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Overview Page 1
America Responds to the
Women’s Health Initiative
(WHI) Study The Women’s Health Initiative (WHI)
study is an NIH-sponsored multicenter
study that began in 1993 and enrolled
161,809 women ages 50-79.1 It is one
of the first randomized controlled
trials with a study population of a size
sufficient to examine the relationship
between hormone replacement therapy
and cardiovascular disease, thromboembolism,
breast cancer, fractures, and
other outcomes. The estrogen plus progestin
arm of the study (n=16,608)
enrolled healthy postmenopausal women
(mean age 63) with an intact uterus.
This arm of the WHI trial was a randomized,
placebo-controlled study of
daily administration of Prempro™ (conjugated
equine estrogen 0.625 mg/day
and medroxyprogesterone acetate
2.5 mg/day). It is the most rigorous
study to date of the effect of combined
estrogen and progestin on breast
cancer risk and cardiovascular disease.
Another arm of the study includes
women who had undergone a hysterectomy
and received estrogen alone or
placebo (n=10,739). Additional, ongoing
WHI studies are evaluating
memory, dementia, calcium, vitamin D,
and low-fat diets.
On July 9, 2002, the National Heart,
Lung, and Blood Institute of the National
Institutes of Health announced that it
had halted the study arm evaluating
the combined use of estrogen and progestin.
After evaluating available data,
they concluded that the risks of therapy,
specifically the increased risk for invasive
breast cancer, outweighed the benefits.
The estrogen-only arm is continuing,
with no reported increase in the risk for
breast cancer to date.
Summary of WHI study results
A major outcome measure was the
risk for cardiovascular disease. The WHI
results showed no benefit in the prevention
of heart disease; in fact, there
was a small but significant increase in
the risk for cardiovascular events among
women taking combined therapy
(Figure 1). There was a 29% increase in
the risk for coronary heart disease (CHD)
[hazard ratio: 1.29 (95% confidence
interval: 1.02-1.63)]. This translates into
seven additional CHD events per 10,000
women per year. The risk is cumulative
over time.
The WHI results also showed a 26% increase
in the risk of invasive breast cancer
with combined estrogen-progestin
use [hazard ratio: 1.26 (95% confidence
interval: 1.00-1.59)] (Figure 2). Again,
the increased risk for the individual is
small, resulting in eight additional cases
per 10,000 women per year. As above,
the risk is cumulative over time.
There was a 41% increase in the risk
for stroke [hazard ratio: 1.41 (95%
confidence interval: 1.07-1.85)], while
the risk for pulmonary embolism was
more than doubled [hazard ratio:
2.13 (95% confidence interval: 1.39-
3.25)] in women taking combined
therapy. These results are consistent with
those of earlier studies. For individuals,
the risk remains low but is cumulative
over time, resulting in eight additional
cases of stroke and eight additional cases
of pulmonary embolism per 10,000
women per year.
The WHI results supported the fracture
benefits suggested by earlier studies.
The incidence of hip fracture was
reduced by 34% in women taking the
combined therapy [hazard ratio:0.66
(95% confidence interval: 0.45-0.98)].
This translates into five fewer hip fractures
per 10,000 women per year.
Vertebral fractures were also reduced by
34% [ hazard ratio: 0.66 (95% confidence
interval: 0.44-0.98)]. This translates into six
fewer fractures per 10,000 women per year.
Total fractures were reduced by 24% [hazard
ratio: 0.76 (95% confidence interval: 0.69-
0.85)], or 44 fewer fractures per 10,000
women per year.
The risk for colon cancer was reduced by
37% among women taking combined therapy
[ hazard ratio: 0.63 (95% confidence
interval: 0.43-0.92)], resulting in six fewer
cases per 10,000 women per year. The
mechanism for this apparent protective
effect is unknown.
Responses to WHI results:
recommendations of
The American College of
Obstetricians and
Gynecologists (ACOG)
The WHI study results overturned much of
the conventional wisdom about the benefits
of combined estrogen-progestin treatment.
The results, which received extensive coverage
in the lay as well as the professional
press, suggest that hormone replacement
therapy using the Prempro™ formulation, can
no longer be recommended for long-term
therapy. Clinicians were flooded with phone
calls from concerned patients and there was
considerable debate among professionals
about the clinical implications of the results.
An ACOG expert panel review of available
data emphasized that the results of the
WHI trial are applicable only to the
estrogen-progestin regimen used in the
study and cannot reasonably be extrapolated
to other formulations. The panel made the
following recommendations:2
The decision to use hormone replacement
therapy (HRT) should be based on an
evaluation of the risks and benefits for
each individual patient. Physicians who
prescribe HRT for vasomotor symptoms
should do so for the shortest possible time
at the lowest effective dose. The WHI
study did not establish what constitutes a
safe period for short-term use.
Women who request long-term HRT therapy
for perceived quality-of-life benefits should
be counseled about the risks and about
available alternative therapies. If they choose
to continue HRT, it should be at the lowest
possible dose and the need for therapy
should be reevaluated periodically. For
nonhormonal alternatives may be effective;
these include selective serotonin reuptake
inhibitors, clonidine, or Bellergal-S.
Combined estrogen-progestin cannot be recommended
for the prevention of cardiovascular
disease; if previously prescribed for this
purpose, the therapy should be discontinued.
Exercise, smoking cessation, and weight loss
should be recommended for all women.
Alternative preventive therapies, such as
bisphosphonates or raloxifene, should be
prescribed for women with osteoporosis.
However, for women with osteoporosis and
vasomotor symptoms, the benefits of HRT
may outweigh the risks.
The benefits of HRT in preventing colorectal
cancer, Alzheimer’s disease, or mood
disturbances have not been conclusively
demonstrated, and HRT cannot be recommended
for these indications.
Some women who discontinue HRT, either
abruptly or incrementally, will experience
vasomotor symptoms and/or vaginal bleeding.
At this time, there are no definitive data
to guide the withdrawal process.
Responses to WHI results:
report from The
North American Menopause
Society (NAMS)
In response to the WHI and Heart and
Estrogen/Progestin Replacement (HERS)
trials, The North American Menopause
Society (NAMS) recently convened an expert
Advisory Panel to develop clinical recommendations
regarding the use of HRT.3 The
panelists developed a list of clinically relevant
questions and answers and then met by conference
call to attempt to reach a consensus.
HERS was a randomized, placebo-controlled
trial of postmenopausal women with documented
heart disease (n=2763). The mean
age of women in this study was 67 years
(range:55-79).
Patients were assigned to estrogen plus
progestin or placebo. The initial study
ended after 4.1 average years of follow-up,
but 93% of the subjects continued treatment
for an additional 2.7 years. Results
showed no decreased risk for coronary
heart disease, a nonsignificant increased
risk for stroke, and a significantly increased
risk for venous thromboembolism [hazard
ratio: 2.08 (95% confidence interval: 1.28-
3.40)]. HERS did not show significant
differences between the groups in the risk
of fracture.
The Advisory Panel reached a consensus on
the following major clinical practice issues:
-
The primary indication for HRT
remains the treatment of vasomotor
and urogenital menopausal symptoms.
-
Women on estrogen therapy who
have an intact uterus should receive
adequate progestin to protect the
endometrium. Women without a
uterus should not be prescribed
a progestin.
-
No HRT regimen should be
prescribed for the prevention of
coronary heart disease.
-
Because of the risks of HRT,
alternative therapies should be
considered for the prevention of
postmenopausal osteoporosis.
-
Use of HRT should be limited to
the shortest duration consistent with
benefits, risks, and treatment goals.
-
Lower-than-standard doses of HRT
should be considered.
-
Candidates for HRT should be
informed of known risks.
The Advisory Panel was not able to reach
a consensus on several questions. These
included: How long should HRT be prescribed
for relief of menopausal symptoms?
Does premature menopause represent an
indication for preventive HRT? Is there a
rationale for extended therapy? To the last
question,a majority of the panelists believed
that extended use would be acceptable in
women with menopausal symptoms who
are at risk for osteoporosis, or if the patient
is at increased risk for osteoporosis and is
unable to tolerate other therapeutic options.
The FDA’s response
The Food and Drug Administration (FDA)
recently advised health care professionals
about changes to the labeling of all estrogen
and estrogen with progestin products.4
The agency’s recommendations are in very
close accord with those of ACOG and NAMS.
The FDA has approved new package inserts
and patient information brochures for
Prempro™, Premphase®, and Premarin® and
has requested that all other manufacturers
of HRT make similar changes to their
labeling. A new “black box” warning highlights
the increased risk for heart disease,
heart attacks, strokes, and breast cancer
and emphasizes that these products are not
approved for the prevention of heart disease.
Two of the indications for these products,
moderate to severe vasomotor symptoms
and prevention of osteoporosis have also
been modified to include consideration
of alternative therapies. Like ACOG and
NAMS, the FDA advises health care providers
to prescribe HRT products at the
lowest effective dose and for the shortest
possible duration.
The FDA’s review of the WHI results
raised some important questions for future
research. These include:Will lower HRT
doses have lower risks? Will different
administration routes, such as transdermal
patches, have different risks? And, what
is the best way to stop taking HRT?
REFERENCES
-
Writing Group for the Women’s Health Initiative
Investigators. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women:
principal results from the Women’s Health
Initiative randomized controlled trial.
JAMA. 2002;288:321-333.
-
ClinicalPracticeDivision@acog.org
-
www.menopause.org
-
FDA News. January 8, 2003.
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