CI indicates confidence interval; HR, hazard ratio.
Dotted vertical line indicates the OR of venous thrombosis with E +
P in the nested case-control sample. CI indicates confidence interval; E +
P, estrogen plus progestin.
Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR, Women’s Health Initiative Investigators FT. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292(13):1573–1580. doi:10.1001/jama.292.13.1573
Postmenopausal hormone therapy increases the risk of venous thrombosis.
It is not known whether other factors influencing thrombosis add to this risk.
To report final data on incidence of venous thrombosis in the Women’s
Health Initiative Estrogen Plus Progestin clinical trial and the association
of hormone therapy with venous thrombosis in the setting of other thrombosis
Design, Setting, and Participants
Double-blind randomized controlled trial of 16 608 postmenopausal
women between the ages of 50 and 79 years, who were enrolled in 1993 through
1998 at 40 US clinical centers with 5.6 years of follow up; and a nested case-control
study. Baseline gene variants related to thrombosis risk were measured in
the first 147 women who developed thrombosis and in 513 controls.
Random assignment to 0.625 mg/d of conjugated equine estrogen plus 2.5
mg/d of medroxyprogesterone acetate, or placebo.
Main Outcome Measures Centrally validated deep vein thrombosis and pulmonary embolus.
Venous thrombosis occurred in 167 women taking estrogen plus progestin
(3.5 per 1000 person-years) and in 76 taking placebo (1.7 per 1000 person-years);
hazard ratio (HR), 2.06 (95% confidence interval [CI], 1.57-2.70). Compared
with women between the ages of 50 and 59 years who were taking placebo, the
risk associated with hormone therapy was higher with age: HR of 4.28 (95%
CI, 2.38-7.72) for women aged 60 to 69 years and 7.46 (95% CI, 4.32-14.38)
for women aged 70 to 79 years. Compared with women who were of normal weight
and taking placebo, the risk associated with taking estrogen plus progestin
was increased among overweight and obese women: HR of 3.80 (95% CI, 2.08-6.94)
and 5.61 (95% CI, 3.12-10.11), respectively. Factor V Leiden enhanced the
hormone-associated risk of thrombosis with a 6.69-fold increased risk compared
with women in the placebo group without the mutation (95% CI, 3.09-14.49).
Other genetic variants (prothrombin 20210A, methylenetetrahydrofolate reductase
C677T, factor XIII Val34Leu, PAI-1 4G/5G, and factor V HR2) did not modify
the association of hormone therapy with venous thrombosis.
Estrogen plus progestin was associated with doubling the risk of venous
thrombosis. Estrogen plus progestin therapy increased the risks associated
with age, overweight or obesity, and factor V Leiden.
Venous thrombosis (VT), including deep vein thrombosis (DVT) and pulmonary
embolus (PE), is a common disorder with an incidence of about 1 to 2 per 1000
person-years among adults.1 The risk of VT
is higher with older age, in men compared with women, in blacks compared with
whites, and in obese individuals, but VT is generally not associated with
other classic atherogenic risk factors.2- 4 Postmenopausal
hormone therapy, such as estrogen with or without progestin, and selective
estrogen-receptor modulators (tamoxifen and raloxifene) are associated with
a 2- to 3-fold increased risk of VT.5- 7
The association of postmenopausal hormone therapy with thrombosis risk
has been confirmed in case-control studies, cohort studies, and clinical trials.8- 15 To
prevent VT among women considering hormone therapy use, it is important to
define the most susceptible subgroups and whether any factors might attenuate
the risk. In studies to date, it appears that the presence of factor V Leiden
increases the risk of VT associated with estrogen use to approximately 15-fold.16,17 Clarification is needed on the effects
of postmenopausal hormone therapy on thrombosis in the presence of other VT
risk factors, especially age, obesity, and purported protective factors, such
as aspirin or statin use.14,18
The Women’s Health Initiative Estrogen Plus Progestin trial reported
a 2.11-fold increased risk of VT among 16 608 women randomized to combined
estrogen plus progestin therapy compared with placebo.19 This
initial article was based on locally adjudicated outcomes through April 30,
2002, with 5.2 years of follow-up. Active treatment in the trial was stopped
early on July 8, 2002, following the recommendation of the external data and
safety monitoring board, after determining that health risks exceeded benefits.
In this article, we extend the previous findings for VT by evaluating centrally
adjudicated incidence of VT through July 7, 2002, with an average follow-up
of 5.6 years. We report the risk factors for VT and the interaction of postmenopausal
hormone therapy and environmental and hemostatic risk factors.
Detailed descriptions of the Women’s Health Initiative have been
published.20,21 Eligible women
were between the ages of 50 and 79 years and were postmenopausal. Exclusion
criteria related to presence of medical conditions associated with shortened
survival or safety concerns, including level of triglycerides higher than
500 mg/dL (5.65 mmol/L). The protocol and consent forms were approved at each
site by institutional review committees and all participants provided written
informed consent. Due to published evidence of increased VT risk with postmenopausal
hormone therapy use, as of July 1997 women with a previous history of DVT
or PE were no longer enrolled.
This article is based on 16 608 eligible women with an intact uterus
at baseline who were randomly assigned in a double-blind fashion to receive
estrogen plus progestin or matching placebo. Combined estrogen plus progestin
was provided in a tablet containing 0.625 mg/d of conjugated equine estrogen
and 2.5 mg/d of medroxyprogesterone acetate (PremPro, Wyeth Ayerst, Philadelphia,
Pa). At baseline, blood was drawn after a minimum 10-hour fast.
Race/ethnicity was self-selected by participants from a list. Baseline
medication use was ascertained by examining medication containers brought
to study centers by participants. Aspirin use was defined as 80 mg/d or more
for at least 30 days, and statin use was defined as any use in the previous
14 days. Overweight was defined as a body mass index (BMI) of between 25 and
30 and obesity as a BMI higher than 30. Body mass index was calculated as
weight in kilograms divided by the square of height in meters.
Study participants were followed up to assess clinical events every
6 months and had an annual in-clinic visit. Overall, 3.3% of women were lost
to follow-up (3.5% in the estrogen plus progestin group and 3.0% in the placebo
group). All hospital records were reviewed locally. Diagnoses of possible
VT, including DVT and PE, first were reviewed by clinic center adjudicators
using standardized criteria.21 These adjudicators
were centrally trained and blinded to treatment assignment. Further review
of locally adjudicated diagnoses was performed by central adjudication. The
agreement between local and central adjudication was 89% for PE and 84% for
DVT. In cases of disagreement, a different central adjudicator reviewed the
records and the local and central adjudication results for resolution. This
article is based on the centrally adjudicated diagnoses through July 7, 2002.
The diagnosis of DVT was based on a physician diagnosis (hospital discharge
summary with a diagnosis of DVT or outpatient treatment) and positive findings
on doppler or duplex ultrasound, venogram, plethysmography, or isotope scan.
The diagnosis of PE was based on a hospital discharge summary with a diagnosis
of PE and positive findings on ventilation-perfusion lung scan, pulmonary
angiogram, or computed tomography. Pulmonary embolus was also confirmed if
signs and symptoms suggested PE in the presence of a documented DVT. Events
were classified as procedure-related if they occurred within 60 days of an
invasive procedure. Study medication was stopped after a diagnosis of VT.
A nested case-control study of biomarkers, treatment assignment, and
risk of vascular outcomes was conducted after early findings indicated increased
vascular risk in women taking estrogen plus progestin. All validated cases
of VT that occurred between randomization and February 28, 2001 (n = 147)
were included, by which time all women were more than 2 years from randomization.
Controls were selected matched on age, randomization date, presence of baseline
vascular disease specific to the case, and follow-up time. The controls selected
to match cases of myocardial infarction and stroke were included in these
analyses (513 total controls). For the women in this nested sample, available
genomic DNA was analyzed using standard methods for factor V Leiden (n = 615),
prothrombin G20210A (n = 616), the thermolabile variant of methylenetetrahydrofolate
reductase (C677T; n = 619), coagulation factor XIII Val34Leu (G100T;
n = 615), the 4G/5G polymorphism of plasminogen activator inhibitor-1
(PAI-1; n = 607), and factor V HR2 (A4070G; n = 614).
The main analyses used time-to-event methods (log-rank tests; Cox regression)
based on intent-to-treat principles. For each outcome, the time-to-event for
VT cases was the number of days from randomization to first diagnosis. For
women without VT, the censoring time was the time from randomization to the
earliest date of either death, loss to follow-up, or July 7, 2002. Outcome
comparisons were presented as annualized rates and hazard ratios (HRs) with
nominal (unadjusted for multiple outcomes) 95% confidence intervals (CIs).
Overall VT was the primary outcome in these analyses, with secondary analyses
assessing DVT and PE separately. Cox models were stratified by age, prior
VT, and randomization status in the dietary modification trial (a concurrent
trial that examined low-fat eating patterns). The HRs by time since randomization
were calculated and tests of trends with time were performed in a Cox proportional
hazards model incorporating a linear time × treatment interaction term.
Sensitivity analysis was performed to assess the impact of stopping study
pills during follow-up by censoring a woman from the analysis 6 months after
Pulmonary embolus was 1 of 7 outcomes included in a global index that
was used in the early stopping recommendation of the trial. Because PE was
relatively rare during follow-up, the nominal 95% CIs reported herein are
likely to be only slightly understated. Accounting for the 7 outcomes, the
Bonferroni-adjusted 95% CI for PE was 1.27 to 3.63.
Analysis of associations of each genetic factor with risk of VT was
performed using logistic regression, adjusting for age, randomization year,
treatment assignment, and prior history of VT.
Interactions between hormone treatment assignment and baseline characteristics
were examined by adding a product term between treatment and the characteristic
to a model that included both variables as main effects. We tested for a value
of zero for the product term coefficient tests to indicate a departure from
a multiplicative interaction. To provide additional insight into the joint
relationship of each genetic polymorphism and treatment with VT risk, we also
tested an additive odds ratio model using a certain synergy index.22 Under an additive model, the increment above unity
in the odds ratio for hormone therapy and a polymorphism combined is the sum
of the increments above unity for treatment and the polymorphism separately.
An additive model implies lower risk for the factors combined than does a
multiplicative model. Statistical analyses were performed using SAS statistical
software (version 9, SAS Institute Inc, Cary, NC).
Baseline characteristics of women in the estrogen plus progestin and
placebo groups were published.19 The distributions
of potential VT risk factors were similar for both estrogen plus progestin
and placebo. One third of the women were aged 50 to 59 years and 22% were
aged 70 to 79 years. Eighty-four percent were white, 7% black, and one third
of each were overweight or obese. Smoking (10%) and diabetes (4%) were uncommon.
Statin use was reported by 7% and regular aspirin use by 20%. Forty-three
percent of women previously took oral contraceptives and 26% previously took
estrogen plus progestin. There were 141 women (<1%) with a prior history
of VT. With a median follow-up of 5.6 years, 243 women developed VT. Of these
243 women, 124 had PE. Of the VT cases, 129 (53%) had DVT alone diagnosed,
while of those with PE, 53 (43%) had recognized DVT. Table 1 shows the baseline characteristics of women who developed
VT compared with those who did not.
As shown in Table 2, VT occurred
in 167 women (3.5/1000 person-years) in the estrogen plus progestin group
and 76 women (1.7/1000 person-years) in the placebo group (HR, 2.06; 95% CI,
1.57-2.70). The HRs were similar for DVT and PE. Twenty percent of cases of
VT were procedure-related and these were not as strongly associated with estrogen
plus progestin. Among 141 women who had VT prior to enrollment, there were
8 cases during follow-up0dash;7 cases among women in the estrogen plus progestin
group and 1 case in the placebo group (HR, 3.87; 95% CI, 0.45-33.34).
Because about 40% of women stopped taking study pills, at least temporarily,
during follow-up, the HRs may underestimate the association if there had been
full adherence. In analyses wherein the follow-up for a woman was censored
6 months after stopping study medication or starting open-label hormone therapy,
the resulting HR estimates were higher than those in Table 2 (VT: HR, 3.22; 95% CI, 2.24-4.64; DVT: HR, 3.30; 95% CI,
2.16-5.05; and PE: HR, 3.77; 95% CI, 2.17-6.55).
The increased risk of VT was present in the year following randomization
and persisted throughout follow-up (Figure 1).
Results were similar for DVT and PE. The yearly HRs for VT were 4.01 in year
1; 1.97 in year 2; 1.74 in year 3; 1.70 in year 4; 2.90 in year 5; and 1.04
in year 6 or later. A test for trend in the HR over time showed diminishing
risk of VT with increasing time from randomization (P = .01);
however, the incidence of VT appeared to increase among placebo-treated women
in later years of follow-up. These yearly HRs did not differ materially, accounting
Compared with women aged 50 to 59 years and when adjusted for treatment
assignment and BMI, women aged 60 to 69 years had an HR of 2.03 (95% CI, 1.43-2.88)
and women aged 70 to 79 years had an HR of 3.72 (95% CI, 2.57-5.36). Considering
age and treatment assignment, the highest incidence of VT was among older
women assigned to the estrogen plus progestin group (Table 3). For each age group, the incidence of VT associated with
estrogen plus progestin was increased by approximately 2-fold.
The HR of VT adjusted for age and treatment assignment was 1.96 (95%
CI, 1.33-2.88) for overweight and 3.09 (95% CI, 2.13-4.49) for obesity. The
incidence rate of VT was highest among obese women assigned to the estrogen
plus progestin group. These women had a nearly 6-fold higher risk than normal
weight women who were taking placebo (Table 4). Within each BMI group, the HR of estrogen plus progestin compared
with placebo was about 2-fold increased.
Among obese women aged 70 to 79 years, the incidence of VT was 8.9 per
1000 person-years in the estrogen plus progestin group and 4.6 per 1000 person-years
in the placebo group. Among normal weight women aged 50 to 59 years, the incidence
was 0.8 per 1000 person-years in the estrogen plus progestin group. There
were not any cases of VT in the placebo group among women with a normal weight.
The HR of VT for the estrogen plus progestin group was not significantly
altered by cigarette smoking, aspirin or statin use, history of cardiovascular
disease prior to enrollment, prior use of postmenopausal hormone therapy or
oral contraceptives, or any lipid measure (total cholesterol, low-density
lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides;
data not shown). The number of events among blacks and other ethnic groups
was too small to evaluate ethnic-specific associations of estrogen plus progestin
Among the genetic variants, in analyses adjusted for age, randomization
year, previous VT, and treatment assignment, only factor V Leiden was associated
with the risk of VT, with a 2.6-fold increased risk among heterozygotes, and
a 7.5-fold increased risk among homozygotes (Table 5). There was a suggestion of reduced VT risk associated with
the homozygous factor XIII variant, but this was also true for the thermolabile
variant of MTHFR , which, if anything, is expected to increase
risk. Because several gene variants are less common among nonwhites, whites
were analyzed separately and results did not differ materially.
Figure 2 shows the association
with VT of genetic conditions in combination with placebo or estrogen plus
progestin. For women with factor V Leiden who were taking estrogen plus progestin,
the data were consistent with either a multiplicative odds ratio model (P = .71) or an additive odds ratio model (P = .50). Restricting analysis to white women,
these significance levels were.74 and.44, respectively. The odds of VT among
women taking estrogen plus progestin who had factor V Leiden was slightly
higher in white women than in the overall group (OR, 8.53; 95% CI, 3.78-19.23).
For the other gene variants, only homozygous factor XIII Val34Leu appeared
to modulate the risk associated with estrogen plus progestin.
Results from this randomized clinical trial of estrogen plus progestin
in healthy postmenopausal women have further documented the increased risk
of VT, including both DVT and PE, among women taking estrogen plus progestin.
Results are consistent with previous studies of unopposed estrogen, estrogen
plus progestin, and selective estrogen-receptor modulators.5- 7,23 Considering
other vascular outcomes of estrogen plus progestin in this study, VT accounted
for the greatest number of excess events with estrogen plus progestin. Based
on projections for 10 years for 1000 women taking estrogen plus progestin,
the estimated excess number of events is 18 for VT, 6 for coronary heart disease,24 8 for invasive breast cancer,25 and
8 for stroke.26
Several conclusions may be made based on these findings. The increased
risk of VT was highest in the first year of therapy, but continued through
5 years of treatment. This is consistent with most reports,9,14 but
inconsistent with studies that suggested no increased risk after the first
year of treatment.11,13 In agreement
with findings in the general population,2- 4 the
risk of VT increased with age and obesity in this trial. While obese women
or those aged 70 to 79 years had a similar relative risk of VT with estrogen
plus progestin as thinner and younger women, there was a substantially higher
number of cases of thrombosis in these groups due to their higher baseline
risk. Among women aged 70 to 79 years, the projected 10-year risk of VT was
6% with estrogen plus progestin. For women aged 50 to 59 years, the age at
which women might currently be considering postmenopausal hormone therapy
use, the projected 5-year risk of estrogen plus progestin in obese women was
1.4% compared with less than 0.5% in normal weight women. While a recent study
reported that the combination of obesity and oral contraceptives synergistically
increase the risk of VT,4 we are unaware of
other studies assessing postmenopausal hormone therapy and obesity.
Use of estrogen plus progestin among women with prior VT should be discouraged
in the absence of ongoing anticoagulation. Although there were only 141 participants
with previous VT, the high risk of recurrence with estrogen plus progestin
observed herein agrees with a previous trial documenting a 1.3-year incidence
of VT of 10.7% with estradiol plus norethistrone acetate among women with
Our data suggest the absence of a protective effect of aspirin or statins
on VT risk among women taking estrogen plus progestin. In high-risk populations
such as surgery patients, aspirin use may be an effective prophylaxis against
VT, especially in combination with other methods.28,29 Among
women with coronary artery disease in the Heart and Estrogen/progestin Replacement
Study (HERS), aspirin use appeared to attenuate the risk of VT associated
with estrogen plus progestin, with a relative risk of 1.68 among women taking
aspirin and 4.23 among women not taking aspirin, however this difference was
not statistically significant and confounders were not evaluated.15 Herein and in the HERS trial, statins did not specifically
protect against estrogen plus progestin-associated VT,14 although
there may be differences among statins that require further study.30
Among the genetic polymorphisms assessed herein, only factor V Leiden
was related to risk of VT and it appeared to combine with estrogen plus progestin
therapy to modify risk in an approximate multiplicative fashion. This finding
agrees with previous findings from a case-control study17 and
from combined results of 2 trials of women with established coronary heart
disease.16 Based on our findings, we estimate
that the absolute risk of VT among women taking estrogen plus progestin with
heterozygous or homozygous factor V Leiden is 0.8% per year. Other studies
estimated this rate as 2.9% per year in families affected by factor V Leiden
and thrombosis,31 and 1.5% per year among women
with coronary artery disease.16 Based on our
findings, if unselected healthy women considering estrogen plus progestin
therapy were screened for factor V Leiden to withhold treatment from women
with the mutation, 795 women would need to be screened to prevent 1 episode
of VT over 5 years of treatment.
Interactions observed herein for estrogen plus progestin with both environmental
and genetic risk factors for VT were weaker than previously reported interactions
of oral contraceptives with VT risk factors. For example, the associations
of obesity4 and factor V Leiden7 with
VT are greatly increased by oral contraceptives and modestly increased by
estrogen plus progestin. While the prothrombin 20210A variant greatly increases
the risk associated with oral contraceptives, we did not observe this for
estrogen plus progestin. It is possible that the lower estrogen dose in the
regimen of estrogen plus progestin explains these differences, but it is also
possible that these interactions are harder to detect in postmenopausal women
due to their higher baseline risk of VT compared with younger women.
The strengths of this study include the randomized double-blind design
and ascertainment of outcome events in a large group of women. The analysis
was limited by power considerations for subgroup analyses, particularly those
related to the nested case-control study that included only 147 cases of VT.
However, apart from factor V Leiden and perhaps factor XIII Val34Leu, given
the lack of evidence for associations of the genetic polymorphisms with VT,
it is unlikely that a clinically relevant interaction of these genetic factors
with estrogen plus progestin exists. Nonadherence to study medications appeared
to attenuate the observed associations of the estrogen plus progestin regimen
with VT. Therefore our risk estimates for all analyses are likely to be underestimates.
Finally, the results herein apply to the hormone formulation studied. Other
data suggest that associations of postmenopausal hormone therapy with VT do
not differ by formulation (estradiol, conjugated estrogens, unopposed vs combined
therapy).7,32 However, there is
limited information on different formulations and their interactions with
genetic risk factors for VT. Furthermore, the association of transdermal estrogen
therapy with VT is controversial,9,11,33 and
no studies have assessed drug-gene interaction.
In summary, there was an increased risk of VT among women assigned to
estrogen plus progestin in the Women’s Health Initiative clinical trial.
Older age and obesity added to the risk associated with a regimen of estrogen
plus progestin. Thinner and younger women were at low absolute risk of VT,
although their risk was still 2-fold higher among women taking estrogen plus
progestin compared with women taking placebo. Women with factor V Leiden,
but not other genetic variants, were particularly susceptible to estrogen
plus progestin-induced VT. The implications of these findings may be important
for the use of postmenopausal hormone therapy in the treatment of menopausal
symptoms among younger postmenopausal women.
Corresponding Author: Mary Cushman, MD,
MSc, University of Vermont, 208 S Park Dr, Suite 2, Colchester, VT 05446 (firstname.lastname@example.org)
Author Contributions: Dr Cushman had full access
to all of the data in the study and takes responsibility for the integrity
of thedata and the accuracy of the data analysis
Study concept and design:Cushman, Kuller,Prentice,
Acquisition of data:Cushman, Kuller, Prentice,
Analysis and interpretation of data: Cushman,
Kuller, Prentice, Rodabough, Psaty, Stafford, Sidney, Rosendaal.
Drafting of the manuscript: Cushman, Kuller,
Critical revision of the manuscript for important
: Kuller, Prentice, Rodabough, Psaty, Stafford,
Statistical expertise:Prentice, Rodabough,
Obtained funding:Kuller, Prentice, Psaty, Rosendaal.
Administrative, technical, or material support:Cushman,
Women’s Health Initiative Program Office: National
Heart, Lung, and Blood Institute, Bethesda, Md: Barbara Alving, Jacques Rossouw,
Linda Pottern, Shari Ludlam, Joan McGowan.
Clinical Coordinating Center: Fred Hutchinson
Cancer Research Center, Seattle, Wash: Ross Prentice, Garnet Anderson, Andrea
LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley
Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah
Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, Emily White.
Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker,
Pentti Rautaharju, Ronald Prineas, Michelle Naughton. Medical Research Labs,
Highland Heights, Ky: Evan Stein, Peter Laskarzewski. University of California,
San Francisco: Steven Cummings, Michael Nevitt, Maurice Dockrell. University
of Minnesota, Minneapolis: Lisa Harnack. McKesson BioServices, Rockville,
Md: Frank Cammarata, Steve Lindenfelser. University of Washington, Seattle:
Bruce Psaty, Susan Heckbert.
Clinical Centers and Investigators: Albert
Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, William
Frishman, Judith Wylie-Rosett, David Barad, Ruth Freeman. Baylor College of
Medicine, Houston, Tex: Jennifer Hays, Ronald Young, Jill Anderson, Sandy
Lithgow, Paul Bray. Brigham and Women's Hospital, Harvard Medical School,
Boston, Mass: JoAnn Manson, Julie Buring, J. Michael Gaziano, Kathryn Rexrode,
Claudia Chae. Brown University, Providence, RI: Annlouise R. Assaf, Carol
Wheeler, Charles Eaton, Michelle Cyr. Emory University, Atlanta, Ga: Lawrence
Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, Vivian Porter.
Fred Hutchinson Cancer Research Center, Seattle, Wash: Shirley A. A. Beresford,
Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, Robyn Andersen. George
Washington University, Washington, DC: Judith Hsia, Nancy Gaba, Joao Ascensao.
Harbor-UCLA Research and Education Institute, Torrance, Calif: Rowan Chlebowski,
Robert Detrano, Anita Nelson, James Heiner, John Marshall. Kaiser Permanente
Center for Health Research, Portland, Ore: Cheryl Ritenbaugh, Barbara Valanis,
Patricia Elmer, Victor Stevens, Njeri Karanja. Kaiser Permanente Division
of Research, Oakland, Calif: Bette Caan, Stephen Sidney, Geri Bailey, Jane
Hirata. Medical College of Wisconsin, Milwaukee: Jane Morley Kotchen, Vanessa
Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, Joan Neuner. MedStar
Research Institute/Howard University, Washington, DC: Barbara V. Howard, Lucile
Adams-Campbell, Lawrence Lessin, Monique Rainford, Gabriel Uwaifo. Northwestern
University, Chicago/Evanston, Ill: Linda Van Horn, Philip Greenland, Janardan
Khandekar, Kiang Liu, Carol Rosenberg. Rush-Presbyterian0dash;St Luke's
Medical Center, Chicago, Ill: Henry Black, Lynda Powell, Ellen Mason. Stanford
Center for Research in Disease Prevention, Stanford University, Stanford,
Calif: Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford,
Linda C. Giudice. State University of New York, Stony Brook: Dorothy Lane,
Iris Granek, William Lawson, Gabriel San Roman, Catherine Messina. Ohio State
University, Columbus: Rebecca Jackson, Randall Harris, Electra Paskett, W.
Jerry Mysiw, Michael Blumenfeld. University of Alabama, Birmingham: Cora E.
Lewis, Albert Oberman, James M. Shikany, Monika Safford, Brian K. Britt. University
of Arizona, Tucson/Phoenix: Tamsen Bassford, Cyndi Thomson, Marcia Ko, Ana
Maria Lopez. State University of New York, Buffalo: Jean Wactawski-Wende,
Maurizio Trevisan, Ellen Smit, Susan Graham, June Chang. University of California
at Davis, Sacramento: John Robbins, S. Yasmeen. University of California at
Irvine, Orange: Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, Bradley
Monk. University of California, Los Angeles: Howard Judd, David Heber, Robert
Elashoff. University of California at San Diego, LaJolla/Chula Vista: Robert
D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, R. Elaine
Hanson. University of Cincinnati, Cincinnati, Ohio: Margery Gass, Suzanne
Wernke, Nelson Watts. University of Florida, Gainesville/Jacksonville: Marian
Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, Yvonne Brinson.
University of Hawaii, Honolulu: David Curb, Helen Petrovitch, Beatriz Rodriguez,
Kamal Masaki, Santosh Sharma. University of Iowa, Iowa City/Davenport: Robert
Wallace, James Torner, Susan Johnson, Linda Snetselaar, Bradley VanVoorhis.
University of Massachusetts/Fallon Clinic, Worcester: Judith Ockene, Milagros
Rosal, Ira Ockene, Robert Yood, Patricia Aronson. University of Medicine and
Dentistry of New Jersey, Newark: Norman Lasser, Baljinder Singh, Vera Lasser,
John Kostis. University of Miami, Miami, Fla: Mary Jo O’Sullivan, Linda
Parker, R. Estape, Diann Fernandez. University of Minnesota, Minneapolis:
Karen L, Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur,
Sarah Kempainen. University of Nevada, Reno: Robert Brunner, William Graettinger,
Vicki Oujevolk. University of North Carolina, Chapel Hill: Gerardo Heiss,
Pamela Haines, David Ontjes, Carla Sueta, Ellen Wells. University of Pittsburgh,
Pittsburgh, Pa: Lewis Kuller, Jane Cauley, N. Carole Milas. University of
Tennessee, Memphis: Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke,
Stephanie Connelly, Fran Tylavsky. University of Texas Health Science Center,
San Antonio: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes,
Charles Mouton. University of Wisconsin, Madison: Gloria Sarto, Douglas Laube,
Patrick McBride, Julie Mares-Perlman, Barbara Loevinger. Wake Forest University
School of Medicine, Winston-Salem, NC: Denise Bonds, Greg Burke, Robin Crouse,
Mara Vitolins, Scott Washburn. Wayne State University School of Medicine/Hutzel
Hospital, Detroit, Mich: Susan Hendrix, Michael Simon, Gene McNeeley.
Funding/Support: The Women’s Health Initiative
was funded by the National Heart, Lung and Blood Institute. Wyeth-Ayerst Research
provided the study medications (active and placebo). Additional funding was
provided by grant 2001.029 from the Netherlands Heart Foundation.
Role of the Sponsor: The National Heart, Lung,
and Blood Institute participated in the design and conduct of the study, collection,
management, analysis and interpretation of the data, and reviewed the manuscript.
A National Heart, Lung, and Blood Institute representative served as a member
of the Women’s Health Iniative Steering Committee. Wyeth-Ayerst provided
study pills but had no other role in the study. The Netherlands Heart Foundation
provided funding, but had no other role in the study.