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 US clinical centers.
Participants.— A total of 2763 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 1 year, and 75% at the end of 3 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 1 and fewer in years 4 and 5. 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.
MANY OBSERVATIONAL studies have found lower rates of coronary heart disease (CHD) in women who take postmenopausal estrogen than in women not receiving this therapy.1– 5 This association has been reported to be especially strong for secondary prevention in women with CHD, with hormone users having 35% to 80% fewer recurrent events than nonusers.6– 12 If this association is causal, estrogen therapy could be an important method for preventing CHD in postmenopausal women. However, the observed association between estrogen therapy and reduced CHD risk might be attributable to selection bias if women who choose to take hormones are healthier and have a more favorable CHD profile than those who do not.13– 15 Observational studies cannot resolve this uncertainty.
Only a randomized trial can establish the efficacy and safety of postmenopausal hormone therapy for preventing CHD. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, double-blind, placebo-controlled trial of daily use of conjugated equine estrogens plus medroxyprogesterone acetate (progestin) on the combined rate of nonfatal myocardial infarction (MI) and CHD death among postmenopausal women with coronary disease. We enrolled women with established coronary disease because their high risk for CHD events and the strong reported association between hormone use and risk of these events make this an important and efficient study population in which to evaluate the effect of hormone therapy.
In this clinical trial, postmenopausal women younger than 80 years with established coronary disease who received estrogen plus progestin did not experience a reduction in overall risk of nonfatal MI and CHD death or of other cardiovascular outcomes. How can this finding be reconciled with the large body of evidence from observational and pathophysiologic studies suggesting that estrogen therapy reduces risk for CHD?
Contrast With Findings of Observational Studies
Observational studies may be misleading because women who take postmenopausal hormones tend to have a better CHD risk profile13,21– 22and to obtain more preventive care14 than nonusers. The consistency of the apparent benefit in the observational studies could simply be attributable to the consistency of this selection bias. The lower rate of CHD in hormone users compared with nonusers persists after statistical adjustment for differences in CHD risk factors,22 but differences in unmeasured factors remain a possible explanation.
The discrepancy between the findings of HERS and the observational studies may also reflect important differences between the study populations and treatments. Most of the observational studies of postmenopausal hormone therapy enrolled postmenopausal women who were relatively young and healthy and who took unopposed estrogen.1– 3,23 In contrast, participants in HERS were older, had coronary disease at the outset, and were treated with estrogen plus progestin. However, some observational studies did examine women with prior CHD, and all of these reported a beneficial association with postmenopausal hormone therapy.6– 12 Similarly, some observational studies did examine the effect of postmenopausal estrogen plus progestin therapy on CHD risk in women, and these generally report a lower rate of CHD events in hormone users that is similar to that reported for estrogen alone4– 5,22,24– 27; however, details in these studies about the specific progestin formulations and dosing regimens used are limited.
Possible Adverse Effects of Medroxyprogesterone Acetate
Several potential mechanisms whereby estrogen therapy might reduce risk for CHD have been proposed, including favorable effects on lipoproteins, coronary atherosclerosis, endothelial function, and arterial thrombosis.28– 29 Progestins down-regulate estrogen receptors and may also have direct, progestin receptor–mediated effects that oppose these actions of estrogen30; medroxyprogesterone acetate may do this to a greater extent than other progestins. In the Postmenopausal Estrogen-Progestin Interventions Trial, medroxyprogesterone acetate blunted the estrogen-associated increase in HDL cholesterol substantially more than did micronized progesterone.31 Oral medroxyprogesterone acetate appears to significantly attenuate the beneficial effects of estrogen on coronary atherosclerosis in nonhuman primates,32 while subcutaneous progesterone does not.33 Animal data also suggest that medroxyprogesterone acetate may inhibit the beneficial effects of estrogen on endothelial-dependent vasodilation,34 but this has not been documented in women.35 Despite these mechanistic data suggesting an adverse effect of medroxyprogesterone acetate, observational studies show a similar reduction in CHD risk in women using medroxyprogesterone acetate plus estrogen as in women taking unopposed estrogen.4
Possible Differences in the Effects of Therapy Over Time
When the results were examined by year since randomization, the estrogen plus progestin regimen appeared to increase risk for primary CHD events in the first year of therapy but to decrease risk in subsequent years. This time trend should be interpreted with caution. It could simply represent random variation, although the level of statistical significance makes this unlikely. More importantly, between-group contrasts that exclude the first several years are not true randomized comparisons, as the remaining study groups may no longer be comparable if, for example, treatment has caused high-risk individuals to have events early in the study.
On the other hand, the time trend is biologically plausible. The early increase in risk for CHD events might be attributable to an immediate prothrombotic, proarrhythmic, or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis, perhaps as a result of beneficial changes in lipoproteins. In trials of lipid interventions, the delay before CHD risk is reduced has ranged from 0 to 2 years.36– 41 After a lag period, the 11% net reduction in LDL cholesterol and 10% net increase in HDL cholesterol observed in the hormone group would be expected to reduce the risk of CHD events36,42 and may account for the trend toward a late benefit observed in HERS.
A pattern of early harm and later benefit could account for part of the discrepancy between the results of this trial and observational studies of estrogen and CHD. Attrition of susceptible individuals soon after starting estrogen replacement could increase the prevalence of survivors available for inclusion in observational studies; most observational studies are not designed to observe the onset of therapy or to detect an early adverse effect.
Previous Clinical Trial Evidence
The CHD data from previous hormone trials in women have been summarized43 but are of limited value because the studies were small, short term, and not designed to examine CHD as an outcome. The only large prior trial of estrogen therapy to prevent CHD events was the Coronary Drug Project, which studied very high doses of estrogen (5.0 mg or 2.5 mg of conjugated equine estrogen daily) in men with preexisting CHD. The estrogen arms of this trial were stopped early because of an excess of MIs, thromboembolic events, and estrogenic symptoms in the 5.0-mg/d group44 and the lack of benefit on the CHD end point and estrogenic symptoms in the 2.5-mg/d group.45 The relevance of this trial of high-dose estrogen in men to postmenopausal hormone therapy in women is uncertain.
Safety and Other Noncardiovascular Outcomes
Venous thromboembolic events were 3 times more common in the hormone group than in the placebo group. Recent observational studies have reported similar relative risks for idiopathic venous thromboembolism among users of both unopposed estrogen46– 49 and estrogen plus progestin therapy.47,49 The excess incidence of venous thrombotic events in HERS was 4.1 per 1000 woman-years of observation, an order of magnitude higher than the excess reported in the observational studies; the higher rate is probably a consequence of the facts that women enrolled in HERS were older and had multiple risk factors for venous thrombosis and that only idiopathic events were counted in the observational studies.
We found an increased risk of gallbladder disease in the hormone group that is likely attributable to the estrogen therapy. Metabolic studies indicate that estrogen enhances hepatic lipoprotein uptake and inhibits bile acid synthesis, resulting in increased biliary cholesterol and cholelithiasis.50
Observational studies have suggested that therapy with postmenopausal estrogen for 5 years or less is not associated with an increased risk of breast cancer but that longer duration of therapy might be associated with a small increase in risk.51 The HERS trial was not large enough and therapy did not continue for long enough to address this issue.
The incidence of fractures in the hormone group was only slightly lower than in the placebo group. Wide CIs around the fracture risk estimates reveal inadequate statistical power and do not exclude a reduction in risk of hip fracture of as much as 51% or a reduction in risk of other fracture of as much as 27%.
Strengths and Limitations of the Trial
The CHD risk factor profile of women enrolled in HERS is similar to that of a random sample of US women with probable heart disease, suggesting that the findings of HERS may be generalized to that population.52 However, HERS did not evaluate the effect of estrogen plus progestin therapy in women without CHD, and it is not known whether our findings apply to healthy women. It is also not known whether use of a different progestin or of estrogen alone would have been beneficial.
HERS exceeded the recruitment goal by 18%, carried out a successful randomization, collected objective, blindly adjudicated disease outcome data, and achieved 100% vital status ascertainment. Compliance with hormone treatment, while lower than projected, was sufficient to produce LDL and HDL cholesterol changes that compare favorably with previous studies.31 The 95% CIs for the effect of treatment assignment on primary CHD events (RH, 0.99; 95% CI, 0.80-1.22) make it unlikely that HERS missed a benefit of more than 20% for the overall 4.1-year period of observation. However, this statistic does not address the possible late benefit of treatment suggested by the time trend analysis, which is plausible based on the finding of a 1- to 2-year lag period observed in lipid trials36– 41; a longer study would be more definitive for investigating this possibility.
HERS is the first large trial of the effect of postmenopausal estrogen plus progestin therapy on risk for CHD events. The findings differ from those of observational studies and studies with surrogate outcomes, emphasizing the importance of basing treatment policies on randomized controlled trials.53 Other randomized trials of postmenopausal hormone therapy are likely to answer some of the questions raised by HERS. The Women’s Health Initiative Randomized Trial54 includes a group of women who have undergone hysterectomy and receive unopposed estrogen as well as women with intact uterus who receive the same estrogen plus progestin regimen used in HERS. Participants are not required to have CHD and are generally younger than the HERS cohort. The Women’s Health Initiative Randomized Trial plans to enroll 27500 women and to report the results in 2005 after 9 years of treatment. Further information will also emerge from HERS as we continue disease event surveillance.
Several interventions have been proven to reduce risk for CHD events in patients with coronary disease, including aspirin, β-blockers, lipid lowering, and smoking cessation.55 The need for encouraging these interventions for women with coronary disease is illustrated by the facts that 90% of the HERS cohort had LDL cholesterol exceeding 2.59 mmol/L (100 mg/dL) at baseline and that only 32% were receiving β-blockers.
First, in the population studied in HERS, ie, postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogens and medroxyprogesterone acetate did not reduce the overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 years of follow-up. This therapy did increase the risk of venous thromboembolic events and gallbladder disease.
Second, we did not evaluate the cardiovascular effect of treatment with unopposed estrogen, commonly used in women who have had a hysterectomy, or other estrogen plus progestin formulations. We also did not study women without coronary disease.
Third, 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 hormone treatment to continue. Extended follow-up of the HERS cohort and additional randomized trials are needed to clarify the cardiovascular effects of postmenopausal hormone therapy.