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

197
HORMONE THIERAPY USE AND RISK OF CARDIOVASCULAR DISEASE
that estrogen may delay the onset of
the earliest stages of atherosclerosis,
which are more likely to be present in
younger women, bilt it may be ineffeclive
or even trigger events in the presence
of existing advanced lesions such
as those found in older women.' The
potential existence of a window of
opportunity to reduce cardiovascular
disease is supported by animal and
laboratory studies.'
Compared with observational studies
of hormone therapy use among
healthy women stich as the Nurses'
Health Study, most women in the randomized
hormone trials were older and
the majority commenced study hormones
more than a decade after menopause
began.'-',' Subgroup analyses in
the 2 WHI trials of hormone therapy
suggested a nonsignificant reduction in
risk of CHD in women aged 50 to 59
years in the trial of CEE' or in women
with less than 10 years since menopause
in the trial of CEE + MPA. 'Risk
of stroke did not appear to be reduced
in these subgroups.'" 0 The numbersof
events in the subgroups in the individual
trials were too small to provide
definitive answers but the similar direction
of the findingssupports the idea
that pooling the trials could yield clearer
In this secondary analysis, statistical
power was improved by the use of
techniques that allow combining the
trial data to examine trends in the effects
of hormone therapy on CHD and
stroke across categories of age and years
since menopause. These results could
apply to a population similar to the
women enrolled in the WHI trials,
which included 40% of women taking
unopposed estrogen (CEE) or placebo
and 60% of women taking estrogen
plus progestin (CEE + MPA) or placebo.
Total mortality and a predefined
global index were examined to capture
the overall effects of hormone
therapy on disease outcomes. Combined
hormone therapy trial analyses
and subgroup analyses by age were prespecified
in the WHI protocol; other
analyses were not prespecified The subgroup
and secondary analyses are ex-
1466 IAMA, Apol 4, 2007-x .9 27.. 13 (Ri t depatei)
ploratory; however, given that these are therapy or first had vasomotor sytnp-
the best available data, the ipotential
toms fte, hot flashes, night sweats). For
clinical implications ofour finsdings
also women who had a hysterectomy with-
are examined.
out bilateral oophorectomy at age 50
METHODS
Study Participants and Out coines
years or older but no use of hormone
therapy or symptoms, the age at meno-
pause was defined as the age when the
The WHI trials enrolled 27 347 pre- hysterectomywasperformed. flthe al-
dominantly healthy postmei nopausal gonthm defined an age at menopause
women aged 50 to 79 years from
Sep- as older than 60 years, it was recoded
tember 1993 to October 1998lat4O
US as 60 years Anymisclassification of age
clinical centers based on hmysterec-
at menopause is likely to he nondiffer-
tomy status. Of these womei i, 10 739 ential atid would tend to bias the re-
had undergone a hysterecu omy and sults toward the null. Age at menowere
randomized to 0.625 mg 1dofCEE pause could not be defined (due to
or placebo and 16608 had rtot
had a missing values) in 1420 (8 5%) women
hysterectomy and were randc,mized
to who had not had a hysterectomy and
0.625 mgld of CEE plus 2.5S
mg/d of in 1610(15%)womenwhohadahys-
MPA or placebo. Details have Ieenpub-
terectomy. These women wvere ex-
fished elswhere.t "
cluded from the years-since meno-
The trials were reviewed and ap- pause analyses, which included 24 317
proved by the institutions I review participants.
boards at each clinical ceniter
and all Studypanicipantscompletedaques-
participants provided wr itten in- tionnaire at baseline thatvincluded a
formed consent. All outcomes werecen- probe-for the presence of vasomotor
trally adjudicated. The mam
out- symptoms (hot flashes or night sweats)
comes for the current anall rses were during the prior 4 weeks If present, par-
CHD (defined as nonfatal myocardial
ticipants were asked how bothersome
infarction, CHD death, or silent
myo- the symptom was. Mild indicated that
cardial infarction) and strolce
Other the symptom did not interfere with
outcomes were mortality antI
a global usual activities; moderate, the symp-
index (defined as the first o0currence
tom interfered somewhat with usual ac-
of CHD, stroke, puimonat ry embo- tivities; and severe, the symptom was
lism. breast cancer, colorectral
cancer, so severe that usual activities could not
endometrial cancer I CEE + i IPA trial be performed.
only], hip fracture, or death ft-om
other Event rate comparisons were based
causes) used for trial monitoring.
Clini- on the intent-to-treat principle using
cal events that were seIf-rTe sorted by failure time methods. For a given out-
participants prior to unblindi ingat trial come, the nome to event was the num-
closure and subsequently adjudicated
ber of days from randomization to the
were included. Due to the co mpressed
timeline for the initial publications,
first diagnosis of the designated event
13 additional adjudicated cas
CH-D and stroke from the CE
trial were available for this a
Statistical Analysis
Age at menopause was defin
age at which a woman last had
strual bleeding, bilateral o
tomy, or began using menop.
mone therapy. For hyste
without bilateral oophorecton
at menopause was the age a
woman either began using
t ll Comparisons of outcomes are preeseachof
sented as Hils and 95% Cls stratified
lE + MPA by prior cardiovascular disease (denalysis.
fined as history of myocardial infarction,
angina, coronary or carotid
revascularization, stroke, transient
ed by the ischemic attack, or peripheral arterial
any men- disease) and randomization status in
ophorec- the Dietary Modification Trial. The
ausal hor- stratified models allow for flexible
rectomy (and possibly different) hazard funciy,tiheage
tions between strata and hence more
t which a accurately capture the effects of htrhormone
mone therapy. Preliminary analyses
DOrloaded fi-m wrtjoma cam at Nitiomtl Itslitaie of HthS, oit April 5. 2007
02007 Aaoefiai Medjsil Aasod.umii. All i5hti .rieod.