Estrogen and Coronary Heart Disease

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Estrogen and Coronary Heart Disease

• by
• Brad Jones

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Case Presentation

• 56 y/o WF PMH significant for TAH on Premarin for
  10 years.
• Cardiovascular risk factors include history of
  early MI in father.
• No documented coronary disease.
• Should this patient be continued on estrogen for
  primary prevention of coronary heart disease
  (CHD)?

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Goals of this presentation

• Discuss history of estrogen in CHD and review
  cardioprotective effects and observational
  studies
• Review course of HRT not being recommended for
  secondary prevention of CHD ie HERS,ERA
• Discuss the results from WHI
• Review data that suggests that estrogen could be
  beneficial in preventing atherosclerosis
  formation
• Attempt to go a step further and understand what
  is happening from a basic science standpoint
• Finally, present some evidence to Dr. Dubose for
  the fishing in North Carolina.

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Introduction

• Coronary heart disease is the leading cause of
  death in women, and mortality rates from this
  disease substantially increase after menopause.
  Bilateral oophorectomy before natural menopause
  increases the risk for CHD. This pattern along
  with over 40 observational studies have suggested
  that HRT reduces the cardiovascular risk in
  postmenapausal women. Furthermore, estrogen has
  been demonstrated to have seemingly beneficial
  effects on the cardiovascular system.

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Effects of estrogen on the cardiovascular system

• Beneficial effects on blood vessels
• Effects on Lipids
• Effects on coagulation cascade, both thrombosis
  and the fibrinolytic cascade.
• Decreases renin,ACE,endothelin-1,vascular
  expression of angiotensin receptor type 1,with
  the net effect of promoting vasodilation

• This increase in vasodilatation has been
  demonstrated by echo to decrease LV mass
• Antioxidant effects

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Many observational studies showing decreased
mortality and cardiovascular events with estrogen

• The most comprehensive observational study is
  the Nurses Health Study. The NHS was first
  published in 1985 and updated in 1991,1996 and
  most recently updated in Annals of Internal
  Medicine(Grodstein et. al.) It began in 1976 when
  121,700 female nurses age 30 to 55 years of age
  completed a mailed questionnaire about hormone
  use and CVD. In the latest report, with 70,533
  post-menopausal women followed for up to 20
  years, current HRT was associated with a relative
  risk reduction of 39 and .625mg and .3mg of
  conjugated estrogen with a relative risk
  reduction of 46 and 42 respectively.

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Tanya and Chief (before Chiefs amazing growth
spurt)
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So when did we first realize that Estrogen was
not beneficial in prevention of coronary heart
disease?
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The Coronary Drug Project

• This study was published in JAMA in 1970 and
  among other interventions, looked at the effect
  of estrogen on CHD.
• This study consisted of men age 30 to 64 with
  documented previous myocardial infarction.
• After 18 months it was noticed that the estrogen
  group had significantly more events of nonfatal
  myocardial infarction than placebo.
• Therefore the study arm receiving 5mg of daily
  estrogen was discontinued.

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Excessive beverage intake
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Excessive pork intake
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Randomized Trial of Estrogen Plus Progestin for
Secondary Prevention of Coronary Heart Disease in
Postmenopausal Women

• The HERS trial was the first randomized,
  double-blind, placebo-controlled trial of daily
  use of conjugated equine estrogens plus
  medroxyprogesterone acetate on the combined rate
  of nonfatal MI and CHD among postmenopausal women
  with coronary disease.
• Briefly the study population was 2,763
  postmenopausal women age 44 to 79 years old(mean
  age 66.7 years) with established coronary
  disease.(defined as history of MI,
  revascularization or angiographic evidence fof
  CAD)
• Follow-up visits were every 4 months during the
  study period of 4.1 years.
• Rsults Primary events(nonfatal MI or CHD death)
  occurred in 172 women in the hormone group and in
  176 in the placebo group 33.1/1000 and 33.6/1000
  respectively.

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Results did not reach statistical significance
however it was noted that during the first year
there was a trend towards increased events in the
hormone group(relative hazard1.52) followed by
decreased events later in the trial.(see graph
below)
Figure 3. Kaplan-Meier estimates of the
cumulative incidence of primary coronary heart
disease (CHD) events (left) and to its
constituents nonfatal myocardial infarction (MI)
(center) and CHD death (right). The number of
women observed at each year of follow-up and
still free of an event are provided in
parentheses, and the curves become fainter when
this number drops below half of the cohort. Log
rank P values are .91 for primary CHD events, .46
for nonfatal MI, and .23 for CHD death. 
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Effects of Estrogen Replacement on the
Progression of Coronary-Artery Atherosclerosis

• In this study published by Herrington et. al. in
  The New England Journal of Medicine, 309 women
  age 41 to 80(mean 65.8)with angiographically
  verified coronary disease (gt to 1 stenoses of gt
  to 30 luminal diameter on angiography)were
  randomly assigned to receive .625mg of
  conjugated estrogen, .625 of estrogen plus 2.5mg
  of medroxyprogesterone, or placebo.
• Patients underwent follow-up angiograms at 3.2
  years.
• Results Repeat angiogram showed the mean minimal
  coronary-artery diameters at follow-up to be
  1.87/-.02mm,1.84/-.02mm and 1.87/-mm in the
  estrogen, estrogen and progesterone and placebo
  groups respectively.
• Conclusions Neither estrogen alone nor estrogen
  plus medroxyprogesterone affected the progression
  of coronary atherosclerosis in women with
  established diseased.

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Risks and Benefits of Estrogen Plus Progestin in
Healthy Postmenopausal WomenPrincipal Results
From the Womens Health Initiative Randomized
Controlled Trial

• The Womens Health Initiative(WHI) is a
  randomized double blind placebo trial that
  enrolled 161,809 post menopausal women in the age
  range from 50 to 79 years.
• The trial was stopped early based on health
  risks that exceeded health benefits over an
  average follow-up of 5.2 years.
• A parallel trial of estrogen alone in women who
  have had a hysterectomy is being continued, and
  the planned end of this trial is March 2005, by
  which time the average follow-up will be about
  8.5 years.
• Results Estimated hazard ratios (HRs) were as
  follows CHD, 1.29 breast cancer 1.26 stroke,
  1.41 PE, 2.13 colorectal CA, .63 endometrial
  cancer, .83 hip fracture, .66 and death due to
  other causes .92. Absolute excess risks per
  10,000 person-years attributable to estrogen plus
  progestin were 7 more CHD events, 8 more strokes,
  8 more PEs, and 8 more invasive breast cancers,
  while absolute risk reductions per 10,000
  person-years were 6 fewer colorectal cancers and
  5 fewer hip fractures. The absolute excess risk
  of events included in the global index was 19 per
  10,000 person-years.

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Coronary Heart Disease in WHI Study

• CHD was defined as acute MI requiring overnight
  hospitalization, silent MI determined from serial
  electrocardiograms(ECGs), or CHD death.
• Overall the rate of women experiencing CHD events
  was increased by 29 for women taking estrogen
  plus progestin relative to placebo(37 vs 30 per
  10,000 person-years). Of note the excess was in
  nonfatal MI with no significant differences in
  CHD deaths or revascularization procedures.
• A small group was eligible for HERS

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Figure 3. Kaplan-Meier Estimates of Cumulative
Hazards for Selected Clinical Outcomes 
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How could it be with the beneficial effects of
estrogen on the CVS, along with multiple
observational trials that these trials have shown
estrogen to have no benefit and even mild
increase in CHD events?

• In interpreting the data one has to realize that
  HERS and ERA are secondary prevention trials.
  Also WHI, which is thought of as a primary
  prevention trial, the mean age of beginning HRT
  was much later than most clinicians institute HRT
  for perimenapausal symptoms. Also some of the
  women in the WHI had documented coronary disease.

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Chief meets Bailey
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Do we have any RCTs for estrogen decreasing
progression of atherosclerosis

• Hodis et. al. published an article in Ann In Med
  2001 titled The Estrogen in the Prevention of
  Atherosclerosis Trial(EPAT).
• This was a randomized, double-blind,
  placebo-controlled, carotid artery ultrasound
  trial designed to test whether unopposed
  estrogen vs placebo reduces progression of
  subclinical atherosclerosis in healthy
  postmenopausal women without preexisting CVD.
• Methods222 subjects with a mean age of 61.1
  years and average time from menopause to
  randomization of 13 years. Carotid ultrasound
  was performed at baseline and every 6 months
  during the trial. The primary endpoint was the
  was the rate of change in the distal common
  carotid artery IMT(intima-medial wall thickness)
  Note Thickening of the intima-media of the
  arterial wall is the earliest detectable
  anantomic change in the development and
  progression of atherosclerosis and carotid
  intima-media thickness is a marker of generalized
  atherosclerosis and is predictive of clinical
  cardiovascular events.

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Results

• After 2 years, there was a significant reduction
  in the progression of carotid IMT in women
  randomized to unopposed estrogen replacement
  therapy versus those randomized to placebo.
• The authors concluded that unopposed
  17b-estradiol reduced the progression of
  subclinical atherosclerosis to the same degree
  as lipid-lowering therapy and lipid-lowering
  therapy appeared not to add any additional
  benefit to unopposed estrogen in reducing the
  progression of subclinical atherosclerosis.

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Data for atherosclerosis prevention in
cynonmologus monkeys

• Dr. TB Clarkson published a review in
  Cardiovascular Research in which they describe
  the life cycle into 3 stages
• Stage 1, or immediately after ovariectomy,
  monkeys given CEE had average inhibition of
  coronary artery atherosclerosis of 70
• Stage 2, monkeys were allowed to develop a
  moderate amount of atherosclerosis before
  surgical menopause. The degree of inhibition of
  CAD by CEE was reduced to 50.
• Stage 3, CEE was held 2 years after surgical
  menopause, and no inhibition of in the
  extensiveness of CAD was observed.

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Therefore, it seems that the effects of estrogen
on the CVS could be beneficial if started prior
to development of significant coronary disease
whereas after coronary lesion development it
could actually precipitate plaque rupture.
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It is possible that the disappointing results
from the previously described trials could be
from the effects of estrogen on the coagulation
cascade or polymorphisms that alter gene
expression of proteins that regulate coagulation
or fibrinolysis. While recognizing this as a
likely reason, I would like to introduce another
possibility.
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To understand what could be causing increased
early events with estrogen therapy, it is helpful
to understand the microstrucure of the
atheromatous plaque within coronary arteries.
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Beach trip 2001
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Estrogen Effects on the Natural History of
Atherosclerosis

• Estrogen Effects in Atherogenesis
• ?LDL oxidation ? ?LDL atherogenicity
• ?LDL binding/accum ? ?lesion prog
• Cell adhesion mol. ? ?monocyte adhesion/
• ?
  macrophage accum
• ?SMC proliferation ? ?lesion progression
• ?Endothelial function ? ?vasodilation

Estrogen Effects in Established
Plaques ?Inflammation ? ?PQ instability
?lesion progression ?MMP expression ? ?PQ
instability/rupture ?Neovascularization ? ?PQ
hemorrhage Loss of Estrogen Benefits ?Methylatio
n of estrogen receptors ?Vascular responsivity
Potentially adverse effects of estrogen on
athero/CHD
Benefits of estrogen on atherosclerosis
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So what causes erosion or more frequently rupture
of the fibrous cap surrounding the prothrombotic
contents in the lipid core?

• It is thought that enzymes that reside in the
  shoulder region of atheromatous plaques may
  digest the collagen matrix and cause plaque
  rupture with resulting thrombus formation.
• These enzymes are intricately tied to the
  coagulation cascade as well as platelet
  aggregation.

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Matrix Metalloproteinases or MMPs

• MMPs are members of a family of Zn-dependent
  endopeptidases capable of cleaving components of
  extracellular matrix. They are secreted as
  inactive proenzymes or zymogens and subsequently
  are activated and are capable of collectively
  degrading all components of the fibrous cap.
• Of interest to the topic at hand MMPs have been
  identified to reside in the shoulder region of
  atheromatous plaques. Furthermore estrogen has
  been implicated in their activation as well
  increased levels of MMP-9.

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Beach trip 2002
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Metalloproteinase and Gelatinolytic Activity of
Human Coronary Artery Atherosclerotic Plaques
From Galis et al, J Clin Invest, 1994
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Divergent effects of hormone therapy on serum
markers of inflammation in postmenopausal women
with coronary artery disease on appropriate
medical management

• In this study 10 women with CAD were randomly
  assigned to .625mg of equine estrogen(progestin
  2.5mg added to women with uterus in tact)
• Results By zymography proteolysis by MMP-9 was
  greater in serum samples from patients on HRT
  relative to placebo. Also MMP-9 levels measured
  by ELISA was greater as well in the serum of the
  HRT users.

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Conclusion Physiologic rationale or an
observational study usually accurately predicts
the results of RCTs. However, this is not
always the case. The problem is, one never
knows in advance if the particular instance is
one in which the preliminary data reflect the
truth, or whether they are misleading. Confident
clinical action must generally await the results
of RCTs.
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Finally I wanted to present some evidence to Dr.
Dubose for the fishing in North Carolina.
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More evidence for the fishing in North Carolina
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So what do I tell my patients and similar
patients in clinical practice?

• I feel that it is obvious from the data that
  patients should not be started on HRT for
  secondary prevention of coronary disease. Also
  the results from the WHI show that women without
  known coronary disease should not be started on
  combined estrogen progesterone for primary
  prevention. It is much less clear about the
  patient at hand, however we do not have RCTs to
  support continuing estrogen. What I plan to do
  is what we should do with all patients, which is
  to educate them to help to collectively make the
  best decision about their health. The risks of
  HRT are small and it is not known if there is
  benefit in the patient at hands case. Of course,
  in all circumstances the effects of estrogen on
  other preventions as well as benefit from
  postmenapausal symptoms must be considered. But
  with respect to CHD we still await completion of
  the estrogen arm of the WHI and studies of HRT
  being started in a younger group of women. Until
  then we have treatment proven for prevention of
  atherosclerosis (i.e. statins) and should use
  these in the interim.

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Chief on the last day of vacation at the beach.
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Special thanks to

• Dr. Herrington
• Dr. Clarkson
• Dr. Hadley
• My, wife Tanya