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

Evidence-based Cardiclogy
unity for each category except transient ischernic attack
(0-90, 95% Cl 0-57-1-42), and the highest relative risk was
for fatal stroke (1-61, 95% Cl 0-73-3-55). The trend
towards an excess of more severe strokes In the hormone
group Is similar to that observed in WEST,
Venous thromboembolism
Observational studies
Early observational studies did not suggest an increased risk
for venous thromboembolism (deep vein thrombosis or puilmonary
embolism) in postmenopausal hormone users; however,
as reviewed elsewnere, several more recent studies have
found a two- to fourfold increased risk in hormone users.6
The studies are consistent in showing an increased relative
risk for current but not past use of hormones. Recent onset of
current use conferred higher risk than long duration of use,
consistent with an immediate effect on coagulation factors.
Some but not all studies reported a dose-response relationship.
Estrogen alone, as well as estrogen with progestn, appeared
to be assodated with higher risk. Though transdermal estradiol
causes less perturbation of coagulation proteins than oral
estrogen, one study suggested that the risk for venous thromboembolism
was present for this formulation also.
clinical trials
Venous thromhoembollsmn Is usually recorded as an adverse
effect In clinical trials of hormone therapy. A pooled analysis
of short-term trials found five thromboembolic events in the
hormone groups and one in the control groups." HERS
found a significant, almost threefold increase in the risk for
venous thromboembolism (34 in the hormone group and
13 in the placebo group, relative hazard 2-7, 95% Cl
1-4-5-0, P= 0-003).6 The trend towards higher excess risk
in the first few years was not significant, and some excess
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persisted over the duration of the study. These findings on at
adverse event from a clinical trial are very similar to those fton
the observational studies. In exploratory analyseR other risi
factors for venous thromboembolism included older age a
menopause, lower extremity fractures, cancer; being withir
90 days of Inpatient surgery, or non-surgical hospitalization
After non-fatal M- the risk was Increased for 90 days. Use o
statins or aspirin appeared to decrease risk; It should be noted
however, that these were non-randomized comparisons ant
that the large number of comparisons performed may have let
to chance findings. The WEST study investigators stated tha
there were no differences in venous thromboemholisir
between treatment groups. 5 3 As noted above, healthy worner
in the WHI have been informed of an excess risk during the
first few years of the study.a5 Some trials with Intermediate o;
surrogate outcomes (for example, the Postmenopausa
Estrogen-Progestin Interventions and ERA) have also notet
small numbers of venous events, with more events In the
active treatment groups than the placebo groups, althougt
nsumbers were too small for statistical testing, Be
One randomized controlled trial, initiated before it wa:
known that estrogen Increases risk for venous throintio
embolism, strongly suggested that hormone therap)
increases the risk for recurrent events.t3 Women with prioi
venous thromboembolisrn =n 140) received either ora
estradiol 2 mg and norethisterone acetate I mg or placebo
for 2 years. Though predefined stopping boundaries had no
been crossed, the trial was stopped prematurely because o
the emergence of data from observational studies and din1
cal trials, and the clustering of end points (recurrent venos
thmrnhoenntvilsmt in moe ,eatment grnup, Them weur
eight events In the active treatment group (I 0-7%) and one
In the placebo group (2-3%) indicating a 4-6-fold increase tri
the hormone group. Al of the recurrent events in the active
treatment group occurred during the 9 months, while the
single event in the placebo group occurred at 14 months
Five of the eight cases with recurrent events in the hormone
group also had familial thrombophilla (three with factor V
Leiden, two with anticardiolipin antibodies).