LE Magazine December 2002
Hormones
Postmenopausal estrogen and progestin
use and the risk of cardiovascular disease.
BACKGROUND: Estrogen therapy in postmenopausal women has
been associated with a decreased risk of heart disease. There
is little information, however, about the effect of combined
estrogen and progestin therapy on the risk of cardiovascular
disease. METHODS: We examined the relation between
cardiovascular disease and postmenopausal hormone therapy
during up to 16 years of follow-up in 59,337 women from the
Nurses’ Health Study, who were 30 to 55 years of age at
base line. Information on hormone use was ascertained with
biennial questionnaires. From 1976 to 1992, we documented 770
cases of myocardial infarction or death from coronary disease
in this group and 572 strokes. Proportional-hazards models
were used to calculate relative risks and 95% confidence
intervals, adjusted for confounding variables. RESULTS: We
observed a marked decrease in the risk of major coronary heart
disease among women who took estrogen with progestin
(multivariate adjusted relative risk, 0.39; 95% confidence
interval, 0.19 to 0.78) or estrogen alone (relative risk,
0.60; 95% confidence interval, 0.43 to 0.83), as compared with
women who did not use hormones [corrected]. However, there was
no significant association between stroke and use of combined
hormones (multivariate adjusted relative risk, 1.09; 95%
confidence interval, 0.66 to 1.80) or estrogen alone (relative
risk, 1.27; 95% confidence interval, 0.95 to 1.69).
CONCLUSIONS: The addition of progestin does not appear to
attenuate the cardioprotective effects of postmenopausal
estrogen therapy.
N Engl J Med 1996 Aug
15;335(7):453-61
Postmenopausal estrogen therapy and
cardiovascular disease. Ten-year follow-up from the
nurses’ health study.
BACKGROUND. The effect of postmenopausal estrogen therapy
on the risk of cardiovascular disease remains controversial.
Our 1985 report in the Journal, based on four years of
follow-up, suggested that estrogen therapy reduced the risk of
coronary heart disease, but a report published simultaneously
from the Framingham Study suggested that the risk was
increased. In addition, studies of the effect of estrogens on
stroke have yielded conflicting results. METHODS. We followed
48,470 postmenopausal women, 30 to 63 years old, who were
participants in the Nurses’ Health Study, and who did not
have a history of cancer or cardiovascular disease at base
line. During up to 10 years of follow-up (337,854
person-years), we documented 224 strokes, 405 cases of major
coronary disease (nonfatal myocardial infarctions or deaths
from coronary causes), and 1,263 deaths from all causes.
RESULTS. After adjustment for age and other risk factors, the
overall relative risk of major coronary disease in women
currently taking estrogen was 0.56 (95% confidence interval,
0.40 to 0.80); the risk was significantly reduced among women
with either natural or surgical menopause. We observed no
effect of the duration of estrogen use independent of age. The
findings were similar in analyses limited to women who had
recently visited their physicians (relative risk, 0.45; 95%
confidence interval, 0.31 to 0.66) and in a low-risk group
that excluded women reporting current cigarette smoking,
diabetes, hypertension, hypercholesterolemia, or a Quetelet
index above the 90th percentile (relative risk, 0.53; 95%
confidence interval, 0.31 to 0.91). The relative risk for
current and former users of estrogen as compared with those
who had never used it was 0.89 (95% confidence interval, 0.78
to 1.00) for total mortality and 0.72 (95% confidence
interval, 0.55 to 0.95) for mortality from cardiovascular
disease. The relative risk of stroke when current users were
compared with those who had never used estrogen was 0.97 (95%
confidence interval, 0.65 to 1.45), with no marked differences
according to type of stroke. CONCLUSIONS. Current estrogen use
is associated with a reduction in the incidence of coronary
heart disease as well as in mortality from cardiovascular
disease, but it is not associated with any change in the risk
of stroke.
N Engl J Med 1991 Sep
12;325(11):756-62
Impact of postmenopausal hormone
therapy on cardiovascular events and cancer: pooled data from
clinical trials.
OBJECTIVE: To examine the incidence of cardiovascular
diseases and cancer from published clinical trials that
studied other outcomes of postmenopausal hormone therapy as
some surveys have suggested that it may decrease the incidence
of cardiovascular diseases and increase the incidence of
hormone dependent cancers. DESIGN: Trials that compared
hormone therapy with placebo, no therapy, or vitamins and
minerals in comparable groups of postmenopausal women and
reported cardiovascular or cancer outcomes were searched from
the literature. SUBJECTS: 22 trials with 4,124 women were
identified. In each group, the numbers of women with
cardiovascular and cancer events were summed and divided by
the numbers of women originally allocated to the groups.
RESULTS: Data on cardiovascular events and cancer were usually
given incidentally, either as a reason for dropping out of a
study or in a list of adverse effects. The calculated odds
ratios for women taking hormones versus those not taking
hormones was 1.39 (95% confidence interval 0.48 to 3.95) for
cardiovascular events without pulmonary embolus and deep vein
thrombosis and 1.64 (0.55 to 4.18) with them. It is unlikely
that such results would have occurred if the true odds ratio
were 0.7 or less. For cancers, the numbers of reported events
were too low for a useful conclusion. CONCLUSIONS: The results
of these pooled data do not support the notion that
postmenopausal hormone therapy prevents cardiovascular
events.
BMJ 1997 Jul 19;315(7101):149-53
Randomized trial of estrogen plus
progestin for secondary prevention of coronary heart disease
in postmenopausal women. Heart and Estrogen/progestin
Replacement Study (HERS) Research Group.
CONTEXT: Observational studies have found lower rates of
coronary heart disease (CHD) in postmenopausal women who take
estrogen than in women who do not, but this potential benefit
has not been confirmed in clinical trials. OBJECTIVE: To
determine if estrogen plus progestin therapy alters the risk
for CHD events in postmenopausal women with established
coronary disease. DESIGN: Randomized, blinded,
placebo-controlled secondary prevention trial. SETTING:
Outpatient and community settings at 20 U.S. clinical centers.
PARTICIPANTS: A total of 2,763 women with coronary disease,
younger than 80 years, and postmenopausal with an intact
uterus. Mean age was 66.7 years. INTERVENTION: Either 0.625 mg
of conjugated equine estrogens plus 2.5 mg of
medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a
placebo of identical appearance (n = 1383). Follow-up averaged
4.1 years; 82% of those assigned to hormone treatment were
taking it at the end of one year, and 75% at the end of three
years. MAIN OUTCOME MEASURES: The primary outcome was the
occurrence of nonfatal myocardial infarction (MI) or CHD
death. Secondary cardiovascular outcomes included coronary
revascularization, unstable angina, congestive heart failure,
resuscitated cardiac arrest, stroke or transient ischemic
attack, and peripheral arterial disease. All-cause mortality
was also considered. RESULTS: Overall, there were no
significant differences between groups in the primary outcome
or in any of the secondary cardiovascular outcomes: 172 women
in the hormone group and 176 women in the placebo group had MI
or CHD death (relative hazard [RH], 0.99; 95% confidence
interval [CI], 0.80-1.22). The lack of an overall effect
occurred despite a net 11% lower low-density lipoprotein
cholesterol level and 10% higher high-density lipoprotein
cholesterol level in the hormone group compared with the
placebo group (each P<.001). Within the overall null
effect, there was a statistically significant time trend, with
more CHD events in the hormone group than in the placebo group
in year one and fewer in years four and five. More women in
the hormone group than in the placebo group experienced venous
thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58)
and gallbladder disease (84 vs 62; RH, 1.38; 95% CI,
1.00-1.92). There were no significant differences in several
other end points for which power was limited, including
fracture, cancer, and total mortality (131 vs 123 deaths; RH,
1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average
follow-up of 4.1 years, treatment with oral conjugated equine
estrogen plus medroxyprogesterone acetate did not reduce the
overall rate of CHD events in postmenopausal women with
established coronary disease. The treatment did increase the
rate of thromboembolic events and gallbladder disease. Based
on the finding of no overall cardiovascular benefit and a
pattern of early increase in risk of CHD events, we do not
recommend starting this treatment for the purpose of secondary
prevention of CHD. However, given the favorable pattern of CHD
events after several years of therapy, it could be appropriate
for women already receiving this treatment to continue.
JAMA 1998 Aug 19;280(7):605-13
Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principal results
from the Women’s Health Initiative randomized controlled
trial.
CONTEXT: Despite decades of accumulated observational
evidence, the balance of risks and benefits for hormone use in
healthy postmenopausal women remains uncertain. OBJECTIVE: To
assess the major health benefits and risks of the most
commonly used combined hormone preparation in the United
States. DESIGN: Estrogen plus progestin component of the
Women’s Health Initiative, a randomized controlled
primary prevention trial (planned duration, 8.5 years) in
which 16,608 postmenopausal women aged 50 to 79 years with an
intact uterus at baseline were recruited by 40 U.S. clinical
centers in 1993 to 1998. INTERVENTIONS: Participants received
conjugated equine estrogens, 0.625 mg/d, plus
medroxyprogesterone acetate, 2.5 mg/d, in one tablet (n =
8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The
primary outcome was coronary heart disease (CHD) (nonfatal
myocardial infarction and CHD death), with invasive breast
cancer as the primary adverse outcome. A global index
summarizing the balance of risks and benefits included the two
primary outcomes plus stroke, pulmonary embolism (PE),
endometrial cancer, colorectal cancer, hip fracture and death
due to other causes. RESULTS: On May 31, 2002, after a mean of
5.2 years of follow-up, the data and safety monitoring board
recommended stopping the trial of estrogen plus progestin vs
placebo because the test statistic for invasive breast cancer
exceeded the stopping boundary for this adverse effect and the
global index statistic supported risks exceeding benefits.
This report includes data on the major clinical outcomes
through April 30, 2002. Estimated hazard ratios (HRs) (nominal
95% confidence intervals [CIs]) were as follows: CHD, 1.29
(1.02-1.63) with 286 cases; breast cancer, 1.26 (1.00-1.59)
with 290 cases; stroke, 1.41 (1.07-1.85) with 212 cases; PE,
2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63
(0.43-0.92) with 112 cases; endometrial cancer, 0.83
(0.47-1.47) with 47 cases; hip fracture, 0.66 (0.45-0.98) with
106 cases; and death due to other causes, 0.92 (0.74-1.14)
with 331 cases. Corresponding HRs (nominal 95% CIs) for
composite outcomes were 1.22 (1.09-1.36) for total
cardiovascular disease (arterial and venous disease), 1.03
(0.90-1.17) for total cancer, 0.76 (0.69-0.85) for combined
fractures, 0.98 (0.82-1.18) for total mortality, and 1.15
(1.03-1.28) for the global index. Absolute excess risks per
10,000 person-years attributable to estrogen plus progestin
were seven more CHD events, eight more strokes, eight more
PEs, and eight more invasive breast cancers, while absolute
risk reductions per 10,000 person-years were six fewer
colorectal cancers and 5 fewer hip fractures. The absolute
excess risk of events included in the global index was 19 per
10 000 person-years. CONCLUSIONS: Overall health risks
exceeded benefits from use of combined estrogen plus progestin
for an average 5.2-year follow-up among healthy postmenopausal
U.S. women. All-cause mortality was not affected during the
trial. The risk-benefit profile found in this trial is not
consistent with the requirements for a viable intervention for
primary prevention of chronic diseases, and the results
indicate that this regimen should not be initiated or
continued for primary prevention of CHD.
JAMA 2002 Jul 17;288(3):321-33
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