The Heart and Estrogen/ Progestin Replacement Study (HERS)
ABSTRACT & COMMENTARY
Synopsis: A secondary prevention trial with daily, continuous combined estrogen-progestin treatment reports no reduction in myocardial infarctions or coronary deaths.
The hers trial was a randomized, double-blind, placebo-controlled clinical trial supported by Wyeth-Ayerst for $40 million. The objective of the trial was to determine whether daily treatment with 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone acetate would reduce coronary heart disease events in women with pre-existing coronary disease. A total of 2763 women (average age, 66.7 years) were enrolled in 20 U.S. clinical centers and randomized to treatment and placebo beginning in February 1993 and ending in July 1998. Overall, there were a total of 172 myocardial infarctions and coronary deaths in the hormone group and 176 in the placebo group. However, over time, the differences shown in Table 1 were recorded. Thus, there was an increase in events in the first year (mostly in the first 4 months) and, after two years of treatment, the appearance of a beneficial effect (although annual relative risks did not achieve statistical significance, the test for the trend was significant). Hulley and colleagues attribute the increasing beneficial effect noted with increasing duration of treatment to a favorable effect on lipids, an 11% decrease in LDL-cholesterol, and a 10% increase in HDL-cholesterol after one year, compared with the levels in the placebo group.
The increased risk of venous thromboembolism reported in observational studies was confirmed (although these women were a high-risk group for this problem). (See Table 2.) The increased risk of gallbladder disease did not reach statistical significance. There were no differences in the incidences of breast cancer, endometrial cancer, other cancers, and fractures; however, the size and duration of the study did not allow meaningful conclusions in these categories.
Hulley et al concluded that combined estrogen-progestin therapy does not reduce the risk of coronary events in postmenopausal women with pre-existing coronary disease. (Hulley S, et al. JAMA 1998;280:605-618.)
Table 1
Differences between the treated and placebo groups
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| Year 1 |
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| Year 2 |
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| Year 3 |
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| Year 4 |
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COMMENT BY LEON SPEROFF, MD
The results of the HERS trial are surprising in view of the overwhelming evidence from observational studies that postmenopausal hormone therapy prevents coronary heart disease. Hulley et al offer two possible explanations for the difference between the HERS trial and previous observational studies. First, they point out the common and favorite criticism of the observational studies: selection bias, specifically, that healthier women choose to use postmenopausal hormone therapy and, therefore, develop less coronary heart disease. Indeed, women who choose to use hormone therapy have been reported to have a better cardiovascular risk profile compared to nonusers.1 This question has been addressed by the Lipid Research Clinics Study, the Leisure World Study, and the Nurses' Health Study.2-4 These epidemiologists have concluded that their evidence strongly indicates that, in women receiving estrogen treatment who have the same risk factors for cardiovascular disease as those not receiving treatment, the same beneficial effect of estrogen is present. A cohort follow-up study in southeastern New England documented similar levels of total cholesterol, HDL-cholesterol, body mass index, and blood pressure in estrogen users and nonusers, indicating that selection of significantly more healthy women for estrogen use cannot fully explain the beneficial effect of estrogen on the risk of cardiovascular disease.5 In a comparison of health variables among users and nonusers in south Australia, there was no evidence to support the presence of a "healthy user" effect.6 This issue will not be settled definitively until data are available from the ongoing, long-term, randomized clinical trials of postmenopausal hormone therapy.
Table 2
Observations recorded in the treated and placebo groups
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| Venous |
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| thromboembolism |
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| Gallbladder disease |
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Hulley et al further emphasize that the HERS trial consisted of older women with significant coronary heart disease, whereas observational studies have focused on primary prevention in younger and healthier women. However, there are some observational studies that examined the effect of hormone therapy in women with preexisting disease and reported a beneficial effect.2,3,7-10 In the Leisure World Study, estrogen users with previous myocardial infarctions, strokes, or hypertension had a 50% reduction in risk for death from a subsequent stroke or myocardial infarction.3 In the Lipids Research Clinics Study, the cardiovascular mortality in women with previous cardiovascular disease was reduced by 85%. And, most impressively, in women with severe coronary disease (documented by arteriography), estrogen users had a 97% survival rate at five years compared to a significantly different 81% rate in nonusers.7 In women with mild to moderate disease, there was no difference at five years, but at 10 years, estrogen users had a 96% survival rate compared to 85% in nonusers. Estrogen therapy reduces the rate of restenosis in women who have undergone either coronary angioplasty or percutaneous atherectomy.11 In women who have undergone coronary artery bypass surgery, the 10-year survival rate in estrogen users was 81.4% compared to 65.1% in nonusers.9 In women who have been treated with estrogen after coronary angioplasty, case-control analysis indicated that the treated women had a better survival rate and experienced fewer subsequent myocardial infarctions.10
The HERS trial is also in disagreement with recent reports that estrogen treatment could produce a regression in atherosclerosis. Imaging studies have documented a reduction in intimal thickening in postmenopausal women who are estrogen users compared to nonusers, and this beneficial effect is not compromised by the addition of a progestational agent to the treatment regimen.12,13 Thus, postmenopausal hormonal therapy has been reported to bring about a reduction in atherosclerosis, and this effect is comparable to that produced by a lipid-lowering drug.12,14
The size of the HERS trial was determined by power calculations based upon specific assumptions shown in Table 3.
Table 3
A comparison of the pretrial assumptions with the actual outcomes
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| Clinical event rate in the placebo group |
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| Dropout rate |
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| Conversion of placebo to treatment rate |
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| Average follow-up |
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| Recruitment |
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These differences between the assumptions and the actual events raise the important question of whether the trial achieved sufficient statistical power to provide confident conclusions. Hulley et al indicate that this concern is "partially" compensated by an 18% increase in recruitment. But, here, too, there is a problem. The reason why the average follow-up is less than expected is that most of the women were enrolled toward the end of the recruitment period. This seriously affects the accuracy of the impact of duration of treatment-an apparent beneficial effect in the HERS trial. Indeed, the late recruitment into HERS would have minimized this effect, and the apparent benefit in years 4 and 5 did not reach statistical significance (although a test for trend was significant). The apparent increasing protection with increasing duration of use is consistent with the preventive effect exerted by hormone therapy in the many observational studies. This is also important information for women who begin hormonal treatment at menopause and are contemplating long-term therapy.
The increases in events recorded in the first year are difficult to understand. The most attractive explanation is to attribute, as Hulley et al do, the increase to prothrombotic effects of estrogen. Diana Petitti, in the accompanying editorial (JAMA 1998;280:650-651) also emphasizes this point, using as an argument the recent contention that certain progestins in oral contraceptives further increase the risk of venous thromboembolism. There are two problems with this explanation. First, studies in the past year have revealed that, when adjusted for duration of use and first-time use, the apparent increased risk of venous thromboembolism with certain progestins is no longer apparent. Second, the increase in clinical events in the first year of the HERS trial consisted of arterial problems, not venous. There is a host of evidence indicating that postmenopausal hormone therapy (with and without progestin) affects clotting factors in a pattern that favors fibrinolysis, an effect that should protect against thrombosis.
Reduced levels of fibrinogen, factor VII, and plasminogen activator inhibitor-1 have been observed in premenopausal women compared to postmenopausal women, and oral estrogen alone or combined with a progestin prevents the usual increase in these clotting factors associated with menopause.15-18 This would be consistent with increased fibrinolytic activity, another possible cardio-protective mechanism probably mediated, at least partially, by nitric oxide and prostacyclin. Platelet aggregation is also reduced by postmenopausal estrogen treatment, and this response is slightly attenuated by medroxyprogesterone acetate.19 However, in a randomized one-year trial, the addition of medroxyprogesterone acetate, either sequentially or continuously, produced a more favorable change in coagulation factors compared to unopposed estrogen.20
Appropriate doses of hormone therapy have been reported to not have an adverse effect on clotting factors.16,21,22 Fibrinopeptide A is an indicator of thrombin generation, and, in three-month studies, no significant alteration was produced by 0.625 mg conjugated estrogens in one and an increase in another.23,24 The clotting story is difficult to unravel. Perhaps one contributor to the uncertainty is a possible difference between short- and long-term effects.21,23,25 And, it also may be that older women with atherosclerosis respond differently than younger, healthier women. In other words, increasing age and disease may change a woman's thrombotic sensitivity to estrogen, perhaps because of the presence of unstable atherosclerotic plaques.
The favorable changes in the clotting system may contribute to estrogen's protection of the cardiovascular system by inhibiting arterial thrombosis. How can there be a beneficial effect on arterial thrombosis when there is an increased risk of venous thrombosis? Why is there a difference between venous and arterial clotting? The venous system has low flow with a state of high fibrinogen and low platelets, in contrast to the high-flow state of the arterial system with low fibrinogen and high platelets. Thus, it is understandable why these two different systems can respond in different ways. Decreases in antithrombin III and protein S associated with estrogen treatment, a hypercoagulable change, may have a greater effect on the venous system.24 (See Table 4.)
Table 4
Coagulation and fibrinolysis factors
| Coagulation Factors: | Factors that favor clotting when increased |
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Fibrinogen
Factors VII, VIII, X |
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| Factors that favor clotting when decreased | |
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Antithrombin III
Protein C Protein S |
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| Fibrinolysis Factors: | Factors that favor clotting when increased |
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Plasminogen
Plasminogen activator inhibitor-7 (PAI-7) |
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| Factors that favor clotting when decreased | |
| Antiplasmin |
The most disturbing thought about the HERS trial is that the results reflect the effect of the continuous presence of medroxyprogesterone acetate. The clotting factor studies fail to find a detrimental effect of medroxy- progesterone acetate. However, there is reason to believe that the continuous presence of medroxyprogesterone acetate could attenuate and even block the favorable effects of estrogen on atherosclerosis and vasomotor function. There is evidence in the monkey that medroxyprogesterone antagonizes the favorable effect of conjugated estrogens on both the process of atherosclerosis and vasodilatation, but progesterone did not interfere with the ability of estrogen to inhibit atherosclerosis.26-29 Could attenuation of these estrogen effects make women with coronary heart disease more sensitive to any thrombogenic or ischemic effect of estrogen? In a study of mechanisms involved in the regression of atherosclerosis, conjugated estrogens did exert favorable activity (aortic connective tissue remodeling in response to lipid lowering) in the monkey, but medroxyprogesterone acetate prevented this action.30
Do the HERS results indicate a difference between sequential and daily continuous regimens of estrogen-progestin treatment? The observational data have consistently failed to find any evidence that the addition of a progestational agent to estrogen therapy produced an attenuating effect on protection against clinical coronary events.8,31-35 However, this evidence is virtually all derived from experience with sequential regimens because the use of the daily, continuous methods is too recent for epidemiologic study.
It's disappointing that $40 million and a lot of effort by a lot of people did not yield some definitive results. But, the inconsistencies with previous biologic studies, the concerns regarding statistical power, and the disagreement with a large number of observational studies mean that definitive judgments must await the results of more studies. (See Table 5.)
Table 5
Ongoing clinical trials
| Primary Prevention | |
| WHI (Women's Health Initiative) | n = 16,500 |
| WISDOM (Women's International Study of Long Duration Oestrogen for Menopause) | n = 34,000 |
| Secondary Prevention | |
| WEST (Western Connecticut Estrogen for Prevention of Stroke Trial) | n = 650 |
| ESPRIT (Estrogen in the Prevention of Reinfarction Trial) | n = 2000 |
| Angiographic End Point | |
| ERA (Estrogen Replacement & Atherosclerosis Trial) | n = 300 |
| WELLHART (Women's Lipid Lowering Heart Atherosclerosis Trial) | n = 214 |
| EAGAR (Estrogen & Bypass Graft Atherosclerosis Regression Trial) | n = 200 |
| WAVE (Women's Atherosclerosis Vitamin/Estrogen Trial) | n = 400 |
Are the HERS data sufficient to indicate an adverse effect due to the daily presence of medroxyprogesterone acetate? In my view, the data by themselves are insufficient. However, the HERS results combined with the experimental data derived from monkeys do raise concern. There are other options, and products with new combinations are around the corner. At this point, treatment decisions must be individual clinical judgments, one of the reasons patients turn to their clinicians for assistance-an enduring and rewarding feature of the practice of medicine.
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