Department of Medicine, Stanford University,
Stanford, Calif (Dr Haskell); Department of Medicine, University of Washington
School of Medicine, Seattle (Dr Knopp); University of Miami School of Medicine,
Miami, Fla (Dr Lowery); Department of Preventive Medicine, University of
Tennessee, Memphis (Dr Satterfield); College of Public Health and Medicine,
University of Iowa, Iowa City (Dr Schrott); and Departments of Medicine and
Pharmacology, University of Minnesota, Minneapolis (Dr Hunninghake).
Corresponding Author and Reprints:
Stephen Hulley, MD, MPH, University of California, San Francisco, San
Francisco, CA 94143-0560 (e-mail: [log in to unmask]).
Financial Disclosures: During the conduct of HERS, all authors were supported by
contracts from Wyeth-Ayerst. Dr Barrett-Connor has received research funding
from Eli Lilly and Merck, and has served on an advisory board for Wyeth-Ayerst;
Dr Cauley has received research funding from Eli Lilly, Merck, and Pfizer, and
honoraria from Eli Lilly and Procter and Gamble; Dr Grady has received research
funding from Berlex and Eli Lilly; Dr Knopp has received research funding
and/or speaking honoraria from Abbott, AstraZeneca, Bristol-Myers Squibb, Kos,
Merck, Ortho-McNeil Pharmaceuticals, and Pfizer; and Dr Satterfield has received
research funding from Eli Lilly, Merck, and Pfizer.
Author Contributions: Dr Hulley, as principal investigator of the HERS II study, had
full access to all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analyses.
Study concept and design: Hulley, Grady, Furberg, Barrett-Connor, Cauley, Haskell, Knopp,
Schrott, Vittinghoff, Hunninghake.
Acquisition of data: Hulley, Grady, Furberg, Barrett-Connor, Cauley, Haskell, Knopp,
Lowery, Satterfield, Schrott, Vittinghoff, Hunninghake.
Analysis and interpretation of
data: Hulley, Furberg,
Barrett-Connor, Cauley, Grady, Haskell, Knopp, Lowery, Satterfield, Schrott,
Vittinghoff, Hunninghake.
Drafting of the manuscript: Hulley, Grady, Vittinghoff, Barrett-Connor.
Critical revision of the
manuscript for important intellectual content: Hulley, Furberg, Barrett-Connor, Cauley, Grady, Haskell, Knopp,
Lowery, Satterfield, Schrott, Vittinghoff, Hunninghake.
Statistical expertise: Vittinghoff.
Obtained funding: Hulley, Furberg, Barrett-Connor, Cauley, Grady, Haskell, Knopp,
Lowery, Satterfield, Schrott, Vittinghoff, Hunninghake.
Administrative, technical, or
material support: Hulley, Furberg,
Barrett-Connor, Cauley, Grady, Haskell, Knopp, Lowery, Satterfield, Schrott, Vittinghoff,
Hunninghake.
Study supervision: Hulley, Furberg, Grady.
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 UCSF. 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 written by the
investigators, but our contract gave the investigators the final decision
regarding content.
Funding/Support: This study was funded by Wyeth-Ayerst Research.
Clinical Center Investigators: Baylor College of Medicine, Houston, Tex: Alan Herd, MD, Melissa
Kulkarni, RN; Cedars-Sinai Medical Center, Los Angeles, Calif: Steven Khan, MD,
T. Keta Hodgson, BSN; Chicago Center for Clinical Research, Chicago, Ill:
Michael Davidson, MD, Marlene Wentworth, RN; Duke University Medical Center,
Durham, NC: Kristin Newby, MD, Rose Marie Smigla, RN; Emory University,
Atlanta, Ga: Nanette K. Wenger, MD, Sally McNagny, MD, MPH, Janice Parrott, RN,
Dana Drummond; George Washington University, Washington, DC: Judith Hsia, MD,
Ginny Levin, MPH, Donna Embersit; Hartford Hospital, Hartford, Conn: David
Waters, MD, Paul Thompson, MD, Jennifer DeDominicis, BSN, Marilyn Siwy, RN;
Johns Hopkins University, Baltimore, Md: Trudy Bush, PhD, Roger S. Blumenthal,
MD, Susan R. Miller, MPH, DSc, Katherine Bass, MD, MHS, Janice Huth, Teresa
Greene; Northwest Lipid Research Clinic, Seattle, Wash: Robert H. Knopp, MD,
Barbara Twaddell, RN; Stanford University, Palo Alto, Calif: William L.
Haskell, PhD, Kathy Berra, MSN, ANP, Laurie Ausserer, BS; University of
Alabama, Birmingham: William J. Rogers, MD, Vera Bittner, MD, R. Edward Varner,
MD, Glenda Blackburn, LPN; University of California, San Diego: Elizabeth
Barrett-Connor, MD, Cynthia A. Stuenkel, MD, Sue Hawley, BSN, RN; University of
Iowa, Iowa City: Helmutt Schrott, MD, Diane Meyerholz, RN; University of Miami,
Miami, Fla: Maureen Lowery, MD, Jose A. Martel, MPH; University of Minnesota,
Minneapolis: Donald Hunninghake, MD, Jean Olson, RN, Larry Kotek, MD, Sue
Krook, PhD; University of Pittsburgh, Pittsburgh, Pa (2 sites): Jane A. Cauley,
DrPH, Alan Goodman, MD, Robert McDonald, Jr, MD, Karen Southwick, Sheree
Schaffer, Michelle Boyd, RN, MS; University of Tennessee, Memphis: Suzanne
Satterfield, MD, Karen C. Johnson, MD, Beth McCammon, RN; Wake Forest
University, Winston-Salem and Greensboro, NC (2 sites): David Herrington, MD,
MHS, Karen Blinson, BS, Marcia Davis, BSN, Vickie Wayne, RN, Lynda Doomy, Kay
Cheshire, MEd, Mary Boozer, LPN, Judy Iannuzzi, BSN.
Coordinating Center: University of California, San Francisco: Stephen Hulley, MD, MPH,
Deborah Grady, MD, MPH, Eric Vittinghoff, PhD, Joel Simon, MD, MPH, Lily
Chaput, MD, MPH, Michael Shlipak, MD, MPH, Feng Lin MS, Christine C. Ireland,
MPH, Judith Macer, BS. Executive Committee:
Stephen Hulley, MD (chair), Curt Furberg, MD, PhD (co-chair), Vera Bittner, MD,
Ginger Constantine, MD, Deborah Grady, MD, David Herrington, MD, Donald
Hunninghake, MD, Nanette Wenger, MD. HERS II
Data Review Committee: Stephen Hulley, MD (chair), Deborah Grady,
MD, Eric Vittinghoff, PhD, Curt Furberg, MD, PhD, Robert Levy, Ginger
Constantine, MD.
Acknowledgment: We thank Steven Cummings, MD, for help with designing and
interpreting the study.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.