WHI Study Finds No Heart Disease Benefit,
Increased Stroke Risk With Estrogen Alone
A large, multi-center heart disease prevention study,
part of the Women’s Health Initiative (WHI),
found that estrogen-alone hormone therapy had no effect
on coronary heart disease risk but increased the risk
of stroke for postmenopausal women. The study also
found that estrogen-alone therapy significantly increased
the risk of deep vein thrombosis, had no significant
effect on the risk of breast or colorectal cancer,
and reduced the risk of hip and other fractures.
The WHI is sponsored by the National Heart, Lung,
and Blood Institute (NHLBI), part of the National
Institutes of Health (NIH).
The estrogen-alone study was stopped at the end of
February 2004 because the hormone increased the risk
of stroke and did not reduce the risk of coronary
heart disease, a key question of the trial. The study
was to have ended in March 2005. Initial findings
appear in the April 14 issue of The Journal of
the American Medical Association.
A separate report on the WHI Memory Study of estrogen
alone’s effects on dementia and cognitive function
will be published soon.
“These findings confirm that estrogen-alone therapy
should not be used to prevent chronic disease,”
said NHLBI Acting Director Dr. Barbara Alving. “We
believe the findings support current FDA recommendations
that hormone therapy only be used to treat menopausal
symptoms and that it be used at the smallest effective
dose for the shortest possible time.”
“The results make clear that hormone therapy
does not protect women against coronary heart disease
and increases their risk for stroke,” said Dr.
Jacques Rossouw, WHI Project Officer at NHLBI. “This
may be especially true for older women, such as those
aged 60 and older in this study.”
As of July 2003, about 10 million American women were
taking some form of hormone therapy. It is estimated
that about 6.7 million of those take estrogen alone
and 3.3 million take estrogen plus progestin. The
drugs tested in the WHI are those most commonly used
in the United States.
The estrogen-alone study involved 40 clinical centers
and 10,739 generally healthy postmenopausal women
ages 50-79 who did not have a uterus. Their average
age at enrollment was nearly 64 and about 70 when
the study stopped. They enrolled in the study between
1993 and 1998.
About 75 percent of the women were white, 15 percent
black, and 6 percent Hispanic. Most of the women were
overweight and about 8 percent had diabetes. About
35 percent of the women had used hormone therapy in
the past and about 13 percent were current users at
the time they enrolled in the study.
The women were randomized to two groups–one received
0.625 mg/day of conjugated equine estrogens (Premarin™)
and the other a placebo. Premarin™ and the placebo
were supplied by Wyeth-Ayerst Research.
The women were followed for an average of 6.8 years.
They visited their clinic at least once a year, and
had annual mammograms and clinical breast exams.
The study was carefully monitored by an independent
Data and Safety Monitoring Board (DSMB). The NIH made
the decision at the beginning of February 2004 to
stop the study drugs. The JAMA article includes data
collected through February 2004.
For every 10,000 women each year, on average, estrogen-alone
use compared to placebo resulted in:
Increased risk for– |
• Stroke (fatal and
non-fatal) |
12 cases more (44 cases in those
on estrogen alone and 32 in those on placebo) |
• Venous thrombosis (blood clot,
usually in one of the deep veins of the legs) |
6 cases more (21 cases in those on estrogen
alone and 15 in those on placebo) (An increased
risk of pulmonary embolism—blood
clots in the lungs—was not statistically
significant—there were 13 cases in those
on estrogen alone and 10 in those on placebo.) |
No difference in risk or uncertain effect
for– |
• Coronary heart disease |
No significant difference
in risk (neither
increased nor decreased)–5 fewer cases (49
cases in those on estrogen alone and 54 in
those on placebo). During the first two
years of use, risk was slightly increased for
estrogen alone, but it appeared to diminish
over time. |
• Colorectal cancer
or total cancer |
No significant difference in risk (neither
increased nor decreased)––1 more
case for colorectal cancer and 7 fewer cases
for total cancer (for colorectal cancer, 17
cases in those on estrogen alone and 16 in
those on placebo; for total cancer, 103 cases
in those on estrogen alone and 110 in those
on placebo) |
• All deaths or those
for a specific cause |
No significant difference in risk (neither
increased nor decreased)–3 more deaths
(for all deaths, 81 in those on estrogen alone
and 78 in those on placebo) |
• Breast cancer
|
Uncertain effect–7 fewer cases (26 cases
in those on estrogen alone and 33 in those
on placebo). This finding was not statistically
significant. |
Increased benefit for– |
• Bone fractures |
6 fewer hip fractures (11 cases in those on
estrogen alone and 17 cases in those on placebo)
|
The results above were not affected by race or ethnicity,
or body mass index (BMI).
Another WHI hormone study, the estrogen-plus-progestin
trial, was also stopped early. It was halted in July
2002 after 5.6 years of followup because of an increased
risk of breast cancer and because the increased risks
of breast cancer, coronary heart disease, stroke,
and blood clots outweighed the benefits of a reduced
risk of hip fracture and colorectal cancer.
The combined hormone therapy study involved 16, 608
participants, who were randomly assigned to receive
either a daily intake of 0.625 mg of conjugated equine
estrogens plus 2.5 mg of medroxyprogesterone (Prempro™),
or a placebo. Combination therapy is used when women
have a uterus to prevent the development of endometrial
cancer.
Key findings of estrogen plus progestin compared to
the placebo for every 10,000 women each year were:
more strokes (8 more cases); an increased risk of
breast cancer (8 more breast cancers); an increase
in heart attacks (7 more heart attacks); a higher
risk of blood clots (8 more women with blood clots
in the lungs and 18 more with blood clots in the legs
or lungs); a reduction in hip fractures (5 fewer hip
fractures); and a drop in the risk of colorectal cancer
(6 fewer colorectal cancers).
Rossouw cautioned that the findings for the two hormone
therapy studies should not be compared directly. “At
baseline, the women in the estrogen-alone study had
a higher risk of cardiovascular disease than those
in the estrogen-plus-progestin trial. Those in the
estrogen-alone study were more likely to have such
heart disease risk factors as high blood pressure,
high blood cholesterol, diabetes, and obesity.”
Women in both hormone trials are now in a followup
phase, due to last until 2007, during which their
health will be closely monitored.
WHI was launched in 1991 and consists of a set of
clinical trials to test the preventive effects of
postmenopausal hormone therapy, diet modification,
and calcium and vitamin D supplements on heart disease,
fractures, breast and colorectal cancer, as well as
an observational study, which is looking for predictors
and biological markers for disease. The diet modification
trial involves nearly 49,000 women, the calcium/vitamin
D trial about 36,000 women, and the observational
study about 94,000 women–all three studies are
continuing.
NHLBI collaborates on the WHI with the National Cancer
Institute, the National Institute of Arthritis and
Musculoskeletal and Skin Diseases, and the National
Institute on Aging, and the Office of Research on
Women’s Health, all parts of the NIH.
To arrange an interview about the WHI, call the NHLBI
Communications Office at (301) 496-4236.
Additional information on menopausal hormone therapy,
including the WHI estrogen-plus-progestin study, can
be found on the NIH Website at www.nih.gov, on the
NHLBI Website at www.nhlbi.nih.gov, and on the FDA
Website at www.fda.gov.
Other online sources of information are:
Women’s
Health Initiative (www.nhlbi.nih.gov/whi)
WHI Estrogen-Alone
Study (www.nhlbi.nih.gov/whi/estro_alone.htm)
WHI
Estrogen-Plus-Progestin Study (www.nhlbi.nih.gov/whi/estro_pro.htm)
Women's Health
Initiative Memory Study (WHIMS) (www.wfubmc.edu/whims/)
FDA
Statement on Postmenopausal Hormone Therapy (www.fda.gov/cder/drug/infopage/estrogens_progestins/default.htm)
Postmenopausal
Hormone Therapy (NHLBI) (www.nhlbi.nih.gov/health/women/index.htm)
Menopausal
Hormone Therapy Information (NIH) (www.nih.gov/PHTindex.htm)
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