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 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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