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Risk of Recurrent Coronary Events in Relation to Use and Recent Initiation of Postmenopausal Hormone Therapy
Susan R. Heckbert, MD, PhD;
Robert C. Kaplan, PhD;
Noel S. Weiss, MD, DrPH;
Bruce M. Psaty, MD, PhD;
Danyu Lin, PhD;
Curt D. Furberg, MD, PhD;
Jacqueline R. Starr, MPH;
Gail D. Anderson, PhD;
Andrea Z. LaCroix, PhD
Arch Intern Med. 2001;161:1709-1713.
ABSTRACT
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Background The finding from the Heart and Estrogen/Progestin Replacement Study
(HERS) of increased coronary risk restricted to the first year after starting
postmenopausal hormone therapy raises new questions about the role of hormone
therapy in women with coronary heart disease. We assessed the risk of recurrent
myocardial infarction or coronary heart disease death associated with the
use and recent initiation of hormone therapy in women who survived a first
myocardial infarction.
Methods The setting for this population-based inception cohort study was Group
Health Cooperative, a health maintenance organization. We studied 981 postmenopausal
women who survived to hospital discharge after their first myocardial infarction
between July 1, 1986, and December 31, 1996. We obtained information on hormone
use from the Group Health Cooperative computerized pharmacy database and identified
recurrent coronary events by medical record review.
Results During median follow-up of 3.5 years, there were 186 recurrent coronary
events. There was no difference in the risk of recurrent coronary events between
current users of hormone therapy and other women (adjusted relative hazard
[RH], 0.96; 95% confidence interval [CI], 0.62-1.50). Relative to the risk
in women not currently using hormones, there was a suggestion of increased
risk during the first 60 days after starting hormone therapy (RH, 2.16; 95%
CI, 0.94-4.95) and reduced risk with current hormone use for longer than 1
year (RH, 0.76; 95% CI, 0.42-1.36).
Conclusion These results are consistent with the findings from the HERS, suggesting
a transitory increase in coronary risk after starting hormone therapy in women
with established coronary heart disease and a decreased risk thereafter.
INTRODUCTION
IN POSTMENOPAUSAL women with established coronary heart disease (CHD),
results of several observational studies1-2
have suggested that hormone therapy is associated with a decreased risk of
recurrent CHD events. Therefore, the results of the Heart and Estrogen/Progestin
Replacement Study (HERS) randomized trial,3
published in 1998, were unexpected: compared with placebo, there was no reduction
in CHD events in recipients of a combined continuous estrogen and progestin
regimen for an average of 4.1 years (relative hazard [RH], 0.99; 95% confidence
interval [CI], 0.81-1.22). Furthermore, the HERS4
actually observed an increased risk of CHD events in hormone recipients during
the first year of the trial (RH, 1.52; 95% CI, 1.01-2.29) and in particular
during the first 4 months (RH, 2.29), although there was decreased risk in
years 4 and 5 (RH, 0.75; 95% CI, 0.50-1.13).
We used data from a population-based inception cohort study of women
who survived to hospital discharge after their first myocardial infarction
(MI) to examine the risk of recurrent CHD associated with postmenopausal hormone
therapy. Detailed information from a computerized pharmacy database on the
type and timing of hormone use permitted us to assess the CHD risk present
during different periods after starting hormone therapy and the risk associated
with various formulations and regimens.
PATIENTS AND METHODS
SETTING
The setting was Group Health Cooperative (GHC), a health maintenance
organization in western Washington State with more than 400 000 members.
STUDY DESIGN
We identified all female GHC enrollees aged 30 to 79 years who were
diagnosed as having a first nonfatal MI between July 1, 1986, and December
31, 1996, from the computerized discharge abstracts for the 2 GHC hospitals,
the bills for out-of-plan services provided by non-GHC physicians and health
care facilities, and Washington State death records. Women with a first MI
between July 1, 1986, and December 31, 1991, were included in a previous study5 about the risk of reinfarction and mortality in relation
to use of postmenopausal estrogen after the first MI. The present study includes
an additional 522 women whose first MI events occurred after December 31,
1991, as well as additional follow-up of the earlier cohort.
For identification of women with a first MI, research assistants were
trained to recognize hospitalized events that clearly were not MIs and events
that clearly were MIs by review of medical records. Borderline or questionable
events were reviewed by physicians (S.R.H. and B.M.P.) without knowledge of
patients' use of hormone therapy. We used these methods in previous studies.6-7 In a masked validation study,6 the completeness of case ascertainment was 95%, and
97% of eligible cases met standard criteria for definite or probable MI according
to cardiac enzyme determinations, electrocardiographic findings, and the presence
of chest pain.8
We excluded women (1) who were enrolled in the health maintenance organization
for less than 1 year or who had fewer than 4 visits before their first MI;
(2) who were not postmenopausal at the time of the first MI; (3) whose first
MI was a complication of a procedure or surgery; (4) who died before discharge
from the hospital after the first MI; or (5) for whom no information was available
in the medical record after the first MI. Menopause was defined as the cessation
of ovarian function due to natural menopause or bilateral oophorectomy before
natural menopause. A notation in the medical record of the cessation of menses,
or, in women with a hysterectomy, symptoms of menopause, were used to establish
the date of menopause. Women older than 55 years for whom menopausal status
at the date of the first MI was not clear from the medical record were assumed
to be postmenopausal. Women younger than 55 years whose menopausal status
at the date of the first MI could not be determined were excluded; only 0.3%
of otherwise eligible women were excluded for this reason.
DATA COLLECTION
Data collection included review of the available inpatient medical records
for the first MI hospitalization and review of the entire GHC ambulatory medical
record for the period before the first MI and the period after the first MI
up to a predetermined date during 1996-1998. Trained research assistants reviewed
these medical records to determine eligibility and to collect information
about CHD risk factors such as smoking status, weight, serum cholesterol level,
and hysterectomy status and medical conditions such as hypertension, diabetes
mellitus, and congestive heart failure. Hypertension and diabetes mellitus
were defined as pharmacologically treated disease present at the time of the
first MI. Congestive heart failure was defined as probable or definite disease
based on the notes of the primary care physician and consultants and on the
results of diagnostic tests for the period before the first MI or during hospitalization
for the first MI. Information on first recurrent MI or death during post-MI
follow-up was obtained from the ambulatory medical record, available inpatient
medical records, and the results of a match between Washington State death
records and GHC enrollment records.
MEDICATION USE
The GHC computerized pharmacy database was used to assess use of hormones
and other medications. Since 1976, the GHC pharmacy database has included
a record for all prescriptions dispensed to GHC enrollees. Each pharmacy record
includes a patient identifier, drug type and dose, date and quantity dispensed,
and dosing instructions. Although several health care plans in GHC include
small to modest copayments for drugs, interview data from this population
indicate that 96% of individuals with a history of MI fill all of their prescriptions
at GHC pharmacies.6
Hormone therapy was defined as the use of unopposed oral estrogen or
oral estrogen plus progestin. The estrogen formulations most commonly used
for postmenopausal hormone therapy during the study were conjugated and esterified
estrogens. The number of days that an estrogen prescription would last was
calculated as follows: [number of pills dispensed/(pills per day prescribed
x assumed compliance of 80%)] x [(number of days in a month)/(days
per month that estrogen was to be taken)]. In the analysis, we allowed hormone
use to vary over time during post-MI follow-up as women started and stopped
hormone therapy. Starting hormone therapy during follow-up included not only
new starting, defined as the use of estrogen with no evidence of previous
use in the pharmacy database, but also restarting estrogen use 60 days or
more after the supply of estrogen pills from the previous prescription was
calculated to have run out. For women who were taking hormones at the time
of the first MI but were not discharged from the hospital taking hormones
and whose first follow-up clinic notes did not indicate hormone use, we defined
starting hormone therapy as restarting estrogen use 60 days or more after
hospital discharge. In a sensitivity analysis, we repeated the analysis and
defined restarting hormone therapy as a lapse of 90 days or more after the
supply of estrogen was calculated to have run out.
STATISTICAL ANALYSIS
Follow-up time started the date of discharge from the hospital after
the first MI and extended until the date of first recurrent MI or CHD death
or the date of censoring. Individuals were censored at the date of death from
causes other than CHD, the date of disenrollment from GHC, or the end of assigned
follow-up. The Cox proportional hazards model with a time-dependent estrogen
exposure variable was used to model the association of hormone use with the
risk of recurrent MI or CHD death after adjustment for potential confounding
factors.9
To investigate the association of CHD risk with time since starting
hormone therapy, follow-up time was divided into 4 mutually exclusive categories:
(1) no hormone therapy (referent category), which included follow-up time
of women who never used hormones after MI and that of women who had not yet
started hormone therapy or had stopped using hormones during the post-MI period;
(2) within 60 days of starting hormone therapy; (3) greater than 60 to 365
days after starting hormone therapy and still using hormones; and (4) greater
than 365 days after starting hormone therapy and still using hormones.
RESULTS
There were 981 postmenopausal women hospitalized for a first MI between
July 1, 1986, and December 31, 1996, who survived to hospital discharge. Average
age was 67.8 years, and average duration of enrollment in GHC at the time
of the first MI was 17.1 years. Follow-up records were complete for 92% of
women; only 8% of women had disenrolled from GHC before the end of follow-up.
Median duration of follow-up after the first MI was 3.5 years (range,
1 day to 9.9 years), and total follow-up was 3599 person-years. Overall, women
used hormones during 686 person-years of follow-up (19%). Of the 2913 person-years
with no hormone therapy, 52% was contributed by women younger than 70 years
and 48% by women aged 70 years or older (Table 1). By contrast, during 686 person-years with hormone therapy,
75% of the time was contributed by women younger than 70 years and 25% by
women aged 70 years or older. Compared with time without hormone therapy,
a larger proportion of follow-up time with hormone therapy was contributed
by women who were younger; were free of hypertension, diabetes mellitus, and
congestive heart failure; and had lower body mass index and total serum cholesterol
level at the time of the first MI (Table
1).
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Table 1. Proportion of Post-MI Follow-up Time Without and With Hormone
Therapy Contributed According to the Characteristics of 981 Women*
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Among the 981 women, there were a total of 186 recurrent MI events or
CHD deaths during follow-up (51.7 per 1000 per year). There were 149 recurrent
MIs (118 nonfatal and 31 fatal) and 37 other CHD deaths. During time without
hormone therapy there were 161 coronary events (55.3 per 1000 per year) and
during time taking hormones there were 25 events (36.5 per 1000 per year).
The unadjusted risk of recurrent MI or CHD death associated with hormone
use was 0.69 (95% CI, 0.45-1.05) (Table
2, model 1). Subsequent models in Table 2 show the effect of adjustment for subject characteristics
on the risk estimate. In sequential Cox regression models, the association
between hormone use and recurrent coronary events was progressively attenuated
by adjustment for age, calendar year of the first MI, and diabetes mellitus.
With adjustment for age, year, and diabetes mellitus (model 4), there was
no difference in the risk of recurrent coronary events during time with hormone
therapy compared with time with no hormone therapy (RH, 0.96; 95% CI, 0.62-1.50).
Further adjustment for congestive heart failure before or at the time of the
first MI, aspirin use, or ß-adrenergic blocking agent use at discharge
from the hospital after the MI changed the risk estimate in only trivial ways
(models 5-7). Further adjustment with other variables, including duration
of enrollment at GHC, body mass index or weight before the first MI, serum
cholesterol level, serum creatinine level, hypertension, smoking status, educational
attainment, and hysterectomy status, also had trivial effects on the RH.
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Table 2. Effect of Adjustment for Patient Characteristics on the Association
Between Hormone Therapy and Recurrent Myocardial Infarction or Coronary Heart
Disease Death in 981 Women*
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Table 3 summarizes the risk
of recurrent coronary events according to the recency of starting hormone
therapy during the post-MI period compared with the risk among women who were
not using hormones. Within 60 days after starting hormone therapy, the rate
of recurrent coronary events was 121.2 per 1000 per year. Relative to women
not using hormones, the adjusted RH was 2.16 (95% CI, 0.94-4.95). After this
initial period, the adjusted RH declined to 0.92 (95% CI, 0.40-2.12) among
women 60 to 365 days after starting hormone therapy and to 0.76 (95% CI, 0.42-1.36)
among women more than 365 days after starting hormone therapy. There was evidence
for a trend of declining risk over time since starting hormone therapy among
users (P = .05 for trend). The rate of recurrent
events during the first year after starting hormone therapy was 57.9 per 1000
per year and the adjusted RH was 1.30 (95% CI, 0.71-2.37). Using the time
intervals reported in the HERS, the adjusted RHs were 2.03, 0.75, and 0.85
for 0 to 4 months, greater than 4 months to 4 years, and greater than 4 years
after starting hormone therapy, respectively. Use of a 90-day cutoff time
to define restarting of hormone therapy produced similar results.
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Table 3. Risk of Recurrent MI or CHD Death Among 981 Women in Relation
to Use of and Interval Since Starting Hormone Therapy*
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For 5 of 6 women with a recurrent CHD event within the first 60 days
after starting hormone therapy, this was the first use of hormones recorded
in the pharmacy database. The sixth woman had last used hormones more than
5 years before her first MI, and the recurrent CHD event occurred in association
with restarting hormone therapy after the MI. None of the women with CHD events
occurring within the first 60 days after starting hormone therapy were taking
hormones at the time of the first MI.
Unopposed estrogen was used 67% of the total time with oral hormone
therapy during follow-up, and estrogen plus progestin was used 33% of the
time. The progestin used was medroxyprogesterone acetate for virtually all
of the time with combined estrogen and progestin therapy. There was little
difference between the unadjusted rate of recurrent coronary events during
use of unopposed estrogen (17 events; 36.8 per 1000 per year) and use of estrogen
plus progestin (8 events; 35.8 per 1000 per year). The age-adjusted RH for
use of estrogen plus progestin compared with unopposed estrogen was 0.96 (95%
CI, 0.41-2.25). The most commonly used formulation of oral estrogen was esterified
estrogen, used 70% of the time with oral hormone therapy. Conjugated estrogen
was used 28% of the time, and other estrogens were used 2% of the time. The
unadjusted rate of recurrent coronary events was similar during time using
esterified estrogen (15 events; 31.3 per 1000 per year) and time using conjugated
estrogen (8 events; 41.8 per 1000 per year). The age-adjusted RH for conjugated
estrogen use compared with esterified estrogen use was 1.35 (95% CI, 0.55-3.30).
COMMENT
In this observational study of women who survived to hospital discharge
after a first MI, there was no overall difference in the adjusted risk of
recurrent coronary events between current users and current nonusers of hormones
(adjusted RH, 0.96; 95% CI, 0.62-1.50). Relative to the risk in women not
currently using hormones, there was a suggestion of increased risk during
the first 60 days after starting or restarting hormone use (adjusted RH, 2.16;
95% CI, 0.94-4.95) and reduced risk with current hormone use longer than 1
year (adjusted RH, 0.76; 95% CI, 0.42-1.36).
The strengths of this study include the use of a population-based inception
cohort of women with a first MI, the validation of diagnoses for the first
MI and for recurrent CHD events, and the use of a pharmacy database to assess
the timing of starting and discontinuing estrogen use. In addition, we were
able to assess the risk associated with various formulations and regimens
of oral hormone therapy.
A main limitation of this study was the small number of recurrent events
during hormone therapy, particularly shortly after starting hormone therapy.
In analyses that examined the recency of starting hormone therapy, our ability
to adjust for confounding factors was also limited because of the small number
of events involved. As with all observational studies10
of hormone therapy, patients and their physicians self-selected hormone therapy
and the timing of its use, and this self-selection might have introduced bias.
Detailed information on medical comorbidity was uniformly available and allowed
us to adjust for characteristics known to be associated with use of hormones
and recurrent events. Nonetheless, there might have been unknown or unmeasured
confounding factors associated with the use and timing of hormone therapy.
In this study, information on hormone use was restricted to that obtained
using pharmacy data. Although this method ensures comparable and unbiased
assessment of hormone use over time, it ignores hormone prescriptions that
might have been filled at non-GHC pharmacies. Because 96% of individuals with
a history of MI fill all of their prescriptions at GHC pharmacies,6 few participants are likely to have filled hormone
prescriptions outside of a GHC pharmacy. Finally, we made several assumptions
about compliance with hormone therapy and about how long estrogen prescriptions
would last. Our sensitivity analyses indicate that the results were not affected
by plausible changes in these assumptions or in the definition used for starting
hormone therapy.
In contrast to an earlier observational study2
in women with established CHD, the present study did not find a reduction
in coronary events associated with postmenopausal hormone use after adjustment
for confounding characteristics. As in studies11
from the primary prevention setting and as previously reported from this study,10 women who used hormones were younger and healthier
than nonusers. Adjustment for these differences attenuated the protective
association seen in the unadjusted analyses for the overall association of
hormone use with recurrent coronary events in this study. We are unaware of
previous studies comparing the risk of coronary events associated with use
of esterified estrogen vs conjugated estrogen. As in previous studies6, 12 in the primary prevention setting,
risks were similar for use of unopposed estrogen and estrogen plus progestin.
In analyses of the risk associated with recently starting hormone therapy,
like the HERS, we found evidence for an early increased risk of recurrent
coronary events. In the HERS,4 the greatest
risk reported was associated with the first 4 months after starting hormone
therapy (RH, 2.29), whereas in the present study, the greatest risk was during
the first 2 months after starting hormone therapy (adjusted RH, 2.16). During
the first year of follow-up with hormone therapy, the risk observed in the
HERS (RH, 1.52; 95% CI, 1.01-2.29) was similar to the adjusted risk in the
present study (adjusted RH, 1.30; 95% CI, 0.71-2.37). Early increased risk
of coronary events was also reported in the Coronary Drug Project trial in
men receiving high-dose conjugated estrogen,13
in a pooled analysis of short-term clinical trial data,14
and in our observational study of women without previous MI at GHC.15 Moreover, participants in the Women's Health Initiative
hormone clinical trial16 were recently advised
that compared with placebo, an early increase in coronary events was observed
in hormone recipients in the first 2 years of the trial, with an apparent
decline in risk subsequently. Several authors3, 17-18
have discussed possible mechanisms for an early increase in risk in this setting.
At present, the only clinical trial data available suggest no beneficial
effect of hormone therapy in women with established CHD and the possibility
of an early increase in risk after starting hormone therapy. Further information
is needed about the mechanisms by which an early increase in risk might operate
and the long-term effects of hormone therapy after MI.
AUTHOR INFORMATION
Accepted for publication January 11, 2001.
This research was supported by grants HL53375, HL40628, and HL43201
from the National Heart, Lung, and Blood Institute, Bethesda, Md.
Corresponding author and reprints: Susan R. Heckbert, MD, PhD, Cardiovascular
Health Research Unit, University of Washington, 1730 Minor Ave, Suite 1360,
Seattle, WA 98101-1448 (e-mail: heckbert{at}u.washington.edu).
From the Departments of Epidemiology (Drs Heckbert, Weiss, Psaty, and
LaCroix and Ms Starr), Pharmacy (Drs Heckbert and Anderson), Medicine (Dr
Psaty), Health Services (Dr Psaty), and Biostatistics (Dr Lin), Cardiovascular
Health Research Unit, University of Washington, Seattle; the Department of
Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx,
NY (Dr Kaplan); the Department of Public Health Sciences, Wake Forest University,
Winston-Salem, NC (Dr Furberg); and the Center for Health Studies, Group Health
Cooperative, Seattle (Dr LaCroix).
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