Bioidentical Hormones - U.S. Senate Special Committee on Aging

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Postmenopausal hormone therapy and cardiovascular disease
group and 62 In the placebo group, P= 0-OS). There was no
reduction In fractures (130 compared to 138).
Thus, HERS provided some results for hormone therapy
that were expected (increased risk for venous thromboembolism
and gallbladder disease) and some that were unexpected
[no overall reduction In CHD, and no reduction in
fractures). The trend over time for coronary disease was also
unexpected, and In fact the investigators anticipated that the
immediate effects of estrogen - for example, on fibrinotysis
and vascular reactivity - might have led to early benefit, sustained
in later years by beneficial changes in plasma lipid
concentrations. The observed early adverse effect needs to
be explained: possibiDlties include that hormone therapy
induces Inflammatory changes In unstable plaques, or that a
procoagulant effect predominates early on. There is no doubt
that menopausal hormone therapy is procoagulant, as shown
by the excess of venous thromboembolism. The findings may
be explained by the existence of a subset of women who are
particularly susceptible to one or more of the adverse metabolic
or local tissue changes Induced by hormone therapy,
and that the remaining women who did not have an early
evens reap the later benefit of lipid lowering. Alternatively,
there may be no real benefit, and the apparent later benefit
may simply reflect a survivor effect in that women most susceptible
to an adverse effect of the treatment have been
removed from the cohort. A post-hoc analysis of HERS data
indicated that women with higher lipoproteLn (a) levels were
less likely to have an initial adverse outcome, and were more
likely to benefit in later years, presumably because some of
the adverse effects of the hormones were counteracted by
a reduction in high llpoprotein (a) levels. 10
other secondary prevention trials for coronary disease and
one for stroke (and as noted above, in the WHI primary prevention
trial, a pooled analysis of short-term studies, and tn
several observational studles).35,42-44 5'53 Stimulated by the
HERS findings, a re-analysis of data from an earlier trial of
CEE 2 5 mg/day In men with exisfing heart disease revealed
a pattern of no overall benefit but with Increased risk for
CHD in the first 4 months after randomization (relative baz
ard 1-58, 95% Cl 1-04-2-40) similar to that found bn HERS
for the same period (2-29, 95% Cl 0-94-5-56).~5 A trial of
transdermal estradtol (with cyclic norethisterone for women
with a uterus) was stopped aher an average of 2-5 years
follow up for reasons of futility and possible harm
(Table 20. I).5 At the time of stopping this trial, 255 women
with anglographically defined CAD had been enrolled and
only 61% of women were still on estrogen. Though clearly
underpowered, with short follow up, and reported only in
abstract form, the results were nonetheless consistent with
HERS In that there was a 23% (P= 0-3) excess of unstable
angina, myocardial infearction, and death. Finally, the
Women's Estrogen for Stroke Trial (WEST) in women with a
recent stroke found that oral estradlol did not prevent recur
rent strokes overall, and compared to placebo there was a
higher risk for fatl strokes, and a higher risk for all strokes
in the first 6 months.
One possible explanation for the HERS findings is that
MPA negated any possible benefit from estrogen, for example
by blocking the direct vascular effects of estrogen and
blunting the rise in HDL cholesterol induced by estrogen.
(Howeveir it is noted that HDL cholesterol levels in fact
increased by 10%.) Another explanation might be that many
participants were receiving medications that would lower
risk for recurrent coronary events (for example, aspirin,
(3 blockers, lipid lowering medications, and to a lesser extent
anglotensm converting enzyme [ACE) inhibitors), thus masking
any potential for benefit from estrogen. This seems
unlikely, but even if true the trial still demonstrates that hormone
therapy is not a useful adjunct to established secondary
prevention treatments. Other possible explanations offered
are that the women in HERS were too old and their arteries
too diseased to benefit from hormone therapy, or that the type
and dose of hormones was not optimalse5 These explanalions
ignore the fact that the observational studies suggesting
benefit and which prompted the need for HERS were conducted
in populations similar to that studied in HE3and the
hormones were the same as those tested be HERS.
Though unexpected and controversial, the pattern of
early harm observed in HERS has found support in two
53 The combined data from these clinical
trials leave little room for doubt that, at least in women
with existing arterial disease (coronary or cerebrovascular),
estrogen use for up to 4 years is unlikely to result In benefit,
and in the first few months to a year Is associated with an
increased risk for arterial complIcations.
One other trial testing estradiol valerate versus placebo in
1017 women with CHD Is due to report results soon.5Y Asecondary
analysis of safety data from a trial of raioxtifene (a selective
estrogen receptor modulator) In 7705 women with
osteoporosis showed no benefit for cardiovascular outcomes
over 4 years of treatment, but suggested a risk reduction of
40% (95% Cl 5-62) In a subset of 1035 women withl
increased cardiovascular risk at baseline.is A randonized controlled
clinical trial of raloxifene (a selective estrogen receptor
modulator) versus placebo is underway in several countries in
order to test whether rafoxifene reduces the risk for CHD and
breast cancer in women with existing heart disease or who are
at high risk for heart disease.56 This trilW has enrolled 10101
women and the study is planned to end after 1670 participants
have experienced a coronary event (expected bn 2W05).