The National Heart, Lung, and Blood Institute (NHLBI) of the
National Institutes of Health (NIH) has stopped early a
major clinical trial of the risks and benefits of combined
estrogen and progestin in healthy menopausal women due to an
increased risk of invasive breast cancer. The large
multi-center trial, a component of the Women's Health
Initiative (WHI), also found increases in coronary heart
disease, stroke, and pulmonary embolism in study
participants on estrogen plus progestin compared to women
taking placebo pills. There were noteworthy benefits of
estrogen plus progestin, including fewer cases of hip
fractures and colon cancer, but on balance the harm was
greater than the benefit. The study, which was scheduled to
run until 2005, was stopped after an average follow-up of
5.2 years.
Participants in this component of WHI, like most women with
a uterus who take hormone therapy, were given progestin in
combination with estrogen. This practice is known to prevent
endometrial cancer. A separate WHI study of estrogen alone
in women who had a hysterectomy before joining the WHI
hormone program continues unchanged because, at this point,
the balance of risks and benefits of estrogen alone is still
uncertain.
The report from the WHI investigators on the estrogen plus
progestin study findings will be published in the July 17
issue of The Journal of the American Medical Association (JAMA);
because of the importance of the information, the study is
being released early on Tuesday, July 9, as an expedited
article on the JAMA Web site. (Full text version available
to all at jama.com.)
"We have long sought the answer to the question: Does
postmenopausal hormone therapy prevent heart disease and, if
it does, what are the risks? The bottom-line answer from WHI
is that this combined form of hormone therapy is unlikely to
benefit the heart. The cardiovascular and cancer risks of
estrogen plus progestin outweigh any benefits--and a 26
percent increase in breast cancer risk is too high a price
to pay, even if there were a heart benefit. Similarly, the
risks outweigh the benefits of fewer hip fractures," said
NHLBI Director Claude Lenfant, M.D.
"Menopausal women who might have been candidates for
estrogen plus progestin should now focus on well-proven
treatments to reduce the risk of cardiovascular disease,
including measures to prevent and control high blood
pressure, high blood cholesterol, and obesity. This effort
could not be more important: heart disease remains the
number one killer of American women," added Lenfant.
The estrogen plus progestin trial of the WHI involved 16,608
women ages 50 to 79 years with an intact uterus. An
important objective of the trial was to examine the effect
of estrogen plus progestin on the prevention of heart
disease and hip fractures, and any associated change in risk
for breast and colon cancer. The study did not address the
short-term risks and benefits of hormones for the treatment
of menopausal symptoms.
About 6 million women in the U.S. are taking estrogen plus
progestin for a variety of reasons, including symptom
relief, because their doctors advised it, or for long-term
health.
"Women with a uterus who are currently taking estrogen plus
progestin should have a serious talk with their doctor to
see if they should continue it. If they are taking this
hormone combination for short-term relief of symptoms, it
may be reasonable to continue since the benefits are likely
to outweigh the risks. Longer term use or use for disease
prevention must be re-evaluated given the multiple adverse
effects noted in WHI," said Jacques Rossouw, M.D., acting
director of the WHI.
According to Rossouw, the adverse effects of estrogen plus
progestin applied to all women, irrespective of age,
ethnicity, or prior disease status.
"When the estrogen-only trial is completed, a comparison of
the results of these two trials may provide a better idea of
the roles of estrogen, compared to estrogen plus progestin,
in health and disease," said Marcia Stefanick, Ph.D., chair
of the WHI Steering Committee and Associate Professor of
Medicine, Stanford University, Palo Alto, California.
Women enrolled in the estrogen plus progestin study were
randomly assigned to a daily dose of estrogen plus progestin
(0.625 mg of conjugated equine estrogens plus 2.5 mg of
medroxyprogesterone acetate) or to a placebo. Participants
were enrolled in the study between 1993 and 1998 at over 40
clinical sites across the country.
In 2000 and again in 2001, WHI investigators complied with a
recommendation from the study's Data and Safety Monitoring
Board (DSMB) to inform participants of a small increase in
heart attacks, strokes, and blood clots in women taking
hormones. The DSMB, an independent advisory committee
charged with reviewing results and ensuring participant
safety, found that the actual number of women having any one
of these events was small and it did not cross the
statistical boundary established to ensure participant
safety. Therefore, the group recommended continuing the
trial due to the still uncertain balance of risks and
benefits.
Then, at the DSMB's regularly scheduled meeting on May 31,
2002, the data review revealed for the first time that the
number of cases of invasive breast cancer in the estrogen
plus progestin group had crossed the boundary established as
a signal of increased risk.
"In designing the trial and following the results, the
safety of the patients was of the utmost importance," said
Garnet Anderson, Ph.D., a biostatistician who led the
analysis at the Fred Hutchinson Cancer Research Center,
Seattle, Washington. "Because breast cancer is so serious an
event, we set the bar lower to monitor for it. We
pre-specified that the change in cancer rates did not have
to be that large to warrant stopping the trial. And the
trial was stopped at the first clear indication of increased
risk," she added. She also noted that, at that point, there
was no indication of increased risk for breast cancer in the
estrogen-only group.
The DSMB's May 31 recommendation to stop the trial was based
on the finding of increased breast cancer risk, supported by
the evidence of overall health risks exceeding any benefits.
Following the NHLBI's decision to stop the study, the
Institute and the investigators have worked intensively to
develop information materials for participants. On July 8,
participants started receiving letters informing them about
the results and telling them that they should stop study
medications. Participants will be contacted by their
clinical centers for further counseling and will continue to
have clinic visits so that their health outcomes can be
followed.
All WHI participants, including those in the other study
components, are also receiving a newsletter with a summary
of the findings and an explanation of risks and benefits.
Dr. Rossouw stressed the importance of understanding how the
risk to an individual woman can be low, but the risk to the
population at large can be great.
"The WHI results tell us that during 1 year, among 10,000
postmenopausal women with a uterus who are taking estrogen
plus progestin, 8 more will have invasive breast cancer, 7
more will have a heart attack, 8 more will have a stroke,
and 18 more will have blood clots, including 8 with blood
clots in the lungs, than will a similar group of 10,000
women not taking these hormones. This is a relatively small
annual increase in risk for an individual woman. Individual
women who have participated in the trial and women in the
population who have been on estrogen and progestin should
not be unduly alarmed. However, even small individual risks
over time, and on a population-wide basis, add up to tens of
thousands of these serious adverse health events," explained
Rossouw.
The National Cancer Institute (NCI) re-emphasized the
recommendation that all women in their forties and older get
screened for breast cancer with mammography every 1 to 2
years.
"Women in the WHI, women taking hormones for any reason, and
any woman over 40 should remain committed to their regular
program of breast cancer screening to allow the earliest
possible detection of breast cancer," said Leslie Ford,
M.D., associate director for clinical research in NCI's
Division of Cancer Prevention.
"The reduction in colorectal cancer risk in the WHI is
intriguing, but the balance of harm versus benefit does not
justify any woman beginning or continuing to take estrogen
plus progestin for this purpose. NCI has a number of
clinical trials under way investigating new methods to
detect and prevent both colorectal cancer and breast cancer
that will provide critical information to help women make
important health decisions," added Ford.
Specific study findings for the estrogen plus progestin
group compared to placebo include:
-
A 41 percent increase in strokes
-
A 29 percent increase in heart attacks
-
A doubling of rates of venous thromboembolism (blood
clots)
-
A 22 percent increase in total cardiovascular disease
-
A 26 percent increase in breast cancer
-
A 37 percent reduction in cases of colorectal cancer
-
A one-third reduction in hip fracture rates
-
A 24 percent reduction in total fractures
-
No difference in total mortality (of all causes)
The WHI involves over 161,000 women who are participating in
a set of clinical trials or an observational study. The
clinical trials are designed to test promising but unproven
preventive measures for heart disease, breast and colorectal
cancer, and osteoporosis. In addition to the trials of
estrogen alone and estrogen plus progestin, other trials are
studying a low-fat eating pattern and calcium/Vitamin D
supplementation. WHI is sponsored by NHLBI in collaboration
with four other components of the NIH-- the National Cancer
Institute, the National Institute of Arthritis and
Musculoskeletal and Skin Diseases, the National Institute on
Aging, and the Office of Research on Women's Health. Note:
Wyeth-Ayerst Research provided the medication (active
hormones and placebo) for the estrogen plus progestin study.
The complete media kit from the July 9, 2002, news
conference is available at
http://www.nhlbi.nih.gov/health/women/kit.htm. General
information about the WHI -- including additional research
results -- is available on the NHLBI Web site at
http://www.nhlbi.nih.gov/whi and at
www.whi.org (for study participants). More information
on breast cancer, including prevention and early detection,
is available from the NCI's Cancer Information Service at
1-800-4-CANCER (1-800-422-6237) and at
www.cancer.gov.
