HRT to protect the heart? Women's Health Initiative (WHI

1

• Estrogen Replacement and Atherosclerosis (ERA)
• 309 postmenopausal women with established
  coronary disease randomized to

0.625 mg/d conjugated equine estrogen (CEE)
Placebo
or
vs
CEE 2.5 mg/d medroxyprogesterone acetate
2

• Estrogen Replacement and Atherosclerosis (ERA)
• At the end of 3.2 years, it was found that
  neither estrogen nor estrogen plus progesterone
  had any effect on the progression of coronary
  artery disease as measured by quantitative
  angiography (within subject mean minimum lumen
  diameter).
• Women in the treatment arms showed significant
  reductions in LDL cholesterol and significant
  increases in HDL cholesterol.

3

• Observational studies suggested cardiovascular
  benefit to HRT
• Observations from the Nurses Health Study showed
  a reduction in the risk of cardiovascular
  mortality of approximately 50 for current users
  of HRT (among 48 470 women free of cardiovascular
  disease at baseline).
• but
• Healthy women are more likely to be prescribed
  estrogen by their treating physician.

4

• Heart and Estrogen/progestin Replacement Study
  (HERS)
• A total of 2763 women under the age of 80 with
  documented CHD and an intact uterus were
  randomized to receive either 0.625 mg/d of CEE
  plus 2.5 mg medroxyprogesterone acetate or
  placebo.
• After an average of 4.1 years of follow-up, no
  significant differences were seen in primary or
  secondary cardiovascular endpoints.
• More CHD events occurred in the treated group
  compared to placebo at 1 year, with fewer events
  in the treated group over 4 to 5 years.

5

• Low dose simvastatin and HRT in postmenopausal
  women
• Multicentered clinical trial in which 140
  postmenopausal women with increased LDL were
  treated with either HRT (PremPro), low dose
  simvastatin, HRT and low dose simvastatin or
  placebo over a 6 week period.
• The average LDL at baseline was 190 mg/dL.

6

• Low dose simvastatin and HRT in postmenopausal
  women

7

• Statins and HRT in postmenopausal women
• In women with established heart disease and
  elevated cholesterol, statins should be first
  line therapy.
• It is unknown whether additional increments in
  lipid lowering from combination of HRT and
  statins translates into additional increments in
  reduction of risk.
• In HERS and ERA trials, estrogen had a beneficial
  effect on lipids, but this did not translate into
  a beneficial effect on slowing the progression of
  disease.

8
We are not sure whether these lipid lowering
effects automatically translate into clinical
benefits. This is the reason that we need
clinical endpoint trials. These surrogate markers
are not necessarily items that will translate
into clinical benefit. Dr Nanette Wenger
Professor of Medicine Emory University School
of Medicine Atlanta, GA
9

• Raloxifene Use for The Heart (RUTH)
• Selective estrogen receptor modulators offer the
  possibility of dissociating the benefits of
  hormone replacement therapy from the risks.
• They do not have adverse effects on uterus or
  breast tissue, and are known to have beneficial
  effects on bone.
• RUTH involves 10 000 postmenopausal women with
  documented CHD or at high risk for its occurrence
  in 26 countries. Primary outcome is nonfatal
  coronary infarction or coronary death.
• At least 5 years of follow up will be required to
  obtain the number of events necessary to
  establish sufficient power.

10

• Womens Health Initiative (WHI)
• A HRT arm includes 16 609 women with a uterus
  randomized to CEE and medroxyprogesterone acetate
  versus placebo, and 10 739 women without a uterus
  randomized to CEE or placebo.
• The National Heart, Lung and Blood Institute has
  recently updated the informed consent for entry
  into the trial following a recent meeting of the
  Data and Safety Monitoring Board.
• Sufficient data were judged to be available from
  the first 2 years of follow-up to indicate that
  women receiving HRT had somewhat more
  cardiovascular events than those receiving
  placebo.

11
It has become abundantly clear over the past
two years that the relationship between estrogen
and heart disease is far more complex than we
ever imagined Women who currently have heart
disease should not be taking estrogen with the
expectation that they will be deriving
cardiovascular benefit from it. Dr David
Herrington Associate Professor of
Medicine/Cardiology Wake Forest University
School of Medicine Winston-Salem, NC
12
One of the most important messages is that we
should be relying on those interventions that
have been proven to be effective for reducing
risk. With regard to the statin drugs, for
instance, we know that they will reduce the risk
of an event. Whether or not a woman chooses to
use HRT is a complex issue that needs to be
individually decided in conjunction with her
physician. Dr Kevin Maki Vice
President Chicago Center for Clinical
Research Chicago, IL
13

• HRT and cardiovascular risk
• The important feature from the Womens Health
  Initiative is the potential for early
  cardiovascular risk, suggesting possibly not only
  for women with heart disease but for healthy
  women as well.
• Proven therapies for women with heart disease
  include blood pressure control, diet, statin use
  and physical activity. These therapies should be
  first-line management.