Noncardiovascular Disease Outcomes During 6.8 Years of Hormone Therapy
Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)
Author Information <http://jama.ama-assn.org/issues/v288n1/ffull/#aainfo>
Stephen Hulley, MD, MPH; Curt Furberg, MD, PhD; Elizabeth Barrett-Connor,
MD; Jane Cauley, PhD; Deborah Grady, MD, MPH; William Haskell, PhD; Robert
Knopp, MD; Maureen Lowery, MD; Suzanne Satterfield, MD; Helmut Schrott, MD;
Eric Vittinghoff, PhD; Donald Hunninghake, MD; for the HERS Research Group
Context The Heart and Estrogen/progestin Replacement Study (HERS) was a
randomized trial of estrogen plus progestin therapy after menopause.
Objective To examine the effect of long-term postmenopausal hormone therapy
on common noncardiovascular disease outcomes.
Design and Setting Randomized, blinded, placebo-controlled trial of 4.1
years' duration (HERS) and subsequent open-label observational follow-up for
2.7 years (HERS II), carried out between 1993 and 2000 in outpatient and
community settings at 20 US clinical centers.
Participants A total of 2763 postmenopausal women with coronary disease and
average age of 67 years at enrollment in HERS; 2321 women (93% of those
surviving) consented to follow-up in HERS II.
Intervention Participants were randomly assigned to receive 0.625 mg/d of
conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380)
or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed
at personal physicians' discretion during HERS II. The proportions with at
least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6)
in the hormone group and increased from 0% (year 1) to 8% (year 6) in the
placebo group.
Main Outcome Measures Thromboembolic events, biliary tract surgery, cancer,
fracture, and total mortality.
Results Comparing women assigned to hormone therapy with those assigned to
placebo, the unadjusted intention-to-treat relative hazard (RH) for venous
thromboembolism declined from 2.66 (95% confidence interval [CI], 1.41-5.04)
during HERS to 1.40 (95% CI, 0.64-3.05) during HERS II (P for time trend =
.08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and 3 of
the 73 women with thromboembolism died within 30 days due to pulmonary
embolism. The overall RH for biliary tract surgery was 1.48 (95% CI,
1.12-1.95); for any cancer, 1.19 (95% CI, 0.95-1.50); and for any fracture,
1.04 (95% CI, 0.87-1.25). There were 261 deaths among those assigned to
hormone therapy and 239 among those assigned to placebo (RH, 1.10; 95% CI,
0.92-1.31). Adjusted and as-treated analyses did not alter our conclusions.
Conclusions Treatment for 6.8 years with estrogen plus progestin in older
women with coronary disease increased the rates of venous thromboembolism
and biliary tract surgery. Trends in other disease outcomes were not
favorable and should be assessed in larger trials and in broader
populations.
JAMA. 2002;288:58-66
JOC20522
The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized,
blinded trial to determine the effects of estrogen plus progestin compared
with placebo in older postmenopausal women with coronary disease. Disease
surveillance continued in HERS II for an additional 2.7 years, during which
many of the women randomized to hormones took open-label estrogen prescribed
by their personal physicians but only a few of those assigned to placebo
did. 1 <http://jama.ama-assn.org/issues/v288n1/ffull/#r1> During the 6.8
years of observation in HERS and HERS II combined, we detected no overall
effect of hormone therapy on cardiovascular disease (CVD) event rates. 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1>
Hormone therapy after menopause can have effects on a variety of disease
outcomes. We present data on non-CVD events over this extended period of
hormone therapy. We examine whether the increase in risk of thromboembolic
events observed in hormone-treated women in HERS 2
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2> diminishes over time, as
observational studies have suggested, 3
<http://jama.ama-assn.org/issues/v288n1/ffull/#r3> , 4
<http://jama.ama-assn.org/issues/v288n1/ffull/#r4> and whether the
increased rate of biliary tract surgery that appeared to be present in
hormone-treated women in HERS 5
<http://jama.ama-assn.org/issues/v288n1/ffull/#r5> is confirmed as
additional events occur. More generally, we present data on the effect of
hormone therapy on other disease outcomes thought to be associated with
hormone therapy, including fractures, cancer, and total mortality.
METHODS
Study Participants and Baseline Measurements
The design and methods of HERS and HERS II have been described. 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1> , 6
<http://jama.ama-assn.org/issues/v288n1/ffull/#r6> , 7
<http://jama.ama-assn.org/issues/v288n1/ffull/#r7> Briefly, participants
were postmenopausal women younger than 80 years at baseline with coronary
artery disease and no prior hysterectomy. Among the reasons for exclusion
were a history of deep vein thrombosis or pulmonary embolism, history of
breast cancer, endometrial hyperplasia or cancer, abnormal Papanicolaou
(Pap) result, any hormone use within the past 3 months, and disease judged
likely to be fatal within 4 years.
During the baseline period of HERS we obtained information by questionnaire
and interview, and participants underwent physical examination, including
pelvic examination with Pap smear and endometrial evaluation and screening
mammography. All baseline measures except demographics and health history
were repeated at the final HERS visit, an average of 4 months before
enrollment in HERS II.
Treatment, Follow-up, and Outcomes
During the HERS trial, women were randomly allocated to receive either 0.625
mg/d of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate or an
identical placebo. After stopping blinded medications at the end of the HERS
trial, decisions about whether to undertake open-label hormone therapy were
left to the women and their personal physicians. During HERS II participants
were called at 4-month intervals and asked about hormone therapy and about
symptoms or clinical encounters for possible disease events 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1> ; assessment of
lipid-lowering drugs (but not bisphosphonates) was also continued during
HERS II.
Disease events were ascertained and documented using the methods from the
HERS trial. 7 <http://jama.ama-assn.org/issues/v288n1/ffull/#r7> For
in-hospital nonfatal events and deaths, we required the hospital discharge
summary and the following information: for pulmonary embolism, clinical
signs or symptoms and a positive ventilation/perfusion scan or imaging
result; for deep vein thrombosis, documentation by venography, impedance
plethysmography, or Doppler ultrasound; for biliary tract surgery, an
operative report; for clinical fracture, symptoms and a definite fracture on
radiography; and for cancer, report of a tissue diagnosis. For all deaths in
which clinical documentation was insufficient, we obtained a death
certificate. For out-of-hospital deaths we interviewed the physician and/or
next of kin for a description of the terminal event. Data pertaining to
suspected outcome events were independently reviewed and classified
according to the prespecified criteria used in the HERS trial by 2
physicians at the University of California, San Francisco Coordinating
Center who were blinded to original treatment assignment and to open-label
hormone therapy. 1 <http://jama.ama-assn.org/issues/v288n1/ffull/#r1> , 6
<http://jama.ama-assn.org/issues/v288n1/ffull/#r6> , 7
<http://jama.ama-assn.org/issues/v288n1/ffull/#r7>
Both the telephone contacts and the documentation of outcomes were carried
out with similar efficiency and completeness in the 2 HERS randomized
groups. 1 <http://jama.ama-assn.org/issues/v288n1/ffull/#r1> The
proportions of all HERS II deaths for which we obtained clinical
documentation beyond a death certificate were 81% among women originally
randomized to hormone therapy and 82% among those randomized to placebo.
Statistical Analyses
As described, 1 <http://jama.ama-assn.org/issues/v288n1/ffull/#r1> the
primary analyses (using SAS version 8.2, SAS Inc, Cary, NC) compared the
risk of events among women assigned to hormone therapy with the risk among
women assigned to placebo using unadjusted, intention-to-treat Cox
proportional hazards models for time to first event. We censored women at
the last contact or at loss to follow-up. In the analyses of biliary tract
surgery, we excluded those with a cholecystectomy prior to enrollment in
HERS.
Mortality was assessed in all HERS participants throughout the 6.8 years of
follow-up, but morbidity surveillance during HERS II was limited to the 93%
of surviving women who enrolled. To control for confounding, we estimated
the effects of hormone therapy in adjusted Cox models that included all
predictors significant at P<.20 in multivariate analysis. The 1993-1994
baseline values were used for all variables except statin use, which was
included as a time-dependent covariate. In as-treated adjusted analyses,
women were censored 30 days after they become nonadherent to randomly
assigned treatment, defined as taking less than 80% of their HERS medication
or its equivalent during HERS II. 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1>
RESULTS
The number of women randomized in HERS was 1380 in the hormone therapy group
and 1383 in the placebo group. Of these, 1156 and 1165 enrolled in HERS II,
representing 93% of the 2485 surviving women. Vital status was known for
99.8% of these women at the end of HERS II, with final telephone contacts
completed in 99.5% of known survivors (see Figure 1
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_f1.html> on page
53 of the printed journal). The mean duration of disease event surveillance
was 6.8 years for women who survived, which included 2.7 years in HERS II.
Risk Factors and Other Characteristics
Table 1 <http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t1.html>
presents risk factors for non-CVD outcomes using measurements made at the
outset of HERS in 1993-1994. All the variables were equitably distributed
between randomized groups for both the HERS and HERS II cohorts.
Treatment With Hormones
Among women randomized to estrogen plus progestin, the proportions reporting
at least 80% adherence to hormone therapy during years 1 through 6 were 81%,
78%, 74%, 67%, 50%, and 45%; comparable proportions for women randomized to
placebo were 0%, 2%, 3%, 3%, 4%, and 8%.
Thromboembolism
There was a 2- to 3-fold increase in incidence of both deep vein thrombosis
and pulmonary embolism in the hormone group during HERS ( Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t2.html> ). The
relative hazard (RH) for deep vein thrombosis was considerably smaller
(1.23) and no longer statistically significant during HERS II. There was no
comparable reduction in RH for pulmonary embolism, although the number of
events available to detect such a time trend was small. When risk for venous
thromboembolism was examined by year of observation ( Table 3
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t3.html> ), the RH
declined after the first 2 years, but the time trend was not statistically
significant (P = .08).
The RH for any venous thromboembolic event over the entire 6.8 years was
2.08 (95% confidence interval [CI], 1.28-3.40). Event rates were 5.9 per
1000 person-years in the hormone group and 2.8 per 1000 person-years in the
placebo group, an excess of 3.1 per 1000 person-years (P = .003). The number
needed to treat (NNT) for 5 years per excess thromboembolic event is 65 when
estimated by intention-to-treat and 50 in the as-treated analysis. Seven of
the 73 women with thromboembolism died within 30 days of the event, and 3 of
these deaths were judged due to the event (all were pulmonary embolisms in
women randomized to hormone therapy). Stratifying the overall findings by
baseline aspirin use, the data are weakly consistent with the hypothesis
that aspirin attenuates the adverse effect of hormone therapy on risk of
thromboembolism (RH, 1.68; 95% CI, 0.96-2.92 for aspirin users; RH, 4.23;
95% CI, 1.41-12.7 for nonusers; interaction P = .14).
Biliary Tract Surgery
The RH for biliary tract surgery in the hormone group compared with placebo
was 1.39 during HERS, 1.70 during HERS II, and 1.48 overall (95% CI,
1.12-1.95) ( Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t2.html> ). The
overall RH after adjustment for statin use, a statistically significant
predictor of lower rates of biliary tract surgery in our study, was 1.44
(95% CI, 1.10-1.90; P = .01).
The rate of surgery was 19.1 per 1000 person-years in the hormone group, an
excess of 6.2 per 1000 person-years over the placebo group (P = .002). The
estimated NNT for 5 years per excess surgery was 32 (intention-to-treat) and
31 (as-treated). Six of the 211 women who had biliary tract surgery died
within 30 days, and 1 of these deaths was judged a consequence of the
surgery.
Cancer
None of the differences between groups in cancer incidence was statistically
significant ( Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t2.html> ). The
overall RH comparing the hormone and placebo groups was 1.27 (95% CI,
0.84-1.94) for the 88 breast cancer cases, 1.39 (95% CI, 0.84-2.28) for the
64 lung cancer cases, and 0.81 (95% CI, 0.46-1.45) for the 47 colon cancer
cases. Death due to these cancers during the period of observation occurred
in 3% of women with breast cancer, 61% of women with lung cancer, and 17% of
women with colon cancer.
Other cancers that occurred in at least 5 women included endometrial cancer
(2 women in the hormone group and 8 in placebo); malignant melanoma (3
hormone and 5 placebo); lymphoma (7 hormone and 1 placebo); and ovarian
cancer (5 hormone and 2 placebo). The total number of women with any cancer
was 159 in the hormone group vs 135 in the placebo group (RH, 1.19; 95% CI,
0.95-1.50).
Fractures
Women randomized to hormone therapy had more hip fractures than women
randomized to placebo; the overall RH during 6.8 years of observation was
1.61 (95% CI, 0.98-2.66; P = .06) ( Table 2
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t2.html> ). The RH
was 1.16 in HERS and 2.11 in HERS II, a difference that is not statistically
significant.
The RH estimates for vertebral, wrist, and other fractures were close to
unity. Based on the total of 452 clinical fractures during 6.8 years of
observation, the RH for any fracture was 1.04 (95% CI, 0.87-1.25).
Prevalence of bisphosphonate use was 2.6% at HERS closeout (in 1998) among
women randomized to hormone therapy and 2.5% among those randomized to
placebo.
Mortality
Death rates were high and increasing in this population of older women with
coronary disease. Total mortality in the placebo group was 22 per 1000
person-years during HERS and 38 per 1000 person-years during HERS II ( Table
4 <http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t4.html> ). The
RH for total mortality in the hormone vs placebo group was 1.06 during HERS,
1.14 during HERS II, and 1.10 overall (95% CI, 0.92-1.31).
During the entire 6.8 years of observation, there were 261 deaths in the
hormone group and 239 in the placebo group. Overall, 61% of the deaths were
classified as due to CVD, 19% due to cancer, and 20% due to other cause.
Among the CVD deaths, 132 women in the hormone group and 122 in the placebo
group died of CHD and the remainder died of stroke (23 and 20) and
peripheral arterial disease (4 and 2). Among the cancer deaths, 3 were due
to breast cancer (all in women randomized to hormone therapy). For lung
cancer deaths 20 occurred in women randomized to hormone therapy and 19 in
those randomized to placebo; for colon cancer deaths, 2 and 6; and for all
other cancer deaths, 26 and 19. Among the non-CVD noncancer deaths, the
numbers in the hormone and placebo groups were 24 and 14 for infectious
diseases (including pneumonia and all forms of sepsis); 15 and 13 for
respiratory failure (primarily chronic obstructive pulmonary disease,
excluding pneumonia); 2 and 9 for traumatic causes, and 10 and 15 for all
other causes.
Adjusted and As-Treated Analyses
In addition to the unadjusted intention-to-treat findings described above,
we also estimated the effects of hormone therapy in Cox regression analyses
that adjusted for covariates that were predictors of the outcome. The
purpose was to adjust for imbalances that could have developed because some
women declined to enroll in HERS II. None of the RH estimates was
appreciably altered by the multivariate adjustment ( Table 5
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t5.html> ).
We also carried out analyses restricted to women who remained adherent to
randomly assigned treatment ( Table 5
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t5.html> ). These
as-treated RH estimates had wider CIs than the intention-to-treat estimates
due to the smaller numbers of events (40%-73% of the total in the various
models). The as-treated RH for venous thromboembolism was higher than the
unadjusted intention-to-treat value (3.04 vs 2.08 for the overall study);
the as-treated RH was 5.83 during HERS (95% CI, 2.23-15.3) and 0.70 during
HERS II (95% CI, 0.14-3.64). Other as-treated RH estimates in Table 5
<http://jama.ama-assn.org/issues/v288n1/fig_tab/joc20522_t5.html> differed
somewhat from those estimated by intention-to-treat, but the CIs largely
overlapped.
COMMENT
This report examines non-CVD outcomes over a total of 6.8 years of
observation during and following the HERS randomized trial of hormone
therapy in postmenopausal women with coronary disease. We found an increased
risk of venous thromboembolism and biliary tract surgery among women
randomized to hormone therapy; rates of other important disease outcomes
were not favorably affected.
Deep Vein Thrombosis and Pulmonary Embolism
HERS 2 <http://jama.ama-assn.org/issues/v288n1/ffull/#r2> , 7
<http://jama.ama-assn.org/issues/v288n1/ffull/#r7> confirmed reports from
observational studies 3 <http://jama.ama-assn.org/issues/v288n1/ffull/#r3> ,
8 <http://jama.ama-assn.org/issues/v288n1/ffull/#r8> , 9
<http://jama.ama-assn.org/issues/v288n1/ffull/#r9> that hormone therapy
after menopause increases risk of venous thromboembolism. The estrogen
component of HERS treatment is the likely cause because estrogen without
progestin is associated with venous thromboembolism 3
<http://jama.ama-assn.org/issues/v288n1/ffull/#r3> , 4
<http://jama.ama-assn.org/issues/v288n1/ffull/#r4> and selective estrogen
receptor modulators also increase the risk. 10
<http://jama.ama-assn.org/issues/v288n1/ffull/#r10> , 11
<http://jama.ama-assn.org/issues/v288n1/ffull/#r11> Risk factors for
thromboembolism in HERS participants included lower extremity fracture,
cancer, surgery, and nonsurgical hospitalization; use of aspirin or statins
appeared to be protective. 2
<http://jama.ama-assn.org/issues/v288n1/ffull/#r2>
HERS participants represent a population at relatively high absolute risk of
deep vein thrombosis or pulmonary embolism. The overall rate in the placebo
group, 2.8 per 1000 person-years, is far higher than that observed in
healthy young postmenopausal women but resembles rates in other populations
of elderly women. 3 <http://jama.ama-assn.org/issues/v288n1/ffull/#r3> , 12
<http://jama.ama-assn.org/issues/v288n1/ffull/#r12> Therefore our estimated
NNT, 1 excess thromboembolic event among every 50 to 65 women taking
hormones for 5 years, is probably much smaller than it would be for younger
and healthier women.
The longer follow-up available in HERS II suggests that the relative risk
for venous thromboembolic events may decrease after the second year of
hormone therapy (P = .08). Similar decreases over time have been reported in
observational studies of postmenopausal hormone 3
<http://jama.ama-assn.org/issues/v288n1/ffull/#r3> , 4
<http://jama.ama-assn.org/issues/v288n1/ffull/#r4> and oral contraceptive
13 <http://jama.ama-assn.org/issues/v288n1/ffull/#r13> use, although there
is generally some residual excess risk. A decreasing risk is plausible,
either through attrition of a susceptible subgroup 14
<http://jama.ama-assn.org/issues/v288n1/ffull/#r14> or by developing
tolerance, and the as-treated analysis suggests that it is not just due to
decreased compliance with hormone therapy during HERS II. However, the
decrease might partly reflect our decision in 1997 (after noting that venous
thromboembolism was more common in hormone-treated women) to emphasize to
study participants the need to stop HERS treatment in the event of fracture,
immobilization, surgery, or cancer. 15
<http://jama.ama-assn.org/issues/v288n1/ffull/#r15>
Biliary Tract Surgery
Several decades ago the Coronary Drug Project randomized trial found that
high-dose estrogen therapy caused gallbladder disease in men, 16
<http://jama.ama-assn.org/issues/v288n1/ffull/#r16> probably due to
alteration of the concentration of cholesterol in the bile, 17
<http://jama.ama-assn.org/issues/v288n1/ffull/#r17> and observational
studies of women receiving postmenopausal estrogen have had similar
findings. 5 <http://jama.ama-assn.org/issues/v288n1/ffull/#r5> We
previously reported a 38% higher adjusted rate of biliary tract surgery in
hormone-treated women (P = .09). 5
<http://jama.ama-assn.org/issues/v288n1/ffull/#r5> The longer period of
observation reported here has revealed the increased risk to be
statistically significant. Gallbladder disease was 3 times more common than
venous thromboembolism in HERS women, and the NNT for 5 years to cause 1
excess surgery was 31.
Cancer
Cancer was 19% more common in the hormone therapy group, but the finding was
not statistically significant, nor were there statistically significant
differences in the rates of any specific cancer. The most common of these,
breast cancer, occurred slightly more frequently in the hormone group; the
second most common, lung cancer, also occurred slightly more frequently in
the hormone group; and the third most common, colon cancer, occurred
slightly less often in the hormone group. For each of these 3 cancers,
statistically significant associations in the same direction have been found
in observational studies and biological plausibility has been discussed.
18-23 <http://jama.ama-assn.org/issues/v288n1/ffull/#r18> However, the wide
CIs and limited duration of follow-up do not permit clear inferences from
these observations of cancer occurrence.
Risk of endometrial cancer was 75% lower among women randomized to hormone
therapy than among those assigned to placebo, but the difference was not
statistically significant. The fact that risk is not increased provides
assurance that the progestin component of HERS treatment prevents the
endometrial hyperplasia and cancer resulting from prolonged use of estrogen.
24 <http://jama.ama-assn.org/issues/v288n1/ffull/#r24> , 25
<http://jama.ama-assn.org/issues/v288n1/ffull/#r25>
Fracture
Estrogen is widely believed to prevent osteoporotic fractures. Observational
studies reveal 50% lower fracture rates among women taking hormones than in
women who are not, 26 <http://jama.ama-assn.org/issues/v288n1/ffull/#r26> ,
27 <http://jama.ama-assn.org/issues/v288n1/ffull/#r27> and there is strong
clinical trial evidence for a favorable effect of postmenopausal estrogen
treatment, with or without progestin, on bone mineral density in various
populations, including older women. 28
<http://jama.ama-assn.org/issues/v288n1/ffull/#r28> , 29
<http://jama.ama-assn.org/issues/v288n1/ffull/#r29> However, the clinical
trial evidence for an effect on fractures has been limited. 30
<http://jama.ama-assn.org/issues/v288n1/ffull/#r30> , 31
<http://jama.ama-assn.org/issues/v288n1/ffull/#r31> Our earlier report from
the HERS main trial revealed little difference between the hormone and
placebo groups in risk of any type of fracture. 32
<http://jama.ama-assn.org/issues/v288n1/ffull/#r32> Surprisingly, the
additional follow-up experience from HERS II suggests a risk of hip fracture
among women in the hormone therapy group that is higher than that in the
placebo group. Chance may explain the finding, which does not meet the
criteria for statistical significance, is considerably smaller in the
as-treated analysis, and lacks biological plausibility.
Chance also could play a role in the larger question as to why we did not
observe any reduction in risk of all fractures in the hormone group,
although the confidence interval makes it unlikely that we missed a large
benefit. The absence of routine spine radiographs limited our ability to
detect vertebral fractures. Women studied in HERS were not selected for
osteoporosis and are therefore not well suited to revealing the effects of
fracture-prevention treatments. Clinical trials of bisphosphonates have
found an effect on the risk of fracture in women with osteoporosis, but not
in women with normal bone density. 33
<http://jama.ama-assn.org/issues/v288n1/ffull/#r33> , 34
<http://jama.ama-assn.org/issues/v288n1/ffull/#r34>
Mortality
We recorded 261 deaths in the hormone group and 239 in the placebo group.
The absence of mortality benefit contrasts with the finding in observational
studies of lower mortality rates among women who use postmenopausal hormones
compared with nonusers. 35
<http://jama.ama-assn.org/issues/v288n1/ffull/#r35> , 36
<http://jama.ama-assn.org/issues/v288n1/ffull/#r36> Population differences
could underlie this disparity, but we believe that the lower mortality rate
among hormone users in observational studies is primarily due to
confounding; women who seek hormone therapy and remain compliant tend to be
healthier and wealthier than those who do not. 37-39
<http://jama.ama-assn.org/issues/v288n1/ffull/#r37> Because these
characteristics cannot be measured precisely, their influence cannot be
adequately addressed by statistical adjustment in observational studies. 40
<http://jama.ama-assn.org/issues/v288n1/ffull/#r40>
Strengths and Limitations
Clinical trials have shown that short-term hormone therapy after menopause
has favorable effects on surrogate markers for disease, such as blood lipid
levels and bone mineral density, and that it relieves menopausal symptoms
such as hot flushes and insomnia, 41
<http://jama.ama-assn.org/issues/v288n1/ffull/#r41> , 42
<http://jama.ama-assn.org/issues/v288n1/ffull/#r42> but the effects of
prolonged hormone therapy in preventing clinical events have not been
established. HERS is the first randomized trial to provide substantial
information on the common disease outcomes that hormones may influence.
HERS II increases the precision of the estimated RHs by adding events that
reflect carryover effects from the randomized treatment phase as well as the
effects of continuation of the originally assigned treatment. About 50% of
the hormone group used open-label treatment during HERS II compared with
less than 10% of the placebo group. Those women who did not continue their
randomly assigned treatment (crossovers) diminish the power to observe
effects of the randomized treatment but do not alter the fundamental value
of randomization. To take advantage of this value, our primary analytic
approach was an intention-to-treat comparison of outcomes measured over the
entire 6.8 years. However, we also examined the findings with as-treated
analyses to compensate for the effects of crossing over and with adjusted
analyses to compensate for baseline differences resulting from the 7% of
women who did not enroll in HERS II. The as-treated and adjusted findings
differ somewhat from those of intention-to-treat, but the overall
conclusions are not altered.
Inferences about the effects of randomized treatments are also contingent on
avoiding unintended interventions applied disproportionately to one
randomized group. Randomized assignment was no longer blinded in HERS II, so
at the HERS closeout visit and in subsequent telephone calls we provided a
neutral message to all women and left advice on hormone use and other
preventive treatments to their personal physicians. We also took steps to
prevent bias in the ascertainment of outcomes by choosing disease events
that were objective and by maintaining the HERS systems for obtaining
records and for blinded adjudication. The success of efforts to avoid
between-group bias is supported by the comparability in the timing and
completeness with which the telephone contacts were made and clinical event
data collected. 1 <http://jama.ama-assn.org/issues/v288n1/ffull/#r1>
Important limitations of HERS stem from the older age of HERS participants,
who averaged 67 years at baseline and 74 years at the end of HERS II, the
presence of coronary disease on entry, and the particular estrogen and
progestin that we chose to study. These characteristics limit
generalizability, and the effects of other hormones in younger, healthier
postmenopausal women may be different. Further information on the effects of
hormone therapy on disease outcomes in healthy postmenopausal women will be
available at the conclusion of the Women's Health Initiative randomized
trial. 43 <http://jama.ama-assn.org/issues/v288n1/ffull/#r43>
CONCLUSIONS
Treatment with estrogen plus progestin in older women with coronary disease
increased the rates of venous thromboembolism and biliary tract surgery and
did not produce favorable trends in overall rates of CVD, 1
<http://jama.ama-assn.org/issues/v288n1/ffull/#r1> fracture, or death.
Postmenopausal hormone therapy should be limited to indications that are
supported by randomized trial evidence that beneficial clinical outcomes
outweigh harmful ones.
Author/Article Information
Author Affiliations: Department of Epidemiology and Biostatistics, School of
Medicine, University of California, San Francisco (Drs Hulley, Grady, and
Vittinghoff); Department of Public Health Sciences, Wake Forest University
School of Medicine, Winston-Salem, NC (Dr Furberg); Division of
Epidemiology, Department of Family and Preventive Medicine, University of
California, San Diego (Dr Barrett-Connor); Department of Epidemiology,
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa
(Dr Cauley); Department of Medicine, Stanford University, Stanford, Calif
(Dr Haskell); Department of Medicine, University of Washington School of
Medicine, Seattle (Dr Knopp); University of Miami School of Medicine, Miami,
Fla (Dr Lowery); Department of Preventive Medicine, University of Tennessee,
Memphis (Dr Satterfield); College of Public Health and Medicine, University
of Iowa, Iowa City (Dr Schrott); and Departments of Medicine and
Pharmacology, University of Minnesota, Minneapolis (Dr Hunninghake).
Corresponding Author and Reprints: Stephen Hulley, MD, MPH, University of
California, San Francisco, San Francisco, CA 94143-0560 (e-mail:
[log in to unmask] <mailto:[log in to unmask]> ).
Financial Disclosures: During the conduct of HERS, all authors were
supported by contracts from Wyeth-Ayerst. Dr Barrett-Connor has received
research funding from Eli Lilly and Merck, and has served on an advisory
board for Wyeth-Ayerst; Dr Cauley has received research funding from Eli
Lilly, Merck, and Pfizer, and honoraria from Eli Lilly and Procter and
Gamble; Dr Grady has received research funding from Berlex and Eli Lilly; Dr
Knopp has received research funding and/or speaking honoraria from Abbott,
AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Ortho-McNeil Pharmaceuticals,
and Pfizer; and Dr Satterfield has received research funding from Eli Lilly,
Merck, and Pfizer.
Author Contributions: Dr Hulley, as principal investigator of the HERS II
study, had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analyses.
Study concept and design: Hulley, Grady, Furberg, Barrett-Connor, Cauley,
Haskell, Knopp, Schrott, Vittinghoff, Hunninghake.
Acquisition of data: Hulley, Grady, Furberg, Barrett-Connor, Cauley,
Haskell, Knopp, Lowery, Satterfield, Schrott, Vittinghoff, Hunninghake.
Analysis and interpretation of data: Hulley, Furberg, Barrett-Connor,
Cauley, Grady, Haskell, Knopp, Lowery, Satterfield, Schrott, Vittinghoff,
Hunninghake.
Drafting of the manuscript: Hulley, Grady, Vittinghoff, Barrett-Connor.
Critical revision of the manuscript for important intellectual content:
Hulley, Furberg, Barrett-Connor, Cauley, Grady, Haskell, Knopp, Lowery,
Satterfield, Schrott, Vittinghoff, Hunninghake.
Statistical expertise: Vittinghoff.
Obtained funding: Hulley, Furberg, Barrett-Connor, Cauley, Grady, Haskell,
Knopp, Lowery, Satterfield, Schrott, Vittinghoff, Hunninghake.
Administrative, technical, or material support: Hulley, Furberg,
Barrett-Connor, Cauley, Grady, Haskell, Knopp, Lowery, Satterfield, Schrott,
Vittinghoff, Hunninghake.
Study supervision: Hulley, Furberg, Grady.
Role of the Sponsor: Wyeth-Ayerst Research funded the study, contributed to
its design, oversaw quality control at the clinical centers, including
periodic site visits, and edited the data collected by the clinical centers
(except for disease outcome data) before sending it to the coordinating
center at UCSF. The sponsor did not have access to the blinding code and
played no role in collecting or adjudicating disease outcomes nor in data
analysis. The sponsor had the opportunity to review and comment on
manuscripts written by the investigators, but our contract gave the
investigators the final decision regarding content.
Funding/Support: This study was funded by Wyeth-Ayerst Research.
Clinical Center Investigators: Baylor College of Medicine, Houston, Tex:
Alan Herd, MD, Melissa Kulkarni, RN; Cedars-Sinai Medical Center, Los
Angeles, Calif: Steven Khan, MD, T. Keta Hodgson, BSN; Chicago Center for
Clinical Research, Chicago, Ill: Michael Davidson, MD, Marlene Wentworth,
RN; Duke University Medical Center, Durham, NC: Kristin Newby, MD, Rose
Marie Smigla, RN; Emory University, Atlanta, Ga: Nanette K. Wenger, MD,
Sally McNagny, MD, MPH, Janice Parrott, RN, Dana Drummond; George Washington
University, Washington, DC: Judith Hsia, MD, Ginny Levin, MPH, Donna
Embersit; Hartford Hospital, Hartford, Conn: David Waters, MD, Paul
Thompson, MD, Jennifer DeDominicis, BSN, Marilyn Siwy, RN; Johns Hopkins
University, Baltimore, Md: Trudy Bush, PhD, Roger S. Blumenthal, MD, Susan
R. Miller, MPH, DSc, Katherine Bass, MD, MHS, Janice Huth, Teresa Greene;
Northwest Lipid Research Clinic, Seattle, Wash: Robert H. Knopp, MD, Barbara
Twaddell, RN; Stanford University, Palo Alto, Calif: William L. Haskell,
PhD, Kathy Berra, MSN, ANP, Laurie Ausserer, BS; University of Alabama,
Birmingham: William J. Rogers, MD, Vera Bittner, MD, R. Edward Varner, MD,
Glenda Blackburn, LPN; University of California, San Diego: Elizabeth
Barrett-Connor, MD, Cynthia A. Stuenkel, MD, Sue Hawley, BSN, RN; University
of Iowa, Iowa City: Helmutt Schrott, MD, Diane Meyerholz, RN; University of
Miami, Miami, Fla: Maureen Lowery, MD, Jose A. Martel, MPH; University of
Minnesota, Minneapolis: Donald Hunninghake, MD, Jean Olson, RN, Larry Kotek,
MD, Sue Krook, PhD; University of Pittsburgh, Pittsburgh, Pa (2 sites): Jane
A. Cauley, DrPH, Alan Goodman, MD, Robert McDonald, Jr, MD, Karen Southwick,
Sheree Schaffer, Michelle Boyd, RN, MS; University of Tennessee, Memphis:
Suzanne Satterfield, MD, Karen C. Johnson, MD, Beth McCammon, RN; Wake
Forest University, Winston-Salem and Greensboro, NC (2 sites): David
Herrington, MD, MHS, Karen Blinson, BS, Marcia Davis, BSN, Vickie Wayne, RN,
Lynda Doomy, Kay Cheshire, MEd, Mary Boozer, LPN, Judy Iannuzzi, BSN.
Coordinating Center: University of California, San Francisco: Stephen
Hulley, MD, MPH, Deborah Grady, MD, MPH, Eric Vittinghoff, PhD, Joel Simon,
MD, MPH, Lily Chaput, MD, MPH, Michael Shlipak, MD, MPH, Feng Lin MS,
Christine C. Ireland, MPH, Judith Macer, BS. Executive Committee: Stephen
Hulley, MD (chair), Curt Furberg, MD, PhD (co-chair), Vera Bittner, MD,
Ginger Constantine, MD, Deborah Grady, MD, David Herrington, MD, Donald
Hunninghake, MD, Nanette Wenger, MD. HERS II Data Review Committee: Stephen
Hulley, MD (chair), Deborah Grady, MD, Eric Vittinghoff, PhD, Curt Furberg,
MD, PhD, Robert Levy, Ginger Constantine, MD.
Acknowledgment: We thank Steven Cummings, MD, for help with designing and
interpreting the study.
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