CV SIG Oct 2012
WHI CV SIG CALL
Wednesday, October 10, 2012
9-10 am PT (noon ET, 11 am CT)

Call number: 1-866-618-2448; Passcode: 9920978
Call Lead By: Marcia Stefanick
Attendees: Matt Allison, Matt Freiberg, Beth Lewis, , JoAnn Manson, Marco Perez, Jacques Rossouw,
Lesley Tinker, Linda Van Horn, Robert Wild
1. Announcements:
a. There was a request for the creation of a CV SIG sub-group for chronic kidney disease (CKD).
Wolfgang Winklemeyer (Stanford) and Nora Franceschini (UNC) have set up a call for today (Oct 10)
at 10:30 Pacific (same call number) to discuss this further. You are welcome to join.
b. Biomarker data, European ancestry cohort (~10,000): these data are now available for analyses of
approved paper proposals. See the WHI website (news).
2. WHI Paper of the Month: Rossouw JE,et al. Relationships of coronary heart disease with 27hydroxycholesterol, low-density lipoprotein cholesterol, and menopausal hormone therapy. Circulation.
2012 Sep 25;126(13):1577-86. Epub 2012 Aug 29. [featured on WHI home page.]
JoAnn, one of the coauthors presented:
Background: Lew Kuller and several other WHI investigators proposed that WHI core resource funds be
used to investigate the relationships of the endogenous estrogen receptor antagonist (27OHC), LDLC,
and MHT 3-4 years ago, based on the WHI findings that MHT increases the risk of CHD in older women
with elevated LDLC and evidence from laboratory studies that prolonged elevation of 27OHC in animals
(mice) prevents the beneficial effects of estrogen on LDLC.
27OHC levels correlate with LDLC levels and serve as antagonists of the estrogen receptor., Laboratory
research suggested that prolonged elevations of 27OHC, such as occurs in older animals (mice/rodents),
blocks or antagonizes the estrogen receptor. It was argued that, whereas administering estrogen in early
menopause reduces LDLC, thereby leading to a favorable effect on atherosclerosis progression, a
hypothesis generated 3-4 years ago suggested that elevated 27OHC levels after menopause reduce the
favorable effects of estrogen on the endothelium (seen in younger women) and may underlie the very
strong relationship seen in several studies of adverse lipid profiles, i.e. high LDLC being associated with a
particularly adverse coronary outcome on estrogen. Jacques and others became interested in looking at
this question in terms of the level of 27OHC, LDLC, and various lipid subtractions in predicting coronary
events, as well as modifying the estrogen effects on CHD in the randomized MHT trials. Jacques
arranged to have 27OHC measured in a case:control analysis. First there was no association between
27OHC and risk of incident CHD events after adjusting for LDLC. This was in contrast to LDL cholesterol
or LDL/HDL ratio, which were strongly predictive of risk in the cohort. Second, 27OHC was not a modifier
of the effect of estrogen, i.e. regardless of the level, there was no difference in terms of hazard ratios. In
contrast, we have seen very strong relationships between LDL cholesterol and the effect of estrogen on
risk of coronary events in the two HT trials. In both trials, women with higher baseline LDLC (above 130
mg) were at increased risk of CHD events if assigned to E+P or E alone vs placebo; whereas, in women
with low baseline LDLC (below 70) there was a suggestion of a reduced odds ratio, i.e. LDLC level is a
much stronger effect modifier than 27OHC. With an adverse lipid profile, it may be that the epithelium is
no longer sensitive to estrogen in terms of vasodilation, the usual benefit seen in laboratory animals when
the epithelium is healthy. So far, LDLC has been the strongest modifier of results, probably stronger than
age or time since menopause and total cholesterol/HDLC ratio. (HDLC level has been a modifier in the
opposite direction of LDLC in previous studies, whereas 27OHC neither predicted events individually nor
was it an effect modifier. The results were strongly null for 27OHC.
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CV SIG Oct 2012
Conclusion: the authors suggested that it might be useful to measure blood lipids before initiating
menpausal hormones because it may aid in counseling individual women about MHT and cardiovascular
risk in general.
JoAnn commented further: There wasn’t adequate power to simultaneously stratify by age or time since
menopause as well as LDLC. Would it make a difference to start with a newly menopausal woman who
is already at low risk, doesn’t have diabetes or other risk factors? It would be unfortunate if, based on
fairly limited data, newly menopausal women who have an LDL of 130 or 140 would be told to go on
estrogen. A lot of these higher LDLs are in older women who have metabolic syndrome and a lot of other
risk factors. Metabolic syndrome was also a strong modifier of the results in Robert Wild’s recent WHI
paper. When there are questions regarding hormone therapy it’s a good opportunity to screen all
cardiovascular risk factors, including lipids, and if LDLC is high they can go on statins. In fact, when
stratifying study populations by statin (yes/no), it appeared that women on statins did not have the
increased risk of coronary events seen in the overall cohort, which had an HR of 1.27.
3. Two New Studies
a. Danish Osteoporosis Prevention Study: a new report on CV risk in younger women that received a
lot of attention – Marcia sent this to the CV SIG before the call. DOPS is following a cohort for an
osteoporosis prevention study with an unconventional design: women were 45-58 when they started,
half of those were randomly assigned to open label to get hormone therapy or to no treatment.
Another 1,000 women were given a personal choice of which 250 opted for hormone therapy. This
particular paper does not include those women; rather, only those assigned to open label menopausal
hormones (2mg of synthetic 17 beta estradiol for 12 days, 2mg of 17 beta estradiol plus 1mg
norethisterone acetate for 10 days, and 1mg 17 beta estradiol for 6 days)* or no hormone were
included. *[i.e. different estrogens and progestin from the WHI trials.]
i. Conclusion – Although the women who were assigned to open label hormone had less heart
disease diagnosed during follow up, there were many methodologic flaws that limited interpretation
of the study.
ii. NOTE: After the call,Jacques drafted a letter to the editor which a few CV SIG members edited and
it was published in BMJ and sent to the CV SIG
b. KEEPS – JoAnn will give a presentation with slides on the November call, but provided a quick report
on the October call. The study was presented for the first time at a NAMS Presidential Plenary on Oct
3, 2012. The researchers acknowledged at the outset that KEEPS did not have statistical power to
evaluate clinical events. There were 727 women, ages 42-58 (average age, 52.7) randomized to one
of three arms: low dose oral conjugated estrogen at a dose of 0.45mg per day; transdermal estradiol
patch at 50mcg per day (both of which received cyclical micronized progesterone for 12 days per
month); and a placebo group which received both a placebo estrogen pill and patch, and 12 days per
month of a placebo cyclical progesterone pill. All women were within 3 years of the onset of
menopause. The main objective was to look at surrogate outcomes for cardiovascular disease,
including the progression of atherosclerosis by carotid IMT and development of coronary artery
calcium. Secondary outcomes were also of strong interest: including quality of life, mood, depressive
symptoms, sexual function, symptom management, and cognitive function. Cognitive function was a
major ancillary study, funded by the NIA. The main trial was funded by the non-profit organization in
Phoenix, AZ called the Aurora Foundation with funds to the Kronos Longevity Research Institute. Nine
U.S. clinical centers participated in the study. The follow up was strong: 80% of participants had
follow-up through 4 years and the overall compliance with hormone therapy was 65% over the 4-year
period.
i. Key Findings – Focusing on the cardiovascular risk factors, blood pressure effects, and
intermediate biomarkers (CVD biomarkers). There was a neutral effect on systolic and diastolic
blood pressure. This was reassuring in contrast to WHI which had a significant increase in systolic
blood pressure. There were expected effects on lipids on oral estrogen– i.e. significant reduction in
LDL, significant increases in HDL and in triglycerides, increases in CRP, but no increase in the
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CV SIG Oct 2012
interleukin 6 level. With the transdermal estradiol, neutral effects were seen for lipids but favorable
effects on the insulin glucose and insulin resistance levels; thus the HOMA-IR measurements were
improved with transdermal estradiol but not with oral estrogen.
In the WHI, both E + P and E alone were associated with improvement in glucose and insulin levels;
as well as the reduction in incidence of diabetes. In terms of progression in atherosclerosis, there
was very little progression in these newly menopausal women, even in the placebo group. There
was little power to see across the three groups in terms of carotid IMT, which showed very similar
progression rates. In terms of coronary artery calcium, there was a suggestive trend toward less
calcium development in the two HT arms compared to the placebo arm; however it was not a
significant difference. In terms of cognitive function, in contrast to WHI which saw adverse effects
(increased cognitive decline) in women 65 and over. Overall the cognitive results were neutral;
however in the women who started out with low cardiovascular risk at baseline we found there was
evidence for improvement in cognitive function with the oral estrogen in the domains of memory and
verbal learning. These benefits were not seen with transdermal estradiol. Quality of life outcomes
included mood, depressive symptoms, the POMS instrument, anxiety, tension, and other emotional
health outcomes. There was significant benefit of the oral conjugated estrogen for mood,
depression symptoms, tension, anxiety; and a more intermediate benefit of the transdermal
estradiol. Where the transdermal estradiol did better than the oral conjugated estrogen was with
sexual function. Both forms of hormone therapy led to improvements in sexual function in terms of
reducing discomfort with intercourse, dyspareunia symptoms, and vaginal dryness/lubrication
outcome. The libido aspects of sexual function (desire, arousal, orgasm) were improved by
transdermal estradiol but not by oral. We will look at SHBG, but the theory is that oral estrogen, by
increasing sex hormone binding globulin, will lead to more binding of testosterone and a reduction in
the free testosterone level. This may not be a favorable effect in terms of sexual function whereas
with transdermal estradiol there will be no increase in sex hormone binding globulin. Sexual
function overall may improve as women are no longer having discomfort with intercourse and their
testosterone levels aren’t falling.
ii. Mammographics –Mammographic density and mammogram follow-up outcomes. Kathy Rexrode
at Brigham Women had an ancillary study (preliminary data) on breast outcomes which showed that
neither form of hormone therapy increase breast density as assessed through the readings of the
mammograms. The digital mammograms will be read by a central reading center and results will be
available in a few months at which point we will be able to tell if there are any differences between
oral, transdermal, and placebo. There was no increase in the need for follow-up testing with oral
conjugated estrogen, but there was a small and significant increase with the transdermal.
iii. Overall – For some outcomes, transdermal estradiol did better and for others, oral estrogen did
better. Transdermal estradiol improved insulin resistance and libido-related aspects of sexual
function. Oral conjugated estrogens did better in terms of lowering LDL, increasing HDL, improving
mood and depressive symptoms, and anxiety/tension; as well as improving cognitive function in the
healthy group. There was no difference in terms of progression of atherosclerosis. Overall the
results underscore the need for individualized decision-making based on the symptoms, risk factors,
and priorities for treatment of the woman. Also, it is clear that newly menopausal women who have
generally healthy arteries will have low progression of atherosclerosis and few coronary events;
thus, these outcomes are not major factors in the benefit/risk equation, and presumed
cardioprotection should not be a reason for starting hormone therapy. Out of 727 women there was
only one MI during 4 years of treatment, zero strokes, and two venous thromboembolic events.
4. Plans for the SIG – Next call: how can we improve the SIG. We came up with some ideas for papers.
What else can we do to improve and make the SIG more interesting?
Future Calls: NEXT CALL: November 14 (9-10 am PT (noon ET, 11 am CT); and December 12
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