progestin Replacement Study (HERS)

Maturitas 31 (1998) 9 – 14

The Heart and Estrogen/progestin Replacement Study (HERS) Leon Speroff Oregon Health Sciences Uni6ersity, Portland, OR, USA

The heart and estrogen/progestin replacement study (HERS) was a randomized, double-blind, placebo-controlled clinical trial supported by Wyeth–Ayerst for $40 million [1]. 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 preexisting coronary disease. A total of 2763 women (average age 66.7 years) were enrolled in 20 US clinical centers and randomized to treatment and placebo beginning in February, 1993, and ending in July, 1998. Overall, there were 172 myocardial infarctions and coronary deaths in the hormone group and 176 in the placebo group, obviously no overall difference. However, over time, differences were recorded (Table 1). Thus, there was an increase in events in the first year (mostly in the first 4 months), and after 2 years of treatment, the appearance of a beneficial impact (although the annual relative risks did not achieve statistical significance, the test for the trend was significant). The authors attribute the increasing beneficial impact 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 1 year, compared with the levels in the placebo group. In addition, a number of overall observations were recorded (Table 2). The increased risk of venous thromboembolism reported in observa-

tional studies was confirmed (although these women were a high risk group for this problem). The increased risk of gall bladder 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). The authors concluded that combined estrogen–progestin therapy does not reduce the risk of coronary events in postmenopausal women with pre-existing coronary disease. 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. The authors 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 [2]. This question has been addressed by the Lipid Research Clinics study, the Leisure World Study, and the Nurses Health Study [3–5]. These epidemiologists have concluded that their evidence strongly indicates that, in women receiving estro-

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L. Speroff / Maturitas 31 (1998) 9–14

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Table 1 Myocardial infarction and coronary death in hormone-treated group and placebo group over a 4-year period

Year Year Year Year

1 2 3 4

Treated

Placebo

Relative hazard (risk) (Confidence Interval)

57 47 35 33

38 48 41 49

1.52 1.00 0.87 0.67

cases cases cases cases

cases cases cases cases

Table 3 Comparison of pre-trail assumptions and actual outcomes for the HERS trial

Clinical event rate in the placebo group Drop-out rate Conversion of placebo to treatment rate Average follow-up Recruitment

(1.01–2.29) (0.67–1.49) (0.55–1.37) (0.43–1.04)

gen 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 [6]. 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 [7]. This issue will not be settled definitively until data are available from the on-going long-term randomized clinical trials of postmenopausal hormone therapy. The authors 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 impact of hormone therapy in women with pre-existing disease, and reported a beneficial effect [3,4,8–11]. In the Leisure World study, estrogen users with previous myocardial infarctions, strokes, or hypertension had a 50% reduction in

Assumption

Actual

5%/year

3.3%/year

5% in year 1 1%/year

18% in year 1 1.7%/year

4.75 years Paced

4.1 years Late

risk for death from a subsequent stroke or myocardial infarction [4]. In the Lipids Research Clinics study, the cardiovascular mortality in women with previous cardiovascular disease was reduced 85%. And most impressively, in women with severe coronary disease (documented by arteriography), estrogen users had a 97% survival rate at 5 years compared to a significantly different 81% rate in nonusers [8]. In women with mild to moderate disease, there was no difference at 5 years, but at 10 years, estrogen users had a 96% swivel rate compared to 85% in nonusers. Estrogen therapy reduces the rate of restenosis in women who have undergone either coronary angioplasty or percutaneous atherectomy [12]. 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 [10]. 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 [11]. Carotid arterial wall thickening and the prevalence of carotid stenosis can be assessed by ultrasonography. In a study, unique because it consisted of women who were 65-years old and older, the same beneficial de-

Table 2 Incidence of venous thromboembolism and gallbladder disease in the hormone-treated group and placebo group

Venous thromboembolism Gallbladder disease

Treated

Placebo

Relative hazard (risk) (Confidence Interval)

34 cases 84 cases

12 cases 52 cases

2.89 (1.50–5.58) 1.38 (1.00–1.92)

L. Speroff / Maturitas 31 (1998) 9–14

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Table 4 Coagulation and fibrinolysis factors Coagulation factors

Fibrinolysis factors

Factors that favor clotting when increased

Fibrinogen Factors VII, VIII, X

Plasminogen Plasminogen activator inhibitor-1 (PAI-1)

Factors that favor clotting when decreased

Antithrombin III Protein C Protein S

Antiplasmin

creases in carotid atherosclerosis could be documented in users of estrogen alone compared to women who were current users of estrogen and progestin [13]. 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 [14,15]. 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 [14,16]. The size of the HERS trial was determined by power calculations based upon specific assumptions. A comparison of the pre-trial assumptions with the actual outcomes reveals important differences (Table 3). These differences between the assumptions and the actual events raise the important question whether the trial achieved sufficient statistical power to provide confident conclusions. The authors 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 statisti-

cal 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 increase in events recorded in the first year is difficult to understand. The most attractive explanation is to attribute, as the authors do, the increase to prothrombotic effects of estrogen. Diana Petitti, in the accompanying editorial (J Am Med Assoc 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 [17]. 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 that indicates that postmenopausal hormone therapy (with and without progestin) affects clotting factors in a pattern that favors fibrinolysis, an effect that should protect against thrombosis (Table 4). 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 [18–21]. This would be consistent

L. Speroff / Maturitas 31 (1998) 9–14

12 Table 5 On-going clinical trials Primary prevention

WHI (Women’s Health Initiative WISDOM (Women’s International Study of Long Duration Oestrogen for Menopause)

n = 16500 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

ERA (Estrogen Replacement and Atherosclerosis Trial)

n = 300

WELLHART (Women’s Lipid Lowering Heart Atherosclerosis Trial) EAGAR (Estrogen & Bypass Graft Atherosclerosis Regression Trial) WAVE (Women’s Atherosclerosis Vitamin/Estrogen Trial)

n = 214 n = 200 n = 400

Angiographic endpoint

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 [22]. However, in a randomized 1-year trial, the addition of medroxyprogesterone acetate, either sequentially or continuously, produced a more favorable change in coagulation factors compared to unopposed estrogen [23]. Appropriate doses of hormone therapy have been reported not to have an adverse impact on clotting factors [19,24,25]. Fibrinopeptide A is an indicator of thrombin generation, and in 3-month studies, no significant alteration was produced by 0.625 mg conjugated estrogens in one and an increase in another [26,27]. The clotting story is difficult to unravel. Perhaps one contributor to the uncertainty is a possible difference between short-term and long-term effects [24,26,28]. 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 estrogens 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 impact on the venous system [27]. The most disturbing thought about the HERS trial is that the results may reflect the impact of the continuous presence of medroxyprogesterone acetate. The clotting factor studies fail to find a detrimental effect of medroxyprogesterone 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 antagonises the favorable impact of conjugated estrogens on both the process of atherosclerosis and vasodilatation, but progesterone did not interfere with the ability of estrogen to inhibit atherosclerosis [29–32]. 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 [33].

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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 impact on protection against clinical coronary events [9,34 – 38]. However, this evidence is virtually all derived from experience with sequential regimens because the use of the daily, continuous methods are too recent for epidemiologic study. It is 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 very large number of observational studies mean that definitive judgements must await the results of more studies (Table 5). 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 treatment options, and products with new combinations are around the corner. At this point in time, treatment decisions must be informed clinical judgements, one of the reasons patients turn to their clinicians for assistance, an enduring and rewarding feature of the practice of medicine. All of the available evidence must be included in this decision making, not just the results of the HERS trial, and this evidence must be balanced with individual patient needs.

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