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

year). These 'drop-in" rates were also
greater than expected.
At the time of this report, clinic gynecologtsts
had been unblinded to treatment
assignment for 3444 women in the
estrogen plus progestin group and 548
women in the placebo group, primarily
to manage persistent vaginal bleeding.
During the trial, 248 women in the estrogen
plus progestin group and 183 in
the placebo group had a hysterectomy.
Intermediate Cardiovascular
Disease End Points
Blood lipid levels, assessed in an 8.6%
subsample of fasting blood specimens
collected from women at baseline and
year 1, showed greater reductions in
low-density lipoprotein cholesterol
(-12.7%) and increases in highdensity
lipoprotein cholesterol (7.3%)
and triglycerides (6.9%) with estrogen
plus progestin relative to placebo (data
not shown), consistent with HERS and
PEPl.iOa Systolic blood pressure was,
on average, 1.0 mm Hg higher in women
taking estrogen plus progestsi at I year,
rising to 1.5 mm Hg at 2 years and
beyond (data not shown). Diastolic
blood pressures did not differ.
Cbnal Outcomes
Cardiovascular Disease. Overall CHD
rates were low (TABLE 2). The rate of
women experiencing CHD events was
increased by 29% for women taking estrogen
plus progestin relative to placebo
(37 vs 30 per 10000 personyears),
reaching nominal statistical
significance (at the .05 level). Most of
the excess wvas in nonfatal Ml. No significant
differences were observed in
CHD deaths or revascularization procedures
(coronary artery bypass grafting
or percutaneous transluminal coronary
angioplasty). Stroke rates were also
higher in women receiving estrogen
plus progestin (41% increase; 29vs 21
per 10000 person-years), wvith most of
the elevation occurring in nonfatal
events. Women in the estrogen plus
progestin group had 2-fold greater rates
of venous thromboembotism (VTE), as
well as DVT and PE individually, with
almost all associated Cis excluding 1.
P2002 Anicrim. itedical Associatio. Alt rights reserved.
162
RISKS AND BENEFITS OF ESTROGEN PLUS PROGESTIN
Table 3. Cause of Death by Randoniation Assignment
No lAasaaiiaed %)
TOtSl deaths
Estrogen raestUn (n . 8506)
231 (0.52)
Placebo In = 81 02
218 (0.53)
Adjuatcated deaths
Cm2oeascutar
Breastvaer
215 (045)
61 (0,15) as
3 (0.01)
201 (0,49)
(0. 1 3)
2 (x0.01)
otheivancer
Othe, kincs se
Unknown causo
104 (0.24)
34(0.08)
(.002)
83 (0.21)
41 (0.10)
17 (0.04)
Rates of VTE were 34 and 16 per 10000
person-years in the estrogen plus progestin
and placebo groups, respectively.
Total cardiovascular disease,
including other events requiring hospitalization,
was increased by 22% in
the estrogen plus progestin group.
Cancer. The invasive breast cancer
rates in the placebo group were consistent
with design expectations. The
26% increase (38 vs 30 per 10000 person-years)
observed in the estrogen plus
progestin group almost reached nominal
statistical significance and, as noted
herein, the weighted test statistic used
for monitoring was highly significant.
No significant difference was observed
for in situ breast cancers. Follow-up
rates for mammography were
comparable in the estrogen plus progestin
and placebo groups. Colorectal
cancer rates were reduced by 37% (10
vs 16 per 10000 person-years), also
reaching nominal statistical significance.
Endometrial cancer incidence
was not affected, nor was lung cancer
incidence (54 vs 50; HR, 1.04; 95% Cl,
0.71-1.53) or total cancer incidence.
Fractures. This cohort experienced
low hip fracture rates (10 per 10000
person-years in the estrogen plus progesun
group vs 15 per 10000 personyears
in the placebo group). Estrogen
plus progesin reduced the observed hip
and clinical vertebral fracture rates by
one third compared with placebo, both
nominally significantly. The reductions
in other osteoporotic fractures
(23%) and total fractures (24%) were
statistically significant (all associated
Cis exclude 1).
The global index showed a nominallysignificant
15% increase in the es-
Dos-sloodet fine swr jasiarei at National Itoiitite of Hlhh on Apil 16, 2007
trogen plus progesuin group (170 vs 151
per 10000 person-years). There were no
differences in mortality or cause of death
between groups (TABLE 3).
lime Trends
The Kaplan Meier estimates of cumulative
hazards (FIGURE 3) for CHD indicate
that the difference between treatment
groups began to develop soon
after randomizatiuon. These curves provide
little evidence of convergence
through 6 years of follow-up. The cumulative
hazards for stroke begin to diverge
between I and 2 years after randomization,
and this difference persists
beyond the fifth year. For PE, the curves
separate soon after randomization and
show continuing adverse effects
throughout the observation period. For
breast cancer, the cumulative hazard
functions are comparable through the
first 4 years, at which point the curve
for estrogen plus progestin begins to rise
more rapidly than that for placebo,
Curves for colorectal cancer show benefit
beginning at 3 years, and curves for
hip fracture show increasing cumulative
benefit over time. The difference
in hazard rates for the global index
(FIGURE 4) suggests a gradual increase
in adverse effects compared with
benefits for estrogen plus progestin
through year 5, with a possible narrowing
of the difference by year 6; however,
HR estimates tend to be unstable
beyond 6 years after randomization.
Total mortality rates are indistinguishable
between estrogen plus progestin
and placebo.
Tests fortinear trends with time since
randomization, based on a Cox proportional
hazards model with a time-
sntued) JAIA. .,ty 17. 20o2-V.1 280. N.. 3 327