From the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

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1 Acta Obstet Gynecol Scand 2000; 79: Copyright C Acta Obstet Gynecol Scand 2000 Printed in Denmark All rights reserved Acta Obstetricia et Gynecologica Scandinavica ISSN OPINION Balancing between observational studies and randomized trials in prevention of coronary heart disease by estrogen replacement: HERS study was no revolution OLAVI YLIKORKALA From the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland Acta Obstet Gynecol Scand 2000; 79: C Acta Obstet Gynecol Scand 2000 Key words: blinding; coronary artery disease; endothelial function; estrogen replacement; HERS study; hormone replacement therapy; medroxyprogesterone acetate; observational study; randomization; randomized clinical trial; selection bias Submitted 19 May, 2000 Accepted 13 June, 2000 Although estrogen (progestin) replacement therapy (HRT) has been in use for longer than 40 years, we have no scientifically indisputable proof of its efficacy in the prevention of coronary heart disease (CHD). A large number of long-term observational studies reporting a significant prophylactic effect of HRT in the primary or secondary prevention of CHD are open to criticism, because healthier women may have started the use of HRT ( selection bias ). This article considers how well, if at all, the criteria of randomized placebo-controlled trial, a gold standard in clinical research, can be met in menopausal research. A randomization (to HRT or placebo) may be difficult (and even unethical) if the established benefits of HRT (control of vasomotor symptoms, bone preservation) are kept in mind. Blinding can be impossible due to the objective effects of HRT (cessation of vasomotor symptoms, occurrence of breast discomfort or bleeding). The progestin com- Abbreviations: HRT: hormone replacement therapy; CHD: coronary artery disease; MPA: medroxyprogesterone acetate; MI: myocardial infarction; RRΩrelative risk. ponent of HRT is an additional obstacle because it opposes the (beneficial?) effects of estrogen and causes several effects of its own which may be potentially harmful; the progestins may not be uniform in this regard. Heart Disease and Estrogen Replacement Study (HERS) was the first randomized trial of the effect of conjugated equine estrogen (0.625 mg daily) combined to medroxyprogesterone acetate (MPA, 2.5 mg daily) in the prevention of CHD events in 2763 postmenopausal, nonhysteroctomized women (mean age 67 years) with pre-existing CHD. HRT was associated with slightly increased risk of CHD events during the first year of trial, but it tended to reduce this risk during the 3rd and 4th trial year. In a subsequent subgroup analysis, HRT was approved to have a more favorable effect in women with high initial lipoprotein (a) levels. HRT increased the risk of venous thromboembolism and tended to increase the risk of gallbladder disease. The concerns of HERS study include a limited statistical power, short duration, impact of too high a dose of estrogen, impact of possibly harmful MPA, low compliance, unbelievably low frequency of reported vaginal bleeding (only 2.4%),

2 1030 O. Ylikorkala and multipharmacy. Preliminary data from two other prospective randomized trials (ERA trial, WHI trial) have also warned of possible untoward vascular effects of HRT during the first two years of its use. For clinicians, there is no sound evidence to change the present prescribing practice of HRT, and even women with pre-existing CHD can continue the use of HRT, at least if it has been used for more than 1 2 years. The final results of the on-going trials will be available in 2005, and then it will be time for the reappraisal. Coronary heart disease (CHD) is the most common cause of death (approximately 30% of deaths) of women living in the western world. Many of these deaths occur in late age and are rapid, rather painless, and thus, CHD often causes a merciful death, which anyway is an inevitable part of human life. However, CHD can develop in younger age groups as well, and the onset of menopause clearly enhances this risk. This brings out the net impact of CHD on female life, because a large number of women developing CHD must suffer from incapacitating symptoms for years and eventually die from this disease at a relatively young age. Several extensive health care interventions, e.g. such as diet and exercise programs and the use of antihypertensives or cholesterollowering agents, have been executed to prevent CHD both in men and women. Women have been thought to have an additional option for a prophylaxis against CHD because hormone replacement therapy (HRT) has reduced the risk of CHD in almost all of the 25 observational studies (1 5). In these studies the start of HRT has been based on the patient s and/or physician s judgement. This may lead to selection bias invalidating the comparability between users and non-users of HRT. Randomized Trial of Estrogen plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women (HERS) was the first study on the impact of HRT on CHD in women with pre-existing cardiac disease, which fulfilled, in principle, the criteria of randomized, placebo-controlled trial (6). Although the results of this model trial appear to be in conflict with the previous extensive knowledge on the impact of HRT in CHD (1 5), many epidemiologists and clinicians feel now that a revolution has taken place in menopausal research. The situation before HERS study Primary prevention HRT has been used with varying frequencies in different countries for longer than 40 years. The initiation of HRT has depended on the judgement of both a woman herself and her physician and often a primary indication for the use of HRT has been a control of invalidating vasomotor symptoms. Gynecologists are primary advocates for the use of HRT, and in Sweden, for example, 88% of the postmenopausal female gynecologists use HRT themselves and 86% of male gynecologists prescribe HRT to their postmenopausal wives (8). Also 33% of Danish nurses reported a use of HRT in 1993 (9). No large-scale, longterm, randomized, placebo-controlled trials have existed. Nevertheless, due to a history of HRT of more than 40 years, and a huge number of women using it in different countries, a sound epidemiological evidence from more than 20 observational studies has accumulated to indicate that the risk of CHD is significantly smaller in HRT-users that that in nonusers (1 5). From these studies it could be calculated that the efficacy of HRT in the primary prevention of CHD (Ωwomen had no CHD at the start of HRT) is of order 40 60%. Principally similar epidemiological evidence has also been obtained in Finland (10). It was further conspicuous that the addition of progestin did not eliminate the vascular benefits of HRT in these observational studies (11). The efficacy of HRT in the primary prevention of CHD was further supported by a number of biologically plausible mechanisms by which HRT could protect heart and blood vessels (Table I) (12 18). Vascular endothelial and smooth muscle cells possess estrogen a- and estrogen b-receptors which are stimulated by estrogen and which regulate the synthesis of a number of vasoactive agents both in the endothelial and smooth muscles cells (16). The balance between vasoactive agents is shifted to the dominance of vasodilating agents by estrogen. In addition, estrogen affects several nonvascular tissues, such as the liver, causing vasoprotective changes in lipids and lipoproteins (17). Table I. Some plausibe biological mechanisms which could explain the beneficial effects of estrogen on heart and blood vessels Immediate effects on endothelial cells Receptor stimulation Prostacyclin Nitric oxide Endothelin-1 Vascular endothelial growth factor Ion channel function Long term effects Benefits in lipids and lipoproteins Prevention of vascular injury Increase in antioxidant activity Fall in homocysteine level Increase in fibrinolysis Fall in insulin resistance

3 Opinion 1031 Secondary prevention There existed also a number of observational studies showing rather convincingly that HRT prevented cardiovascular effects in women who had evidence of coronary artery occlusion in angiography or who had already had myocardial infarction (Ωsecondary prevention) (19 25) (Table II). The methodologies and patients series differ markedly in these studies and therefore it has not been possible to perform a sound meta-analysis of the studies. Nevertheless, these data (Table II), combined with the efficacy of 40 60% in the primary preventive against CHD by HRT, as discussed briefly above, were commonly taken as a proof that HRT would prevent the recurrence of CHD event in women with pre-existing CHD. Are observational studies unreliable? Observational studies reporting protective effect of HRT both in primary and secondary prevention of CHD are open to criticism, because the women in these studies were not randomized between the HRT and non-hrt group. Therefore it is possible that women with subsequent use of HRT may have had more favorable life styles and reduced levels of different CHD risk factors already before the initiation of HRT. There are indeed some data to support this claim. Matthews et al. (1996) (26) interviewed 541 women in and again in 1992 when a total of 355 had become menopausal. Women who had decided to use HRT after menopause had had more favorable levels of coronary risk factors before the onset of menopause than those who had decided not to use HRT. Similar data have been reported from a prospective population based study from Sweden (27). However, more recent data from Sweden show that education, occupation and the frequency of exercise did not influence the prevalence of HRT use (28). It is anyway possible that selection bias in the old observational studies could account for at least a part of the protective effect of HRT against CHD. Presently the situation might be slightly different because women with increased risk factors for CHD may have been advised to start HRT during the last decade due to the common belief that HRT could prevent the appearance of CHD. Although differences in lifestyles and risk factors between users and nonusers during the earlier era of HRT appear so modest (26, 27) that they hardly can explain the 40 60% efficacy of HRT in the cardioprotection (1 5), we all agree that observational studies have limitations and wish to base our clinical judgement on the evidence provided by properly conducted randomized, placebo-controlled trials. Is a randomized, placebo controlled trial in menopause research possible? It is easy to design a randomized, placebo-controlled HRT-trial in the office but to conduct such a study in postmenopausal women in practice faces several difficult obstacles (Table III). First, one can wonder how it is possible to truly randomize women to the prolonged use (up to 10 years) of either HRT or placebo, because there is anyway scientifically sound evidence for a number of benefits of HRT outside the heart and cardiovascular system (e.g. alleviation of hot flushes, bone preservation, etc.) or hazards (risk of breast or endometrial cancer). I feel strongly that intelligent women receiving objective, balanced, information of HRT benefits and hazards will refuse such a randomization. And if they agree to become randomized, one can wonder if such a population really represent nonselective normal population and are devoid of biases. Second, it can be questioned if the use of placebo treatment (lasting for more than 3 months) is ethically possible, at least in women seeking relief for climacteric complaints or preservation for bones. Third, it is a leading principle in a randomized, placebo-controlled trial that a code (ΩHRT or placebo) will be kept totally secret to Table II. Non-randomized epidemiological studies on the efficacy of HRT in the secondary prevention of coronary heart disease in postmenopausal women Results Design Estrogen No estrogen Authors Prospective, women with CHD CHD death 1.38/ /1000 Bush et al (19) Survival after coronary angiography 5-y 97%; 10-y 97% 5-y 81%; 10-y 60% Sullivan et al (20) Prospective, women with a history of angina or MI Mortality of 0.028% 0.042% Henderson et al (21) Survival after coronary angiography showing marked stenosis 5-y 99%; 10-y 69% 5-y 81%: 10-y 46% Sullivan et al (22) Survival after coronary angioplasty 5-y 98%; 7-y 95% 5-y 90%; 7-y 78% Kim et al (23) Prospective, women with prior MI RRΩ0.64 for death /MI Newton et al (24) Prospective after angioplasty RR 0.38 for death or MI ( ) O Keefe et al (25) MIΩmyocardial infarction.

4 1032 O. Ylikorkala Table III. Some obstacles in performing a truly randomized, placebo-controlled trial on the efficacy of HRT in cardiovascular protection in postmenopausal women Goal Randomization? Blinding? Effect of estrogen? Effect of Estrogen π Progestin Obstacle How to get informed consent if the information is balanced and fair? Ethical or unethical? (note: many benefits of HRT are established) Difficult, even impossible: Cessation of vasomotor symptom Breast enlargement and other symptoms Bleeding Only feasible in hysterectomized women Women with intact uteri Endometrial safety Impact of progestin the investigators or patients during the trial. The code can be opened only after the analysis of the results of the trial (Ωe.g. occurrence of CHD event). It is precisely this principle which makes a placebo-controlled trial a gold standard in research, and epidemiologists hardly set any value on other types of research. However, the reality in menopause research is far from being that ideal. Women who have had climacteric vasomotor symptoms will detect with 90 95% accuracy if they receive HRT or placebo. Moreover, women with intact uterus must receive, in addition to estrogen, also progestin for endometrial protection because a sole estrogen replacement increases the risk of endometrial cancer up to ten-fold, depending on the time of exposure (29). Progestin can be added in a sequential manner when it causes cyclic withdrawal bleeding and the code will certainly be revealed. Progestin can also be given in a continuous manner ( nonbleeding alternative ) when the women are not supposed to have cyclic withdrawal bleeding, and this was the mode of administration in HERS study (6). However, at least 40 60% of women using continuous combined HRT regimen will experience scanty bleeding or spotting during the first year of use (30). Furthermore, endometrial safety must be confirmed by repeat ultrasound examination and endometrial biopsies in any woman using HRT. There is no doubt that a majority of participants in placebo-controlled trial on HRT effect know the code and report this also to the investigators. Progestin use, regardless of the mode of its administration, invalidates also the trial assessing the effect of estrogen, because progestin is, as a rule, a biological antagonist of estrogen and thus eliminates or diminishes the effects of estrogen. Progestin may also have biological effects which are totally independent on estrogen component. Estrogen π progestin-combination probably tells little if anything of the effect of estrogen alone e.g. in the secondary prevention of CHD. These are just a few clinical points which cause strong concerns among gynecologists against the representativeness and the success of randomized, pla- cebo-controlled trials in menopausal research, although these trials appear so reliable and produce beautiful convincing publications. HERS-study In HERS-study, a total of 2,763 nonhysterectomized postmenopausal women with documented, preexisting CHD started using conjugated equine estrogen (Ω0.625 mg) and medroxyprogesterone acetate (MPA) (2.5 mg) daily (continuous combined regimen) (6). The women (average age 67 years) were enrolled in 20 clinical centers in USA since the beginning of February 1993, and the study was closed in July Thus, the average duration of trial was 4.1 years. The collection of this group was difficult, since the investigators interviewed a total of 68,561 patients of whom only 4,830 (7%) attended the first screening visit, 3,463 (5%) attended the second screening visit and finally only 2,763 (4%) were included in the trial. No details for a poor recruitment rate were given, but it may illustrate the difficulty of proper randomization. One can ask if the final study group really presents a nonselected group of women with CHD which is devoid of any bias. The study groups taking estrogen π MPA (nω 1,380) or placebo (nω1,383) were comparable at recruitment, confirming the success of randomization. Estrogen π MPA caused beneficial changes in lipids and lipoproteins at 1 year follow-up suggesting that the patients would have used HRT as instructed. Although the final figures of HERS study (7) are slightly different from those in the original publications (6), the conclusions remain virtually the same. There was no difference in the total number of events (HRTΩ179 events; placeboω182 events). Nevertheless the risk of myocardial infarction and coronary death in women using estrogen π MPA was higher than that in placebo group during the first year whereas during the 3rd and 4th year there was a trend in favor of the hormone-treated group (Table IV). The risk of venous thromboembolism was significantly increased in

5 Opinion 1033 Table IV. Coronary heart disease (ΩCHD) event as well as venous thromboembolism and gallbladder disease in hormone-treated and placebo group in HERS study. These are final figures (7), available also through internet, and slightly different from the original numbers (6) Relative risk CHD Hormone Placebo (confidence interval) Year 1 57 women 38 women 1.52 ( ) 2 47 women 49 women 0.98 ( ) 3 35 women 42 women 0.85 ( ) 4 40 women 53 women 0.75 ( ) Venous thromboembolism 34 women 13 women 2.66 ( ) Gallbladder disease 89 women 67 women 1.38 ( ) hormone users whereas the risk of gallbladder disease in hormone users showed only a trend (p 0.07) to increase (7). Concerns of HERS trial The failure of estrogen π MPA regimen to provide secondary prevention against cardiac events in women with pre-existing CHD is in disagreement with the previous knowledge on the efficacy of HRT in secondary prevention (Table II) or in primary prevention, as observed in nonrandomized observational studies. Because, however, these data were obtained from the first randomized trial, there are nowadays many who regard the results of HERS study as a final truth. Yet HERS study raises many concerns (Table V). The authors of HERS study elegantly addressed many strengths (randomized, double-blind) and limitations (short duration) of their trial in the original publication (6). The fact that the rate of CHD event was smaller (approximately 3.3%/year) than assumed during the power calculation (5%/ year) is curious and difficult to explain; it decreases the impact of the study. Careful reading of the newest version of the data reveals that in the placebo group during the first year only 38 events happened but already 49 events happened in the second year, in the third year 42 events and in the fourth year 53 events (Table IV). In the HRT-group the number of events during the first year was 57, in the second 47 and in the third and fourth year 35 and 40. One must wonder why the first year figure in the placebo group differed so markedly from the others in the placebo group. If the placebo group in the first year had behaved more logically, conclusions of the first year findings (HRT increases the risk) would have been different. It is also likely that HRT-induced vascular benefits need much more time than 4 years to become apparent and therefore a trend in favor of HRT in the 3rd 4th year is interesting (Fig. 1). One can ask what would have happened if the trial could have continued for up to 5 10 years. The continuous use of MPA causes another great concern, because MPA has untoward vascular effects and attenuates the vascular benefits of estrogen use (31 34). Thus MPA may have interfered with any possible positive effect of estrogen or estrogenic metabolites of equine. It is unfortunate that MPA had been selected to this study, because other progestins may be more gentle and perhaps more suitable to be used in combination with estrogen for secondary prevention of CHD, and in this regard local intrauterine administration of progestin may hold a considerable promise (35, 36). Furthermore, the investigators of HERS study may have overlooked general pharmacological knowledge that hepatic and renal clearance of sex steroids decreases rather rapidly with advancing age. Clinicians prescribing HRT regimens appreci- Table V. Concerns on HERS study Limited statistical power Not only estrogen, but estrogen π MPA Possible negative impact of MPA on vascular health Too high dose of estrogen Unbelievably low frequency of vaginal bleeding (2.4%!) Low compliance; 82% took hormones at the end of 1st year and 75% at the end of 3rd year Multipharmacy Fig. 1. Rates of cardiovascular events in participants using HRT or placebo in HERS study (6).

6 1034 O. Ylikorkala ate this wisdom and advocate using smaller doses of HRT with advancing age. Therefore conjugated equine estrogens at the daily dose of could have been too high a dose to women who were anyway on average 67 years old at recruitment. I would anticipate that such a big dose of estrogen, as combined with 2.5 mg of MPA, could have caused mastalgia and other side-effects revealing the code and explaining also the poor compliance; only 82% of women took hormone regimen at the end of the first year and 75% at the end of 3rd year (Table V). Moreover, the doses of estrogen and MPA were so high that they must have caused vaginal bleeding much more often than reported in the paper; only 34 of 1380 women (2.4%) were reported to have had vaginal bleeding (6). It is common knowledge, and a big concern among gynecologists that non-bleeding continuous-combined therapy, as applied in HERS study, causes scanty bleeding and/or spotting at least in 40 60% of women during the first year of use (30); the previous comments on HERS study have neglected to address the unbelievably low frequency of vaginal bleeding (37, 38). There are a number of explanations for this curious finding. First, women with vaginal bleeding and spotting may have stopped using hormone regimen during the first year providing one explanation for a poor compliance. One can just wonder if the women showing a biological response (Ω vaginal bleeding ) to HRT, and perhaps discontinuing the trial, were precisely the same women who would have demonstrated another biological consequence; it is a protection against CHD if the regimen had continued long enough. Second, it is possible that the lack of bleeding episodes reflect a failure to use HRT as instructed. This alternative, if true, undermines the whole trial and calls for the assessments of blood estrogen or MPA levels during HRT to confirm the compliance. The patient series in HERS study had established CHD and used a number of different drugs (6). The drugs list aspirin (78%), b-blockers (32 33%), lipid-lowering agents (45 47%), calcium channel blockers (45 47%), angiotensin converting inhibitors (17 18%), and diuretics (17 18%). Judging from the high frequencies of the use of different drugs, many patients must have used several drugs simultaneously with hormone regimen or placebo, and this may have further disturbed the elimination and metabolism of sex steroids in the liver. The presence of CHD, high age and/or the use of different drugs may in part explain why the frequency of venous thromboembolism in placebo users (21.6/10,000 women years) was about 20 times higher than that risk in healthier women (approximately 0.9/10,000 women years). This risk was markedly increased in women in the hormone group (Table IV) and, once again, the relatively high estrogen dose may have been a contributing factor. The thrombogenic activity of the hormone regimen may even explain, at least in part, the slight increase in the CHD events during the first year of use, because some of these events may have been consequences of increased thrombotic activity in the diseased coronary arteries, especially during the first months of treatment. The authors of HERS study have continued to re-evaluate their data (39). A subgroup analysis of their series, based on the level of lipoprotein (a) (Lp (a)) reveals that HRT appeared to have a more favorable effect on the risk of CHD recurrence in women with high initial Lp (a) than in women with low levels (39). This may imply that we could perhaps screen with the aid of Lp (a) assessment those women with CHD who would benefit most from HRT. It is further likely that Lp (a) is not the final word, other prognostic markers will be detected as well. Estrogen replacement and artherosclerosis trial (ERA) There are at least three randomized on-going trials in USA to assess the efficacy of HRT in the primary or secondary prevention of CHD. The designs and conduct of these trials are open to the criticism as discussed above. Preliminary data from estrogen replacement and arteriosclerosis trial (ERA) were presented in the congress of American College of Cardiology in March In this trial approximately 800 apparently healthy postmenopausal women had undergone coronary angiography and 300 of them had showed some narrowing in coronary arteries. These patients (mean age 66 years) with established cardiac disease were randomized to receive mg of conjugated equine estrogen alone or in combination with continuous 2.5 mg of MPA daily or placebo. Repeat angiography 3 years later revealed that restrictions in coronary arteries had progressed similarly in each study group. Preliminary findings have been distributed also from Women s Health Initiative (WHI) study, which is probably the largest medical study ever conducted. The National Institute of Health started this study in 1991 and it consists of randomized trials, observational studies and community approaches to develop healthful behavior. Approximately 27,000 women are participating in the hormone portion of WHI study. The participants were informed in April 2000 that a little more than 1% of the participants had suffered either a heart attack, stroke or thrombosis and this

7 Opinion 1035 risk was slightly higher in hormone treated women than placebo-treated women. Thus, the preliminary data of these two studies appear to support the findings of HERS study but they both are also open to similar criticism as HERS study. The final results of ERA trial will probably be published this year, whereas the results of WHI study will be available in 2005 and they may well be totally different from the first two years data. few definitive answers and raised so many questions (6). Clearly, obtaining indisputable evidence of the effect of HRT in the primary or secondary prevention of CHD may prove to be too difficult and too precious a goal. If a postmenopausal woman with CHD is presently using HRT, HERS study does not justify the discontinuation of HRT but rather its continuation, at least if she has used it for more than one year. No revolution yet in menopause research or treatment HERS study was an ambitious and expensive (approximately 40 million US dollars) enterprise to assess the value of HRT in secondary prevention of CHD, a question which carries great public health consequences. Yet it is disappointing to state that this study failed to provide a definite answer to this question. The editorial of the same issue of JAMA (40) which published HERS study (6) concluded that these findings are a sobering reminder of the limitations of observational research, the incompleteness of current understanding of the mechanisms of vascular disease and the dangers of extrapolation. All these concerns and reservations have been known and discussed for years before the HERS study and from that point of view the whole HERS study was futile. HERS study did not change much the present clinical practice, because HRT is most commonly prescribed for the control of vasomotor symptoms, sleeping difficulties, depressive moods, or for the prophylaxis of osteoporosis. There exist a number of randomized trials to show that HRT is effective in these indications of HRT. For some years, HRT has been advocated for secondary prevention of CHD events even in patients using different cardiac drugs. HERS study shows that mg of conjugated estrogen in combination with 2.5 mg of MPH is useless, and perhaps potentially hazardous, during the first year of use, but probably protective against CHD event after 3 4 years of use. However, it tells nothing of the effect of a smaller, and more physiological dose of conjugated estrogen in this age group, or of other types of estrogens, if used alone or in combination with continuous, or sequential progestin (also other than MPA). 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